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of LIFE

# 1

An exhibition that examines
the history of asthma,
the experiences of people
with asthma, and contemporary
efforts to understand and
manage the disease.

National Library of Medicine
National Institutes of Health
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Breath of Life

National Library of Medicine

National Institutes of Health

U.S. Department of Health and Human Services

Bethesda, Maryland 20894

An exhibition March 23, 1999-March 28, 2001

An exhibition that examines the history of asthma, the
experiences of people with asthma, and contemporary
efforts to understand and manage the disease.

Exhibition Director
Elizabeth Fee, Ph.D.

Special Advisor

Sheldon G. Cohen, M.D.

Exhibition Curators
Robert Aronowitz, M.D.
Carla C. Keirns

Catalogue Essay Author
Charles Marwick

This catalogue was made possible hy the generous support of
the American College of Allergy, Asthma, and Immunology.

This catalogue is published in conjunction with the exhibition Breath of Life, organized by the
Exhibition Program of the History of Medicine Division, National Library of Medicine. The
National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious
Diseases, and the National Institute of Environmental Health Sciences provided additional
support for the exhibition.

Friends of the National Library of Medicine
1555 Connecticut Avenue, NW
Suite 200

Washington, DC 20036

Printed in the United States of America.

Cover photo credits (clockwise):
Elizabeth Bishop

Courtesy Prints and Photographs Division, Library of Congress
John Locke

History of Medicine Division, National Library of Medicine
Moses Gunn

Nancy Hogshead

Courtesy Tony Duffy/Getty Images

John E Kennedy

Courtesy John Fitzgerald Kennedy Library

Table of Contents

Page

Director's Statement vii

Breath of Life 1

Symptoms of Breathlessness 5

Asthma and Western Medicine 9

Asthma: From Symptoms to Disease 13

A New Century and New Knowledge • 23

Immune System Research Clarifies Asthma 33

Effective Medicines for Treating Asthma 39

Asthma and Genetics 43

The Future of Asthma Research 45

The Faces of Asthma 48

Exhibition Credits and Acknowledgements 57

Breath of Life

National Library of Medicine
Director's Statement

The creation of the exhibition Breath of Life at the National Library of Medicine reflected not only
the intellectual enthusiasm and involvement of so many of my colleagues, but also a gathering sense
of urgency. We all came to realize that great strides had been made in understanding — at least in
large part — the bodily processes and treatment of asthma, and yet we saw enormous numbers of
new cases — especially in children — -arising every day. Indeed, the basic incidence of asthma in the
United States continues to soar.

Thus we began to see the exhibition as more and more urgently needed as a means to help children
and parents to understand the real nature of this treatable and manageable disease.

Many distinguished administrators, scientists, and clinicians, and Congressman William Young,
attended the opening reception of the exhibition on March 22, 1999. Joining the crowd were
children from the National Institutes of Health Children's Inn, junior high-school athletes, local
and national press, and a fascinated crowd of adults. Also in attendance were the Muppets, who
introduced their asthmatic member, Dani, to the audience. In spite of being an event centered
on medicine and science a good time was had by all.

Three American winners of Olympic gold medals (Tenley Albright, figure skating, 1956; Nancy
Hogshead, swimming, 1984; and Jackie Joyner-Kersee, heptathlete, 1988, 1992) presided over
the evening's events. They gave assurances to the audience that great athletic feats — such as winning
Olympic gold medals — are possible for people with asthma who collaborate with their physicians
in striving for excellent management of their own health. I have personally seen on many occasions
that children and adults are consistently gratified and sustained by this message of Breath of Life.

The electronic (DVD) version of the exhibition has circulated widely and is available online at
http://emall.nhlbihin.net. The DVD frequently offers a "gathering point" for conversation and
planning by groups concerned about asthma and finding help for patients. This printed catalogue
of the exhibition will also, I hope, find a wide audience. May it permit the unhurried and careful
consideration of this vexing problem that a book affords.

Lastly I congratulate and thank all those who helped in creating this fine exhibition.

Donald A.B. Lindberg, M.D.

Director, National Library of Medicine

Breath of Life 1

Breath of Life

In the United States, fifteen million people are affected by asthma, and five
thousand die of the disorder or its complications every year. Between 1980
and 1 996 the incidence of asthma more than doubled, with children under
five years old experiencing the highest rate of increase.

Breath of Life is the story of our increasing knowledge and the continuing
challenge of asthma, one of the oldest known human disorders. The causes of
asthma are varied — some known, some unknown — manifested by symptoms
of wheezing, shortness of breath, and tightness of the chest. The patient with
asthma suffers from inflammation, constriction, and mucus plugging of the
airways to and from the lungs — which obstruct the free flow of air through
the bronchial airways. With air trapped in the lungs, the person with asthma
has difficulty expiring air through the narrowed bronchial tubes. Forced
air passes through mucus plugs like the reed of a wind musical instrument,
producing the characteristic vibratory sound of wheezing.

In susceptible persons, this chronic disorder may be triggered by a variety of
factors: respiratory tract infections, industrial air pollutants, environmental
agents such as airborne pollens and molds, allergenic foods, household
dusts, inhalant allergens, and even sudden changes in the weather. It
is becoming increasingly evident that asthma is the outcome of these
triggers and their common roles in effecting bronchial inflammation.

The Lord God formed man of
the dust of the ground and
breathed into his nostrils
the breath of life; and man
became a living soul.
— Genesis 2:7

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...............................

Four Perspectives of Asthma

The efforts to unravel the causes of asthma are challenging.
Identifying the triggers of the disorder with precision remains
elusive. Over the years, four distinct perspectives have evolved.

First, asthma has been viewed as a disorder of the lungs.
Physicians have adapted the tools and techniques originally
developed for anti-tuberculosis therapy for the treatment of asthma.

Winter Carnival parade at
Saranac Lake, New York, ca. 1900

In the late 1800s and early 1900s, Saranac Lake
was one of the most prominent spa areas in the
United States for patients with tuberculosis and
other lung diseases.

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Instructor's

Guide____

a i m i «" " ~

.Open
\irways

Uings during an asthma episode

Open Airways for Schools
flip chart, Curriculum Guide,
and Instructor's Guide, 1998

The American Lung Association
has conducted public education
campaigns, health advocacy, and
research since the early 1900s.
Asthma and other chronic lung
diseases are now the focus of
their work.

Courtesy Adirondack Collection. Saranac Lake Free Library

Courtesy American Lung Association

National Library of Medicine

Secondly, asthma has been viewed as an allergic condition. Consequently,
researchers identified the character of the antibodies that cause allergic reac-
tions and developed injection techniques for blocking and reducing antibody
production by an immunization-like procedure known as immunotherapy.

A third perspective linked asthma to emotional distress. In the 1940s and
1950s, physician M. Murray Peshkin (1892-1980) of New York noticed
that some of his most severe asthma patients markedly improved when they
were removed from stressful situations. In the case of children, for whom
he founded a retreat in a controlled environment at the Children's Asthma
Research Institute and Hospital in Denver, he coined the term "parentectomy"
to describe his therapeutic method involving separating children from
their parents.

Finally, asthma was viewed as the result of exposure to environmental irri-
tants— one reason why asthma sufferers sought refuge in clear mountain air,
warm dry climates, and air-pollution free atmospheres. Certainly it is now
appreciated that a healthy environment at home and at work is critically
important in the control of asthma.

Each of these perspectives provided insights into causative, triggering,
and exacerbating factors in asthma, and led to the design of corresponding
approaches to managing the disease. Advances in the biomedical sciences have
taken management of asthma beyond the historical panorama of balancing the
four humors, the letting of blood, the smoking of tobacco, and the breathing
of medicated aerosols. The search for the causes and treatment of this ancient
disorder continues.

Seventy-five allergen patch test kit

When they began allergy injections
in the 1910s and 1920s, allergists
had to collect, purify, and sterilize
allergen extracts themselves. In the
late 1940s private companies began
to manufacture extracts for skin
testing and immunotherapy.

Courtesy Mutter Museum, The College of
Physicians of Philadelphia

Skin Testing

When a patient undergoes
a skin test, diluted extracts
from allergens are injected
under the skin. A positive
reaction is indicated by a
small, raised, reddened area
(called a wheal). The doctor
measures the extent of the
reactions by drawing a line
around each of the wheals
on the patient's arm.

Courtesy National Institute of
Allergy and Infectious Diseases

Breath of Life

North Shore Health Resort, Winnetka, Illinois,
late nineteenth century

People have long traveled to ocean or mountain locations —
thought to have especially pure air or water — to improve their
health. With widespread rail and steamship travel and extensive
advertising, nineteenth-century spas and resorts opened in
remote locations and attracted a broad clientele. People with
tuberculosis, asthma, and hay fever often moved permanently
to places thought to have air or water conducive to good health.

M. Murray Peshkin and philanthropist
Fannie E. Lorber with two children from
the National Asthma Center (formerly the
National Home for Jewish Children) in
Denver, 1956

A founder and former president of the American
College of Asthma, Allergy and Immunology.

Courtesy National Jewish Medical and Research Center

Construction worker

Bending over using a handsaw,
this construction worker inhales
a great deal of sawdust, which
can trigger asthma as a general
lung irritant or a specific allergen.

Courtesy National Institute for
Occupational Safety and Health

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Breath of Life 5

Symptoms of
Breathlessness

Virtually all cultures in all times have recognized the importance of breathing
and have tried to identify the circumstances that inhibit airflow to and from
the lungs. To cite one modern example, the student of yoga, learning to
breathe properly during exercise postures, is practicing the spiritual discipline
developed by ancient Hindu philosophers who linked adequate breathing,
prana — to use the Sanskrit word — with the soul. The breath, they believed,
builds a connection between the mind, the body, and the spirit.

Perhaps the earliest description of what is assumed to be asthma dates back
to ca. 2700 BC. Shen-Nung, sometimes called the Fire Emperor of China
and regarded as a founder of Chinese medicine, described remedies for the
treatment of multiple disorders including those that affected the chest. As the
first known herbalist, he recorded what he had learned about the medicinal
effects of many plants.

Ma huang plant (Ephedra sinica):
(female/male). Illustration from
B.E. Read, Chinese Medicinal Plants:
Ephedra, 1930

Plants of the Ephedra genus are native to
Asia and the Americas, but many varieties
are not effective stimulants. Species from
India and China are particularly potent;
those native to North America are not.

Courtesy Harvard University,
Cambridge, Massachusetts

Three Chinese Emperors
of Medicine, 1798
Artist unknown
Japanese painting

The legendary founders of
Chinese medicine, Huang Di
(r. 2697-2597 BC) (left),
Fu Xi (center), and Shen-Nung
(ca. 2700 BC), were thought to
walk with the gods. In Chinese
stories they are said to be
among the first humans. Fu Xi
is credited with introducing yin
and yang, the principles that
separate the universe into male
and female, light and dark.

Courtesy East Asian Collection,
The Library and Center for Knowledge
Management, University of California,
San Francisco

lit m

'1 ilj M 1

Female

Male

National Library of Medicine

One of these was the plant ma huang, the botanical source of what is known
today as ephedrine. Identified as a treatment for what Shen-Nung termed
"coughing up," ma huang was used for centuries in China for the relief of
cough and bronchial asthmatic symptoms. We believe that the condition
described by Shen-Nung was asthma.

To the Chinese, breathlessness was a symptom of the body's balance falling
into disorder. Relief could be found in the restoration of balance. According
to the ancient Chinese concept, health and well-being are controlled by the
flow of energy — the life force they call ch'i — and breathing difficulties are a
symptom of its imbalance. Indeed, for centuries, traditional Chinese medi-
cine has advocated treating asthma by "restoring the balance" of the body.

Lilly Syrup No. 110,
Ephedrine Sulphate, 1932

Lilly Inhalant No. 20,
Ephedrine Compound, 1932

Swan-Myers Ephedrine
Inhalant No. 66, ca. 1940

Courtesy National Museum
of American History,
Smithsonian Institution

°NE Pint (475 CO

-.SYRUP No. 110_

EPHEDRINE

^SULPHATE_^

p «>NTAINS ALCOHOL 12 PERCENT

r**** in one fluid ounce | 100 cc.

Sulphate lgr. |0^Gm'

^-ChiUten, 1/2 to 1 fluid A*»
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Breath of Life

Ephedrine

Confirmation of Shen-Nung's observations of the therapeutic properties
of ma haung came in the early 1920s when the Japanese investigator
Jokichi Takamine (1854-1922) isolated ephedrine from the plant. Later,
the research team of Ko Kei Chen (1898-1988), a Chinese physician, and
American pharmacologist Carl F. Schmidt (1893-1988), conducted the
first investigation of ephedrine's cardiovascular effects while working at the
Peking Medical College in 1924. They found the effects of ephedrine and
adrenaline on bronchial spasm to be similar, but they noted the advantages
of ephedrine being taken by mouth compared to adrenaline, which required
administration by hypodermic injection. For the relief of asthma, they
suggested that it was reasonable to expect beneficial results from ephedrine,
although the action of adrenaline was prompt and effective.

