. — = rr = -_— = 7 ‘ —— . 2 ~ - a . = - ——— = = = a — =~ . ——= ~ —es = —— : = —~ = ——— — , = = = = = : : = ——— a = ~ es = = eS = - = = = — ——— = = —— —— —— = = - be i 4 f s , ie mii + J in 2010 with funding fi University of Toront = af s i ‘ é = —* 4 1 ; pee a — a i} = a = —— _http://www.archive.org/details/harv THE HARVEY SOCIETY — 7 - THE HARVEY LECTURES Delivered under the auspices of THE HARVEY SOCIETY OF NEW YORK Previously Published. FIRST SERIES . . 1905-1906 SECOND SERIES . 1906-1907 THIRD SERIES. 1907-1908 FOURTH SERIES . 1908-1909 « * wy INTESTINAL INFECTION AND IMMUNITY IN TUBERCULOSIS * PROF. A. CALMETTE Director of the Pasteur Institute of Lille, France ERMIT me to express, first of all, my gratitude for the great honor which you have bestowed upon me in inviting me to discuss before your illustrious society the present state of our knowledge of the réle of the digestive tract in tuberculous infection and in immunization against tuberculosis. For several years this question has been the principal object of my laboratory researches, which I have pursued with the aid of some of my scholars, particularly of C. Guérin. It has en- gaged the attention in an equal degree of a large number of workers in every country. There are but few of greater inter- est, as the discussions of our recent congress in Washington will bear witness. I do not pretend-that I can cast sufficient light upon this question to warrant us in expecting in the very near future the establishment of a method capable of protecting humanity against the most terrible of the scourges which desolate it. I do wish, however, to make an effort to acquaint you with the principal experimental facts upon which we can build to-day so as better to comprehend the mechanism of the tuberculous infection, and I trust that you may be brought to regard the hopes which have been raised so many times in vain, as at least partly realizable. It is forty-three years since Villemin announced that tuber- culosis is inoculable and contagious, and twenty-six years separ- ate us from the memorable epoch at which Robert Koch, dis- covering and cultivating his bacillus, made the demonstration * Lecture delivered October 24, 1908. 13 14 HARVEY SOCIETY of its specificity. Notwithstanding the enormous accumulation of publications in the last quarter of the century, we are still but very imperfectly informed upon the respective importance of the different ways by which the virus of tuberculosis can penetrate into the bodies of man and of susceptible animals. Until lately, the greater number of scientists, clinicians or ex- perimental workers, have considered as an indisputable dogma the respiratory origin of pulmonary tuberculosis, and the cele- brated debates which took place at the International Conferences at The Hague in 1906 and at Vienna in 1907, and since then in various learned societies, are so fresh in your minds that it would be useless to recall them. It appears, however, that the impression that a final decision had been reached is not correct, and that, as is always the case, the truth lies between two extremes. If it appears undeniable that in certain probably very rare cases, direct infection of the lung takes place through the respired air, notwithstanding the many and very efficacious natural defenses which line this route, it is also manifest that the path to the pulmonary parenchyma normally followed by the tubercle bacillus is most often through the lymph- or blood-vessels, the great portal of entry being the digestive tract. Experimentation has shown that to effect primary tuber- culous infection of the lung by the air, it is necessary to place the animal under pathological conditions, as has been done by Nocard, Fliigge, and, more recently, Kuss, in immobilizing the animals so as to oblige them to breathe for a long time an atmos- phere charged with infectious particles, liquid or dry. Very fine spray is certainly dangerous, above all for young infants, and it is evident that pneumonia with early caseation and acute pulmonary tuberculosis of infants are almost always of respira- tory origin. When a mother or a nurse, the subject of an active pulmonary tuberculosis, coughs or sneezes at a short distance from the lips of an infant breathing through its open mouth or erying in expectation of the breast, contagion by inhalation is all but fatal. But this mode of infection is cer- tainly exceptional for the older child or for the adult, INTESTINAL INFECTION IN TUBERCULOSIS 15 Infection by dust laden with bacilli is more exceptional still; and the positive results of Cornet, as well as those of Kuss, accomplished by shutting up the immobilized animals in an inclosed space, in an atmosphere of taleum powder or of the débris. of vegetable fibres mixed with dried sputum, invalidate in no way the much more numerous negative results described by Baumgarten, Tappeiner, Cadéac and Mallet, and Petersson, and by myself with Vansteenberghe. Does not, however, the normal asepsis of the respiratory tract attest strongly the protective efficiency of the defensive apparatus of this region, when not affected by pre-existing lesions of the nasopharynx, of the larynx, and of the larger bronchi ? . The primary lesions of the tracheal and bronchial nodes, which certain authors consider as always related to a respiratory infection, can no longer be invoked as a convincing argument in favor of this view. If it be true that, following the law of Parrot, the nodular lesion should always be accompanied or preceded by one or several pulmonary tubercles, there is noth- ing to prove that these last must be of aérial origin, since they make their appearance with great frequency in animals artifi- _ cially infected through the digestive tube. Breton and myself have observed this regularly upon a great number of guinea- pigs which had absorbed through the rectum or been given by an cesophageal sound, a small quantity of a fine emulsion of a pure culture of the bacillus of bovine tuberculosis. These ani- mals when killed after four or five weeks very often presented no other lesions than one or two superficial tubercles, as large as the head of a pin, in one of the anterior lobes of the lung, with a co-existing extensive tuberculosis of the peribronchial lymph-nodes. An observer who was ignorant of the conditions under which the infection had been experimentally produced, would undoubtedly have stated that the lesion was due to respiratory infection. It can then hardly be denied that if primary tuberculosis of the lung or of the tracheobronchial lymph-nodes by the direct 16 HARVEY SOCIETY inhalation of particles carrying bacilli is quite possible in some cases, it is certainly exceptional. Quite frequent, on the other hand, but also less serious, is infection of the body through the digestive tract. When I state that tuberculosis is most often contracted through the intestine, I do not wish to be considered as saying that I attribute to the food, and consequently to the milk of tuberculous cows, the essential réle in the tuberculous infection of man. I am convinced, on the contrary, that the importance of infection through milk has been very largely exaggerated in the last few years. The fact that tuberculosis is so common, both in infants and in adults, in countries where the use cows’ milk as human food is exceptional, for example, in Egypt, India, Indochina, and Japan, shows that the propagation of tuberculosis from man to man is infinitely more common than the infection of man by cattle. Without doubt the ingestion of the milk of tuberculous cows is dangerous, principally for young children, though even for healthy adults, and much more for those in whom the intestinal mucosa is not intact, when the ingestion of virulent material is frequently repeated. But infinitely greater and more frequent is the danger from human bacilli freshly expelled from the lung of a consumptive, when these bacilli are carried by the sputum to the food or upon the mucous membrane of the mouth by direct or indirect contact of the lips, the hands, soiled objects, ete., or by flies. The tuberculous mother who tastes the dish prepared for her child or who wipes its face with her handkerchief, and the nurse who moistens her breast with her saliva, subject the infant in their care to the danger of tuberculous infection. The child who handles its food after crawling about the floor, and the man who wets his fingers to turn the pages of a book, or to handle type, or who works