THE SUPPRESSION OF TUBERCULOSIS.THE CASSEL LECTURE.[1]
THE CASSEL LECTURE.[1]
Although in this lecture I have planned to discuss mainly the suppression of human tuberculosis, my experiences with bovine tuberculosis cannot be omitted; for not only have I strong reasons for believing that bovine tuberculosis plays an important rôle in the etiology of human tuberculosis, but I am also firmly convinced that by means of the knowledge gained from the study of bovine tuberculosis, we shall be able to prevent to a great extent human tubercular consumption, and favorably influence the course of already existing tubercular diseases.
Both human pulmonary consumption andperlsuchtof cattle (which often leads to consumption) are caused by minute vegetable organisms, which it is impossible to differentiate either microscopically or culturally,—the tubercle bacilli of Koch. It is impossible to have either tubercular pulmonaryconsumption orperlsuchtwithout the presence of these tubercle bacilli; and no matter how susceptible to tuberculosis an individual may be, a tubercular infection cannot take place if these bacilli be absent.
In order for the disease to develop, three factors must always be present: first, the susceptible organism; second, the vegetable parasite; and third, the necessary opportunity to infect. Under the last I understand all the conditions necessary to bring the virus to such a part of the living organism as will enable it to enter either into the circulation or into other body juices.
Every human individual is by nature susceptible to the action of tubercle bacilli which have entered his body juices. This is true not only of human but also of bovine tubercle bacilli. I emphasize this now but shall give my proofs later. But not every tubercular infection of the tissues leads to consumption. Frequently the tubercular infection is followed by such slight disturbances of health that it remains latent throughout an entire lifetime and is only discovered at autopsy.
Whether the entrance of tubercle bacilli into the tissue juices of an individual shall end disastrously or not, depends on a large number of factors.Congenitaldifferences in the degree of susceptibility undoubtedly play a subordinate rôle. A more important factor is the degree of virulence of the inoculated virus, and this may fluctuate withinwide limits. Of great importance also is the amount of the virus and whether the inoculation is single, repeated, or almost continuous for a longer time. Of transcendent importance, however, are the age of the individual, his physiological or pathological condition at the time of infection, other previous diseases, mode of feeding, occupation, hygienic conditions of his surroundings, etc. In short, all that we understand by the termacquired susceptibility, oracquired predisposition. Finally, I must mention the location and character of the point of entrance of the virus.
We see at once, therefore, that, in the analysis of a tubercular infection, it is not sufficient to have determined the presence of the three necessary factors, susceptibility, the tubercular virus, and the opportunity for infection. If we wish to understand the manifold variety of the reaction phenomena exhibited by an individual infected with tubercular virus, we must thoroughly study all the conditions above mentioned as well as a great variety of accidental conditions.
Nowadays the term tuberculosis is applied to everything which constitutes a change in the organism excited by the entrance into it of tubercle bacilli. In statistics, galloping consumption is thus classed with tubercular local infection of a joint, gland, abdominal organ, of a little nodule in the skin of the face, etc. Calcified as well as other remains of previous lesions are classed as tubercular.We have every reason to praise as a great scientific advance the discovery that in manifestations so varied in their importance to life and health the etiological factor is the same. One must not, however, make the mistake of classing as one and the same thing tubercular infection and consumption and prognosticate an inevitable and painful end on making the diagnosis of tubercular infection. How little the facts justify such a course is seen in the statistics of bovine tuberculosis and will be seen also when I come to speak of the statistics of human tuberculosis.
In studying the statistics of bovine tuberculosis of this province, I have had the hearty support of the government officials as well as of many county veterinary surgeons. After my colleague, Dr. Römer, had examined several thousand head of cattle we ceased our labors because we were confronted by the depressing fact that larger herds of cattle were rarely ever free from tuberculosis. As a test to discover the presence of tuberculosis we made use of small infections of Koch’s tuberculin. We are aware that there are tuberculous animals which do not react to this test.On the other hand, if the method of making the test be faultless, a positive reaction always indicates that the animal in question is infected with tuberculosis.Our figures for these cases are therefore without doubt too low. Despite this, and despite the fact that young cattle, even though infected with tuberculosis,often do not react to the usual dose of tuberculin, we found frightfully high figures for herds of more than twenty animals. We had to admit that in this respect we were no better off than other countries. I will cite one of the most experienced of the investigators of tuberculosis, Prof. Bang of Copenhagen, who says that in Denmark, in stables of more than fifty head of cattle, an average of 60% of the animals are tuberculous. Bang says further: “If one is dealing with a large herd in which tuberculosis has existed for many years, one may as well omit testing the full-grown animals.Most of them will react, even though they appear perfectly healthy.” To this, as a result of many years’ observation, I should like to add,and though they may apparently remain perfectly healthy for their entire life.
As a rule a herd of cattle on a large farm, though infected with tuberculosis, presents a fine appearance. Nor does their state of nutrition, milk production, or calf-raising leave anything to be desired. Now and then a cow coughs, or, despite plentiful food, loses flesh. This animal is put aside and the herd, as such, resumes its magnificent appearance. If in a herd reacting to tuberculin things are allowed to go on in this way for a number of years, especially if the cattle be barn-fed, then, to be sure, the number of coughing animals increases, the offspring deteriorate, the milk and meat production decrease, until finally the scourge of tuberculosis is plainly marked.