Flegmaticvs i "3

Id NVL&S [N ■miTiS ACVNIMEVIRES

IDCUKS MERlT^MILaVOQ? LAVDISaHABENT

Breath of Life

Asthma and
Western Medicine

The word "asthma" derives from the classic Greek word for gasping.
Greek and Roman physicians used the term to describe a shortness of breath
believed to be the result of an imbalance between the four body humors that
controlled health — yellow bile, black bile, blood, and phlegm. Imbalances in
the humors determined an individual's propensity to sickness and the kinds
of disorders to which he or she was susceptible. Asthma, characterized by
coughing, wheezing, and respiratory congestion, was regarded as an excess
of phlegm. Treatment of the condition involved adjusting the balance of the
four humors. One effort to achieve this objective, blood letting, influenced
medical practice well into the eighteenth century.

The first description of asthma as the disease we know today is attributed
to a Greek physician, Aretaeus, who practiced in Rome after training at the
Greek library and medical center in Alexandria. He noted the symptoms of
"heaviness of the chest, difficulty of breathing when running or during other
exertions, there is wheezing and hoarseness. The cheeks become ruddy, the
eyes protuberant, there is a need for air, there is an incessant and laborious
cough and if the symptoms persist, suffocation" (Aretaeus of Cappadocia.
"On the Causes and Symptoms of Chronic Diseases." In Francis Adams,
ed. and trans., The Extant Works of Aretaeus the Cappadocian [London:
Sydenham Society, 1856] Book I,
Chapter XI, pp. 316-18).

Flegmaticus 3

Virgilius Solis, the Elder

(1514-1562)

Engraving

An excess of phlegm made a
person phlegmatic, and also
lazy, sleepy, and languid. This
was thought to be the most
common cause of asthma in
ancient Greek medical study.

A20MATO2.

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De Cous/s et S/gn/s Acutorum
et Diuturnorum Morborum,
Libri Quatuor (Of the Causes and
Signs of Acute and Morbid Disease)
Aretaeus of Cappadocia (81-138?)
Oxford, 1723

Aretaeus of Cappadocia carefully
described asthma, attributing it to
thick and viscid phlegm caused by
coldness and humidity experienced
by the patient.

"It,-'——-3"-

II II A T O £

National Library of Medicine

Following the decline of the Roman Empire in the fifth century, progress in
medicine slowed as Western medical practice became embroiled in alchemy
and astrology. As the seat of medicine and culture moved eastward from
Rome, Byzantine physicians played important roles in preserving the writings
of the Greek physicians by translating their works first into Arabic, and
subsequently into Hebrew and then Latin.

The first treatise on asthma was written in 1 190 by Moses Maimonides.
Born in Cordova, Spain, the philosopher, rabbi, and physician fled to Egypt
to escape religious persecution by Islamic invaders. There, as physician to
the court of Saladin, Sultan of Egypt and Syria, Maimonides was given
responsibility for the care of Saladin's asthmatic son, Almalik Alafdal. From
this circumstance, Maimonides wrote De Regimine Sanitatis ad Soldanum
Babyloniae (Regimen of Health for the Babylonian Sultan), in which he
provided advice and recommendations for a program of prevention and
treatment for the Prince to follow.

Recognizing that he did not have a cure for asthma, Maimonides recom-
mended measures for living with the disorder. He noted that dry air was
preferable to the humidity prevailing in Alexandria, situated as it is in the
Nile delta, and thus suggested that the Prince live in Cairo. He counseled the
Prince to keep an even temper, and adopt a moderate lifestyle in food, drink,
and sleep. One of Maimonides' recommended remedies was chicken soup.

For all practical purposes Maimonides' advice was the only available course
of action for the relief of asthma for the next several hundred years and in
fact his advice is still given to the asthmatic patient today: avoid substances
and factors that can trigger an asthmatic attack.

Aretaeus, the Cappadocian
Artist unknown

Illustration from Johannes Sambucus
(1531-1584), Icones Veterum
aliquot ac Recentium Medicorum
Philosophorumque (Images of Some
Ancient and Recent Physicians and
Philosophers), 1901

Breath of Life 11

Breath of Life

Asthma: From
Symptoms to Disease

Following the Renaissance, with both the rediscovery of classical Greek
thought and advancing knowledge of anatomy and pathology, asthma
became more widely recognized as a specific disorder. The concept of its
manifestation due to spasm of the bronchial tubes was proposed by the
English physician and neuroanatomist Thomas Willis in about 1670. Willis
had wide interests, among which were the convulsive and spasmodic nature
of asthmatic paroxysms (from which he suffered) and their relationship to
the innervation of the bronchi. These studies led to a better understanding
of asthma as a bronchial disease.

A generation later another English physician, Sir John Floyer, identified
asthma as an entity distinct from other pulmonary diseases, and as different
from simple breathing difficulties. His definition revolutionized approaches
to the mechanism and management of the disease.

Antoine-Laurent Lavoisier
and His Wife, 1788
Jacques-Louis David (1748-1825)
Photographic reproduction of
a painting

Antoine-Laurent Lavoisier, a French
chemist, is pictured in his study with
his wife, Marie-Anne, whose drawings
illustrated all of his works. To the
right of the quill pens is a gasometer
of the type Lavoisier used to deter-
mine the composition of air in
the 1780s.

Courtesy The Metropolitan Museum of Art,
Purchase, Mr. and Mrs. Charles Wrightsman
Gift, in honor of Everett Fahy, 1977.
(1977.110) 0 1989 The Metropolitan
Museum of Art

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Thomas Willis (1621-1675)
Dr. IV/V/z's's Practice of Physick
London, 1684

English physician Thomas Willis
was one of the first European
medical scholars to synthesize the
observation of symptoms, which
was the province of physicians,
and the careful study of the dis-
sected body, which had been the
realm of the separate professions
of surgeons and anatomists.

14 National Library of Medicine

who have attempted
a^ofthatChrotucalDiltem-

Mfcv?ry difficult, and frecjuent-
1ulu.l.cr the true Natureoftto^
ifeij not thoroughly underftood by
dwiuorthey have not yet found out
the Medicine, by which the Cure may
be cftfcd. B g

Floyer is best known for his focus on counting the pulse. He used a watch
to time different pulse and respiratory rates resulting from the influence of
emotions, diet, climate, temperature, and various drugs and diseases. As an
asthma sufferer, he wrote about his own experience after exercise, and after
exposure to environmental factors such as tobacco smoke, dust, and specific
foods. He noted the constriction of the bronchi and the wheezing that
characterizes asthma, speculated on the causes, and was one of the first to
note that asthma ran in families — that there was a heritable predisposition
to the disorder.

In his book, The Treatise of the Asthma published in 1698,
Floyer described the condition: "I have assigned the immediate
cause of asthma to the straightness, compression, or constriction
of the bronchia. The slowness of inspiration and expiration
depends on the stiffness or straightness of the lungs . . . which
resist the action of the pectoral muscles: 'tis a long time before
the air can be drawn in, and almost as long before it can
be forced out, because of the constriction of the bronchia "
(Floyer, Sir John. The Treatise on the Asthma [London: Richard
Wilkins, 1698]).

Sir John Floyer (1649-1734)
The Treatise of the Asthma
London, 1698

Sir John Floyer, an asthmatic English
physician, wrote his Treatise of the
Asthma, which made the case for
considering asthma a separate disease
from other causes of breathlessness.
The authoritative text on asthma for
over a century, Floyer's book went
through four English editions and
was translated into French.

About the same time Floyer was working in England, an
Italian physician, Bernardino Ramazzini, published De Morbis
Artificum (Diseases of Workers), his original observations on the
sources and causes of illnesses among workers in a large number
of occupations and trades. It was the first comprehensive
account of occupational diseases. It is largely due to Ramazzini that many
modern physicians note patients' social, environmental, and occupational
circumstances as integral factors in recording and evaluating medical histories.

Bernardino Ramazzini (1633-1714)

De Morbis Artificum (Diseases of Workers)

Padua, 1713

Bernardino Ramazzini, an Italian physician,
described "asthma" in bakers, miners,
farmers, gilders, tinsmiths, glass-workers,
tanners, millers, grain-sifters, stonecutters,
ragmen, runners, riders, porters, and
farmers. Ramazzini outlined health hazards
of the dusts, fumes, and gases that such
workers inhaled. The bakers and horse
riders described by Ramazzini would today
probably be diagnosed as suffering from
allergen-induced asthma. The lung diseases
suffered by most of the other workers would
now be classified as "pneumoconiosis,"
a group of dust-related chronic diseases.

Breath of Life

Among the occupations Ramazzini studied were baking and milling, and the
conditions he referred to as bakers' and millers' asthma. He noted that those
who worked with wheat, barley, and other grains could not help inhaling
floating particles of the grains liberated during the measuring and sifting pro-
cess. He envisioned the formation of balls of dough that clogged the bron-
chial tree. These particles, he said, "ferment in the salivary juice and stuff
not only the trachea but the stomach and lungs with a sort of paste" produc-
ing coughs, shortness of breath, hoarseness, and finally asthma (Ramazzini,
Bernardino. Diseases of Workers. Wilmer Cave Wright, trans., De Morbis
Artificum, 1713 [New York, London: Hafner, ca. 1964]).

The Oxygen Revolution

In the eighteenth century, advances in chemistry
shed new Light on the understanding of the role
and function of the respiratory system.

In 1774, the English chemist Joseph Priestley
devised experimental techniques for preparing and
collecting gases that included focusing sunlight
through a lens to generate heat directed to a
sample of mercuric oxide in a closed vessel.
The released gas vigorously enhanced the burning
of a candle. In Priestley's own words, "I have
discovered an air five or six times as good as
common air." He named this "good air" dephlo-
gisticated air and estimated that it accounted
for some 20 percent of the atmosphere. A
decade later, the French chemist Antoine-Laurent
Lavoisier, repeating Priestley's experiment, named
the "good air" oxygen. Subsequently, he demon-

strated the body's requirement for oxygen
to convert food into energy.

Asthma is life-threatening when the disorder
deprives the body's vital organs of oxygen. The
shortness of breath in asthma is oxygen hunger.

Joseph Priestley
Artist unknown
Engraving

In 1791, the home and laboratory of
English clergyman and scientist Joseph
Priestley (1733-1804) were burned by
a mob angered by his unconventional

religious beliefs and support of the French
Revolution. Priestley left England in secrecy in 1794, settling
in Philadelphia, where he founded the first Unitarian church in
North America. In 1804, he died in Northumberland, Pennsylvania.

Plate 12

Marie-Anne Lavoisier's illustration from Antoine-Laurent
Lavoisier (1743-1794), Traite elementaire de chimie
(Elements of Chemistry) , Paris, 1789

Lavoisier's gasometer was the first instrument to make accurate
measurements of gases. Because gases can be compressed, in order
to measure the amount of a gas used in an experiment, Lavoisier
had to find a way simultaneously to measure both changing volume
and changing pressure or to hold one constant while measuring the
other. He used a piston to hold gas pressure constant while mea-
suring the volume of gases used in his experiments. In the 1850s,
British and Australian physician John Hutchinson (1811-1861)
modified a gasometer to make the first spirometer for measuring
the volume of a patient's breath.

National Library of Medicine

"Almost all who make a living sifting or measuring grain are short of breath
and cachectic and rarely reach old age," wrote Ramazzini. "The dust is so
irritating that it excites intense itching over the whole body, of the sort that
is sometimes observed in nettle rash. I have often wondered how so noxious
a dust can come from grain as wholesome as wheat." Further, he suspected
that the dusts these workers were exposed to harbored "minute worms
imperceptible to our senses and that they are set in motion by the sifting
and measuring of the grain and broadcast by the air; then they readily adhere
to the skin and excite that great heat and itching over the body" (Ramazzini,
Bernardino. Diseases of Workers. Wilmer Cave Wright, trans., De Morbis
Artificum, 1713 [New York, London: Hafner, ca. 1964]). In conjecturing some
hidden substance at work, he came close to the later concept of an allergic
response. What Ramazzini attributed to plugging of the bronchial tubes by
"dough balls" is recognized today as an allergic reaction to wheat and rye.

John Bostock (1773-1846)
Medico-Chirurgical Transactions
London, 1819

Hay fever or allergic rhinitis (known
commonly as "allergies") can be
brought on in sensitive individuals
by many of the same substances that
bring on asthma symptoms. In 1819,
John Bostock described this condition
as a "periodic affliction of the eyes
and chest," presenting the details
of the case of one "J. B."— himself.

The view that there might be extrinsic factors that could trigger an asth-
matic attack was further explored by the Scottish physician William Cullen
(1712—1790), founder of the medical school at the University of Glasgow
and a professor of medicine and chemistry. Since the disorder could not be
easily treated, he reasoned that the patient could only escape the disease by
avoiding "exciting" causes.

Cullen noted that different asthmatic patients have different reactions to
external factors: one asthma sufferer may find it easiest to live in the city,
another cannot breathe except in the free air of the
country. In also noting that asthmatic patients did
better if the air was tolerably dry, Cullen could well
have been reading Maimonides.

1,i:KIO0ICALAFFFXT.ON

EYES ANP CBEST.

k«rtl,tr un ulcroting I" the .-"ouei;,
^Lolcofanunusoa. U* of symptoms

tffjtil Motion, f-wn in having occurred m UK
jhmb, of (he narrator.

