OBSERVATIONS CONCERNING THE STUDY OF PHTHISIOGENESIS IN MAN AND IN ANIMALS.

1. It is possible in experiments on guinea-pigs to produce pulmonary phthisis by infecting these animals from the oral cavity in such a manner that every direct infection of the lungs (alveolar infection through the trachea = aerogenous infection of the lung) is excluded.

(a) Infection through the parenchyma of the tongue.(b) Feeding of tubercle bacilli with milk.

(a) Infection through the parenchyma of the tongue.

(b) Feeding of tubercle bacilli with milk.

2. Ascribing the pulmonary phthisis which I succeeded in producing experimentally to a lymphogenous or hæmatogenous infection of the lung following previous scrofulous disease. Definition of the term “scrofula”: multiple, caseating areas of disease in lymph-glands and in other organs, caused by Tb. infection. Concerning the etymology of the word “scrofula” (Greek = choeraden), see Virchow’s “Geschwülste,” Vol. II, p. 558.

3. Other varieties of experimental phthisiogenesis;

(a) v. Baumgarten’s experimental method of causing pulmonary phthisis by means of primary infection of the urogenital apparatus.(b) The experiments of Troje and Tangl with tubercle bacilli artificially weakened in virulence.

(a) v. Baumgarten’s experimental method of causing pulmonary phthisis by means of primary infection of the urogenital apparatus.

(b) The experiments of Troje and Tangl with tubercle bacilli artificially weakened in virulence.

4. Critical analysis of the so-called “Inhalation Tuberculosis” of guinea-pigs and rabbits.

(a) My own experiments, in which the typical picture heretofore regarded as that of an inhalation tuberculosis, in the sense of an aerogenous alveolar infection, was produced by lymphogenous or hæmatogenous introduction of tubercle bacilli, with the complete exclusion of a primary alveolar or bronchial infection.(b) The experiments of Weleminsky (Hüppe).(c) Signs distinguishing tubercular pulmonary consumption from so-called inhalation tuberculosis.

(b) The experiments of Weleminsky (Hüppe).

5. Improbability, so far as importance as a phthisiogenetic factor is concerned, of a primary bronchial, or even primary alveolar Tb. infection following aerogenous introduction of Tb. into the mouth and nose, through the inhalation of dust or droplets containing tubercle bacilli.

6. Proof for my assumptions,

(a) That inhaled tubercle bacilli under circumstances occurring in nature are taken up by the lymphatic receptive apparatus without exciting, at the point of entry into the lymph-channels, any tubercular disease.(b) That inhaled tubercle bacilli, after they have entered the lymph-channels of the throat, take the following courses: some find lodgment in the submental glands and glands of the neck; some are transported to the mediastinal (bronchial?) glands; some gain the circulation and thus cause hæmatogenous infections, especially at the peripheral (sub-pleural) endings of the pulmonary artery, from which then the lung parenchyma can be infected; finally, some are carried through the stomach to the lowest portions of the intestines, from where they can reach the mesenteric lymph-glands, the portal vein, and the peritoneum.(c) That the introduction of Tb. into the lymph-channels is accomplished primarily by the leucocytic wandering cell, which takes up the tubercle bacillus.

(b) That inhaled tubercle bacilli, after they have entered the lymph-channels of the throat, take the following courses: some find lodgment in the submental glands and glands of the neck; some are transported to the mediastinal (bronchial?) glands; some gain the circulation and thus cause hæmatogenous infections, especially at the peripheral (sub-pleural) endings of the pulmonary artery, from which then the lung parenchyma can be infected; finally, some are carried through the stomach to the lowest portions of the intestines, from where they can reach the mesenteric lymph-glands, the portal vein, and the peritoneum.

(c) That the introduction of Tb. into the lymph-channels is accomplished primarily by the leucocytic wandering cell, which takes up the tubercle bacillus.

