FOUNDERS OF OUR KNOWLEDGE

INT J TUBERC LUNG DIS 19(3):256–266 Q 2015 The Union http://dx.doi.org/10.5588/ijtld.06.0636-v

On the virulence and specificity of tuberculosis ´ ´ Read at the Academie de Medecine on 8 August 1868 Dr J. A. Villemin ˆ Professor at the Ecole du Val-de-Grace, Paris, France

SIRS, The unexpected discovery that led me to carry out my studies and research on tuberculosis has serendipitously given rise, within this Academy, to one of the most brilliant and, undoubtedly, fertile discussions: indeed, the repercussions that it has had outside the confines of this institution will provoke, both in France and abroad, numerous experiments that will soon completely dissipate the remaining doubts in some minds concerning the very fact of inoculation, whilst the objections against the virulence and specificity of tuberculosis formulated in this building will identify the contentious issues in this question of doctrine, by defining them. As for me, the person whose works have the honour of having instigated these debates, whilst the subject remains fresh in the minds of all, I come, with a profound sentiment of respect and gratitude, to request the Academy to allow me to examine, in a few words, the diverse sorts of difficulties that bring inoculation with tuberculosis into opposition with its virulence and, consequently, its specificity. Let us first specify the experimental finding at the source of all these discussions. If one shaves a narrow area on the ear of a rabbit or at the groin or on the chest under the elbow of a dog, and then creates a subcutaneous wound so small and so shallow that it does not yield the slightest drop of blood, and then one introduces into this wound, such that it cannot escape, a pinhead-sized packet of tuberculous material obtained from a man, a cow or a rabbit that has already been rendered tuberculous; or if, alternatively, one uses a Pravaz syringe to instil, under the skin of the animal, a few droplets of sputum from a patient with phthisis, rendered more liquid by mixing with a little water, the following is observed: The day after the operation, even the most attentive palpitation reveals no further trace of the inoculated material, and the edges of the wound are agglutinated. Then, after four or five more days, a slight Excerpt from the Gazette hebdomadaire de medecine et de ´ chirurgie. Translated from Villemin J A. De la virulence et de la specificit e´ ´ de la tuberculose. Paris, France: Masson, 1868. Translated by Julie Sappa and Alex Edelman, from Alex Edelman and Associates. Edited by Clare Pierard and Hans Rieder.

swelling is observed, accompanied in some cases by redness and warmth, and one observes the progressive development of a local tubercle of a size between that of a hemp seed and that of a cobnut. When they reach a certain volume, these tubercles generally ulcerate. In some cases, there is an inflammatory reaction, which dissipates or gives rise to slight suppuration. When these animals are autopsied, the tubercles at the site of inoculation can be observed to consist of a caseous mass, around which one often observes small yellowish granulations, in some cases infiltrating some distance into the intermuscular connective tissue. The lymph nodes communicating with the inoculation wounds often swell, becoming covered with scattered grains or tuberculous nodules, sometimes even leading to a complete caseous transformation. Finally, in some cases, one also observes an alteration to the lymph vessel linking the nodes to the local tubercles; the walls of this vessel thicken and are transformed into tuberculous tissues, and its lumen narrows at the points infiltrated by granulations. The lymph, hindered in its course, is subject to inspissation, and the vessel thus forms a solid cord, analogous to those present quite frequently in the lymphatic cavities of phthisis patients when they have tubercles or tuberculous ulcerations in the intestinal mucosa. This alteration is highly reminiscent of the farcinous cords in horses with glanders, and we will see later that experimentation has confirmed this analogy. During the initial period after inoculation, the animals present no appreciable change in health. Only after 15, 20 or 30 days does it become evident that they are losing weight, and have lost their appetite, gaiety and vivacity of movement. Some, after going into decline for a certain period, regain some weight. Others gradually weaken, falling into the doldrums, often suffering from debilitating diarrhoea, finally succumbing to their illness in a state of emaciation. We therefore fail to understand why it has been claimed that experimental tuberculosis probably does not progress like the human disease and that, by sacrificing the animals, it is not possible to affirm that the disease would have led to death, leaving room for doubts about the nature of the lesions following

On the virulence and specificity of tuberculosis

257

inoculation. If one considers the experiments that we have described, together with those of several other observers, one can see that the inoculated animals can be divided into two groups. The first comprises those that succumbed as a direct result of phthisis, and in a degree of low spirits, justifying the name of this illness. Death may be explained by asphyxia due to the countless tubercles infiltrating the lungs and the cavities formed, by digestive problems resulting from the tuberculisation of the mesenteric nodes and intestine, by intestinal haemorrhages resulting from tuberculous ulcers, by the dissemination of tubercles to all organs or by the consumption specific to this disease. There are here, I believe, an entire series of fatal terminations imprinting the stamp of spontaneous tuberculosis, as observed in men, on experimental tuberculosis. As for the second group, comprising animals that are sacrificed, one may indeed ask if a certain number of these animals would not have succumbed later in any case had they been left to live. That would appear most likely. Some might also have been cured, which is in no way contrary to what we know about tuberculosis. Even if cure was found to be more frequent in animals than in men, would this constitute a radically different character of the illness? Besides, and furthermore, must we not also take into account the cases in which inoculation did not succeed, a situation that, as in all inoculated diseases, is observed in a certain number of instances? Yes, we believe that we are in a position to affirm that inoculated tuberculosis runs the same course and has the same ending as human phthisis. Like the human disease, it occurs with all degrees of intensity, from acute generalised eruptions, leading to the rapid demise of the subject, to these examples of more discreet tuberculosis of indeterminate duration. On autopsy of the animals that succumb or are sacrificed, the presence of tubercles in the lungs can generally be noted. The law of Monsieur Louis* is quite constant. Among the already considerable number of inoculations that we have carried out, we have found only five or six exceptions in favour of lymphatic and intestinal ganglia. The pulmonary tubercles occur in all sizes, from the finest granulations to infiltrating masses occupying a large proportion of the organ. The tuberculous eruption is not limited to the lungs; it is abundant to various degrees in the lymphatic ganglia, intestine, liver, spleen, kidneys, etc. Very often, these organs are full of tubercles. The serous membranes, particularly the omentum and mesentery, are sometimes riddled with countless granulations. Depending on the time elapsed since inoculation and the speed at which the