J.B.M. 46, is of a spare »n<l rather Mfc*
fabt, but capable of considerable exertion, and

;. no hereditary or constitutional affection, ex-
cept >»riou< stomach complaints, probably con-
noted with, or depending upon, » tendency lo
int. About the beginning or middle of June in
enrr year the following symptoms make their ip-
psrjncf , with a greater or less degree of violence.

Because there were no specific medicinal measures
for treating asthma, Cullen's recommendations for
avoiding asthmatic triggers evolved into a mainstay of
asthma management well into the nineteenth century.
Indeed, as noted, avoidance of substances such as
pollens, house dust, and perennial airborne inhalant
allergens, as well as some foods, remains a major tool
in managing asthma today. It is bolstered by modern-
day tests for determining the specific allergens to
which the patient is sensitive and reactive.

Although the term "allergic response" dates only
from the earliest years of the last century, its general
description goes back a century earlier. In 1819, English physician John
Bostock linked excessive watering of the eyes and nasal congestion with the
summer season. Since childhood, Bostock had had what is known as hay fever.

Breath of Life

10s

*»l • t..inl SrST* ,'i,'CCtl1"' *« Sfci

4 270. Though not ,,
MlccUM for e.. of «>c dtrik ,

„ uu> experiment, *u - , } lh« I'Uc

average city rc<i,i,.n^ " ■* » RO»d „M, , ' «»

0 would ha

the kjsu ti wci,!,l i . no*rer ccntnj of H ■
(In •>, tX|««.d,:„nj M u ; _ " » ™ only ,„„

} 271. The tnhlu oT curvn IT.M ill .

I^U^Z:™'. ";*' ,J"> "" "l.ioL the" ftattal
"how,, in T I I V " , '"""'■'J' «*artly tho *""C i,
barinniii ' r manm't. too. there a at the

r> «nuux The highest pout in tl,„ scale w„ ~ "2
l« W by the table, reached on June ;M «' ,
carl.er than i„ „,„ ymr ^ „„ ^ ««

>>' "olc-hook to the following effect ' I ,„

mud, uiore -.Orel, ,fcW th„„ | L»„ ^.„ on . «
mi ee the attack commenced. The eye, are very ho, and
itch intently, and havo a .light homing »ei„atiu„ „, u,e
antcnorpart of the eyeball,, a» if hot Moid of M, ki„d
had Inm dropped on lo thorn. The no.tril.havc div l„„..„|
freely, and I fa ave had wvcral violent atlaek, of .nee.ing ■

About the middle of June every year, he reported, a sensation of heat and
fullness of the eyes developed into an acute itching and smarting. This was
followed by nasal irritation, sneezing, tightness of the chest, and difficulty
in breathing. Although Bostock did not know the cause, he conjectured
these symptoms came from flowering plants, thus establishing a seasonal
connection to asthmatic attacks.

The allergenicity of grasses and ragweed was established later in the century
by two physicians with very different backgrounds working on opposite sides
of the Atlantic.

In Manchester, England, Charles Blackley established the cause of what we
today call hay fever.

Like Bostock, Blackley suffered from hay fever and asthma. Not content
just to describe the condition, he designed an instrument to count pollen at
different locations: at ground level and at various heights, which he investi-
gated using a kite. In his home and office laboratory setting, he conducted
systematic experiments into the role of pollen in triggering attacks of hay
fever. In his greenhouse, Blackley cultivated various plants and grasses, and
induced them to flower out of season, in the winter. Then, subjecting himself
to inhaling their pollen, he showed that such exposure triggered the symptoms
of hay fever.

Charles Harrison Blackley
(1820-1900)

Hay Fever: Its Causes, Treatment,
and Effective Prevention,
Experimental Researches
London, 1880

Charles Blackley invented the pollen
counter in the late 1860s. The first
pollen counter was simply a glass
slide smeared with a sticky substance.
Blackley used it to collect pollen from
the air. He then counted the grains
of pollen under a microscope. (Current
models use the same principle.) Blackley
and others used the pollen counter
to collect extensive data on seasonal
variations in airborne pollen in order
to show why hay fever, asthma, and
other allergic diseases were more
severe at particular times of the year.

National Library of Medicine

UNITED STATES

Experimenting on himself, Blackley conducted what amounts to the first
skin test for an allergic response. He put pollen on the abraded skin of his
forearm and, recognizing the need for a control, also abraded an area of skin
on his other forearm but did not apply pollen. Within a few minutes, on
the arm that had been treated with pollen, a hive-like wheal appeared, along
with intense itching. But the untreated arm experienced no such reaction.
Blackley 's studies were not widely recognized at the time, largely because
he was a private medical practitioner in Manchester, not associated with a

university. Also, as a homeopathic physician, he was not part of
mainstream medical practice, and his work was not disseminated.

Concurrently, on the other side of the Atlantic, a contemporary of
Blackley's, Morrill Wyman, initiated a similar line of investigation.
Wyman suffered from hay fever. When studying the effects of
another pollen source obtained from Roman wormwood, a plant
member of the ragweed family, he identified it as the agent of
what he termed "autumnal catarrh."

Wyman noted that there was no hay fever in the White
Mountains of New Hampshire and believed that its absence
was due to the fact that Roman wormwood did not grow in the
area. He collected and packed pollen from flowering plants in
Cambridge, Massachusetts and took them to New Hampshire,
where the packages were opened and both he and his son
sniffed the pollen. He reported that they were both "seized with
sneezing and itching of nose, eyes, and throat . . . my nostrils
were stuffed and my uvula swollen" (Wyman, Morrill. Autumnal
Catarrh [New York: Hurd and Houghton, 1872]). Serving as a
control, his brother Jeffries Wyman, who did not have a history
of autumnal catarrh (hay fever), did not develop any symptoms
when he sniffed the pollen.

Morrill Wyman (1812-1903)
Autumnal Catarrh (Hay Fever)
New York, 1872

American physician Morrill Wyman's
pollen maps of the United States
helped physicians and patients select
places (shaded area) for vacations
or migration where hay fever and
asthma sufferers might be less likely
to encounter allergens.

Wyman further observed that some families were more affected by autumnal
catarrh than others; in his own family his father, two of his brothers, his
sister, and his son were all affected. He also recognized that nonseasonal
inhalants, such as the fumes of sulphur from burning matches or the gases
emanating from burning coal, could induce difficulty in breathing because
of what he described as a "peculiar sensitiveness of the respiratory nervous
system." His observation may be one of the earliest on hyper-reactivity of the
bronchial airways, appreciated today as a common pathophysiologic disorder
of asthma sufferers.

Breath of Life

In 1860, the English physician Henry Hyde Salter wrote On Asthma: Its
Pathology and Treatment, the most authoritative text on asthma at that time.
His book was widely read well into the twentieth century and was considered
the basic treatise on asthma. As an asthma sufferer himself, Salter recorded
various triggers that could induce an attack, including animal dander, impure
air, hay fever, and foods. He thought of asthma as a spasmodic disease, repre-
sented by constrictions of the bronchial tubes. In later years, it was discovered
that the pathogenesis of asthma was more likely due to swelling, rather than
constriction of the airways. Salter's concept led to attempts at therapy with
antispasmodic drugs that included the use of ma huang, or ephedra, thus
explaining the benefit derived from the plant the Chinese had identified
for managing breathing difficulty millennia before.

Salter and the French physician Armand Trousseau (1801-1867) agreed that
one way of controlling an asthmatic attack was to deliver an antispasmodic
agent via bronchial intake through the breath, by smoking or inhalation. They
studied several different medications for depressing irritability of the bronchial
passages; one method investigated was the inhalation of smoke from burning
paper that had been dipped in a chemical solution of nitrate. Additionally
they found that one of the more effective treat-
ments for controlling an asthmatic attack was
to smoke a cigar — likely due to its nicotine
content, which had pharmacological activity.

Salter made the interesting observation that
cigar smoking helped those who were non-
smokers, but not patients who were habitual
smokers. He was noting the fact that the
treatment only worked for those who had
not developed tolerance through frequent
smoking. Largely because of Salter's authority,
inhalation therapy for asthma (although not
necessarily cigar smoking) became widely
practiced, and indeed is still used today.

Another therapeutic agent Salter recommended
was coffee, based on his observation that
asthmatic attacks were preceded by drowsiness
and were often triggered when the patient was
asleep. Drinking strong, hot coffee would keep
the patient awake, he argued, thus avoiding an
asthmatic attack. Additionally the caffeine of
coffee or tea had the pharmacological property
of relaxing bronchial spasms; the chemical
analogs of caffeine, for example theophyline,
worked even better in treating asthma.

Henry Hyde Salter (1823-1871)

On Asthma: Its Pathology and Treatment

London, 1860

National Library of Medicine

Asthma Remedies

The development of modern chemistry in the
nineteenth century encouraged ingenious initia-
tives to uncover and define agents to relieve
airway constriction and reduce the excess mucus
and bronchial swelling that produce the short-
ness of breath, wheezing, and chest tightness
typical of asthmatic attacks. Most early measures
were aimed at reducing symptoms and were
refinements of traditional, partially efficacious,
herbal remedies.

Pharmacists and physicians derived and com-
pounded their own medicaments until chemists
in the nineteenth century isolated what they
believed to be the active ingredients of tradi-
tional agents for alleviating asthmatic symp-

toms. By the latter part of the century, these
agents were being produced in quantity for
the commercial market, and often extravagantly
advertised. Drug companies promoted their
products to asthma sufferers without the need
for a physician's prescription.

It is questionable whether most of these agents
did in fact relieve asthma. Many contained alco-
hol or narcotics such as cocaine or morphine,
which, in addition to having pharmacologic
actions, were more likely to mask asthmatic
symptoms and permit the patient to feel better
than to play a true therapeutic role. There
could also be untoward side effects of morphine
derivatives, such as depressed respiration.

Directions for Using
Kutnow's Anti-Asthmatic
Powder and The Carbolic
Smoke Ball

Courtesy William H. Helfand
Collection, New York

Pastilles Salmon

Courtesy William H. Helfand Collection, New York

Dr. J. D. Kellogg's Asthma Remedy

Courtesy William H. Helfand Collection, New York

Marshall's Prepared Cubeb Cigarettes,
ca. 1882

Courtesy William H. Helfand Collection, New York

Kutnow's Anti-Asthmatic Powder
Dr. Whetzel's Powder for Temporary

Relief of Paroxysms of Asthma
Samuel Kidder & Co.'s Asthmatic Pastilles
Brater's Powder for Spasms of Asthma and Brater's Powder
Courtesy National Museum of American History, Smithsonian Institution

Breath of Life 21

Early Epidemiological Research

The measures recommended for managing asthma in the nineteenth century,
of necessity, relied on material gleaned from individual case reports, and
represented the experiences of physicians involved in treating asthma. There
were, however, some investigators, among them Salter, who innovatively
searched for common features of asthma and tabulated information gathered
from observations of large numbers of patients. Salter noted familial asso-
ciations with asthma in 84 of 217 patients surveyed. This type of statistical
investigation represented a divergence from the case-study approach to study-
ing disease, which concentrated on each individual's experience rather than
trying to understand the traits common to all sufferers.

In the late nineteenth century, New York physician George Beard, looking
for a common factor in hay fever and asthmatic disorders, sent out a detailed
questionnaire to patients. Beard received two hundred replies and used the
responses to assess the impact of such respiratory symptoms on the popula-
tion. He observed that more men than women and more tradespeople than
professionals were affected, that symptoms occurred more frequently among
married persons, and that symptoms occurred more frequently in "persons of
nervous temperament."

These efforts represent early steps toward epidemiologic investigation of
hay fever and related respiratory disorders. While case studies of individual
patients are always useful, epidemiology adds to knowledge of a disease
through the study of its effects on populations. By Beard's time, it had long
been recognized that without a good measure of the incidence and preva-
lence of a disease it is difficult to mount effective attacks against it. Adequate
epidemiologic study of any disorder is the cornerstone of effective public
health practice and a useful guide for the clinician.

By the nineteenth century, epidemiologic investigation was well established
as a means of measuring the impact and discovering the cause of disease. In
1740, Percivall Pott (1714-1788) identified soot as the cause of scrotal cancer
among London chimney sweeps, and in 1857, John Snow (1813-1858)
linked cholera to the water supply from the Broad Street pump. Adequately
performed surveys of diseases such as asthma had not yet been mounted. It
was only in the mid-twentieth century that data began to provide a more
reliable picture of the impact of asthma on the general population.

2nd

New York Hospital

4k .

-Patient department

DATE

AGE SEX

^ 7 ^ 3 i>

NATIONALITY

OCCUPATION

^-vy f_

Breath of Life (23

A New Century
and New Knowledge

At the turn of the twentieth century, a distinguished Philadelphia physician,
Solomon Solis-Cohen (1857-1948) proposed that the immediate mechanism
resulting in an asthmatic attack was the obstruction of respiration from a
swelling of the bronchial mucosa, related to angioneurotic edema. Suggesting
that increasing the bronchial vascular tone might prevent these attacks, he
introduced a therapeutic extract of adrenal glands from animals to treat his
own hay fever. He reported that it cut short an asthmatic paroxysm, was
useful in preventing a recurrence, and relieved the fear of attack. Solis-Cohen
proposed the use of adrenal extract as a "measure applicable in certain cases."