Carefully conducted epizootic researches in our province have led me to the discovery that a single, native, mountain breed of cattle, that of Vogelsberg, was probably free from tuberculosis as late as twelve years ago. Through imported cattle the tubercular infection was then introduced. But even now the percentage of animals responding to the tuberculin test is about one-quarter that of other breeds. What is curious, however, in these cattle is, that whereas, according to common experience in all other breeds, the percentage of reacting animals increases with their age, in these Vogelsberg cattle the percentage from the fifth year on even decreases. This may depend on the smaller number of animals infected five years ago. Some of the exceptions, however, I must account for by the definite healing of lesions and a consequent disappearance of the reaction. The favorable termination of the tuberculosis in these Vogelsberg cattle I ascribe to the smaller accumulation of the tubercular virus in the still relatively little-infected stables, or, what amounts to the same thing,to a smaller dose of the virus infecting the suckling calves. These, of course, take up the infecting agent not only from the mother cow, but also from the other cattle.One can plainly see how the percentage of reacting cattle in this Vogelsberg breed increases from year to year, and I feel certain that ten years hence these cattle will be as badly off in this respect as other breeds, provided measures are not taken to check the advancinginfection. Such measures we have had at our command for some time, and their usefulness has been thoroughly proven. I know of a large number of herds which, by means of Bang’s rules, have been made free from tuberculosis and kept so. It is, however, an expensive procedure and requires the constant supervision of an expert, and even then is usually possible only on large estates where any reacting animal may immediately be separated from the unaffected herd. When, therefore, I published a method of protective inoculation against tuberculosis, one which I had proved in my own stables, I was pleased with the spirit of hearty cooperation shown by the owners of large dairies who had already experimented largely with Bang’s procedures.
Through the courtesy of Count Zedlitz I was enabled to make numerous preventative inoculations on cattle in three counties of Hesse-Nassau; from there the experiments were extended to the neighboring grand duchy of Hesse, and to the large dairy of Bolle in Köpenik near Berlin. As a result of this work I was able in the beginning of this year to establish the harmlessness of the procedure. Since then I have had abundant opportunity to inoculate calves under three months on the immense Hungarian possessions of Prince Ludwig of Bavaria; also on those of Archduke Frederick of Austria. Under my direction scientific researches regarding the protection afforded by the inoculations havebeen undertaken by Prof. Eber in the veterinary school of the University of Leipzig and by Prof. Schlegel in that of the University of Freiburg; further also by Ober-med. Rath Lorenz in Darmstadt and by Prof. Hutyra in Budapest. In Marburg I myself have made studies on highly immunized cattle regarding the production of anti-bodies, have reared calves on cows immune to tuberculosis, and have investigated the subject of immune milk.
All the details have been carefully recorded. Some of these protocols have already been printed, and at the close of this year I hope to commence the publication and working out of the rest of this enormous mass of material in my “Beiträge zur experimentellen Therapie.”
In the mean time, however, the practical application of my immunizing procedure continues steadily to gain in extent. Austrian as well as Swedish investigators, sent by their governments to study the inoculation technique at Marburg, are to make extensive inoculations in their native countries. The government of the grand duchy of Hesse has ordered that the counties use part of their police fund to defray the expense of inoculating all calves free of charge, provided that the owners bind themselves to allow the county veterinarian to supervise the inoculated animals. From all sides I receive requests for this preventative virus.
Until recently I prepared this virus myself and distributed it free of charge with the help of private funds. I was able to do the entire scientific, technical, and administrative work with only a few assistants. But this is no longer possible, for the expenses have outgrown not only my financial means, but also, even with great zeal for the work, my bodily strength. I should gladly have postponed any change in the manufacture and distribution of the virus until the Prussian government was ready to take charge of the entire matter. But the daily increasing labor has made it necessary for me to rid myself of this burden now, and I have therefore provisionally arranged that the firm of Drs. Seibert & Ziegenbein of Marburg undertake the manufacture.
That this free distribution of the protective virus for tuberculosis of cattle has been completely justified is seen by the report of Koch’s Institute, entitled, “Ueber Immunisierung gegen Tuberculose.” To be sure, this report contains nothing positive that, as a result of a large number of experiments, I had not already maintained for some years. And it lacks, what is especially important in the practical immunization of cattle, namely, proof in the form of protocols. Possibly these were omitted because they would fail to substantiate Neufeld’s assertion that Koch, previous to my publication regarding protective inoculations of cattle with living tubercle bacilli, had already made use of the same procedure.I cannot refrain from observing that Neufeld treats this question of priority in rather unusual fashion, for he now claims for Koch an immunizing procedure which I had published as long ago as 1901. It would surely have been more reasonable to have made these claims sooner, before the success of the method became so generally recognized in agricultural circles. Finally I must criticise the author for making similar uncalled-for claims for the English investigator Macfadyan. As the one most concerned, such claims might have been made by Macfadyan himself, yet, so far as I know, that investigator has not even suggested such a thing. In the case of my diphtheria-serum discovery I can entirely overlook similar baseless and unjust claims for Roux and for Ehrlich. Such claims have often been made by medical authors, but neither Roux nor Ehrlich has ever authorized such a perversion of facts.
However, apart from these inaccuracies, the report of Neufeld regarding Koch’s tubercular immunizing experiments shows an agreement with my results which extends into the smallest details. This, then, must demonstrate to the world the absolute reliability of my immunizing principle. The entire suppression of bovine tuberculosis is now only a question of conscientious and properly conducted protective inoculations, and, of course, also a matter of time.
Just now I am studying the important practicalpoint which for a long time occupied the attention of students of vaccination. We now know that protection against variola is only then secured when the vaccination is followed by a typical inflammatory reaction. Are the requirements the same for bovine tuberculosis? This I cannot yet definitely answer; and even under the most favorable conditions I shall be able to answer it only after a lapse of two years. By that time the calves that were injected only once and that did not, so far as we could ascertain, react to the inoculation, will have grown to maturity.
Another important problem, one regarding hereditary immunity, is already nearer solution. I believe I am warranted in saying that, as a rule, the immunity against tuberculosis is not transmitted by the cow to her calf during intra-uterine life. One can readily be deceived by cases of apparent hereditary immunity. For example, in examining the fourteen-day-old calf of a highly immunized cow, I found the calf to possess a comparatively high degree of immunity againstperlsuchtbacilli. Without my previous experience with infantile immunity to guide me, I might easily have been led into the error of assuming this to be a case of hereditary immunity. Comparative tests, however, have made it very probable that the immunity, undoubtedly possessed by this calf, was derived from the milk of the immune cow with which the calf was nourished.