with tools belonging to a consumptive whose sputum contains the bacilli, may ingest at any moment a number of virulent bac- teria; and the risks of contagion are much more serious the more abundant and frequently repeated these ingestions are. And how can one doubt that the réle of flies is particularly INTESTINAL INFECTION IN TUBERCULOSIS 17 important and dreadful in the unhealthy tenements where, among the sick persons, children and adults, living side by side in the closest contact, these insects swarm in compact masses alternately upon the sputum and upon the food? Careful study of the tuberculous infection in animals fur- nishes abundant clinical proof of the predominance of infection through the digestive tract. For example, it is known that the flesh-eating animals such as the lion, the tiger, the hyena, and the jackal, when confined in a menagerie and fed upon tuberculous meat, often become infected with tuberculosis, either pulmonary or visceral, whereas these animals never show spontaneous tuberculosis in the wild state. The dog becomes tuberculous when he swallows the sputum of his sick master; the calf, the cat, and the pig contract the disease when they are fed upon milk rich in the bacilli. Insistence has rightly been laid, in recent times, upon the complete absence of tuberculosis in American pigs fed ex- clusively upon corn or other vegetable substances which may have been cooked, whereas this disease is extremely common in the pigs of our European farms, above all where the animals are fed upon the unpasteurized waste from dairies. It is evident that tuberculosis thus developed—most often with primary lesions in the pleura or bronchial lymph-nodes— in pigs fed upon the milk of tuberculous cows, results from the absorption of the bacilli through the digestive tube. These ingested bacilli are able to penetrate the intestinal wall, and enter into the blood or lymphatic circulation, and are carried about in the body for a greater or less time before they produce the lesions characteristic of the tuberculous infection. This fact was first demonstrated experimentally by Chau- veau, in 1868 to 1872, and then by Villemin, Aufrecht, Gerlach, Klebs, Gunther and Harms, and a number of other observers, among whom one may mention Saint-Cyr, Viseur, Bollinger, Orth, Toussaint, Baumgarten, Rabinovitch, Parrot, Ravenel, Schroeder and Cotton, etc. Nevertheless, certain negative re- sults attract attention, particularly those published by Colin (of Alfort) and by Moeller, which seem to demonstrate that Q 18 HARVEY SOCIETY animals can swallow with safety large quantities of tuberculous material. We now know the reason of this. It is because artificial infection through the digestive tract is not invariable unless one takes certain precautions which I have definitely pointed out in studies with C. Guérin. It is necessary to cause absorption of the bacilli in a divided state so that they remain finely emulsified, as they are in the sputum or in milk. Under these conditions a single administration of infectious material is ordinarily sufficient to produce the tuberculous lesions, which in young animals most often remain localized for a longer or shorter time in the mesenteric lymph-nodes, but which in adults, on the contrary, appear at once in the lungs. In studying the mechanism of the absorption of inert dust by the intestinal mucosa, I have been able to establish, with Vansteenberghe, that the same phenomena can be observed. The ingestion of finely powdered lampblack, or, better, of India ink, mixed with the food, produces in the adult guinea-pig the typical lesions of anthracosis of the lung, whereas in the young guinea-pig the colored granules remain for a longer or shorter time in the mesenteric nodes. Sections of the small intestine fixed during digestion allow one to recognize these colored granules surrounded by leucocytes in the chylous vessels of the villi. In repeating our experiments upon this subject, Six William Whitla* and Symmers have recently reached the same con- clusions; and these workers have described an ingenious pro- cedure which permits them to produce simultaneously tuber- culosis and anthracosis of the lung or of the mesenteric nodes. This procedure consists in causing young or old guinea-pigs to swallow an emulsion of tubercle bacilli and India ink in olive oil. Experimentation upon large animals such as cattle permits the determination with still greater certainty of the path which the tubercle bacilli follow to the lungs, if the animals are sacri- ficed, as in my experiments with Guérin, at successive intervals *The Etiology of Pulmonary Tuberculosis. Cavendish Lecture, 1908. Lancet or British Medical Journal, July 11, 1908. INTESTINAL INFECTION IN TUBERCULOSIS 19 from the time of a single ingestion of the infectious material. One can thus convince himself, as has been shown by Chauveau, afterwards by Dobroklowski, that these bacilli penetrate the in- testinal mucosa, even when this is entirely intact, and that they generally leave no trace of their passage. They are trans- ported by the polynuclear leucocytes from the chylous vessels of the villi to the nearest mesenteric nodes. In suckling animals and in young infants, they are fre- quently retained in the lymphatic organs which act as an almost perfect filter for the lymph. Sometimes they are destroyed in the nodes; sometimes they give rise to tuberculous lesions which, developing towards caseation, throw off their microbes into the efferent lymphatic canals, or occasionally into the peritoneum. In older subjects, in whom the mesenteric nodes—as has been shown by Weigert—are much more permeable, the bacilli, always surrounded by polynuclear leucocytes, are carried with the lymph through the thoracic duct as far as the right ventricle of the heart, and thence forced into the capillaries of the lung. If the leucocytes carrying the bacteria have lost their ameboid movement because of the intoxication resulting from the tuber- culin secreted by the bacilli, they are incapable of penetrating the walls of the capillaries by diapedesis, and they then give rise to fine emboli which become the starting point for a correspond- ing number of tuberculous lesions at the expense of the en- dothelial vascular walls (the gray granulations of Laennec). The tuberculous lesions thus formed go on later to ealcifi- cation or to caseation. In the second case, where the leucocytes do leave the capillaries, the tubercles drain into the alveoli or into some lymphatic vessel or vein, more rarely into an artery. They thus bring about a dissemination more or less rapid and more or less grave, of the virus into other parts of the body. In my researches with Guérin, I have always been able to show the extreme frequency of adenitis of the tracheobronchial glands in young cattle, when the bacilli have penetrated the filter formed by the mesenteric nodes, and have reached the 20 HARVEY SOCIETY lung. This adenitis is in constant relation with one or several tuberculous subpleural lesions which it is easy to discover. The digestive origin of these lesions is entirely evident. We have reproduced them many times and Vallée (of Alfort) has also obtained them, either by feeding calves on milk proved to be from tuberculous cows, or by inoculating the bacilli directly into the mesenteric nodes after laparotomy. Further, we have observed in some of our animals infected through the digestive tract, primary localizations of tubereu- losis in other organs than the mesenteric nodes or the lungs. We have seen these appear under the form of pleurisy, of arthritis, of orchitis, and, in one very remarkable case in a young kid, of iritis. These exceptional localizations occurred only in animals infected by a single administration of small quantities of bacilli. One can suppose that these, because of their small number, had remained for a long time in the cireu- lating blood, carried about by some polynuclear leucocytes, and that they had finally established a tuberculous lesion only in the organ where these leucocytes were when they succumbed. Whatever interpretation may be accorded to these facts, it remains certain that so-called primary pulmonary tuberculosis and many other forms or localizations of tuberculous infection, manifestly result in a great number of cases from the penetra- tion of the poison through the digestive tract. Partisans of the theory that infections by inhalation pre- dominate, above all Fliigge in Germany and Kuss in France, bring