The real importance of Solis-Cohen's preliminary work with adrenal extract
lay fifty years in the future. His was probably the first use of an agent to
modify an immune mechanism in asthma. In 1949 the work of Philip Hench
(1896-1965) and Edward Kendall (1886-1972) made it possible to use
adrenal gland-derived cortisone in treating autoimmune disorders when they
isolated the adrenal hormone. Solis-Cohen's finding also marked the beginning
of an increasing interest in the immune system — the body's reaction to foreign
invaders — which furthered much of twentieth-century biomedical research.

By the last years of the nineteenth century, largely due to Louis Pasteur's
(1822-1895) work on germ theory, an increasing interest developed in the
mechanisms by which the immune system recognizes and rejects disease-
causing invaders such as bacteria. To many researchers interested in asthma,
it must have seemed a natural step from studying bacterial pathogens and
the efforts to neutralize them, to studying the adverse reactions of asthmatic
patients to plant pollens and animal proteins.

Robert A. Cooke's patient notes, 1916

Robert Cooke set up the first allergy
clinic in the United States at New York
Hospital in 1920. Patients' skin was
exposed to concentrates of common
allergens to learn which substances
brought on each individual's allergic
responses. Patients could then either
avoid the substances that made them
sick or undergo "immunotherapy,"
periodic injections of specific allergens
designed to reduce the immune response
that caused asthma and other symptoms.

Courtesy Sheldon G. Cohen, M.D.

In the late 1870s, a German physician, Robert Koch (1843-1910), working
with the tubercle bacillus, pioneered the development of techniques for
staining pathogenic microorganisms, thus marking them for identification
by microscopic visualization. His work made possible the identification of
microbes associated with infectious processes and the diagnosis and treatment
of several bacterial diseases. Information thus gained stimulated efforts to
develop antisera against disease-causing organisms and their toxins.

Anaphylactic Shock

One of the earliest antisera, anti-streptococcal horse serum, had been
developed to treat the complications of scarlet fever. In the early years of the
twentieth century, the Viennese physician Clemens von Pirquet (1874-1929)
noted the development of altered reactivity in some persons treated with the
anti-streptococcus serum produced in horses. After they had been sensitized
by a previous injection, they manifested evidence of hypersensitivity to horse
serum proteins.

Clemens von Pirquet coined the word "allergic" — from the Greek words
alios meaning "other" and ergon meaning "work" — to describe this altered
reaction and pointed out that horse-derived allergens, the substances that
induced this adverse effect, were antigenically different from the substances
that stimulated antibody production against the streptococci. "The term
allergen is far more reaching," he wrote. "The allergens comprise, besides the
antigens proper, the many protein substances which lead to no production
of antibodies but to super-sensitivity" (von Pirquet, Clemens. "Allergie,"
Munch Med Wochenschr, 1906; 53:1457. C. Prausnitz, trans, in P.G.H. Gell
and R.R.A. Coombs, eds., Clinical Aspects of Immunology [Oxford, Blackwell,
1963]). He went on to note that allergens included mosquito bites, bee stings,
the pollen that causes hay fever, and the swelling and itching caused by
substances such as strawberries and crabs. He would later learn that allergens
do engender production of antibodies of a different type, not detectable by
test-tube techniques, but identifiable only by their untoward reaction against
susceptible tissue cells.

In addition to a hypersensitivity serum-sickness reaction which may take as
long as ten days to develop, another type of allergic reaction became known
as immediate hypersensitivity. Within minutes, seconds sometimes, a sen-
sitive individual after exposure is struck with symptoms of hives, itching,
swelling, respiratory difficulty, even a precipitous drop in blood pressure and
shock. If the situation is not immediately neutralized, it may lead to death.
This immediate systemic allergic reaction is called anaphylaxis. The reaction
was initially observed in experimental animals by two French physicians,
Charles R. Richer (1850-1935) and Paul J. Portier (1866-1962). The
manner of their discovery is a colorful story of scientific research.

Breath of Life

When Portier and Prince Albert I of Monaco became friends, the Prince
often invited Portier to cruises on his yacht. On one of these occasions
Richet was also invited and the Prince asked them to try and solve a problem
for him. He was concerned that visitors to Monaco were unwilling to swim
in the Mediterranean because it was becoming overpopulated by stinging
jellyfish. He was losing tourists and in Monaco, then as now, tourism was
its lifeblood. He asked them to develop a vaccine against jellyfish stings.

The idea of a vaccine was then popular because in the 1870s Pasteur had
shown the protective effect of an attenuated strain of anthrax bacillus in
sheep, similar to the action of English physician Edward Jenner's cowpox
vaccine against the development of smallpox. The idea that one might
be able to prevent illness by immunization against jellyfish toxin had
some appeal, especially in the light of Emil von Behring's (1854—1917)
development of an effective diphtheria antitoxin.

Edward Jenner

The body's ability to neutralize foreign pathogens
has been utilized therapeutically for centuries.
As early as the eleventh century, the Chinese,
noting that patients who had once experienced
smallpox were immune to subsequent attacks,
inoculated persons against the disease with
small amounts of fluid or powdered scabs recov-
ered from skin lesions. From China, the method
spread westward to Turkey, then to England and
to other parts of the world. The procedure was
risky, in that it could induce a full-blown case
of the disease and deaths sometimes occurred.
It was considered an acceptable risk only
because smallpox was such a serious disease
in which a quarter of those infected died.

A safer method of inoculation was developed by
the English country physician, Edward Jenner in
a 1796 experiment. Following the experience of
English milkmaids, Jenner inoculated a boy with
cowpox, a milder disorder related to smallpox.

He subsequently
tested this method
of inoculation with
fluid from smallpox
pustules and found
that the tested
recipient did not

develop smallpox. I .

Edward Jenner (1749-1823)

Jenner, although

unaware of the specific mechanism, was making
use of what we now recognize as an antigenic
similarity between two biologically related disease-
causing microorganisms: i.e., through shared
chemical character, the ability of one to induce
an immune response to another. For example,
the recent introduction of childhood immuniza-
tion against chickenpox virus also carries the
potential for preventing or at least mitigating the
occurrence of herpes zoster (shingles) in later life
since the two agents are antigenically similar.

The Prince had outfitted a laboratory on his yacht for the two scientists to
extract the incriminated component of the jellyfish toxin, which they then
injected into dogs in increasingly potent doses to test for a possible vaccine.
Although some of the animals died from the poisonous effects, those that
survived were given a second injection of the toxin to see if they were protected.

"At this point an unforeseen event occurred," wrote Portier and Richet.
"The dogs which had recovered were intensely sensitive and died a few
minutes after the administration of small doses." In one experiment they
reported that a few seconds after the second injection "the animal became
extremely ill, breathing became distressful and panting; it could scarcely
drag itself along, lay on its side, was seized with diarrhea, vomited blood and
died in twenty-five minutes" (Portier, Paul and Richet, Charles, "De Taction
anaphylactique de certain venins," Comptes rendes Societe de Biologie (Paris),
1902; 54:170). The animals had experienced, a newly recognized phenomenon,
anaphylactic shock.

The two essential and sufficient requirements for inducing this response,
Portier and Richet noted, were "increased sensitivity to a poison after previous
injection of the same poison and an incubation period for this increased
sensitivity to develop." For this pioneering discovery of anaphylaxis, Richet
(not Portier) received the 1913 Nobel Prize in physiology or medicine.

During this same decade, in 1905, two physicians working in the Laboratory
of Hygiene in Washington, D.C., the predecessor of today's National Institutes
of Health, were studying a very similar response in guinea pigs. Milton J.
Rosenau (1869-1946), the laboratory's director, and John F. Anderson
(1873—1958), the assistant director, were following up on reports of severe
reactions, some fatal, in patients who had been treated with diphtheria and
tetanus antitoxins. In addition to the studies by Poitier and Richet,
anaphylaxis had by this time been reported by others.

In carefully controlled experiments with guinea pigs, using horse serum-
derived diphtheria and tetanus antitoxins, Rosenau and Anderson studied
anaphylaxis in great detail. They demonstrated the requirements for specific
antigen-antibody interaction, the amount of the dosages, and the time inter-
vals between the first sensitization dose and the second challenging injection.
Their studies eliminated a long list of possible cofactors on the anaphylac-
togenic properties of sera such as aging, drying, heat, irradiation, filtration,
dialysis, and treatment with enzymes.

They noted that reactions differed between species, indicating some distinction
in species-specific target organs. In one demonstrated example, they found
that while a guinea pig suffers bronchial spasm and dies of respiratory failure,
a rabbit, by contrast, dies of cardiac arrest. Nevertheless, they concluded:
"The fact that humans, guinea pigs, and other animals react to a second
injection of horse serum would seem to indicate that we are dealing with
one and the same action."

During this period, related studies led some investigators to believe that
immunology was a useful model for studying human asthma. Theobold Smith
(1859-1934), a microbiologist at the Rockefeller Institute, reported findings
that guinea pigs get bronchial spasms when pre-sensitized to an antigen and
then challenged. Although the guinea pigs had respiratory deaths, their pathol-
ogy was not similar to human asthma, in which there is also inflammation of
the bronchial membranes and sputum formation.

American investigator William Schultz (1873-1953), a member of the
Laboratory of Hygiene in Washington, D.C., described an experiment of
suspending sensitized guinea pig ileum in a physiologic solution. He noted
that, as susceptible target tissue, it would contract when the corresponding
antigen was added to the solution. The following year, Sir Henry Dale
(1875-1968), working at the Wellcome Physiological Research Laboratories
in England, took up the study of anaphylaxis — an immediate and severe
systemic reaction to antigens — in guinea pigs.

Dale, interested in the chemical transmission of nerve impulses, then used
a smooth muscle strip taken from another target organ, sensitized uterine
tissue. He exposed it to a chemical, beta-iminazolylethylamine, otherwise
known as histamine, and showed that the muscle contracted when histamine
was added to the solution in which it was suspended — the reaction is known
today as the Schultz-Dale phenomenon. Dale concluded that released hista-
mine was the cause of anaphylaxis. In 1936 Dale shared the Nobel Prize for
physiology or medicine with the German physician-physiologist Otto Loewi
(1873-1961) for their work on the chemical transmission of nerve impulses.

Today histamine, along with other chemical mediators, is known to be
released from a class of cells — named mast cells in 1877 by Paul Ehrlich
(1854-1915) — following stimulation by an allergen reacting on its surface
membrane. Histamine plays an important role in some immediate allergic
responses, such as the swelling and itching experienced by hay fever sufferers,
but it plays a lesser role in asthma. Histamine was later synthesized, and in
1933, another Nobel Prize winner, Daniel Bovet (1907-1992), developed
the first antihistaminic drug. However, antihistamines only relieve symptoms
and do not prevent or remove the underlying cause of the allergic state or
its reactions.

The concept that allergens such as ragweed and grass pollens are foreign
bodies much like bacteria and could, therefore, be countered by mounting
an immune response was the driving force behind an experiment in London
in 1902. Sir Almroth Wright's (1861-1947) Inoculation Department at
St. Mary's Hospital became world-famous for its studies in immunization.
The department was particularly recognized for Wright's immunization
of the British Army in India against typhoid fever.

28 National Library of Medicine

Robert Anderson Cooke, 1940

Wright had assembled a small group of investigators, among them Leonard
Noon (1878-1913) and John Freeman (1877-1962). Noon, an immunolo-
gist, had studied tetanus toxins and antitoxins and, believing that the caus-
ative agent of hay fever was a toxin in pollen similar to those in microbes,
prepared extracts of grass pollen with which he attempted to immunize
affected subjects by subcutaneous injection. There was some success in that,
as his coworker and successor, Freeman, later reported: "Where a patient
has been inoculated for one year he has in the next year complete, or almost
complete, immunity, but in the third year he has only slight immunity left.
Where patients have been successfully inoculated for two years they have,
as might be expected, complete immunity during the third year, and time
will show how long this complete immunity will last" (Freeman, John.
"Vaccination against hay fever: Report of results during the last three years,"
Lancet, 1914; 1:1178).

Noon and Freeman believed they were producing a protective immune
response, that is immunizing their patients against pollen toxin. But, reexami-
nation showed that they were inducing a lessening of a hyposensitization of
their patients, a form of immunotherapy. Regardless of their misunderstand-
ing of the cause, their work had a major influence on the clinical management
of allergic disorders for the next several decades. The injections of pollen
extract were the beginnings of what are popularly called today "allergy shots."

Noon's and Freeman's approach was adopted by many clinicians, most
notably two American physicians, I. Chandler Walker (1883-1950) in
Boston and Robert Cooke in New York, who figured prominently in taking
this idea further. Walker and Cooke were among the first to set up allergy
clinics using injection treatments for asthma and allergic diseases. Between
them they popularized the treatment of asthma by desensitization.