It will still be some time before I can present any experimental evidence to show whether a cow, less highly immunized than the one just mentioned, also produces a milk which possesses protective immunity, and if so, how far it is possible to increase this property; whether such a milk can be used to combat human tuberculosis; and finally, whether it can be transported long distances without losing this property. I have, to be sure, every reason to hope that we are on the right track when we believe that immune milk constitutes a remedy for tuberculosis with which no other remedy can even remotely compare. You will, I am sure, believe that I shall leave nothing undone which will lead to a realization of these hopes.
Right here, perhaps, it is well to say that, for the purpose of making very careful therapeutic experiments, I am delivering immune milk to only a few of my medical friends. I cannot, therefore, meet the many demands for this remedy coming from medical and other sources. They are so numerous that I cannot even answer them all. When, as a result of these clinical experiments, the conditions and restrictions are determined under which immune milk exerts its therapeutic action, I shall make public all the facts in regard to this remedy, and thus make it accessible to every one.
In the mean time I believe it will serve a very useful purpose if I publish in readily comprehensible form the scientific facts on which my plans forthe suppression of tuberculosis rest. With this, of course, will come a discussion of controversial points in the field of tuberculosis investigation which have attracted the attention not only of the medical profession, but also of the laity.
I shall commence with the question as to what relations exist between human and bovine tubercle bacilli. Two years ago, in London, Koch said that the excitants of bovineperlsuchthave nothing to do with human consumption. If this be true, then I must at once admit that my hopes regarding the utility of cattle immunization for human therapeutic purposes have very little foundation. It is well known that the protection afforded by immune bodies excited by the injection of any virus extends only to the same species of virus, not to that of different species. Nor, in our entire investigations in immunity, do we possess a single example showing the possibility of protecting animals or man by means of one infectious agent against the action of another of a different species. All this is now so well known that I need not discuss it. When, therefore, the researches at the Koch Institute show that it is possible to protect goats, donkeys, and cattle againstperlsuchtby inoculating them with human tubercle bacilli, does it not show that in these diseases there is no difference of species?
According to the recently expressed opinion of his co-workers, Schütz and Neufeld, Koch in his London address did not maintain that there is adifference in species. He merely maintained that the virus of human consumption is not identical with the virus of bovineperlsucht, and that, likewise, bovine tuberculosis is not identical with human tuberculosis. That, to be sure, would be something quite different from what the rest of the world understood. Human pulmonary consumption and bovineperlsuchtare anatomically so dissimilar that it required extraordinarily clever researches and keen reasoning to lead to the discovery of a common etiological factor in these diseases. But one can easily go further than this. One can maintain without exaggeration that tubercular lupus, tubercular scrofula, and other human tuberculosis localized in joints, serous surfaces, etc., are just as little identical with pulmonary consumption as are the cases of bovineperlsucht. The termidenticaldoes not even fit all cases of consumption. Strictly speaking, a process or thing is identical only with itself. Certainly not all tubercle bacilli are identical, nor yet all kinds of tubercle bacilli. Koch’s assertion that there is an essential difference between human and bovine tubercle bacilli, and that these differences are not bridged by any connecting links, provoked the strongest opposition. This assertion has since called forth observations from all over the world which positively demonstrate the existence of intermediary stages in the virulence of tubercle bacilli derived from mammals. Generally, tuberclebacilli derived from cattle are more virulent for all animal species, thus far examined, than are human tubercle bacilli. And the opinion is constantly gaining ground that bovine tubercle bacilli are also more virulent for man.
In the scientific controversy as to whether the virus of consumption and that ofperlsuchtbelong to the same species or not, various misunderstandings have prevented an agreement. Very often the terms “similar species” and “different species” have been used in a different sense. It is, of course, wholly a matter of individual judgment where to draw the line limiting the membership of what, in our minds, constitutes a species. Even if we apply Darwin’s definition and include under the term “species” only “organisms of similar origin,” the term is still very elastic. However, in the light of our present biological knowledge, based on Darwin’s theory of evolution, we are under no circumstances permitted to take as a criterion for like and unlike species such an easily influenced factor as the degree of virulence, i.e., the capacity for giving rise to pathological changes in another organism.Nowadays all botanists and zoologists are agreed on this, that membership in a species is determined by the origin of the organism.An anthrax culture, which has been made entirely avirulent by means of Pasteur’s procedure for reducing virulence, surely belongs to the same species as does the virulent variety from which it was derived. And in thiscase the difference in the degree of virulence is far greater than it ever is between human and bovine tubercle bacilli. If we keep in mind all the functional differences that have experimentally been shown to exist between tubercle bacilli which have long lived in a human body and those which have long lived in a bovine body, we shall surely not go wrong when we assume that with a little patience and expert knowledge we shall be able to make these two varieties absolutely similar again, even in respect to their virulence.
Passing now to the discussion of the real subject of my lecture I shall try to give you an idea of the distribution of tuberculosis in the human species. Although the number of persons dying of consumption is frightfully large, the number of tubercular, and tubercularly infected, persons is much larger. Not until recent years have we secured tolerably reliable data to enable us to judge of the distribution of tuberculosis in civilized countries.
If we classify as tuberculous every case in which there are pathological changes due to tubercle bacilli, then surely the oft-quoted saying of the noted Greifswald physician is true, “We are all a bit tuberculous.” It has not been easy to demonstrate this fact scientifically, and it would have been impossible of demonstration without the two epoch-making discoveries of Robert Koch, that of tubercle bacilli, and of tuberculin.
