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Boston
Medical Library
8 THE FENWAY
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VOLUME I 1922
MEDICINE
Analytical Reviews . \tA
of
General Medicine
Neurology and Pediatrics
EDITED BY
DAVID L. EDSALL JOHN HOWLAND
Harvard Medical School Johns Hopkins Medical School
ASSOCIATE EDITOR
PAUL D. WHITE
Massachusetts General Hospital
WILLIAMS & WILKINS COMPANY
BALTIMORE, MD.
1922
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JAN, 11 ^n
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■'*■ 7
•'. P-
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CONTENTS
Number 1, May, 1922
The Therapeutic Use of Digitalis. G. Canby Robinson 1
The Treatment of Meningococcus Meningitis. Kenneth D. Blackfan 139
Number 2, August, 1922
The Etiology and Epidemiology of Influenza. Hans Zinsser 213
The Specific Dynamic Action of Various Food Factors. Graham
Lusk 311
Hemolytic Jaundice. Wilder Tileston 355
Number 3, November, 1922
A Bacteriological and Clinical Consideration of Bacillary Dysentery
in Adults and Children. Wilburt C. Davison 389
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ERRATA
The editors of MEDICINE regret very much that the following errors appeared in
the article entitled "The. Specific Dynamic Action of Various Food Factors" by Dr.
Graham Lusk, in MEDICINE, Volume I, No. 2.
Page 313, line 6: Read 24 for 14.
Page 316, line 16: (36 a) delete. •
Page 318, line 5: Read in the first instance was deposited.
Page 318, line 25: Read Magnus-Levy.
Page 325, line 6, paragraph 5: Read must have affinities for must be affinities.
Page 325, last line: Read molecules for molecule.
Page 327, table, line 1, column 3: Read 24.98 for 24.81.
Page 333, line 1 : Read When glucose.
Page 334, line 1, paragraph 4: Read oxidations for oxidation.
Page 336, line 21: Read less for more.
Page 339, legend of chart III: Should be one sentence in small caps.
Page 341, paragraph 3: Read whereas for whereas, as.
Page 342, line 17: Read who showed that for and showed that.
Page 343, table, line 5: Read 30 (calories per hour) for 70 (calories per hour).
Page 343, foot of page: Read COOH for COOHi. Delete bond between formulae of
serin and acetic acid.
• Page 344, line 8: Read Jonas for Jones.
Page 345, line 6: Read See page 315.
Page 345, paragraph 4: Read HOOC- for HOO-C.
Page 347, line 13: Read glycollic acid /or glycocoll acid.
Page 350, line 16: Read See page 342.
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JAN. 11 in^
"V^J-IBRA*^ ..
THE THERAPEUTIC USE OF DIGITALIS
G. CANBY ROBINSON
Professor of Medicine, Vanderbilt University, Nashville, Tennessee
TABLE OF CONTENTS
I. Introduction 2
II. Historical data 4
m. Hie digitalis group 6
1. Digitalis 7
2. Sources of digitalis 9
3. Strophantus 10
4. Other members of the group 11
IV. The potency of the digitalis bodies 11
1. The biological assay 11
2. Relative potency of the digitalis bodies 16
3. Variations in potency 17
V. Animal experimentation 20
VI. The newer methods of clinical study of digitalis 22
VII. The toxic effects of digitalis 24
1 . Gastric effects 25
2. Toxic effects on the heart 31
a. Premature contractions 32
b. Depression of conduction 34
c. Other disturbances of the heart beat 36
3. Fatalities resulting from digitalis bodies 38
Vm. The therapeutic effects 42
1. The effect on the heart muscle 42
a. The effect on ventricular contraction 42
b. The effect on the electrocardiogram 45
c. The effect on the size of the ventricles 47
d. Chemical aspects of digitalis action 48
2. The effect on the cardio-inhibitory mechanism 50
a. Vagus stimulation 50
b. The effect on cardiac rate 52
c. The effect on conduction 56
3. The effects on the blood vessels 58
a. The effect on blood pressure 58
b. The effect on the coronary circulation 64
c. The effect on the venous blood pressure 65
4. The effect on the kidneys 65
1
MSDICXNB, VOL. X, WO. 1
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2 G. CANBY ROBINSON
DC. The use o! digitalis in heart failure 69
1. Classification of heart failure 70
2. Disturbed cardiac mechanism 71
a. Auricular fibrillation 71
b. Auricular flutter 81
c. Cardiac contractions of abnormal origin 83
d. Paroxysmal tachycardia 85
e. Heart-block 86
3. Heart failure with normal cardiac mechanism. 87
a. Myocardial insufficiency 87
b. Pulsus alternans 90
4. Valvular heart disease 92
5. Disturbances of the nervous mechanism 93
a. Effort syndrome 94
b. Hyperthyroidism 94
X. Digitalis in infectious diseases 95
1. Fever in relation to the action of digitalis 95
2. Pneumonia 96
3. Diphtheria 99
XI. Dosage of the digitalis bodies 100
1. Oral administration 100
a. The amount of the drug 100
b. Absorption of digitalis 110
c. Speed of action 115
2. Intravenous administration 117
3. Subcutaneous and intramuscular administration 120
4. Rectal administration. 121
XII. Persistence of action 122
Xm. Elimination of digitalis 125
XIV. Preparations of digitalis and its allies 127
I. INTRODUCTION
Digitalis was introduced into medicine by William Withering (163),
who published at Birmingham, England, in 1785, his book entitled
"An account of the foxglove and of its medicinal uses, with practical
remarks on dropsy and other diseases." This book deserves a place
among the medical classics, not only because it introduced digitalis into
medicine, but also because it reveals an attitude of mind which should
serve as a model for all who wish to bring forward any new therapeutic
agent.
The words of Withering form a fitting introduction to this review.
He says:
It is much easier to write upon a disease than upon a remedy. The
former is in the hands of nature, and a faithful observer, with an eye of
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THERAPEUTIC USE OF DIGITALIS 3
tolerable judgment, cannot fail to delineate a likeness. The latter will
ever be subject to the whims, the inaccuracies and the blindness of mankind.
Withering^ views on pharmacology did not differ widely from
those of today, as is indicated by the opening paragraphs of his
account of foxglove.
As the more obvious and sensible properties of plants, such as color,
taste and smell have but little connexion with. the diseases they are adapted
to cure, so their peculiar qualities have no certain dependence upon their
external configuration. Their chemical examination by fire, after an im-
mense waste of time and labour, having been found useless, is now aban-
doned by general assent. Possibly other modes of analysis will be found
out, which may turn to better account, but we have hitherto made only a
very small progress in the chemistry of animal and vegetable substances.
Their virtues must therefore be learnt, either from observing the effects
upon insects and quadrupeds; from analogy, deduced from already known
powers of some of their congenera, or from the empirical usages and ex-
perience of the populace.
The first method has not been much attended to, and the second can
only be perfected in proportion as we approach toward the discovery of a
truly natural system; but the last, as far as it extends, lies within the reach
of every one who is open to information, regardless of the source from
whence it springs.
It was a circumstance of this kind which first fixed my attention on
foxglove.
Withering indicates, at the outset, some of the various phases of
study through which digitalis was destined to go. First, the empiri-
cal studies which have almost invariably marked the beginning of
progress in therapeutics. Second, the study of the effects of the
drug in lower animals, the period of experimental pharmacology.
Third, the study of the effects of the drug on man by exact methods
which allow observations approaching in accuracy those made on
lower animals, the recent, present-day period. The relation of chemi-
cal structure to pharmacological action, although "abandoned by
general assent" in Withering's day, represents the pharmacology of
the future, which is today beginning to show far-reaching possibilities.
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4 G. CANBY ROBINSON
As far as digitalis is concerned, however, scarcely a beginning has been
made.
The literature on digitalis and its allies is very extensive, and an
attempt to cover it completely has not been made. This review will
include the more recent work dealing especially with the action of the
drug on man, and particularly on patients suffering from heart and
circulatory diseases. The literature of experimental pharmacology
will be reviewed only in so far as is necessary to lead up to and
explain the effects of digitalis as observed in therapeutics. There
remain certain points which are better known on animals and the
direct application of experimental results is necessarily made, in
some instances, in the therapeutic use of digitalis. The direct ap-
plication has certain difficulties which will be pointed out, and as the
methods for studying the effects of the drug on patients become more
and more exact, the application of experimental facts becomes less
and' less necessary. The relation of experimental pharmacology to
the therapeutic use of digitalis will be discussed subsequently.
II. HISTORICAL DATA
Foxglove was first "noticed" according to Withering (163) by
Fuchsius in 1542, who gave it the botanical name Digitalis purpurea
because of the resemblance of its flowers to a finger or a thimble
("finger-hut") and because of its purple color. Fuchsius also men-
tioned the emetic action of the plant when eaten. Boerhaave con-
sidered foxglove a poison but Alston held that it was one of the native
plants of England which should be considered a medicine of
great virtue. Haller mentioned foxglove as a purge. Withering
also relates the observations of Salerne, who made apparently the
first experiments with the plant on animals in 1 748. He fed the leaves
to turkeys and described both the fatal and non-fatal effects which he
observed. The emetic and purgative effects of foxglove were
known before Withering's time, and the plant had been used in oint-
ments and also as an expectorant.
Withering undertook the use of foxglove because he was informed
of a secret remedy by which an old woman of Shropshire was often
able to relieve and cure patients with dropsy to whom no help could
be given by some of the leading medical men of the day. He obtained
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THERAPEUTIC USE OF#DIGITALIS 5
the formula which she used, consisting of some twenty herbs, and
from his knowledge of medicinal plants, concluded that foxglove
was the one whose action was beneficial. Withering's book was
written after an experience with the drug covering a period of ten
years. He gives an account of one hundred and sixty-three patients
to whom he had given the drug, and also published communications
from other physicians whom he had told of his early results. He
states that in order to prevent any unwarranted enthusiasm for the
drug, he has reported all patients to whom the drug was given without
selection, and warns his readers from being led astray by the communi-
cations of other physicians from whom he had received reports of
selected cases. The case reports are concise, clear and graphic but,
strange to say, deal exclusively with the diuretic effects of the drug
and the disappearance of dropsy. Withering observes the fact that
digitalis slowed the pulse, especially when given in large doses, but he
did not associate this effect with the benefit of patients suffering from
heart disease. In fact it is evident that he considered the diminution
of the heart rate as a sign that the maximum dose of the drug had been
given, for he says: "Let the medicine be continued until it either acts
on the kidneys, the stomach, the pulse or the bowels; let it be stopped
upon the first appearance of any one of these effects." This is
sound advice, which for many years, has been disregarded.
The appearance of Withering' s book one hundred and thirty-seven
years ago represents the beginning of the period of study of digitalis
by direct observations on patients, the drug being given for purely
empirical reasons. The manner or method of its action were unknown
and there were but few established facts on which to base hypotheses.
i Cushny, Morris and Silverberg (32) have given a brief review
pf the varying opinions regarding digitalis following the publication
|y Withering. In 1799 Ferriar published "An essay on the medical
properties of Digitalis purpurea or foxglove" in which he said that
"the power of reducing the pulse is the true characteristic" of the
drug, diuresis being a less constant and a less essential quality of the
plant.
Beddoes in 1801 stated that "in a certain dose, digitalis will increase
the activity of the arterial system." In this same year, Kinglake also
showed that the force of the pulse was increased by the drug; and in
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CANBY ROBINSON
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1839, according to Cushny, Blake discovered that digitalis caused
an elevation of blood pressure. In spite of these observations, digi-
talis was generally considered a cardiac sedative. Its use was advised
by Pereira in 1840 in cases of pulmonary hemorrhage and aneurism.
This idea was supported by Traube, who discovered that digitalis
stimulated the vagus nerves during his pioneer experiments on animals
in 1851, but it was abandoned after Schmiedeberg's (138) classical
work published in 1874, which showed the effect of digitalis on the
frog's heart. A comprehensive view of the history of the pharma-
cology of digitalis up to 1883 is given by Schmiedeberg (139) and will
not be taken up here.
In spite of the masterly presentation of Withering, digitalis did not
gain a firm foothold in medical practice until recent years. Pratt
(122) has reviewed the various treatises on heart disease written
eminent English authors, in order to find out the dependence that was
placed in the drug. Beginning with Allan Burns, who in 1809,
published the first general treatise on heart disease, and going through
Hope, Stokes, Latham and Walshe, as well as our own Austin Flint,
he found that they paid little or no attention to Withering's teaching
and never discovered for themselves the great value of digitalis in
cardiac failure. Pratt is unable to say who deserves the credit for
impressing upon the medical world the value of Withering's work.
He says, however, that " Sir James Mackenzie, working over a hundred
years later, was the first clinician to demonstrate conclusively the
correctness of Withering's instructions regarding the administration of
digitalis."
HI. THE DIGITALIS GROUP
There are a number of drugs which resemble digitalis more or less
closely from the point of view of their pharmacological action, which
are usually included in the so-called digitalis group. They act upon
the heart muscle and the musculature of arteries and stimulate certain
nervous structures including the vagus centre. In this group are to
be included digitalis, strophanthus, squill, apocynum, convallaria,
adonis, hellebore and oleander. Abel and Macht (1) have isolated
a digitalis-like body from the poison of the tropical toad, Bufo agua.
They call this substance bufagin. Its marked action on the heart,
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THERAPEUTIC USE OF DIGITALIS 7
its vaso-constrictor action and its powerfully stimulating action on the
vagus centre led them to class this drug with the most effective mem-
bers of the digitalis series. Many substances, of which barium may
serve as an example, have a superficial resemblance in their action to
digitalis, but should not be considered as members of the group.
The characteristic digitalis effects are produced in experimental
animals by all the drugs that belong properly in the group, the differ-
ence between them being quantitative. For this reason the various
members of the group have been used more or less interchangeably
in experimental work. In their use in clinical medicine, differences
have been discovered, especially in dosage, rapidity and duration
of action and absorption from the gastrointestinal tract which makes
their differentiation important.
As digitalis and strophanthus are by far the most important drugs of
the group from the therapeutic standpoint, this review wiU deal with
them almost exclusively.
i. Digitalis
The drug is usually derived from the leaves of Digitalis purpurea*
The leaves are gathered and dried and then the drug is prepared for
use by powdering the leaves or by extracting their active principles
by water, alcohol or other solvents. Digitalis and its active principles
have been prepared in many forms for therapeutic purposes and the
best known of the preparations will be discussed when the question
of the administration of the drug to man is considered.
• The active principles contained in Digitalis purpurea were first
studied by Schmiedeberg (138). He found that from fresh digitalis
leaves, at least three active glucosides could be obtained which he
called digitoxin, digitalin and digitalein. Digitoxin is the most
highly active of these substances, and produces all the characteristic
pharmacological effects. It is practically insoluble in water, but is
easily soluble in alcohol. Roth (136) has recently given a brief
review of the chemical investigations of the digitalis bodies. He says
that Kiliani, who has made the most important chemical study of
digitalis, gives CmHmOu as the formula for digitoxin, while the true or
crystallized digitalin has the formula C*HMOi4. Digitalin is easily
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8 G. CANBY ROBINSON
soluble in alcohol and very slightly soluble in water. It is found in
larger quantities in the seeds than in the leaves of digitalis.
The term "digitalin" has been used to denote a variety of prepara-
tions which has served to bring into the literature considerable con-
fusion. Hatcher and Eggleston (78) state that the name is meaning-
less without a qualifying term, and it has been used to mean digitoxin,
true digitalin, or a mixture of the latter with digitonin, a saponin-
like substance. Other instances of such confusion are found in the
literature dealing with the digitalis group. This is much to be re-
gretted and careful consideration should be given to this question
of terms. A general agreement in this connection is much desired.
Digitalein is a water-soluble glucoside which Schmiedeberg con-
sidered a pure substance, while Kiliani looked upon it as a mixture.
Besides the active substances that have been mentioned, digitalis
also contains a saponin-like body called digitonin. It is inert as
regards the characteristic digitalis effects, but according to Roth
(136), it is due to the digitonin that aqueous solutions of digitalis
leaves contain the water-insoluble substances, digitalin and digitoxin.
As stated by Roth, Kraft in 1912 isolated from a watery extract a
glucoside which he named "gitalin" which he considered a purified
digitalein. Both Kiliani and Rosenthaler worked with gitalin in
1914, and concluded independently that it was not a definite substance
and could be resolved into constituents having unlike chemical
and pharmacological properties. Several other investigators have
attempted to shed further light on the chemical constituents of digi-
talis and in 1913 Kolipinski isolated an acid resin which he named
"digitalic acid." He concluded from his many animal experiments
that "digitalic acid" possessed all the virtues, without any of the
poisonous properties of digitalis when used in therapeutic or larger
doses. He also considered that it produced no cumulative effects and
wasnotirritating when used subcutaneously. The work of Kolipinski
would have held promises of definite advance in the therapeutic use
of digitalis, if it had been confirmed by further study, but the inves-
tigations of Sharp and of Smith in 1914, failed to substantiate Kolip-
inski's claims, as both reached the conclusion that digitalic acid has
no pharmacological effects whatever, being an inert substance.
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THERAPEUTIC USE OF DIGITALIS 9
2. Sources of digitalis
For many years, the English-grown leaf, especially those marketed
by Allan, was considered the standard source. During recent years,
however, the greater part of the supply of digitalis used in the United
States came, according to Roth (135), from Germany and Austria.
When this source of supply was cut off during the years following 1914,
by the turmoil of war, attention in the United States was turned to
the home-grown product. Wilbert pointed out that Digitalis purpurea
grew abundantly in California, Oregon and Washington and, to some
extent, in West Virginia. In these states, it is found growing wild,
and is considered a " weed" in various parts of the country. American
leaves were used by Rowntree and Macht (137) in 1916, who prepared
infusions from them as well as from European leaves, and when the
pharmacological activity of these infusions was determined on cats
they found that the highest potency was possessed by the infusions
of American leaves.
Roth (135) investigated the activity of wild American digitalis in
1917 using leaves gathered in the States of Oregon and Washington.
The leaves were air-dried and tinctures were made of them, the assays
being conducted by the one-hour frog method. He found that the
wild digitalis from the Northwestern States was of sufficient strength
to allow its use as a source of supply in making the various official
preparations of digitalis, and he concluded that by the use of ordinary
methods in handling and preparing the leaves, a highly active prod-
uct could be secured which compared favorably with the activity of
cultivated leaves grown under more favorable conditions.
A new species of the American-grown plant, Digitalis lutea, has
recently been employed and its efficiency tested on both animals
and patients. White and Morris (139) have used this form of digitalis
grown in Minnesota, and have compared its activity with Digitalis
purpurea. They find that Digitalis lutea possesses the same thera-
peutic value as purpurea and seems to have less effect on the gastro-
intestinal tract. Christian (16) reports that he has had excellent
clinical results with American-grown digitalis, and Pratt (122) who
has used both American-grown purpurea and lutea, says that active
leaves grow in various parts of the United States from Maine to the
Pacific Coast.
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10 G. CANBY ROBINSON
Pratt and Morrison (123) tested out twenty-five samples of Ameri-
can grown digitalis by the one-hour frog method, using both purpurea
and lutea. Their work shows that the best American digitalis, both
wild and cultivated, is equal in activity to the best European digitalis.
They obtained specimens of high potency from Virginia, Nebraska,
Wisconsin, Minnesota, Oregon and Washington. There was, however,
a definite difference in the potency of various samples, and seventeen
out of twenty-five were below the standard of strength required by
the United States Pharmacopeia. The average strength of the
American-grown leaves was greater than that of the various im-
ported leaves examined. Pratt and Morrison suggest that samples
from a crop of digitalis should be tested biologically before it is
gathered in large quantities for therapeutic use.
It may be considered as established that digitalis of good potency
grows in America in both the wild and cultivated state so that de-
pendence need no longer be placed upon the European market.
The species Digitalis lutea seems also at least as useful as the Digitalis
purpurea, and may prove to have some advantages over the better
known species.
3. Strophantkus
This drug was introduced into medicine by Sir Thomas Fraser
(55), who discovered it during an investigation of the arrow poisons
used by certain African tribes. Several variations of the plant
Strophanthus Komb6, S. hispidus, S. Gratus, and others contain the
active principle of the drug, the seeds being especially rich in it, and
are used in making the various preparations for therapeutic use.
Hatcher and Eggleston (78) have pointed out the uncertainty of
origin of much of the strophanthus of commerce, and state that they
are not convinced that all commercial specimens of strophanthus —
even those obtained from reputable dealers — are sold under their
correct botanical names. This is perhaps more of an academic
question than one of importance from the point of view of therapeutics,
as the active principle, strophanthin, appears to be identical in its
pharmacological properties, regardless of its source. Hatcher and
Eggleston state that the active principle, strophanthin, has also been
considerably confused. The term is properly employed only as
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THERAPEUTIC USE OF DIGITALIS 11
applied to amorphous strophanthine but it has also been used for
ouabain and "crystalline strophanthin-g." Ouabain is a crystalline
substance obtained from strophanthus and represents the purest
chemical substance, possessing the most potent activity of any body
belonging to the digitalis group. It was isolated in 1888 from ouabain
wood by Arnaud, who gave it its name and established its identity
with that of the active substance obtained from Strophanthus gratus.
This same substance was called by Thorns sixteen years later "crys-
tallized strophanthus-g." As amorphous strophanthin and crystal-
line strophanthin or ouabain are both used therapeutically and may
differ much in potency, this confusion of names is very unfortunate
and should be avoided.
Strophanthus and its active principle possess all the pharmacological
properties of digitalis, and the solubility and potency of strophanthin
and ouabain make them important members of the digitalis group,
being especially valuable for intravenous administration.
4. Other members of the group
Other members of the digitalis group have not a well established
place in therapeutics, although some of them have been extensively
used. Recently the action on man of several members of the group
have been studied by modern methods by White and his collaborators.
Squills, apocynum and convallaria have been administered to patients
in whom the action of these drugs was compared with that of digitalis.
These studies will be referred to when preparations are considered,
but it may be stated at this time that they showed several reasons
why these drugs are not as suitable, not as efficient as digitalis, and
that they should not be used in the treatment of heart disease. Less
is known about other members of the group. For these reasons the
discussion of their action and their therapeutic use will not be included
in this review.
IV. THE POTENCY OF THE DIGITALIS BODIES
i. The biological assay
The determination of the potency of a drug by quantitative chemical
analysis is seldom feasible when the activity of the drug depends upon
the presence of one and often of several chemically complex substances.
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12 G. CANBY ROBINSON
This has proved especially true of members of the digitalis group to
which biological or pharmacological assays have long been applied.
According to Hamilton (65) the earliest recorded attempt to standard-
ize digitalis bodies by means of their effects when injected into animals
was that of Fagge and Stevenson in 1866. The drug is administered
to an animal in such a way that the amount necessary to produce a
clearly defined and constantly occurring phenomenon can be accu-
rately measured. By this method of assay the potency of various
members of the digitalis group can be compared, and the various
preparations for therapeutic use can be standardized.
A number of methods for the biological standardization of digitalis
have been employed. Generally speaking, they depend on the
termination of the minimal amount of drug required to kill the animal
used. This method has been objected to as inapplicable to therapeu-
tics as physicians do not want to kill their patients but to cure them.
Hatcher (67) has made the following reply to this criticism:
talis
jde-l
imal ]
peu-N.|
While it is perfectly true that physicians do not wish to kill their pa-
tients, it is equally true that the action of digitalis which they utilize in
curing them is that which kills if it be carried too far, and it seems to me
that it would be quite as logical to object to testing the strength of strands
of cable by raising the tension to the breaking point, on the ground that
engineers wish the cable not to break, as it is to object to the method
in vogue for testing the activity of the digitalis bodies on the grounds
mentioned.
There seems to be no better method of standardizing the digitalis
bodies than that which depends on their power to kill.
The animals most commonly used for biological assays of digitalis
bodies are the frog, the cat and the guinea pig, although the dog and
the rabbit have been used by some experimenters, and one method has
been suggested which depends on the determination of the minimal
lethal dose for gold fish. The original method used by Fogge and
Stevenson depended, according to Hamilton (65) upon the time re-
quired for the systolic stoppage of the exposed heart of the frog, after
the drug was injected subcutaneously into the thighs. This general
principle has been widely applied, and it has been recently especially
elaborated and advocated by Focke (53). The frog test as employed
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THERAPEUTIC USE OF DIGITALIS 13
in 1916 (Roth, 136) by the Hygiene Laboratory of the United States
Public Health Service, aims to determine the quantity of digitalis
which will produce permanent systole of the ventricle, in an hour, when
injected into the ventral lymph sac. Certain conditions, such as
temperature at which the tests are carried on, the concentration of
the injected fluid and its alcohol content, are kept constant. Roth
states that a very disturbing factor in the one-hour frog method is
that of absorption. The assay of digitalis by the frog method has been
used with a number of modifications. In determining the minimal
dose causing permanent systolic stoppage, the heart is necessarily
exposed after the frog has been pithed, while in determining the mini-
mal lethal dose this is not done. Hamilton (65) who has recently
reviewed all the various methods of biological assay of digitalis that
have been employed, apparently prefers the frog method and con*
siders that there are advantages in determining the minimal lethal
dose, namely, that less work and time are involved, that the factor
of slow absorption is eliminated and that the end-point of the test
is not obscured by rough handling necessitated by the pithing and
laying bare of the frog's heart. However, in testing digitalis, it is not
the general toxicity as much as the potency of the drug on the heart
itself that is the essential feature, and therefore the systolic stoppage
method with the heart exposed should be considered that giving the
more exact information.
Hatcher and Brody (74) in 1910 proposed their cat method of stand-
ardization. This method determines the minimal lethal dose per
kilogram of cat when the drug is injected slowly into the femoral vein.
This amount, these authors have termed " the cat unit." For crystal-
line ouabain, the cat unit has been found to be 0.1 mgm., this amount
of the drug per kilogram of cat being fairly constantly fatal when in-
jected during a period of about ninety minutes. In testing other
digitalis bodies Hatcher and Brody found that the accuracy could be
increased by the following procedure. A measured amount of the
digitalis body (tincture or infusion of digitalis, or digitoxin) is in-
jected into the femoral vein in the first period of about ten minutes
and after an interval of twenty minutes, the injection is resumed
but a solution of crystalline ouabain is substituted for that of the
digitalis body. This injection is continued slowly until the death of
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14 G. CANBY ROBINSON
the animal occurs. The difference between the amount of crystalline
ouabain actually used to complete the assay and 0.1 mgm. per kilo-
gram of animal (the amount which would have been required in the
absence of the digitalis body) represents the activity of the digitalis
used. There are certain precautions which the authors state, espe-
cially regarding the selection of animals, which should be followed.
This method was adopted after the authors had assured themselves
that ouabain was capable of replacing the other digitalis bodies.
The cat method is given in detail because of its increasing popular-
ity especially with those administering digitalis accurately and care-
fully to patients. It is suitable for the standardization of the generally
used therapeutic preparations, such as. the tincture of digitalis, and
can be carried out in any properly equipped laboratory, but its use by
the retail pharmacist, as suggested by the authors, seems to the writer,
to be, generally speaking, somewhat idealistic although highly de-
sirable. The method has been criticized by Eckler (35) as compli-
cated, time-consuming and expensive, and he points out a number of
unknown factors that are involved, but he concedes that it has one
point of superiority over all other methods in that the matter of ab-
sorption is entirely eliminated.
Macht and Colson (105) express as their opinion that the "cat
method" gives more uniform results than the frog method, but they
found that the fatal dose varies considerably in cats. They con-
ducted two series of experiments: one in which the vagi were cut
while the nerves were left intact in the other. Using digitalis, digitalin
and strophanthin, they found that the results were more uniform in
the series in which the vagi had been cut, but that the drugs were
more toxic for these animals.
Hamilton (65) states that "the cat method is purely a toxicity test
and can be classed with that on guinea pigs as objectionable because
death is almost invariably due to paralysis of the respiratory center
and therefore, not directly a measure of the heart toxic value." The
experience of the writer with this method is not in accord with this
statement. Respiratory changes practically always occur after the
heart has ceased. to beat, as revealed by the electrocardiograph.
Auscultation of the cat's heart is also a helpful method of determining
the end-point of the experiment, when digitalis is being injected
intravenously.
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THERAPEUTIC USE OF DIGITALIS 15
Eggleston (41) has published a criticism of the cat method of
Hatcher and has compared it with the twelve-hour frog method of
Houghton, the one-hour frog method of Famuleuer and Lyons, and
the guinea pig method of Reed and Vanderkleed. He discusses in
detail the various factors which he considers important in the choice
of a method for the biological standardization of the digitalis bodies.
Eggleston concludes that there is no perfect or ideal method, but
that each of the four methods discussed has certain advantages not
possessed by the others. He considers, however, that the cat method
of Hatcher possesses the greatest number of advantages which are as
follows:
(a) It is accurate to within 10 per cent, (b) It gives constant results
from year to year, (c) It provides a means of detecting the presence of
deterioration, (d) It is the least affected by adventitious factors, (e) It
tests the action of the drug upon which its therapeutic use depends. (J) It
is not too difficult for general use. (g) It is neither time-consuming nor
too costly, (A) By it, widely different preparations can be compared
accurately, (t) Its results are transferable to man. (j) It has the widest
range of applicability of all the methods.
Neither the frog nor the guinea pig method fulfils so many of the essential
requirements as does the cat method. The cat method fails in no single
requisite and has far fewer disadvantages th$n any other method yet
proposed.
Another advantage which the cat method of standardization
seems to the writer to possess over the frog method may perhaps be
described as psychologic. It is easier to think of dosage in terms of
cat units than it is in terms of frog units. Hatcher and Brody quote
Focke as saying that he believes it is not feasible to accustom physi-
cians to thinking and calculating the strength of digitalis preparations
in frog units. On the other hand, the cat unit strength of the various
forms of digitalis is becoming widely accepted. The figures are larger
and therefore more nearly approach the therapeutic doses, and they
also tend to fall into certain multiples which make them readily ap-
plicable for calculations of dosage. Eggleston is of the opinion
that the relative toxicity of the various digitalis bodies for the cat
corresponds more accurately to the relative potency of these drugs for
man than does their toxicity for the frog or guinea pig.
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16 G. CANBY ROBINSON
It is very desirable that all forms of digitalis should be biologically
assayed by a uniform method, preferably by the cat method for rea-
sons that have been given. The strength of every preparation put
upon the market should be indicated preferably in terms of the cat
unit, and the date of manufacture and of assay should be stated.
In the case of some preparations, and probably in many, the strength
of the drug can be adjusted so that a fixed amount has a constant
strength. For example, 1 cc. of the tincture should always represent
1 1 cat unit no matter by whom it is manufactured. This adjustment
of strength is very desirable. When this becomes a uniform proce-
dure, the medical profession will learn to use the preparations of
digitalis according to their individual potency, and not follow a rule
of dosage which may have but little bearing on the preparation being
used.
Even though the strength of a preparation of digitalis, as determined
by the biological assay method is known, the physician should always
study the relation between the amount of the drug given to patients
and its effect upon them. He should endeavor to determine the
average amount of every preparation that is used necessary to produce
well defined digitalis effects. If opportunities are afforded for doing
this adequately, as can be obtained in modern hospital practice,
perhaps the best method of digitalis standardization for practical
purposes is available.
2. The relative potency of the digitalis bodies
The potency of a number of the more important members of the
digitalis bodies was determined by Hatcher and Brody (74) and later
Hatcher (68) repeated some of this work, correcting a few of the
figures reported with Brody. From these two papers the relative
potency of these drugs may be tabulated, the number of milligrams of
the drug which represents 1 cat unit, or the number of milligrams
which is the fatal dose for the cat on the basis of 1 kilogram of body
weight of the animal, being used to express their potency.
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THERAPEUTIC USE OF DIGITALIS 17
Ouabain, crystalline 0. 10
Strophanthin, amorphous, Boehringer and Sons 0. 13
Merck... 0.17
Digitoxin, crystalline 0.30-0.50
Digitoxin, so called amorphous 1 .20
DigitaHnum verum, Kiliairi 1 .50
Adonidin. 3.00
Strophantus, Komb£ 3.00
Digitakin 3.50
Digitalin, German 3.60
Digitalis, German 82.00
Digitals, English 92.00
This table indicates clearly the relative potency of the three active
principles of digitalis, digitoxin, digitalin and digitalein, and shows
also the relative toxicity of ouabain and amorphous strophanthin.
3. Variations in potency
The varying strength of the preparation of digitalis has been a
problem which has caused much uncertainty and discussion. It has
confused the question of dosage. The chief sources of the difficulty
have been variations in the digitalis content of different specimens of
leaves, deterioration and probably variations in absorbability from
the gastrointestinal tract. Roth (136) found that in 1916 the methods
of biological standardization employed by American drug manufac-
turers were not uniform and, in some instances, manufacturers were
not carrying out a biological standardization of their digitalis products.
Pratt (12)1) was among the first to show the inefficiency of some of
the digitalis on the market. By using the thirty-minute frog method
he assayed nine samples of digitalis leaf obtained from leading apothe-
caries and hospitals in and about Boston, and found only one strong
digitalis leaf among the number. A sample obtained from Germany
prepared and standardized by Caesar and Loretz proved to be twice
as strong as the best leaf obtainable in the American market. Pratt
concluded that the available tinctures were also low in potency, as he
was unable to obtain the therapeutic results with them which were
immediately obtained in the same patients when good powdered
leaves were used. Goodall, according to Fulton (56), examined a
number of tinctures of digitalis over a period of three years and found
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18 G. CANBY ROBINSON
that during this time, nearly half the number had departed from the
standard strength, the limit of variation being from 275 per cent
over-strength to 40 per cent under-strength. Goodall found that the
tincture was apt to deteriorate within a year. The writer found that
one lot of the tincture kept in the drug room of a hospital in a 5-gallon
container, and which had a cat unit of 1 cc. when first tested, had
deteriorated so that the cat unit was approximately 2 cc. at the end of
one year.
Roth (136) found by the one-hour frog method a variation of over
250 per cent in the thirteen samples of commercial "fat-free" tincture
of digitalis and a variation of 150 per cent in five samples of German
commercial digitalis. No definite reason could be given for the initial
variations in the samples of the fat-free digitalis.
Newcomb and Rogers (115) who also found differences in the
strength of various preparations, consider that the chilling of the
tincture of digitalis to a temperature of 40°F., even for a brief period
of time, causes an increase in the natural precipitation, which carries
down some of the active principles of the drug.
On account of the opinion prevalent among physicians and pharma-
cists that digitalis and its preparations undergo deterioration with
considerable rapidity, Hatcher and Egglestoii (76) reviewed this sub-
ject and undertook an investigation on the keeping properties of
digitalis and some of its preparations. The cat method and, in some
instances, the one-hour frog method were employed for estimating
the activity of the specimens. They used samples of leaves, ground
and unground, tinctures, extracts and fluid extracts ranging from
less than one to more than thirty years old. Their findings do not
confirm the common belief regarding deterioration, as they found that
commercial digitalis leaves of good quality do not undergo any de-
terioration in many instances as the result of age. In a few cases
they do appear to have deteriorated but only with extreme slowness —
at a rate probably not exceeding 1.5 to 2 per cent a year. Although
the presence of moisture has been emphasized as a cause of deteriora-
tion, several of their specimens of leaves had not been protected from
moisture. Mouldy leaves, however, must be considered as worthless.
Pharmacopial preparations made with a menstruum containing at
least 50 per cent alcohol showed no greater deterioration than the
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THERAPEUTIC USE OF DIGITALIS 19
leaves. Of course, the infusion of digitalis is notoriously unstable
and those using it carefully usually insist on its preparation within a
few days of its administration. Hatcher and Eggleston (77) studied
the stability of the infusion, using the same methods employed in
their previous work. The most striking facts shown by their experi-
ments are that an infusion of digitalis made without alcohol and kept
without the least care, in fact under more unfavorable conditions than
should obtain in practice, may retain its activity with little impairment
for periods varying from six to nineteen days; and that when the hot
infusion is bottled with reasonable care, it will often keep practically
unchanged for many weeks even during the summer.
The stability and constancy of the purer substances, such as the
single glucosides and especially the crystalline substance such as
ouabain would be expected to render them above reproach, from the
point of view of stability. But such is not the case. Sollman (142)
has pointed out several factors, especially variations in temperature
and concentration of the solution which affect the toxic dose of ouabain
in frogs, and which may cause errors in the biological assay of the drug.
Deterioration of crystalline strophanthin has been found by Levy and
Cullen (95) in the preparations marketed for therapeutic purposes.
They studied the cause of this deterioration and propose a well founded
remedy for it. Many of the glass containers commonly used in the
laboratory and most of the glass ampules employed in marketing sterile
solutions for hypodermic or intravenous medication yield sufficient
alkali on autoclaving to change the reaction of distilled water from pH
6 to pH 9. This increase in alkalinity is sufficient to render biologi-
cally inert and practically to decompose aqueous solutions of crystal-
line strophanthin in the concentration employed in clinical medicine.
Levy and Cullen suggest that for clinical use crystalline strophanthin
be dissolved in 0.02 M standard phosphate solution at pH 7 and mar-
keted in hard glass ampules, thereby insuring stability of reaction and
preservation of the biologic activity of the drug. This work views the
question of deterioration of the digitalis bodies from a new angle,
from which the deterioration of some of other members of the group
should be studied.
The relative potency of the tincture of squill when administered
orally as compared with the tincture of digitalis is shown by the recent
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20 G. CANBY ROBINSON
work of White, Balboni and Viko (158). They investigated the
effect of a standardized tincture of squill on the hearts of a series of
patients and found that although squill has a definite digitalis-like
action on the heart, it appeared only after doses eight to sixteen times*
as large as those generally recommended. These observations con-
firm the opinion of Cushny (30) that, considered clinically, squill has
only one-half or one-quarter the effect of digitalis.
The question of absorption from the gastro-intestinal tract is one
that complicates the problem of the effects which the various digitalis
bodies exert when administered by mouth. As it is not primarily a
matter of the relative potency of the various members of the group, it
is best discussed after the question of dosage has been taken up.
V. ANIMAL EXPERIMENTATION
The effects of digitalis and its allies on animals have been studied by
many investigators and there is an extensive literature on the subject.
Those studies in which mammals have been used have furnished the
more valuable results from the therapeutic point of view, and some of
these studies will be reviewed. These experiments have served as a
basis for the analysis of the effects observed in man during the so-
called empirical period of the use of digitalis, and they have also
pointed the way to the improvement in methods of administration.
They have been of great value in rationalizing the therapeutic use of
the drug, so that today a fair degree of scientific accuracy is possible
in regard to its use. On the other hand, animal experimentation has
too strongly dominated the ideas concerning the results to be expected
when the drug is administered to patients with heart or circulatory
disease.
As Cohn (20) has pointed out, Schmiedeberg and his pupils have
emphasized, that the main action of a digitalis body is on the heart
muscle; while the school of Gottlieb has been particularly interested
in the effects the drug has on the blood vessels, and maintains that it
has an important action on the walls of the arteries. "Both schools
find that the drug increases the excursion of the heart in contraction,
both believe that it elevates blood pressure, both believe that it in-
creases the amount of renal secretion." Recent observations on
patients by methods which allow an accuracy closely approaching
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THERAPEUTIC USE OF DIGITALIS 21
that of animal experimentation, make it necessary to readjust our
ideas, as the predominating effects on patients on which the beneficial
results of the drug depend are not those predicted by animal experi-
ments. The careful clinical observations of Cohn have been of
importance in bringing out this point, and he says:
It is perhaps not an overstatement to say that in a general way clinicians
have been too much influenced by these experimental results and have
felt obliged to find that the administration of the drug in patients results
in parallel phenomena. It requires a very small experience in treating
patients suffering from heart disease to find one's self disappointed because
the expected results did not occur. And when discrepancies were noticed,
the discovery was not often followed by an effort to explain them, the
subject was often dismissed by finding fault with the potency of the drug
or by discovering an idiosyncrasy in the patient. But even if drugs were
always potent and there were no individual idiosyncrasies, it is extremely
likely that patients would continue to react in different manners to the
drug. And the reason for that must be that individuals, although they
suffer from what, in a general sense, is called heart disease, yet present
a great variety of clinical pictures.
There can be no question of the usefulness to therapeutics of these
experiments; as guides, they are indispensable, but it must be clear that
they neither replace nor parallel the clinical conditions we must treat.
That there has consequently been a divergence between the results of the
pharmacologists and clinicians in a practical sense is inevitable. The
responsibility for it is probably shared equally by both. Pharmacologists
have dealt usually with simple normal conditions; clinicians with complex
pathologic ones.
This review attempts to emphasize the recent careful studies of the
effects of digitalis on patients and gives preference to the work from
the clinic over that from the laboratory, when the clinical studies are
such as to justify this preference. The more exact clinical studies of
digitalis were inaugurated by Mackenzie (107) and he was perhaps
the first to point out in 1911 that the clinician must exercise great
judgment in the application of pharmacological knowledge in the
treatment of his patient. The confusion of results from the laboratory
and of those from the clinic is caused mainly by the fact that observa-
tions have been made on widely different species and that great differ-
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22 G. CANBY ROBINSON
ences in dosage have been employed. Uniform criteria have not been
employed, and the tissues on which the drug acts have not been exactly
ascertained. •
The most important statement regarding the question of the value
of animal experiments on the therapeutic use of digitalis is that made
in 1918 by Cushny (31) one of the foremost experimentalists with
digitalis. He said:
More than a century after the introduction of digitalis, the knowledge
of its therapeutic action had made but little progress and was meagre and
unsatisfactory, because no accurate knowledge of the clinical action was
attainable, and the facts of the laboratory could not be confirmed for man.
Cushny who studied patients with Mackenzie has done much to
introduce the new chapter in the study of digitalis, the chapter of exact
clinical observations. In his important experimental work, published
in 1897, he employed a method which was a forerunner of one of the
clinical methods that have thrown much light on the problem of
digitalis action. Cushny (28) studied the action of the drug directly
on the heart of the dog and observed, by means of the myograph the
action of the auricles and ventricles separately, thus making it possible
to differentiate the various forms of disturbed cardiac mechanism
which have become so important in the clinical study of the drug.
VI. THE NEWER METHODS OF CLINICAL STUDY OF DIGITALIS
The newer methods may be put into two groups. In the first group
belong those methods that give accurate information regarding the
movements of the various parts of the heart. In the second group,
may be put the quantitative clinical methods such as the accurate
measurement of the intake and output of fluids, the quantitative
estimation of kidney function, the measurement of blood pressure and
of the vital capacity of the lungs, together with the variety of useful
procedures that have been developed by the application of biochemis-
try to clinical medicine. All of these methods have been used, not
only directly in the study of digitalis in man, but they have also
served to differentiate with greatly increased accuracy the many con-
ditions belonging to the general class of heart and circulatory disease,
and have so added a degree of specificity to digitalis studies which was
hitherto impossible.
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THERAPEUTIC USE OF DIGITALIS 23
The introduction of the polygraph by James Mackenzie inaugurated
the methods by which the movements of the auricles and ventricles of
man can be studied separately, and by which the efficiency of the
mechanism conducting the cardiac impulse from one chamber of the
heart to the other can be determined. The value of this method is
demonstrated by the masterly studies of digitalis published by
Mackenzie (106, 109) in 1905 and 1911 which have added much to
our knowledge of the action of the drug in heart disease.
The adaptation of the string galvanometer by Einthoven furnished
the second great advance in this direction, and the electrocardiograph
has added much to the modern concepts of digitalis action in man.
In it we possess a method that not only clearly differentiates all the
disturbances of cardiac mechanism, but which also gives us information
of importance regarding the direct action of digitalis on the heart mus-
cle, allows the detection of very early toxic effects of the drug on the
heart, and serves as an aid in determining pathological conditions of
the myocardium.
Although these two methods are not perhaps as yet available to
all practicing physicians, the information which they yield is trans-
latable, as Christian (14) remarks "into the terms of general practice,
that is, brought into the range of such observations as is possible with
fingers, eye and stethoscope."
Of the methods belonging to the second group, comment is necessary
perhaps in only one instance, namely the measurement of the vital
capacity of the lungs as a means of studying the effect of digitalis.
Several years ago, Peabody showed that the vital capacity of the
lungs (the amount of air, measured by a spirometer which can be
forced from the lungs after the deepest possible inspiration), varied
directly with the efficiency of the circulation. He also showed that
normal individuals of the same sex, weight and height gave vital
capacity readings of sufficient constancy to allow the establishment of
a normal standard. West and Pratt (156) have recently reported a
series of cases to which digitalis was administered and in which the
vital capacity of the lungs was taken as one of the criteria for the
estimation of the effect of the drug. Although it is not entirely clear
how the improvement of the circulation causes an increase in the vital
capacity, the method holds promise as a means of estimating quantita-
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24 G. CANBY ROBINSON
tively the functional efficiency of the circulation, and may therefore
fulfill, at least in part, one of the greatest needs in the study of the
effect of digitalis in heart disease. This method, the technique of
which is quite simple, should be included in all comprehensive studies
of the effects of digitalis on man.
VH. THE TOXIC EFFECTS OF DIGITALIS
In considering the effects of digitalis on man, they are naturally
separated into those that are advantageous and those that are deleteri-
ous, especially to patients suffering from heart and circulatory dis-
turbances. These two groups of effects may be spoken of as the
therapeutic and the toxic effects. In most instances, the two groups
can be separated by the ultimate results of each on the circulation as
a whole, but sometimes the prevailing conditions of the circulation
may make this separation somewhat difficult, as effects which would be
considered toxic, under most circumstances, may have, under some
conditions, therapeutic value. Therapeutic and toxic effects may
also occur simultaneously when the drug is being administered in
large doses to patients, and the close relation between the optimum
therapeutic dose and that producing early toxic symptoms presents
one of the greatest problems involved in the skilful use of the drug
in therapeutics. For instance, Bailey (quoted by Bastedo (5)) found
that of ninety patients in Bellevue Hospital taking digitalis, about 25
per cent showed one or more toxic effects of the drug.
The characteristic effects of all members of the digitalis group are
those on the heart and on the central nervous system, but in order to
understand the action of these drugs so that they may be intelligently
employed in the treatment of disease, a close analysis of their effects
must be made and careful consideration must be given to the various
pathological conditions they may be expected to benefit.
The first requisite for the successful employment of digitalis as a
remedy is the recognition of its toxic effect, especially of those early
effects which serve as indications for the discontinuance of the drug.
For this reason the deleterious or toxic effects of the drug will first be
discussed.
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THERAPEUTIC USE OF DIGITALIS 25
i. Gastric effects
In the earliest accounts of digitalis, reviewed by Withering (163),
the effects of the drug on the gastro-intestinal tract were described, and
it was spoken of as a poison having an emetic and a purgative action.
All modern study of digitalis has taken into account the gastric
symptoms, loss of appetite, nausea and vomiting which constantly
follow the use of all members of the digitalis group in large doses;
and they have been recognized as among the earliest toxic symptoms
which the drug produces.
Anorexia, nausea and vomiting are symptoms observed by all who
have used digitalis in sufficient doses, as they are probably the com-
monest of the "side-actions" as Eggleston puts it, encountered in the
clinical use of the digitalis bodies.
The peculiarities of the emetic action of digitalis were noted by
Withering (163) who wrote:
It is curious to observe that the sickness, with a certain dose of this
medicine, does not take place for many hours after its exhibition has been
discontinued The sickness then excited is extremely different
from that excited by any other medicine; it is peculiarly distressing to the
patient; it ceases, it recurs again as violent as before; and then it will con-
tinue to recur three or four days at distant and more distant intervals.
Vomiting should be avoided if possible, especially when digitalis is
being given to patients with severe symptoms of heart failure. This is
an important reason for the recognition of the earliest toxic effects
of the drug, in order that it may be stopped before the onset of vomit-
ing. As Pratt (122) says,
Vomiting may be preceded by a day or two of complete anorexia, which
should be a sign for the immediate discontinuance of the drug, when it
seems evident that the anorexia is caused by the digitalis. It is then an
indication that the so-called physiologic limit has been reached, and that
nausea and vomiting will follow if more digitalis is given. The stoppage
of the drug at the first appearance of anorexia does not always prevent
vomiting, but it does not, as a rule, last more than a few hours under these
conditions. When the drug is administered until vomiting actually occurs,
nausea and vomiting may be present for two or three days and occasionally
for a week, passing off and recurring several times, even after the drug has
been stopped, as Withering observed.
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26 G. CANBY ROBINSON
A difficulty in avoiding nausea and vomiting during digitalis ad-
ministration is the fact that in some cases, the desired effects of the drug
on the heart are obtained with the same dose as that producing the
gastric symptoms. Mackenzie (107) noted in his cases that the car-
diac effects usually preceded the gastric symptoms, but the two
occurred synchronously at times, and Cushny (30) states that minor
toxic symptoms, loss of appetite, headache, nausea and vomiting
and often diarrhoea usually accompanied the improvement of the
circulation produced by the drug. Clinical judgment is the only
guide in dealing with individual cases which present this dilemma.
Confusion sometimes arises in patients whose stomachs are in a
highly irritable state, as is not infrequently seen in heart failure, and
who vomit when anything is taken into the stomach. Such patients
will often vomit within a few minutes after a dose of digitalis, and
then it is safe to say that the drug is not responsible for the vomiting.
The reason for this statement will become evident when the mechanism
of the emetic action of the digitalis is discussed. Such vomiting
should not be taken as a sign for the discontinuance of the drug, as
the gastric symptoms may disappear with an improvement of the
circulation. A method of administration other than oral may have
to be resorted to, however, in such cases.
The relation of the therapeutic use of digitalis to nausea and vomit-
ing has been studied by Eggleston (40) in a series of 15 patients, all
of whom were suffering from heart disease. Digitalis was given in
the form of the infusion or tincture in the usual or slightly larger doses,
as a rule, every four hours. Eleven cases were instances of auricular
fibrillation. In this series nausea alone, or nausea and vomiting de-
veloped on an average of five days from the beginning of the digitalis
administration, when an average of 3.08 grams, corresponding to
7} drams of the tincture had .been taken. In the 4 cases with regular
cardiac rhythm, nausea or vomiting occurred in seven days, after the
average dose of 2.4 grams of the drug had been given. The average
dose in these cases was smaller than that given to the patients with
auricular fibrillation. In none of the 15 cases did the onset of nausea
\ or vomiting bear any constant time relation to the administration of
the individual doses of the drug. In most cases nausea or vomiting
persisted or recurred for some hours after the last dose had been given
and the drug withdrawn.
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THERAPEUTIC USE OF DIGITALIS 27
In estimating the total amount of digitalis which will, on an
average, lead to nausea and vomiting, the question of elimination of
the drug during the days of its administration must be taken into
account, and only rough estimates can be made which have any value
when applied generally to patients. Large single doses of digitalis
were administered to about 100 patients by Robinson (130), the doses
usually ranging from 15 cc. to 25 cc. of a standardized tincture, or
1.5 to 2.5 gram of digitalis. The patients were all adults, and suffered
from a variety of cardiac disorders. Only about 10 per cent of these
patients showed the toxic gastric symptoms caused by digitalis.
Nausea and vomiting came on in these cases in from one-half to one
hour after the large doses had been given. Eggleston (40) has col-
lected and tabulated 95 cases from the literature to which digitalis
bodies were given in the usual doses until nausea or vomiting appeared.
The cases of this series were divided into three groups. The first
consisted of cases of auricular fibrillation, the second group of non-
fibrillating cases and the third group receiving digitalis bodies other
than the leaf. In reviewing the first two groups, it is seen that the
dose of digitalis producing nausea or vomiting varies from 1.25 grams
to 8.50 grams and the figures are not sufficiently constant to war-
rant an average of significance to be obtained from them. The
dosage falls, however, most often between 2.5 grams and 3.5 grams.
A comparison of these two groups of cases leads to the conclusion
that the type of heart disease has no direct influence on the amount
of digitalis required to produce gastric symptoms, which occur also
with approximately the same doses in individuals with normal hearts.
The analysis of cases of the third group shows that crystalline digi-
toxin (Nativelle's digitalin granules), tincture of strophantus and
of squills, and the extract of apocynum also cause nausea and
vomiting, when given in sufficient doses. Cushny (30) concluded
from clinical observations that digitalis had perhaps less effect on
the gastrointestinal tract than strophanthus and squills.
The mechanism by which the digitalis bodies produce their emetic
action has been only recently clearly demonstrated, although much
speculation and some experimentation had been carried on regarding
it. In 1912, Hatcher and Eggleston (75) pointed out that the emetic
action of the drug had been generally attributed to its irritant action
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28 G. CANBY ROBINSON
on the gastric mucosa, but that there were several discrepancies
between the deductions which had been drawn from animal experi-
ments and the occurrence of nausea and vomiting in patients receiv-
ing therapeutic doses of the drug. They observed that the digitalis
bodies, as a rule, produced emesis more rapidly and with smaller
doses when given intravenously than when introduced into the
stomach. In order to eliminate the possibility of action of the drugs
during excretion from the blood stream into the stomach, digitalis
and several of its allies were injected intravenously into dogs from
which the gastro-mtestinal tract had been removed. Sixteen of the
21 eviscerated animals went through the motions of vomiting, after
the injection of these drugs, and three others showed signs of severe
nausea. They injected digitalis, digitoxin, true digitalin, ouabain,
strophanthus, amorphous strophanthin and adonis. Hatcher and
Eggleston conclude from their experiments that the emetic action of
these drugs is exerted upon the vomiting centre in the medulla aad
is not caused by the local irritation of the gastric mucosa. They
consider the purgative action also as obviously of central origin.
Just as this review is going to press, the report of Hatcher and
Weiss (78 a) on the emetic action of the digitalis bodies has appeared
in a preliminary form. They state that Thumas has shown that the
direct application of the digitalis bodies to the vomiting centre in
the medulla does not cause emesis. By means of a series of experi-
ments on cats in which various nervous structures were cut, Hatcher
and Weiss have shown that digitalis causes emesis only when the
nerve supply to the heart is intact. The vomiting centre is not
stimulated directly, but by impulses reaching it from the heart,
passing up by way of the sympathetic, and to a less, though probably
variable extent, by way of the vagus. Ouabain usually failed to
produce vomiting after the sympathetic only was cut.
These investigators consider their experiments as evidence that
the digitalis bodies induce emesis by reflex action due to irritation of
the heart or its appendages. The effect they consider as almost
certainly a protective mechanism for the heart such as is recognized
in the case of other organs. With the establishment of the fact
that emesis is not an effect produced by the direct action of digitalis
on certain structures of the medulla, but is secondary to the direct
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THERAPEUTIC USE OF DIGITALIS
29
action of the drug on the heart, a new attitude must be taken regard-
ing its relation to the cardiac effect of the drug. The effect of the
drug on the heart and its effect in producing nausea and vomiting
cannot be dissociated and the latter would seem to have a more
significant place than has been given to it in evaluating the cardiac
action of digitalis.
In a second paper Eggleston and Hatcher (48) investigated the
relative emetic activity of a number of more commonly used digitalis
bodies and also of several proprietary preparations for which dimin-
ished emetic action was claimed. They determined the percentage
of the fatal dose required to produce emesis in cats when injected
intravenously. The minimal dose and the average of the emetic
doses of various digitalis bodies and specialties in percentage of the
minimal lethal dose of each drug are given in their paper as follows:
DRUG OR SPECIALTY
True digitalin
Strophantus
Ouabain
Digitalis
Crystalline digitoxb
Amorphous strophanthin
Digipuratum
Fat-free tincture of digitalis,
Digitalysatum
Digalen tablets
Digalen, liquid
EMETIC DOSE IN PERCENTAGE
OF FATAL DOSE
Minimal
Average
18
27
22
47
30
49
31
40
46
58
61
65
25
42
28
34
29
36.5
29
40
30
38
Eggleston and Hatcher have shown therefore that all these digitalis
bodies and preparations have an emetic action which do not differ
quantitatively very markedly. True digitalin is the most active
emetic, while amorphus strophanthin and digitoxin are the least
active in percentage of their fatal doses. There is very little differ-
ence between digitalis and various specialties, and these experiments
furnish no evidence that digalen, digipuratum, digitalysatum and
the fat free tinctures have any advantage over the less expensive
galenical preparations of digitalis from the point of view of being
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30 G. CANBY ROBINSON
less disturbing to the stomach when used therapeutically. These
authors conclude that there is at present no means of securing the
cardiac action of the digitalis bodies without subjecting the vomiting
centre to the influence of these agents at the same time, and there
is no advantage in substituting one mode of administration, or one
member of a group for another, in an attempt to prevent or lessen
the gastric symptoms which these drugs cause. They also express
their disapproval of the employment of opium as has been advocated
to prevent the gastric symptoms, as it may serve to mask the toxic
symptoms which should serve as a signal for the discontinuance of
the drug or the reduction of the dose.
These experimental studies were followed by the clinical study of
Eggleston (40) to which reference has already been made, and in
which he correlated clinical experience with the facts of the experi-
ments. He showed in his. own series of 15 cases and in 95 cases
from the literature, nausea and vomiting almost never occur as a
result of digitalis until it had been absorbed sufficiently to produce
its characteristic effect on the heart. His study shows that there
is no valid evidence that therapeutic doses of the digitalis bodies
cause nausea or vomiting through local irritation on the alimentary
tract, but that there is strong evidence to the contrary. He concludes,
therefore, that the nausea and vomiting resulting from the thera-
peutic use of digitalis and its allies in man are due to their direct
action on the vomiting center in the medulla. Eggleston draws the
deduction from his conclusions that preparations which fail to produce
nausea and vomiting when administered in large doses are either
weaker than those that do produce these effects or are less well
absorbed.
Vomiting may be considered as a desirable effect from one point
of view, as it may prevent further toxic symptoms from following
an overdose of the drug when taken by mouth, as part of the drug
may be eliminated when the stomach is emptied by the vomiting
which it produces.
The purgative action of digitalis has not been prominently described
in recent clinical studies, and its absence was noted in the 42 patients
carefully studied by Mackenzie (107) to whom sufficient digitalis
was given so that gastric symptoms usually occurred. He found,
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THERAPEUTIC USE OF DIGITALIS 31
however, that diarrhoea was produced by strophanthus and squills.
Bastedo (5) also noted that diarrhea is much less frequent than
anorexia, nausea and vomiting as a sign of overdose in digitalis
administration. The writer's experience confirms these statements.
2. Toxic effects an the heart
Although the gastric disturbances are the most obvious unfavorable
effects of digitalis, the cardiac disturbances must be regarded as the
most serious in the clinical use of the drug. It is the direct effect of
digitalis on the heart which produces death in animals to which a
lethal dose is administered, and certain disturbances of the heart-beat
resulting from an overdose of the drug to man must always be con-
sidered as the forerunner of effects which profoundly lower the effi-
ciency of the circulation and which render the heart eventually
incapable of maintaining the circulation. For this reason, the
early recognition of the unfavorable effects of the drug on the heart
is a matter of paramount importance.
When Cushny (28) first studied the effect of digitalis on dogs by
a method that allowed the activity of auricles and of ventricles to
be distinguished in graphic records, he discovered early effects which
he attributed to the stimulating action of the drug on the vagus
centre and later effects which he considered as the result of the direct
action of the digitalis on the heart muscle. These later effects,
constituting the second stage of digitalis action, were attributed
mainly to an increase in the irritability of the myocardium.
Robinson and Wilson (134) administered digitalis intravenously
to cats and followed the effect of the drug on the heart by electro-
cardiograms. It was found that when about 75 per cent of the
lethal dose was administered, evidence of increased irritability of
the ventricles appeared, manifesting itself as premature contractions
which were soon followed by idioventricular rhythm, when cardiac
impulses were being generated at a more rapid rate in the ventricles
th^tn in the auricles. This state of affairs was followed, during
further administration of the drug, by ventricular fibrillation and
death.
More recently Levine and Cunningham (94) using the same methods
have found that when various preparations of digitalis were injected
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32 G. CANBY ROBINSON
into cats, premature ventricular contractions or extrasystoles ap-
peared when an average of 48 per cent of the lethal dose was
administered, and they considered the appearance of this phenom-
enon to mark the onset of increased ventricular irritability. They
used the appearance of ventricular extrasystoles therefore as evidence
of the first toxic sign of digitalis.
The analysis of unfavorable effects of the drug on the heart when
administered to man had its inception with the first of Mackenzie's
studies published in 1905, when he described the bigeminal pulse and
recognized that its production resulted from frequent ventricular
extrasystoles. He also showed that the conduction of the cardiac
impulse is disturbed by the drug. In 1911, Mackenzie pointed out
that digitalis may cause irregularities of impulse production, extra-
systoles, partial heart-block, and pulsus alternans. The cardiac
manifestations of overdose in digitalis administration were studied
by Bastedo (5) who made polygraphic records of patients receiving
the drug, and demonstrated the occurrence of auricular and ventric-
ular extrasystoles, partial heart-block, paroxysmal trachycardia and
possibly pulsus alternans. Bastedo recommends that digitalis be
discontinued whenever the radial impulse rate goes below 60 per
minute, whenever sudden slowing of the heart rate indicates the
occurrence of heart block, whenever a regular ventricular rhythm
becomes irregular, whenever tachycardia occurs or whenever coupled
rhythm or phasic arrythmia appear in hearts showing auricular
fibrillation.
a. Premature contractions. The two outstanding disturbances of
the cardiac mechanism which digitalis causes in patients are those
resulting from increased irritability of the ventricles and from depres-
sion of the conduction of the cardiac impulse from auricles to ven-
tricles. The effect of digitalis on the ventricles leads to the occur-
rence of premature contractions of ventricular origin, commonly called
extrasystoles. They are, generally speaking, always detrimental
to the efficiency of the heart. Premature ventricular contractions
tend to occur in diseased hearts and are, in many patients needing
digitalis, readily provoked by relatively small doses of the drug.
They appear to be provoked especially readily in patients with
auricular fibrillation, when coupled rhythm replaces the absolutely
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THERAPEUTIC USE OF DIGITALIS 33
irregular cardiac action. At times these premature beats occur so
frequently after small amounts of digitalis that it is the better part
of judgment to discontinue or diminish its use before the optimum (
therapeutic effects are obtained.
The occurrence of ventricular premature beats may be readily
recognized by the stethoscope with the finger on the pulse when
they occur in hearts beating otherwise regularly. Except when
definite coupled beats occur, it is impossible to recognize premature
ventricular contractions however in cases of auricular fibrillation
without electrocardiograms, which alone show, by the variations
in form of the ventricular complexes, that some of the cardiac con-
tractions are arising from ectopic points in the ventricles. The
frequent occurrence of ectopic ventricular contractions during the
use of digitalis in auricular fibrillation may be sometimes responsible
for the failure to get the ventricular slowing that the drug usually
produces in these cases.
There is a great difference in patients as to the amount of the
drug which causes the onset of premature ventricular contractions,
and no statement as to the average amount required can be made.
It is evident, however, that in many patients ventricular contractions
occur with an amount of the drug which is a much smaller proportion
of the lethal dose than has been observed during the intravenous
administration of the drug to cats.
Edens and Huber (38) have discussed the production of premature
ventricular contractions by digitalis, and the occurrence of the
bigeminal pulse. They consider it probable that the bigeminal
pulse follows the administration of digitalis only in hypertrophied
hearts with lowered muscular efficiency. They believe that the
production of the bigeminal pulse by digitalis is an unfavorable
prognostic sign. They also point out the great variability in the
size of the dose which brings about the bigeminal pulse. Although
their ideas regarding the relation of cardiac hypertrophy and inef-
ficiency to the digitalis bigeminal pulse have not been confirmed, it
is a point worthy of close attention.
The frequency of apparently spontaneous premature beats may
lead to some difficulty in fixing the responsibility for them during
digitalis administration, but it should be emphasized that it is a
MEMCDOt, rOL. I, MO. 1
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34 G. CANBY ROBINSON
definitely established fact that they may be caused directly by
digitalis, and should always be considered as a probable toxic effect
whenever they occur during the administration of any member of
the digitalis group. The influence of digitalis on apparently spon-
taneous premature contractions will be discussed later.
The production of the so-called auriculo- ventricular rhythm by
digitalis is an effect of the drug closely related to the production of
premature ventricular contractions. This type of disturbed cardiac
mechanism has been observed by Cohn (20) to follow the adminis-
tration of digitalis and to disappear when digitalis had been completely
eliminated. In auriculo-ventricular rhythm, the auricles and ven-
tricles beat independently but each at nearly equal rates. Electro-
cardiograms indicate that the auricular stimulation is not usually
disturbed, while the auriculo-ventricular node (of Tawara) assumes
the rdle of ventricular pace-maker, by generating stimuli at a slightly
faster rate than the sino-auricular node. Auriculo-ventricular
rhythm is associated only with various forms of cardiac intoxicants,
notably digitalis.
b. Depression of conduction of the cardiac impulse from auricles
to ventricles is one of the most striking effects of digitalis, which
may lead to partial or complete heart-block. This action of the drug
is generally considered to result, for the most part, from its stimu-
lating effect on the cardio-inhibitory mechanism, although there is
not entire agreement as to the relation of this effect to the direct
action of the drug on the cardiac tissues.
The great value of digitalis in certain forms of heart disease depends
largely upon its ability to block impulses in their passage from auricles
to ventricles, and for this reason the action of digitalis on conduction
will be discussed when the therapeutic effects of the drug are consid-
ered. On the other hand, heart-block produced by the adminis-
tration of digitalis may definitely lower the efficiency of the circulation ,
and it must be considered therefore as a toxic manifestation of the
drug. Its recognition and the means of avoiding its production will
be briefly discussed at this time.
Mackenzie (106) first demonstrated heart-block as an effect of
digitalis in man in 1905. Since that time, the influence of digitalis
on conduction has been extensively studied by graphic methods.
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THERAPEUTIC USE OF DIGITALIS 35
As Bastedo (5) has pointed out, when a rapidly beating heart becomes
suddenly slowed during the administration of the drug or if an inter-
mittent cardiac rhythm unassociated with premature beats develops,
it is safe to infer that heart-block exists. These events should be
taken as indications for discontinuing the administration of digitalis.
Uncertainty of the diagnosis of heart-block will always exist,
however, without the employment of the polygraph or the electro-
cardiograph. It is only by these methods that the earlier effects of
digitalis on conduction, when the cardiac impulses are merely delayed
in their passage from auricles to ventricles, can be detected. It is
distinctly advantageous, therefore, to employ these methods during
the administration of digitalis in order to detect its effect on conduction
before a stage is reached which may lower the efficiency of the heart.
A number of students of digitalis, among whom are Edens (37)
and Cushny (29) have expressed the opinion that digitalis affects
especially the conducting system of heart in which auriculo-ventric-
ular conduction has been previously damaged by disease. Although
Cohn and Fraser (22) have shown that this is by no means a necessary
condition for the production of digitalis heart-block, it must be a
predisposing factor in some instances. It is very desirable to know
the functional state of the conducting system before the adminis-
tration of the drug to patients with heart disease, and this information
is furnished by measuring the tfine between the onset of auricular
activity and ventricular activity. When this time is found delayed
beyond the normal limits, it should be taken as a contraindication
for the use of digitalis or it should call for caution, careful obser-
vation, and alteration of dosage.
R. H. Halsey (64) has reported a case showing profound effects
brought on apparently by excessive vagus stimulation producing
severe subjective symptoms. Following the administration of
digitalis to a patient with auricular fibrillation, severe cardiac failure
and Cheyne-Stokes breathing, marked variation in the ventricular
rate from 100 to 50 beats per minute were observed, the rapid rate
occurring during the periods of apnea. This phenomenon appar-
ently interfered with the interchange of Oj and COt , and was relieved
by atropin when the ventricular rate became 150 per minute.
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36 G. CANBY ROBINSON
Windle (161) studied the comparative effects of digitalis, stro-
phantus, squill and apocynum on the conduction of cardiac impulses
in a case of mitral stenosis which required treatment on four occasions*
He used a different drug each time, the tincture of each being
employed. Apocynum had no effect on conduction, while the other
three drugs caused partial heart-block with approximately equal
amounts.
630 minims of the tincture of digitalis were given in 14 days
540 minims of the tincture of strophanthus were given in 19 days
480 minims of the tincture of squill were given in 4 days.
When heart-block was observed in each instance it is evident that
these three members of the digitalis group required total amounts
which are comparable to produce partial heart-block in this case,
although the rate of administration was different.
c. Other disturbances of the heart beat have been observed occa-
sionally following large doses of digitalis. The auricles are affected,
although less frequently, in the same manner as the ventricles, and
premature auricular beats sometimes occur during the digitalis
administration, presumably as a result of the action of the drug.
Bastedo (5) has reported a case of paroxysmal tachycardia which he
considered as produced by digitalis, but the relation of the inception
of this disturbed cardiac mechanism and the action of the drug seems
uncertain.
Special interest is attached to the influence digitalis may have in
causing auricular fibrillation. Cushny (30) has stated that digitalis
may cause the onset of auricular fibrillation and Danielopolu (33)
has reported three cases in which auricular fibrillation followed the
administration of the drug, in each instance the onset of fibrillation
occurring coincidently with the maximum digitalis action. Daniel-
opolu considered that in his cases the auricles were predisposed to
fibrillation which was provoked by the stimulating effect of the
drug on the vagus. Mackenzie (107) has reported a case in which
auricular fibrillation set in at the time when an amount of digitalis
sufficient to cause maximal effects had been given, and disappeared
four days after the discontinuance of the drug. Robinson (126)
studied a case of paroxysmal auricular fibrillation to whom digitalis
was administered, but was unable to draw any definite conclusion
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THERAPEUTIC USE OF DIGITALIS 37
as to the influence of the drug on the persistence of the fibrillation.
Agassiz (2) administered strophanthin intravenously to such a case,
with the result of apparently prolonging the paroxysm of auricular
fibrillation, although the ventricular rate was slowed by the drug.
It is these cases of transient auricular fibrillation in which the question
of the relation of the drug to the production of this cardiac disturbance
is especially important. The evidence seems sufficient, as Fulton
(56) points out, to warrant the conclusion that digitalis does predis-
pose the auricles to fibrillation, and its use may therefore be disad-
vantageous in cases where it is desirable to prevent recurrent attacks
of fibrillation, or where a cessation of fibrillation may be expected,
although the drug may be very useful when fibrillation is present.
Clinical judgment can be the only guide under such conditions.
Auricular standstill has been observed by White (157) as an effect
of digitalis in cases of heart disease. In these cases, both electro-
cardiograms and graphic records from the jugular vein failed to
show any evidence of auricular activity during the height of digitalis
action. In all three cases, the auricular activity returned when the
effects of the drug passed off. White considers this phenomenon as
a rare result of digitalis administration, and no other similar cases
are to be found in the literature. Atropin was administered in one
case, but had no effect upon the cardiac mechanism except for
a slight increase of rate.
White and Sattler (160) have also described a curious arrhythmia
consisting of blocked auricular premature beats occurring in a healthy
subject after 3 grams of digitalis had been taken. Sinus arrhythmia
in which the rhythm of impulse formation is disturbed, is com-
monly observed with large doses of digitalis, as first pointed out
by Wenckebach (155). A number of cases of sino-auricular block
produced by digitalis have also been observed by the electrocardio-
graphic method, as a result of digitalis action.
Pulsus alternans, a condition in which the regularly beating ven*
tricles contract with alternating force, is generally considered a
sign of disturbed contractility of the heart muscle, and of serious
prognostic significance. Mackenzie (107) and Windle (162) each
state that they have observed this phenomenon as a sequel of digi-
talis administration in two cases. Bastedo (5) reports one case
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38 G. CANBY ROBINSON
which he considered as possibly pulsus alternans produced by digi-
talis, but his records do not allow him to make a definite diag-
nosis, and his published curves are not characteristic of this condition.
These cases are important as an indication that digitalis may affect
the heart muscle, presumably directly, in such a way as to lower its
efficiency. Bastedo believes that pitlsus alternans results from a
constriction of the coronary arteries produced by digitalis, but this
idea must be considered purely hypothetical, as there are no definite
facts to support it.
Weil (154) has brought forward a criterion for the early recogni-
tion of digitalis intoxication which is somewhat different from those
that have already been mentioned. He has shown that, under the
influence of the drug, the heart becomes more responsive to pressure
over the vagus nerves in the neck, and he believes that a well
marked vagus response during digitalis administration in a heart
which was previously less responsive may be used as indicating the
onset of toxic digitalis effects.
3. Fatalities resulting f torn digitalis bodies.
It is not within the scope of this review to discuss fatalities result-
ing from amounts of digitalis far in excess of those used for thera-
peutic purposes. According to Sollmann (143) 2.5 grams of digitalis
have proved fatal when taken at one dose, while 4 grams have
been followed by recovery. Sollmann states that the symptoms of
a fatal dose are those of "cumulation" — gastro-intestinal disturb-
ances, slow and arrhythmic pulse, etc., lassitude, muscular weakness
and sensory derangement. Death generally occurs suddenly, with
dyspneic convulsions. Consciousness persists late.
Sudden death has been seen occasionally following the administration
of the drug' in the treatment of heart disease, and fatalities occurring
under these conditions must be considered as possibly caused by the
drug. During the administration of digitalis by mouth in the usual
doses, it is difficult to say what rdle the drug might play as a cause of
sudden death. Since the introduction of the intravenous method of
administration, however, fatalities have apparently resulted from the
injection of the digitalis bodies into a vein. These have most often
followed the use of strophanthin, and according to inquiries made by
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THERAPEUTIC USE OF DIGITALIS 39
the writer, have been seen more often than the literature would make
one believe. Bastedo (5) remarks that he has heard of one death
following the intravenous injection of digitalis in a man and of several
such fatalities occurring in from three minutes to an hour after the
injection of strophanthin. The writer has observed 1 case in which
death occurred suddenly about five minutes after 1 mgm. of strophan-
thin was given intravenously, and at least 3 other such cases have
been related to him by others. Recently Rahn (123 a) has reported
2 fatalities following intravenous injections of strophanthin and has
reviewed 16 other cases collected from the literature in which death
occurred in such close connection with the intravenous injection of
the drug as to make a relation of cause and effect seem very likely.
In 11 of the cases the causal relation seems certain. Rahn discusses
the clinical significance of these deaths and is of the opinion that
some of these could have been avoided by smaller doses, longer
intervals between doses and a better knowledge of previous admin-
istration of digitalis. He believes that the drug should be given by
this method only after careful study of the patient. The sudden
fatal termination and the relatively short interval between the
injection and death seen in a number of these cases leads to the
conclusion that strophanthin caused the ventricles to fibrillate, a
cardiac state incompatible with life. Ventricular fibrillation is the
final stage of cardiac intoxication in most cases when the digitalis
bodies are injected intravenously into cats, as shown by Robinson
and Wilson (134) and by Levine (92). It is likely that the fatal
cases under discussion occurred in patients in whom cardiac damage
had already rendered the ventricles prone to fibrillation.
Garrey (57) has investigated the underlying factors responsible
for fibrillation of the cardiac muscle, and has advanced an explanation
of this phenomenon on the basis of his experiments. The essential
points in Carrey's conception of fibrillation are these. Fibrillary
contractions of the heart muscle depend upon the establishment
within the musculature of multiple regions of block or impaired
conductivity. The impulses thus blocked or delayed take abnormal
or circuitous paths, and return to the same portion of the muscle
after the refractory state has passed off, but while other portions are
still refractory. The latter portions are subsequently involved in a
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40 G. CANBY ROBINSON
similar manner, and the whole tissue mass is then thrown into a con-
tinuous incodrdinated contraction, which is not initiated or sustained
by new impulses arising from any definite location.
With these points in mind it seems reasonable to consider evidence
of impaired conduction within the ventricles as a contraindication
to the intravenous use of full doses of strophanthin or other digitalis
bodies. Such evidence is sometimes obtained by the study of electro-
cardiograms, as certain abnormalities in the form of the ventricular
complexes indicate delay or abnormal conduction routes in the
ventricles. The bearing of these abnormal complexes to the admin-
istration of strophanthin has been discussed by Robinson and Bredeck
(131), who express the opinion that such electrocardiographic findings
should be taken as a contraindication to the intravenous use of
strophanthin, and they show the relation these abnormal electro-
cardiograms may have to ventricular fibrillation.
Although the danger entailed in the intravenous administration of
strophanthin has been generally recognized, other digitalis bodies
have not received as much consideration from this point of
view. Levine and Cunningham (94) however have studied the so*
called margin of safety of intravenous digitalis administration in
cats, and draw certain conclusions from their experiments bearing
on the intravenous use of the drug. They determined the percentage
of the lethal dose which produced the earliest demonstrable toxic
signs. The minimal toxic dose was calculated in their experiments
as the smallest dose that is required to produce ventricular extra-
systoles, demonstrable by electrocardiograms. The margin of safety
was taken as the difference between the minimal lethal dose and the
minimal toxic dose. They have introduced
the concept of the margin of safety of digitalis preparations because, in
the practical use of the drug, the therapeutic dose is very dose to the toxic
dose. Therefore, it is of great importance to know how far removed the
lethal dose is from the toxic dose, and whether the margin is greater in some
preparations than in others.
They used aqueous extracts of several different samples of leaves,
several different tinctures, and ampoules of Digifoline, Digalen and
Digipuratum. They found considerable variations in different
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THERAPEUTIC USE OF DIGITALIS 41
animals both in susceptibility to the drug and in the margin of safety
which varied from 27 to 64 per cent. The average margin of safety,
however (the difference between the percentage causing death and
that causing earliest evidence of toxicity), was 48 per cent of the
lethal dose. This difference is identical with the results which
Levine (92) obtained in previous work with crystalline strophanthin
or ouabain. Levine and Cunningham (94) state on the basis of
their findings that
the practical consideration that follows from these experiments is that
although the various digitalis bodies, when given by mouth, are generally
regarded as much safer than intravenous administration of strophanthin,
when the entire digitalis glucosides (either the aqueous or the alcoholic
extracts) are given intravenously, the same risk is encountered as in using
strophantus
They found also but little difference in the rapidity with which
the various digitalis bodies and crystalline strophanthin act on the
heart when introduced directly into the circulation.
If these experiments can be applied to man, and it seems only safe
to assume that they can, it must be borne in mind that the risk of
introducing digitalis directly into a vein appears to be as great as
when strophanthin is used.
The question of the percentage of the lethal dose which is employed
in the treatment of heart disease has been discussed by Robinson
and Wilson (134) in the light of their experiments in which the tincture
of digitalis was administered intravenously to cats. They consider
the inversion of the T wave of the electrocardiogram the digitalis
effect offering the most useful comparison of the effects of the drug
on the cat's heart and the effects obtained in man. The T wave
became inverted in their experiments when from 20 to 30 per cent
of the lethal dose had been injected. The maximum therapeutic
effects of digitalis usually occur with a dose not much in excess of the
amount sufficient to cause inversion of the T wave. Robinson and
Wilson, taking these facts into consideration, have expressed as
their opinion that the maximum therapeutic effects are probably
produced in man by the administration of from 30 to 40 per cent at
most of the lethal dose of the drug.
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42 G. CANBY ROBINSON
Vm. THE THERAPEUTIC EFFECTS
The beneficial effects exerted by the digitalis bodies upon patients
suffering from heart disease are dependent, not upon a single mode
of action of the drug on a single organ, but upon a combination of
effects. The relative importance of the various activities of digitalis
in its therapeutic use has been the subject of much controversy for
many years, and although much of this controversy has been cleared
up, several points remain about which there is no unanimity of
opinion. As has been stated, animal experimentation has added
confusion, in some respects, to the problem of determining how
digitalis benefits patients with heart disease, and the question can
receive its final answer only by the study of patients.
The various effects which may enter into the therapeutic action
of digitalis will be discussed separately and their relative importance
will be considered in connection with the use of the drug in various
forms of heart disease.
1. The effect on the heart muscle.
a. The effect on ventricular contraction. The relation of the effect
of digitalis on ventricular contractions to its beneficial influence in
heart disease has been much discussed, but this problem has not
yet been definitely solved. Its solution is difficult, partly because
there has been no certain means of measuring the direct influence
of the drug on the efficiency of the heart muscle, and partly because
the various factors entering into the therapeutic action of the drug
cannot be sharply differentiated from one another. In spite of the
uncertainty which actually exists, digitalis ha£ been generally con-
sidered for many years as a so-called "heart tonic," and its beneficial
effect has been considered as mainly due to an increased output of
the heart by its action on the muscle itself.
The older conception is well illustrated by a statement made by
Balfour in his clinical lectures on Disease of the Heart, quoted by
Schmoll (141).
All the benefits we obtain from digitalis are inseparably connected with
its tonic action; they flow from the power that digitalis has of increasing
muscular activity, and the improved metabolism of all the tissues, but
especially of the myocardium.
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THERAPEUTIC USE OF DIGITALIS 43
Schmoll expresses his belief that the drug acts as a specific by its
effect on the tonicity of the heart muscle.
Schmiedeberg (140) basing his opinion apparently on the results of
animal experiments states in the seventh edition of his text book,
that the therapeutic action of digitalis is due almost exclusively to
its effect on the heart muscle. He considers an increase in the elas-
ticity of the heart muscle the most important effect of the drug and
that the change in elasticity is also responsible for the systolic stand-
still of the heart produced by the drug. Schmiedeberg believes that
all other effects of digitalis are mainly secondary to the increased
force of the cardiac contractions which the drug calls forth.
Other students of the effects of digitalis on animals, notably Cushny ,
have found that the drug causes an increase in the output of the
mammalian heart under experimental conditions, which occurs in
excess of that which results from the slowing of the heart rate alone.
Another experimental pharmacologist Gottlieb (59) states that the
work of a single contraction of the isolated mammalian heart may
increase under the influence of digitalis two and a half to three times,
and Gottlieb summarizes his conception of the therapeutic action of
digitalis as due principally to more complete contraction of the
ventricles and re-distribution of the blood in the vessels. He believes
the drug may strengthen the contractions of the "weakened heart."
It does not seem profitable to enter into a discussion of the experi-
mental studies of this subject, as the conditions under which facts
have been adduced are not applicable to a consideration of the thera-
peutic action of digitalis. In this connection, Cohn (20) has said
Those effects reported earlier, of changes in the magnitude of ventricular
contractions gained in experiments, are more recently admitted (Joseph)
to have been obtained by doses far too great. The much smaller doses
now used are still much larger than are permitted in therapeutics, but even
these fail to show marked changes in the extent of the excursion of the
ventricular wall which was formerly held to indicate the nature of effective
digitalization. The methods employed in pharmacology are not superior
to those now available in clinical medicine. Both are on a par in respect to
obtaining objective records of this phase of digitalis action.
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44 G. CANBY ROBINSON
In the absence of accurate means of measuring the therapeutic
action on the heart muscle, the opinion of various clinical investi-
gators must be considered more as impressions than as well founded
convictions. In Mackenzie's (106) first studies on digitalis, he says
that the good effect on the cardiac contractions may be due to the
slowing of the cardiac rate, but under certain circumstances, the fact
that digitalis may effect the function of contractability directly can
be demonstrated in a most striking and convincing manner. In his
later clinical studies, however, when he was in possession of a more
extensive knowledge of the cardiac mechanism and its derangements,
he stated that he was unable to determine that the drug affected the
heart muscle, but admits that changes may take place in the heart
which we cannot detect.
Wenckebach (155) believes that digitalis increases the strength of
the human heart by its direct action on the heart muscle, but that
there is no evidence that the drug acts on the obscure property, tone
of the muscle. Edens (37) has advanced the hypothesis that the
poor nutritional condition of the myocardium which is presumably
present in heart disease tends to prevent digitalis from exerting its
effort on the cardiac contractions, and offers this explanation for his
inability to observe any direct action on the heart muscle. Cohn
(20) in speaking of the effects of the drug when administered to
patients in doses calculated to produce the optimum effects in heart
disease stated in 1915, "that if digitalis increases the ability of the
ventricles to pump blood, it does so by means of a change which is
more subtle than can be distinguished by our methods/'
With this limitation of the knowledge regarding this important
factor in explaining the action of digitalis in mind, Cohn and Levy
(26) have undertaken an investigation of the effect of therapeutic
doses of digitalis on the contraction of heart muscle by means of
animal experiments. They have been careful to use doses of th$s
drug which were comparable in percentage of the lethal dose to those .
administered to patients. The tincture of digitalis and g-strophan-
thin were injected intravenously into dog* and cats, and alterations
in volume output were studied in curves obtained by the use of the
Roy and Adami myocardiograph.
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THERAPEUTIC USE OF DIGITALIS 45
The curves represent longitudinal linear alterations in the form of ven-
tricles, and may, under the condition of cardiac contraction, represent
changes in volume of the cavities and consequently of volume output.
The results are reported as changes in the degree of contraction.
In 30 dogs, they obtained increased contractions 24 times; while
other phenomena of digitalization revealed by electrocardiograms were
less constantly observed. In 14 cats the degree of contraction
increased 4 times, decreased 6 times and was unchanged 4 times,
with even more frequent effects on electrocardiograms than in dogs.
The effect on contraction differed, therefore, in cats and dogs. Blood
pressure readings were also made in some of the experiments in
which ether was administered and the chest opened. In order to
rule out the effect of these procedures, several experiments were
performed on unetherized dogs without operative procedures; the
blood pressure being obtained from the carotid artery which had
been previously freed from the tissues of the neck (van Leersum's
method). In these experiments the electrocardiographic and blood
pressure changes were similar to those of the dogs on which opera-
tions were performed. From these experiments, the conclusions are
drawn that digitalis and strophanthin with doses of therapeutic
range increase the contractile power of the cardiac muscle, and by
so doing, increase the volume output. This result supplies a firm
basis for the statement that these drugs may exercise a beneficial
action on the normally beating heart by their action directly on the
cardiac muscle. Their results regarding blood pressure and electro-
cardiography will be mentioned when these phases of the digitalis
problem are considered.
b. The effect on the electrocardiogram. The effect of digitalis on the
T wave of the human electrocardiogram has furnished evidence of a
different kind from that which has been discussed, and it has served
as apparently clear proof that the drug acts directly on the heart
muscle when administered in therapeutic doses. Although no direct
relation has been established between the change in the T wave and
the efficiency of the cardiac action, the discovery of this effect has
been very useful in studying digitalis and has marked a definite
advance in our knowledge.
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46 G. CANBY ROBINSON
Cohn and Fraser (22) first reported briefly in 1913 that they had
"found that as the result of digitalis intoxication, the T wave in the
electrocardiogram often becomes negative or diphasic, but returns
to normal after the effect of the drug has passed off. It is an inter-
esting fact that, although atropin may cause rate and conduction to
return to normal, this change in the electrocardiogram persists/'
The influence of digitalis on the T wave of the electrocardiogram
was studied in a series of patients by Cohn, Fraser and Jamieson (23)
who made the first comprehensive report on this subject, although a
number of scattered observations on animals and* man had been
previously reported by others. Cohn and his coworkers found that
an alteration of the T wave occurred in 30 of 34 patients to whom
full doses of digitalis were given, and that this alteration was generally
observed before alterations in rhythm or conduction time had occurred
or before gastro-intestinal symptoms disturbed the patients. For
the most part, the changes in the T wave consisted, first, in a dimi-
nution in the height of the wave, and finally in an inversion. In
cases yielding downwardly directed T waves before treatment,
digitalis produced eventually upwardly directed waves and other
variations in the T waves occurred. This portion of the electro-
cardiogram was affected in patients with auricular fibrillation and
flutter, and in one patient with complete auriculo- ventricular disso-
ciation, as well as in those with normally beating hearts. It is
pointed out that the sign attains greater importance on account of
its appearance early after the beginning of the administration of the
drug. Changes in the T wave were detected after an equivalent of
1.2 grams or even less of the dried leaves of digitalis had been given.
The influence of atropin on the altered T wave was repeatedly
tested, and full doses of the drug intensified the changes in the T wave
during its transient action. Atropin alone, however, produced no
changes in the T wave. The altered T wave persisted for some days
after digitalis was discontinued, resembling, in this respect, other
effects of the drug.
In discussing their results, Cohn, Fraser and Jamieson bring for-
ward convincing arguments to prove that the alteration of the T
wave is caused by the action of digitalis on the heart muscle. The
effect that atropin has on the phenomenon indicate, however, that
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THERAPEUTIC USE OF DIGITALIS 47
the cardiac inhibitors, the vagus nerves, are capable of exerting an
influence upon it. The effect of full doses of digitalis on the T
wave of the electrocardiogram of healthy children was studied by
McCulloch and Rupe (112). They found that the drug did not
produce the same effects as readily or as frequently as in adults as
shown by the observations of Colin, Fraser and Jamieson, although
larger amounts of the drug per unit of. body weight were given to
the children, and other evidence of digitalis action was abundant.
Since the appearance of the paper by Cohn and his coworkers,
their results have been abundantly confirmed, both for man and
animals. Robinson and Wilson (134) found the inversion of the T
wave was the first constant sign of digitalis action to be detected by
electrocardiograms when the drug was injected intravenously into
cats. It occurred in their series when approximately 25 per cent of
the minimum lethal dose had been injected, and the dosage necessary
for its production was not altered when the vagi were cut.
Cohn and Levy (25) have recently compared the effects on patients
of g-strophanthin given intravenously with the effects of comparable
doses of digitalis (digipuratum) given by mouth. Only a prelimi-
nary report has been published. They studied the relative effect of
the two drugs oa the T wave of the electrocardiogram and found
that strophanthin had little or no influence on the form of the T wave,
which at most underwent only transient changes, while the usual
effects were produced by digitalis.
c. The effect on the size of the ventricles. Several attempts have been
made to determine whether the administration of digitalis leads to
the development of hypertrophy of the ventricles. Cloetta (18) found
that the continuous subcutaneous administration of digitalis to
young rabbits had absolutely no effect upon the size of their hearts,
as compared with a series of controls. Of a series of animals in
which aortic insufficiency was artificially produced, those treated
with digitalis showed less cardiac enlargement than those that were
not treated.
Caro (12), on the other hand, noted cardiac hypertrophy in animals
to which digitalis had been given over a long period of time as did
Reinike (125) who compared the cardiac muscle with the skeletal
muscles. The latter muscles did not participate in the hypertrophy
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48 G. CANBY ROBINSON
observed in the heart. This work is based on a very small number
of animals (four rabbits and two dogs) and so the conclusions drawn
can hardly be considered as justified. Gelbart (58) repeated Cloetta's
experiments with rabbits in which aortic insufficiency was artificially
produced, and found that four weeks after the valve damage, cardiac
hypertrophy had developed which was, in no way, influenced by
digitalis. In view of the conflicting evidence, the relation of digitalis
to cardiac hypertrophy must be considered as an open question.
The influence of digitalis on cardiac dilatation presents an important
question. Although ventricular dilatation may be favorably effected
by the administration of the drug it is impossible to say whether
this result is brought about by direct action on the heart muscle or
whether it is secondary to other beneficial effects.
d. Chemical aspects of digitalis action. The action of digitalis on
the cardiac muscle has been studied from the chemical view-point by
Burridge (8), who made some pioneer contributions which may
bring results of fundamental importance to the therapeutic use of
digitalis in the future. He has concerned himself especially with
the interaction of digitalis and calcium on the perfused heart. He
studied changes in the degree of cardiac contractions resulting from
changes in the calcium content of the perfusion fluid. During some
observations on the cardiac reserve, he found that calcium determines
the amplitude or the percentage of the contractile material possessed
by the heart which is used up with each spontaneous beat. And
further that, under certain conditions, digitalis is a drug which
enables a given tension of calcium in the perfusion fluid to evoke the
activity of a greater proportion of the whole contractile material
than is the case in its absence.
Burridge (9), in a second paper, discusses some factors of the
cardiac mechanism illustrated by reference to certain actions of
barium and digitalis. He interprets his experiments to mean that
digitalis renders the heart more susceptible to calcium, as a given
amount of calcium had more effect on the heart after treatment with
digitalis than before. Crystalline digitoxin was used. He studied
(a) the effect of digitalis on changes in the amplitude of contractions
with fixed amounts of calcium, and with amounts of calcium neces-
sary to evoke a fixed proportion of the whole contractile material;
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THERAPEUTIC USE OF DIGITALIS 49
(b) on the amount of tonus produced by a given amount of calcium
and vice versa; and (c) on the amount of shortening of the refractory
period produced by a given amount of calcium. Not only was
calcium more effective but less calcium was required to produce
constant effects after the heart had been exposed to digitalis. The
response of the heart to calcium could be increased five to tenfold by
treating it with digitalis, the effects of which persisted after the drug
was withdrawn. The amount of calcium necessary to allow normal
contractions may produce systolic standstill of a digitalized heart.
A difference was noted in this respect, however, in hearts that had
been long perfused and in fresh hearts, digitalis causing more marked
effects in the latter.
Burridge believes that digitalis may be considered as a cardiac
"lubricant," and should be classed with the secretions of the adrenals
and pituitary gland in this regard.
Loewi (104) has also studied the relation of the effects of calcium
and digitalis. He is of the opinion that in cases of heart disease the
capacity of the heart for stimulation by the physiological calcium
content of the blood is depressed. Strophanthin, Loewi believes,
brings the sensitiveness of the heart to calcium back to normal.
These studies on the perfused heart represent conditions so far
removed from those obtained in the treatment of heart disease that
direct application is unwarranted. On the other hand, the work of
Burridge and Loewi is very interesting and should not be lost sight *
of in attempts to find the fundamental principles underlying the
action of digitalis on the human heart.
Levine (92) has discussed the question of whether the action of the
digitalis bodies on the heart is a physical or a chemical process. His
review of the work bearing on this question shows how difficult it is
to find its answer. Certain facts indicate that probably chemical
changes and physical action each play a part. - The general condition
of the heart, the temperature, rate and pressure of the perfusion
system, and its organic and inorganic constituents are all factors
difficult to resolve. Levine's perfusion experiments with strophan-
thine have led him to believe that the heart utilizes only a small
portion (in the neighborhood of 10 per cent) of the drug to which it
is exposed, regardless of the concentration at which it reaches the
heart.
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A toxic effect results when the heart has taken up a certain total of the
drug, which is a definite small fraction of its own weight If this theory
be correct, it explains why, in concentrated solutions, the total amount is
not important, for the small part that is taken out by the heart does not
appreciably alter the concentration, while when very dilute solutions or
small quantities are used, the amount taken up by the heart diminishes the
remaining concentration appreciably; that is, the "digitalis pressure"
becomes lessened. In these experiments, the rapid injections forced an
adequate amount of strophanthin into the heart rapidly, and produced the
toxic effect; in the slow injections, the same total amount of the drug was
taken up by the heart, only more slowly.
2. The effect on the cardio-inkibtiory mechanism.
Since the demonstration by the Weber brothers of the cardio-
inHibitory mechanism, much interest has been shown in its relation
to the action of drugs affecting the heart, and pharmacologists have
had to take into account the possibility of indirect action of drugs on
the heart through its nervous mechanism. The illuminating analysis
of the cardiac action of the vagi by Engelmann has been of much
value in attempts to understand the action of drugs affecting the
heart. He showed that the heart possessed the properties of contrac-
tility, conductivity, rhythmicity and irritability, and that all
these properties were depressed when the vagus nerves were stimu-
lated. This conception has not only done much to form a basis for
the explanation of abnormalities of the heart beat, but it has also
been useful in understanding the effects that digitalis exerts on the
heart.
a. Vagus stimulation. Traube was the first experimenter to find
that cutting the vagus nerves altered the effect of digitalis on the
heart. His later studies led him to conclude that digitalis stimulated
the cardio-inhibitory centre in the medulla, and affected the heart
through the vagi. Acketmann, according to Boehm (6) demonstrated
in 1871 that digitalis failed to slow the heart of animals after atropin
had been injected. Boehm, who was also one of the earliest experi-
menters with digitalis, concluded from his work with frogs, that the
drug heightened the irritability of an inhibitory centre in the heart,
and thus increased the susceptibility of the heart to vagus action.
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THERAPEUTIC USE OF DIGITALIS 51
Cushny (29) made an important contribution to the action of
digitalis by his studies on the mammalian heart. He showed that the
drug acted both by direct action on the muscle and by stimulation of
the cardio-inhibitory centre. He divided its action into the inhibitory
and the muscular stages, and concluded that the beneficial stage of
its effect in heart disease resulted from its action on the heart muscle,
while its inhibitory action was undesirable from the therapeutic
standpoint. The fact that digitalis has two modes of action on
the heart has made it difficult to reach definite conclusions as to
their relative importance, and to give a clear conception of its effects.
Although the vagus effects of digitalis have been considered by most
students of the subject to result entirely from the direct stimulation
the cardio-inhibitory centre, other opinions have been held. Schmicde-
berg (140) considers that vagus stimulation is secondary to the
increased blood flow produced by the action of digitalis on the heart
muscle. Kockmann (89) concluded from his experiments on dogs
that digitalis causes slowing of the heart at least in part by stimulation
of the peripheral end of the vagi. He obtained cardiac slowing in
dogs by intravenous injections of various digitalis bodies after the
vagi had been cut and found that this slowing was replaced by ac-
celeration when atropin was given. Etienne (50) repeated these
experiments and was unable to confirm Kockmann' s observations.
Green and Peeler (60) studied the action of digitalis on the cardio-
inhibitory centre when perfused through the isolated head and brain
of the turtle. In their experiments, the head was completely isolated
from the general circulation, and all tissues in the neck region except
the vagus nerves were severed; the connection through the nerves
being the only one maintained between the head and the body. The
cardiac movements were recorded by a direct attachment of the ven-
tricular apex to the recording lever. They found that when digitalis
was perfused through the turtle's brain, the cardio-inhibitory centre
was strongly stimulated and that not only was the rhythm of the
heart inhibited, but the conduction of the cardiac impulses was also
depressed. The weight of evidence is strongly in favor, therefore, of
the conception that the vagus effects of digitalis on the heart are
mainly or entirely the result of the direct stimulation of the cardio-
inhibitory centre, although other factors may take some minor part
in their production.
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52 6. CANBY ROBINSON
b. The effect on cardiac rate. The two chief cardiac effects of digw f*
talis stimulation of the vagus centre are slowing of cardiac rate and
depression of conduction of the cardiac impulse from auricles to
ventricles. The other cardiac effects of vagus activity, inhibition of
contractility and of irritability may be masked or overcome by the
effect of the drug directly on the heart muscle, for they are not ob-
served.
Reduction of the rate of the heart beat was the first digitalis effect,
to attract attention in experiments on animals, and these observations
profoundly influenced* the conceptions regarding the therapeutic
use of the drug. Digitalis has been used by physicians for many years
with the expectation of slowing the heart rate of patients in the same
manner in which slowing is produced in animals. It is true that the
reduction of the accelerated cardiac rate is without doubt the most
important effect of digitalis in heart disease but this valuable effect
occurs in a striking manner only in one form of cardiac disturbance,
namely, auricular fibrillation, in which digitalis accomplishes the
reduction of cardiac rate by an action quite different from that causing
the slowing observed in animals and in man with normally beating
hearts. This point will be discussed later when the use of the drug in
auricular fibrillation is considered, but to avoid confusion, it is neces-
sary to draw the distinction at this time between the action of digitalis
on the normally beating heart and on the heart in which the auricles
are in a state of fibrillation. It is only when these two conditions are
differentiated that reliance can be placed on statements regarding the
influence of the therapeutic action of digitalis on the cardiac rate.
As it was not possible to determine with certainty the existence of
auricular fibrillation before the employment of the electrocardiograph,
only the literature of approximately the last ten years can be said to
furnish reliable evidence on this point.
The question under discussion here is the ability of digitalis to slow
the rate of impulse formation in the normally beating human heart by
inhibition through the vagi of the rate of impulse formation.
Divergent opinions have been expressed by various students of
digitalis. Wenckebach (155) states that the regularly beating heart
is slowed by the action of digitalis on the vagus nerves and compared
its action to the effect obtained by stimulation of the vagi by pressure
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THERAPEUTIC USE OF DIGITALIS 53
over their trunks in the neck. On the other hand, the drug was found
to have almost no effect in most cases with normal rhythm in the
series carefully studied by Mackenzie (107). He observed occasion-
ally, however, striking slowing of the cardiac rate in cases with normal
rhythm following the administration of digitalis, which he thinks is
possibly due to the stimulation of the vagus nerves by the drug.
Cushny (29) observed slowing of the heart in 6 of 18 patients with
normally beating hearts to whom full doses of digitalis were given.
The relation of the slowing in the cases in which it does occur due to
vagus action was studied later by Cushny, Mams and Silverberg
(32). They noted the effect of vagus paralysis by a tropin in patients
affected by digitalis, and attempted to distinguish between the effects
of the drug directly on the heart muscle and those induced through
vagus stimulation. They concluded that the effects produced through
the vagi do not play any part in the beneficial action of the drug.
Conn and Fraser (22) have reported repeated observations on the
effect of digitalis on twelve patients with normally beating hearts.
Daily electrocardiograms were taken and the drug was administered
until a disturbance in the rhythm of the heart was effected, at which
time the patients usually had gastric symptoms. In regard to the
effect of digitalis on the heart rate they say:
Slowing of the heart, even when the rhythm is normal, is still taken in
many quarters as a measure of the efficiency of digitalis. The slowing of
the heart which takes place after the onset of the symptoms of intoxication
can hardly be taken to be of benefit But before the symptoms occurred,
slowing took place in only one patient, and this one was the subject of
abrupt fluctuations in rate without the use of drugs. Slowing was observed
in five more patients, but not until two days after rather severe symptoms
of intoxication had set in. Two of these patients had quite normal hearts,
anatomically and functionally. It appears then that if the patients are
divided into two groups, those in whom slowing occurs before and those in
whom it occurs after the onset of digitalis intoxication, slowing will rarely
be observed in the first group — and the slowing which is observed in the
second group is an effect which can, in the long run, scarcely be desirable.
In a later publication, Cohn (20) states:
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54 G. CANBY ROBINSON
We have been led to conclude from our observations that digitalis slows
the sinus rhythm only in the group of hypodynamic hearts, and that to
produce slowing is not a primary function of digitalis in therapeutic doses.
White and Sattler (160) report the effects of large doses of digitalis
on ten healthy young adults. The effects of the drug were observed
by daily electrocardiograms. Marked slowing occurred in two sub-
jects, the heart rate reaching 43 beats per minute in each instance.
In two other subjects, the heart rate became lower than usual at night
when under the influence of the drug. In the other six cases, no
change in heart rate occurred.
Parkinson (119) administered digitalis in full doses to 20 soldiers
with cardiac symptoms, a rapid pulse rate and with normally beating
hearts. (Effort syndrome.) He reports that the heart rate was re-
duced but little, and that the group of patients was scarcely influenced
by digitalis. Pratt (122) states that his experience with digitalis
confirms the findings of Mackenzie and Cohn and Fraser that digitalis
rarely slows the rate of normally beating hearts until toxic symptoms
are produced.
Robinson (130) has reported the effects of large single doses of
digitalis on a series of approximately one hundred patients, and al-
though striking effects were obtained in cases with auricular fibrilla-
tion, practically no change in the heart rate was observed in patients
with normally beating hearts to whom the same amounts of digitalis
were given.
On the other hand Sutherland (147) reports slowing of the normally
beating heart by digitalis. He treated a series of cases of rheumatic
heart disease with rapid cardiac rates, usually in children or in young
patients. He states that digitalis caused slowing of the cardiac rate
practically uniformly and the results in these cases were as definitely
good as those usually seen in cases of auricular fibrillation.
McCulloch and Rupe (112a) have quite recently confirmed Suther-
land's observations. They studied the effects of the drug on a series
of children with heart disease, and found that slowing of the heart-
rate of ten or more beats occurred so constantly when full therapeutic
doses were given, that this effect could be used as a sign of digitalis
action. They recommend the use of the drug in children with heart
disease for the purpose of slowing the heart rate when it is more or less
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THERAPEUTIC USB OF DIGITALIS 55
persistently accelerated, and when such causes of acceleration as
pain, fatigue, excitement and fever have been removed.
Pardee (118a) has also observed slowing of the normally beating
heart following the administration of large single doses of the tincture.
The onset of the slowing in the nine cases studied was noted to occur
before the changes in the T wave of the electrocardiogram in three
patients. The two effects occurred synchronously in four patients,
while the T wave changes occurred first in two. The heart was con-
sidered as slowed when the rate was found to be ten beats per minute
slower after the drug was given than in several counts before. The
size of the single doses was determined by giving 1 minim of a fairly
good tincture per pound of body weight.
Certain facts that have been demonstrated by animal experiments
seem to show why the reduction of the cardiac rate is not more often
seen in patients. Halsey (63) found that the dose which causes slow-
ing and other signs of vagu^ stimulation lay between 30 and 40 per
cent of the minimum lethal dose of g-strophanthin, of digipuratum and
of a fluid extract of digitalis given intravenously in dilute solutions in
about fifteen minutes. Robinson and Wilson (134) slowly adminis-
tered a diluted tincture of digitalis intravenously into a series of cats
and followed the effects of the drug by electrocardiograms. In these
experiments, the heart rate was slowed gradually, the effect being
first seen with about 25 per cent of the minimum lethal dose, while
the maximum slowing occurred when about 70 per cent of the mini-
mum lethal dose had been given. In a second series of cats in which
the vagi had been cut, practically no slowing of the heart rate was
observed.
It seems evident that the amount of digitalis which is necessary to
stimulate the cardio-inhibitory centre sufficiently to cause slowing of
the heart-beat is usually greater than the amount that can be given
to patients without the production of toxic symptoms. However,
individuals whose vagus centres are more easily stimulated than usual
or whose hearts are unusually susceptible to the slowing action of the
vagi, are exceptions to this rule. Children apparently fall into this
category. It is evident that the reduction of the rate of the normally
beating heart should no longer be looked upon as an effect which
digitalis should be expected to produce at least in adults although such
an effect is desirable in many cases, of heart disease.
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56 G. CANBY ROBINSON
c. The effect on conduction. The depression of the conduction of
the cardiac impulse between the auricles and ventricles has already
been discussed briefly as a toxic manifestation of digitalis. As
this effect plays an important part in the therapeutic action of the
drug, and as it is at least in part brought about through the cardio*
inhibitory mechanism, it deserves further consideration at this point.
The experimental studies of von Tabora (148) drew attention to
the fact that digitalis depresses conduction through its action on the
cardio-inhibitory centre. He concluded that this effect is produced
both through the vagi and by the direct action of the drug on the
conducting pathway. He also showed that digitalis is more effec-
tual in animals when the A-V bundle had been injured.
Although the clinical recognition of the influence of digitalis on con-
duction has been general since it was first pointed out in patients by
Mackenzie (106) there has been a discussion as to whether it should be
regarded mainly as an effect of vagus stimulation or as an effect
produced by the direct action of the drug on the heart.
Although the general opinion seems to favor the idea that vagus
stimulation is largely responsible for the effects of digitalis on conduc-
tion, Cushny, Marris and Silverberg (32) concluded from their study
of this problem on patients that the cardio-inhibitory mechanism is
of minor importance, and they emphasize the direct action of digitalis
on the heart. Cushny (31) expresses the opinion in a later publica-
tion, however, that digitalis may effect conduction by either method,
and the condition of the heart is the factor determining which of the
two methods will predominate. He seems to believe that in normal
hearts the conduction is depressed through the inhibitory mechanism;
while in diseased hearts, where conduction is already damaged,
heart-block or delayed conduction is caused by the direct action of the
drug.
Wedd (152) who studied the effect of atropin after full doses of
digitalis in a large series of cases, concludes that in all cases the action
of digitalis is both central, in the medulla, and local, in the myocar-
dium. He observed that in 100 per cent of his cases of auricular
fibrillation, and in 76 per cent of those with normal mechanism, the
heart rate failed to return after atropin injections, to the level at
which it was before being slowed by digitalis. He believes that it is
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THERAPEUTIC USE OF DIGITALIS 57
possible to measure the local action of the drug by the degree which
atropin fails to restore the heart to its original rate. Wedd considers
that Cushny has perhaps gone too far in ignoring the action of digitalis
on the cardio-inhibitory centre in certain types of heart disease,
in which the local action on conduction seems to predominate.
The observations of Cohn and Fraser (22) show clearly the manner
by which digitalis affects the conduction of normally beating hearts
when presumably not extensively damaged by disease. The twelve
patients to whom digitalis was given until symptoms of intoxication
appeared, were studied by means of electrocardiograms. In all but
one, conduction was affected by the drug, as evidenced by lengthened
conduction time or by blocked auricular impulses. The adminis-
tration of atropin by subcutaneous injections caused the conduction
to return practically to its normal condition, in all cases, regardless
of the degree of depression that had been present. It is evident there-
fore that in these cases the effect on conduction was entirely produced
by stimulation of the cardio-inhibitory mechanism, as it was abolished
with vagus paralysis. The interesting observation was also made
that the rate of the heart when reduced was not restored by atropin in
a manner that paralleled the restoration of conduction.
White and Sattler (160) confirmed these observations in ten healthy
young adults. They found that atropin completely removed the
effect of digitalis on auricula-ventricular conduction, and they con-
cluded that the effect on conduction was almost entirely, if not
entirely due to increase of vagal tone and irritability.
The foregoing observations demonstrate that the conducting system
is capable of being effected by digitalis when the heart is presumably
normal. However, depression of conduction does not become marked
until large doses are given. Cohn (20) has observed delayed con-
duction forty-eight hours after the administration of the drug was
begun, and in many instances, the conduction time gradually
lengthened during the succeeding three to five days until partial block
occurred. Heart block may occur, however, with extreme abruptness
within a few hours. In the healthy young subjects studied by White
and Sattler (160) the first effects on conduction were seen after 1.5
to 1.8 grams of the leaf had been administered; but there was no
marked prolongation of the conduction time until 2.7 grains had been
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58 G. CANBY ROBINSON
taken. This latter dose is about that which, on an average, produces
toxic symptoms.
There is no doubt that in heart disease when the tissues of the con-
ducting pathway are damaged, digitalis heart-block may be produced
by much smaller doses of the drug than those producing it in normal
hearts, but it can no longer be said that digitalis produces heart-
block only in hearts in which the conducting mechanism is already
damaged. The problem of the conduction effects of digitalis in
heart disease is a complicated one, and considerable light is still needed
on this subject for its complete understanding.
Depression of conduction may be an important factor in the
beneficial effects of digitalis in two ways. In the first place, it prevents
the improper stimulation of the ventricles by the auricles. As will
be seen when auricular fibrillation is discussed, the ability of digitalis
to prevent stimuli from reaching the ventricles is of paramount im-
portance in the treatment of certain forms of heart disease. In
the second place, depression of conduction allows a longer period to
elapse between auricular and ventricular systole, and Cohn and Fraser
(22) have suggested that this may be a matter of some importance
in the treatment of patients who have mitral stenosis. They point
out that in these patients,
the initial and most important of the factors which tend to disturb the
circulation is the narrow auriculo-ventricular orifice, which prevents the
complete empyting of the left auricle within the time allowed before the
ventricles contract. If one could lengthen the conduction time and could
keep it lengthened, thus separating the contractions of the auricles and
ventricles as widely as possible, much aid could be given patients of this
class in maintaining a satisfactory circulation. There is reason to believe
that this can be done.
3. The effects on the blood vessels
a. The effect on blood pressure. Cushny (28) states that Blake
discovered in 1839 that digitalis caused an elevation of blood pressure
in experimental animals. From that time until quite recently,
this effect and the effect on the heart rate have almost predominated
the field of digitalis action. It was generally believed that the arterial
pressure was raised by increased force of the ventricular contractions
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THERAPEUTIC USE OF DIGITALIS 59
and by the constriction of the blood vessels. It is an interesting fact
that neither of these effects has been demonstrated in man as a direct
action of the drug, although there is indirect evidence that the first
of these effects occurs, as was pointed out, when the action of
digitalis on the heart muscle was considered. The effect of digitalis
on the blood pressure is of such importance that it is desirable to
consider briefly some of the experimental work bearing on this subject
before reviewing the more recent clinical studies.