Robert Cooke (1880-1960)
Allergy in Theory and Practice
W.B. Saunders Company,
Philadelphia and London, 1947

In 1916 Cooke began seeing patients and in 1920 set up a laboratory and
allergy clinic at New York Hospital where he developed standards for diag-
nosis and treatment and for training programs in allergy. In that setting, he
was responsible for training a large number of physicians who then returned
to their home cities to develop their own clinics along similar lines. He
became a dominant force in the field and through his leadership created
the subspecialty of allergy in internal medicine in the United States.

Cooke himself suffered from asthma, a factor that, as with so many other
earlier investigators, influenced his professional interest. His investigations
covered a broad spectrum of problems in allergy in addition to asthma. He
developed a system for standardizing the protein extracts used in hyposensiti-
zation therapy, examined drug reactions, and studied the role of heredity.
He noted that sensitized individuals transmitted to their offspring, not their
own specific sensitization, but the unique hereditary capacity for developing
a reaction to foreign proteins. Cooke was getting close to the underlying
factor of allergic disorders in general, and asthma in particular, when he
found that there was a genetically transmitted aberration that made the
subjects susceptible to sensitization to foreign proteins.

YORK HOSF

Department

f 7

NEW YORK HOSPITAL OUT-PATIENT DEPARTMENT

3 » £a ? -i^^^sa - -

iJLj fa i£~Z.L, f Kj.c

Robert Cooke's patient notes, 1916 and 1919
New York Hospital Out-Patient Department

Courtesy Sheldon G. Cohen, M.D.

Another influential member of the select New York study group that founded
the Society for the Study of Allergy and Allied Conditions was Francis M.
Rackemann (1887-1973), the Society's second president after Cooke. Early
in his career, Rackemann became interested in research in experimental
anaphylaxis and the developing field of clinical allergy. On returning to
Boston and joining the staff of the Massachusetts General Hospital and the
Faculty of Medicine at Harvard University in 1916, he turned his attention
to asthma. Two years later he published his noteworthy study of 150 patients
with asthma. In a monumental effort he followed some of them for up to
thirty years.

From this work came his most frequently quoted conclusion: that bronchial
asthma was a symptom that might have multiple causes, which he defined
as either "extrinsic" or "intrinsic." Extrinsic causes related to allergenic,
skin test-positive agents; intrinsic causes of asthma were the result of some
constitutional disorder.

One of Cooke's associates, Oscar M. Schloss (1882-1952), a pediatrician,
developed the scratch test as a diagnostic procedure for detecting hypersen-
sivity, using it to detect diagnostic leads in studies of patients sensitive to
various foods. Schloss had become interested in von Pirquet's scratch test
for tuberculosis and Bela Schick's (1877-1967) intracutaneous test with
diphtheria toxin. Concerned over what he called the alarming reactions to
toxic foods, he reasoned that a skin test, rather than actual feeding of the
suspected food, was needed to identify adverse reactions.

Schloss found that, within five to fifteen minutes after an active substance
was rubbed into the skin, like Blackley's study years before with pollen,
a distinct wheal was raised at the inoculation site. The reaction was always
immediate and disappeared within thirty minutes to an hour. He did exten-
sive experiments that showed the reaction was specific for the test food and
not caused by chemical or mechanical irritation.

For many years the scratch test and the intracutaneous modification were
the bases for the investigation and treatment of allergic disease: first, skin
testing for allergens to which the patient was suspected to be sensitive, then
development of injection treatments designated to hyposensitize the patient.

Breath of Life 31

At first glance it might seem as if these and the continuing studies on allergic
responses had little to do with asthma. Persons who have experienced skin
reactions from substances to which they are allergic do not necessarily have
coexisting or complicating asthma. There is, however, an association. Studies
during the latter half of the twentieth century have demonstrated that sensi-
tization among those genetically susceptible to some indoor allergens, such
as house dust mites, animal dander, and cockroaches, poses a risk for develop-
ing asthma, particularly in children. There is less risk from outdoor pollens,
although grass and ragweed pollen have been associated with seasonal asthma.
It has also been found that sensitivity to perennial inhalant allergens as a cause
of asthma declines with age. Food allergens may, but do not commonly, give
rise to symptoms of asthma. Even those who are highly susceptible and may
experience anaphylaxis as a result of eating certain foods do not have lower
respiratory tract symptoms.

There is also clinical evidence that an allergic reaction in the airways, as a
result of exposure to allergens, leads to an increase in inflammatory responses,
increased airway hypersensitivity, hyperreactivity, and an increase in eosino-
phils, white blood cells contained within the bronchial effusions that play
a role in effecting immune-mediated allergic reactions. These findings are
bolstered by evidence that when exposure to allergens, such as house dust
mites, is reduced, asthmatic symptoms in those predisposed to allergies
are also reduced. These and similar studies emphasize the importance of
minimizing or eliminating exposure to allergens in treating hypersensitivity-
related respiratory tract disorders, and they open doors to new knowledge
of asthma.

R. Voorhorst, F. Th. M. Spieksma,
H. Varekamp, MJ. Leupen, and A.W. Lyklema
"The house-dust mite (Dermatophagoides
pternyssinus) and the allergens it produces.
Identity with the house-dust allergen,"
The Journal of Allergy, June 1967

In 1967 the Dutch research team of R. Voorhorst,
F. Th. M. Spieksma, H. Varekamp, M.J. Leupen, and
A.W. Lyklema explained why millions of allergic and
asthmatic patients were sensitive to common house
dust— their pillows, mattresses, couches, curtains,
and clothes were infested with millions of invisible
dust mites.

Courtesy Mosby Publishing Company

Breath of Life 33

Immune System
Research Clarifies
Asthma

Recent research into the mechanisms of allergy has thrown new light on
the role of the immune system. Researchers have discovered that when the
immune system deviates from normal function, there are powerful secondary,
inflammatory, and constricting effects on bronchial tissues. Hence, studies
on immune function and hypersensitivity mechanisms in allergic individuals
have played major roles in clarifying some of the causes of asthma.

The immune system is the body's defense against the microbial world.
Without adequately functioning immune systems, animal populations could
not survive infection. We live in a world of potentially deadly germs — viruses,
bacteria, fungi, protozoa, and parasitic worms. We survive because the body
has evolved a complex defense system able to recognize these invaders; attack,
destroy, or neutralize them; and keep them under control.

As we have seen, the existence of the immune system has been recognized
for hundreds of years and through intervention has been manipulated to
control disease, by Jenner and others. But not until after Pasteur advanced
the germ theory of disease did the specific components of the immune sys-
tem come under close study. The last half of the twentieth century has seen
remarkable progress in our understanding of the components and products
of the immune system and their function. As a result, the diagnosis, preven-
tion, and treatment of many disorders, including asthma, have improved.

Kimishige Ishizaka (1925- )
and Teruko Ishizaka (1926- )

Working together, in 1967 husband-and-
wife team Kimishige and Teruko Ishizaka
showed that people with allergic disease
have a type of antibody that healthy
people do not have. Every person with
a healthy immune system has antibodies
to many different substances, and these
antibodies begin the process of immune
response to disease-causing microbes.
People with allergies and allergic diseas-
es, though, have IgE antibodies, a kind
that healthy people do not normally
possess. IgE antibodies are the key to
allergic asthma because allergic people
form these antibodies upon exposure
to common and harmless substances,
resulting in immediate and chronic
symptoms of the disease.

Courtesy William Coupon

National Library of Medicine

Sometimes the immune system malfunctions and mounts an attack on the
host's own tissues. The result is an autoimmune disease, examples of which
include rheumatoid arthritis, systemic lupus erythematosus, and glomerulo-
nephritis. It has been suggested that, in some instances, asthmatic syndromes
may also be the result of such an aberrant immune response. Whether
autoimmune reactivity plays a role in asthma remains to be determined.

ragweed'
pollen

The first time the allergy-prone
person runs across an allergen
such as ragweed,

.he or she makes IgE
antibody against ragweed.

Ig£
antibody

These IgE molecules attach
themselves to mast cells.

The second time that person

has a brush with ragweed,

the IgE primed mast cell
will release its powerful chemicals,

"-'vi •*••:♦'' and tnat person will suffer the

chemicafs SympiOmSwnee2|ng and/ or sneezing,
"• runny nose, watery eyes

and itching of allergy.

The Immune Response

The immune response in allergic disorders such
as hay fever and asthma begins with exposure
to a causative agent, the allergen, an inhaled,
injected, or ingested foreign protein. When
the allergen reaches the lungs, it encounters a
macrophage, which engulfs the foreign molecular
particle. As the macrophage ingests, degrades,
and processes the allergen, it undergoes changes
on its surface through expressed proteins that
send out a signal to attract a precursor of the
T lymphocyte called the T-helper cell.

The T-helper cell picks up the signal
carrying the imprint of the allergen from the
original encounter, and, in an evolving matura-
tion process, migrates to a lymph node where
it encounters a B lymphocyte and transmits the
allergen-derived imprinted message. This begins
the transformation of the B cell into a mature
immunoglobulin-producing cell known as the
plasma cell, which generates antibodies that
switch on and off depending on the need.

In essence, the T-helper cell's job is to try and
keep the foreign agent, whether infectious or

When allergic people are exposed to allergens, their immune
system responds by producing antibodies called IgE.

allergenic, under control and localized as much
as possible, while the other arm of the immune
system, the B cell, creates antibodies directed
against the antigen.

The symptoms of asthma result from a series of cellular events in the human
immune system. There are several specific cell types involved: the macrophage,
so named because of its large size and its ability to ingest particles from
outside its own cell walls; the lymphocytic T and B cells; the plasma cells
which evolve from the B cells and produce different classes of antibodies;
and, finally, the mast cells, a particular type of cell whose intact granules
contain chemicals that on release are capable of inducing inflammation,
a reaction that plays a role in allergic asthma.

Antibodies belong to a group of proteins known as immunoglobulins (Ig), of
which there are five major classes: IgA, IgD, IgG, IgM, and IgE as identified
by their molecular structures and sites of formation and action. Each plays a
role in forming defenses against foreign substances that challenge the body.

The immunoglobulin of most interest to the study of asthma is IgE. It is
now known that IgE is responsible for the majority of allergic reactions of the
immediate skin test positive type. The main protective immune function of
this immunoglobulin is to protect against or repel invasion by tissue-invasive
parasitic worms. Thus IgE levels in the blood of those who live in those
parts of the world where these tissue— invasive parasitic worms are common
are generally elevated. In persons not normally exposed to such parasites,
IgE is present in very small amounts. Allergic persons synthesize IgE against
allergens such as extrinsic or atmospheric pollen, dusts, animal danders,
molds, and certain foods. When IgE was identified in 1966 by Kimishige
Ishizaka and his wife Teruko Ishizaka, it opened a door to an approach to
asthma therapy through efforts to suppress or modify IgE formation.

Working as an immunology team at the Children's Asthma and Research
Institute in Denver, Colorado, they isolated the antibody responsible for the
skin sensitivity in specifically allergic people. The Ishizakas showed that IgE
was, by molecular structure and by its demonstrable effect on allergically
susceptible tissues, a "distinct class of immunoglobulins," unrelated to any
of the other immunoglobulins. It could be differentially identified in test
tube reactions. They named it immunoglobulin E.

National Library of Medicine

New Discoveries: Leukotrienes

Not all allergic reactions are mediated by agents
from mast cell granules. A group of chemicals
known as leukotrienes are produced by the action
of antigen on sensitized tissue. They are of
special interest to the study of asthma because
they are potent constrictors of the small
bronchial airways.

Leukotrienes have only recently been chemi-
cally characterized, but the discovery of their
role in allergic reactions dates back to 1930.
An American physician-investigator, Joseph
Harkavy (1890-1980), working at the Institute
of Pharmacology in Leiden, The Netherlands, dis-
covered a substance in the sputum of asthmatics
that caused spasms in isolated smooth muscle
strips. In experiments, somewhat similar to those
of Sir Henry Dale with histamine, he recorded
the pattern of the contractions of the suspended
test muscle strip. The contractions were immedi-
ate, suggesting, he said, that there were two
substances responsible for the spasms. Histamine
was one; the other remained unknown.

Harkavy's studies were followed up in the late
1930s by two Australian investigators, Charles H.
Kellaway (1889-1952) and Everton R. Trethewie
(1913-1984). Studying the antigen-antibody
reaction of anaphylaxis, they showed that the
substance Harkavy had postulated was present
in the sputum of asthmatic patients and caused
a slow, long-lasting, and profound constriction
of the bronchial airways. They called it the slow
reacting substance of anaphylaxis or SRS-A.

Its exact nature remained a mystery until forty
years later, when Bengt I. Samuelson (1934- ),
of the Karolinska Institute in Stockholm,
identified and chemically characterized SRS-A.
He named the group of component chemicals
leukotrienes because they are made by leuko-
cytes (white blood cells). He and his associates
demonstrated the role of leukotrienes in asthma,
showing that they are potent bronchial constric-
tors, cause increased vascular permeability, stimu-
late mucus secretion, and have pro-inflammatory
effects. In 1982 Samuelson shared the Nobel
Prize in medicine or physiology with scientists
working in the same biomedical area, Sune
Bergstrom (1916- ) and the English scientist,
John Vane (1927- ).

