Part 22

According to modern views on suppuration, the experiment of Neusser and the observation of Leredde and Perrin can only be explained by the hypothesis, that the eosinophil and neutrophil cells, as we have already several times mentioned, are of different chemiotactic irritability. Hence the eosinophil cells only emigrate to those parts where a specific stimulating substance is present. From this point of view experiments and clinical observations known up to the present on eosinophilia may be readily explained. Neusser's experiment for instance may be explained in the following way. In the pemphigus bullæ a substance is present that chemiotactically attracts the eosinophils. Hence the cells normally contained in the blood emigrate into them, and produce the picture of an eosinophilous suppuration. Should the disease assume from the first a localised distribution only, the essential feature of the process is excluded. =A totally different appearance, however, is produced= when the disease has attacked large areas. =Under these circumstances large amounts of the specific active agent reach the blood-stream by absorption and diffusion. Here it exercises a strong chemiotactic influence on the physiological storage depôt of the eosinophils, the bone-marrow; leading to an increase of the eosinophils of the blood to a greater or less degree. The bone-marrow, according to general biological laws, is by the increased emigration now further stimulated to a fresh production, and during a protracted illness can hence keep up the eosinophilia.=

In this way other clinical observations may be explained. Gollasch has found that the sputum of asthmatic patients contains, in addition to Charcot-Leyden's crystals, eosinophil cells only. One must therefore assume that within the bronchial tree there exists material which attracts the eosinophils. This supposition is also supported by the close connection that obtains, according to many observations, between the severity of the disease and the eosinophilia. Thus v. Noorden records that the eosinophil cells are more numerous about the time of an attack. They accumulated in especially large numbers after attacks had rapidly occurred several days in succession. =That the increase of the eosinophil cells in this instance is directly connected with the attacks, and is not the expression of a permanent constitutional anomaly=, is shewn by a case in which v. Noorden found 25% eosinophils during the attack, and a few days later could only observe one example in twelve cover-slip preparations: a diminution therefore of this group of cells.

The observations of Canon in skin-diseases are quite similar, for he shewed that the extension of the disease determines the degree of eosinophilia more than its intensity. And it is the former factor which directly determines the quantities of the specific agent that pass into the blood.

To the Müller-Rieder hypothesis, and the chemiotactic theory of eosinophil leucocytosis a third has lately been added, which may be shortly called =the hypothesis of the local origin= of the eosinophil cells. A. Schmidt has, with special reference to asthma, raised the question "whether in the extensive production of eosinophil cells in asthma, local production in the air passages is not more probable than origin from the blood. One may well regard the increase of the eosinophil cells in the blood of an asthmatic as secondary." This view, which has also been advocated by other authors, rests more particularly on the following facts and considerations:

1. That in various diseases of the nose, especially in mucous polypi and hyperplasia of the mucous membrane (Leyden, Benno Lewy and others), a great accumulation of eosinophil cells is found in these tissues, whilst they are apparently not increased in the blood. This objection is easily laid aside from the chemiotactic point of view. For if in the places in question substances are present which act chemiotactically on the eosinophil leucocytes, in the course of time marked accumulation must occur, without an increase of their number in the blood. One might as well conclude from Neumann's experiment in lymphatic leukæmia, for example, where the artificial suppuration consisted only of polynuclear neutrophil cells, that the polynuclear cells were formed in the tissue, since in the blood they were present in very small percentage. For in this case too the same incongruity between the blood and the particular tissue exists.

2. Adolph Schmidt has urged the converse argument. He shewed that in the sputum of patients with myelogenic leukæmia no more eosinophil cells were present than are commonly to be found in the bronchial secretion, although the blood was unusually rich in eosinophil cells. In our opinion however this observation does not support the hypothesis of local origin, but on the contrary is clear evidence that not the larger or smaller number of eosinophil cells in the blood decides their emigration, but the presence of specifically active chemical stimuli. For we know from our observations on leucocytosis in infectious diseases that the bacterial stimulating substances act on the eosinophil cells rather in a negative than in a positive sense. And if ordinary sputum is not rich in eosinophils in spite of a marked eosinophilia of the blood, this only corresponds to our experience in general. Indeed, this phenomenon is quite similar to Neusser's pemphigus experiment, where the specific foci of disease shewed an eosinophilia, whilst abscesses produced artificially, on the contrary, only neutrophil cells. Finally we may employ, to support our view, another analogous experiment of Schmidt himself. He found numerous eosinophil cells in the sputum of an asthmatic patient, but only neutrophil cells in an artificially produced suppuration of the skin.