forward the objection that in order to produce tuber- culosis experimentally by ingestion, it is necessary to cause the animals to absorb thousands or millions of the bacilli, whereas a few individuals alone suffice to produce tuberculous lesions of the lung when they are inhaled. Those who think thus forget too often that among the millions of ingested bacilli there is only a small number—undoubtedly only a few individuals— which succeed in penetrating the intestinal mucous membrane, and that the greater part of those which break through are sub- sequently destroyed in the mesenteric nodes. Finally, there are only a few which are carried by the leucocytes as far as the INTESTINAL INFECTION IN TUBERCULOSIS 21 flow of lymph in the thoracic duct or as the capillaries of the lungs. But those bacteria which attain these situations estab- lish the intravascular tuberculous formations so well described by Borrel, and later by Letulle, the slow development of which in successive steps finally gives rise to phthisis. If so many physicians still persist in believing that man _ behaves differently from animals in the face of tuberculous in- fection, it is perhaps because the old ideas on miasma still weigh upon our brains. Without doubt, some among us have exag- gerated the importance and the frequency of the infection of man by milk, and those who contend to-day that tuberculosis is contracted through the intestine more often than through the respiratory tract, bear the burden of these exaggerations. We must protest also against this tendency to identify intestinal origin with alimentary origin. It is very certain that for our species the human patient is—I cannot repeat this with too much emphasis—the principal factor in the dissemina- tion of tuberculosis. But I believe it necessary to declare strongly that while man can exceptionally contract tuberculosis, above all in infancy, by the inhalation of the bacilli, he con- tracts it much more often by intestinal absorption, repeated frequently for a long time, of some of these same bacilli freshly thrown off by a consumptive. At the Congress of Veterinary Medicine at Cassel, on Sep- tember 26, 1903, Von Behring advanced the theory that pul- monary tuberculosis of the adult might well be merely a tardy manifestation of a tuberculous infection contracted in infancy. He laid emphasis to support this opinion upon the frequency with which pulmonary lesions are observed in adult cattle, whereas in young cattle the mesenteric lesions are the most frequent. My experiments with Guérin, and also those of Vallée (of Alfort) have shown the inaccuracy of so absolute a statement. We know to-day that a primary pulmonary tuberculosis can be produced in adult cattle, goats, monkeys, and guinea-pigs, by feeding these animals on infected material once or several times. Since infection by the digestive tract is so easy, there is 22 HARVEY SOCIETY reason for astonishment that tuberculosis is not a still more widely spread and deadly disease among live-stock than it is. Now then, veterinarians and stock breeders have frequently stated that certain animals remain immune, although they have been in contact for years with animals suffering from the dis- ease. More often still it happens that cattle react sharply to tuberculin at the first trial, cease to react a little later, and retain all the appearances of the most perfect health. Must it then be admitted that in the first subjects the tuberculous poison has not been able to gain a foothold, and that the second are capable of complete recovery after a first attack? Here again, experimentation will enlighten us. When we compel young calves to swallow, in a single con- taminated meal, a small dose of tubercle bacilli of bovine origin, which have been very finely divided in order to facilitate their absorption, we notice that all these animals, without exception, contract tuberculosis. They react, on an average, thirty days later to the tuberculin test; and if we test them again each month following we find that after three, four, or five months, some of them cease to react. On being slaughtered these last present no tuberculous lesions, and if, having saved them, one attempts to reinfect them a short time after, by making them absorb a fresh dose of poison certainly capable of infecting other calves of the same age, one finds that they remain immune. These animals then have really recovered from the primary lesions, and they should be considered as vaccinated, at least during a certain time the duration of which is still undecided. On the other hand, if we administer to calves, not a single time but in several successive feedings, at close intervals, a series of small doses of the bacilli, not only do they never cease to react to the tuberculin, but we find that in them tuberculosis develops very quickly and becomes rapidly fatal. It is then the animals which are exposed to a series of suc- cessive reinfections, so close together that they have not time to recover from the first attack, which become definitely and fatally tuberculous. We understand from this why, under conditions moderately INTESTINAL INFECTION IN TUBERCULOSIS 23 predisposing to infection, certain subjects resist contagion for a longer or shorter time: it is because they have actually been vaccinated or rendered insusceptible by a previous attack, the lesions of which had time to heal before a new occasion for infection offered. It is not easy to furnish proof that this state of immunity acquired by a previously successfully resisted attack exists also in man. Prolonged clinical observation of old cases, how- ever, permits us to affirm that it is, at least in many cases, very probable. It appears especially evident in old cases of scrofu- lous lesions, and since the statements of Marfan in 1886, numer- ous doctors have described it. One must inquire whether this is a question of a true immunity, of longer or shorter duration, supported not only by the absence of the reaction to tuberculin—which is not suffi- cient demonstration—but also by the non-persistence of the virulent bacilli in the different groups of lymph-nodes in the body. The experiments which I have carried out upon this subject with Guérin demonstrate that at the end of the fourth month after the ingestion of the bacillary vaccine, a lymph-node is no longer virulent for the guinea-pig. The bacilli have then been absorbed and have completely disappeared. We have attempted to prove the resistance of animals thus vaccinated through the digestive tract, with reference to an intravenous inoculation so serious as surely to produce in the control subjects the rapid development of an acute miliary tuberculosis with death in four to six weeks. This proof has been accomplished in six cattle, eight and twelve months after the administration of the vaccine. All the vaccinated animals were resistant and preserved the appearance of the most perfect health. But suddenly, about eight months later, one among them, although strict isolation was maintained so that infection from an outside source was impossible, manifested the first symptoms of a serious tuberculosis of the udder. All the others were then slaughtered ; they did not react to tuberculin, nor did they show any visible tuberculous lesions, but their bronchial 24 HARVEY SOCIETY and mediastinal lymph-nodes still contained living bacilli which were virulent when inoculated into guinea-pigs. The bacilli which had been injected intravenously, then, were not absorbed after eight months, whereas the bacilli which had previously been introduced by the digestive tract were not discoverable at the fourth month. And these bacilli remained latent in the body, not exciting any pathological trouble, up to the day when, the immunity ceasing, they became capable of suddenly producing disorders more or less grave. From other experiments we are able to state that the cattle already suffering from benign tuberculous lesions and reacting to tuberculin, or that healthy cattle prepared by two or three large intravenous injections of tuberculin, manifest a resistance entirely exceptional to the severe tuberculous infections taking place through the veins. While the new subjects succumbed to the acute miliary tuberculosis in four to six weeks, the ani- mals already tuberculous or prepared as I have above described contracted constantly a chronic form of tuberevlosis with a very slow development. They showed, then, a resistance, incompara- bly superior to