The chief exponents of the idea that digitalis has a direct action on
the blood vessels have been Gottlieb and the members of his school.
Numerous investigations have been reported from his laboratory
bearing on this subject.
The most important study to lead to the belief that the digitalis
bodies are capable of producing marked vascular constriction through
direct action on the vessel walls has been, according to Eggleston
(43) that of Gottlieb and Magnus, published in 1902. By the use of
doses of various digitalis bodies which were five to fifteen times the
minimum lethal dose, they produced striking elevation of blood pres-
sure in experimental animals, which was in part caused by constriction
of the splanchnic vessels by direct action of the drug upon their walls.
Among other publications from Gottlieb's laboratory which are of
interest, several may be mentioned. Kasztan (87) in 1910 showed
that when Ringer's solution containing not more than 0.05 mgm.
of crystalline strophanthin to 100 cc. was perfused through the kidneys
of dogs, cats and rabbits, arterial dilatation took place; while if the
solution contained 0.1 mgm. of strophanthin, arterial constriction
occurred. The weaker solution when perfused through the intestinal
vessels, however, caused them to constrict. This work was confirma-
tory of that of Jonescu and Loewi (85) , who considered that dilatation
of the renal vessels occurred as a direct peripheral effect on the vessels.
Fahrenkamp (51) repeated the work of Kasztan, using, however,
digitoxin instead of strophanthin. He obtained an effect on the renal
and intestinal vessels, similar to that observed by Kasztan. He found
further that concentrations of digitoxin which contracted the kidney
and intestinal arteries had no effect on the vessels of the skin and
muscles. Cats and rabbits were used, and Fahrenkamp found that
0.7 mgm. of digitoxin per 100 cc. Ringer's solution caused dilatation
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60 6. CANBY ROBINSON
of the renal vessels of the cat; that 0.48 mgm. produced the same
effects in rabbits, and that 1.2 mgm. of digitoxin caused contraction
of these vessels in both animals.
Later Joseph (86) investigated a similar subject in Gottlieb's
laboratory and studied simultaneously the effect of small doses of
strophanthin and digitalis (digipuratum) on the heart and on the
vessels. He attempted to use doses comparable to those employed
in the therapeutic use of these drugs; but, as a matter of fact, his
doses appear to be considerably larger as a rule. He found that in
rabbits and cats the action of these drugs on the heart and on the
vessels are not synchronous and that they seem therefore to be in-
dependent. Digitalis was found to cause at first a dilatation and then
a constriction of the vessels, which in the intestines, outlasted all
other effects. The kidney vessels dilate while the intestinal vessels
contract. Joseph considers that he succeeded in demonstrating vas-
cular effects with any dose that affected the heart. The slowly de-
veloping and persistent narrowing of the intestinal vessels is the
most frequent and most striking digitalis effect which he observed.
Gottlieb (59) has laid great stress on these and similar investiga-
tions. He holds the view that the power of digitalis to alter the size
of important vascular systems is of prime importance, and that the
alteration of the distribution of the blood which digitalis causes is the
main factor in its curative action. He believes also that the vascular
changes caused by digitalis are, in large measure, responsible for an
elevation of the blood pressure in man when the drug is given in
therapeutic doses.
Krehl (90) has also recently stated that he considered the best re-
sults from the use of digitalis were obtained in patients in which there
is altered blood distribution.
Eggleston (43) has recently published a critical review of the
investigations of the Gottlieb school and has commented upon their
bearing on the question of blood pressure changes caused by digitalis
in man. He points out especially the great divergence in dosage
under the two conditions and says
it must be quite obvious to anyone who gives the matter a moment's
thought that it is utterly fallacious to reason from such experiments that
similar effects would be produced in man from the therapeutic use of
digitalis or its congeners.
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THERAPEUTIC USE OF DIGITALIS 61
The discovery that elevation of blood pressure is not a constant or
conspicuous effect of digitalis in man occurred when the sphygmo-
manometer was introduced into clinical medicine, and when accurate
objective observation began to replace deductions from animals and
observations strongly influenced by preconceived ideas. In 1901
Sahli (quoted by Eggleston) stated that in cases with circulatory
stasis and high blood pressure, digitalis not only relieved the stasis,
but also very often reduced the blood pressure by from 30 to 40 mm.
of mercury. The findings of Sahli have been amply confirmed by
such careful students of the effects of digitalis on man as Mackenzie
(108), Cushny (29) and Cohn (21). Eggleston (43) has summarized
the findings of a number of observers1 who have studied the effect of
digitalis on blood pressure. He says:
We find that the systolic blood pressure was recorded for 181 cases.
In 66 of these, or about 36 per cent, the systolic pressure is stated to have
risen or to have tended to rise; in 57 or 31 per cent, it fell; and in 58, or
32 per cent, it is recorded as having shown no change. In 116 instances in
which the diastolic pressure is mentioned, it is stated to have been increased
in 24, or 15 per cent; and to have fallen in 76 or 65 per cent. While the
actual extent of the changes is not always stated, it would seem that digitalis
is about as likely to influence the systolic pressure in one direction as in
another, or not to alter it at all. With the diastolic pressure, however, the
chances are nearly two to one that digitalis will cause some reduction, and
the chances are more than three to one in favor of its reducing if as com-
pared with the likelihood of its raising it. Other things being equal, this
evidence certainly does not point to the occurrence of any marked vaso-
constrictor action of the drug in man. The opinions expressed by the
several authorities cited are in very general agreement that digitalis has
little constant influence on the systolic blood-pressure when used therapeu-
tically, and some even go so far as to suggest that it actually often causes
some vasodilatation which would account for the reductions observed in
the diastolic pressure.
Eggleston's own observations have been perhaps the most valuable
contribution to the study of the influence of digitalis on blood pressure
1 The work here summarized is that of Czyhkrz, Gross, Neu, Geisbock, Schwartz,
FeDner, Szinnyei, Price, Lawrence and Cadbury. References to their papers are given
by Eggleston.
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62 G. CANBY ROBINSON
in man. The various conditions of the study were carefully controlled.
An assayed extract of digitalis or digitoxin in the form of tablet
triturates or of the granules of Nativelie's digitaline crystaliste were
given in large doses. The full amount calculated, according to body
weight, was administered in twelve or eighteen hours and the effects
of the drug on the heart were followed by polygraphic and elec-
trocardiographic methods. The blood pressure was recorded for
three days before and three days after the drug was given. Eggle-
ston's series consist of 14 patients, 6 of whom had high initial pressure
while 8 had normal or low initial pressure. His study revealed the
fact that
the administration of large doses of digitalis or digitoxin has very little
tendency to elevate the systolic pressure, this having been increased by
11 mm. of mercury in one, and 15 mm. in a second case. In only one case
was the systolic pressure materially reduced, namely by 23 mm. of mercury.
On the other hand, the diastolic pressure was significantly lowered in 7,
or 50 per cent of the cases, while it was never significantly raised.
It is evident, therefore, that digitalis and digitoxin have very little
influence on the systolic pressure in either direction, that they tend to
produce a significant reduction in the diastolic and more decidedly, to
produce a material increase in the pulse pressure.
Eggleston found that alteration in the pulse rate did not offer an
explanation for the changes occurring in the diastolic pressure. The
facts brought out by this study abundantly warrant the conclusion
that "there is no evidence that either digitalis or digitoxin has any
direct action on the vessels when given to man even in large thera-
peutic doses."
Eggleston's observations show that the net changes in the systolic,
diastolic and pulse pressure differ in different cases in order best to
meet the condition prevailing, and they indicate that studies on the
blood pressure effects of digitalis must always take into strict account
the condition of the patients under observation.
It will no doubt be some time before clinicians generally learn that
arterial hypertension does not contraindicate the use of digitalis,
but may in fact be advantageously affected by its action. However,
clinicians have reported favorable results from the drug in cases
with elevated blood pressure. Windle (162) has recently stated that
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THERAPEUTIC USE OF DIGITALIS 63
digitalis is valuable to patients with degenerated arteries, high blood
pressure and anginal symptoms and may bring about an immunity
from angina. Lawrence (91) has expressed similar views after a care-
ful study of the blood pressure in 26 cases, during treatment with
digitalis. Danielopolu (34) treated 36 cases of arterial hypertension
with Nativelle's digitaline, although he remarks that the work deal-
ing with the action of digitalis on the arteries made him hesitate to
do so. His patients had arterial sclerosis and nephritis. Of the
36 patients a fall in the systolic pressure occurred in 19, while in 24
patients, the diastolic pressure was reduced: In 2 patients, a fall in
systolic pressure alone was observed. The reduction of the arterial
pressure amounted to 10, 20 or even 30 mm. of mercury.
During a study of one hundred patients, some of whom had hyper-
tension, to whom very large single doses of the tincture of digitalis
were given, Robinson (130) noted that the systolic pressure tended
to approach more nearly the normal level after the drug was given.
In other words, elevated blood pressure fell, while abnormally low
pressure rose after the drug was given. These observations confirm
Eggleston's more detailed study.
It is by no means desirable that the state of the blood pressure
should be no longer taken into consideration in determining the in-
dications for the use of digitalis or in studying its effects in man.
Recent experimental observations by Cohn and Levy (26) indicate
that under conditions kept as nearly similar as possible to those per-
taining in the clinical use of digitalis, the blood pressure of dogs may
be elevated by g-strophanthin and the tincture of digitalis. During
a study of the effects of therapeutic doses of digitalis on the contrac-
tion of the heart muscle, they studied the blood pressure of normal
dogs when not under operative conditions by the method of van
Leersum, and noted the effect of the drugs used when given in doses
on the same body weight basis as used in patients, which produced
no evidence of severe intoxication. In the few animals thus studied,
they found that the blood pressure usually rose, the increase varying
from 20 to 66 mm. of mercury.
Cohn and Levy seem to attribute the rise of blood pressure which
was transient, to the effect of the drugs on the contraction of the
heart muscle.
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64 G. CANBY ROBINSON
It is not possible to dismiss the subject of the effect of digitalis on
blood pressure as non-existing, but the older ideas must give place to
those resting upon the accurate clinical studies that have been made
since the introduction of the sphygmomanometer, and arterial hyper-
tension must not be accepted as a reason per se for withholding digitalis
when it is otherwise indicated.
b. The effect on the coronary circulation is a subject about which
there has been a certain amount of speculation and which has also
been studied experimentally. Although theoretically it is of much
interest, practically, no facts have been established which bear directly
on changes in the coronary arteries with therapeutic doses of the drug,
and no definite information regarding the effect of digitalis on the
coronary circulation of man has been obtained.
Eggleston (47) has recently reviewed this subject. He points out
that it assumes some importance because of statements that appear
in some recent textbooks to the effect that digitalis may cause a danger-
ous constriction of the coronaries, and is therefore contraindicated
in angina pectoris. There seems to be no evidence for the idea that
digitalis causes coronary constriction. The experiments of Felix
Meyer and of Sakai and Saneyoshi (quoted by Eggleston) have shown
that the coronaries do not contract under the influence of digitalis
but if they are affected at all, they probably dilate. Bond (10)
investigated the influence of digitalis and strophanthus on thecoronary
blood flow of dogs, measuring the coronary flow by the number of
drops in a given interval of time coming from the coronary veins.
He could find no effect attributable to these drugs, and concluded that
the coronary blood flow is probably regulated by the systemic blood
pressure, as it was decreased when the blood pressure was lowered
by nitroglycerin and amyl nitrate.
Voegtlin and Macht (150a) investigated the action of a number of
drugs of the digitalis group on strips of mammalian coronary arteries.
They found that digitoxin, crystallized German digitalin of Merk and
bufagin especially caused coronary constriction under the conditions
of their experiments, while digitonin and preparations containing this
saponin-like body caused relaxation. Strophanthin was found to be
practically inert in this respect. Voegtlin and Macht think that these
observations have considerable importance in the therapeutic use of
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THERAPEUTIC USE OF DIGITALIS 65
digitalis especially in the treatment of angina pectoris, when they
believe a nitrite which they find causes coronary relaxation should be
combined with the digitalis.
Eggleston (47) also discusses the relation of the blood supply to
the heart muscle through the coronaries to pulsus alternans, and
expresses the opinion that although this derangement of the heart may
occur apparently as a result of digitalis, this is no reason for consider-
ing that digitalis brings on this derangement by coronary constric-
tion. Pulsus alternans may also disappear when digitalis is given.
It is safe, therefore, to say that at present there is no reason to be-
lieve that the digitalis bodies affect the blood flow through the coro-
nary arteries by direct action on these vessels.
c. The effect on the venous blood pressure in man has been studied by
Capps and Matthews (11), who used both digitalis and strophanthin,
and obtained no evidence of changes in the venous pressure.
4. The effects on the kidneys
The use of digitalis as a diuretic begins with its introduction into
medical practice in 1785, as Withering (163) recommended it espe-
cially for the removal of dropsy and emphasized its action on the kid-
neys rather than its action on the heart. Withering mentions diuresis
as one of the cardinal effects of digitalis, and recommends that its
occurrence should be taken as an indication for discontinuing its
administration.
The manner in which digitalis causes diuresis has been one of the
controversial points regarding the action of the drug. The chief dis-
cussion has arisen over the question as to whether diuresis is in
reality a direct effect of the drug on the kidney and its vessels, or
whether it is secondary to an improved state of the general circulation.
Various opinions are held regarding this point.
The experimental studies of Gottlieb and Magnus, Jonescu and
Loewi (85), Kasztan (87), Fahrenkamp (51), and Joseph (86) have
already been referred to in discussing the action of digitalis on the
blood vessels. The fact that dilatation of the renal vessels is caused
by weak solutions of the digitalis bodies cannot, as it was previously
pointed out, be taken as evidence from which conclusions can be
drawn regarding the effects of therapeutic doses of the drug in man.
VOL. I, HO. 1
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66 G. CANBY ROBINSON
The conditions are far from comparable. On the other hand, these
experiments clearly indicate that the kidney vessels differ in their
reaction to digitalis from other vessels, especially those of the splanch-
nic area. This fact is inviting as a basis upon which to build a
theory of digitalis diuresis, as Gottlieb and others have done. Gen-
erally speaking, the ground is considered insecure, and the results of
clinical studies show that the diuretic effects of digitalis do not occur
as they would were the theory of Gottlieb correct. The quantitative
study of diuresis has recently been much improved by the organiza-
tion in hospitals of means of accurately measuring the intake and
output of fluids of patients and accurate records of body weight.
Since the introduction of such methods, Mackenzie (108) has re-
ported that diuresis is not very evident in patients even when digi-
talis is given to the stage of toxic symptoms, and he considers that no
definite conclusions are justified regarding diuresis from his careful
study of the action of digitalis. Cushny (29) observed diuresis
only in patients in whom dropsy was present, and Agassiz (2) ob-
tained similar results from the intravenous administration of rather
small doses of strophanthin in cases of auricular fibrillation. Diu-
resis occurred only in the presence of edema. Cohn (20) has also
emphasized this distinction, and reports that in the group of patients
which he studied with much care, diuresis was never seen in patients
without edema. He concludes from his experience that a specific
effect on the urinary output does not occur as the result of giving
digitalis to patients with normally beating hearts without the pres-
ence of edema. Cohn (21) has also found that diuresis is usually
marked when edema is present. Christian (16) in emphasizing the
beneficial effects which may be obtained from digitalis in chronic
cardiac cases with edema in whom there was no irregularity of the
pulse, points out the striking diuresis and loss of body weight which
may occur in these patients, and publishes a series of charts illustrat-
ing his results. There seems to be in his cases a relation between
the amount of edema and the extent of diuresis. The reports of
other observers tend to confirm these findings. It is evident that
some factors other than dilatation of the renal vessels take part in
the increased flow of urine produced by digitalis. The question of
the effect of digitalis on water exchange has been recently discussed
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THERAPEUTIC USE OF DIGITALIS 67
by Krehl (90) who is no doubt more or less influenced by the views of
his colleague, Gottlieb.
The question of the action of digitalis on the kidneys has been
investigated by Reinike (124) by an experimental method differing
from those already mentioned. Digitalis was administered over a
long period of time to rabbits, and was found to cause an enlargement
of the kidneys as compared with those of control animals. This
suggested that the kidneys had undergone excessive activity under the
influence of the drug. No definite conclusions, however, are justified
from Reinike's experiment, as the drug was given to only four animals,
and they did not show uniform results.
In spite of the fact that there is nothing definite on which to base a
claim that digitalis produces diuresis by direct action on the kidneys,
the position that the kidneys play no part in digitalis diuresis, does
not seem to be entirely justified. However, several pharmacologists
who have been especially interested in the action of the drug state that
diuresis is entirely a secondary effect.
Hatcher (70) says:
None of the drugs of this group are actively diuretic through any direct
action on the kidneys. They induce diuresis solely through an improved
circulation. That does not mean either a higher or a lower blood presure
in every case; it means a more effective circulation, one better adapted to
the needs of the individual patient This sometimes means an increase,
sometimes a decrease, in pressure.
Sollmann (143) holds a similar opinion regarding the diuretic
action of the drug.
In Eggleston's (47) most recent paper on digitalis, he says:
While it has been claimed that digitalis exerts a specific diuretic action
on the kidneys, or that it produces diuresis by selective vasodilatation of
the renal arterioles, the evidence for these claims is quite unsatisfactory,
and careful studies have shown conclusively that the drug is not a diuretic
in normal animals. It has also been observed repeatedly that no diuresis
follows the administration of digitalis to normal human beings or to those
with heart failure uncomplicated with edema or serous effusions. In cases
of nephritis with edema, or even with general anasarca, digitalis also pro-
duces no diuresis when heart failure is not associated with the nephritis.
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68 G. CANBY ROBINSON
When, however, heart failure is accompanied with edema or anasarca,
profuse diuresis may follow the administration of digitalis, but this is found
to occur only when the heart failure is more or less effectively overcome by
the drug, and when the heart failure is not affected, no diuresis ensues from
its administration. It is clear, then, that the diuretic action of digitalis in
man, is essentially secondary to its capacity to relieve heart failure and
restore the circulation; and when it is effective in edematous cases of heart
failure, it is often one of the earliest of the manifestations of the action of
the drug, though other evidences can be detected if looked for. When
adequate digitalization fails to produce diuresis in a patient with edema
and heart failure, it will almost invariably be found that either the heart
failure has not been relieved or that the failure is complicated by nephritis,
which then demands appropriate treatment.
At variance with Eggleston's idea regarding the relation of nephritis
to digitalis diuresis are the findings of Hedinger (quoted by Edens,
37) that digitalis has a direct diuretic action on the diseased kidney,
which is independent of its action on the heart. However, there is
considerable chance for differences of opinion as to what is meant by
a diseased kidney.
The idea that pathological changes may influence the effect of
digitalis on the kidneys appears again in a recent paper by Jarisch
(84). He reports two cases of syphilitic aortitis in which diuresis
was inhibited by therapeutic doses of digitalis but was increased by
very small doses. Jarisch makes use of an idea of Meyer (113) in
order to explain these results that increased excitability of the renal
vessels lowers the threshold for both the vasoconstricting and vaso-
dilating action of digitalis. He suggests that both patients had in-
creased excitability of their renal vessels as the result of the incipient
stage of contracted kidneys that was present. He states that his
findings are in accord with those of Meyer who found that in early
nephritis diuresis was produced by smaller doses than when the
kidneys were normal. Jarisch considers that small doses of digitalis
should be used when nephritis is present, and that caution as to
dosage should be used in heart cases that have low specific gravity
of the urine, which points to renal sclerosis.
The relation of the output of urine and alterations in blood pressure
has been studied by Lawrence (91) who found that in his 26 patients,
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THERAPEUTIC USE OF DIGITALIS 69
diuresis was always accompanied by a fall in blood pressure, and 88
per cent of the cases showing a fall of blood pressure had diuresis.
These findings, although of interest, do not, at present, add evidence
of value in determining the manner of production of diuresis by
digitalis.
The question as to a primary or direct action of digitalis on the
kidneys or its vessels in cases of cardiac failure with edema, should be
considered as yet unsettled, although it has been abundantly demon-
strated that digitalis has no diuretic action except under very special
conditions.
Cohn (20) has reported that a diminution in the output of urine is
sometimes seen when well marked toxic symptoms appear. This
phenomenon is adequately accounted for, he believes, by the pres-
ence of nausea and vomiting, which diminishes the fluid intake and
may result in the loss of considerable fluid by emesis. This observa-
tion is confirmatory of a statement by Withering who said that
large doses of digitalis may check the flow when smaller doses had
increased it.
IX. THE USE OF DIGITALIS IN HEART FAILURE
Digitalis has attained the reputation of being the most valuable
drug in the treatment of heart disease, and by the term heart disease
is usually meant a group of symptoms such as dyspnea, cough, chest
pain, edema, cyanosis, weakness, and palpitation. These symptoms
are in reality not evidence of heart disease, but of heart failure, and
they occur as a group only when the heart is unable to maintain the
normal circulation of the blood. Heart failure may result from a
variety of cardiac disorders; some of which are much more susceptible
to a favorable influence by digitalis than others. The great reputation
of the drug in heart disease doubtless rests upon the striking benefits
which it produces in cases of heart failure dependent upon one particu-
lar type of cardiac derangement. On the other hand, fault has been
found with the drug when it has been used in heart failure dependent
upon other causes with the expectation that similar results are to be
obtained. In considering the therapeutic use of digitalis, it is just
as necessary to take into account the various cardiac derangements
responsible for heart failure as it is the effects produced by the drug.
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70 G. CANBY ROBINSON
In fact, it is only when these two aspects of the subject are brought
together that a rational basis for the therapeutic use of the digitalis
bodies can be established. It is undoubtedly because clinicians have
not fully understood the action of digitalis and because pharmacolo-
gists have not fully understood heart failure, that so many miscon-
ceptions have existed in the past regarding the therapeutic use of digi-
talis. The cooperation of clinicians and pharmacologists which has
recently come about has been responsible for some of the most valuable
contributions to the. present-day knowledge of digitalis. Examples
of this cooperation and collaboration are those of Mackenzie and
Cushny in England and of Eggleston and Hatcher in America. This
type of cooperative work is greatly to be desired, and is destined to
bring forth results of great value in many fields of medicine.
2. Classification of heart failure
In the following part of this review, the relative value of digitalis
will be discussed in the various disorders of the heart which are com-
monly seen; and which may lead to the failure of that essential organ
to maintain an efficient circulation of the blood. Cohn (20) has
emphasized the desirability of considering the action of digitalis in
its relation to various forms of heart failure, which he has divided for
this purpose according to the following table.
A. Normal rhythm.
B. Auricular fibrillation .
nri.L . , /l. With normal blood pressure
a. Without edema <- W.A, ,. , , , ,
12. With high blood pressure
l w*i_ j /3. With normal blood pressure
b. With edema <, nrit , , , , . , ^
(4. With high blood pressure
w*l * j /5. With normal blood pressure
a. Without edema <- W.A, ,, , , . .
(6. With high blood pressure
I u wa j h' With normal blood pressure
b. With edema <0 —.,,.,., .
1 \S. With high blood pressure
This classification shows the importance Cohn has placed upon the
type of cardiac rhythm, the presence of edema and the state of the
blood pressure in the reaction of the heart and circulation to digitalis.
He has discussed his observations on the action of the drug in patients
with normal cardiac rhythm, without edema and with normal blood
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. THERAPEUTIC USE OF DIGITALIS 71
pressure; and a comparison of the action of the drug in these patients
with those in other groups has led him to conclude as follows:
It seems important to emphasize the fact that it is essential to distinguish
differences which patients suffering from heart disease present and to study
them in groups, with these differences in mind. Rhythm certainly offers a
prime basis. The effect of digitalis on rate and on a number of other capaci-
ties varies with the nature of the disturbed function.
In actual practice, it is often impossible to classify sharply cases of
. heart failure on the basis of the derangements of function underlying
their production. Nearly every case results from a combination of
causes, and these causes must be evaluated relatively to one another,
in any attempt to arrive at a clear understanding by which treatment
may be intelligently instituted. The ability to determine the rela-
tive importance of the various factors underlying the production of
heart failure is an essential requirement for its successful. treatment.
The disorder of the heart revealed most prominently by all the means
of examination now available may often be unimportant or only con-
tributory in the production of heart failure in any particular case. The
relative importance of valvular and muscular lesions of the heart may
be cited as an example. In many cases, a valvular defect obtrudes
itself upon the physician, while muscular inefficiency, so difficult or
impossible to determine directly, is in reality the actual cause of heart
failure. It is necessary to point out the difficulties regarding the
classification of heart failure on the basis of its causation, because a
discussion of the effects of digitalis in this relation to the various
disorders of the heart cannot take into account many of the practical
problems involved in the use of the drug in the treatment of heart
failure. These can only be solved by the careful study of patients,
in whom a great variety of conditions and circumstances are encoun-
tered, calling forth constantly the exercise of clinical judgment, which
cannot be acquired from books, but only at the bedside or in the con-
sulting room.
2. Disturbed cardiac mechanism
a. Auricular fibrillation. Following the suggestion of Cohn, rhythm
is taken as a prime basis for distinguishing the various types of
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72 G. CANBY ROBINSON
disorders of the heart, and those disorders associated with or consist-
ing of disturbed cardiac mechanism will be considered before those
with normal mechanism and regular beating hearts are taken up. It
seems desirable to adopt this order and to discuss first the use of digi-
talis in auricular fibrillation, because it is in this type of deranged car-
diac rhythm that digitalis produces its most brilliant results, a point
which it is well to emphasize at the outset.
A clear understanding of auricular fibrillation is essential for the
intelligent employment of digitalis. It has been especially well
described by Lewis (100, 101), to whose work the reader is referred.
The salient features by which this condition is recognized may be
summarized as follows: The pulse and the cardiac sounds occur
irregularly without any order to the arrhythmia, and usually with a
considerable increase in rate. There is no evidence of the normal
auricular contractions in the veins of the neck, as shown by polygrams,
and the auricular waves, the so called P waves, of the electrocardio-
gram disappear. A constant succession of small waves may sometimes
be seen in the venous pulse curve, while the electrocardiogram shows
almost constantly a series of small rapidly recurring waves, lacking
uniformity and well defined form, seen throughout the diastolic por-
tion of the curve. All these phenomena are readily appreciated when
it is realized that the auricles no longer contract as a whole in a rhyth-
mical fashion, but stand in diastole with their separate fibers con-
tracting and relaxing one after another constantly. This abnormal
type of auricular action sends down impulses to the ventricles more
frequently than the normally beating auricles and the rhythmical
character of the impulse formation is lost. A rapid irregular ven-
tricular action therefore results which is distinctly less efficient in
the maintenance of the circulation than is the slower regular normal
beat. This increase in rate is often an important factor in the failure
of the heart when auricular fibrillation is present.
Auricular fibrillation was recognized as a common disturbance of
the human heart-beat in 1909, when Rothberger and Winterberg and
Lewis simultaneously demonstrated its existence by means of electro-
cardiograms. Several years previously, however, Mackenzie (108)
drew attention to the fact that there were striking differences in the
effects of digitalis in cases with irregular heart action and in cases
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THERAPEUTIC USE OF DIGITALIS 73
with regular rhythm, and he stated that "no rational idea of the man-
ner in which digitalis acts can be obtained unless this change in
the heart's action is appreciated." He was also perhaps the first to
study the effect of digitalis in patients with auricular fibrillation after
this condition became established as a clinical entity. His paper
which appeared in 1911 was followed shortly by important contribu-
tions by Cushny (29) and Edens (37) and, since that time, the value of
digitalis in this condition has been generally recognized. It is scarcely
necessary to review the papers of other students of this subject, such
as Fahrenkamp (52), Fulton (56), Christian (14), Robinson (128),
Weil (153), Cohn (20), Borultau and Stadelmann (7), Pratt (122),
Wedd (152) and others who have all borne witness to the striking
benefits obtained by the use of digitalis in auricular fibrillation. Their
papers are referred to in regard to special phases of this subject.
It has been repeatedly shown that the great value of digitalis in
auricular fibrillation lies in the fact that the drug slows the abnormally
rapid and irregularly beating ventricles, and this effect of the drug is
generally considered its most important accomplishment. Lewis (99)
has recently expressed what is perhaps an extreme view of this matter.
He says:
The chief value of digitalis lies in the power to control the ventricular
rate when fibrillation of the auricles has come. In most patients in whom
this disorder of the heart is discerned, the ventricles beat rapidly, at rates
of 120, 140, 160 and even more per minute. It is this rapid action which
fatigues the heart, and digitalis, by lessening the rate, lessens the fatigue.
The normal heart rate, while the body is at rest — to take approximate and
convenient numbers — is 60 beats to the minute. Each ventricular cycle
lasts one second; of this, one-third is occupied by systole; two-thirds by
the resting period of diastole. The heart works one shift and sleeps for two.
But if the rate is 120 beats to the minute, then each cycle lasts half a second;
systole lasts quarter of a second and so does diastole. Work and rest alter-
nate in equal shifts. As the rate of beating rises, so is systole increased
relatively at the expense of diastole. Very important is it, therefore, to
reduce the heart rate when this is excessive. A chief cause of rapid heart
action when heart failure threatens or has come, is fibrillation of the auricles,
and it is in this condition that digitalis acts so beneficially; it reduces and
holds the rate within normal bounds.
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74 G. CANBY ROBINSON
The reduction of accelerated ventricular rate is the only important
action of the drug upon the human heart of which we have knowledge.
There are few, if any, instances, of which we know with certainty, in which
digitalis acts beneficially, except cases of accelerated action; there are few
instances of acceleration in which the drug produces unquestionable benefit
apart from those provoked by fibrillation of the auricles.
The principle of digitalis therapy — and when I speak of digitalis, I
include the allied drugs, strophanthus and squills — is that, administered
to suitable cases, the heart, by means of it, obtains rest. The giving of
this drug to unselected cardiac cases is much to be deplored. Those who
regard digitalis as a cardiac stimulant mistake its character; its chief action
is to rest the heart. To the heart, foxglove is not tonic, but powerfully
hypnotic It controls the diastoles of the heart; it extends the period of
sleep.
Although most students of digitalis do not share entirely the idea
of Lewis regarding the relative uselessness of the drug in conditions
other than auricular fibrillation, he has well expressed the consensus
of opinion regarding its use in auricular fibrillation.
Agassiz (2) has treated a series of cases of auricular fibrillation
with small doses of strophanthin administered intravenously and
has shown that this drug has a very similar action to that of other
members of the digitalis group when employed upon cases of auricular
fibrillation. He states that it is a powerful and serviceable remedy
when a rapid reduction of the heart rate is desired in cases of auricular
fibrillation in young subjects or in those cases which give a history of
rheumatism. The heart rate may be reduced from 180 or 160 to
100 or 80 per minute within six or eight hours. Agassiz's method of
administration of strophanthin will be taken up later.
As stated previously, the slowing of the heart is brought about by a
different mechanism than that by which digitalis slows the normally
beating heart. When the auricles are fibrillating, stimuli are sent
down to the ventricles unrhythmically and at a rate much higher
than from the normally beating auricles. Digitalis depresses the
conductivity of the pathway between the auricles and the ventricles,
which then allows fewer stimuli to pass. In this way, the rate of the
ventricles is slowed and the arrhythmia reduced. This effect is
very desirable because the rapid irregular ventricular activity which
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THERAPEUTIC USE OF DIGITALIS 75
the fibrillating auricles engender is much less competent to maintain
the circulation than the ventricular activity of normally beating
heart. The ventricles become more competent when they are slowed
and regulated by digitalis. The tumultuous action of the fibrillat-
ing auricles is not appreciably affected by digitalis as revealed by
electrocardiograms. The manner in which digitalis affects the
conduction of the cardiac impulse has been already considered.
The question has been raised whether other factors may not enter
into the slowing of the ventricles which digitalis produces in hearts
with auricular fibrillation, which are not involved 'in the depression
of conduction in the normally beating heart. Cushny has been
especially interested in this subject, and has raised the question as
to whether the action of digitalis on the cardio-inhibitory centre is
the important factor in slowing the ventricles in auricular fibrilla-
tion. Cushny, Marris and Silverberg (32) found that the ventricular
rate, slowed by digitalis, was not restored to its original rate when the
vagi were paralyzed by atropin. They came to the conclusion that
in auricular fibrillation, the ventricular slowing was accomplished by
other means than by stimulation of the cardio-inhibitory mechanism,
which seemed to play no part in the action of digitalis in auricular
fibrillation.
They believe that the conductive pathway from auricles to ventricles
becomes less excitable when the nutritional condition of the tissues is
improved, and that this improvement may result not only from the
increased efficiency of the circulation brought about by the direct
action of digitalis on the ventricular muscle, but also by lessening
the demands on the heart by rest. They explain in this way the ven-
tricular slowing which occurs when patients with auricular fibrilla-
tion are put to bed. Their hypothesis calls for the existence of ab-
normally increased conductivity in the hearts of patients with auricular
fibrillation caused by malnutrition of the tissues. This idea is hard
to accept in the light of the state of conduction in other types of heart
disease in which it can be accurately determined, and is not infre-
quently found to be decreased.
In a later publication, Cushny (31) gives the results of further work
on this subject in which he attempted to reproduce the cardiac con-
dition of cases of auricular fibrillation in perfused hearts. He states
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76 G. CANBY ROBINSON
his belief in two independent reactions of conduction to therapeutic
doses of digitalis. The first is that observed in the normal heart of
experimental animals and in the normally beating human heart.
It is the result of stimulation of the cardio-inhibitory centre.
The second is that observed in cases of auricular fibrillation in man,
and results from the direct action of the drug on the conducting
system. Cushny believes that the ventricular slowing which digitalis
produces in cases of auricular fibrillation is independent of the action
of the drug on the inhibitory mechanism, for it is not prevented by
atropin. The primary reason why digitalis acts directly on the con-
ducting mechanism in these cases is the malnutrition of the heart and
auricular fibrillation merely favors its appearance by accentuating
the fundamental cardiac malnutrition. Wedd (152) has also studied
a number of cases of auricular fibrillation and has injected atropin
during thorough digitaJization. He has come to the conclusion that
in all cases digitalis affects conduction both by its stimulation of the
cardio-inhibitory centre and by its direct action on the heart, with
relatively greater local action in auricular fibrillation. Exception
is taken to the statement of Cushny that in fibrillation there is no
digitalis action through the inhibitory mechanism. Eggleston (47)
has recently discussed Cushny's experiments and conclusions and is.
in substantial agreement with Wedd.
It is well known that some cases of auricular fibrillation are unusu-
ally susceptible to digitalis. Robinson and Draper (132) have shown
that in cases of auricular fibrillation prolonged stoppage of the ven-
tricles may be brought about by pressure over one of the vagi of the
neck. Weil (154) has also found vagus pressure more effectual
in auricular fibrillation than in other conditions, a result which he
attributes to an impaired state of the heart. He also found that the
normally beating hearts of patients to whom digitalis had been given
were more apt to respond to vagus pressure by depression of con-
duction than were the hearts of untreated patients. Weil believes
that digitalis stimulates the cardio-inhibitory centre and, at the same
time, renders the conducting system more susceptible to the influence
of the vagi. Fahrenkamp (52) found that in cases of auricular fibrilla-
tion pressure over the vagus nerves was sometimes effectual in stopping
the ventricles after the administration of digitalis in cases in which
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THERAPEUTIC USE OF DIGITALIS 77
vagus pressure was ineffectual before the drug was given. These
findings suggest that the conduction mechanism is rendered more
susceptible to vagus action by digitalis, which is in accord with the
experimental results of von Tabora (148).
Hirschfelder (80) investigated the action of the drug on dogs in
which auricular fibrillation was produced by faradization and found
that the irregularly beating ventricles were markedly slowed by digi-
talis, but the rapid arrhythmia promptly returned when the vagi were
paralyzed by atropin. Further slowing was obtained by very large
doses of digitalis after atropin had been given and complete heart
block with slow ventricular rhythm could be induced. Cushny (31)
performed similar experiments with cats and found that after the
vagi had been cut, strophanthin failed to remove the irregularity and
acceleration of the ventricles until a late phase of the action of the
drug set in, with auriculo-ventricular dissociation. He contends,
however, that these experiments are not comparable to auricular
fibrillation in man in which malnutrition of the cardiac tissues pre-
sumably exists.
It has been suggested that digitalis is especially potent in blocking
impulses sent down by the fibrillating auricles. In order to deter-
mine whether this is true Robinson (127) studied the effect of vagus
stimulation in dogs, both with normally beating hearts and with
auricular fibrillation induced by faradization of the auricles. The
results were recorded by electrocardiograms. The experiments show
that the type of auricular activity has no influence on the degree
to which impulses are blocked by vagus stimulation. In the light of
these experiments it would seem that the character of the auricular
activity, whether coordinated or fibrillary, plays no part in the effec-
tiveness of digitalis in depressing conduction by stimulation of the
cardo-inhibitory centre.
An examination of the evidence bearing on the question of the
manner by which digitalis reduces the ventricular rate in auricular
fibrillation must lead to the conclusion that various phases of the
subject remain unsettled, and little or nothing is known regarding
certain of its aspects. It seems established that the ventricular
slowing is brought about by the dual action of digitalis on the cardio-
inhibitory centre and directly on the conduction pathway, but the
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78 G. CANBY ROBINSON
relative importance of these two effects is not clearly understood.
Furthermore, it is not yet determined to what extent cardiac mal-
nutrition or other changes in the heart influence the action of the
drug, nor what relation exists between the ventricular slowing in
cases of auricular fibrillation produced by bodily rest and that caused
by digitalis. A clearer understanding of these problems would doubt-
less place the use of digitalis in auricular fibrillation on a more
intelligent basis, and would probably lead to its more effectual
employment.
There is some evidence in favor of the belief that digitalis may be
beneficial in cases of auricular fibrillation independent of the ventricu-
lar slowing it produces. Edens (37) for instance, has observed
clinical improvement without any diminution of the ventricular
rate. Increased efficiency of the ventricular contraction by the direct
action of the drug on the heart muscles may play some part in its
valuable effects in this condition.
Patients with auricular fibrillation are not all equally susceptible
to the beneficial effects of digitalis. The cases may be roughly divided
into two groups, those in which auricular fibrillation follows the so-
called rheumatic infections and those in which arterial sclerosis,
with presumably accompanying cardiosclerosis is present, and
frequently with a preceding syphilitic infection. The first group is
composed, as a rule, of young or middle aged persons who show very
rapid ventricular rates. Cases of this group are, as a rule, those
that show the most striking benefit from digitalis. The cases of the
second group may be much less benefited. They do not show such
high ventricular rates, and, in some cases, it is not above the average
normal level, although evidences of heart failure are well defined.
Mackenzie (109) who first pointed out this distinction, attributed the
difference to changes in the cardiac muscle, and holds that the reaction
to digitalis is much more easily induced in cases with presumably
slight myocardial damage than in cases with extensive degeneration.
This distinction is undoubtedly correct, but it does not take into ac-
count the state of the conduction pathway, which is presumably more
damaged in the second group of cases than in the first. Digitalis
is often of little value in cases in which the ventricular rate is slow
before digitalis is given. In these cases, the tissues involved in the
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THERAPEUTIC USE OF DIGITALIS 79
conduction of the cardiac impulse are damaged and are therefore not
capable of transmitting impulses at a rapid rate. This damage may
be taken as an evidence of a widespread involvement of the myo-
cardium which is unable to maintain an efficient circulation even
when the ventricles are contracting slowly. Under these circum-
stances, further slowing may cause no improvement in the circulation,
and sometimes may be distinctly harmful.
On the other hand, in many cases of auricular fibrillation, the
myocardium is sufficiently preserved so that the ventricles can main-
tain the circulation efficiently when their rate is held within bounds
by digitalis. Certain conclusions regarding prognosis are justified
therefore from the response to the drug. Patients should be studied
with this point in mind. Physicians should also learn to distinguish
between cases in which excellent results are to be expected from those
less liable to benefit, before drawing conclusions as to the efficiency
of the preparation of the drug being used.
The ventricular rate, in many cases, can be regulated at will by the
amount of digitalis administered. The optimum rate and the doses
required to maintain it, must be determined by trial in each case.
The dosage has to be varied frequently, and no rule applies to all
cases. The proper amount of the drug to be given is to be deter-
mined by the effect of various doses on the symptoms of heart failure
and by the ventricular rate.
It must be borne in mind that the radial pulse cannot be relied
upon for determining ventricular rate, as when the ventricles are
beating rapidly and irregularly, many contractions may fail to produce
a palpable pulse at the wrist. For this reason the ventricular rate
should always be determined by counting the number of heart beats
per minute by means of the stethoscope. It is very useful in follow-
ing the effect of digitalis in auricular fibrillation to determine the
number of ventricular contractions that fail to produce a palpable
pulsation at the wrist. The number of such beats per minute
constitute the so-called pulse-deficit, a term invented by George
Draper (personal communication). A pulse deficit of 20, 30 or more
a minute is often found in untreated cases, and the disappearance
or reduction of the pulse-deficit should be taken as an important
guide for the proper dosage of digitalis.
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80 G. CANBY ROBINSON
It is usually desirable to reduce the .ventricular rate to between 70
and 80 beats per minute, although some cases seem to have a
better state of cardiac efficiency when the rate is higher, and Pratt
(122) has found that the circulation is sometimes best maintained
at a rate much lower than that of the normal heart. In one of his
patients under constant administration of digitalis, the heart rate
was rarely above 50 per minute during a period of two years.
The constant employment of digitalis is usually necessary to keep
the ventricular rate continuously slowed, and the benefits of constant
use of digitalis have been pointed out by Schmoll (141), Borultau
and Stadelmann (7), Fulton (56), Pardee (117) and others. Pardee
has brought out the fact that the body must be kept nearly full of
digitalis and not nearly empty, and in order to accomplish this,
the drug must be given at a rate comparable to that of its elimination
from or destruction in the body. Fulton (56) remarks that many
cases need continuous administration of the drug and by the use of
small doses the heart may be controlled so that the patient may be
able to go on with his ordinary routine of life indefinitely.
It is certainly one of the most gratifying experiences in medical
practice to see the great benefit digitalis frequently brings about
and maintains in these patients for months and years by its constant
administration in doses so regulated that toxic symptoms do not
appear, while the heart is kept continually under its influence.
Excessive amounts of digitalis in auricular fibrillation may produce
complete heart-block, causing the ventricles to assume a regular
rhythm at an excessively slow rate. Taussig (149) has reported two
such cases in which permanent complete block developed during
digitalis administration. Slow regular ventricular action occurring
in cases of auricular fibrillation during digitalis medication should
always be taken as an indication of excessive action of the drug and
should lead to its discontinuance. Complete heart-block may occur
without other evidences of intoxication, as happened in a case reported
by Robinson (128).
Another disturbance of the heart beat which is prone to follow the
administration of the drug in cases of auricular fibrillation is the
so-called bigeminal pulse or coupled rhythm. It may appear when
relatively small amounts of the drug have been given, which do not
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THERAPEUTIC USE OF DIGITALIS 81
ordinarily produce toxic symptoms. The absolutely irregular rhythm
is replaced by pairs of beats followed by pauses of varying lengths.
There is usually a fairly constant time relation between the coupled
beats. Coupled rhythm may be detected by the study of the heart
sounds and radial pulse as Christian (14) has stated, but electro-
cardiograms reveal their true nature. Coupled rhythm is produced
by the occurrence of a premature contraction of ventricular origin
following regularly each ventricular beat stimulated by the auricles.
Its occurrence is to be taken as a sign for discontinuing digitalis.
Edens and Huber (38) have studied this phenomenon and consider
that it probably only occurs in hypertrophied insufficient hearts.
They regard its occurrence with relatively small amounts of digitalis
as an unfavorable prognostic sign. They found that coupled rhythm
was always dependent on ventricular premature contractions which
resulted, they believed, from an increase in the irritability and stimu-
lus formation in the ventricles produced by digitalis in damaged
hearts where there was a high calcium content in the blood. The
amount of the drug producing coupled rhythm was quite variable.
The beneficial action of the drug on the peripheral circulation in
auricular fibrillation has been demonstrated by Stewart and Scott
(145) who studied the blood flow in the hands by means of calorim-
eters. They found that in three of four cases, the blood flow was
increased in the hands within twenty-four hours after the tincture of
digitalis was given. This finding is merely a quantitative corrobo-
ration of the effects of the drug when determined by the clinical
study of signs and symptoms of heart failure.
The striking action of the digitalis bodies in slowing the ventricular
rate in auricular fibrillation has been put to useful purposes in studying
certain aspects of the digitalis problem, as the ventricular slowing
usually occurs as a sharply defined reaction on the part of the heart
which may be readily distinguished as of digitalis origin, the onset
and duration of which can be determined.
b. Auricular flutter is a disturbance of the heart beat caused by
an excessively rapid auricular rate, usually about 300 contractions
per minute, accompanied by varying degrees of heart-block. Recent
studies of Lewis, Feil and Stroud (102) indicate that auricular flutter
is in reality closely allied to fibrillation. They interpret the very
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82 G. CANBY ROBINSON
rapid auricular activity as dependent upon a continuous circuit of
the cardiac impulse through the auricles, along a constant path at a
rate constant for each case. They account in this way for the prac-
tically absolute regularity of the auricular rhythm which they have
demonstrated, and for other features of this cardiac disorder. The
ventricles do not participate in the excessive auricular rate, but may
respond to every second, third or fourth auricular contraction.
Flutter generally persists for months or years, and does not tend to
cease spontaneously. The recognition of auricular flutter can be
readily accomplished by electrocardiograms and less easily in poly-
graphic tracings. Without the use of graphic methods, it cannot be
distinguished with certainty.
Digitalis has proved of definite value in treating cases of auricular
flutter. Lewis (96) first showed conclusively that flutter passed
into fibrillation during the administration of the drug, although
Mackenzie (108) and Turnbull (150) had previously recorded cases
of the same nature. In a later paper, Lewis (97) recorded other
instances of this action of digitalis, and has pointed out that when
fibrillation surplants flutter it is usually temporary and the normal
cardiac rhythm may be resumed permanently. These observations
have been frequently confirmed, and Lewis states that the production
of fibrillation by digitalis administration is an important therapeutic t
measure in cases of flutter. The action by which auricular flutter
is transformed into fibrillation is uncertain. The drug renders the
auricles more liable to fibrillation than beforehand this may be
accomplished either by direct action on the auricular tissues or by its
action through the vagi. It seems possible that the conduction of
impulses through the auricles is interfered with and areas of block
are produced, a change which is, according to recent investigations,
an important factor in the causation of auricular fibrillation. When
first set up, fibrillation tends to disappear, and in the cases under
discussion the normal rhythm is resumed before fibrillation becomes,
so to speak, firmly established. Lewis has shown that auricular
flutter may be abolished by the administration of digitalis after it
has persisted for months.
Digitalis may serve another useful purpose in auricular flutter as
Lewis has also pointed out. With the auricular rate as high as 300 per
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THERAPEUTIC USE OP DIGITALIS 83
minute the ventricles may respond to every second contraction, and
so attain a rate of 150 beats per minute. Digitalis by its action on
the conduction pathway between auricles and ventricles may increase
the degree of heart-block which is already present, presumably because
of the excessive auricular rate. After the depression of conduction
the ventricles may respond to only every third or fourth auricular
contraction and so be decidedly reduced in rate, much to the improve-
ment of the cardiac efficiency. Thorough digitalization of patients
with auricular flutter is therefore a valuable procedure whenever this
disturbance of the heart beat is encountered.
c. Cardiac contractions of abnormal origin. Impulses leading to
cardiac contractions may arise in some point in the auricles or ven-
tricles quite outside the region of the heart in which the normal
rhythmical stimuli are generated. Such impulses may arise occa-
sionally or frequently at fairly regular intervals causing the single
premature ectopic beat, or extrasystole, or they may arise rhyth-
mically and so rapidly that they dominate the cardiac rhythm causing
a high grade of tachycardia. These various conditions dependent
upon cardiac contractions of abnormal origin will be discussed
separately in their relation to the action of digitalis.
Premature contractions or extrasystoles occur in association with
.various cardiac disorders, as well as in hearts that show no other
abnormalities. They have no material influence on the circulation
when occurring only occasionally, but when frequent, as often for
instance, as every second or third regular heart beat, they tend to
lower the efficiency of the heart, often produce annoying subjective
symptoms and are therefore undesirable. There are two questions .
that arise concerning the relation of digitalis to premature contrac-
tions. Has the drug any effect in preventing their occurrence and
is their spontaneous occurrence a contraindication to the therapeutic
use of the drug?
It has long been known that large doses cause premature contrac-
tions which are recognized as one of the most constant manifestations
of the influence of the drug on the heart, and as such have been
discussed previously. Although Wenckebach (155) was aware of this
effect of large doses, he reported several cases, and published curves of
two of them in which small doses of digitalis caused the disappearance
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84 G. CANBY ROBINSON
of premature contractions after they had been present over long
periods of time. He considered this effect as due to the direct action
of the drug on the heart muscle. Mackenzie (109) has given digitalis
to patients in whom spontaneous premature contractions of ven-
tricular origin were occurring and was unable to observe any effect
on them.
Edens (37) has perhaps studied the subject more closely than any
one else. He reports the results of the use of digitalis in a variety
of cases with premature contractions, and he has attempted to differ-
entiate these cases on the basis of the possible causation of the
premature beats. He concludes that premature contractions depend-
ent upon recent rheumatic lesions of the heart are not influ-
enced while those that appear to be associated with insufficiency of
the coronary circulation are probably cleared up by digitalis. He
found that the type of premature contractions that occur in persons
who use tobacco excessively, the so-called nicotine extrasystoles, are
not affected by the drug, and those occurring in nervous persons
sometimes disappeared and sometimes were unaffected by digitalis.
Edens considered that the variable effects are dependent upon the
fact that there are different forms of premature contractions and that
sharp differentiation on the ground of further experience is urgently
needed. He considers that premature contractions should be taken
as contraindications for the intravenous use of digitalis.
So little is known regarding the underlying causes of ectopic prema-
ture contractions that a satisfactory hypothesis regarding the means
by which digitalis may effect them and the manner in which they
may respond to the drug cannot be put forward. It is possible that
the heart muscle may be rendered less irritable by the stimulation of
the cardio-inhibitory centre, as Wenckebach (155) has suggested.
The production of premature contractions by the direct action of the
drug probably occurs in hearts not already disposed to them only
after very large doses, approximately 50 per cent of the minimum
lethal dose. It is possible therefore that this action does not come
into play even in hearts showing spontaneous premature contractions,
while other effects of the drug tend to cause their disappearance.
Their presence should not be taken as a contraindication for the
therapeutic dose of digitalis, although it should lead to caution, and
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THERAPEUTIC USE OF DIGITALIS 85
should indicate a reduction of dosage. The favorable influence of
digitalis in bringing about the disappearance of premature beats is
not to be viewed with any great expectations of success, although in
small doses it may have this effect in some cases. Christian (19)
has stated that
this question of the exact relation of digitalis to extrasystoles is one still
under discussion. In most cases, extrasystoles are more an incident in,
rather than a cause of cardiac decompensation and their presence can be
neglected in considering the probable efficiency of digitalis therapy.
d. Paroxysmal tachycardia has been shown by electrocardiographic
studies to be a disturbance of the heart beat dependent upon the
mechanism closely allied to that responsible for the occurrence of
single premature contractions. It is characterized by the sudden r
onset of a very rapid cardiac rate, usually between 150 and 250
beats per minute, which terminates as suddenly as it begins, the rate
usually returning to normal after a period of some hours or days.
Very short paroxysms are also seen. These periods of tachycardia
are apt to recur, once they have been established. The tachycardia
is brought about by the production of cardiac impulses in some point
removed from the region of normal impulse formation. The ectopic
focus generates impulses at an abnormally rapid rate, and assumes .
the r61e of cardiac pace-maker. The ectopic focus is usually in one
of the auricles but ventricular foci have also been found to produce
such paroxysms.
Digitalis has proved to be without influence on the high rate of
the heart brought about by this disturbance of its mechanism. Edens
(37) has reported a case in which the paroxysm stopped during digi-
talis administration, but the relation of cause and effect cannot be
established. During the attack the degree of heart failure varies
greatly from patient to patient; but, in most instances, when the
attacks are not prolonged, the evidence of cardiac insufficiency is not
marked. Individuals who have these paroxysms of tachycardia not
infrequently show no definite evidence of heart disease between
attacks, and have, presumably, hearts that can adjust themselves to
the abnormal rate. In prolonged attacks, however, the heart may
show signs of muscular fatigue, which may be considered as an indi-
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86 G. CANBY ROBINSON
cation for the use of digitalis. Robinson and Hermann (133) have
recently reported a case of prolonged tachycardia of ventricular
origin in which digitalis was given without any beneficial effects.
e. Heart-block. The depression of conduction is one of the most
definite effects which digitalis produces, as has already been brought
out. Therefore in partial heart-block, when further interference
with the passage of the cardiac impulses from auricles to ventricles
is decidedly undesirable, digitalis is contraindicated.
Cases are occasionally seen in which the conduction time is length-
ened on account of faulty nutrition of the functional tissues between
the auricles and ventricles. This depression in conduction is com-
parable to that which occurs during asphyxia, and may disappear
with an improvement in the state of the circulation. In these cases
digitalis has been observed to bring about an improvement in the
auriculo-ventricular conduction, and to shorten the conduction time
to within normal limits. Careful study by those experienced in
abnormal cardiac physiology is necessary to differentiate these cases
from those showing depression of conduction produced by structural
changes in the conducting system.
In complete heart-block, when the ventricular contractions are
being stimulated by the inherent rhythmicity of the ventricles, the
. action of the drug on conduction may be disregarded. Under these
conditions an improvement of the efficiency of the ventricles and
especially the quickening of their slow rate is the result to be desired,
and there is evidence to show that this may sometimes be attained
by digitalis.
Jagic (82) noted improvement of a patient with complete heart
block when small doses of digitalis (0.05 gram per day) were given.
Martinet (110) has also advocated the use of digitalis in complete
heart-block, and has warned against its use when the block is partial.
He believes that digitalis acts both on the vagi and directly on the
heart muscle, and he points out that the latter action may be effectual
in complete heart-block while the independently beating ventricles
are not under the control of the vagi, and so the former action can
be disregarded. Bachmann (3) has studied a case in which stro-
phantus was given with beneficial results and with an increase in the
ventricular rate while the auricles were slowed. Bachmann (4)
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THERAPEUTIC USE OF DIGITALIS 87
reported a second case with similar results, in which the ventricular
rate increased from 23 to 31 beats per minute during the adminis-
tration of the drug. He is of the opinion that strophanthus is of
more benefit in complete heart-block than digitalis.
Hewlett and Barringer (79) report a case in which digitalis produced
auriculo-ventricular dissociation and in which the ventricular rate
exceeded that of the auricles. They suggest on the basis of this
observation that the drug may be of value in complete heart-block.
They failed, however, in the one case that afforded them an oppor-
tunity of testing their hypothesis to get any increase in the ventricular
rate following the administration of digitalis.
Cushny (29) has suggested that helleborein might be especially
useful in heart-block, as he says it has an effect on the heart muscle
similar to that of digitalis, but is without effect on the cardio-inhib-
itory mechanism. Recent investigation of cases of complete heart-
block have shown that the rate of the independently beating ventricles
is, in most instances, free from the control of the vagi, and therefore
the inhibitory action of digitalis should not be considered of moment
in these cases. The direct action of the drug on the heart muscle
may be advantageous in increasing the output of the heart even
without a change in rate. Complete heart-block is not a contra-
indication for digitalis according to Mackenzie (108) but the drug
should be withheld in cases of temporary heart-block where a return
of the normal heart beat is anticipated.
J. Heart failure with normal cardiac mechanism
a. Myocardial insufficiency is the name now frequently applied to
that form of heart disease in which the power of the heart muscle is
apparently impaired, and in which no other cause can be discovered
to account for the failure of the heart to maintain the circulation
adequately. The term myocarditis has been used to express the
same condition, but myocardial insufficiency is to be preferred,
as it expresses functional rather than structural damage of the
heart. In many instances, no satisfactory explanation can be
found by the present day methods of examination of tissues for
obvious myocardial inefficiency on the basis of structural changes
in the heart muscle.
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88 G. CANBY ROBINSON
In the case under consideration, ample evidence of heart failure
is present, while there is no conspicuous disturbance of the cardiac
mechanism, no demonstrable structural damage to the valves, no
alterations in the vascular system sufficient alone to account for the
symptoms. The patients, who are usually past middle life, are short
of breath, unable to lie flat in bed and often have anginal pain,
especially on exertion. They frequently have edema and cyanosis,
evidence of congestion of the lungs and liver, with hydrothorax and,
at times, ascites.
The heart is enlarged and the character of the heart sounds may
be altered. There is often a systolic murmur at the apex. The
urine usually contains albumen and casts, and there may be other
evidence of renal insufficiency. The blood pressure is frequently
elevated and the heart rate is often increased.
The clinical picture may vary considerably and only the most
obvious symptoms have been enumerated in order to define this
frequently encountered condition. The value of digitalis in the
type of myocardial insufficiency that has been described is not nearly
so well established as it is in cases of heart failure with auricular
fibrillation. This is to be expected, as heart failure in these cases is
dependent upon some fundamental change in the cardiac muscle
which no known means can remove; while in auricular fibrillation a
definite factor of heart failure can be altered advantageously. The
difference in the effects of digitalis in these two types of heart disease
is noted consistently in the literature on digitalis since it was first
brought out by Mackenzie (108) in 1905, and since these types have
received definite clinical differentiation.
The prime object in the use of digitalis in myocardial insufficiency
is to improve the ability of the heart in propelling the blood and in
restoring the balance between the arterial and the venous side of
the circulation. It has already been shown how difficult it is to
obtain any definite direct evidence of changes in the output of the
heart. Various elaborate methods have been devised for its indirect
determination, but these have not been extensively used in the study
of the problem now under consideration. It is necessary therefore
to rely on the improvement of symptoms by digitalis, and this evidence
is often difficult to evaluate.
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THERAPEUTIC USE OF DIGITALIS 89
It has been repeatedly shown by Cushny (29), Mackenzie (109),
Edens (37), Pongs (120), Cohn (20), Pratt (122), Christian (16) and
others that the cardiac rates of these cases is usually not slowed by
digitalis, and the action of the drug on the cardio-inhibitory mechanism
apparently plays as a rule no part in the favorable results which the
drug may accomplish in cases with regularly beating hearts. Cohn
(20) has emphasized the importance of differentiating cases with
edema from those without it, and there is general agreement that in
cases of myocardial insufficiency with edema, diuresis follows the
administration of digitalis, the edema is diminished or disappears
and there is a general improvement in symptoms. At the same time,
the idea prevails, as recently stated by Eggleston (47) that the diuretic
action of the drug is essentially secondary to its capacity to relieve
heart failure and to restore the circulation. Diuresis must be looked
upon, if this idea is correct, as evidence of a beneficial influence of the
drug on the heart muscle, although this conclusion is not as yet
warranted as final. This question has already been discussed.
The various statements of those who have studied properly the
effect of digitalis in myocardial insufficiency indicate that benefit is
often derived from its use, but the manner of its action is still obscure.
Cushny (29) noted improvement in such symptoms as dyspnea,
cyanosis and edema without any change in the cardiac rate, and
attributed the improvement to the direct action of the drug on the
heart muscle. Edens (37) also observed clinical improvement with-
out slowing of the heart rate, and he believes the contractility of the
heart is effected favorably by digitalis, but considers that myocardial
damage limits its influence in this regard. Cushny' s (31) later work
emphasizes the relation of malnutrition of the heart to the action of
the drug, and he believes the drug is more likely to act directly on
the heart when malnutrition is present. Mackenzie (109) has always
been skeptical regarding the idea that heart failure may be relieved
by the effect of the drug on the heart muscle. Christian (15) in
discussing what he terms chronic myocarditis says that it consti-
tutes a group of cases in which digitalis is very effective, whether
auricular fibrillation is present or not, but with recurrences of heart
failure the drug becomes less and less able to bring relief. Windle
(162) has also observed definite improvement in the cases under
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90 G. CANBY ROBINSON
discussion, but says that the improvement in advanced cardiac failure
is often only temporary, and the drug becomes less and less effective
as the cardiac inefficiency advances. Christian (16) has recently
reported a series of cases of myocardial insufficiency with regularly
beating hearts and with edema in which digitalis produced satisfactory
effects.
Pratt (122) has employed strophanthin intravenously in these
cases, and says that as improvement has occurred in forms of heart
failure that are rarely, if ever, relieved by digitalis, it is suggested at
least that strophanthin given intravenously exerts an effect on the
contractility or tonicity of the heart muscle that is not obtained
from digitalis in therapeutic doses. West and Pratt (156) have
recently remarked that there is little doubt in the minds of most
clinicians that much good can be expected from proper dosage in
patients showing regular rhythm, when their symptoms are evidence
of heart failure. They gave full doses of dried aqueous extract of
digitalis to a number of such patients and in many obtained effects
that were quite as gratifying as in those showing auricular fibrillation.
The heart is often unusually susceptible to digitalis in the class
of cases under consideration, and toxic effects may be produced by
relatively small doses, so that careful study of these cases is especially
necessary when digitalis is administered. It is evident that digitalis
is of definite value in cases of heart failure dependent upon myocardial
insufficiency, especially when edema is present. The manner in
which the drug acts is still a matter of uncertainty. The fact that
abnormalities exist in the heart which have not as yet been closely
duplicated in animals renders comparison with experimental results
unwarranted. The influence of digitalis in cases of myocardial
insufficiency needs further study.
b. Pulsus alter nans, a phenomenon dependent upon myocardial
weakness, consists of an alternation in the regularly beating heart of
relatively strong and weak cardiac contractions which gives an
alternating character to the radial pulse. This abnormality of the
cardiac contractions is a grave sign of myocardial insufficiency. It
has been observed following the administration of digitalis, apparently
as an effect of the drug; and as such it has already been considered
as a toxic effect. Questions have been raised as to whether the
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THERAPEUTIC USE OF DIGITALIS 91
presence of pulsus alternans is a contraindication for the use of
digitalis and what effect the drug has upon it when already present.
Windle (162) has made an extensive study of these questions. He
considers pulsus alternans as being invariably the expression of an
overtaxed heart, and says that it is the only form of pulse rhythm
giving definite information regarding the functional efficiency of the
heart. Windle was, among the first to demonstrate the fact that
the presence of pulsus alternans is to be considered a sign of impending
death, even when circulatory failure is not extreme. He has studied
the effect of digitalis in over 100 cases of heart failure showing alter-
nation, and although the condition does rarely follow the adminis-
tration of the drug, he never found that digitalis increased the alter-
nation of the pulse or produced harmful effects when it was present.
On the contrary the alternation and irregularity in rhythm of the
pulse frequently became lessened, and not seldom was abolished.
The presence of high blood pressure does not contraindicate the use
of the drug in these cases. Windle points out the relation of rate to
alternation, and shows that as the diastolic periods of cardiac rest
lengthen, the tendency to alternation of contractions diminishes.
On the other hand, the slower the rate at which alternation is observed,
the more serious is the prognostic significance, as the more extensive
exhaustion of the heart muscle is indicated. Pulsus alternans may
disappear permanently under digitalis in cases of myocardial damage
following rheumatism, but Windle believes it practically never
permanently disappears in aged patients. Christian (14) who pub-
lishes some excellent records of pulsus alternans, has obtained good
results in patients showing this phenomenon. He reports a case in
which digitalis produced striking slowing with definite clinical im-
provement, but without disappearance of alternation. Christian
remarks that it is to be remembered
that a pulsus alternans is a sign of a very much impaired myocardium, and
when the myocardium is greatly impaired the likelihood of functional
improvement from digitalis is much decreased. To push digitalis in such a
case may do much damage. Here it is particularly difficult to judge how
far to carry digitalis therapy if no evident effect is produced. It would
seem that in many of these cases the margin between no therapeutic effect
and a serious toxic effect is a very narrow one.
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92 G. CANBY ROBINSON
Windle, in the light of an extensive experience, advises, on the
other hand, to continue the drug until vomiting or coupled rhythm
occurs.
4. Valvular heart disease
Valvular heart disease as such is not an indication for the employ-
ment of digitalis. Much misconception has been prevalent in medical
practice regarding this fact. On the other hand, many cases with
structural changes in the valves are much benefited by digitalis
when heart failure follows or accompanies valvular defects. No
one can conceive that the condition of the valves can be altered by
the drug, and the presence of a valvular murmur, even when it is
dependent upon a structural change in a valve, is never to be taken
as a reason for giving digitalis. Experimental destruction of one or
more of the heart valves in animals is not followed, as a rule, by
marked disturbances of the circulation. However, under these
conditions, the heart is otherwise undamaged, and is able to compen-
sate for the faulty valves.
In patients with valvular disease the myocardium and the coronary
arteries are likely to participate in the damage that has affected the
valves, and share in the causation of heart failure. Various disturb-
ances of the heart may therefore occur when valvular disease is
present, and these disturbances rather than those of the valves should
serve as an indication for the use of the drug. This is the attitude
expressed by all students of the drug who have considered this matter,
but it has not been discussed in the recent literature, because no
doubt it has appeared self-evident.
One possible benefit of digitalis in valvular heart disease has,
however, been recently suggested by Cohn and Fraser (22). They
point out that a delay in the conduction of the cardiac impulse from
auricles to ventricles may be of advantage to the heart when mitral
stenosis is present, as such an effect would increase the time available
for the left auricle to empty itself before the onset of ventricular
contraction. They suggest that the action of digitalis in bringing
about this delay of conduction may be a factor in its beneficial effect
in cases of mitral stenosis, and that by the proper regulation of
dosage, the conduction time may be constantly lengthened. No
observations bearing directly on this suggestion have as yet appeared.
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THERAPEUTIC USE OF DIGITALIS 93
One form of valvular disease, aortic regurgitation, has gained the
reputation of being a contraindication for digitalis. This tradition
no doubt goes back to the original description of the lesion by Corrigan
(27) in 1832, for there he says that digitalis lengthens diastole and so
allows more blood to regurgitate through the incompetent valve.
All of his patients with this lesion who received the drug seemed to
have become worse from its action. Corrigan does not state, however,
that the heart rate can be slowed by digitalis. Christian (16) has
commented on this subject and says:
There still lingers the tradition that aortic insufficiency contraindicates
digitalis, because digitalis would prolong diastole and the large regurgitant
flow of the blood under these conditions would stop the heart in diastolic
paralysis; a good enough theory; only it seems to have no basis in fact.
Pratt (121) also states that this lesion is not a contraindication
for the use of digitalis, and this has been the general experience of
all who have paid particular attention to this subject.
It may be said therefore that in determining the indications for
the use of digitalis, valvular lesions as such should be ignored, and
other evidences of cardiac disorder should always serve as the guides
for the use of digitalis in valvular heart disease. However, the
suggestion of Cohn and Fraser (22) concerning the possible value
of the drug in mitral stenosis is worthy of consideration and careful
study.
5. Disturbances of the nervous mechanism
Certain disorders of the heart are encountered in which without
any disturbance of the cardiac mechanism, the heart assumes an
abnormally rapid rate. The underlying cause of these disorders is
not well understood, but the more prominent symptoms seem to be
dependent upon a functional derangement of the nervous mechanism
controlling the heart, and are perhaps caused by an overbalancing
of the inhibitory nerves, the vagi, by the accelerators. Two examples
of such disorders seem worthy of consideration: the so called effort
syndrome or neurocirculatory asthenia, and hyper-throidism, since
digitalis has been employed in the hope of lessening the tachycardia
in each instance.
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94 G. CANBY ROBINSON
a. The effort syndrome is a condition which has come into promi-
nence during the years of the recent war. It seems to be particularly
prone to occur in young men of military age under emotional stress
and strain incident to war, and affects probably those whose nervous
make-up renders them predisposed. The chief symptoms consist of
palpitation of the heart with tachycardia, breathlessness and cardiac
pain on exertion, and manifestations of a disturbed nervous system,
such as headache, giddiness and disturbed sleep. The symptom
complex serves as a good example of what is generally called a cardiac
neurosis, and because the more prominent symptoms are referable
to the heart, digitalis has been used, especially with the idea of over-
coming the tachycardia. Parkinson (119) has reported a study of
the effects of digitalis on these cases carried on at the English Heart
Hospital at Colchester, which was under the direction of Sir Thomas
Lewis. Parkinson's results and conclusions serve as an example of
the general experience with the use of digitalis in this condition. He
administered full doses of the drug to a series of 20 patients. The
heart rate was reduced but little, and the increase of rate which
occurred with exercise or with standing was not controlled, to any
appreciable extent, by digitalis. There was no effect on either the
systolic or diastolic blood pressure. Parkinson states that digitalis
scarcely influences this group of patients, even when the puke is
rapid, and he concludes that it is not indicated in the condition known
as effort syndrome or neurocirculatory asthenia.
b. Hyperthyroidism or exophthalmic goitre serves as another
example of tachycardia which is primarily independent of any anatom-
ical lesion of the heart or of any alteration in the mechanism of the
heart beat. Several possible causes present themselves. The toxic
substance generated by the thyroid gland may act directly on the
heart or its nervous mechanism, producing the characteristic accel-
eration of rate; or there may be some fundamental change in the
nervous system which manifests itself in part by causing tachycardia;
or the increased cardiac rate may be secondary to the generalized
increase in metabolic processes of the body. Without a better
.understanding of this subject, no rational therapy directed at the
heart alone can be devised. Digitalis has been used with the hope
of slowing the heart rate; but, as Cohn (20), Fulton (56) and others
have pointed out, always without success.
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THERAPEUTIC USE OF DIGITALIS 95
It may be said that not only in the two examples of cardiac neuroses
that have been considered, but in all types of disturbances of the
nervous mechanism, digitalis fails to produce any beneficial effects.
The tachycardia, usually the most prominent symptom, is not influ-
enced by the drug. Whenever the diagnosis can be established with
certainty, if should be considered unwise to use digitalis in the cardiac
neuroses with any expectation of obtaining beneficial results.
X. DIGITALIS IN INFECTIOUS DISEASES
L Fever in relation to the action of digitalis
During the course of severe infections, the possibility of heart
failure is naturally constantly before the physician. Digitalis
has been used both as a preventive measure with the idea of
"supporting" the heart through a period of unusual strain and
also as a curative measure when signs of heart failure have appeared
as a complication of an infectious disease. In this connection, the
relation of fever to the action of the drug has been a matter of dis-
cussion. Cohn and Jamieson (24) have reviewed this subject and
state that definite differences of opinion exist among American,
English and German clinicians. Some consider the drug is without
power in the presence of fever; while it has been used extensively by
others, especially in pneumonia. Mackenzie (109) states that digitalis
has little effect upon the heart rate when it is elevated by agents
which increase its excitability, and cites the effect of fever as an
example. Cushny (30) also says that digitalis is especially apt to
be inefficient when fever is present. •
Cloetta (19), however, has recently recommended the use of
digitalis in acute infections, combined with camphor and believes
that it is important to begin the administration early in the course
of acute infections. His recommendations are apparently based on
somewhat empirical reasons however.
The relation of the body temperature to the action of digitalis has
been subjected to animal experimentation. According to Jamieson
(83), Gunn studied the effect of strophanthin on the perfused heart
at temperatures ranging from 28° to 41°C. and found that the drug
acted more quickly at higher temperatures. Recently Hirschfelder,
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96 G. CANBY ROBINSON
Bicek, Kucera and Hanson (81) have studied the effect of high tem-
perature on the action and toxicity of digitalis. They injected the
tincture intravenously into cats, the body temperatures of which
were elevated by immersion in water, heated to 43° to 46°C. They
found that digitalis produced effects in these animals similar to those
observed in normal animals, but there was a decided influence on
the minimal lethal dose per kilo of body weight which is shown in
the following table.
TEMPERATURE
AVERAGE LETHAL DOSE
•c.
cc. p*r kilogram
37-39
0.94
41
0.78
42
0.59
43
0.375
On the basis of these results Hirschfelder and his collaborators
warn against giving large doses of the drug to patients with high
temperatures.
2. Pneumonia
Pneumonia is the infectious disease in which digitalis has been
most extensively used, and in which its action has been especially
studied. These studies furnish valuable information regarding the
action of digitalis in the presence of fever.
Fulton (56) in 1914 expressed the general opinion prevalent at
that time regarding the employment of the drug in pneumonia.
Where there is cyanosis with low blood pressure and a rapid, feeble pulse,
the question always arises whether digitalis should be administered. The
evidence in regard to its value in such cases is not satisfactory. It is not
likely to do harm unless there is some involvement which might encourage
the formation of heart-block, in which instance it should not be used.
Since this time, Cohn and Jamieson (24) have carried out a syste-
matic study of the action of the drug in pneumonia, and have obtained
results that give definite answers to the questions involved. They
studied a series of 105 cases of pneumonia, 49 of which received
digitalis, while 56 cases served as controls and were studied with
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THERAPEUTIC USE OF DIGITALIS 97
equal care. Electrocardiograms were obtained at frequent intervals,
and particular attention was paid to the length of the conduction
time, variations in the T wave of the electrocardiogram and the
ventricular rate in cases of auricular fibrillation.
Digitalis was given by mouth in the form of digipuratum. They
state:
In general the criteria we employed permitted us to judge satisfactorily
whether digiatlis was acting. We found that the signs appeared after the
same amount had been given and following the same length of time in which
these signs appeared in non-febrile cases originally studied. When no
digitalis was given the signs did not appear.
Cohn and Jamieson conclude that digitalis acts during the febrile
period, and produces a beneficial, possibly a life-saving effect when
auricular fibrillation or flutter occurs during the course of pneumonia.
Whatever beneficial action digitalis has on the function of the normally
beating non-febrile heart may be expected from its use in the febrile
heart in pneumonia.
Cohn (21) observed auricular fibrillation or flutter in 12 out of
123 cases of pneumonia; or in practically 10 per cent. He considers
the frequency of these cardiac derangements in pneumonia sufficient
ground for keeping patients under the influence of digitalis during
the course of this disease. The drug was consequently routinely
administered to pneumonia patients according to the following plan,
the dose being indicated in grams of the leaf.
DAY Of DISEASE
1
0.5
2
0.5
3
4
1.0
5
0.5
6
0.5
0.5
7
0.5
s
9
If seen early.
If seen late
Stone, Phillips and Bliss (146) studied the effect of digitalis in a
large series of cases of pneumonia in an army hospital during the
recent war. They attempted to digitalize thoroughly the cases
during the first forty-eight hours in the hospital by administering
0.17 cc. of a standardized tincture per pound of body weight in
several large doses. The total amounts ranged from 20 to 30 cc.
MEDICINE, VOL. I, NO. 1
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98
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With these doses vomiting occurred in only 4 to 5 cases; partial heart-
block appeared in one, and there was a considerable rise of blood
pressure in another. There were 871 cases in their series and the
administration of the drug was begun at a certain date after about
half the number of cases had been seen. The conditions under which
these patients were observed did not allow detailed study but there
was a striking difference in the death rate after the use of digitalis
was begun. This is shown in the following table:
uroum
USB 01
NGITALn
Armm
usb or
f?TfffTATTg
Deaths not associated with sepsis.
pcrunt
25.8
17.1
46.3
PCTftU
11.8
Itaiths from uncomplicated pneumonia
11.2
Deaths from pneumonia complicating measles
14.8
Stone and his co-workers believe the tincture of digitalis was
responsible for the decrease in the percentage of deaths in the cases
not associated with empyema or other "septic" conditions, being
definitely valuable in the type of cases whose deaths are associated
with cardiac failure.
Caution must be exercised in drawing sweeping conclusions from
this study, as under the circumstances, it cannot take into account
certain possibilities such as variations in the virulence of the infecting
organisms or other conditions altering the severity of the infections.
Jamieson (83) carried out an investigation on the action of the
lethal dose of strophanthin in normal animals and in animals
with experimental pneumonia. Cats and dogs were used and
strophanthin was given by intravenous injections. Pneumonia was
produced by intratracheal insufflation. Jamieson studied the effect of
strophanthin in 21 cats that were not given pneumonia and 12 animals
were studied that had pneumonia but were not given strophanthin.
The action of the drug was studied in a large series of infected animals.
The results of these experiments led to the following conclusions:
1. When a like amount of strophanthin is injected intravenously,
the mortality is the same in both normal cats and in cats suffering
from experimental pneumonia.
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THERAPEUTIC USE OF DIGITALIS 99
2. The minimal lethal dose is the same in normal dogs and in dogs
suffering from experimental pneumonia.
3. The presence of an acute infection in these animals does not
interfere with the action of strophanthin on the heart.
4. Electrocardiographic changes occurring in the heart's action
when strophanthin is injected are found to be similar in normal and
in infected animals.
5. The identity of strophanthin action in infected and in normal
animals renders it probable that a like similarity may be anticipated
in man, under normal conditions and in pneumonia.
This work corroborates the idea expressed by Cohn and Jamieson
that the action of digitalis is the same in pneumonia as it is under
non-febrile conditions. Probably the unfavorable influence of fever
on the action of digitalis arose from the observations that the drug
failed to slow the heart in febrile conditions, but it is now known
that the drug usually fails to slow the normally beating heart when
fever is not present except under special and rare conditions. Further
work is necessary to substantiate the idea that digitalis "supports"
the heart during pneumonia, although the work of Stone, Phillips
and Bliss is suggestive and Cohn considers it desirable to give the
drug to patients with the disease in anticipation of auricular fibril-
lation. The question may be raised, however, as to whether such
use of digitalis may not tend to bring on auricular fibrillation in
these cases.
3. Diphtheria
Diphtheria is another infection which deserves special consideration
because of the frequency of cardiac damage as one of its most severe
complications. The view has been held for a long time that the drug
does not benefit the cardiac disorders following diphtheria and is
possibly harmful in this condition. Only recently, however, has
this matter been subjected to careful study by modern methods.
McCulloch (111) after an extensive study of the heart in diphtheria
by means of the electrocardiograph, and after many careful obser-
vations on the effect of digitalis in children, has drawn attention to
the close similarity between the cardiac disturbances produced by
diphtheria and the toxic effects of digitalis on the heart. In diph-
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100 G. CANBY ROBINSON
theria presumably through the action of the toxin on the heart, con-
duction is often damaged, premature contractions frequently occur, or
there may be striking changes in rate, either a high grade of tachy-
cardia or marked slowing. McCulloch attributes the slowing of the
heart in diphtheria to vagus stimulation, and he has studied the effect
which atropin has upon it. This interpretation is perhaps open to
question. There is, however, such a close resemblance between the
effects on the heart of diphtheria toxin and of digitalis that it seems
to be adding insult to injury to administer the drug to patients with
the cardiac complications of diphtheria. McCulloch's paper is a
valuable contribution to the knowledge of indications for the use of
digitalis.
XI. DOSAGE OF DIGITALIS
1. Oral administration
a. The amount of the drug. Withering laid down a sound prin-
ciple for determining the proper dosage of digitalis when he wrote,
"Let the medicine be continued until it either acts on the kidneys,
the stomach, the pulse or the bowels; let it be stopped upon the first
appearance of any one of these effects." He recognized the neces-
sity of regulating the dose of the drug by its action, rather than by
accepting a standard dose as applicable for various samples of the
drug and for various types of disease in which it might be employed.
In spite of his directions, standards of dosage of wide variations have
been advocated.
Eggleston (42) states that the doses of the tincture of digitalis
recommended by recognized authorities range from 2 minims (less
than J gram of the leaf) three times a day to 30 minims (3 grains of
the leaf) three times a day; the larger dose being fifteen times as
great as the smaller. Hatcher and Bailey (72) have discussed the
use of the tincture of strophanthus and strophanthin, and have drawn
attention to the great diversity of opinion regarding the dosage of
these drugs, and to the apparent confusion relative to the activity
of various preparations. It seems probable that variability of
absorption is largely responsible for the lack of uniformity of dosage,
as will be brought out later. It is apparent that many misconcep-
tions have existed regarding the dosage of digitalis and its allies.
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THERAPEUTIC USE OF DIGITALIS 101
There has been recently a tendency to attribute poor results of digi-
talis to its use in inadequate doses.
During the past few years considerable attention has been focused
on the matter of dosage, and much progress has been made towards
establishing sound principles, based on accurate determinations in
the laboratory and in the clinic. Eggleston and Hatcher deserve a
large share of the credit for this progress, and their contributions to
various phases of the subject have proved of much value.
The fundamental problem involved in the dosage of digitalis is
the determination of the average amount of standard preparations
required to produce maximum therapeutic results in the types of
patients to whom the drug is usually given and which does not produce
severe toxic symptoms. The method that has recently come into
use is essentially the same in principle as that advocated by Withering,
and consists in the administration of the drug to series of patients
until well defined evidence of digitalis action appears. Modern
methods, however, allow the detection of specific effects of the drug
with greater precision and at an earlier stage than was possible in
Withering's day.
After the determination of the average amount of the drug neces-
sary to produce the desired effects in a series of patients, attempts
have been made to convert this finding into a rule designed to allow
others to employ the drug in the amount most likely to benefit similar
patients, and to allow its use under conditions which do not permit
the determination of the early evidences of its toxic action.
Following such carefully conducted studies as those of Mackenzie
(109), recommendations as to dosage were made which reflected the
results obtained in each series of patients. All of the students who
employed accurate methods for the detection of digitalis action
advocated larger doses than had been previously customary, but the
earlier students of the present period of accurate objective clinical
observation pointed out the fact that the dose must not only be fairly
large but also that the drug must be continuously administered until
definite effects were produced, when it should be either discontinued
or much reduced in amount.
The study of Eggleston (42) marks the beginning of much progress
in digitalis dosage. His paper published in 1915 brought out a
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102 G. CANBY ROBINSON
number of points of permanent value, and is an excellent example of
clinical observation based on a sound training in the pharmacological
laboratory. Eggleston undertook to determine whether or not it
was possible to establish the dose of digitalis for man on the basis of
the activity of the drug as determined by a biological assay. He
studied, at the same time, several other problems directly concerned
in the question of the dosage of digitalis and its allies and pure prin-
ciples. These problems were:
1. The rate, degree and uniformity of the absorption of the crude
drug and its active principles.
2. The influence of sex, age and weight on the dose.
3. The influence of the preparation-infusion, tincture, etc., on
the dose.
4. The influence of the cardiac condition.
5. The influence of the size of the daily dose on the total dose
required.
Eggleston used tinctures and infusions of digitalis, made from leaves
of different sources and varying in activity, and crystalline digitoxin
dissolved in 70 per cent alcohol or made into tablet triturates. The
activity of each preparation was determined in terms of cat units by
the method of Hatcher and Brody (74). These drugs were admin-
istered by mouth to a series of patients, some of whom had auricular
fibrillation. Care was taken that none of the patients had received
any one of the digitalis group of drugs within a period of not less
than three weeks prior to the beginning of the observation. The
patients were kept under observation in bed for from three to seven
days before digitalis or digitoxin was given, whenever their condition
justified such a period without medication. Body weight, intake
and output of fluids, blood pressure, polygraphic — and in some
instances — electrocardiographic records were obtained as indicated,
as well as frequent physical examinations. Personal bias was, as far
as possible, eliminated in judging changes in the condition of the
patients.
The study was carried out on 47 patients, 6 of whom had two
courses of treatment, making 53 in all. Fifteen studies were made
on cases with auricular fibrillation and 38 on non-fibrillation cases.
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THERAPEUTIC USE OF DIGITALIS 103
The action of digitalis was determined by subjective and objective
improvement in the symptoms and signs of heart failure and in the
appearance of minor toxic effects. The phenomena included in this
latter category were marked sinus arrhythmia, partial heart-block,
premature contractions, nausea and vomiting.
The details of the method used by Eggleston are given because
his work is a good example of the methods of clinical studies which
have yielded valuable results, and indicate the various procedures
necessary to prevent faulty observation and false conclusions when
studying the effect of these drugs on patients.
The most important feature of Eggleston's study is that it enabled
him to determine the amounts of the drugs in terms of cat units
per pound of body weight required to produce therapeutic and toxic
effects. In other words, he introduced two quantitative factors
into the consideration of dosage that had previously received only
indefinite consideration, and had not been brought into accurate
relation with each other. Eggleston brought to the problem of
dosage drugs of known activity and measured their effects in terms
of the total amount used in relation to the weight of the individuals
receiving them.
No definite difference was found between the amounts of the drugs
necessary to produce comparable therapeutic or minor toxic effects
in cases with auricular fibrillation and in non-fibrillation cases.
Eggleston draws the following conclusions and deductions from
his studies:
1. The cat method of standardization of digitalis yields results
on which the dose for man can be based.
2. The average therapeutic dose of digitalis given orally to man
in the form of tincture is 0.146 cc. of an average high grade tincture
per pound of body weight as established by thirty-three observations.
3. Fifteen observations have established 0.066 cat unit, or 0.023
mgm., per pound as the average therapeutic dose of crystalline
digi toxin.
4. Approximately half of a total of 48 courses of administration
of either digitalis or digitoxin, full therapeutic effects were secured
with doses falling within IS per cent above or below the average
dose.
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104 G. CANBY ROBINSON
5. Doses considerably larger than the average were taken in 17
instances without the production of more than mild toxic symptoms.
6. The activity of the preparation of digitalis has no material
influence on the dose required in terms of cat units.
7. Age, sex and cardiac condition do not seem to influence the size
of the dose required.
8. Both digitalis and digitoxin are probably rapidly and fairly
uniformly absorbed from the alimentary canal of man, but digitalis
is less completely absorbed than is digitoxin.
9. Strophanthus, the strophanthins, ouabain, true digitalin, and
some other digitalis substances are poorly or irregularly absorbed
when given by mouth to man or to the higher animals and are unsuited
for therapeutic use in this way.
Eggleston has pointed out the practical application of his results.
In dealing with the tincture of digitalis, the dose may be taken for
convenience as 0.15 cat unit per pound of body weight when- the
tincture possesses a strength of 1 cc. to the cat unit. This has been
found to be the average strength of high grade tinctures and repre-
sents 100 mgm. of the crude drug. This strength may be accepted
as a basis for the calculation of the total amount probably necessary
to produce the maximum therapeutic results. A patient weighing
150 pounds would therefore require 22.5 cc. of such a tincture.
Eggleston states:
On the basis of the patient's actual or estimated weight, the total amount
which would probably be required should be calculated and this quantity
could then be divided into single or daily doses according to the rapidity
with which it was desired to induce the full therapeutic effects. If, after
the total calculated amount had been taken, the patient failed to show the
full therapeutic effect or some minor toxic action indicated that enough
had been given, the administration should be continued in small repeated
doses until one or the other of these evidences called for its withdrawal.
In this way it is possible to give a third to half of the total calculated
therapeutic dose at a single administration, to follow this in from four to
six hours with a quarter to a third of the total dose, and to give the remain-
der in a few doses of smaller size at intervals of from four to six hours.
By this plan of administration, the full effects can be secured in from twelve
to thirty-six hours in the majority of cases.
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THERAPEUTIC USE OF DIGITALIS 105
The administration of half of the total dose may call for the giving of
from 5 to 15 cc. of the tincture at once, and it might be feared that such a
large dose might cause gastric irritation and nausea or vomiting. I have
given such doses repeatedly since the completion of the greater portion of
this work and have never seen the least disturbance of any kind arising as
a consequence. This is due to the fact that the nausea and vomiting
following the administration of the digitalis bodies is of central origin and
results only after the absorption of a sufficient quantity of the drug into
the circulation.
It should be reiterated in this place that the use of such large doses of
either digitalis or digitoxin as are mentioned is not a safe procedure unless
the patient can be under nearly constant observation and unless the effects
of the treatment can be graphically recorded at frequent intervals. This
practically limits such procedures to hospital practice and to those well
versed in the significance of polygraphic and electrocardiographic records.
Certain precautions necessary in using digitoxin according to the
calculations he describes are pointed out.
Eggleston (45) has recently published a brief description of his
plan for administration of digitalis by the body-weight method, and
has given simple formulas for the determination of the dose of the
leaf, the tincture and the infusion when the weight of the patient
and cat unit strength of the drug is known. The average relative
strength of these forms of the drug have been found by Hatcher and
Eggleston to be
100 mgm. of the leaf = 1 cat unit
1 cc. of the tincture = 1 cat unit
10 cc. of the infusion = 1 cat unit
When the activity of a particular specimen given is not known, it is
safe to use these figures for purposes of calculation; but then only
75 per cent of the calculated dose should be given in order to allow
for the possibility of excessive activity of the specimen.
He recommends differentiating urgent and non-urgent cases, and
points out the importance of reducing the dose when any member
of the digitalis group has been taken in the preceding ten days,
particularly when evidences of partial digitization are present.
Eggleston also prescribed certain safeguards which should be carefully
followed. The signs of minor digitalis intoxication, such as nausea
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106 G. CANBY ROBINSON
and vomiting, reduction of the heart rate below 60 per minute, and
the appearance of frequent premature beats; of definite heart-block;
of marked phasic arrhythmia, or of coupled rhythm are to be taken
as indications for the cessation of further administration. By the
Eggleston method the calculated total amount of the drug may be
given to urgent cases in twenty-four or thirty-six hours. By giving
an initial dose of the drug consisting of one-third to one-half of the
total calculated amount, and then by giving smaller parts of it at
six-hour intervals, over-dosage is prevented as digitalis action becomes
evident in six hours when the drug is given by mouth.
Eggleston comments on this method of administration as follows:
The employment of this method of administration of digitalis is without
danger to the patient if the directions are followed in detail and if the safe-
guards are carefully observed. By its employment it is usually possible
to produce maximal digitalis action in from twelve to eighteen hours, and
marked therapeutic effects are frequently observed within six hours after
the initial dose. By its use, it is possible to dispense with the intravenous
or intramuscular administration of ouabain, amorphous strophanthin, or
other digitalis body in the great majority of cases of heart failure.
The demonstration of the necessity for using digitalis and its allies
according to its activity as determined by biological assay is one of
the most important results of Eggleston's work, and for that reason,
the question of biological assay was taken up quite fully in the earlier
part of the review. The relative strength of the various members
of the digitalis group were also taken up, and the figures given in
that portion of the review may be taken for the determination of
dosage for their oral administration. However, the problem of
absorption from the gastrointestinal tract must always be borne in
mind, and it will be brought out presently that this has a striking
influence on the action of various drugs and preparations when
administered orally.
Emphasis should be given to the work of Hatcher (68) on the
persistence of the action of the digitalins in connection with dosage.
He showed by animal experiments that all the digitalis bodies are
synergistic and that the action of one is added to that of another.
For this reason, the effect of any drug of this group contraindicates
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THERAPEUTIC USE OF DIGITALIS 107
the administration of any other of the digitalis bodies. Warning is
gravely expressed by Cohn (21) that
digitalis should, under no circumstances, be given to a patient who has
previously been given digitalis in any form or by any route. The faOure
to obey this warning has, on many occasions, been followed by disastrous
results to the patient.
The actual amount of digitalis in terms of the powdered leaf which
is usually required to produce the maximum therapeutic results for
an average adult weighing about 150 pounds is, according to Eggle-
ston's calculations, 2.25 grams. Mackenzie (109) states that 5 to 8
drachms of the tincture usually produces the desired effects in his
cases, an amount which should equal 2 to 3.2 grams of the crude
drug. Cohn (20) found that slowing of the heart rate in cases of
auricular fibrillation occurred after from 2 to 2.8 grams of the leaf
had been given, and Cohn and Fraser (22) found that when the digi-
talis was administered as the tincture or as digipuratum, a disturbance
of the rhythm was usually effected when an equivalent of from 2 to
4 grams of the leaves had been given, although symptoms of intoxi-
cation usually appeared before half of this quantity was given.
West and Pratt (156) using a dried aqueous extract of digitalis
obtained satisfactory therapeutic effects with a preparation having
a cat unit strength of 0.1 gram when from 1.4 to 2.2 grams had been
given, while Cohn and Levy (25), obtained the desired therapeutic
results when 1 gram of digipuratum of the same activity was given.
White and Morris (159) and Kay (88) have confirmed Eggleston's
principles of dosage. Robinson (130) has also administered a stand-
ardized tincture in large single doses, calculated according to Eggles-
ton's formula, to 100 cases of heart disease; the doses ranging, as a
rule, from 15 to 25 cc. or 15 to 25 cat units, the amount being regu-
lated by the body weight. He observed excellent therapeutic results
without encountering any serious toxic effects. He found that the use
of large single doses is apparently not dangerous under proper con-
ditions of study, and brings the heart rapidly under the influence of
the drug.
Pardee (118) has published the results of a study of sixteen patients
to whom the tincture was administered. His results also closely
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108 G. CANBY ROBINSON
confirm the findings of Eggleston. He found wide variations similar
to those seen by Eggleston which occur in the amount of the drug
required by different individuals to produce the same effects, the
variations in his series being from 36 per cent below to SO per cent
above average.
When digitalis is being administered in liquid form it should always
be remembered that there is a great difference between the amount
contained in a drop and in a minim. Cloetta (19), Pratt (121) Chris-
tian (16), Pardee (118), and others have referred to the inadequacy
of dosage which has resulted from considering a drop equal to a
minim, while in reality, according to Pratt, 1 cc. or 15 minims of
the tincture contains 35 to 40 drops when the ordinary medicine
dropper is used.
In summing up the work of these several students of digitalis
dosage, it may be concluded that the average total amount of the
drug necessary to produce therapeutic effects when administered
orally has been firmly established, provided the activity of the prepara-
tion and the body weight of the patient are taken into consideration.
This average total amount may be given in large single doses under
proper conditions and when certain precautions are carefully followed,
or it may be given in relatively small doses, at regular intervals pro-
vided doses are sufficiently large to allow the drug to accumulate in
the body and are not below the rate of elimination of the drug, a
matter to be considered later.
Pardee (118a) in his second paper on digitalis dosage expresses
the opinion that when a tincture of unknown strength is being used,
it is safe to follow the rule of giving 1 minim for each pound of body
weight in a single dose when the effects of the drug are desired rapidly.
This dose is well under the calculated maximun dose of Eggleston,
and allows for a considerable increase in the strength of the tincture
above that of the average preparation.
The question of applying the body-weight method to children has
recently been investigated by McCulloch and Rupe (112). They
observed the amounts of the tincture of digitalis necessary to pro-
duce definite effects in 36 children varying from one to fifteen years,
none of whom had heart disease. Frequent electrocardiograms were
obtained and the usual methods of clinical observation were carried
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THERAPEUTIC USE OF DIGITALIS 109
out McCulloch and Rupe give the weight of the children in kilo-
grams, but for purpose of comparison with the work already reviewed,
it will be given here approximately in pounds, two pounds being
allowed for each kilogram. The weights of the children ranged from
17 to 100 pounds.
The tincture employed was standardized at frequent intervals and
had continuously a strength of approximately 1 cc. per cat unit. It
was found to produce therapeutic effects in adults when given in
doses of 0.15 cc. per pound of body weight. In normal children
considering the group as a whole, from two to five times as much
digitalis per pound of body weight was necessary to produce recog-
nized digitalis effects as was found necessary to produce an optimum
therapeutic effect in adult patients with heart disease. The difference
of children in this regard was especially true for those weighing over
40 pounds. There were 12 such cases in the series, 8 of whom showed
no response to closes of 0.29 to 0.48 cc. per pound, while the other
4 required from 0.62 to 0.87 per pound of body weight before
showing evidence of the action of the drug.
Among the 24 children weighing less than 40 pounds, 14 responded
to less than 0.5 cc. per pound while 8 required from 0.5 to 0.87 cc per
pound.
Two children aged twelve and twenty-one months respectively
weighing 19 pounds each did not respond to the drug until 19.2 cc
had been given in 24 doses, requiring approximately 1 cc. per pound
of body weight before showing evidence of digitalis action. The total
amount of the tincture was given in this series in from 5 to 24 doses,
being administered 4 times a day. Elimination therefore probably
had little or no influence on the total amount taken, although of
course absorption is a factor difficult to evaluate.
McCulloch and Rupe conclude that children weighing from 16 to
40 pounds, or up to about the age of four years, respond more readily
as a rule to digitalis, than do those above this weight and age while
the older children required a distinctly larger amount per unit of
body weight than is required to produce comparable effects in adults
with heart disease. Considerable variation in the amount of the
tincture necessary to bring about a response in the hearts of the chil-
dren was found, but it is evident that relatively large doses of digitalis
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110 G. CANBY ROBINSON
can be administered to children with comparative impunity. McCul-
lock and Rupe (1 12a) have studied a second series composed of children
with heart disease. In this series they found no qualitative difference
in the effect of digitalis when compared to the action of the drug
on adults. They found, however, that children with heart disease
require about 50 per cent more of the drug per pound of body weight
on an average than do adults to obtain the same results. Some of
the cases required 100 per cent more of the drug, that is a quantity
double the estimated dose, while others required only 10 per cent
additional amount.
b. Absorption of digitalis from the alimentary tract is a problem
which has an important bearing on the dosage of the drug when ad-
ministered by mouth, and has recently received considerable atten-
tion. The relative rates of absorption of the various members of the
digitalis group, variations in absorption of a single preparation and
influences delaying absorption have been studied both in the labora-
tory and in the clinic.
Schmiedeberg (139) states that the active principles of digitalis,
digitoxin, digitalin and digitalein are slowly absorbed from the gastro-
intestinal tract.
Ogawa (116) called attention to the delay in the time required for
digitalis to affect the heart when given by mouth as compared with
the time required after intravenous injection. He concluded that
the slowness of absorption is the greatest factor in the "latent period"
of digitalis action. He states that digitoxin is not absorbed from the
stomach and only with relative slowness from the intestines. He
found that by examining the withdrawn gastric contents that different
preparations of digitalis have different rates of absorption, and that
digitoxin for which he applied a colorimetric test, remains for a shorter
period in the stomach when taken as digipuratum than when taken as
powdered leaves or as the infusion.
Ogawa is of the opinion that the absorption of the digitalis bodies
is further delayed by congestion of the abdominal vessels, as he found
that experimental obstruction to the portal circulation prevented
their absorption. Cloetta (19) also considers that congestion of the
intestinal vessels and of the liver interferes with the absorption of
digitalis. Eggleston (42) on the other hand, states that prompt and
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THERAPEUTIC USE OF DIGITALIS 111
efficient absorption of digitalis and digitoxin seems to take place even
in the face of considerable abnormality of the alimentary canal,
for patients manifesting evidence of marked congestion of this region,
resulting even in repeated vomiting, respond quite as promptly and to
the same doses as do those who are apparently free from disturbance.
Haskell, McCants and Gardner (66) studied the relative rate of
absorption of various digitalis bodies from the gastrointestinal tract
of animals. They determined the amount of digitalis intravenously
injected necessary to produce emesis after constant amounts had
been given orally, and took as the measure of absorption from the
gastro-intestinal trace the size of the intravenous dose necessary to
produce this result, as the larger the amount absorbed from the gastro-
intestinal tract, the less is needed by vein. They found that the
tincture of digitalis was much better absorbed than the infusion, and
that the expensive preparations, digipuratum, digalen anddigipoten
had no advantages over the tincture in regard to absorbability.
The most important work that has been done on the matter of
absorption is that from the laboratory of Hatcher and from the
clinic of Eggleston. Their numerous papers contain many references
to this matter. Hatcher and Baily (61) called attention to the fact
that the tincture of strophantus is poorly absorbed from the gastro-
intestinal tract, and Eggleston has recently stated in discussing the
work of White, Balboni and Viko (158) which has already been referred
to, that the tincture of squill owes its relative inactivity to its poor
absorption. Hatcher and Bailey (73) have also pointed out that
dangerous variations in absorption of strophantus may take place.
Eggleston (47) has recently summarized his ideas regarding the use
of members of the group other than digitalis as follows:
The materia medica of the digitalis group of drugs is large, but digitalis
alone is well absorbed from the alimentary tract of man. Strophantus,
convallaria, squills, etc, are alike poorly absorbed and irregularly absorbed.
Strophanthus deserves special mention, because it is 100 times as active
as digitalis, yet the official dose is only half that of digitalis, and it is often
given in equal doses. The irregularity of its absorption is of greater im-
portance than the fact that its absorption is generally poor, for in some
cases, serious poisoning has resulted from the rapid absorption of the
customary dose. We are convinced that strophanthus should never be
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112 G. CANBY ROBINSON
used for oral administration to roan on account of the danger of serious
accident, despite the fact that it often has been so used with satisfactory
results.
J. T. Halsey (62) has expressed similar views regarding the oral
administration of strophanthus, and contends earnestly that the poor
and irregular absorbability of strophanthus from the alimentary
canal should prohibit its use by mouth.
Recent interest has centered largely on the absorbability of the
tincture of digitalis, the most widely used form of the drug. Many
references are found in the older literature regarding the slow absorp-
tion of the drug in any form, but the recent clinical studies furnish
definite facts regarding the absorption of digitalis from the gastro-
intestinal tract in man. Eggleston (47) states that the absorption of
a single dose of a high grade tincture is apparently completed in six
hours and he quotes the results of Pardee and of Levy, both of whom
obtained electrocardiographic evidence of digitalis action in from two
to four hours after the drug was given by mouth. Robinson (129) ad-
ministered large single doses to 26 patients with auricular fibrillation
and observed the onset of ventricular slowing constantly in from 2
to 5 hour after the administration of the drug. These findings indi-
cate that with the tincture he used a fairly rapid and uniform rate of
absorption took place from the alimentary tract.
Pardee (118a) has studied the rate of absorption of digitalis from
the gastro-intestinal tract. He gave the drug in the form of the
tincture in doses determined by allowing 1 minim for each pound of
body weight, and administered this amount in a single dose. He
then followed the action of the drug in frequently taken electrocardio-
grams, noting especially variations in the T wave and in the heart rate.
Changes in the T waves indicative of digitalis action were observed
within two hours of taking the drug in three of nine patients, while
within three hours, these changes were observed in seven of the nine
patients. Pardee's observations are confirmatory of those of Robin-
son, although the doses used by the former were considerably smaller.
Pardee considers that the variation in the size of the dose within certain
limits does not appear to have a marked influence on the time of onset
of the digitalis action.
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THERAPEUTIC USE OF DIGITALIS 113
Eggleston (42), has compared the absorption of the tincture of
digitalis with that of digitoxin, digitalin and digitalein. The last two
substances are so poorly absorbed from the alimentary canal as to
render them unsuitable for therapeutic use, while the absorption
of digitoxin is slightly less rapid than that of the tincture.
Attention has been directed recently, however, to marked varia-
tions in dosage required to produce well defined digitalis action when
tinctures carefully assayed by the cat method were used. Wedd
(152) found that in one patient 100 cc. of a standardized tincture
produced no effect while six months later definite digitalis action
followed the administration of 35 cc. of another equally active tincture.
Of the first tincture 280 cc. were given to another patient during a
period of ten weeks and produced no clinical symptoms. He found
that from 24 to 34 cc. of the first tincture were required to cause
inversion of the T wave of the electrocardiogram while it occurred
with 10 cc. or less of the second equally active tincture. Wedd
attributes this difference in the action of the two tinctures to varia-
tions in absorption, and says that it is evident that biological standard-
ization is no guarantee of the clinical efficiency of a given preparation
of the drug.
A similar experience occurred to Oppenheimer (quoted by Eggleston
(46)), who gave 5 to 9 times the usual dose of the tincture without
evidences of either therapeutic or toxic action. Although individual
susceptibility may play some rdle in producing these marked dis-
crepancies, the variations in absorption seem to be the prime factor.
Hatcher (71) has taken cognizance of these variations in digitalis
action, the frequency of which is not yet known, and has investigated
them. He says that
Certain of the digitalis principles are readily absorbable from the gastro-
intestinal tract of man, as well as that of animals, while others are absorbed
much less readily, and it seems probable that the failures just mentioned
arose from the fact that preparations contained relatively large proportions
of the less readily absorbable active principles.
Hatcher has found that the more readily absorbable principles are
soluble in chloroform, and he describes a method for separating the
chloroform soluble from the chloroform-insoluble principles. He has
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114 G. CANBY ROBINSON
obtained a chloroform-soluble substance resembling somewhat digi-
toxin, both chemically and pharmacologically. It may be dissolved
in alcohol and is miscible with water without precipitation. The
resulting weak alcoholic solution has been found to undergo little
change during a period of a year since it has been under observation.
This preparation seems to exert the typical cardiac action of digitalis,
and has all its other advantages.
The clinical use and especially the absorbability by patients of this
preparation has been studied by Eggleston (46) who has published
some preliminary observations. He shows the marked uniformity
of absorption of the chloroform-soluble extract of digitalis prepared
from a variety of different leaves. This uniformity contrasts sharply
with the variations noted in the use of certain tinctures from a variety
of sources.
The chloroform-soluble extract is shown to be absorbed at least as rapidly
as the best tincture of digitalis, and its persistence of action is apparently
of the same order as that of digitalis of the best grade. The observations
indicate that for oral administration the chloroform-soluble extract is not
superior to a well absorbed tincture of digitalis, but it is far superior to
tinctures which are derived from a variety of sources, the absorption of
which shows very marked variations when individual specimens are com-
pared. The chloroform-insoluble extract is very poorly absorbed from the
human alimentary tract as well as from that of the cat.
It is evident that absorption must be taken into more strict account
than it has been in the past in determining the efficiency of a digitalis
preparation, and means must be devised if possible to determine its
absorbability as well as its activity in the standardization of the digi-
talis intended for oral administration.
The effect of the gastrointestinal secretions on the digitalis bodies is
a problem closely allied to that of absorption. Ogawa (116) studied
this problem in animals and in man, and found that strophanthin
was destroyed by the gastric ferments, just as Holste (quoted by
Ogawa) concluded that the pancreatic secretion destroyed digitalin.
Ogawa's study revealed, however, that the glucosides of the digitoxin
fraction are resistant for several hours to the juices of the gastro-
intestinal tract.
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THERAPEUTIC USE OF DIGITALIS 115
Cloetta (19) has investigated the effect of gastric juice on digitalis
in vitro, his digalen preparation being subjected to shaking for one
hour at 38°C. with varying percentages of hydrochloric acid. The
percentage of the drug destroyed was then determined and the follow-
ing results were obtained:
with 22 per cent HCL 100 per cent digalen destroyed
with 12 per cent HCL 60 per cent digalen destroyed
with 4 per cent HCL 40 per cent digalen destroyed
with 3 per cent HCL 35 per cent digalen destroyed
with 2.5 per cent HCL 35 per cent digalen destroyed
with 1 .5 per cent HCL 25 per cent digalen destroyed
Cloetta considers that a "nerve poison" is generated by the action
of hydrochloric acid on digitalis, the therapeutic properties of which
are destroyed. He recommends giving the drug when the stomach is
empty, and giving it with an alkaline mineral water, weak tea or a
mucilage. He also believes that his findings indicate the usefulness
of giving digitalis by rectum, which he advocates. Further study of
these subjects is needed before they can be adopted as principles in-
fluencing the therapeutic use of digitalis.
The problem of the decomposition of various digitalis bodies by
acids and digestive ferments has been discussed by Hatcher and Eggles-
ton (78) in their studies in elimination, and a review of a number of
experimental studies of this subject is given, including that of Holste
quoted by Ogawa. Following their analysis of these various investi-
gations, they say that there is no convincing evidence that any of the
digestive juices or their ferments have any important destructive
action on any of the digitalis glucosides following their therapeutic
administration by the mouth.
c. The speed of action or time elapsing between the oral adminis-
tration of digitalis and the appearance of its effects is also a matter
on which absorption has an important bearing. The fact that digi-
talis requires many hours or even days to affect the heart when given
in the customary doses has been perhaps the chief disadvantage in
the use of the drug in cases of heart disease in which prompt action is
urgently indicated.
Cushny has stated that one great limitation in the use of digitalis
is caused by the slowness with which its action is elicited. "Rarely
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116 G. CANBY ROBINSON
is any distinct change to be seen before the fourth day of treatment,
and this precludes its use in the most acute cases." (Quoted by
Eggleston (42)). Recent clinical studies have shown, however, that
it is the size of the dose rather than the delay in the absorption or in
the action of the digitalis that is the most important factor in regulat-
ing the speed of action of the drug. It is necessary for a certain
amount of the drug to be present in the body before the action appears,
and the action appears much more quickly with large than with
small doses, several or many of which are needed to supply the amount
of the drug necessary to exert its action. It has been the time re-
quired for the accumulation of a sufficient amount of digitalis that has
become largely responsible for the ideas regarding the very slow
speed at which the drug exerts its action.
Eggleston (42) has shown the relation between dosage and speed
of action for digitalis and digi toxin, large doses of the digitalis bodies
becoming active on an average in 13 hours; small doses in thirty-eight
hours while large doses of digitoxin required fifteen hours to produce
their earliest effect, and smaller doses required forty-two hours. He
demonstrates that both these drugs when given in large doses can
induce full therapeutic effects within comparatively few hours after
the administration of the first dose.
Robinson (129) has investigated the question of the rapidity of
the action of digitalis by giving the full calculated amount of the tinc-
ture in a single dose to patients with auricular fibrillation. In a
series of patients in whom digitalis caused a striking reduction of the
ventricular rate, he found that ventricular slowing (or disappearance
of auricular flutter) began in. from two to five hours, in all of the 16
cases where the initial effect was observed, and that maximum slowing
in 26 cases occurred in from six to twenty-six hoUrs. As only one dose
was given in most of these cases, the question of the accumulation
of the drug played no part.
These results have been confirmed by Eggleston (46) and by Pardee
(118a), who found that two or three hours after a single large dose of
the tincture slight changes in the T wave of the electrocardiogram
characteristic of digitalis action usually appeared. Eggleston also
quotes Scott as having obtained digitalis effects in from one to two
hours by the administration of 10 cc. of the chloroform-soluble ex-
tract of digitalis given in a single dose.
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THERAPEUTIC USE OF DIGITALIS 117
Cohn and Levy (25) have compared the speed of action of compara-
ble doses of digitalis (digipuratum) when given by mouth and g-stro-
phanthin when injected intravenously. An effect with digitalis has
been observed in a little more than two hours, while the speed of
action is often faster with strophanthin than with digitalis, though
when strophanthin is given in divided doses it may require nearly two
hours to obtain an effect. In other instances, an effect may be ob-
tained, as is well known, in twenty minutes or less.
This matter of speed of action of digitalis has been recently summed
up in a vigorous way by Hatcher (70).
It is necessary to call attention again to the difference between an im-
mediate action and immediate effect, because it ,has long been taught,
without a particle of real evidence, that the action of digitalis cannot be
induced promptly. The whole range of digitalis action up to the maximum,
that is, cardiac stoppage, can be induced in from five to fifteen seconds by
the intravenous injection of digitalis tincture deprived of its alcohol, or
digitoxin. This simple experiment disposes forever of the mischievous
claim that digitalis action is slow. The effect of therapeutic doses is gradu-
ally induced; the action is immediate. A bullet fired through the heart
acts instantaneously; the effect is a fatal hemorrhage, the rapidity of which
depends largely on the size of the wound. With suitable dosage, digitalis
exerts its action in much less time than was formerly believed to be possible.
2. Intravenous administration
The value of the intravenous administration of ouabain, strophan-
thin, and some other principles of this group is generally recognized,
and it is considered a life-saving measure because of the promptness
with which the action of these drugs can be obtained in urgent cases
of heart failure. In emergencies, however, the cause of heart failure
may be difficult to determine and when it occurs under such con-
ditions as during a surgical operation, its cause is often incorrectly
attributed to "cardiac dilatation," as Levine has recently pointed
out. The use of large doses of digitalis by mouth and the prompt
action which usually results makes the use of these drugs by intra-
venous injections rarely necessary. It must always be employed
with caution, as has been pointed out in discussing fatalities fol-
lowing its use, and intravenous injections should never be given to
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118 G. CANBY ROBINSON
patients who have been receiving full doses of the digitalis bodies in
any form.