7. In the herbivora the Tb. are most commonly carried from the cæcum to the mesenteric lymph-glands. In man, the agminated lymph-follicles of the small, and the solitary lymph-follicles of the large intestine also serve as points of entry (cf. Carl Hof, “Ueber primäre Darmtuberculose,” Kieler Dissert., 1903. Compare also v. Hansemann, “Ueber Fütterungs Tuberculose,”Berl. klin. Wochenschr., 1903, No. 7).

8. Reference to the peculiar features of the stomach of ruminants and remarks on primary tuberculosis of the stomach (Schottelius).

9. The primary development of localized foci in the lesser omentum after infection through the stomach in early nursing period.

10. Peculiarities of the infection of nurslings through the alimentary tract, experimentally and statistically determined.

(a) Feeding experiments with anthrax bacilli and other bacteria.(b) Feeding of spores.(c) Tubercular virus behaves in many ways more like the resistant form [spore form] of anthrax virus, especially when the Tb. virus is present in cheesy pus.(d) The observations of Adalbert Czerny and Paul Moser on the occurrence of bacteria in the blood of living human nurslings (1894).(e) Carl Weigert’s statements concerning the penetrability, for Tb. virus, of the intestinal apparatus of very young children. (From 1883, cited inDeutsche medizin. Wochenschr., 1903, No. 41.)(f) Raw’s communication (British Med. Journ., 1903) concerning 300 cases oftabes mesenterica, not one of which was found to have developed in a child nursed exclusively at the breast, but rather in those who had been nourished for a considerable time on cow’s milk.

(a) Feeding experiments with anthrax bacilli and other bacteria.

(b) Feeding of spores.

(c) Tubercular virus behaves in many ways more like the resistant form [spore form] of anthrax virus, especially when the Tb. virus is present in cheesy pus.

(d) The observations of Adalbert Czerny and Paul Moser on the occurrence of bacteria in the blood of living human nurslings (1894).

(e) Carl Weigert’s statements concerning the penetrability, for Tb. virus, of the intestinal apparatus of very young children. (From 1883, cited inDeutsche medizin. Wochenschr., 1903, No. 41.)

(f) Raw’s communication (British Med. Journ., 1903) concerning 300 cases oftabes mesenterica, not one of which was found to have developed in a child nursed exclusively at the breast, but rather in those who had been nourished for a considerable time on cow’s milk.

11. It is probable that in thickly populated countries practically every person is at some time or other infected with tuberculosis. Aside fromthe quantity and quality of the Tb. virus, the outcome of the tubercular infection is dependent to a high degree on the physiological state of the infected individual and on accidental conditions of infection. (Intercurrent pathological factors; endogenous and exogenous conditions of infection.)

12. Not a single unexceptionable case has been brought forward to show that under the conditions of life usually present in civilized lands, an adult person has ever contracted pulmonary, bronchial, tracheal, or laryngeal tuberculosis without having previously been infected and thus rendered oversensitive to the tubercular poison.

13. Against the action of tubercle bacilli entering the intestinal apparatus, healthy, full-grown persons apparently possess sufficient protection in the character of the mucous surfaces and the anti-bacterial action of the digestive juices. It has, too, still to be proved that healthy, full-grown persons become ill with tuberculosis as a result of eating food (milk, butter, meat) derived from tuberculous cattle.

14. Very probably adult persons frequently acquire intestinal tuberculosis through food containing tubercle bacilli, if the epithelial covering of the intestinal mucosa is defective, or if perhaps there exist ulcers which extend down to the parenchyma of the wall of the alimentary tract. (Exanthematic diseases, typhoid, dysentery, carcinoma, etc.)

15. Whether adult persons in whom the conditionsare favorable for an intestinal infection with Tb. will develop primary tubercular lesions in the intestinal wall, or in the mesenteric glands and the peritoneum, will depend mainly on the circumstance whether or not, owing to a previous infection, they have become oversensitive to tuberculin.Individuals oversensitive to tuberculin are inclined to develop lesions at the point of entry of the tubercular virus, if opportunity is given for the introduction of the virus by means of leucocytic wandering cells. This opportunity is lacking in the virile infecting period at such places where the lymphatic receptive apparatus is destroyed [verödet]. (Mucous surfaces of the faucial ring of consumptives?)