eruption occurs, one finds transparent grey, yellow caseous, soft tubercles, with cavities and ulcerations. If the animals are sacrificed before the fifteenth day, tubercles are rarely observed in the organs. Between the time of inoculation and that of the tuberculous eruption, there is a lapse of time which we have found to vary between about ten and twenty days. The inoculation of rabbits is generally successful. We can say that, in our hands, results are obtained in about eight in ten cases. In dogs, it appears to be successful less frequently. As most of our experiments have been performed on rabbits, for reasons that can readily be surmised, the objection has been raised that what we have considered to be a consequence of inoculation might actually be no more than a coincidence, the rabbit being reputed to be abundantly tuberculous. This assertion is absolutely contrary to everyday observations; despite routine sequestration and the tortures that the vivisectionists force them to endure, rabbits are almost never tuberculous. I have explored more than a hundred lungs from these rodents from markets and I found none to be tuberculous. The notion of the high frequency of tuberculosis in rabbits is an error that has been transmitted by word of mouth; it gained considerable credibility from Dupuy,† who took the white, sometimes chalky, material present in the cystic pockets of the peritoneum to be tubercles, together with the transparent or caseous nodules of the liver, in the middle of which one finds oviform or cysticerci (Dupuy, De l’affection tuberculeuse, etc., Paris, 1817). I call, with the most absolute confidence, on support from the testimony of physiologists. At the start of my experiments, I also shared this prejudice; furthermore, to protect myself from the objections to which it gave rise, I set up parallel and comparative series of animals between which origin, age, habitat conditions and food, everything indeed other than inoculation, were identical. We have seen that the tuberculous material deposited under the skin contaminates the surrounding tissues and the pathways it follows. It provokes the formation of tubercles in the subcutaneous cellular tissue, in the walls of lymph vessels, in the ganglia and throughout the bodily system. However, as the development of tubercles in the splanchnic‡ organs appeared to us to occur after the occurrence of local phenomena and to arise only a certain number of days after the insertion of the tuberculous material, we compared this period of apparent silence with that known as incubation for virulent diseases. We then asked ourselves this question, which is often applied to syphilis, that is, is the local tubercle not, like the

* Editor’s note (EN): Pierre Louis (1787–1872), known for his development of the ‘numerical method’, precursor to epidemiology and the modern clinical trial.

† EN: Alexis Casimir Dupuy (1775–1849), French veterinarian, professor of botany, pharmaceutical chemistry and medicine. ‡ EN: viscera.

258

The International Journal of Tuberculosis and Lung Disease

chancre, a primary phenomenon leading to subsequent events? Against these facts and our interpretation of them, different views and conceptions have been opposed. The development of a local lesion has been denied and it has been claimed that the tuberculous mass found at the inoculation site is a relic of the inoculated material and that this material, passing slowly through the lymphatic system, only arrives in the lungs after several weeks. It has also been claimed that we were wrong to call the time taken for it to reach its destination ‘incubation’. As a consequence of this explanation, the tubercles developing in the organs have been considered to consist mostly of the inoculated material, transported mechanically and in substance, and it has been asserted that tuberculisation is proportional to the quantity of tuberculous material deposited under the skin. However, we do not believe that this way of seeing things conforms to the observed facts. When one introduces into a wound the volume of a pinhead, or even of a hemp seed, of tuberculous material and one finds, after two months, at the same site, a mass the size of a cobnut, one evidently cannot regard this mass to be the remains of the material deposited there. When one injects hypodermically a few drops of sputum diluted in water or defibrinated blood and one observes, in the cellular tissue into which these liquids have been instilled, granulations and tuberculous masses, one cannot accept that these are the relics of the substances inoculated. Must one also believe that this blood serum, these sputum droplets, have taken twenty to thirty days to travel throughout the lymph system? No, these liquids are absorbed almost immediately, and the tuberculous material itself does not remain for long in the wound; the next day, it is no longer perceptible. The tubercles found later in the cellular tissue, in the walls of the lymph vessels and in the nodes are the product of a new formation; they do not represent the inoculated material, which in some cases they exceed a hundred times in volume. This applies even more strongly to those of the internal organs, the abundance of which is sometimes such that certain viscera become little more than a tuberculous mass. Led by our studies to the idea that tuberculosis was a specific disease, and wishing to test the hypothesis of its inoculability, we sought, based on first principles, to create the conditions of all true inoculations, that is: a very small wound and a very small amount of substance inoculated. We never departed from this method of doing things, and all our inoculations were practised with a portion of tuberculous material varying in size from that of a pinhead to that of a hemp grain at most. Despite this constant uniformity in the procedure and in the volume of substance inoculated, we nevertheless obtained tuberculisations that were extremely

