Pathology. — The bacteriological in vestigations of recent years have materi ally affected our views of the pathology of diphtheria. We have learned that the local lesions of the mucous mem branes really constitute a very subsidiary part of the process. In them the diph theria bacilli grow and multiply, devel oping in their growth certain organic substances, termed toxins, which are readily absorbed into the circulation and by their action produce constitutional symptoms and remote affects more char acteristic of the disease than the local lesions themselves. The diphtheria ba cilli have been found not only upon the mucous membranes, but in the lungs, liver, spleen, lymph-nodes, kidneys, and even upon the valves of the heart. They are not, however, present in great num bers in any of these organs; in fact, they are, except possibly in the case of the lungs, so few in number as to be demon strable only by means of cultures. Their presence in the viscera does not excite characteristic lesions of these parts, and seems to be an accidental accompaniment rather than an essential part of the dis ease. The action of the toxins, on the other hand, is characteristic and impor tant. These substances have been iso lated and studied especially by Brieger and Fraenkel, Roux and Yersin. They have been found to be allied to the al bumins, and have been designated as toxalbumins. In experimental inocula tions in susceptible animals, as shown by Welch and Flexner and. others, they have been found to produce all the char acteristic features of diphtheria except the membrane, especially the character istic post-diphtheritic paralysis. The most striking of their remote effects are produced in the lymph-nodes and liver. In the lymph-nodes they produce a dis tinct hyperplasia; in the liver necrosis or death of small areas of liver-cells, focal necroses, similar to those seen in the liver in typhoid fever and other in fectious diseases.
We must, therefore, believe that the presence of these soluble poisons in the circulation constitutes a very important feature of diphtheria. These toxins, as already noted, are elaborated in the local lesions of the mucous membranes, and not by the bacteria that may be present in the various viscera. The quantity and quality of the toxins generated seem, as a rule, to be proportionate to the severity of the local process.
The following results are reached from a study of the constitution of the diph theria poisoning: 1. The diphtheria ba cillus produces two kinds of substances: (a) toxins and (b) toxons, both of which combine with the antitoxin. Toxins and toxons have been found in three flesh bouillons in the same quantitative rela tion. 2. The toxins, and probably also the toxons, are not simple bodies, but they break up into various subdivisions, which differ in their affinity for the anti toxin. Three groups can be distin guished: prototoxins, deuterotoxins, and tritotoxins. 3. This division does not exhaust the complication, for it must be assumed that each species of toxin con sists of exactly two equal parts of differ ent character, which have the same rela tion to the antitoxin, but differ in their destructive influence. They probably differ from each other like dextrorota tory and levorotatory substances. 4. One of these constituents is called x-modiflea tion, and this is readily transformed in all toxins into toxoids. This transfor mation begins already in the incubator.
Owing to the disappearanue of one-half of the poison, the complete metamorpho sis into toxoid causes a sentivalent toxin to remain, called hannatoxin. 5. The sec ond modification, beta-modification, is in the different species of poisons, prototox ins. deuterotoxins, and tritotoxins of variable permanency. The beta-modifi cation of the deuterotoxins is the most stable. This explains the fact that after a time diplitheria-bouillon reaches a stage of definite toxicity that is perma nent: whence only those poisons that have entered this state should be used as diseased toxins. G. In the change of toxin into toxoid the affinity of the anti toxin is not in the least modified, and the toxoid of the prototoxin, for example, binds the antitoxin in the same way as the prototoxin itself does. The varieties of poisons combining less promptly with the antitoxin are le.ss readily destroyed by the latter than those that combine with it more promptly. 7. Regarding the significance of the L and the I.+ do.se, it is to be noted that the L 0 dose is sub ject to greater variation than the L+ dose. S. The facts developed are best ex plained by assuming that in the toxin molecule two independent atom-com plexes are present. One of these is hap tophorous, which causes the binding of the antitoxin to the corresponding lateral chain of the cells. The other is tox ophorous; i.e., the caue of the specific action. The same is true of the toxons. 9. The haptophorous group is responsible for the combination of the toxin-mole cule with the cells and thus of render ing the latter amenable to the influence of the toxophorous group. 10. The effects of the haptophorons and fox ophorous groups can in certain eases be separated experimentally. 11.1org.enroth has shown that the nervous system of the frog fixes tetanns-poison in the cold: disease-phenomena do not arise under these circumstances. If the frogs, which have been treated at proper intervals, first with poison and then with anti toxin, are placed in the incubator, tet anus develops even when all tbe circu lating poison has combined with the antitoxin, and even when the latter is present in excess. The haptophorous group thus acts already in the cold, the toxophorous only after the application of beat. 11. The temporal difference in the action of the haptophorous and tox ophorous groups explains also the incu bation period. 12. The toxophorous group is more complicated and less permanent than the haptophorous. The anti-bodies produced by the influence of the poison act exclusively on the haptophorous group. By combining, through the medi ation of this haptophorous group, with the entire toxin-moleeule, they prevent the toxophorous group from acting upon the organs. 13. The specific antitoxin can also be produced with toxoids, but the immunity cannot be used to procure curative serum. The toxons probably play an important role: In natural im munity, i.e., in the form in which, not the poisons isolated, but the causative agents themselves are the factors. Tox olds are decomposition-products of the prepared toxin. 14. It is probable that prototoxins also are, under certain cir cumstances, capable of bringing about a direct cure, by displacing the poison from the tissue-elements by reason of their stronger affinity for the latter. Paul Ehrlich (Dent. med. Woch., Sept. 22, '98).