Digalen, the so called soluble digitoxin, prepared by Cloetta (17)
is the first form of digitalis recommended for intravenous employment.
Edens (36) was among the first to report favorable results with the
intravenous administration of this drug, and he emphasizes especially
the rapid action thus obtained, and the fact that the drug can be
used in cases where absorption from the gastrointestinal tract would
probably be distinctly faulty. He considers its use not without dan-
ger, however, and recommends its use by slow injection in desperate
cases. Cloetta (19) has recently expressed his belief in the intra-
venous use of digalen as the ideal method of giving digitalis.
Strophanthin was introduced as a drug for intravenous adminis-
tration by Fraenkel, and its use is fully discussed by Fraenkel and
Schwartz (54). They recommended a dose of 1 mgm. (uV of a grain)
but say it should not be given more often than once a day. Agassiz
(2), studied the effect of intravenous injections of strophanthin on
a series of cases of auricular fibrillation and recommends doses of
■rfv to Trfo grain repeated several times every one to three hours for
several doses. Ventricular slowing usually resulted from one injec-
tion. It may appear as early as half an hour after the injection,
but the ventricular rate may continue to be further slowed during
the following twenty-four hours. Two or three injections are
usually sufficient to produce the normal ventricular rate in 4 to 9
hours. Strophanthin employed intravenously seemed to possess
action quite similar to the other members of the digitalis series.
Agassiz found the most suitable method of administration to consist
in the injection of t*v grain repeated after three hours, and followed
after a further interval of three hours by an injection of irta grain if
required. The injection may be followed by pain at the site of in-
jection and by a rise of temperature. In one instance, a patient died
unexpectedly some twelve hours after the injection had ceased, but
the relation of cause and effect was not definitely established.
Fulton (156) reports a case of auricular fibrillation treated by in-
travenous strophanthin in which the pulse reduced from 144 to 34
within a period of about twenty-four hours, after two doses had been
given, the first of ?H of a grain and the second of tJtf of a grain.
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THERAPEUTIC USE OF DIGITALIS 119
The condition of the patient passed quickly from one of extreme dis-
comfort with dyspnea and restlessness to a condition of perfect
comfort.
Such observations as those of Agassiz and Fulton indicate that doses
of 1 mgm. (bV grain) as advocated by Fraenkel are too large, and fatal
accidents have resulted from the use of strophanthin in such doses,
as has been brought out when digitalis fatalities were discussed.
However, the work of Levine and Cunningham (94) indicates that it
is no more dangerous than digitalis intravenously administered when
the so-called margin of safety is considered, the average difference
between the minimum lethal dose and the minimum toxic dose being
48 per cent in each instance. They have also found that various digi-
talis preparations act as quickly on the heart when injected into the
veins as does strophanthin. They observed toxic effects two minutes
after the intravenous injection of digitalis and cardiac standstill in
sixteen minutes. All effects produced by either digitalis or stro-
phanthin were seen to occur within six minutes after the injections.
Levine (92) has suggested a fractional method of intravenous in-
jection of strophanthin on the basis of his experimental studies of the
action of the drug on the living cat's heart. He points out that
numerous fatalities have resulted from the intravenous administra-
tion of strophanthin, but most of them have occurred when the drug
was given to patients who recently had taken digitalis, or when large
doses were repeated on the same day. His experiments show that it
is practically impossible to foretell the toxic dose for patients but they
indicate that a "margin of safety" exists between the minimum lethal
dose and the minimum toxic dose. Levine recommends that strophan-
thin be injected in several fractions of the desired dose, a half hour
intervening between the fractions, during which time, the signs of
intoxication are watched for. This procedure will prevent giving
more than one fraction, say 0.1 mgm. in excess of the amount neces-
sary to produce the earliest toxic signs. Electrocardiograms are
very useful in showing premature beats or changes in the P-R interval
as a result of the drug. This procedure should certainly diminish or
avoid the dangers of the drug. According to Levine, Vaquez and
Lutembacher have reported almost 2000 intravenous injections of
ouabain without harm or fatality.
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120 G. CANBY ROBINSON
Danielopolu (34a) has also recently stated that strophanthin can
be safely given only in small doses, and recommends the use of 0.25
mgm. intravenously two or three times a day. This he calls the
method of fractional doses, and says that by observing the patient
carefully before each dose, the drug can be given to patients with
extreme myocardial derangement or with kidney disease, which are to
be taken as contraindications when larger doses are employed.
Cohn and Levy (25) report that the g-strophanthin which they have
used in their comparison with digitalis had an average cat unit of
0.104 mgm. and was given usually in two doses at an interval of one
hour — the first of from 0.4 to 0.5 mgm., and the second from 0.3 to
0.5 mgm. No serious untoward effects were observed after these
doses.
The drug produced premature beats and ventricular ectopic tachy-
cardia in 52 per cent of the cases of auricular fibrillation and 12.5
per cent of the cases with normal hearts. These toxic effects always
appeared within twenty minutes after the injection causing them and
disappeared within eight hours. Nausea and vomiting were noted in
10 per cent of the cases. Comparable doses of digitalis by mouth
caused undesirable effects in a much smaller percentage.
An important indication for the intravenous use of a digitalis body
is persistent vomiting which may be associated with heart-failure as,
under such circumstances, it may be impossible to administer the drug
orally. Under these circumstances, strophanthin had best be used,
for although other digitalis bodies have been employed intravenously,
they have not as yet been placed upon as sound a basis for this purpose
as strophanthin.
J. Subcutaneous and intramuscular administration
Subcutaneous and intramuscular administration has not proved
desirable, and it has not been employed in any of the recent studies of
digitalis. Several preparations have been recommended as suitable
for subcutaneous and especially intramuscular injections, but all are
decidedly painful and apt to cause necrosis, and their dosage has not
been accurately determined. Hatcher and Eggleston state emphati-
cally as a conclusion from their studies on the absorption of drugs in
general that no rule can be formulated for the calculation of the ap-
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THERAPEUTIC USE OF DIGITALIS 121
propriate dose by one mode of administration from the dose by any
other mode of administration. Such determination can be made
only be experiment.
4. Rectal administration
Rectal administration has been recommended by Eichhorst (49) in
the treatment of chronic myocardial insufficiency. He described
several cases which were not benefited by the usual drugs and which
did not respond favorably to three powders a day composed of
0.1 gram of powdered digitalis, 1 gram of diuretin and 0.5 gram of
saccharin. These cases showed beneficial results from small daily
enemata containing 10 drops digalen (Cloetta), 10 drops of the
tincture of strophanthus, 0.3 gram of theocin and 5 cc. of lukewarm
water. This prescription was injected daily into the bowel and re-
tained. Eichhorst has continued their use over periods of years with-
out difficulty. Five to ten drops of the tincture of opium is added
when there is pain or difficulty in retaining the enemata. Eichhorst
states that very striking results were obtained by the use of such
enemata.
Cloetta (19), has commented upon Eichhorst's results, and he is
favorably disposed toward the method. He believes that one ad-
vantage of rectal administration is that it does not subject the drug to
the action of the gastric juice, which his experiments indicate may
destroy it. He believes the favorable results that have been reported
are accounted for also by the fact that some of the veins leading from
the rectum, the inferior and part of the middle hemorrhoidal veins,
empty directly into the inferior vena cava, and do not send the blood
through the liver. Because of this, some of the drug introduced into
the rectum would probably reach the heart without going through the
liver, where'it may be destroyed.
The rectal administration has not been extensively used, but it
deserves further study, and more should be known regarding the
action of the digitalis bodies when introduced into the body by this
route.
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122 G. CANBY ROBINSON
XH. PERSISTENCE OP ACTION
It has long been known that the action of digitalis persists after
the drug is discontinued. Withering (163) recognized this fact in
regard to nausea and vomiting, and recommended that the drug be
stopped as soon as its activity became manifest, inferring that
its beneficial effects persist thereafter. A number of problems are
involved in the persistence of action of digitalis. Absorption, fixa-
tion by the tissues and especially the destruction or elimination
of the drug from the body, may all play some part in determining the
continued action of the drug, and as there is but little known regarding
any of these matters, no satisfactory explanation of the fundamental
problem can be offered.
A number of clinical observations have been made with exact ob-
jective methods which show the length of time patients remain
under the influence of the drug after full digitalization has been ac-
complished and the drug withdrawn. Bastedo (5) observed the
continuation of digitalis heart-block for three and a half weeks after
the withdrawal of the drug. Cohn (20) found by means of electro-
cardiograms that delayed conduction always persisted for two days in
relatively healthy hearts and exceptionally for two weeks after the
discontinuance of digitalis, while Cohn, Fraser and Jamieson (23)
observed the persistence of the T wave changes in the electrocardio-
gram for from five to twenty-two days after the drug was stopped.
Eggleston (39) has studied the relative duration of various cardiac
manifestations of digitalis action in fifteen cases of his own and from
the literature. Coupled beats persisted from four to twelve days,
heart block three to six days, combined phenomena six days, auricular
fibrillation three days, extrasystoles and sinus arrhythmia two days.
Conclusions regarding the relation of digitalis and the disappearance
of transient auricular fibrillation is hardly justified.
Robinson (129) followed the ventricular rate of a number of cases
of auricular fibrillation after it has been slowed by large single doses
of the tincture of digitalis. In twelve cases which were carefully
controlled, the ventricular rate began to accelerate in from four to
fifteen days after the administration of the dose of digitalis which had
caused marked slowing. This acceleration was taken as evidence
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THERAPEUTIC USE OF DIGITALIS 123
that the heart had ceased to be under the action of the drug. The
drug was active on an average, for nine days and six hours in these
cases. Kay (88) has reported ventricular slowing in auricular fibrilla-
tion for from three to five days after doses of digitalis given by the
"Eggleston method."
It is evident that various manifestations of digitalis action persist
after the drug is withdrawn for from two to twelve days in most cases,
but may persist for three weeks or more.
The action of strophanthin when administered by vein has been
found by Agassiz (2) to retard the rate of the ventricles of cases of
auricular fibrillation for two or three days, when acceleration begins,
and the original rate, present before treatment, is seen again in about
one week.
Cohn and Levy (25) have compared the persistence of action
of digitalis (digipuratum) and g-strophanthin given in comparable
doses to cases of auricular fibrillation and found that while the digi-
talis effect endures usually beyond ten days, and has lasted as long
as twenty-three days, it is rare for strophanthin to keep the ventric-
ular rate low for more than five days. It did so once for nine days,
however.
A question closely allied with the persistence of action is the so called
cumulative action of digitalis. Eggleston (39) has discussed the term
"cumulative," which is a very loose one. It is generally taken to
express the development of signs of action during the administration
of small repeated doses of a drug which are much more marked than
those caused by a single small dose. Toxic symptoms are usually im-
plied. Accepting this definition, the cumulative action in the case
of digitalis is simply the result of a summation of amounts absorbed
and active in the body when the intake of the drug is greater than its
elimination. The continued use of small doses of the drug raises by
the process of summation, the total amount of the drug active in the
body, and perhaps fixed by the heart or the nervous tissues to such a
point that toxic symptoms develop. When the persistence of action
of digitalis is borne in mind the fear of its so called cumulative action
can be put aside.
Hatcher (68) has investigated the persistence of the digitalins by
means of animal experiments, especially with the hope of throwing
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124 G. CANBY ROBINSON
some light on the cumulative action of the drug, which generally
means, he says, action which is manifested rather suddenly after the
continued use of doses which singly do not cause perceptible effects.
The method he employed was as follows: The fatal dose of the digi-
talis body for a given species was determined in a series of experi-
ments. After toxic, but sublethal doses of the drug had been given,
the animals were kept under observation for periods of one to thirty
days, and then the percentage of the standard fatal dose required to
kill in a characteristic way was determined. The decrease in the
amount necessary to produce a fatal result was taken to represent the
amount of the drug remaining in the body of the animal. Hatcher
and Brody (74) had previously shown that the various digitalis bodies
are synergistic, and that ouabain was capable of replacing the various
digitalins in the estimation of the fatal dose, and this drug was gen-
erally employed for the second injection. Cats were found to be the
most useful laboratory animal for this purpose. The many experiments
will not be reviewed. Certain conclusions are of importance from
the point of view of the therapeutic use of digitalis. Hatcher says
that the production of the phenomena commonly called "cumulative
action" of the digatalins depends on the relationships existing among a
number of factors, including absorption, elimination, and persistence of
action, all of which are in need of investigation. The use of the term
cumulation tends to perpetuate a misconception. The action of the
digitalis persists for periods of time which vary widely with different
members of the group, the action of digitalis and digitoxin persisting
much longer than those of the other digitalins in common use. The
cardiac action of a single very large intravenous dose of digitalis
or digitoxin may persist for a full month in the cat, while similar doses
of digitalin, ouabain or strophanthus persist for only a day or at most a
few days.
Careful regulation of the therapeutic dosage of the digitalins is
necessary in order to avoid accidents. This is especially necessary
when they are used in such a way that the action is elicited promptly
during the period when the action of a previously used digitalin per-
sists, and in this connection it must be remembered that every digi-
talin is a synergist of every other member of the group.
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THERAPEUTIC USE OF DIGITALIS 125
Xin. ELIMINATION OF DIGITALIS
Little is known and relatively little has been thought apparently
regarding the matter of the ultimate fate of digitalis in the body, its
destruction and its elimination. It is a matter of real importance,
however, in the therapeutic employment of digitalis, when frequent
doses of the drug are being given, and especially when it is desirable
to keep a patient constantly under the influence of the drug without
producing toxic symptoms. This is apparent from the foregoing
discussion of the "cumulative action" of the drugs of the digitalis
group.
Schmoll (141) recommends that 0.1 gram of digitalis be given daily
to heart cases in order to take advantage of what he calls the tonic
use of the drug, and he says this dose causes no toxic effects because
it is the amount of the drug which can be excreted daily.
The rate of disappearance from the body has been the subject of a
clinical investigation by Pardee (118). He points out that when
digitalis is given for the purpose of keeping a patient constantly under
its influence, improper dosage makes the patient liable to pass gradu-
ally out from under the influence when too small a dose is given, or with
over-administration, leads to toxic symptoms. As animal experi-
ments cannot give a definite answer as to the rate of disappearance of
the drug from the human body, Pardee investigated the question
directly in patients by the following method. The tincture of digitalis
was given until mild toxic symptoms appeared, when it was stopped
entirely for a number of days. It was then given again until the
same toxic symptoms reappeared. The difference between the
amount of the drug used in the second and in the first course, divided
by the number of days between the two toxic points, is taken to indi-
cate the daily average amount of the drug that had disappeared from
the body in the interval. It is assumed that there is no change in the
patient's tolerance for the drug, a fair assumption in the light of the
results with repeated courses in the same patients. The initial doses
were so arranged that toxic symptoms appeared in from two to six
or eight days; while the second course was usually complete in an
average of five days, although it was sometimes prolonged.
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126 G. CANBY ROBINSON
Vomiting was the usual toxic symptom employed. Twenty-two
tests were carried out on 16 cases, all of whom had a rather marked
degree of heart failure before the initial course, but were in better
condition when the second course was given. A standardized tincture
having a strength of 1.25 cc. per cat unit was used.
The method employed by Pardee showed an average daily rate of
disappearance of the drug from the body of 22 minims of the tincture.
In half the cases the amount was below and in half above the average,
the maximum variations being from 55 per cent below to 82 per cent
above. The results of this investigation resemble other work on digi-
talis in the variability of figures, but in 18 of the 22 tests, the results
lay between 12.3 and 30.6 minims per day; while in eleven tests, half
of the total, it was between 13.3 and 27 minims, the latter a total
variation of only 62 per cent. Pardee says:
It is evident from this that the average figure of 22 minims per day would
afford a fairly satisfactory basis for long continued digitalis medication,
since in only half of the cases would it be much more or much less than the
patient's ability to dispose of the drug. These results demonstrate the
reason for the approximate efficiency of a dose of ten minims of the tincture
twice a day, which has commonly been considered sufficient to maintain
constantly the digitalis effect. They also demonstrate a new phase of the
variability from one individual to another, in the action of digitalis, a
variability in the rate of disappearance from the body.
It is interesting that Schmoll's figure of 0.1 gram of digitalis
which is equal to about 15 minims of the tincture recommended a
number of years ago, should approximate Pardee's figure fairly closely.
The importance of this subject warrants its further clinical inves-
tigation.
Hatcher and Eggleston (78) have recently published extensive
studies in the elimination of certain of the digitalis bodies from the
animal organism. Their review of the literature shows that the sub-
ject is in an unsatisfactory state. Their studies deal mostly with the
elimination of various pure digitalis bodies in the rat, while the elimina-
tion of ouabain in the cat and dog was also investigated.
Ouabain disappears rapidly from the blood following injection, and
seems to be taken up by the liver where it is apparently decomposed.
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THERAPEUTIC USE OF DIGITALIS 127
Both destruction in the body and elimination by the kidneys probably
occur. Many points regarding the elimination of the digitalis bodies
remain to be settled, and this work of Hatcher and Eggleston does not
appear to present any facts which can be applied directly to the
therapeutic use of digitalis.
XIV. PREPARATIONS OF DIGITALIS AND ITS ALLIES
The number of digitalis preparations is very great and they have
been shown to vary greatly in activity. It is hardly worth while to
attempt a description and criticism of the many proprietary prepara-
tions. It seems more desirable to attempt to review the rules by which
the useful preparations can be distinguished from the less valuable.
Of course activity as established by a reliable form of biological assay,
preferably the cat method of Hatcher and Brody (74) is essential.
The cost and recently the availability, especially of foreign prod-
ucts are to be considered even when the medicinal qualities are
satisfactory. As Eggleston (47) has recently stated:
Of the many proprietary preparations and speciali ties which are offered
with high claims for oral administration, none is superior to the powdered
leaf or a tincture of high grade, and most are decidedly inferior. All are
quite costly and the price of some is exorbitant. If one feels impelled to
employ one of these, digipuratum or digipoten will be found to be the best,
but these are merely carefully assayed, purified preparations from good
digitalis leaves.
The dried aqueous extract recently described by West and Pratt
(156) at first seemed to be an excellent preparation but has since
proved too hydroscopic. It was used by them in capsules containing
0.1 gram. The chloroform-soluble extract which Hatcher (71) has
obtained has been successfully employed by Eggleston (46), and may
prove to be superior to the ordinary tincture, on account of its uni-
formity of absorption.
The infusion of digitalis has no advantage over the tincture or pow-
dered leaves, and the large amount necessary for proper dosage make
it less desirable.
Weiss and Hatcher (54a) have recently investigated the relative
merits of the infusion and the tincture once more. They found that
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128 G. CANBY ROBINSON
the infusion of digitalis prepared according to the method prescribed
in the United States Pharmacopoeia does not represent the drug
completely, so that its strength cannot be determined from that of the
leaf from' which it was made. They give a method by which all
water-soluble active principles can be obtained. They show that the
full strength of the drug is represented by the tincture, and neither
the infusion nor the tincture contain amounts of the saponin bodies
sufficient to cause undesired effects. Weiss and Hatcher point out
that they can find no evidence of any qualitative difference between
the actions of the tincture and those of the infusion. The common
belief that the infusion deteriorates rapidly is apparently much exag-
gerated, because Weiss and Hatcher report that an infusion prepared
by the method they recommend, kept in hermetically sealed bottles
for two years and five months retained its activity unimpaired, as
shown by tests on cats and by its therapeutic results. A properly
prepared and preserved infusion would seem therefore to have a
usefulness quite similar to that of a good high grade tincture.
None of the preparations claiming to be devoid of effects on the
gastro-intestinal tract should be used on that account. The absence
of this effect must be viewed as evidence of inactivity, because of lack
of potency or poor absorption, and if gastric symptoms are not pro-
duced, the desirable effects can not be expected.
Strophanthus and squills as well as most of the purer derivatives of
digitalis are so poorly and irregularly absorbed from the gastro-in-
testinal tract that they should never be used for oral administration.
Crystalline g-strophanthin is the most satisfactory drug for intrave-
nous use provided it is protected against deterioration by regulation
of its reaction and by its being marketed in hard glass containers.
The importance of this has been shown by Levy and Cullen (95). •
The French preparations, Arnaud's ouabain and Nativelle's crys-
tallized digitaline have been assayed by Levine (93), using the cat
method, and he found that this ouabain had a cat unit of 0.059 mgm.
It is nearly twice as active as the ouabain used in America, w!iich
Hatcher has shown to have a constant unit of 0.1 mgm. Nativelle's
crystalline digitalin in sterile oil capsules had a cat unit of 0.86
mgm., the tablets of 0.71 mgm. Levine suggests that the dose
of 0.25 mgm. of digitalin advised by the manufacturers is too small
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THERAPEUTIC USE OF DIGITALIS 129
for good therapeutic effects. Perhaps the sterile oil preparation is
the most satisfactory for intramuscular injection if such use of the
drug be found necessary. It was stated, when the so called digitalis
group of drugs was discussed as a whole, that this review wduld deal
almost exclusively with digitalis and strophantus. Recently three
other members of the group, squill, apocynum and convallaria have
been investigated from the point of view of their therapeutic effects
by White and his collaborators. As their therapeutic value has
been compared with that of digitalis, a brief statement may be
made regarding their use in the treatment of heart disease. The
digitalis-like action of squill was studied in fourteen patients by White,
Balboni and Viko (158). Thirteen of their cases showed auricular
fibrillation, most of which had been previously shown to respond well
►to digitalis. They found that ventricular slowing and the charac-
teristic changes in electrocardiograms were produced by the drug,
indicating that squill does have a definite digitalis-like action, but only
when doses much larger than those usually recommended were given.
They administered the tincture of squill, and found that from 8 to
16 cc. were necessary at each dose instead of the recommended dose
of 1 cc. (IS minims). No definite diuretic effect could be attributed
to the action of the drug. Eggleston, as previously mentioned, stated
in discussing this paper that in his opinion the large doses were nec-
essary on account of the poor absorption of the drug from the gastro-
intestinal tract. He further says that he can see no reason for using
squill in place of digitalis in the treatment of heart disease.
Apocynum and convallaria have been similarly studied by Marvin
and White (110a). Apocynum was administered by mouth in the
form of the fluid extract to twelve patients. Although the drug was
found to have an action similar to digitalis when given to patients
with auricular fibrillation, it produced pronounced gastro-intestinal
symptoms, which occurred with the smallest doses that had any de-
monstrable effect on the heart. Its persistence of action was transient,
lasting only twenty-four to forty-eight hours. The drug was much
less effective in doses that could be given than digitalis in the treat-
ment of heart disease. Convallaria was also given to twelve patients
in the form of the fluid extract. It was found to be distinctly less
efficacious than digitalis, causing clinical improvement in only two of
, VOL. I, NO. 1
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130 G. CANBY ROBINSON
the twelve cases. Nausea and vomiting occurred in nine and diar-
rhoea in six cases. Its action was transient. Marvin and White
conclude that
it would seem from our results that neither apocynum nor convallaria can
be substituted for digitalis. In our experience digitalis has been charac-
terized by quicker action, more pronounced effects, less discomfort, and
more prolonged improvement, than are seen following either of the other
drugs. We are convinced that both these members of the digitalis series
have no place in the rational treatment of heart failure.
In spite of the fact that these studies bring out, apocynum and
convallaria are used to a considerable extent, as two American phar-
maceutical companies reported to Marvin that their annual sales
amounted to about 15,000 pints.
In the therapeutic use of digitalis certain requirements should be
insisted upon by the medical profession. All products put upon
the market should be labelled not only with the results of the biologi-
cal assay, but also with the date of manufacture and of the assay.
The dose should be indicated according to the actual strength of that
particular preparation. When the medical profession learns to regu-
late the dosage of the digitalis bodies properly, and to understand
thoroughly the indications for their use, the great value of this group
of drugs in the treatment of heart-failure will be more generally
appreciated even than it is at present. The selection of the form
in which the drug is used is relatively unimportant if activity and es-
pecially dosage are properly controlled, and if the use of the unsuitable
members of the digitalis group is avoided.
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THE TREATMENT OF MENINGOCOCCUS MENINGITIS
KENNETH D. BLACKFAN
From Ike Horrid Lane Home, Johns Hopkins Hospital, and Ike Department of Pediatrics,
John Hopkins University, Baltimore
Received for publication March 1, 1922
TABLE OF CONTENTS
Historical resume* of meningococcus meningitis 140
First appearance 140
Mortality before serum treatment. 141
Treatment before discovery of antimeningococcus serum 142
The meningococcus and its strains 144
The discovery of a specific serum. 146
The preparation of antirneningococcus serum 147
Rapid method of preparing serum. 148
Standardisation of serum. 149
Serum for diagnostic purposes. 151
Diagnosis of meningococcus meningitis 151
Prophylactic measures in meningitis. 154
Meningococcus carriers. 154
Hygienic measures. 155
Treatment of carriers 158
Passive immunity as a prophylactic measure 160
Active immunity as a prophylactic measure 161
Treatment 163
The premeningitk stage of meningitis.. .! 163
Intravenous serum therapy 164
Lumbar puncture in relation to the treatment of meningitis 167
The intraspinous administration of serum in meningitis. 172
Action of the serum 172
Symptoms caused by the injection of serum. 175
Dosage of serum. 176
Frequency of injection ? 178
Discontinuance of serum 179
Early intraventricular injection of serum. 182
Amount of serum used during the treatment 183
Reinfection and relapses. 184
Immunity conferred by attack of meningitis 188
The use of monovalent or polyvalent serum. 188
Drugs in treatment of meningitis. 190
Other measures employed in treatment 191
139
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140 KENNETH D. BLACKFAN
Vaccines in, treatment of active stages. 194
Hydrocephalus. 196
Intraventricular injection of serum. 200
Other locations recommended for injection of serum 201
Other complications and sequelae of meningitis. 203
Serum disease 205
Anaphylaxis 207
Influence of serum therapy on the disease 207
HISTORICAL RESUME OF MENINGOCOCCUS MENINGITIS
First appearance
In the early part of the nineteenth century there appeared a form
of epidemic disease which had not been observed before or at least
it had not been recognized by the physicians of that time. According
to Hirsch, it is not clear from the reports in the literature whether
the disease previously had really existed. There is no reason to
doubt that it had, but if so, it had been confused with many of the
other forms of epidemic disease. This new entity was characterized
by an inflammation chiefly or entirely localized in the cerebral and
spinal meninges and it was accompanied by the symptoms of an
acute epidemic constitutional malady.
The disease was first accurately described by Vieusseux, who
observed a small epidemic at Geneva in 1805. Small outbreaks
followed among the soldiers in the garrisons at Paris (1814), at Metz
and Geneva (1815) and at Westphalia (1822). In the United States,
cases were reported as far west as Kentucky and Ohio in 1808, and
there was a widespread epidemic most prevalent in New England
from 1814 to 1816.
The disease was first spoken of as "meningitis cerebrospinalis
epidemica" or "typhus cerebralis." In this country it was known
as "sinking typhus" or "spotted fever." From the date of its first
appearance, meningococcus meningitis, epidemic meningitis or cere-
brospinal fever has been epidemic in various places from time to time.
These epidemics are followed by quiescent periods in which isolated
cases appear and these quiescent periods are in turn followed after
greater or less intervals of time by fresh outbreaks. This onward
march has continued throughout the last century and up to the
present day, so that either in sporadic or epidemic form meningo-
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TREATMENT OF MENINGOCOCCUS MENINGITIS 141
coccus meningitis may justly be spoken of as an endemic disease.
When once implanted in a new community, it there remains just as
is the case with measles, scarlet fever and other similar diseases
so that at present it still prevails in those countries in which it first
appeared a century ago.
For many years meningococcus meningitis was regarded as a
disease which followed none of the laws which govern the progress
of other epidemic diseases. An epidemic would begin as a perfectly
isolated incident in a locality that had been altogether free before,
run its course there, and thai spring up in some quite distant region.
The cause of such transmission by means of "carriers" was of course
not then known. While the disease is most commonly seen in children,
with bad sanitary and overcrowded housing conditions it quickly
develops epidemic proportions and affects people of all classes and
of all ages. The statistics compiled by Compton show that the most
susceptible age for the sporadic form is under five years and the least
susceptible from thirty-five to forty years; during epidemics persons
of all ages are attacked. Even in epidemics and in the outbreaks
occurring in army barracks during the world war, the disease has a
seasonal prevalence. The majority of the epidemics have begun
in the winter months, the maximum intensity of the epidemic being
reached during the spring months and from then on the incidence of
disease falls steadily and the epidemic is usually over by the early
summer months. Our present conception of meningococcus menin-
gitis is that of an infectious disease, occurring sporadically or in
epidemics, due to the diplococcus intracellularis meningitidis, dis-
covered by Weichselbaum. The disease affects children and young
adults most frequently, the latter especially when closely confined
in army barracks and institutions. It prevails chiefly in the winter
and spring months. The mode of infection is by direct contact
either with a patient suffering from the disease or contact with a
healthy person harboring the organism, a so-called carrier.
Mortality before serum treatment
From a review of the literature it is apparent that the severity of
the disease unmodified by treatment has not changed materially
since its first recognition. In the earlier epidemics the mortality is
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142 KENNETH D. BLACKPAN
given from 20 to 75 per cent by Hirsch, who collected the statistics
from 41 epidemics. The figures before the days of serum treatment,
compiled by Flexner, show that the death rate in 18 epidemics was
between 42.5 and 90 per cent. In one epidemic the mortality was 42.5
per cent; in three, 60 per cent; in nine, 70 per cent; in two, 80 per
cent, and in one, 90 per cent. Statistics show, moreover, that the
mortality varies considerably with different epidemics and at different
periods of the same epidemic. Fulminating and rapidly fatal cases
are by far more frequent at the beginning of epidemics and mild and
abortive cases much more frequent toward the close. Sporadic
cases are usually mild and the mortality with this form of disease
is relatively low.
Treatment before discovery of antimeningococcic serum
As with other diseases whose etiology and pathology have not been
clearly understood and in which the views regarding the nature of
the disease have changed from time to time, so with meningococcus
meningitis the methods of treatment have been ever changing and
many diametrically opposed therapeutic measures have been adopted
from time to time. Among the most prominent and characteristi-
cally different methods have been: a stimulating and tonic method
pursued because the disease was one of "utter prostration ;" vigorous
antiphlogistic measures such as the use of mercury in large -quantities
or of repeated bleeding, and sedative measures such as the use of
large doses of opium.
Emetics were held to be useful if not indispensable in the early
stage of the disease and Vieusseux in the first epidemic said "The
first principle and often the only remedy was tartar emetic." A half
grain was given every ten minutes to produce full and free vomiting
and the dose was repeated five or six times or more often according
to its effect. "Sometimes it arrested the vomiting, the fever and
the pain in the head immediately, and was generally sufficient for
the cure." Some writers were less sanguine as to the beneficial
effects of emetics and a few indeed condemned their use. Nearly
all writers advised them during the early period of the disease with
the idea in mind "to scatter the congestion which produced the exu-
dative inflammation of the cerebrospinal membrane, and to aid in
eliminating the morbid material of the disease."
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TREATMENT OF MENINGOCOCCUS MENINGITIS 143
In the early epidemics, with the exception of mercury which was
not then regarded as a purgative, it was the general consensus of
opinion that there was no room for cathartics in this disease. They
were even regarded as harmful to the patient. One writer says
"The constipation, if any exists, yields usually without purgative
medicine; constipation is in fact and as far as it goes a sign of health
rather than of disease."
In such an extremely fatal disease and one in which but little hope
was held of its arrest by natural means, active measures were used
frequently and boldly. Venesection was employed by all. Large
quantities of blood were taken from the arm or jugular vein at one
time or several bleedings were made in quick succession. As much
as 48 and 44| ounces of blood have been removed from an adult on
separate occasions. In a child, 48 ounces of blood were taken by
cups from the neck and occiput and 26 ounces from a vein in the arm
within eighteen hours. Local blood-letting did seem to be followed
by some good results, especially in the sthenic cases. The effects
were not regarded as satisfactory although in many cases there was
noted an improvement in the pulse rate and relief from the excruci-
ating pain in the head. But the general impression prevailed that
while blood-letting afforded considerable relief to the patient in the
early stages, it was a disappointment from a curative point of view.
Cold to the head and spine, leaches to the head, blisters and dry
and wet cupping were used for the relief of the severe pain and afforded
some relief and comfort to the sufferers. Great stress was laid upon
the necessity for maintaining the bodily heat and for keeping the
skin moist. Warm and hot baths, bottles of hot water, billets of
wood heated in boiling water and wrapped in flannels, hot infusions,
etc., were considered of great help in combating the violent symptoms
as well as the symptoms of collapse.
Alcohol, opium, iodide of potassium and other drugs were used
generously and their usefulness and indications were the subject of
much discussion. There were many who believed that alcoholic
stimulants were absolutely necessary* "to support the vital energy,
to raise the patient from his depressed state and to hold him up until
the disease passes off." Other writers, especially the European
writers, were more skeptical of the use of stimulants and condemned
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144 KENNETH D. BLACKFAN
their liberal and indiscriminate administration. Opium enjoyed the
reputation of being a specific for meningococcus meningitis. It was
given by some in small doses and by others in large doses; although
its curative effects were grossly overestimated, it was observed that
"the pain and spasm subsided, the skin became warmer, the pulse
fuller and the entire condition of the patient became more hopeful"
after its administration. Iodide of potassium was extensively
employed to promote absorption during the late stage of the disease.
Among the active measures advised in the treatment in the early
epidemics, mercury perhaps was used more generally than any other
medicine. Mercury was given by mouth or inunction even to the
point of salivation, but as with the other measures adopted, we find
a diversity of opinion regarding its beneficial effects. Other measures
such as the proper use of a nutritious diet and of tonic medicines
received their share of attention.
Still6 concisely stated the opinions regarding the peculiarities of
the disease and its treatment which were held during the early history
of the disease. He said:
In epidemic meningitis as in other acute and especially epidemic diseases,
many cases are fatal from the outset; the first symptoms of the attack are
the first phenomena of death; on the other hand many are so slight as
scarcely to require medicinal interference for their cure. But the event
of many others is determined by the appropriateness and the opportuneness
of the treatment .... but their successful application depends upon
the sagacity of the physician.
The use of the more modern measures, repeated lumbar puncture,
the intraspinous injection of antiseptics, permanent drainage, etc.,
in the treatment of meningococcus meningitis will be discussed
later.
THE MENINGOCOCCUS AND ITS STRAINS
The micrococcus intracellularis meningitidis was first accurately
described by Weichselbaum in 1887 as a Gram-negative coccus,
usually occurring in pairs. Prior to, as well as subsequent to his
report, it had erroneously been stated that this organism was Gram-
positive. The meningococcus, except for older laboratory strains
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TREATMENT OP MENINGOCOCCUS MENINGITIS 145
which can thrive on plain agar, grows only on media enriched with
blood, ascitic fluid or starch. The colonies are round, perfectly
lenticular with smooth edges, are translucent by transmitted light
and a bluish gray by reflected light. They are rarely over 2 mm. in
diameter. The optimum temperature for growth is 37.5°C. ; compar-
atively slight variations from this will retard the growth on culture
media. The meningococcus is sensitive to drying and cultures rarely
survive longer than seven days. Recently it has been demonstrated
that reduced oxygen tension greatly facilitates cultivation of the
meningococcus.
Like the gonococcus, the meningococcus ferments dextrose and
maltose. For a time it was difficult to differentiate these two
organisms except by noting their origin. They are, however, distinct
as was rather drastically proven by injecting cultures of each into
the urethra of two healthy men. The individual receiving the gono-
coccus developed gonorrhea while the one receiving the meningo-
coccus had no reaction. These two organisms are frequently agglu-
tinated by the same sera, but Ellis in 1915 demonstrated that the
immediate agglutination reactions are specific, i.e., that even at
dilutions of 1:2, meningococcus sera would only agglutinate the
meningococcus immediately or within one-half hour while after an
interval of an hour or so the gonococcus would also be agglutinated.
In 1909, Dopter isolated an organism from the spinal fluid of a
patient with meningitis that had all of the morphological and cultural
characteristics of the meningococcus but was not agglutinated by
the usual meningococcus serum. This organism he called the
parameningococcus. Wollstein not only corroborated Dopter' s obser-
vation but found that there were a number of intermediate strains
which although similar could be distinguished serologically from the
normal and the parameningococcus. Later, still further variants
were reported. Gordon immunized a series of rabbits with 34 cultures
of meningococci collected during the early part of the war and carried
out agglutination and absorption reactions with his strains. He
found that they fell into four groups which he designated as I, II,
III and IV. I and III, and II and IV were closely related, and their
sera showed cross agglutination but they could be separated by
absorption tests. Groups I and II were the more common. Ellis
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146 KENNETH D. BLACKFAN
by more or less similar methods described three groups. Nicolle
and his co-workers at the Pasteur Institute reported four divisions of
meningococci, namely, A, B, C and D, of which B was identical with
Dopter's parameningococcus. At the Rockefeller Institute two
main groups of meningococci, the normal and paranormal and two
or more intermediates are recognized. Many attempts have been
made to classify the groups described by these various authors. In
Davison's experience, the Pasteur A, Gordon's I and III and the
Rockefeller Institute paranormal are agglutinated by the same sera
and the Pasteur B, Gordon's II and IV and the Rockefeller Institute
normal by the same sera. These two main divisions of four groups
each are those most frequently encountered. It is interesting that
in England in 1914 and 1915 the members of the first group were
the more common, not only in the army but also among the civilian
population while during 1917 and 1918 the members of the second
group were the more frequent, possibly indicating that an immunity
had arisen against the members of the first group. The Pasteur C
and D, Gordon's III and IV and the Rockefeller Institute inter-
mediates are comparatively rare.
THE DISCOVERY OF A SPECIFIC SERUM
The discovery of the meningococcus and the gradual development
of the routine employment of lumbar puncture resulted in a clearer
understanding of meningococcus meningitis and made it possible to
establish an accurate diagnosis, which before had been impossible.
In spite of these important observations, no therapeutic measures
were suggested which in any way influenced the heavy mortality
until the discovery of antimeningococcus serum. The production
of the specific serum is the direct result of the world wide epidemic
which continued almost without cessation from 1904 to 1910. Almost
simultaneously Jochmann in Germany and Flexner in New York
studied the production of specific immune sera which would protect
small animals against infection with meningococci. They could
protect small animals and Flexner was able to cure meningitis, arti-
ficially produced in the monkey by the intraspinous injection of an
immune serum which he prepared. Antimeningococcus serum for
use in human beings was produced on a large scale by the immuni-
zation of the horse.
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TREATMENT OF MENINGOCOCCUS MENINGITIS 147
In 1906, Jochmann reported the results with 11 cases of meningitis
in human beings treated by the intraspinous injection of serum, and
in 1907, Kolle and Wassermann who also had prepared an immune
serum reported the results of treatment in 57 cases of meningococcus
meningitis. In 1908, Flezner and Jobling published a comprehensive
report of serum treated cases. There was an appreciable alteration
in the death rate in all cases treated when the injection was made into
the subarachnoid space. Park in 1905 had used an antimenigo-
coccus serum which he had prepared in the treatment of 20 cases by
subcutaneous injection. The results were not satisfactory. The
serum was at first injected subcutaneously and intravenously as
well as intraspinously , but later the intraspinous method alone was
employed by all. Thus, as the direct result of scientific research, a
satisfactory specific serum therapy was finally developed. For
more than fifteen years antimeningococcus serum has now been used
and its efficacy is universally admitted.
THE PREPARATION OF ANTIMENINGOCOCCUS SERUM
The production of antimeningococcus serum was first accomplished
by Jochmann by injecting cultures of the meningococcus heated to
60°C. for one-half hour intravenously into horses. Increasing doses
of killed organisms were injected at stated intervals and later the
horses were injected with cultures of living meningococci. Kolle
and Wassermann in addition to the killed and living organisms
injected the autolysate as well, as they thought the soluble products
of the meningococcus increased the potency of the serum. Flexner,
who used at first increasing doses of killed organisms, then increasing
amounts of autolysate and then living cultures by the combined
subcutaneous and intravenous method, finally discarded the intra-
venous method as the injections were followed by such severe and
alarming reactions and resorted to the subcutaneous injection of
cultures and autolysate alternately at seven-day intervals. Subcu-
taneous inoculations were followed by a mild febrile reaction during
which the animal ate less but did not suffer from other symptoms.
The dose was gradually increased from 1 to 2 and 3, etc., loops of cul-
tures to the amount contained in one and a half small culture bottles
and the dose of autolysate was increased to the equivalent of one and
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148 KENNETH D. BLACKPAN
one-half bottles of the cultures. Many different strains of menin-
gococci were employed in the production of Flexner's serum. As
new strains were found, they were added to those already in use in
order to have antibodies in the serum which corresponded to all the
recognized strains. Immunization in the horse is a slow process
and sera withdrawn less than six months after the beginning of
injections are apt to be deficient in antibodies. The antiserum first
used by Flexner was obtained from a horse who had* been in process
of immunization over one year. After the discovery of the two main
types of meningococci, the normal and parameningococcus, repre-
sentatives of these two types were used in the preparation of sera
either in mixtures or with alternate injections of the two types. It
was learned that the employment of representative normal and
representative parameningococcus strains was not sufficient for
immunization as within each group there were organisms which reacted
weakly to the specific antibodies produced by other strains of the
same group. When the weakly reacting strains were inoculated,
antibodies were formed to which they reacted strongly. So not only
one but several strains of each group were employed for the purpose
of immunization of the horses. It is of the utmost importance that
serum used therapeutically contains the antibodies specific for the
infecting strain.
Rapid method of preparing serum
As mentioned before, from six to twelve months were required to
produce a meningococcus serum of high potency by the old method
of immunization. The increase in the number of cases of menin-
gococcus meningitis which was evident in the early days of the great
war made it imperative that a larger amount of serum would be
necessary than could be supplied by the ordinary methods of pro-
duction. For this reason and because much of the sera prepared
by the commercial houses had given such irregular and disappointing
results, the preparation of serum in large quantities was undertaken
at the Rockefeller Institute. Amoss and Wollstein have produced
a polyvalent serum of high titre. By first desensitizing the horse
before employing the full inoculation of the culture, according to the
technique of Briot and Dopter, the severe reactions usually occur-
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TREATMENT OF MENINGOCOCCUS MENINGITIS 149
ring after intravenous injection were avoided. Three successive
cultures of representative strains of meningococci and their autolysate
were injected intravenously at regular intervals. Specific immune
bodies appear early in this serum and increase rapidly. A potent
serum was produced in eight or twelve weeks instead of the eight
or twelve months which the older method required. This serum has
been successfully employed in the treatment of meningococcus
meningitis.
Many sera of high potency are prepared and can be obtained. The
most satisfactory, however, have been those prepared by research
laboratories: the Rockefeller Institute in this country and the Pasteur
Institute in France. The Lister Institute now prepares a polyvalent
serum in which the horses are immunized by the four representative
strains of meningococci differentiated by Gordon. The experience
of the. British forces with commercially prepared antimeningococcus
sera should not be forgotten for it emphasizes the necessity for the
standardization of sera prepared by commercial laboratories. Sera
should not only contain antibodies for the four representative strains
of meningococci and be of high titre but they should not be colored
by hemoglobin compounds and a harmless chemical preservative
should be used. Tricresol not only will prevent contamination of
serum which has been collected and bottled in a sterile manner but
it has an analgesic effect also.
Standardization of serum
Different opinions are held regarding the methods for determining
the therapeutic value of antimeningococcus serum, as it is much more
difficult to determine the potency of an antibacterial serum than
of an antitoxic serum, such, for instance, as diphtheria antitoxin.
Krauss and D5rr believe that the chief action of the serum depends
upon its antitoxic properties; Jochmann, Flexner and Wassermann
believe that the chief action of antimeningococcus sera is to increase
phagocytosis of the microorganism, to destroy the meningococcus
and to neutralize toxins. It has been shown that antimeningococcus
serum probably contains bacteriolysins, opsonins, antiendotoxins,
agglutinins, precipitins and complement fixation bodies. The
presence of many of these does not necessarily have any influence on
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150 KENNETH D. BLACKFAN
the therapeutic activity of the serum. Different writers have sug-
gested the use of various tests to fix a proper standard for antimenin-
gococcus serum but the difficulty in using any one criterion as a
standard for measuring the several forms of activity is apparent.
The opsonin and the complement fixation methods have practically
been discarded as it is not possible to determine by them the antibodies
representing the different types of meningococci. The an tiendo toxic
standard as applied by Dopter, Wassermann, Krause, Leuchs and
others has been criticized by Gordon on the ground that the content
of endotoxin was too low to be used for purposes of standardization.
Before this method becomes an acceptable method of standardizing
meningococcus serum, the presence of a meningococcic endotoxin
must definitely be proven. The workers in the Hygienic Laboratory
in Washington have failed so far to confirm the presence of an anti-
endotoxin in the sera which they have tested (Leak). The protec-
tive power of antimeningococcus serum for small animals has been
used as a method of standardization. The test is made by mixing
varying amounts of a meningococcus emulsion with a definite quan-
tity of immune serum and injecting this mixture into the peritoneal
cavity of animals. Hitchens and Robinson have described a protec-
tion test with mice and believe that the animal protection test is more
nearly indicative of the potency of the serum than is the agglutina-
tion test or the complement fixation test. They also suggest that
the amount of serum necessary to protect against one minimum lethal
dose of culture be used as a uniform standard for antimeningococ-
cus sera. Amoss and March were unable to confirm their results
and regard the protective power of antimeningococcus serum for
laboratory animals as a variable and unsuitable index of its value.
At the present time the determination of the agglutinin content of
sera is considered, in this country, the most reliable method for the
standardization of antimeningococcus sera. Although the part played
by agglutinins in overcoming infection is not known, it has been
demonstrated that a high agglutination titre is usually accompanied
by a strong complement binding power and a high opsonic index.
It is therefore reasonable to suppose that a serum possessing these
properties has a relatively high antibody content. Practical experi-
ence has shown that sera showing a high agglutination titre for the
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TREATMENT OF MENINGOCOCCUS MENINGITIS 151
meningococci isolated from patients' cerebrospinal fluid as a rule
give good therapeutic results. On the other hand, as the French
writers have pointed out, satisfactory clinical results may at times be
secured by the use of sera with a low agglutination power. At present
it must be admitted that the methods of determining the potency of
antimeningitis sera leave much to be desired. The New York State
Board of Health requires that serum should be prepared from four
properly chosen cultures of meningococci and a standard value based
on the agglutination titre. Serum used in treatment of this disease
should contain antibodies for the two main types of organisms and
the subtypes.
Serum for diagnostic purposes
Polyvalent and monovalent antimeningococcus sera are used, in
the laboratory, for identifying the meningococcus, for determining,
the various types of meningococci and for testing the potency of
different sera. The therapeutic polyvalent serum prepared in the
horse is used for this purpose. Monovalent sera are made in young
rabbits according to two methods. Amoss prepares his serum by
suspending a sixteen-hour growth of the meningococcus in 10 cc. of
0.8 per cent salt solution. Of the suspension 0.1 cc. is diluted to 2
cc. and injected intravenously. The same dose with a fresh culture
is repeated on the second day and one-eightieth of a culture on the
third day. After five days, one-eightieth of a culture, then one-fif-
tieth and finally one-twenty-fifth on the third day are injected.
Two days later the rabbit is sacrificed and the serum collected. Hines
prepares his serum by injecting increasing doses of an emulsion of
meningococci killed by heat. The serum is preserved with phenol.
By either one of these methods satisfactory sera for identification of
the type of meningococcus by the agglutination test are prepared.
The reader is referred to text books for a description of these tests.
DIAGNOSIS OF MENINGOCOCCUS MENINGITIS
In the early stage of meningococcus infections before the localiza-
tion of the organism in the meninges with the resulting symptoms of
meningeal irritation, diagnosis is well nigh impossible except in the
presence of an epidemic. Even with the aid of blood cultures diag-
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152 KENNETH D. BLACEFAN
nosis before the onset of meningitis is most difficult. The symptoms
at the onset may be so mild and so insidious that several days may
elapse before the true nature of the infection is recognized, or it may
be so severe and fulminating that the patient dies within the first
twelve to thirty-six hours. A sudden onset with chills, marked pros-
tration and headache, together with vomiting, is highly suggestive
of meningococcus meningitis, especially when there is a petechial or
purpuric rash. The characteristic but by no means pathognomonic
eruption occurs at some time or other during the course of the disease
in about 50 per cent of the cases. As it is not a constant finding, it
cannot always be relied upon. Occasionally one sees patients within
the first few hours of the onset without meningeal symptoms when
petechiae are present but in the majority of cases meningococci will
be found in the cerebrospinal fluid if it is examined even at such an
early period. Although a tentative diagnosis of meningococcus
meningitis may be made when a patient who previously has been
well has an acute onset with headache, vomiting, a chill or convulsions
and who presents the signs of meningeal irritation (cervical rigidity,
hyperaesthesia, Kernig's sign, Macewen's sign or a tense and bulging
fontanelle), the final diagnosis always rests on the actual demonstra-
tion of meningococci in the cerebrospinal fluid. A differentiation
between meningitis due to the pneumococcus, streptococcus, staphy-
lococcus aureus and other organisms and between other diseases,
pneumonia, typhoid fever, typhus fever, cerebral abscess, simulating
meningococcus meningitis, can be made in no other way than by
lumbar puncture and the demonstration of the organism. A clinical
diagnosis without bacteriological proof is always open to criticism.
In the very early stages the cerebrospinal fluid may appear clear
yet the meningococcus can often be demonstrated in both stained
• smears and cultures. As the disease progresses the cerebrospinal
fluid becomes turbid and intracellular and extracellular Gram-nega-
tive diplococci can usually be made out readily. In almost all cases
they will be found after prolonged search. In the subacute and chronic
cases the demonstration of the meningococcus may be attended with
great difficulty. I have seen patients in whom it was impossible to
demonstrate the organism either by smear or by culture in the cere-
brospinal fluid at the first puncture but in subsequent punctures
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TREATMENT OF MENINGOCOCCUS MENINGITIS 153
they appeared in large numbers. In some patients, particularly
children, when the disease has been present for some days, there may
be an obstruction to free communication between the spinal sub-
arachnoid space and the interior of the ventricles. In these circum-
stances it sometimes happens that no fluid can be obtained by lumbar
puncture or the fluid that is obtained may be free from meningococci
whereas the ventricular fluid contains the organisms in large number.
Only by means of a ventricular puncture is it possible to obtain cere-
brospinal fluid and so demonstrate meningococci. This may readily
be accomplished in children with an open fontanelle which is the
age at which the severance of the communication is more likely to
occur. Relatively few cases are seen in which meningococci cannot
be demonstrated by persistent search in the cerebrospinal fluid
removed from the ventricle or lumbar subarachnoid space at dif-
ferent times. That such cases do occur and recover after specific
therapy should be borne in mind. In a series of 202 cases of menin-
gococcus meningitis which I have seen during the past few years,
there were 13 cases in which meningococci were not demonstrated
in smear or by cultivation. Corroborative evidence of the existence
of meningococcus infection may be had by demonstrating the
organism in the rhino-pharynx of such patients. The following
case is cited as an example:
J. D., white, age seven years. Patient was admitted to the Harriet
Lane Home on the 114th day of the disease, with a history of recurrent at-
tacks of fever, headache, vomiting, drowsiness, muscular rigidity and opis-
thotonus. On admission, examination revealed nothing abnormal except
emaciation, hyperactive reflexes and slight engorgement of the vessels of the
fundi.
Temperature, 99.6°F, white blood cells, 16,700. Pirquet negative.
Wassennann negative. Urine normal. Blood culture sterile. Throat
culture showed meningococci.
Spinal fluid: No increase of pressure, slightly cloudy, 2800 white blood
cells; 76 per cent polymorphonuclears. Pandy strongly positive, Wasser-
mann negative. No organisms found in smears. Culture sterile.
Treatment: Six lumbar punctures were done and an timeningococcus serum
injected three times. The spinal fluid gradually became dear, cell count
fell to 32 per cubic millimeter. Pandy test remained positive. Repeated
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154 KENNETH D. BLACKFAN
examinations failed to show organisms in smears and repeated cultures were
sterile. The patient was apparently well 122 days after the onset of the
disease.
PROPHYLACTIC MEASURES IN MENINGITIS
Epidemiological studies of meningococcus meningitis have estab-
lished without doubt that the disease is spread by direct contact from
one person to another, as is the case with diphtheria, poliomyelitis,
etc. More than twenty years ago Councilman, Mallory and Wright,
Kief er and others demonstrated that the meningococcus is present in
the rhino-pharynx of patients suffering from meningococcus menin-
gitis. In 1901, Albrecht and Ghon demonstrated its presence in
healthy persons. Since then it has been generally accepted that the
disease is spread by means of the rhino-pharyngeal secretions that
harbor the meningococci. Therefore, from the standpoint of the
management of meningococcus meningitis, prophylaxis may be said
to equal in importance specific serum treatment. As ill persons are
usually confined to their beds, they are of menace only to physicians,
to attendants and to other patients and do not become a menace to
others until the convalescent stage.
Meningococcus carriers
The healthy carrier is the greater menace to the community. The
disease is spread by those who have suffered from the disease, and by
those who have never been ill. The meningococcus may remain
in the rhino-pharynx of a carrier for a variable length of time and
for that reason two classes of carriers can be distinguished, the acute
or transient carrier and the prolonged or chronic carrier. Attendants
and relatives constitute the larger percentage of the acute carriers,
and usually the meningococcus remains in the rhino-pharynx for
only a short period of time. It may be found at one examination and
not at subsequent ones. The British Medical Research Committee
found that of 119 people who had been in contact with meningitis
patients, themselves not being ill, 94 harbored organisms of the same
type as had caused disease in the patient with whom they had been
in contact. The chronic carrier is different. He has usually suffered
from the disease himself and the organism persists for months, even
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TREATMENT OF MENINGOCOCCUS MENINGITIS 155
years, and while it occasionally disappears, it subsequently reappears.
The spread of the meningococcus, an organism which does not with-
stand, easily, exposure to air, is accounted for by chronic carriers.
These are in all probability responsible for the spread of the disease
from place to place and for the causation of epidemics. If it were
not for them the disease might readily die out. The cycle of events
which leads to contamination and to infection has been summarized
by Flexner as follows: "A meningococcus carrier is introduced into a
group of persons of the more susceptible ages. Of the latter a certain
number become contaminated through aspirating the rhino-pharyn-
geal secretions which he ejects. Of those thus contaminated a vari-
able number actually become infected and develop meningitis while
a larger number are converted either into temporary (evanescent)
or more enduring (chronic) carriers. The patient during the acute
illness and for an indefinite period while convalescent is also a carrier.
Hence the number of carriers produced exceeds the number of cases
of infection, from which it may be concluded that the individual sus-
ceptibility to epidemic meningitis is low." It has been shown by a
number of workers (Mayer) that the percentage of healthy carriers
both in the civil population and in garrisons is generally about 3 per
cent. The constant occurrence of sporadic cases of meningococcus
meningitis is thus readily explained. There must be subsidiary fac-
tors, however, to explain the occurrence of local and general epidemics.
It is difficult to account for the sudden occurrence of a widespread
epidemic of meningitis in a city in which meningitis has been en-
demic for years. An alteration of the type and virulence of the
bacterium or the introduction of a new type of increased virulence
suggest themselves as explanations but they are explanations with-
out proof.
Hygienic measures
The regulation of the factors that produce local epidemics con-
stitute the more important hygienic measures which should be ob-
served in the management of patients with meningococcus meningitis.
These factors are chiefly overcrowding and poor ventilation. Proper
ventilation must be maintained at all costs and the prevention of
overcrowding is imperative. By these measures especially in insti-
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156 KENNETH D. BLACKTAN
tutions, in barracks and on ships the risk of the contamination of
persons by contact with carriers is greatly lessened. The rise in the
incidence of the disease during the cold and damp months of the year
undoubtedly is to be explained by the tendency of individuals to
congregate together in poorly ventilated and overheated rooms. In
a British naval barrack during the month of October, there were 23
cases of cerebrospinal fever, the number of cases immediately fell
to 6 for November and 2 for December with the order that the windows
should be open day and night and the hammocks hung not closer
than every 2\ feet (Rolleston). Free ventilation, isolation and a
proper amount of space are as necessary for the treatment of patients
with meningococcus meningitis as for the prevention of the disease.
Attention should be given to the prevention of overfatigue and the
control of rhino-pharyngeal infections — factors which have a tendency
to favor the spread of the disease. The proper observing of these
principles is of particular importance during time of war and in epi-
demic areas where there are large numbers of individuals crowded
together in barracks improperly ventilated. It was shown by Mayer
and his colleagues that there were 2.46 per cent carriers among 1911
soldiers in barracks during epidemic free times whilst the Medical
Research Committee found 8.53 per cent among 1629 soldiers who
had been in contact with 60 cases of meningococcus meningitis.
The prevention of infection of attendants in charge of patients
with meningococcus meningitis is chiefly concerned with the dis-
charges from the rhino-pharynx. It is advisable that patients be
isolated either in separate cubicles or by the less expensive method of
separating the beds by intervals of 2\ feet and hanging sheets between
them. The attendants should not expose themselves to the breath
of the patients; they should be protected by wearing caps, gowns and
mouthpieces when caring for patients. Nurses should thoroughly
cleanse their hands with soap and water and a disinfectant solution
after each contact with patients and with all articles used by patients.
The discharges from the nose and throat, the conjunctivae, and
herpes, and excreta should be destroyed. All articles which come in
contact with patients should be kept separate and thoroughly disin-
fected. Cerebrospinal fluid and the apparatus used in giving treat-
ments should receive special care and sterilization. Cultures should
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TREATMENT OF MENINGOCOCCUS MENINGITIS 157
be taken at stated intervals from those in attendance on patients to
be sure that they have not become carriers. Convalescent patients
should not be discharged from quarantine until it has been proved
that meningococci are not present in the rhino-pharynx.
Prevention of the spread of meningococcus meningitis depends on
the detection of carriers, their isolation and their treatment. Hie
question of general examinations for the detection of carriers of the
meningococcus has received much attenton especially during the
epidemic which occurred among troops during the late war. Cer-
tain investigators (Flexner, Parkes, etc.) believe that the incidence
of the disease was lower among the troops in which routine search
for carriers had been carried out, whilst others, notably Galambos
Klinger, Rouman, etc., believe that the incidence of the disease is
not influenced by the detection and segregation of the healthy car-
riers. The bacteriological control of carriers with their detention
and proper treatment is the only means of properly checking and
preventing the spread of the disease. Indeed, the disease might be
exterminated if it were possible to detect and isolate all the carriers
of the meningococcus. The difficulties, however, are too great at
the present time to carry out such drastic measures as this would
entail. The search for carriers among contacts should, however, be
carried out whenever meningococcus meningitis arises and the car-
riers should be isolated and proper treatment instituted. The car-
riers should be kept isolated until three successive negative cultures
at five-day intervals have been obtained. A regulated period of
quarantine is quite useless and effective control can only be had by
bacteriological proof of negative cultures. The bacteriological detec-
tion of carriers necessitates careful technique in the making of
the cultures and the cultivation of the meningococcus, the identifica-
tion and differentiation from other Gram-negative cocci, which fre-
quent the rhino-pharynx, agglutination tests and the recognition of
tie different types.1
The transient carrier usually becomes free from meningococci in a
week or ten days and the number of colonies grown from the rhino-
1The reader is referred to the standard technique of meningococcus carrier detection
adopted by the Medical Department of the United States Army and Navy and the United
States Public Health Service for detailed information regarding the methods in use.
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158 KENNETH D. BLACEFAN
pharynx is much fewer than is the case with the chronic carrier.
Carriers should be separated from those who have become nega-
tive in order to prevent reinfection and carriers should be separated
according to the type of organism to prevent cross infection. The
chronic carrier is the greatest menace to the community and offers
the greatest problem in treatment. As Flack has shown, the persis-
tence of the carrier state varies within fairly wide limits. Among
185 carriers, 124 were known to have been in contact with a case of
meningitis or another carrier, whereas 61 had not been in contact
either with a patient or with a carrier. The average duration among
the former was 4.65 and among the latter 3.68 weeks. Twenty per
cent of the 185 carriers became free of organisms within the first
two weeks, 52 per cent within the first four weeks and 5 per cent
persisted beyond twelve weeks. It was noticed that sunshine and
dry weather apparently influenced the rapidity with which the car-
riers became free. In February and March, the rate of discharge of
carriers from isolation was slow whilst with the coming of sunshine
and dry weather in April the rate of discharge was increased.
Although in the great majority of carriers the rhino-pharynx is
normal, the meningococcus persists for a longer time in those who
are subject to inflammatory conditions of the rhino-pharynx and
accessory sinuses.
Treatment of carriers
It is clear that the meningococcus disappears from the rhino-pharynx
spontaneously in the overwhelming majority of carriers. Fresh,
dry air and sunshine undoubtedly have an important and favorable
influence on the rapidity with which the meningococci disappear.
Chronic inflammatory conditions of the rhino-pharynx require appro-
priate treatment. Aside from these measures the efforts to hasten
the disappearance of the meningococci in convalescent patients and
carriers by antiseptics have been most discouraging. As the menin-
gococcus is one of the least resistant of the pathogenic organisms to
disinfectants, it seems surprising that a means of destroying it has
not been found. The reason probably is not so much its resistance
to the various antiseptics which have been employed as the difficulty
in bringing the solution actually in contact with the organism in the
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TREATMENT OF MENINGOCOCCI] S MENINGITIS 159
rhino-pharynx and accessory sinuses. Strong antiseptics by injuring
the mucous membrane and setting up inflammatory conditions actually
prolong the carrier state (Fulloch). Many methods with mild anti-
septics have received careful trial. Swabs, douches, sprays and
vapors have been employed. Antiseptics which destroy the men-
ingococcus in vitro fail to destroy the organisms when they are used
in the human being. Colebrook and Tanner in tests made upon the
meningococcus contained in a film of nasal secretion found that weak
carbolic acid solutions and a 5 per cent suspension of "argentine"
killed the meningococci. The substance was non-irritating to the
mucous membrane and temporarily rendered the carrier free from
meningococcus; the organism, however, reappeared in the majority
of cases. Attempts with zinc sulphate and pyocyanase have also
been unsuccessful. Kutscher after the recommendation by Kolle
and Wassermann reported satisfactory results with the nasal sprays
of dry antimeningococcus serum. Their results were not confirmed
by other observers. Many different substances have been tried in
the form of vapors and inhalants. Compounds of iodine, guaiacol,
thymol and alcohol were tried by Vincent and Vellot. These like-
wise have not been followed by very satisfactory results. Sophian
found that a 0.5 per cent hydrogen peroxide solution used as a nasal
spray and gargle rendered the rhino-pharynx free from meningococci
in the majority of cases within a few days to two weeks. Normal
salt solution and potassium permanganate solution have likewise been
tried, but as has been the case with the other methods which have been
employed, although the organism tends to disappear, it usually reap-
pears after a few days; Worster-Drought and Kennedy used exten-
sively a solution of chloramine T of 2 per cent strength diluted with
warm water just before use. The solution was applied for three days
before cultures were taken. If positive cultures were then obtained,
a second course of treatment was usually given. They concluded
from their results that chloramine T used as a nasal douche is of
definite value in the treatment of meningococcus carriers. It should
be carried out, however, under personal supervision. Inasmuch as
chloramine compounds do not cause albuminous precipitation in
secretions, it would seem that they might find a useful place in the
treatment of carriers. The value of chloramine T, however, has not
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160 KENNETH D. BLACKPAN
been substantiated by other workers. Inhalation chambers as used
by Kuster and automatic spraying apparatuses suggested by Gordon
and Flack, in which chloramine T and zinc sulphate were used
have given only fairly satisfactory results. Dichloramine T as
suggested by Dunham and Dakin dissolved in eucalyptol in 2 per
cent solution has also been used. It should be borne in mind that
inasmuch as so many different measures cause the meningococcus
temporarily to disappear from the rhino-pharynx a sufficient length
of time should pass between the cessation of treatment and the taking
of swabs before an individual is discharged and regarded as free from
meningococci. Although there is some difference of opinion as to
the value of these different local antiseptics in the treatment of men-
ingococcus carriers, the majority of authors regard local treatment
as a valueless procedure.
The specific treatment of meningococcus carriers has lately re-
ceived considerable attention. This has been carried out by means
of active immunization with vaccines given subcutaneously in doses
of from 50,000,000 to 2,000,000,000. The injection of the vaccine
used by Colebrook and Tanner gives very slight constitutional dis-
turbances which pass off quickly. In their series five out of the ten
carriers became negative and the other five cases were unaffected.
The meningococcus later reappeared in the negative cases. It is
scarcely to be expected that the immunization of carriers would have
any effect upon the meningococci in the rhino-pharynx inasmuch as
recently shown by Gates the blood serum of chronic carriers does
already contain agglutinins.
Passive immunity as a prophylactic measure
The production of passive immunity by the injection of antimen-
ingococcus serum and of active immunity by treatment with
vaccines has been advocated as a prophylactic measure by a num-
ber of different workers. The experiments of Jochmann in 1906 when
he produced passive immunity in animals by the use of serum sug-
gested to him that this might be a useful measure in the prevention
of the disease. With the exception of Ruppel who recommended its
use in 1907, the method was not employed extensively until the 1912
epidemic in Texas. Sophian advised its use as a prophylactic measure
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TREATMENT OF MENINGOCOCCUS MENINGITIS 161
among the attendants who came in direct contact with the patients
with meningococcus meningitis. He recommended the subcutaneous
injection of 10 to 20 cc. of serum. The dosage is necessarily arbi-
trary and depends on the serum used. The duration of the immunity
afforded was considered one month and in Sophian's cases only one
of the persons inoculated contracted the disease. He was a porter
who developed meningitis six weeks after the preventive treatment.
The chief objection to the prophylactic use of antimeningococcus
serum is that the passive immunity conferred is only temporary.
The occurrence of serum sickness and the danger of anaphylactic
shock if subsequent injections of serum are necessary should not be
considered as contraindications to its use any more than they are
contraindications to the use of diphtheria or tetanus antitoxin pro-
vided the antimeningitis serum is an effective prophylactic That
there is doubt of this is shown by the fact that in the epidemics of the
world war it was not extensively employed.
Active immunity as a prophylactic measure
Active immunization by means of meningococcus vaccines had
not been used extensively before the war. It has been known for a
long time that a certain degree of immunity develops during the active
stage of meningitis. This has been demonstrated by complement
fixation tests, by agglutination tests and by the estimation of the
opsonic index. These same tests have shown that the immune bodies
increase in laboratory animals after vaccination. Because of these
facts and because of the analogy of meningococcus meningitis to other
bacterial diseases, Sophian employed vaccination as a prophylactic
measure in the epidemic in Texas in 1912. The results were incon-
clusive as most of the vaccinated persons did not complete the series
of injections. Later Sophian and Black studied the agglutination
and the complement fixation of the serum of ten students who had
been vaccinated with two or three doses of a monovalent vaccine.
The doses given were 500,000,000 to 2,000,000,000 organisms at
seven-day intervals. Following the vaccinations severe constitu-
tional reactions occurred. They found the agglutinin titers of the
sera of their vaccinated subjects to range from 1:200 to 1:1500.
Complement was fixed in serum dilutions up to 1:250. Comple-
ifKDicDfE, vol. I, WO. 1
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162 KENNETH D. BLACKFAN
ment fixing antibodies were found in low dilutions in the serum of
seven of these men after an interval of two years. Sophian and Black
refer to Hall's experience in Kansas City in the vaccination of about
280 persons in families in which meningitis had occurred. A number
of doctors and nurses were likewise vaccinated. In no instance did
the disease occur subsequent to vaccination.
During the war preventive vaccine therapy was extensively em-
ployed. Greenwood believes from his experience with 4000 men inoc-
ulated twice, first with 250,000,000 to 300,000,000 and after a week
with 1,000,000,000 bacteria, none of whom contracted the disease,
that vaccination is a valuable prophylactic procedure. Gates using
a vaccine prepared from the two main types of meningococci vac-
cinated 2700 soldiers at three-week intervals with 2,000,000,000,
4,000,000,000 or 8,000,000,000 cocci. He found that these doses
rarely caused more than a mild reaction except in certain susceptible
individuals. In the severe reactions the symptoms simulated the
onset of meningitis but they lasted only a few hours. He demon-
strated specific agglutinins for meningococci in the blood serum of the
vaccinated men. Among the men treated by Gates two patients
who had, probably, been vaccinated during the incubation period of
the disease developed meningococcus meningitis. Another patient
developed meningitis at a time when immunity should have been
established. During a period of four months while under observa-
tion, no cases of meningitis were known to have occurred among the
others who were vaccinated. Chalmers and O'Farrell working in the „
Soudan report somewhat similar results using much smaller doses.
They began with 5,000,000 and never exceeded 100,000,000,
Treadgold using 50,000,000 and one week later 100,000,000 organisms
vaccinated 79 carriers, none of whom developed meningitis and Aaser
gave two doses of 300,000,000 organisms each at five-day intervals to
1200 soldiers. No vaccinated soldiers developed the disease. Re-
cently Whitmore and his colleagues, using a polyvalent lipo-vaccine,
inoculated 55 men with 40,000,000,000 and 80,000,000,000 organisms
subcutaneously in one or two injections. They reported that the
use of such vaccines diminish the risk of reaction. In the first days
after vaccination agglutination formation was observed against three
of the vaccine strains. Although the evidence thus far collected
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TREATMENT OF MENINGOCOCCUS MENINGITIS 163
would seem to favor prophylactic meningococcus vaccination, further
studies need to be carried out, on account of the resistance to the
disease which most persons possess, before it can be stated that the
measure is as important in preventive medicine as is typhoid vac-
cination. There are no insurmountable objections to its use.
TREATMENT
Specific serum therapy has established itself by tests under such a
variety of conditions and over such a long period of time that the
efficacy of this form of treatment in meningococcus infections cannot
be questioned. There is however a very considerable mortality,
in the neighborhood of 25 per cent, even when patients are treated
intelligently and energetically. It is not surprising therefore that
efforts have been made still further to improve the methods of
treatment.
The premeningitic stage of meningitis
It is becoming more and more evident not alone from clinical ob-
servation but as the result of experimental work that the first stage
of a meningitis in all probability is usually preceded by a bacteriemia.
It is generally but not invariably a transitory invasion, the bacteria
disappearing as a rule from the blood stream in a very few days.
While the older view, that the infection results from the direct exten-
sion of the organism through the cribiform plate of the ethmoid or
from the sphenoidal or ethmoidal sinuses to the base of the brain,
has not been disproven, the majority of observers are of the opin-
ion that the meningococcus gains access to the blood stream through
the upper air passages and then becomes localized in the meninges.
The question then arises is it possible to recognize meninococcus in-
fection in the premeningitic stage and if it is possible, is treatment
at that stage effective. It is very difficult to answer these questions.
Meningococci may be found in the blood in a certain proportion of
cases of meningitis. They disappear rapidly shortly after the time
of their localization in the meninges. They disappear whether anti-
meningococcus serum is used or not for it is very difficult, usually
impossible, to cultivate them from the blood even in untreated cases
after the meningitis has lasted several days. It is very likely, indeed
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164 KENNETH D. BLACKPAN
most probable, that meningococci often find their way into the blood
and are there destroyed and never become localized in the meninges.
In these circumstances the illness would be passed over as a febrile
reaction of undiscoverable origin. If blood cultures were made from
such cases, as might be done in the midst of an epidemic in an army
or navy, meningococci discovered and some form of therapy insti-
tuted, favorable results might be ascribed to this form of therapy
which were hot merited, in the same way that favorable results might
be ascribed to some form of therapy in abortive cases of poliomy-
elitis. Furthermore there are certain cases of meningococcus sepsis
in which meningeal localization never occurs. They run their course,
recovery often taking place, uninfluenced by treatment.
Intravenous serum therapy
As a result of many studies during the recent war intravenous serum
therapy has been warmly recommended by some authors or believed
to be indicated by others. These authors are Herrick, Baeslack,
Worster-Drought and Kennedy, Golden, Loch and Hebert, Hayden
and others. It is maintained that the serum should be given intra-
venously in large doses to overwhelm the infection within the first
twelve to twenty-four hours before the localization of the organism
in the meninges. When meningitis has been established it is recom-
mended that the combination of serum both intravenously and
intraspinously with repeated spinal punctures should be carried out.
The routine method outlined by Herrick is as follows: On admission
a patient presenting the early symptoms of meningococcus meningi-
tis is subjected to lumbar puncture. If the spinal fluid is cloudy,
enough is removed to reduce the intraspinal pressure to an approxi-
mate normal and a less amount of serum is at once allowed to run
into the spinal canal. If the spinal fluid is clear, no intraspinal in-
jection is made. The fluid is immediately examined. Meanwhile
the patient receives a desensitizing dose of serum. One hour later
SO to 120 cc. of serum are administered by vein, the first 15 cc. at the
rate of 1 cc. per minute. Large glass syringes are used for this, as
the flow is easily controlled and a cumbersome arrangement of tubes
and stopcocks is not necessary. In a case of ordinary severity this
intravenous dose is repeated every twelve hours until the tempera-
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TREATMENT OF MENINGOCOCCUS MENINGITIS 165
ture becomes normal, or until six or eight injections have been given.
In severe cases the serum is repeated every eight hours. If meningitis
is present or if it subsequently develops, intraspinous injections of
serum are given and repeated once in twenty-four hours until the
organisms disappear from the spinal fluid and lymphocytes make
their appearance in numbers. In Herrick's experience with large
intravenous injections of serum combined with intraspinous treatment
meningococci disappear from the cerebrospinal fluid more rapidly
than when intraspinous therapy alone is employed. Herrick believes
that when antibodies are present in the blood stream removal of
cerebrospinal fluid allows the passage of antibodies from the blood
stream into the subarachnoid space. He states that he has seen no
ill effects from these large amounts of serum intravenously. In 129
cases treated by Herrick by intraspinous method alone or with small
doses of serum intravenously the mortality was 37 per cent. In
79 cases treated with large amounts of serum intravenously and
average amounts intraspinously it was 16.4 per cent. In 138 cases
reported by Golden the mortality was 21 per cent. It cannot be
denied that the intravenous injection of serum is a logical procedure
when the disease is recognized during the premeningitic stage of the
disease, which is infrequently the case. The diagnosis at this stage
of the disease is difficult to make and except in the midst of epidemics
the vast majority of the cases are not recognized before the develop-
ment of the meningeal symptoms. After this there is usually no
bacteriemia. It is contended that the course of the disease is short-
ened and the mortality is reduced by the combined intravenous and
intraspinous method of treatment. Whether this is so only in cases
of meningitis with an associated blood infection or applies as well to
cases of meningitis without organisms cannot be proven until more
data become available. The great variation in the mortality during
an epidemic in cases treated by the same methods makes one regard
the statistics relating to the intravenous use of serum conservatively
(chart 1).
Although Herrick states that he has seen no ill effects from the
use of large doses of serum intravenously, other clinicians have not
had such good fortune. Golden found that the intravenous injec-
tion of 20 to 40 cc. were usually followed by more or less shock with
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166 KENNETH D. BLACKTAN
failure of the pulse and respiration lasting about fifteen minutes,
followed by chill and fever. The French clinicians, Sainton, Netter
and Brules, while recognizing the theoretical advantage of intrave-
nous serum, consider it a dangerous procedure and advise the use of
intramuscular and subcutaneous injections. Although many writers
refer to the reaction from the intravenous injection of serum, no fatal-
Chart I.
Very Severe Case. Death on Fifth Day in Spite op Intraspinous and Intra-
venous Treatment
ities have been recorded. I have seen two children whose death
was apparently hastened by its use and for that reason I am inclined
not to use serum intravenously except in specifically indicated in-
stances. Intravenous serum therapy in meningococcemia alone or
in those cases of meningitis in which the meningococcus persists or
reappears in the blood stream is a rational and highly advisable
procedure. A special serum freshly prepared and free from sediment
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TREATMENT OF MENINGOCOCCUS MENINGITIS 167
and preservative should, however, be prepared for intravenous use.
Too great care cannot be taken in properly desensitizing the patient
when serum is to be administered intravenously.
The question has recently been raised as to whether a preliminary
lumbar puncture should be made in all cases where meningitis is
suspected on account of the danger of producing a meningitis if there
be an associated septicemia. Weed and his co-workers found that
in animals the removal of cerebrospinal fluid during an artificial
septicemia was followed by a localization of the infection in the men-
inges. Wegef orth and Latham report that the cerebrospinal fluid was
normal in 55 out of 93 patients in whom meningitis was suspected
and in whom lumbar puncture was done. Six of these patients at
the time of puncture gave as positive blood culture and 5 of them
subsequently developed meningitis. They are of the opinion that
the logical procedure is to treat the blood infection and to avoid
spinal puncture until signs of involvement of the meninges is evident.
The experimental work of Flexner and Amoss, Austrian and others
also shows that the introduction of a foreign serum favors the locali-
zation of the blood infection in the meninges. This question is one
of practical clinical importance in the treatment of meningococcus
meningitis. It seems imperative until we have a better means of
recognizing meningococcus sepsis and an entirely accurate method
beside lumbar puncture of excluding meningitis not to delay early
lumbar puncture so that if meningitis is present patients may receive
the benefit of serum at the earliest possible treatment.
Lumbar puncture in relation to the treatment of meningitis
Although the credit of perfecting the technique of lumbar puncture
and of introducing it as a method for use in clinical medicine belongs
to Quincke, the procedure was first employed by Corning in 1885
who injected various drugs into the lumbar subarachnoid space to
induce spinal anesthesia. Wynter in 1889 also performed lumbar
puncture to relieve the cerebrospinal pressure in patients with tuber-
culous meningitis. The first patient on whom Quincke performed
lumbar puncture was suffering from hydrocephalus which had
resulted from meningococcus meningitis. Since his admirable and
complete study, lumbar puncture has been adopted generally in the
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168 KENNETH D. BLACKPAN
study and treatment of disease of the central nervous system. Punc-
ture of the subarachnoid space is generally performed in the lum-
bar region as here the spinous processes are short and widely sepa-
rated. The subarachnoid space is more spacious at this point than at
the upper part of the spinal canal and there is no danger of injury
to the cord. The site of election is between the fourth and fifth lum-
bar vertebrae, or on a level connecting the highest points of the iliac
crests. At this point the subarchnoid space is entered below the
conus medullaris through the comparatively thin layer of lumbar
muscles. Punctures at other levels while less desirable may be
made as high as the eleventh or twelfth thoracic vertebra or at the
lumbosacral interspace below. Above the level of the eleventh inter-
space lumbar puncture is seldom successful, it may indeed be danger-
ous. Lusk found above this point that the posterior subarachnoid
space was frequently obliterated by adhesions even in normal persons
and that in this situation fluid could not be obtained unless the cord
were perforated and the anterior subarachnoid space entered. From
the time when Wynter in 1889 made a small incision along the spine
of the second lumbar vertebra and introduced a Southey tube and
trocar into the subarachnoid space many forms of apparatus, many
of them elaborate, have been devised for this procedure. Simple
instruments are entirely satisfactory. The needles measure from 3
to 10 cm. in length and from 0.8 to 1.6 mm. in diameter. They
should be stiff but allow of a certain amount of flexibility. It should
be possible readily to withdraw the stylet from the needle. The stylet
should be beveled and flush with the end of the needle. The needle
should have a short bevel and should be sharp so as to pass readily
through the dura and not push it in front of it and thus prevent the
flow of cerebrospinal fluid. Strict surgical asepsis is imperative.
The needle and other apparatus should be boiled and the site of
the puncture properly prepared according to the usual surgical
methods. Great care should be taken to avoid secondary infection.
Lumbar puncture may be performed in either the upright or
recumbent posture but in meningitis it is always the conservative
plan to perform the operation in the recumbent posture. It is diffi-
cult to maintain patients in the upright position for as long a time
as is necessary and there is greater danger from collapse. It is more
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TREATMENT OF MENINGOCOCCUS MENINGITIS 169
convenient to puncture adults in bed. Infants and children may be
moved to a firm table or surgeon's carriage. The patient is moved
to the edge of the bed or table on either side with the buttocks at
the edge; the knees are flexed on the abdomen and the head and neck
are bended forward so that the whole spine is flexed to its fullest
extent. The patient must be maintained in the required position
quietly and without struggling. As the position is a matter of the
greatest importance ih facilitating the operation, a competent assis-
tant is necessary. Carelessness on the part of the assistant in main-
taining the patient in the proper position is the cause of more unsuc-
cessful punctures than is lack of skill on the part of the operator.
With the patient in the proper position, the lateral or the median
route may be selected to enter the subarachnoid space. In either
route the anatomical landmarks are the same. The puncture should
be made between the fourth and fifth lumbar vertebrae at a point
about on a line drawn between the iliac crests. The spinous process
of the fourth lumbar vertebra is located and the needle is inserted
into the interspinous space next below this. In the median route
the needle is inserted directly through the interspinous ligament and
dura-mater. The depth of the puncture varies from 1 inch in chil-
dren to 3 inches in adults. With experience a sense of touch is de-
veloped which indicates that the subarachnoid space has been entered.
The median method is preferred with children. Many clinicians
prefer the lateral method in adults as the firm interspinous ligament
is avoided and nothing except soft tissues are met until the ligamentum
subflavum is reached. The technique for this method given by Foster
and Gaskell is as follows: The needle is held with the butt resting in
the hollow of the palm, the shank steadied by the forefinger and thumb.
A point is then selected mid-way between the fourth and fifth lum-
bar spines, £ inch laterally to the middle line, and preferably on the
dependent side. The skin is steadied by the forefinger and thumb of
the left hand. The needle is pushed toward the middle line, forwards
and slightly upwards. Should the needle impinge upon the bone, it
must be slightly withdrawn and the point directed lower down. If
no bone is encountered, the point of the needle is felt to pass through
the ligamentum subflavum, which gives the sensation of piercing
gristle, and then through the dura mater. The piercing of the dura
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170 KENNETH D. BLACKFAN
mater has an entirely different feel, which has been described as
being like passing a knitting needle through sacking. When the
dura mater has been pierced, the needle can be felt free in the sub-
arachnoid space. In either method the needle should not be pushed
farther after it has pierced the dura mater, otherwise it may reach
the body of a vertebra and injure one of the anterior longitudinal
veins. Blood is then obtained. This is a much more frequent occur-
rence in children than in adults. Having entered the subarachnoid
space, the stylet is removed and the cerebrospinal fluid is permitted
to flow. The stylet should never be withdrawn completely until
after a few drops of fluid have escaped so as to permit the cerebro-
spinal pressure to be lowered gradually rather than rapidly. After
the first few drops the fluid for examination is collected in a sterile
test tube. The amount of fluid withdrawn is determined by the
rate of flow and the general reaction of the patient. Usually when
the flow reaches a rate of one drop to every three seconds it indicates
that about a sufficient amount has been withdrawn. The patient
should be observed most carefully during this procedure. Headache,
alteration in pulse and respiration are warnings that further amounts
of fluid should not be withdrawn. Although Sophian has shown that
the evacuation of cerebrospinal fluid in very large amount has but
little effect on the blood pressure, I do not believe it is a wise procedure
to withdraw the fluid completely. I have seen a number of
patients suffer severe collapse by withdrawing too completely the
fluid from the subarachnoid space. Manometers have been devised
by Quincke, Kroenig, Crohn and others to indicate the sudden fall
in cerebrospinal pressure but these are unnecessary if the pulse and
respirations are watched and the fluid allowed to escape slowly and
to run until it has reached the normal rate.
Lumbar puncture as a rule is a comparatively easy procedure but
even in the hands of those who have developed a considerable degree
of skill unsuccessful punctures occur not very infrequently, especially
in infants and young children. The most common causes of failure
to obtain fluid are that the needle has not been within the subarach-
noid space, that it has not penetrated the dura or that it has been
obstructed by a nerve. Rotating the needle or moving the needle
slightly backwards or forward, reinserting and withdrawing the
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TREATMENT OF MENINGOCOCCUS MENINGITIS 171
trocar often are followed by a free flow of fluid. Sometimes the
fluid may be so thick that it cannot flow through the needle. In
such cases it may be impossible to obtain even a few drops of fluid.
Small particles of exudate may obstruct the lumen. Reinserting
the trocar or moderate suction by a syringe may obviate these diffi-
culties. Blood in the spinal fluid may be due to the puncture of a
small blood vessel in the subcutaneous tissue, or an injury to a
branch of the venous plexus in the spinal cavity. Blood appearing
toward the end of the collection of cerebrospinal fluid may mean
that there has been a rupture of the capillaries within the subarach-
noid space as the result of the relief of pressure. In exceptionally
fulminating cases the cerebrospinal fluid is sometimes hemorrhagic.
A successful puncture in nearly all cases is possible but many times
it requires great perseverance. It is questionable whether one should
speak of a so called "dry tap." I have never seen but one instance
in which fluid could not be obtained and that was in a patient with
a congenital obstructive hydrocephalus from whom a meningocele
had been removed. Even in obstructive hydrocephalus a certain
amount of cerebrospinal fluid can be obtained.
As mentioned above, too rapid lowering of the cerebrospinal pres-
sure seldom produces symptoms of shock or collapse: Incontinence
of urine and feces, sharp pains along the thighs, headache, pain and
weakness in the back, etc., sometimes follow the procedure but they
are usually temporary. As in the case of lumbar puncture for spinal
anesthesia, temporary paralysis of the bladder and anus and even
paraplegias have been described following lumbar puncture and the
introduction of serum. It is difficult in meningitis to account for
these sequelae entirely as the result of lumbar puncture. The dan-
gers from lumbar puncture itself are remote and for the most part
with proper precautions may be disregarded.
As it is necessary during the course of the disease to make repeated
punctures from day to day and often over a long period of time, the
interspace entered should be varied from one puncture to another
and every precaution taken to prevent secondary infection. With
sterile technique the skin wounds seldom become infected.
The question of anesthesia during lumbar puncture has received
considerable attention both in this country and in Europe. Some
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172 KENNETH D. BLACKFAN
authorities regard a general anesthesia as unnecessary while others
advise either the use of a local or general anesthesia in all cases.
Sophian regards general anesthesia as dangerous while Horder, Robb
and others recommend its use in all cases unless the patient is uncon-
scious or it is definitely contraindicated. A general anesthesia is to
be preferred to local anesthesia as the discomfort of inserting the
lumbar puncture needle as a rule is no greater than is that from the
needle puncture used to inject the local anesthetic. The chief argu-
ment against a general anesthesia is that it further increases the
dangers from the disease and as the discomfort from puncture is not
excessive it is unwarranted with a procedure no more painful than
lumbar puncture. With a patient who is delirious and struggling
it is necessary, otherwise it would be impossible to keep the patient
quiet and in position long enough to carry out the necessary treatment.
Anesthesia may also be advantageously used with some patients who
have to be repeatedly punctured on account of the fear of the opera-
tion. Anesthesia affords a sufficient amount of mental and physical
relief to some adults to warrant its use but as a general rule the opera-
tion is accompanied by so little pain that it is not necessary. It is
seldom necessary in infants and young children. Ether is probably
the best and safest anesthetic to use.
The inlraspinous administration of serum in meningitis
The successful treatment of meningococcus meningitis depends upon
the early recognition of the disease and upon the early and efficient
administration of antimeningococcus serum. It is essential that the
serum should be of high potency and contain antibodies specific
for the causative type of organism; that it be maintained within the
cerebrospinal system at high concentration and in direct contact
with the meningococci. Free drainage should be obtained from time
to time by spinal puncture. There are also certain general and sympto-
matic measures that must be carried out in addition to the specific
serum treatment.
Action of the serum
The chief action of the serum is doubtless due to bacteriolysins
which destroy the organisms and in part also to those substances which
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TREATMENT OF MENINGOCOCCUS MENINGITIS 173
promote phagocytosis. For these reasons it cannot be too much
emphasized that the serum used in the treatment of a given case of
meningococcus meningitis must contain antibodies specific against
the infecting strain of meningococcus. By examination of the cere-
brospinal fluid in the course of treatment it is appreciated that the
direct action of antimeningococcus serum is on the meningococci.
These become reduced in number and become altered in size and
staining property. They are more readily taken up by leucocytes
and their growth is inhibited. The toxic products liberated by the
death of meningococci are perhaps neutralized by the antiendotoxin
in the serum if such a substance be found in the serum. The extra-
cellular organisms diminish rapidly so that after the first or • second
injection of serum they are almost all intracellular, gradually they
disappear altogether from stained smears. The viability of the or-
ganism also diminishes so that it is impossible to cultivate them.
Sometimes even when seen in smears, they fail to grow on culture
media. Levy has shown that the meningococcus disappeared from
the cerebrospinal fluid in 114 cases after the intraspinous injection
of serum as follows: After the first injection of serum it disappeared
in 18 cases, in 33 after the second injection, in 35 after the third in-
jection, in 14 after the fourth injection, in 9 after the fifth injection,
in 4 after the sixth injection and in 1 after the eleventh injection. I
found that in the majority of cases the meningococci disappeared
after five injections of serum. In the following summary the num-
ber of injections of serum required to destroy the meningococcus as
shown by culture and smears:
In 5 cases the organism disappeared after 1 injection
In 4 cases the organism disappeared after 2 injections
In 7 cases the organism disappeared after 3 injections
In 4 cases the organism disappeared after 4 injections
In 9 cases the organism disappeared after 5 injections
In 2 cases the organism disappeared after 6 injections
In 1 case the organism disappeared after 7 injections
In 1 case the organism disappeared after 9 injections
As the result of the reduction in number and the disintegration of
the meningococci and the diminution in the number of leucocytes,
the turbid or purulent cerebrospinal fluid gradually becomes clear.
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174 KENNETH D. BIACKFAN
But aseptic meningitis which may be caused by the introduction of a
foreign serum may be sufficient to cause a certain amount of turbidity
in the fluid until treatment is discontinued. The polymorphonuclear
cells are finally replaced by mononuclear cells at first in increased
number and eventually these are reduced within normal limits. At
the same time the globulin content in the cerebrospinal fluid and the
amount of cerebrospinal fluid diminishes progressively from day to
day. The fluid in cases recovering from cerebrospinal meningitis
may closely simulate, with the exception of the presence of bacilli,
that found in tuberculous meningitis. It may be increased in amount
and clear but may contain an excess of mononuclear cells and globu-
lin and* may even form a film on standing. It may require days or
even weeks before the fluid becomes normal. Besides acting directly
on and destroying meningococci and neutralizing the endotoxins
liberated, antimeningococcus serum undoubtedly hastens the solu-
tion of the exudate.
Antimeningococcus serum should be injected directly into the
subarachnoid space. The subcutaneous and intramuscular injec-
tion of serum in meningitis is valueless. Previous to the introduction
of the gravity method by Heiman in 1908, serum was introduced into
the meningeal spaces by means of a syringe. After the cerebrospinal
fluid was withdrawn the syringe was attached to the lumbar punc-
ture needle and the serum injected slowly and with very little pres-
sure. The gravity method is the one of choice, however, as the serum
runs in slowly and at a regular rate with no sudden and pronounced
increase in intracranial pressure. The cerebrospinal pressure may be
directly controlled by raising or lowering the level of the fluid in the
gravity apparatus. Elaborate equipments for the introduction of
serum by this method may be obtained but for practical purposes
it is only necessary to have a graduated funnel with rubber tubing
which is connected with the lumbar puncture needle by a close fit-
ting metal attachment. After the cerebrospinal fluid has been with-
drawn the attachment is made and the serum, which has been warmed
to body temperature, is allowed to run from the graduated cylinder
into the subarachnoid space, care being taken that all air has been
expelled from the tubing. The rapidity of flow is regulated by raising
or lowering the funnel.
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TREATMENT OF MENINGOCOCCUS MENINGITIS 175
Symptoms caused by the injection of serum
The injection of serum invariably causes severe, often agonizing
cramp-like pains which radiate down the back of the legs, to the
epigastrium or up the back. These pains usually begin as soon as
the serum flows in and are due to the sudden rise in pressure and stimu-
lation of the nerve roots. They can be lessened somewhat by allowing
the serum to run in at first very gradually. Serum warmed to body
temperature before injection causes less pain than when it is cold.
The pains disappear shortly after the cessation of the injection and
often before it is terminated. After the serum has been injected
the stylet should be replaced and the needle left in place. By follow-
ing this routine procedure the cerebrospinal pressure can be quickly
lowered if any serious disturbances develop from the injection. After
a few minutes the needle is withdrawn and the wound closed with a
sterile dressing. It is advised that the foot of the bed be elevated
in order to facilitate the flow of serum to the cerebrum and that the
patient lie on his face so that the serum will be directed to the region
of the optic chiasm. As it has been shown that dyes when injected
into the lumbar subarachnoid space pass upward within a few minutes
and are quickly distributed over the brain, these measures are not
absolutely necessary.
Sophian in observations on patients and Carter in experiments
on dogs have shown that the symptoms of collapse which fortunately
are not frequently met with are due to a sudden increase of intra-
cranial pressure and a resulting depression of the respiratory center.
This sudden increase results from a too great pressure used in the
injection of the serum, too rapid an injection or too large a quantity
of fluid injected at one time. The first sign of danger is an altera-
tion in respiration, the breathing becoming slow, shallow and irregu-
lar. Respiration may suddenly cease. Dilatation of the pupils
and incontinence of urine and feces also occur. The heart continues
to beat for a long time. In one of my patients to whom serum
was being given by the syringe method the respiration ceased but
the heart's action continued actively for over an hour. Lowering
the intracranial pressure by removing some of the serum that had been
injected and active respiratory stimulation were unavailing. Sophian
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176 KENNETH D. BLACKFAN
recommends that the injection of serum should be controlled by
blood pressure readings and that a drop of 20 mm. of mercury in the
blood pressure of an adult is a contraindication to the further injection
of serum. This procedure may advantageously be used in adults
but with children in whom blood pressure determinations at best are
variable, it is unsatisfactory. By the use of the gravity method,
allowing ten to twenty minutes for the serum to run into the cerebro-
spinal space, alternately raising and lowering the funnel so that the
flow of serum is carefully regulated and watching the patient closely
for signs of impending relapse, the dangers of intraspinous treatment
are materially lessened. Should signs of collapse appear, the injection
should be stopped at once, the apparatus disconnected and the serum
allowed to drain out. Artificial respiration should be started and
atropine and adrenalin should be injected in full doses. In animals
Carter showed that the symptoms could be relieved immediately by
the injection of cocaine.
Dosage of serum
Inasmuch as the serum acts directly on meningococci, the impor-
tant indication is to inject as much serum as is consistent with safety.
As there is no standard measurement of activity of the serum and -as
it is ndt known accurately how much serum is necessary to destroy
the organisms and neutralize their effects, the dose is measured by
volume. The chief objects of the intraspinous treatment are to
relieve the intracranial pressure, to remove the infectious cerebrospinal
fluid and to inject the bactericidal serum so that it comes into direct
contact with the meningococci. It is the custom of nearly all clini-
cians to inject a smaller amount than the quantity of cerebrospinal
fluid withdrawn. If 45 cc. of cerebrospinal fluid are withdrawn,
it has been regarded as safe to inject 30 cc. of serum. In this way
it is thought that there is no danger of increasing unduly the intra-
cranial pressure. While in general this is a relatively safe rule to
follow, it cannot be sufficiently emphasized that the injection must
be made slowly and even when these precautions are observed,
patients are occasionly met with in whom alarming symptoms result
from the introduction of even small amounts of serum. As the result
of Sophian's experience in controlling the dosage of serum by blood
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TREATMENT OF MENINGOCOCCUS MENINGITIS 177
pressure readings together with the clinical experience of many other
observers, the following arbitrary standard of dosage according to
the age of the patient may be generally considered safe:
1 to 5 years 5tol5cc.
5 to 10 years 10 to 20 cc.
10 to 20 years 20 to 30 cc.
20+ years 30+ cc.
However, it should be borne in mind that the dosage varies with each
individual patient and that the volume of serum introduced should
never be greater or as great as the amount of cerebrospinal fluid
withdrawn. It is far better to inject an inadequate amount of serum
and repeat the injection with no harm to the patient than to inject
a larger dose with serious consequences.
In patients with thick plastic exudates and in those in whom only
a few drops of cerebrospinal fluid can be obtained, the injection of
small amounts of serum at frequent intervals, even under a certain
amount of pressure, is compulsory for in no other way is it possible
to introduce the serum and the danger of introducing serum in this
way is less than allowing the patient to go untreated. In patients
with a very thick cerebrospinal fluid which will not flow through the
needle, two needles may be inserted at different levels and the canal
irrigated with sterile salt solution. This sometimes sufficiently
dilutes the cerebrospinal fluid as to allow it to flow and so permits
the injection of larger doses. But even if free drainage can be estab-
lished by repeated intraspinal injections the process is time consuming
and irremediable damage, such as obliteration of the foramina between
the ventricles and the cerebrospinal space, may be done in the mean-
time. Moreover, a very thick exudate means a very severe inflam-
matory process, the presence of a very large number of organisms
and an urgent demand for early and intensive treatment. Intra-
ventricular treatment is under these circumstances clearly indicated.
The method of accomplishing this will be described subsequently.
An instructive example of what may be accomplished under such
conditions are afforded by the following case:
The patient, three months of age, was admitted to the Harriet Lane Home
on the third day of the disease, with a history of vomiting, fever, restless-
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178 KENNETH D. BLACKFAN
ness and convulsions. On physical examination there were the character-
istic signs of acute meningitis and several small petechiae on the face. The
temperature was 101.6°. As no cerebrospinal fluid could be obtained by
lumbar puncture, a ventricular puncture was immediately done. The
cerebrospinal fluid was cloudy and contained many polymorphonuclear
leucocytes and numerous intra- and extra-cellular Gram-negative diplo-
cocci. The meningococcus was grown in culture. The blood culture was
negative. Twenty cubic centimeters of serum were injected into the ven-
tricle at once. Twelve hours later a few cubic centimeters of thick, turbid
fluid showing meningococci were obtained by lumbar puncture. Five
cubic centimeters of serum was injected under pressure with a syringe.
On the following day, thirty cubic centimeters of serum was injected into
the ventricle and although only a few cubic centimeters of cerebrospinal fluid
was obtained by puncture, five cubic centimeters were again injected into
the lumbar subarachnoid space by a syringe. At the time of the second
lumbar puncture the spinal canal was irrigated with sterile normal salt
solution but this did not have an effect on the amount of fluid which
could be obtained. Phenolsulphonephthalein injected at this time into the
lumbar subarachnoid space had not appeared in the ventricles the follow-
ing morning. Thereafter thirty cubic centimeters of serum was injected
into the ventricle and five cubic centimeters of serum was injected with
a syringe into the lumbar subarachnoid space every twenty-four hours.
The amount of cerebrospinal fluid removed by lumbar puncture slowly
increased and after the seventh day thirty cubic centimeters of fluid was
obtained. Phenolsulphonephthalein at this time flowed freely from the
ventricle. The meningococci disappeared.
Frequency of injection
The frequency with which antimeningococcus serum is to be
injected depends upon the severity of the infection and the duration
of the infection before treatment is instituted. In a suspected case
of meningitis lumbar puncture should be performed and if a cloudy
fluid is obtained antimeningococcus serum should be administered
without waiting for a bacteriological examination. Should the case
eventually be shown not to be due to the meningococcus, no harm
will have been done. In cases of average severity when seen within
the first two or three days after the onset, the injection should be
repeated every twenty-four hours for three or four doses. Hoher,
Dochez, Debre and others have demonstrated that the serum is
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TREATMENT OF MENINGOCOCCUS MENINGITIS
179
practically all absorbed within twenty-four hours. No greater
interval of time should therefore elapse between treatments. In
cases of greater severity the injection should be repeated every eight
or twelve hours for three or four doses and thereafter every twenty-
four hours. This is for the reason that the activity of the serum may
be exhausted in a short period of time even before the fluid portion
of the serum is absorbed. The appearance of the cerebrospinal
fluid at each puncture, the number of organisms and their relationship
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Mild Case of Meningococcus Meningitis Reacting Promptly to Intrasplnous
Injection of Antmeningococcus Serum
to the leucocytes and their ability to grow upon proper culture media
together with the general condition of the patient are the only safe
and reliable indications to follow as to the frequency with which
serum is administered.
Discontinuance of serum
In the average uncomplicated case of meningococcus meningitis,
serum treatment is discontinued when the cerebrospinal fluid becomes
clear and the organisms can no longer be demonstrated in smears or
in culture. By this time also there is a general improvement in the
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180 KENNETH D. BLACKFAN
condition of the patient and the fever has usually nearly disappeared.
With serum treatment the average duration of active symptoms is
from eleven to fourteen days.
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Chart m.
This Patient Rbquibed Intensive and Persistent Intraspinous Treatment
The spinal fluid, which would become apparently clear at one puncture, would at
the next be very turbid and filled with organisms. Sixteen intraspinous treatments were
required with a total injection of 320 cc. of serum before the spinal fluid became clear and
meningococci disappeared.
Unfortunately the indications are not always definite and it requires
sound judgment in determining when the injections are to cease.
Although the general clinical condition of the patient as a rule may
be relied upon as an indication, one often sees patients who are
apparently recovering but viable organisms persist in the cerebro-
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Characteristic Febrile Reaction in an Untreated Case
While serum therapy is usually not very effective late in the course of the disease, it
may at times bring about rapid cure. This patient was ill twenty-two days with an
obscure fever, the cause of which had not been recognized. The temperature record had
been kept. After 3 intraspinous injections of serum the patient made an uninterrupted
recovery.
181
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182 KENNETH D. BLACKFAN
spinal fluid. The reverse is also often true. The patient may remain
unimproved with persistence of the signs of meningeal irritation and
yet the organisms cannot be demonstrated in the cerebrospinal fluid.
The fever as a rule subsides with the disappearance of the organisms
but it should also be remembered that irregular febrile paroxysms
may often be caused by the injection of the foreign serum and in
prolonged cases by the development of serum sickness. The only
reliable criterion for the discontinuance of serum treatment is the
disappearance of the organisms from the smears of the cerebrospinal
fluid and their failure to be cultivated upon proper media. As the
meningococcus grows slowly upon media it requires two or three
days to be sure that a growth will not take place. When treatment
is employed once in each twenty-four hours, two or three injections
have thus been made after the cerebrospinal fluid is free from viable
organisms. This is an added safeguard and produces no unfavorable
effects. After that the character of the cerebrospinal fluid is followed
by lumbar puncture at irregular intervals. Repeated lumbar puncture
serves a double purpose in permitting cytological examination of the
cerebrospinal fluid and relieving the increased intracranial pressure
which frequently follows meningococcus meningitis.
Turbidity of the fluid is not an unfailing criterion for the contin-
uation of treatment. The fluid may be free from organisms and yet
contain so many cells as to be definitely cloudy or "ground glass"
in appearance. The recent studies of Weed and his collaborators
have shown the influence of the injection of foreign serum in bringing
about such changes.
Early intraventricular injection of serum
In a series of articles which have recently appeared, Lewkowitz
in discussing the serum treatment of meningococcus meningitis
concludes that inasmuch as the lateral ventricles are the principal
and essential seat of the infectious process, the meningococci spread
from this focus throughout the entire subarachnoid space. He
advises therefore that the serum should be injected into the lateral
ventricles at the beginning of treatment and that daily injections m
alternate sides or simultaneously on both sides should be made. In
addition he recommends the use of vaccines. He describes the
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TREATMENT OF MENINGOCOCCUS MENINGITIS 183
method: The skull is punctured with a Gotze grooved hand drill,
1.5 mm. wide. The needle is 1 mm. in diameter and 7 or 7.5 cm.
long. A brass guide inside the needle prevents obstruction with
tissue. The tip of the needle is not sharp, as the only obstacle it has
to force is the dura. The puncture is made anywhere along the top
of the skull, 3, 4 or 5 cm. from the median line, pointing the tip of
the needle toward the center of the skull. The depth of the puncture
should be about 40 mm. for infants, 50 to 60 mm. for older children,
and 60 to 75 mm. for adults. The fluid should not be injected until
the needle is certainly in the ventricle. This is proved by the fact
that cerebrospinal fluid flows from the needle and by the drop in
tension as the antiserum spreads in the ventricles. The tension
should not surpass 60 to 80 mm. mercury for older children and
adults, and 40 to 50 for infants. Lewkowitz advises therefore that
a manometer with a three-way stopcock be interposed between the
needle and the syringe. The injections are always made through a
new opening. In the first series of cases which he reported the
mortality was 36 per cent and this rather high mortality he accounts
for on the basis of an inactive serum and fulminating types of cases.
He warns against the use of horse serum for a period longer than 13
days on account of an anaphylactic reaction in one case. After the
thirteenth of fourteenth day he is inclined to rely on the use of
vaccines. He believes that all cases should be treated by the early
ventricular injection of serum. Undoubedly this would be the
procedure of choice were it definitely established that the organism
gained entrance to the meninges by way of the ventricles. The
weight of evidence in meningitis produced experimentally is against
this view. Although the intraventricular injection of serum has its
indications in small infants and in patients with a thick plastic
exudate with or without hydrocephalus, the early injection of serum
into the ventricles in the average uncomplicated case is not necessary.
Amount of serum used during the treatment
The amount of serum required in each individual case varies within
wide limits and depends entirely upon the course of the disease. In
one of my patients who was treated four hours after the onset of
meningeal symptoms, only one injection of 20 cc. of serum was given
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184
KENNETH D. BLACKFAN
and was followed by rapid recovery. Netter, Worster-Drought and
Kennedy and others have given as high as 600 to 800 cc. during the
course of the disease without ill effects. It is not so much the amount
of serum that is important as it is the quality of the serum and the
time at which it is employed (chart V).
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First and Only Injection Given Four Hours After Onset
Cerebrospinal fluid dear, containing many Gram-negative extracellular organisms.
Complete recovery.
REINFECTION AND RELAPSES
The reappearance of meningococci in the cerebrospinal fluid either
with or without the appearance of signs of meningeal irritation may
take place even while serum is being given or after the discontinuance
of treatment. These relapses are not nearly so frequent since the
introduction of serum therapy but they occur in a small proportion
of patients. Worster-Drought and Kennedy observed a relapse in
less than 5 per cent of their cases. In my experience they have been
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TREATMENT OP MENINGOCOCCUS MENINGITIS 185
met with only in the cases running a chronic course and in the cases
above referred to. They probably result from the fact that a certain
number of organisms are walled off in patches of exudate which the
serum cannot penetrate or else are contained in small superficial
abscesses in the brain or cord. It is not always easy to recognize
the beginnings of a relapse for it may occur with the onset of serum
sickness and there may be strikingly few meningeal symptoms. A
positive and early diagnosis of a relapse is only to be made by an
examination of the cerebrospinal fluid. The treatment of a relapse
is the same as the treatment of the original disease. The dangers
from anaphylaxis in the treatment of relapse are considered under
the heading of anaphylaxis.
During the course of meningitis there are certain symptoms that
are in all probability the result of increased intracranial pressure or
at least they are made worse by the pressure. These are headache,
often agonizing in character, vomiting, retraction of the neck and
some elevation of temperature. The mere removal of cerebrospinal
fluid often brings about a distinct amelioration. These symptoms
may be present sometimes to a marked degree, even after all menin-
gococci have been killed and the serum treatment discontinued*
They apparently depend upon the disproportionate production of
cerebrospinal fluid due to a too rapid production or to a too slow
absorption. The disease itself and the treatment by foreign serum
may each be responsible for this condition of affairs. A rapid im-
provement results from lumbar puncture and the withdrawal of
fluid but the symptoms may return again and again. It is imperative
to continue the withdrawal of fluid until there is no return of any of
the symptoms. This may require occasional lumbar puncture for
several weeks. The following illustrates the results of repeated
lumbar puncture after discontinuance of serum treatment (chart VI).
W. G., white, aged three years. Patient was admitted on the fifth day of
the disease with typical picture of meningitis of severe form. Twelve in-
traspinous treatments with serum were given in the eight days following
admission. No organisms were seen in smears from the spinal fluid after
the ninth puncture. In spite of the apparently dear fluid he did not im-
prove, the retraction of the head and the hyperesthesia persisted, he
was extremely restless and there was a coarse tremor of the extremities.
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186 KENNETH D. BLACKFAN
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Chart VI.
Repeated Lumbar Puncture After Discontinuance of Serum Treatment
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TREATMENT OF MENINGOCOCCUS MENINGITIS 187
The eye grounds were normal. On the twelfth day the temperature rose to
103° and all the symptoms were exaggerated. A lumbar puncture was done
and a large quantity of clear fluid containing no organisms spurted out
under greatly increased pressure. There was marked relief following this
procedure and the temperature fell. Thereafter, at intervals of about
one week it was necessary to repeat the treatment. The symptoms were
relieved each time by the removal of a large quantity of clear fluid. He was
discharged as well on the fifty-seventh day of the disease.
Every one with experience in the treatment of meningococcus
meningitis has seen alarming symptoms follow the injection of anti-
meningococcus serum. Death at times has followed treatment with
serum so promptly that it is apparent that the treatment rather than
the disease has been responsible. A number of views have been held
as to the cause of these accidents. It has been claimed that the
deaths were due to rapid lysis of the meningococcus and the conse-
quent liberation of a toxic amount of bacteriotoxin, to the production
through the introduction of large amounts of a foreign protein of
anaphylactic shock, and to increased intracranial tension due to the
too rapid or too free use of the antiserum. In 1912, Kramer advanced
the view that cases of sudden death might be due to the presence in
the serum of tricresol. Kramer injected a mixture of antimeningitis
serum and a 0.5 per cent tricresol solution into the region of the fourth
ventricle and directly into the subarachnoid space in dogs and as
the result respirations were temporarily checked. One of the animals
died after the injection of the serum into the subarachnoid space.
Hall as the result of experiments also believed that tricresol is a
dangerous preservative for serum which is to be introduced into the
subarachnoid space and so come directly into contact with the nervous
centers. He stated that death from the introduction of serum may
result either from an increase in intracranial tension or from the
presence in such serum of tricresol.
Flexner does not believe that the tricresol in antimeningococcus
serum is responsible for the sudden deaths which have followed the
use of serum. He points out that such deaths have been reported
by Dopter using a serum which contained no preservative, also that
there is no relationship between the conditions of the experiments
and the conditions occurring in the subdural injection in human
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188 KENNETH D. BLAGKFAN
beings, and that the injection of serum directly into the ventricle is
not followed by serious symptoms. It is his belief that the alarming
symptoms and death are most probably due to a rapid increase of
the intracranial pressure occasioned by the injection of serum. That
they can be avoided to a great extent by careful technique is evident
from the experience of Sophian who reports some 1500 injections
without a serious accident.
IMMUNITY CONFERRED BY ATTACK OF MENINGITIS
The degree of immunity conferred by meningococcus meningitis
is apparently very small. Worster-Drought and Kennedy were able
to demonstrate agglutinins in only 3 of 39 patients who had recovered
from the disease. Authentic cases are reported in which "second
attacks" occurred as early as 33, 45 and 73 days and as late as
four and eleven months after the primary attack. It is probably
better to consider such cases as relapses rather than second
attacks. Although second attacks are rare, they do undoubtedly
occur.
THE USE OF MONOVALENT OK POLYVALENT SERA
Since the recognition of the different types of meningococcus and
the preparation of monovalent as well as polyvalent therapeutic sera,
the procedure which is advised in the routine treatment of suspected
or a proven case of meningitis has varied according to the experience
of different writers. All are in accord that in a case of suspected
meningitis if turbid or cloudy cerebrospinal fluid is obtained by
lumbar puncture that a polyvalent serum should be administered
pending the results of the bacteriological report. Whether treat-
ment should be continued with a polyvalent serum of a monovalent
serum is still the subject of much discussion. French observers at
one time favored the injection of 20 cc. of antiserum A with 30 cc. of
antiserum B until the type of the organism could be determined.