variable in intensity and generalisation. All degrees were observed, from sparse granulations to appalling dissemination in which almost all the organs were full of the pathological product specific to tuberculosis: providing clear proof that the intensity of tuberculisation is completely independent of the amount of substance used for inoculation. The question of quantity does not appear to us to apply to inoculations with blood, for which success seems to require the use of a certain volume of this liquid, consistent with what we know about other specific diseases, such as syphilis in particular. It was also based on the lesions of lymph nodes and vessels in the vicinity of the inoculation site that attempts were made to explain the formation of tubercles in the organs through a sort of close-range propagation of local tubercles. However, these tubercles are very often extremely small, and the alteration of ganglia and of lymph vessels, in particular, is far from constant. In subjects with abundant tuberculisation of the viscera, one frequently finds lymph vessels displaying no alteration and the tubercle at the inoculation site is very rudimentary. The number and extent of the internal lesions are not at all related to the development of lesions at the injection site. Besides, progressive development would suppose an absence of interruption between the sites of arrival and departure and would demand a trail impossible even to imagine, linking the point of inoculation to the lungs, spleen, kidneys, peritoneum, etc. The tuberculisation of the ganglia next to the inoculation site is hardly surprising. In animals, as in man, the cause of tuberculosis has a clear affinity for the lymphatic system, and one often finds that the ganglia that cannot have been touched by the direct passage of the inoculated substance, including the mesenteric ganglia, are completely tuberculous. Otherwise, things occur in a very similar manner in inoculations of syphilis and glanders. It is therefore wrong, in our opinion, to have used this explanation to raise the well-known result of tattooing. We know that individuals bearing indelible drawings of various colours on their arms have axillary ganglia that are coloured and penetrated by the mineral substances used. As experiments have shown that the pigmented matter of a melanin tumour and even of the normal choroid behaves like the colours of a tattoo, this has been used as an example to explain what happens during inoculation with a tubercle. However, we think that a fragment of tuberculous material the size of a grain of millet, which, on introduction under the skin, leads to wasting and death within a few months, after filling all the organs with tubercles, does not constitute a phenomenon similar to the penetration of the tissues by a coloured substance, because otherwise it would

On the virulence and specificity of tuberculosis

also be necessary to consider the impregnation of bones with madder in the same light. Attempts have also been made to explain the transmission of the tubercle in terms of grafting. But how could grafting account for the myriad of tuberculous granulations scattered throughout the parenchymatous and serous organs? Grafted tissues continue to live and to develop at the site at which they are deposited, but they do not reproduce within the body. The insertion of the periosteum under the skin has never given rise to bones in the lungs, kidneys or peritoneum. This theory could, at most, explain the development of the tubercle located at the injection site, but even then it would require the tuberculous material used for the inoculation to be composed of elements endowed with a very active life. Now, if one takes some of the soft substance from the centre of the tubercle, it no longer contains figured elements, only detritus is used for the inoculation. How can we suppose, amongst other things, that the tubercle provided by a cadaver devoid of life for thirty six hours would be likely to come back to life and to proliferate with this activity that directs a tuberculous eruption? How can grafting explain inoculation with sputum, and particularly with sputum droplets dried for twenty days, as achieved in our entirely novel experiments? Does this not prove that the inoculated matter acts through a principle independent of the histological elements of which it is composed? The supposition that these elements are carried in the lymphatic system, subsequently becoming implanted, living and multiplying in different regions of the body, is tantamount to gratuitously according them, against the laws of physiology, the possibility of crossing the ganglia, attributing the soft caseous matter a living form that it no longer has, and ceding to this morbid, dissociated product and to sputum and blood serum, an imaginary life. When we used tubercles from humans for inoculation, it was suggested that the effects obtained were a cadaveric phenomenon; when we used fresh tubercles from recently killed animals, a grafting effect was suggested. Finally, should we consider the entire chain of phenomena observed in experimental tuberculosis as the result of a traumatism due to inoculation? This is an enigma that we cannot resolve. A simple incision into the skin with the point of a narrow bistoury blade, without effusion of blood, the prick of the tiny, narrowed point of a Pravaz syringe, are such light wounds that very few animals can have escaped accidental lesions of such a small scale during the course of their lives. It has been asked whether the lesions produced in the viscera following inoculation with tuberculous matter are veritable tubercles. This doubt, which was initially entirely legitimate, is hardly permissible today, after so many histologists have confirmed the

259

absolute identity between the tubercles of inoculated animals and of man. Not only can neither the naked eye nor the microscope find any difference between these two pathological products, but, providing, in itself, an irrefutable proof of much greater value than microscopic examination, inoculation with tubercles from experimentation reproduces tuberculosis like that obtained with tubercles from humans. It is not that one does not find sometimes in humans, and especially frequently in animals, an entire category of lesions bearing a strong resemblance to the anatomical manifestations of tuberculosis. They are represented by small grey, transparent, yellowish white, caseous nodules or by masses of various extents and similar appearance. These lesions originate from plant or animal parasites. We have considered elsewhere all the ramifications pertaining to this issue (Villemin, Etudes sur la tuberculose, Paris, 1868, p. 478). These lesions often bear such a striking resemblance to those of tuberculosis that observers have long suggested that this disease might begin with these parasites (Jenner, Dupuy, Baron, Kuhn ¨ §). This opinion has never garnered much support but, by confusing parasitic pseudotubercles with the true tubercles of phthisis, the tuberculosis of animals has been rendered obscure. We are persuaded that, in this question of inoculability, several errors have slipped into the experimental findings, due to the presence of parasites. The confusion between the spontaneous development of diverse alterations of tuberculous appearance extends to lesions provoked by experimentation. Thus, attempts have been made to describe the effects of tubercle inoculation as being identical to those of the injection, into the bronchi and veins, of dust, mercury, fat, irritant substances of various sorts, or even pus. In this way, the inoculability and specificity of tuberculosis have been opposed by arguments derived from experiments involving nothing comparable to inoculation, in their mode of execution, their pathogenic action or their final result. When foreign substances, such as those we have just listed, are injected into the veins, one observes in the lungs a process that appears to be more or less analogous to that of the tubercle, the mechanism of which is easy to explain. These bodies, which enter the circulation immediately, make their way to the right heart and are then projected into the lung, where they give rise, according to the calibre of the obstructed vessels, to embolic infarcts, pneumonic nuclei or small irritant processes circumscribed like the foreign bodies themselves. At the start of their formation, these processes consist of young connec§ EN: Edward Jenner (1749–1823), English scientist and physician, notable for being the pioneer of the smallpox vaccine. John Baron (1786–1851), English physician, and Jenner’s biographer. Jean Kuhn (1802–1868), Alsatian physician.