Leukotrienes originate from the breakdown
products of cells that are disrupted following
injury, infection, hormonal stimulus, or an
allergic response. The membranes of the cell are
converted by enzymatic action into a substance
called arachidonic acid. This in turn is broken
down into biologically active compounds, one
of which forms the leukotrienes.

When Samuelson summarized his studies in
1983, he noted that their discovery opened the
way to developing new and more specific agents
designed to antagonize the key inflammatory-
producing leukotrienes. In fact, at least two such
agents have since been developed that function
in this way and are now available. They represent
a major advance in the management of asthma.

When allergic persons respond to an allergen to which they are sensitive,
they produce specific IgE antibodies. This first encounter does not produce
an allergic reaction but it primes the sensitive individual so that when that
individual re-encounters the same antigen it triggers an allergic response.
Thus an individual who is allergic to horses, dogs, or cats makes IgE in
response to a particular protein in horse or dog dander or cat saliva, although
that individual may tolerate exposures to other animals perfectly well. Similarly
a person allergic to oysters makes IgE that recognizes and interacts with a
protein in oysters, but that person is able to eat non-mollusk foods without
any reaction.

IgE does not mediate the allergic reaction itself; rather it primes an effector
cell — the mast cell first identified in 1877 by Paul Ehrlich. Ehrlich noted
that these cells were stuffed with large granules. It was assumed at the time
that the granules had been engulfed by the cells, hence, the name "mast"
from the German word for a fattening feed. However, it is now known that
the granules are produced within the cells and are filled with histamine and
other chemical mediators of the allergic reaction.

When an IgE antibody on the mast cell encounters its specific corresponding
allergen, the granules move to the surface of the mast cell, and, through
a process known as degranulation, release chemical mediators into the
surrounding tissue.

Breath of Life

Effective Medicines
for Treating Asthma

While one of the best methods for treating asthma and allergic disorders
is careful management of the environment to avoid substances that trigger
reactions in sensitive persons, there are a number of effective drugs available
for treating and, in some cases, preventing asthma.

Some drugs have been derived from remedies used in the past. In recent
years scientists have isolated the active chemical components from many of
the botanical agents favored by the ancient healers, and constructed synthetic
versions of them.

One such agent is sodium cromoglycate, known by its trade names Intal®
or Cromolyn. It is an anti-inflammatory agent that inhibits the release of
histamine and thus prevents swelling and inflammation of the airways,
allowing air to flow more freely.

The leading figure in the development of cromoglycate was Roger E.C.
Altounyan, an Armenian physician who worked in England. He is recog-
nized for his determined pursuit of a single idea — the development of an
anti-allergic, anti-asthmatic agent from a weed called khellin, derived from
a herb indigenous to Egypt and North Africa. A soup made from khellin
was used 5000 years ago in ancient Egypt to relieve spasmodic muscular
contractions. Reasoning that khellin might relieve the bronchial contrac-
tions that occur during an attack of asthma, Altounyan and his associates
decided to try and improve on its action by isolating and synthesizing
derivative compounds.

May 9, 1963 chart

Roger Altounyan (1922-1987) tested
hundreds of extracts of khellin on
himself, taking it before and after
exposing himself to a solution of
guinea pig hair — to which he was
allergic. Extract K84, which would
later be shown to contain sodium
cromoglycate, reduced his response
to the allergen, and he wrote
"Hurrah!" on his chart.

112 Mete
NDC 0585-0675-02

?d inii., i., i,

Intal Inhaler

(cromolyn sodium
inhalation aerosol)

METERED 00SE INHALER
FOR ORAL INHALATION ONLY.

CAUTION: Federal law prohibits
dispensing without prescription

Carton contains one canister with
mouthpiece

112
Metered
Inhalations
(8.1 g)

Courtesy Mrs. Hello Altounyan and Family,
Cheshire, England

Intal Inhaler inhalation aerosol, 1998
Rhone-Poulenc Rorer Inc.

Courtesy Robert Aronowitz, M.D.

Jatafi
whaler

40 National Library of Medicine

Altounyan suffered from asthma and, like many medical researchers through-
out history, experimented on himself. He would induce asthmatic attacks by
inhaling mixed pollen antigens to which he was allergic and then determine
if the compounds isolated by the chemists had any mitigating effect. Over
the course of eight years, he tested 670 compounds. While most of them
failed to relieve his asthma during an actual attack, he found one compound
that, if inhaled before he induced an attack, stopped the attack from devel-
oping. The compound was identified as sodium cromoglycate.

Cromoglycate is delivered by inhalation into the airways. Altounyan devel-
oped a device called the spinhaler to move the drug efficiently. The device
works on the same principle as an airplane propeller, with whose mechanism
Altounyan was familiar, having been a Royal Air Force pilot during World
War II. Inside the device is a miniature propeller. When the patient breathes
in, the propeller rotates and this releases the drug into the air stream. Thus
there is an automatic coordination between the drug's entry into the airways
and the patient's intake of breath.

Cromoglycate prevents or at least slows the release of chemical mediators,
such as histamine, which are released by the degranulating mast cell and
trigger an attack of asthma. Once degranulation occurs, treatment has to
be directed at blocking the effects of the mediators on their target tissues
or otherwise counteracting them. In this respect, theophylline, a bronchial
muscle relaxant; the corticosteroids, which have an anti-inflammatory effect;
and the long-standing first choice in an emergency, epinephrine, which
enlarges the bronchial airways, are all useful.

i<4

•r

• - u <~/U» . nil

1 5-<J

<2c

AO.

May 9, 1963 chart

Courtesy Mrs. Helta Altounyan and Family,
Cheshire, England

Breath of Life 41

Unfortunately most of these agents have side effects. Theophylline, a chemical
analog of caffeine (thus explaining the beneficial effects some asthma sufferers
obtain from coffee), needs strict monitoring. Too high a dose and gastroin-
testinal effects, headaches, and high blood pressure can occur. Too low
a dose and it is ineffective.

Side effects of epinephrine include an increased heart rate, central nervous
system symptoms such as anxiety, and sometimes nausea and vomiting.
However, newly developed drugs known as beta adrenergic agents have an
epinephrine-like action. They are longer acting and have fewer side effects
than epinephrine itself.

Corticosteroids reduce inflammation and airway irritability, and decrease
mucus production and swelling. Unfortunately, if taken orally over the long
term, steroids cause severe side effects, including the characteristic "moon
face," osteoporosis, acne, and cataracts, as well as increased blood pressure and
elevated blood sugar levels. They can also suppress the normal growth pattern
in children. Some of these undesirable systemic effects can be avoided by the
use of inhaled steroids, which primarily act locally on respiratory tract tissue.

Report No. 18, January 20, 1961

Physician Roger Altounyan's first
report on the khellin extract project
includes diagrams of some of the
molecules he thought might prevent
or treat asthma attacks.

Courtesy Mrs. Hella Altounyan and Family,
Cheshire, England

Spirometer, mid-twentieth century

Altounyan used this spirometer from
1959 to 1967 during his tests to find
the active ingredient of khellin, a
Middle Eastern folk remedy for asthma.
It measures the volume of air entering
and leaving the lungs.

Courtesy Rhone-Poulenc Rorer Ltd.

Breath of Life

Asthma and Genetics

Studies suggest that humans develop asthma because of an interaction
between their predisposing genes and the environment in which they live.
The earliest students of asthma, such as the seventeenth-century English
physician Sir John Floyer, noted that the condition runs in families. In the
coming years, the data anticipated from the Human Genome Project at the
National Institutes of Health, supplemented by findings by other institutions,
will help to elucidate the mode of inheritance of asthma. A recent report from
the University of Southampton, England, reported a gene for asthma located
on chromosome 5. However, the current thinking is that there is likely to
be more than one gene involved. Identifying a person who is genetically
susceptible to asthma is not expected to be a simple matter.

One reason is that not everyone who carries the familial susceptibility to
allergy expresses it clinically. A study of twins in Sweden suggests that about
18 percent of the population carries a genetic susceptibility to allergy but
that less than half of that number are clinically affected.

Another indication of the variability of the genetic expression of such disor-
ders as asthma comes from a study in the United States that found that two
clinically allergic parents had a 58 percent chance of having an allergic child.
Where one parent was clinically allergic the risk of an allergic child was
38 percent and where neither parent was clinically allergic the risk was only
12.5 percent.

Courtesy National Institute of
Allergy and Infectious Diseases

Breath of Life

The Future of
Asthma Research

Asthma affects fifteen million Americans, and causes, directly or indirectly,
five thousand deaths annually, but what especially concerns public health
authorities is the increasing number of people with the disease. Between
1980 and 1994 the incidence of asthma rose by 75 percent. In children
under the age of five, asthma increased by 160 percent.

The need to manage and control asthma is urgent. From an economic stand-
point, the disorder is a major burden on the population. In the United States
alone, it is estimated that the costs of asthma to the health care system are over
six billion dollars a year. Nearly 500,000 persons are admitted to hospitals
and 1.9 million visit hospital emergency rooms for asthma-related conditions
each year.

The National Institutes of Health has mounted a major effort to discover
effective ways to manage and treat asthma by supporting and funding scientists
conducting research on the disease throughout the world. Three Institutes
lead the effort: the National Heart, Lung, and Blood Institute, the National
Institute of Allergy and Infectious Diseases, and the National Institute of
Environmental Health Sciences. Some examples of specific research projects
currently underway include a study of the role of respiratory infections in
childhood asthma, a study on the origins of asthma in early life, and a study
on environmental intervention in the primary prevention of asthma
in children.

Asthma affects persons of all ages, races, and ethnic groups but not equally.
In the United States, low income, minority, and disadvantaged inner city
populations have significantly higher numbers of emergency room visits,
hospital admissions, and fatalities due to asthma. This may be because of a
higher level of exposure to environmental allergens and air pollutants. But it
is also likely to reflect a number of complicating socioeconomic problems,
such as the reduction in use and availability of health care services, a lack of
education and guidance on management needs, and difficulties maintaining
a management program, rather than a greater susceptibility to the disease.

Courtesy National Institute of
Allergy and Infectious Diseases

Ir is not only in the United States that the prevalence of asthma is increasing.
Asthma is on the rise practically everywhere in the world, with rates increasing
in all age groups, but particularly in children. It is probably the most com-
mon chronic disease in children, according to World Health Organization
(WHO) data.

The most striking increases are occurring in Australia, where about one-
quarter of primary school children are diagnosed with asthma, a prevalence
higher than in any other nation. In Western Europe asthma has doubled in
the past ten years. In Switzerland 8 percent of the population suffer from
asthma compared with only 2 percent twenty-five to thirty years ago. In
Finland, from 1981 to 1996, the number of asthmatic sufferers increased
threefold. In the Latin-American countries of Brazil, Costa Rica, Panama,
Peru, and Uruguay, the prevalence of children with asthmatic symptoms is
between 20 and 30 percent. In Japan there are an estimated three million
asthma sufferers, in India there are fifteen million. The worldwide cost of the
disease is greater than that of tuberculosis and AIDS combined, according
to WHO.

The situation is raising widespread concern among public health officials
throughout the world, because the reasons for the increase in asthma
are unknown. The WHO describes it as one of the "biggest mysteries
in modern medicine."

There is a general consensus that the increase is not a result of improved
diagnosis, although that may account for some of it, according to the
U.S. Centers for Disease Control and Prevention.

Certainly there is no lack of hypotheses attempting to account for the
increase. They include exposure to diesel fuel exhaust, diet, smoking, viral
infections, cold air, the increase in obesity, changes in nutrition, and
alterations in living patterns that have reduced physical exercise.

One conjecture is that something has occurred in industrial countries in the
past four decades that has resulted in some new environmental exposure.
For example, housing construction practices have changed since the 1970s.
People are more likely to be exposed to allergens at higher critical concentra-
tions than in the past. At the same time, though, there are no reliable data
on what these allergens might be.

One view gaining increasing support is that there's been a change in the kinds
of exposures that children are now experiencing early in their lives. This sets
the juvenile immune system on track for an increased allergic response.

Another theory includes an increase in air pollution and what has sometimes
been called the hygiene hypothesis. In terms of chemical pollutants, it has
been clearly demonstrated, for example, that components of diesel particles
enhance allergic responses. The hygiene hypothesis focuses on the early
treatment of infectious diseases and argues that it is to the benefit of infants
and children to be exposed to endotoxins and to undergo some experience
with infections, which have the potential to move them away from the
allergic phenotype — susceptibility and aberrant immune responses to
environmental allergens.

The present consensus is that there are at least three factors that underlie
asthma: the allergic response, viral infections, and air pollution. They can
act singly or in concert in ways that are not yet fully understood.

The story of our search for the causes of asthma is far from complete. There
are basic biomedical and clinical aspects of the disorder that are obscure and
need active investigation. Certainly, there are new tools available to scientists
today, such as developments in molecular biology that allow detailed study
of the immune response. Ultimately the results of such studies will help us
understand the immune system and will put new therapies and avenues of
management at the disposal of physicians and patients.

But laboratory science, by itself, is unlikely to provide all the answers. To be
successful, the attack on asthma will need scientific research, environmental
studies, public health investigations, and improvements in health and medical
services. Based on accumulating evidence, society will have to be willing to
implement measures and adopt policies aimed at minimizing the disease.