Not even a man of the scientific attainments ofVirchow was able to judge what constitutes tuberculosis, although during fifty years he had endeavored to formulate data for the differential diagnosis of post-mortem findings. Since we have learned that Koch’s bacillus is the bond of union between all the various tubercular diseases, we see that many inflammatory processes which Virchow described as entirely distinct and different are nothing else than special stages in the tubercular infection. The anatomical unit of the tubercular process is the tiny, translucent gray nodule of millet-seed size described by Laennec and Virchow, the miliary tubercle. But what may develop from this may take the form of most widely divergent pathological lesions, and it was not granted to Virchow to puzzle out the endless variety of things etiologically the same. Yet it isetiologicallythat the vital processes must be analyzed if we wish to have a firm basis for our struggle against preventable diseases. This has more and more become the opinion of modern physicians. The progress that has been made, first in surgery and then in internal medicine, progress that only fifty years ago was declared by the most eminent representatives of medicine in those days to be impossible, has been possible only through the etiological investigations developed by Pasteur and by Koch.
The first principle in the etiological investigation of all vital processes, and therefore of those concerned in infectious diseases caused by micro-organisms,is thus formulated by Darwin: “That which is of the same origin belongs to the same species.” Two infectious agents may resemble each other ever so closely, but if they have not the same genealogy, i.e., if they are phylogenetically widely separated, then, biologically, they belong to different species. And conversely, size, form, and other properties of certain micro-organisms may be ever so different. If, however, the organisms are of the same origin, then, biologically, they belong to the same species. The virus of anthrax occurs in two forms: as bacilli, and as oval spores. The quotidian malaria parasite has an extraordinarily complicated cycle of development. Nevertheless we have no hesitancy in speaking of either an anthrax virus or of a malaria parasite.[2]
The virus of human tuberculosis, the tubercle bacillus of Koch, possesses narrowly limited morphological characteristics. It is readily recognized since Koch published his very accurate description of it in 1882, and especially since Ehrlich, shortly afterward, published a specific staining procedure. The tubercle bacilli are familiar to us as rods of varying length, but of fairly constant thickness, which occasionally show granular degeneration. I believe it is now everywhere acceptedthat the presence of these bacilli in a lesion in the human body indicates the tubercular character of that lesion. Leprous lesions with somewhat similar bacilli must, of course, be taken into account, but these, as a rule, can already be differentiated macroscopically.
Recognizing this significance of the presence of Koch’s bacilli and applying all other known methods for the identification of tuberculosis, Dr. Naegeli of Zürich, working under the direction of Prof. Ribbert, was unable to discover at autopsy a single body over thirty years old in which there were not some signs of the occurrence of a tubercular infection. Between the ages of 18 and 30 there were 96%; between 14 and 18, 50%; between 5 and 14, 33%; and between 1 and 5 years, 17%, which showed the presence of tubercular lesions. In the bodies of infants under one year, on the other hand, definite tubercular signs were invariably absent.
The astonishing results of these careful anatomical investigations have been verified by reports from pathological anatomists in other cities; yet at first sight, they seem to contradict all medical and other experience, for according to these results all of us assembled in this hall are tuberculous! But the perfected diagnosis of tuberculosis in the living person leaves no doubt that Naegeli’s figures, at least for thickly populated centers, possess general applicability. To be sure, if we count only the patients who come to the physicianbecause of tubercular or supposedly tubercular symptoms, then our figures do not agree with Naegeli’s; nor will the statistics of living persons in whom we can discover tubercle bacilli agree with the autopsy statistics. The agreement, however, becomes very close if we make use of a diagnostic method furnished us by the second of Koch’s above-mentioned discoveries, the tuberculin injection.
Koch’s tuberculin is a water-soluble tubercular toxin, given off from the bodies of the tubercle bacilli to the culture medium, and concentrated together with glycerine. Injected either subcutaneously or intravenously it causes no reaction in persons free from tubercular infection. On the other hand, it is one of the strongest poisons for those who are under the influence of such an infection. Even before the infection has led to clearly recognizable lesions, and long before there are any symptoms of tubercular disease, and even if the most careful physical examination fails to discover a suspicion of tuberculosis during the entire lifetime of the individual, his peculiar susceptibility to this tuberculin injection shows that somewhere in his tissues or body fluids tubercle bacilli are producing their peculiar changes.
The nature of these changes is becoming somewhat clear to us since there have been discovered in the extra-vascular blood of tubercularly infected men and animals coagulation and agglutination phenomena which are entirely absent in the bloodof non-infected individuals. It appears that the activities of the tubercle bacilli in the body of the host excite the production of a soluble anti-body. When this anti-body comes into contact with the water-soluble substances derived from the tubercle bacilli, Koch’s tuberculin, it is transformed into an insoluble body. According to my own researches I believe it probable that this anti-body is formed by the smallest arterioles in the neighborhood of the infected area. The extent of the agglutination phenomena varies according to the amount of anti-body and of the tuberculin with which it comes into contact. This manifests itself clinically, by the degree of fever, and anatomically, by intravascular coagulations. The latter, in some cases may lead to exudations or to the escape of blood from the pathologically altered vessels. As a result of the tubercular poisoning, we would then have, at autopsy, the typical picture of a tuberculin reaction.
Tuberculin, in its action as a blood poison for an individual infected with tuberculosis, behaves like many other infectious poisons. Very small fractions of the amount sufficient to threaten life cause a distinct reaction. This is manifested by a rise of temperature preceded by a sharp fall. I know, through personal experience, of a case of human tuberculosis in which more than a hundred times the usual diagnostic dose of tuberculin was administered. But aside from several days of high feverand a considerable feeling of illness, it had no damaging influence on the patient’s general condition. Koch, the discoverer of tuberculin, once took a strong dose of tubercular poison in the form of dead tubercle bacilli and became very ill. In his case probably a hundredth of the amount would have sufficed to cause transient temperature changes and thus have demonstrated that he also had once been infected with tubercle bacilli. Ten years ago I myself reacted to a dose of 4 mg. with fever and a pronounced feeling of illness which confined me to my bed for several days in San Remo. Therefore I have no doubt about the tubercular infection of my body.