Recently Nicolle, Debains and Jouan have prepared a bivalent serum
made with organisms A and B, for immediate use prior to a bac-
teriologic diagnosis. After this they have advised the use of a mono-
valent serum according to the type of the infecting strain of menin-
gococcus. In England a similar routine has been carried out and
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TREATMENT Of MENINGOCOCCUS MENINGITIS 189
as type I and type II are the most prevalent, a serum representing
these two strains of meningococcus has been given at the first injection
and after the causative strain has been determined, the corresponding
monovalent serum has been given. The objection to the use of
only bivalent serum is obvious. If there is difficulty in typing the
organism a delay in using a highly potent serum might arise. But
excellent results from the use of a monovalent serum have been
reported from both England and France. The routine followed by
Gordon and Hines is as follows: A bivalent serum made from type I
and type II is used until the type of the infecting meningococcus is
determined. Then the corresponding serum for the type of menin-
gococcus found is given. Out of 83 cases, 34 were due to type I and
the mortality was 3 per cent; 32 were due to type II and the mortality
was 21.9 per cent. Ten were due to type III, no deaths, and 7 to
unknown types and the mortality was 28.6 per cent. Out of the 83
cases the mortality was 12 per cent. The monovalent serum for
type II is less effective than the sera for the other types for Gordon
and Hines say that it contains less antiendotoxins for the homologous
meningococcus than the other sera do. Sir Humphrey Rolleston
observed a small outbreak of 10 cases due to type II. All of the
patients died although treated vigorously both intravenously and
intraspinously with a monovalent serum from type II organism.
Munro used a pooled serum containing 50 per cent of antibodies to
type H and a monovalent serum was used after the type was deter-
mined. He treated twelve consecutive cases of cerebrospinal fever
in this manner and he says that in his experience no patient has died
where it was possible to treat by monovalent serum. Recently a
polyvalent serum has been used in this clinic in a few cases at the
initial injection and thereafter the corresponding monovalent serum.
The results so far have been sufficiently satisfactory but the number
of cases treated have been too few from which to draw conclusions.
If it can be proved that the activity of a monovalent serum against
the corresponding type of the meningococcus is greater than the
activity of a polyvalent serum against the same organism, then it
would seem logical to employ the monovalent serum after the type
of organism has been determined. Unless this can be proved, there
are great advantages in using the polyvalent serum. Studies from
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190 KENNETH D. BLACKFAN
the Hygienic Laboratory in Washington have shown the titre of the
polyvalent sera to be as high as that of the monovalent sera that
have been tested. At present therefore it would seem that for general
use a polyvalent serum is preferable.
In all cases of meningococcus meningitis the type of organism from
the cerebrospinal fluid should be determined by agglutination tests
and a serum containing antibodies specific for that type of organism
should be used. If the types of organism used in the preparation of
the serum are not known, the agglutinating power of the serum
toward the specific type of organism should be tested. Sera showing
a low agglutination titre should not be employed. It is the universal
opinion that the polyvalent serum prepared by the Rockefeller Insti-
tute has given better results than sera prepared at other laboratories.
On account of the practical difficulty in making prompt and accurate
type diagnoses, all antimeningococcus sera sold in interstate traffic
in the United States are now required to be polyvalent with high titre
against strains representing four different serological groups. These
groups roughly correspond to those of Gordon, but are not perhaps
identical with them. Sera now being made in the United States
are from horses which have received intravenous injections of living
meningococci. At least twelve different strains representing different
types and variants sent out by the Hygienic Laboratory are used in
its production.
DRUGS IN TREATMENT OF MENINGITIS
Drugs, except for the relief of symptoms, have proved valueless.
Hexamethylenetetramine (Hexamine) since it was shown by Crowe to
be excreted into the cerebrospinal fluid has been used extensively
but apparently it has no influence upon the course of the disease. In
1914, Thomas Walker suggested the use of hexamethylenetetramine-
anhydromethylene-citrate (Helmitol) as a substitute for hexamine
inasmuch as it liberates formaldehyde in alkaline as well as in add
media. It has been shown that this drug exerted an inhibitory
effect on the meningococcus in vitro and as a result of these experi-
ments the drug was tried in the treatment of meningococcus menin-
gitis. Given intravenously hemitol appears in the spinal fluid within
half an hour and 15 grains administered by mouth could be demon-
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TREATMENT OF MENINGOCOCCUS MENINGITIS 191
strated in the cerebrospinal fluid within twenty-four hours. It was
impossible, however, in any of the cases in which it was used to
demonstrate the presence of free formaldehyde. Clinical results
with this drug have been very unsatisfactory. Fairly and Stewart
combined hemitol with normal saline or horse serum and injected
this in 10 cases of meningococcus meningitis. Six of the 10 patients
recovered. Besides the administration of hexamine and hemitol
intravenously the arsenical preparations together with soamin have
also been employed intravenously but without appreciable effect on
the course of the disease. Soamin has been used principally in the
East and was tried in meningococcus meningitis inasmuch as it has
been thought to be of value in trypanosomiasis. Shiroore and Ross
and Gilks and Butler have used the drug in British East Africa quite
extensively. They reported its use by intramuscular injection in
127 cases. The mortality was over 50 per cent. Iodide of potassium
and mercury and antimonium tartrate likewise have been used
but without effect. The results reported by all writers show that
there is little clinical or experimental evidence at hand to support
the use of drugs in the treatment of this disease and they cannot be
recommended unless combined with the use of antimeningitis serum.
OTHER MEASURES EMPLOYED IN TREATMENT
In the literature one finds, constantly, reference to other methods
of treatment than the use of the specific serum. These methods
have been tried either alone or in combination with serum. It is
rather confusing to determine exactly the effects of these various
added methods of treatment for the observations have not been suffi-
ciently accurate or extensive to permit of a comparison between the
cases treated with serum and those in which a combination of methods
has been employed. It is an interesting commentary that even in
spite of a proved specific therapy methods which have been discarded
and regarded as valueless should be taken up from time to time and
that beneficial results should be claimed for them. This, however,
is constantly occurring in the treatment of other diseases besides
meningitis.
Recently one of the earliest methods of treatment, venesection,
has been revived. Fairly and Stewart contend that in the acute
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192 KENNETH D. BIACEFAN
cases in which there are symptoms of respiratory failure, venesection
combined with the application of cold compresses is beneficial. They
also caution against the use of lumbar puncture in comatose patients,
particularly if respiratory failure is imminent.
Long before the days of serum treatment various antiseptics were
recommended and used intraspinously. In 1902 Seager recommended
the use of lysol as a means of combating the disease and in 1904
Manges tested its effects upon a number of patients. Wolff as a
result of the recovery of 5 out of 8 patients whom he treated with the
intraspinous injection of protoargol recommended this substance and
said although its curative value had not been proved, that it can be
injected in the subarachnoid space without hum. In 1916, Flexner
and Amoss presented the results of their experiments with lysol and
protoargol in the treatment of meningococcal infections in guinea
pigs and monkeys. They found that these substances possess none
of the properties which are essential for combating meningococcus
infection. On the other hand, they showed that the use of such
drugs might have a harmful effect when combined with serum treat-
ment inasmuch as they prevent leucocytosis and inhibit the phagocy-
tosis of the organism. Carbolic acid, flavine and eusol and many
other antiseptics have likewise been recommended for intraspinous
treatment. The consensus of opinion is that there is no favorable
influence from the injection of other substances than antimeningo-
coccus serum upon the course of the meningococcus meningitis.
As a result of their experiments regarding the antibactericidal
properties of human serum MacKenzie and Martin in 1908 injected
from 15 to 20 cc. of fresh human serum into the spinal canal of 16
patients with meningococcus meningitis. Ten of these patients
recovered. Since then a relatively large number of cases have been
reported in which either the patient's own serum or convalescent
serum has been used intraspinously in the treatment. Both favorable
and unfavorable results have been reported, but on the whole the
use of human serum has not been followed with brilliant results.
Fairly and Stewart as well as Kolmer and his collaborators have
endeavored to reinforce the complement activity of antimeningococcus
serum by the addition of human and of rabbit serum. In Fairly
and Stewart's cases thus treated the mortality was about 30 per
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TREATMENT OF MENINGOCOCCUS MENINGITIS 193
cent whereas in cases treated with serum alone the mortality was 50
per cent.
Much dissatisfaction with the results of serum treatment was ex-
pressed in England during the early months of the war and for a
time the medical authorities were unable to decide how much benefit
was derived from the intraspinous injection of antimeningitis serum
and how much from the associated puncture. Indeed some authori-
ties stated that in their opinion the old method of lumbar puncture
and drainage without serum was the better form of treatment. As
is well known, the explanation for the failure of serum was found
when it was shown that the strains of meningococci causing the in-
fection were in the majority of cases different from those used in
preparing the antimeningococcic serum that was employed. As
a result of this experience, however, numerous reports have been
made regarding the beneficial effects of repeated lumbar puncture
without serum administration. Olitsky in an epidemic in Southern
China in 1918 had the opportunity of seeing cases which received no
treatment and those in which lumbar puncture alone was performed.
The mortality rate without treatment in 104 cases was 84.6 per cent,
with repeated lumbar puncture in 346 cases it was 54.1 per cent.
On the other hand, a number of authors have reported most unsatis-
factory results from the use of repeated lumbar puncture without
serum. This has been true not only during recent epidemics but in
the treatment of the disease before serum treatment. In general,
it would seem that by lumbar puncture alone the mortality from
meningococcus meningitis can be reduced to a very slight degree,
if at all.
Farmachidis has recently reported the successful employment of
a normal salt solution in rinsing out the spinal cavity in a patient
with meningococcus meningitis. He employed 360 cc. daily for
twenty-five days. He would first withdraw 30 cc. of cerebrospinal
fluid and then inject the same amount of salt solution. After a
few minutes this was aspirated and allowed to flow out and 30 cc.
were injected again. This was repeated 10 or 12 times at a sitting
or until the cerebrospinal fluid finally came away clear. The cere-
brospinal fluid became and remained clear after the twenty-third day.
Aubertin and others have employed the same treatment. In my
experience this method has not been attended with satisfactory results.
MEDlCOfE, VOL. I, NO. 1
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194 KENNETH D. BLACKPAN
VACCINES IN TREATMENT OP ACTIVE STAGES
Meningococcus vaccines as a curative measure were employed but
little before the war. In the epidemics following 1915 they have
been used by a large number of workers and there is a considerable
literature on the subject. Inasmuch as they have been used for
the most part in conjunction with other remedies such as serum and
repeated lumbar puncture, their usefulness is rather difficult to de-
termine. Sophian referred to their use in 1913 and stated that in
certain cases they may be more efficacious than serum. Rolleston
refers to 32 cases treated with autogenous vaccines together with
serum or soamin in which there was a mortality of 25 per cent. Many
of his cases were recovering but vaccines did not seem to alter the
course of the severe infections. Worster-Drought and Kennedy
report in detail several cases which apparently were favorably in-
fluenced by vaccine treatment in conjunction with serum therapy.
Chalmers and O'Farrell report a case of recovery from severe and
protracted meningitis with septicemia. They discontinued serum
treatment and ascribe the cure to an autogenous vaccine. They
advise the use of vaccine with serum therapy in all cases from the
onset. Horden reports the case of a seven year old child to whom
vaccine was given on the thirty-ninth day and after six days the
temperature fell to normal. A relapse occurred two weeks later and
vaccine again seemed to influence the disease as recovery took place.
Crowe also speaks of vaccines as having a favorable influence on the
temperature. Fairly and Stewart say that it is not uncommon
to see a patient who has been having an irregular fever become afeb-
rile shortly after vaccines are given. Out of 52 chronic cases they
had a mortality of 32 per cent. Lewkowitz urges their early use and
says that they tend to induce a general immunization which is a
potent aid in the cure. Colebrook believes that they increase the
antibactericidal content of the blood and so increase the value of the
serum in its action against the meningococcus in the cerebrospinal
fluid. Nearly all workers advise the use of an autogenous vaccine
but when it cannot be obtained, a polyvalent vaccine containing the
representative strains of meningococci may be substituted. The
dosage advised has varied considerably. Worster-Drought and
Kennedy inject 250,000,000 organisms subcutaneously at some time
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TREATMENT OF MENINGOCOCCUS MENINGITIS 195
during the first three days and gradually increase the dose, 500,000,000
a dose, up to 2,500,000,000. The dose is modified for children. If
there is a reaction to a particular dose, the same dose is repeated four
days later. Walker-Hall gave a polyvalent vaccine in increasing
doses from 25,000,000 to 500,000,000 every two days. Boidon gives
from 200,000,000 to 750,000,000 every four days and MacLagan
advises from 50,000,000 to 100,000,000 for the first dose. For the
most part vaccines are recommended in the subacute or chronic
stages of the infection when serum seems to become inefficient. In
the acute cases but little benefit has been reported. No harmful
effects with the exception of a temporary febrile reaction have been
observed. Although the efficacy of vaccine therapy is not dear
airing to its combination with other forms of treatment, until more
information is available it would seem f ram so many favorable reports
that in tfce subacute and chronic types of meningococcus infection
tins mode of treatment is worthy of trial.
As in other diseases for which there is a specific therapy certain
general and symptomatic measures must be carried out in the treat-
ment of meningococcus meningitis. The patient should be kept
isolated in a quiet room or if in a hospital ward the patient should be
separated from his fellow patients by a screen. The room or ward
sbo«rid be provided with an abundance of fresh air. Careful nursing
is of the greatest importance particularly for delirious patients or
those who are in coma. Much can be done to relieve the suffering
of patients who are in a state of rigidity. Changing the position
from time to time and supporting the head and knees with pillows
will not only add to comfort but does much to prevent the develop-
ment of hypostatic pneumonia and bed sores in those patients with a
severe and prolonged form of the disease. The throat and nasal
passages should be cleansed frequently with antiseptic washes and
the eyes irrigated twice daily with boric acid solution. The diet is
regulated according to the condition of the patient and every effort
should be made to supply the patient with an adequate diet. A
liquid diet is advisable during the acute stage. In unconscious and
delirious patients feeding with a nasal tube or stomach tube must be
employed. In patients with severe toxemia, water must be supplied
freely. If there are evidences of desiccation, dryness of the skin and
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196 KENNETH D. BLACKFAN
mouth, loss of tone in the skin or a great diminution in the amount of
urine, salt or glucose solutions may be given intravenously, subcu-
taneously, by rectum or directly into the peritoneal cavity. I have
seen several children during the acute stages of meningitis who were
greatly improved after several intraperitoneal injections of normal
saline. This method has been described by Blackfan and Maxcy.
It has been found experimentally by Weed and McKibben that
the volume of the brain can be controlled by a change in the concen-
tration of certain elements in the blood stream. They showed that
the intravenous injection of hypertonic solutions of certain electro-
lytes and crystaloids causes a transient rise in the pressure of the
spinal fluid which is followed by a marked fall which persists for a
considerable period of time. With this idea in mind Hayden treated
two patients by means of the intravenous injection of a 25 per cent
glucose solution and thought that the favorable outcome was partly
the result of a decrease in the intracranial pressure brought about
by a change in the bulk of the brain. Hayden advises the intrave-
nous injection of a 25 per cent glucose solution, as a routine measure
every twelve hours from the onset of the disease until there is no
longer any evidence of increased intracranial pressure. Rest is essen-
tial and should be secured by the use of morphine or other sedatives.
Relief from headache, vomiting and other intracranial pressure symp-
toms are best relieved by repeated lumbar puncture. Symptoms of
cardiac and respiratory failure should be combated with atropine
adrenalin, camphorated oil and citrated caffeine in full doses adminis-
tered intramuscularly.
HYDROCEPHALUS
Early in the history of meningococcus meningitis it was recognized
that "the disease was distinguished by the slowness of its cure and
that its duration might be a matter of several months." Unfortu-
nately this is true and while recovery from the infection may take
place, irremediable permanent damage may have occurred.
One of the most frequent of the sequelae is hydrocephalus. It
has been customary to speak of the manifestations of increased in-
tracranial pressure which are seen at the onset and throughout the
course of the disease as symptoms of acute hydrocephalus. We know
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TREATMENT OF MENINGOCOCCUS MENINGITIS 197
that these symptoms are largely due to the increased amount of
cerebrospinal fluid which results partly from the stimulation of the
choroid plexus and partly from the inflammatory process in the men-
inges which cannot be sufficiently rapidly removed by absorption
even though this is but little interfered with in uncomplicated cases.
There is a certain justification for speaking of acute hydrocephalus
in some cases for the exudate may be so thick as partially or com-
pletely to obstruct for a time the foramina of exit from the ventricles.
With time, especially when serum is used, this exudate frequently
disintegrates and disappears and thus the channels of communication
between the ventricles and the subarachnoid space are reestablished.
In patients never treated with serum chronic hydrocephalus is the
most common of the sequelae and even in those actively treated by
serum it results in a small but regrettable number of instances. This
is especially the case with children. Hydrocephalus causes most of
the striking symptoms seen in the subacute or chronic types of men-
ingitis the rigidity of the limbs, the opisthotonos, the periodic vomit-
ing, the peculiarity of the cry, the change in mentality and the enlarge-
ment of the head. The hydrocephalus is caused in the majority of
instances by partial or complete blockage of the foramina Magendie
and Luschka at the base of the brain or by obliteration of the cister-
nae (magna, interpeduncularis and pontis). The spinal subarach-
noid space may also be more or less obliterated. In any event the
free distribution of the cerebrospinal fluid throughout the cerebra
and spinal subarachnoid spaces is prevented and its normal absorp-
tion is interfered with. Consequently there is an accumulation and
retention of the cerebrospinal fluid within the ventricle. Anatomi-
cally, two types of hydrocephalus have been demonstrated: (a) the
obstructive, and (b) the communicating. Obstructive hydrocephalus
develops because the cerebrospinal fluid cannot pass from its place
of origin \xL the cerebral and spinal subarachnoid space where absorp- ^
tion takes place. Communicating hydrocephalus — the channels
of communication between the ventricles and the spinal subarachnoid
spaces being patent to a greater or less degree — results because the
cerebral subarachnoid space where the greater part of absorption takes
place is partially or completely obliterated. In the majority of
instances it is due to adhesions which obliterate the various cis-
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198 KENNETH D. BLACKPAN
teniae or centers and obstruct the foramina. A combination of the
two types of hydrocephalus may result if there is partial obstruction
to the foramina and partial obliteration of the cisternae.
Attention must be directed to a hydrocephalus developing in men-
ingitis by the onset of certain symptoms. The diagnosis is readily
established when the condition is of long duration and the symptoms
of increased intracranial pressure — headache, stupor, vomiting, en-
largement of the head and changes in the eye grounds — are present.
The early manifestations of hydrocephalus, however, are so closely
interwoven with the symptoms of the meningitis itself that they are
often difficult to recognise. Hydrocephalus should always be sus-
pected with the persistence of symptoms of meningeal irritation
(fever, hyperesthesia, irritability or drowsiness, rigidity of the mus-
cles of the neck and extremities, hyperactive reflexes, tremors, etc.)
or their reappearance after the symptoms of meningitis have sub-
sided. Infants invariably have a tense and bulging fontanel and in
older children and adults Macewen's sign is positive. It should
be remembered that these symptoms cannot always be referred to
the hydrocephalus alone.
Lumbar puncture yields the most information regarding the develop-
ment of hydrocephalus, though it is not absolutely dependable. In
hydrocephalus the cerebrospinal fluid is under greatly increased
pressure and either an abnormal amount is readily obtained or it
is obtained in small amount and with difficulty. A definite increase
in the amount of cerebrospinal fluid of 50 cc. or more, withdrawn
repeatedly when the other signs of the acute infection of the meninges
have subsided, is significant of a communicating hydrocephalus.
In obstructive hydrocephalus a large amount of cerebrospinal fluid
may be recovered at the first lumbar puncture and then the quantity
lessens so that only a few drops are obtained at successive punctures.
Corroborative evidence of the presence of hydrocephalus may be
shown by the results from puncture of the ventricle, as in such cases
the cerebrospinal fluid in the ventricles is under increased pressure
and an excessive amount can be withdrawn. During the acute stages
of meningitis a small amount of fluid obtained by lumbar puncture
suggests an obstructive hydrocephalus, for if the subarachnoid space
has been entered and the fluid is not too thick to run through the
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TREATMENT OF MENINOOCOCCUS MENINGITIS 199
needle, the prevention of a free flow of cerebrospinal fluid from the
ventricles to the spinal subarachnoid space can hardly be caused by
anything else than a thick exudate so situated as to obstruct the
foramina of exit applied from the ventricles.
The differentiation between the two types of hydrocephalus by
clinical signs alone, however, may be very difficult and for that reason
I have employed in a number of cases the phenolsulphonephthalein
tests used by Dandy and Blackfan in their study of chronic hydro-
cephalus. When phenolsulphonephthalein is injected into the ven-
tricle in obstructive hydrocephalus, the dye does not appear in the
cerebrospinal fluid obtained from the lumbar subarachnoid space
within forty minutes, if at all. In patients who do not have hydro-
cephalus and in those with the communicating type of hydrocephalus,
the phenolsulphonephthalein appears promptly (in from six to twelve
minutes). When phenolsulphonephthalein is injected into the lum-
bar subarachnoid space in communicating hydrocephalus, absorption
of the dye is greatly lessened. Less than 20 per cent is excreted in
the urine within two hours, as compared to 35 or 60 per cent in normal
persons. In obstructive hydrocephalus, when the cisternae and the
meninges are not affected, absorption is as prompt as in normal indi-
viduals. In 17 cases of meningococcus meningitis communicating
hydrocephalus developed in 8 patients and obstructive hydrocephalus
in 9 patients. Ten of the 17 patients died. Two of the other 7 pa-
tients had an obstructive hydrocephalus and improvement followed
promptly after the introduction of serum into the ventricles. The
process in the 4 patients with communicating hydrocephalus became
arrested after treatment. One patient with communicating hydro-
cephalus developed a chronic hydrocephalus in spite of the intensive
intraventricular and intraspinous administration of serum.
Whenever in the course of meningitis fluid is obtained with difficulty
or after temporary improvement there is a reappearance of the symp-
toms of meningeal irritation (hyperesthesia, vomiting, drowsiness,
increased rigidity, etc.), or when in spite of active treatment improve-
ment does not occur, an obstruction to the free passage of fluid from
the ventricles and into the cisternae of the subarachnoid space is to
be suspected. This not only leads to hydrocephalus but prevents
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200 KENNETH D. BLACKFAN
the serum when injected below from reaching the inflammatory
processes in the ventricles and over the surface of the brain. The
injection of serum directly into the ventricles is then indicated.
INTRAVENTRICULAR INJECTION OF SERUM
The injection of serum directly into the ventricles was first
employed by Cushing and Sladen. Since then it has been in rather
general use. It is inadvisable to delay making use of this method.
It should be resorted to in severe and complicated cases much more
frequently than it has been in the past. Improvement may often
and often does follow one or two injections of serum but repeated injec-
tion may be necessary. The dangers attending ventricular puncture
are insignificant; in children it is oftentimes much easier than lumbar
puncture. In infants the method of procedure is as follows: The
patient should be wrapped in a blanket and placed in the recumbent
posture on a table. The head must be firmly supported. An area
corresponding to the anterior fontanelle having been shaved and the
skin sterilized, the anterior fontanelle is outlined and an ordinary
lumbar puncture needle with stylet is introduced just to one side
of the mid-line to avoid the longitudinal sinus. The needle is
pointed in a direction forward and slightly outward on a line with
the optic foramen, and is pushed in to a depth of about lj inches
(3 cm.). When the ventricles are much dilated and the cerebral
cortex thinned, the needle entering in almost any direction will usually
find fluid. In older children and adults the method of trephining as
devised by Keen or Kocher may be employed. It is always advisable
to withdraw by aspiration large quantities of cerebrospinal fluid.
Far larger amounts of serum can be introduced without danger into
the ventricle than by the intraspinous route. It is preferable to
enter each ventricle on alternate days but in the cases requiring tre-
phine it has been our custom to inject through a single opening.
Complete drainage of both ventricles can be accomplished easily by
changing the position of the head during the process. Care should
be observed when one opening is used that there is free communica-
tion between the ventricles. Cases have been reported in which the
exudate has blocked the foramina of Munroe and under such circum-
stances the serum would not circulate freely within the ventricular
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TREATMENT OF MENINGOCOCCUS MENINGITIS 201
cavities. Various surgical procedures having for their objective
continuous drainage have been employed but such methods offer no
improvement over the method of ventricular puncture, with serum
administration during the period of acute symptoms.
fjj!J>S3SS§253S§838§|lj?
Chart VII.
Slight Improvement with Intraspinous Therapy but Immediate Cure when Com-
bined with Intraventricular Treatment
OTHER LOCATIONS RECOMMENDED FOR THE INJECTION OF SERUM
The introduction of fluid in other locations in order to overcome
obstruction has been attempted by different clinicians. Chartier,
Cantas, Ravaut and Krolunitsky and Netter have injected serum
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202 KENNETH D. BLACKFAN
in the dorsal and cervical regions. Punctures of the subarachnoid
space in these locations were followed in some of their patients by
convulsions. A patient so treated by Cantas recovered- Cazamian
treated three patients by the injection of serum through the orbifco-
sphenoidal route. One patient recovered. The technique of sphe-
noidal puncture is as follows: A pointed trocar and cannula is intro-
duced at a point 2 mm. from the supraorbital notch, the trocar is
then pushed slightly upwards and inward to reach the bony vault
of the orbit. The pointed trocar is withdrawn and a blunt one sub-
stituted. By a little probing the most external portion of the sphe-
noidal fissure is reached. A fibrous membrane is pierced. The
trocar, the inner end of which is in contact with the base, is then
withdrawn and cerebrospinal fluid escapes. Serum is then injected
through the cannula left in position.
Wegeforth and co-workers have used the space between the occi-
put and atlas to obtain cerebrospinal fluid from animals and believe
that it may readily be used in man. They state that by this proce-
dure specific therapy could be given more efficiently in early meningitis
and indicate that it should prove of value in reaching the upper
fluid reservoirs of the central nervous system when the spinal sub-
arachnoid space is blocked. At the present time the method is
the most satisfactory that has been devised when there is obstruction
and when for any reason serum cannot be injected directly into the
ventricles. Whether it has an advantage over the ventricular route
remains to be determined.
In the chronic form of hydrocephalus after adhesions have taken
place and when viable organisms cannot be demonstrated, the proc-
ess cannot be further influenced by the injection of antimeningococcus
serum. In the communicating type of hydrocephalus repeated
lumbar puncture may be tried in the hope that the removal of large
amounts of cerebrospinal fluid at regular intervals will retard the
further development of the hydrocephalus until an equilibrium between
the production of cerebrospinal fluid and its absorption is established.
Although this does take place in a small percentage of cases, re-
peated lumbar puncture should only be tried temporarily, as perma-
nent relief by more radical surgical methods cannot be expected if
the hydrocephalus has reached an advanced degree. In obstructive
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TREATMENT OF MENINGOCOCCUS MENINGITIS 203
hydrocephalus eariy surgical interference is indicated. Operative
measures for the relief of chronic hydrocephalus heretofore have been
uniformly unsuccessful. It is hoped that by the methods devised
by Dandy successful results will be secured for the reKef of this other-
wise hopeless sequela of meningococcus meningitis.
OTHER COMPLICATIONS AND SEQUELAE OP MENINGITIS
To those who have had experience with meningitis before and
after the introduction of serum treatment, it is very evident that by
serum treatment the complications and serious sequelae have been
greatly reduced. Statistics bear this out. Recovery in the great
majority of cases treated is complete. Flexner states that formerly
there were sequelae in about 20 or 25 per cent of the 25 per cent of
patients that recovered from meningococcus meningitis. In the
recent epidemics with serum treatment they have been reduced to
about 6 per cent.
\V0r3ter-Dr0ught and Kennedy have collected the more serious
sequelae which have occurred in 120 patients from two months to
one year after recovery. Their summary follows:
Strabismus.... 2
Blindness 1
(One eye)
Monoplegia 1
(Function restored 7 months after recovery)
Hemiplegia 2
(Function restored 7} months after recovery)
True neurasthenia 4
Deafness 2
Deaf ness partial 1
Of 94 patients in military service 11 were discharged because of the
following sequelae:
cases
Neurasthenia 5
Deafness 2
Strabismus 1
Blindness 1
Residual weakness of 1 foot after hemiplegia 1
Persistent pain in htmbar region on exertion 1
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204 KENNETH D. BLACKFAN
According to Flexner's figures in the preserum period deafness was
found in 12 to 33 per cent of the cases recovering. Among the serum
treated cases it occurs in only 3.5 per cent. Deafness of central
origin resulting from meningococcus meningitis is an early symptom
and when it occurs it is almost always permanent. It is not influenced
by treatment.
Eye complications are less frequent and take the form of a con-
junctivitis, a severe uveitis, panophthalmitis and oJ>tic atrophy.
Four to 6 per cent of the cases formerly developed eye complications.
In Flexner's series the incidence was only 1 per cent. Uveitis may
be and usually is followed by a panophthalmitis. As loss of vision
is the usual sequel, the drastic method of the early intravitreous in-
jection of serum has been advised. Netter reports two cases in
which this was followed by improvement and the preservation of
sight. Optic atrophy resulting from hydrocephalus is permanent
and incurable.
Arthritis as a complication of meningococcus meningitis has been
recognized for many years. Herrick and Parkhurst and Sainton have
recently reported series of cases of arthritis which they have observed
in recent epidemics. They found that arthritis not only might be
associated with meningitis butitmight be associated with meningococ-
caemia apart from a meningitis. A distinction has to be made be-
tween the arthritis resulting from meningococcus infection and that
which occurs with serum sickness. Symptoms of arthritis depending
upon an infection may occur at the onset of the disease or they may
appear as late as the fifth or sixth day. The swelling may be great
but there is always a striking disproportion between the amount of
swelling and the other signs of inflammation, redness and pain, etc.
Cure is usually spontaneous. The injection of serum directly into
the joint in severe cases has been advised.
In the subacute and chronic stages of meningococcus meningitis,
a secondary bronchopneumonia frequently occurs as a terminal event.
Most frequently it is due to the pneumococcus, streptococcus or
staphylococcus aureus. It is not unusual to recover the meningococcus
from the sputum and from the lungs postmortem in such cases. That
the meningococcus may produce a fatal pneumonia has also been
recognized. Holm and Davison, as the result of their studies of pneu-
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TREATMENT OP MENINGOCOCCUS MENINGITIS 205
monia in France found that the meningococci present in the lungs in
cases of meningococcus pneumonia were essentially the same type of
organisms as those present in the cerebrospinal fluid. They showed
that the organism may produce either a lobular or a lobar pneumonia
with or without a meningitis. Treatment with serum intravenously
or with vaccines should be tried in such cases.
Other complications such as pericarditis, myocarditis, endocarditis,
pyelitis, tystitis, paralyses, etc., are to be treated according to the
usual methods.
In the convalescent period of meningococcus meningitis various
symptoms may appear. These are paralyses, irritability, pain,
weakness and stiffness of the back, mental impairment, neurasthenia,
etc. There is often awkwardness in walking and even paralysis of
the bladder and rectum have been reported. Much attention has
been directed to these symptoms since the introduction of serum
treatment. It has been considered by some authors that these symp-
toms are the direct result of the repeated lumbar punctures and the
injection of antimeningococcus serum. Whether they are or whether
they are sequels of the disease itself it is hard to determine. Some
writers have maintained that lesions of the cauda equina are respon-
sible for many of the symptoms. Worster-Drought and Kennedy
carefully examined 120 patients who had recovered from meningitis
for evidences of such lesions. The number of punctures which had
been performed on the patients varied from four to thirty-five. In
no case were there any areas of anesthesia corresponding to the dis-
tribution of the fourth and fifth sacral nerves. Worster-Drought
and Kennedy believe that pain and weakness in the back are a sequel
of the disease and are not dependent on the punctures and admin-
istration of serum. Fortunately the symptoms that have been
described are relatively rare. They are more common with adults
than with children. They may disappear early in convalescence
or they may persist for weeks or months. Recovery is usually
complete.
SERUM DISEASE
The manifestations of serum disease in general that follow the
injection of antimeningococcus serum are much the same as those
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206 KENNETH D. BLACKTAN
that follow the injection of any therapeutic sera made by immun-
izing horses. It was believed at one time that the manifestations
were more frequent after the intraspinous injection than after the
intramuscular or subcutaneous; injection of serum but RoUeston and
Kerr are of the opinion that this has not been proven. The incidence
of serum sickness is influenced by the source of the serum as it is
weH known that serum from some horses is more apt to provoke
serum sickness than that from others. The amount of serum injected
may have some influence upon the incidence of serum sickness.
Longcope and Rackemann believe that the smaller the amount of
serum the less frequent and severe the reactions. Judging from
clinical experience, however, there seems to be no constant relation
between the incidence of serum disease and the amount of serum
injected at one dose or the total amount used in the treatment of a
patient. The symptoms usually appear from the 7th to the 10th
day after the first dose of serum, although they may appear earlier
or later than this. The commonest symptom to appear is an
urticarial or erythematous rash and with its appearance there may
be an initial rise in temperature. In many cases joints become red,
swollen and tender and even an effusion into the joint may take
place. There are muscular pains especially in the back. Edema of
the face and tongue and of the penis and the scrotum may develop.
Inasmuch as the meningeal symptoms are often intensified during
serum sickness, care must be taken not to mistake the recrudescence
of meningeal symptoms due to a serum disease for a recrudescence of
the meningitis. When in doubt as to a differentiation between them,
the safest procedure is to make a lumbar, puncture and examine
the cerebrospinal fluid for meningococci. In many of the patients
the symptoms are so mild that treatment is not necessary. In the
more severe reactions with itching of the skin, the local application
of sodium bicarbonate solution, a 1 per cent menthol solution or
calamine lotion often affords relief but sedatives sometimes are
required for the itching and it is frequently necessary to give them
for the pain which accompanies arthritis. The hypodermic admin-
istration of adrenalin in full doses often will cause the edema and
urticaria rapidly to disappear.
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TREATMENT OF MENINGOCOCCUS MENINGITIS 207
ANAPHYLAXIS
Although a primary injection of serum does not always sensitize
an individual, symptoms of anaphylaxis do occur in about 75 per
cent of the patients if they receive serum at such intervals that a
week or more elapses between doses. The symptoms may be as
mfld as those txxurring in serum sickness, or they be very severe and
alarming. There may be an universal urticaria or a marked edema
especially of the mouth, ears, eyes and larynx. The patient may
become cyanosed with great respiratory distress. The temperature
is often elevated. As a rule the symptoms gradually subside but
marked prostration is apt to continue for several days. The severe
reactions may occur after a short latent period of time or they may
come on immediately (Goodall) . Fatal results following the injection
of serum are rare. Most of the cases reported have been in indi-
viduals who were hypersensitive to protein such as those who have
suffered from asthma or in people with the habitus known as status
thymicolymphaticus. In such patients a death almost always
occurs immediately following the first injection of serum.
A patient who is sensitive to foreign protein or who has shown
symptoms of anaphylaxis at a preceding injection should always be
desensitized before the reactivating therapeutic dose is administered.
This may be done by diluting 5 cc. of serum with SO cc. of normal
saline solution and injecting intravenously small amounts (1 to 25
cc. of the dilution) slowly at intervals over a period of fifteen minutes.
Fifteen minutes after the last injection the full dose may safely be
administered. At any time during the administration of serum,
if symptoms of anaphylaxis appear, the injection should be discon-
tinued. The attempt may be repeated later after desensitization.
The alarming symptoms are combated by epinephrin 1:1000 solu-
tion, 5 to 20 minijns and atropin grains t$V to rhr injected intramuscu-
larly or intravenously. Whenever serum is being administered these
solutions should be ready for immediate use in case symptoms of
anaphylaxis develop.
INFLUENCE OF SERUM THERAPY ON THE DISEASE
Statistics which show the effect of the serum treatment of menin-
gitis in comparison with the results of preserum treatment are striking.
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208
KENNETH D. BLACKFAN
Jochmann in 1906 had a death rate of 27 per cent as compared with
53 per cent in the untreated cases; Kolle and Wassermann in 1907
reported a mortality of 47.3 per cent in serum treated cases. Levy
had a mortality of 16.2 per cent and 21.7 per cent in two epidemics
and Flexner and Jobling reported a mortality of 25 per cent in 393
cases. When it is remembered that the average mortality of meningo-
coccus meningitis untreated by serum was from 60 to 80 per cent
whereas the average mortality for three years following serum therapy
was 36 per cent, the benefits from the serum can readily be appre-
ciated. The following table of statistics compiled by various ob-
servers illustrates the mortality rate before serum treatment com-
pared with that following its use. These figures leave no doubt as
to the effectiveness of this form of treatment.
AUTHOR
CASES BLEATED
WITH SERUM
8ERUM USED
SERUM TREATED
MORTALITY
CASES MOT TREATED
WITH
SERUM MORTALITY
Flexner
1300
100
300
402
165
2280
Flexner *s
Flexner *s
Flexner 's
Dopter's
Kolle-
Wassermann
Flexner's
30.9
28.0
30.0
16.4
18.4
37.0
70
Netter
49
Robb
72
Dopter
65
Levy
Steiner
52
77
So far as the benefits of serum treatment are shown, one need not
look further than the figures which are given above.
The beneficial results of the serum are particularly apparent in
the results obtained with small infants. Children under two years
of age without serum almost always died and the mortality in those
under a year was nearly 100 per cent. While meningitis is still most
fatal in young children, a considerable number of infants may be
saved, even some as young as three months of age. Seventy-eight
patients under two years of age with meningococcus meningitis have
been treated in this clinic and the mortality has been 52 per cent.
Furthermore with serum treatment the number of complications
and sequelae has been greatly lessened as has been pointed out.
The mortality even with serum therapy is likely to vary greatly
in different epidemics and at different times in the same epidemic.
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TREATMENT OF MENINGOCOCCUS MENINGITIS
209
Early in epidemics there are a larger number of fulminating cases than
at the close and the virulence of the infection tends to subside and
to be least in sporadic cases. For these reasons the mortality even
with serum treatment is apt to be high at the beginning of the epi-
demics. The duration of the disease before treatment is begun has a
great influence upon the mortality. This has been the experience of
all observers as shown in the following chart:
Mortality per cent compared with day of beginning therapy
DAY
TLEXNER
NETTER
DOPTER
CHR1ST-
MANOS
LEVY
FLACK
Before 3
percent
18
27
36
percent
7
11
23
percent
8
14
24
percent
13
25
47
percent
13
29
28
percent
9
From 4to7
After 7
50
Finally the factor which has the greatest influence on the mortality
of meningococcus meningitis is the potency of the serum employed.
During 1914 to 1915 when meningococcus meningitis appeared among
the armed forces of Great Britain, the results of serum treatment
were so unsatisfactory that a number of workers were inclined to
believe that as much benefit was obtained from lumbar puncture
alone as by the use of serum. Foster and Gaskell in their monograph
on cerebrospinal fever not only advocate lumbar puncture as the
only reliable therapeutic procedure but suggest that the injection of
serum may even do harm. Many of the cases were not treated suffi-
ciently early and the dosage of the serum and frequency with which
it was administered varied within wide limits. It was then shown
that the quality of the serum was of low standard and its potency
practically nil owing to the fact that the strains of meningococci
causing the infection were not used in the preparation of the serum.
Later when a serum was employed which contained all the types of
the organism criticism of the effectiveness of antimeningococcus serum
ceased. In the first year of the war the mortality in serum treated
cases was 61 per cent. In the following years when a properly pre-
pared and standardized serum was used, it was about 27 per cent.
This experience has demonstrated that the commercial manufacturer
cannot be permitted to determine the method of preparation and
choose his own standard of potency.
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210 KENNETH D. BLACKFAN
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THE ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA
HANS ZINSSER
New York
TABLE 07 CONTENTS
Introduction 213
Historical r&ume' 215
Clinical course of influenza '. 217
Etiology of influenza 223
Former epidemics 223
Carriers 230
Recent epidemic of 1918 232
The bearing of serological evidence on etiology 247
Vaccination 251
Inoculation experiments 253
Filtrable virus 258
Summary 264
Epidemiology of influenza 268
Former epidemics 268
Manner of transmission of influenza 271
Onset of epidemics of influenza 277
Secondary outbreaks 280
The origin of epidemics of influenza, with particular reference to the origin and
course of the last pandemic outbreak 285
Course of the pandemic of 191 8 : 291
The problem of immunity in influenza 296
Fluctuations of virulence, and epidemiology 299
Summary 303
References 304
INTRODUCTION
The etiological and epidemiological problems of no disease can be
intelligently discussed until we can precede discussion with a clear cut
definition of the disease itself. In infectious diseases like smallpox,
scarlet fever, measles, diphtheria, and pneumonia, investigation is
sure to deal with a material which is amenable to reliable selection on
clinical grounds. In the case of influenza it is the difficulty of sharply
defining the disease, which has been, and still is, at the bottom of the
confusion prevailing in research. Whenever widespread epidemics
213
UBDionra, vol. i, mo. 2
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214 HANS ZINSSER
of so-called "catarrhal fever" have swept over large sections of the
world, the epidemic characteristics in themselves, as well as a certain
regularity of onset, sequence and similarity of course, have sufficiently
indicated the basic identity of the cases. It has been clearly recog-
nized, however, that except at the very beginnings of every epidemic,
clinical manifestations have been dominated by the complications,
rather than by the original infection. And these complications, in
their localizations, pathology and bacteriology have been subject to
wide variations. For these reasons the diagnosis of influenza made
upon isolated cases of respiratory infection at times when no epidemic
prevailed, has been admittedly more a clinical surmise than a scientif-
ically formulated conclusion. This has been clear to well trained
physicians for many years, and the term "influenza" has been used
by them during interepidemic periods as a term of clinical convenience,
to characterize conditions ranging in seriousness from severe coryza,
with systemic symptoms, to fatal lobular pneumonia. It may well be
that many of these cases have had a specific influenzal basis, and rep-
resent the smouldering embers from which the flames of new epide-
mics are lighted, but there is no way at the present time of being sure
of this in individual cases.
It would be a relatively simple matter if we could base the diag-
nosis of true influenza upon the isolation of Pfeiffer bacilli, just as
we determine the diagnosis of diphtheria by the isolation of the
Klebbs-Loeffier bacillus. But for reasons which will become clear
presently, this cannot be done. For, even through the Pfeiffer
bacillus should eventually prove to be the specific etiological factor
in influenza, it is still so frequent as a complicating agent in other
respiratory infections, or perhaps as a symbiant in the upper air
passages of normal individuals, that its mere presence in the secretions
of a catarrhally inflamed mucosa, does not characterize the infection
etiologically.
The relationship of this bacillus to the disease presents a problem of
great complexity and of many uncertainties which will be discussed
more extensively below. Before we can proceed to this, however, it
will be necessary to specify more precisely just what we believe should
be the proper characterization of uncomplicated influenza in a clinical
sense. For unless this is clear it will be impossible to determine
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 215
whether bacteriological or other etiological investigations have dealt
with the disease itself or with one or another of the manifold
complications.
HISTORICAL k£sUM£
In the older works many accurate descriptions of uncomplicated
influenza are available. Huxham writing of the epidemic which
occurred in Plymouth in the first half of the eighteenth century, de-
scribes the disease as one of very sudden onset, chilliness and fever,
usually lasting about four days, and rarely ending fatally. He men-
tions catarrhal inflammations of the nose and throat, and the fre-
quent occurrence later in the disease, of a cough, but lays stress not
upon these catarrhal symptoms, but rather upon the suddenness of
onset, the fever, the short duration and the low mortality. Arbuth-
not in 1732 speaks of a remarkable uniformity of symptoms, "a small
rigor or chilliness, succeeded with fever of a duration seldom above
three days." He says, "this disease was not in itself mortal, but it
swept away a great many of poor, old and consumptive people."
Thompson in his Annals of Influenza (London, 1852) summarizes
the clinical manifestations by laying stress upon the sudden feverish
onset, chilliness, and pains in the neck, back and loins, suffusion of
the eyes; coryza and bronchitis are mentioned as later developments.
Most of these writers, more especially Thompson, recognized the
inflammations of the bronchi, pleura, and lungs as probable complica-
tions frequently present, but not as uniformly characteristic as the
fever, pains, an!d the prostration which was often extreme without
sufficient apparent reason in any discoverable lesions. It is interest-
ing to note that these early writers described an intestinal form.
Thompson speaks of it as follows: "When the lungs are not materially
affected, the force of the morbid influence is in some instances directed
to the bowels, producing pain and tenderness of the abdomen, and
diarrhea, with mucous or dysenteric evacuations."
Leichtenstern described "typical influenza" as follows (we translate
literally):
Typical influenza consists in a sudden fever which is initiated by a chill
or frequent chilly sensations, and lasts from one to several days, is associated
with severe headache, especially in the frontal regions, vertigo, pain in the
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216 HANS ZINSSER
back and legs, disproportionately severe prostration, and loss of appetite.
After ten to twelve hours perspiration ensues, and in twenty-four to forty-
eight hours the fever has usually subsided in many of the patients, leaving
them with great weakness and with pains in the muscles and joints which
disappear within a few days.
In almost all of the patients in whom the onset is violent there is an
immediately apparent diminution of urine. Many of the sick may not void
more than 200 to 300 cc. of urine in twenty-four to tbirty-six hours, and
with this there is often constipation. Many may show an enlargement
of the spleen.
By the third or fourth day as the patients recover, the constipation is
relieved, the urine becomes more plentiful, the albumin disappears, and
the splenic enlargement recedes.
This is the classical picture of influenza as Leichtenstern sets it
down in the summarizing paragraphs at the beginning of his clinical
chapter. He adds that: "symptoms of catarrhal inflammations of
the respiratory passages and especially of the nasopharynx often
supervene upon the manifestations described above, an occurrence
which is perfectly natural in view of the localization of the influenza
bacilli." Although, therefore, he does not make the direct statement,
he implies that he considers the catarrhal inflammations as probably
incidental.
It is a singular fact that, in spite of these and other accurate de-
scriptions of uncomplicated influenza, published since the time of
Sydenham, the disease has usually escaped general recognition in
epidemics until complications have become frequent.
Thus, Heyfelder, who observed the beginnings of the 1889 epidemic
in Russia and the East writes of "Sibirisches Fieber," which was at
first looked upon as malaria owing to the apparently complete absence
of the complicating lesions habitually associated in our minds with
influenza. Of particular interest is his statement: "Auch fehlten bei
den meisten die Katarrhalischen Affektionen der Respirations-
Organen." When the disease appeared in Petrograd, in November,
Heyfelder found that it corresponded accurately to the descriptions
of an epidemic of "Dengue fever" which was said to have been prev-
alent in Constantinople during the preceding September.
The recent pandemic furnishes many similar examples of early
confusion. When the disease first appeared at Camp Oglethorpe,
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 217
Georgia, in March 1918, its precise nature was long undetermined
though its similarity to influenza was recognized. Vaughan and
Palmer writing of this outbreak say; "The identity of the disease
has not been positively determined after nearly a month of obser-
vation;" and again they speak of it "as a disease with a strong
resemblance to influenza." In Italy Sampietro suggested Sandfly
fever, a thought which seems to have occurred to a number of British
writers, and which led us, as well, to make a brief study of prevailing
insects upon our first contact with the epidemic at Chaumont in May,
1918. Wherever the disease was first seen during the spring and
summer of 1918 it was characterized by explosive suddenness of onset,
and an enormous morbidity in individual groups within a few days;
but it was mild in nature, with little or no mortality, rare complica-
tions and so few of the catarrhal symptoms usually associated with
clinical conceptions of influenza that those that did occur were not
always regarded as characteristic manifestations of the "new disease."
Many of the earlier reports received in the spring of 1918, therefore,
were unanimous in agreement with the typical description of Leich-
tenstern. These made later in the year began progressively to em-
phasize the greater frequency of mild or severe inflammatory processes
in the upper air passages. Fortunately placed observers could follow
with considerable clearness the gradual transformation of the clinical
types encountered in successive outbreaks, from the mild "three-day
fever" of early spring to the grave respiratory illness of autumn.
But there was still in the minds of a considerable number of people
some question as to the basic identity of the early mild cases, and the
severe epidemic bronchopneumonias of October and November.
CLINICAL COURSE OF INFLUENZA
It will be useful to discuss briefly the early cases as we saw them
during the Chaumont epidemic, not because the observations made
there add much that is new from a clinical point of view, but because
they will remove any possible ambiguity concerning our conception
of influenza in its pure uncomplicated form.
As far as we can judge, the little outbreak at headquarters was
typical of the first advent of epidemic influenza in many places. The
population of the town, at the time, consisted of a large office per-
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218 HANS ZINSSER
sonnel attached to the military administration, scattered as to billets
and places of work; of military units living in barracks and eating at
common misses; and of the townspeople. The epidemic descended
upon individual military units with the suddenness of a storm, strik-
ing a considerable percentage of the men, perhaps most of the sus-
ceptible material, within less than a week, and ending almost as
abruptly, with only a few isolated cases trailing behind. Among the
more scattered office workers and among the townspeople it was
disseminated more gradually and trailed along for a longer period.
These early cases were clinically so uniform that a diagnosis could
be made from the history alone. The onset was almost uniformity
abrupt. Typical cases would become ill suddenly during the night
or at a given hour in the day. A patient who had been perfectly
well on going to bed, would suddenly awake with a severe headache,
chilliness, malaise and fever. Others would arise feeling perfectly
well in the morning, and at some time during the day would become
aware of headache and pains in the somatic muscles. Occasionally
there was nausea. A few of the patients could state fjie exact hour
at which they were taken ill. • One of them became suddenly ill
at the moment at which he was stepping into line for inspection.
Another was taken ill while standing guard, and again another while
being shaved. There were of course some cases in which the onset
was more gradual, but our personal impression is that the sudden
onset was the characteristic one, the more gradual one, the less usual
or modified.
The typical course of these cases may be exemplified by that of
J. T. W., a draftsman attached to the 29th Engineers. He was
perfectly well until May 20, working regularly, his bowels and appe-
tite normal, considering himself healthy. On May 21, at 4:30 a.m.
he awoke with a severe headache. He arose, forced himself to eat
breakfast and tried to go to work. He began to feel feverish and
chilly. At the same time his headache became worse, with pains
in the back, and burning in the eye balls. At 2 p.m. he reported sick,
and was taken to the hospital with a temperature of 102.8°. At
midnight his temperature dropped to 101.6°, and came down to nor-
mal by noon of May 22. As he recovered he developed a slight sore
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 219
throat, great soreness of the legs and a very slight cough. He recov-
ered completely within a few days.
These cases with a few exceptions developed no rashes. One or
two of them had blotchy red eruptions which we felt incompetent to
characterize dermatologically. The leucocyte counts ranged from
5000 to 9000. A very few went above this. Sometimes there was a
relative increase of lymphocytes, but this was by no means regular.
The few spinal fluids that were examined were normal. As to en-
Fig. 1. J. T. W. Company H., 29ih Engineers1
Draughtsman. Perfectly well Monday, May 20. Woke up Tuesday, 4:50 aon. with
violent headache. Got up and ate a little breakfast and went to work, then began to feel
feverish and chilly. Pain in back and headache and pain in eyes (burning), slight cough
and pain in legs. Reported sick 2:00 p.m. Since arrival in hospital cough worse and
slight sore throat.
largement of the spleen, we can say nothing definitely. Although
we looked for spleens and failed to find enlargements, we are not
willing, in view of our limited clinical habits, to say that they could
not have been felt by more experienced men.
1 These charts are taken from the report of Major Hans Zinsser, to the Chief Surgeon,
A. £. F., May 31, 1918. Blocked spaces indicate night periods in this and following
charts.
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We add a few typical charts.
Fig. 2. H. W. Company H., 29th Engineers
Slept in bunk next to W. Draughtsman, same office as W. Got sick on day after W.
On Tuesday, May 21, afternoon, headache, pain in bones, fever, burning in eyes. Did
not report sick until Wednesday, May 22. Slight sore throat. Felt better all over
before he came to hospital.
Fig. 3. S. L. Company C, Hq. Bn.
Was living with Company D when taken sick. Company Clerk. No one near him
sick in same way. Messed with Company D. Felt well Monday, May 20. Tuesday,
a.m. felt well until after breakfast, then headache. In afternoon went to dispensary and
was sent to hospital. Very slight cough since arrival in hospital. Throat not sore now,
and no pains. Is feeling well.
220
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other symptoms, went to dispensary because he felt feverish. Slight cough since arrival
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Monday, May 20. M. began to feel sick Wednesday, May 22, at night. Dizziness and.
headache, weakness, pain in back and legs. No nausea, nothing referable to intestines*.
221
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222
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Fte. 6. R. S., A. M. T., Company 504
Cook. Worked all day Wednesday. Began to fed sick about 4:00 p. m. Headache
after supper, nausea. Not very sick, sent to hospital by attendant at dispensary.
Soon after this we observed the disease in a division, the 42nd,
then holding a part of the line in front of Baccarat. Here it had al-
ready developed a somewhat different nature, due, we believe, to the
fact that the men of this division were not, as were those at Chaumont,
living in a rest area, but were actively engaged in military operations,
working, sleeping, and eating under conditions that involved greater
fatigue, less protection against weather, and greater crowding in
sleeping quarters. The Baccarat cases were much more frequently
catarrhal; sore throats, coughs and more serious respiratory com-
plications were more common. However, they were usually coupled
unmistakably with an underlying typical influenzal attack, sudden
onset, pains and short lived fever. Moreover, there were a great
many of the entirely uncomplicated cases interspersed with the
others.
Still later, in September, October and November, respiratory com-
plications were so frequent and severe, came on so early in the disease,
and the pneumonia mortality became so high that the fundamental
identity of these later cases with the early three-day fever might
easily have been lost sight of by observers who had not followed the
gradual transformation.
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 223
In consideration of these facts, it is apparent that etiological or
other investigations can throw no light upon the problems of influenza
unless they are carried out with a clear understanding of the dif-
ferentiation between the complications and the basic disease.
The serious respiratory infections of the bronchi and lungs we can
set down with reasonable certainty as complications due, certainly in
the overwhelming majority of cases, to secondary bacterial invaders.
It is a matter of considerable difficulty, however, to know exactly
where the basic disease stops and the complications begin; and
whether we must regard the mild sore throat and conjunctival in-
fection which so often accompany the simple cases as a part of this
basic clinical picture, or as the simplest variety of complication.
This is much more than an academic question, since, as we shall see,
the bacteriological analyses of such lesions have played an important
rdle in etiological investigations.
ETIOLOGY OF INFLUENZA
Former epidemics
The significance of sharp clinical definitions for etiological research
in influenza is obvious. The simple form of the uncomplicated disease
is common only during the early stages of epidemics. After this,
most of the cases may perhaps begin with this basic condition, but
are very rapidly complicated by more or less serious inflammatory
involvement of the respiratory passages. Some of the milder and
perhaps some of the more serious and even fatal of these complica-
tions may be due to the infectious agent which causes the original
disease; but a great many of them we know are caused by secondary
invaders, and for this reason bacteriological analyses made from the
secretions and the lesions of the respiratory passages in such cases
must be interpreted with constant realization of the possibility that
we are dealing with secondary invaders and not with the primary
infectious agent. This has been the difficulty in etiological influenza
research, and in the light of this confusing state of affairs, no results
are of great value unless combined with a correspondingly careful
clinical analysis of the cases from which the material has been taken.
When the pandemic of 1889 was beginning to trail into its last stages
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224 HANS ZINSSER
there seemed to be little doubt in the minds of investigators concerning
the etiological significance of the Pfeiffer bacillus. At the present
time, with the experiences of another outbreak behind us, we are less
certain of this relationship than we were before.
It will be well to state, at the beginning, that we do not believe that
final conclusions concerning the etiology of influenza are warranted
at the present time. The problem has been a singularly difficult one,
largely owing to the indefinite clinical conceptions of the disease
alluded to above. For these reasons one cannot do justice to the
etiological problem without discussing at some length the more im-
portant investigations which have dealt with this subject during the
two last epidemics and in the interepidemic period.
After 1889 many etiological "suggestions" (we had best term them)
were made, prior to the publication of Pfeiffer's observations. Klebs
reported that he had found protozoa in influenza lesions, a claim which
finds an interesting parallel in the recent reports of Binder and Prell
who have described minute coccoid bodies in the tissue spaces around
blood vessels in influenza lungs, and the subsequent development in
cultures from such material of small organisms which they regard as
"chlamydozoa." Comment on such findings is unprofitable at the
present time. We can merely "file" them in our minds for reference
and, perhaps, future explanation. The past has been too rich in
misleading interpretations of so-called "chlamydozoan" cell inclusions
(variola, trachoma, etc.) to encourage optimism concerning such
claims.
As in the recent outbreak the preceding one was the occasion for
etiological proposals involving the Gram-positive cocci, more parti-
cularly the pneumococcus and streptococcus groups. However, it
is perfectly natural that bacteria which habitually inhabit the upper
respiratory passages, and are potentially pathogenic, should be
isolated with great frequency from influenza cases, and, therefore,
incite suspicion of etiological importance; but none of these can be
seriously considered. Indeed, in the light of our present differentia-
tion between the basic disease and the complications, the streptococci
and pneumococci may be regarded as practically eliminated as pri-
mary causations of influenza. The same is true to an even greater
degree of organisms like micrococcus catarrhalis, meningococcus, para-
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 225
typhoid bacilli, and many other bacteria which have been isolated
from time to time as characteristic findings in small groups of cases
occurring in special localities. Some of these investigations will be
briefly dealt with in a later paragraph.
We believe, indeed, that we are justified in basing our discussion of
etiology upon the assumption that none of the bacteria so far described
can be seriously considered in this connection except the group of
haemophile organisms of which we speak as "Pfeiffer bacilli.,, If
influenza is truly a disease of bacterial causation these precede all
other bacteria in etiological likelihood.
Pfeiffer published his first announcement in 1892, reporting that
he had found the organisms, which are now familiar to us as the typi-
cal influenza bacillus, in the sputum of patients, but had failed to
find them in normal controls. In a subsequent article in the Zeit-
schrift fur Hygiene (13, 1892) he brought together the large material
of his researches, the results of which may be stated briefly as follows.
The organisms were present in large numbers in the sputa of early
cases and, at this early stage, were largely extracellular. Later,
most of the sputum organisms became intracellular and, in the
milder cases, gradually disappeared. In cases with pulmonary com-
plications which came to autopsy, if the bacterial contents of the
respiratory passages were examined in progressively downward stages
from the pharynx into the lungs, influenza bacilli were found with
increasing predominance as the examination proceeded toward the
smaller bronchi and bronchioles. In the pulmonary tissues them-
selves they were sometimes present in pure culture. (Compare with
observations of Richard Taylor, 1918. Vide infra.) He cultivated
the bacilli on haemoglobin media and described definite cultural and
morphological characteristics.
The great importance of Pfeiffer's announcement naturally led to
extensive work on the isolation of haemophile bacilli all over the world.
The results seemed to indicate rapid and complete confirmation of
his claims. Weichselbaum found the bacilli in the lungs of a con-
siderable number of autopsies on cases that had died of broncho-
pneumonia secondary to typical influenza. Huber, Baiimler, Kretz,
Chiari found them in sputum, lungs and nasopharyngeal cavities of
many typical cases. Kruse found them in 100 per cent of the early
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226 HANS ZINSSER
cases he examined. With increasing frequency the organisms were
isolated not only from the respiratory passages, but from other organs
in which lesions secondary to influenza had developed. Pfuhl found
them in the spinal fluids of soldiers that had died of meningitis, com-
plicating influenza, and Nauwerck found them in sections of the brain
in a similar cases of encephalitis. It would be possible to multiply
indefinitely the accounts of similar findings. Careful investigations
during these years seemed to yield positive results with such regu-
larity that isolation of the bacillus was utilized diagnostically, and
very little or no doubt concerning its etiological significance remained
at the end of this epidemic. A few such accidents, moreover, as that
of Kretz who infected himself from a pure culture and came down
with an acute respiratory catarrh and many of the symptoms of a
typical influenzal attack, appeared to remove all remaining uncer-
tainty. Pfeiffer's original claims seemed to have been satisfactorily
confirmed, and his own conclusions were accepted by most of his
contemporaries.
The term "influenza" which had hitherto represented a purely
clinical conception was now changed to an etiological one, and its
diagnostic use was governed largely by isolation or failure to isolate
influenza bacilli. This conception was further strengthened by
studies such as those of Tedesco and of Scheller who found that,
during the years following the epidemic period, the isolation of in-
fluenza bacilli from respiratory lesions became more and more infre-
quent as the epidemic receded into the past. At the same time fewer
and fewer carriers of the organism were found among normal indivi-
duals. Even in patients who appeared to present the clinical picture
of so-called "grippe" the bacilli became more and more rare in the
course of successive years. Leichtenstern states that, in 1892, toward
the end of the epidemic, a very large number of pure influenza bacillus
infections of the bronchial tree occurred all over Germany, but that,
in 1900, Wassermann had the greatest difficulty in finding influenza
bacilli at all, even in cases clinically diagnosed as Influenza in Berlin.
A similar statement in regard to work done in 1903 was made by Beck;
and, indeed, most bacteriologists will probably confirm our own
experience to the effect that, during the years immediately preceding
the war, the discovery of influenza bacilli in the respiratory passages
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 227
of adults, was not particularly frequent. And when it did occur
the clinical condition was rarely one which could properly be spoken
of as influenza.
Thus, the frequent association of the organisms with typical cases
both in complicating and secondary lesions, their presence in a con-
siderable number of normal individuals during times of epidemic
prevalence and the progressively diminishing frequency of such
findings in the course of the years following the epidemic, all these
observations seemed to indicate clearly that the bacilli were etiologi-
cally related to the disease.
Nevertheless, during subsequent years evidence accumulated to
show that even in the interepidemic period the Pf eiffer bacillus group
was present in a variety of human lesions, sometimes as a harmless
saprophyte, sometimes with definite pathogenic properties, and many
times in conditions which had little or no resemblance to clinical
epidemic influenza. It appears that after the epidemic had subsided
the organism was still widely distributed among human beings, and
a study of this interepidemic distribution is necessary in order that
we may possess a complete picture of the pathogenic possibilities of
bacteria of this group. For if we should find that these organisms
can exist either as harmless saprophytes or as pathogenic agents never
giving rise to typical influenza in these periods of interval, this would
detract considerably from the trustworthiness of any conclusions
formulated in regard to their specific pathogenic properties.
Leichtenstern has made extensive studies of the literature with
the purpose of ascertaining the nature of the lesions with which in-
fluenza bacilli were most frequently associated during the years
following the pandemic of 1889 to 1892. These and subsequent
studies reveal an astonishingly wide distribution of the organisms,
and their association with a variety of lesions second only to that of
the Gram-positive cocci.
The presence of the bacilli in tuberculous processes was noted by
Pfeiffer in his early studies, and since then has been observed by
Ortner and many other workers. It is especially frequent when
bronchiectatic cavities exist. A series of such cases was reported by
Boggs, in which the influenza bacilli were apparently symbiotic with
other bacteria in the cavity fluids, without being responsible for
symptoms of any considerable severity.
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228 HANS ZINSSER
In the blood, at autopsy, influenza bacilli have frequently been
found. Jaehle (Zeit. f. Heilkunde, 1901, XXH, 190) isolated the
bacilli from the heart's blood in two of 48 scarlet fever autopsies.
In 19 of these pulmonary influenza bacillus infection was present.
In 23 autopsy blood-cultures of patients dead of measles, he found
the influenza bacillus 15 times. In one of these he found the bacilli
in the blood when the only other influenza bacillus lesion in the body
was a massive infection of the tonsils. He found them 5 times in
the blood of 9 cases of chickenpox, and twice in 24 cases of whooping
cough. He found them also in the respiratory passages in 15 cases
of diphtheria; in one of these the bacillus was present in the blood as
well.
Wynekoop in* 1903 studied the presence of influenza bacilli in
inflammations of the larynx, pharynx and nose. In certain forms of
chronic laryngitis he often obtained the organisms in pure culture.
He found them in tonsillitis, and described a peculiar form of severe
pharyngitis in which they were present with considerable regularity.
Some of these cases simulated mild diphtheria. He often obtained
the bacilli from the conjunctivae, and emphasized the fact that pure
influenza bacillus infections usually tend to rapid recovery.
Madison has collected 30 cases in which influenza bacilli were
grown from the blood during life. He himself reported a primary
influenza bacillus bronchopneumonia in which smears from the
sputum constantly showed large numbers of influenza bacilli, and in
which a positive blood culture was obtained. Similar cases have
been described by Meunier, Horder, Smith, Slawyk and others.
Infections of the central nervous system with influenza bacilli
have been reported by Pfiihl; influenza meningitis has been extensively
studied by Wollstein, by Dudgeon and Adams, Saathoff and many
others. A curious observation of interest in this connection has been
related to us by Dr. Emmet Holt, who tells us that although influenza
meningitis had not been infrequent in the Baby's Hospital in New
York during the interepidemic period, he had seen practically none
of these cases during the recent epidemic.
The presence of the organisms in suppurations of the nasal cavities,
the orbit and frontal sinuses, has been reported in a great many cases.
We have seen several examples of this, some in children, some in
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 229
adults, in which a chronic influenza bacillus infection of the nasal
cavities and antrum was apparently responsible for intermittent
asthmatic attacks; and the persistence with which these organisms
may remain chronically present in the deeper respiratory passages of
children following bronchopneumonia, bronchitis, or whooping cough,
and their apparent responsibility for prolonged cough and general
malnutrition are too well known to require comment.
The bacillus has also been occasionally found in acute and chronic
gallbladder infections (Heyrowsky and Kuina).
Among the most interesting studies on the association of influenza
bacilli with interepidemic pulmonary disease are those made by
Wollstein upon children at the Babys' Hospital in New York. In
1906 at a time about midway between the two last pandemics Woll-
stein published observations on children suffering from various types
of respiratory infection. Briefly summarized, her results were as
follows: Influenza bacilli were present in 16 of 53 cases of broncho-
pneumonia, and in 1 of 8 cases of lobar pneumonia, when the cultures
were taken during life. Of 13 cases of bronchopneumonia studied
at autopsy the organisms were found three times. They were found
6 times in connection with tuberculosis, and in isolated cases in various
other conditions in which the lungs were inflamed. In agreement
with other workers, she frequently found the organisms in whooping
cough, and 9 times in 27 cases of measles. This last result is in keep-
ing with many other investigations upon measles. Liebscher for
instance found the organism in 11 of 57 measles cases during life, and
3 times in the lungs at autopsy; he observed a higher death rate in
the influenza bacillus cases than in the others. Slisswein saw the
bacilli in the nasal secretions in almost 50 per cent of such cases, and
3 times in the lungs at autopsy. Jaehle and Jochmann have made
similar observations, and Albrecht and v. Preyss obtained the or-
ganisms from the lungs in post-measles pneumonia.
The great frequency of conjunctival infection with the influenza
bacillus has been mentioned. It is quite probable (Williams, Woll-
stein, and others) that the so-called Koch-Weeks bacillus should be
regarded as belonging to the group of the true influenza bacilli, and
many mild and severe conjunctival inflammations have been found to
be due to these organisms. Zur Nedden, Wynekoop, Williams, Woll-
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230 HANS ZINSSER
stein, and others have described a great many such cases, and Wyne
koop and Wollstein particularly have reported instances in which
severe hemorrhagic inflammations of the conjunctivae have shown
influenza bacilli in pure culture. In some of these mild systemic
symptoms were present.
It is interesting to note, that Wollstein in her extensive studies
on influenza bacilli in babies has found the organisms very rarely
in the throats of healthy children or in the throats of children who
did not have respiratory lesions. She states that whenever the or-
ganisms were found, they seemed to exert a definite influence upon
the severity of the disease. Death rates were higher, and in the
bronchopneumonias with influenza bacilli there was higher tempera-
ture, greater prostration, and a longer duration of the illness. Such
observations would particularly incline one to accept Ortner's opinion
that true influenza may remain endemic in the intervals between
epidemics as a definite clinical condition, an opinion confirmed to us
on purely clinical grounds by a number of experienced physicians.
Indeed, in the intervals between large influenza epidemics there
may be occasional isolated epidemics in closed institutions, such as
asylums and homes for the aged. Such epidemics were reported by
Sturrock in 1900, and by Nobecourt and Paisseau in 1905, Un-
fortunately etiological investigations of such outbreaks have yielded
little additional light.
Carriers
That the carrier state may persist after infection with influenza
bacilli is unquestionable. During the last epidemic Pritchett and
Stillman cultivated the influenza bacillus from the mouths of 93 per
cent of cases of influenza and bronchopneumonia, and at the same
time they found it in 43 per cent of normal individuals. Lord, Scott
and Nye during the same epidemic found influenza bacilli in 76 per
cent of 34 men in the Harvard Students' Training Corps. At Camp
Funston, Opie, Freeman, Blake, Small and Rivers found influenza
bacilli in the mouths of 35.1 per cent of healthy soldiers. Subse-
quently, Winchell and Stillman f ound that the percentage of influenza
bacilli in the throats of normal people during post-epidemic periods
was as high as it was during more active epidemic stages. In ISO
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 231
individuals they found the organisms in 41 per cent. In a boys'
orphan asylum in which no influenza had occurred during the epi-
demic, 39 per cent of the throats were positive, a percentage which
was equal to that found in convalescents in an institution in which
about half of the inmates had had the disease. They found carriers
who had retained the organisms for four and five months after
convalescence.
The experiments of Bloomfield have to a certain extent contradi-
cated this in that Bloomfield introduced three different strains of the
bacilli in large quantities into the upper air passages of normal in-
dividuals without being able to produce the carrier state. He ob-
tained neither local nor general pathological results, and the organisms
rapidly disappeared. We will recur to this work of Bloomfield below.
He draws the conclusion that we can tell very little about the persis-
tence of influenza bacilli in the throats until we know more about
the subclassifications of these organisms, since he sometimes isolated,
from the inoculated individuals, strains which differed in serological
grouping from the strains which he had introduced. Kretz, on the
other hand, found influenza bacilli in the throats of patients months
after their attacks, and Rosenthal has isolated the organisms from the
larynx and the trachea in about 15 per cent of the cases he examined.
Davis's studies have shown the organism in 10 per cent of normal
people. Klopstock found influenza bacilli in 5.1 per cent of 1000
routine sputum examinations made at a Berlin hospital, and Wohlwill
has made similar observations.
We may summarize, therefore, our knowledge of the influenza
bacillus up to the time of the last epidemic somewhat as follows:
During the epidemic of 1889 influenza bacilli were found in a large
percentage of the cases examined , often in pure culture and in all parts
of the respiratory passages. They were found in pure culture particu-
larly in early cases, but as the epidemic trailed towards its endings
and severe complications were more common, fewer and fewer pure
cultivations were obtained. At this stage of the epidemic the or-
ganisms were still the predominating ones in most of the cases, but
were now almost always found admixed with pneumococci, strepto-
cocci and other bacteria. They were present also in a great many of
the complications which occurred in parts of the body, other than the
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232 HANS ZINSSER
respiratory tract. During the last stages of the epidemic and during
the years immediately following, there seems to have been a gradual
diminution of frequency of influenza bacillus findings in respiratory
diseases, even in those which clinically resembled the complicated
epidemic cases.
When finally it seemed that epidemic influenza had completely
disappeared it was found that bacilli of the hemophile group had
become established as common inhabitants of the respiratory pas-
sages of man, sometimes playing the r61e of harmless symbiants,
sometimes definitely associated with pathological processes. They
have been found associated with suppurations of the cavities of the
head, various forms of conjunctivitis, and with a variety of other
diseases. A curious development is that in pulmonary complications
of conditions not primarily caused by them, they have been found
with considerable regularity. Thus, they are now recognized as
almost universally present in the later lesions of whooping cough and
as commonly present in the pulmonary complications of measles, less
commonly in scarlet fever and diphtheria. In such cases especially
when they occur in children, they seem to be distinctly pathogenic,
either independently causing lobular forms of pneumonia, or else
as shown by Wollstein, contributing definitely to the severity of the
disease.
It has also been found that the carrier state can exist at such time,
and that the bacilli may be present for long periods in the nasopharyn-
geal mucous membranes of normal individuals or in bronchiectatic
cavities without causing injury either by invasion or by toxemia.
In our final summary we will attempt to coordinate these facts with
the results of more recent studies.
Recent epidemic of 1918
When we turn to the bacteriological analyses that have been made
during the recent epidemic, we are overwhelmed by the wealth of
reported material, but confused at the same time, by its indefiniteness
in description of technique and by the frequently defective clinical
characterization of the cases studied.
It will be noticed that during the early phases of this epidemic,
workers all over the world failed to find influenza bacilli. Thus in
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 233
Germany the earliest reports (Kolle of Frankfurt, Friedemann of
Berlin, Mandelbaum of Munich, Citron of Berlin, and Bernhardt of
Stettin) agree in failure to find influenza bacilli. Coca and Sapata
made a similar negative report from Spain. Sampietro in Italy sug-
gested the similarity of the disease to sandfly fever, owing to incon-
clusive bacteriological reports, and Mcintosh, writing in 1918, em-
phasized the widespread failure to find influenza bacilli throughout
the world. He himself made negative examinations on early cases
in London in 1918; and similar negative results were noted in a sum-
mary in the Medical Supplement to the Daily Review of the Foreign
Press brought out by the British Medical Research Committee in
October, 1918. Of American workers in France the same thing was
true. Indeed, the clinical picture of the cases first observed was such
that there seemed to be no focus of localized inflammation from which
it would have seemed profitable to take cultures. Our own experience
in this respect was similar.
It must be remembered that when the epidemic first appeared, there
were many who felt quite uncertain about its nature, and the syste-
matic and purposeful search for influenza bacilli did not generally
begin until an increased number of sore throats, upper respiratory
catarrhs, etc., began to appear. Soon after the outbreak at Chau-
mont, the writer saw a similar epidemic in troops that were in the
line and in reserve, and in these the presence of respiratory symptoms
gave a more definite clue to the importance of cultural work on the
nose and throat. In consequence, both the local laboratory officers,
Lieutenants Jacobs and Avery and the writer, began to take throat
cultures, and influenza bacilli were found in a considerable number of
cases. Soon after this, on the writer's return to Dijon on temporary
duty, a small epidemic of early uncomplicated cases was reported to
Dr. MacNeal who was then the commanding officer of the Head-
quarter^ laboratory, and MacNeal and the* writer obtained pharyn-
geal cultures from 14 of these men during the first 24 to 48 hours of
their disease. None of these showed more than a mild reddening of
the pharynx with very slight discomfort, and in all of them influenza
bacilli were demonstrated either by smear or culture. There can be
little doubt of the fact that, at least in part, the failure to find influenza
bacilli in the upper respiratory secretions of the early cases must be
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234 HANS ZINSSER
attributed to two factors, first, the omission of systematic culture
because of failure to recognize the disease as originating in the respira-
tory organs, and, second, because of inadequate technique on the
parts of workers. It seems that technique was universally defective
during the early phases of the epidemic, and it was not until media
were improved (trypsinized blood agar was introduced in England,
and modifications of what we speak of as the "chocolate" broth and
agar in America and Germany) that results of reasonable accuracy
were obtained. Also, a large number of workers, who had had little
experience with the influenza bacillus, rapidly learned to manipulate
this organism more skilfully. Following this, as the nature of the
disease was recognized, a large number of analyses were made, and
influenza bacilli were demonstrated in increasingly higher percentages.
It would be extremely difficult to attempt a complete review of all
the bacteriological work done during this epidemic. We have selected
from the literature a group of reports which are representative of the
best work done in this connection during the epidemic. It has seemed
useful to append to such a tabulation a statement, in each instance,
of the nature of the cases and the source of the material. (See pages
236-242.)
A cursory survey of these reports shows that in the large majority
of carefully investigated cases influenza bacilli were found in a high
percentage of the examinations. The organisms have been present
in over 70 per cent of most of the carefully studied series, and in a
number of instances they have been present in over 90 per cent. Our
own small group of early cases, like the series investigated by Schmidt,
Deitrich and a few others, have shown the Pfeiffer bacillus in 100 per-
cent, and a large majority of the workers who have had occasion to
study autopsies as well as sputum and nasopharyngeal material,
declare that no other organism was found with comparable regularity.
In many instances it was found in pure culture. Thus, Wolbach
in 28 carefully studied autopsies, found it 14 times in pure culture.
Dick and Murray had similar results, and Lister and Taylor in South
Africa as well as Leichtentritt in Austria found it alone in no small
number of their cases. Mayer, working in Vienna states that when-
ever he found the organisms in pure culture, the cases were mild,
corresponding more nearly to the uncomplicated disease. He adds
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 235
that he thinks that all fatal cases are due to complications, a statement
which we believe to be true in general, but to which there are not a
few exceptions. An interesting contribution is made by Capt.
Richard Taylor, who studied the flora of the respiratory tract, from
the pharynx downward toward the lungs, in cases which came to
autopsy, a procedure similar to that carried out by Pfeiffer in 1891.
He states that influenza bacilli were found rarely in pure culture in
the trachea and secondary bronchi. Here they were usually asso-
ciated with various Gram-positive and Gram-negative cocci. As he
proceeded downward toward the alveoli of the lungs the bacilli were
more and more free from other organisms; and in the smallest bronchi
and bronchioles they were either alone or together with only one form
of coccus. In the lungs themselves, however, pneumococci and
streptococci predominated, though influenza bacilli were often pres-
ent. We agree with the comment upon these findings made by
MacNeal who takes them to indicate that the infection was primarily
due to the influenza bacillus, with secondary invasion advancing along
the trelisses of inflammation so produced. Similar observations have
been made by Loewenthal in Vienna, and a number of other observers
have laid stress upon the fact that influenza bacilli, even in
complicated cases, are often found quite low down in the bronchial
passages.
It is important to note that blood cultures have rarely been positive.
When taken during the very early stages of the disease, or at stages
in an epidemic during which the mild three day or four day fever
types predominated, blood cultures have almost invariably been
sterile. In severe cases occasional positive results have been obtained,
but this has been rather the exception than the rule, and the great
majority of blood cultures taken on severe and complicated cases of
influenza have yielded either streptococci or, more often, pneumococci
of one or another type.
The difficulty with most of the etiological investigations has been
the inability of the investigators to select and control their material,
and for this reason percentage results obtained in many cases may be
misleading. The researches from which the most useful information
can be obtained are those in which workers have been able to group
their cases and control their material, both as to the time of the
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disease at which it was obtained, and in the manner of taking. Among
the most satisfactory researches in this respect are those of Park,
Williams and collaborators from the New York Department of Health
Laboratories. These investigators with an extensive experience of
the influenza bacillus as a background, and the large material of the
Department of Health available, carefully chose their cases and con-
trols. The first group studied consisted of early cases occurring in
a children's home, many in the first day of the disease. These all
showed almost pure cultures of influenza bacilli. Ninety-eight per
cent of the later cases in this home also showed the bacilli. The only
fact which detracts from the significance of the high percentage in
this series is that a number of cases of whooping cough had existed
in the institution during the preceding summer. In their next group
they studied 30 marines who had just come to New York in a body,
and were cultured almost immediately upon the establishment of the
diagnosis. In all of these influenza bacilli were found, and in these
cases both whooping cough and measles, diseases with which the
influenza bacillus is so often associated, could be definitely excluded.
At about the same time Park and Williams obtained 34 cultures from
a girls' home in which there had been no influenza, and found the
organisms in two of these only. In a similar institution where there
had been a number of influenza cases, 33 per cent of the inmates
harbored the bacilli. Of 30 autopsy cultures, influenza bacilli were
found in the lungs in 24, and in 5 of them they were in pure culture;
the bacilli were also present, in considerable numbers, in 26 out of 27
tracheas examined. In 40 per cent of the cultures taken from nurses
who had been in contact with cases, influenza bacilli were present,
whereas, those that had not been in contact with cases showed them
in 9 per cent only. Of all the studies which have resulted from this
epidemic those of Park and Williams and their assistants are perhaps
the most encouraging to the assumption of the etiological importance
of influenza bacilli. And yet as Park himself points out, the bacilli
were also found in 67 per cent of measles cases examined at about this
time.
We would not be doing justice to the problem as a whole did we not in-
clude in our analysis of the bacteriological findings an account of some of
the other bacteria which have been described by observers as perhaps having
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244 HANS ZINSSER
etiological relationship to the disease. In a malady in which the secondary
invaders give character to a large majority of the severe cases, it is to be
expected that many different organisms should be described. Mathers at
Camp Mead found an unusual number of cases in which the predominat-
ing organism was a Gram-positive diplococcus probably belonging to the
streptococcus group. This organism was found by Jordan in cases studied
in Chicago. Orticoni isolated an aerobic non-motile bacillus from influenza
cases, and from an epidemic of so-called influenza which occurred among
horses in the same neighborhood. In this connection it is interesting to
remember that MacNeal and Pease, in their studies of an epidemic at a
Veterinary Hospital and Remount Unit at which a so-called influenza
epidemic among the horses coexisted, were able to exclude any connection
between the two outbreaks.
Fry in 1919 isolated oval Gram-negative yeast-like bodies from the blood
of two German prisoners which upon subculture, took the form of small
Gram-negative bacilli. He speaks of them as "Pfeiffer-like" organisms
which, however, were not hemophylic and grew rapidly on ordinary agar.
With this organism Fry and Lundie later claim to have made an antigen
which gave specific complement fixation with influenza blood. Edelmann
in Vienna on several occasions found paratyphoid "B" bacilli in the blood
and intestines (!) of influenza cases.
The many reports in which pneumococcus and streptococcus have been
found as predominating organisms we may dismiss without analysis since
all investigators will now agree that no specific etiological significance can
be attached to these bacteria.
Of more than passing interest, however, are the frequent reports of Gram-
negative micrococci of various kinds. Most of the workers in this country
have commented upon the frequency withwhichmicrococcuscatarrhalisand
other Gram-negative cocci closely related to this organism have been found
in influenza sputum. In our own work, especially during the Baccarat
epidemic we noticed the great number of cases in which Gram-negative
micrococci seemed to predominate in smears and cultures of the pharynx
and throat. We were not able, however, to study these organisms in detail
at the time. Kinnicutt and Binger, who worked during July and August
of 1918 at an American Base Hospital in France have reported a series of
cases in which the predominating organisms were true meningococci.
They describe two epidemics, one which occurred at Mirmizan in the
Department of Landes, in which there were 350 cases among 553 men, and
30 bronchopneumonias with 15 deaths. Another outbreak occurred at
Le Courneau, Department of Gironde where there were 3915 cases with
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 245
275 pneumonias and 65 deaths. The epidemics began as the typical mild
fever, rapidly becoming complicated and ending with many severe cases.
In the first epidemic they took a considerable number of blood cultures
all of which were negative except one which showed meningococci of type
C (Pasteur Institute serum). Four out of 10 autopsies showed meningo-
cocci in the lungs. In the Le Courneau epidemic they took 25 naso-
pharyngeal cultures, 22 of which showed Gram-negative diplococci. Of
14 strains so obtained, 9 were true meningococci as tested with agglu-
tinating serum. They took 4 cultures of sputum, all of which showed Gram-
negative micrococci and 2 of which agglutinated like true meningococci.
Of 15 blood cultures, they obtained 4 Gram-negative diplococci, 3 of
which agglutinated like true meningococci. Of 24 heart's blood cultures,
4 showed similar organisms, 3 of which were proved by serum. Of 22
cultures from the lungs, 12 showed Gram-negative diplococci, 5 times in
almost pure culture; and 11 of these strains agglutinated like meningococci.
In another epidemic at St. Andr6 de Cubzac they took 29 cultures, 55
per cent of which showed Gram-negative diplococci Only 3 of these cases
showed Pfeiffer bacilli.
Fletcher in 1919 reported studies on autopsies of 36 American soldiers
who died of bronchopnuemonia following influenza. In 11 of the 36 cul-
tures taken from the lungs he found Gram-negative diplococci on blood
plates, and most of these turned out to be meningococci of Gordon types
I and II. Fletcher, however, also found a considerable number of cases
in which influenza bacilli were present without meningococci.
Similar findings have been reported by Leitner and by Trawinski and
Cori in Vienna.
It is of course difficult to make any conclusive statements about findings
of this nature. There can be no question about the fact that observations
so reported are accurate, and, indeed, any one who has studied the
bacteriology of cases of this kind knows that the manifold nature of the
flora of the respiratory passages which normally exist is tremendously en-
hanced in the presence of a catarrhal inflammation. It would seem to us
judging from experiences such as those of Kinnicutt and Binger, from our
own observations, and from reports made from various camps and base
hospitals during the war that the nature of the flora of the nose and throat
may take on a local character owing to infection from man to man under
crowded military conditions. The predominance of streptococci in one
place, pneumococci of a particular type in another, and Gram-negative
micrococci at again another would necessarily influence the bacteriology
of the fatal infections. During the first year of the American entrance
M EDICIXX, VOL. I, WO. 2
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246 HANS ZINSSER
into the war, this was noticed at training camps where streptococcus
pneumonias or infections with pneumococci of types I or II, of ten. pre-
dominated numerically as secondary invaders in measles, etc.
That influenza, whatever its etiology may be, increases susceptibility to
invasion with all sorts of other bacteria cannot be questioned. As far as
the meningococcus observations are concerned, these may well be explained
by greatly increased susceptibility to this organism, induced by influenza
and coincident with a high meningococcus carrier rate. Carrier rates in
troops of 10 and more per cent have frequently been observed by Gordon,
Glover and others, and we ourselves have seen a number of cases which
began as typical influenza and ended as meningococcus sepsis or typical
meningitis.
Because of the great complexity of the etiological problem we
believe it wise, at the end of each block of reported data, to outline
tentative summaries of the evidence so far presented. Surveying,
therefore, the purely cultural work which has been done on the in-
fluenza bacillus since 1889, we may now add to the statements made
in a preceding summary that the bacteriological studies made during
the pandemic of 1918 and the following years have confirmed the
fact that influenza bacilli may be found in a very large percentage of
early and late cases of influenza; that they have been found by Park
and his collaborators, by Deitrich, Schmidt and, in a similar series,
MacNeal and ourselves, in 100 per cent of early cases: and that a
great many of these workers have found them as the predominating
organisms in cases with pulmonary complications; they have also
been found by a considerable number of investigators in pure culture
in autopsies of fatal cases. They have been found more frequently
than any other organism in connection with the disease in all its stages.
By some investigators the organism has been found in the throats
of contacts in a higher percentage than in those of non-contacts.
The failure of many investigators to find the organisms in simple
cases in the early stages of the epidemic may well have depended upon
the same difficulties that determined our own early failures, namely,
insufficient attention to cultivation from the nasopharynx (owing
to the absence of or the mild character of subjective symptoms re-
ferred to this locality) and perhaps imperfect cultural technique.
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 247
Failure to find the organisms in blood cultures in these early cases
has been practically universal, and might be considered a strong
argument against the etiological significance of the influenza bacillus,
because these early cases suffer from serious systemic symptoms in
spite of their mild local lesions. We do not feel confident ourselves
that the blood culture failures are sufficiently conclusive to warrant
the assumption that the organisms are absent from the blood stream,
since there have been isolated instances of positive blood culture re-
sults even in apparently uncomplicated cases. A few such have been
reported by British observers during the early phase of the 1918
outbreak and there are many technical reasons why it may be very
difficult to cultivate these organisms from the blood stream.
Moreover, recent observations upon the powerfully poisonous prod-
ucts that can be obtained in influenza cultures, made in our own
laboratory by J. T. Parker and confirmed by Huntoon, Wollstein, and
others indicate the possibility that a severe systemic disease may
well be explained by a relatively small influenza lesion in the throat.
It is plain from cultural studies alone that the influenza bacillus is
either the cause of influenza, or that it is an almost universal compli-
cating invader, which gains a foothold in the body almost immediately
upon the establishment of the original infection. The decision con-
cerning this must eventually rest upon the same grounds that will
decide for us whether the mild sore throat and bronchitis that occur
in most, and perhaps in all cases, are complications or represent a
part of the basic disease.
One of the great difficulties in the way of formulating final con-
clusions is the great frequency of influenza bacilli as harmless sapro-
phytes and as secondary invaders in measles, whooping cough, etc.,
during non-epidemic periods. This, it is true, is a puzzling phase of
the problem which must receive much further study. While, on the
one hand it tends to weaken any positive etiological conclusions, on
the other hand it might be explained by acquired immunity in the
invaded subject, by fluctuation of virulence in individual strains of
bacilli, or by a multiplicity of races.
The bearing of serological evidence on etiology
We might expect to obtain indirect light upon the problem of eti-
ology from investigations of specific antibodies for the influenza
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248 HANS ZINSSER
bacillus in the blood stream of patients during and following the
disease. This line of investigation has been taken up by a consider-
able number of workers. Thus, Loewenthal in 1918 found that his
cultures were agglutinated up to 1 to 400 by the serum of his patients.
He claims that the agglutination reaction may be of specific diagnostic
value. Similar claims have been made by others. But there have
also been a considerable number of contradictions, and during the
last few months the entire question of specific agglutination in the
influenza group has been in a state of great confusion. The problem
is interwoven with the question of the antigenic uniformity or multi-
plicity of the Pfeiffer group, a problem which must be. discussed
briefly before we can pass judgment upon the value of the "antibody"
evidence.
In 1915 Wollstein made a comparative study of different strains of
the influenza bacillus isolated from various sources. She found that
there was a wide difference, in pathogenic power for animals, of
influenza bacilli isolated from different processes in man, Those
obtained from the blood and meninges and some of those obtained
from pneumonic lungs were highly pathogenic, while those from the
upper respiratory passages. were less so. So far as agglutination,
complement fixation, and opsonin tests were concerned, there was no
sharp difference between these two classes, and she concluded that in
spite of differences in pathogenicity, all these organisms belonged to
the same class or race, irrespective of origin. In 1919, Rappoport
studied complement fixations by the serum of influenza patients with
influenza bacillus antigens. He found 54.5 per cent positive fixations
with sera of such cases, in contrast to a percentage of 9.67 per cent of
30 controls. Kolmer, Trist, and Yagle made similar observations
on influenza cases, using a number of different antigens, one of which
consisted of influenza bacilli, and found that 45 to 50 per cent of their
sera reacted with the Pfeiffer bacillus, whereas 38 per cent reacted
positively with streptococcus and micrococcus catarrhalis antigens.
Wollstein carried out a similar series of studies, first attempting
agglutination, a method which she subsequently abandoned because
she found it unsatisfactory and irregular. She then did complement
fixations in which she used antigens consisting both of bacilli sus-
pended in salt solution and of heated broth cultures. By this method
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 249
she found that normal controls did not fix complement in the presence
of the antigen, but that the blood of recovered patients gave reactions
in dilutions varying from 1 : 5 to 1 : 20. She found that it was neces-
sary to use more than one strain of the organisms, in order to obtain
regular results. Her reactions appeared constantly at the end of the
first week, increased in intensity for two weeks, and remained demon-
strable for as long as from two to four months. Of great importance
is her observation that the antigens prepared with the epidemic strains
were serologically similar to those produced with strains isolated from
influenza cases in interepidemic years, differing from them only in
quantitative relations. She draws no definite conclusions, but says:
"The patient's serological reactions indicate the parasitic nature of
the bacillus, but are not sufficiently stable and cleancut to signify
that the Pfeiffer bacillus is the specific inciting agent." And further
below : "Its presence influences the course of the pathological process."
A short time ago in our own laboratory similar complement fixation
tests were carried out with convalescent influenza sera by Mrs.
Parker, experiments in which as many as six different antigens
were used on every serum. It was found that a large number of
supposedly normal sera gave fixations as powerful as those obtained
from convalescent cases. Although the cessation of the epidemic
prevented the completion of this work, it was so carefully done and
controlled that it has persuaded us that complement fixation is at
any rate not sufficiently sharp to throw conclusive light upon the
problem.
An astonishing and confusing turn has been given investigations
of this nature by the agglutination experiments carried out by Valen-
tine and Cooper in the New York Department of Health Laboratories.
These workers isolated organisms from autopsies and active influenza
cases and then attempted to classify them by agglutination reactions.
Their primary purpose was to find out whether there was any single
epidemic strain, and they paid particular attention to those strains
which were obtained from lungs at autopsy and other lesions in which
it seemed fairly definite that they were not dealing with saprophytic
habitual symbiants. It is impossible to detail all their results, but
it is sufficient to say that they found a surprising multiplicity of races.
The following examples may suffice to indicate the degree to which
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250 HANS ZINSSER
this was true. Of 10 autopsy strains no two were found alike by
agglutination. One autopsy strain was identical with one of the
miscellaneous strains, and another autopsy strain was identical with
another of the micellaneous ones. Of 73 miscellaneous strains, no
two were found to be identical. Of 54 strains obtained from military
patients, only 2 strains from different individuals were found identical.
But in one case the third day isolation was identical with the seventh
day, but the one on the fourteenth day was different. Of 28 strains
obtained from a Hebrew orphan asylum only 2 were found to be
identical. And of a family of 6, from each member of which an
organism was obtained, all the strains were found to be distinct.
Park states that in 9 of the autopsy strains the "unlikeness" of the
strains was so sharp that absolutely no cross-agglutination took place.
Bloomfield who introduced influenza bacilli into the nasopharynges
of normal people, states that in 5 instances which he isolated influ-
enza bacilli more than twenty-four hours after he had introduced
them, the organisms recovered differed from those introduced, the tests
applied being the biological differential methods suggested by Rivers.
The strain introduced was in some cases an indol former and agglu-
tinated with stock sera, whereas the recovered strain formed no indol,
and did not agglutinate with the serum. In another case the strain
introduced was non-hemolytic and formed no indol, whereas, the one
recovered from a tonsillar crypt after four days was hemolytic and
formed indol.
It is plain even from the few investigations that we have mentioned
that no help can be expected at this time from serological investiga-
tions. The agglutination reaction is obviously useless for this pur-
pose at the present time. When investigators as careful and experi-
enced as Park and Williams and their assistants report six different
agglutination types from six members of the same family, the first
thought that comes to us is not that these strains are all different, but
rather that agglutination in this group, for some reason or other
(perhaps because of the minuteness of the organisms, and peculiar
surface tension relations), is not specific; and the frequency with which
normal sera have fixed with influenza bacillus antigens of six different
races in our own laboratory, leads us to believe that complement
fixation too is a method of small promise in this problem. And even
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 251
though specific antibody reactions could be regularly observed in
active and convalescent cases, it is doubtful whether this would show
much more than the organism is pathogenically significant; whether
as the original etiological factor, or as a secondary invader, however,
would still be in doubt.
Evidence derived from vaccination
Another set of observations which must be included in our considera-
tion of the etiological importance of influenza bacilli, are those which
deal with artificial immunization or vaccination, prophylactically
employed during influenza epidemics. Such evidence would possess
the same indirect value as antibody investigations, in that protection
with influenza vaccines would indicate specific relationship. Such
investigations are fraught with many possibilities of error, since during
an epidemic it is difficult to safeguard the vaccinated and the controls
from accidental infection, and to impose upon them conditions
which would approach experimental accuracy.
The general impressions of Park who thoroughly realizes the
difficulties attending accuracy in such work, are unfavorable to the
assumption of any protective effect.
Eyre and Lowe inoculated 16,000 men, leaving 5700 controls which
were either uninoculated or had received only one dose. The vaccines
contained pneumococcus, streptococcus, influenza bacilli, staphylo-
coccus aureus, micrococcus catarrhalis, Friedlander bacilli and a
bacillus which they call bacillus septus. They tabulate their results
as follows:
Percent
Incidence among inoculated 1.3
Incidence among uninoculated 4.1
Mortality among inoculated 0.26
Mortality among uninoculated 2.2
Cadham in 1919 reported studies in which he used mixed vaccine?
of streptococcus, pneumococcus and influenza bacilli upon soldiers.
He claims that the incidence of pneumonia was one-half and the
mortality less than one-third among the inoculated as compared with
the uninoculated. The mortality of inoculated soldiers was 2.5 per
1000, whereas, in the town nearby among the general population it
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.252 HANS ZINSSER
was 6.28 per 1000. This particular experiment proves nothing in
our opinion, since the mortality in influenza is generally due to
secondary infections, and since the soldiers were all vigorous young
people, while the inhabitants of the town included the aged, tuber-
culous and very young.
Wirgman in the same year reported observations upon 11,000
people of whom 800 were inoculated in November and December,
1918, and January, 1919. His figures are as follows:
percent
Incidence among inoculated 5
Incidence among non-inoculated 10
Death tate among inoculated 0
Death rate among non-inoculated 19
Friend reports observations at a public school in West Horsham
made during this epidemic. Of the boys 633 were inoculated and 186
uninoculated. The school remained free of influenza, although the
disease was prevalent in West Horsham itself. But it is recognized
by Friend that physical training, careful supervision, hygiene, and
good nutrition played important rdles in holding down the sick rate.
McCoy in a criticism of vaccination in influenza has pointed out
a number of significant sources of error in such investigations. The
chief one of these lies in the fact that the inoculations have usually
been done during the progress of an epidemic and that the case-
incidence among the inoculated has been compared with the case-
incidence among the general population or controlled groups calcu-
lated from the beginnings of the epidemic. It is obvious that a num-
ber of the cases in the general population may have occurred before
the vaccine was given, and among the vaccinated are included a
number of people who are probably insusceptible. Also he points
out that a vaccine cannot ordinarily be expected to have any appre-
ciable prophylactic effects in less than seven or ten days after it is
given, and considers that the only fair comparison is one which takes
into account calculations on vaccinated and unvaccinated beginning
ten days after the vaccinations have been made. In summarizing the
evidence he selects a number of instances in which these criteria have
been observed. Thus Hinton and Kane vaccinated about one-half
the patients is an epileptic colony, the vaccinations being completed
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 253
some ten days before the disease became prevalent in the institution.
The vaccine contained 8,000,000 bacilli per centimeter, and a total of
2,000,000,000, was given to each person. There were 461 people
vaccinated, and 538 not vaccinated. Among the vaccinated, there
was a morbidity of 35.4 per cent, with 17 per cent deaths, while among
the unvaccinated there were 34.3 per cent cases with 13.5 per cent
deaths. A similar experiment was done on naval personnel at the
Pelham Bay Training Station (Notes on preventive medicine for
medical officers, United States Naval Bulletin, nos. 50 and 51). Nine
per cent of the 154 inoculated, and 5 per cent of the 800 uninoculated
developed the disease. Similar results were obtained at a naval base
in South Carolina. McCoy reports a few experiments carried out in
various institutions by members of the United States Public Health
Service in which a comparison between 484 vaccinated and 842 un-
vaccinated controls were made. Among the vaccinated there were
31.6 per cent cases, with no deaths, and among the unvaccinated there
were 26.3 per cent cases with 1.8 per cent deaths* In this case the
vaccine was a pure influenza bacillus suspension.
We may summarize this phase of the work, in complete agreement
with McCoy, to the effect, that, in spite of the general impression
favoring the value of vaccination in the prevention of influenza,
gained from the study of poorly controlled experiments, the evidence
furnished by experiments that have been controlled in every particular
has so far failed to demonstrate any effects whatever upon either
incidence ,of mortality.
Cfi*
Inoculation experiments
The most perfect proof of the etiological relationship of influenza
bacilli with the disease could of course be obtained by the production
of the typical disease in normal human beings by inoculation with'
pure cultures of influenza bacilli. During the earlier pandemic it
seemed that certain laboratory accidents had definitely indicated that,
such transmission was possible, the one most frequently cited being
the laboratory infection of Kretz whose nose touched a plate he was
fishing, and who in consequence developed an acute inflammation of
the respiratory passages with influenza bacilli persisting in his sputum
for several months. In such cases, however, just appraisal of the
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254 HANS ZINSSER
evidence is difficult because these accidents occurred during an epi-
demic or its early post-epidemic periods and happened to individuals
the nature of whose work brought them into contact with infectious
material. Also the symptoms described were usually those of local-
ized catarrhal inflammations rather than of true influenza. Purpose-
ful and well controlled experiments upon man would be more con-
clusive and extensive attempts in this direction have accordingly been
made by a number of investigators during the last pandemic.
Since typical influenza cannot be produced in any of the lower
animals, the only species which besides man are worth considering
for such work are the monkeys and the higher apes. Within recent
months Cecil and Blake working at the United States Army Medical
School in Washington, have succeeded in producing typical lobar
pneumonias by intratracheal inoculation of pneumococci in various
species of monkeys. This encouraged them to experiment upon these
animals with pure cultures of influenza bacilli. They used a Philip-
pine monkey, Macacus Syrichtus, and a Central American species,
Cebus Capucinus. The strains of Pfeiffer bacilli employed were
isolated from an influenzal pneumonia in a child. The virulence of
the strains, which has been on artificial media for six weeks, was raised
by successive mouse passages and subsequent intraperitoneal passage
through a series of 13 monkeys. They then inoculated a group of
22 monkeys. The material used for inoculation consisted of first or
second subcultures of organisms isolated from animals dead of pneu-
monia or peritonitis, and of peritoneal exudates from such animals,
used directly from the body.
In some monkeys the material was introduced into the nose by
application with a sterile cotton swab or with a pipette. In another
group the material was introduced low down into the trachea by
injection with a syringe.
Twelve monkeys were inoculated by the nasal method and in
every instance acute respiratory disease developed; three to five hours
after inoculation there was prostration, in some cases with a tempera-
ture of from 103° to 106°F. in others there was very little or no fever.
Sneezing, rubbing of the nose and other signs of catarrh became
manifest. In most cases at the end of twenty-four to forty-eight
hours the infection spread to the lower passages and a cough developed.
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 255
Five of the monkeys developed acute sinusitis from which the influenza
bacillus could be obtained. Two animals developed pneumonia
on the third and fourth days, and the influenza bacillus was obtained
in pure culture from the lungs. Ten monkeys received intratracheal
injections of 1 to 5 cc. Again prostration and temperature developed
in most of them with respiratory symptoms. In one case general
infection with speticemia and pericarditis ensued. None of these
died. Seven developed pneumonia and were killed during the active
stage, and from the lungs influenza bacilli in pure culture were re-
covered. The pneumonia which developed was widespread, and
lobular in type, with extensive hemorrhage and edema appearing to
Blake and Cecil similar to that occurring in man.
The experiments of these investigators show that the bacillus of
influenza can produce a violent infection of the upper respiratory
tract with catarrhal symptoms and other manifestations, common
in man at the time of prevalence of influenza epidemics. There can
be no doubt about the fact that these experiments add considerable
weight to the assumption that the bacillus of influenza causes the
disease in man. We will recur to this in our final discussion of this
phase of the general evidence.
More directly pertinent are inoculation experiments on man.
David J. Davis in a letter written to the Journal of the American
Medical Association of May 3, 1919, writes that in 1906, having
isolated influenza bacilli from a considerable number of cases of
whooping cough, measles and varicella, he inoculated a young healthy
man with pure cultures of the bacilli. Preliminary cultures showed
no similar organisms in the subject's throat; he had had no serious
illness of any kind within the immediately preceding period. The
washings of 6 blood agar tubes were taken up in salt solution and the
throat, tonsils, and nasal mucosa were smeared with the suspension.
Forty-eight hours after the inoculation he complained of chilliness
and great weakness. A temperature of 100.2° developed, but rapidly
subsided, returning to normal on the third day. He complained of
headache, general malaise, and coughed slightly. The throat was
slightly congested, and the pharynx coated with thick, stringy mucus.
The local condition persisted for about four weeks during which there
was a very slight cough which did not in any sense resemble that of
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256 HANS ZINSSER
whooping cough. During the first few days an almost pure culture
of influenza-like bacilli was recovered. In the course of the next
three weeks the influenza bacilli gradually disappeared from the
throat. There were no complications. The description of this case,
as given in Dr. Davis's letter has certain important points of similarity
with early cases of epidemic influenza, especially as regards the mild-
ness of the local symptoms with the sudden development of tempera-
ture, severity of the systemic symptoms and short duration of the
fever.
In 1919, Rosenau, McCoy and collaborators, working under Govern-
ment auspices, carried out a series of important experiments on man
carefully controlled and elaborately planned. The group conducting
the investigation were officers of the United States navy and of the
Public Health Service; McCoy, Goldberger, Leake and Lake on the
part of the Public Health Service, cooperating with Rosenau, Keegan
and Richey, on the part of the United States navy. The experiments
were carried out at Gallops Island, the quarantine station near
Boston. The volunteers were all between eighteen and twenty-five
years of age and in good physical condition. Of the 100 men used,
none of them had had influenza or any febrile attack during the
preceding winter. Preliminary experiments in which pure cultures
of the influenza bacillus in moderate amounts were instilled into the
nostrils of a few of the volunteers were entirely negative. In con-
sequence, a more drastic experiment was decided upon. Nineteen
volunteers were given a considerable quantity of a mixture of 13
different strains of Pfeiffer bacillis, some of them recently obtained
from the lungs at autopsy, others representing subcultures of different
culture-generations obtained from recent cases. Suspensions of the
bacteria were sprayed into the nostrils, eyes, and throats with
atomizers while the volunteers were inspiring. Several billions of
the organisms were used on each one, but not a single one of them
developed any kind of illness.
Following these negative experiments an attempt was made to
infect directly with mucous secretions obtained from the mouths,
noses, throats, and bronchi of active cases of influenza. The material
was obtained from febrile cases by washing out nostrils and throats
with 5 cc. of salt solution and allowing the patient to blow his nose
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 257
vigorously into a sputum dish. They were then made to gargle with
some of the solution and this was added to the rest. Bronchial mucus
was obtained after coughing, and the nares and throats were swabbed.
The swabs with all the materials were then put into bottles with glass
beads, and this (properly, called "stuff" by Rosenau) was administered
to the volunteers. Ten men were used and each of them received
about 1 cc. sprayed into nose and throat while inspiring, and into the
eyes. None of them became sick. Other experiments done at this
time by the same Board will be recorded when we come to speak of
titrable virus. Most astonishing of all of the work done by this
Board are the entirely negative attempts to infect such volunteers by
bringing them into the closest possible direct respiratory contact with
cases in the active stages of the disease.
McCoy and Richey carried out similar experiments at Goat Island
in San Francisco Harbor, also with entirely negative results.
It is very difficult to comment upon these experiments. Their com-
pletely negative character would lead one to assume not only that
influenza bacilli did not convey the disease, but the upper respira-
tory secretions of influenza patients were not the vehicle of infection.
The latter conclusion can hardly be credited in view of the large volume
of epidemiological evidence in favor of such transmission; and when
we consider the experience and reliability of the investigators who
carried out these experiments we must assume that some third factor,
the most likely one being insusceptibility on the part of the volunteers
must have played a part. Even this, however, would seem unlikely
in view of the large number of men used and the careful scrutiny
made before the experiment. As a matter of fact there is no satis-
factory explanation for these failures at the present time.
Wahl, White and Lyall in 1919 also applied saline emulsions of
fresh Pfeiffer strains from epidemic influenza cases to the nares and
nasopharynges of 5 healthy men, absolutely without success; and these
investigators did not succeed, except in a single case, in recovering
the influenza bacilli from the nares forty-eight hours later. To this
point we will refer in our summary since we consider it of considerable
importance.
Bloomfield, investigating more particularly the length of time dur-
ing which influenza bacilli would persist in the upper respiratory pas-
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258 HANS ZINSSER
sages of healthy individuals, introduced 3 different strains of influenza
bacilli in large amounts into the upper air passages, and in none of
his 5 cases observed any local or general pathological effects. More-
over Bloomfield found that the organisms disappeared within from one
to two days, and that a carrier state was produced in none of them.
Yamanouchi, in connection with his experiments on filtrable virus,
has reported completely negative experiments with the Pfeiffer bacil-
lus in man.
Lister and Taylor though unsuccessful with filtered material, inocu-
lated 5 controls with unfiltered material from influenza lungs. Two
of these had typical attacks of influenza, coming down with the disease
thirty-six hours after the material had been instilled into the naso-
pharynx. One volunteer was sprayed with a pure culture of influenza
bacilli and came down with a "mild attack."
More recently, Cecil reported to the Medical Section of the New
York Academy of Medicine (May 19, 1920) a few experiments in
which he introduced Pfeiffer bacilli (the virulence of which had been
raised by methods analogous to those used in his previous monkey
experiments) into 6 persons. He obtained moderate local and
systemic symptoms which suggested very mild influenzal attacks,
curiously enough there was absolutely no temperature in any of them.
Attempts to produce typical influenza with cultures of influenza
bacilli have, therefore, been negative in most cases. With the ex-
ception of the few instances of apparent success by Lister and Taylor
and the last suggestive experiments of Cecil no encouragement has
been obtained along these lines. But it should be remembered that
it has been shown that it is extremely difficult (as in Bloomfield's
work) to induce the influenza bacillus to gain a foothold on the normal
mucosa, and negative experiments cannot be taken as conclusive
until a failure to obtain symptoms persists in spite of the establish-
ment of the organisms in the inoculated throats for at least forty-eight
to seventy-two hours.
Filtrable virus
Before we can attempt to summarize views on the etiological im-
portance of the influenza bacillus, it becomes necessary to consider
in some detail a series of investigations inspired by the suggestion that
influenza may be due to a filter-passing virus.
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 259
The thought that such a virus might be responsible for influenza
is suggested by the nature of the mild cases which appear early in
epidemics, the extreme infectiousness of the disease, and the lack of
uniform bacteriological findings in such early cases. Moreover, the
clinical similarity of the catarrhal features of mild grippe with the
ordinary common cold, in which the work of Kruse, Foster and others
has indicated a possible "filtrable virus" etiology aroused hopes of
similar "leads" in the influenza problem.
In October, 1918, at the Academy of Sciences in Paris, Nicolle and
Lebailly made a preliminary report on studies which later they de-
scribed in detail in the Annales of the Pasteur Institute. These
workers first inoculated mice and guinea pigs, intraperitoneally and
intracerebrally, with blood and secretions from a typical case of un-
complicated grippe. These attempts were unsuccessful. They then
inoculated nasal and buccal secretions of a typical case into the
conjunctiva and the nasal cavities of several monkeys (Macacus
Sinicus) using the secretions both filtered and unfiltered. At the same
time they inoculated two healthy human beings. The monkeys
became sick in six days with a temperature of 40°C. and with diarrhea
and great depression. Both of the human beings who had been
subcutaneously inoculated with the filtrate became ill at about the
same time, and in the same way as the monkeys. Blood from the
first monkey was injected into a man twenty-two years old without
result.
Subsequently, they injected blood of a typical case into a man
intravenously. The result was doubtful, but this subject was older
than the others, a fact to which they attribute their partial failure.
They concluded that: (1) Influenza secretions are virulent. (2)
Macacus sinicus and Cynomologus are susceptible by conjunctival
and nasal inoculation; (3) the agent is filtrable since the filtered secre-
tions produced disease in 2 human beings after subcutaneous inocula-
tion. (4) intravenous inoculations and blood inoculations are un-
successful; (5) virus is easily destroyed by drying or by prolonged
exposure to conditions outside the body.
At about the same time Dujarric de la Riviere took blood from 4
severe influenza cases and after dilution filtered it through Chamber-
land filters. He injected himself subcutaneously with 4 cc. of this
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260 HANS ZINSSER
filtrate. On the third day after the inoculation he developed intense
headache, pains in the limbs, chilliness and weakness. His tempera-
ture went to 38°C. and fluctuated from then until the fifth day, after
which he rapidly improved; great weakness and cardiac disturbances
remained. He seemed to be immune to subsequent inoculations of
the sputum filtrate sprayed into his nose and throat.
Selter in 1918, failing to find influenza bacilli with any regularity,
tried the same thing. He filtered nasopharyngeal mucus and gargle
water of patients early in the disease, through Berkfeld filters, and
sprayed his own throat and that of a woman assistant with this
material, both of them inhaling the spray. In both cases a "mild
influenza" resulted within seventeen to twenty hours.