Courtesy National Institute of
Allergy and Infectious Diseases

48 National Library of Medicine

The Faces of Asthma

Asthma has many different faces: it is more than just the symptoms that patients experience.
Asthma is also about people— individuals and their families, communities, health care providers,
and medical scientists.

Some people who have asthma benefit from current asthma treatments and achieve great honors
in their chosen profession. Others learn to manage their asthma and lead full and productive
lives. The faces of asthma are many and varied — some of these people may be your family
and friends.

Baruj Benacerraf (b. 1920)

American immunologist and Nobel Prize winner

Baruj Benacerraf shared the 1 980 Nobel Prize in medicine for his
discovery of the genetic basis of autoimmune diseases. His child-
hood experiences with asthma fostered his interest in immunology.
Benacerraf continues his work at Boston's Dana-Farber Institute.

Courtesy Baruj Benacerraf, M.D.

Leonard Bernstein (1918-1990)

American composer, conductor, and pianist

As a sickly infant, Leonard Bernstein sometimes turned blue from
asthma. He became a prodigious pianist, conductor, composer,
and lecturer, although he suffered from asthma throughout his
life. Audiences often heard him wheezing above the orchestra.

Courtesy Carl A. Koenig

Elizabeth Bishop (1911-1979)

American poet, teacher, and author

Elizabeth Bishop won almost every important literary prize of
her day, while battling asthma unsuccessfully throughout her life
with injections of adrenaline, calcium, and antihistamines. Her
treatments also included transfusions, electroshock, cortisone,
and alcohol — all to no avail.

Courtesy Prints and Photographs Division, Library of Congress

Breath of Life 49

Bruce Davidson (b. 1949)

American equestrian champion

Bruce Davidson manages his allergic asthma with medications
so he can continue to compete in equestrian events. He has won
a silver and a gold Olympic medal, seven American and two
world championships.

Courtesy Bruce Hewitt/Getty Images

Charles Dickens (1812-1870)

British novelist

Charles Dickens found relief from his "chest troubles" only
with opium, a popular asthma remedy of his day. Mr. Omer,
one of the asthmatic characters in the autobiographical novel,
David Copperfield, reflects Dickens's own suffering.

Courtesy Prints and Photographs Division, Library of Congress

Benjamin Disraeli (1804-1881)

British statesman and author

For Benjamin Disraeli's disabling asthma, Queen Victoria's
physician prescribed mustard poultices and a change of scene.
Other physicians recommended arsenic, a popular new remedy,
but all treatments were unsuccessful.

Courtesy Prints and Photographs Division, Library of Congress

Tom Dolan (b. 1976)

American swimming champion and spokesperson for asthma

Despite severe chronic asthma, Tom Dolan is a fierce competitor
and often trains to exhaustion. He is an Olympic gold medallist
and a world champion swimmer.

Courtesy Reuters/Gary Hershorn/Archive Photos

50 National Library of Medicine

Robert Donat (1905-1958)

British stage and screen actor

Sudden explosive asthma attacks shortened Robert Donat's career
and life, despite the efforts of physicians around the globe. Donat
starred in dozens of films and plays, sometimes with oxygen tanks
ready to treat his asthma.

Courtesy of the Academy of Motion Picture Arts and Sciences

Kurt Grote (b. 1973)

American swimming champion

Kurt Grote's doctor recommended he start swimming at age
fifteen to help his chronic asthma. He won an Olympic gold
medal in 1996 in the breast stroke.

Courtesy Tony Duffy/Getty Images

Ernesto (Che) Guevara (1928-1967)

Argentine physician and freedom fighter

Although he was weakened by asthma from infancy, Ernesto
Guevara fought in three revolutions, sometimes using his rifle
as a crutch. During a skirmish in Bolivia, he suffered an asthma
attack, was captured by government troops, and executed
shortly thereafter.

Courtesy Prints and Photographs Division, Library of (Congress

Moses Gunn (1929-1993)

American actor

Moses Gunn won nominations for a Tony and an Emmy award
for his work on stage and television, in addition to awards for
his Off-Broadway theater performances. During his final years,
he required annual hospitalizations for asthma, and he died of
complications of the disease.

Breath of Life

Helen Hayes (1900-1993)

American actress and author

Helen Hayes, often called the "First Lady of American Theater,"
made frequent trips to hospitals because of asthma attacks
aggravated by backstage dust. When asthma ended her theatrical
career, Hayes wrote books and raised funds for organizations
that fight asthma.

Courtesy Culver Pictures, Inc.

Nancy Hogshead (b. 1962)

American swimming champion and spokesperson for asthma

Despite breathing difficulties, Nancy Hogshead won three gold
medals and one silver in the 1984 Olympics. When a bronchial
spasm kept her from winning medal number five, a physician
discovered the problem was asthma.

Courtesy Tony Duffy/Getty Images

Robert Joffrey (1928-1988)

American dancer, choreographer, producer, and teacher

Robert Joffrey began dancing at age six to counteract his asthma.
Founder of the Joffrey Ballet, a world-renowned innovative modern
dance company, Joffrey battled lifelong asthma with acupuncture,
herbs, and medications, but hardly ever missed a performance.

Courtesy ©Herbert Migdoll 2002

Jackie Joyner-Kersee (b. 1962)

American track and field champion

Olympic triple gold medalist Jackie Joyner-Kersee became the
world's top woman athlete in the heptathlon and long jump
competitions despite severe asthma. She retired from track
competition after the 1996 Olympic Games.

Courtesy Tony Duffy/Getty Images

National Library of Medicine

John F. Kennedy (1917-1963)

Thirty-fifth president of the United States of America

Asthma resulting from allergies to dogs, horses, and dust troubled
John F. Kennedy throughout his adult life. Steroids prescribed to
treat his Addison's disease probably also helped control his asthma.

Courtesy John Fitzgerald Kennedy Library

Alyce King Clarke (Alyce King) (1915-1996)

American singer

Best known as one of the four King Sisters, Alyce King performed
for six decades with members of her musically gifted family.
Asthma plagued her as a child and caused life-threatening attacks
in her sixties and seventies.

Courtesy Brown Brothers

Bill Koch (b. 1956)

American cross-country skier

The only American ever to win the World Cup overall
cross-country title, Bill Koch also won a silver medal at the
1976 Olympic Games. He manages his asthma with medications.

Courtesy David Cannon/Getty Images

John Locke (1632-1704)

British physician, philosopher, and scientist

As a political leader, John Locke was drawn to London, the
seat of English government. But persistent asthma, unrelieved
by physicians, forced Locke to live in the country, away from
London's polluted air and political life.

Breath of Life

Ernest (Dutch) Mortal (1929-1989)

American political, legal, and civil rights leader

Ernest Morial, a two-time mayor of his native New Orleans and
pioneer in civil rights and government, broke the color barrier at
every stage of his municipal and national career. Twenty-five years
of asthma led to his untimely death at age sixty.

Courtesy Marc H. Morial

George Murray (b. 1947)

American wheelchair marathon champion

George Murray began racing in his chair to manage his asthma.
He became world wheelchair marathon champion, was first
to break the four-minute mile, and first to cross the country
in a wheelchair.

Courtesy AP/World Wide Photos

Peter the Great (1672-1725)

Russian czar

An ambitious ruler with an insatiable drive to reform Russia,
Peter the Great seemed unhindered by health problems.
But during his last ten years, severe asthma and other diseases
seriously hampered his ability to function and govern.

Courtesy Hulton Getty/Liaison Agency

Joseph Pulitzer (1847-1911)

American publisher and philanthropist

Although Joseph Pulitzer consulted physicians worldwide, none
was able to remedy his asthma. After forty-three years of suffering,
he died on the yacht the breezy deck of which often alleviated
his breathlessness.

Courtesy Prints and Photographs Division, Library of Congress

54 National Library of Medicine

Theodore (Teddy) Roosevelt (1858-1919)

Twenty-sixth president of the United States of America

Severe asthma made Theodore Roosevelt a sickly infant and
a virtually homebound child. His parents tried all available
remedies and traveled worldwide to find him a salutary climate.
But it was vigorous exercise that helped turn him into a healthy,
productive adult.

Courtesy Prints and Photographs Division, Library of Congress

Arnold Schdnberg (1874-1951)

Austrian composer

Undaunted by chronic asthma, acclaimed Viennese composer
Arnold Schdnberg revolutionized music by composing in a 12-tone
scale. Schonberg's healthiest, most productive years were spent
in Los Angeles, far from the Nazi terror in Europe and the harsh
winters that compounded his asthma.

Courtesy Arnold Schdnberg Center, Vienna

Martin Scorsese (b. 1942)

American film director

Martin Scorsese dropped out of seminary to study film. An
asthmatic youngster, he watched movies on television and became
an insatiable fan. Scorsese recently received the American Film
Institute's Life Achievement Award.

William Tecumseh Sherman (1820-1891)

American general in the Civil War s Union Army

Asthma was William Tecumseh Sherman's lifelong enemy.
Ironically, although he led an infamously destructive march
through Georgia, it was the Souths temperate climate that
brought him relief from his symptoms.

Courtesy Prints and Photographs Division, Library of Congress

Breath of Life 55

Howard Thurman (1900-1981)

American clergyman, educator, and author

Howard Thurman struggled against poverty and racism in the
South as a child and against asthma in later years. He became
a world-renowned spiritual and intellectual leader, pursuing a
dream of unity — one community that would cross all lines of
race, religion, and national origin.

Courtesy the Howard Thurman Educational Trust

Tseng Kuo-Fan (1811-1872)

Chinese statesman, general, and scholar

Tseng Kuo-Fan's asthma caused incessant coughing and an
inability to work. Diagnosing a yin deficiency, his physician gave
him "an excellent prescription, but I really detest medicine and
therefore did not take it," Tseng wrote.

Courtesy Prints and Photographs Division, Library of Congress

John Updike (b. 1932)

American writer

John Updike, prolific writer of novels, poetry, short stories,
and essays, thought he was dying during his first attack of
breathlessness in his twenties. The diagnosis was bronchial
asthma, aggravated by his cats.

Courtesy Frank Capri/Archive Photos

Amy Van Dyken (b. 1973)

American swimming champion

Amy Van Dyken's doctor suggested she start swimming to relieve
her severe asthma. Diligent training and asthma medications
helped her become the first American woman to win four gold
medals in one Olympic Games.

Courtesy Reuters/Gary Hershorm 'Archive Photos

56 National Library of Medicine

Benjamin Ward (b. 1926)

American police commissioner and criminal justice specialist

Brooklyn-born Benjamin Ward joined the New York City Police
Department, the nation's largest, in 1951, becoming the city's first
black police commissioner in 1984. He resigned after six years.
"I am yielding," he wrote, "to the chronic asthma that has sapped
my strength."

Courtesy Benjamin Ward

Harold D. West (1904-1974)

American medical educator, administrator,
scientist, and humanitarian

As president of Meharry Medical College, Harold D. West
fostered remarkable expansion of academic offerings, facilities,
and endowments. West was plagued and often hospitalized
by severe asthma, which hastened his death.

Courtesy Meharry Medical College

Edith Wharton (1862-1937)

American novelist and short story writer

Edith Wharton suffered from occasional bouts of asthma
throughout her literary career. Wharton wrote short stories,
travel books, and many successful novels, including
Age of Innocence, which earned her a Pulitzer Prize in 1921.

Courtesy Archive Photo

Woodrow Wilson (1856-1924)

Twenty-eighth president of the United States of America

Exhausted by eighteen-hour work days at the Versailles Peace
Conference, weakened by severe asthma, and impaired by
arteriosclerosis, Woodrow Wilson was virtually incapacitated.
Yet even after he was paralyzed by a stroke, his health problems
were kept secret from the American public.

Courtesy Prints and Photographs Division, Library of Congress

Breath of Life

Exhibition Credits and Acknowledgements

The National Library of Medicine wishes to thank Sheldon G. Cohen, M.D. for his inspiration and persistence
without which this project would not have been possible. In addition, the Library extends its appreciation to
Anthony S. Fauci, M.D., Claude Lenfant, M.D., and Kenneth Olden, Ph.D., for their collaboration on this exhibition.

Donald A.B. Lindberg, M.D., Director
National Library of Medicine

PROJECT STAFF

Elizabeth Fee, Ph.D.
National Library of Medicine
Exhibition Director

Patricia Tuohy

National Library of Medicine
Head, Exhibition Program

Robert A. Aronowitz, M.D.

Robert Wood Johnson Medical School

Visiting Curator

Carla C. Keirns, M.D.-Ph.D. candidate
University of Pennsylvania
Visiting Curator

Dot Sparer
Athens, Georgia
Exhibition Scriptwriter

Edwina Smith

Washington, D.C.

Exhibition Graphics Coordinator

Christina A. Popenfus
Washington, D.C.
Collections Manager

Athena Angelos
Washington, D.C.
Image Researcher

Michael Sappol, Ph.D.
National Library of Medicine
Research Consultant

Abigail Porter
Washington, D.C.
Researcher

Roxanne Beatty

National Library of Medicine

Bibliographic Researcher

Carol Clausen, M.L.S.
National Library of Medicine
Conservation Coordinator

Mary Parke Johnson
Orange, VA
Book Conservator

Melanie Modlin

Paul Theerman, Ph.D.