The most instructive evidence to confirm the general truth of Naegeli’s figures is furnished by the results of investigations made by the Austrian army surgeon, Dr. Franz, on soldiers of two regiments of infantry. In order to avoid injuring the health of the individuals tested, Franz used only very small doses of tuberculin, 1 to 3 mg., which, in case the injection was repeated, was increased to 5 mg. In spite of this, and in spite of the fact that the soldiers represented the healthiest individuals of the population, he found in one regiment in the first year of service (1901) 61%, and in the second year of service 68% of tubercularly infected cases. Franz adds to his report, which at present I have only in manuscript, that when he employed the dose originally recommended by Koch, namely onecentigram, his percentage for the twenty-first year of life approached Naegeli’s very closely, 96%!
On the other hand the Hungarian investigator Dr. Nikolaus Berend has not obtained a single positive tuberculin reaction in ninety-six very young children, in spite of the fact that among these were some very feeble individuals, and children of parents manifestly tubercular; and further, despite doses as high as 1 cg. We see then that herein also the statistics coincide with Naegeli’s post-mortem statistics.
Another proof that human tuberculosis is much more widely disseminated than was heretofore believed is furnished us by a diagnostic method devised by the French clinician André Jousset, namely “inoscopy.” By means of inoscopy we can examine microscopically, for tubercle bacilli, coagulable inflammatory exudates and the blood of suspected cases of tuberculosis, even though only very few bacilli are distributed in large amounts of fluid. And we examine these fluids directly, not indirectly by means of cultures. As a result of the coagulation the bacilli are fixed by the fibrin, from which they are freed by dissolving the fibrin with an appropriate digesting fluid.[3]The bacilliare then separated by centrifuge and can be examined directly in microscopical preparations. With the aid of this very valuable diagnostic method we are enabled to demonstrate the tubercular origin of almost all serous pleurisies, of many exudative peritonites, of accumulations of fluid in the peritoneal cavity of alcoholic individuals with liver cirrhosis, of joint inflammations, of exudative meningites, of many cases of heart-disease and of other classes of symptomatic affections, where formerly most physicians did not think of the possibility of these affections being tubercular.
I cannot fail to express my conviction of the general diffusion of tuberculosis in densely crowded populations, and of the consequent futility of all attempts to suppress the disease by means of isolation and segregation. What would be the outcome if we were to adopt the suggestion seriously put forth, to send all the tubercularly infected soldiers to hospitals, later discharging them as unfit for service? We should not have more than 5% left for active service, and even this small number would probably after the lapse of a few years be declared tuberculous. At the most I can assent only to the separation of the coughing consumptive from the apparently healthy individual; and these should be sent, not to sanitaria [Heilstätten], but to homestead colonies [Heimstätten] such as we formerly maintained for lepers.
We need not, however, idly fold our hands andbecome fatalists who see the inevitable destruction of the human race by tuberculosis.Tubercular infection does not by any means signify tubercular consumption.It is just this enormous diffusion of tubercular infection which demonstrates, better than anything else, the curability of many tubercular diseases, theirliability to spontaneous cure; for I must admit that I have little faith in the curative action of any of the numerous methods of treating tuberculosis. Here also the maxim formerly applied to diphtheria holds true, “mild cases go on to recovery, severe infections are fatal”; and here as in diphtheria I was confronted by the question whether there are ways and means to prevent severe infections with bad prognoses, or to convert severe infections into mild ones with favorable prognoses. You will be able to answer this question yourself if I now give you the results of my experimental investigations on the occurrence and prevention of tubercular consumption. I shall begin by discussing the requirements necessary for the development of tubercular consumption in man.
But first of all I must say that according to my ideas there has not yet been a single well-authenticated case in which pulmonary consumption has originated in adult persons as the result of a tubercular infection developing epidemiologically, i.e., under essential conditions for infection occurring in nature. Even counting those cases in which mortuary assistants, butchers, and laboratoryworkers have been severely infected through the subcutaneous tissues, I still fail to find any proof that a traumatic infection has caused pulmonary consumption in an individual not yet infected with tubercle bacilli.
I am well acquainted with the argument by which it is sought to prove that pulmonary consumption may develop as a result of inspiration of particles of dust or moisture containing tubercle bacilli. The facts on which this argument is based are the greater occurrence of tuberculosis and a higher mortality rate from that disease among nurses, occupants of houses in which there are pronounced cases of phthisis, among the inmates of prisons, etc. But, considering the figures previously given, showing the enormous diffusion of tuberculosis, the objection is surely justified that the persons thus dying of consumption already had a tubercular focus in the lungs and that this pulmonary disease, under a mode of life favorable to tuberculosis, was converted into florid phthisis.
In order not to be misunderstood, I wish to emphasize here that I do not at all deny that infection can be caused in adults by inoculation with tubercular virus. In fact, I assume that few of us in advanced life escape such infection. But that this infection leads to cavity formation in the lungs, is, I believe, fully as unproved as the assertion that bovine tubercular virus has caused human pulmonary consumption in even a single instance.Koch has very properly pointed out the entire absence of proof for this last statement. I can go still further in my concessions to the prevalent view that consumption results from the inhalation of particles of dust or moisture laden with tubercle bacilli. I concede not only the possibility but the actual occurrence of pulmonary tuberculosis going on to consumption, as a result of infection of an adult person. I concede this in the sense that on the basis of an infantile infection a pulmonary tuberculosis has developed which becomes manifest only through the agency of the additional infection. However, the opportunity for infection with tubercle bacilli cannot by itself be a deciding factor in the development of pulmonary consumption. I can here cite the experience of Dr. Moritz Schmidt of Frankfurt a. M., who has examined a great number of cases of tubercular laryngitis. In his experience of over forty years he has certainly been exposed, more than others, to tubercular infection. But neither he nor any of his numerous assistants has ever become consumptive.