Binder and Prell in the same year described minute bodies smaller
than cocci in the tissue spaces around the vessels of the lungs in all
cases of influenza and failed to find similar bodies in other pulmonary
infections. These coccoid bodies were as small as those described by
Noguchi in poliomyelitis, and could be stained by iron hematoxylin
and Giemsa, but not by Gram. They believed that they could
cultivate these bodies in serum-sugar-broth, but were extremely
cautious in drawing etiological conclusions.
V. Angerer, soon after this, inoculated rats with the serum of in-
fluenza cases. When the animals became sick he filtered their blood,
and cultured the filtrates in glucose bouillon. In these cultures he
found minute granules similar to those described by Binder and Prell.
Similar bodies he claims to have cultivated directly from the serum
of human influenza cases. He, too, was extremely cautious in drawing
conclusions from these findings.
In October, 1918, Bradford, Bashford, and Wilson published results
of studies upon six diseases including trench fever and influenza
in which they claimed to have shown that filter-passing organisms
were involved in all of them. With their filtrates they produced illness
in guinea pigs and monkeys; and in anaerobic cultures prepared by a
modification of the ordinary technique employed for Treponema
pallid they observed certain small Gram-positive bodies which they
regarded as the causative agents.
Similar, though less extensive experiments were reported by Gibson,
Bowman and Conner.
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 261
Later, Arkwright who had been working along the same lines
criticized the results of Bradford, Bashford and Wilson, reporting
negative experiments carried out by the war office upon three volun-
teers inoculated with the supposed cultures of Captain Wilson. He
also pointed out the frequency of the appearance of small coccoid
bodies in control tubes of media prepared by the method used by the
other investigators. Indeed, the almost regular observation of
cloudiness and of minute coccus-like bodies in tubes prepared by the
anaerobic method mentioned above has puzzled many workers in the
past. We have noticed it again and again in work with syphilis and
poliomyelitis and are quite sure that it is dependent upon the action
of the tissue enzymes upon the protein of the medium. Bradford and
Wilson admit the inconclusiveness of their results, at least as far as
the minute bodies are concerned, in statements appended to Ark-
wright's article.
In 1919, Yamanouchi, Sakakami and Iwashima reported experi-
ments on the filtration of influenza virus which, if they could be com-
pletely accepted, would settle the entire matter, conclusively. These
results were as follows:
1. An emulsion made of the sputa of 43 influenza patients in Ringer's
solution was injected into nose and throat of 12 healthy people.
2. Filtrates of the same emulsion was injected into noses and throats of
12 other healthy people. Six who had already had influenza showed no
symptoms, but all of the other 18, those who had had the emulsion and those
who had had the filtrate, came down with the disease after an incubation
of two to three days.
3. Filtrates of blood of influenza patients were injected into noses and
throats of 6 other healthy people with similar positive results.
4. Filtrates of sputa were inoculated into 4 healthy people; and 4 others
received filtrates of the blood of influenza patients subcutaneously. All of
them developed the disease after two or three days with the exception of
the one who had had influenza.
5. A pure culture of Pfeiffer bacilli and a Pfeiffer bacillus culture mixed
with pneumococci, staphylococci and streptococci was injected into nose
and throat of 14 healthy people who had not had influenza. No symptoms
followed these injection*.
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262 HANS ZINSSER
Lister and Taylor working in South Africa filtered material from the
lungs and throats of typical influenza cases and instilled the filtrates
into the nostrils and throats of human volunteers and monkeys. All
were negative. Of 5 controls receiving unfiltered material, 2 had typical
attacks of influenza 36 hours after inoculation. All the monkeys,
even those that received unfiltered material, remained well. They
sprayed the nasal passages of one volunteer with a pure culture of
influenza bacilli, and in this case a "mild attack" resulted.
Wahl, White, and Lyall in 1919 sprayed the nasopharyngeal cavities
of several men with Berkfeld filtrates of material from pneumonic
lungs of typical influenza cases, with entirely negative results.
Leschke, in the same year, used bronchial secretions and juices
expressed from the lungs of influenza cases and filtered them through
Berkfeld filters. He inoculated these into ascites broth. After
forty-eight hours, minute round bodies were noticed which could be
stained with heated concentrated carbol fuchsin and were Gram-
negative. They could not be transferred successfully to new cul-
tures, but these minute bodies were also visible in bronchial sercretions
of dead influenza cases as well as in lung sections. Lung filtrates,
incubated for several days and vaporized, were inhaled by a number
of people for several minutes. These individuals came down with
"typical influenza !"
Fejes (in 1919) filtered the sputum of influenza pneumonia cases
and iniected it subcutaneously into rabbits and guinea pigs without
result. The same material was injected on four separate occasions
into monkeys, two monkeys being used in each experiment. In these
cases one monkey was injected with the material immediately after
filtration, and the other after heating for one hour at 65°. The
animals that received the heated filtrate remained well. All the
monkeys treated with the unheated filtrate died several days after
the inoculation, with clinical and pathological appearances of general
hemorrhagic sepsis. The material from which the filtrates were
made showed in one case a pure pneumococcus, in the second a
streptococcus hemolyticus, and in the other two mixed cultures with
Pfeiffer bacilli. The bacteriological analysis of the animals that died
is unsatisfactory as described.
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 263
Minute bodies in smears of throats, noses and exudates of influenza
cases also have been described by Kronberger and Poppelmann.
Experiments made by the United States Public Health Service and
the United States navy under the direction of Rosenau and McCoy
are among the most extensive that have been carried out upon human
beings. They have been referred to, in part, in a preceding section.
After unsuccessful attempts to produce the disease with pure influenza
bacilli, they instilled filtered nasopharyngeal mucus from fresh cases
into the tonsils, throats and eyes. The results were entirely negative.
Subcutaneous inoculation of similar filtrates into 10 volunteers, each
one receiving 3 cc., were entirely unsuccessful. Negative results
were also obtained when blood was injected and when the volunteers
were brought into close respiratory contact with active cases.
In the May 29 issue (1920) of the Journal of the American Medical
Association, Olitsky and Gates published a series of experiments also
dealing with a filtrable infectious agent in influenza. They used
filtered and unfiltered influenza secretions, and filtered and unfiltered
lung tissue suspensions prepared from previously inoculated rabbits.
The inoculations were carried out directly into the lungs by means of
the intratracheal catheter, 3 cc. of the material being used for rabbits
weighing from 2\ to 3 kgms. From 7 to 8 fresh cases, that is cases
less, than thirty-six hours old, they obtained definite effects in rabbits
which they describe as follows: Within twenty-four to forty-eight
hours after inoculation, fever developed, with listlessness and general
illness of the animal. With this there was conjunctivitis and a marked
leukopenia. These symptoms lasted for about three days, after
which the animal returned to normal. They never died except in
cases where obvious secondary infection had taken place. When
killed during the period of illness, the respiratory organs alone showed
pathological changes. The lungs were enlarged and edematous, and
often hemorrhagic. There were hemorrhagic foci on microscopic
sections, and there was a cellular exudate in the alveoli. Controls
made by many different methods failed to show similar effects. After
this, repeated filtration did not interfere with the effects described
above. The agent, whatever it was, seemed to resist 50 per cent
glycerine for nine months. They draw very conservative conclusions.
Since the first writing of this paper, Olitsky and Gates have con-
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264 HANS ZINSSER
siderably extended their researches by further animal inoculations
and cultivation experiments by anaerobic methods corresponding to
those used in treponema cultivation, namely, anaerobiosis with tissue
and ascitic fluid. They have cultivated from filtered nasopharyngeal
washings of influenza patients in the first thirty-six hours, a minute
bacilloid body capable of indefinite propagation on artificial media,
which they have named the bacteria pneumosintes because of its
peculiar pathological reactions in lung tissue. They have also re-
covered this organism from the lungs of infected rabbits. This
minute Gram-negative bacillus-like organism is apparently strictly
anaerobic and retains its virulence for rabbits for only a limited num
ber of generations after cultivation from the human body. They
obtained it again during the short influenzal wave of the past winter,
1921-1922, and the characteristics of this organism are similar to the
original one. After prolonged cultivation, the organism appears
considerably larger than one would expect from a filtrable virus, but
still they continue to obtain growth from filtrates through N and W
filters. Similar but distinctly different organisms of a somewhat
larger size and slightly fusiform appearance were obtained from com-
mon colds and normal throats. There seems to be no doubt in the
writer's mind, after seeing their cultures, that Olitsky and Gates
have observed a group of organisms hitherto undescribed, and the
relationship of the true pneumosintes to early influenza, its apparent
preparatory influence for secondary infection must lead one to take
it seriously as one of the possible etiological suggestions. The diffi-
cult nature of the entire problem, however, does not permit acceptance
of this, though strict attention to their methods and results will be
necessary for all investigators who approach the influenza problem
when another wave becomes eminent.
Summary of evidence bearing upon etiology
In the course of every scientific investigation, it becomes necessary,
from time to time, to classify and analyze the available data in order
that there may be a clear differentiation between experimentally
determined facts, probabilities amenable to further experimentation
and pure surmise. It is a systematization not only of our knowledge
but of our ignorance as well. For in subjects as involved as are the
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 265
problems of influenza, on which so many different people have written
from so many different points of view, the few 'available facts may
easily be lost in an accumulation of clinical and Experimental slag.
Conclusions cannot be drawn. But we can segregate the obviously
misleading from the proven facts and can perhaps formulate more
clearly the directions of study which appear most promising of even-
tual light.
It is entirely in this sense that we submit the following summary:
Influenza in its simplest clinical form is a mild fever, with sudden
onset, characteristic pains in head, back, and limbs, great prostration
and a fever curve which rarely lasts longer than three or four days.
It is in this form that it usually makes its first epidemic appearance,
and, at this stage, causes almost no mortality. The slight sore throat,
mild bronchitis and injection of the conjunctivae which are present
in a large number of the cases may represent secondary infections
or complications, but are more probably characteristic features of the
basic disease.
It is the causation of this basic condition which constitutes the
true etiological problem of influenza. While it is generally acknowl-
edged that the influenza bacillus appears early in the disease and is
present with considerable regularity, it has been suggested that,
preliminary to this, there may be infection by some other agent,
perhaps a filtrable virus which paves the way for secondary invasion,
first by the influenza bacillus, followed by other bacteria habitually
present in the upper air passages.
In favor of attributing the entire process to influenza bacilli are:
The frequent isolation of the bacilli even from the earliest and simplest
cases; the high percentage of influenza bacillus isolations from all
varieties of early and late complications; the peculiar distribution of
these bacilli in the large and small bronchi in fatal cases; their frequent
presence in pure culture at autopsy; the wide distribution of the
organisms throughout populations at times of epidemic, and their
gradually diminishing frequency in normal and diseased respiratory
passages as epidemics fade into the past. Recently acquired knowl-
edge, furthermore, regarding the potent poisons formed by influenza
bacilli in culture, permits us to account for the entire clinical complex
of the simplest variety of case by the establishment of a relatively
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266 HANS ZINSSER
small influenza bacillus focus in the throat or nasopharynx of a sus-
ceptible individual.
Against the assumption of the etiological importance of the influenza
bacillus are the frequent failures of competent bacteriologists to
find the organisms in the early cases, the presence of the bacilli in
the throats of normal individuals; their presence in pathological con-
ditions obviously not clinical influenza; their frequent presence as
complicating invaders in whooping cough, measles, etc., the antigenic
multiplicity of strains isolated at times of epidemic; and the infre-
quency of positive blood culture findings in early cases. None of
this negative evidence is conclusive for reasons that have been indi-
cated in the text.
Investigations on the appearance of antibodies in the serum of cases
that are sick with or convalescent from influenza permit of absolutely
no conclusions at the present time, owing to the irregularity in anti-
body reactions done with influenza bacillus antigens, whether the
method used be that of agglutination or that of complement fixation.
The curious results obtained by Cooper and Valentine show either an
enormous multiplicity of influenza bacilli or non-specificity of the
agglutination reaction with this group. Experiences with comple-
ment fixation have not given uniformly reliable results when human
sera were used. Moreover, were we to find an increased concentra-
tion of antibodies against influenza bacillus antigens, it would serve
to prove nothing more than the pathogenic significance of the influenza
bacilli which we know from cultural studies to be present in most
cases, and would not help us to decide whether the organism were the
primary cause of the disease or merely secondary invader. It would
show nothing more than do the frequent positive serum reactions
which have been obtained in influenza and in some other diseases
with streptococcus antigens.
Protection experiments with vaccines have been absolutely incon-
clusive; indeed, they seem to indicate that influenza vaccines do not
protect to any considerable degree. This, however, throws little
light upon the etiological problem since successful vaccination is
delicately dependent upon manner of vaccine production, dosage,
mode and frequency of administration, and has yielded negative or
doubtful results even in diseases in which the etiological problems are
settled.
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ETIOLOGY AND EPIDEMIOLOGY 07 INFLUENZA 267
Attempts to produce the disease in human beings with pure cultures
of influenza bacilli have been in general unsuccessful. There are,
however, a few very suggestive experiments in the literature particu-
larly the isolated cases of Lister and Taylor, of Wahl, White and
Lyall, that of Dick and the more recent ones of Cecil, which at least
show that occasionally mild systemic illness may follow the introduc-
tion of the bacilli. The completely negative results of Rosenau and
McCoy and their collaborators, of Yamanouchi and others are dis-
couraging, but if we consider that in such experiments two factors
must be simultaneously adjusted to each other in a perfect way,
namely, the virulence of the strain and the susceptibility of the
individual, it may well be that failure of one or the other of these
prerequisites may account for many negative attempts. It is worth
noting in this connection, too, that in many cases where negative
results were obtained the organisms rapidly disappeared from the
nasopharyngeal mucosae of the inoculated individuals; whereas, in
those that partially succeeded, as well as in some accidental infections
with cultures the organisms remained present for some time, showing
that in the former they were quickly removed by the protective mecha-
nism, whereas, in the latter, they were able to establish a foothold.
Although the burden of the evidence so far cited seems to point
in the direction of probable causation by the influenza bacillus, it is
obvious that there are a number of elements of uncertainty. To
these there is added, as a very serious objection, the report from
several sources which cannot be ignored, of successful production of
an influenza-like disease in human beings with filtrates of influenzal
material — the conditions so produced cannot be positively identified
as true influenza. Nevertheless, they are sufficiently suggestive to
necessitate further experimental study.
This leaves the entire subject in a very unsatisfactory condition.
The temptation to draw definite conclusions from material of this
kind is always a strong one. But to profess certainty when available
evidence does not justify definite conclusions is as serious an error as
to put forth inconclusive experimental work, and would serve merely
to mask the truth.
One thing seems distinctly worth emphasizing in closing a discus-
sion of influenzal etiology at the present time, and that is the advisa-
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268 HANS ZINSSER
bility of constant attention to the entire influenza literature on the
part of bacteriologists working in well equipped laboratories with
assistants and equipment sufficient to attack large problems of this
kind when occasion arises. The problem of influenza etiology will
not, in our opinion, be solved at times when influenza epidemics are
in full swing or in their secondary or tertiary waves. Solution will
come from laboratories that are prepared to pounce upon the oppor-
tunity when epidemics are in their adolescence, and bacteriologists
will miss this opportunity of swinging their equipments and energies
for a few intensive months into this extremely important problem
unless they are familiar with the clinical aspects of early influenza,
such as we have outlined it in a previous paragraph, and unless they
are thoroughly and critically familiar with the important etiological
work that has been done. This alone we would regard as sufficient
excuse for an inconclusive summary of etiological studies such as that
in the preceding section.
THE EPIDEMIOLOGY OF INFLUENZA
Former epidemics
In diseases like smallpox, diphtheria, scarlet fever, etc., in which
sharp clinical and etiological definition is possible, epidemiological
data can be obtained with considerable accuracy. In influenza such
studies are rendered incomparably more difficult because of the
diagnostic difficulties emphasized in preceding sections, and because
of the complete lack of any etiological criterion of recognition.
During periods of epidemic and especially during the initial stages
of outbreaks, the diagnosis of the disease can be established with
a considerable degree of certainty. But the widespread catarrhal
infections of many different causations, which accompany such epi-
demics and bring about generalized opportunities for interchange of
respiratory organisms, lead to an increased morbidity in which many
factors besides the influenzal ones are involved.
Particularly confusing are the problems of recognition in the
interepidemic periods during which physicians are forced to use the
terms "influenza" and "grippe" upon vague clinical grounds, fully
conscious of the diagnostic uncertainty which such a terminology
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ETIOLOGY AND EPIDEMIOLOGY OP INFLUENZA 269
entails. As we shall see, epidemiologists have been forced for these
reasons to base many of their calculations upon atypical fluctuations
in seasonal curves of the morbidity and the mortality of the common
accompaniments and consequences of influenza, bronchitis and
pneumonia.
During widespread epidemics, however, the suddenness of onset,
the singular rapidity of rise and fall in each locality, the speed of travel
and the general'basic similarity of cases and complications, have
served to characterize the outbreaks themselves sufficiently to permit
their recognition as true influenza. In spite of the uncertainty of
diagnosis, therefore, information of considerable reliability concern-
ing the epidemiological history of this disease is available in the writ-
ings of past centuries, such as those of Calenus of Greifswald (1579),
Jacques Pons of Lyon (1596), Sydenham, (1675), Slevogt (Jena,
1712), Haygarth and Hamilton (1775), Pringle and Huxham, Massin
(Strassburg, 1858) and many others. The history of influenza has
been dealt with by a number of writers to whose extensive mono-
graphs the reader is referred.
Both Thompson and Leichtenstern tabulate the sequence of great
influenza epidemics somewhat as follows:
1510 — Epidemic, spreading from Malta to Sicily, Spain and all of
Europe.
1557 — Asia, Constantinople to Europe and America.
1580 — First great pandemic. Origin in Orient — to Europe and
entire world.
For the seventeenth century the records are very incomplete, but
Leichtenstern speaks of an epidemic in North America in 1647.
Less extensive outbreaks seem to have prevailed in different parts
of the world between 1709 and 1712.
Between 1729 and 1733 the disease, travelling from Russia west-
ward, spread over Europe in two great waves, one in 1729, the other
in 1732.
Another epidemic started on the shores of the Baltic in 1742.
In 1757-1758, 1761-1762, and 1767, epidemics occurred of which
we have but poor geographical records.
Of the epidemic of 1742, Friedrich states that all but about one-
tenth of the entire population of Germany was attacked.
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270 HANS ZINSSER
From 1781 to 1782, an epidemic supposed to have started in China
spread through Siberia to Russia and thence to Europe.
Another travelled approximately the same route in 1788.
The same thing occurred between 1799 and 1803.
In 1827, there was an outbreak of Europe less extensive than most
of the others.
Between 1830 and 1833 there were two or three pandemic waves,
the first one supposedly originating in China.
Other outbreaks, again travelling from East to West, occurred in
1836 and in 1847. During this last named epidemic the Prussian
army is said by Friedrich to have been attacked in its entire personnel
These brief data, which bring us up to the pandemic of 1889, are
condensed chiefly from Leichtenstern, who summarizes the general
characteristics of influenza epidemics as follows:
1. True pandemic waves.
2. Origin in a specific part of the world. Asia (Netter) ; China (Pearson) ;
Hirsch believes that some of the epidemics have probably started in North
America.
3. Speed of travel over the globe.
4. Sudden mass infection.
5. Rapid burning out after several weeks in one locality.
6. Independence of season or weather.
7. Enormous morbidity with slight mortality.
8. Little influence of age, sex, or occupation on morbidity.
The degree to which these criteria may still be accepted as accurate
will appear below.
When we study the records left to us by physicians who described
the disease as it occurred in the early epidemics we find close coin-
cidence with observations made during the last outbreak, not only as
to the clinical data, but in regard to the chief epidemiological charac-
teristics as well.
Huxham of Plymouth (1743) writes: "About this time a disease
invaded these parts which was the most completely epidemic of any
I remember to have met with; not a house was free from it
Scarce a person escaping either in town or country; old and young,
strong and infirm shared the same fate." He described the disease
almost exactly as we ourselves observed it at Chaumont and Baccarat
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 271
in France in May 1918, its sudden onset, fever, chilliness, pains and
rapid deferescence in about four days.
These and many other physicians recognized the essentially second-
ary nature of the serious pulmonary complications.
The pandemic of 1889 is supposed to have originated in the East,
though records are available of the existence of an independent focus
in Greenland almost synchronous with the observation of early cases
in Russia and Siberia. Heyfelder saw cases in Bokhara in May 1889,
and traced the enormous speed of travel of the disease north-westward
into Siberia and European Russia. By October, it had reached
Petrograd, by November it had entered Germany. Rapidly sweeping
Westward and Southward it reached France and Austria, Italy and
Spain, during this month and December. By the middle of December
it had reached London and New York. Its early appearance in
New York suggested to some observers the possibility that the
epidemic had travelled Eastward from its original focus as well as
Westward, encircling the globe, and appearing on our Atlantic coast
at about the same time at which it reached the Atlantic coasts of
Europe. Its course could be traced by railroad and steamship routes.
The percentages of the populations attacked in each country were
enormous.
To some extent the speed of travel of influenza can be seen in this
epidemic to have increased in the course of the centuries, proportion-
ately with the increased facilities for communication. Thus, in the
1872 epidemic, it took the disease eighteen days to reach Amsterdam
from Leipzig, a time which corresponded to the time it took Dutch
merchants to reach home from the former place (Leichtenstern).
Transmission
The suddenness of onset of influenza epidemics and the almost
simultaneous affliction of a considerable percentage of a community,
was perhaps the chief reason for the older beliefs that influenza may
be conveyed by means other than contact; and in the past the idea
that it was air borne or conveyed by dust and perhaps by insects,
has had many adherents. The careful epidemiological studies which
were made during the 1889 epidemic and, more recently, during the
last pandemic, indicate with considerable certainty that these older
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272 HANS ZINSSER
beliefs are not tenable, and that at least the chief means of conveyance
is direct and indirect contact with other human beings. The disease
does not travel more rapidly than human communication, a belief
formerly held. This point was studied with particular thoroughness
by observers during the '89 epidemic, more especially by Parsons,
Friedrich, Leichtenstern and Teissier. Numerous examples can be
cited in which communities that were out of touch with the main
population of a country, because of geographical isolation, were
spared, or did not begin to develop cases until the reopening of routes
of travel. It was noticed, by German observers particularly, that
places along the railroad were the first to be affected, while the out-
lying country with which communication was more difficult, was
several weeks late in developing the disease. Often the epidemic
would reach points considerably farther away from the places of dis-
tribution if they were on main routes of travel, than it would the
immediately surrounding but less accessible country districts. This
was true of Kiel, one of the earliest of the German cities to be invaded.
Extension to distant cities was rapid, while the country surrounding
Kiel itself did not begin to report any considerable number of cases
until two months later. And even as country districts were reached
more slowly than were the centers through which main routes of
travel passed, so also did the epidemics percolate through them more
slowly and remain in them for relatively longer periods, proportionate
probably to the greater dispersion of the population and the lessened
opportunities for contact. Thus, Parsons noted that in some of the
rural communities of England the epidemic trailed along for some
four months during which it swept over the crowded industrial dis-
tricts with the sudden blazing and subsidence of burning straw.
In large cities the epidemic has usually burnt itself out in a relatively
short time. Leichtenstern who has carefully gone over most of the re-
ported data of the 1889 epidemic, generalized in the following way:
The first cases are usually followed within two weeks by true epidemic
prevalence. After that a very rapid extension occurs which is at its
peak in three weeks, and subsides almost completely within the follow-
ing fourteen to twenty-one days. In Munich, a city which was very
carefully studied, the epidemic began about the first of December and
from December 27 to January 4 there were 1100 to 1600 cases daily.
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 273
By the middle of February the epidemic was almost over. Abbott's
careful study of the epidemic in Massachusetts shows that about
seven to eight weeks covered the first epidemic period. It reached
its peak throughout the State of Massachusetts during the week of
January 4 to 11, 1890, and was practically over by February 10.
During this brief period over 800,000 people were attacked, that is
about 40per cent of the population. In London the epidemic appeared
first in December, 1889, and during January attained a death rate
of 28.1 per 1000. During February it rapidly declined and ended
during March. It is interesting to note that in some of the large
industrial cities of England the epidemic was three to four weeks later
than in London, the death rate in London in January not being
equalled by most of these towns until February.
During this epidemic also there were a number of more or less
isolated communities which were spared. Thus, there was no in-
fluenza on the Isle of Man and in the Bahamas. On the Santis
Mountain which is about 7000 feet high there was no contact between
the inhabitants of the observatory and the valley and there were no
cases of influenza during the epidemic. On the Island of Borkum,
Leichtenstern states, there was a period of freezing weather in late
December and earlv Tanuarv, during which the Island was com-
pletely isolated. The first cases did not appear until three days after
arrival of the first ship. He adds that similar conditions prevailed
at Vladivostok and Sachalin, places in which the disease did not ap-
pear until the spring of 1890 when the thaws made the resumption of
travel possible. Friedrich cites definite data to show that the disease
was brought from Danzig to Hadersleben by ship. In France the
same thing was observed, and there seems to be very little doubt
about the fact that human communication lies at the bottom of
transmission from place to place.
During the pandemic of 1918 the same thing was probably true,
but because of the active transportation of large masses of men
incident to the state of war, the routes of transmission were so com-
pletely interwoven that it has not been easy to unravel them.
Whether the epidemic spread from France to the United States as
suggested by MacNeal, whether it travelled the other way, of whether
it began in several places at the same time, are questions that prob-
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274 HANS ZINSSER
ably will not be settled until more complete data have been collected
by epidemiologists throughout the entire world and have been scru-
tinized by men as well versed in epidemiological analyses as Frost and
others. There is, however, a very interesting example of travel by
ship during this epidemic, reported by Colonel Delaney of the Ameri-
can army from England which we cite from MacNeal's paper. On
August 26 and 27, a British vessel, the Mantua, with influenza on
board, stopped at Sierra Leone for consultation with two British
ships, the Chepstow Castle and the Tahiti, the Chepstow Castle
acting as a transport for New Zealand troops, the Tahiti carrying
navy ratings from East Africa. Influenza appeared on board both
of these ships forty-eight hours after this call, with sixty-eight deaths
on the Tahiti and thirty-eight deaths on the Chepstow Castle before
arrival in port. New Zealand and East Africa had not been reached
by the epidemic when these boats started. But on October 23 the
steamer Mozambique arrived at Lisbon from Cape Town with 200
deaths during the voyage, and reported an epidemic of influenza at
Cape Town at the time it left. Writing in the Lancet (1918, ii, 455)
the Medical Officer of Health in India states as his opinion that the
epidemic appeared in India with such terrible consequences in the
summer of 1918 was not endemic, but was introduced by shipping.
The opinion of direct and indirect transmission from man to man
is also well supported by a detailed study of the epidemiology of
individual outbreaks. In our own experience with local epidemics
such as those at Chaumont, Baccarat and other places, the sudden-
ness with which the malady attacked large numbers of people at
almost one and the same time, caused us at first to be exceedingly
skeptical of accepting transmission by contact as the only means of
conveyance. We considered food and insect transmission as possi-
bilities, and tried our best to find grounds for involving such agencies.
But in every case we were forced to return to the conclusion that
direct and indirect contact between men came nearest to doing justice
to all observed facts.
An interesting small hospital outbreak has been described by Foster
and Cookson which dearly exemplifies contact infection. A surgical
ward, free from medical illness for some time before, on June 6 re-
ceived an influenza convalescent suffering from a surgical lesion.
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 275
This man spit a great deal, and was dirty in his habits. On June 9
the man in the bed next to him developed influenza and the blood
culture of this case contained influenza bacilli (1). On the same day
the man on the other side of the original case developed a temperature
of 104° with symptoms of influenza but negative bacteriological
findings. The disease then travelled from bed to bed, along the line
of beds on that side of the ward, until it stopped at both ends when
it came to empty beds. Another influenza case was admitted to the
other side of the ward, and from it the neighboring bed was infected.
But on this side the disease remained limited to these two because
the adjoining beds were screened from them by elaborate surgical
traction arrangements. The diagram of this little epidemic is suffi-
ciently instructive to warrant reproduction.
fepty tod llth ilth 9th 7th 11th 13th testy tod
0®€€€#e€€"
«th 7th f
000€#000
J x
Diagram A
(Taken from article by Foster and Cookaon, Lancet, 1918, 2, 585)
Bearing upon the same point are certain data which we take from
a report of Stanley concerning an epidemic in the St Quentin Prison,
California. Stanley definitely traced the origin of this epidemic to
the admission of a prisoner from the county jail in Los Angeles. The
man had been sick before he came in with symptoms described ac-
curately as influenza. On his entrance to the prison he mingled with
1900 men congregated in the ward, and ate in the general mess with
them. At night he was locked in the receiving room with 20 other
prisoners. On the day following this he had an apparent relapse of
his influenza, and was admitted to the hospital with a temperature
of 101°, chilliness, pains in the back and bones. Following this an
epidemic of unusual severity started in the hospital, reaching its
height ten days after the new prisoner had been admitted. On the
tenth and eleventh day after the arrival of this man, 1900 or one-half
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276 HANS ZINSSER
of the entire prison population were ill. The ordinary daily sick-call
of the prison was about 150 to 200, whereas, on these days 700 to 750
appeared at the doctor's office. Stanley also noticed that during
the period of the epidemic, which lasted a little over a month, the
largest number of cases occurred on the Tuesdays and Wednesdays
of the second and third weeks, and explains this by the fact that on
every Sunday morning two moving picture shows were given, one at
8:00 a.m. and the other at 10:00 a.m., respectively, in a poorly venti-
lated room. Almost the entire 1900 sick men had attended these
shows. Stanley places the incubation period, accordingly, at about
thirty-six to sixty hours. (This corresponds roughly to our own
observations in which several cases in which the time of contact could
be reliably ascertained showed incubation periods of about forty-eight
hours.) About six months after the first epidemic, a second one
broke out in the prison, again introduced by a new arrival from
Los Angeles. This prisoner became ill on the day after admission,
showing the characteristic symptoms. Before becoming ill, however
he had spent one night in the receiving ward, and had taken his
meals with the 1900 other prisoners. This epidemic went through
the prison more slowly, and there were fewer cases than in the first
epidemic. How much this may have been due to immunity of the
remaining prisoners, we will discuss further below. In part, the
lessened morbidity may have depended upon the very rigid precau-
tions which were taken, the prevention of assembly of prisoners in
large numbers, and other sanitary and hygienic measures which were
enforced. A third epidemic occurred a month after the second, but
lasted only about nine days. During this outbreak a number of
interesting additional observations were made. A prisoner, "A,"
reached the St. Quentin Prison by train on November 21 from Colusa
County where an epidemic was then raging. He felt badly the next
day, but did not report to the doctor and was put in a room with
twelve other prisoners. Though feeling sick he attended the moving
picture show on Sunday, on the evening of which day he was removed
to the hospital. In the receiving room "B" and "C" slept in adjoining
beds. "A" sneezed and coughed into "B's" face at about 4:00 p.m.
Sunday afternoon. At 9 a.m. on Tuesday, "B" began to have chills
and fever. "C" was also closely associated with "A" and "B," and
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 277
became sick on the same day that "B" did. Stanley made a careful
study of the distribution of cases in the auditorium where the moving
picture shows were held, and found that there were approximately
five centers about which the infected men sat; the largest one was in
the middle of the room, and in each corner there was a separate
focus. Nobody was infected in the orchestra pit, where there were
10 men. The orchestra sat 9 feet in front of the first row of audi-
torium seats. There was a women's department of this prison which
had, at the time, 30 inmates. This is a separate building, and abso-
lutely without contact with the men. None of these women had in-
fluenza during the three epidemics. Stanley's studies seem to indicate
not only that contact is the method by which the disease is conveyed,
but also, that fairly close contact is necessary; and his results show
that complete isolation, when it can be rigidly carried out, as in closed
institutions, is effective.
Jordan has carefully studied three groups in Chicago, namely, the
Students' Army Training Corps, the high and elementary schools of
the University of Chicago, and the Chicago Telephone Company.
In the Students' Army Training Corps there were two sections, A
and B. They lived under the same conditions, but most of the
boys in section B came from small towns in Illinois, while most of the
boys in section A came from Chicago itself. For some reason or other,
section A was closely supervised, with prompt removal of those who
were slightly ill, whereas in section B these precautions were not
carried out to the same degree, and 3 of these boys were ill on arrival
in Chicago. Section A had 26 cases, whereas section B had 92 cases
within six days. In the elementary school group Jordan's analyses
show definitely that there was a sharp rise about November 30 fol-
lowing the Thanksgiving recess from Wednesday until Monday,
during the family gatherings, etc., formed an opportunity for infection,
and at which none of the precautions were probably taken which
were habitual at this time in the routine of school attendance.
Onset of epidemics of influenza
In regard to the suddenness with which the disease attacks large
numbers of people in one and the same place, at almost the same time,
recent records thoroughly confirm the observations of the past. In
MBDICIN 1, VOL. I, MO. 2
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278 HANS ZINSSER
our own experience during the first outbreak at Chaumont, 54 men
of a single company were attacked within 11 days, out of a total
strength of 172, and no less than 41 of these 54 men were taken ill
within two days, May 15 and May 16. Thus:
On May 13 there were 3 cases
On May 14 there were 3 cases
On May 15 there were 19 cases
On May 16 there were 22 cases
On May 17 there were 3 cases
From then on until May 23 when the disease stopped in this unit,
there were only 4 additional cases.
In another place we saw as many as 73 cases, developing in the same
day in a single infantry company. Wirgman writing in 1918 speaks
of an outbreak at a camp of 560 men in which almost the same sort
of thing happened. In a report on an epidemic in Rest Camp no. 4,
Base Section no. 2, American Expeditionary Forces, near Bordeaux,
Ward reports that in one camp with a strength of 3400 men there
were 82 cases within two days, and in a camp of 180 men, there were
20 cases on one day.
Therefore, although the total morbidity and mortality statistics
of any influenza epidemic compiled for a large territory usually
covers periods of months, yet when the individual local outbreaks
are studied, it is found that in any given locality the disease burns
itself out within an extremely short time, then passing on to the next.
The speed of travel in influenza may to a certain extent be explained
by the almost universal susceptibility of the race to this disease, and
to the fact that a large percentage of the cases (especially the early
ones) are extremely mild. The percentage of the recognized sick,
who seek medical advice does not represent the total number of the
afflicted since a very large number of people during such epidemics
suffer from perhaps nothing more than headache, general malaise,
and trifling fever of short duration. In a military unit which we had
occasion to study, we were able to determine that although the num-
ber who came to sick call and needed hospital care was very large,
there were, in addition to this, a considerable number of men who
were unquestionably infected, but who were so slightly ill that they
continued on duty. It is not at all unlikely that during epidemics
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 279
(and this is a thought also expressed in connection with the ;89 epi-
demic by Leichtenstern) a large number of people are well enough to
travel and to go about their daily business, although in the active
stages of mild attacks and, therefore, capable of transmitting the in-
fection. In most other infectious diseases the majority of the sick
are immobilized, at least for a time, and transmission by travel is
thus prevented in the majority of cases.
The free circulation of large numbers of people who represent
unrecognized, potential sources of infection, and their unrestricted
intercourse with others in all the activities of business life, family
relations and travel, coupled with an almost universal susceptibility
of the population at times preceding epidemics, would go far to ex-
plain both the tempestuous beginnings and the rapidity of extension.
Moreover, as regards the suddenness with which a large number of
people are simultaneously afflicted, a feature which has kept alive
some skepticism regarding the contact method of infection, such state-
ments should be made with qualifications. Parsons, in his studies of
the epidemic in England in 1889, 1890 and 1891, calls attention to
the fact that the rapidity of onset in influenza is not essentially dif-
ferent from that which formerly prevailed in smallpox before the day
of universal vaccination. It is probable that, when the disease
strikes a community, its explosiveness is actually much less marked
than it appears to be from morbidity statistics; and, as Leichtenstern
and others have noted, it was usual during the '89 epidemics, that
outbreaks were clearly recognized as possessing true epidemic dimen-
sions not earlier than two weeks or more after the first cases had
actually occurred, a fact not generally brought out until subsequent
studies have been made on the basis of completely available data.
Parsons, furthermore, has found evidence which indicates that in
many cases in which the onset of a local outbreak was particularly
explosive, this could be traced to the assemblage of large crowds in
meetings or conventions, during the days just preceding the epidemic.
In the small town of St. Davids the outbreak followed a large public
meeting. In Eccleshall an epidemic followed two or three days after
an Odd Fellows picnic. In Kington in 1891 the outbreak was
associated with the May fairs.
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280 HANS ZINSSER
During the last pandemic this phenomenon of explosive onset was
noticed chiefly in connection with military units where association in
closely related groups was one of the exigencies of military life. It
was quite evident in at least one of the epidemics which we had oc-
casion to study that the characteristics of the outbreak in the military
groups differed in this respect considerably from those prevailing
at the same time among the surrounding population. Thus, at
Chaumont, while the outbreak among the Marines and in some of
the other military units took the form of the steep peak which we
have described above, the disease extended more gradually and
trailed along more irregularly and for a longer time among the clerical
force who were scattered in many different billets and offices. And
this was still more noticeable as regards the civilian inhabitants of the
town, among whom the percentage morbidity was much lower and
was scattered much more widely both as to time and place.
Moreover, even in military units like the Marine Company men-
tioned above, where the explosiveness seemed extreme and "mysteri-
ous," simple analysis removes much of the mystery. If we take this
little outbreak as an example we see that 6 recognized cases had oc-
curred on the two days preceding the sudden appearance of 19 cases
on a single day. These 6 had been in the incubation stage for at
least twenty-four and forty-eight hours previously, and probably
did not represent the total of infected men; for it is more than likely
that there were a number of others who were not sufficiently ill to
report at sick call. If we consider, therefore, that at least 6 and prob-
ably more men circulated freely among the remaining 166, and ate
and slept in close association with them, we find that the apparent
suddenness of the rise in morbidity on the third and fourth days of
the outbreak is not out of keeping with the assumption of contact
infection. The impression conveyed by the steep graphs of such
outbreaks is, therefore, apt to be misleading.
Secondary outbreaks
In the wake of almost all influenza epidemics there have followed
secondary outbreaks which are often spoken of as "waves." This
has apparently been the case in all the large epidemics of which we
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 281
htfve definite knowledge. Leichtenstern has commented upon it
extensively in connection with his study of the '89 epidemic.
After the epidemic of 1729 to 1730 there were secondary waves in
1732 and 1733.
The 1789-1791 outbreak did not become entirely quiescent until a
definite secondary wave had followed in 1792.
The 1798 epidemic was followed by one in 1800.
After the outbreak of 1836 to 1837, others followed in 1838 and 1841.
The 1847 to 1848 epidemic was followed by another within a year,
and conditions in the world did not return to normal until 1851.
Parsons writing for the British Isles states that there were three
definite waves from 1889 to 1892. The first began in the winter of
1889 to 1890. Another occurred in the spring of 1891, a third in the
winter of 1891 to 1892. The following chart (page 282) taken from
the article by Frost and tabulated by months, from 1887 to 1916 for
Massachusetts, from death rates per 100,000 from influenza and
from all forms of pneumonia, shows that here, too, the epidemic of
1889 to 1892 developed in three distinct waves, the first one com-
ing to a head in January, 1890, the second in April and May, 1891,
and the third in January, 1892. The same thing occurred all over
the world, and tabulations of individual cities like New York, New
Orleans, Chicago, as well as studies in other parts of the world indi-
cate a similar wave-like repetition.
Brownlee has attempted to find a law of periodicity for the large
intervals between pandemics, and the intervals between the separate
waves of each outbreak. Since statistical studies of pure uncompli-
cated influenza alone would for many reasons hardly be accurate
enough as a basis for such calculations, Brownlee, Frost and other
epidemiologists have reduced the factor of error by making their
calculations both from influenza statistics and from total reports of
all pneumonias, comparing these with the pneumonia incidence and
mortality of interepidemic years. Brownlee has studies the weekly
number of deaths for London from 1870 on. He finds the period be-
tween influenza outbreaks, between 1889 and 1896, to be about
thirty-three weeks. There is no such periodicity in regard to bron-
chitis and pneumonia in the absence of influenza, and Brownlee con-
cludes that if such periodicity appears after the return of influenza,
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282
HANS ZINSSER
TABLE 1
Death rates per lOOflOO of population from pneumonia (all forms) and from influenza in
Massachusetts, 1887-1916, inclusive
PNEUMONIA
YKAft
I
i
8
!
1.9
22.6
S
16.1
7.7
I
1
i
a
as
|
1887
138.8
19.5
16.7
5.5
4.1
5.6
9.0
14.8
15.3
1888
172.7
24.7
25.1
26.4
21.3
16.4
8.0
5.5
4.0
6.2
11.4
9.8
13.9
1889
156.6
17.9
16.3
21.1
19.8
14.9
7.5
5.3
5.2
5.4
10.6
13.2
19.3
1890
180.0
47.8
17.7
17.6
20.1
12.7
8.5
6.2
4.8
5.0
9.4
11.8
18.3
1891
188.5
20.6
16.4
20.6
25*1
23.9
10.1
5.9
4.0
4.0
7.7
13.8
36.4
1892
213.0
61.5
25.2
23.1
21.4
17.0
8.3
5.4
4.2
6.8
8.5
12.5
19.0
1893
225.8
27.3
25.4
28.6
33.1
27.3
11.1
8.0
5.0
6.1
9.8
14.3
31.9
1894
166.0
32.8
19.9
22.7
18.5
14.0
8.5
5.1
5.1
6.8
8.2
11.3
13.6
1895
184.1
19.1
34.4
30.8
20.9
14.4
7.6
5.6
5.3
4.7
10.5
13.4
17.3
1896
182.0
19.5
20.7
24.9
25.9
18.7
10.3
7.6
4.5
7.6
10.7
12.7
18.8
1897
181.6
21.1
24.9
31.5
19.7
15.2
10.2
7.0
4.5
6.0
11.7
13.1
16.9
1898
156.0
18.8
17.1
18.5
18.7
15.7
6.6
6.0
4.8
5.6
10.6
12.8
21.0
1899
181.3
37.5
25.8
20.6
18.4
14.0
8.9
5.0
4.8
5.8
8.2
13.2
19.0
1900
188.3
22.7
21.1
42.0
30.5
17.6
8.7
5.3
4.3
5.3
6.2
9.9
14.7
1901
167.7
22.6
26.6
26.2
19.9
13.9
7.7
3.4
3.4
5.7
9.1
14.2
15.1
1902
158.9
15.7
18.9
19.9
16.8
15.5
8.0
6.2
5.3
5.7
11.8
14.5
20.6
1903
172.5
25.2
25.8
25.4
18.1
16.8
8.2
7.0
4.5
4.6
7.7
13.3
18.9
1904
172.1
22.6
22.7
24.1
21.2
14.2
6.7
5.9
4.4
6.5
9.4
15.0
19.5
1905
178.3
24.7
27.7
23.6
17.1
15.5
8.5
5.4
4.8
6.2
8.9
15.8
20.0
1906
174.1
22.5
21.9
24.1
21.7
14.9
5.1
6.2
5.0
6.0
9.4
13.8
21.0
1907
180.4
25.5
24.4
23.4
18.3
14.3
9.5
5.1
5.1
7.1
9.3
12.7
26.9
1908
165.8
26.6
22.2
21.1
19.4
13.5
6.6
4.9
5.8
6.4
9.2
12.4
17.6
1909
170.3
22.1
20.0
26.1
20.1
16.0
9.7
5.1
5.0
5.4
8.9
13.6
18.3
1910.
197.6
24.1
20.7
27.5
23.3
16.9
9.7
7.3
6.3
9.1
12.3
17.0
23.6
1911
174.4
22.6
27.1
23.9
20.2
16.9
7.2
.6.7
6.1
6.7
9.0
11.8
16.2
1912
152.0
19.8
20.2
21.2
16.4
13.3
6.2
5.0
4.1
5.8
9.5
10.5
19.9
1913
172.2
23.5
22.8
24.9
19.3
17.1
10.7
6.2
5.4
6.7
8.3
10.4
16.8
1914
166.0
22.9
20.1
23.2
20.4
15.2
8.2
5.1
5.5
6.0
10.1
12.6
16.8
1915
176.0
17.8
19.3
28.5
27.7
13.6
6.6
7.1
5.8
6.0
8.8
9.8
22.1
1916
176.6
35.6
25.5
23.0
17.3
14.0
7.4
5.3
4.1
5.9
7.6
12.8
18.3
Taken from Frost, Public Health Reports, U. S. Public Health Service, xanriv, no. 33,
p. 4.
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 283
it must be definitely associated with this disease. From 1876 to 1889
the thirty-three-week recurrence was missed in regard to bronchitis
and pneumonia, but in the years 1889 to 1896 it was marked. Com-*
paring the monthly statistics of Glasgow, Aberdeen and Massachu-
setts he finds that there is nothing which differentiates them in prin-
ciple from the phenomenon in London. Stallybrass supports these
calculations of Brownlee, and speaks of a minor cycle of thirty-three
weeks within the pandemic periods and major one of about ten years
between pandemics. We are not ourselves in a position to comment
upon these findings.
Pearl's paper "Influenza Studies" published in 1919, incidental
to an analysis of the mortality curves of 40 American cities takes up
the time manifestations as they occur in local outbreaks. He finds
that such curves are of two main types, one showing a single well-
defined peak, others showing a first high peak followed by one or more
smaller ones. The latter type was of the usual form. A further
analysis of these curves showed that there was a definite tendency for
the "two-peak" curves to fall into two groups. About one-third of
them had their second mortality maximum about eight weeks after
the first peak. The remaining two-thirds had their second mortality
maximum on an average of about thirteen weeks after the first peak.
Those in which there was a third peak had their second one about
7.1 weeks after the first, and the third on an average of about 13.1
after the second. Pearl believes that according to this, the cycle in
such successive waves appears to be nearer a multiple of seven rather
than of ten weeks.
A great many statisticians, far more capable of judging of these
matters than ourselves, are now engaged in a study of the cyclic
phenomena and no doubt will publish their conclusions in time.
Meanwhile, we wish merely to mention the matter as one of the im-
portant problems of influenza study undertaken at the present
moment.*
The second and third waves of epidemics have been marked by a
number of characteristics which are of important significance. Both
f For a more extensive discussion of the problem of periodicity and its probable sig-
nificance, we may refer the reader to the extensive monograph of Warren T. Vaughan,
published since this paper was first prepared.
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284 HANS ZINSSER
Parsons and Frost find that in the epidemic of thirty years ago the
mortality was progressively higher during the 1891 to 1892 waves
than during the original outbreak in 1889. Leichtenstern states that
although the mortality, which of course is largely due to secondary
infection, is greater during the secondary waves, the general morbidity
of influenza is smaller. This corresponds with the observations of
Wutztorff who analyzed the epidemic in Germany with considerable
care. Wutztorff admits that it was extremely difficult to obtain
accurate estimates of influenza morbidity during the later waves of
the pandemic. But, although he finds that in some towns, especially
in North Germany, the 1891 to 1892 wave was almost as extensive
as that of 1889 to 1890 had been in other places, in general the mor-
bidity in Germany was much lower. To some extent his conclusions
are derived from indirect evidence such as, for instance, the fact that
the hospitals in the various cities were not taxed to overflowing during
these later waves as during the first, massive infection of the entire
personnel of many industries and of railroads did not take place to
the same extent, and the statistics of the government physicians
stationed in various parts of Germany showed that a much lower
percentage of the population sought medical advice. As a rule,
from 6 to 7 per cent of the population sought treatment during the
first epidemic, whereas only from 2 to 3 per cent reported during the
later waves. It would be impossible to reproduce the extensive
statistical and other evidence brought forth by Wutztorff in support
of his contention, but we may assume as probably correct that in the
later waves morbidity is usually lower and the percentage mortality
somewhat higher than during the first.
Noticeable also is the fact that secondary epidemics do not travel
with the same speed and to the same geographical extent as does the
first wave. There is generally slower progress, a greater scattering
of cases, and a somewhat more prolonged period of prevalence in the
subsequent waves; and, judging from the careful study of mortality
statistics in years following the pandemics, it is more than likely that
after the so-called third wave there may be a succession of what we
may term gradually diminishing "ripples" which finally fade out, in
the course of some years, into practical quiescence. Leichtenstern
seems to believe also that the secondary outbreaks are characterized
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 285
by the fact that they originate in many different foci simultaneously
instead of proceeding (as he and some others assume that first waves
do) from a single focus. Netter holds the same opinion. He says of
the secondary waves of the 1889 pandemic that "they have appeared
in separate, synchronous or successive explosions, and we have not
been able to trace any connection between various reappearances in
different places, as this was possible in 1889. There seems to have
been an independent reawakening of the epidemic in different locali-
ties." In a general way this is probably true, but we will see, when
we come to discuss the course of the first wave of the last pandemic
that some of the most experienced epidemiologists are reluctant to
assume that this outbreak proceeded from any single world focus.
The origin of influenza epidemics with particular reference to the
origin and course of the last pandemic outbreak (1918)
In a recent address to the Congress of American Physicians and
Surgeons, Flexner made the interesting suggestion that perhaps the
most effective method of forestalling epidemics in the future would be
to search out and attempt to circumscribe the endemic foci in which
the cinders of disease are constantly smouldering during the inter-
epidemic periods. This method of procedure has been effectually
initiated in the case of yellow fever, and would seem to be an eminently
logical one for application to other insect borne diseases. It might
also be successfully applied in plague and conditions like it in which
interepidemic propagation is carried on largely in animals. In regard,
to other diseases the promise of even partial success would be directly
dependent upon the question as to whether the particular condition
is kept alive, between outbreaks in special centers in the world or
whether the foci are widely scattered in all populations in the persons
of carriers, constantly increasing in number along the trail of sporadic
cases, as in typhoid and the paratyphoid fevers, etc.
The idea is an extremely important one since any step in the direc-
tion of interepidemic control of foci, if attended by even a slight
degree of partial success, would accomplish more at smaller expense
than the most energetic attempts at suppression after epidemics
have started. Moreover, the splendid efforts which are being made,
at the present time, to internationalize public health activities pro-
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286 HANS ZINSSER
vide an opportunity for possible accomplishment of such a project
which has never before been within reach.
In the case of no disease should this proposal be more seriously con-
sidered than in that of influenza, since no other condition attains a
comparable degree of destructiveness, none travels so sweepingly over
the whole world, and in none other are we so totally helpless to ob-
struct its progress. It is, therefore, of great importance to determine,
if possible, whether influenza epidemics have truly emanated from
definite endemic foci, or whether they have started in various parts of
the world at times when conditions such as the declining resistance-
values of populations, or some other unknown factors have created
epidemic possibilities.
In the tabulation cited from Leichtenstern and others we have
indicated that many of the epidemics of the past were supposed to have
emanated from the East. Flexner, unquestionably following similar
reports, assumes that the region on the border between Russia and
Turkestan may possibly be regarded as one of the important endemic
foci. At any rate, the reports of earlier writers have again and again
referred to China, the Caucasus, Eastern Siberia and Turkestan as
furnishing the initial blaze which then spread, Westward and East-
ward, to encircle the world. The possibility of the regional delimi-
tation of influenza foci is, therefore, more than a surmise and should
be examined with care, especially as light has been thrown upon it
by the more exact epidemiological investigations of the last two great
outbreaks.
The beginnings of the outbreak of 1889 seemed again to be traceable
to the East. The reports of Heyfelder and others to this effect have
been mentioned in preceding sections, but there seems to be evidence
that the disease appeared in Greenland and in Northern Canada at a
time so early in this epidemic that it cannot be accounted for by
Northwesterly spread from the South Eastern continental sources.
It appears also from the studies of statisticians that influenza re-
mained widely dispersed throughout the world for many years after
this epidemic had subsided; so long in fact that it seems very unlikely
that we can ever speak of well defined endemic potential sources of
origin except in a relative way. Indeed, the permanently increased
influenza incidence in places like China, if considered from this point
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 287
of view, may be due to nothing more than to defective conditions of
hygiene and sanitation coupled with greater crowding. Prof. Ray-
mond Pearl in commenting upon the probability that the 1918 epi-
demic will be followed by a long period of increased influenza mor-
bidity, makes the statement that the curve of mortality from influenza
in England and Wales was higher in 1907, seventeen years after the
1890 epidemic, than it had been in any of the forty years immediately
preceding this outbreak. He adds that a similarly slow decline of
mortality followed the epidemic of 1848.
It is likely, therefore, that for many years after pandemic waves
have subsided, perhaps throughout the interepidemic periods, the
virus remains freely scattered among-the populations of the world,
ready to flare up in renewed mass infections when gradually declining
incidence over a period of years has brought about a reduction of
community resistance; and at such times it would be most likely that
the points of least resistance, (and, therefore, the most frequent
sources of widespread epidemics) should be located in the most
crowded and least sanitated communities.
It is too soon to come to any definite conclusions regarding the
origins of the 1918 epidemic. Epidemiological methods have devel-
oped considerably since the last preceding outbreak, and no final
judgment canberendered until properly qualified epidemiologists have
had the opportunity of gathering and studying all available evidence.
Like others who cannot pretend to anything more than a superficial"
knowledge of statistical methods, we must be content to await these
analyses. Meanwhile, however, it will be of interest to discuss avail-
able information on this problem in a tentative way.
As in the case of previous epidemics this one is supposed by some
writers to have originated in the East. McNalty, in the article re-
ferred to above, states that in March, 1918, the disease was prevalent
in China, and that, in the same month and in April, the Japanese navy,
perhaps infected in Chinese ports, suffered from a serious outbreak.
This is particularly interesting to us, since we remember distinctly
hearing of a curious, mild febrile disease reported among Chinese
labor troops on the coast of France early in the spring of 1918, about
which we have never been able to obtain definite clinical or epidemio-
logical information. These facts would incline one again to suspect
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288 HANS ZINSSER
the existence of a single source of origin. More searching inquiry into
the beginnings of this pandemic, however, throws considerable doubt
upon such a simple solution of the problem. Frost who has given
particular attention to the study of general mortality rates from in-
fluenza and pneumonia has, among other things, analyzed these
rates for a number of American cities during the years 1910 to 1918.
He finds that in December, 1915, and January, 1916, there occurred
in New York and Cleveland a sudden and considerable rise in the
mortality rates from these diseases. In January, 1916, he states,
influenza was reported to be epidemic in twenty-two states of the
Union (U. S. Public Health Reports, January 7, 1916) — epidemics
which "were so mild that they attracted little attention at the time
and were generally forgotten." Even though we make all due allow-
ance for the looseness of the clinical term "influenza" by which many
of these cases were reported, these facts are significant in pointing
to unusual conditions in regard to the prevalence of diseases of this
type some years before the pandemic gathered sufficient velocity to
be seriously regarded.
During the winter of 1917, when the army concentration camps
were being filled in the United States, pneumonia occurred in many
of them in an epidemic form, which, however, was in most cases
unassociated with any influenzal element. In a few cases, however,
mild influenza-like outbreaks preceded or accompanied these pneu-
monia epidemics. When recently we described influenza as we first
saw it at Chaumont, France, in May, 1918, we were told by Dr.
George Draper that he had seen a number of exactly similar cases
at Fort Riley in the winter of 1917. For Europe, too, there is evidence
that indicates that influenza was endemic during the years preceding
the great outbreak and that a number of minor epidemic explosions
had occurred in the years just preceding 1918. MacNeal who has
investigated military reports, particularly, states that small epidemics
occurred in the British Army in 1916 and 1917. A chart constructed
by him, from the American Expeditionary Force reports, shows that
a considerable rise in reported influenza cases took place in November
and December, 1917, and in January, 1918, gradually declining to-
ward spring. MacNeal, compiling the data available in the office of
the chief surgeon, American Expeditionary Forces, states that the
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 289
influenza morbidity reported per 100,000 for succeeding months in
1917, were as follows:
July 321
August 438
September. 404
October. 1050
November 1980
December 2480
Robertson who studied many of the secondary pneumonias which
came to autopsy at this time found an unusual type of lobular pneu-
monia in which Pfeiffer bacilli were frequently found. In many of
these cases the organisms could be obtained from the nasal sinuses and
antra. Similar findings were reported by British bacteriologists
(Hammond, Roiland and Shore, Lancet, 1917, ii, 41, and Hallows,
Eyre and French, Lancet, 1917, ii, 377) who studied the cases that
occurred in the British Armies both at home and in France. We have
also found in reports by Austrian physicians reference to outbreaks
of typical influenza on the Austro-Russian front early in 1917.
There seems little doubt, therefore, that for some years before the
pandemic of 1918 influenza was endemic in many parts both of Europe
and of America. As early as 1915-1916, Frost finds evidence of
limited epidemic outbreaks in the United States. During the winter
immediately preceding the true beginning of the pandemic small
outbreaks occurred among the allied troops in France, the British
troops in England, and probably among American troops gathered
in home concentration camps as well. MacNeal in a summary of the
conditions prevailing among American troops in France concludes
that epidemic influenza in that country originated from the endemic
foci there existing and that the disease was probably carried from
Europe to the United States by shipping. The former assumption,
namely, that the epidemic occurrence of the disease may have been
due to the fact that an enormous and concentrated newly introduced
material of susceptibles may have been lighted into flame after arrival
in France at the numerous endemic "smoulders," may well be correct.
The latter, however, concerning the transportation of the disease from
Europe to America may justly be questioned. For, in the first place,
Frost's studies have shown that prepandemic outbreaks were quite
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290 HANS ZINSSER
as frequent in the United States as in Europe during 1915 and 1916,
and, though we have no definite proof of this there is reason to believe
that influenza was prevalent in concentration camps during 1917.
Moreover, when the disease was beginning to gather headway in
the rise of the first wave in 1918, definite outbreaks in the United
States seem to have preceded those in Europe. The earliest reports
from Europe, so far available, seem to place the beginnings of the
epidemic somewhere in April, 1918. Yet in March there was a very
definite though mild epidemic at Oglethorpe, Georgia, which was re-
ported by Vaughan and Palmer and has been referred to above.
Similar epidemics seem to have occurred in Chicago in March, and
the epidemic which occurred in St. Questin Prison in April was,
according to Stanley, started by the reception of an infected prisoner
from Los Angeles, where the disease must have been prevalent at
that time. It was at about this time that the writer heard of the
curious disease among French Indo-Chinese troops on the Coast of
France, a matter that is mentioned only in order that some one who
may have access to suitable records, may on reading this, look for
evidence more definite than rumor. The first concise reports in
Europe seem to have come from Spain in May. The course of the
epidemic after this time is extremely difficult to follow owing to the
concentration of large bodies of men under active military conditions
and the transportation of troops from one country to another. With-
in a month it had spread to Portugal, France, Holland, Germany,
Austria, Hungary, Russia, Switzerland, Norway and Denmark.
What the exact order of appearance from one country to another may
have been, we are not in a position to say. Nor are we sure that it
will ever be possible to trace this even when all records are available.
Certain it is that outbreaks soon became almost simultaneous in
many different parts of the continent. By June it had appeared in
the Philippines and India. (In India too there had been mild out-
breaks earlier in 1918 in the Province of Tana, presidency of Bombay,
but a report from Major White to the government of India indicates
that a fresh introduction of the disease seems to have taken place in
May when cases were reported in Bombay, subsequent to the arrival
of a transport from Mesopotamia.) A little later it spread through
South Africa and in July appeared in Egypt whither it is said to have
been brought from Malta and Salonica.
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 291
It seems fairly definite, therefore, that the last pandemic cannot
be said to have started in any single endemic focus. It appears to
have grown from roots that can be traced back to 1915 and 1916 at
least, and according to studies such as those of Pearl it seems quite
possible that none of the crowded communities of the world had be-
come entirely freed from the disease after the 1889 outbreak. It is
not impossible, however, that the last pandemic may have been
epidemiologically abnormal owing to the unusual conditions incident
to war, the creation of great foci of respiratory transmission in the
camps and the transportation of infected men in large numbers under
conditions eminently suitable for the dissemination of disease. More-
over, there was a constant rearrangement of human association, a
constant addition of fuel to the centers of epidemic prevalence, in the
form of recruits sent to camps, American susceptibles sent to France
and transport-infected individuals unloaded into dense populations
in both directions between Europe, America and other continents.
It is a suggestion at least worth considering whether this pandemic
might not have been delayed in its advent, or perhaps limited in its
scope had there not been a state of war throughout the world.
Thus, although the last epidemic unquestionably started from a
number of different sources, and although it will probably take many
years before the respiratory disease rates have returned to normal
interepidemic levels, it will still be eminently worth while to study
the problem as to whether there are localities in the East in which,
owing to particularly unfavorable sanitary conditions or other factors
the disease is more prevalent than in the rest of the world, and to
begin prophylactic epidemiology in these places.
Course of the pandemic of 1918
Like the 1889 epidemic the last pandemic appeared in successive
waves. It is a little difficult at the present time to say exactly when
we should consider the first wave to have started. In the United
States the sharp rise of influenza mentioned by Frost as occurring in
1915 to 1916 might be considered a preliminary wave.
According to the report of the surgeon general of the United States
for 1918, it is not impossible that a definite influenza epidemic existed
in the United States in 1917. During this year he states that approx-
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292 HANS ZINSSER
imately 4572 cases of influenza were reported in the United States
army, but no separate tabulations by camps were made at that time
for the Annual Report. Practically none of the 1917 cases were
reported as associated with pneumonia, but in analyzing his tabulations
the surgeon general concludes that in a large number of the camps
in the United States in 1917 there were epidemics of influenza which
began in October, extending through November, usually decreasing
in December, with further decrease in January, decided decrease in
February, and a subsequent increase either in March or April.
Furthermore, a number of cases of the disease were reported during
the summer months together with a considerable number of pneu-
monias. The surgeon general also notes that from the very beginning
of 1918 there was a respiratory disease rate above normal.
A similar early appearance of the disease in 1917 in minor outbreaks
in the British army and in France generally has been alluded to
above in the attempt to analyze the possible origins of the last
pandemic. When the history of the epidemic is finally written by
competent statisticians on the basis of accurate data it may well be
found that it did not appear in its maximum force in a first overwhelm-
ing wave, but that there was a gradual sequence of progressively in-
creasing wavelets which led up to the main outbreak, analogous in a
reverse way to the gradual decline in waves as the epidemic subsided;
and, although, this seems quite different from the story of past epi-
demics, it is not impossible that this is due only to the fact that in
earlier epidemics the preliminary outbreaks were insufficiently recog-
nized and studied. Thus, we have already noted above that Hey-
felder speaks of the similarity of his early cases in 1889 to cases of
so-called dengue fever which occurred in Constantinople in 1888.
However this may be, the first generally recognized wave of the
last pandemic seems to have occurred in the spring of 1918. This
probably began in March, April and May, at which time there were
reports emanating from China and Japan almost simultaneous with
similar reports from Camp Oglethorpe in America, followed rapidly
by outbreaks in France among civilians and American, French and
British troops. It seems at that time to have been prevalent in
American cities, especially New York and Chicago, appearing in
Spain in the latter part of May and early June, reaching England in
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 293
June and July. According to the information we can gather from
the German medical press, the disease must have been prevalent in
Germany and Austria prior to July, 1918. At probably the same time
it reached South Africa. According to a report of Major Norman
White, high sanitary commissioner of India, the disease began epi-
demically at Bombay in June, 1918, but the first sporadic cases seem,
to have occurred in May on a troop ship coming from Mesopotamia
which indicates that the disease must have been in Mesopotamia
previous to that. According to Findlay the first cases in Egypt
occurred at Port Said in the middle of July, introduced by shipping
from Malta and Salonica.
According to Frost the rise in the Central and Western cities of the
United States occurred in April when the pneumonia reported showed
an unmistakable departure from the normal; and the increased
mortality extended into May. But Frost notes that on the Atlantic
seaboard, especially in New York there was a definite increase
generally during the January, February and March, preceding.
It seems definite then that the first well defined wave of this epi-
demic started in different parts of the world between the months of
January and June, 1918, the largest number of outbreaks taking place
finally about the middle of June.
There is no complete interval of freedom between the first and
second waves, a thing which we are inclined to believe probably
never occurs, but the first wave declined very susceptibly.
By September and early October, the second wave which was the
really destructive one in this epidemic, had gathered its full velocity.
In the United States it came at that time with such sudden force
that it appeared as the first onset of the epidemic, the importance
from an epidemiological point of view of the earlier outbreak men-
tioned above not being generally appreciated at the time. The
following chart taken from the article on the epidemiology of influenza
by Frost which has been repeatedly quoted above, illustrates the
manner in which the outbreak appeared in Boston, Washington, and
San Francisco. Events identical in principle occurred in Philadelphia
and New York, beginning at about the same time. The New York
curve was, however, much less extensive than that which occurred
in Philadelphia at this time, and the curve as charted by Frost for
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HANS ZINSSER
St. Louis is a little later in advent, did not reach its maximum until
the middle of December and was much less high than either of the
others. This wave seems to have affected the entire world, and be-
fore the end of October had swept over Russia, China, South Africa,
and parts of South America.
ANNUAL KtfNRATCS PE* lOO?
nwMAucAuses
akmtim* ?mki
_ t*8J»7 M9A4 M«tt I ) tf 8
NfrlMtCftJ&COMie* I JANUARY IfttWAI^
t
Chart taken from article by W. H. Frost, The Epidemiology of Influenza, U. S. Public
Health Reports, August 15, 1919, no. 550, p. 1823-1836.
The second wave was also present in India, reaching its greatest
intensity in the central, northern and western parts of the Indian
Empire. The greatest number of deaths in India seemjto have oc-
curred in October and November, and by November was on the
decline in all parts of India. By the end of the month, mortality had
become almost normal. In Great Britain the second wave appears
to have begun a little later than in America, according to McNalty
beginning in October, reaching its maximum in the last week of
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 295
October, and lasting about three or four weeks. By the end of
December it had practically ceased.
A third wave followed almost immediately upon the second in many
parts of the world, in Great Britain appearing so soon after the
decline of the second that there was hardly any interval. It began
approximately in the latter part of January, reached its height in the
middle of February and had come down to almost normal by the
beginning of April.
Another rise took place in America also in the month of January
during which over 50,000 cases were reported from 17 states for one
week, over 59,000 in the following week.
It is not our intention to attempt a statistical tabulation of the
epidemic throughout the world at this time, further than to indicate
that three very distinct waves occurred in rapid succession in most
parts of the world in which epidemic studies were made. But this
did not by any means end the history of this epidemic. In the fall
of 1919 and the beginning of the year 1920, a very distinct rise of
influenza cases again occurred in the United States. A general in-
crease of cases as reported to the United States Public Health Service
from the various state and city officers of public health is indicated
in the tabulations of early January of this year which grew materially
larger in February and declined in March. It is more than likely
that recrudescences will continue to occur for some time, especially
in crowded centers.
The mortality in the second wave was enormous. Pearl estimates
that in the United States alone, the deaths from the influenza epidemic
were not less than 550,000, "which is approximately five times the
number (111,179) of American soldiers officially stated to have lost
their lives from all causes in the war." A fair index of the severity
of the epidemic can be gathered from the surgeon general's report.
Influenza together with its complications is charged in this report
with over 600,000 admissions of American and native troops for the
year 1918. The total rate was 273.52. It caused 23,007 deaths.
If to these are added deaths from bronchitis, bronchopneumonia,
lobar pneumonia, and other conditions probably secondary to in-
fluenza, the total number of deaths would be 39,371. Approximately
82 per cent of all the deaths could be attributed to acute respiratory
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296
HANS ZINSSER
diseases. An idea of the death rate in India as taken from the report
of Major Norman White (Bulletin of International office of Public
Hygiene, Paris, May, 1919, p. 471-490) can be gathered from the
attached table taken from this report as quoted by the United States
Public Health Service.
POPULATION
(census or 1911)
OPl
INFLUENZA
nOTLUENZA DEATBS
PES 1000
POPULATION
Ajmere-Merwara
Central Provinces and Berar.
Delhi
Bombay
Punjab
Northwestern Frontier
United Provinces
Coorg
Madras
Assam
Bihar and Orissa
Burma
Bengal
501,395
13,916,308
416,656
19,587,383
19,337,146
2,041,077
46,820,506
174,976
40,005,735
6,051,507
o4,4oV,o40
9,885,853
45,329,247
33,407
790,820
23,175
900,000
816,317
82,000
1,072,671
3,382
509,667
69,113
359,482
60,000
213,098
66.6
56.8
55.6
45.9
42.2
40.0
22.9
19.0
12.7
11.4
10.3
6.0
4.7
Total for British India 238,527,635
4,933,132
20.7
Table taken from Report of Major Norman White, Bulletin of the International
Office of Public Hygiene, Paris, May, 1919, p. 471-490.
The problem of immunity in influenza and its epidemiological
significance
The explanation of the peculiar phenomenon of successively fading
waves, of course, suggests the gradual development of immunity.
This would be the simplest explanation and the one on the basis of
which we could reason with some clearness. The question, therefore,
of whether an individual and, therefore, a community as a whole
develops immunity upon an attack of influenza has been the subject
of many inquiries. To base any opinion upon the numerous reports
of second attacks in individuals would be entirely misleading. The
writer himself believes that he had three attacks during the last
pandemic; the first and second mild ones, and the third complicated
and, therefore, severe; and innumerable others with whom he has
spoken have had similar experiences. But, although such observa-
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 297
tions indicate with great definiteness that any immunity resulting
from an attack of influenza can be a relative one only, and far less
protective than the immunity conveyed by an attack of typhoid
fever, smallpox, etc., a judgment of the problem as a whole can be
obtained only by statistical studies of large numbers of people during
the secondary waves. For even a very limited immunity might be
sufficient to prevent infection in a majority of people who, in the
ordinary course of association with others, are subjected to very in-
direct contact with minute doses of a virus which has often attenuated
by conditions outside the body; and this might be sufficient to de-
termine the difference between true epidemic prevalence and a limited,
sporadic sick rate.
It is a fact that Germany and France were spared to a great extent
in the spring of 1891 when North America and England suffered more
severely. Parsons believes that his studies have shown definitely
that there is a transitory state of resistance in a population that has
been thoroughly permeated by the first wave. In his analysis in
England he found that a number of communities that had suffered
severely during the early epidemics were afflicted but slightly during
the second, and vice versa. At Winton near Manchester at a boys'
school there was a serious outbreak in March, 1890, dining which 171
out of 589 children came down with the disease. In 1891, this school
had almost the same inmates, 449 of the children in attendance at
that time having been there throughout the earlier epidemic. In
1891, there were only 25 cases; and only 4 of the 150 who had had the
disease in 1890 had it again in 1891. Two hundred and ninety-nine,
who did not get the disease during the first epidemic, although
thoroughly exposed, were perhaps insusceptible, since only 17 of these
came down dining the second wave. Conversely, a town on the Tye
which escaped lightly during the first two waves, suffered heavily
dining the third. In Brighton there was a low death-rate during the
first epidemic, and a higher one during the second and third waves;
similar facts are cited for Portsmouth and Plymouth. In the St.
Quentin prison epidemic which we have mentioned above, Stanley
states that the second epidemic was less severe than the first, and the
third far less severe than the second and, in analyzing these facts
further, he finds that the men who entered prison after the first
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298 HANS ZINSSER
epidemic had subsided, were attacked in greater numbers than those
that had been there before, although there were more of the latter
than the former. Frost has studied immunity conditions during the
last epidemic, a matter that is still fraught with great difficulties
because of the incompleteness of records of the second and third waves
at the present time. He made a canvass of many thousands of people
in Baltimore between November 20 and December 11, 1918, and a
second inquiry during January among 320,600 people; 724 cases of
influenza were found to have occurred since his first survey. Of
these only 26 were confirmed by reliable methods as having been true
second attacks, and in not all of these was the diagnosis absolutely
definite. He states that in view of the fact that "23 per cent of the
population had had influenza previous to December 11, the propor-
tion of second attacks should have been very much greater if no
immunity had been acquired." Warren T. Vaughan has made an
excellent and extensive analysis of the literature on this question in
which he has collected a considerable number of reports which point
in the same direction as the studies of Parsons and of Frost quoted
above. Thus, the observations of Lemiere and Raymond, of Gibon,
of Dopter, of Opie, Barthelemy, of Hamilton and Lennard, of Niven
and others, all indicate that influenza leaves the individual and, there-
fore, the community through which it has swept, relatively more
resistant than normal for a limited period. This period is appraised
by Warren T. Vaughan as not shorter than three months, the acquired
resistance gradually and rapidly fading thereafter. Such a concep-
tion would explain the apparently contradictory results of Jordan
and Sharp, and of some observations of Frost, courteously placed at
our disposal by him in a letter dated June 18, 1920. In a recent
paper (Journal of Infectious Diseases, May, 1920, p. 463) Jordan and
Sharp have analyzed the incidence of influenza, in subsequent waves,
at the Great Lakes Training Station and at Camp Grant at Rockf ord,
Illinois. In each of these places they divided the men into groups of
those attacked and those not attacked in 1918-1919, and compared
the incidence among these two groups with the respective incidence
in January, 1920. Their results indicate that no marked immunity
exists twelve to fifteen months after its attack. Frost states that,
"in Baltimore those persons who were attacked during the 1918 to
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 299
1919 epidemic showed no relative immunity during the epidemic
of 1920." This is not therefore in contradiction to the earlier Balti-
more studies cited above, since in that case the interval between the
epidemic waves was not more than about three months.
It thus appears that, as far as we can gather from careful studies
of many workers in different parts of the world, a definite increase of
resistance if left behind after an attack of influenza which, though
insufficient to protect all individuals, is still adequate to leave the
community in a condition of relatively high resistance for a limited
period. This period is variously estimated as approximately three
or four months, and is certainly less than one or two years.
The bearing of such an immunity upon periodicity and wave-like
curves of influenza epidemics is obvious.
The problem of the fluctuation of virulence of the virus
In the analysis of the conditions which govern the rise, fall and
disappearance of epidemics, however, account must be taken of
another influence, the reciprocal of the immunity factor, namely, the
possible fluctuations in the virulence of the causative agent. It is
perfectly clear to every one who has studied epidemics that the
- development of immunity alone cannot satisfactorily explain many
of the peculiar manifestations of the outbreaks. Thus, even in
epidemics in which the disease leaves behind a permanent immunity
and in which, therefore, survivors represent an ever increasing non-
susceptible bulwark of transfer between the infected and the sus-
ceptible populations, the decline of epidemics is not often a simple
downward curve, and the mortality percentage declines with the
morbidity. This last fact we have noticed particularly in typhus
epidemics where, in the Serbian one for instance, a death rate of 50
or more per cent at the height of the outbreak declined to between
IS and 20 per cent as the morbidity became less. There are many
other observations which would incline one to assume the manifesta-
tions and the general course of a prolonged epidemic are influenced
as much by changes on the part of the infecting factor as they are by
the acquisition of generally increased resistance.
The analysis of this problem is not an easy one. On the one hand,
we know from laboratory experimentation that, in general, it is pos-
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300 HANS ZINSSER
sible to enhance the virulence of a race of microorganisms for a given
species of animals by successive passages through such animals,
avoiding intervening cultivation on artificial media; this, of course,
provided that the organism in the first place renders the animals
severely sick, or kills them. Thus, passing a pneumococcus or strep-
tococcus from mouse to mouse, directly from the peritoneal exudate
or heart's blood, will, with many races (though not with all races of
streptococci) result in a considerable increase of infective power.
Even a short sojourn on artificial media, interrupting this serial
transmission, will definitely reduce infectiousness in many cases, as
has been shown most clearly perhaps by the Barber method with
anthrax bacilli. Passage through one species of animal may reduce
or increase virulence for other species, according to the particular
germ and animal species used, but this has no direct epidemiological
bearing. Thus, it is not unlikely that as an epidemic spreads rapidly,
a tremendous enhancement in the virulence of the germ may follow
and the morbidity, as well as mortality increase rapidly. Such an
enhancement of virulence by rapid transmission directly from man to
man is entirely analogous to repeated animal passage, and as an ex-
cellent epidemiological example of such a case, Warren Vaughan cites
the havoc played by streptococcus hemolyticus in American army
camps after it had been disseminated for some time as a secondary
invader of measles, subsequently acquiring virulence which enabled
it to become an independent etiological agent or a fatal primary
respiratory disease.
Such an enhancement of virulence, however, will rapidly reach a
maximum and at the time when this maximum is reached, the general
resistance of the surviving community will probably have attained
a level somewhat above normal. In a disease like influenza where
initial susceptibility is general and mortality of the pure, uncompli-
cated disease is low, this increase of resistance on the part of the
community may almost keep pace with the increased virulence of the
organism, and under ordinary conditions the initial wave will subside
when fewer and fewer of the individuals infected with the now fully
virulent virus are normally susceptible.
The conditions now established are those of the approximation of
a balance between virulence of infectious agent and resistance of the
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 301
community which balance, however, is nfcver perfectly established
and, therefore, numerous individuals of relatively low resistance or
who have escaped sufficient contact during the earlier period of the
epidemic, are still afflicted with the disease, and among these we may
assume that an increasing proportion have attained a resistance
somewhat greater than normal, if not sufficient to protect completely,
and this element may contribute to the lessened mortality which
accompanies the declining morbidity.
At this point another well known biological principle may be intro-
duced, a principle which has been most clearly and thoroughly dis-
cussed by Theobald Smith. Theobald Smith speaks of highly patho-
genic organisms as "incompletely adapted parasites." "The less
complete the adaptation to the host, the more violent the disease
produced." Thus, the acutenessof an infectious disease isan evidence
of the tempestuous manner in which the host is trying to rid himself of
the invader, a struggle in which the bacteria develop the defenses of
capsule, etc., and the offensive weapons of poison formation and
perhaps rapid multiplication. As long as this reaction on the part of
the bacteria carries the upper hand the increase in virulence will
continue. Conversely, however, as Theobald Smith points out,
indeed, has long pointed out in some of his former papers, the chron-
icity of a disease is largely dependent upon an adaptation between host
and invader in which the reaction to the parasite is less violent, and
a condition approaching more and more closely to a sort of symbiosis,
is established. As Theobald Smith puts it in a recent paper which is
also quoted by Vaughan "there is a struggle on the part of the para-
sites to adapt themselves and to establish some equilibrium between
themselves and their host;" again, "the final outcome is a harmless
parasitism or some disease of little or no fatality unless other parasites
complicate the invasion."
Such adaptation unquestionably takes place. On the other hand,
it cannot take place unless host and invader are in contact at, at
least, an approximate balance for periods longer than the ordinary
acute infectious disease. During the rapid rise of an epidemic,
therefore, while the organisms responsible are passing rapidly through
a large series of susceptible individuals in whom death or recovery
takes place, the virus transmitted rapidly from person to person,
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302 HANS ZINSSER
developing its offensive properties to a high degree, overcomes the
defenses of its new hosts too rapidly to permit of much mutual adapta-
tion. Later, as the community becomes more resistant, infections
are apt to become more subacute and chronic and carriers may be
established, and under such conditions the process of biological adapta-
tion which in the course of time may result in conditions almost
symbiotic, are perhaps responsible for the entirely altered manifesta-
tions of epidemics.
It is quite possible, therefore, not only in influenza but in other
epidemics, that after the initial wave has reached its peak and the
organisms attained full virulence, their subsequent spread consisting
in a more and more delayed passage from susceptible to susceptible
individual, their sojourn in contact with the tissues and secretions
of cases and carriers and the slower and less violent progress of the
infections in partially immunized individuals may lead to a gradual
adaptation, resulting in a new balance between the invasiveness of
the causative agent and the resistance of the individual.
It is quite conceivable, then, that if the immunity is a rapidly fading
one, as in influenza, organisms of considerable virulence, smouldering
in carriers or in mildly reacting partially immunized individuals,
may pass through a new period of violent spread as the susceptible
percentage is again developed to a larger extent.
In influenza, we are confronted with a particularly difficult problem
in that, as we have seen above, we are in possession of no definite
knowledge concerning the causative agent. As far as the influenza
bacillus, itself, however, is concerned, while we are, of course, entirely
in doubt as to its etiological significance, its unquestionable fluctua-
tions in virulence are of considerable interest. Recently, in our own
laboratory, J. T. Parker and Frederic Parker, Jr., studied a meningeal
strain of influenza which was obtained originally from the meninges
of a child which died at the Nursery and Child's hospital in New York.
This organism was kept alive on artificial media for some six weeks
and then used in a series of experiments on rabbits. Intratracheally
injected into rabbits, this bacillus produced fatal disease, the organism
appearing in the pleura and usually in the general circulation of the
animals. Within 6 rabbit passages with the pleural exudate of pre-
viously killed rabbits, the organisms acquired a virulence so high
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ETIOLOGY AND EPIDEMIOLOGY OF INFLUENZA 303
that less than 0.05 cc. of pleural exudate would kill the rabbits in
a short time, sometimes with pneumonia, sometimes passing through
the lungs and causing a general septicaemia without noticeable
pathological changes in the lungs. On further preservation in rabbit's
blood media for about two weeks longer, this organism again lost its
virulence to such an extent that lately large amounts injected into
rabbits produced no noticeable effect.
It is not supposed that these considerations will throw any consid-
erable light upon the fluctuation of epidemic waves in influenza,
but they are inserted merely to indicate the lines of thought and
experimentation along which these problems may eventually be
elucidated.
Summary
I have sketched the epidemiology of this disease in a fragmentary
way only. I have neither the material nor am I sufficiently versed
in statistical studies to go more deeply into this phase of the subject.
Furthermore, it is too early to attempt to complete analysis of such
records, which are being carefully worked over by statisticians at the
present time and will be published in due time with greater accuracy
than I could bring to bear upon them.
It is quite probable that influenza will continue to be prevalent in
outbreaks of varying intensity all over the world for some years to
come, and that the disease will remain endemic in a scattered, sporadic
manner for many years after that. May we hope that etiological and
epidemiological work which is being followed so assiduously all over
the world at the present time will furnish us with more competent
methods for prevention and delimination before the world is visited
by another pandemic.
The writer is indebted to the surgeon general of the United States
army and to Col. J. F. Siler for access to his own military reports
and to those of others. A number of helpful suggestions and
opinions from Dr. W. H. Frost are also acknowledged with grateful
appreciation.
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304 HANS ZINSSER
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THE SPECIFIC DYNAMIC ACTION OF VARIOUS FOOD
FACTORS
GRAHAM LUSK
Professor of Physiology, Cornell University Medical College, New York City
I. Introduction 311
A. Runner's conception of the specific dynamic action of food-stuffs 315
B. A critique of Runner's experiments 318
II. The influence of carbohydrate on the heat production 320
A. Summary 329
B. Conclusion 331
III. The influence of fat ingestion upon the heat production 331
A. Summary 336
B. Conclusion 337
IV. The influence of protein upon the heat production 337
A. Summary 350
B. Conclusion 352
V. A theory of metabolism 352
I, INTRODUCTION
The appetite controls the ingestion of food so that an average man
may pass through decades without material gain or loss of weight
The sense of appetite must be an extremely delicate regulator to
prevent the gain or loss of body fat through the intake of too much
or too little energy in the food.
Life depends upon the continued existence of the component cells
of an organism, and these cells must be nourished with food if they
are to survive. Phenomena of life are phenomena of motion. The
motions within the living cells are maintained at the expense of
energy derived from the oxidation of fragments of broken down food-
stuffs, that is to say, of disintegrated particles of protein, fat and
carbohydrate.
The inquiry, therefore, ultimately concerns the utilization of
materials present in the fluid bathing the individual cells.
A broad, clear visioned conception of the underlying fundamentals
has been presented by Rubner (33) in his volume on the "Nutritional
311
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312
GRAHAM LUSK
Physiology of the Yeast Cell." He presents comparative figures
establishing the Law of Surface Area and these may advantageously
be studied.
Calories predmced per tqman
meter ef body surface
im 24 hours at
15X.
Man 1042
Pig 1078
Dog 1039
Rabbit 917
Guinea-pig 1246
New-born mouse 1122
These comparative values of the heat production per square meter
of surface are based upon the general assumption that the surface is a
factor of the mass following the formula
Surface -J/ Volume'
Those investigators, present or future, who would upset the valid-
ity of the law that in the resting mammal the heat production is
proportional to the surface area, should demonstrate the falsity of the
general relations exhibited above if they wish to establish their case.
Rubner has carried the investigation of the metabolism from the
gross results obtained in highly developed mammals to the metab-
olism which may be computed as arising daily from a square meter
of cell surface. These results may be thus summarized:
WKIOHT
CALORIES
FEE
KILOGRAM
CALOBZB8
FERBQUAEE
METE* CELL
gUREACB
CELL
SUE* ACE DC
8QUAEE
METERS TO
EJLOOftAM
Hone
450.0 kgm.
70.0 kgm.
1.0 gram
0 . 000, 000, 000, 5 gram
11.1
30.0
654.0
1743.0
0.03
0.2
3.69
3.0*
Man
150
New-born mouse
Yeast cell (38°)
600
* Rubner gives this figure as 1.25, which is apparently an error in calculation.
The heat production of a unit of mass of yeast is therefore threefold
that of a new-born mouse, 58 times that of a man and 157 times that
of a horse.
The heat production per square meter of cell surface, however, is
quite the same in the yeast cell and in the new-born mouse, but it is
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS
313
15 times greater in the yeast cell than in man and is a hundred times
greater than in the horse.
Rubner has further calculated the quantity of protein and sugar
absorbed by a square meter of cell area and also the quantity of
cane-sugar necessary to furnish cells presenting a square meter of
surface with sufficient energy for the maintenance of life for 14
hours.
These values may be thus tabulated:
CALORIES PER
SQUARE METER
CELL SURFACE
CANE-SUGAR
EQUIVALENT
GRAMS
PROTEIN K»
MAXIMAL
GROWTH PER
SQUARE METER
CELL SURFACE
Horse
0.03
0.2
3.69
3.00
0.007
0.05
0.89
8.38*
0.002
Man
New-born mouse
0.030
Yeast cell
0.948
* Anaerobic.
The yeast cell achieves its maximum activity in solutions of cane-
sugar which vary between 2.5 to 20 per cent in concentration. Within
these limits the fermentation process is independent of the concen-
tration of the solution. When the yeast cells are suspended in a
solution of cane-sugar having a strength of 20 per cent., the quantity
of sugar contained in a film 0.04 mm. thick would afford a sufficiency
of nourishment for their support during twenty-four hours. In
like manner it may be calculated that in man, whose cells are bathed
in a liquid containing 0.1 per cent of sugar, the quantity necessary
to support life for the period of one day would be contained in a layer
which, if spread around a cell, would have a thickness of 0.05 mm.
If one continues this manner of calculation it may be estimated
that the quantity of sugar in a 0.1 per cent solution necessary fully to
maintain an average active cell in the human body during a period of
one minute would be present in a film 1/300,000 mm. thick or one
having approximately 1/200 of the diameter of a red blood corpuscle.
It is probable that the entire circuit of the blood is accomplished in
between twenty and thirty seconds. The blood plasma in man is
separated from the tissues by a capillary wall so thin that no compu-
tation of its size has been made. The existing experimental evidence
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314 GRAHAM LTJSK
indicates that there is no oxidative disintegration with resultant
heat production in the blood itself. The blood stream is the trans-
portation system to the ultimate consumers, which are the individual
tissue cells.
One can therefore picture a tissue cell whose requirement for
maintenance for a minute may be held in a film of fluid containing
0.1 per cent sugar solution having the thickness of 1/200 the diameter
of a blood cell, and that this fluid may be replenished through an
indeterminably thin capillary wall by the diffusion of materials
such as sugars, fats and amino-acids passing in a constant stream,
no part of the current of which rests in a given capillary for a time
exceeding two seconds. One can well imagine that if the nutrient
fluid should contain food particles in abundance, the nutritive con-
dition in the cells might be modified thereby. In what way do these
body cells react to an increased bombardment by glucose, by fat,
by glycocoll, by alanin, by acetic acid or by lactic acid? And how
are the results obtained to be interpreted?
In 1913 Rubner (34) spoke as follows in the Prussian Academy of
Sciences:
To follow nutrient particles to the cells, to measure them quantitatively
and to vary them experimentally, belongs to the unsolved problems of
today. It is scarcely to be expected that the difficulties standing in the
way will soon be overcome.
Though the methods employed be crude and the results obtained
be often merely suggestive, yet it is these problems with which the
present paper deals.
Under conditions of fasting or under "post-absorptive" conditions
when there is no longer any food in the intestine, when the sugar
content of the blood is regulated by the liver, when amino-acids
are produced in but small quantity, when fat is available in probably
restricted amount, if, under these conditions, the heat production of
the quiet, resting organism be determined, it will be found that a
constant level of minimal metabolism has been established. This
level is known as the basal metabolism. Ingestion of the three classes
of the food-stuffs, whether these be fats, carbohydrates or proteins,
increases the quantities of fats, of sugar or of amino-acids in the
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS 315
blood and therefore in the nourishing plasma surrounding the tissue
cells and, under these influences, the production of heat by an animal
increases, as may be measured by weighing the oxygen absorbed or
by determining directly the heat produced. The increase of heat
production under these influences is different with the different
kinds of food-stuffs administered. Rubner has defined the increase
in the heat production of the organism under the influence of a food-
stuff as being the specific dynamic action of that food-stuff. It is
necessary to picture the plethora of the particles of a food-stuff
reaching the living cells and to consider the reaction of the cells to
this changed nutritive environment. In other words, the heat
production increases when there is a heightened concentration of
glucose or of fat or of certain amino-acids in the nutrient fluid bathing
the cells of the organism. What is the cause?
A. Rubner' s conception of the specific dynamic action of food-stuffs
One of the earliest papers by Rubner (35) is entitled "The Substi-
tution Values of the Principal Organic Food-stuffs in the Animal
Body.'1 In this paper the constancy of the fasting metabolism is
noted and Rubner comes to the conclusion that when fat, carbo-
hydrate or protein is ingested, each replaces in the body metabolism
isodynamic equivalents of body fat or body protein which would
otherwise have been consumed in fasting. In other words, 100
calories contained in ingested fat would prevent the destruction of
100 calories contained in body fat, or 100 calories contained in sugar
would have effected the same result. This was the basis of Rubner's
isodynamic law. Throughout Rubner's writings one finds this
conception of a fundamental basal metabolism attuned to the minimal
requirements of cell life, upon which other forms of metabolic activ-
ity are superimposed.
When at a later date he (36) formulated the doctrine of the specific
dynamic action of the individual food-stuffs, Rubner held to the
conception that the basal metabolism was not itself augmented by
the ingestion of food, but that it was supplemented by the addition
of heat resulting from the cleavages and oxidations of minor fragments
produced in the destruction of food particles. According to Rubner
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316 GRAHAM LUSK
when 100 calories are administered to a dog in the form of sucrose
(cane-sugar), the heat production is increased by 5.8 calories. He
illustrated the formation of this small quantity of extra heat by
comparing it with the quantity of heat eliminated when glucose and
fructose are formed as cleavage products of sucrose. He believed
that similar cleavages of ingested fat produced the extra 12.7 calories
which he observed were liberated in the body when 100 calories in
fat were ingested. His conception was that the basal metabolism
was satisfied by the utilization of sugar or fat radicles, and that any
heat produced aside from that was extra heat which did not involve
cellular dynamics. His subsequent discovery that during the life
of the yeast cell the major part of the energy is liberated within the
yeast cell itself and a small part only is due to enzymotic fermentation
outside of the cell, contributed to his mental picture of the strictly
dual character of (1) the satisfaction of the fundamental energy
requirement and (2) the production of extra heat (36a).
When protein was administered to a dog Rubner interpreted the
very great increase in the heat production as being due to the fact
that only a part of the protein metabolized could be used to furnish
the basal metabolism with life giving energy, whereas a goodly portion
of the fragments of the amino-acids were oxidized so that they yielded
free heat which could not be utilized for cellular dynamics. For
example, in so far as sugar was produced from protein it could be
used in the service of the maintenance of the basal metabolism.
Rubner (36) furthermore discovered that the great rise in protein
metabolism which Lusk had shown to be a feature of the metabolism
in phlorhizin glycosuria in a fasting dog was accompanied by a greatly
increased heat production although no protein had been ingested.
Rubner calculated the increased heat production for every 100 calories
of protein ingested or metabolized, as follows:
Increase in
calorUs
Meat protein 30.9
Gelatin 28.0
Body protein (phlorhizin glycosuria) 31 .9
A very important relation brought out by Rubner is that when the
environmental temperature is lowered in the fasting dog the heat
production is thereby increased, but such an increase does not take
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DYNAMIC ACTION OF VAMOUS FOOD FACTORS
317
place if the dog has been given meat in quantity. The following
experiment illustrates this point:
XNVIRON1IXMTAL
CAZOKXE8FZE
TKXPESATUKX
JOLOORAM
7°
None
86.4
30°
None
56.2
7°
81 calories in meat per kilogram of dog
87.9
30°
81 calories in meat per kflgoram of dog
83.0
The basal metabolism in this instance was 56.2 calories. On reducing
the environmental temperature from 30° to 7° it was increased through
the reflex influence of cold (the chemical regulation of temperature) to
86.4 calories. On giving meat the heat production rose from 56.2 to
83.0 calories if the environmental temperature were 30°. But if
the meat were given at an environmental temperature of 7° the heat
production was 87.9 calories or practically the same as 86.4 calories
found when the dog was fasting in the cold. This experiment
reinforced Buhner's doctrine of a fundamental basal metabolism
which must be provided with definite fuels. The condition of extra
heat requirement, such as is produced through the influence of cold,
could be supplied not only from the body stores of fat in fasting,
but also from those extra heat producing metabolites of protein
which are not directly concerned in the support of cell life.
The theory of Rubner appeared fascinating and was wholly accepted
by me in the first two editions of the "Science of Nutrition."
An important contribution of Rubner to the subject of the increased
heat production after giving food was the demonstration that the
factor of intestinal activity, "Darmarbeit" in the sense of Zuntz (27),
had nothing whatever to do with the rise in heat production Thus
Rubner (36) demonstrated that administration of bones or of Liebig's
extract of beef or of the quantity of water contained in the meat
previously given to the dog were without influence upon the produc-
tion of heat.
Lusk (20) has shown that when urea is given there is no increase
in the heat production and that sodium chloride is also without
influence.
The absence of "Darmarbeit" as a factor in the specific dynamic
action of food-stuffs has been confirmed by others. The work of
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318 GRAHAM LUSK
Benedict (6) showed that cathartics administered to men caused no
increase in the basal metabolism. Johansson (17) showed that
administration of glucose to a fasting man or to a diabetic individual
might cause no increase in the elimination of carbonic acid, because
the greater quantity of the glucose in the first instance deposited as
glycogen, and in the second instance was eliminated unoxidized in
the urine. Lusk (21) has also shown that the administration of
glucose (up to 70 grams) or of fructose to a dog rendered diabetic by
phlorizin does not increase the heat production of the animal. The
extra heat production after giving sugar is therefore due neither to
the absorption of the material nor can it be due to extraordinary
kidney activity. Since the cells of the body are readily permeable
to glucose and since glucose must diffuse into them after its admin-
istration in phlorizin glycosuria, it is evident that the phenomenon
of osmosis does not contribute an increase in the heat production.
This is reinforced by the fact already stated that the administration
of a solution of common salt is without effect upon metabolism.
The conclusion is therefore warranted that an increased metab-
olism is due to the interrelation between the food-stuffs brought by
the blood stream and the metabolizing cells themselves.
B. A critique of Rubner's experiments
j>
The third edition of Zuntz and Loewy*s 'Tehrbuch der Physiologie1
(1920) contains an article written by Zuntz on "Stoff und Kraft-
wechsel" which must have been revised just before he died. In
this he writes:
It follows from the comprehensive experiments of Mangus-Levy (25)
that the rise in metabolism after the ingestion of fat is about 2.5 per cent
of the calorie content of the same; about 9 per cent after giving starch;
about 17 per cent after giving protein.
Rubner found similar values.
However, Rubner's values were quite different
ptrctnt
After cane-sugar 5.6
After fat 12.9
Afterprotein 30.0
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DYNAMIC ACTION OP VARIOUS FOOD FACTORS 319
Rubner's work was based upon metabolism experiments which
continued for twenty-four hours and therefore the finer transitions
which can be measured from hour to hour were not observed. No
record was kept of the bodily movements of the dog within the box,
and in the course of twenty-four hours this might, under certain
circumstances, have become an important factor. Furthermore,
in Rubner's experiments 30, 31 and 32 in which he fed to the dog a
given quantity of meat, the metabolism rose 21.8 calories per kilo-
gram of body weight and in experiments 37 and 38 the same quantity
of meat ingested caused it to rise only 16.3 calories. These two
figures were averaged in the computation of Rubner's results. Another
element open to criticism has been set forth on another occasion.
Rubner (36) himself showed that when protein is added to the body
it exerts no specific dynamic action and this has been beautifully
confirmed in my laboratory by Hoobler (16) after he administered
"Eiweissmilch" to a baby. Rubner based his calculations of the
percentage quantity of extra heat production upon the calories
contained in the meat ingested, although it would appear that the
controlling factor is in reality dependent wholly upon the quantity
of extra protein metabolism over and above that which occurs in
fasting.
If I take the values found in my laboratory and calculate them
according to Rubner I find the following figures:
100 calories ingested as protein of meat increase heat production 30.0 calories (43)
100 calories ingested as fat increase heat production 4.1 calories (28)
100 calories ingested as glucose increase heat production 4.9 calories (20)
If, however, the intensity of the specific dynamic action be measured
by subtracting the calories of protein of the basal metabolism from
those of the hours after giving meat, and determining what relation
these extra calories of protein metabolism bear to the total increase
in calories for the hour, one finds the following relations (43) :
Every extra 100 calories of protein
wutaboliud increases ike heat
Food production in calories
1200 grams meat 45
700 grams meat 48
This calculation merely assumes that the portion of ingested protein
which is not metabolized but which replaces the "wear and tear"
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520 GRAHAM LUSK
quota of the basal protein metabolism contributes no part to the
"specific dynamic action" of protein. One must conclude, therefore,
that about one-half of the calories of the extra metabolized protein
contributes to increasing the heat production of the body. Since
Lusk has shown that 51 per cent of the calories of meat protein may
pass through a glucose stage, this calculation would of itself be a most
perfect demonstration of Rubner's contention that the glucose
obtained from protein may be used for the support of the basal
metabolism, whereas the other fragments burn, liberating pure heat.
Rubner's observation that the elevation of the level of metabolism
was proportional to the quantity of meat given, is confirmed. The
regularity of the appearance of a definite proportion of extra heat
certainly gives intellectual foundation to the theory of Rubner that a
part of the calories latent in protein always follows a given course.
As regards the interpretation given by Rubner of the extra calories
formed by cleavage after the ingestion of fat, the suggestion is less
dear, for in fasting the body lives principally upon its own body fat
though at a lower level of metabolism than prevails after fat ingestion.
Ingested glucose also causes a specific dynamic action, though glucose
is always present in the blood and available for the production of
cellular energy.
Recent experiments in my laboratory conducted with modern
methods have traced the metabolism process in hourly periods and
have confirmed and extended many of the early and often neglected
experiments of Magnus-Levy published in 1894. It has been our
experience that the experimental work of both Rubner and Magnus-
Levy is accurate, but in the light of newer facts other interpre-
tations follow.
In the account hereafter given the experimental evidence is based
largely upon the author's own experience. The historical background
has been presented above and more fully in the "Elements of the
Science of Nutrition."
H. THE INFLUENCE OF CARBOHYDRATE ON THE HEAT PRODUCTION
It is nearly forty years since Carl Voit (41) with prophetic insight
wrote as follows:
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DYNAMIC ACTION Or VARIOUS FOOD FACTORS 321
The mass and capacity (LeistungsftLhigkcit) of the metabolising cells,
on the one hand, and the quality and quantity of the food materials brought
to them, on the other, determines the height of metabolism; however, the
cells can only be active within certain given limits beyond which an addi-
tional food supply can no longer be destroyed.
The principal changes in metabolism are induced by the differences in
the quality and quantity of the materials used by the cells as brought to
them in the circulating blood. The quantity of protein brought in the
blood stream is the especially influential factor, but the non-nitrogenous
substances are also concerned.
These words of Voit were penned before it was conceived that the
protein molecule is a mass of amino-acids bound together. Further-
more, he wrote
The requirement for energy cannot possibly be the cause of metabolism
any more than the requirement for gold will put it into one's pocket. How-
ever, the production of energy has a very definite upper limit which is af-
forded by the ability of the cells to metabolize (42).
When glucose is given to a dog it is rapidly absorbed. Fisher and
Wishart (13) found that after the administration of 50 grams of the
substance in 150 cc. of water the material was nearly all absorbed
within the first three hours and completely so during the fourth
hour. During this last hour two things happen — a large volume of
urine (100 cc.) is eliminated and glycogen in increased quantity is
deposited in the liver. During the second, third and fourth hours
the metabolism rises about 20 per cent but falls to the basal level
during the fifth hour. It is found that the level of blood sugar rises
during the first hour but, though it returns to normal thereafter,
there is a dilution of the blood, as indicated by a reduced percentage
of hemoglobin. The greater volume of more dilute blood therefore
carries a greater largesse of blood sugar to the cells than before. The
respiratory quotient during the third, fourth and fifth hours is unity,
indicating that the source of energy for the living cells is glucose.
With the cessation of absorption the liver assumes control of the
distribution of sugar molecules in the blood stream, the respiratory
quotient falls, indicating a resumption of the oxidation of fat as well
as sugar by the cells and the metabolism returns to the basal level.
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322
GRAHAM LUSK
These factors have led me to define this form of metabolism as the
metabolism of plethora. Voit stated that an increase in metabolism
was dependent on the flow of metabolizable material to the cells.
And he also stated that the intensity of the metabolism has a well
defined upper limit beyond which it was uninfluenced by additional
excess of nourishing materials. This has been substantiated in the
following experiments (20).
DogXVm
DogH....
DogI
GLUCOSE
INOESTXD
MXTABOUSM IN
SECOND HOUR
grams
percent
8
0
20
15
50
20
75
20
103
20
0.91
1.08
0.98
1.05
1.02
When 8 grams of glucose were given the material caused only a
slight increase in the respiratory quotient and there was evidently
no such overwhelming of the body cells with an excess of sugar
molecules as to cause their utilization to the exclusion of fat. In the
other cases, however, the sugar was given in sufficient quantity to
cause respiratory quotients near to unity or over, which demon-
strates the exclusive combustion of carbohydrate instead of fat.
When 50, 75 or 100 grams of glucose were given the same height of
metabolism was always attained. This confirms Voit and also is in
line with Rubner's discovery (see p. 313) that within wide limits the
intensity of the metabolism of yeast cells is independent of the con-
centration of the sugar solution in which they are living.
It should be remembered that all sugars diffuse with great rapidity
throughout the body. Thus, if lactose, which can not be oxidized
in the body, be introduced intravenously into a dog, it is found that
within half an hour 75 per cent of the injected material has diffused
into the tissues (40). But it is not this movement of sugar molecules
but their oxidation which is the cause of the specific dynamic action
of carbohydrate, for it has been shown (21) that when 70 grams of
glucose are given to a dog rendered diabetic with phlorhizin, the
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS
323
respiratory quotient may remain at 0.72 instead of rising to 1.00,
the urinary sugar may rise from 1.5 to 7.9 grams per hour, and yet
with all this movement of sugar molecules within the diabetic organism
the heat production of the dog remains unchanged.
Johansson (17) has shown that when glucose is given to a man
after prolonged fasting the carbonic acid elimination is not increased
through a deposition of glycogen in the body. This experiment
demonstrates that when glycogen is deposited in the organism there
is no appreciable increase in the heat production.
In another series of experiments the differentiation in the behavior
of various carbohydrates has been investigated. The results obtained
are set forth in the following table:
The relative influence of 50 grams of glucose, fructose, sucrose, galactose and lactose upon
metabolism
Glucose, 50 grams .
Glucose, 70 grams .
Fructose, 50 grams,
Sucrose, 50 grams .
Galactose 50 grams
Lactose 50 grams . .
I 2, 3 AMD 4
EASBOVKE
BASAL VmCEMT
30
35
37
34
22
3
In this dog it is apparent that milk sugar was not utilized, probably
because of the absence of lactase from the dog's intestine. It was
also noted that galactose caused a lesser rise in metabolism than did
either glucose or fructose, and the respiratory quotient shows this
sugar to be less readily oxidized than are glucose and fructose. Of
the latter two, fructose has a slightly greater power to increase metab-
olism than is possessed by the same amount of glucose. This attribute
of fructose may lie in the fact that it must be transformed into smaller
molecules before it can be converted into glucose and laid down as
glycogen, whereas ingested glucose may be directly removed from the
body fluids and be converted into glycogen. The formula for the
conversion of fructose into glucose may thus be written:
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324
GSAHAM LUSK
CH,OH
1
CHO
1
CHO
1
1
CO
1
HOCH
1
HCOH
1
- H, 0 COH
II
CH,
► CHO
+ H, 0
1
HCOH
1
HOCH
1
HCOH
I
1
HCOH
1
CH,OH
1
- H, 0 COH
II
CH,
+ H.O
1
HCOH
1
CH, OH
d-fructose
methyl glyoxal
d-glucose
That methyl glyoxal is an important intermediary product of
carbohydrate metabolism has been especially emphasized by Dakin
(10) who finds that tissue rapidly converts it into lactic acid in vitro,
and that it is converted into glucose and eliminated in the urine
when given to a phlorhizinized dog.
If one looks further into the subject of the intermediary metabolism
of carbohydrate it appears that, although methyl glyoxal may be
readily converted into lactic acid according to the following formula,
CHO O
I
COH + H
II
CH, H
Methyl glyoxal
COOH
I
► CHOH
I
CH,
d-lactic add
yet, Levene (19) has shown that neither tissue nor leucocytes will
oxidize lactic acid further.
It was originally suggested to Magnus-Levy (26) by Spiro that
acetaldehyde might be an intermediary product of lactic add metabo-
lism. If methyl glyoxal underwent this transformation the formula
would read as follows:
CHO HO HCOOH + O -* C Q, + H, O
| Formic acid
COH + -> CHO
II I
CH, H CH,
Methyl glyoxal Acetaldehyde
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DYNAMIC ACTION OF VARIOUS POOD FACTORS 325
Spiro propounded this pathway of sugar destruction as a possible
explanation of the synthetic construction of fat from carbohydrate,
which, written in its simplest form, would present the following
chemical changes:
C Hf C Hi C Hf
I I I
CHO CHOH H, CH, + H, O
-I + - I
C Hf C Ht C Hj
.1 r i
CHO CHO O COOH
Acetaldehyde Aldol Butyric add
Stepp (40a) finds that after the ingestion of a large quantity of
carbohydrate the results obtained on analysis of blood serum for
sugar by the optical and the reduction method do not agree and offers
this as evidence that acetaldehyde radicles are present in the blood
under these circumstances.
It is interesting to note at this point that, whereas acetaldehyde
is convertible into glucose in the phlorhizinized dog,1 as shown by
Ringer (31), yet if it be oxidized to acetic add (32) or reduced to ethyl
alcohol (IS) or by hydrolysis be converted into butyric add (30), it
is then no longer convertible into glucose.
Ringer (31) believes that acetaldehyde is the main antiketogenic
substance derived from carbohydrate metabolism, and that it reacts
with /3-hydroxybutyric add to form a substance containing six carbon
atoms three of which are convertible into glucose.
It has been shown that when alcohol (21) or acetic add (unpub-
lished, see p. 335) are given with glucose to a dog the heat production
rises above the level manifested when glucose alone is given by the
addition of that increment of heat which dther ethyl alcohol or acetic
add, when given alone, would have induced. Therefore, it seems
that these two substances must be affinities of their own in the heat
augmentation process which are not affected by the deavage products
of glucose. If one conceives a deavage of carbohydrate with the
production of acetaldehyde molecule, one must consider it probable
1 My colleague, Stanley R. Benedict, has found the conversion of acetaldehyde, to be
complete in the phlorhizinized dog (Unpublished; quoted by permission).
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326 GRAHAM LUSK
that there is a limit beyond which its oxidation through acetic acid
is not effected.
Still other unpublished experiments show that, although lactic
acid ingested alone may increase the heat production, yet when
given with glucose there is no augmentation above that which glucose
alone produces. This is because its metabolites are of the same order
as those of glucose.
The picture that presents itself, therefore, is that a glucose molecule
carried by the blood stream rapidly diffuses into the cells, that it
may be broken in two within the cells into methyl glyoxaTmolecules,
thereby increasing the number of metabolizable compounds and also
their chemical lability. The next step might be the conversion of
methyl glyoxal into formic acid, which might at once be oxidized,
and into acetaldehyde, which when present in excess of the require-
ment of energy for the cell might react with formic acid and be
condensed into fat. Its oxidative pathway through transformation
into acetic acid would then be inhibited.
Remembering these possibilities, one can consider the bearing
of certain experimental results upon the interpretation of the cause
of the specific dynamic action of carbohydrates. For one may
explain the slightly greater increase in the metabolism of the dog
after giving fructose than after giving glucose by imagining that the
whole mass of the ingested fructose becomes available for the main-
tenance of cell activity because it must, perforce, pass through the
methylglyoxal stage, whereas glucose itself could have been laid
down directly as liver glycogen and thereby could have reached the
blood stream and the tissue cells in lesser concentration than fructose
would have done.
If carbohydrate be given in considerable quantity at a time when
the glycogen reservoirs are filled and the body cells have reached
their optimum of carbohydrate destruction, then carbohydrate is
converted into fat. Such fat production may be illustrated by the
following formulae:
CeHuOt + Qt - CH,(CHi)t COOH + 2CO, + 2H,0
Glucose Butyric acid
» 40^1,0. + Oi - CH,(CH,)14 COOH + 8C0, + 8H,0
Glucose Palmitic acid
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS
327
The respiratory quotient when palmitic acid is formed from glucose
would be 8.0. Bleibtreu (7) took into consideration the production
of the glycerin and fatty acid content of animal fat and wrote the
formula:
270.6 grams glucose « 100 grams fat + 115.45 grams CO» + 54.6 grams H,0
997.2 calories - 950 calories
I have added the caloric values and have estimated that 4.7 per
cent of the original heat content of the glucose was lost in its chemical
transformation into fat. From this it may be estimated that for
every liter of carbon dioxide eliminated 0.80 calories are produced.
Similar calculations were made by Magnus-Levy (25) in 1894, who
used a formula written by Hanriot (14). He concluded that there
was very little extra heat production when either carbohydrate or
protein was converted into fat That this was a true conclusion was
proved by Lusk (21) from experiments in which he gave 70 grams
of glucose to a dog. In one of the experiments (no. 91) the results
may thus be calculated:
Indirect calorimetry
Indirect calorimetry (corrected) . . .
Direct calorimetry
Respiratory quotient (non-protein)
2
3
4
A113
24.52
24.91
24.81
74.41
24.78
25.38
25.49
75.65
25.31
25.63
25.12
76.06
1.08
1.14
1.16
It is evident that the correction of the heat production on account
of the transformation of carbohydrate into fat introduces only a
slight element of increase in the sum total of heat produced. That
the calculation is sound is confirmed by the agreement between
the calculations thus made and the heat as determined by direct
calorimetry.
In the above experiment 1.73 liters of extra CO2 were expired by
the dog as the result of converting 8.1 grams of glucose into 3 grams
of fat. In another experiment (no. 90) the production of fat from
sugar was only half the above quantity, though the metabolism was
practically at the same level, 75.30 calories in three hours.
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328
GRAHAM LUSK
It is therefore evident that if the level of optimum metabolism is
reached, the process of conversion of carbohydrate into fat involves
the cells of the organism in virtually no additional heat production.
It has been suggested that acid radicles are the cause of the increase
in heat production; that they stimulate the cells after carbohydrate
ingestion. However, it was first shown in my laboratory by A. L.