16. In order to explain the mode of origin of cheesy pneumonias and tubercular broncho-pneumonias it is necessary at autopsy to regard most carefully the possible direct extension of the infection from cheesy mediastinal and bronchial glands to the bronchi and their branches, before thinking of aerogenous or hæmatogenous pathogenesis. (Compare [Ribbert] Sievers, “Marburg Dissertation,” Aug. 14, 1902.)

17. Critical analysis of several statistical statements which seek to show that alveolar pulmonary tuberculosis is referable directly to inhaled tubercle bacilli; especially the statement of Knopf (New York) cited by Mitulescu (Zeitschrift für Hygiene, 1903), that in Lansing, Mich., twenty employés of a library became consumptive through handlingTb. laden books.[5]Probability of the correctness of my assumption that Knopf was misled by unscientific communications from Lansing. Proof that Mitulescu again misunderstood Knopf.

18. It has not yet been proved that persons cutaneously infected with human or bovine Tb. have as a result of this developed phthisis. (My own observations on cases of infection on the hand in persons working with tubercle bacilli of various origins.)

19. Justification of the statement by Virchow in his “Phymatie, Tuberculose und Granulie,” that “the history of phthisis is concerned much more with cheesy hepatization than with tubercles” (Virchow’s “Tuberkel,” Begriff).

20. The analysis of the origin of pulmonary consumption must begin with the primary attack (primary regionally as well as chronologically) of the Tb. introduced into the organism.

21.As a rule we can regard as points of primary infection polynuclear leucocytes in the blood and lymphatic receptive apparatus; next in order are the muscular elements in the walls of the smallest blood-vessels.Endothelium and epithelium may become carriers of Tb. through the action of polynuclear leucocytes which have wandered into these tissues.

22. In studying the results of an infection with tubercular virus, aside from the degree of virulence,from the dosage, the single or repeated Tb. inoculation, and the primary point of attack (regional and cellular), we have particularly to consider the age at which the primary infection occurs. I distinguish four periods:

(a) Infantile period of infection;(b) Puerile”””(c) Virile”””(d) Senile”””

(a) Infantile period of infection;

(b) Puerile”””

(d) Senile”””

23. It seems to me that in the epidemiological origin of pulmonary consumption the infantile Tb. infection, followed by latent or manifest scrofula in the puerile period, is of great significance, so that we can formulate the following doctrine: “An infantile tubercular infection predisposes to tubercular pulmonary consumption.” Under “scrofula” I here include the alteration in the muscle of the blood-vessels, caused by the Tb. infection, which finds its expression in the increased sensitiveness to tuberculin, and which in general is equivalent to “scrofulous diathesis” of the older authors.

24. The primary infection from the mouth or nose with tubercular virus derived from food or even from inhalation, in the small quantities that under ordinary conditions of life are concerned, is followed after the bacilli have entered the circulation, by alterations in the walls of the smallest vessels. These manifest themselves as follows:

(a) Microscopically, by a loosening of the vessel wall, between whose elements, shortly after theinfection, tubercle bacilli can be found. These bacilli, brought here by the wandering cells, are set free on the destruction of the cells.(b) In primary functional disturbances which can be recognized by the temperature curve and the heart action.(c) In secondary tuberculin hypersensitiveness.

(b) In primary functional disturbances which can be recognized by the temperature curve and the heart action.

25. Following mild infections the alterations in the vessel walls may retrogress with a suppression [Beseitigung] of the tubercle bacilli. Without exception, however, the hypersensitiveness to tuberculin remains, varying in degree and length of time according to the virulence of the infecting Tb. and to their more or less locally limited action on the vascular system.

26. After a moderately severe infection there is a formation of transparent, submiliary eruptions (nowadays our “gray miliary tubercle”), especially about the smallest vessels of serous membranes.These eruptions are capable of becoming organized. In fact, when they have healed they form a tissue entirely identical with the tissue in which they originated.(Bichat, Lebert, Empis, and many other older investigators.) Aufrecht,Deutsch. Arch. f. klin. Med., Vol. LXXV.