My experiments on animals have shown me that the lesions characteristic of human pulmonary consumption are developed only after there have been extensive and long-continued disturbances of the vital functions of the organism. Our ancestors introduced the term “dyscrasia” and “diseased constitution” to express this idea. I have succeeded, especially in goats, but also in otheranimals, in producing a clinical picture exactly similar to that of human pulmonary consumption. In these animals I first produced a moderate degree of immunity against tuberculosis by a lengthy course of treatment, and then I injected a strong tubercular virus into the circulation. I regard the lesions in pulmonary consumption as being produced in similar fashion. They are the expression of an infection in an individual who, owing to a very early previous infection with tubercle bacilli, is less susceptible to the new infection. These late infections may in isolated cases be referable to the inhalation of tubercle bacilli. They may, however, be due to already existing tubercular lesions, and so be regarded as auto-infections or metastases.Were we to inject into the tissue juices of a person not yet partially immunized against tuberculosis an amount of tubercle bacilli equal to that usually found in the lungs of consumptives, the person would die of an acute miliary tuberculosis, but he would never develop pulmonary consumption.
There is another argument against the common assumption that primary infection by way of the respiratory organs is the cause of consumption, and this is furnished by an analysis of the anatomical findings. If we allow an individual, entirely free from tuberculosis, to breathe tubercle bacilli, the opportunity for an intestinal[4]infection is surelypresented; on the other hand, that any bacilli whatever reach the lungs directly cannot be positively affirmed. Infection of the organs of the pharynx and larynx in these cases always corresponds to disease of the lymph-vessels and glands in the neck, and gives the individual the scrofulous habitus. Now let us recall the neck of consumptives. It appears almost as if, at the time when an individual may be designated as being a candidate for consumption, the organs of the neck were already quite immune against a vulgar tubercular infection.
I could multiply the arguments in favor of my assertion that, in order to have pulmonary consumption follow infection with inspired tubercle bacilli, it is necessary to have constitutional changes in the organism due to an early previous infection. I hope, however, to have sufficiently established my reasons for rejecting the current theory of the origin of consumption, a theory due mainly to the valuable and detailed researches of Cornet.
I must decline to accept another wide-spread view, namely, that hereditary influences are deciding factors. Theoretically an intra-uterine infection with tuberculosis is certainly possible, and in a few cases such an infection has actually been proven. But neither the parental nor the pre-parental transmission of tubercle bacilli, nor the hypothetical transmission of a body predisposition to tuberculosis, is of any practical importance. Nevertheless, according to my researches, the view prevalentamong the laity regarding the important influence of parents, grandparents, and other near relatives, in the etiology of consumption, is entirely justified and proper. I, too, am of the opinion that one can properly speak of the bad prognosis in cases offamily tuberculosis. If, in taking the history of a patient, I should elicit the fact that several near relatives had died of consumption, and if, then, by means of the tuberculin reaction or of inoscopy, I made the clinical diagnosis of a tubercular infection, I should be very pessimistic in my prognosis, even though the infection were not otherwise manifest.
I may very properly be asked how I can deny hereditary transmission and yet place so high a rating on the influence of the ancestors, cognates, and house-fellows, in the production of pulmonary consumption. A little explanation regarding the meaning of certain terms will make my ideas perfectly clear.
The expressionhereditary transmission of tuberculosis, or rather,of tubercle bacilli, may be construed in several different ways. It may mean the hereditary transmission from father or mother, or from grandfather or grandmother, or from ancestors still further back. If we designate the parental transmission ascongenital heredity, transmission from further back aspregenital heredity, then in my view of the origin of pulmonary consumption, generally neither congenital nor pregenitalheredity comes into play. And, looking at the matter as I do, if one is still desirous of speaking of the hereditary influences of relatives, one ought to use the termpostgenital. It is now almost everywhere conceded that human tuberculosis as a rule is actually of postgenital origin.
Experience has taught me that if, in scientific investigation, one wishes to discover something new, one should study the exceptions to the rule. In actual practice, on the other hand, it is well to keep to the rule. We may therefore safely ignore the cases of congenital tuberculosis, but must all the more thoroughly study the circumstances which in extra-uterine life govern the tubercular infections which lead to consumption. And here I believe I have discovered a new principle which may be expressed thus:
“The milk fed to infants is the chief cause of consumption.”
This assertion will at first sight be surprising, for it has long been maintained that the suckling infant receives milk free or almost free from germs. Mother’s or nurse’s milk is taken by the child in this condition, and the cow’s milk for artificially nourished children is usually first boiled or scalded. In later life, to be sure, much less attention is paid to securing a milk as sterile as possible. How, then, is this to be reconciled with the above statement, that it is especially themilk fed to infantswhich constitutes the chief danger in causing tuberculosis?
And yet this statement is true, not because the milk fed to infants is at all worse than other milk, but because the human infant, like the young of all other mammals, is destitute of the protective agencies in his alimentary system which at a later period of life prevent the entrance of disease germs into his tissues. It has taken many years of experimental work to demonstrate this fact conclusively. At present, however, the chain of evidence is so strong that I have not the least hesitancy in building on it my entire plan for the suppression of tuberculosis.
In this lecture I can do no more than summarize the main proofs for my assertion regarding the ready penetrability of the infantile alimentary tract for all disease germs, but especially for tubercle bacilli.
I began with a very interesting fact discovered by my fellow-worker, Dr. Römer. He showed that true albumins penetrate unchanged the intestinal mucous membrane of new-born foals, calves, and smaller laboratory animals, and that they produce the same action on the organism as when they are injected directly into the circulation. In adult animals of all species, on the contrary, the true albumins must first be digested into peptones before they can pass through the mucous membrane. The anti-diphtheria serum and the anti-tetanus serum contain curative substances in the form of true albumins. If such a serum be introduced into the stomach of a healthy, full-grownanimal or man, not a trace of these bodies passes into the blood. On introducing the serum, however, into the stomach of the new-born, the unchanged antitoxic albumin can almost entirely be demonstrated in the blood. This discovery indicates that the mucous membrane of adults, acting as a dialyzing membrane, does not allow the large molecules of true albumins to pass through unchanged, whereas the mucous membrane of sucklings behaves more like a very porous filter.