that of the healthy animals. One observes the same phenomena in eattle artificially or spontaneously tubereulinized through the digestive tract, when one inoculates them later with a culture of tubercle bacilli sub- cutaneously. Thus Koch had already described in the tubercu- lous guinea-pig, at the time of his first work upon tuberculin, the formation of an abscess at the point of inoculation, but the neighboring nodes did not become infected, and the abscess healed when it opened on the surface. Analogous facts are frequently established in clinical work on man. Every one knows that a local tuberculous suppuration occurring in a person with pulmonary tuberculosis, ameliorates the condition of the patient and considerably increases his re- sistance. Inversely, it is rare that patients in whom pulmonary tuberculosis has had a rapid development have been attacked previously by suppurations of the lymph-nodes, or bony or cutaneous tissues, except in the cases where an inopportune sur- gical operation has provoked an infection of the blood. It is a INTESTINAL INFECTION IN TUBERCULOSIS 25 well-known fact that about a quarter of the persons suffering from lupus present the auscultatory signs characteristic of pulmonary tuberculosis, and that these generally develop in them with very great slowness; likewise that many lupus patients live to an advanced age. If one recalls that certain clinicians have pretended to obtain in phthisical patients real amelioration following the subeutaneous inoculation of cultures of virulent bovine tubercle bacilli (F. Klemperer), or of dead bacilli (Maragliano), or of cultures of human tubercle bacilli modified by passage through the body of a cold-blooded animal (crocodile) (Moeller) the experimental facts of which I have just spoken are of a nature to justify such assertions in a certain measure. But such a therapeutic method is certainly to be condemned; and so much the more because we possess in tuberculin a means as efficacious and less dangerous of attaining the same end. Upon the whole, the resistance conferred by tuberculin and that which is observed in animals or in man already attacked by benign forms of tuberculosis (tuberculosis of the lymph- nodes or scrofula, tuberculosis of the bone, or of the skin, lupus) appear to be of the same nature as that which is artificially effected, whether by intravenous inoculation of human or bovine bacilli, following the methods of Behring or of Koch and Schiltz, or by subcutaneous inoculation of the same bacilli (Ligniéres, Arloing), or by the insertion under the skin of collo- dion sacs containing cultures of human or bovine tuberculosis (Heymans). In each of these cases it is not a question of true immunity, since the animals thus prepared, although not giving the tuber- culin reaction, remain indefinitely carriers of living and virulent bacilli, and these are capable when the resistance begins to diminish of giving rise in the bodies of these same animals to serious lesions. Let us recall, indeed, on the one side, that in the experiments of Melun (1906) on animals vaccinated with the ‘‘bovovaccin’’ of Behring, the inoculated bacilli were proved not to be absorbed at the end of six months (Vallée and Rossignol, Mossu), and, 26 HARVEY SOCIETY on the other hand, that Roux and Vallée have demonstrated that vaccination intravenously or subeutaneously does not pro- tect against infection. On the contrary, the experiments which I have reported strongly support the statement that by the, intestinal absorp- tion of a weak and single dose of tubercle bacilli very finely divided, one can obtain at the same time the total absorption of the bacilli in the lymphatic system, and a state of immunity such that the animals are insusceptible, during a year at least, to large infections through the digestive tract. Of course, we are not concerned here with a method of vaccination which one could think of employing in preserving the human race from this terrible scourge of tuberculosis. It would be rash to consider as very near a definite solution of this sort. But so difficult a study can proceed only by stages. Fol- lowing Villemin and Robert Koch, who have laid the founda- tions upon which we build, a great number of research workers have brought their stones. Others will follow, and the work will be accomplished for the glory and for the salvation of humanity. FEVER * W. G. MacCALLUM, M.D. Johns Hopkins University, Baltimore ROM the earliest times fever with all its remarkable symp- toms has been familiar not only to physicians but even to the general public, and the term is one so honored by age and by the good that must consequently inhere in it, that it can- not be discarded or dismembered. It is, nevertheless, very difficult to define this conception clearly because even yet we are unable to say with certainty at what point the direct effects of the cause of the disease end and what really belong to the fever. For, although the elevation of the body temperature is one of the most salient points, it is by no means the only char- acteristic nor is it itself always to be regarded as an infallible sign of fever, for such elevation of temperature may occur in a perfectly healthy person, if, for example, he be immersed in a hot bath. There are other readily recognizable signs of fever, such as thirst, and weakness, and alterations in the character of the urine, but it is difficult, indeed, to be sure what part of each of these is produced by the bacterial poisons that cause the disease, what part by the fever itself. Kraus,’ in his recent review, has, on this account, written of fever and infection together. It is clear, from the fact that the ideas that prevail as to its general character are so uniform throughout the world, that, no matter what the nature of the disease that brings fever with it, the fever itself is the same. Sometimes it is ushered in with a chill, sometimes it begins gradually; it may be constant or intermittent; it may end abruptly or slowly disappear—but always it is recognizable as fever. Therefore, it seems proper that we should speak of it as the febrile reaction—as something * Lecture delivered November 7, 1908. 27 28 HARVEY SOCIETY characteristic of the body and not of the disease, and it is from this point of view that I shall consider it. The significance of this reaction I shall discuss later after reviewing the facts con- cerning the phenomena which are peculiar to it and the up- heaval in the whole economy of the body which accompanies it. We shall be particularly interested in comparing it with other reactions, for it is evident to the most casual observer that nearly everything that affects the body at all is responded to by some sort of reaction, and that most of these are processes which have been evolved in order to maintain the life and health of the individual. For example, the swallowing of food is followed by the most complicated reactions—muscular move- ments comminute it, ferments are secreted to digest it, changes in the whole metabolism follow its absorption, and so on. Ex- posure to heat or cold, hunger or thirst brings into play pro- tective reactions which regulate the body temperature or cut off the lavish expenditure of foodstuff and water still stored in the body so as to protect and prolong life as far as possible. In- deed, it would be difficult to produce such a state of repose that none of these responses would be in progress. TEMPERATURE REGULATION. Perhaps the most striking characteristic of fever is the ele- vation of the body temperature above the normal. The fact that in certain classes of animals the temperature of the body is maintained nearly at a fixed level is in itself a matter to arouse our wonder and interest, and the reason for this regula- tion of the temperature above that of the surrounding atmos- phere (for even in the tropies the average temperature is far below that of the body), and for the constancy of its level would afford much material for discussion. With the exception of mammals and birds, all animals seem to be devoid of any such mechanism and are in consequence poikilothermic.? The temperature of their bodies, like that of inanimate substances, quickly adapts itself to that of the surroundings, <.nd heat pro- duced in the course of their metabolic processes is at once dissi- pated, the more rapidly the smaller the animal on account of its FEVER 29 relatively greater radiating surface. In mammals and birds, however, there are special