27. The introduction of a tubercular virus so strong as to cause the smallest vessels to become occluded, especially Cohnheim’s terminal arteries of the spleen, lungs, and kidneys, results in the exudation of a coagulable fluid and in necrobiosisof the extra-vascular region supplied by those vessels. (Aufrecht,Arch. f. klin. Med., Vol. LXXV.) Into this dead area tubercle bacilli are dragged by the wandering cells. These bacilli multiply and cause chemical changes which manifest themselves first in a fatty (steatomatous) and then in a cheesy metamorphosis. (Cf. Koch, Volume II of theMittheilungen aus dem Kaiserlich. Gesundheitsamt, p. 21, and Plate IX, Figs. 45 and 46); my own observations; Aufrecht, 1. c.; compare also the critical reference by Virchow to the works of older authors, such as Vetter, Gendrin, Lobstein, Cruveilhier, Bayle, Baillie, Laënnec, Rilliet and Barthez, Vulpian, Craigie, etc., in “Phymatie, Tuberculose und Granulie,” and in Vol. II of “Die Krankhaften Geschwülste.”

28. We may enumerate as the result of primary tubercular focal disease

(a) Anatomically demonstrable residues.(b) Functional alterations.

(a) Anatomically demonstrable residues.

(b) Functional alterations.

29. Functional alterations may remain without any anatomically demonstrable residues of the primary infectious processes. I divide functional alterations into

(a) Alterations which leave behind them an immunity against living Tb. virus, probably to be sought for in the peculiar condition of the vessel musculature and, in the beginning at least, always associated with hypersensitiveness to the soluble tubercular poisons.

(b) Scrofulous diathesis, consisting in such changes in the vascular system and the lymphatic apparatus that a renewed Tb. infection very readily causes cheesy tubercular lesions.

30. As scrofulous infectious processes, I regard

(a) Lupus, which I interpret as a cutaneous additional effect of a tubercular infection.(b) Gland scrofula,[6]inclusive of tuberculosis of the mediastinal, bronchial, and mesenteric glands.(c) Bone scrofula and joint scrofula.(d) Scrofula in the domain of the external body covering, of the mucous membranes, and of the lymph-channels.(e) Cheesy metamorphosis in internal organs, inclusive of the organs of sense, and the vessel intima.

(a) Lupus, which I interpret as a cutaneous additional effect of a tubercular infection.

(b) Gland scrofula,[6]inclusive of tuberculosis of the mediastinal, bronchial, and mesenteric glands.

(d) Scrofula in the domain of the external body covering, of the mucous membranes, and of the lymph-channels.

(e) Cheesy metamorphosis in internal organs, inclusive of the organs of sense, and the vessel intima.

31. The acute miliary tuberculosis in man, which can be clinically diagnosticated, is to be regarded as a provocative secondary infection, resulting from scrofula of the blood-vessels’ intima when, on the disintegration of cheesy intima tubercles, a great many tubercle bacilli are thrown into the circulation at once. (Weigert-Ponfick.)

32. Disease of the lung apices occurring in thevirile period of infection and, because of its important bearing on the origin of consumption, considered separately, is preceded by the consequences of an infantile infection. Foremost among these is the secondary hypoplasia of the smooth muscle tissue (of vessels, bronchi, and intestinal wall); next in order come wasting [Veröding] of the lymphatic apparatus (quantitative and qualitative reduction of the follicular receptive apparatus of thetubus alimentarius); destruction of lymph-glands; and the secondary hypoplasia of other primary points of attack for Tb. action (in the spleen, bone-marrow cavities, on serous surfaces of the large body cavities, and of the joints). The predilection of the thoracic dome for immobilizing changes can probably be ascribed to its exposure to the Tb. infection in connection with precedent mediastinal-gland scrofula; while the predilection of the lung apices for caseating lesions can again be brought into causal relation with secondary ossifying processes, of scrofulous origin, in the joint structures of the thoracic dome (cf. Aufrecht, 1. c.).