Elizabeth Tunis, M.L.S.

Anne Whitaker, M.L.S.

National Library of Medicine

Proofreaders

NATIONAL HEART, LUNG,
AND BLOOD INSTITUTE

Claude Lenfant, M.D.
Director, National Heart, Lung,
and Blood Institute

Suzanne Hurd, Ph.D.
Scientific Advisor

Virginia Taggart, M.P.H.
Exhibition Advisor

Ellen Sommer, M.B.A.
Exhibition Advisor

NATIONAL INSTITUTE OF ALLERGY
AND INFECTIOUS DISEASES

Anthony S. Fauci, M.D.
Director, National Institute of Allergy
and Infectious Diseases

Daniel Rotrosen, M.D.
Scientific Advisor

Marshall Plaut, M.D.
Scientific Advisor

Karen Leighty
Exhibition Advisor

Judy Crowell, M.P.A.
Exhibition Advisor

NATIONAL INSTITUTE OF
ENVIRONMENTAL HEALTH SCIENCES

Kenneth Olden, Ph.D.
Director, National Institute of
Environmental Health Sciences

George Malindzak, Ph.D.
Scientific Advisor

William Grigg
Exhibition Advisor

CONSULTANTS

Sheldon G. Cohen, M.D.
National Institute of Allergy and
Infectious Diseases

William H. Helfand
New York, New York

Esther Sternberg, M.D.

National Institute of Mental Health

TRANSLATORS

Margaret Feng
Candace Keirns, M.D.
Rosita Lecuona
Marta Melendez
Ekaterini "Katy" Perry
Roma Samuel
Emanuel Stadlan, M.D.
Anne Whitaker, M.L.S.

DESIGN AND PRODUCnON

Lou Storey
Red Bank, NJ
Exhibition Designer

Exhibits Unlimited, Inc.
Alexandria, VA

Exhibition and Graphics Fabricator

MFM Design
Washington, D.C.
Graphic Identity, Website, Brochure
and Catalogue Designer

Andrew Petitti
Knowtis Design Inc.
Graphic Designer

Anne R. Altemus

National Library of Medicine

Audiovisual Coordinator

58 National Library of Medicine

Thomas I leld

c iermantown, MI)
Faces of Asthma Producer

John M. Harrington

Madison Film, Inc.

Faces of Asthma Video Producer

Renate T. Funk

Rodel Productions, Inc.

Erica's Story Audio Producer

Kyle Chepulis
Technical Artistry

Video System Design and Lighting Design
Young Rhee

National Library or Medicine
Online Resources Design
and Programming

Lillian Kozuma

National Library of Medicine

Online Resources System Design

John Gibb
Medical Illustrator

Jennifer Parsons
Medical Illustrator

Jennifer N. Gentry
Mcdic.il Illustrator

"WINNING WITH ASTHMA"
A dynamic interactive soccer game
for young people that highlights facts
regarding exercise-induced asthma.

James S. Main

Wun mi. il 1 ibrar) ol Medicine
Producer

Anne R. Altemus

National Library of Medicine

Producer

Glive Downey
EA Sports/FIFA
Licensing Arrangements

Thomas Held
Germantown, MD
Instructional Design

Sonalysts Studios

Graphic Design and Programming

LENDERS AND DONORS
TO THE EXHIBITION

Mrs. Hella Altounyan and Family
American Lung Association
Daniel Aronowitz
Robert Aronowitz, M.D.

Gardionics

College of Physicians of Philadelphia

Sheldon G. Cohen, M.D.

Donna King Gonkling

Kathleen Cravedi

Dura Pharmaceuticals, Inc.

Mrs. Margaret Egeberg and Family

Joe Fitzgerald

Food and Drug Administration
Glaxo Wellcome Inc.
Global Equipment Company
Asal Goldschmidt
Miss Sylvia Grauer, in memory

of Miss Rhoda Grauer
Maxcy G. Hanna II
William H. Helfand

The Johns Hopkins Medical Institutions,

The Alan Mason Chesney

Medical Archives
Candace Keirns, M.D.
Library of Congress, African and Middle

Eastern Division, Hebraic Section
Dr. and Mrs. M. Stephen Miller
Melanie Modlin

Mutter Museum, College of Physicians

of Philadelphia
National Jewish Medical and

Research Center
National Museum of Health and Medicine-
Nat ra Bio'"-

New York Daily News

New York Transit Museum

New York University Medical Archives,

Frederick J. Ehrman Medical Library
National Heart, Lung, and Blood Institute
National Library of Medicine
Parke-Davis Pharmaceutical Research

Division Library
Christina A. Popenfus
Priorities
Newsweek Inc.
Rhone-Poulenc Rorer Inc.
Rhone-Poulenc Rorer Ltd.
Sanofi

Schering-Plough Corporation
Smithsonian Institution, National

Museum of American History
Spirometries Medical

Equipment Company
University of California, San Diego,

Medical Center
University of California, San Francisco,

The Library and Center for

Knowledge Management
University of Michigan, Historical Center

for Health Sciences
University of Pennsylvania, Walter H. and

Leonore Annenberg Rare Book and

Manuscript Library

EXHIBITION PHOTOGRAPHS,
GRAPHICS, AND VIDEOS

Academy Foundation
Stephen (Steve) Allen

Allsport* Photography (USA). Inc.

American Lung Association

AP/Wide World Photos

Archive Photos

Brown Brothers, Sterling, PA

The British Museum

Albert Bonniers Fcirlag

Angelika Buske-Kirschbaum, Ph.D.

Children's Television Workshop

College of" Physicians of Philadelphia

Sheldon G. Cohen, M.D.

Francis A. Countway Library of Medicine

Culver Pictures Inc.

The Dallas Morning News

The Denver Public Library

District of Columbia Public Library,

Martin Luther King Memorial Library
Alan M. Edwards, M.D.
FPG International
Glaxo Wellcome Inc.
Harvard University, Economic Botany

Library of Oakes Ames
Hulton Getty/Liaison Agency Inc.
John Fitzgerald Kennedy Library
The Johns Hopkins Medical Institutions.

The Alan Mason Chesney

Medical Archives
Library of Congress, Prints and

Photographs Division
Library of Congress, Geography and

Map Division
Mayo Clinic Scottsdale, Charles B.

Carrington Memorial Pulmonary

Pathology Leaching Collection
Meharry Medical College
The Metropolitan Museum of Art
Herbert Migdoll, Joffrey Ballet of Chicago
Jon Naso, New York Daily News
National Archives and

Records Administration
National Jewish Medical and

Research Center
National Library of Medicine,

History of Medicine Division,

Prints and Photographs Collection
New York Philharmonic Archives
National Heart, Lung, and Blood Institute
National Institute of Allergy and

Infectious Diseases
National Institute of Environmental

Health Sciences
National Institute for Occupational Safety

and Health
Eric O'Connell
Katherine Ott, Ph.D.
Pan American Health Organization/

World Health Organization
Photofest

Rockefeller University
Saranac Lake Free Library
David Scharf

Arnold Schonberg Center, Vienna
Science Source/Photo Researchers
Esther Sternberg, M.D.
Teresa Teng Foundation

Breath of Life

Uniphoto Picture Agency
University of California, San Diego,

Medical Center
Benjamin Ward
Jean Weisinger
Ann J. Woolcock, Ph.D.

SPECIAL THANKS

Peter L. Allen, Ph.D.

Al Abrams, Bethesda MD, print broker

Bridie Andrews, Ph.D., Harvard University

Liz Antry, Dalloz Safety

Janet Banks, Glaxo Wellcome Inc.

Rosalynn Benson, National Human

Genome Research Institute
Abigail Bosk
Charles Bosk, Ph.D.,

University of Pennsylvania
Emily Bosk

The Collateral Group, Baltimore,

brochure printer
Chandra Buie, New York Transit Museum
Caron Capizanno, New York University
Medical Archives,

Frederick J. Ehrman Library
Judy Chelnick, National Museum

of American History, Smithsonian

Institution
Kim Clough, National Institute for

Occupational Safety and Health
Thomas V. Colby, M.D., Department of

Pathology, Mayo Clinic of Scottsdale
Luke Demaitre, Ph.D.,

University of Virginia
Luigi Di Rico,

Global Equipment Company
Carol Doughty, Spirometries Medical

Equipment Company
Alan M. Edwards, M.D.,

Vectis Allergy Ltd., England
Steven Feierman, Ph.D.,

University of Pennsylvania
David Fridberg, MFM Design
Veronica A. Graham, Glaxo Wellcome Inc.
Charles B. Greifenstein, Curator,

College of Physicians of Philadelphia
Cedric F. Grigg, Medical/Science Focus

Groups & Education, New York
Veronica G. Grosshandler,

Glaxo Wellcome Inc.
Li Gwatkin, National Jewish Medical

and Research Center
John Hart, M.D., Rhone-Poulenc

Rorer Ltd., England
Thomas F. Harrington,

New York Transit Museum
Andrew Harrison, The Johns Hopkins

Medical Institutions, The Alan

Mason Chesney Medical Archives
Alan Hawk, National Museum of Health

and Medicine
Tish Holbrook, MFM Design
Keith Johnson, Cardionics

Tambra Johnson, Library of Congress
Ruth Kasloff, American Lung Association
Maneesha Lai, Ph.D.,

University of Wisconsin
Margaret L. Lyman, Mutter Museum,

College of Physicians of Philadelphia
Greg Mann, Dura Pharmaceuticals, Inc.
Patricia Mansfield, National

Museum of American History,

Smithsonian Institution
Howard Markel, M.D., Ph.D., University

of Michigan, Historical Center for

Health Sciences
Laurie McCarriar, McCarriar Graphics
Russell R. McGuire, American Society of

Composers, Authors and Publishers
Christopher Meehan, University of

Michigan, Historical Center for

Health Sciences
Nicole Mitchell-Weed
Jon Naso, New York Daily News
Delia Naughton,

American Lung Association
William Obermeyer, Ph.D., Food and

Drug Administration
Samuel Page, Ph.D., Food and

Drug Administration
Pan American Health Organization
Deborah Parrish, Priorities®
Wendy P. Phipps, Rhone-Poulenc

Rorer Ltd.
Charles Rosenberg, Ph.D.,

Harvard University
Michael T. Ryan, M.D., University of

Pennsylvania Van Pelt-Dietrich Library,

Department of Special Collections
Charles L. Sachs, New York

Transit Museum
Nathan Sivin. Ph.D.,

University of Pennsylvania
Lisa Sparer, New York Daily News
Tom Stewart, Exhibits Unlimited, Inc.
Joanne Eunhee Suh, M.D., University of

California, San Diego, Medical Center
Wendy Thurman, National Museum

of Health and Medicine
Steve Turner, National Museum

of American History,

Smithsonian Institution
Jeff Watts, Arlington VA,

catalog photography
Luise White, Ph.D., University of Florida
Leona Williams, Parke-Davis

Pharmaceutical Research

Division Library
( Iretchen Worden, Mutter Museum,

College of Physicians of Philadelphia

SPECIAL APPRECIATION

Bill Boyd, Systems Support,
National Library of Medicine

Linda Brown, Medical Arts
and Photography Section,
National Institutes of Health

Becky Cagle, Website Designer,

National Library of Medicine
Pat Carson, Special Assistant to the

Director, National Library of Medicine
Kathleen Gardner Cravedi,

Public Information Officer,

National Library of Medicine
Bob Cross, Facilities Coordinator,

National Library of Medicine
Michael J. Detweiler, Editor,

National Library of Medicine
Rebecca Dittmar, Library Associate,

National Library of Medicine
Joe Fitzgerald, Graphic Designer,

National Library of Medicine
Friends of the National Library

of Medicine
Adam Glazer, Reference Librarian,

National Library of Medicine
Victoria Harden, Ph.D., Stetten Museum,

National Institutes of Health
Alvin Harris, Deputy Chief, Office of

Administration, National Library

of Medicine
Deborah Hawkins, Contracting Officer,

National Heart, Lung, and

Blood Institute
Troy M. Hill, Graphic Designer,

National Library of Medicine
Betsy L. Humphreys, Associate Director,

National Library of Medicine
Karlton Jackson, Staff Photographer,

National Library of Medicine
Bill Leonard, Producer,

National Library of Medicine
Lockheed Martin Technical Support
James S. Main, Chief, Audiovisual

Program and Development Branch,

National Library of Medicine
Robert Mehnert, Chief, Office of

Communications and Public Liaison,

National Library of Medicine
Pamela Meredith

Melanie Modlin, Public Affairs Specialist,

National Library of Medicine
Donald C. Poppke
Elizabeth G. Rosso, Assistant

Administrative Officer,

National Library of Medicine
Candace Sammons, Designer, Medical

Arts and Photography Section,

National Institutes of Health
Kent A. Smith, Deputy Director,

National Library of Medicine
Livie Spearman III, Contracting Officer,

National Heart, Lung, and

Blood Institute
Patricia Williams, Administrative Officer,

National Library of Medicine
Monique Young

Theodore E. Youwer, Chief, Office of
Administration, National Library
of Medicine

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