arrangements for preventing such loss of heat, or under other circumstances of facilitating it. Thus the development of the sweat glands in some animals affords them an especially effective method of cooling off the body, while the too great dissipation of heat is prevented in others by the thick layer of subeutaneous fat or the covering of hair or feathers. Man alone finds it necessary to resort to artificial modifications of the temperature of the air and to artificial protection in the form of clothing. It may well be a matter of speculation as to whether after all, it was not this need of artificial heat regulation which brought about our sud- denly acquired knowledge of good and evil rather than the reverse, aS is so generally conceded. Different animals have, of course, different standards of temperature and even for one species there are slight individual variations; nor is the temperature of various parts of the body the same, largely because certain portions are more protected from loss of heat than others, but partly also because, as it seems, heat is more abundantly produced in certain organs than in others. This point may be discussed more advantageously later, but here it may be said that this inequality in local heat production is continuously compensated by the rapid heating of the blood which comes into such close contact with these tissues and then hurries away to warm others. Although the variations are relatively slight, even warm- blooded animals are subject to changes of a periodic character in their temperature. This is particularly noticeable in birds, in which there is a considerable fall of temperature during the night. I have observed that in normal crows the curve of the temperature, when taken every three hours, shows a regular daily variation of 3° F. or more, the minimum temperature of 104.5° F. being recorded at midnight or at 3 a.m., while the maximum of 108° F. is reached at 3 o’clock in the afternoon.* To a certain extent, then, the crow must be regarded as poikilo- thermic. But even in human beings a similar periodic fluctua- 30 HARVEY SOCIETY tion of not more than 1.5° C. is observed and has been recorded in the form of curves by Jiirgensen,* Benedict and Snell,> and others. In these curves, as in the case of birds, the lowest tem- perature occurs in the early morning hours, while the maximum is reached in the afternoon. In addition to the effects of bodily activity of all sorts during the day, it seems possible that there may be causes of a more fundamental character, perhaps even a rhythmicity in the regulation of the temperature, which main- tains this uniform curve. That the temperature of the body is not kept at a perfectly constant level is shown further in the temporary alterations which can result from outward influences and the exercise of bodily functions in the normal individual. Slight elevation of the temperature may follow the taking and digestion of food, and muscular work, if violent enough, may result in a distinct rise in temperature. Ordinarily, however, in freely moving normal animals, such changes are insignificant and compensated at once by the regulating mechanism, and if we observe a marked elevation of temperature in the course of violent muscu- lar activity, it is probably because the normal compensatory dissipation of heat can not take place rapidly enough to keep the body cool. Interesting examples of this are found in tetanus and the status epilepticus, in which very high tempera- tures are sometimes observed. I had the opportunity recently of following the temperature in a dog in which after parathy- roidectomy the most violent tetany developed with intense spas- modic muscular contractions affecting the whole body. The temperature, which had been 39° C., reached 43.2° C. during this attack, in spite of the fact that the respiration had become extremely rapid (300 to the minute). The administration of calcium acetate stopped the convulsions in a few minutes, and within half an hour the temperature dropped to 38.9° C. Exposure to excessive heat or cold does not, as a rule, alter the temperature of the normal animal unless the exposure is so protracted and the difference in temperature so great that the mechanism of heat regulation finally becomes inadequate. FEVER 31 At a certain limit the control is overpowered and the animal’s temperature rises or sinks, as the case may be. These exceptions to the normal maintenance of a practically constant body temperature, unimportant and transient as they are for the greater part, I have mentioned in order to emphasize the wonderful efficacy of the mechanism of heat regulation. A few words will recall to mind the general char-; acter of this mechanism which has at its disposal means for the generation of heat as well as contrivances for the rapid dissi- pation of the heat produced or for its retention and husbanding within the body. The control of these matters has been clearly shown to reside in the brain, for the severance of nervous con- nection with the higher parts of the cerebrospinal system leaves the body in the condition of a poikilothermic animal. Whether this is due, as Tigerstedt ® tends to believe, to the bathing of the brain with blood too hot or too cold or to the transmission of sensations of heat or cold by the nerves, it is difficult to say with certainty.* Nor are we satisfactorily informed as to the precise portion of the brain which is concerned in this process of heat regulation, although the discovery of many so-called thermoregulatory centres has been reported. That one found by Aronsohn and Sachs’ in the anterior medial portion of the corpus striatum has been most generally accepted, and many investigators have confirmed their statement that the puncture of this area will cause an elevation of temperature which lasts several days. This sort of hyperthermy has been studied a great deal in connection with fever, and we shall refer to it frequently. The generation of heat can be effected by the nervous system in the musculature either by the production of actual move- ments, including such as are evident in shivering, or by the heightening of the muscle tonus. Whether the brain by send- * Of great interest in this connection would be the accurate study of heat regulation in patients suffering from syringomyelia in whom all appreciation of heat and cold is lost. Except for the existence of disturbances of the vasomotors of the skin and the sweat secretion, I ean find no satisfactory evidence on this point. 32 HARVEY SOCIETY ing out impulses of any sort to the muscles or to the other tissues can directly accelerate or intensify the chemical processes which lead to the production of heat is still questionable. The regulation of the dissipation of heat, on the other hand, is very directly controlled by the nervous system, and the mechanism employed is adjusted with great delicacy. Thus radiation and conduction of heat from the surface of the skin depends on the calibre of the cutaneous blood-vessels, which ean be changed within very wide limits by the vasomotor nerves; in order to keep the body from becoming too warm, whether from excessive production of heat or from the high temperature of the surrounding medium, the skin is flushed with blood, while exposure to cold is quickly followed by such contraction of those vessels that the body surface becomes very pale and the warm blood is restricted as much as possible to the interior and pro- tected from cooling. Even more effective is the secretion of sweat, the evaporation of which keeps the body cool even when exposed to very high temperatures. In all animals, but espe- cially in those which possess no sweat glands, a similar result is attained by the exhalation and evaporation of water from the lungs, and it is well known that in such animals as the dog this is an extremely important method of eliminating heat, the evaporation being greatly increased by acceleration of the respiration. If, as in the experiments of H. Winternitz,® the mechanism for the dissipation of heat can be incapacitated by immersing the person in a hot bath at a temperature above the normal body temperature, a curious change occurs in the respiration. Apparently there is no mechanism in the human being to respond to such circumstances by accelerating the respiration, but it becomes greatly increased in volume, pos- sibly in the attempt to compensate for the usual cooling effect of sweating. In dogs so immersed, on the other hand, the rate of respiration increases from about 15 to 300 or more, for the dog still has his normal method of cooling himself. In such experiments the body temperature and heat produc- tion as measured by the chemical changes are greatly elevated and may here be regarded as escaping from the contro] of the FEVER 33 regulating mechanism. On the other hand, if the animal is exposed to cold, as long as its heat-regulating mechanism retains its control and the body temperature remains constant, the heat production as measured by the chemical changes is also in- ereased, but sinks when the regulation is no longer maintained and the temperature falls.