It was but a step from this discovery to the assumption that the mucous membrane of infants might behave similarly toward bacteria. For my first experiments I selected anthrax bacilli, which, when free from spores and given in milk per stomach, do not affect adult guinea pigs at all. They are quite rapidly thrown off with the excreta, remaining, however, a little longer in the cæcum. When the same dose of bacilli was administered in this way to guinea-pigs less than eight days old, they died just as rapidly of anthrax as by the customary method of infection. Next I tried anthrax bacilli whose virulence had been reduced. These are harmless when injected subcutaneously into guinea-pigs.After feeding these weakened bacilli to new-born guinea-pigs, the blood of the animals contained anthrax bacilli, though the animals did not die. Incidentally, a fact of considerable theoretical importance was discovered: that the anthrax bacillipossess a very intimate affinity for the endothelium of the heart and blood vessels.
Having thus studied the fate of anthrax bacilli introduced into the stomach of new-born and adult guinea-pigs, I now turned to a similar study of tubercle bacilli. Together with Dr. Römer I studied the behavior of guinea-pigs toward a definitely weighed quantity of tubercle bacilli given inone single feeding. And here also, as in the case of anthrax bacilli, it was found that when the tubercle bacilli could be demonstrated microscopically nowhere else in the alimentary tract, they were often present in the cæcum. After a single feeding of a small quantity of tubercle bacilli, only the new-born or the few-days-old guinea-pigs became tuberculous. When larger doses were administered it happened that older animals also became tuberculous. At the post-mortem examination of the new-born, a few days later, there were found submiliary thickenings, with tubercle bacilli in the great and the lesser omentum. There were also little nodules at a point on the root of the mesentery, not far from the cæcum. Of especial interest is the further development of this alimentary tuberculosis in the guinea-pigs which survived. In these animals, even while their general health remains good, it is always possible to demonstrate a tuberculosis of the glands of the neck, a type of disease which may be said to correspond to scrofula in man. Not infrequently there is later ondeveloped that type of guinea-pig tuberculosis which has heretofore been regarded as the expression of an inhalation tuberculosis.
In the results of all these investigations I see experimental support for the view I have for some time maintained, namely, that the origin of the epidemiological pulmonary tuberculosis in man and that of the epizootic pulmonary tuberculosis in cattle is a primary intestinal infection occurring in very early infancy. In this I leave undecided whether the bacilli gain access to the body through feeding or through inspiration.
Upon reflection it will at once be seen that from these experimental data showing the ready penetrability of the infantile mucous membrane, another logical deduction follows: If even non-virulent anthrax bacilli introduced per stomach gain ready access to the circulation of the new-born, then it must be possible for all the bacteria of milk to do the same, and we may therefore expect that the accidental presence of pathogenic bacteria in the milk fed to infants will exercise a damaging influence on the infant organism. In considering their pathogenic possibilities the amount of the infectious germs which enter the system must, of course, be a matter of some importance. Under certain conditions, however, even a few germs may be sufficient to excite disease, for in the intestines, especially in the cæcum, they find an excellent place of incubation wherethey can multiply. A milk very poor in disease germs may thus lead to a virulent infection. In breast-fed infants the danger of introducing disease germs, excepting tubercle bacilli, of which I shall speak later, is not very great, for it is very unusual for living germs derived from the interior of the body to appear in the milk. The germs which can be found, even in perfectly fresh milk, are derived from the surface of the body, or from the mouths of the lacteals, or possibly even from the glandular epithelium, as researches conducted by myself, assisted by Mr. Rösler, have shown.
But inartificially nourished infantsthe matter is altogether different. It would be a miracle if, after all the manipulations to which the milk supplied to our large cities is subjected, it did not occasionally contain disease germs derived from the milker or from other persons who have handled the milk.
If, by the time the milk reaches the city, the proliferation of these pathogenic micro-organisms has already gone on to a considerable extent, then usually the milk will contain a number of poisonous substances in addition to the micro-organisms. Some of these germs are killed by the scalding to which the milk is usually subjected before feeding, and the virulence of the rest is much diminished, so that in boiled milk practically no danger is to be apprehended from the micro-organisms. We are not at all sure, however,that we have made the toxins innocuous by this boiling, and probably a great many cases of intestinal catarrh in artificially nourished children are due, not to a parasitic, but to a toxic infection.
I said it would be a miracle if artificially nourished infants did not frequently suffer from milk infections, and I can add that this miracle does not, in fact, occur. One need only glance at the mortality statistics of artificially nourished infants in order to realize that my experimental results absolutely agree with the facts. The following figures are taken from the excellent report, “Gesundheitswesen des preussischen Staates im Jahre 1901,” which has recently been published by the Prussian government.
In the city of Stettin, the mortality for the first year of life was 473.52 for every 1000 living children of the same age; whereas in the period of 10 to 15 years the mortality was 2.94 to each 1000 living children of that age. In other words,during the same length of time 161 times as many infants up to one year died as did children over ten years.
Berlin, with a mortality of 286.29⁰⁄₀₀ for the first year of life, stands about midway in the list of Prussian cities having over 100,000 population. Cassel, with 183.54⁰⁄₀₀, shows about the lowest figure, and even this is inordinately high, for it is not in the nature of things that this is so. We are not facing a necessity of nature to which we must submit like fatalists. This can be readily seen byobserving that there are towns and whole regions in which the mortality figures for the first year are kept within moderate limits. In Ireland and Scotland, as well as in Norway and Sweden, the mortality for this period scarcely exceeds 10⁰⁄₀₀, about one-fiftieth the mortality in Stettin. In Stockholm I visited a foundling asylum with an organization bound to excite admiration and wonder, in which, as I recollect, the mortality was still less.
Nowadays the assertion that the character of the milk fed to infants is responsible for the great differences in the mortality statistics is nowhere seriously questioned. There are, however, wide differences of opinion as to what the determining factors are, and how, in places where the mortality figures are so outrageously high, we can remedy the evil.