33. In my experiments on tubercular cattle I succeeded in producing eruptions of gray, non-caseating tubercles, running an acute course, by means of injections of tuberculin. At the same time it was noticed that not infrequently after the intercurrent exacerbation had subsided, the old infectious process had been favorably influenced.

34. Even when caseating lesions are present, thesimultaneously developing submiliary transparent eruptions (granulie, of the older authors) are to be regarded as capable of being organized and spontaneously cured. They are much more numerous in man than has heretofore been assumed. This is shown, for example, by the fact that upon opening the abdominal cavity of such young individuals as showed no clinically diagnosticated symptoms of a miliary tuberculosis, these eruptions were by chance demonstrated.

It is of the highest interest to determine the fate of such individuals with a healed miliary tuberculosis of the peritoneum, that is, whether in virile period of life the disposition in them to pulmonary consumption is increased or diminished.

35. The clinical picture of scrofula in the puerile period of infection is etiologically complicated by other infectious processes, especially in the domain of the outer body covering. The functional alterations in the vascular system, due to an infantile Tb. infection, find their expression not only in the organism’s increased sensitiveness to tuberculin, but also in a marked instability [labilität] of the dynamic equilibrium of the circulation (lymphatic constitution). In consequence of this, eczematous eruptions due to parasitic and toxic agents result much more readily in these individuals than in those who have not suffered such an infantile Tb. infection (one incompletely healed).

36. The symptoms of the so-called “inclinationto consumption” are the expression of a defective overcoming of the infantile and puerile infectious periods. The hindered development and weakness of the organs made up of smooth muscle fibres (muscles of the blood-vessels, intestinal wall, and bronchi) are comprehensible when we remember the great share that the smooth muscle tissue has in the reaction against the Tb. circulating in the blood. The question whether the weakened conditions and hindered development in the domain of the striped muscles are due directly or indirectly to the Tb. infection cannot be answered without further investigations. Similarly, we do not yet know the mechanism of the origin of the chest anomalies seen in candidates for consumption. A partial impoverishment of the intestinal lymphatic receptive apparatus is presumably accountable for the fact that even a plentiful supply of food is unable to increase the accumulation of fat.

37. The possibility must also be considered that in the course of the puerile period of infection the development of a caseating tubercle may proceed in the joint tissues between costal cartilage and breast-bone, and that such a scrofulous thoracic affection is clinically much less readily diagnosed than a similar affection in bones of the extremities. Further, that such a lesion in the lower extremity is much more readily recognized than one in the upper extremity, since even slight alterations in the bony tissues of the lower extremity, because offunctional disturbances in walking and running, make themselves manifest.

38. For a detailed analysis of the origin of pulmonary consumption, beside the results of infantile and puerile infections, there must still be considered

(a) Additional virile Tb. infections (cf. Romberg,Deutsch. Arch. f. klin. Med., 1903).(b) Combined action of a complicating infection.(c) The co-action of general hygienic and dietetic injuries.

(a) Additional virile Tb. infections (cf. Romberg,Deutsch. Arch. f. klin. Med., 1903).

(b) Combined action of a complicating infection.

39. For my plans for suppression of tuberculosis, therefore, the following points are essential:

(a) Prevention of the introduction of Tb. with food, especially with milk, during infantile life.(b) Introducing Tb. anti-bodies with the milk in earliest infancy in order to render innocuous any inhaled tubercle bacilli.

(a) Prevention of the introduction of Tb. with food, especially with milk, during infantile life.

(b) Introducing Tb. anti-bodies with the milk in earliest infancy in order to render innocuous any inhaled tubercle bacilli.

40. I have made separate communications regarding feeding with Tb.-free milk. The production of such a milk will be very easy if my method of cattle immunization in practice fulfils the hopes, which I have for it; and these hopes I am convinced are fully justified.

41. In order to produce immunity by means of anti-bodies it is probable that anti-bodies derived elsewhere will have to be added to the milk given to infants.

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