260

The International Journal of Tuberculosis and Lung Disease

tive tissue rich in cellular elements, strongly resembling that of the tubercle. This is, essentially, what the Germans have called granulation tissue. It leads either to the creation of small purulent foci, or, frequently, to a small, fibrous, grey transparent nodule representing an islet of cirrhotic, interstitial pneumonia. It is in the heart of these pseudotubercles that one finds the irritant substance, which if solid is encysted. The same thing happens there as happens everywhere, in all tissues, if there is a foreign body. One sometimes finds similar nodules in the lungs of game animals, but these nodules are much more voluminous, forming an envelope around the small grains of lost lead that are not responsible for the death of the animal. However, these lesions never become generalised, and their number corresponds to the number of powdery particles that become lodged in the organs; they are formed by a mechanism similar to that of the tubercles caused by intestinal worms. Grains of dust, mercury, etc., provoke the same inflammatory processes around themselves as the microscopic larva of these helminths that one finds so frequently in certain animals. Do these alterations have the slightest relationship to those of tuberculosis? Can one compare the injection of powdery, irritant, obstructive substances into the bloodstream with an inoculation, that is, the introduction of a minimal amount of tuberculous substance into a wound so small and so shallow that it rarely yields the smallest droplet of blood? If we had just announced that we had generated tubercles by injecting tuberculous material into the vessels of our animals, our assertion would not have merited the honour of a debate at the heart of this learned society; our findings would not have been novel, because the results of such experiments have long been known. They have been reproduced by all those who have studied the question of embolism experimentally: Virchow, Panum, Cornil and Trasbot, Damaschino, etc.|| Billroth, whilst trying to transmit cancer by injecting tumour detritus into the veins, twice found small nodules in the lungs of his animals, but he refrained from referring to them as cancerous or tuberculous products, despite their reasonably strong resemblance to such products. He interpreted these formations just as he should. ‘We find in the lungs,’ he said, ‘some small nodules the size of a pinhead, containing fibres of connective tissue (relics of pulmonary embolisms).’ (Billroth, in the Gazette hebdomadaire, 1867, p. 747). || EN: Rudolf Virchow (1821–1902), German anthroplogist, pathologist and biologist. Peter Ludwig Panum (1820–1885), Danish physiologist and pathologist. Andr e´ -Victor Cornil (1837–1908), French histologist, pathologist and politician. Laurent L e´ opold Trasbot (1838–1904), French veterinary pathologist. Fran c¸ ois Th e´ odore Damaschino (1840–1889), French pathologist. Theodore Billroth (1829–1894), Prussianborn Austrian surgeon.

The injection of foreign bodies into the veins does indeed give rise to pseudotubercles in the lungs, but these lesions are not found elsewhere. Nevertheless, very fine dusts or irritant liquids may cross the lung capillaries and make their way into the general circulation. However, I am not aware that this has been reported to occur for any substance other than pus. Completely different results are obtained for tubercle inoculation; the appearance of certain omenta riddled with myriad granulations following inoculation should be sufficient to sweep away the doubts of the most obstinate. However, as the singular property of being able to generate a lesion that differs in no way from tuberculosis has been attributed to these foreign bodies, it should be pointed out that if one inoculates these dusts, granules of mercury, fats, etc., in small quantities, as we do for tubercles, they never provoke a morbid dissemination, tuberculous in nature, within the body. It is also based on the effects of the injection of pus into the veins and the supposed migration of a large quantity of the inoculated substance, presumed to be found throughout the body, that tubercle inoculation has been compared to purulent infection. We do not believe that it is necessary to counter this objection formally. The resorption of pus, with its lesions and symptoms, is one thing; tuberculosis, with its progression and particular process, is another. Nevertheless, it should be borne in mind that small, purulent, metastatic foci in the lungs, liver and kidneys have sometimes been mistaken for tubercles. Pus injected into the vessels acts in two ways: it behaves, on the one hand, like an irritant substance, provoking the formation of small inflammatory foci, as indicated by cell proliferation leading to suppuration or the creation of fibrous nodules. On the other hand, it acts like embolic dusts, provoking the accumulation of globules in the blood capillaries. It is now possible to infer the meaning of two experiments carried out by Monsieur Lebert in 1851,# which have been used to oppose our work. The pseudotubercles obtained after repeated injections of pus into the vessels were, as stated by M. Lebert himself, a truly exceptional result among the many experiments of this type, and were accompanied by accentuated symptoms of purulent infection. Clearly, no question has preoccupied doctors more than that of purulent infection. For many years, almost all the observers that have written on this subject, of which there have been a substantial number, have tried to support their views through experimentation. Hundreds of animals have under# EN: Hermann Lebert (1813–1878), German naturalist and physician. Traite´ pratique des maladies cancereuses. Paris, ´ France: Baillie` re, 1851. [Practical treatise on cancerous diseases.]

On the virulence and specificity of tuberculosis

gone inoculation and injections with pus of all kinds, and these treatments have never been shown to provoke tubercles or tuberculosis. If such an important event had taken place, it would certainly not have passed unnoticed. Nevertheless, it would not be impossible for pus collected from a patient with phthisis to give rise to tubercles, because this result has already been obtained with sputum and blood from such subjects. The importance of this cannot be stressed too strongly, because it could account for certain divergences. We would recommend adhering to the use of pure and simple inoculation with the morbid product and abstaining from the use of injections into vessels, the effects of which inevitably give rise, as we have just seen, to ambiguous interpretation. From the above, is it not clearly evident that experimentation reproduces two types of lesions, corresponding to those occurring in the natural state? On the one hand, true tubercles generated by inoculation with tuberculous material, on the other, pseudotubercles generated by the injection of irritant bodies into the bronchi and veins. Confusing these two groups of facts would be like wanting, on the basis of distant analogies, to identify the pustules generated by friction with antimony with those of smallpox, or redness due to rough brushing of the skin with a scarlatina rash. ‘But how can the tubercle be considered as a virulent material,’ our objectors have asked, ‘because the inoculation of other substances, such as cancers, pus, etc., can produce tubercles, and because tubercles can even be induced by banal traumatisms, such as the application of setons**?’ We have repeated these diverse experiments: we have inoculated pus of all types, various pathological products, we have observed the application of setons, etc., and we have never yet observed anything that imitates tuberculosis. Cancer, amongst other substances, has been used for inoculations by a considerable number of investigators and, to my knowledge, none has confirmed the results of the two experiments, one from Germany (Lebert) and the other from England (Clark††), announcing the production of tubercles by cancerous matter. However, we are far from wishing to dismiss results of this kind out of hand and invalidating them by our negative experiments. On the contrary, we believe that the explanation can probably be found by closer inspection of their studies and controls. These findings are not the only ones that do not perfectly fit our theories on virulence and specificity. We will see later that very similar experiments provided conflicting results concerning the virulence and specificity of glanders, but who ** EN: a cord inserted into a wound to allow it to drain. †† Sir Andrew Clark (1826–1893), Scottish pathologist, member of the Royal College of Physicians.