® 1° HEAT PRODUCTION AND LOSS IN FEVER. If we now turn our attention to the condition of the tem- perature, heat production and loss, in fever, we find that so much light has been shed on the subject in the past few years that we may speak of certain questions with some degree of security, although there remain many points which are still obscure. It is evident that there are several possible ways in which the temperature of the body may be elevated. The heat pro- duction may increase while the heat loss remains constant, or, the heat production remaining constant, the heat loss may be diminished, or both may be elevated but not proportionately. Any disproportion, however slight, between the two which leaves a positive balance of heat will in time bring about an elevation of the body temperature. In this sense we are reminded of the wonderful symmetry of action of the two sides of the heart. The slightest continued disproportion between the output of the two ventricles such that the left ventricle ejects less than the right will in a short time lead to the enormous overdistention of the pulmonary vessels and edema of the lungs. It is plain, therefore, that a great increase in the production of heat is by no means unconditionally necessary for the elevation of the body temperature, and we can readily understand that the continued accumulation of slight excess may quite rapidly lead to a very striking pyrexia. Traube attempted to explain fever on the basis of the second alternative mentioned—temperature elevation from excessive retention of heat alone, and supported his theory ingeniously, but it needed only the determination of any increased heat production in cases of fever to shatter this theory. And this 3 34 HARVEY SOCIETY proof has been brought by many workers, chiefly by means of a study of the respiratory gaseous exchanges, which showed that oxidation and consequent heat produced is increased, but also by the direct measurement of the heat produced by an animal during fever, a measurement which can be carried out by the aid of a suitable calorimeter (direct calorimetry). It is important to observe that the more recent writers on this subject estimate the increase in the heat production during fever at a much lower figure than did the earlier observers (Senator, Finkler, Colasanti, Lilienfeld and others), who often found an increase of 75 per cent. or even more. With Krauss” there began a series of more accurate investigations, in which stress was laid on the importance of keeping the animal under observation in a state of muscular repose, since he recognized that the earlier work was untrustworthy on ac- count of the great variations produced by muscular contractions, shivering, ete. After eliminating these sources of error, he found the febrile increase in heat production to be represented by an increase in oxidation of 20 per cent. at the utmost. Lowy” also found the inerease in combustion relatively slight, sometimes sinking within the limits of normal and at the highest rising to 51.8 per cent. Nebelthau,”* recognizing the inaccuracy of this indirect method of estimating the heat production when applied for short periods, studied the heat production and loss in febrile rabbits by direct meas- urement in a calorimeter, the observations being made to extend over a long period. He, too, found a distinct increase in the output of heat, but thought it still conceivable that fever might arise from the coexistence of a constant heat production and diminished heat loss. Krehl and Matthes “ found an increase in heat production of 14 to 60 per cent. in the height of certain fevers, while Staehelin™ in his febrile dog observed at first a diminished heat production, al- though later in the height of the fever the normal was exceeded by 45 to 47 per cent. May” in febrile rabbits similarly found a normal heat production on the first day of the fever, 5 a rise of 5 to 28 per cent. on the second day. All these authors agree, therefore, that in fever there is a distinct increase in the heat production. When they speak of an increase of 25 to 50 per cent. in the heat production as compared with the normal it seems at first sight an enormous change. The true significance of this statement is not clear, however, until we examine the heat production under some other conditions, and a hint of the relative importance of the influence of these other conditions is given by the refusal of the FEVER 35 recent workers to accept the results of their predecessors because they had not carefully attended to the exclusion of the effects of chance muscular movements during the observations. Speck 27 even goes so far as to assert that there is no increased heat production in fever, that even the modern figures are a delusion based on the overaction of the respiratory muscles, the intensification of the heart beat, ete. The amount of heat produced in the body on the ingestion and absorption of a full meal is very greatly increased over that produced by the same person when at rest and with an empty stomach. Many earlier workers have demonstrated this, and Staehelin,** in his recent careful study, has shown very clearly the effect of various forms of food, the increased energy production being greatest after a meal composed of carbohy- drate and proteid. Such an increase in heat production may surpass by a great deal that observed in fever, but there need be no rise in temperature. With muscular work the increased heat production is enormously greater. In contrast with the febrile patient at rest, in whom, as we Have seen, heat produc- tion reaches a moderate excess, the normal man, in the course of muscular labor, produces an amount of heat often several hundred per cent. in excess of that developed while he is at rest —and still there need be no elevation of his body temperature. He differs from the febrile patient in the extraordinarily rapid discharge of heat by all the means at his disposal. Although it is obvious from the direct calorimetric esti- mations mentioned that the heat loss is increased during fever as well as the heat production one must gather, from the knowl- edge of the normal methods of heat regulation during great elevations of the heat production, that in fever the dissipation of heat is relatively restricted, and that, even though the body has not at its disposal the enormous quantity of heat produced by the well-fed and working man, the metabolism is somewhat accelerated and some of the excessive heat is retained. This is sufficiently clear, although I can not find perfectly precise measurements of the amount of heat produced during a certain period contrasted with the amount lost in the same period in 36 HARVEY SOCIETY order to show concretely the direct cause of the elevation of temperature. Liebermeister,*® as is well known, entertained the view that the regulating mechanism is in fever peculiarly altered to react for a different standard of body temperature. As he expresses it, the regulating mechanism is tuned up to a higher pitch so that it begins to allow of the escape of heat only at a higher level, exactly as we might screw up the thermoregulator of a thermostat so that its temperature would stand at 40 in- stead of 35. There is something very attractive about this idea, but it must be said that the experiments which might establish it as a fact have not been carried out satisfactorily.