According to my researches into this subject this problem will not be successfully solved by the efforts now being made to secure the use of sterilized milk. I am, in fact, in doubt whether milk sterilization as at present practised can much longer pass as a hygienic measure. For the present, to be sure, we have nothing better. But the discussion of this question does not fall within the scope of this lecture. I have quoted the statistics of the high infant mortality in our large cities merely in order to advance a further epidemiological argument for my assertion that the infant alimentary tract is defenseless against infectious agents whether theseare living or not. Even the infectious toxins pass unchanged through the intestinal mucous membrane of very young individuals, though not through that of healthy older ones. A real advance in milk hygiene can, however, be begun even now if the milk be pasteurized at the dairies and not at the large receiving-stations in the cities. In the raising of calves, this procedure has proven of great value.
I have made exhaustive studies to discover why the intestinal mucous membrane of the young should offer so little resistance to the passage of corpuscular infectious substances. I shall content myself here with the statement that the mucous membrane of new-born individuals possesses no continuous epithelial covering and that the gland-tubes of the ferment-producing glands are little, if at all, developed at this time.
By having thus presented to you the results of my experiments and explained my epidemiological views, I have not really deviated from the subject of the suppression of tuberculosis. We have seen that the tubercle bacilli which gain access to the system through the alimentary tract in infancy constitute the important etiological factor in the production of the tubercular infection which leads to consumption, and I believe that the realization of this great fact will supply us with a rational plan for combating tuberculosis. It will be necessary to strive more than ever to secure a suitable milk diet for new-born and very young children,one based on sound experimental investigations. The as yet unsolved problem, that of a rational milk hygiene in the suppression of tuberculosis, coincides with the problem of milk-feeding of infants in general. The mode of infection is everywhere the same, but the infectious agents are of great variety. Most of them excite acute diseases which end either fatally or in entire recovery; in the latter case with a simultaneous development of immunity. The virus of tuberculosis, however, behaves quite differently, creeping in most insidiously, all unnoticed, and being in this respect analogous only to the virus of leprosy, of syphilis, or possibly of malaria in tropical countries. It may be months, years, or decades before the infection leads to manifest disease. This depends on the virulence of the virus, which is generally much greater in the virus of bovine tuberculosis than in that of human tuberculosis. It also depends on the number of bacilli introduced per stomach, and whether such introduction is single or oft repeated. In the human being months and years may elapse before the infection is followed by any sensitiveness to tuberculin injections in the usual dose. If, then, at the time of puberty, or after an exhausting puerperium, after too great a demand on the milk secretion (especially with insufficient food), after so-called colds and other unfavorable meteorological conditions, after muscular over-exertion, under conditions unfavorable to life, suchas improper nourishment, confinement in insufficiently or badly ventilated rooms, etc., if, after any of these, pulmonary disease develops whose tubercular nature we cannot doubt, then we are dealing with thebeginning of consumption; thebeginning of tubercular lesionsis much further back; and the first introduction of the disease germs, in other words, thebeginning of the infection, is far back in earliest infancy. This must be so, for we see many individuals, though subject to the most unfavorable conditions, for example, those confined in unsanitary prisons, wholly escape tuberculosis.
The results of all these scientific investigations lead us back to the old folk belief in family tuberculosis and hereditary consumption, with this difference, however, that now we believe the germs of consumption to be transmittedpostgenitallyfrom parents, relatives, or house-companions. If a coughing consumptive lives together with a new-born child, especially if cleanliness leaves much to be desired, it is impossible for this child to avoid infection with tubercle bacilli. They are present in the particles of sputum which are scattered about everywhere, and they thus gain access to the mouth and nose of the infant. From there they reach the intestinal mucous membrane, which they penetrate, and so they invade the body juices. Not alone infants, but older persons as well, are endangered in the home of the consumptive. Inthese, however, there must previously have been pathological changes in the alimentary tract, or an overwhelming dose of the infectious agent, in order to effect an intestinal infection. Pathological changes, accompanied by the shedding of epithelium, occur especially in the exanthemata, and particularly after measles. The laity has long noticed this close relation between measles and tuberculosis. In the infant, the disposition to intestinal tubercular infection is entirely physiological and normal. The healthiest and strongest infant is exposed fully as much as the weak, sickly one, and perhaps more so, for in the latter other parasites are contending for the cells on which they feed.
I have now given you a general idea of the origin and spread of the tubercular infections ending disastrously. This brings us at once to certain practical points in dietetic hygiene which, though never entirely neglected, are now brought into prominence.
It is unnecessary for me to further emphasize the necessity, in infant feeding, to insist under all circumstances on milk absolutely free from tubercle bacilli; nor, what is equally obvious, that it is absolutely necessary to keep coughing consumptives away from infants. But I should like to observe that not only infants but also older persons should be protected against the possibility of infection, if we have any reason to fear that thealimentary tract is anywhere deficient in its protective epithelial covering. I have already pointed out the importance of the exanthemata in this respect, and I need only remind you of the many other disturbances associated with the shedding of epithelium, disturbances due to catching cold, to indigestion, or the after-effects of certain diseases associated with intestinal ulceration, etc. There is one other condition which I must not fail to mention, namely, the temporary exacerbations of a tubercular process, in which one cannot be too careful in ordering the diet. For that large class of individuals threatened with consumption, I believe we have a valuable healing agent in the dietetic therapy made prominent during the past decade, especially by von Leyden and his pupils. In the same sense we must regard the temporary residence of tuberculous individuals in sanitaria as most valuable, for even if the lesions do not heal there, the progressive downward course of the disease is checked and the patients learn for the rest of their lives to appreciate what will benefit and what will harm them. In many cases, therefore, these sanitaria will prove themselves homes for the prevention of consumption, even if they are not homes for the cure of tuberculosis.
My own efforts in the field of tubercular therapeutics do not, to be sure, concern themselves with sanitarium treatment.Their last aim is to make all homes for the prevention of consumption, all sanitaria,etc., unnecessary by means of a protective agent similar to that by which Jenner made smallpox pest-houses unnecessary.Institutions for persons bodily wrecked are like those for persons morally wrecked; they are products of our civilization, but not desirable products. At best they are necessary evils.