261

today would contest that glanders is an inoculable, virulent and specific disease? Regardless, the generalisation of tuberculosis in certain animals after the insertion under the skin of a minute amount of tuberculous material is an almost absolutely constant experimental finding; it cannot be explained by pure and simple transport of the material deposited in the wound, nor by an embolic process, nor by close-range communication of the extension of inflammation from the site of the injection to the organs, where new tubercles are created, grafting or traumatism, and consequently one arrives at the inevitable conclusion that the events observed correspond to true inoculation. Are there not, besides, all the characters of other inoculation events revealed to us by experimental pathology? Does not this packet of morbid material introduced into the body reproduce the disease that engendered it and identical morbid material, as this material, if inserted in turn into another subject, would produce the same pattern, and so on? If this experiment is not to be considered inoculation, it must be shown in what ways it differs from inoculation. And, if this cannot be done, how can the right to affirm the inoculability of the tubercule be contested? Well, so be it, we say; we accept that the tubercle is inoculable, but we should refrain from drawing conclusions about its virulence from its inoculability. What is to be said, sirs? Have we not always believed, until now, that inoculation is the pathognomic characteristic of virulence? And, is this word ‘virulence’ applied to anything other than the expression recapitulated by the effects of inoculating a morbid material, reproducing the material that engendered it in the body? It is entirely true that not all virulent diseases can be inoculated with a lancet, but declaring that a disease can be inoculable but not at all virulent is a complete contradiction in both terminology and thought, if we use the word ‘virulent’ (derived from virus) with its usual meaning. However, we must insist on this point. It has been claimed that tuberculosis is neither virulent nor specific, because ‘the tubercle is heterogeneous. . ., derived from a primarily and essentially organic and diathesic disease. . ., that it possesses readily necrobiotic properties. . ., that it is a product incapable, to the highest degree of the force of incubation, latent and refractory vitality, by virtue of which the viruses and contagious agents maintain and communicate their properties with no knowledge of space or time. . .., because nothing is less alive and concentrates less morbid action than the tubercle. . .’, etc., etc. And this is why . . . tuberculosis is not virulent, specific or contagious.’ I believe that I have responded to these arguments: is tuberculosis not virulent? Yes it is, I inoculate it! However, the arguments continue, your ‘inoculations practised with the aid of solid materials or

262

The International Journal of Tuberculosis and Lung Disease

histological elements bear only a deceptive, external resemblance to the inoculations carried out to date. . . Prior inoculations made use of true liquids, described as ‘virulent’ and produced by virulent diseases. These liquids, when examined under the microscope and subjected to chemical analysis, presented no corpuscular elements or specific characters.’ If by ‘true liquids’ one means those containing no corpuscular element, then we are aware of no such liquids in the body; urine perhaps, and even then! Mucus, pus and blood contain histological elements in as great an abundance as the tubercle. Cowpox, smallpox, syphilis and glanders are inoculated with products rich in corpuscular elements. Should they therefore cease to be considered specific, inoculable diseases? Monsieur Depaul recently used a vaccine consisting of solid cowpox scabs for inoculation.‡‡ The contents of smallpox pustules include abundant microscopic elements. After induration, the syphilis chancre has the same histological structure as the tubercle, and the detritus generated by its ulceration is physically identical to that of an ulcerated or softened tubercle. The glanders spots that give rise to pituitary ulcers also have the same composition and the same course as the tubercle. Furthermore, investigators inoculate glanders granulations from the lungs or other organs, in the same way that we inoculate with tuberculous granulations. We find written proof of this in the highly interesting work of Monsieur SaintCyr: ‘I inoculated this mare,’ he states ‘with acute glanders virus taken from the pulmonary tubercles of a donkey.’ (Saint-Cyr, Nouvelles etudes historiques, ´ critiques et experimentales de la contagion de la ´ morve. Paris, 1864, page 72).§§ It should not be forgotten that these glanders tubercles are, anatomically, almost identical to those of phthisis, that it is really very difficult to differentiate them with the naked eye or under the microscope, that they have the same site, the same structure, the same degrees of progression and the same termination, etc. If one reads the autopsies of horses with glanders described by learned men (Dupuy, Saint-Cyr, etc.), they are true copies of the lesions of our phthisis cases, right up to and including lobular caseous pneumonia. Now, I do not see how tuberculosis is any more primarily and essentially organic and diathesic than glanders. The tubercles of the latter are just as heterogeneous as those of the former. Glanders tubercles may possess properties more readily necrobiotic than those of phthisic tubercles, given that they seem to soften sooner and more rapidly in many cases. Are they more capable of the force of incubation, latent and refractory vitality and do they concentrate a greater morbid action? We ‡‡ EN: Jean-Anne-Henri Depaul (1811–1883), French surgeon, professor of obstetrical surgery. §§ Franc¸ ois Saint Cyr (1824–1892), French veterinarian.