Meyer that the CO* combining power of the blood plasma was
unchanged after giving glucose in large quantity, and repeated
experiments have recently confirmed this observation. Moreover, it
has also been discovered that after giving hydrochloric acid sufficient
to reduce the CQt combining power of the blood plasma from 54 to
48 volumes per cent of CQt in the blood plasma, the metabolism is
only very slightly increased and not at all to such an extent as is
effected by glucose ingestion. It has also been suggested that when
fructose is given to a diabetic the heat production is increased through
the stimulating effect of acid intermediate products (5). However,
Lusk (21) found no increase in the heat production of a phlorhizinized
dog after giving 10 grams of fructose which was largely converted
into glucose and eliminated in the urine. The intermediary metab-
olite, probably methylglyoxal, exerts, therefore, no stimulating effect
upon the heat production. This result has been confirmed by Falta
(12) in experiments on man.
Another experiment (2) of especial significance is, that when 70
grams of glucose are given to a dog and the dog forced to run at a rate
of 4800 meters per hour (3 miles), the heat production of the animal
is slightly less than when the animal runs in the morning without
food (see p. 336). Even on the thirteenth day of fasting the cost
of energy in the dog for the movement of 1 kgm. of his body weight
one meter is the same as when the animal is well nourished. This
may be expressed thus:
Running morning without food ,
Running after 70 grams glucose
Running 13th day of fasting . . .
woum
KILOGRAMS TO
MOVE 1 KGM.
IK.
E.Q.
0.578
0.555
0.584
0.79
0.92
0.73
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS 329
The respiratory quotient did not reach unity when the dog ran
after glucose ingestion. It is probable that glucose reaching the
cells was immediately utilized for the work of the movement and
that there was no surplus of metabolizable particles to raise the
metabolism of the cells. Certainly, no intermediate metabolites of
glucose exercised a specific dynamic effect to lift the cellular metab-
olism to a higher level upon which the metabolism necessary for
muscular effort had to be superimposed.
A. Summary
1 . When 50 grams of glucose are given to a dog it is rapidly absorbed
and glucose molecules are furnished to the body cells in increased
number.
2. All sugars diffuse into the body cells with great rapidity.
3. Increased movement of unoxidized glucose molecules in diabetes
is without influence upon the heat production.
4. The deposition of glycogen does not increase the heat poduction.
5. If SO, 75 or 100 grams of glucose be given to a dog it is possible
to increase the heat production by 20 per cent above the basal metab-
olism during the hours of glucose absorption, but increasing the
quantity of glucose ingested does not increase the level of metabolism,
which may therefore be described as the optimum level of glucose
metabolism.
6. Another dog, whose metabolism had been raised 30 per cent
above the basal level after giving 50 grams of glucose, suffered an
increase of 35 per cent after receiving 70 grams of glucose and one of
37 per cent after taking 50 grams of fructose. It is suggested that,
whereas part of the 50 grams of glucose could have been laid down
as glycogen and removed from the circulation, all of the fructose
must first break up into methyl glyoxal radicles, thereby increasing
the mass of these readily oxidizable metabolites.
7. If carbohydrate be given in excess it may be converted into fat,
but this process transpires with only a slight energy loss and does not
appreciably increase the total cellular heat production which the
already reached its maximum.
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330 GRAHAM LUSK
8. When lactic acid is given with glucose the total metabolism
is not appreciably affected, for lactic acid is directly derivable from
glucose and may satisfy the cellular affinities for this material.
9. When acetic acid or ethyl alcohol is given with glucose there is
a summation of effect, the metabolism being raised by the sum of the
increases which each substance given alone would induce. Possibly
acetic acid and alcohol are not metabolites of glucose. If acetal-
dehyde be a normal product of glucose metabolism, one must conclude
that there is a limit beyond which its oxidation through acetic acid
is not effected.
10. Ingestion of glucose in large quantity does not reduce the COt
combining power of the blood and hence one can infer that acid metab-
olites are not causative of the increased heat production.
11. When carbohydrate is converted into fat there is a largely
increased elimination of CO* without concomitant increase in the
metabolism. Therefore an increase in CO* production can not be a
stimulus to increased heat production.
12. The transmutation of fructose into glucose, presumably through
methyl glyoxal, does not increase the metabolism in the dog made
diabetic with phlorhizin. The mere presence of unoxidixed inter-
mediary fragments of fructose is therefore without influence upon
metabolism.
13. Though there is a reduction of the CO* combining power of
the blood plasma after the ingestion of hydrochloric acid, it has a
very slight effect upon metabolism in comparison with that induced
by the administration of glucose.
14. When a dog is caused to run at a rate of 4800 meters or 3 miles
per hour, the additional energy production for the unit of work is
slightly more without food than when 70 grams of glucose are given.
The influx of glucose molecules is immediately used in the production
of work. There is no excess of metabolites with which to raise the
metabolism to a higher level and the intermediary metabolites of
glucose, though formed in largely increased measure, exert no specific
power to raise the level of that basic metabolism upon which the
definite quota of energy necessary to accomplish work is superimposed.
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS 331
B. Conclusion
One can not escape the conclusion that in the presence of an
abundant quantity of oxidizable fragments of carbohydrate metab-
olism the heat production is raised to a higher level. Definite affin-
ities for carbohydrate consumption are satisfied which are not involved
when the extra supply of glucose is being continually depleted under
the influence of work or is reduced, as in fasting, when the blood
stream is under the regulatory control of the liver. The production
of increased heat after carbohydrate ingestion may be termed the
metabolism of carbohydrate plethora.
m. THE INFLUENCE OF FAT INGESTION UPON THE HEAT PRODUCTION
In the experiments of Magnus-Levy already cited glucose was
given to a dog at the same time as lard and therefore the results
obtained are not technically above reproach.
Murlin and Lusk (28) made a study of the behavior of the metab-
olism of a dog after administering an emulsion of fat and noted also
the influence upon the metabolism when fat and glucose were admin-
istered together. The results obtained are shown in charts T and II.
It appears that when fat alone is administered the heat production
gradually rises until about the sixth hour when it reaches its maximum
and then gradually falls until the twelfth hour when the basal level
is regained. The maximum level of metabolism is 30 per cent above
the basal level. The work of Bloor (8) has shown that after giving
fat to a dog there is a gradual rise in the fat content of the blood, the
maximum being attained in the sixth hour, after which there is a
fall. Here, then, as in the case of glucose ingestion the metabolism
is influenced by the mass of metabolites reaching the cells.
The respiratory quotients after giving fat were always lower than
the general average of such quotients found in the determinations of
the basal metabolism with which they were compared. It was calcu-
lated that all the extra heat produced was at the expense of an added
increment of oxidized fat.
When the fat emulsion containing 75 grams of fat was given together
with a solution of 70 grams of glucose there was a primary increase
in the metabolism due to the combustion of glucose, as indicated
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332 GRAHAM LUSK
by high respiratory quotients, and this state was followed by a con-
tinuance of the high level of metabolism with a fall in the respiratory
Chart I. The Effect of Fat, of Glucose, and of Glucose Plus Fat upon the Heat
Production (28)
quotients due to the subsequent absorption and combustion of fat.
This is the reason why a mixed diet of fat and carbohydrate is satis-
fying for a longer period than when carbohydrate alone is taken.
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS
333
The glucose is given four hours after the ingestion of fat, so that
the maximum effect of glucose falls at the same time as the maximum
DQfi II
HQ11BS
^ElEB eeedi
K6
1 Z
3 2 5 6 j
P *
\
l__ .
76 Ci _
C59 tj*-.
EEILHUUL
2LA
vV
aLififtjLE ^
i HRS
u. P
^£s ;
lQ
T*<^
*< k,
.*'
ok Bujil£
?F L •#<5">^
" 3- Efl
?s:::?r s,
^- - 5
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■•..
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■■■■.*.—.
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J_B
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3
Chart II. The Effect of Fat and of Glucose Plus Fat upon the Heat
Production (28)
effect of fat, the resulting increase in the heat production is equal to
the sum of the increases which each substance given alone would
have induced. This appears as follows:
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334
GRAHAM LUSK
Basal
Fat, 75 grams
Glucose, 70 grams
Glucose 70 grams, four hours after fat, 75 grams.
E.Q.
0.85
0.80
1.00
0.93
21.5
25.0
28.6
32.3
DICftXASB ABOVE
NOUCAL
Calories Per cent
3.5
7.1
10.8
16
33
50
It is evident that when carbohydrate is given at the height of fat
ingestion, the respiratory quotient is lower than unity and betokens
the coincident oxidation of fat and carbohydrate Therefore when
these two materials are transmitted through the blood stream together
there is a direct summation of effect. Since the metabolism of
glucose is at a maximum when 70 grams are given, it follows that for
the utilization of fat an entirely different mechanism is invoked.
There must be definite individual affinities within the cell which
utilize fat metabolites when transported to them in the blood stream.
A question of some difficulty arises at this point. Why should
not the fat formed synthetically after glucose ingestion be immedi-
ately oxidized as is ingested fat when given with glucose? One can
explain this only on the assumption that the synthesis of fat from
carbohydrate is limited to a restricted area or locality of body tissue,
whereas the oxidation of carbohydrate and of fat is a property
common to all tissue. The localized production of fat from carbo-
hydrate is indicated by the fact that, whereas the theoretical respir-
atory quotient for this reaction is 8.0, the actual quotient obtained
from an entire animal after stuffing it with carbohydrate rarely
exceeds 1.30.
According to the well-known experiments of Knoop (18), fatty
acids are oxidized on the /3-carbon atom, yielding successively two
carbon atom chains. The oxidation of caproic acid would follow
the course shown by formula on following page.
If palmitic acid broke up by successive oxidation into acetic add
the following equation would represent its transformation:
Ci«HttOt + 14 O
Palmitic acid
1 gram >
9.353 calories <
■ 8C,H«Oi
Acetic acid
< 1.348 grams
■ 4.706 calories
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS
335
This reaction involves a loss of heat of 50 per cent. There is
nothing to indicate that the energy evolved in the oxidative trans-
formation of palmitic acid is physiologically distinct from that
produced in the oxidation of acetic acid itself. The whole of the
oxidation process may be affected through the mechanism of a single
affinity of the cell.
CH,
I
CH,
I
CH,
I
e— ch,
I
CH,
CH,
I
CH,
I
CH,
CH,
I
CH,
I
CH,
CH,
CH,
+ 0 CHOH+O COOH
+ 0 CHOH +0 COOH
COOH
Caproic
add
I
CH,
I
COOH
^-hydroxy
caproic acid
CH,
I
COOH
Butyric and
acetic adds
I
CH,
I
COOH
^-hydroxy
butyric acid
CH,
I
COOH
Recently performed and still unpublished experiments done in
my laboratory show that when acetic acid is given with glucose there
is an increase in metabolism equal to that produced by the individual
substances acting severally. This supports the theory of its being an
intermediary metabolite of fat. Acetic acid is quickly absorbed and
must be immediately oxidized after absorption, for it exerts no influence
upon the COt combining power of the blood.
The results may be thus expressed:
INCUABX ABOVX BASAL
METABOLISM
Caloric
Percent
Glucose, 58 grams
+4.71
+3.13
+27
Acetic acid, 3 grams
+18
Sum of both
+7.84
+45
Glucose, 50 grams + acetic acid, 3
grams
+7.23
+41
Diabetic acidosis has its origin from 0-hydroxybutyric acid when
it is retained in the body as an unoxidized residuum of fat metabolism.
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336 GRAHAM LUSK
If the condition of acidosis were determinative of a higher level of
metabolism after fat ingestion, one would expect that the height of
metabolism in diabetes would be proportional to the height of the
acidosis. However, in an analysis of 23 cases of diabetes, Allen and
Du Bois (1) found that no relation existed between the intensity of
acidosis and the height of the metabolism. The patient who had the
highest metabolism showed very slight acidosis.
It has already been stated that the energy required to move a
running dog was the same per horizontal kilogram meter, whether
the energy were obtained from ingested glucose or from the dog's
own body fat after the dog had fasted thirteen days. Furthermore,
the basal metabolism of this dog was the same on the fifteenth day of
fasting when the respiratory quotient was 0.73 as it was after two
days of a carbohydrate-containing diet, at which later date the
respiratory quotient was found to be 0.93. As sources of energy
for the basic needs of the body fat and carbohydrate are therefore
mutually interchangeable according to the law of isodynamic equiv-
alents. It is only when the concentration of either or both rises
high in the nutrient fluid that the special separate affinities come
into play and cause or enable the metabolism to reach higher levels.
The influence of fat ingestion upon the metabolism has been more
rigorously investigated than the influence of carbohydrate and of
protein have been.
A. Summary
1. The heat production in the dog after giving fat gradually rises
to a maximum in the sixth hour, when the increase above the basal
level may amount to 30 per cent. It then gradually falls and reaches
the basal level in twelve hours after its administration. The sixth
hour is the time of the maximum fat content of the blood (Bloor).
2. The additional heat produced is at the expense of the oxidation
of fat.
3. When glucose and fat are given together the former is first
oxidized, the heat production rises and the respiratory quotient
approximates unity; the level of increased heat production continues
through subsequent hours on account of the absorption of fat, the
respiratory quotient falling on account of the increased oxidation of
the latter substance.
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DYNAMIC ACTION OP VARIOUS FOOD FACTORS 337
4. When glucose is given four hours after the ingestion of fat so
that the maximum effect of glucose ingestion falls at the time of the
maximum metabolism induced by fat, there is a summation of effect,
the heat production reaching a level above that of the basal metab-
olism by the sum of the two several increments which each substance
would have produced. The respiratory quotient indicates themetab-
olism of fat as well as carbohydrate.
5. If glucose and acetic acid are administered together the same
summation of effect occurs.
6. Hence, in the presence of an amplitude of fat and of glucose
molecules, the affinities entering into the mechanism of the increased
destruction of either appear to be separate and different.
7. The reason why fat, which is synthetically produced from
carbohydrate, is not oxidized as is fat when ingested with carbo-
hydrate, may possibly be that the production of fat from carbohydrate
may be limited to a restricted area or locality of tissue, whereas
the oxidation of carbohydrate or of fat is a property of all tissues.
8. The basal metabolism is independent of the height of the respir-
atory quotient, and therefore the basic requirement may be sup-
ported by isodynamic equivalents of fat or carbohydrate.
9. The severity of diabetic acidosis is no criterion of the height
of the metabolism in diabetes.
B. Conclusion
The same conclusion is reached regarding fat as regarding carbo-
hydrate, that in the presence of an amplitude of fat particles there
is a metabolism of fat plethora, due to the utilization of fat by special
fat receptive cellular affinities.
IV. THE INFLUENCE OF PROTEIN UPON THE HEAT PRODUCTION
The general conclusions reached by Rubner as regards the influence
of protein ingestion upon the heat production have been set forth
in the introduction. It should be recalled that when Rubner wrote
his book, "Die Energiesetze," in 1902 it was still permissible to consider
the protein molecule as a complex containing a glucose radicle. It
was not until later that the conception of protein as consisting of
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338 GRAHAM LUSK
a chain of amino-acids came to be generally accepted. At the present
time one must not only consider the effect upon metabolism of the
ingestion of meat, but also the behavior of the individual metabolites
into which the protein may be resolved. The story might be spun
into a tale of considerable length, but it may be well here to emphasize
only the more significant points.
After giving 1200 grams of meat to a dog weighing 13.5 kgm.
Williams, Riche and Lusk (43) determined the hourly heat production
by both direct and indirect calorimetry. The results are presented
in the accompanying diagram (chart III). The basal metabolism
measured 22.3 calories but after giving meat it rose to a height of
36 calories in the second hour and to 42 calories in the third hour,
a maximum increase above the basal of 88 per cent. The heat
production was maintained at a level above 40 calories through the
tenth hour. In the fourteenth hour it had fallen to 37 calories and
then remained at 30 calories up to the eighteenth hour, falling rapidly
to 25 calories in the twenty-first hour.
Except in the earlier hours of the experiment the curve of urinary
nitrogen elimination is quite parallel to the heat production. The
small elimination of urinary nitrogen in the early hours is due to the
accumulation of urea within the blood and tissues and not to a much
lower protein metabolism.
During ten hours of the experiment the quantity of carbon elimi-
nated in the respiration was less than the amount which would have
been so eliminated had the protein metabolized, as measured by the
nitrogen in the urine, been wholly oxidized. This carbon retention
amounted to the equivalent of a retention of 34.5 grams of glucose.
Calculated on the presumption of this retention of glycogen from the
protein metabolism of the period, the oxygen absorption should have
been 184.55 grams. Actually consumed, there were 186.2 grams of
oxygen. If carbon had been retained as fat only 169.7 grams of
oxygen would have been required. It is therefore apparent that
glucose may be formed normally from protein and not merely in
diabetes as a pathological by-product.
As a second illustration of this phenomenon, McCann (24) has
shown that the administration of the protein of meat to a normal
man on the eleventh day of fasting resulted in the initial establishment
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DYNAMIC ACTION OF VARIOUS POOD FACTORS 339
of respiratory quotients of 0.68 in two successive hourly periods.
The quotients betoken the retention as glycogen of the whole of the
glucose formed from protein, for they are quotients hitherto obtained
ChastIH. Showing the Respiratory Quotient
The total metabolism by indirect calorimetry (solid line), by direct calorimetry (dotted
Hue) and the nitrogen elimination during hourly periods alter the ingestion of 1200 grams
of meat by a dog (43).
only in severe diabetes under circumstances in which the sugar
derived from protein was not oxidized but was eliminated in the
urine. The greedy cells of the fasting body laid hold of the sugar
produced from protein and deposited it as glycogen.
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340 GRAHAM LUSK
It has already been shown that the deposition of glycogen is effected
without increasing the heat production.
Conditions, however, may be such that fat also may arise from
protein. Thus, in certain experiments (23a) the basal metabolism
of a dog was determined and then 1000 grams of meat were given in
the early morning, the standard diet containing 75 grams of carbo-
hydrate in the evening, and again 1000 grams of meat the following
morning. These conditions would tend to produce glycogen satu-
ration of the repositories for glycogen in the body and the carbon
retained from protein might then be laid down in the form of fat, as
is set forth in the following analysis:
Basal metabolism per hour
1000 grams meat, average fifth, sixth, seventh hours
Increase
The "respiratory quotients of the retained pabulum were calcu-
lated to be 0.708, 0.688, 0.685, betokening a deposit of fat. Had the
0.84 gram carbon, which was retained hourly, been deposited in the
form of glucose, indirect calculation would have shown 30.30 calories
to be the heat production. The evidence is therefore that protein
carbon can be synthesized both into glucose or into fat and retained
in the body as such. It bias been shown that the production of fat
from glucose takes place with the formation of but little extra heat
liberation and here the same process must prevail.
Following the ingestion of 1000 grams of meat given to the animal
mentioned above, the respiration rate rose from a basal level of 7§
per minute to 23 J per minute, the animal resting quietly throughout.
A great increase in the heat production may also be observed in
man after taking meat in large quantity, though the rise is not as
great as in the dog. A dog weighing 10 kgm. may devour 1000 grams
of chopped meat within a minute, whereas it requires about half an
hour or more for a man to take 660 grams of the same material. In
the dog the protein metabolized may be of greater energy value than
the total heat production, whereas in man only a fraction of the total
heat production will be derived from the meat ingested. The fdllow-
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS
341
ing chart (chart IV), showing the influence of the ingestion of 660
grams of meat by (1) a normal man, (2) an achondroplastic dwarf,
and (3) a legless man, is taken from the work of Aub and Du Bois (4).
It appears that the sulphur elimination precedes that of nitrogen,
illustrating the presence of a lag in nitrogen elimination. In the
achondroplastic dwarf there is a maximal increase in the heat produc-
tion of 46 per cent above the basal level. This increase is not rela-
tively as large as in the dog, but the difference observed is probably
due to the limitations of the digestive tract. The dog mentioned in
the last experiment would never partake of more than 1200 grams of
meat at one time, and the upper limit of metabolism must have been
nearly or quite reached in the case described.
CalsN-S- Normal Control -W.B.
•0 20
00 M 1.5
40 I* IjO
ACHON0R0PLASU-R.DC P.
Legless Man-HJ.
20 01 Off
0 0 0
/'
s
•
«i
*
/
/
—
—
f
IT
i * 3 4 s • Basal i 2 3 4 5 6 Basal i 2 3 4 5 •
Chart IV. Illustrating the Specific Dynamic Action op Protein in Man
The colums show the basal heat production in calories per hour rising after the subject
has eaten meat containing 23 to 25 grams of nitrogen. The dotted line represents the
excretion of sulphur in the urine in decigrams, the continued line, the nitrogen elimination
in grams per hour (4).
Whereas, as in the dog, it was noted that after giving meat the
increase in heat production might amount to 50 per cent of the calories
of the extra protein metabolized, in man it was discovered that fully
75 per cent of the energy content of the extra protein metabolized
reappeared in the form of the heat of specific dynamic action. It is
obvious that a meat diet is physiologically wasteful.
In the achondroplastic dwarf, with large body and short legs, and
in the legless man the specific dynamic effect of protein was more in
evidence than in the normal controls. Possibly this may have been
due to the fact that in the former individuals the liver or some other
organ or organs bore a greater proportion to the total weight than
normally, and this suggests the possibility that the seat of the
MIDKIira, TOL. I, NO. 2
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342
GRAHAM LUSK
"specific dynamic action" of protein may reside in the liver or some
other organ or organs in greater degree than in the muscles.
However, Aub and Means (4a) find that the response of the human
organism to the specific dynamic action of meat is just as great in
severe cirrhosis of the liver as in the normal condition. They conclude
that the liver is not the main site of the specific dynamic action or
that it can adequately perform that function even in disease.
The increase in the heat production after protein ingestion greatly
transcends that which follows the giving of carbohydrate and fat,
and it is of a different character.
One sharply characteristic quality of the specific dynamic action
of protein is that when once the level of heat production is increased
after giving meat any energy necessary for the production of work is
superimposed upon this higher level of metabolism. This was first
demonstrated by Rubner (37) in man and may be recorded as follows*
No food, rest
Cane-sugar, 600 grams, + HjO, 3000 grams, rest
Same + work (100,000 kgm)
Protein, large amount of meat
Same + work (100,000 kgm)
Per day
Ibctcms
due to work
1976
2023
2868
845
2515
3770
855
This work was confirmed and extended by Anderson and Lusk (2)
and showed that the energy of metabolism was the same when a dog
ran 3 miles an hour whether or not glucose had been given in large
quantity; also that the energy expenditure required for running was
superimposed upon the higher metabolism induced by meat ingestion
or by such a fragment of protein metabolism as alanin. This dis-
tinction has important theoretical bearing.
Their results may be epitomized as tabulated on following page.
The attractive theory of Rubner is that when protein is metab-
olized it can be utilized for cell life only in so far as it is convertible
into glucose, and that such fragments as are not so converted are
oxidized with the production of free heat which is of as little value
for the maintenance of the living mechanism as heat produced in the
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DYNAMIC ACTION OP VARIOUS FOOD FACTORS
343
body through high powered electric currents, for example. The
latter form of heat does not alter the fundamental metabolism.
This theory lent itself to experimental proof for Ringer and Lusk
(32) found that, whereas glycocoll and alanin were completely con-
verted into glucose in the organism of the diabetic dog, only three
of the five and four carbon atoms contained respectively in glutamic
and aspartic acids were convertible into glucose.
No food, rest
No food, work
Glucose, 70 grams, rest . .
Glucose, 70 grams, work .
Meat, 750 grams, rest . . .
Meat, 750 grams, work . .
Alanin, 20 grams, rest. . .
Alanin, 20 grams, work . .
CALOUU
DISTANCE
FS&HOUK
ft. Q.
arums
17.2
0.86
76.1
0.79
4806
21.0
1.07
77.1
0.92
4771
70.0
0.80
92.4
0.80
4704
21.0
0.84
82.0
0.78
4777
WORXZN
DLOORAMS
TO MOV*
Iron.
11
0.578
0.555
0.587*
0.583t
* Corrected for influence of meat,
t Corrected for influence of alanin.
Ringer and Lusk suggested that glutamic acid might be oxidized
on its 0-carbon atom which on cleavage might yield serin, the latter
being converted into glyceric acid on deamination. Glyceric acid,
when given to the diabetic dog, was converted into glucose. Recently
Dakin (9) has isolated a new amino-acid, 0-hydroxyglutamic acid
from caseinogen, and has also produced it synthetically. This acid,
he finds, yields glucose to the extent of three of its carbon atoms
when it is given to the diabetic dog.
Perhaps the transformation of glutamic acid proceeds as follows:
COO H
I
CH,
I
CH,
COO H
I
CH,
COOH
I
CH,
CH.OH
+ 0 CHOH +H, CHtOH
I I I > i
CHNH, CHNH, CHNH, +HOH CHOH
I
COOH,
COOH
COOH
Glutamic
^-hydroxy-
Serin
add
glutamic add
COOH
Glyceric
add
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344 GRAHAM LUSK
Or since yeast cells may convert glutamic acid into ketoglutaric
acid (29) and this again into succinic acid (11) and, since succinic
acid if fed to the phlorhizinized dog, is convertible into glucose,
(31a) the following intermediary reactions constitute a second
possibility:
COOH COOH COOH COOH
I I I I
C H, — — ► C H, — ► C H, — ► C H, > Glucose
I I I I
C H, C H| C H, C H|
I I I
CHNH.+0 CO COOH CO,
I I
COOH COOH CO,
Dakin (9) believes that the metabolism of glutamic acid probably
takes place through malic acid as an intermediate metabolite. Ringer,
Frankel and Jones (31a) have shown that malic acid is convertible
into glucose. Dakin's suggestion follows the formulae:
COOH COOH
I I
CHNH, CHNH, COOH COOH
I I I I
CH, +0 CHOH CHOH — ► CHOH
I I I I
C H, — ■♦ C H, ■— ► C H, C H,
I I I
COOH COOH COOH
Glutamic 0-hydroxy- Malic acid Lactic add
acid glutamic acid
Whatever the intermediary reactions, the energy relations may
be written as follows:
2C<H^N0, + 3H,0 + 30, - CH„Os + CN,H40 + 3H,0 + 3C0,
Glutamic acid Glucose Urea
1 gram - 0.612 gram -f 0.204 gram
3.662 calories - 2.298 calories -f 0.516 calory
This reaction is therefore exothermic, 3.662 calories in glutamic
acid yielding 2.298 calories in glucose, 0.516 calories in urea and
0.848 calories in the intermediary oxidative processes. The physio-
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DYNAMIC ACTION OP VARIOUS FOOD FACTORS 345
logically available calories in glutamic acid are 3.662 minus 0.516
contained in urea, or 3.146 per gram. Hence, in calculating the
calories available one would say that 73 per cent of the total passed
through the glucose stage and 27 per cent passed through other
oxidative channels
If Rubner's theory (see p. 000) of specific dynamic action were
correct, then glutamic acid would furnish energy to the cells in so far
as it was convertible into glucose, whereas the rest of the energy
content would be liberated as free heat. Its specific dynamic action
could be measured as 27 per cent, which almost coincides with the
figure 30 per cent, as given by Rubner. Since the protein of meat
yields 22 per cent of glutamic acid and that of gliadin nearly 50 per
cent (Osborne), it follows that an important fragment of protein
metabolism is represented in this amino-acid.
However, it has been discovered that the ingestion of 20 grams of
glutamic acid by a dog gives absolutely no specific dynamic action
(22) and this is also true of its hypothetical cleavage product, succinic
acid (3). The demonstration that glutamic acid exerted no specific
dynamic action after its ingestion is a proof that the process of
deamination and urea production have no influence upon the heat
production.
It has furthermore been shown that aspartic acid, HOO-CCHr-
CHNH2-COOH, exerts no specific dynamic action (3) and this further
substantiates the above conclusions.
Other experiments showed that neither 20 grams of leucine nor
20 grams of tyrosine caused any conspicuous rise in metabolism after
their ingestion (22), although tyrosine at least would present a multi-
tudinous array of oxidative products.
It was only when two amino-acids which are completely converted
into glucose by the diabetic organism were given, that the heat produc-
tion of a normal dog was very greatly increased. These two amino-
acids are glycocoll and alanin. Serin has never been tested but would
probably behave like alanin. These experiments overthrow the
validity of Rubner's theory of the specific dynamic action of protein.
In one experiment 20 grams of glycocoll were given to a dog and
the metabolism rose 33.7 per cent above the basal level. The 20
grams of glycocoll contained 42 physiologically available calories of
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346 GRAHAM LUSK
which 34 calories or 81 per cent were available for metabolism between
the second to the seventh hours in the calorimeter experiment after
giving the substance. Since the heat production was increased by
33.75 calories, or by 80 per cent of the calories in the ingested sub-
stance, it is evident that the extra heat production after giving
glycocoll may equal the entire energy which can be furnished by the
metabolism of glycocoll itself.
This at once raises the question: Is the energy in glycocoll merely
freed and given off without affecting the basal metabolism? Does it
merely explode with a puff?
If one writes the reaction and the energy involved in the conversion
of glycocoll into glucose and urea the following equation results:
6CH4NA + 3CO, + 3H<0 - 2CeHiiO, + 3CH«N<0 + 30,
Glycocoll Glucose Urea Oxygen
20 grams 16 grams 8 grams 4.26 grams
62.2 cals. 60.08 20.22 14.0 as oxidized fat
According to this equation 62.2 calories in glycocoll become con-
verted into glucose and urea, containing together 80.3 calories with
the intermediary liberation of a compound yielding oxygen in such
quantity that it can effect the oxidation of an amount of fat which
can produce 14 calories. The reaction would therefore be rewritten
as follows:
Glycocoll + fat + CO» + H.0 - Glucose + CH«N|0 + CO, + H.0
20 grams — 16 gm. + 8 gm.
62.2 cals. + 14 cals. - 60.08 cals. + 20.22 cals.
Hence, material containing 76.2 calories is converted into material
containing 80.3 calories. The reaction is still endo thermic.
When, however, glycocoll is given to a dog diabetic with phlorhizin
the heat production is very greatly increased, far beyond the require-
ment of satisfying this endothermic quota of energy.
See following table for the results.
The extra calories produced over and above the basal metabolism
for four hours amounted to 25.9 calories, which corresponds with
24.5 extra calories produced in the same dog when he was normal in
the experiment already described.
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS
347
Dog III, March 25, 1915, Experiment 104. Basal pklorhirin metabolism as affected by
20 grams of gfycocoU in 210 cc. of water at 38° plus 1 gram of IAebifs extract
HOUBS
R.Q.
CALORIES
Indirect
Direct
1
Basal
0.733
0.716
23.78
23.82
24 53
2
Basal
23 84
Average
0.724
0.707
0.745
0.700
0.702
23.80
34.21
31.65
29.24
25.99
24 18
3
Glycocoll, 20 grams
4
GlycocoH, 20 grams
32 34
5
GlycocoD, 20 grams
29.47
6
Glycocoll, 20 grams
30 07
7
Glycocoll, 20 grams
26 85
Average
0.720
30.27
29.38
This is the txperimentum crusts which demonstrates that the specific
dynamic action of glycocoll is independent of its oxidation. Rather,
there must be chemical intermediates produced which act upon the
protoplasm of the cells, lifting them to a higher level of metabolism
without it being necessary that they themselves furnish the energy
of metabolism. I have therefore spoken of this condition as the
metabolism of amino-ocid stimulation. This does not necessarily
mean that acid is actually liberated.
To investigate this point I have given to a dog 9.6 grams of glycocoll
neutralized with 10 grams of sodium bicarbonate and have witnessed
the heat production increase 5.2 calories per hour during the second
and third hours. The bicarbonate given alone was without influence.
When 7.6 grams of glycocoll acid were given the heat production
rose 1.6 calories per hour and when 10 grams of glycollate of sodium
were ingested a rise of only 1.2 calories was recorded. The admin-
istration of glycollic acid greatly reduced the carbon dioxide com-
bining power of the blood, which testifies to its slow oxidation.
It would seem likely that glycollic acid would be the first inter-
mediate product of glycocoll deamination, as follows:
CH,NH,+HOH C H, O H
COOH
+ NH,
-► COOH
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348
GRAHAM LUSK
However, glycollic add is not convertible into glucose in the
organism. It may be, however, that the reduction of the acid group
takes place before or simultaneously with the deamination process
and glycolaldehyde is generated, which substance it has been shown
is convertible into glucose (39). If so, the stimulation of cellular
metabolism probably occurs before this step because the synthetic
production of glycogen does not involve a stimulation to increased
heat production.
The experiments may possibly be explained after another fashion.
It may be that the amino-acid is greedily absorbed by the cell and
that the alkali neutralizing it is not. Under these circumstances
the liberation of free acid may possibly be the stimulus which
increases cellular metabolism. Under this hypothesis the cell mem-
brane would be largely impermeable to the sodium salt of glycollic
acid present in the blood after the ingestion of either the acid itself
or glycollate of sodium and little result would be noticed in the way
of cellular stimulation.
When glycocoll is given the extra heat production is proportional to
the quantity ingested; that is to say, it is proportional to the intensity
of the chemical stimulus.
When glycocoll is administered with glucose the extra heat pro-
duction is the equivalent of the sum of the extra quantities of heat
which either substance would have induced alone. Furthermore,
when glucose and glycocoll are given at the height of fat ingestion
the extra heat production rises to a level which is the equivalent of
the influences exerted by the substances as individuals. This is
seen in chart V and may be illustrated in the following table:
HOURLY
INCREASE
INCALORHS
ABOVE
BASAL
PEftCEKT
Glycocoll, 20 grams .,...,.,
4.9
6.9
3.9
25
Glucose, 70 grams
30
Fat, 75 grams
17
Sunt of all T . ,
15.7
72
Glycocoll, 20 grams -+- glucose, 50
grams
4 hours after fat,
75
grams.
14.6
64
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS 349
It is obvious that glycocoll, which is completely convertible into
glucose, does not behave like glucose (1) in substituting its energy
for the energy of glucose in metabolism; (2) in being passively elimi-
Chart V. The Effect of Fat, of Glycocoll, of Glucose, of Glucose Plus Glyco-
coll, and of Glucose Plus Glycocoll Plus Fat upon the Heat
Production (28)
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350 GRAHAM LUSK
nated as glucose in the urine of the diabetic dog, It follows, also,
that ingested glucose can not synthetically form glycocoll under
normal conditions.
The behavior of alanin is in every way similar to that of glycocoll.
It is completely convertible into glucose, perhaps through a lactic
acid intermediary product. When given with glucose it does not
replace glucose in metabolism but itself increases the metabolism by
that quota which, acting alone, it would have induced. It stimu-
lates to a higher heat production when given in phlorhizin glyco-
suria, though it is completely converted into glucose without under-
going oxidation in the process. Likewise, when given alone, it
increases the basal level of metabolism upon which the energy for
work is superimposed, while glucose molecules entering in large
quantities have no power to augment the basal level of metabolism
when the work done is accomplished at the expense of their energy
content (see p. 330). In this last factor the behavior of alanin is
but characteristic of the whole complex of the protein molecule.
When lactic acid is given (33) to a dog there is quite an increase
in the heat production and it seemed to the writer that this gave an
explanation to the specific dynamic action of alanin. However,
unpublished experiments show that lactic acid, when given with
glucose, does not cause a summation in the extra heat production as
transpires when glucose and alanin are given together (see p. 326).
Hence, it appears likely that the specific dynamic action of alanin
is dependent on a specific stimulus imparted to cellular protoplasm
when after its absorption into the cell it suffers transformation into
simpler substances. In all its reactions alanin resembles glycocoll
except that its action is not quite as powerful per gram of substance
metabolized. However, the evidence points to the fact that the
specific dynamic action of the two substances is proportional to the
number of molecules metabolized (21).
A. Summary
1. The extra heat which is the product of the specific dynamic
action of protein may be used in substitution for the extra heat in-
duced by the effect of environmental cold (Rubner).
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DYNAMIC ACTION O* VAMOUS FCK)D FACTORS 351
2. The increase in heat production is proportional to the protein
metabolism of the time. It occurs when endogenous protein metab-
olism increases as in the case of phlorhizin glycosuria (Rubner).
3. A dog given 1200 grams of meat showed a maximum increase
in metabolism of 88 per cent above the basal metabolism, an increase
which remained nearly at this height during the first ten hours after
meat ingestion. Another dog, after taking 1000 grams of meat,
showed an increase in metabolism of 93 per cent above the basal.
These quantities of meat were approximately the maximum which
the dogs would eat. Fifty per cent of the energy content of the in-
creased protein metabolized appears in the form of heat of specific
dynamic action.
4. When meat is thus given in excess of the nutritive needs of the
cell there may be a retention of a part of the energy of the protein
metabolized, deposited either in the form of glycogen or in the form
of fat, depending upon the condition of the glycogen reservoirs of
the body. Neither of these processes involves an appreciable libera-
tion of energy.
5. In man the ingestion of 660 grams of meat caused a maximal
rise in the basal metabolism of 46 per cent. Of the energy content
of the increased protein metabolized 75 per cent appears in the form
of the heat of the specific dynamic action.
6. If the energy required to accomplish a given quantity of work
be determined before and after meat ingestion it is found that the
energy requirement for work in the first instance is superimposed
upon the metabolism as induced by the specific dynamic action of
protein in the second instance. This strictly differentiates between
the character of the specific dynamic action of protein and of glucose.
In this regard alanin behaves exactly like protein and not like glucose.
7. Glutamic acid with its five carbon atoms exerts no specific
dynamic action when given to a dog. The process of deamination
and urea formation may therefore take place without increasing the
heat production. Succinic add, a possible intermediary metabolite,
exerts no specific dynamic action.
8. Aspartic acid behaves like glutamic acid.
9. Neither leucin nor tyrosin cause a conspicuous rise in metabolism.
10. Administration of 20 grams of glycocoll to a normal dog causes
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352 GRAHAM LUSK
a very great increase in the heat production. The quantity of extra
heat produced (25.9 calories in four hours) may amount to the entire
energy of the glycocoll metabolized during the period.
11. When 20 grams of glycocoll were given to a dog diabetic with
phlorhizin the quantity of extra heat produced in four hours (24.5
calories) was exactly the same as when the material was given to the
same animal when normal in spite of the fact that the ingested glyco-
coll is completely converted into glucose and urea without oxida-
tion. Therefore, some intermediary metabolites act as chemical
stimuli to metabolism (Experimentum crucis).
12. Glycocoll neutralized with sodium bicarbonate has the same
influence upon the heat production as when given alone. The bicar-
bonate given alone is without influence upon the metabolism.
13. Glycollic acid and sodium glycollate have little influence upon
the heat production. It is indicated that glycollic acid may not be
as readily permeable to cell membranes as is the readily diffusible
glycocoll.
14. When glucose is given with glycocoll or when the two combined
are given at the height of fat metabolism, the total specific dynamic
action of the mixture is equal to the sum of those quantities of extra
heat production which each substance acting separately would have
induced. The calories of glycocoll can not, therefore, be substituted
for the calories of glucose.
15. The behavior of alanin is analogous to that of glycocoll. Mole-
cule for molecule, it exerts the same specific dynamic effect.
B. Conclusion
The specific dynamic action of protein consists in a specific chemi-
cal stimulus of the cellular protoplasm, which is independent of the
oxidation of the material through which the stimulus is applied. It
may be termed the metabolism of amino-acid stimulation.
V. A THEORY OF METABOLISM
It may be well to restate a theory of metabolism already advanced
(23a) which is a modified form of one enunciated by Rubner (38).
One may conclude that the influence of food ingestion upon the
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DYNAMIC ACTION OF VARIOUS FOOD FACTORS 353
basal metabolism of the quiet, resting cell may be upon three inde-
pendent mechanisms within the cell:
a. A mechanism which is receptive to a chemical stimulus derived
from such amino-adds as glycocoll and alanin.
b. A mechanism of carbohydrate plethora which allows the metab-
olism of carbohydrate up to the limits imposed by "self regulation."
c. A mechanism capable of receiving power from that quota of
fat which, when in excess, increases the heat production of the cell.
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HEMOLYTIC JAUNDICE
WILDER TELESTON
New Haven, Connecticut
TABLE 07 CONTENTS
Introduction 355
Historical. 356
Types 357
I. The congenital type 357
Etiology 358
Pathogenesis 360
Clinical picture: jaundice, spleen, blood, urine, stools, metabolism, com-
plications 364
II. The acquired type 369
Classification 369
Etiology 369
Pathogenesis 371
Clinical picture 373
Pathology of hemolytic jaundice 376
Differential diagnosis 379
Diseases with jaundice 379
Diseases with splenomegaly *. 380
Diseases with anemia 383
Treatment 383
Medical 383
Surgical 384
Prognosis 385
References 386
INTRODUCTION
Definition
In general, any jaundice may be said to be hemolytic when it is
due to increased destruction of the red blood cells, and not to obstruc-
tion of the bile passages. A good illustration is afforded by the jaun-
dice which follows the transfusion of blood in cases where there is
incompatibility between the patient's blood and that of the donor.
Such a jaundice corresponds to the "hematogenous" jaundice of the
older writers, a term which is again coming into use since Whipple
355
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356 WILDER TTLESTON
and Hooper (93) have shown that bile pigment may be formed out-
side of the liver and in the general circulation.
For the purposes of this article however, the term hemolytic jaun-
dice will be restricted to a form of jaundice, usually chronic, in which
diminished resistance of the red cells to hypotonic salt solutions is a
conspicuous feature, while bile pigment is present in the stools and
absent from the urine. Enlargement of the spleen and anemia com-
plete the picture.
The disease occurs in two forms, the congenital and the acquired,
the former being by far the commoner. The congenital type belongs
to the inheritable diseases, occurring often in several successive
generations, occasionally in several members of a family without
cases among the ascendants, and also in a strictly congenital form,
a single member of a family being affected from birth.
Synonyms
A great variety of names has been employed, according to different
conceptions of the nature of the process, viz., chronic acholuric jaun-
dice, chronic infectious jaundice with splenomegaly, chronic familial
jaundice or cholemia, hemolytic splenomegaly, hemolytic anemia,
and hemolytic jaundice. The last named, however, is the one almost
universally used at present.
HISTORICAL
The recognition of the disease is of recent date. Imperfect
accounts of the congenital form were given in 1885 by Murchison
(65) and in 1890 by Wilson (103), but it was not until 1900 that the
first accurate description was published by Minkowski (60). This
was soon followed by articles in France by Gilbert, Castaigne and
Lereboullet (32), and in England by Barlow and Shaw (4). Ten
years later the condition was first recognized in America by Tileston
and Griffin (85) and shortly afterwards by Thayer and Morris (83).
The nature of the disease was little understood till 1907, when
Chauflfard (14) discovered the significant fact that the red cells
showed a markedly diminished resistance to hypotonic salt solutions.
In the following year he reported (15) the presence of reticulated
red cells in large numbers.
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HEMOLYTIC JAUNDICE 357
Widal (94) was the first, in 1907, to describe the acquired type in
detail and recognize its hemolytic nature, though Hayem (39) had
reported similar cases in 1898.
For these reasons the congenital form often is alluded to as the
Minkowski-Chauffard type, and the acquired form as that of
Hayem-Widal.
TYPES
I. THE CONGENITAL TYPE
The important features are as follows: Jaundice appears either at
birth, or during childhood or youth, and persists throughout life.
It is usually noted in more than one member of the family, and
frequently in two, three, or even four generations. At times, how-
ever, though dating from birth, no other members of the family
are affected. The icterus is not intense, there are no signs of obstruc-
tion of the bile ducts, and symptoms of cholemia, such as itching,
bradycardia and xanthomata, are lacking. The urine shows the
presence of urobilin, but no bile, while the stools are highly colored,
and contain an excess of urobilin. Enlargement of the spleen,
which may reach large proportions, is an almost constant feature,
while the liver is only slightly or not at all enlarged. • A moderate
degree of anemia is the rule. The resistance of the red cells to
hypotonic salt solutions is diminished, in marked contrast to the
increased resistance met with in obstructive jaundice. Reticulated
red cells are present in large numbers. The leucocytes may be
either normal, increased, or decreased in number.
In spite of the long duration of the disease, the health does not
suffer much, and many patients attain an advanced age, death being
almost never due to the disease itself. As Chauffard has aptly
remarked, the patients are rather jaundiced than sick. Except in a
few cases, such as those of Weber (91) and Turk (87), the growth is
not interfered with.
In the history a characteristic feature is the occurrence of the
so-called "crises;" after an indiscretion of diet, a period of consti-
pation, or without obvious cause, attacks take place in which there
is repeated vomiting of bile, often accompanied by fever and pain
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358 WILDER TILESTON
in the region of the spleen or liver. The jaundice deepens during
these attacks, the spleen enlarges and if counts are made, it will be
found that the red cells have diminished, often with great rapidity.
These "crises of deglobulization," as they are termed by the French,
occur more frequently in youth, diminishing in number and severity
with advancing age.
Between attacks the patient feels fairly well. There is a marked
tendency to nose-bleeds during childhood, but hemorrhages from
other organs are not met with, an important distinction from Banti's
disease and cirrhosis. The enlarged spleen often causes a sense of
weight and oppression in the left hypochondrium, and pain may
occur in this region, apart from "crises," as a result of perisplenitis.
Etiology
Heredity. The disease is often an exquisitely hereditary affection
involving three or even four generations. It is transmitted equally
by the male and by the female, and Wilson's (103) statement that
it tends to pass from father to daughter, and from mother to son,
does not hold good for most instances. The sexes are affected about
equally. There seems to be no racial predisposition. Some of the
children almost always escape, and the offspring of those who do,
remain free from the affection. It has not been found possible to
apply the Mendelian laws of the inheritance of dominant and recessive
characters.
As in the case of other hereditary diseases, the etiology is obscure.
Certain observers, notably Chauffard, attempt to ascribe the disease
to hereditary syphilis and to tuberculosis. This seems the more
plausible on account of the analogy of hemolytic jaundice with
paroxysmal hemoglobinuria, a condition which is usually associated
with inherited syphilis.
Chauffard (17) bases his argument on observations on a family
in which the usual picture of hemolytic jaundice occurred in twins,
the subjects of hereditary syphilis. The father was jaundiced from
birth and showed a positive Wassermann reaction. Interesting
phenomena were noted after injections of neosalvarsan. In all
three splenic "crises" occurred, with pain and increased swelling
of the spleen; in one of the twins there had been no previous crises.
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HEMOLYTIC JAUNDICE 359
The resistance of the red cells was decreased in two after the injection
and increased in the other. The temporary appearance of isolysins
was also noted. After a few injections these reactions appeared
no longer.
Chauffard regards these phenomena as being in the nature of a
Herxheimer reaction, or local reaction in the spleen due to the sudden
liberation of toxins from spirochetes which have been killed by the
drug. His observations, interesting as they are, cannot be said to
prove his point, for he made no control tests on the effect of salvarsan
injections in cases of hemolytic jaundice without syphilis, or in cases
of syphilis without jaundice. Nor have syphilitic lesions ever been
demonstrated in the spleen in hemolytic jaundice.
Guizzetti (38) has also reported a family in which hereditary
syphilis is supposed to have played a part. Hemolytic jaundice
occurred in four generations, and in two cases, brothers, a marked
thickening of the frontal bone, claimed to be syphilitic, was found
at autopsy. The husband in the first generation was said to have
been syphilitic, but his wife, who was his first cousin, also suffered
from splenomegaly, so that it is possible that syphilis had nothing
to do with the jaundice transmitted to the offspring. It should be
noted that in this family the disease ran a severe course, resulting
in the early death of several members. Such malignancy has been
noted in no other cases in the literature; it seems possible that it
was due to the fact that both parents suffered from the disease, or
that it was due to the complication with syphilis.
In general, however, the incidence of syphilis in hemolytic jaundice
is not greater than in the population at large; thus Giffin (31) reports
only one positive Wassermann reaction out of thirteen patients.
Moreover, in the cases of the congenital type where active syphilis
has existed, the employment of anti-syphilitic treatment has in no
single instance resulted in a cure of the jaundice. It seems fair to
conclude that syphilis is not of importance in the causation of
the disease.
In the case of tuberculosis, the argument is even weaker. Apart
from the casual occurrence of tuberculosis in these patients, it rests
essentially on the result of tuberculin injections. It is again to
Chauffard (17) that we owe observations on this point. In one
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360 WILDER TILESTON
patient jaundice appeared at the age of fifteen during an attack of
pleurisy with effusion. (The congenital type not infrequently first
becomes manifest at this age after an acute infection.) When seen
by Chauffard at the age of thirty there were signs of active tuber-
culosis at the left apex. An intradermal injection of tuberculin was
followed by a marked local reaction, by pain and increased swelling
of the spleen and increase in the jaundice. In another case, a man
of twenty years, with a history of tuberculous peritonitis in infancy,
still more striking events followed the intradermal injection of
tuberculin. Besides an intense local reaction, there was fever of
several days duration, the spleen doubled in size, the jaundice
increased, acute anaemia supervened and the resistance decreased
from 0.64 per cent to 0.76 per cent.
Chauffard considers these cases as showing a local reaction of the
spleen to tuberculin, which he regards as proof of the tuberculous
origin of the disease. According to him, hemolytic jaundice is a
symptom, not a disease, with hereditary syphilis and tuberculosis as
the most common factors. But as against this theory it may be
objected, in the first place, that tuberculosis of the spleen has never
been encountered in the numerous specimens examined, and secondly
that hemolytic crises have often been reported in the congenital type
in connection with acute infections of various sorts. Now a severe
tuberculin reaction is certainly analogous to the toxemia produced
by the acute infectious diseases. A verdict of "not proven" may
therefore be returned in the case of tuberculosis also.
In conclusion it may be stated that the cause of congenital hemo-
lytic jaundice remains to be discovered.
Pathogenesis
Any theory must take into account the increased fragility of the
red cells and the splenomegaly. All writers are agreed that the
jaundice is of hemolytic origin, as shown by the increased, urobilin
excretion (one molecule of hemoglobin gives rise to one molecule
of bilirubin), the pigmentation of the organs, and probably certain
of the blood changes.
Widal and his school believe that the primary factor is the decreased
resistance, the abnormally fragile cells being destroyed in great
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HEMOLYTIC JAUNDICE 361
numbers by the normal hemolytic processes of the body, and the
enlargement of the spleen being "spodogenous," or simply the result
of the increased number of red cells destroyed there.
Troisier (86) on the other hand maintains that the primary condi-
tion is the formation of a hemolysin which becomes fixed in the red
cells and renders them less resistant, and supports his view by the
finding of hemolysins and decreased resistance of red cells in the
pleural fluid in cases of hemothorax. Widal (97) accepts this view
as applied to the acquired type, and believes that hemolysis does not
occur in the circulating blood on account of adeficiency of complement.
Banti (2) however, was unable to demonstrate any lack of comple-
ment in the serum, and states that other observers have failed to
find increased fragility in red cells that have fixed hemolysin. He
believes that the primary fault lies in the spleen, and that hemolysins
are produced in this organ in hemolytic jaudice. He states that
he was able to reproduce the disease experimentally by the injection
of hemolytic sera, observing after a single injection progressive
anemia, with similar blood changes and decreased resistance. Both
in normal animals and in those who had received injections, he
observed that the splenic vein contained more hemoglobin in the
serum than was found in other parts of the body, and that the fragility
of the red corpuscles was also greater in the splenic vein. Two
cases of splenectomy for hemolytic jaundice in man are said to have
shown greater fragility in the splenic venous blood than in the
peripheral circulation. He concludes that the spleen has an important
hemolytic function and diminishes the resistance of the red cells
which pass through it.
Banti believes that the pathogenesis of the disease in man is iden-
tical with that of his experimental anemia following injections of
hemolytic sera, and assumes in the human disease the presence of
substances, as yet unknown, which act on the spleen and cause it
to produce hemolysins in excess.
Pearce (70, page 93), however, working with normal dogs, was
unable to find any free hemoglobin in the serum of the splenic vein,
and concludes that Banti's results were due to faulty technique.
He found the resistance of the red cells usually the same in the splenic
vein and in the artery, and only occasionally slightly less in the vein.
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362 WILDER TTLESTON
Since the corpuscles in the femoral vein were also at times less resist-
ant he asks if the changes which have been found in the splenic
vein are not those of venous blood in general.
In this connection the experimental studies of Joannovics and
Pick (43) on toluylendiamin poisoning in dogs are of interest.
They attempted to explain the fact that this substance is hemolytic
in vivo but not in vitro. Following the lead offered by Faust and
Tallqvist (28) who showed that the bothriocephalus latus contains
oleic acid, a highly hemolytic substance, to which the anemia caused
by this worm is probably due, they demonstrated in the livers of
dogs poisoned with toluylendiamin the presence in large amounts
of hemolytic substances of the nature of fatty acids. These were
of two sorts: First, in dogs dying of very acute poisoning, a substance
belonging to the fatty acids, but not oleic acid, and not associated
with fatty metamorphosis in the liver, and the occurrence of which
was not influenced by previous splenectomy; and second, in the
more chronic cases, hemolytic higher and lower fatty acids, including
oleic acid, associated with marked fatty changes in the liver. In
these latter dogs, if a splenectomy was done previous to the poison-
ing, the amount of hemolysis shown by the liver extract was reduced
to one-sixth of that of the controls, and very little fatty change was
encountered in the liver. The authors also showed that proteins
inhibit to a marked degree the hemolytic action of the unsaturated
fatty acids.
The above results are of particular interest in view of the fact that
touylenediamin poisoning leads to a condition strongly resembling
hemolytic jaundice in man, with jaundice, anemia, enlargement of
the spleen, and as Widal (95) has shown, increased fragility and nu-
merous reticulated red cells.
Eppinger (27), King (47) and Medak (58) have worked along these
lines in human pathology, and have reported in two cases of hemolytic
jaundice a very high iodine number in the blood, indicating the pres-
ence of unsaturated fatty acids in excess. After splenectomy these
patients showed a reduction of the iodine number to normal, along
with other indications that the excessive hemolysis had ceased. These
authors also found after splenectomy in normal dogs a decrease in the
iodine number and an increase of the total fats of the blood and
usually of the cholesterol.
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HEMOLYTIC JAUNDICE 363
Dubin and Pearce (25), however, were unable to confirm these
findings in so far as they relate to dogs, and Csonka (22) has criti-
cized the technic employed in determining the iodine number, and
also the method of calculation. The results of Eppinger and his school
are, therefore, in need of confirmation.
The part that cholesterol plays in hemolysis within the body re-
mains obscure. While there is no doubt that free cholesterol inhibits
hemolysis in the test-tube by saponin and many other hemolytic
agents, the figures obtained from chemical analysis of the blood in
our disease are conflicting, and even should they be consistently low,
they would not indicate whether the lower protecting power of the
serum against hemolysis were primary or secondary. Further study
in this direction is needed.
The presence of hemolysins in the pathological spleen has not been
demonstrated as yet. In four cases of splenectomy for hemolytic
jaundice, those of Vaquez and Giroux (88) Antonelli (1), and two of
Kahn (45) they have been looked for in vain.
However, the influence of the spleen on hemolysis in this disease
is evidently very important, for after splenectomy a virtual cure
is attained, with rapid disappearance of the jaundice, and return of
the blood to normal so far as red count and morphology are concerned.
The fact, on the other hand, that the diminished resistance almost
always persists, is against the view that the primary fault lies in the
spleen.
It is possible to explain the benefit derived from splenectomy with-
out the hypothesis of abnormal formation of hemolysins in this or-
gan. The extensive researches of Pearce and his associates (70)
have shown that splenectomy in normal dogs results in a marked re-
duction in the hemolytic processes, so that jaundice is much more
difficult to produce with hemolytic agents than in the unoperated
animal. This is partly due to the fact that normally by far the greater
part of hemolysis takes place in the spleen; after splenectomy the
other portions of the hemolytic system, the lymph nodes, the stellate
or Kupffer cells of the liver, and the bone marrow, are unable to com-
pensate to any marked degree for the loss of the spleen. Partly it is
due to a mechanical factor, as indicated in the work of Krumbhaar,
Musser and Peet (49) ; the hemoglobin reaches the liver after splenec-
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364 WILDER TILESTON
tomy in a more dilute form, because it comes by way of the general
circulation instead of through the splenic vein. The liver is, there-
fore, able to handle the hemoglobin and to excrete it as bile pigment
without the production of jaundice. A third factor in the difficulty
of causing jaundice in the splenectomized is the increased resistance
of the red cells which is uniformly present after removal of the spleen
in the normal animal; apparently this does not hold good for hemo-
lytic jaundice in man.
To sum up, our present knowledge indicates that the diminished
resistance of the red cells is the leading factor in the causation of
hemolytic jaundice in so far as the congenital type is concerned. It
is possible that the same explanation applies to the acquired type
also. Cases with normal resistance to hypotonic salt solutions might
be accounted for by the assumption of abnormal fragility of a differ-
ent sort, as indicated by the work of Hijmans van den Bergh (41),
who demonstrated in his case increased fragility on exposure of the
red cells to carbon dioxide. The spleen is a necessary link in the
chain for the production of the other signs of the disease, and it is
possible that its function is perverted, but that has not been proven
as yet.
The pathology, diagnosis and treatment of the two types will be
considered together.
Clinical picture
The jaundice. This is usually the first symptom noted, and may
be present from birth, or first attract attention in childhood or early
youth; exceptionally it does not occur until the age of 25, as in the
case of Benjamin and Sluka (6). In well marked instances the
sclerae are of a lemon-yellow color, and the skin of the body is dis-
tinctly yellow, while the face may be of a peculiar buff color which is
quite characteristic. The greenish tint seen in long-standing com-
plete obstruction of the bile ducts is never present. The jaundice
may be so slight as to be apparent only on careful scrutiny. It
varies in intensity from time to time, often being increased by fatigue,
emotion, exposure to cold, during pregnancy, and particularly at the
time of crises.
Exceptionally jaundice may be lacking, as in the family reported
by Ward (89), in which the mother and maternal uncle showed mas-
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HEMOLYTIC JAUNDICE 365
sive splenomegaly and anemia, but no jaundice, while the child showed
jaundice but no enlargement of the spleen. Gotzky and Isaac (34)
encountered a family in which the grandmother and father were
jaundiced, while the three children were anemic with enlarged spleen
and increased fragility, but no icterus. Occasionally, as in the family
described by Poynton (74) the jaundice is recurrent, and between
attacks there are anemia and splenic tumor without icterus.
The spleen. The presence of splenic tumor constitutes one of the
most striking features of the disease. Its size corresponds roughly
to the severity and duration of the condition; in well marked instances
it reaches to the umbilicus or even to the lowest part of the abdomen.
During the crises the spleen enlarges rapidly, and there is apt to be
pain in the left hypochondrium. The splenic tumor is usually dis-
covered after the jaundice, though in the case of Schlecht (81) it was
noted two and one-half years before jaundice appeared, the child
being under medical observation all this time.
In a few instances, otherwise typical, enlargement of the spleen
has been lacking. It was so in two brothers and a sister reported by
Pick (71), and in Pollak's (72) family, in which the mother, jaundiced
since birth, showed no splenic tumor, although both of her daughters
had large spleens.
The blood. A moderate anemia with counts varying from 3,000,000
to 4,500,000 is the rule, but in severe crises there may be a great de-
struction of red cells, as in Thursfield's case (84), with 1,000,000.
Guinon, Rist and Simon (37) on the other hand have reported a
case, the classification of which is doubtful, in which there were jaun-
dice and splenomegaly, but the resistance was increased and there
was a transitory polyglobulia of 7,600,000.
The hemoglobin is usually proportionately reduced, so that the
color index is about one. In this respect the picture resembles per-
nicious anemia, but it has been suggested that the high hemoglobin
reading is apparent rather than real, being due to the dark color of
the serum. The average size of the red cells is usually decreased;
there are considerable anisocytosis and polychromia, but poikolocy-
tosis and stippling are unusual. Normoblasts are often present in
small numbers, while megaloblasts are rarely met with.
The chief interest, however, lies in the decreased resistance of the
red cells to various hemolyzing agents, but especially to hypotonic
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366 WILDER TTLESTON
salt solutions. This feature has been found in almost all of the re-
ported cases, but like the other cardinal signs of this disease, it is
occasionally lacking, as in the cases of Claus and Kalberlah (21),
Lommel, (52) and Cade (12) while in that of Widal and Ravaut (101),
the resistance was actually increased. It has been noted that the
resistance may be normal at one time and decreased at another, es-
pecially during acute infections (Renaux, 75). In this connection
the importance of technic should be emphasized, for if the sodium
chloride is not thoroughly desiccated, too high figures will be obtained.
In most cases both the minimum and the maximum resistance are
decreased, hemolysis often beginning at 0.60 per cent and being com-
plete at 0.40 per cent, the normal figures being 0.44 to 0.48 per cent
for the former, and 0.30 per cent for the latter. Sometimes only the
minimum resistance is affected. Usually the results are the same
with whole blood and with washed corpuscles, though some observers
have found lower figures with the latter. For the technic the reader
is referred to Pearce (70), page 273, and to Kolmer (48).
The resistance has also been found to be decreased to other hemo-
lytic agents, such as anti-human hemolytic serum, cobra venom, and
sometimes to saponin. Bittorf (9) showed that the resistance to
acids was decreased; Grote (35) confirmed this and found the same
to obtain for alkalies. Widal and others have noted that the red cells
were hemolyzed by contact with normal sera, which did not hemolyze
red cells derived from other persons.
Reticulation of the red cells is present to a degree met with
in no other disease. This phenomenon consists in a net-work
within the red cell, brought out by the so-called "vital" methods of
staining, and especially well by brilliant cresyl-blue. This feature
of hemolytic jaundice was first noted by Chauffard (15), who called
it granular degeneration. This name should be dropped, as leading
to confusion with the granular degeneration of Grawitz, or stippling,
with which it has nothing to do. These reticulated or "skeined"
cells occur in normal blood in small numbers, from 0.5 to 1 per cent,
and in other forms of anemia up to about three per cent, while in
hemolytic jaundice they make up from 10 to 20 per cent of the whole,
and in the acquired type even up to 50 per cent. They are usually
regarded as a sign of regeneration of the blood, as young cells that
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HEMOLYTIC JAUNDICE 367
have reached the circulation in an immature state. It has been
suggested that they are less resistant than normal cells, but this has
been found not to be the case.
The white cells show no constant variations, being usually normal
in number, sometimes increased, and sometimes diminished. Some
observers have noted a polynuclear leucocytosis at the time of crises,
in contrast to the increased leucopenia which recurs at such times in
pernicious anemia, but this is not a constant finding. The differen-
tial count is about normal, with a tendency toward increase of the
polynuclears. Exceptionally a few myelocytes are seen. Lommel
(52) reported a very unusual case in which myeloblasts were found
during pregnancy in large numbers (65 per cent), but disappeared
after the induction of abortion.
The serum is almost always highly colored, owing to the presence of
bilirubin. Urobilin has usually been reported absent, but according
to Guillain and Troisier (36) may be found if tested for by the deli-
cate method of Grigaut. The freezing point has been found to be
markedly lowered, which indicates an increased molecular concen-
tration of the blood. Troisier (86) explains this as a result of diffusion
of the salts of the red corpuscles into the plasma.
The presence of signs pointing to increased hemolysis naturally led
to a search for hemolysins in the blood, but these have been found to
be almost invariably absent in the congenital type. This subject
will be dealt with more fully later, under the acquired type.
Hemagglutinins likewise are very rarely encountered.
The urine. The urine is high colored, owing to an increase of uro-
chrome, the normal urinary pigment. Bile pigment is almost in-
variably absent, being noted only as a transitory phenomenon in some
cases at the time of crises of deglobulization. Bile salts are also
absent. Urobilin and urobilinogen on the other hand are very con-
stantly present, being absent only in cases of slight intensity. Other
pigments derived from hemoglobin, such as hematoporphyrin, are
absent. Albumin and sugar are not found in uncomplicated cases.
The stools: The feces are never clay-colored, but as a rule are highly
colored, and show quantitatively a marked increase of urobilin. For
example, Eppinger (27) found in one case a total daily excretion of 3
grams, the normal being given as 0.15 gram. This he calculates
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368 WILDER THESTON
amounts to the destruction (and renovation) of the entire blood in
the space of two days!
Metabolism. Complete studies have been made by McKelvy and
Rosenbloom (54) by Goldschmidt, Pepper and Pearce (33), and by
Denis (24). The fat metabolism was normal, both as regards absorp-
tion and fat-splitting. The elimination of iron was markedly in-
creased; this is to be attributed, as is the increased urobilin excre-
tion, to the excessive destruction of red cells. With regard to nitro-
gen, McKelvy and Rosenbloom found a negative balance, due, they
believed, to a toxic destruction of protein, while Goldschmidt and
Denis obtained positive balances.
The excretion of endogenous uric acid was found much increased
by Tileston and Griffin (85), and high values were reported also by
the above-mentioned writers and by Kahn (46).
McKelvy and Rosenbloom (55), in a second paper, reported a
considerable loss of cholesterin in the feces, the output exceeding the
intake by 7 grams in a five-day period.
The cholesterol of the blood is of interest, owing to the relation of
this substance to hemolysis. According to Windaus (104), the in-
hibitory effect on hemolysis is exerted only by free cholesterol, not
by the estets. The older publications are not of great value, owing
to the lack of accurate methods. Chauffard, La Roche, and Grigaut
(16) reported normal figures, as contrasted with an increase in ob-
structive jaundice. Studies by the more exact method of Windaus
(105) and of Bloor (10) by which both free cholesterol and esters are
determined, have been made in a few instances. Thus Medak (58)
in one case found a low value for free cholesterol, which increased
after splenectomy, mainly at the expense of the esters. King (47),
however, reported a normal amount in his second case (his first case
appears to have been the same patient as Medak's). In two un-
published cases studied by the writer no important variations from
the normal were found.
Complications. The complication with cholelithiasis is so fre-
quent that it might almost be considered a part of the disease. In no
other condition do gall stones occur with such frequency, being
present in 58 per cent of the cases operated on by W. J. Mayo (57).
It is therefore natural to attribute lie attacks of pain in the right
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HEMOLYTIC JAUNDICE 369
hypochondrium, which are of frequent occurrence, to this cause.
Occasionally, however, attacks of hepatic pain occur in connection
with crises, and may be due simply to the overloading of the liver
with the products of blood destruction.
Gout has been reported by Murchison (65), in two of the families
of Tileston and Griffin (85), and in a few other cases. While it may
be only a coincidence, it is also possible that the long-continued in-
creased uric acid production might be a factor predisposing to gout.
The latter differs from hemolytic jaundice in that the elimination of
uric acid is diminished instead of increased.
II. THE ACQUIRED TYPE
Classification
Acquired hemolytic jaundice is divided by the French writers
into two groups: first, the cryptogenetic and second, the secondary.
To these a third, the hemolysinic icterus of Chauffard and Vincent
(19), is sometimes added.
Etiology
The cryptogenetic group, as the name implies, is of unknown
causation. The secondary variety occurs in the course of a number
of diseases, chiefly infections.
Syphilis. Cases of florid lues in the secondary stage, associated
with the syndrome of hemolytic jaundice have been reported by
Gaucher and Giroux (30), de Beurmann Bith and Cain (7), and by
Nicolas (66). The resistance was decreased in all. The striking
feature is that all were cured of their hemolytic jaundice by anti-
syphilitic treatment. In the case of Sabl6 and Darrel (78) heredi-
tary syphilis with active bone lesions was the cause of similar
symptoms, which promptly disappeared under treatment with ars-
phenamin. These facts contrast strongly with the negative results
obtained by anti-syphilitic treatment in cases of the congenital type
in which syphilis is present.
Malaria. Sacqu6p6e (79) and others have described cases of
hemolytic jaundice appearing at the time of the acute attack in
malaria, and cured by quinine; the type of parasite present was not
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370 WILDER TILESTON
specified. Such cases present analogies with malarial hemoglobin-
uria or black-water fever.
Tuberculosis. Landouzy (50) has reported a case occuring in the
"third stage" of this disease.
Other infections. The syndrome of hemolytic jaundice has been
observed by Sacqu6p6e (80) in connection with streptococcus septi-
cemia, disappearing during convalescence. Lewin (51) found it
dating from attacks of paratyphoid fever and dysentery, but in his
cases the condition did not disappear with recovery from the acute
infection, but became chronic. Widal, Lemierre and others (100)
have described a remarkable case of septicemia due to the gas bacillus
(B. aerogenes capsulatus) with hemoglobinemia and hemoglobinuria.
In this case the hemolysis could be demonstrated as directly due to
the action of a hemolysin secreted by the bacteria, for cultures hemo-
lyzed blood very rapidly in vitro, a very exceptional phenomenon for
this bacillus.
A case in which a toxic origin seems probable is that of Widal,
Abrami and Brul6 (98), in which the disease appeared following proc-
titis and ischio-rectal abscess, and got worse with the development
of a stricture of the rectum; the hemolytic syndrome disappeared
within a few days after the relief of the stricture by making an
artificial anus. The patient remained well so long as the artificial
anus functioned, but would have minor hemolytic attacks as soon
as it became plugged.
Pregnancy. Roque, Chalier and Cordier (76) report a case asso-
ciated with the toxemia of pregnancy. The usual signs of hemolytic
jaundice were present, including diminished resistance and auto-
agglutination, and in addition there were multiple hemorrhages into
the skin and mucous membranes. The patient was eight and one-
half months pregnant and showed, as evidence of toxemia of preg-
nancy, general edema, amaurosis, neuroretinitis and albuminuria.
Recovery ensued after the birth of a dead child.
Cirrhosis of the liver. The association with cirrhosis has been noted
by Mouisset, Chalier and Nov6-Josserand, (64), Chevallier and Tom-
kine (20) Eppinger (27) and a few others. Hemolytic jaundice occurs
in both the periportal and the biliary types; the liver is almost always
enlarged, and the spleen more so than is usual in ordinary cirrhosis.
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HEMOLYTIC JAUNDICE 371
It is to be regarded as a complication of the cirrhosis and is frequently
a terminal event, being in that case usually associated with infectious
processes and the hemorrhagic diethesis.
A remarkable case was reported by Mosse (62), in which there
was marked polyglobulia with cyanosis, splenomegaly and acholuric
jaundice. The resistance was not tested. The autopsy disclosed
cirrhosis of the liver.
Carcinoma. Widal and Joltrain (99) observed hemolytic jaundice
in a case of carcinoma of the bladder with abundant hematuria.
Leukemia. In Gaisbdck's (29) case of acute lymphatic leukemia
the hemolytic syndrome, with marked diminution in resistance, was
a striking feature.
Pathogenesis
In the case of the secondary form, the pathogenesis is probably dif-
ferent from that of the congenital type. When it occurs in connec-
tion with acute infections, the condition may be due to the action
of bacterial hemolysins, and in the other instances a toxic origin seems
probable.
The pathogenesis of the idiopathic variety, however, is probably
similar to that of the congenital form. There is one feature that
differs and that required detailed discussion, namely the presence of
hemolysins in the serum. This has been noted, almost exclusively
in the acquired form, by a number of observers, chiefly French. They
have been chiefly isolysins, i.e., the serum hemolyzes the red cells of
other persons, but not those of the patient. This is an interesting
observation, but hardly explains the occurrence of hemolysis in the
patient. The value of this work is considerably impaired by the
fact that isolysins have been found in normal persons, Moss (61)
reporting them in no less than 23 per cent. Troisier (36), however,
with the technic employed, found them in only 4 per cent of 125 cases
of diseases other than hemolytic jaundice.
Chauffard and Vincent (19) have set up a separate type, the so-
called hemolysinic icterus, in which isolysins are present in the serum,
and the resistance of the red cells is normal: a fair number of cases
coming within this category has been reported. On account however
of the fact that intermediate forms are met with, showing both isoly-
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372 WILDER TILESTON
sins and diminished resistance (Chauffard, Troisier and Girard, (18)),
and because of the occurrence of isolysins in health, it seems best not
to separate these cases.
The presence of autohemolysins on the other hand is always patho-
logical. They have been reported in hemolytic icterus by three ob-
servers only. In the case of Chauffard and Vincent (19) in which
there were hemaglobinuria and hemoglobinemia, there was slight
additional hemolysis on mixing the patients serum with his own
corpuscles. In view of the fact that clear serum could not be ob-
tained for the test, there is a possibility of error.
Roth (77) reported an interesting phenomenon in a case of perni-
cious anemia, in which autolysins were apparently present. It was
found however that the patient's red cells were hemolyzed by the
sera of fifty other patients, some of which sera were hemolytic only
for the red cells of the patient. He concludes that the hemolysis was
due not to the presence of autolysin, but to injury to the red corpus-
cles, so that hemolysis occurred with the isolysins which are probably
present to a greater or less degree in all sera. He points out that
these tests were not made in the case of Chauffard and Vincent.
Beckmann (5), however, reported two cases (one congenital and
one acquired) in which the objection of Roth was met. The hemoly-
sis however, was but slight, so that there is a possibility of an error
in technic.
Ludke (53) has recently published some interesting observations,
which if confirmed, would go far to establish the rdle of hemolysins
in hemolytic jaundice. Out of four cases (two of each variety) he
found autolysins present in two (one congenital, one acquired), but
only during crises. Both of these cases showed slight hemaglobinuria
during crises. All four showed the presence of isolysins. The test
was made by mixing the patient's clear serum with the patient's
washed corpuscles and adding complement (amount and kind not
stated). The fact that autolysins were found during crises, but were
regularly absent during the intervals, would seem to point to some j
causal relationship between the two.
Llidke was apparently able to obtain experimental confirmation
of his findings. He made dogs anemic by bleeding and then inject-
ing red corpuscles from the same dog. After a single injection both
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HEMOLYTIC JAUNDICE 373
auto and isolysins appeared in nine of eleven experiments. The sple-
nic extracts of such dogs showed a strong hemolytic action on their
own corpuscles. The splenic extract from dogs showing the presence
of hemolysins, when injected intravenously into healthy dogs, caused
a marked anemia with diminished resistance, while the extract of
spleens from healthy dogs had no such effect. He concludes from
these experiments that hemolysins may be elaborated in the spleen.
It is impossible to form a judgment of Lttdke's work without further
details, which he promises to supply in a later publication. It should
be noted however, that his cases were peculiar in that the Donath-
Landsteiner test was positive in both, while other observers have found
this test constantly negative. The demonstration of autolysins is
difficult, and a standard technic has not yet been developed.
Hemagglutinins. Isoagglutinins have been shown in some cases
of both types. Since, however, no attention has been paid to the
presence of normal agglutinins, which Moss (61) has shown to be
present in 89 per cent of healthy individuals, this work is without
value. It is much to be desired that in future the agglutination*
group to which the patient belongs should be determined, according
to the method of Moss.
The presence of autoagglutinins9 however, is always pathological,
and is rarely met with outside of hemolytic jaundice. It has
considerable theoretical as well as practical importance, since agglu-
tination is considered by many to be a preliminary step in the process
of hemolysis.
Clinical picture
The acquired type is much less frequent than the congenital, and
as described by Widal (96) differs from it in several important respects.
The clinical course is more severe, ending not uncommonly in
death. The anemia is more marked, the average red count according
to Krumbhaar (70, page 258) being 2,000,000, against 3,300,000 for
the congenital form. Counts of 1,000,000 or below are no rareties.
The crises of deglobulization are more marked, and give to the dis-
ease a very chequered picture. The regeneration is at times extra-
ordinarily rapid, as in Pollitzer's case (73), where the count rose in
thirty days from 640,000 to 4,000,000. The jaundice is often less
marked than in the congenital type and may be lacking.
MBDICINK, TOL. I, NO. 2
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374 WILDER TILESTON
The resistance of the red cells is less constantly diminished, and
to a lesser degree. Widal states that in this type the resistance is
normal with whole blood, and diminished with washed corpuscles,
but further experience has shown that this does not always obtain.
Hijmans van den Bergh (41) has described an interesting case in
which the resistance was normal to salt solution, but hemolysis oc-
curred if a mixture of the patient's corpuscles and normal serum was
placed in an atmosphere of carbon dioxide. The same occurred with
a mixture of the patient's corpuscles and his own serum, but never
in the case of normal corpuscles. He concludes that a special form
of fragility was present.
Widal, Abrami and Brute (96) have described the presence of a
phenomenon, auto-agglutination of the red cells, which is almost
constantly absent in the congenital type. Liidke (53) alone has
reported its occurrence in the latter. It is tested for by mixing in a
watch glass one drop of the patient's corpuscles with ten drops of
his own serum, and letting the mixture stand fifteen minutes at room
temperature. The red cells become agglutinated into a dense pedicle
which cannot be broken up by shaking. The results may be con-
firmed by microscopical examination. They state that auto-agglu-
tination was present in all their acquired cases, but never in the
congenital type, or in other diseases. Other authors, however,
have reported less constant results, e.g., Biffis (8) found the test posi-
tive in only one of five cases.
There are in the literature a number of border-line cases between
acquired hemolytic jaundice and pernicious anemia, such as those of
Widal and Weissenbach (102) Weber (90) and case II of Biffis. Here
with diminished fragility of the red cells and jaundice, some or all
of the signs of pernicious anemia were present, and it is a question
whether they should be classified as pernicious anemia with jaundice,
or as a pernicious type of hemolytic jaundice. It should be noted
that in pernicious anemia the resistance is almost always normal or
increased. The writer has recently encountered a similar case (un-
published) in which, with increased fragility there was a rapidly
progressive fatal anemia, without jaundice. The color index was
Low and the average diameter of the red cells not increased, normo-
blasts exceeded megaloblasts in number, but the autopsy disclosed a
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HEMOLYTIC JAUNDICE 375
megaloblastic bone marrow and blood-forming foci in the liver and
spleen.
Another variation from the usual type has been reported quite
often, in which hemaglobinuria is a prominent feature. This may
occur over long periods of time, as in case V of Biffis, or in a fulminat-
ing manner, as in that of Chauffard and Vincent (19). The Donath-
Landsteiner test was negative in all. Hemoglobin was usually
detected in the serum also.
An acute case of acquired hemolytic jaundice has been described
by Gaisbock (29). A man twenty-two years old was seized acutely
with high fever and rapidly progressive anemia, with death at the
end of six weeks, after a single remission. There was constant though
slight icterus; the spleen was not enlarged, except slightly during the
remission. The blood showed the following signs: The red count
sank to 500,000; the color index varied between 0.6 and 1.3; there
was microcytosis with numerous normoblasts; leucopenia was present.
The minimum resistance was much decreased while the maximum
was increased. The autopsy showed a normoblastic bonemarrow,
and blood-forming foci in the liver and spleen with increased pigment
in the latter. Such a case may be considered as simply a more malig-
nant form of the disease, in which death has occurred early during a
crisis of deglobulization.
The question of the unity of the two types (congenital and acquired)
may be considered at this point. In favor of the view which regards
the two as separate entities may be advanced (a) the different clini-
cal picture (b) the different age of onset (c) the lack of familial or
hereditary influences, (d) the different etiology. As regards the first
point, it should be noted that a number of congenital cases have
been reported that have resembled clinically the acquired type,
with grave crises and very low blood counts, while on the other
hand some acquired cases, like these of Biffis (8) have shown an evei\
course without periodic attacks, thus resembling the congenital type.
The more marked fragility in the congenital type is by no means a
constant difference, and even the presence of autoagglutination has
been noted, though rarely, in the congenital type, as by Ludke (53).
The resemblance of the clinical picture in the two types may be so
strong that cases reported at first as acquired have been shown later,
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376 WILDES. TILESTON
by the discovery of cases among the relatives, to belong to the con-
genital group, as in Hayem's case (40). In one of Giffin's cases
(31) the finding of increased fragility in the mother, though she was
free from symptoms, was the only sign leading to the correct inter-
pretation.
The age at onset is an unreliable criterion, it being by no means
uncommon to have the congenital type begin in the second decade
or even somewhat later. Cases beginning after thirty, however, and
these form a minority of the cases reported as acquired, apparently
never show any evidence of a hereditary factor.
The third point, the lack of hereditary influences, is not of much
value as a distinguishing sign. For many of the hereditary diseases,
such as progressive muscular dystrophy, occur at times in only one
member of a family. The fact, however, that in cases of the acquired
type recovery may occur constitutes an important difference.
The most valid reason, however, for separating the two types
appears to rest in the etiology. For while the cause of the congenital
type remains obscure, in many of the acquired cases the treatment of
some associated condition, such as lues, malaria, a stricture of the
intestine, has resulted in a cure of the jaundice. This is never the
case in the congenital type, even in those rare cases accompanied by
hereditary syphilis.
To sum up, it is best for the present to distinguish a congenital
and an acquired type. But it will be safer to consider all cases as
congenital unless it can be shown that they belong to the secondary
group, with undoubted relation to some infection, intoxication, or
malignant disease, or unless they begin late in life, after the third
decade.
PATHOLOGY OF HEMOLYTIC JAUNDICE
Our knowledge of the pathology has been derived partly from au-
topsy reports, partly from the examination of excised spleens. Since
no differences have been found between the congenital and the ac-
quired types, the two may be considered together.
The spleen. The gross appearances are as follows: The organ is
greatly enlarged, the average weight of 12 excised spleens being 1070
grams according to Giffin, (31), and of nine spleens at autopsy 716
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HEMOLYTIC JAUNDICE 377
grams. The capsule is often thickened and there may be adhesions
to the diaphragm, both the result of old perisplenitis. The trabeculae
are not thickened, the follicles appear few and small. The striking
thing is the marked engorgement with blood, Guizzetti (38) remark-
ing that the organ became reduced to one third its former size after
the blood was squeezed out. Infarction has been noted in a few
cases, in the absence of heart disease.
On microscopic examination the most striking thing is the marked
congestion. This may be general, but often it is confined to the
pulp (or "cords of Billroth"), the sinuses being empty. This pecu-
liar distribution of the congestion was first noted by Vaquez and
Giroux (88). It is unusual in other conditions; in chronic passive
hyperemia for example the sinuses are engorged.
The trabeculae and reticulum show no marked degree of thicken-
ing. This constitutes an important point of distinction from
Banti's disease.
The follicles appear fewer because they are widely separated owing
to the congestion. They are usually normal except for the condition
of the follicular arterioles, which often show a hyaline thickening, as
described by Guizzetti (38), Sisto (82) and others. This change may
be found also in the arterioles of the pulp, but to a lesser degree. A
moderate degree of fibrosis of the follicles is sometimes encountered.
Pigment is present in the organ in varying amounts, being often
very abundant, at other times scanty, or even absent, as in the case
of Goldschmidt, Pepper and Pearce (33) . It is chiefly within endothe-
lial cells in the sinuses, and usually gives the iron reaction. The
amount of pigment does not depend entirely on the duration of the
disease, for Elliott and Kanavel (26) found very little in a man of
fifty-seven years, jaundiced since birth. Phagocytosis of red cells
is sometimes observed. The endothelial cells lining the sinuses may
be changed from the normal flat type to an oval shape, as noted by
Guizzetti and Sisto.
Liver. The size is about normal. There are no signs of cirrhosis,
except in the rare cases of acquired hemolytic jaundice secondary to
cirrhosis. The bile ducts are always normal, except where changes
due to gall stones have occurred, as in Sisto's second case (82) with
marked cholangitis and calculi in the common duct, and in the second
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378 WILDER TUESTON
case of Tileston and Giffin (85). There is no deposit of bile pigment
in the liver cells. Pigmentation to a greater or less degree is the rule,
being absent only in the case of Marchiafava and Nazzari (56). It
may be so abundant as to compare with that of hemachromotosis;
as in an unpublished case recently seen by the writer. The pigment
occurs in the form of coarse brownish granules, which usually give
the iron reaction. It is situated mostly in the hepatic cells, especially
at the periphery of the lobules, and in the stellate or "Kupffer" cells,
though some may occur in the periportal spaces. Otherwise there
are no changes, except those due to intercurrent diseases. Gall
stones are present in a little over 50 per cent of the cases.
Bone marrow. The bone marrow of the long bones has been found
red and in a very active state, with numerous normoblasts and mye-
locytes, in all the cases, with the exception of case II of Sisto, in
which the anemia was not marked. Pigmentation is not noted in
the records.
The lymph nodes. Pigmentation has been found in a few instances;
in the writer's unpublished case it was extreme, the pigment being
within endothelial cells in the sinuses and giving the iron reaction.
Three cases have shown the change to hemolymph nodes, with con-
gestion, phagocytosis of red cells and pigmentation.
Kidneys. There was a very marked siderosis in the case of Min-
kowski (60), who isolated J gram of iron from one kidney; also in
the case of Marchiafava and Nazzari (56), and to a lesser degree in
that of Oettinger (67). The pigment is chiefly deposited in the con-
voluted tubules. In Marchiafava's case the pigmentation was ex-
clusively confined to the kidneys, and the urine showed casts contain-
ing hemaglobin. This variation in the place of deposition of the
pigment is interesting, suggesting that in such cases the hemaglobin
is set free in the general circulation and reaches the kidneys, while
as a rule the hemolysis takes place in the spleen and the pigment is
deposited here, or is transported to the liver.
To sum up, the spleen shows marked congestion, often of a pe-
culiar sort, involving the pulp but not the sinuses. The reticulo-
endothelial apparatus, as Aschoff calls it, namely the endothelial
cells of the spleen, liver, bone marrow and lymph nodes, shows signs
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HEMOLYTIC JAUNDICE 379
of hemolytic activity, such as phagocytosis of red cells and pigment
deposit. The bone marrow shows the usual change from fatty to
red marrow, as met with in most severe anemias.
DIFFERENTIAL DIAGNOSIS
Since most of the cases belong to the congenital type, a careful
history, with special inquiry into the occurrence of jaundice among
the relatives is of the greatest importance. The history of crises
with pain and anemia is very suggestive. Any case of chronic non-
obstructive jaundice, with or without enlargement of the spleen,
should have the resistance of the red cells tested, and if this is low-
ered, the diagnosis of hemolytic jaundice is practically certain. If
the resistance is normal, this does not exclude the diagnosis, provided
the picture is otherwise typical. The resistance should also be tested
where there is chronic anemia with splenomegaly, because hemolytic
anemia without jaundice sometimes occurs. The presence of a con-
siderable number of reticulated red cells, e.g., over 4 per cent, is
valuable confirmatory evidence. The other important signs are
anemia, increased urobilin excretion, the absence of bile pigment in
the urine, highly colored stools and splenomegaly. Occasionally,
however, any one of the above signs may be absent, and the diag-
nosis must rest upon the clinical picture as a whole.
In general, the diagnosis is to be made from other diseases accom-
panied by jaundice, diseases with splenomegaly and diseases with
anemia
L Diseases with jaundice
Obstructive jaundice. This is excluded by the increased urobilin
content and absence of decoloration of the feces, by the absence of
bile pigment and bile salts from the urine, and by the absence of
fatty stools. The resistance of the red cells is increased rather than
diminished in obstructive jaundice.
Cholelithiasis. This is the most frequent source of error in diag-
nosis, owing to the fact that ho less than sixty per cent of the cases
of hemolytic jaundice are complicated by gall-stones. Many pa-
tients have undergone operation on the gall bladder, under the mis-
taken belief that the jaundice was due to calculi. It should be
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380 WILDER TELESTON
borne in mind that in disease of the gall bladder, jaundice, if present,
is of the obstructive variety, and that splenic tumor is absent unless
cholangitis complicates the picture, and even then is of only moder-
ate proportions.
Acute infectious diseases with jaundice. In yellow fever and spiro-
chetal jaundice, icterus constitutes the most striking feature. In
pneumonia and streptococcal septicemia, jaundice is not infrequent.
In all of these diseases it is probably hemolytic in origin. Since in
such cases it is purely symptomatic, it does not require further dis-
cussion here.
Familial icterus of the new-born. This is a very rare disease, in
which several children of a family are seized with deep jaundice shortly
after birth, and usually die within a few days with hemorrhages and
cerebral symptoms. The etiology is obscure. In the exceptional
cases of recovery the jaundice disappears, so that confusion with
hemolytic jaundice should not arise. It is not an hereditary disease.
2. Diseases with splenomegaly
Only those diseases associated with chronic enlargement come into
question.
Banti's disease. This name is employed instead of splenic anemia
as being more precise. Many cases of hemolytic jaundice have been
mistaken for Banti's disease, for the two have several points in com-
mon. Banti's disease in the early stage is excluded by the presence
of jaundice and of lessened resistance of the red cells, and in the later
stage by the absence of indications of cirrhosis of the liver. Retic-
ulated red cells are not abundant in Banti's disease. The occurrence
of other cases in the family clinches the diagnosis of hemolytic jaundice.
Gaucher' s disease, or large-celled splenomegaly. This rare disease
tends to occur in several members of a family, usually the females,
but is never hereditary. There is a yellowish discoloration of the
skin, but true jaundice is lacking, and so far as known, the resistance
of the red cells is normal. The spleen is enormously enlarged, and
the liver considerably. A moderate anemia of the secondary type
is present. Brill and Mandlebaum (11) have called attention to a
yellowish wedge-shaped thickening of the conjunctivae, seen on both
aides of the cornea, which they regard as diagnostic.
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HEMOLYTIC JAUNDICE 381
Syphilis. Syphilis of the liver may be accompanied by great
enlargement of the spleen, but jaundice is rare. The clinical pic-
ture may resemble that of Banti's disease so closely, that the diagnosis
is made only at the autopsy-table. Occasionally, as noted above,
both the acquired and the hereditary forms of lues may lead to true
hemolytic jaundice of the acquired type, which is curable by anti-
syphilitic treatment. Or again, syphilis, either acquired or heredi-
tary, may occur as an accidental complication of the congenital type
of jaundice. In such cases the finding of a positive Wassermann
reaction may be misleading, but the results of a resistance test, of
anti-syphilitic treatment, and the possible occurrence of jaundice in
other members of the family will lead to a correct diagnosis.
Cirrhosis of the liver. The late stage of this disease is readily ex-
cluded by the absence of ascites, of signs of collateral circulation and
of hemorrhage. The early stages of cirrhosis do not show much en-
largement of the spleen, nor jaundice, except in the Hanot's type,
where the liver is much enlarged, while in hemolytic jaundice the
size is normal or only moderately increased. There is a rare juvenile
form of cirrhosis, described by Jollye (44) and others, which may be
familial and hence lead to difficulty. The growth is stunted, the
liver is greatly enlarged and presents the lesions of biliary cirrhosis.
The jaundice is of the obstructive type, the resistance presumably
increased, and ascites occurs as a late feature; these points will suffice
for diagnosis.
In cases of cirrhosis with an unusual degree of splenic enlargement,
the possibility of a superadded hemolytic jaundice should be borne
in mind, and the resistance of the red cells and the urobilin excretion
measured.
Malaria. The spleen may be greatly enlarged in chronic malaria,
but in the absence of acute attacks, there is no jaundice. As already
noted, the syndrome of hemolytic jaundice has been observed occa-
sionally in connection with acute malaria, in which case plasmodia
can be found in the blood.
Tropical diseases with splenomegaly. Kala-azar has in common with
hemolytic jaundice the splenomegaly and the anemia. There is no
jaundice. Periods of fever alternate with periods of normal tem-
perature. There are marked leucopenia and lymphocytosis. A
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382 WILDER TILESTON
positive diagnosis is made by finding the causative organism, Leish-
mania Donovani, in material obtained by puncture of the liver or
spleen. There is also, according to Castellani and Chalmers (13)
a form of tropical splenomegaly not due to this parasite, which re-
sembles Band's disease, but is distinguished from it by the occur-
rence of irregular attacks of fever.
Leukemia. The examination of the blood will suffice for diag-
nosis. Very rarely the occurrence of the hemolytic syndrome has
been noted in this disease.
Hodgkin's disease. The spleen is often much enlarged, but in the
ordinary form the marked enlargement of the lymph nodes and the
absence of jaundice render confusion with hemolytic jaundice un-
likely. Very rarely, however, in Hodgkin's disease, there is spleno-
megaly without involvement of the peripheral lymph nodes, the ab-
dominal nodes alone being affected. In such a case jaundice may
occur from pressure on the bile passages by an enlarged node; the
obstructive character of the juandice and the absence of diminished
resistance are sufficient to exclude hemolytic jaundice.
Polycythemia. In this disease the increased number of red cells
is in marked contrast to the anemia of hemolytic jaundice. The
spleen is usually considerably enlarged, but jaundice is rare. Con-
fusion could occur only in the very exceptional borderline cases, or
in the end stage of polycythemia, when there may be anemia, some-
times combined with a leukemic blood picture.
Diseases of infancy with splenomegaly. Difficulty need arise only
in regard to sporadic cases of hemolytic jaundice, in which no other
members of the family are affected. The so-called Von Jaksch dis-
ease and the enlarged spleen of rickets and tuberculosis are readily
differentiated by the absence of jaundice. Hereditary syphilis,
however, sometimes leads to icterus, and here it may be necessary
to resort to a test of the resistance of the red cells as well as the Was-
sermann reaction, on account of the occasional association of the
two diseases. In congenital obliteration of the bile ducts jaundice
is intense and of the obstructive type, and therefore easily distin-
guished. In sepsis of the new born the presence of fever and the
almost inevitable fatal outcome are distinguishing features; it should
be remembered that septicemia may be, though, rarely, accompanied
by the hemolytic syndrome.
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HEMOLYTIC JAUNDICE 383
3. Diseases with anemia
Pernicious anemia is the only form that may give rise to diagnostic
difficulties, and then only in the case of the acquired type of hemo-
lytic jaundice. As already noted, a few cases occur in which it is a
mere matter of opinion whether they should be classified as pernicious
anemia with jaundice, or as a pernicious type of hemolytic jaundice.
The resistance in pernicious anemia is usually increased, but occa-
sionally it is diminished, as noted by Hill (42).
TREATMENT
Medical treatment
It goes without saying that all the usual methods of treatment
for anemia have been tried, especially iron and arsenic. Though
Widal speaks warmly of the long-continued administration of iron
in the acquired type, it should be remembered that spontaneous re-
missions are frequent in this disease, and other writers have not
noticed much benefit from this drug. The use of arsenic has also
been without effect, except in those cases of the acquired type asso-
ciated with active syphilis. In the congenital type of hemolytic
jaundice, where hereditary syphilis is associated, no cure of the
jaundice is to be expected from anti-syphilitic treatment, though
some improvement in the general condition of the patient may result.
The fact that cholesterol in the test-tube inhibits hemolysis has
lead to the administration of this substance. Parisot and Heully
(69) noted a marked temporary improvement in the general condition,
with some diminution in the jaundice and anemia, cessation of the
painful crises, and increase of the resistance. Oulmont and Boidin
(68) gave it to a patient with the acquired type showing diminished
cholesterol in the blood, and noted that the cholesterol increased to a
normal figure and the resistance also increased, but the jaundice
remained unaffected. As was to be expected the effect was only
temporary, ceasing as soon as the drug was stopped.
Treatment by means of the Rontgen rays has been practised by
Barjon (3), Mosse (63) and others, with the result that the spleen
has decreased somewhat in size, but the other signs of the disease
have persisted. It is therefore not to be recommended.
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384 WILDER TIIESTON
Surgical treatment
The importance of the spleen as a factor in hemolysis, and the
marked enlargement of the organ, soon led to the attempt to cure
the disease by removal of the spleen. The operation of splenectomy
for hemolytic jaundice was first performed in the case of Vaquez
and Giroux (88) and ended fatally. In 1911, however, Micheli
(59) removed the spleen in a case of the acquired type with brilliant
results, amounting apparently to a cure. Since then the operation
has been performed with increasing frequency and most happy con-
sequences. The jaundice disappears within a few days, and does
not return. The red count rises to a normal figure, usually within a
few weeks, and the urobilin excretion rapidly drops to normal, indi-
cating a cessation of the excessive hemolysis. The lower resistance
of the red cells, however, usually persists. Thus Dawson (23) re-
ports abnormal fragility of the red cells in a patient, otherwise healthy,
whose spleen had been removed twenty-seven years previously by
Spencer Wells. In a few cases, however, as in that of Thursfield
(84), the resistance has risen to normal and remained there.
The case of Whipham (92) has been cited as one of failure of sple-
nectomy to cure. It occurred in a girl of six, with negative family
history. The spleen was greatly enlarged and there was progressive
anemia, with a red count under one million. The operation resulted
in great improvement in the condition, with a return of the resistance
to normal, and of the red cells to above normal (6,000,000). Three
months later, however, the jaundice returned, and death occurred in
a few days, without marked anemia. There was no autopsy. The
intensity of the jaundice, which is described as a deep olive-green,
and the fact that bile pigment was constantly present in the urine,
renders this case very atypical, with a strong probability of organic
disease of the liver. The case can be excluded on the ground that
it was not one of pure hemolytic jaundice.
In the congenital type, a permanent cure may be predicted. Thus
in Giffin's (31) series, reported from the Mayo clinic, all but
one of ten patients reported themselves as well at periods up to five
years after operation, and the remaining case was an atypical one
of the acquired type, with probable biliary cirrhosis and a blood pic-
ture like that of pernicious anemia. Also in cases of the acquired
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HEMOLYTIC JAUNDICE 385
type, unless they are secondary to grave and incurable disease (cir-
rhosis, carcinoma, etc.) the prospects for cure are excellent.
The immediate mortality, high in earlier cases, has been greatly
reduced, so that Mayo (57) was able to report nineteen operations
with but one death (5.3 per cent) . This has been accomplished partly
by improvement in technic, partly by the transfusion of blood be-
fore, and also afterwards if much blood has been lost.
The operation is therefore to be recommended in the congenital
type if the symptoms are sufficiently severe, and in the "primary"
cases of the acquired type. Where the condition is secondary to
other disease, each case will have to be decided on its merits, bearing
in mind that splenectomy will almost certainly decrease the hemol-
ysis, but will not influence organic disease in other parts of the body.
The question of an operation for gall stones often arises in these
patients. It is probably best to do the splenectomy first, and if
the condition of the patient permits, to remove the gall stones at
the same operation. This was successfully accomplished in a case
recently studied by the writer. The removal of the spleen alone
usually does not suffice, the attacks of biliary colic recurring after
the operation.
PROGNOSIS
In the congenital type the prognosis is good as to life, there being
almost no instances of death from the disease itself. But the fre-
quent complication by gall-stones, the chronic anemia and crises of
deglobulization, make the condition of many of these patients more
or less miserable. Usually as old age approaches, the anemia becomes
less and crises rarer, but apart from operative measures, this is the
most that can be held out to the sufferer, for the condition persists
throughout life. The brilliant effects of splenectomy have been con-
sidered above.
The prognosis in the acquired type is less favorable, death in many
instances resulting directly from the anemia or from intercurrent
infections. Recovery may occur spontaneously, but is not the rule.
The course is in general more severe than in the congenital type,
and the patient is usually incapacitated for work for long periods.
The operation of splenectomy offers excellent chances for cure in
the primary or cryptogenetic form, except in the cases bordering on
pernicious anemia.
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386 WILDER TTLESTON
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A BACTERIOLOGICAL AND CLINICAL CONSIDERATION
OF BACILLARY DYSENTERY IN ADULTS
AND CHILDREN
WILBURT C. DAVISON
Baltimore, Maryland
TABLE OF CONTENTS
L Introduction 391
Dysentery among the civilian population (historical data) 392
Dysentery in children (historical data) 393
Dysentery in troops (historical data) 394
II. Etiology .' 395
Progress toward the discovery of B. dysenteriae 395
Stool cultures (historical) 396
Etiology of "bloody diarrhoea" in children 398
The toxins of the Shiga bacillus 400
The divisions of the mannite fermenting (Flexner) group of dysentery
bacilli 402
The toxins of the mannite fermenting (Flexner) group of dysentery bacilli. 405
Geographical distribution of Shiga and Flexner dysentery bacilli 406
Intermediate or atypical varieties of dysentery bacilli 406
Table I. Biological characteristics of the various types of dysentery bacilli. 408
Add production by dysentery bacilli 408
Mutation of dysentery bacilli 409
Relation of length of disease to excretion of dysentery bacilli 410
Table II. Graph representing success in recovering dysentery bacilli from
the stools at different periods after the onset of the disease 411
Collection of stool specimens 412
Viability of dysentery bacilli 412
Technique of stool cultures 413
Agglutination reactions of the patient's serum 414
Agglutination technique 416
Blood cultures 416
Urine cultures 418
Bacteriological diagnosis (summary) 418
III. Filterable "substance" antagonistic to the dysentery bacillus (drHerelle,s
phenomenon, bacteriophage, bacteriolytic agent, bacteriolysant, etc.) .... 419
Source 419
Non-specificity of bacteriolysants 421
Variations in the titre of bacteriophagic activity 421
389
VOL. I, NO. 3
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390 WILBURT C. DAVISON
Factors influencing bacteriophagk activity 422
Temperature 422
Reaction and oxygen supply of the media 422
Chemicals 423
Other factors 423
Separation of cultures into "resistant" and "sensitive" types by the action
of bacteriophages 423
Results of inoculations of bacteriophages in animals 425
Bacteriorysants as therapeutic agents 426
Theories in regard to the nature of bacteriophages 427
Discussion 429
Conclusion 431
IV. Experimental dysentery 432
Susceptible animals 432
Nervous lesions due to exotoxin (neurotoxin) 434
Intestinal lesions due to endotoxin (enterotoxin) 435
Besredka's theory of Intestinal immunity 438
V. Pathogenesis of bacfllary dysentery in man 439
VI. Clinical data in adults 443
Incubation period 444
Onset 444
Course 446
Stools, vomiting, tongue, temperature, pulse, physical examinations,
constipation 447
Nervous symptoms 448
Recovery, duration, relapses, reinfections 449
Chronicity 4S0
Dysentery carriers 451
Complications 452
Perforations, peritonitis, liver abscess, abscesses, arthritis, parotitis,
edema, ascites, cardiac complications, appendicitis, beriberi, stenosis
of colon, suprarenal insufficiency, chronic gastritis and colitis, rare
complications 453
Blood 454
White and red blood cell counts 454
Differential diagnosis (summary) 455
Presumptive diagnosis, definite diagnosis, differentiation of amebic and
bacfllary dysentery 456
.VII. Clinical data in children 457
Diagnosis of dysentery in children (summary) 459
VIE Prognosis in adults and children 460
Mortality 461
Factors influencing mortality and morbidity 462
DC. Treatment 463
Rest and diet 463
Enemata 463
Injections of normal saline 465
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 391
Specific serum therapy 466
Shiga infections 467
Flexner infections 469
Vaccine therapy 469
Proteosotherapy 470
Drug therapy 470
Irrigations of the colon, colostomy, appendicostomy 471
X. Means of spread (epidemiology) 472
XL Prophylaxis 475
Prophylactic vaccination 476
X II. Bibliography 477
I. INTRODUCTION*
The term dysentery (Awreirapia) (bowel trouble) was introduced
by Hippocrates (1) to denote a condition characterized by the fre-
quent passage of stools containing blood and mucus, accompanied by
straining and tenesmus. Some of the cases that were described at
that time (1) were doubtless amebic in origin for the occurrence of
liver complications is mentioned. The outbreak in Xerxes* army
during the Grecian campaign in 480 B.C. (2), however, was very
likely bacillary.
Not until the discovery of the ameba histolytica and B. dysenteriae
at the end of the last century could epidemics of bacillary dysentery
be accurately differentiated from those of the amebic variety. Only
by noting the absence of liver complications in the older chronicles
can it be assumed that bacillary dysentery was the type described, and
even then one is not always justified in so doing, for other infectious
processes in the intestinal tract (paratyphoid-Gaertner group) may
occasionally present a clinical picture similar to bacillary dysentery.
It is now well known that large single abscesses of the liver complicate
only the amebic form of the disease while even multiple small pyemic
abscesses are rare in bacillary dysentery. Rogers (3) states that the
conditions under which dysentery occurs may be of assistance in de-
termining the type of the disease. "Epidemic dysentery in asylums,
jails or in long occupied and unsanitary military camps during war is
nearly certain to be bacillary, while sporadic cases in a warm climate
are more frequently amebic."
*I am indebted to Hirsch (4), Eartulis (5), Rogers (3), Gettings (6), Castellani and
Chalmers (7) for many historical details.
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392 WILBURT C. DAVISON
Dysentery among the civilian population (historical date)
Epidemics of dysentery prior to the time of Hippocrates cannot be
differentiated into amebic and bacillary varieties. The disease is
mentioned in Papyrus Ebers (8). Atisar is its name in the older com-
mentaries of British India (9). Although acute and chronic types of
dysentery were mentioned, hepatic complications are not recorded.
Probably amebic and bacillary types were considered together for
both occur in India (10, 11, 12). The etiology of the cases of dysen-
tery described by Aretaeus (13), Celsus (14), Archigenes (IS), Caius
Arelianus (16) and Avicenna (17) is doubtful. The outbreaks noted
in Europe throughout the middle ages (18, 19, 20, 21, 22, 23) were
probably bacillary in origin for the intestines appeared to be the sole
seat of the disease. Sydenham's (24) (1669) descriptions of the disease
in London and Pringle's (25) reports of the outbreak of dysentery in
the army in Flanders (1752) do not mention hepatic complications
and are but little different from the records of the dysentery epidemics
in recent years which have been proved to have been due to infection
with B. dysenteriae. Symptoms, autopsies and, it might be men-
tioned, even medicinal treatment are practically identical. In the
middle ages, epidemics of dysentery were apparently of very frequent
occurrence (4).
In England (6, 26) from the beginning of the seventeenth to the
middle of the nineteenth century epidemics of bacillary dysentery
appeared more or less regularly at twenty-year intervals. It would
seem as if the disease would attack each generation, render the sur-
vivers immune and then wait for the non-immune offspring.
It would be merely repetition to record the extensive epidemics of
dysentery that have been reported. From Iceland to Africa they have
been numerous. Epidemics were recorded in North America in the
middle of the eighteenth century (27) probably introduced from
Europe. Hirsch (4), Kartulis (5), Rogers (3), Gettings (6) and others
(7) have completely covered this historical aspect. The importance and
efficacy of modern sanitation in times of peace are clearly illustrated
by the practical disappearance of extensive epidemics of dysentery
from the civilian population. It is not to be denied that the disease
is still a menace (28, 29), for it claims many victims especially among
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 393
children and the inmates of jails and asylums. In such institutions
the high incidence of badllary dysentery is noteworthy. Baly (30)
in 1847 focused attention on its prevalence in English jails and pointed
out that not a single liver abscess had been found in Milbank prison
among the hundreds of dysentery necropsies from 1823 to 1847 and
furthermore that in his experience ipecac which physicians in India
had found so efficacious was useless. MacKinnon (31) in 1848 re-
ported a similar condition in the Indian jails. In the insane asylums
of England (6, 32) and of the United States badllary dysentery has
proved to be a serious problem. These cases of so-called "asylum
dysentery" have now been proved to be due to infection with B.
dysenteriae (33, 34, 35, 36, 37, 38). It does not appear (39) to be a
seasonal disease whereas the dysentery of barracks and camps is
generally much more prevalent in summer and autumn.
Mild, sporadic cases of badllary dysentery still occur in England
(40) and in the United States more frequently than is generally
recognized.
Dysentery in children (historical data)
The reduction of the inddence of dysentery in children has not been
as marked as in adults (dvilians). This may be due to the fact that
until the present century it was not recognized that many of the
bloody diarrheas of childhood were really cases of dysentery although
since 1829 various surmises have been advanced in regard to its in-
fectious or "miasmatic" nature (4). Aretaeus in the second century,
Harris in London in 1650 and others (26) mentioned infantile diarrhea
and Benjamin Rush (41) in 1777 emphasized the prevalence and
serious consequences of bloody diarrhea in infants in the United
States. The condition was probably unknown among the American
Indians (42). During the nineteenth century the disease was dis-
cussed under various names. The medical literature, both American
and European, is replete with descriptions of, and observations on,
"cholera infantum." This term covered a multitude of sins and not the
least of these was badllary dysentery. The clinical descriptions and
autopsies reported by Jackson, Warren (43), and Horner (44) of Boston
and others (45, 62) in children with "cholera infantum" and "bloody
diarrhea" are similar to those we have had in the past few years
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394 WILBURT C. DAVISON
in cases from which B. dysenteriae was isolated. Ekiri (46) was the
name given to epidemic infantile diarrhea in Japan and this also is
now proved (47, 389) to be bacillary dysentery. At present the
disease in children frequently escapes official notice by masquerading
under other names of which ileocolitis and "infectious diarrhea" are
the more common. Under the blanket term "summer diarrhea"
many cases of infantile dysentery are hidden. Although we seldom
see epidemics such as were recorded in this country in Revolutionary
times, yet many sporadic cases still occur (48).
Dysentery in troops (historical data)
Practically every long campaign and extended siege since the
memory of man has produced an epidemic of dysentery. The "erne-
rods" with which the Bible states the army of the Philistines was
smitten are now interpreted (350) as prolapses of the rectum occurring
in epidemic dysentery. During military campaigns, Edward I and
Henry V of England died of this disease. Seventy-five per cent of the
latter's army succumbed to dysentery (6). The armies in the Pelo-
ponnesian war (4), the British campaigns in the 18th century (49, 50),
Napoleon's campaigns, the Crimean war (51), the American Civil war
(52), the Franco-Prussian war (6) and the Chino- Japanese war prob-
ably paid heavier toll to B. dysenteriae than to Mars. In 1914
Osier (53) said that while typhoid fever would be controlled, dysentery
would play havoc. It did. Early in 1915 the hospital ships returned
from the Dardanelles (54) laden with cases of dysentery. The
Belgians and British in Flanders (55, 56, 383), the British in Salonika
(57, 58), Gallipoli (54, 59), Mesopotamia (60, 61, 370), Palestine (63,
380), and Egypt (64), and the French in the Argonne (65) and the
East (66) suffered also, while the American army, though later in
entering the war, had numerous cases at Chateau Thierry and at the
base ports (67, 68). The Germans (69, 70, 71, 72, 73, 433) and the
Austrians (74, 75) suffered especially along their Eastern fronts, and
even found a new type (Schmitz) (76) of dysentery bacillus among
their Roumanian prisoners.
In fact, from the standpoint of the prevention of dysentery in
campaigns we are nearly as badly off as Xenophon (2) was during the
Greek retreat from Persia.
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BAOLLARY DYSENTERY IN ADULTS AND CHILDREN 395
II. ETIOLOGY
0
Progress toward the discovery of B. dysenteriae
Emanations from the soil, humidity, altitude, atmospheric changes
and other conditions were formerly believed to act as causes of dysen-
tery, and occupation, age, race and previous health as predisposing
factors.
Pringle (25) in 1752 after discussing heat and humidity as the re-
mote causes and putrefaction of the blood and scurvy as predisposing
factors, concludes with the prophetic statement "But having since
perused the curious dissertation of Linnaeus in favor of Kercher's
suggestion of contagion by animalculae, it seems reasonable to sus-
pend all hypothesis until that matter is further inquired into."
Lambl (81) in Prague in 1859 made the first step toward unshroud-
ing the mystery by describing amebae in the stools of a child dying of
diarrhea. Although he strongly urged the possibility that this
might be the real cause of the disease, others (82) were not absolutely
convinced of it. Eighteen years later Loesch (83) in Petrograd found
numerous amebae both before and after death in dysentery cases.
He went one step farther and produced symptoms of dysentery in
dogs with this parasite. Kartulis (84) (1883) in Egypt demonstrated
amebae in sections of the intestinal walls of all of the 150 dysentery
necropsies he studied. This apparently settled the question until
Massiocetine (85) in 1889 found amebae in patients without dysenteric
symptoms. Grave doubts were then expressed in regard to the
pathogenicity of amoebae.