* In gen- eral it is known that muscular effort during fever may drive the temperature up—that the taking of food may elevate the temperature, and that even after convalescence has begun the temperature regulation of a febrile patient is very labile and easily disturbed. But we do not know precisely whether the output of heat produced by muscular work during fever would be regulated at this higher standard in a way resembling that in the normal. If Liebermeister’s theory is to hold, the heat produced from muscular work should be dissipated after the requisite amount to maintain the heightened body temperature has been accounted for, in the same way as in the normal. Much interest is attached to the variations in heat produc- tion and loss, and the consequent temperature in the various stages of fever. It seems probable that this must vary in dif- * Efforts have been made by Stern, Filehne and others to show that there is some such constancy in the activities of the heat regulating mechanism, but Krehl points out, very justly as it seems, the fact that there is rather a weakening of the control so that febrile patients are more subject to external influences than normal persons—they are more easily cooled in a cold bath and more subject to the effects of antipyretics. Of course, the abnormal condition of the cutaneous vessels and other instruments of the regulatory mechanism must be remembered, but the very inconstancy of the body temperature during fever seems to him enough to indicate that here we are not dealing with an adequate regulating mechanism which is merely tuned to a higher pitch, but rather with one which to a certain extent has lost its control. FEVER 37 ferent types of fever, for the characters of these stages differ so much, but it is certain that in the initial stage, especially in those cases in which fever is ushered in by the appearance of a chill, every mechanism is set to work by the body to limit, as far as possible, the escape of heat and by increasing at the same time the heat production to elevate the temperature as rapidly as possible. The skin becomes livid and blue and cold as the result of the energetic contraction of the cutaneous vessels; the very important methods of heat loss, radiation and conduction, are thereby restricted to the maximum degree. Evaporation from the skin and from the lungs is also decreased, although in some cases that from the lungs has been observed to be height- ened. Further, the patient, from the very sensation of cold produced by these changes, draws his body into the smallest compass and covers himself thickly with clothes. On the other hand, heat production is greatly increased, and especially so by the increased tension of the muscles, by the shivering, and even by the goose fiesh. Liebermeister found an increase of 21 to 24 per cent. in the heat production in the hot stage of a malarial attack, in the chill 147 per cent. increase. Naturally the muscu- lar contractions are chiefly responsible for this high figure. Krehl and Matthes *° find that in this stage both heat production and heat loss fluctuate a great deal, but that they diverge from one another far more than in the normal. During the fastigium or height of the fever the dispropor- tion between heat production and heat loss is less striking. Conduction and radiation of heat from the skin and evapora- tion approach the condition found in the normal person on the same diet ** and in the same surroundings, but this in itself is abnormal, for in a healthy person with such an elevated heat production these regulating mechanisms would be greatly stimulated. The blood supply to the skin in the height of fever under- goes remarkable fluctuations, as Senator ** pointed out; the dilatation and contraction of the vessels may vary from hour to hour and even from one part of the skin surface to another, and consequently it seems probable that if we could determine 38 HARVEY SOCIETY > the heat loss from the skin for very short periods we would obtain a curve showing very marked irregularities. In this stage, then, we have an irregular and moderate increase in the heat production associated with an irregular increase in the heat loss. However much the heat production may increase, the heat loss keeps a place somewhere behind it, and there is no parallelism between the temperature and the heat production or between temperature and the amount of oxidation going on. Krehl and Matthes point out the fact that the special cause of the fever does not necessarily govern the intensity of the heat production, over which the nutritive condition of the patient and the individual type of reaction have a great influence. The young strong patient tends to show a higher heat produc- tion than does the aged, weak one, and it is a commonly appreci- ated fact that the lack of an intense febrile reaction, like the absence of adequate leucocytosis, is often an index of the low powers of resistance of the patient. When a patient is overcome by the intensity of the infection, it is also usual to observe a fall of body temperature to a subnormal level. In the last stage of fever, that of defervescence, there is a gradual or sudden strengthening of the mechanical dissipation of heat and at the same time a decrease in the heat production. One receives the impression that the mechanism of heat elimina- tion, having been held in leash by the regulating nervous sys- tem, is now set free when the poisoning is overcome and the saving of heat no longer necessary. Especially in the critical forms of defervescence is this outbreak of heat dissipation seen — to advantage, merely because there the phenomena are concen- trated into a short period of time. TOPOGRAPHY AND MECHANISM OF FEBRILE HEAT PRODUCTION. Since I wish to discuss in some detail the changes in metabo- lism which underlie these disturbances of the heat economy of the body, the limits of this lecture will not allow me to enter on a consideration of the topography of heat production further than to say that the muscles are commonly regarded as the great source of heat, although, of course, every tissue is concerned to some extent in its development. In fever there FEVER 39 are, as we shall learn, certain special reasons for thinking that heat production is brought about chiefly in the muscles. There are, however, those who disagree with this assumption and be- lieve that the liver is even more prominent in this connection. Hirsch and Rolly ** find that after the influence of the muscles is destroyed by curare, it is still possible to produce hyper- thermy by heat puncture, and, since this is not successful in glycogen-free animals, they ascribe the production of heat to the combustion of carbohydrates in the liver, and by thermo- electric methods show that it is only after the temperature rises in the liver that it does so in the muscles. Hirsch and Miller ** apply the same thermometric and thermo-electric methods to the-mapping out of the heat production in the body, and find in fever that the liver is far warmer than the muscles, and that even the subcutaneous tissues have a higher temperature. They regard the low temperature of the muscles as notable, and hold that Heidenhain’s view that the muscles are warmer than the aortic blood is thus disproved. The methods employed in these researches seem not entirely above criticism, for we have again a conclusion as to heat production based on the temperature of an organ, and, in my judgment, we must still defer our ultimate conclusion as to the relative importance of the muscles until further work is brought out. Nor can I consider at length the interesting discussion as to the claims of the theories of the neurogenic and toxogenic nature of fever. The precise character of the nervous mechan- ism which presides over the heat economy of the body is far from being well understood, but I have already mentioned the fact that there are certain localities in the brain, irritation or injury of which causes hyperthermy, and have drawn especial attention to that so-called heat centre which was discovered by Aronsohn and Sachs in the anterior medial portion of the corpus striatum. The character of its action is, however, not under- stood; we are far from possessing definite proof of the existence of any special nerves which preside over the production of heat, and it is at this point that the neurogenic theory of fever is attacked. Hirsch, Miiller and Rolly ** put forward the idea that it is not from the action of the nervous system that the 40 HARVEY SOCIETY febrile intensification of metabolism arises, but rather from the introduction of poisonous substances which directly injure the cells. While the neurogenic chemical heat regulation occurs in the muscles with the increased burning of carbohydrate, the increased burning in fever is probably universal and affects especially the proteids, the part played by each organ depending on the intensity of its specific function in metabolism. Fever is thus a specific reaction against injurious materials which affect the tissues. Krehl and Soetbeer** find that in cold- blooded animals, such as the frog, infection results in a marked heat production and dissipation ; and, inasmuch as these animals have no nervous mechanism controlling heat regulation, they see in this result a proof of the toxogenic theory of fever. It would seem perfectly possible to control the part played by the nervous system in fever by a variety of experiments. No one doubts the dependence on the nervous system of the mechanism governing the dissipation of heat, and the question is rather as to the relation of the heat production to the superior nerve elements. Of course, it is plain that by causing muscular contraction or increasing muscular tone the motor nerves can increase heat production, and one might be inclined to say that in all probability this is the way in which the heat production is stimulated in all cases. But it is frequently observed that when the spinal cord high in the neck is severed there occurs a febrile rise in temperature with increased heat production,?’ although often it is the reverse, a gradual sinking of tempera- ture. Section of the medulla near the pons causes a rise in temperature, and the injury of the corpus striatum spoken of above very regularly brings this about. Analysis of such effects shows that the elevation of temperature is not due solely to limitation of heat dissipation, for Schultze ** finds that ani- mals with heat puncture react to outward changes in tempera- ture precisely as do normal animals. There is, on the contrary, an actual increase in the production of heat, even though the animals remain perfectly quiet, and, although there has been some disagreement as to the actual source of the heat in these cases, it seems probable that we must accept the results of Senator and Richter,?® who find that there is not merely an FEVER : 41 increased combustion of carbohydrates, but that proteid metabo- lism is also increased. In no essential particular, then, does this hyperthermy differ from that of fever. Despite all this evidence that a somewhat peculiar febrile reaction can be produced by injury of the brain and despite the perfectly certain and generally accepted fact of the nervous control of the heat-dissipating apparatus, I feel that there is much to be said for the view that the circulating poisons affect directly all the cells of the body, and that the latter in their quality of living protoplasmic creatures react with an increased metabolism. It appeals to me as a reaction quite analogous to that in which leucocytes are produced in enormous numbers in the far-off bone-marrow when they are needed in the pneu- monic lung, and is no more easily explicable than this. METABOLISM IN FEVER. Having discussed the general subject of heat regulation in connection with fever, in some of its aspects, we may now turn to the consideration in somewhat greater detail of the chemical processes which underlie the production of heat. It may be said in general that these processes, in so far as they are connected with heat production, consist chiefly in the com- bination of oxygen with carbon and with hydrogen with the formation of carbon dioxide and water. That this outcome may be interrupted by the formation of intermediate products detracts in no way from the truth of this statement, and if only sufficient time be devoted to observation the final results are the same. That there are other oxidations going on is, of course, true, but their role in comparison with those mentioned is almost negligible. Further, the amount of heat produced in the various decompositions and syntheses is very slight, and we shall not go far astray in restricting our attention to the oxidation. Something has already been said concerning these processes in discussing the production of heat in so far as the amount of heat produced in fever was compared with that produced in other conditions. Now, however, it is important that we should be able to compare more accurately the figures which result from 42 HARVEY SOCIETY the estimations of oxygen in varying conditions, and at the risk of becoming tedious I shall quote the statements of various authors as to the total oxidation products in various stages of hunger and nutrition, in muscular work, in exposure to heat and to cold and finally in fever. Naturally these results may vary widely because of the size and characteristics of the in- dividual observed and because of difference in the character of the nutrition, but they will doubtless diverge so far from the normal that there can be no question as to the effects of the conditions which they are meant to illustrate. For the sake | of convenience, they may be set down in the form of a table. TABLE SHOWING STATEMENTS OF VARIOUS AUTHORS AS TO OXIDATION PRODUCTS IN VARIOUS CONDITIONS. COz be = ted Oxygen ee Subject Condition per min. per hour per i min, per hour Author Healthy Man— In bed, fasting. Especially QUE. eC. peas ee pe eave dot se AD AS | = ate Ordingtaly. Quiek 554.055 Gb sice- B82. | \ideeioe vig \ ronannsonse Healthy Man— i eee eee toy tare 4a S63" . i. bole During and after meal.. ..... 41.5-49..... IAD |. pics vim iy abies Rane ee | ey es oak After five days’ hunger. Johannson! At reet. or ‘reading: 263.5%) 24-29 ..... aes During and after a walk. ..... Be BD | vis seen ainbontpeiyichh Reinaht ae fu vices Healthy Man— Exposed to cold and heat. Surroundingtemp.,4.4°C. .... 35.16 ..... oo Lrates Surrounding temp.15.2°C. .... 26.33 ..... | r Surroundingtemp.,30°C. .... 28.5 ..... ape og Man— OE A ccas ans bb oe ve ses sete | DIO) pean Walking eee aes chee SOOT. aaa (inerease 13-45) Climbing 2 Bone snvie- te ooo 0 SO-131 | samen (inerease 50-104) FEVER 43 CO2 vans apeventt Absorption Subject Condition ee oe per rica er mits, ee han hour Author Healthy Man 67.2 kg.— 4, oe aeege repose. Fast- BR eh nick = shee vetes 19.86 ©... 17A5 2. Pandiets repose. Pro- teid meal, 75 Gm. proteid ..... 25 | 22.54 may 3. Complete repose. Fat ath ei, meal, 7 Gm. proteid, 77.4 fat, 30 carbohydrate ..... aE a 21.88 4. Complete repose. Car- bohydrate meal, 32 Gm. proteid and_ carbohy- NES ee FADR deta s 21.41 5. Complete repose. Pro- — teid and carbohydrate t 90 Gm. proteid, 34 Gm. grein _ fat, 113 Gm. carbohy- IN Sak GF cdi as usta Fine e pa! 23.61 Healthy Man, 48 kg.— At rest. Temp. 36.2.... 133.8 15.86 172.9 14.38 After 35 min. in bath at : , 40-41 C. Temp. of pt. jr a? Ia 316.2 37.50 363.6 31.18 Woman, 61 kg.— Erysipelas. Temp. 40 C... 303.91 36.02 321.41 27.57 Fever-free one month later 224.68 25.64 245.18 21.3 Man, 48.5 kg.— Typhoid, 2nd week. Temp. Krauss LG) ac de eens tina ce 284.12 33.69 3504 30.02 Man, 48.5 kg.— Pneumonia. Temp. 38.9- AE Ad clay 4 din wens «dae 234.9 27.85 25.56 21.91 Man, 58 kg.— Pleuritis. Temp. 39.5.... 254.78 30.21 315.1 27.02 Man— Typhoid. Temp. 39.5.... 263.99 31.30 398.32 34.16 Man, 50 kg.— Typhoid. Temp. 39.5.... 205.79 2440 291.72 25.02 ; Lowy” Man, 50.5 kg.— Tuberculosis. Temp.normal 206.29 24.43 255.95 21.95 Tubereulin injection. Temp. MTV aheg's vis vievn ele ¢ 280.96 33.12 316.25 27.15 tA HARVEY SOCIETY es Output oxygen Aleertine Subject Condition per main. bale ta hour per Pini. per hour Author Woman, 61.4 kg.— Suspected tuberculosis, 36-37 .....6- eee ees 289.51 34.22 381.41 32.71 SRD 45. bie pees cae 310.84 36.86 417.20 35.78 Woman, 46 kg.— Kraus and Pulmonary tuberculosis. Chvostek*s TOR iSie iss eek as bs 184.15 21.83 268.07 22.99 Tuberculin injection. Temp. NEE iy cco hie's Wea wih 258.97 30.71 399.17 34.32 This table suffices to show that in fever in man the oxidation is usually but not necessarily increased, but that the increase is not very great. Kraus estimates it as not exceeding 20 per cent. at the highest, while in some eases it is not elevated at all. And Léwy, Riethus and others coneur with him in this opinion, believing that the higher per- centages given by the earlier workers (Senator 75 per cent.) were probably dependent on the muscular unrest which prevailed during their observations. Similar results have ,been obtained in the case of animals in which fever has been experimentally Produced, and I need only refer here to the careful studies of May” and Staehelin.” May gives the result in one of his hungering rabbits in which he produced fever by inoculation with the bacillus of swine erysipelas as follows: CO. Oxygen cy Rabbit E output absorption quotient Before infection... 5.4