humbly admit they we have no ideas about these properties, However, what appears to us to be absolutely clear, is that all the cumulative arguments against the virulence, specificity and inoculability of the phthisic tubercle can also be applied, point by point, to the glanders tubercle and cutaneous glanders tumours. If we are opposed by the argument that cutaneous glanders is not inoculable, we would refer our opponents to Gohier, Rayer, Saint-Cyr and many others (Gohier, Memoires et observations sur la chirurgie et la medecine vet Paris, 1837; ´ ´ erinaires. ´ Saint-Cyr, p. 77).|||| Undoubtedly, most inoculations of glanders have been carried out with the nasal mucus of horses, but tuberculosis inoculation can also be achieved with sputum from patients with phthisis, a true mucus with a composition identical to that of the nasal mucus. We would request that the experiments carried out with this product be taken into account. Are we to deny sputum the characteristics of a virulent liquid but accord these properties to the nasal mucus of solipeds? Or would tuberculosis, which is virulent and specific with sputum alone, cease to be so because the tubercle is considered to be inoculable? Thus, unless we deny the significance of experimental findings that have long been considered valid and refuse to see the most striking analogies, it must be agreed that our tubercle inoculations were carried out in conditions entirely identical to those that have long presided in many operations of the same type, and even, if we compare them to those of cutaneous glanders, the number of similar circumstances increases to the point that we can constitute a collection of almost identical phenomena. These are undeniable facts that no discussion, however urgent, can obliterate. They raise questions about the place of the serum regarded as necessary for the constitution of a virus, and considered to be present in glanders granulations, cutaneous glanders tumours, the nasal mucus of solipeds, but not found in the tubercle or in the sputum of phthisis patients. Moreover, what do we know about the physical state of the contagious material? Is it solid, liquid or gaseous? Do not the elegant and judicious experiments of Mr Chauveau## demonstrate, on the contrary, that certain virulent humours are active only when they contain solid corpuscles? ||||

We would like to remark, as an aside, that, despite the zoological relationship between the donkey and the horse, only acute glanders is observed in the former of these solipeds {Translator’s Note: now equids}, whereas chronic glanders is particularly frequent in the latter. We should not lose sight of this curious feature in the inoculation of virulent diseases that may behave differently, as we can see, in different animal species. EN: Jean Baptiste Gohier (1776–1819), French veterinarian. Pierre Rayer (1793–1867), French physician and dermatologist ## Auguste Chauveau (1827–1917), French veterinarian, physician, physiologist and anatomist.

On the virulence and specificity of tuberculosis

Despite all the efforts made to deny the tubercle the properties of virulent substances, it is not possible to prevent the recognition that its inoculation rejoices in the remarkable power of leading to the formation, throughout the body, of many tuberculous products disseminated to the most distant organs. Now, what can be considered comparable to this phenomenon if not the inoculation of viruses? However, this clear analogy has been contested and we have been reproached for having created two problems at once: ‘The first is to establish the existence of the virulent agent, the second to explain how it engenders the tuberculous material.’ We believe that there is no greater proof of the virulence of a pathological product than its inoculability and, as for the explanation as to how the tuberculous virus engenders the tubercle, the difficulty is no more or less great than determining how the glanders virus engenders the glanders tubercle or how the syphilis virus engenders the syphilitic gumma. As we have already said elsewhere: the relationships between any particular phenomenon and its cause are observed and not explained. It is by virtue of a catalytic action, analogous to that of ferments it has been said, that the inoculated tubercle infects the body with tubercles. Well, have we not compared viruses to ferments, and does not the name ‘zymotic’ given to virulent diseases validate this analogy? It is not in the fashion of viruses or through a catalytic operation, it was then said, that the inoculated tuberculous material acts; it is by an action analogous to that of fertilisation. One could, undoubtedly, ask whether, following fertilisation, it is the fertilising agent that reproduces and multiplies, if we collect the sperm or pollen from the fertilised subject, but a comparison does not imply the identity of all the terms. Nevertheless, there is here a sort of fertilisation and it also exists for all other virulent substances. Following inoculation, the detritus of a chancre gives rise to a chancre, smallpox pustules riddle the skin with further smallpox pustules, the glanders tubercle seeds the organs with glanders tubercles, just as the phthisic tubercle infects the viscera with phthisic tubercles. This hypothesis of fertilisation is no more than a manner of conceiving and explaining the action of the virus; it is no less ingenious than all the other explanations attempted to date and, as we will see later, tuberculosis is not the only disease to which it has been applied. However, at the point that science has reached, I do not believe that there is any advantage to substituting the word ‘fertilisation’ for the word ‘inoculation’, applied in this way to a disease transmitted from one individual to another via a packet of morbid material. If, rather than seeking comparisons among unexplained chemical operations and very distantly

263

related physiological acts, we take them from findings of a similar order, if we observe, for example, what happens in inoculations of glanders, this disease so closely related to tuberculosis, what do we see? We note that all the particular features observed in tubercle inoculation are also found in inoculations with glanders disease. In terms of physical characteristics, the same matter is inoculated, the same alterations to the lymphatic system are observed, the same generalised anatomic processes are observed in the viscera, with preference for the respiratory organs, etc. When one introduces some nasal mucus fluid, a little of the caseous matter of a glanders tubercle or the detritus of a cutaneous glanders spot into a wound, a small tumour, which often becomes ulcerated, forms at the point of inoculation after several days. A cord then develops from this tumescence, extending to hard, painful, hypertrophied ganglia (Bouley, Bulletin de l’Academie de ´ Medecine, 1838–1839, p. 593).*** Usually, if the ´ inoculation is carried out on only one side, only the corresponding ganglia become diseased. On incision, these ganglia appear to be full of glanders tubercles and the afferent lymph vessels themselves and their walls are infiltrated with the same product. Here, a chain of lesions is produced in a fashion entirely identical to that in phthisis inoculations. At the same time as these local alterations are observed, one notes nodules of various numbers and sizes in the lungs, respiratory mucosa, liver, testicles, intestine, etc. (Saint-Cyr, loc. cit., p. 65). Are there, in pathology, two processes with a larger number of analogies than for the results of inoculation for glanders and tuberculosis? In syphilis, do we not also see something comparable? Does not the host of ganglia attest to the role played by the lymphatic system neighbouring the site of insertion of the virulent material? Thus, the objections raised against our work in terms of the substance inoculated, local events close to the inoculation site, the mode of generalisation of the anatomic lesions, etc., apply equally well to glanders and to tuberculosis and, curiously, these objections were indeed raised when, as today, the inoculation, virulence and specificity of glanders were being discussed. When we established, in a recently published work, a parallel between tuberculosis and cutaneous glanders, and we showed the many analogies between these two conditions, we little suspected that these analogies would be completed and continued by the similarity between the arguments raised against the virulence of each of these diseases (Villemin, Etudes sur la tuberculose, Paris, 1868, p. 431). *** EN: Henri Bouley (1814–1885), French veterinarian.