However, after Kartulis (84) in Egypt in 1886 had demonstrated
amebae in the liver abscesses of patients who had had dysentery and
Osier (86) in 1890 had confirmed the finding, Councilman and Lafleur
(87) (1891) settled the pathogenicity of amebae by differentiating
amebae coli which occur in normal stools from amebae dysenteriae
which produce dysentery. They also remarked that a diphtheritic
type of dysentery, which we now know to be bacillary, could be dis-
tinguished from amebic dysentery. These researches were soon veri-
fied by Schaudinn (88) and the name axneba histolytica was applied
to the pathogenic variety.
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396 WILBURT C. DAVISON
It now appears that in rare cases, symptoms of dysentery may be
due to certain other parasites such as balantidium coli (89, 90),
lamblia (91), trichomonas (92, 93), ankylostoma, schistosoma, para-
gonimus (265), chilomastix mesnili (364) and bilharzia (94), which up
to the present have received little attention.
Stool cultures (historical)
During this period of controversy over axnebae, many investigators
still clung to the belief that some, if not all, cases of dysentery were
caused by bacteria. In 1869, ten years after Lambl's discovery,
Basch (95) reported the presence of leptothrix filaments in sections of
the intestines of patients dying of dysentery. From that date on,
various workers described different organisms as the cause of this
disease. The earlier investigators believed that many species of
organisms (polymicrobic theory) could cause dysentery but Klebs (96)
(1887), Chantemesse and Widal (97) (1888) Grigoriew (98) (1892),
Ogate (99) (1892) and Celli (100) (1896) each advocated a single
variety of bacillus as the etiological agent. Many authorities believe
that Chantemesse and Widal described a bacillus similar to that
finally reported by Shiga although it was claimed that their organism
could produce dysentery in guinea pigs, a phenomenon that cannot be
reproduced with B. dysenteriae. Maggiora (101), Arnaud (102) and
numerous others (103, 104) claimed that B. coli of exalted virulence
produced dysentery. B. pyocyaneus was urged as the cause of
dysentery by Calmette (105) (1893) working in Cochin China and
also by others (106) in America. The streptococcus was reported as
the cause in 1896 by Durham, Mott (32) and others (107, 351). B.
proteus has also had many supporters (62, 108) . B . fecalis alkaligenes
(406, 432), B. enteritidis sporogenes (169) and B. lactis aerogenes
(407), are occasionally reported as causes of dysentery.
All of these investigators found these various organisms in the
excreta of dysentery patients but no one advanced any real proof
that there was a causal relationship between any of these bacteria
and the disease dysentery. We know now that the streptococci,
B. pyocyaneus, B. proteus and these other organisms, although fre-
quently present in dysentery stools are probably without etiological
significance.
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BAOLLAKY DYSENTERY IN ADULTS AND CHILDREN 397
In 1898 Shiga (77) conclusively proved that a specific organism
which has been named after him was present in the stools of many
patients with dysentery and that agglutinins for it were present in the
patient's serum. Furthermore, it was not present in normal stools.
When injected into rabbits, symptoms of dysentery and toxemia
resulted. It soon became apparent that this organism was the
cause of the cases of dysentery that Shiga studied.
Two years later Flexner (109) found bacilli which were supposed
to be identical with Shiga's organism in cases of dysentery in the
Philippines. In the same year Kruse (34) found in Westphalia an
organism identical with that of Shiga. In an epidemic of dysentery
occurring in a German insane asylum, he also discovered a bacillus
that differed in its agglutination reactions from the original Shiga
organism. This he called B pseudodysenteriae. Both types were
soon demonstrated (33) in cases of dysentery in the United States.
In 1902 Martini and Lentz (1 10) developed a method for distinguish-
ing the Shiga bacillus from Flexner's bacillus and Kruse's pseudodys-
entery bacillus by means of agglutination tests and the fermentation
of mannite. The former failed to ferment this carbohydrate while
the two latter produced acid and no gas.
Park (111) carried out mannite fermentation tests on the organism
Flexner had recovered in the Philippines and noted that it produced
acid and no gas and therefore was similar to Kruse's B. pseudodys-
enteriae and not to the Shiga bacillus. It also fermented maltose
and saccharose. This is the organism which is now known as the
Flexner-Harris bacillus.
In 1902-1903 Strong (112) isolated a mannite fermenting bacillus
differing in maltose fermentation from Flexner's organism that also
satisfied all of Shiga's postulates for a causative organism. It was
found in dysentery stools, it was agglutinated by patients' sera and
furthermore when fed to a condemned prisoner it produced dysentery.
In 1903 Hiss and Russell (113) found a mannite fermenting bacillus
in the stools of a child with dysentery. This organism, which was
christened the Y bacillus, failed to ferment maltose and saccharose and
thus differed from the the Flexner-Harris and Strong bacilli. Some
authors (133) differ in their reports on the maltose and saccharose
reactions of these organisms.
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398 WILBURT C. DAVISON
The four organisms, Shiga, Flexner-Harris, Strong and Hiss-Russell-
Y have been considered distinct varieties and the most common types
The first does not ferment mannite; the last three do, but are separated
from each other by differences in the fermentation of maltose and
saccharose. The serum of rabbits immunized with the Shiga bacillus
will agglutinate practically all strains of dysentery bacilli of similar
cultural characteristics. Solimano (373) believes that the biochemi-
cal reactions of the Shiga bacillus are its only constant factor and that
its agglutination reactions are variable. Cultures of B. dysenteriae
(Shiga) it is true are encountered that are or can be rendered inagglu-
tinable (114, 115) but the instances are rare. Ordinary laboratory
cultivation usually causes these organisms to become more sensitive
to agglutination (431). Serum from animals immunized with the
Shiga bacillus will not usually agglutinate any of the mannite fer-
menting cultures to very high titres.
Monovalent sera made from the three main members of the man-
nite fermenting group (Flexner-Harris, Strong and Y) although usually
agglutinating the homologous strain to higher titres will also often
agglutinate the other members of the mannite-fermenting group to
partial titre and will sometimes even agglutinate the Shiga bacillus in
lower dilutions. In other words, it appears that there are two dis-
tinct groups, the non-mannite fermenting bacilli with a single variety,
Shiga, and the mannite-fermenting bacilli with three subgroups,
Flexner-Harris, Strong and Hiss-Russell-Y.
Etiology of "bloody diarrhea" in children
A great advance in the study of diarrhea in children was made by
Duval and Bassett (215) who in 1902 showed that many cases of so-
called "summer diarrhea" in infants were due to infection with B.
dysenteriae. The Rockefeller Commission (138) in the following
summer confirmed the discovery. Similar findings have been re-
ported by other investigators in various parts of the United States,
Europe and Japan (40, 47, 48, 124, 149, 150, 151, 152, 153, 154, 389).
Tenbroek and Norbury (154) in Boston found dysentery bacilli and
agglutinins in the blood of 80 per cent of their patients with bloody
diarrhea. My results (48) in a series of patients with bloody stools in
Baltimore and Birmingham were identical with those of Tenbroek
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 399
and Norbury (154). A clinical analysis of all of these cases of dysen-
teric infection in children reported by various authors shows that it is
practically only from patients who have, or have had, bloody, purulent
and mucous stools that B. dysenteriae is isolated. In this country
and Japan, bacillary dysentery in children is usually due to infection
with B. dysenteriae Flexner. Only 12.5 per cent of my cases (48)
and 10 per cent of Mita's cases (389) were of the Shiga variety.
Dysentery bacilli have occasionally been reported in the stools of
apparently normal infants (153, 155, 156) and adults (47, 117) who
have usually, however, been in contact with patients with dysentery
and are probably carriers. They have been isolated from sources
having no connection with dysentery patients (157). Many of these
cultures are inagglutinable (158) and probably are not true dysentery
bacilli. I was unable to find typical dysentery bacilli in the stools of
100 normal children and of 63 children with diarrhea (48) whose stools
contained no blood and but little mucus.
Dysentery in children stands out sharply on clinical as well as
bacteriological grounds. In fact, in the published studies (138, 154,
48) made in several of the larger cities in the United States, approxi-
mately 80 per cent of all of the cases of bloody and mucous diarrhea
in children have been proved to be due to infection with B. dysenteriae.
It is thus apparent that ileocolitis and bacillary dysentery in chil-
dren are one and the same disease. They should be called dysentery..
There seems no justification for calling the same disease in children
and adults by different names. Nevertheless, many types of diarrhea
in children during the warm months, regardless of etiology, are often
classed together as "summer diarrhea."
Many bacteriological studies of the stools of children with diarrhea
have been made and numerous different organisms have been brought
forward as the etiological agents of this condition. The old contention
(159) that B. welchii (gas bacillus) was one of the causes of diarrhea
in children has been discredited. Numerous investigators (48, 154,
160, 161, 162, 163) have shown that this organism is present in the
stools of many normal children and has nothing to do with the etiology
of diarrhea.
Several investigators have maintained that B. Morgan No. 1 was
the cause of diarrhea in children (164, 165) and also in adults (354).
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400 WILBTOT C. DAVISON
Numerous investigations (48, 63, 66, 68, 154, 166, 167, 168, 430),
have disclosed the fact that this organism is a motile Gram-negative
bacillus characterized by the production of acid and gas in the mono-
saccharides only, the formation of indol and the non-liquefaction of
gelatin. It produces an endotoxin fatal for rabbits but no exotoxin
(430). B. Morgan probably represents a wide group of bacilli rather
than a single type. It is also present in the stools of many normal
children and adults. Furthermore the serum of patients with diarrhea
in whose stools B. Morgan No. 1 is found, do not have agglutinins for
this organism (48, 154, 166) so that it would seem highly improbable
that B. Morgan No. 1 is of etiological importance in diarrhea.
The claims that B. pyocyaneus (106), streptococcus fecalis (107),
B. proteus (63, 108, 170) and highly virulent colon bacilli are the
cause of diarrhea in children have all been frequently refuted (48,
154, 163).
Several investigators (171, 172) have advanced the theory that the
diarrheas of children are caused by the effects of a putrefactive or a
fermentative flora. The idea has been recently emphasized in the
United States (173). Our studies (163) have revealed the fact
that the so-called putrefactive and fermentative intestinal flora
that have been supposed to produce diarrhea, frequently exist in
normal children without causing the slightest change in the patient's
health. The putrefaction and fermentation theory of intestinal
disease in children is an old one and originated with Jackson (43) of
Boston in 1812. "In some cases in which symptoms of dysentery had
occurred there was postmortem inflammation of the large intestine
which is attributable to the putrefaction of animal food and the
acetous fermentation of that which is vegetable." Proof has not yet
arisen that gives this theory any more stability than it had in 1812.
The toxins of the Shiga bacillus
Shiga (77) first pointed out that the bacillus which bears his name
was highly toxic for rabbits. The Shiga bacillus or its poisonous
products induces two kinds of marked lesions in the rabbit (77, 78, 116,
117, 118, 119, 120, 121) ; one is localized in the intestine, and the other
in the central nervous system. Olitsky and Kligler (119) have iso-
lated two toxins from cultures of B. dysenteriae (Shiga) and have dem-
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 401
onstrated that they are physically and biologically distinct. The
Shiga bacillus grown in egg albumen broth yields in the first few days
of the cultivation, at the beginning of the alkaline phase of its growth
and before bacterial disintegration sets in, a toxic product which
appears in the bacteria-free filtrate. This toxic product is precipitated
with the globulin fraction of the protein, is relatively heat labile,
being destroyed when heated to 75°C. for one hour, and is capable of
inciting antitoxin formation. It is constant in its properties, regard-
less of the source of the Shiga culture, i.e., an antitoxin produced by
the injection of one Shiga culture will neutralize the toxins of other
Shiga cultures from widely separated sources. This toxin will produce
in rabbits after a definite incubation period, typical lesions of the cen-
tral nervous system (hemorrhages, necroses, and possibly a perivas-
cular infiltration in the gray matter of the upper spinal cord and
medulla) with paralysis of the limbs and urinary bladder (vide infra).
It will not produce any obvious intestinal lesions. Olitsky and Kligler
(119) regard it as an exotoxin and a neurotoxin.
The production of the endotoxin of Shiga bacilli does not differ
essentially from that of other bacteria. The principle underlying all
of the methods is that of autolysis or dissolution of the bacterial cell
with the resultant liberation of its intracellular components. Most
observations with the Shiga bacillus have been made with endotoxins
produced in broth cultures by prolonged incubation (beyond fourteen
days), but endotoxin may be produced more rapidly by incubating
at 37°C. for forty-eight hours a saline suspension of a twenty-four-
hour agar slant culture and then filtering through a Berkefeld N
candle (119).
Usually small amounts of exotoxin are found in preparations of
endotoxin and vice versa but they may be separated by heat for the
exotoxin is destroyed when heated to 75°C. for one hour while the
endotoxin will withstand this temperature although it is destroyed
when heated to 85-90°C. for one hour. These two toxins may also
be separated by neutralization, i.e., by adding anti- exotoxin, all of
the exotoxin present is combined and neutralized and only the endo-
toxin remains free and active. Anti-exotoxin will not neutralize
endotoxin. Endotoxin, however, is neutralized by an antibacterial
serum prepared by actively immunizing horses with Shiga bacilli.
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402 WILBURT C. DAVISON
The endotoxin exerts a typical action on the intestinal tract of
rabbits producing edema, hemorrhage, necroses, and ulcerations
especially in the cecum and large intestine (vide infra). The Shiga
endotoxin is probably of intracellular origin, and has the properties
of the Endotoxins as a class (119). Neitz (122) extracted a nucleo-
protein from Shiga bacilli that was toxic for animals. The serum of
animals injected with this nucleoprotein would agglutinate the Shiga
bacillus.
Horimini (341) has reported that by means of washing and neu-
tralization he has been able to separate the toxins of the Shiga bacillus
into four fractions. One attacks the cecum, another the central
nervous system, another the small intestine and the fourth produces
lesions in the colon.
The mannite fermenting dysentery bacilli, on the other hand, pro-
duce endotoxin but usually no exotoxin.
The divisions of the mannite fermenting (Flexner) group of dysentery
bacilli
The existence of the Flexner-Harris, Strong and Y types of mannite
fermenting dysentery bacilli has been confirmed (36, 80, 123) in
various parts of the world and furthermore it has been shown on the
basis of the differences in fermentation of other carbohydrates such
as sorbite, dextrin, dulcite and rhamnose, that there are probably
additional members of the mannite fermenting group of dysentery
bacilli (7, 80, 124).
A tremendous impetus was given to the study of bacillary dysentery
by the Great War. The publications of the workers of the Medical
Research Committee of England, the Royal Army Medical College
and others have placed our knowledge of the disease on a new plane.
At first there was considerable confusion in regard to the different
varieties of mannite-fermenting dysentery bacilli. It had previously
been shown that divisions of this group into Flexner-Harris, Strong
and Hiss-Russell- Y on the basis of the fermentation of maltose and
saccharose were unreliable (35, 37, 56, 57, 110, 130, 222). An organ-
ism may be isolated from a patient's stool that gives the fermentation
reactions of the Hiss-Russell- Y organism, i.e., not producing acid in
maltose and saccharose. If the fermentations are repeated after a
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 403
lapse of a few months, they may be identical with those of the Flexner-
Harris bacillus, i.e., forming acid in maltose and saccharose. If this
organism is then injected into an animal and then recovered and its
fermentation ability retested, a reversion to the original Hiss-Russell- Y
type may be noted (1 10) . The question then is, what type of bacillus
caused this patient's dysentery? Serological results did not always
help for many Flexner-Harris and Y monovalent sera will cross-agglu-
tinate to such high titres that it is impossible to decide which is specific.
The changing fermentative ability of these divisions probably accounts
for the frequent confusion of the sera, for in the example I have just
quoted, a diagnostic serum made with the freshly isolated organism,
while it gave fermentative reactions similar to a Y bacillus, would of
course be called a Y serum. After a few months, however, if a diag-
nostic serum was made with the same culture which then fermented
as a Flexner-Harris bacillus, would this new serum be a Flexner-
Harris serum? At any rate, both the original and the new sera will
agglutinate this organism that was at one time a Y bacillus and later
a Flexner-Harris type, for the agglutinins of the serum do not change
their type (222). If a serum reacts with a freshly isolated organism
at a dilution of 1/100, it will usually react to the same or a higher
titre with this organism after a few months of laboratory cultivation
(431). As an exception to this, Benians (114) has just shown that
injecting an agglutinable Shiga bacillus suspended in mucilage of
tragacanth into a guinea pig may render it inagglutinable. This may,
perhaps, be due to the same process involved in Bordet's and Ciuca's
(233) experiment (bacteriophage or d'Herelle phenomenon) (vide
infra). Cultivation in bouillon containing antidysenteric serum will
produce the same result (115, 452). In some instances (378) long
cultivation alone may decrease the agglutinability of a strain of
dysentery. Werdt and Kopatschek (367) found that all strains of B.
dysenteriae when grown on a protein free medium to which test sugars
had been added, failed to ferment dextrose, mannite, maltose, lactose
or saccharose. Other members of the colon-typhoid group produced
their typical sugar reactions. Addition of a small amount of peptone
to this protein free medium reestablished the usual sugar fermentations
characteristics of the dysenteries. These investigators conclude
from this that dysentery bacilli do not form carbohydrate splitting
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404 WELBUBT C. DAVISON
enzymes in the absence of protein. It may be seen therefore that in
the whole series of dysentery bacilli marked changes may occur or be
brought about that will greatly alter both the fermentation capacity
and the agglutination characteristics of these organisms. However,
although the agglutinability of a dysentery bacillus may occasionally
be reduced to zero, yet a distinct change from one serological variety
to another does not occur, whereas a change from one fermentative
variety to another is quite common within the mannite-fermenting
group.
Murray (131) and others (132, 133) have attempted to clarifythis
question. Murray found that 34 mannite fermenting dysentery
bacilli isolated from cases of dysentery in different parts of the world
fell into five divisions on the basis of their agglutination reactions with
monovalent rabbit sera. These five divisions were designated as the
V, W, X, Y, and Z divisions of the Flexner group by a committee of
bacteriologists appointed by the British War Office Committee on
Dysentery. The names of the various subgroups based on differences
in fermentation of maltose and saccharose have been discarded. The
name Flexner41 is now usually applied to the whole mannite fermenting
group and the subdivisions based on agglutination noted, i.e., B.
dysenteriae (Flexner, type V, etc.).
I used fermentation tests with maltose, saccharose, dulcite and
rhamnose, and also agglutination tests with Murray's five (English)
Flexner monovalent rabbit sera types V, W, X, Y and Z to differentiate
eighty-nine cultures of mannite fermenting dysentery bacilli isolated
from the stools of cases of dysentery in adults and children (132).
On the basis of the fermentation tests, these cultures fell into seven
groups which did not correspond with the groups obtained by the
agglutination tests, i.e. of the organisms that fermented maltose and
not saccharose, some were agglutinated by the Y serum and others
by the Z serum. Of the organisms agglutinated by the X serum,
some fermented maltose and saccharose and others did not ferment
saccharose. In order to avoid this confusion either fermentation
or agglutination methods must be adopted as the criterion for
classification.
* In the remainder of this paper by B. dysenteriae (Flexner) or the Flexner bacillus
I shall refer to the whole mannite fermenting group of dysentery bacilli.
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BACnXARY DYSENTERY IK ADULTS AND CHILDREN 405
Agglutination tests were performed with V, W, X, Y and Z stock
cultures and the sera of the patients from whose stools dysentery
bacilli were obtained and a general correspondence was found between
these serum reactions and the serological grouping of the stool organ-
isms. That is, if the patient's serum agglutinated the V and Y stock
cultures, his stool organisms would be agglutinated by the V and Y
type sera.
As the fermentation reactions of these cultures may change after sub-
culture and as the serological typing is fairly constant (222) , a grouping
on the basis of agglutination is preferable. Inasmuch as Murray
studied organisms from such widely distributed sources it would seem
advisable to adopt his serological classification and to add to it the
types that fail to be agglutinated by his V, W, X, Y and Z sera.
Polyvalent sera for diagnostic and therapeutic purposes should include
antibodies for the more common of these types.
There are probably other types of Flexner bacilli in addition to the
V, W, X, Y and Z types (57, 449), for from the stool of one dysentery
patient I isolated a mannite fermenting dysentery bacillus that^was
not agglutinated by any of the five diagnostic sera and there were no
agglutinins in this patient's serum for the V, W, X, Y and Z stock
cultures (132).
Flexner cultures are rarely agglutinated by only one of these five
sera; for example, a strain may react with the Y serum at a high titre
and with the W and X sera in lower dilutions. Murray believes that
there are five or more antigens in the Flexner group, one of which pre-
dominates in a given culture.
Absorption tests and the Michealis "acid agglutination" reaction
(57, 134, 135) are of little assistance in the division of the Flexner
group.
The toxins of the mannite fermenting {Flexner) group of dysentery
bacilli
It has usually been assumed that the Flexner group of dysentery
bacilli caused nothing but intestinal lesions because they only pro-
duced endotoxin, an enterotoxin, but Thjotta and Sundt (442) have
reported that filtrates of eight-day bouillon cultures of one of the sub-
groups of mannite fermenting dysentery bacilli contained a neuro-
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406 WILBURT C. DAVISON
toxin. When these filtrates were injected into animals, nervous
lesions occurred after an incubation period, but no intestinal lesions
were encountered. These bacilli also possessed an endotoxin which
caused intestinal disturbances, usually of a mild character. Repeated
injections of the two toxins rendered animals immune. A weak anti-
toxin could be prepared for each of these toxins.
Geographical distribution of Shiga and Flexner dysentery bacilli
During the war the predominating type of organism varied with
the epidemic. On the Gallipoli peninsula (54) , along the German and
Austrian Eastern fronts (69, 71, 72, 73, 74), in Russia (136), Brittany
(137), Albania (90), Macedonia (355), Norway (455), and in the recent
British outbreaks (29, 356), the Shiga bacillus was usually more pre-
valent while the Flexner bacillus was the more common along the
Western front in the Allied (69, 55) as well as in the German armies
(73), along the Serbian front (70), in Salonika (222), in Brussels (415)
and among the civilians in Germany, Austria (69) and South
America (387). Two small Shiga epidemics have, however, recently
been reported in Germany (357, 368). Flexner and Shiga infections
were about equally frequent in Mesopotamia (370). Blackburn (380)
states that Flexner infections were more common in Palestine.
In the sporadic cases of dysentery in children the Flexner bacillus is
more common than the Shiga variety (48, 124, 138, 139, 140, 389, 418).
The statement is sometimes made (140) that mixed Flexner and Shiga
infections in children are more common than infection with the Shiga
bacillus alone. This has not been true in our series of cases (48).
In 35 cases of bacillary dysentery in children in Baltimore and Bir-
mingham, Alabama, I found 31 due to infection with B. dysenteriae
Flexner and 4 with B. dysenteriae (Shiga). I did not find any cases
of mixed infection.
Intermediate or atypical varieties of dysentery bacilli
In addition to the Shiga bacillus and the various members of the
Flexner group, intermediate varieties have been described (141, 389).
Three of these types of dysentery bacilli deserve mention. One, a
bacillus that forms acid and no gas in lactose, was called B. pseudo-
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BACnXARY DYSENTERY IK ADULTS AND CHILDREN 407
dysenteriae type E by Kruse (34) andiscolloquiallyknownasKruseE.
There is probably a whole group of these bacilli that produce acid
and no gas in lactose (39, 142, 143). Andrewes (134) calls the mem-
bers of this group, B. dispar and doubts their pathological significance.
There is no absolute proof that these organisms can cause dysentery
but it is not at all unlikely that some of them are pathogens. Hilgers
(384) isolated several strains of Kruse E from children suffering with
follicular enteritis. He considered it to be identical with Sonne's
group III (123). I have recovered Kruse E bacilli (68) that agglu-
tinated with Murray's Kruse E serum in six cases of dysentery in
adults and from the intestines of one fatal case of dysentery in a
child, and an inagglutinable variety in six additional cases of dysentery
in adults and four non-dysenteric cases in children. The sera of
several normal individuals agglutinated B. dispar (Kruse E) in dilu-
tions of 1/50.
Schmitz (76) in 1916 during an epidemic of dysentery among Rou-
manian prisoners isolated a new type of bacillus. This organism is
non-motile, produces indol and forms acid and no gas in dextrose and
rhamnose. Ornstein (365) working with eight strains of the Schmitz
bacillus isolated from dysentery patients has confirmed these results.
He also showed it to be distinct from B. fallax. Blumental (377)
isolated the Schmitz bacillus in Galicia and considered it agglutino-
genically identical with Kruse J bacillus. Andrewes calls this B.
ambiguus and is doubtful, as this name implies, of its pathogenicity.
Nevertheless it produces dysentery (57). A laboratory technician
(144) pipetted a mouthful of culture of the Schmitz bacillus and
developed mild dysentery two and a half days later. The Schmitz
bacillus was recovered from the stools. Broughton-Alcock (145)
recovered this bacillus in two outbreaks of mild dysentery among
British troops. Kirschner and Segall found it in cases in Vienna
(406). I have recovered it in two cases during an epidemic of dysen-
tery in the A. E. F. (68). No serum that I have tested either from
dysentery patients or from normal individuals has agglutinated the
Schmitz bacillus in dilutions of 1/20. Somewhat similar organisms
have been isolated by other workers (124, 140, 146, 389) and called
by various names such as "alkaline" or pseudodysentery bacilli.
Flexner believes them to be non-pathogenic (39).
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408
WILBURT C. DAVISON
A third organism called B. alkalescens by Andre wes is a mannite
fermenting bacillus differing from the Flexner group in that it forms
acid (no gas) in dulcite. Three of the four strains that I have en-
countered in cases of dysentery have not been agglutinated by any of
the Flexner type sera. I have not recovered B. alkalescens from nor-
mal individuals. The biological characteristics of these various organ-
isms are expressed in table 1.
TABLE 1
Biological characteristics of the various types of dysentery bacilli
TYPE OF BACILLUS
B. dysenteriae (Shiga)
B. dysenteriae (Flexner). . ,
B. dysenteriae (Kruse £)
or B. dispar ,
B. dysenteriae (Schmitz)
or B. ambiguus ,
B. alkalescens
0
Var
Var
+
+
Var
Var
0
+
0
Var
+
0
0
0
Var
+
0
0
0
+
0
+ indicates formation of indol, or production of acid and no gas in carbohydrate media.
0 indicates negative gram staining, non-motility, non-indol production, non-liquefac-
tion or non-fermentation of carbohydrate media (twenty-eight-day incubation).
Var (variable) indicates that some members of the group form indol or produce add
and no gas in carbohydrate media while other members fail to do so.
— indicates that a test was not made.
Acid production by dysentery bacilli
Zoller and Clark (416) have shown that under aerobic and anaerobic
conditions, in the presence of 1 per cent dextrose, Shiga, Flexner,
typhoid and paratyphoid bacilli produce approximately the same
total amounts of volatile fatty acids and about the same proportions
of formic and acetic acids. When these organisms are grown aerobi-
cally on sugar-free peptone water, volatile fatty acids are formed in
appreciable amounts. Formic acid, however, is not produced but
propionic acid is found in its place. When cultured anaerobically
on non-sugar media, these bacteria produce formic acid and also a
certain amount of butyric acid. Zoller and Clark suggest that the
enormous amounts of formic acid produced by these bacilli may
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BACILLA&Y DYSENTERY IN ADULTS AND CHILDREN 409
play a significant part in causing the digestive disturbances and
toxic symptoms accompanying their infection of the human gastro-
intestinal tract.
Mutation of dysentery bacilli
A certain amount of mutation can be produced in dysentery bacilli.
Fletcher (147) has isolated bacilli from the stools of a dysentery car-
rier and of a convalescent patient that were apparently capsulated
and that formed mucoid colonies. Organisms resembling dysentery
bacilli (mannite-fermenting) were obtained by plating out peptone
water cultures of these mucoid bacilli. These organisms were agglu-
tinated by dysentery serum but did not absorb agglutinins. May-
mone (148) reported that Shiga bacilli isolated from the stools of the
same patient might differ in agglu tin ability, absorption and dextrose
fermentation.
Arkwright (38) from a single strain of B. dysenteriae (Shiga) as
well as from single strains of several different members of the typho-
coli group, has obtained two forms. One of these made a stable
emulsion in physiological salt solution and the other yielded an emul-
sion which was spontaneously agglutinated in normal saline (without
the addition of serum). These two types were also distinguishable
by the difference in their growth. Both of these variants of B. dys-
enteriae (Shiga) were agglutinated to the same titre by a stock Shiga
serum. Sera, made by immunizing animals with each type, however,
agglutinated only their homologous strains in high dilutions and showed
but very slight cross-agglutination. De Kruif (435) has had some-
what similar results with the organisms of rabbit septicemia.
Twort (348) reported that repeated subcultures of young Shiga
cultures eventually showed a preponderance of large thick bacilli.
When these were grown anaerobically, and then subcultured aero-
bically, two types of colonies resulted, A, a large mottled colony com-
posed of waxy long spirochaete like bacilli containing a few granules
and B, a gray colony which later became mottled and was formed by
long bacilli with swollen ends, some of which appeared to split open
and to liberate free granules. When type B colonies were replated,
a third type of bacillus was found. These type C organisms were
shorter, thick bacilli and they formed waxy colonies. The A, B and
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410 WILBURT C. DAVISON
C types gave rise to mixed forms on subculture but they did not
revert to their original form. Cultures of the A, B and C types
were agglutinated by Shiga serum to higher titres than the orig-
inal Shiga culture, but spontaneous agglutination was frequent.
Type C produced a large amount of acid in maltose, type B formed
a fair amount, while type A produced little or none. Twort suggests
that these different types represent sexual forms, or that each type has
a special function such as toxin production, food production, repro-
duction, etc. They do not represent a life cycle as they do not revert
to their original form.
It is possible that this mutation depends upon the same process
that is responsible for the changes in the form of the colonies and in
the characteristics of the bacilli that are seen in dysentery cultures
which have been acted upon by bacteriolytic filtrates (bacteriophages,
d*HereJle phenomen). This will be discussed later.
Relation of length of disease to excretion of dysentery bacilli
It is frequently stated (56, 63, 64) that after the sixth day of the
disease in adults it is impossible in the majority of cases to isolate B.
dysenteriae even though the stools contain mucus. The percentage
of positive stool cultures in typical cases of bacillary dysentery is
rarely high (69, 74). Seligman (69, 71) found B. dysenteriae in 38
per cent of all of his acute cases. His highest percentages were in the
first few days of the disease (see table 2). Martin and Williams (56)
have made an interesting analysis of their 1050 positive stool cultures
in cases of dysentery among the Mediterranean Expeditionary Force.
Only 15 per cent were positive at the first examination. This em-
phasizes the necessity for repeated cultures and that single negative
examinations are worthless. The earlier in the disease the cultures
are made, the higher the percentage of positive results (see table 2),
which is somewhat different from the experience with typhoid fever.
However, occasional patients excrete the organisms for months (69)
and even years (174). Fletcher and MacKinnon (175) have applied
the term persistent carriers to individuals harboring dysentery bacilli
over three months. Many of them cease to have clinical symptoms
of dysentery.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 411
I
I
£
► Days after onset of disease
TABLE 2
Graph represents success in recovering dysentery bacilli from the stools at different periods after
the onset of the disease. figures from 1050 cases (Martin and Williams) (56),
figures of Seligmann (71)
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412 WILBUM C. DAVISON
Collection of stool specimens
For an accurate bacteriological examination the proper collection
of stools is of the utmost importance. It is preferable for the bacterio-
logist himself to collect a specimen of blood and mucus directly from
the bed pan or with a rectal swab. When this is impossible, a portion
of blood and mucus should be collected on a sterile swab or spatula
and sent to the laboratory in a sterile tube or jar as soon as possible.
With children, the napkin containing the stool should be placed in a
clean container and sent to the laboratory at once. In the majority
of cases B. dysenteriae is greatly outnumbered by B. coli and unless
the specimens are fresh, the isolation of dysentery bacilli is difficult
and often impossible. Friedman (125) suggested that the difficulty
in isolating dysentery bacilli from dysenteric stools might possibly
be due to the presence of a bacteriophage in the specimen which killed
or inhibited the organisms before they could be cultivated. Re-
peated stool cultures are usually necessary. A negative culture is of
no value in the exclusion of the possibility of dysenteric infection. In
many mild cases stool cultures are valueless and the agglutination reac-
tions of the patient's serum should always be performed.
Viability of dysentery bacilli
Many of the negative results obtained with typical cases of dysen-
tery are due to the age and dried condition of the stool specimens.
Dysentery bacilli cannot, as a rule, be cultivated after two days so-
journ in feces or eight days in milk unless the mixtures have been
kept on ice (34). Pfuhl (176), however, found that the dysentery
bacillus remained alive for one hundred and one days in a mixture of
feces and moist earth kept at 1° to 5°C. but for only twelve days in
dry soil. Schmidt (450) claimed that B. dysenteriae survived all
winter in moist soil. Kligler (448) found that Flexner dysentery
bacilli survived eight days in feces, seventy days in moist soil and
eight days in the fluid from a septic tank when the reaction was be-
tween pH 7.4 and 7.8 but only three days at pH 8.6 or over, They
could not be cultivated after twenty days in dry soil and ten days in
acid soil (pH 5-5.5). I have alternately frozen and thawed a saline
suspension of Flexner bacilli once daily for thirty-three days and
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 413
found that the organisms remained alive (395). Lauber (368) found
that dysentery bacilli soon died out in stools kept at 37°C, becoming
overgrown by B. proteus; in the ice box, however, specimens remained
positive for B. dysenteriae for as long as ten days. Organisms may
survive in dry feces twelve days, in soiled linen nineteen days, in water,
in butter, and in cheese nine days (57, 176, 322). I have found that
a peptone water culture of Flexner bacilli remained alive after one
hundred and fifty two days at 37°C. The bacilli are killed in half an
hour by one per cent carbolic acid and immediately by 5 per cent
carbolic and 1:2000 solution of corrosive sublimate (39). B. dysen-
teriae is usually killed by being kept at 0°C. for two months and also
by being heated to 60°C. for ten minutes (180, 222). The thermal
death point however may vary with different strains. Direct sun-
light is said to kill this organism in thirty minutes (222). Stools of
dysenteric patients are usually markedly acid in reaction. With
increasing acidity of the stool it becomes more and more difficult to
find dysentery bacilli by bacteriological methods (371, 382). In
Salonika (57) it was found that by mixing equal parts of 3 per cent
sodium hydroxide with the specimen the viability of dysentery bacilli
was increased so that stool cultures were satisfactory twelve hours
after the collection of the specimen.
Technique of stool cultures
A loop full of bloody mucus (unwashed) is streaked over the surface of
one Petri plate of Teague's or Endo's medium and then without flaming
the loop, it is streaked over another plate. This will usually result in
separate discrete colonies on the second plate. I have found Endo's medium
(48) satisfactory but now prefer Teague's medium (177,178, 179) of methy-
lene blue eosin lactose agar, as the differentiation of B. coli and B. dysenteriae
is more definite. English investigators recommend McConkie's Bile Salt
agar (180).
After eighteen hours incubation at 37.5°C. the colorless typhoid-like
colonies are fished into tubes of Russell's double sugar medium (178, 180,
181) (Andrade's (182) indicator). Those cultures that have colorless slants
and red butts without gas after eighteen hours incubation are subcultured
into gelatin and seven Durham fermentation tubes of peptone water con-
taining respectively 1 per cent of lactose, dextrose, mannite, maltose,
saccharose, dulcite and rhamnose (brom-cresol purple indicator) (183).
The first three carbohydrates are the most essential.
i
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414 WILBURT C. DAVISON
The growth from the original culture (Russell's slant) is then emulsified
in saline and agglutinated macroscopically at 55°C. for five hours with
polyvalent dysentery, Flexner and Shiga type sera. Six to eight hour pep-
> tone water cultures are examined for motility and seven-day peptone
water cultures are tested for indol by ether extraction and Ehrlich's
reagent (48, 184).
The fermentation cultures are read at intervals for over fourteen days
and the gelatin cultures are left at room temperature for twenty-eight
days.
The necessity for prolonged incubation of fermentation cultures is shown
by the fact that 12 per cent of the cultures from children in our series (48)
and 29 per cent of those from the series in adults (68) were late lactose
fermenters, that is, formed colorless colonies on Endo's or Teague's medium
but fermented lactose after the second day of incubation. All fermenta-
tions were practically complete by the 14th day and only very slight changes
occurred during the remaining time of the twenty-one day incubation. It
would seem that fourteen days incubation for fermentation cultures is
sufficient.
Subsequent agglutination work to confirm the original tests or to deter-
mine the V, W, X, Y or Z type if the culture ferments mannite is done
(macroscopically) with eighteen-hour peptone water cultures.
Agglutination reactions of the patient's serum
Inasmuch as the isolation of dysentery bacilli from the stools
requires considerable time as well as training, the agglutination reac-
tions, which are positive after the sixth to the tenth day of the disease,
are frequently used in the diagnosis of dysentery. It is often stated
that the patient's serum reactions in dysentery are uncertain (46, 70,
185, 186, 187, 222, 356, 385). It is just as commonly claimed that
they are of the greatest value (48, 69, 71, 72, 73, 150, 154, 184, 188,
189, 368, 409) and that the serum of normal individuals does not agglu-
tinate B. dysenteriae (190).
The confusion in regard to the reliability of the diagnosis of bacillaiy
dysentery by agglutination is largely due to two things; first that
there are five or more types of the Flexner bacillus and if any of these
types are omitted in agglutination tests, the sera of some dysentery
patients which may agglutinate one of these omitted types, may be
reported as negative (48, 57); and second because living cultures are
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 415
frequently employed as antigens (191, 222). Living cultures vary
from time to time in their agglutinability (114, 115, 192, 193, 194,
195, 431). Therefore agglutination tests made with dysentery cul-
tures killed by formol (standard agglutinable cultures) whose agglu-
tinability does not vary, are much more reliable. It is of the
greatest importance that only those dysentery cultures whose sensi-
tiveness to agglutination has been thoroughly tested should be selected
for the preparation of "standard agglutinable cultures." Many
strains even of the same serological type as the organism producing
the patient's disease are not agglutinated by the patient's serum. On
the other hand, dysentery cultures are frequently encountered which
are agglutinated to comparatively high titres by the sera of normal
individuals. Some investigators (196) have, it is true, reported
unsatisfactory results with Dreyer's formolized cultures, but the
majority find the method extremely useful. Employing the technique
outlined below, I have found that agglutinins in a patient's serum in
a dilution of 1 to 30 or over, are usually diagnostic of previous or pres-
ent dysentery infection. In all patients in our series (48) from whom
an agglutinable B. dysenteriae was recovered and whose sera were
tested, specific agglutinins were found. Very rarely the sera of ty-
phoid patients or of normal children and adults with no history of
dysenteric infection will give positive dysentery agglutination reactions.
There is evidence to prove that non-specific agglutinins may be pres-
ent in the sera of typhoid patients (197, 198, 199). Occasionally
the serum of patients with dysentery may agglutinate B. paraty-
phosusB (379).
Agglutinins for B. dysenteriae are usually demonstrable after the
sixth day of the disease, although they are occasionally reported earlier
(38, 200). The serum of one child was positive on the second day
(48), the titre rising on the fourth (198) and ninth days. The maxi-
mum titre is probably reached on the seventeenth to twenty-first day as
it is in typhoid fever (57). The titre of a dysentery patient's serum
for dysentery bacilli is practically always lower than that of a typhoid
patient's serum iox typhoid bacilli, probably because dysentery bacilli
are usually less agglutinable than typhoid bacilli. A dilution of 1 to
250 especially in Shiga infections is the usual limit at the height of
the disease (seventeenth to twenty-first day) but in a few cases of
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416 WILBUM C. DAVISON
Flexner infection I have found agglutination for the Flexner bacillus
as high as 1 to 1000. However, these titres depend upon the agglu-
tinability of the cultures used in the test. Agglutinins may persist
longer than four months. In the sera of four children tested after
six months they were still present (48, 57, 69). Agglutination for
both Shiga and Flexner groups is occasionally found in single infections
with either one of these bacilli (55,. 57, 69, 201). I found this in two
of our cases (48) . True double infections with both Flexne* and Shiga
types have, of course, been reported (57, 69, 138, 140, 202).
Agglutination technique
I have obtained consistent results with Dreyer's technique (48,194,203)
but inasmuch as I have used eleven different antigens I have adopted the
following modification of this method for all routine agglutination tests
in diarrhoea! diseases:
One cubic centimeter of the patient's serum is diluted ten times. 0.5
cc. (or 10 drops) of this diluted serum is placed in each of 11 agglutination
tubes, 0.5 cc. (or 10 drops) of a formolized standard agglutinable culture
of each of the following organisms is each placed in one of these 11 tubes:
B. typhosus, B. paratyphosus A, B. paratyphosus B, B. shigae, B. dysenteriae
(Flexner), English types V, W, X, Y, and Z, B. dysenteriae (Kruse E)
or (B. dispar) and B. dysenteriae (Schmitz) (or B. ambiguus). In localities
where other types of pathogenic intestinal organisms, such as atypical
paratyphoid bacilli (69, 204, 205, 206, 207) (Salonika, Bagdad and India)
or B. Gaertner (208) are common, they should be added to the series.
These tubes are incubated in a water bath at 55°C. for four and one-half
hours. If agglutination is positive for any of these 1 1 antigens at this 1 to 20
dilution, tests are set up according to Dreyer's directions, using only those
standard agglutinable cultures for which there have been agglutinins in
the preliminary test.
Blood cultures
Blood cultures, as a general rule, are of but little assistance in cases
of dysentery for only in rare instances do dysentery bacilli enter the
blood stream. Tenbroek (209), Schloss (210) and others (188, 211,
212, 218) have reported occasional positive antemortem blood cultures
for B. dysenteriae. Caussade and Marbais (213) found the Shiga
bacillus in the blood stream of one patient although stool cultures
were negative.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 417
Dysentery bacilli have been found in a few instances (37, 57, 140,
188, 214, 215) in the heart's blood, mesenteric glands and spleen
at autopsy but such findings are the exception (138). Recently posi-
tive blood cultures of B. fecalis alkaligenes (216) have been reported
in a few cases of bloody diarrhea in children, as well as in an adult
with a typhoid like disease (432).
Urine cultures
In one child with bacillary dysentery we found (217) typical B.
dysenteriae (Flexner) in the catheterized urine. Fraenkel (218) cul-
tured the urine of 39 patients with mild bacillary dysentery and found
B. dysenteriae (Flexner) in three. In the urine of another patient
B. dysenteriae and B. typhosus were associated. Sonne (123) re-
ported the presence of Flexner bacilli in the urine of a typhoid con-
valescent and others have occasionally found bacilli morphologically
and culturally indistinguishable from B. dysenteriae in the urine of
patients with pyelocystitis (219) and other diseases (218, 220) but
proof that all of these urinary organisms were true dysentery bacilli
was not brought forward.
The infrequence of positive cultures of B. dysenteriae in the blood
and urine renders the taking of blood and urine cultures of little or
no diagnostic assistance.
Bacteriological diagnosis {summary)
The highest percentage of positive cultures of dysentery bacilli is
obtained from culturing the postmortem scrapings of the mucous
membranes of the ulcerated intestines of patients, both adults and
children, dying of dysentery. Frequently over 80 per cent of these
cultures are positive. The next highest percentage is obtained by
culturing the bloody mucus of the feces of children with dysentery;
from 50 to 60 per cent of these cultures are positive if cultures are
made from several specimens during the height of the disease (from
the fourth to fourteenth day). It has been reported (221, 405, 406)
that the diagnosis of dysentery is rendered easier by the examination
of the rectal mucosa and by obtaining cultures directly from the in-
testinal ulcers of adults, infants and young children by means of a
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418 WILBURT C. DAVISON
proctoscope. However, perforation of the intestine and death from
peritonitis has occurred from the use of a sigmoidoscope (446). The
lowest percentage of positive stool cultures is obtained in adults
(56, 69, 71); 25 to 40 per cent of the cultures of the feces of adults
with dysentery may be positive if cultures are repeated during the
height of the disease (up to the fourth week).
These percentages of positive cultures of dysentery bacilli are
usually only obtained under ideal conditions, i.e., fresh fecal speci-
mens that have not been allowed to become dry and an experienced
bacteriologist with good media. Frequently the percentage of posi-
tive stool cultures is not sufficiently high to be of great assistance in
clinical diagnoses, for even repeatedly negative stool cultures do not
rule out the presence of dysentery. Moreover, two to three days are
usually required for stool cultures. However, after the sixth to the
tenth day of the disease a method is available that is more rapid
and that is positive in practically all cases of dysentery and negative
in practically all non-dysenteric cases. The agglutination reactions
of the patient's serum fulfill all of these conditions after the sixth
to the tenth day of the disease in adults and are frequently positive
in low dilutions on the fourth day of the disease in children. As I
have pointed out, this method is reliable with standardized technique
and should be used as an aid to the diagnosis of all diarrheal disease.
If the agglutination reaction of the patient's serum is positive for any
of the dysentery bacilli, a diagnosis of past or present dysentery (or
of prophylactic vaccination) can be made. The exceptions to this
are infrequent. If the agglutination reaction is repeated quantitat-
ively after an interval of four days and a marked increase or decrease
in the titre of the serum is present, a diagnosis of active dysentery can
be made as the titre of the serum of patients who have had dysen-
tery some time previously or who have received prophylactic inocu-
lations of vaccine soon reaches a constant level and tests made at
short intervals will show no change. If the agglutination reaction
of the patient's serum is negative for all of the dysentery bacilli, the
disease can usually be ruled out but the test should be repeated two
or three days later.
For a bacteriological diagnosis before the sixth day of the disease
stool cultures are necessary. If negative, they should be repeated.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 419
BACILLUS (D'HERELLE'S PHENOMENON, BACTERIOPHAGE,
BACTERIOLYTIC AGENT, BACTERIOLYSANT, ETC.)
Under these names, which have been used interchangeably, an
extensive literature has accumulated in regard to a "substance"
contained in filtrates of stool cultures and also obtained from other
sources which when added to young cultures kills and dissolves dy-
sentery bacilli and other organisms. It has usually been assumed
that Twort (126) was the first to describe this phenomenon though
Hankin (426) in 1896 demonstrated that the water of the Ganges and
Jumna rivers in India was bactericidal for bacteria in general and
for the cholera vibrio in particular. Inasmuch as heating the water to
115°C. for a half hour (a temperature which destroys bacteriophagic
activity) did not totally destroy its bactericidal activity, Hankin
was probably not dealing with a bacteriophage. Nicolle (425) in 1907
reported that cultures or filtrates of B. subtilis would dissolve pneumo-
cocci, staphylococci, B. typhosus, B. coli, V. cholerae and B. shigae.
Though not recognized as such, this is perhaps the first mention of
"bacteriophagy."
Source
There have been at least five methods described by which a bacterio-
phage may be obtained.
1. Twort (126) in 1915 noted in a culture of staphylococci obtained
while plating out glycerinated calf vaccine, transparent areas in which
no cocci grew or if they had grown, they had become degenerated. If
one of these transparent areas was touched with a sterile platinum
loop and the loop was then drawn (without flaming) across the sur-
face of a twenty-four hour agar culture of staphylococci, a streak
marking the track of the loop became clear and transparent within
a few hours. He then passed the material from these transparent
areas through a Berkfeld filter and found that it would dissolve and
kill most of the organisms in fresh staphylococcus agar cultures even
when diluted one to a million. This bacteriolytic property could be
passed on to numerous generations by adding a filtrate to successive
fresh staphylococcus cultures and then refiltering. Gratia (376) has
recently confirmed Twort's work.
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420 WILBUM C. DAVISON
2. D*Herelle (125) in 1917 inoculated two to three drops (or a piece
the size of a pea) of a stool from a convalescent dysentery patient in
20 cc. of broth and filtered this culture through a Chamberland No. 12
filter. A trace of this filtrate would dissolve and kill broth or agar
cultures of B. shigae. A loopful of the filtrate obtained by filtering
this dissolved culture through a Chamberland filter would again
dissolve a fresh culture of B. shigae. By similar methods bacteriolytic
filtrates active against various strains of organisms have been ob-
tained from the urine of a convalescent dysentery patient (125), from
the urine of patients with pyelonephritis (125), from the stools of
patients suffering from dysentery (125, 391, 392, 395, 397), typhoid
and paratyphoid fever (125, 392, 394), gastric carcinoma (392),
rheumatic fever (392), pthisis (392), peritonitis (392, 397), and diar-
rhea (126, 395), from the stools of cases of avian typhoid in chickens
(125), of hemorrhagic septicemia in cattle (125), of plague in rats (125),
of flacherie in silk worms (125), of distemper in dogs (126) from the
blood of white rats fed on typhi murium (125), in Paris city water
(391), in water from the Seine (391), in earth (391) as well as from the
stools of normal adults (125, 391), children (395) and animals (125,
391).
3. Bordet and Ciuca (233) injected a culture of B. coli intraperi-
toneally into a guinea pig. The day after the third injection they
found that a small quantity of the resulting peritoneal exudate as
well as the culture of B. coli isolated from this exudate would dissolve
an eighteen-hour culture of the strain of B. coli that had been used for
these inoculations. This lysis was not complete and a few colonies
could be cultivated. If these surviving organisms were inoculated
into another eighteen hour colon culture, lysis would again result.
This bacteriolytic action could in this way be repeated indefinitely.
The bacilli exposed to the lytic substance acquired the ability to
transfer the lytic property to subsequent generations. Wollstein (397)
repeated this work using a strain of the Shiga bacillus instead of B.
coli and obtained a bacteriophage active against dysentery and other
bacilli.
4. Kuttner (394) found that a filtered glycerine extract of the small
intestine of a guinea pig and a saline extract of a guinea pig's liver were
bacteriolytic for typhoid bacilli. This lytic principle could be trans-
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 421
mitted by passage through successive typhoid cultures. Glycerine
extracts of the large intestine and of muscle tissue were not
bacteriolytic.
5. I found that if one to sixty day old broth or peptone water cul-
tures of recently isolated or old laboratory strains of B. dysenteriae
(Shiga) or (Flexner) were filtered (395), the filtrate in many instances
was slightly bacteriolytic against Shiga and Flexner bacilli. Bacterio-
lytic substances have been reported by others in cultures of B. dys-
enteriae (126, 397, 438) and D. mucoides (423).
Non-specificity of bacteriolysants
Originally it was thought that the lytic action of a filtrate was specific
(125, 126, 233) and that only the organism producing it or causing
the patient's infection would be attacked. Later it was reported
(125, 429, 376) that no two bacteriophages were alike, some were
active against several species of bacteria, others only against one.
At present it is believed that all bacteriophages can be made practi-
cally omniverous by adding them to cultures of other bacilli, incuba-
ting and then filtering the preparation. This may have to be repeated
several times before the filtrates will lyse the organism with which it is
being cultivated. In this way "bacteriophagy" has been extended to
several stains of the following groups, Shiga, Flexner, typhoid, para-
typhoid A and B, colon, proteus, hog cholera, etc. (125, 233, 376, 395,
397). Other organisms such as Friedlander's bacillus, B. avisepticus,
B. Morgan, etc. have been tested with negative results (397).
Variations in the titre of bacteriophage activity
Some filtrates may cause lysis when diluted over a million times
while others are only active after passage through several successive
cultures. The potency of the lytic principle of subsequent generations
of filtrates may vary, however, in some being greater than that of the
original filtrate (125) in others less (395) and in others the same (394).
The lytic power of filtrates which have become contaminated by air
or stool bacilli and have been refiltered are sometimes greater and
sometimes less than that of the original uncontaminated filtrate (395).
Filtrates obtained from the stools of a dysentery patient were some-
uwDicnrm, vol. i, no. 3
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422 wilbuxt c. davison
times more and sometimes less active against the dysentery bacillus
isolated from that patient than against other strains. The bacterio-
lytic power of a filtrate may vary for different subcultures of the same
strain, for cultures isolated from the same patient at different stages of
the same disease (125, 395) as well as for subcultures of different colo-
nies fished from the same stool culture (395). The greater the con-
centration of the bacteriophage, the more rapid and complete is the
bacteriolysis (125, 395), i.e., a filtrate which dissolved a culture in
three hours when diluted 1 : 10 usually required 12 hours when diluted
1 : 100 (394). There are evidently two steps in the d'Herelle phenom-
enon, first, the organisms are killed and second, they are dissolved.
If there were more than 500 million bacteria per cc. only the first step
occurred (125). This may possibly be due to the fact that the bac-
teriolytic principle is adsorbed by the more concentrated bacteria.
I found (395) that broth cultures of Flexner bacilli which contained
100 million bacilli or more per cubic centimeter at the commencement
of the experiment contained less than 30 viable organisms per cubic
centimeter after twenty-four hours contact with an anti-Flexner
bacteriolysant. The number of bacteria killed was usually propor-
tionate to the amount of bacteriolysis. Th$re is evidently an optimum
concentration of bacteria for if the numbers present were very small,
they were destroyed more slowly than when in large numbers (438).
Factors influencing bacteriophagic activity
Temperature. The lytic power of a filtrate is destroyed by being
heated to 75°C. for a half hour (127, 394). It is still active after one
hour at less.than 0°C, four years at 37°C. (127), one hour at 64°C to
65°C, or a half hour at 70°C. (127, 394), though its power may oc-
casionally be diminished by these two latter temperatures (395).
The rate of lysis was twice as rapid in a culture and bacteriophage
incubated at 41° to 42°C. than at 37°C. (394) : at 15° to 16°C. it pro-
ceeded very slowly (125) and did not occur at all when the incubation
temperature was from 45° to 50°C. (394).
Reaction and oxygen supply of the media. Gratia (376) showed that
the inhibition by the lytic agent on the growth of B. coli was slight at
pH 6.8, 7.0 and 7.4 but much more pronounced at pH 8.0 and 8.5.
Lysis was more complete at pH 8 and 8.2 than at pH 6 to 7.7 (395).
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 423
A bacteriophage was active in media with reactions from pH 2.5 to
8.4 but lost its power when the hydrogen ion concentration was above
pH 2.5 and below 8.4 (424). Wollstein (397) reported that the lytic
action proceeded as rapidly and as completely in the absence of oxy-
gen as in its presence.
Chemicals. A substance having bacteriolytic power has been pre-
cipitated from filtrates by the addition of acetone (127), alcohol (127)
ammonium sulphate and tricalcium phosphate (439). Kabeshima
(127) reported that the lytic agent was soluble in ether and that the
addition of 1 per cent sodium fluoride would not destroy the lytic power
of a filtrate but both statements have been denied (125, 128). Bablet
(128) claimed that glycerine and chloroform inhibited lytic activity.
Eliava and Pozerski stated that twenty-four hours' contact with 2.5
per cent phenol or 2.5 per cent sodium fluoride did not affect a bac-
teriophage but that 0.75 per cent quinine chlorhydrate reduced the
lytic activity of a filtrate and that 1.0 per cent destroyed it. De
Poorter and Maisin (439) reported that the lytic agent was destroyed
by phenol and certain metallic salts and that it was insoluble in animal
and plant fats and lipoids. Lytic activity was destroyed by the addi-
tion of N/5 sodium hydroxide (395). Four per cent collodium mem-
branes were impermeable to bacteriophages (422).
Other factors. Young living cultures are essential for the action of
a bacteriophage (125). Two to eight hour cultures are the most
sensitive (394, 395, 397). Dead cultures are unaffected (125, 395).
Although young organisms suspended in bouillon peptone water or
serum are lysed, saline suspensions are not affected (233, 391,392,
394) unless the reaction is near the optimum (395). A bacteriolytic
filtrate loses its power after three or four passages in sterile broth
(125, 126, 392) or peptone water (395).
Separation of cultures into "resistant" and "sensitive" types by the
action of bacteriophages
When a lytic strain of organisms or a culture that had been attacked
by a bacteriophage was plated on agar, two types of colonies appeared
(125, 233, 376, 394, 395, 397, 424, 428). These two types were also
noted in a culture of a stool of an infant with dysentery (397), as
well as in platings of peptone water cultures of normal Flexner bacilli
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424 WILBURT C. DAVISON
(395). One was regular and round, resembling a typical colony of
the organism. Subcultures of these always gave rise to round colonies.
They were not readily dissolved by the lytic agent and were desig-
nated the "R" or resistant type. The other colonies were irregular
in outline and had a "moth eaten" appearance. They were readily
lysed by the lytic culture and were spoken of as the "S" or sensitive
type. Subcultures of these gave rise to both regular and irregular
colonies.
The resistant strains of Shiga bacilli were composed of regular,
equally sized and evenly staining bacilli with some larger forms but
few if any coccoid or swollen round forms. Threads were seen in
older cultures of the "R" type (397). They grew slowly (376).
Broth cultures were not uniformly cloudy and the bacilli rapidly
sedimented to the bottom of the tube (424). Resistant organisms
were practically inagglutinable and very virulent (125, 233, 276, 397).
The "R" type of B. coli was extremely motile, decolorized neutral
red and was only slightly phagocy table (376). D'Herelle (125)
stated that resistant forms might become coccoid and acquire capsules.
Resistant forms may lose their resistance after subculture (125, 428).
The sensitive strains of Shiga bacilli were composed of short bacilli
and many coccoid and round swollen forms (397). The "S" type of
B. coli grew rapidly in artificial media, was non-motile and did not
decolorize neutral red (376) . The filtrates of sensitive cultures usually
had bacteriolytic power (395, 397) while only a few of those of resistant
organisms were active (428). These lysogenic resistant strains might
afterwards lose their lysogenic power (428). Sensitive bacilli might
gradually die out after repeated subcultures (397) though Bordet and
Cuica (233) found that lysogenic colon bacilli retained their lytic
power even after 150 transfers.
Gratia (376) isolated eleven types from the original Bordet strain
of B. coli that differed in resistance, motility, mucoid growth, ability
to yield mucoid growth, fluorescence and sero-agglutination. All of
these types produced indol and fermented carbohyrates except
saccharose.
There is a striking similarity between the various types of organisms
that may be obtained from a culture as a result of the action of a
bacteriophage and those that have been described as occurring spon-
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BACILLAJtY DYSENTERY IN ADULTS AND CHILDREN 425
taneously or as the result of changes in environment (vide supra,
Mutation of dysentery bacilli). Inasmuch as strains closely resemb-
ling resistant and sensitive types may be obtained in platings of aged
cultures (376, 395) and in cultures of B. coli of different motilities
(376), it is probable that this separation of a culture into various types
is a result of several independent factors rather than of the action of a
bacteriophage.
Results of inoculation of bacteriophages in animals
The injections of bacteriolytic filtrates into rabbits (125, 127, 233,
395, 428, 429) and into the larvae of the beeswax moth (129) have
demonstrated that bacteriophages were non-pathogenic and that
animals and larvae became immunized to the organisms against which
the bacteriophage was active (125, 127, 233, 395). After injection
into an animal, the bacteriophage persisted in the intestine for several
days (454). The rabbit sera would agglutinate these organisms
(395, 397) and were also antilytic, i.e. would precipitate a lytic filtrate
(233, 395, 453) and when added to a bacterial suspension and a bac-
teriophage (even bacteriophages other than the one used in the pro-
duction of the antilytic serum (429)) would prevent lysis for at least
forty-eight hours (125, 233, 438). The sera of animals immunized
with lysogenic cultures were also antilytic, though sera produced
by the injection of normal organisms had little (438) or no such power
(233). Treatment of lysogenic colon cultures (233) and of resistant
forms (428) with antilytic sera caused the former to become resistant
and to lose their lytic power and the latter to lose their resistance.
However, the colon bacilli that had lost their lytic activity became
lysogenic again after twenty-one transfers on culture media (233).
An antilytic serum apparently had an "anti-immunizing" effect for
a mouse injected with one-tenth of a lethal dose of Shiga toxin plus
0.2 cc. of an antilytic serum died in thirty hours. Control mice
inoculated with full lethal doses died in four days (125).
It would seem possible that the properties acquired by the sera of
these inoculated animals are not due to the antigenic effect of the
bacteriophage per se but are a response to the injection of the proteins
of the dissolved bacteria although this has been denied (422). The
anti-lytic power of the serum is probably a response to the injection
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426 WII3TOT C. DAVISON
of the bacteriolytic ferment which the filtrate contains and is perhaps
comparable to the anti-tryptic power of serum of animals inoculated
with trypsin. The immunization of rabbits with anti-Shiga bacterio-
phages (125, 127) is perhaps due to the formation of dysentery
antitoxin, for a bacteriophage obtained by the lysis of Shiga bacilli
contains Shiga toxin for several days (127).
Bacteriolysanis as therapeutic agents
It was obvious to many observers (125, 395, 397) that this filterable
"substance," which would kill and dissolve dysentery and other or-
ganisms in vitro, was non-pathogenic and would immunize animals,
should be tried therapeutically. D'Herelle (125) reported that in
seven cases of severe dysentery in children, three and one-half to
twelve years of age the ingestion of 2 cc. of an anti-dysenteric bacterio-
phage was followed in from twenty-four to thirty-six hours by the
disappearance of blood and bacilli from the stools. Friedmann (125)
was unable to. confirm this. D'Herelle also reported striking thera-
peutic and prophylactic benefit from the ingestion and injection of
0.25 cc. to 1 cc. of appropriate bacteriophages in epidemics of avian
typhoid in chickens, plague in rats and hemorrhagic septicemia in
cattle. He stated that the intravenous injection of 500 cc. of blood
from one of these inoculated cattle would protect another animal
from a lethal dose of living organisms. It is difficult to reconcile this
result with his earlier work on the "anti-immunizing" effect of the
serum of a rabbit inoculated with an anti-Shiga bacteriophage.
I have treated twelve children two months to four years of age
suffering from Flexner dysentery with bacteriolysants which were
tested and found to be active against the organisms causing the
patients' infections (395). In this small series, even though I ad-
ministered amount of 5 to 1381 cc. by rectum, by mouth or by nasal
tube into the stomach, I was unable to observe the slightest benefit
or harm from bacteriophagic therapy. It would seem probable that
these large amounts in young children would be as beneficial as the
ingestion of 2 cc. which d'Herelle found so efficacious in older chil-
dren. Larger series alone will demonstrate the practical value of
bacteriolysants.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 427
As a matter of fact although it has been frequently proven to be
harmless in animals with various infections it is theoretically difficult
to explain why the administration of an anti-dysentery bacteriophage
to dysentery patients is not harmful. The intestinal lesions of dysen-
tery are due to endotoxin (119) and it would seem probable that if the
dysentery bacilli in the intestinal tract were lysed as a result of the
administration of a bacteriophage, a large amount of endotoxin would
be liberated.
Theories in regard to the nature of bacteriophages
There are at least five hypotheses advanced to explain the nature
and mode of action of bacteriophages;
1. D'Herelle (125), inasmuch as he was able to preserve his bac-
teriophages for over a thousand successive transfers from one Shiga
culture to another with no diminution of the strength of the lytic
agent (in fact the lytic power increased) believed it must be a living
culture and not a ferment. This culture he called the "microbe fil-
trant bacteriophage" or "bacteriophagum intestinale." He reported
that the clear bare areas, which were noted when a bacterial suspen-
sion to which a bacteriophage had been added, was plated out on agar,
were proportional to the amount of bacteriolytic filtrate added to the
preparation and not to the number of bacilli in the suspension, and
that therefore these areas represented colonies of the bacteriophage
and did not result from the lysis of sensitive organisms as others
(233, 376, 394) have maintained. D'Herelle (125) summarized his
views as follows:
The bacteriophage is an ultra microscopic organism, which is very widely
disseminated in nature. It only multiplies in contact with living bacteria.
It penetrates into the interior of an organism and forms a colony of 15 to
25 elements in the space of an hour and a half. The organism then bursts,
liberating the young ultramicrobes. These utilize for their development
the bacteria which they dissolve with the aid of the lytic diastase which
they secrete. There is only one species of bacteriophage and this can
acquire activity against any organism. Bacteria on the other hand can
also acquire resistance to the bacteriophage. Infection and death or im-
munity and recovery depend upon whether the organism or the bacterio-
phage triumphs in this battle. The products of the bacteria which have
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428 WILBURT C. DAVISON
been dissolved by the bacteriophage also play an active rile in stimulating
the formation of antibodies. The outcome of an epidemic also depends
upon these two forces for the active bacteriophage, the agent of immunity,
as well as the bacteria causing the epidemic can spread from one individual
to another.
D'Herelle (125) suggested that wholesale protection of the popu-
lation might be accomplished by introducing a quantity of the bac-
teriophage into the central supply of drinking water.
2. Kabeshima (127) suggested that the phenomenon depended upon
the interaction of a catalyst and a proferment, the former being de-
rived from the host while the latter was present in or produced by
the bacterium. He believed that this catalyst was produced by
some intestinal gland or by the intestinal leukocytes of dysenteric or
typhoid patients as a result of an invasion of pathogenic bacteria, i.e.,
as a protective measure against infection. This catalyst caused
bacteria to produce autolytic ferments. These ferments then acted
as catalysts to other bacteria and so on from generation to generation.
The fact that this substance would withstand being heated to 70°C,
that a very minute quantity of filtrate would dissolve a large number
of bacilli in a few hours, that it could be kept at 37°C. for four years
without undergoing deterioration, that the bacteriolytic substance
was not affected by chemicals which destroy most forms of bacteria,
suggested that the lytic principle was a ferment and not a living
organism (127). D'Herelle (125), however, protested that spore-
bearing and other bacteria could satisfy all of the chemical and ther-
mal conditions which Kabeshima had advanced against the hypothesis
that a bacteriophage was a living microbe.
3. Bordet and Ciuca (233) suggested that the ability to produce the
lytic substances was acquired by bacteria as a result of contact with
some external stimulus such as the leukocytic exudate of the peri-
toneum of a guinea pig. This external influence possibly represented
a defense mechanism on the part of the animal. These bacteria
were then able to transmit to their descendants the apitude to form
this lytic substance or this apitutude for autolysis.
4. Salimbeni (393) suggested that the d'Herelle phenomenon
was probably due to some stage in the history of a pleomorphic or-
ganism. He examined in a van Tieghan chamber the changes induced
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BACILLAItY DYSENTERY IN ADULTS AND CHILDREN 429
in a culture of B. shigae by a bacteriophage. He found in addition
to the dysentery bacilli a number of small, round or slightly elongated
bodies. These developed into typical myxamoebae which ingested
and digested the Shiga bacilli. He suggested the name Myxomyces
shigophagus for this myxamoeba. Dumas (391), Pettit (393) and
Wollman (422) have reported the presence of myxamoebae in their
preparations but d'Herelle (125) could find none in his. Whether
all instances of bacteriophagy are due to Myxomyces shigophagus
or whether these observers were dealing with preparations contami-
nated by myxamoebae awaits further study.
5. Kuttner (394) proceeded on the theory that the so-called phenom-
enon of d'Herelle might be due either to an activation of the natural
autolysin present in all bacteria, or to the removal of an autolysin
inhibiting substance. Once this natural autolysis was liberated,
it could in turn liberate an active autolysin from the next generation
of bacteria and so on indefinitely. The fact that the autolysin of
old or dead cultures cannot be thus reactivated would seem to invali-
date this theory.
Discussion
Although much of the evidence is contradictory and unconfirmed,
so that it is impossible to form a definite conclusion in regard to the
nature of this lytic agent, yet at present the most probable hypothesis
is that the lytic agent is an enzyme. The majority of the data
with the marked exception of Salimbeni's (393) observation can best
be explained on the basis that the lytic principle is an enzyme.
Temperature, chemicals, the reaction of the media and the concen-
tration of bacteriophage and bacteria all have an influence on bac-
teriophage processes which is similar to that which they have been
demonstrated to have on enzymatic phenomena. The optimum reac-
tion for bacteriophagy corresponds very closely to that of the enzyme
trypsin. The fact that cultures of lytic organisms as well as bacterioly-
tic filtrates will not liquify gelatin, however, suggests that the bac-
teriolytic principle is not trypsin (395). The addition of trypsin to a
dysentery culture will not cause the culture to become lytic. It is
possible that the bacteriolytic enzyme may be similar to erepsin for
the extracts of intestine and liver that Kuttner (394) found to be
lytic probably contained erepsin.
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430 WILBURT C. DAVISON
It is probable that this bacteriolytic enzyme is both extracellular
and intracellular. If the growth of irregular sensitive colonies on an
agar plate is suspended in saline and the suspension centrifuged at
high speed and the supernatant fluid passed through a Mandler filter,
the filtrate is lytic. If the sediment of organisms is resuspended
in saline and this suspension ground in a rotary agate mortar and
then filtered, this filtrate is equally lytic (395). The fact that living
bacteria are necessary for the transmission of the lytic agent suggests
that the lytic agent is not the result of the disintegration of dying or
dead cells, but represents either the metabolic excreta of bacteria
or the synthetic product of the medium elaborated by the action of
the bacteria.
If it is granted that the bacteriophage principle is enzymatic there
are at least two possibilities as to its origin. First, as a result of the
stimulus of intestinal secretions, tissue extracts, leukocytes, etc.,
the bacteria acquire the ability to produce bacteriolytic enzymes and
this property becomes an hereditary one. This hypothesis requires
the assumption that entirely new characteristics can arise as the result
of an external stimulus and though perhaps possible is not probable.
Second, certain of the bacteria in any culture already have this
ability to produce bacteriolytic eryzmes even though it is only slightly
developed and that as a result of the action of intestinal secretions,
tissue extracts, leukocytes etc. the multiplication of these lytic or
sensitive organisms is favored. Such an hypothesis would also ex-
plain the facts that filtrates of normal stock cultures were slightly
lytic and that irregular colonies were occasionally f ound in subcultures
of normal strains. Bail's (438) demonstration that broth in which
normal Shiga bacilli were repeatedly grown and then centrifuged out,
was bacteriophage strengthens this hypothesis. The small amount
of lytic substance produced by each growth of organisms remained
in the broth and after several reinoculations it became sufficiently
concentrated to be readily demonstrable.
Furthermore the explanation is comparable to other bacteriologic
phenomena. For instance Teague and Morishima (440) demon-
strated that cultures of so-called non-xylose fermenting typhoid bacilli
contained a certain number of organisms which fermented xylose
slowly and that by suitable cultivation, rapidly fermenting subcultures
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BAOLLARY DYSENTERY IN ADULTS AND CHILDREN 431
could be obtained. Another comparable example is furnished by
the increase in virulence of cultures which is produced by animal
passage. Growth within the animal probably favors the multiplica-
tion of virulent organisms of the culture at the expense of the non-
virulent. Gratia (376) has demonstrated that 11 different types
could be isolated from the original Bordet strain of B. coli, so that
the second hypothesis appears plausible.
The nature of the external influence contained in intestinal secre-
tions, tissue extracts, leukocytes, etc., which favors the development
of organisms is unknown. The one factor that is common to all of
these stimuli is that they apparently contain a bacteriolytic enzyme
similar to, if not identical with that of the lytic organisms.
It would seem that inasmuch as bacteriolytic filtrates may be
obtained from so many sources having no relation to the type of
organism attacked by the lytic principle that d'Herelle's phenomenon
is not an immunological reaction. The fact that Gengou (427)
demonstrated that an extract of the leukocytes of normal animals
was non-specifically bacteriolytic would seem to invalidate the sug-
gestion of Bordet and Ciuca (233) that the bacteriolytic power of
the peritoneal exudate of guinea pigs inoculated with B. coli was evi-
dence of a protective mechanism against bacterial invasion.
Conclusion
According to the data available at present, d'Herelle's phenomenon
probably depends upon a bacteriolytic enzyme produced by bacteria.
The amount of this enzyme produced by a culture can be increased
by external influences such as intestinal secretions, tissue extracts,
leukocytes, etc. The action of these external influences is probably
to favor the development of lysogenic organisms at the expense of the
non-lysogenic. This enzyme not only dissolves organisms but also
favors the multiplication of bacteria which produce this enzyme. In
this way the bacteriolytic principle is carried from generation to
generation. It is highly improbable that this phenomenon represents
a defense mechanism on the part of an animal against bacterial
invasion.
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432 WILBUHT C. DAVISON
IV. EXPERIMENTAL DYSENTERY
Virchow (223) and Rokitansky (224) before the discovery of B.
dysenteriae and its toxins attempted to explain the localization of
the lesions of dysentery. The tendency of the membranous lesions
of the intestine to confine themselves to the caecum and colon led
Virchow (223) to assume that these lesions resulted from the action
of products of decomposition upon the intestinal mucosa which was
already the seat of catarrhal inflammation, and that the projecting
points, the cecum, rectum and flexures of the colon were the most
affected because the faeces remained in contact with these parts the
longest. It is still believed by many clinicians that dysentery, es-
pecially in children, is preceded by a non-specific intestinal catarrh.
Rokitansky (224) compared the action of dysentery to that of caustic
acids and suggested that the necrosis was due to a direct chemical
change in the tissues caused by an action starting from the surface.
Zoller and Clark (416) suggested that the enormous amounts of formic
acid produced by Shiga and Flexner dysentery bacilli might play a
significant part in causing the digestive disturbances and toxic symp-
toms in dysentery. Rokitansky believed that dysentery began as a
very superficial inflammation of the mucous mucosa, a simple catarrh,
although the typical dysenteric lesions were not encountered until
the membranous condition had appeared.
After the discovery of B. dysenteriae and its toxins many experi-
ments were performed on animals to explain the mechanism of in-
fection in bacillary dysentery and to discover the reason for the lo-
calization of the intestinal and nervous lesions. Practically all of
these attempts have been made with either the cultures or the toxins
of B. dysenteriae (Shiga). The results, however, are probably equally
applicable to infections with B. dysenteriae (Flexner) if the nerve
paralyses produced by the Shiga exotoxin (neurotoxin) be disregarded
for nerve lesions caused by Flexner infection are rare (442).
Susceptible animals
The rabbit has been the animal generally used for these experi-
ments. If cultures of the Shiga bacillus or its toxins (119) are in-
jected subcutaneously, intravenously or intraperitoneally into a
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 433
rabbit, a fatal diarrhea usually develops. This is in striking con-
trast to the absence of characteristic reactions to injections of B. dys-
enteriae in cats, mice and guinea pigs. The resulting anatomical
lesions of the intestines and nervous system are more or less identical
with those to be described in man (vide infra). Dogs will develop
ulceration of the intestines following injections of Shiga toxin (121)
but not after feeding with toxins or cultures although they may suc-
cumb to diarrhea. A case of naturally acquired Shiga dysentery
in a dog has recently been reported (408). Both large and small
varieties of monkeys are susceptible to infection with B. dysenteriae
(Flexner) for an epidemic of dysentery has been reported (225) among
monkeys in a zoo. The infection orginated from an orangoutang,
which arrived ill from the East, and spread to chimpanzees, macaques,
and rhesus monkeys and finally to the keeper and his wife. B. dys-
enteriae (Flexner) was isolated from both animal and human stools.
Serious epidemics of clinically and pathologically typical bacillary
dysentery have been reported (443) among lambs, but dysentery
bacilli have not been isolated.
Conradi (117) produced diarrhea, collapse and paralysis followed
by death in rabbits by injecting a large dose of a toxin made by
allowing a dysentery culture to autolyse. In four rabbits which sur-
vived longer than twenty-four hours there was a diphtheritic mem-
brane of the intestine accompanied by ulceration. Vaillard and
Dopter (121) by similar methods found that if the rabbits died in
eighteen to twenty-four hours following small subcutaneous doses
of toxin, the lesions were in the small intestine but with larger doses
the lesions were in the large intestine. With injections of a prepara-
tion of dysentery bacilli ground under liquid air and extracted with
saline, Liidke (226) reported that the lesions were chiefly in the small
intestine and but rarely in the large intestine. Eikuchi (227) in-
jected the peritoneal exudate of guinea pigs who had had injections
of dysentery bacilli, into rabbits and noted that paralysis was the
main result. The chief discrepancies in experimental results with
dysentery toxin may perhaps be due to the failure to distinguish
between the endotoxin and exotoxin of the Shiga bacillus.
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434 wilbum c. davison
Nervous lesions due to exotoxin {neurotoxin)
Dopter (228) made the first comprehensive study of the effect ol
dysentery toxin on the central nervous system. He found in rabbits
after subcutaneous inoculations of twenty-four hour broth cultures
of the Shiga bacillus, or of culture filtrates, that serious lesions might
occur in any portion of the nervous system although the medulla was
most often affected. The gray matter, and almost exclusively the
anterior horns, showed chromatolysis of the nerve cells in a varying
degree and occasionally areas of necrosis in which the cellular ele-
ments and myelin fibers were destroyed so that scarcely a vestige
of them was left. At the same time there was an intense hyperemia,
and even hemorrhages might invade the tissue. The white matter
was intact. In short, the lesion was that of an acute myelitis, often
an anterior poliomyelitis and sometimes a polioencephalitis as well.
In addition, Olitsky and Kligler (119) described a perivascular infiltra-
tion of small round cells either as a single layer about the sheaths or
actually in the sheaths of the vessels of the brain and spinal cords of
rabbits who had received exotoxin intravenously. Less frequently
these round cells were present as a dense heaped up infiltration about
the arterioles and capillaries of the central nervous system especially
of the medulla and cervical cord and only slightly of the lumbar cord.
These authors, working with exotoxin that had been carefully separ-
ated from the endotoxin, stated that a sublethal dose injected intra-
venously in rabbits resulted in the development of paresis or
paralysis of the extremities in two to four days. Both anterior and
posterior extremities might be affected; the former more frequently.
This paralytic or paretic stage might endure for one to three days
and might then be followed by complete recovery. Although the
animal might be apathetic, have no appetite and lose weight, yet
there were no intestinal symptoms. A lethal dose injected intra-
venously resulted in paralysis and prostration within twenty-four to
forty-eight hours. There was considerable loss of weight. Invol-
untary evacuations of the bowels occurred but were without blood
or mucus. There were no intestinal lesions at autopsy. The incu-
bation period depended on the dose.
Ellinger and Adler (229) believe that the principal action of the
neurotoxin is on the heat-regulating and vasomotor centers. Ani-
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 435
mals became poikilothermous after injections of exotoxin. If the
body temperature fell very low the animals were unable to compensate
in any way. With this fall in temperature the respiratory center
was injured and this led to the death of the animal.
Intestinal lesions due to endotoxin (enterotoxin)
Olitsky and Kligler (119) with intravenous injections of a sublethal
dose of Shiga endotoxin free from exotoxin produced diarrhea, loss
of weight and subnormal temperature in rabbits after twenty-four to
forty-eight hours. The stools were frequent and mucoid and occa-
sionally blood-tinged. This state, during which no nervous symp-
toms occurred, endured for two to three days after which gradual
recovery took place, or death followed. If a larger but still sublethal,
or a lethal dose was injected intravenously, the animal reacted within
twenty-four hours with subnormal temperature, considerable loss of
weight and prostration. Severe diarrhea resulted, the stools being
fluid and containing much mucus and more or less blood. The sensory
and motor functions appeared normal. This state lasted for one to
three days after which recovery took place or death followed. At
autopsy the peritoneum was dull and its blood vessels injected and
the peritoneal cavity contained a serous fluid. The small intestines
were usually unaffected except that the vessels in the serosa might be
injected. Occasionally the ileum was involved in the same extensive
way as the large intestine. The walls of the latter were greatly thick-
ened, edematous, injected and showed small discrete hemorrhages.
A glairy gelatinous material covered the serous coat. On opening the
intestines, the contents were found to consist of blood tinged mucus.
The villi were hyperemic, the mucosa was swollen and revealed
discrete hemorrhages and small ulcerations. In some instances
necrotic areas were seen, and in one instance an area 2.5 cm. wide
encircling the cecum was gangrenous. Microscopically, destruction
of the glandular elements, as well as a superficial general necrosis
was noted. There was a cellular exudation in the submucosa and
considerable edema and degeneration of the muscular layers. There
were no lesions in the cerebrospinal nervous system. Hence this
poison can be regarded as an enterotoxin, in contradistinction to the
exotoxin which is a neurotoxin.
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436 WILBURT C. DAVISON
The intestinal lesions were studied by Flexner and Sweet (120)
who stated that rabbits were not subject to infection with dysentery
bacilli when they were fed by mouth or when the cultures were in-
jected directly into the abdomen. They noted no effect when an
autolysate of Shiga cultures, which is largely endotoxin, was fed per
os or even injected into the duodenum, so it was assumed that dysentery
bacilli and their toxins could not produce intestinal lesions in rabbits
by mere contact with the mucosa. They believed that although man
undoubtedly absorbed dysentery toxin from the intestines where it
was produced by the bacilli, yet rabbits had no such power of ab-
sorption. Dysentery toxin is destroyed by pepsin and more slowly
by trypsin yet this did not explain the absence of intestinal lesions
when toxin was fed by mouth. They could produce intestinal lesions
only when the dysentery toxin was injected intravenously, subcu-
taneously or intraperitoneally. These lesions varied in intensity.
The coats of the large intestine were greatly thickened by inflam-
matory edema. The mucosa was yellowish white and thrown into
deep folds and corrugations. Occasionally more or less hemorrhage
was associated with the edema. In some of the animals the trans-
verse folds of mucous membrane were affected chiefly; they were
swollen, the edges were hemorrhagic and a pseudomembrane was
scattered over the surface. The hemorrhage in some cases extended
into the serous coat. They believed that the character of the histo-
logical lesions in the cecum of these rabbits pointed to an action upon
the substance and not primarily upon the surface of the intestine.
After dysentery bacilli were injected intravenously, they were
found in the bile so these authors cut the bile ducts to prevent the
direct action of the bacilli on the intestinal mucosa and after inject-
ing dysentery bacilli found that the intestinal lesions were negligible
but the rabbits died of nervous lesions (neurotoxin). This was anal-
ogous to the findings in mercurial colitis. When fatal doses of mer-
cury were injected into normal rabbits, the cecum and the first part
of the colon were the seat of hemorrhagic necrosis, and diphtheritic
and ulcerative lesions, whereas in rabbits with biliary fistulae the
changes in the cecum were much less intense. Flexner and Sweet
(120) therefore concluded that the intestinal lesions were the result
of repeated excretion of bacilli and toxins with the bile and also through
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 437
the intestinal mucosa of the large intestine especially at the cecum
and that they were not due to the direct contact of the bacilli and
their products with the mucosa.
Besredka (230), however, has recently shown that when B. dysen-
teriae (Shiga) and its toxins came in contact with the intestinal mu-
cosa an erosion was formed. He fed one series of rabbits with cul-
tures of living dysentery bacilli and another with killed organisms.
Intestinal lesions were produced in both series. Dysentery bacilli
did not give rise to septicemia when injected intravenously but pure
cultures of these organisms were obtained from the bile and intestinal
contents from the duodenum to the distal end of the small intestine.
The blood, urine and organs remained sterile. The intestinal
lesions were the same whether living bacilli, bacilli killed by heat,
or endotoxin were injected intravenously, subcutaneously or fed by
mouth. The intestinal lesions following intravenous injections of
bacilli or toxins were the most severe, those after feeding by mouth
the least severe and after subcutaneous injections they were midway.
Following subcutaneous inoculations the bacilli at first remained
localized and underwent a certain amount of autolysis. The sur-
viving bacilli were then taken up by the circulation and transferred
to the mucosa of the small intestine. The severity of the lesions de-
pended upon the directness of the route that the virus traveled from
its entrance into the body and its consequent diminution. The gen-
eral resistance of the animal as well as the size of the dose injected
determined whether death or survival would result.
If it is true that intestinal lesions are produced in rabbits by the
contact of dysentery bacilli and toxins with the mucous mucosa, the
mechanism of infection and the localization of the intestinal lesions
in dysentery is very simply explained. These observations of Bes-
redka (230) would seem to substantiate the views of Rokitansky
(224) that the initial catarrh of the mucosa in dysentery was due to
a direct chemical action starting from the surface, as well as those of
Virchow (223) that the transition from the catarrhal to the diphtheri-
tic membrane stage occurred in the cecum and colon because the
intestinal contents remained and were in contact with the mucosa
at these points the longest time. That Flexner and Sweet (120)
did not find intestinal lesions following contact of toxin and mucosa
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438 WELBUM C. DAVISON
might be explained by the smallness of the dose, for Besredka, in
one series of rabbits to which a small dose of toxin was fed, failed to
find intestinal lesions. The reduction of the severity of the lesions
in rabbits with biliary fistulae is explained by the fact that after in-
travenous inoculations of toxin, this toxin is excreted by the bile
and as the bile ducts were cut the toxin could not reach the mucosa.
Besredka, Flexner and Sweet all assumed that the intestinal mucosa
excreted toxin and bacilli but it would seem possible that the bile
is the chief if not the only means for the virus to reach the intestines
from the blood. The production of the intestinal lesions could then
be explained by the contact of the mucosa and the toxin as it passes
downward from the opening of the common bile duct. This would
not necessitate the assumption that the lesions of dysentery are pro-
duced by the excretion of the toxin through the intestinal mucosa.
Besredka9 s theory of intestinal immunity
Besredka (230) as a result of his work suggested that the immunity
against bacillary dysentery conferred by one attack of the disease
or by prophylactic vaccination was due essentially to the sensitiza-
tion of the intestinal mucosa to dysentery bacilli and that the anti-
bodies of the blood had a small r61e, or none at all, in the protective
mechanism. He based this theory on the fact that the feeding of
killed dysentery bacilli (heated vaccine) to rabbits produced agglutinins
in the blood. Subsequent feeding of large doses of living dysentery
bacilli was harmless for these rabbits although fatal for control ani-
mals. The serum of the rabbits who have had this prophylactic
feeding of killed dysentery bacilli, however, would not protect other
rabbits against feedings of live dysentery bacilli. Moreover sub-
sequent feedings of killed dysentery bacilli to these immunized rabbits
did not markedly raise the agglutinin titre of the blood. Besredka's
(230) explanation was:
That the preliminary feeding of killed dysentery bacilli produced an ero-
sion of the intestinal mucosa by contact and when this healed the immunity
was complete and subsequent feeding of lethal doses of living dysentery
bacilli would not produce death, or feedings of killed dysentery bacilli
would not increase the antibody titre of the blood for the sensitized intestinal
barrier was impassable. The reason that the antibodies of the blood had
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 439
been looked upon as an index of immunity was because previous methods of
prophylactic vaccination had been by subcutaneous and intravenous inocu-
lations. These antibodies, however, merely indicated that there had been
a systemic reaction to the vaccine. The real immunity, however, depended
upon the excretion of the vaccine with the bile into the intestine and the
consequent erosion of the mucosa, healing and immunity. By oral vaccina-
tion, immunity was produced without this systemic reaction.
Some doubt has been thrown upon this theory by Zingher and Solet-
sky (441) who were unable to produce immunity in rabbits by giving
them B. paratyphosus B. by mouth in accordance with the plan
outlined by Besredka (230). Kanai (445) found that the immunity
produced in rabbits by the oral administration of Shiga vaccines was
inferior to that produced by subcutaneous inoculations.
V. PATHOGENESIS OF BACILLARY DYSENTERY IN MAN
The mechanism of the production of the lesions of human bacillary
dysentery is doubtless similar to that described by Besredka (230)
in experimental dysentery in rabbits. The dysentery bacilli in
practically all instances are taken into the mouth with food or drink
and pass directly to the intestines. There is no evidence that dysen-
tery is primarily a septicemia such as is typhoid fever. The organ-
isms can be cultivated at autopsy from the whole length of the colon
and even from the small intestine (120) where there may be no patho-
logical lesions but owing to the peristalsis of the small intestine, a
prolonged lodgment of bacilli there in any great numbers is prevented
and it is not until the cecum and colon are reached that the organisms
have an opportunity to multiply appreciably and produce toxins.
The breaking down and autolysis of the bacterial cells (both Flex-
ner and Shiga varieties) liberates an endotoxin. This endotoxin is
a local irritant. To it are to be ascribed the great majority of the
intestinal lesions. It may doubtless cause hyperemia alone. It
may cause a catarrhal, an ulcerative or a pseudomembranous type of
inflammation. Not only is the mucosa affected but also the submu-
cosa, the muscularis and in a few cases even the peritoneal covering.
There is an exudation of lymph and cells into the intestinal coats.
It is the edema of the submucosa that causes most of the thickening of
the intestinal wall. This may be double that in health. The mucous
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440 WILBUM C. DAVISON
membrane may be only hyperemic with an excess of mucus or it
may have superficial ulcerations upon the summits of the rugae.
It may be covered by a false membrane. In long standing cases the
ulcerations may be numerous and confined almost entirely to the
lymphatic elements of the intestinal wall. Deep ulceration is not
very common in children- even after the pseudomembranous type of
inflammation.
Bacillary dysentery does not always involve the whole length of
the colon even in cases proving fatal in the acute stage, but when
only a portion of the intestine is attacked that part will be more or
less uniformly affected and no extensive and abruptly defined healthy
areas will remain within it, as is so commonly the case in advanced
amebic dysentery (3). This difference is perhaps due to the dif-
ferent mechanism of infection in these two diseases. In the former,
the lesions are probably the result of the direct contact of the mucous
membrane with the endotoxin which diffuses uniformly in the area
in which it is liberated. Amebae, on the other hand, may attack
the intestinal wall singly or in groups and thus leave healthy areas
between the erosions.
As a rule the ulcerations of bacillary dysentery are numerous and
have clean surfaces, elevated edges and a base formed by the submu-
cosa. In contradistinction to the ulcers of amebic dysentery, the
edges of the ulcers of the bacillary variety are not undermined. The
borders are irregular, reddened, swollen and infiltrated. The ulcers
of bacillary dysentery in adults may be very extensive leading to
the separation of large sloughs, or may extend deeply into the coats
of the bowel, causing in extreme cases gangrene, (400) perforation
(403) and peritonitis or in less serious cases inducing the exudation
of much lymph into the peritoneal coat subsequently producing ad-
hesions. Actual suppuration of the intestinal wall never occurs in
uncomplicated cases of bacillary dysentery. However, mucous cysts
and submucous abscesses of the wall of the large intestine may occur
in chronic cases (374). The ulcers heal with the formation of con-
nective tissue leaving a scar in the mucous membrane that is often
pigmented. Many bacilli and cocci are found in the inflamed mucous
membranes and are especially numerous in the necrotic portions.
In the deeper layers the bacilli are found in small numbers, but in
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 441
the glands, between the gland cells and in the glandular stroma they
are very numerous. Cocci are not as a rule found in these latter
locations. In the submucosa and often in the muscularis the cell
infiltration is accompanied by numerous bacilli. Cultures from
these regions have shown the presence of B. dysenteriae in pure
culture (77).
What part organisms other than dysentery bacilli play in the pro-
duction of intestinal lesions is hard to say. It is probable that pyo-
genic cocci — streptococci chiefly (39) — multiply in the necrotic tissue
that results from the local irritation of the dysentery endotoxin.
Whether they actually attack the intestinal wall it is impossible to
state. Doubtless they play an important part in the production
of pus which is often present in large amounts in the exudate and
stools.
During the early stages of bacillary dysentery, there is a marked
febrile reaction. This is probably the result of a systemic reaction
to absorbed endotoxin, as well as to the "cleavage products" that
may be absorbed from the necrotic intestinal mucous membrane.
It would seem justifiable to assume that this absorbed endotoxin is
excreted into the intestines again with the bile as Flexner and Sweet
(120) and Besredka (230) have shown to be the case with dysentery
toxin that has been introduced parenterally in rabbits. The active
peristalsis of the small intestine probably prevents the endotoxin from
remaining there long enough to produce irritation of the lining of the
jejunum. As with the originally ingested bacilli, it is not until the
lower ileum and colon are reached that there is sufficient stasis for
the excreted endotoxin to produce dysenteric lesions. This absorp-
tion of the endotoxin from the colon and its excretion by the bile
thus form a vicious circle.
If the lesions of bacillary dysentery were the result of the excre-
tion of this absorbed endotoxin by the intestinal wall as Flexner and
Sweet (120) suggested, the distribution of the lesions would be re-
lated to the blood supply and they would probably be more numerous
at the attachment of the mesentery. This does not appear to be
the case.
The Peyer's patches of the ileum are unaffected or only moderately
swollen in bacillary dysentery. The solitary lymph nodes in the
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442 WILBURT C. DAVISON
small intestine may be hyperemic and swollen though they are rarely
ulcerated, thus contrasting with the frequency of the ulceration of
these nodules in the large intestine.
The severity of the damage to the intestines evidently depends upon
the virulence and the endotoxin producing properties of the infect-
ing organism. In patients dying of the so-called " terminal dysentery"
(3, 138) in whom malnutrition, scurvy, rickets, pneumonia or other
disease is more responsible for death than the dysenteric infection,
the intestines may merely be hyperemic or have slight ulceration
of the lymph follicles of the colon and lower ileum. The length of
the illness does not necessarily determine the severity of the lesions
for ulceration and membrane formation are not unusual in infants
dying of bacillary dysentery of but a few days duration.
The most essential difference between the lesions of typical acute
and chronic bacillary dysentery (which is practically confined to
adults) is in their extent. In the former, the whole, or nearly the
whole, length of the colon and often also the lower part of the ileum
are uniformly involved in an acute inflammatory process which may
rapidly prove fatal. In the latter, the process is usually limited to
the lower half of the colon and the patient survives long enough to
allow of more extensive destruction of the mucous membrane of the
affected areas, which presents a worm eaten appearance. The char-
acter of the lesion differs mainly in that the earlier fibrinous changes
in the mucosa have usually disappeared in the chronic stage and only
very extensive irregular depressed ulcers are left which usually run
into one another with some general thickening of the mucous mem-
brane. In some instances the intestinal wall may be found to be
gangrenous along part of its course, (400, 403). In keeping with
this long period of intoxication, the wall of the intestine as well as
other organs sometimes shows amyloid change (39).
In infections with the Shiga bacillus the central nervous system
(228) may be the seat of lesions due to the prolonged absorption of
exotoxin to which B. dysenteriae (Shiga) gives rise, as a product of
its growth, in the intestine. However, as man seldom absorbs as
much exotoxin from his intestines as is usually injected experimentally
into a rabbit, these lesions are rarely fatal. Consequently there are
but few reports of the postmortem examinations of the brains and
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 443
spinal cords of patients who have died of paralysis following Shiga
dysentery. The findings that have been published (343) are similar
to those seen in experimental Shiga infections in rabbits, and are
analogous to those of poliomyelitis and encephalitis.
VI. CLINICAL DATA IN ADULTS
Hippocrates'1 original statement that dysentery was a condition
characterized by the frequent passage of stools containing blood and
mucus, accompanied by straining and tenesmus, has not been improved
by any later clinical description. A provisional diagnosis of dysentery
is justified with that fundamental picture. Not until the advent of
laboratory methods could this syndrome be divided into bacillary
and amebic dysentery, typhoid, paratyphoid, cholera and food poison-
ing. The demonstration of the relationship of liver abscesses to
amebic dysentery rendered it possible to diagnose many cases of
amebic dysentery without stool examinations but not only do mixed
amebic and bacillary infections (46, 60, 355) occur but all liver abscesses
are not due to amebae (234) so that reliable cultural methods are
usually necessary for a final diagnosis.
Typical cases of amebic and bacillary dysentery, typhoid, paraty-
phoid (394, 206, 235), cholera and food poisoning present characteris-
tic clinical pictures so that when seen side by side they can, as a gen-
eral rule, be distinguished. However, it must be remembered that
even in the presence of an epidemic of any one of these diseases it
occasionally is impossible, without laboratory confirmation, to state
that an individual case is of the prevailing type. Among a number
of cases sent back from the Dardanelles as amebic and bacillary dys-
entery I have found some due to infection with B. paratyphosus B,
although clinically they were indistinguishable from the remainder
of the convoy.
Inasmuch as we have effectual specific remedies for amebic and
Shiga dysentery (in adults), an accurate laboratory differentiation
of these cases of bloody diarrhea is most essential. Clinical appear-
ances alone are not reliable.
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444 WILBURT C. DAVISON
Incubation period
The time from the initial ingestion of the dysentery bacilli until
they have become sufficiently numerous to produce enough toxin to
cause clinical symptoms may vary from one to eight days. Dysentery
bacilli probably multiply rapidly in the intestine but cultures of the
stools rarely show viable dysentery bacilli in great numbers. One
to ten colonies for each gram of faeces cultured is a high number
even in severe cases. This may be due to the great acidity of the
stools that occurs in bacillary dysentery (371, 382), or possibly is a
result of d'Herelle's phenomenon (125). Great numbers probably
die and autolyse in the intestine and thus liberate a large amount
of endotoxin. This endotoxin has two effects; one local, due
to contact with the intestinal mucosa according to Besredka (230)
and the other systemic due to absorption into the blood stream.
The length of the incubation period probably depends upon the quan-
tity and the virulence or toxin producing properties of the infection
bacilli that were originally ingested. Lemoine (236) reported a case
of twenty-four hours' incubation in which infection occurred via the
rectum from the use of a chamber containing dysenteric stools although
the soiling of the fingers at stool cannot be excluded. In one instance
(231) a culture of the Shiga bacillus came in contact with the conjunc-
tiva and dysentery resulted within twenty-four hours. It is well
known (232) that bacteria quickly pass from the conjunctiva to the
nose and throat. Laboratory infections of twenty-four to forty-eight
hours incubation were observed by Flexner (39), Strong (112) and
Kruse (34). In an epidemic caused by river water in a Japanese
village (46) the incubation period was in most cases from four to
five days.
Onset
The prodromal symptoms of general malaise, fever and headache,
that are frequently present during the latter part of the incubation
period, are probably due to the systemic reaction to the foreign pro-
tein of the absorbed endotoxin. The loss of appetite and nausea
either may be due to the same cause or are possibly reflex from the
local irritation of the intestinal mucosa by the endotoxin. Frequently
there are no prodromata and all of the symptoms are attributable to
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 445
the local effect of the endotoxin. The onset is usually characterized
by a griping pain in the abdomen and an urgent desire to defecate,
resulting in the passage of ordinary formed feces, which temporarily
relieves the pain. The pain, however, soon returns, usually in the
umbilical region although other locations are frequent, associated
with a desire to defecate and the passage of stools which are now of
softer consistency and may be streaked with blood. These attacks
are repeated at decreasing intervals so that the patient is more or
less continuously at stool. Frequently the stools contain nothing
but blood and pus. They are usually acid in reaction and Jacoby
(371) believes that this is of diagnostic importance. The griping
pains in the abdomen are doubtless due to the passage of the intestinal
contents over the inflamed mucous membrane. They may become
very intense in severe cases and are plainly distinguished from tru^
tenesmus, the bearing down pain experienced in the rectum during
and for a time after the actual evacuation of the bowels. Straining
and griping are quite constant features. Tenesmus is commonly
associated with dysenteric lesions in the rectum, which usually occur
early in the disease. Prolapse of the rectum and consequent incon-
tinence of feces may occur in severe cases with marked tenesmus.
In a choleraf orm type of bacillary dysentery described by Castellani
(7), the onset is sudden, with rice water or serous stools; the patient
may vomit and usually becomes rapidly worse. Blood may occa-
sionally appear in the stool. The infecting bacilli in these cases are
probably exceedingly virulent and rapidly produce a potent toxin so
that the maximal effect is noted early.
Many afebrile cases of non-bloody, non-mucous diarrhea of but
twenty-four hours' duration have been proved (57, 58) to be due to
infection with dysentery bacilli. The so-called epidemic diarrhea is
usually mild dysentery (413). These cases may occur during epi-
demics of typical dysentery and so be diagnosed but frequently they
are sporadic and occur during the winter months. The attack may
in no way differ from an ordinary attack of diarrhea due to other
causes. In the Northern cities of the United States, the majority
of the cases occur sporadically and are of this type. Extensive epi-
demics, even in asylums, and severe cases are the exception. These
isolated cases are frequently overlooked unless the bacteriologist as
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446 WILBURT C. DAVISON
well as the clinician diligently searches for them. In one large hospi-
tal but eight cases of bacillary dysentery were diagnosed in eight
years, yet in one month when repeated stool cultures were done on
all patients with diarrhea, two cases of Shiga infection and one of
Flexner infection were discovered. It is probably through these
sporadic, mild and frequently undiagnosed cases that bacillary dys-
entery is often spread (117).
The term pseudodysentery that is sometimes applied to these
mild cases of dysentery would seem to be not only superfluous but
also misleading. They are just as much true dysentery bacteriologi-
cally as the more severe types and, if they are not clearly recognized
as such, are dangerous from the public health point of view. These
mild cases are due in all probability to dysentery bacilli that produce
but a small amount of toxin, so that there is only a catarrhal inflamma-
tion of the mucous membrane of the intestine without erosion.
Course
As a rule, the stools become slimy and bloody on the second or
third day and very soon are composed of pure blood and mucus.
Later the mucus becomes thick and colorless with less blood and finally
there is the mucopurulent stool so characteristic of bacillary dysen-
tery. The stools are usually small. They have a stale, spermic odor
and are generally not offensive. In the severe cases, however, they
may become exceedingly foul and contain pus. It is possible that
this represents a secondary infection by streptococci or other pus
producing organisms. Extremely foul stools are an unfavorable
sign. Not infrequently the endotoxin may be so destructive that
shreds of mucous membrane and occasionally tubular sloughs (39)
may be passed by rectum. In early bacillary dysentery the usual
number of stools is from six to fifteen per day. It is impossible in
most cases to distinguish the amebic and bacillary varieties by the
gross appearance of the stools. Microscopic smears of the stools
(222) may be of assistance in diagnosis. If there are no amebae and
many cells, the infection is probably bacillary (399). There are,
however, many large phagocytes that resemble amebae in the stools
of patients with bacillary dysentery. Early in the course of bacillary
dysentery smears of the mucus contain a fair number of cells most of
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 447
which are epithelial with some mononuclears and polymorphonu-
clears. Red blood cells are in clumps and scattered throughout the
smear. Later in the disease, the cells increase and are predominately
polymorphonuclear.
The urine diminishes in amount and at times may contain a trace
of albumin. Urination may be painful (dysuria) (39) when the rec-
tum is markedly affected by the endotoxin. Thirst is rarely present
in mild cases but in severe ones due to the loss of body fluid, it may
become marked.
Vomiting is relatively unusual in mild cases. The tongue is usually
coated with a white fur. The temperature in all but the very mildest
cases rises to 101° to 104°F. In mild cases the febrile curve may be
intermittent throughout but it often assumes a remittent type for
the first few days and gradually declines to normal in the morning
while still rising to 100° or 102° in the afternoon. There seems to
be no relation between the temperature and the severity of the intest-
inal lesions (55). A slight return of fever after the curve has been
normal for a time is almost always accompanied by an exacerbation
of the symptoms except in serum treated cases, when the elevation may
be due to serum sickness. As convalescence becomes established,
the temperature often becomes subnormal. The pulse increases in
frequency and in the more severe infections becomes very small.
In adults, if the patient is to die, the stools become serous, the pulse
rapid and irregular, the temperature drops to subnormal, the num-
ber of stools may diminish, hiccough appears and death due to ex-
haustion generally occurs during the second or third week.
If lesions are present in the upper portion of the colon or in the
small intestine, various intoxication symptoms appear, such as head-
ache, general malaise, muscular pains, sleeplessness, numbness and
stupor. Delirium is rare except as a terminal symptom. The clini-
cal picture may simulate that of typhoid fever. As a matter of fact,
in many of these cases, B. typhosus as well as B. dysenteriae has
been isolated (237). I have encountered cases of bacillary dysentery
in troops that have become secondarily infected with B. paratyphosus
B. (68). Under conditions in which trained nurses are scarce, it is
relatively simple for these mixed infections to occur (207) and the
possibility should always be considered.
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448 WILBURT C. DAVISON
Physical examinations are usually of no diagnostic importance.
Extreme emaciation, atrophy of the general muscular tissues, Hip-
pocratic facies and a retracted, scaphoid and tender abdomen are
striking features in cases of long duration. On careful palpation,
the thickened bowel may at times be felt, but usually the abdomen
is too tender to allow such manipulation. The tenderness is especially
acute over the course of the colon. The spleen is not enlarged except
in very severe cases (344) or unless malaria, typhoid or other diseases
coexist (55).
Severe hemorrhage from the bowel is less common than in the ame-
bic form, but Rogers (3) reports the fatal loss of blood from a deep
ulcer in the upper part of the rectum in chronic bacillary dysentery.
In occasional cases instead of diarrhea, constipation may be the
predominating symptom for the disease may be limited to the lower
bowel, and feces may be accumulating in the higher region of the
colon — a condition which may be recognized by distention. Shiga
(77) describes an ascending variety of acute dysentery, which, begin-
ning in the rectum, spreads upwards along the large bowel.
Nervous symptoms
The nervous symptoms due to the Shiga exotoxin are not constantly
present in all cases of Shiga infections. This may be due to the fact
that the effects of the exotoxin are manifest later in the disease than
those of endotoxin. The former must be absorbed into the blood
and then probably be accumulated in the nervous tissues to produce
sufficient lesions to give rise to clinically detectable nervous symptoms.
In many severe cases the patient succumbs to the intestinal lesions
before the exotoxin has had time to produce lesions in the central
nervous system while in many mild cases in which the dysentery
bacilli produce toxin in small amounts the patient has time enough
to manufacture antiexotoxin to neutralize the exotoxin before it
has sufficiently accumulated in the nervous tissues to produce paraly-
sis. Peripheral neuritis is the most common condition caused by
the exotoxin. It is generally mild and often confined to one nerve
(55, 338). Schlesinger's (240) work would indicate that this neuritis
is due to the slow effect of absorbed dysentery toxin similarly to
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 449
the nerve lesions in diphtheria, for he reported polyneuritis in twenty
soldiers after the dysentery bacilli had disappeared from the stools.
Paralysis, chiefly paraplegia, is occasionally reported (52, 274, 338).
Recovery
Recovery takes place as soon as the body can produce sufficient
antiendotoxin to neutralize the endotoxin and thus prevent further
destruction of the mucosa. Besredka (230) believes that the pro-
tective mechanism does not involve the antibodies of the blood but
that the intestinal mucosa itself, after the erosion caused by the endo-
toxin has healed, becomes sensitized to dysentery bacilli and acts
as a barrier against further infection. That may be true, but it
would seem impossible to avoid the assumption that an antiendotoxin
must be formed by the blood or other antibody forming center, to
•neutralize the endotoxin and allow the erosion to heal. Bacterio-
cidal bodies evidently are not essential to recovery for although dys-
entery bacilli usually disappear from the intestines a few days after
the cessation of the acute symptoms yet some patients after recovery
from dysentery may harbor these bacilli in their intestines for months
and even years without symptoms. Although these carriers have suf-
ficient antiendotoxin to prevent dysentery bacilli causing inflammation
and erosion of the intestinal mucosa and although bactericidal bodies
are demonstrable in their sera, yet the mere fact of the continued
presence of dysentery bacilli in the stools would seem to indicate
that bactericidal substances are not ^essential. However, as per-
sistent carriers of dysentery bacilli are the exception, the bactericidal
bodies may be excreted into the intestines of the majority of patients
and account for the disappearance of dysentery bacilli from the stools
after recovery. These findings are comparable to those of individ-
uals who become chronic carriers of diphtheria bacilli after conva-
lescence from the disease. The part played by d'Herelle's (125)
"bacteriophage" or Kabeshima's (127) bacteriolytic ferment, in
determining the patient's recovery is impossible to state at present,
(vide supra).
The duration is four to eight days in light cases and three to six
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450 WILBUXT C. DAVISON
weeks in those that are severe. Shiga (46) found an average dura-
tion for all cases of 40 days under medicinal treatment and 25 days
under serum therapy. During recovery the stools regain their fecal
consistency, the number lessens, and the appetite and strength begin
to return. Relapses, however, are common, due to dietetic errors,
exposure and allowing the patient to get up from bed or to resume a
general diet (222) too early.
Reinfections, except for relapses (58), are rare in bacillary dysentery.
Shiga (77) noted but four cases among 10,000 patients. However,
during mixed epidemics, a convalescent from Flexner dysentery may
acquire a new infection with Shiga bacillus (57, 69, 138, 140, 202)
and vice versa.
Chronicity
Bacillary dysentery in adults has often been divided into two types,
the acute and the chronic. The latter is usually, though by no means
always, due to infection with B. dysenteriae (Shiga). Sonne (238)
states that the Flexner bacillus was found mainly in mild and sporadic
cases. Remlinger, (65) however, reported a severe Flexner epidemic
in the Argonne. Many physicians report that no clinical difference
can be detected between patients infected with Shiga and Flexner
bacilli (69, 140). Moreover, the Shiga and Flexner bacillus may
often exist in the same patient (57, 69, 138, 140, 202). Inasmuch
as the chronic cases begin in a manner similar to those that are acute,
this differentiation is not distinct. Chronicity is perhaps better
described as a complication of dysentery rather than as a distinct
variety.
Although the acute stages insensibly merge into the chronic dis-
ease, so that no definite line can be drawn between them, yet for pur-
poses of analysis Rogers, (3) has taken a duration of one month or
more to indicate chronicity. As a general rule, bacillary dysentery
terminates in either death or recovery within a few weeks, and but
comparatively rarely lingers on with longer or shorter remission for
several months, as is not uncommonly the case with inadequately
treated amebic disease. Some observers (260, 402, 409), however,
have reported that 5 per cent of all cases of dysentery become chronic.
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BACILIARY DYSENTERY IN ADULTS AND CHILDREN 451
Chronic dysentery in children is extremely rare. The remissions
are not so complete and lengthy in the bacillary type as in the amebic
variety, the disease tending to run on unchecked until the patient
eventually develops some immunity to the infection and slowly
recovers, or, worn out by his sufferings, succumbs to exhaustion, inani-
tion, steady loss of body fluid or to some intercurrent infection.
Dysentery carriers
There is no definite division of convalescent dysentery patients,
whose stools continue to harbor B. dysenteriae, into chronic cases
and persistent carriers. Fletcher and MacKinnon (175) in a recent
study of 1782 British soldiers convalescent from dysentery, some of
whom gave histories of intermittent dysentery dating from the Boer
War, found 74 still excreting dysentery bacilli. The average Flexner
carrier was in good health, his stools were formed and free from blood
and mucus. He was fit to carry on his work unless subjected to very
adverse conditions of feeding, temperature or labor which might
induce attacks of diarrhoea. The Shiga carrier, on the other hand,
was generally an invalid, his stools usually contained blood and
mucus and he had frequent attacks of diarrhoea. Furthermore, he
often became a mental wreck. Cases of this chronic carrier state,
lasting from two to ten years, have been noted. Arnheim (187)
regarded the Shiga carriers as the more important. Other Germans
(73) stated that Flexner carriers were too numerous to quarantine.
The number of dysentery carriers found appears to depend on the
epidemic and also possibly on the conditions under which the bacteriol-
ogist must work. The usual percentage is rarely more than one
per cent (151, 186, 239) but one author reported that 13 per cent of
his convalescent patients became carriers of the Flexner bacillus (75).
One investigator (186) suggests that B. dysenteriae in chronic
carriers may lurk in the bile as is frequently found to be the case
with B. typhosus carriers. Briickner (214) in an autopsy on a dys-
entery carrier who died of an intercurrent infection, found Flexner
bacilli in the small bile ducts in the liver. There were no intestinal
lesions. Others (213), however, reported that bile had a destructive
and restraining influence on B. dysenteriae both in the intestine and
in vitro. Hannon (342) has shown that bile salts were inhibitory
to the growth of dysentery bacilli.
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452 WILBUXT C. DAVISON
Complications
Perforation and gangrene of the colon and peritonitis are rare
(241, 400, 403) although the abdomen may be sufficiently tender and
rigid to simulate these conditions. However, in 108 fatal Civil War
cases studied by Woodward (52) perforation occurred in eleven.
The incidence of liver abscess and portal pyemia is negligible. Rog-
ers (3) in 45 autopsies in Calcutta did not find a single instance.
Abscesses in other locations are occasionally reported. Shiga (46)
noted one in a convalescent in the upper portion of the rectus ab-
dominalis and in a second case in the gluteal region. The ischiorectal
fossa may also be the seat of abscesses (7). They are probably due
to secondary infections.