264

The International Journal of Tuberculosis and Lung Disease

But please allow us, before going any further, to correct an error that has formed in some minds. It has been suggested that we think that glanders and phthisis are identical. We have never thought any such thing. The chapter of our book in which we established the similarities between these two conditions was entitled: Glanders is the disease most closely related to tuberculosis. In this chapter, we highlighted the affinities between these morbid entities, just as one could do, I imagine, for scarlatina and measles, whilst maintaining a complete and essential separation of the two elements being compared. One should not imagine that the inoculation and virulence of cutaneous glanders were accepted without contestation. The experimental findings excited considerable emotion and, as for tuberculosis, were consequently strongly fought and even radically denied. Veterinary surgeons were long divided into two camps: the contagionists and the non-contagionists. When Gohier, in 1813, made known the results of his experiments on inoculation, the non-contagionists found many expedients. They initially denied the finding and opposed their failures against the success of their adversaries. They denied even that the findings were possible. ‘Next we will be asking,’ said Dupuy, ‘how solid material such as that constituted by the tubercle (glanders) could become contagious (Dupuy, loc. cit., p. 455). More than fifty years ago this argument was used against glanders, and now it is being used against phthisis. It is above all against the chronic form of glanders, which more precisely resembles phthisis, that these attacks were directed. And what reasons were given for contesting its contagiousness and virulence? The same, absolutely the same, as those used to oppose the virulence of tuberculosis. Listen to Delafond:††† ‘Among the many diseases of the chronic type in domestic animals, do we encounter a single one that is evidently contagious? None that we know of. So why would glanders be an exception? We ask, is it possible to find, among all the characteristics presented by this disease, a single one comparable with the many, so distinctive characteristics of primarily contagious diseases? No, all contagious diseases have an acute or very acute type; the causes giving rise to them are generally unknown; the symptoms signalling them are constant and unequivocal, they have a very fast course, a short duration, and their termination, although variable, is generally adverse; all have a known, palpable virus transmitting the disease by inoculation. Now, it is precisely the opposite characteristics that are displayed by glanders.’ (Delafond, †††

EN: One´ sime Delafond (1805–1861), French veterinarian.

Traite´ sur la police sanitaire des animaux domestiques, Paris, 1839, p. 603). For the proponents of these theories, glanders, like the phthisis of our adversaries, recognised no other cause than slow action resulting ‘from long, sustained, difficult-to-bear fatigue;. . .feeding for long periods on rotten food or food of low nutritional quality;. . . periods spent in cold, damp, poorly aired and dark places;. . .the cessation of sweating;. . .. long periods of suffering from the presence of chronic internal and external diseases, morbid resorptions of all types taking place during the course of many diseases (Delafond, loc. cit., p. 595). The contagion between the horse and man is not even sufficient to convince them. Who does not recall the brilliant battles of 1836? And, two years later, Delafond, refuting the statements of Rayer, was still crying: ‘No, the cause of cutaneous glanders is not specific. For use, it is the result of an infection originating from fixed or volatile animal matter, altered by the presence of the air, which, when introduced into the body by absorption, determine morbid effects that are more intense in the most debilitated subjects already predisposed to putrid infection’ (Delafond, loc. cit., p. 684). But when, in the face of overwhelming evidence, the non-contagionists can no longer hold out against the force of the facts, they shift their ground. What, they ask, does the inoculation of glanders products signify, and what of their virulence and specificity, given that other substances are just as effective at transmitting glanders, because this disease can even be provoked by simple traumatisms? Dupuy, distinguishing between chronic and acute glanders, which he called gangrenous coryza, was able to induce the latter in healthy horses, by inserting under the skin a fragment of spleen from a horse that died following pneumogastric sectioning. Putrefying substances of animal origin, like blood, muscle fragments, etc., produce the same effects according to Dupuy. He also transmitted glanders to horses by inoculation with a puriform matter that ran from the nostrils of a horse without glanders (Dupuy, Bulletin de l’Academie de Medecine, 1836, p. 481; De ´ ´ l’affection tuberculeuse, Paris, 1817, p. 244; De l’affection tuberculeuse, Paris, 1817, p. 454). Renault subjected to the scrutiny of the Academie ´ de Medecine, on several occasions, pathological ´ evidence attesting to the provocation of glanders by injections of non-suspect pus and, to confirm that the glanders induced was real, he successfully inoculated healthy horses with it. He published detailed observations of cutaneous glanders occurring after fistulous withers, contusion of the upper eyelid or a fistula of the spermatic cord following castration; finally, Dupuy noted that the setons used on the shoulders of the horses had given them glanders. In Germany, Erdt caused glanders in four horses, by inoculating them