Arthritis. Sydenham (24) noted that dysentery was sometimes
associated with rheumatic pains. A swelling of one or more of the
large joints and inflammation of the tendon sheaths of a very ob-
stinate character have been noted in certain outbreaks (39, 242) and
as a sequel to bacillary dysentery during the Boer War (3). Arthritis
of the knees and occasionally of other joints was not an infrequent
finding in the cases during the Great War (55, 57, 64, 243, 403, 411,
421) both in untreated cases as well as those under serum therapy.
Graham (360) stated that the usual time of onset was between the
sixth and twenty-third day after the first symptoms of dysentery.
There was no relationship between the time of onset of the arthritis
and the severity of the dysentery. In severe cases there was consid-
erable rise of temperature which might oscillate for weeks. In mild
cases there was very little if any fever. The swelling and pain were
usually though not always confined to one joint. It appears to be due
to absorption of endotoxin from the bowel and its excretion into the
joint cavities as is known to be the case during the absorption of
toxins of septic and gonorrheal origin (244). Joint involvement
occurs in both Flexner and Shiga infections. This arthritis tends
toward recovery, without going on to suppuration, although it may
take some months to resolve. Stiffness may continue for a long
period but apparently always ends in complete recovery (360). Cul-
tures of the fluid of these joints have with few exceptions (57) been
sterile but the presence of agglutinins in these exudates has frequently
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 453
been demonstrated (55, 57), in some cases in higher dilution than in
the blood serum of the patient.
Parotitis may occur in severe cases, and also in moderate cases
which run a chronic course (46, 421). It is usually bilateral and
appears during the third to the fifth week of the disease. Among
436 patients Shiga (46) found only eight instances of parotitis. The
dysentery bacillus was never found in the pus and tissues removed.
There is probably no connection between parotitis and the dysentery
bacillus. It results from a secondary infection by other organisms
present in the mouth (77).
Edema and ascites are often seen in debilitated patients or during
convalescence (245) or during the terminal stages of protracted cases
and are frequently combined with general anemic edema. Isen-
schmid (246) believes that the edema following dysentery, which
is usually ascribed to weakness of the heart, is probably of the starva-
tion edema type. Some of the instances of war edema (Kriegso-
edema) seen in Germany were probably sequelae to bacillary dysentery
(247). Oberndorfer (248) in autopsies on patients dying of war
edema found typical lesions of dysentery in the large intestines.
Functional disturbances of the heart have been prominent in some
epidemics (249, 250). Simple endocarditis is not infrequent (251)
but the malignant form is rare. Myocarditis and pericarditis may
occur in severe cases (251, 411).
Appendicitis has been cited (7, 421) as a complication during con-
valescence from bacillary dysentery. Vives and others (252), how-
ever, state that appendicitis is more frequent in amebic than bacil-
lary dysentery.
Beriberi has been noted as a frequent complication in Japan (46)
possibly due to the exclusive diet of rice water gruel so frequently
prescribed in the East. The prognosis is not good.
Stenosis of the large bowel, more particularly of the sigmoid flexure,
proctitis (403) and periproctitis (256), due to cicatricial contraction
of the healing ulcers are among the most important though infrequent
sequelae of dysentery as Cantlie (257) has emphasized. The symp-
toms are: constipation of insidious onset (sometimes alternated with
attacks of diarrhoea) associated in due course with a sensation of
distension in the abdomen, recurrent colic, loss of appetite, nausea
MEDICINE, VOL. I, NO. 3
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454 WILBUBT C. DAVISON
and vomiting. Stenosis of the intestines is a serious condition and
must be energetically treated. A case of almost complete obstruc-
tion of the rectum (258) and a fatal case of intestinal obstruction
following dysentery have been reported (259).
Suprarenal insufficiency and postmortem lesions of the suprarenal
glands almost identical with those due to diphtheria toxin have been
found during epidemics of severe Flexner dysentery (65, 69).
Chronic gastritis and intestinal ulceration with pain, meteorism,
diarrhoea and dyspepsia (260, 353, 409) may follow dysentery. They
are probably the result of direct and reflex irritation due to the cica-
tricial tissue of the original dysenteric ulcers rather than to a con-
tinued action of endotoxin. Alexander (261) found achlorhydria and
apepsia in some of his patients after recovery from dysentery. Glaess-
ner (361) has also reported a diminution of pepsin. He believes
that the prognosis is more unfavorable in cases with a deficiency of
pancreatic secretion and that this should be taken into account in
treatment.
As rare complications (212, 251, 253, 338) of bacQlary dysentery
there may be pleurisy, thrombosis, acute and chronic nephritis (419),
acute conjunctivitis (345, 346), cyclitis, iridocyclitis (360), iritis (411),
prostatitis, rectal carcinomata (398), tetany from hemorrhage in the
parathyroid glands (254), pyelocystitis (217, 218, 219), urethritis
(345), vaginitis (347), meningomyelitis (362), hemorrhagic enceph-
alitis (363), pyemic manifestations such as pylephlebitis, and men-
ingitis (255). The presence of the last was probably a coincidence.
Conjunctivitis was noted in a patient with a Shiga infection but as
no dysentery bacilli could be isolated from the eyes, it was assumed
to be due to Shiga toxin (346). Nolf (55) reported labial and nasal
herpes in a large percentage of his cases (Flexner dysentery).
Blood
The blood picture is often of assistance in distinguishing amebic
from bacillary dysentery. In the former white blood cell counts of
from 20,000 to 40,000 are comparatively common (275) while in the
latter, although a slight polymorphonuclear leukocytosis is frequent,
the count rarely exceeds 15,000. In more severe Flexner infections
Nolf (55) found the average number of white cells to be 25,000
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 455
predominately polymorphonuclears, rising to 47,200 in fatal cases.
The leucocytosis disappeared as the dehydration decreased. Mar-
covici reported (410) that 60 per cent of acute cases had a moderate
leukopenia, 6 per cent had a slight leukocytosis (up to 10,900 per
cmm.) and that in 34 per cent the white blood count was normal.
During convalescence the number of leukocytes was normal. In
chronic cases there was usually a leukocytosis (up to 9,400) and oc-
casionally an eosinophilia (3 per cent eosinophils) . He concluded
that white blood cell counts were of but little assistance in differen-
tiating dysentery from other forms of diarrhoea. Martinez (444)
stated that in bacillary dysentery there was a polynucleosis but no
increase in eosinophils while in amebic dysentery there was a slight
eosinophilia and there might be a mononucleosis. Helminthiasis
induced a polynucleosis with eosinophilia.
Findlay (263) has recently reported the possibility of differentia-
ting amebic and bacillary dysentery in 90 per cent of cases by the iodin
reaction and the production of nuclear pseudopodia in the polymor-
phonuclear leukocytes.
The red blood cell counts are at first relatively increased from the
drain of fluid by the bowel, but fall below normal if blood persists
in the stools.
Differential Diagnosis, summary
A presumptive diagnosis of bacillary dysentery can be made in
temperate climates or during epidemics when the patient has had a
febrile onset, passes frequent bloody mucous stools and has colic,
tenesmus, resistance over the large bowel, palpable thickening of the
wall of the colon, and pain on abdominal pressure. It must be remem-
bered that tenesmus is not a constant symptom because in the ma-
jority of instances it only exists when the rectum is affected. The
presence of pus in the stool is strongly suggestive of bacillary dysen-
tery (399). The diagnosis of the abortive form of dysentery, which
often occurs sporadically in the winter, or in the beginning of epi-
demics, is very difficult. Similarly too, the diagnosis of dysentery
simulating typhoid is not easy. Repeated microscopic examinations
of the stools for amebae, and other parasites, numerous stool cultures
for dysentery and other bacilli and probably of most importance,
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456 WILBTOT C. DAVISON
studies of the agglutination reactions of the patient's serum (after
the sixth day) with standardized methods should be undertaken in
all cases. A cutaneous reaction for dysentery bacilli similar to the
Shick test for diphtheria has been introduced (39) but its value has
not been proved.
The conditions necessary for a definite diagnosis of bacillary dysen-
tery are the isolation of the bacillus from the patient's stools or a
positive agglutination reaction of the dysentery bacillus with his
serum (after the sixth day) (235, 264).
Attention must be paid to exclude carcinomata, tuberculosis,
polypi, syphilis of the rectum (265), hereditary syphilis (266), hemor-
rhoids, foreign bodies intussusception, mercurial poisoning, malaria
(369), and pressure from uterine tumors (267) as causes of the dis-
charge of blood and mucus from the bowel. Amebic dysentery as well
as the cases of diarrhoea that may be due to balantidium coli (89,
90), lambia (91), trichomonas (92, 93) ankylostoma, schistosoma,
paragonimus (265) chilomastix mesnili (364) or bilharzia (94) must
be differentiated etiologically, clinically and anatomically from bacil-
lary dysentery. It must not be forgotten, however, that mixed
infections with amoebae or other parasites and dysentery bacilli
may occur (46, 60, 355). The following are perhaps the most im-
portant points (46, 404) in the differentiation of amebic and bacillary
dysentery:
1. The onset is usually acute in bacillary dysentery and gradual
in amebic.
2. Amebic dysentery usually runs a chronic course.
3. In the amebic form, no dysentery bacilli can be found, except in
the mixed infections of both amebic and bacillary dysentery.
4. In amebic dysentery, toxic symptoms such as high fever, gen-
eral malaise, anorexia, rapid emaciation, or various nervous symptoms,
are not usually observed.
5. In bacillary dysentery liver abscess is never present; it is a very
frequent complication of amebic dysentery.
6. The diagnostic value of the emetine treatment. The failure of
hypodermic injections of emetine to bring about very marked ameliora-
tion of dysenteric symptoms within two to three days is usually
sufficient to exclude the presence of amebic disease and thus makes it
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 457
so extremely probable that bacillary infection is present as to indicate
active treatment against the latter disease (3). However, emetine
therapy is not devoid of danger, for deaths have been reported (268)
from its toxic effects. This drug should only be given when the
presence of amebic dysentery is suspected and not as a routine method
of differential diagnosis.
7. The anatomical processes are also different According to
Kartulis (269) and Kruse (34) the edges of the ulcers are peculiarly
undermined in amebic dysentery, while in bacillary dysentery this
is never the case and the ulcers are situated on the surface of the folds
of the mucous membrane.
VH. CLINICAL DATA IN CHILDREN
Infants and young children are much the worst sufferers from
bacillary dysentery. When a household becomes infected, the adtilts
may merely have a mild diarrhea often without blood in the stools,
lasting twenty-four to forty-eight hours. The children on the other
hand usually have a severe bloody diarrhea which is frequently fatal.
In other words the same variety of dysentery bacillus may have but
slight effect on the intestinal mucosa of an adult, possibly because of
his acquired immunity, while in an infant the organisms usually pro-
duce marked inflammation with profound pathological changes.
It is unfortunate that bloody diarrhea in children has not been more
generally recognized as dysentery and that names such as summer
diarrhea, infectious diarrhea and ileocolitis have been applied. Bac-
teriological studies (47, 48, 124, 138, 149, ISO, 151, 153, 154, 215, 270)
in many cities have repeatedly proven that the great majority, if
not all cases, of bloody diarrhea in children are due to B. dysenteriae.
Bacillary dysentery in children can be recognized in nearly all instances
by the clinical data alone.
The onset is usually sudden, the first symptom being a loss of
appetite, feverishness and irritability or drowsiness. Vomiting and
convulsions are not infrequent during the first twenty-four hours.
Within a few hours of the initial symptoms there is an increase in the
number of stools. These are usually watery for the first day. Blood
does not usually appear in the faeces until the second day of the dis-
ease. Within three or four days the stools consist almost entirely
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458 WILBUM C. DAVISON
of blood and mucus for the endotoxin has, .by this time, produced
a marked inflammatory reaction. The number of bowel movements
ranges from three to thirty per day. After the first twenty-four
hours, the individual stools are exceedingly small, perhaps a tea-
spoonful of mucus and blood passed after much straining.
A clinical diagnosis of bacillary dysentery is justifiable only when
the patient has had an acute febrile onset and the passage of mucous
and persistently bloody stools. Children who have diarrhea and
have blood in their stools (usually bright blood) on only one or
two occasions are usually not suffering from dysentery. The ag-
glutination reactions and stool cultures show this. It is true, how-
ever, that infants whose stools contain much pus even without
blood almost always have dysentery. Smears of the stool stained
with methylene blue should be made to distinguish mucus from pus,
for differentiation by the naked eye, is frequently exceedingly dif-
ficult. The presence of mucus alone in stools is not significant of
dysentery.
Children with bacillary dysentery are usually quite ill and greatly
prostrated. For the first few hours they are frequently restless and
irritable. Later they become drowsy and apathetic. The appetite
may entirely disappear. Loss of weight is rapid. If the stools are
very loose for the first day or two and if there is a great disinclination
to take water as well as food, dehydration may become a marked and
important condition. The numerous and often painful bowel move-
ments frequently make rest and sleep impossible without sedatives.
In most non-fatal cases the temperature falls to normal by the fifth
to eighth day. The blood gradually disappears from the stools during
the second week. The bowel movements become less numerous and
assume a fecal character if the appetite improves so that food is taken.
If the child has been suffering from simple diarrhea or some other
disease at the time of the infection with bacillary dysentery, the
character of the onset is frequently masked. Usually, however,
there is a history of a sudden rise in temperature followed by an
increased number of stools containing blood and mucus. Mild
non-bloody diarrhoea due to B. dysenteriae may occasionally occur
in children as well as in adults.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 459
With most of the cases in well nourished children who die in the
early stages of bacillary dysentery as the result of an overwhelming
intoxication, a pseudomembranous type of inflammation is found.
Doubtless the process in the milder cases is catarrhal in type with or
without superficial ulceration. Deep ulceration is found in protracted
cases and is especially localized in the lymphoid tissue of the colon
and the lower part of the small intestine. This extensive ulceration
is common only with poorly nourished children such as are seen in
asylum practice.
The leucocyte count is usually slightly increased (48, 200) but is
of no diagnostic importance (103).
The physical findings are usually negative. The spleen is rarely
palpable. Abdominal tenderness is sometimes present.
Occasionally bronchopneumonia, pyelitis (271), otitis media ul-
cerative stomatitis (447) and acidosis of the acetone body type (272)
may complicate the course of bacillary dysentery in children.
As a general rule the appetite returns when the fever disappears
but occasionally there may be persistent refusal to take food so that
gavage is necessary for days and even weeks. Three months after
recovery from bacillary dysentery, most children have regained their
weight. Very few cases become chronic except in asylum practice.
Death within the first three weeks or complete recovery is the usual
course.
Diagnosis of dysentery in children (summary)
It would seem that in countries where amebic dysentery is not
endemic (amebic dysentery is rare among children in the United
States (273)), a presumptive diagnosis of bacillary dysentery can
safely be made in children who have had a sudden febrile onset and
are passing bloody stools. However, as in adults, the laboratory
findings are the only absolute criteria. The bacteriological diagnosis
of dysentery in children is much simpler than in adults for the in-
testinal reaction to dysentery bacilli is much more severe in the former
and consequently the children's stools consist almost entirely of
blood and mucus so that B. dysenteriae is quite readily isolated. In
adults the presence of much fecal matter increases the number of B.
coli in stool cultures to such an extent that B. dysenteriae is frequently
overlooked.
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460 WILBUBT C. DAVISON
fcifty to sixty per cent of the cultures of stools of children with
dysentery are positive for B. dysenteriae, while in adults the percentage
of positive stool cultures ranges from twenty-five to forty. Higher
percentages may be obtained if several successive stool cultures are
made. The agglutination reaction of the patients serum is the simplest
method of laboratory diagnosis and is even more satisfactory than
in adults for non-specific agglutinins are rare in the serum of a child
even at the low dilution of 1:20; there is less likelihood of the child
having had a previous dysenteric infection, from which agglutinins
might persist and confuse the diagnosis; the agglutination reaction is
frequently positive earlier in the disease in children than it is in adults
(occasionally the test may be positive on the second day.)
Vffl. PROGNOSIS IN ADULTS AND CHILDREN
In epidemic outbreaks, whether in an institution or in a household,
and in infants under one year and in adults over fifty years, the disease
is likely to be especially severe, while in the very acute choleraic cases
the mortality is also high. With these exceptions, in the great ma-
jority of bacillary dysentery cases coming under early observation,
especially in Flexner infections, the ultimate prognosis is good although
convalescence may be tardy. It is far otherwise with neglected patients
who have suffered from dysentery from one to several months, often
without any treatment, so that extensive ulceration of much of the
large bowel is already present on their admission to the hospital.
Albu (260) regards complete and permanent recovery from bacillary
dysentery as an extremely rare event. Schmidt (402) and Strasburger
(409) reported that 5 per cent of their cases of dysentery became
chronic. This is a higher percentage than is usually noted. Schmidt
stated that the mortality was 40 to 50 per cent among chronic as
against 2 per cent in acute cases. In short, chronic bacillary dysen-
tery is a much more difficult disease to deal with satisfactorily (3).
The prognosis is poor in mixed infections with B. typhosus and B.
dysenteriae especially when typhoid fever is the preceding infection
(262). Job and Hirtzmann (369) state that malaria and bacillary
dysentery are frequently associated. Owing to the injurious effects
of malaria upon the intestines, convalescence from dysentery is apt
to be prolonged in malarial subjects.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 461
Mortality
The mortality among adults appears to have diminished during
the past two centuries. In one epidemic in Holland in 1729 five
thousand people died. The death rate at present varies consider-
ably. Shiga (77) found for the whole of Japan that it was from 22
to 26 per cent. According to Kruse (34) the mortality in Germany
is 10 per cent. In a small recent outbreak of Shiga dysentery in
Dublin (356) the mortality was about 10 per cent. In Russia (78)
and in the British Solomon Islands (404) it ranges from 9 to 18 per
cent. Manson (79) reported the mortality from bacillary dysentery
among Europeans in India to be from 3 to 22 per cent and among
natives from 36 to 40 per cent. At El Tor (80) among the Mecca
pilgrims the mortality was 64.4 per cent in 1909. Recent observa-
tions by Hotzen (359) in Germany have shown that the dysentery
cases in the hot summer of 1917 amounted to 69 per cent of all the
cases of acute disturbance of nutrition in infants. Of 123 patients
in whom the diagnosis of dysentery was established bacteriologically r
44 per cent succumbed, and, even if only those cases be considered
in which diseases other than dysentery could be excluded, the mor-
tality was still 23 per cent. In a series of dysentery cases in Ameri-
can children (48) there were 67 white children with 14 deaths and
4 colored with 1 death, a total mortality of 21 per cent. All of the
deaths were in children under 15 months of age. Among 114 cases
treated at the Harriet Lane Home for Invalid Children from 1912
to 1918 inclusive, there were 33 deaths, a mortality of 29 per cent.
The reduction of the mortality among troops is very striking.
At the siege of Dundalk, Ireland, in 1689 (6), 6000 men among 10,000
dysentery patients died, while in the Great War in spite of many cases
there were comparatively few deaths. A quarter of 1 per cent of
Nolfs patients (Flexner infections) in the Belgian sector died (55).
In a total of 5000 cases, 79 per cent of which were Shiga infections,
among the allied troops in Macedonia in the summer of 1918, the
mortality was 3.5 per cent (355). Among 1023 cases in three epi-
demics in German troops on the western front the mortality was 0.4
per cent (433). In one American area in France several hundred
mild cases occurred with no deaths. In Salonika the mortality was
1 per cent (58).
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462 wilbuet c. davison
Factors influencing mortality and morbidity
This reduction in mortality may be due to decreased virulence of
the organisms, to the absence of famine with which former epidemics
were so frequently associated or more probably to better dieting and
nursing. With the exception of serum therapy in Shiga infections,
the medicinal treatment of dysentery is not sufficiently improved to
account for the difference in mortality unless it be that it is now less
meddlesome.
Shiga (46) states that the mortality among females is higher
than among males. The incidence of bacillary dysentery is great-
est among young men from twenty to thirty years of age and
children under two years, perhaps because of more frequent exposure,
for younger men are not as careful of the origin of their food and drink,
while the milk diet of babies, which is an ideal medium for B. dys-
enteriae, is not as carefully handled as it should be. In infants under
one year of age and adults over fifty years the mortality is higher.
The majority of the deaths in the dysentery epidemic reported by
Csernel (366) were in infants under two years of age and in adults
over 70. In the epidemic at Barmen in 1899-1901 (359) the mortality
among children was 6.3 per cent as compared with 4.6 per cent among
adults. In the recent Dublin epidemic of Shiga dysentery (356) at
ages up to forty-five years the mortality was 3.8 per cent and from
45 upwards 43.3 per cent. Kuntze (414) reported that the mortality
in nurslings was 41 per cent as contrasted with 20.7 per cent in
children over one and a half years. During the occasional epidemics
of dysentery that still occur, the mortality is often low in the beginning
of the epidemic season (May, June and July) and increases gradually,
reaching the maximum in November and December. In winter the
mortality is higher, due perhaps to the influence of the season and the
chronic course of many of the cases. Rainfall has little influence on
the prevalence of dysentery (4). Altitude, however, appears to
influence the incidence of the disease. Other things being equal,
dysentery decreases as the altitude increases (39).
All races are equally liable to dysentery. Individuals following
indoor occupations are less liable to infection than agricultural laborers,
soldiers, sailors and explorers (39) . Dysentery is notably a poor man's
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 463
disease and a disease of enlisted men rather than of officers. Fa-
tigue, hardship, exposure, starvation and restricted diet are frequently
reported as predisposing factors of dysentery.
DC. TREATMENT
There are three fundamental principles in the treatment of bacillary
dysentery in adults and children. First, to maintain the patient's
nutrition and general condition by rest, nursing, diet and the relief
of pain so that he may survive long enough to allow his immunity to
rise and conquer the disease; second, to combat the effects of the dis-
ease in the patient by replacing the loss of body with saline; third,
to kill the causative organism and to neutralize its toxins with specific
sera and antitoxins. In addition to these three cardinal procedures,
numerous drugs have been recommended to increase the elimination
of intestinal contents.
Rest and diet
As soon as a presumptive diagnosis of dysentery has been made,
the patient should be sent to bed and kept as quiet as possible. He
should not be permitted to get up until the stools are practically
normal and the fever has subsided. Rest in bed alone has a marked
beneficial influence. Every effort should be made to keep the patient
comfortable and free from pain. Morphine, hypodermatically has
proven useful if the patient, either adult or child, becomes exhausted
from frequent straining and the consequent loss of sleep. Paregoric,
however, is the usual preparation of opium given to children. Bis-
muth has been recommended as a means of coating the inflamed
mucosa and relieving griping and tenesmus. It usually fails, how-
ever. Bismuth, as roentgenology has proven (277), does not adhere
to gastric or duodenal ulcers and leaves filling defects over tubercu-
lous ulcers of the colon (278), so why should it be assumed to cling
to dysenteric ulcers? Bismuth subnitrate should never be used
for it may produce the serious features of nitrite poisoning. The
subcarbonate is harmless. Hot water bottles on the abdomen fre-
quently relieve pain. Application to the anus of ointment contain-
ing 4 per cent tannic acid or 5 per cent cocaine or the use of cocaine
suppositories has been recommended (276). Enemata of warm
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464 wiLBUM c. davison
normal saline, starch solution or 4 per cent sodium bicarbonate at the
outset have proven useful, especially in children. They not only
clean the lower colon but also give the patient relief by reducing the
tenesmus.
It is advisable to stop all food and to supply water as long as vomit-
ing persists. Water must be given freely and offered as often as
every hour through the febrile stages of the disease (279) . Saccharine
(1 grain to the quart) may be used for children who persistently refuse
plain water. After the first twenty-four or forty-eight hours of the
illness, vomiting usually ceases to be a prominent symptom. For
children under two years, protein milk has been one of the best, if
not the best food. This may be given in small amounts even in the
first twenty-four hours; 1 ounce every four hours for the first day and
then if this is well taken and vomiting does not interfere, it may be
increased in amount up to 6 to 7 ounces every four hours according
to the age and weight of the child. This food is offered whether or
not the patient refuses it. As soon as the diarrhea abates and the
child shows definite signs of improvement some carbohydrate may
be cautiously added to the protein milk in small amounts (usually
by the fourteenth day). In case a child is breast fed, this feeding
should be continued but it is usually advisable to give alternate feed-
ings of buttermilk or protein milk, as breast milk alone is too laxative
in almost all instances.
The claim that a diet of lactose is beneficial in dysentery is not
proved. It has been recommended partly because B. dysenteriae
does not ferment lactose and also because a high carbohydrate diet
changes the stool flora (171, 172, 173, 337). However, the ingested
lactose is broken down into galactose and dextrose long before it
reaches the distal third of the ileum and the colon where the dysentery
bacilli are harbored. B. dysenteriae will readily ferment dextrose.
Whether or not the stool flora is sufficiently changed by a high car-
bohydrate diet and whether these changes have any marked beneficial
effect (171, 172, 173, 321) on the condition of the patient is not at
all clear (163).
In older children and adults a milk diet (280) supplemented by
broth, eggs and vegetable purees is probably the best.
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BACTLLARY DYSENTERY IN ADULTS AND CHILDREN 465
The main consideration, as in typhoid fever, is to give as much
non-irritating food as possible without producing nausea and diar-
rhea. The lack of appetite makes feeding extremely difficult and
emaciation is frequent. In children this anorexia may be so pro-
nounced as to cause death from inanition. It is advisable to wait
until the temperature falls to normal before commencing forced
feeding. Changing the diet from protein milk to buttermilk or even
sweetened whole milk formulae does not appear to influence this lack
of appetite. If a child refuses one type of food he usually refuses
all food. If the desire for food does not return within one week, how-
ever, and the patient becomes very weak from inanition 2 to 6 ounces
of water may be given by stomach tube every four hours for the first
twenty-four hours. If vomiting does not result, one ounce of protein
milk or breast milk is substituted for one ounce of water and the child
is gavaged with the mixture. The strength of the mixture is increased,
unless the patient vomits, until undiluted protein milk is given.
Usually the child will regain his desire for milk given by bottle or
cup after a week of gavage feeding. Picard (352) recommends the
value of cocoa as a food for children with dysentery.
Injections of normal salt solution
In the more severe cases when the loss of water by the bowel has
been extreme and when the patients are markedly dehydrated and
cannot retain fluid given by mouth or rectum, sterile normal saline
or 5 per cent dextrose should be given intravenously in amounts of
125 to 500 cc. according to the size of the patient. Instead of normal
saline Von Jaksch (339) recommends the injection of a solution con-
taining sodium chloride 15 parts, calcium chloride 0.45 parts and
potassium chloride 0.7 parts in a liter of water. Weinberg, Singer
and others (339) inject hypertonic saline. In small children the
saline or 5 per cent dextrose may be administered intraperitoneaUy
(281). Normal saline is preferable as it is more readily absorbed.
This procedure has undoubtedly saved many lives. In many cases
repeated injection of saline or dextrose either at twelve or twenty-four
hour intervals may be necessary to replace the great loss of body fluid.
Subcutaneous injections are painful and do not allow the adminis-
tration of sufficient fluid. They may be used, however, in children
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466 WILBUBT C. DAVISON
if the abdomen is distended. Fluid administered by rectum either
by syringe or by a Murphy continuous drip is seldom retained or
absorbed by children. However, fluid, either saline, 5 per cent dex-
trose or boiled tap water, may be given from a continuous drip appara-
tus into the stomach by a nasal tube fastened in place by adhesive.
Stewart (434) has found that in children a drip delivering fifteen
drops per minute may be continued four to five days without pro-
ducing nausea. It may be given continuously or in periods of a half
hour alternating with equal periods of rest. In this way 500 to 1000
cc. of fluid may be given daily. If the infant has persistently refused
his feedings, protein milk may also be administered through the nasal
tube by disconnecting the drip apparatus and substituting a fun-
nel. The prolonged use of a nasal drip is not without danger, however,
for fatal erosions of the oesophagus and stomach have occasionally
occurred (451).
Specific serum therapy
As B. dysenteriae (Shiga) and (Flexner) are absolutely different
culturally and serologically, the success of the serum treatment of
bacillary dysentery will depend upon an accurate knowledge of the
type of the causative organism in each case and the use of serum
containing antibodies for that variety. Polyvalent sera (57, 121,
282, 283, 381) containing antibodies for both Shiga and Flexner
varieties are, of course, obtainable and should be used in severe cases
until stool cultures or the agglutination reactions of the patient's
serum have revealed the type of the infection. However, as the
results in Shiga infections have been more favorable than those in
Flexner infections, they will be discussed separately.
The therapeutic sera are prepared by the immunization of horses
with cultures of Flexner and Shiga bacilli or with the toxins of the
Shiga organism. Flexner and Amoss (283) have reported a rapid
method for the production of potent antidysenteric serum. Agglu-
tination tests with the dysentery bacillus isolated from the patient^
stool and the available therapeutic serum (unless Shiga antitoxin is
used) should be made whenever practical (57) to determine whether
there are antibodies for this particular strain. Otherwise, serum
therapy is often useless. Attempts are now being made (284) to
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 467
standardize Shiga toxins and antitoxins in much the same way as
those of the diphtheria bacillus.
a. In Shiga infections
A potent antidysenteric serum should contain antibodies against
the exotoxin as well as the endotoxin. Such sera and antitoxins
are now obtainable (119, 283). Antitoxin (made by immunizing
horses with toxins) is preferable in the treatment of Shiga infections
but sera made by the injections of the organisms themselves are also
efficacious. Olitsky and Kligler (119) found that a polyvalent anti-
dysenteric serum, although prepared by injecting the cultures alone,
contained at least 2000 anti-exotoxic units per cubic centimeter as
well as anti-endotoxin and other antibacterial bodies.
Shiga (46) in the Institute for the Research of Infectious Diseases
in Tokio has formulated the following rules for the administration
of antidysenteric serum or Shiga antitoxin:
1. In mild cases the serum is injected once in a dose of 10 cc.
2. In cases of medium severity the serum is twice injected in doses
of 10 cc. The interval is from six to ten hours.
3. In severe cases the largest amounts are injected (40 to 60 cc.)
but the daily dose does not exceed 20 cc.
This dosage is very conservative. I have used twice this amount
subcutaneously and intramuscularly in children without reactions
(285). The doses for adults could be trebled advantageously. The
best method of injection is intravenously, care being taken to intro-
duce the serum slowly and to avoid shock. Should a patient give a
history of having had asthma, or of being sensitive to horse serum or
of having had previous serum treatments, one drop of sterile diluted
horse serum (diluted 1:10 with normal saline) should be injected
intradermally (401). If the patient has a local or general reaction
to this within one hour, 1 cc. of serum should be injected subcuta-
neously for desensitization. Six to eight hours later the full dose of
serum may be given slowly, either subcutaneously or intravenously.
If the patient fails to react to the intradermal serum test within one
hour, the full dose may be injected at once.
For adults many authorities (286, 287) advise the intravenous
injection of 60 to 100 cc. of polyvalent serum as early as possible
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468 WILBURT C. DAVISON
after admission, followed by 40 to 80 cc. subcutaneously or intra-
muscularly within 12 hours in severe cases. Shiga antitoxin or Flex-
ner serum should be used as soon as the type of infection is known.
In children, however, the reactions to intravenous serum are often
so severe that injections should be subcutaneous or intramuscular.
Serum sickness with fever, urticaria and arthralgia frequently follows
serum therapy on about the tenth day (55) both in adults and children
but is rarely alarming.
Lantin (288) reports that serum given by rectum is efficacious.
If Besredka's (230) theory that the intestinal lesions are due to the
contact of dysentery endotoxin with the intestinal mucosa is correct,
the administration of antitoxin or antiserum by mouth or rectum in
large doses is the most logical method, for it is in the intestine that
the endotoxin must be neutralized. Serum given intravenously or
subcutaneously must first be excreted into the intestine to counteract
the effect of the endotoxin on the intestinal mucosa. Intravenous
or subcutaneous serum therapy then in dysentery might be compared
to similar procedures in the serum treatment of cerebrospinal men-
ingitis for the administration of specific serum intraspinously in
meningitis is obviously the more direct and efficacious method. It
may be found that the direct administration of antidysenteric serum
by duodenal tube, as Smith (289) suggests, or by rectum (288)
or even by appendicostomy or colostomy wounds will reduce the
mortality in dysentery more than by the intravenous and subcutaneous
routes. Perhaps the efficacy of intravenous and subcutaneous serum
therapy in Shiga infections and the apparent lack of benefit from this
procedure in Flexner infections may be due to the fact that the Shiga
bacillus produces part of its effect by the action on the central nervous
system of absorbed circulating exotoxin while the whole picture in
Flexner infections is the local action of the endotoxin on the intestinal
mucosa.
Under serum therapy in Shiga infections in adults, the disease in
its first stages according to Shiga (46) and Flexner (381) is quickly
cured or the symptoms markedly ameliorated. In one or two days
after the injection, the blood and mucus usually disappear from the
stools, pain and tenesmus cease and the patient seems entirely well.
On the later use of the serum (at the end of the first week) improve-
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BAGELLA&Y DYSENTERY IN ADULTS AND CHILDREN 469
ment of all symptoms is usually noted after a few days. Recovery
usually occurs after a week. The effect of the serum upon the fever
is very striking; in the majority of cases the temperature may be
lowered to normal or even below normal on the next morning after
injection. In the ulcerative stage, the action of the serum is not so
pronounced as in the earlier stages; nevertheless healing of the ulcers
with cicatrization often takes place. Even in the later stages the
results are far better than those by any other method of treatment.
The mortality in Shiga infections in adults under the use of serum
is usually reduced by one-half (54, 78, 117, 243, 290, 291, 292, 390)
(from 22 to 26 per cent under medicinal treatment to 9 to 12 per cent
(46)). Shiga antitoxin has also been very successful in reducing mor-
tality (78, 118) in adults. In children with Shiga infections, serum
and antitoxin, in my limited experience (285), has been rather disap-
pointing. This may perhaps be due to the fact that children often
do not respond as well as adults to large subcutaneous and intramus-
cular injections of horse serum.
b. In Flexner infections
Treatment of Flexner infections with bactericidal and agglutinat-
ing sera has been attempted in many epidemics. The therapeutic
effects are not nearly as striking as those in Shiga infections and in
fact are rather disappointing both in adults (55, 253, 390) and chil-
dren (138, 200, 285, 293). With large intravenous doses of 40 to 100
cc. of anti-Flexner or polyvalent serum in Flexner infections some
authors have noted a reduction in mortality (54, 64, 80 286, 287, 291,
381) but equal benefit is frequently noted with the same amounts of
horse serum (73) or normal saline injected intravenously or intraperi-
toneally. In a few cases of Flexner infection in children which I have
treated or seen treated with anti-Flexner serum there has been little
or no beneficial result (285). Perhaps the administration of anti-
Flexner or polyvalent antidysenteric serum by mouth, duodenal
tube or rectum so that it will reach the intestine directly may be of
benefit.
Vaccine therapy
Following Shiga's (46) work with vaccines as a prophylactic measure
in dysentery epidemics, other observers (55, 253, 310, 311, 405, 415)
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470 WILBURT C. DAVISON
have reported benefit from similar procedures in the treatment of the
disease. On the other hand, Rogers and others (312) have had disap-
pointing results with vaccine therapy. As no well controlled experi-
ments have been reported with this method, it is reasonable to suppose
that the benefit is more apparent than real as Whittington (313)
has proved for the vaccine treatment of typhoid fever. In the treat-
ment of carriers of B. dysenteriae, vaccines have apparently been
more successful (7, 55, 175).
Proteosotherapy
Nolf (55, 309) and others (104) have advocated intravenous and
subcutaneous injections of 1 per cent Witte's peptone as a valuable
therapeutic measure in dysentery. The resulting peptone shock is
however occasionally alarming and the dose of the peptone solution
must be accurately graded. The injection should be made very
carefully and slowly. As a matter of fact, the majority of Nolf s
cases were Flexner infections (55) and inasmuch as the mortality with
this type is extraordinarily low, "proteosotherapy" should await
more confirmation before being widely used.
Drug therapy
Bleeding, purgation, ipecacuanha and occasionally opium were
the armamentarium of the past century and a half (10, 11, 12, 25,
30, 52, 294). The first procedure has fallen into disrepute and purga-
tion and ipecac will probably follow. Morphine (420) and paregoric,
as has been stated previously, are probably the only drugs at all use-
ful in the treatment of bacillary dysentery.
Cathartics have little to recommend them. Purgation cannot
assist the rapidly moving intestine to evacuate its contents and the
mucosa has already had sufficient irritation. That castor oil, sodium
or magnesium sulphate (295) and calomel (271) at the onset are of
value would seem improbable for the infection itself will increase the
number of bowel movements before these drugs will have time to
produce catharsis. If cathartics and frequent evacuations could
rid the intestine of the offending bacteria, all dysentery cases would
be of short duration.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 471
Ipecacuanha (39) has been highly rated as efficacious in the treat-
ment of bacillary dysentery. That it and its active principle emetine
are practically specific for amebic dysentery there is no doubt, but
the majority of observers deny its benefit in the bacillary variety.
In fact many physicians in practice away from laboratories make a
diagnosis of bacillary dysentery if ipecac and emetine fail to cause
improvement within a few days. One patient with bacillary dysentery
treated with benzyl benzoate (372) was apparently benefited. Koh-
ler (412) recommends a German drug mixture called "antidysten."
One observer (296) advocates the use of belladonna to counteract the
excessive activity of the thyroid and suprarenal glands in dysentery,
while another (297) prescribes adrenalin by mouth and rectum to
quiet tenesmus. Inasmuch as suprarenal insufficiency has been
reported (65) as a complication of dysentery, the adrenalin is perhaps
the more logical of these drugs but it is doubtful whether either is
really useful.
The ingestion of 300 grams of kaolin or animal charcoal in oatmeal
is advocated as a means of adsorbing dysentery organisms and also
rendering the stools more solid (270, 314). Hirsch (315) states that
rectal injections of kaolin are more efficacious than the administra-
tion by mouth. Weise (316) on the other hand, advises against the
use of kaolin on the ground that it forms irritating lumps and does
more harm than good. In young children with watery non-dysenteric
diarrhea I have found that kaolin and animal charcoal in daily
doses of 10 to 20 grams administered in milk will reduce somewhat the
number of stools and render them solid by their mechanical action
of adsorbing fluid but their beneficial effect has not been particularly
apparent.
Irrigation of the colon
In the later stages of the disease and especially in chronic cases,
rectal irrigations with tap water (298), 0.01 per cent silver nitrate
(79, 299, 300), 0.25 per cent tannin, 0.01 per cent methylene blue
(301), permanganate (3), 2.0 per cent sodium salicylate (302) and
other solutions (303) have been recommended but their benefit is
not striking. Ohly (353) found a 10 per cent ichthyol salve or a 2
per cent silver salt salve useful for local treatment, followed by
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472 WILBURT C. DAVISON
astringents. Schiff (304) reported that rectal injections of 300 cc. of
1 per cent formalin twice a day and continued until the stools were
more consistent and then once a day for the next week, were beneficial
in Shiga infections. This mode of therapy is painful however. The
pain due to repeated introductions of a rectal tube may be largely
obviated by the preliminary use of cocaine suppositories, but injec-
tions in many cases are not tolerated or retained. In obstinate cases
irrigations and flushing of the colon with these solutions through a
colostomy or appendicostomy wound have also been advocated (7,
305, 421) but have not met with enthusiasm (390). Allowing the
intestinal contents to drain through a caecostomy wound and thus
reducing the irritation of the mucosa of the large intestine has been
reported as advantageous (336).
Cooke (306) and others (307) advise touching all chronic ulcers
that can be reached through a proctoscope with a solution containing
60 to 120 grains of silver nitrate to the ounce until tenesmus is re-
lieved. The use of sigmoidoscope, however, is occasionally danger-
ous (446). According to Rogers (3) copper sulphate in a strength of
1 grain to the ounce similarly used is also often of great value and
has the advantage of being less painful than silver nitrate. The same
author (308) has shown experimentally that silver nitrate in a dilu-
tion of 1:10,000, would kill B. dysenteriae in five minutes.
X. MEANS OF SPREAD (EPIDEMIOLOGY)
That dysentery is a communicable disease has been shown, by the
review of the numerous epidemics that have occurred among the
civilian population and among troops. No one exclusive method
of spread or conveyance has been proved but it is probable that,
as in typhoid fever, the Oslerian triad (317) of fingers, food and flies
is the most important factor. m
Graham Smith (318) and others (319, 356, 358, 368, 382, 383)
have shown that flies are capable of spreading dysentery. The
curves of the case incidence of dysentery among the British troops in
Salonika (57) in the A. E. F. (67) and in our series of cases in children
(48) demonstrated that the greatest incidence occurred during the
summer and autumn months in which flies were the most numerous.
B. dysenteriae was isolated from the feet of flies caught in one of the
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BACILLAEY DYSENTERY IN ADULTS AND CHILDREN 473
Salonika hospitals. After contact with food infected with dysentery
bacilli flies could carry and disseminate these organisms for twenty-
four hours (320). Bishopp and Laake (388) have reported that flies
may frequently travel eight miles from the point of liberation in
less than a single day. Paraf (358) made the following observations
in a hospital containing patients with bacillary dysentery where flies
were very prevalent: (1) Flies swarming round the dejecta of dysen-
tery patients were frequently found to be carriers of the Shiga bacil-
lus. (2) The Shiga bacillus was found in the bodies of flies caught in
wards in which dysentery had occurred. (3) The dysentery bacillus
was found in food exposed to the air in surgical wards in which there
were swarms of flies. (4) As regards the mode of transmission, cul-
tures of flies1 legs and wings were positive in only two out of sixteen
cases, whereas cultures of the alimentary canal were positive in eleven
out of twenty-four cases. (5) The maximum duration of the survival
of the dysentery bacillus in the fly's intestine was found to be five
days. After that time the cultures were negative.
Through the winter and early spring there are comparatively few
cases and in some parts of the country the disease disappears alto-
gether to reappear the next summer. During the flyless months
the infecting of food by fingers that have handled the excreta of dys-
entery patients and contact infections from contaminated clothing
and utensils are logical explanations of the spread of dysentery (335).
Direct ascending infections from the use of infected latrines (236)
and syringes may possibly occur but are surely not frequent. The
infection in these cases is probably not ascending but more likely due
to the soiling of the fingers.
Carriers of dysentery bacilli have frequently been reported (47,
73, 75, 117, 151, 175, 186, 187, 214, 239, 335, 213). Convalescents may
harbor the organisms for many months (46). It is probably by means
of these carriers and convalescents that dysentery is carried over
from one epidemic season to the other and from one locality to another.
Lentz (110) reported the experience with a soldier who, after recovery
from dysentery, left his regiment and was the source of a dysentery
epidemic in his native village. Other widespread epidemics have
similarly been traced to individuals who were convalescent or sup-
posedly cured of dysentery (29, 176, 357, 366).
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474 WILBTJKT C. DAVISON
Direct contact with a neighbor's child suffering from dysentery
or with an adult with a mild diarrhea are responsible for many cases
of dysentery in children (48). Two cases of dysentery in newly born
infants whose mothers had dysentery have been reported (417).
Two or more cases frequently occur in the same house. Small hos-
pital epidemics are not uncommon. The institution of special wards
for and the strictest isolation of dysentery patients usually reduces
the incidence of infections acquired in hospitals.
Water-born epidemics of dysentery are sometimes reported (57, 322).
Dysentery bacilli have occasionally been isolated from the suspected
rivers or wells (46) and it has been shown experimentally (176, 322)
that these organisms can survive nine days or more in samples of the
water (57). Shiga (46) reported one outbreak due to bathing in a
stream. It was found that an epidemic of dysentery existed in a
village higher up the river and the water had been contaminated by
the washing of the infected clothes. Another epidemic in Japan
was traceable to the use of a common bath house. An epidemic in
Metz in 1870 was restricted to two regiments who derived their water
supply from fecally polluted wells (323). The substitution of dis-
tilled water in the British Navy (324) and of artesian well water among
the Dutch troops in Java reduced the incidence of dysentery nearly
to a tenth. Kligler (448) has shown that soil pollution by dysentery
is very limited. It probably plays little or no rile in the spread of
the disease.
Amebic dysentery, however, is more likely to be spread by drinking
or bathing in infected water while flies are probably the more common
method of dissemination of badUary dysentery during wars (57,
319, 322).
In my experience the infection of the milk and food in the individ-
ual households or army messes by flies or attendants' fingers is the
probable explanation of its spread. Lorenz (375) in an epidemic of
dysentery in an orphanage reported that the milk was probably in-
fected after sterilization by one of the servants who suffered from a
dysentery-like condition.
The institution of Baby Welfare Clinics and Feeding Stations in
several cities has probably been a great factor in the reduction of
dysentery in children, for in the past few years since these have been
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 475
established the number of cases of dysentery in children admitted
to hospitals has become steadily smaller. Mothers are taught to
keep their infants clean and to give them clean food. Occasionally
in epidemics of dysentery among children the milk supply has been
suspected (139). I was unable to trace any relationship between
any of my cases (48) and the source of the milk supply. The pas-
teurization of milk and its distribution in bottles instead of being
sold in bulk at corner grocery stores have had an important influence
in reducing dysentery. This has probably not been because dysen-
tery bacilli in the original milk have been killed by pasteurization,
for B. dysenteriae has rarely, if ever, been found in a milk supply,
but because the use of pasteurized and bottled milk has educated
the public to the necessity of the careful handling of this readily
infected food. Knox and Powers (325) were able to reduce the inci-
dence of dysentery among the children whose feedings were super-
vised by the Babies Milk Fund Association of Baltimore, by insisting
that the infants be fed only milk mixtures that have been boiled
directly in the feeding bottles (so that the possibility of contaminating
the boiled mixture by transferring it to the bottle is obviated). Dys-
entery is rare in breast fed children (152).
XI. PROPHYLAXIS
When cases occur or are suspected either among adults or children,
the patient should be promptly isolated. Those engaged in caring
for patients with dysentery should not prepare food for other indivi-
duals. The breast feeding of infants should be encouraged. When
this is impossible the milk mixtures and the bottles or containers
should be boiled. Flies should be suppressed and food and feces
rigidly separated. Excreta from patients and all open latrines must
be adequately covered or disinfected with lysol, carbolic or other
antiseptics. Before a patient is discharged as cured and released
from quarantine he should have three negative stool cultures (69)
over a period of two weeks. Inasmuch as it is sometimes impossible
to detain for long periods ex-soldiers who have chronic dysentery
or who are carriers of dysentery bacilli, the British (386) notify the
local health officer of the man's home town before discharging any
of these patients so that he may enforce precautions. Only by the
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476 WILBTJKT C. DAVISON
rigid application of these measures can the spread of dysentery be
prevented.
The first great step toward the reduction of the incidence of bacillary
dysentery in children will be made as soon as it is more generally recog-
nized that the great majority of cases of bloody diarrhea in children
are true dysentery. The second step will consist in making this
disease both in adults and children reportable to the Health Authori-
ties so that the same measures that have made typhoid fever a com-
paratively rare disease can be instituted against bacillary dysentery.
Prophylactic vaccination
Inoculation with dysentery vaccines may prove as valuable as
is the prophylaxis of typhoid fever particularly for children in cities
in which dysentery is prevalent. Heretofore, however, the severe
reactions to these vacines have made their general use impractical
(222, 230, 326, 327). The immunity conferred probably lasts two
to three months (222). Vaccines of the Shiga bacillus are very toxic
and frequently give rise to sterile abscesses at the point of inocula-
tion. To avoid this Shiga (46, 241) first used simultaneous injec-
tions of vaccine and serum. Various methods of reducing the toxicity
of Shiga vaccines have been advocated (328, 366). Busson (329)
recommends prophylactic inoculations with dysentery toxin-anti-
toxin mixtures. Graeme Gibson (330) was able to eliminate the
reaction to dysentery vaccine and still establish protection by the
injection of a saline suspension of B. dysenteriae (Shiga) and (Flex-
ner) mixed with an equal quantity of absorbed polyvalent antidysen-
teric serum. The results of this technique are encouraging and
further experience may establish its usefulness.
Vincent (349) using an ether killed polyvalent antidysenteric
vaccine, containing five Shiga and seven Flexner strains, in doses of
500,000,000 to 750,000,000 bacilli in a series of 2175 men found that
during a severe epidemic the incidence of infection was twelve times
greater among unvaccinated individuals than among his vaccinated
series. The reactions to the injections were very slight. Spolverini
(351) recently stated that in a small series of children a vaccine made
with various strains of B. coli was useful as a means of curing and
preventing enterocolitis.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 477
Whether or not Besredka's (230) method of administering prophy-
lactic vaccines by mouth will prove effectual in man remains to be
seen.
Dysbakta (Boehncke) a German proprietary vaccine (probably a
combination of dysentery bacilli, toxin and antitoxin) in spite of
earlier favorable reports (328, 331) has recently been shown (332)
to have nothing to recommend it. Lipovaccines made according to
Le Moignac's (333) method have been advocated (334) because of
their mild reaction, but the difficulty of insuring their sterility has
detracted from their value.
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(63) Douglas, S. R., Colebrook, L., Morgan, W. Parry: Report upon a series of
cases of dysentery received from Mediterranean expeditionary forces. Med.
Res. Com. Sp. Rep. Series London, 1917, No. 6.
Manson-Bahr, Philip: Correlation of the pathology and bacteriology of bacfllary
dysentery. Jour. R. A. M. C, 1919, xxxiii, 117.
(64) Klein, B. G.:*t Serum treatment of bacfllary dysentery: Dysentery arthritis,
Lancet, London, 1919, ii, 775-8, and Jour. R. A. M. C, 1919, xxxiii, 343.
Cowan, J. N., and Miller, H.: Dysentery: "A clinical study." J. R. A. M. C,
1918, xxxi, 277.
Lunn, W. £. C: Toxemic arthritis as a complication of acute dysentery. J. R.
A. M. C, London, 1914, xxii, 310.
(65) Remltnger, P., and Dumas, J. : La Dysenteric de l'Argonne, Itude bacteriobgkrae.
Ann. de PInst. Pasteur, Paris, 1915, xxix, 498.
Remltnger, P., and Dumas, J.: Syndrome capsulaire aigu au cours de la dysen-
terie baciflaire. Ann. de m&L, Paris, 1914-15, ii, 605.
Remltnger, P.: Compt. rendu de la Soc. de Biol., Paris, 1915, lxxviii, 423 and 433.
Remltnger, P. : Surun nouveau bacille dysenterique atypique. Ibid, 1916, tarix, 576.
(66) Tribondeau, L., andFichet, M.: Results de Tanalyse bacteriologique des selles
dans 217 cas de dysenteric provenant du corps expeditionaire d*Orient (C
E. O.). Bull. Acad, de MeU, Paris, 1916, 3.s. Ixxv, 317.
Tribondeau, L., and Fichet, M.: Note surles dysenteries des Dardanelles. Ann.
de llnst. Pasteur, Paris, 1916, xxx, 357.
Armand-Deltlle, Paisseau and Lematre: Note sur une epidemic de dysenteric
bacfllarie a l'armee d 'Orient. Bull, et mem. soc. med. d. hop. de Paris, 1916,
3.s. xl, 1302.
(67) Vaughn, V. C, Jr.: Typhoid fever (and dysentery) in the A. E. F. Jour. Amer.
Med. Assn., 1920, Ixxiv, 1074.
(68) Davison, W. C: The aerobic flora of dysentery stools in adults and children.
Transactions of Society of American Bacteriologists, 21st arm. meeting,
Boston, Dec. 31, 1919; Abstracts of Bacteriology, Baltimore, 1920, iv, 15.
(69) Rajchman, L., and Western, C. T.: Report upon 878 cases of bacillary enteritis.
Med. Research. Comm. Special Rep. Ser., London, 1917, No. 5.
(70) Walko: Wien. klin. Woch., 1915, xxvii, 197 and 236.
(71) Seligmann, E., and Cossman: Zur Bakteriologie der Ruhr im Kriege. Munch.
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(72) &I8SKALT, K.:* Seasonal occurrence of cholera, dysentery, typhoid and typhus.
Deutsch Med. Woch., Berlin, 1915, xli, 579.
(73) Rumpel, T.,* and SraGA, G.: Dysentery among the troops. Munchn. Med.
Woch., Munich, 1915, fcrii, 180, 657, 1021.
Sibbest, H.: Erfahrungen fiber die Ruhr bei deutschen Soklaten in der Turkei.
Beihefte z. Arch. I. Schiffa- u. Tropenhyg., Leipzig, 1919, acriii, 97-113.
(74) Paltaut: Report of meeting of Med. Soc., Vienna, Dec., 1914. Wien. klin.
Woch., 1915, zxvii, 44.
Landstetnkr: Ibid., 485.
Sternberg: Ibid., 486.
Falta, W., and Kohn: Ibid., 583.
(75) Vekzar, F.,* and Wes4eczky, O.: Carriers of B. dysenteriae (Flezner) (ueber
BazfiDentriger bei Flexner-Dysenterie). Munch. Med. Woch., 1916, Ixiu.
(76) Scmarz, K. E. F.: Ueber einen bisher noch nicht bekannten Krankheitserreger
aus der Dysenteriegruppe. Ibid., 1918, Izv, 1571.
Sodotz, K. E. F.: Ein neuer Typus aus der Gruppe der Ruhrbazfllen als Erreger
einer grosseren Epidemic Ztschr. f. Hyg. u. Infectkmskrankh., Leipz., 1917,
hcndv, 449-516.
Schmttz, K. E. F.: Centr. f. Bakt., Jena, 1918, lzxzi, 1 abt. Orig. 213.
Schmtk, K. E. F.: Neue Mitteilungen uber Verwandlnngsfihigkf.it, Paragglu-
tination unsw. in der Ruhr, Typhus-Coligruppe auf Grand experimentaller
Beobachtungen., ibid, 1919, Izzz, HI.
(77) Shiga, K.: Ueber den Erreger der Dysenteric in Japan. Centr. f. Bakt., Jena,
1898, joriii, lte abt, 599.
Shiga, K.: Ueber den Dysenteriebazfllus (B. dysenteriae), ibid, 1896, xxiv, 817,
870 and 913.
Shiga, K.: Studien uber die epidemische Dysenteric in Japan unter besonderer
Berucksichtigung der Bacillus dysenteriae. Deutsch. Med. Woch., 1901,
Nos. 43, 44, 45 and 48.
Shiga, K.: Weitere Studien Uber den Dysenterfcbaziuus. Ztschr. f. Hyg., 1902, xli.
Shiga, K.: Die Priorit&t der Entdeckung des Ruhrbazillus und der Serumtherapie
bei der Dysenterie. Deutsch. Med. Woch., 1903, No. 7.
Shiga, K.: Ueber Versuche zur Schutzimpfung gegen die Ruhr. Deutsch. Med.
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Shiga, K.: Observations on the Epidemiology of Dysentery in Japan. Philippine
Jour, of Science, 1906, i, 485.
(78) Rosenthal, L.: Centr. f. Bakt., 1904, xxxiv, lte Abt., Ref., 503.
Rosenthal, L.: Zur Atiologie der Dysenterie (Moscow). Deutsch. Med. Woch.,
1903, nk, 97.
Rosenthal, L.: Ibid., 1904, xxx, 235.
(79) Manson, P.: Tropical Diseases. 2 ed. (text book), London, 1903.
(80) Ruffek, M. A., and Willmoxe, J. G.: On the Etiology of Dysentery. Brit. Med.
Jour., London, 1909, ii, 862.
Rotter, M. A., and Willmoxe, J. G.: The serum treatment of dysentery with
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Castellani, A. : La Malattia del sonno. Riv. Critics di clinica med., 1903, iv, 652.
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Zeitachr. f. Hyg., 1901, zzzvii, 381.
Casxellani, A.: Some researches on the etiology of dysentery in Ceylon. Jour.
Hyg., Cambridge, England, 1904, iv, 495.
Castsllani, A., and Chalmebs, A. J.: BadDary dysentery in Manual of Tropical
Medicine, 2. ed., London and New York, 1913, 1380.
(81) Lambl: Beobachtung und Studien aus dem Gebiete der Path., Anatomic a.
Histologic aus dem Franz-Josef Kinderhospitale in Prag., I860, p. 365.
(82) Cunningham, D. D., and Lewis: Seventh annual report of the Sanitary Com-
mission with the Government of India; Report on cholera. Calcutta, 1870.
Cunningham, D. D.: On the development of certain organisms occurring in the
intestinal canal. Quart. Jour, of Microscopical Science, 1881, rri, 234.
(83) Loesch: Massenhefte Entwickelung von Amebae in Dichdarm. Virchow's
Archiv., 1875, Ixv, 196.
(84) Raktuus: Ueber tropische Leberabscesse und ihr Verhaltnis cur Dysenteric;
Amoeben im Eiter der dysenterischen Leberabscesse und ihre Verhiltnisse
aur Dysenteric. Cent, f . Bakt., 1887, ii, 745.
Kaktulis: Zur Aetiol. der Dysenteric in Aegypten. Virchow's Archiv., 1886,
cv, 521.
Kastuus: Ueber Reisenamoebcn bei chronischen Darmctaundungen der Aegypter.
Virchow's Archiv., 1885, xdx, 145.
(85) Massiocetine (Massiuttn): 1889, Kiev; Ob. amoebakh kak tchougeiadnykh
toslstiah kishok. Wratach 25, abstracted in Centralblatt fur Bakt, vi, 451.
(86) Osler, William: On the amebae coli in dysentery and in dysentery liver abscess.
Johns Hopkins Hospital Bull, 1890, i, 53.
Oslsr, William: Ueber die in Dysenteric und dysenterischen Leberabszess
vorhandene amoeba. Centr. I. Bakt., 1890, vii, 736.
(87) Councilman, W. T., and Laflsur: Amebic dysentery. Johns Hopkins Hospital
Repts., 1891, ii, 395.
Councilman, W. T.: Dysentery. Trans. Ass. Am. Phys., 1892, vii, 113-140.
(88) Scbaudinn: Untersuch. liber die Fortpflanaung einiger Rhiaopoden, arb. aus dem
Kais. Gesundhcitsamte, 1903, ziz, Heft 3, 563.
(89) Taoliatekbo, J. A.* Balantidium dysentery in Venezuela. Gaceta Med. de
Caracas Venezuela, 1918, zzv, 145.
Mason, C. W.:* Case of balantidium coli dysentery. Jour. Parasit, Urbana,
HI., 1919, v, 137.
Steen, P. H.:* Balantidium colitis. Ugeskrit for Laeger, Copenhagen, 1921,
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deBellakd,E.P.:* Balantidium dysentery. Gaceta Med. de Caracas, Venezuela,
1919, xxvi, 27.
(90) Sangiokgi, G.:f Dysenterie in Albania. Pathologka, 1919, zi, 141-4.
(91) Fleming, R. A. :f Disease in Macedonia. Edinburgh Med. Jour., 1919, i, 215-25.
Mantovani, M.:f Lambliosi intestinale. Gaza. d. osp., 1919, xi, 66-9.
Labbe, M.:f La frequence des dysenteries amibiennes meconnues. BulL Acad.
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BAULLARY DYSENTERY IN ADULTS AND CHILDREN 483
(92) Besson, A., and Hutchens, H. J.: Practical bacteriology, microbiology and serum
therapy. Eng. trans, of 5th French ed., London and New York, Longman &
Co., 1913, 362.
(93) Chatteeje, G. C.:* Flagellate dysentery. Indian Jour, of Med. Research,
Calcutta, 1917, iv, 393.
Rhamy, B. W., and Mstts, F. A.: Flagellate protozoa as an etiologic factor of
dysenteric diarrhoea, report of a series of cases of trichomonas dysentery
including a local epidemic with 17 deaths. Jour. Am. Med. Assn., Chicago,
1916, Ixvi, 1190.
Gkothusan: Ruhrartige Erkrankungen durch Flagellata. Arch. f. Schiffs- u.
Tropen-Hyg., 1920, xxiv, 49.
(94) Low and Castellani, A.: Ibid., 1904, viiL
(95) Basch.: Anatomische und klinische Untersuchungen tiber dysenterie. Virchow's
Archiv, xlv, 204.
(96) Klebs: Die allgemeine Pathologic oder die Lehre von den Ursachen und dem
Wesen der Krankheitsprozesse, Jena, 1887.
(97) Chantemesse and Widal: Sur le microbe de la dysenterie, epidemique. Bull.
de l'acad. de meU, Paris, 1888, nx, 522.
Chantemesse and Widal: Deutsch. Med. Woch., 1903, xxix, 204.
(98) Gsxgokiew (Grigokjeff), A. W.: Zur Frage der Mikroorganism bei Dysenterie
(Woermomedkinsky Journal, Tl, Lad, 1891, S. 73-102) (Russian) abstracted
in Centr. f. Bakt, 1892, rii, Ref. 876.
(99) Ogata: Zur Xtiologie der Dysenterie. Centr. f. Bakt, 1892, xi, 264.
(100) Celli: Etiologiadelkdissenteriane^oirapporticoliecollesuoetossine. Annalo
d'igien. sperim., 1896, vi, 204.
Celli: Zur Xtiologie der Dysenterie. Internat. Beitr&ge zur Inneren Medizin,
Berlin, Bd. 1.
Celli und Valenti: Nochmal ttber die Xtiologie der Dysenterie. Central, f.
Bakt., 1899, zzv, 481.
Celli und Fiocca: Ueber die Aetiologie der Dysenterie. Centr. f. Bakt.,
xv-xvii.
(101) Maggioea, A.: Quelques observations microscopic et bacteriologique faites durant
une epidemie d'enterocolite dysenterique. Turin, H. Loescher, 1892, repr.
from Arch. Ital. de Biol. Turin, 1891-2, xvi.
(102) Aenaud: Recherches sur l'etiologie de la dysenterie aiguC des pays chauds. Ann.
de rinst. Pasteur, Paris, 1894, 495.
(103) Gilbert, Gieod, Lesags and Macaignein, Peaundlsr, M., and Schlossmann,
A.: The diseases of children. Eng. transl. ed. by H. L. K. Shaw and L. La
Fetra, Philadelphia and London., 1908, J. B. Lippincott Co., vol. iii, 295-297.
Rossi, Doria T.: Ueber einige durch das Bacterium coll commune an Kindern
hervorgerufene Diarrhoen mit epidemischen Character. Centr. f. Bakt.,
1892, xii,Orig. 458.
Lavesan: Etiologie de la dysenterie. Semaine Med., November 8, 1893.
Fineelstein: Deutsch. Med. Woch., 1896.
Esgherich: Ibid., 1898.
Eschesich: Verh. d. Kongr. f. innere Medizin, 1899.
Esgherich: Zur Aetiologie der Dysenterie. Centr. f. Bakt., 1899, zxvi, Orig.
1 abt., 385.
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484 WILBURT C. DAVISON
B&och, C. E.:* Acute digestive disturbances in infants. Ugeskrift for Laeger,
Copenhagen, 1920, Ixxxii, 745.
Janowski, W.:* Etiology of dysentery. Paris Medical, Paris, 1921, xi, 152.
(104) Ftjrno, A.:* Protein therapy in colitis. Rivista Critica di Clinica Medica. Flor-
ence, 1920, zxi, 37.
Danysz, J.:* Entero antigens in treatment of dysentery. Presse Meaicale, 1921,
xrii, 362.
(105) Calmette: Note sur la presence du bacille pyocyanique dans le sang et l'intestin
de dysenteriques en Cochinchine. Arch, de m6d. navale, 1892, lx, 207.
(106) Lartigan (U.S.A.), Adami (Canada): B. pyocyaneus as the cause of dysentery,
in Castellani, A., and Chalmers, A. J. Manual of tropical medicine, 3 ed.,
London, 1919, BaHliere, Tindall & Cox, p. 1841.
(107) Logan, W. R.: The' intestinal flora of infants and young children. Jour. Bath
& Bacterid, Cambridge, 1913-14, xviii, 527-551.
Bravo and Frias :* Acute colitis in children. Sigio mod., Madrid, 1919, Ixvi, 1025.
Oppenheim, C. J.:* The human fecal streptococci. Jour. Infec D2s., Chicago,
1920, xxvi, 117-129.
Blackader, A. D.:* Epidemic of hemorrhagic diarrhoea due to streptococcus
mucosus. Proc. Am. Ped. Soc., June, 1920, Jour. Am. Med. Assn., 1920,
1920, Ixxv, 128.
Weiss, H.:* On the etiology of an outbreak of infectious diarrhoea. Arch. Int
Med., Chicago, 1921 ,xxviii, 37-49.
Ross, S. M., and Peckam, C. F.: Enterococcus in certain types of dysentery.
Lancet, London, 1920, i, 1362-3.
(108) Tsikunsky, Mlle: Contribution a 1'etiologie des diarrhees des nourrissons.
Ann. de l'lnst. Pasteur, Paris, 1917, xxxi, 517-536.
(109) Flexner, S.: On the etiology of tropical dysentery. Philadelphia Medical Jour-
nal, 1900, vi, 414.
Flexner, S.: On the etiology of tropical dysentery. Centr. f. Bakt, 1900,
xxviii, lte abt, 625.
Flexner, S.: A comparative study of dysentery bacilli. Ibid, 1901, xxx, lte
abt, 449.
Flexner, S.: A comparative study of dysentery bacilli. Brit. Med. Jour., London,
1901, ii, 786.
Flexner, S. : On the etiology of tropical dysentery. Johns Hopkins Hosp. Bull.,
Baltimore, 1900, xi, 231.
Flexner, S., and Barker, L. F.: Report of a special commission sent to the
Philippines by the Johns Hopkins University to investigate the prevalent
diseases of the islands. Johns Hopkins Univ. Circular, 1900, xix, 13.
(110) Martini, E., and Lentz, O.: Ueber die Differenaerung der RuhrbaciOen mittels
der Agglutination. Ztschr. f . Hyg. u. InfcctJonskrankh., Leipc, 1902, xli, 540.
Lentz, O.: Vergleich, Cultur, Untersttber die Ruhrbax. Ibid., 1902, xli, 559.
Lentz, O.: Dysenteric, in Handbuch d. Mikroorg. (Kolle & Waascnnann), 2 aufl,
Jena, 1913, iii, 899.
(111) Park, W. H.: Personal communication.
Park, W. H., and Dunham: A clinical and bacter. study of a number of outbreaks
of disease due to the dysentery bacillus. N. Y. Univ. Bull, of the Med.
Sciences, 1902, ii, 187.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 485
Park, W. EL, Collins and Goodwin: The dysentery bacillus group and the varie-
ties which should be included in it. Jour. Med. Res., 1904, xi, 553.
Park, W. H., and Cabby: The presence of the Shiga variety of dysentery bacilli
in an extensive epidemic of dysentery. Ibid., 1903, ix, 180.
Park, W. H. : On the interpretation of reactions of agglutination among the badOi
of dysentery. Med. Rec. N. Y., 1903, lxni, 358.
(112) Strong, R. P., and Musgrave, W. E.: Reports on the etiology of the dysenteries
of Manila. Report of the Surgeon General of the Army, Washington, D. C,
1900, 251.
Strong, R. P., and Musgrave, W. E.: The bacillus of Philippine dysentery.
Jour. Am. Med. Assn., Chicago, 1900, xxxv, 498.
Strong, R. P.: BadUary dysentery. Therap. Int. Dis., (Forscheimer), New York
and London, 1914, v, 253.
(113) Hiss, P. H., and Russell, F. F.: Study of a bacillus resembling the bacQlus of
Shiga. Med. News, 1903, 289, and Med. Record, New York, 1903, lxui, 357.
Hiss, P. H.: On the fermentation and agglutination characteristics of bacilli of
the "Dysentery Group." Jour. Med. Research, 1904-5, xiii, (New Series
vm),i.
(114) Bsnians, T. H. C.:*f§ Inagghrtinable form of Shiga's dysentery bacillus, experi-
mentally derived from an agglutinable culture. Jour, of Path, and Bact,
Cambridge (Eng.), 1920, zxin, 171.
(115) Marshall and Knox, quoted by Davidson, A., and Flexner, S.: In Syst. of
Med. 2 ed., (AHbut, T. C, and Rolleston, H. D.), London, 1912, ii, part II,
493.
(116) Neisser, M., and Shiga, K.: Ueber freie Receptoren von Typhus-u. Dysenterie-
bazillen und uber das Dysenterietozin. Deutsch. Med. Woch., 1903, xxix,
61.
(117) Conradi, H.: (a) Ueber cine Kontaktepidemie von Ruhr in der Umgegend von
Metz. Festschr. z. 60. Geburtst. v., Robert Koch, Jena, 1903, 551-570.
Conradi, H.: (b) Ueber losleiche, durch aseptische Autolyse erhaltene Giftstoffe
von Ruhr- und Typhus-bacillen. Deutsch. med. Woch., 1903, xxix, 26.
Conradi, H. : (c) Verdfflent aus dem Gebiete des MffitSr-Sanit&ts-Wesens, Heft 20.
(118) Todd, C: On a dysentery toxin and antitoxin. Jour. Hyg., Cambridge, Eng.,
1904, iv, 480.
Todd, C: On a dysentery antitoxin. Brit. Med. Jour., London, 1903, ii, 1456.
(119) Olxisky, P. K.* and Klioler, I. J.:* Toxins and antitoxins of B. dysenteriae
(Shiga). Jour. Exper. Med., 1920, xxxi, 19.
(120) Flexner, S., and Sweet, J. E.: The pathogenesis of experimental colitis in ani-
mals and man. Jour. Exper. Med., Baltimore, 1906, viii, 514.
(121) Vaillard and Dopter, C: Etiologie de la dysenteric epidemique. La Presse
Med., 1903, 375.
Vaillard and Dopter, C: La dysenterie epidemique. Ann. de l'Inst. Pasteur,
Paris, 1903, xvii, 463 and 486.
(122) Nettz, E. A.:* Nudeoproteids of B. dysenteriae (Shiga). Russky Vrach, Petro-
grad, 1914, xiii, No. 25.
(123) Sonne, C.:f On the bacteriology of the paradysentery bacilli. Centr. f. Bakt,
Jena, 1915, lxxv, 1 abt. orig, 408.
Sonne, C.:f Hypotoxic dysentery bacilli. Kj0benh., 1914, 230, 8°.
M BDICHTK, VOL. I, NO. 8
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486 WILBURT C. DAVISON
(124) Tosbey, J. C: A comparative study of dysentery and dysentery-like organisms.
Pt. I, Bacilli producing a typical reaction in litmus milk; Pt. II, Dysentery-
like organisms which produce an atypical reaction in litmus milk and should
probably be included within the group of pseudodysentery bacilli. Jour.
Ezper. Med, Baltimore, 1905, vii, 365 and 385. <
(125) d'Heselle, F.:f Sur un microbe invisible antagoniste des badlles dysenteriques.
Compt. rend. Acad. d. sc., Paris, 1917, clxv, 373.
d'Heselle, F.: On the role of the filterable bacteriophagic microbe in baciUary
dysentery. Ibid, 1918, clxvii, 970.
d'Heselle, F.: On the role of the filterable bacteriophagic microbe in typhoid
fever. Ibid., 1919, clxviii, 631.
d'Heselle, F.: On the role of B. bacteriophage in avian typhoid. Ibid., 1919,
cbdx, 932.
d'Heselle, F. : Mechanism of defense against intestinal bacilli and their etiology.
Ibid., 1920, cLn, 72.
d'Heselle, F.: Le microbe bacteriophage agent d'irnmunit6 dans la peste et le
barbone. Ibid., 1921, clxzii, 99.
d'Heselle, F.:f Technique de la recherche du microbe filtrant bacteriophage
(Bacterophagum intestmale). Compt. rend. Soc. de bioL, Paris, 1918,
lzzzi, 1160.
d'Heselle, F.:f§ Sur le microbe bacteriophage. Ibid., 1919, Ixzzii, 1237.
d'Heselle, F. :f Sur la culture du microbe bacteriophage. Ibid., 1920, lxxziii, 52.
d'Heselle, F. :f Sur la resistance des bacteries a l'action du microbe bacteriophage.
Ibid., 97.
d'Heselle, F.: Sur le microbe bacteriophage. Ibid., 247-9.
d'Heselle, F.:f Sur le microbe bacteriophage. Ibid., 1318-20.
d'Heselle, F.:f Sur le microbe bacteriophage. Ibid., 1320-22.
d'Heselle, F.: Sur la nature du bacteriophage. Ibid., 1921, lxrriv, 339-40.
d'Heselle, F.: Phenomena coincident with the acquisition of resistance by the
bacteria to the action of bacteriophage. Ibid., 384-6.
d'Heselle, F.: Role of bacteriophage in immunity. Ibid., 538-40.
d'Heselle, F.: Sur rhistoriquedu bacteriophage. Ibid., 863-4.
d'Heselle, F.: Sur la nature du bacteriophage. Ibid., 908r-9.
d'Heselle, F.:§ Le microbe bacteriophage. Ibid., 1921, lzzxv, 767-^8.
d'Heselle, F.:* Le bacteriophage — son role dans Pimmunite\ Presse MM.,
Pfcris, 1921, niz, 463-4.
d'Heselle, F.:* Le Bacteriophage, Son Role dans l'immunitt. Masson & Cie,
Puis, 1921, 227.
d'Heselle, F., and Eliava, G.:§ Antibacteriophage serum. Compt. rend. Soc
de bioL, Paris, 1921, bmriv, 719-21.
d'Heselle, F.,g and Eliava, G.:g Unicite* du bacteriophage; sur la lysine du
bacteriophage. Ibid., 1921, lzzzv, 701-2.
Fsiedemann, U.: (Review), Ueber das d'Herelle-phanomen.' Die Naturwissen-
schaften, Berlin, 1921, ix> 1010-1014.
Ameuille, P.:* (Review), DUerelle's Bacteriophagum. Annales de M6d., Paris,
1921, ix, 197.
Machado, A.,* and Costa Csuz.:* The bacteriophagum, Brazil-Medico, Rio de
Janiero, 1921, ii, 347.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 487
Puntoni:* (Review), Ann. d' Ig., 1920, xxx, 643.
Editorial: Do bacteria suffer from infectious diseases? Jour. Amer. Med. Assn.,
Chicago, 1921, Ixxvii, 126-7.
Otto, R.,* and Munter, H.:* The d'HereUe Phenomenon. Deutsche Med.
Woch., Berlin, 1921, xlvii, 1579.
Gjorop, E.:* (Review), Bacteriophagum intestinale. Hospitalstidende, Copen-
hagen, 1921, bdv, 214 and 234.
(126) Twort, F. W.:f An investigation on the nature of ultra-microscopic viruses.
Lancet, London, 1915, ii, 1241.
(127) Kabrshdea, T.rf Sur un ferment d'immunite' bacteriolvsant du mecanisme d'im-
munite infectieuse intestinale, de la nature du dit "microbe filtrant bacterio-
phage" de d'Herdle. Compt. rend. Soc de biol., Paris, 1920, lxxxiii, 219.
Kabeshdia, T.: Sur le ferment d'immunite* bacteriolvsant. Ibid., 1920, lxxxiii,
471-3.
Kabeshdia, T.: Experimental research on prophylactic vaccination against B.
shigae. Compt. rend. Acad. d. sc., Paris, 1919, cbrix, 1061.
Kabkshtka, T.rf Therapie experimentale des porteurs de germes. Ibid., 1920,
dxx, 71.
(128) Bablet, J.:f Sur la principe bacteriophage de d'HereUe. Compt. rend. Soc. de
biol., Paris, 1920, lxxxiii, 1322-24.
(129) Metalnikow, S.rf B. dysenteriae and dUerelle's bacteriophage in the larvae of
Galleria meUonella. Ibid., 667.
(130) Barber, M. A.: The variability of certain strains of dysentery as studied by the
single-cell method. Philippine Jour. Science, Manila, Sect. B. Trop. Med.,
1913, viii, 539.
(131) Murray, E. G. D.: An attempt at classification of B. dysenteriae based upon an
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1918, xxxi, 257 and 353.
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Winslow, C. W., Kligler, I. J., and Rothberg: Classification of the colon-
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Andrewes, F. W.,f and Inman, A. C.:f A study of the serological races of the
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diarrhea in infants. Boston Med. and Surg. Jour., 1916, clxxiv, 785-788.
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(174) SchCrer, F.:f Ueber die Pathogenese der Dauerausscheider und Bazillentrftger.
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of the Gaertner-Paratyphoid group. Jour. R. A. M. C, 1919, xxxiii, 140,
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Mackie, F. P., and Bowen, G. J.: Lancet, London, 1920, ii, 154.
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Berlin, 1919, lvi, 1059.
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originale, Heft 6, 434.
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Dean, A.:* Isolation of organism resembling paratyphoid group. Med. Jour.
of Australia, Sidney, 1920, i, 27.
Maruta, M.:* Bull, of Naval Med. Assn. of Japan, Tokyo, 1918, No. 20, p. 1.
Broughton-Alcock* and Lagane:* Atypical strain of B. paratyphosus. Lancet,
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xxxv, 55; m. Some cultural characteristics and their relation to host-origin.
Ibid., 357.
Sghittenhelm, A.: J Infections with B. enteritidis, Breslau. Munch. Med.
Woch., 1920, lxvii, 1309-11.
(206) Morse, M. E.,* and Tryon, G. :* Epidemic of dysentery at Boston State Hospital
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Jour., 1917, clxxvii, 255.
Tryon, G.:* Leukocytic reaction in paratyphoid, dysentery and following vaccine
. inoculation. Ibid., 1920, clxxxiii, 643.
(207) Fletcher: Several anomalous organisms of the Salmonella group in stools of
dysentery and enteric convalescents. Jour. R. A. M. C, 1918, xxx, 57.
Zondek, S. G.:* Ueber kombiniertes Auftreten von Infektbns-krankheitea.
1. Typhus and Ruhr, 2. Fleckfieber u. Ruckfallneber. Berl. klin. Woch.,
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(208) Perry, H. M., and Ttdy, H. L. : Med. Res. Com. Spec. Repts. London, 1919, No. 24.
(209) Tenbroeck, C. : A note on the invasion of the bodies of infants by B. dysenteriae.
Boston Med. and Surg. Jour., 1915, clxxiii, 284.
(210) Schloss, O. M.: Personal communication.
(211) Kendall, A. L.: The isolation of B. dysenteriae (Shigae) from the blood of an
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Rosenthal: B. dysenteriae from the heart' sblood at autopsy (adult). Deutsch.
Med. Woch., 1903, 97.
Boyd, J. S. K.: Case in which B. dysenteriae (Flexner Y) was recovered from the
blood stream during life. Lancet, London, 1919, ii, 482.
Darling and Bates: The isolation of B. dysenteriae (Shiga) from the blood
stream (adult). Am. Jour. Med. Sc., 1912, czliii, 36.
Gildemeister and Berthlein: B. dysenteriae (Flexner) in the blood stream of
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Assn., Chicago, 1914, briii, 1853.
(212) Markwald: Ein Fall von epidem. dysenteric beim Fdtus. Munch. Med. Woch.,
1901, No. 48, p. 1920.
Markwald: Deutsche. Med. Woch., 1901.
(213) Caussade, G.,f and Marbais, S.:f Septkemie a badlle de Shiga et absence de
ce bacille dans les selles. Bull, et mem. soc. m6d. d. hop. de Paris, 1919,
3. ser., zliii, 145-151.
(214) MtteLMANN: Arch. f.Hyg., 1909, box, 401.
Bruckner: Deutsch. Med. Woch., 1910, p. 2047.
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(216) Webster, R.:* Blood culture in summer diarrhoea. Med. Jdur. of Australia,
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(219) Htlgers, W. E.:f Pseudodysentery bacilli as a cause of cysto-pyelitis. Centr. f.
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(223) Virchow: Virchow's Archiv., 1863, v, 348.
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(228) Dopier, C: Les Dysenteries, Paris, 1909, 75 ff.
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(231) Dodge: Jour. Trop. Med., March 1, 1905.
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(278) Brown, L., and Sampson, H. L.:f The early roentgen diagnosis of ulcerative
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(512) Rogers, L.: Sensitized Shiga and Flexner vaccines in the treatment of chronic
bacillary dysentery. Brit. Med. Jour., London, 1916, i, 7.
Godson, (East Bengal): Dysenteries, their differentiation and treatment
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Kakstrom, W. :* Vaccine therapy in epidemic of paradysentery. Upsala LSkare-
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(313) Whittington,T.H.: The use of stock vaccines in infection by the bacfllus typhosus
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(314) Stukpf, J.:f Bolus alba in diarrhoea, dysentery and cholera. Munch. Med.
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Wolf-Eisner:* Kaolin-charcoal treatment of diarrheic processes. Therapie der
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(315) Hissch, C. :* Ueber Ruhr und ihre Behandlnng im Felde. Deutsche Med. Woch.,
Berlin, 1915, xli, No. 40.
(316) Wiese, O:* Zur Behandlung der Bazflknruhr. Deutsch. Med. Woch., 1916,
zlii, 1443.
(317) Osler, William: The Principles and Practice of Medicine, 8. ed. New York
and London, 1918, Appleton & Co., p. 5.
(318) Graham-Smith, G. S.: Bacilli isolated from flies in normal surroundings and in
surroundings associated with epidemic diarrhoea. Loc. Gov. Board Reports,
1911-1912, xli, Appendix B.,<No. 4, p. 304.
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gations on dysentery in Fiji during the year 1910. London, 1912, Witherby &
Co., 77, p. 80. Suppl. no. 2, J. Lond. School Trop. M.
Cox, G. L., Lewis, F. C, and Glynn, E. E. : The number and varieties of bacteria
carried by the common house fly in sanitary and unsanitary city areas.
Jour. Hyg., Cambridge, 1912, xii, 290-319.
Woodcock, H. M.: Note on the relative proportions of amoebic and bacillary
dysentery among the troops of the Egyptian Expeditionary Force during the
season of 1917; together with some remarks on the question of cyto-diagnosis.
Jour. R. A. M. C, London, 1920, xxxiv, 121-130.
(320) Dudgeon, L.:f Bacillary dysentery. Brit. Med. Jour., London, 1919, i, 448-451.
(321) Vincent: Quoted by Dopter, C: Les Dysenteries, Paris, 1909.
(322) Buchanan, G.E.:* Study of an outbreak of bacillary dysentery. Lancet, London,
1918, ii, 166-168.
Stookey, G. V.:*f An epidemic of water-borne dysentery. Jour. Infec Dis.,
Chicago, 1919, xxv, 331-334.
(Current comment.) Another water supply "accident." Jour. Amer. Med. Assn..
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(323) Read: Mem. de Med., Milit., 1871.
(324) Coppinger: Hygiene and Diseases of Warm Climates (Davidson, A.). Edin-
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(325) Knox, J. H. M., Jr., and Powers, G. F.: Report of the babies milk fund associ-
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(326) Stttt, E. K.: The diagnosis and treatment of tropical diseases. 2. ed., Philadel-
phia, 1917, P. Blakiston's Son & Co., p. 120.
(327) SiNNHUBER, F.:* Bekampfung der Kriegsseuchen durch Schutzimpfung. Deut-
sche Med. Woch., 1915, xli, No. 22.
(328) Dean, H. R.,* and Adamson, R. S.:* Method for preparation of non-toxic dysen-
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Jotten, E. W.:f On the use of neutralized antiformin solutions of bacteria for
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munit&tforsch. u. ezper. Therap., 1920, xxix, Orig. 267.
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(329) Busson, B.: Immunization against dysentery with toxin-antitoxin mixtures.
Wien. Klin. Woch., Vienna, 1915, xxviii, 853.
(330) Gibson, H. Graeme: A new method of preparation of a vaccine against bacillary
dysentery which abolishes severe local reaction. Also experiments with this
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Gibson, H. Graeme: Results obtained from the use of anti-dysenteric sero-
vaccine in the field, with regard to the reduction of case incidence. J. R. A.
M. C, London, 1918, xxx, 476-485.
(331) Sachs, MttEE:t Beitrag zur Ruhrschutzmipfung mit Dysbakta Boehncke. Med.
Klin., Berlin, 1918, xiv, 317.
SxEUESNAGEL.'t Med. Suppl., London, 1918, i, 216a.
BiscHon:t Med. Suppl., London, 1918, i, 341a.
(332) Hoffmann, W.:f§ Dysentery prophylaxis. Deutsche. Mil. arztL Zeitschr.,
Berlin, 1918, Nos. 13-14, and Schweiz. Med. Woch., 1920, i, 17.
PAETSCHrf Erfahrungen mit dem Boehnckeschen Ruhrimpfstoff Dysbakta.
Deutsche Med. Woch., 1919, xlv, 403-404.
Scheer, Kurt and Abe: Ztschr. fur bnmunit&tsforschung u. Exp. Therapie, Octo-
ber 23, 1919, Tefl. I, Heft 6, 377.
(333) Le Moignac and Pinoy: Les vacdns en emulsion dans les corps gras ou lipo-
vacdns. Compt. rendu, Soc. de Biol., Paris, 1916, barix, 201.
Le Moignac and Pdjoy: Application a 1'homme des vacdns en emulsion dans
les corps gras (tipo-vacdns). Ibid., 352.
(334) Whitmors, E. R., and Fennel, E. A.: An experimental Investigation of lipo-
vaccines. An additional note, with a note on triple dysentery lipo-vacdne.
Jour. Amer. Med. Assn., 1918, hoc, 902.
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de la Soc. MeU des Hop. Par., 1919, xlni, 1022.
(336) Leveuf, J.,* and Heuyer:* Surgical intervention in dysentery. Paris Medical,
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Muller, P. :f Contribution a l'ltude des dysenteries et leur traitement chirurgkal.
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Jena, 1920, xxxii, 49.
(337) Morgan, E. A.:41 Infectious diarrhoea. Canadian Med. Assn. Jour., Toronto,
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(338) Lavsran: De la phlebite, de la thrombose etdes paralysies comme complications
de la dysenteric Arch, de M6d. mil., Paris, 1885.
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(559) Von J axscn, Weinberg and Sonant: Quoted by Whitmore, E. R., and Graham,
D.: Bacillary dysentery. Nelson Loose Leaf Medicine, New York and Lon-
don, 1920, ii, p. 175.
(340) Artwright, J. A. : Variation in bacteria in relation to agglutination by salts and
by specific sera. Proc. of Path. Soc. of Great Britain and Ireland; abs. in
Jour, of Path and Bact., Cambridge, England, 1920, rriii, 3SS.
Arkwright, J. A.: Jour, of Path, and Bact, Cambridge, England, 1921, xxiv, 36.
(341) Hormini, K. : Ueber die pathogenen Wirkungen der Dysenterietozine. Centr. f.
Bakt., Jena, 1913, Ixviii, Orig. lte Abt, 342-358.
(342) Hannon, R. R.: Personal communication.
(343) Roger and Dqmasghxno: Soc. de Biol., Paris, 1871.
Delioux de Savignac: Union M&licale, 1867.
(344) Brauer-Eppendorr, L.: Die Ruhr, ihr Wesen und ihre Behandlung, Berlin,
1918, p. 15.
(345) Mayer, A.: Berl. Klin. Woch., 1918, 378, abstracted in Central, f. Bakt, Jena,
September 14, 1920, 177.
(346) Zlocisix, T.: Klin. Monatsbl. f. Augenheilk., 1918, bd, 393, abstracted in
Central f. Bakt, Jena, September 14, 1920, 177.
(347) Lemann, 1. 1.:* A case of bacillary dysentery with pseudomembrane in the vagina
and oedema of the abdominal walk Jour. Amer. Med. Assn., Chicago, 1920,
lxxv, 1716. Also published in Am. Jour. Trop. Med., Baltimore, 1921, i, 53.
(348) Twort, F. W.:* Researches on dysentery. British Jour. Ezp. Path., London,
1920, i. 237-243.
(349) Vincent, H. :* Vaccination against bacillary dysentery with ether vaccine. Jour.
of State Med., London, 1921, zziz, 54, and Compt rend. Soc de bfoL, Paris,
1921, lxxxv, 965-967.
(350) Bonnet, E.,* and Sicard, J.:* De la dysenterie epidemique dans la Bible. Bull
Acad, de MecL, 1920, 3rd ser., lzxiv, 166-169.
(351) Spolvertni, L. M.:* Vaccine therapy in enteritis in children. Rivista di Gin.
Ped., Florence, 1921, ziz, 162-169.
(352) Picard, M. S.:* Cocoa in acute ileocolitis in infants. New Orleans Med. and
Surg. Jour., New Orleans, 1921, lzxiv, 165-171.
(353) Ohly, A.:* Treatment of sequelae of dysentery. Archiv. f. Verdauungs-Krank-
heiten, Berlin, 1921, zzvii, 191-217.
(354) Besson, A.,* and De Lavergne:* Infection with Morgan's bacillus. Paris
Medical, Paris, 1921, xi, 449.
Rey, J. F.:f§ A fatal case of dysentery in an adult caused by Morgan's bacillus.
Practitioner, London, 1920, civ, 466-467.
Dopter, C.:§ Le pouvoir pathogene des badlles de Morgan et de Casteuani.
Bull. Acad, de MeU Par., 1921, lxzzv, 301.
(355) Vallardi, C.:f§ Studi intorno ad una epidemia di dissenteria bacillare ....
delle forme miste amebo-bacillari. Ann. d'ig., Rome, 1920, xxx, 544-560.
Vallardi, C.:f On mixed amoebic and bacillary dysentery. Atti d. Soc. lomb.
di sc. med. e. biol., 1920, ix, 419.
(356) Stokes, A.,f{ and Bigger, J. W.rft A short account of dysentery in Dublin in
the autumn of 1919. Dublin Jour. Med. Sc, 1920, 4th ser., i, 5-8.
(357) Jennicke, E.rf Zur Ruhrepidemk in Thtiringen. Deutsch. Med. Woch., Berlin,
1920, xlvi, 1308-1309.
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BACTLLARY DYSENTERY IN ADULTS AND CHILDREN 505
(558) Pabaf, J.:f fctude expcrimcntak du rMe des mouches dans le propagation dc la
dysenteric badllaiie. Rev. dTiyg., 1920, xlfi, 241-244.
Wollman, E.: Le role des mooches dans le transport des gezmes pathogenes
6tudi6 par la methode des dlevages aseptiques. Ann. de llnst. list., Paris,
1921, xaw9 431-449.
Auche, A.: Transport des bacffles dysenteriques paries mouches. Compt rend.
Soc de Mol., Paris, 1906, hriii (2), 45fr-452.
Kkonlowski, A.: Zur Frage uber die Typhus- and Dysenterie-verbieitung durch
Fliegen. Centr. f. Bakt., Jena, 1913, bcvii, Orig. I. abt., 586-590.
(359) Vogt, H. rf Zur Bedeutung der Ruhr fur des SaugUngsalter. Monatsch. f . Kinder-
heilk., 1919, xv (orig.), 193-198.
(360) Graham, G.rf Arthritis in dysentery. Proc. Roy. Soc. Med., London, 1919,
zin (Sec of Med.), 25-42.
(361) Giaxssnxk, K.^t( Psnkreasstarungen bei Dysenteric Wien klin. Woch., 1920,
xniii, 859-860.
(362) Moorhead, T. G.:f Myelitis as a complication of bacillary dysentery. Med.
Press & Circ., 1920, ii, 245.
(363) Button wbiser, S.:f Ein Fall von Encephalitis hemmorrhagica bei Dysenteric
Munchen. Med. Woch., 1920, lxvii, 1472.
(364) Boxck, W. C. :* Chilomastiz mesnili and method for its culture. Jour. Exp. Med.,
Baltimore, 1921, zzziH, 147.
(365) ORNSTEiN:t Bacteriology of Schmitz bacillus. Ztschr. f. Hyg. u. Infekt., 1920,
xd, 152-178.
(366) Csernel, E.:f Vaccination against dysentery with sensitised vaccines. Ibid.,
53^56.
(367) v. Werdt, F.,*t and Kgpatschrr, F.:*t The growth of dysentery bacilli on albu-
min-free media. CentralbL f . Bakt, Jena, 1920, i, 95.
(368) Laubee, L. 4 J Dysentery epidemic at Mannheim. CentralbL f . Bakt., Jena, 1920,
knriv, I. Abt Orig. 201-214.
(369) Job, E.,t and Hdltzmann, L.:f Dysenterie badDaire et paracbsme. Bull, et
mem. soc. mod. d. H6p. de Par., 1919, 3* ser., xfaii, 714-718.
(370) Ledtngham, J. C. G.: Dysentery and enteric disease in Mesopotamia from the
laboratory standpoint. Jour. R. A. M. C, London, 1920, xxxiv, 189.
(371) Jacoby, F.: Hie importance of acidity of dysenteric stools in the bacteriological
diagnosis of dysentery. Ztschr. f. Hyg. u. Infekt., 1920, zc, 1.
Esss, R., and Sgheer, K.: Reaction of infants' stools and its relation to causal
agents of dysentery. Arch. f. Kinderh., 1921, Lrix, 370^377.
(372) Haughwout, F. G.,f and Lanttn, P. T.:f Protoaoologic and clinical studies on
the treatment of protozool dysentery with benxyl bensoate. Arch. Int.
Med., Chicago, 1919, zziv, 383-^397.
(373) SoiiifANO, G.:f Agglutination and disintegrative biochemical activities of B.
dysenteriae "Shiga." Pathologica, 1920, xfi, 113-124.
(374) Sm, H. T.:f Bacteriological investigations on pathological-anatomical dysenteric
material Ztschr. f . Hyg. u. Infekt, 1920, zc, 337.
(375) Loksnz, F.:f A milk-borne epidemic of dysentery Y. Ibid., 423.
(376) Gratia, A.: Studies on the lytic agent of Bordet and Ciuca. Proc. of the Soc.
of exper. BioL and Med., New York, 1921, xviii, 192-193.
Gratia, A.: Preliminary report on a staphylococcus bacteriophage. Ibid.,
217-219.
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506 WILBTOT C. DAVISON
Gratia, A.:f Studies on the dUerelle phenomenon. Jour. Ezper. Med., Balti-
more, 1921, xxxiv, 115.
Gratia, A.: The Twort-d'HereUe phenomenon, II Lysis and microbic variation.
Ibid., 1922, xxxv, 287-^302.
Gratia, A.: Influence de la reaction du milieu sur l'autoryse microbienne trans-
missible. Compt. rend. Soc. biol., Paris, 1921, lxxxiv, 275-276.
Gratia, A.:§ De l'adaptation heriditaire du colibacille a l'autolyse microbienne
transmissible. Ibid., 750-751.
Gratia, A.:§ Dissociation d'une souche de colibacille en deux types d'individus
de proprie'tes et de virulence diffcrentes. Ibid., 751-753.
Gratia, A.:§ De la signification des "colonies de bacteriophage" de d'Herelle.
Ibid., 755-754.
Gratia, A.:§ Sur la spedfite1 du prindpe lytique. Ibid., 755.
Gratia, A. : J L'autolyse transmissable du staphylocoque et Taction coagulante des
cultures lysees. Ibid., 1921, lxxxv, 25-26.
Gratia, A.: Autolyse transmissible et variations microbiennes. Ibid., 251-252.
Gratia, A.,{ and Jaumain, D.:§ Identity du phenomene de Twort et du pheno-
mene de d'Herelle. Ibid., 880-881.
Gratia, A.,§ and Jaumain, D.:§ Duality du prindpe lytique du colibacille et du
staphylocoque. Ibid., 882-£84.
(377) Blumenthal, G.:f On the aetiology of badllary dysentery. Ztschr. f. Hyg. u.
Infekt., 1920, xd, 335.
(378) Goldzteher,M.:§ Bacteriological and serological studies on dysentery. CentralbL
f. Bakt., Jena, 1921, lxxii, I. Abt. Orig., 437-439.
(379) Simon, G.:§ The agglutination of B. paratyphosus B in cases of badllary dysen-
tery. BerL klin. Woch., 1919, No. 3; also Schweiz. Med. Woch., 1920, i, 37.
(380) Blackburn, C. B.:{ Some experience with dysentery in the Palestine campaign.
Med. Jour. Australia, Sydney, 1919, ii, 148-150.
(381) Flsxner, S. :§ Serum treatment of badllary dysentery. Jour. Amer. Med. Assn.,
Chicago, 1921, lxxvi, 106.
(382) Stremfel, R.:( Observations on dysentery. Centralbl. f. Bakt, Jena, 1920,
lxxxv, I. Abt. Orig., 68-80.
(383) MacLeod, G.:§ Notes on the epidemiology of badllary dysentery. Pub. Health,
London, 1921, xxxiv, 81-84.
(384) Hilgers, W. E. :{ On the £ race (lactose race) of pseudo-dysentery bacilli. Ztschr.
f. Immunitilt u. exper. Ther., Jena, 1920, xxx, I Teil, Orig., 77-94.
(385) Lowenthal, W.:§ Investigation to explain the agglutination of dysentery bacilli
by the sera of pregnant women. Ibid., 439-467.
(386) London letter: The treatment of dysentery in the army. Jour. Am. Med. Assn.,
Chicago, 1919, lxxii, 742.
(387) Buenos Aires letter: Epidemics of dysentery at Rioja and Catamarea. Ibid., 56.
(388) Bishop, F. C.,* and Laaxe, E. W.:* Dispersion of flies by flight. Jour. Agric
Res., 1921, xxi, 729.
(389) Mtta, K. :*f Personal communication and: Dysentery-like diseases (paradysentery,
paratyphoid) in children and their causes. Jour. Inf. Dis., Chicago, 1921,
xxix, 580.
(390) Job, E.:* Badllary dysentery. Arch, de M4d. et Pharm. Mffltaires, Paris, 1921,
lxxiv, 368-408.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 507
Stawell, R. R.: Treatment of badllary dysentery. Med. Jour. Australia,
Sydney, 1921, i, 496-497.
(391) Dumas, J.:f On the presence of bacteriophage in the healthy intestine, in soil
and in water. Compt. rend., Soc. de biol., Paris, 1920, lxzziii, 1314-1315.
(392) Debke, R.,t and HAGUSNAu:t Some peculiarities of the "d'Herelle phenomenon."
Ibid., 1348-1349 and 1368.
(393) SALDOENif and (Pettit, A.):f Sur le bacteriophage de d'Herelle. Ibid., 1545-
1548.
Saltmbeni and (Pettit, A.): Sur le nature du bacteriophage de d'Herelle. Compt.
rend, de l'Acad. des Sc., Paris, 1920, ebon, 1240-1242.
(394) Kuttnex, A.: Preliminary report on a typhoid bacteriophage. Proc. Soc. Exp.
Biol, and Med., New York, 1921, zviii, 158.
Kuttnee, A.: On the influence of tissue enzymes on the bacteriophagic principle.
Ibid., 222-225.
(395) Davison, W. C: Observations on the properties and nature of bacteriolysants
(dUerelle's phenomenon, bacteriophage, bacteriolytic agent, etc.). I and II.
Jour. Bact., Balto., 1922, vii, 475-490, 491-504
Davison, W. C: Bibliographic Review. Filterable "substance" antagonistic to
dysentery and other organisms (d'Herelle's phenomenon, bacteriophage, bacte-
riolytic agent, bacteriolysant, etc.). Abst. Bact., Balto., 1922, vi, 159-177.
Davison, W. C: The bacteriolysant therapy of badllary dysentery in children.
Am. Jour. Dis. Child., Chicago, 1922, xxiii, 531-34.
(396) McLeod, J. W., and Gavenlock, P: Lancet, London, 1921, i, 900.
(397) Wollstein, M.:f Studies on the phenomenon of d'Herelle with B. dysenteriae.
Jour. Exp. Med., Baltimore, 1921, zxxiv, 467-476.
(398) Foges, A.:f Ueber schwere postdysenterische Rektalver&nderungen und deren
Behandlung (Lichttherapie). Wien klin. Woch., 1919, xxrii, 1250-1251.
(399) Haughwout, F. G.rf The differential diagnosis of the dysenteries. Philippine
Islands Med. Assn., Jour., 1921, i, 53.
(400) Johnson, J. G.: Gangrene of caecum and colon in case of acute dysentery. Ca-
nadian Med. Assn., Jour., 1920, z, 564-566.
(401) Avery, O. T., et al: Intradermal test and desensitizatbn in the serotherapy of
lobar pneumonia. The Rockefeller Inst, for Med. Res., 1917, Monograph
No. 7, 62H54.
(402) Schmidt, A.: Zur Kenntnis der Colitis suppurativa. Grenzgeb. d. Med. u. Chir.,
Bd. xxviii.
Schmidt, A.: Die Schweren entzundlichen Erkrankungen des Dickdarms. Arch,
f. Verd. Krankh., Bd. xxii, H. I.
(403) Hughes, B., and Banks, H. S.: Immediate surgical complications of dysentery.
Brit. Med. Jour., London, 1920, ii, 934-936.
(404) Cmchlow, N. : Acute badllary dysentery. Jour. Trop. Med., 1921, zziv, 204-206.
(405) Egen, £., Kt.emtf.kei>, P., and St&isower, R.: Zur Klinik und pathogenese der
Ruhr (mit besonderer Berucksichtigung der rektoskopischen Befunde),
Ztschr. f. exper. Path. u. Therap., 1920, xxi, 182-212.
(406) KntscHNEK, L., and Seoall, I.: Zur Bakteriologie der Ruhrerkrankungen des
Jahres 1920 in Wien. Wien. klin. Woch., 1920, xxzni, 1125-1126.
(407) Czaplewski: Zur Bakteriologie der Ruhr. Centr. f. Bakt., Jena, 1920-1921,
lxxxv, I. Abt., Orig. 105-113.
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508 WILBURT C. DAVISON
C408) Dold, H., and Fischer, W. : Ein Fall von naturikh erworbener, badlllier Dysen-
terie beim Hunde (mit glcichzeitiger Schistosomiasis, Ankylostomiasis und
Ffliaxiosis). Ibid., 198-206.
(409) Sikasburger, J.: Chronic bacillazy dysentery and sequels. Deutsch. Med.
Woch., 1921, xlvii, 441-443.
Brandeis, M.: Die subakuten und chronischen Veidauungstorungen nach Ruhr.
Arch. f. Veidauungskr., Berlin, 1920, xxvi, 399-429.
Leusden, J. T.:* Ulcerative Colitis. Neder Tijd. v. gen. Amsterdam, 1921,
ii,2890.
(410) Marcovigi, £.: Das leukozyUre Blntbild bei Dysenteric; bei chromschem and
akutem Darmkatarrh; Cohca Mucosa; Darmtuberkulose. Folia HaematoL,
Leipz., 1920, zxvi, I. Teil, 41-44.
(411) Dew, H. R., and Fatrley, N. H.: Dysenteric infections. M. J. Australia,
Sydney, 1921, i, 453-460.
(412) Kohler, M. D.: Zur Ruhrbehandlung mit antidysten. Med. Klin., Berlin, 1920,
xvi,1138.
(413) Patterson, S. W., and Williams, F. £. : Epidemic diarrhoea. Med. J. Australia,
Sydney, 1921, i, 460-464.
(414) Kuntze, G. : Dysentery in childhood. Med. Klinik, 1921, xvii, 307-311.
(415) Kxzrsmakbrs: Small epidemic of dysentery. Arch. Med. Beiges, 1921, lzzhr, 1-8.
(416) Zollee, H. F., and Clark, W. M.: Bacilli, production of volatile fatty adds by
bacteria of dysentery group. Jour. General Physiol., 1921, iii, 325-330.
(417) Walz-Georges, M. : Two cases of epidemic dysentery in the newly born. Monat-
schr. f. Kinderh., 1921, xix, 477-479.
(418) Manson, J. S., and Mitchell, H. A. : Small outbreak of dysentery in a provincial
town. Lancet, London, 1921, i, 802.
(419) Jaxpe, R. H., and Sternberg, H.: Ueber die vakuol&re Nierendegeneration bei
chronische Ruhr. Virch. Arch, f . path. Anat, Berlin, 1920, ccxxvii, 313-318.
(420) Auprecht, E.:* Morphine in pneumonia and dysentery. Therap. Halbmonat-
schr., 1920, xxxiv, 412.
(421) Love, R. J. M.: Surgical complications of dysentery. Practitioner, 1920, cv,
11-25.
(422) Wollmann, E.:f Concerning the note of Bordet and Ciuca (drHcreue's pheno-
menon, transmissible microbe autolysis of Bordet and Ciuca and Darwin's
theory of pangenesis). Compt rend. Soc. de biol., Paris, 1920, LmJii, 1478-
1479.
Wollmann, E.:f On the phenomenon of d'Herelle. Ibid., 1921, hccdv, 3-5.
Wollmann, E.§ and Goldenberg, L. :§ Le phenomene de d'Herelle et la reaction
de fixation. Ibid., 1921, lxxxv, 772-774.
(423) Ptnoy, P. E.: R61e des myxobacteries. Ann. de PInst. Past, Paris, 1907, zzi,
622-656.
Ptnoy, P. E.: Sur les myxobacteries. Ibid., 1921, xxxv, 486-495.
(424) Eliava, G.,§ and Pozerski, E.:§ Sur les characteres nouveaux presentes par le
bacille de Shiga ayant resists a Taction du bacteriophage de d'Herelle. Compt.
rend. Soc. de biol., Paris, 1921, lxxxiv, 708-710.
Eliava, G., and Pozerski, E.: De racrJon destructive des sds de quinine sur le
bacteriophage de d'Herelle. Ibid., 1921, lxxxv, 139-141.
425) Nicolle, M.: Action du "Bacillus subtifis" sur diverses bacteries. Ann. de
l'lnst. Past, Paris, 1907, xxi, 613-621.
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BACILLARY DYSENTERY IN ADULTS AND CHILDREN 509
(42© Hanktn, E. H.: Lcs microbes des rivieres de Plnde. Ibid., 1896, x, 175-176.
Hanrin, E. H.: L'action bactericide des eaux de la Jumna et du Gange. Ibid.,
1896, x, 511-523.
(427) Gengou: Contribution a P6tude des substances bacteriolytiques des leukocytes.
BulL Acad. Roy. de MeU de Belg., Bruxelles, 1920, 4. s., xxx, 993-999.
GENGOU.f Les substances bacteriolytiques des leucocytes et kurs rapports avec
l'alexine. Ann. de llnst. Past., Paris, 1921, xxxv, 497-512.
(428) Bruynoohb, R.,f and Maisxn, J.:f Au sujet des microbes devenus resistant au
prindpe bacteriophage. Compt. rend. Soc. de bioL, Paris, 1921, lxxxiv,
847-848.
Bruynoghe, R. :* Au sujet de la guerison des germes devenus resistants au prindpe
bacteriophage. Ibid., 1921, lxxxv, 20-23.
Brttynoghb, R. : Au sujet de la nature du prindpe bacteriophage. Ibid., 258-260.
(429) Maisin, J.:§ Au sujet de la nature du prindpe bacteriophage. Ibid., 1921,
lxxxiv, 467-468.
Maisin, J. :§ Adaptation du bacteriophage. Ibid., 468-470.
Maisin, J. :§ Au sujet du prindpe bacteriophage et des antfcorps. Ibid., 755-756.
(430) Besson, A.,§ and de Laveegne:§ Sur le Bacilk de Morgan. Ibid., 77-79.
(431) Fabry, P. : Sur l'aggiutination des microbes attenues. Ibid., 1921, lxxxv, 237-238.
(432) de Magalbaes, A.:j B. fecahs alkahgenes isolated from blood of an individual
with a typhoid4ike disease. Ibid., 1921, lxxxiv, 591-592.
(433) Hilozss, W. E.: Vkrjanrige Eriahnmgen uber die Ruhr im Fdde bd einen Trup-
penteil im Westen. OffentKche Gesundhdtspnege, 1920, v, 171-180.
(434) Stewart, H. G.: Personal Communications.
(435) Arthos and Huber: Arch, de Physiol, 1892, iv, 651.
(436) De Krttif, P. H.: Dissociation of microbic species I. Jour. Exper. Med., Balti-
more, 1921, xxxiii, 773.
De Kruif, P. H. : H, HI and IV, Proc. Soc. Exp. Biol, and Med., New York, 1921,
. xix, 34-37, 37-38 and 38-40.
(437) Ganter* and van der Reis:* The bacteriddal function of the small intestine.
Deutsch. Arch. klin. Med., Leipzig, 1921, cxxxvii, 348-358.
(438) Bail, 0.:*§ Ueber Shiga Bacteriophage!!. Wicn. klin. Woch. Vienna, 1921,
xxxiv, 555-556.
(439) Poorter, P. de, and Maisin, J.: Contribution a l'ltude de la nature du prindpe
bacteriophage. Arch. Internat. de Pharmacodyn. et de Therap., 1921,
xxv, 473-484.
(440) Teague, O., and Morishima, K-L: The action of B. typhosus on xylose and
some of the other less frequently used sugars. Jour, of Inf. Dis., Chicago,
1920, xxvi, 52-76.
(441) Zinghbr, A.,§ and Soletsky, D.:§ Besredka's method of oral immunization of
rabbits with ox bile and paratyphoid bacilli. Proc. N. Y. Path. Soc, New
York, 1920, xx, 133-141.
(442) Thjotta, T.,f and Sundt, O. T. :f Toxins of Bact. dysenteriae, Group m. Jour.
Bact., Baltimore, 1921, vi, 501.
(443) Gaiger, S. H.,§ and Dalung, T.:§ Badllary dysentery in lambs. Jour. Comp.
Path, and Therap., Edinburgh and London, 1921, xxxiv, 79-105.
(444) Martinez, A. G.:* Leukocyte count in dysentery. Repertio de Med. y. Chir.,
Bogota, 1921, xxi, 600.
(445) Eanai, S.:*f Dysentery immunization in rabbits by oral and subcutaneous
methods. Brit. Jour. Exper. Path., London, 1921, ii, 256.
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510 WILBURT C. DAVISON
(446) London letter: Fatal use of the Sigmoidoscope. Jour. Amer. Med. Assn., Chicago
lxxviii, 829.
(447) Kundkattiz, N.:* Ulcerosa cachetka as a complication in badDary dysentery.
Monatschr. f. Kinderh., Berlin, 1921, zzi, 366-373.
(448) Kliglxr, I. J.:* Investigation on soil pollution and the relation of the various
types of privies to the spread of intestinal infection. Monographs of the
Rockefeller Inst for Med. Res. New York, 1921, No. 15, pp. 75.
(449) Aoki, K.:f tTber die agglutinatorische Fin telling von dysenteriebazfllen, Tohoken.
Jour. Exper. M., 1921, ii, 142.
(450) Schmidt, G.: Centr. Bakt., Jena, 1902, zxxi, lte abt, orig., 522.
(451) Powers, G.F.: Personal Communication.
(452) Ainley, Walker E. W.:f Studies in bacterial variability, on the occurrence and
development of dys-agghitinable, eu-agglutinable and hyper-agghitinablc
forms of certain bacteria. Proc. Roy. Soc., Ser. B., 1922, zciii, 54.
(453) de Necxxe, J.:§ The inhibitory action of the bacteriophagous principle upon the
development of susceptible organisms. Compt. rend. Soc. de biol., Paris,
1921, kxxv, 742-744.
(454) Applemans, R.:§ The bacteriophage in the body. Ibid., 722-724.
(455) Thjotta, Tb.,§ and Sundt, O. F.:f A small epidemic of dysentery caused by
dysentery of Group I (B. sbigae). Nord. hyg. Tidsskr., 1921, ii, 1.
* Abstracts of these references may be found in the Journal of the American Medical
Association, (Chicago), 1916-1921. LXVI-LXXVU.
f Abstracts of these references may be found in Medical Science, Abstracts and
Reviews, Oxford University Press, 1919-1921. I-V.
% Abstracts of these references may be found in the International Medical Digest,
(W. F. Prior Co., Hagerstown, Md., publishers), 1920-1921. I-H.
{ Abstracts of these references may be found in Abstracts of Bacteriology, (Bald-
more), 1920-1921. IV-V.
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