On the virulence and specificity of tuberculosis

with pathogenic products of scrofula (1834) (Renault, Bulletin de l’Academie de Medecine, 1839, p. ´ ´ 69 and 1840, p. 402; Recueil de M edecine ´ Vet 1840, p. 257; Receuil de Medecine ´ erinaire, ´ ´ Vet 1835, p. 393; Dupuy, Bulletin de ´ erinaire, ´ l’Academie de Medecine, 1836, p. 481).‡‡‡ ´ ´ All these experiments, all these affirmations, all these arguments, do they not oppose the virulence and specificity of glanders with even more authority and force than those that have been opposed to the virulence and specificity of tuberculosis? Thus, if one wishes to maintain these arguments to refuse the admission of phthisis to the group of virulent diseases, one must also, absolutely, remove cutaneous glanders from this group, as this disease has no greater or lesser right than tuberculosis to membership of this group. The objections opposing, not the inoculation of the tubercle which is undeniable, but its virulence and specificity, have been raised not only against glanders, its first cousin, but also against syphilis, which is more distantly related. The syphilis virus, just like the glanders and tuberculosis viruses, has had its sworn enemies, and the arms used to oppose it were none other than those recuperated by the adversaries of the specificity of tuberculosis. The first line of argument was also to deny inoculability and to oppose negative or contradictory experimental results against positive results. This is what des Brus did, and, to take into account venereal events, he accepted the existence of a venereal mode of disease explained physically by electricity (des Brus, Nouvelle methode de traiter les ´ maladies ven par les gateaux toniques mer´ eriennes ´ curiels, Paris, 1789)§§§. Caron followed in des Brus’ footsteps, assimilating the transmission of syphilitic events to the impregnation of females; he explained these events in terms of fertilisation, rather than the absorption and multiplication of a virus. ‘It is thus not a virus that is inoculated during venereal contagion’, he said, ‘but an occult defect that develops within us; it is nature, it is life that establishes the syphilitic constitution. . . The venereal infection initially has a purely local action, which successively extends to certain parts’ (Caron, Nouvelle doctrine des maladies ven Paris, 1811). ´ eriennes, ´ This theory of fertilisation is already old, as one can see, and with it we return to the close-range propagation that has been used to explain the development of tubercles in the organs. Jourdan also denied the existence of the syphilis virus, refusing to ‡‡‡

EN: Euge` ne Renault (1805–1863), French veterinarian, director of the School of Veterinary Science, Maison-Alfort. W E Erdt, German scientist. §§§ EN: Louis Richond des Brus (1798–1856), French army surgeon and politician. Jean-Baptiste Franc¸ ois Caron (1763– 1814). Antoine Jacques Louis Jourdan (1788–1848), French physician. Henri M Desruelles (1791–1858), French physician.

265

accept any specificity of the venereal disease or signification of inoculations; he affirmed that one ‘sees similar and even more serious results dependent on a simple injection’ (Jourdan, Traite´ complet des maladies ven Paris, 1826). According to ´ eriennes, ´ Jourdan, the constitutional signs of syphilis depended on a host of different causes. Richond des Brus, in his book De la non-existence du virus ven (Paris, ´ erien ´ 1826), and Desruelles continued to wage war against the virulence and specificity of syphilis. The former considered this disease to be spontaneous, and the latter sought causes in the seasons, temperature, rainfall, etc. (Desruelles, Traite´ pratique des maladies ven Paris, 1836, p.20). ´ eriennes, ´ There was thus a time when both glanders and syphilis, just like tuberculosis, according to our detractors, arose from everything and could be inoculated with everything. What should one conclude from the lessons of history? That the facts that have provoked such an analogy of arguments and contradictions must necessarily also display a very large analogy in terms of their nature. Indeed, syphilis, glanders and tuberculosis form a nosological group, the species of which display incontestable affinities. If tuberculosis is specific and virulent, it must by definition be contagious, but the mode and conditions of its transmissibility remain to be determined. I believe that I have experimentally demonstrated that phthisis, like syphilis and glanders, is communicable by inoculation. It can be inoculated from humans to certain animals, and from these animals to others of the same species. Can it be inoculated between humans? It is absolutely forbidden for us to provide experimental proof of this, but all the evidence is in favour of an affirmative response. Claiming the contrary simply because we have observed no case to date is tantamount to refusing the inoculability of tuberculosis the right to appear at its own time, like all scientific truths. A discovery consists precisely of the demonstration of a fact that had previously escaped observation. At the first description of a case of glanders in humans, for example, it was also objected that such a thing had never before been seen. Who, thus, had noticed the relationship of pericarditis to articular rheumatism before the discovery of the law of coincidences? Furthermore, the transmission of tuberculosis through cohabitation, although regarded as highly probable by a certain number of distinguished physicians, is nevertheless, not so evident that it is beyond contestation. Here there is an obscurity imposing the greatest reserve, and in which clinical practice, particularly that of large hospitals, has no right to arm itself to deny absolutely this mode of transmission of phthisis. The large towns and the vast establishments accumulating so many patients and impregnated with so many disease-causing materials,

266

The International Journal of Tuberculosis and Lung Disease

are far from being favourable environments for the sometimes difficult study of contagiousness. In this context, for example, the transmission of typhoid fever is almost always dissimulated, whereas it is revealed in hamlets, in families living in almost complete isolation, to observers positioned in less complex, more precise, clearer, and thus more convincing circumstances. Moreover, for what communicable disease has transmissibility not been contested? Clinicians therefore do not have the authority that one might believe to affirm everywhere and always that tuberculosis is spontaneous and to refuse absolutely the possibility of its transmission by contamination. However, clinicians are correct in saying that they cannot infer anything against the inoculability of phthisis. It is, therefore, better to agree, modestly, that the

solution to questions relating to the propagation of tuberculosis in the human species should be left to the future, which, let us be sure about this, will conclude not on the basis of arguments and theories, but on the basis of positive, perfectly demonstrated facts. For my part, with the assistance of experimentation, I have tried to specify the circumstances that seem to play a preponderant role in the transmission of phthisis. The curious and important results that I have already obtained appear to me to throw some light on this point. With the authorisation of the Academy, I would be honoured to communicate them. I terminate, sirs, by thanking the Academy for the indulgence with which it has deigned to listen to the explanations that I have just submitted; I am aware, furthermore, that I owe this indulgence entirely to the importance of the subject that I have addressed.