Thus we see that the chief reasons brought forward by the supporters of the theory of local origin are not proof against the most obvious objections that can be raised from the chemiotactic standpoint. Moreover, neither histological nor experimental proof has been given for this theory in spite of numerous investigations in this direction. All the same, it should not be out of place to explain the possibilities that are given for a local origin of the eosinophil cells. First, the eosinophil cells might be the result of a progressive metamorphosis of the normal tissue cells. That such a process is possible, is proved by the local origin of the mast cells. These may arise, as Ehrlich and his school have always assumed, by transformation of pre-existing connective tissue cells; but that the same holds good for the eosinophil cells as well, has nowise as yet been proved. Secondly, it is conceivable, that isolated eosinophil cells, pre-existing in the tissues, should rapidly multiply, and so produce the local accumulation only. Numerous mitoses could be considered an adequate proof of this process. But so far no figures of nuclear division have been observed; indeed A. Schmidt, who has directed special experiments thereto from the standpoint of his theory, has found them entirely absent.

As a =third= possibility for the local origin of the eosinophil cells, their direct descent from neutrophil cells is conceivable, and is by many regarded as a kind of ripening. This assumption nevertheless must be described as unsound, since the necessary condition of its foundation, namely the observation of corresponding transitional stages, has not so far been fulfilled.

By the inductive method then we conclude that a local origin of the eosinophil cells can hardly come under discussion. And this conclusion is strengthened by comparison with the behaviour of the mast cells, which are related to the eosinophils in many points, and only differ from them essentially in the nature of their granulation. The mast cells too, like the eosinophils, form a normal constituent of the bone-marrow, and occur regularly besides in normal blood, though in very small number--according to Canon they amount to 0.28% of the leucocytes. We know that the mast cells are produced in large quantities locally, wherever an over-nutrition of the connective tissue occurs, for instance in chronic diseases of the skin, elephantiasis, brown induration of the lungs. In the case of the mast cells, then, we see the conditions actually realised, which the supporters of the theory of the local origin of the eosinophil cells only assume. We should therefore expect that an increase of mast cells in the blood or in certain inflammatory exudations would be by no means seldom. With this point in mind Ehrlich has subjected the sputum in emphysema and brown induration of the lungs to exact examination for 20 years. Nevertheless he has obtained =entirely negative= results. The special blood investigations of Canon have likewise proved to be practically negative. In 22 healthy persons Canon entirely failed to find the mast cells on nine occasions, in the others he found on the average 0.47%; the highest percentage number obtained was 0.89%. Only in a few cases of skin disease was a slight increase indicated. The average amounted to 0.58%, a number, therefore, which is often to be found in healthy individuals. A leucocytosis of mast cells, comparable with the eosinophil or neutrophil forms of leucocytosis, has not been demonstrated in the cases of Canon or other observers. On the other hand, the mast cells undergo a considerable increase in myelogenic leukæmia, in many cases equalling or even exceeding that of the eosinophils. We shall not err in deriving the mast cells of the blood solely from the bone-marrow, on the grounds of this fact; or in conjecturing that their origin is not from the connective tissue, even when they are there excessively increased.

We think we have shewn in the preceding paragraphs that the evidence, so far brought forward for a local origin of the eosinophil cells, does not withstand the objections that have been raised. The task now lies before us, to produce positive proof that the accumulations of eosinophil cells in the organs and secretions must be explained by emigration from the blood.

This proof offers great difficulties in as much as we normally find eosinophil cells in many places. Here then we cannot trace a process step by step, but we have to deal with final conditions. Could we observe the genesis of eosinophil cells in organs usually free from them, it would be easier to clear up this question. Up to the present but a single observation on this point is available. Michælis established the interesting fact, that on interrupting lactation in suckling guinea-pigs, in the course of a few days numerous eosinophil cells collect in the mammary glands, but not in the lumen of the canaliculi. The eosinophil cells are further polynuclear, exactly corresponding to those of the blood, and therefore to be regarded as immigrants. We may explain this condition according to modern views as follows. Under certain conditions the mammary gland is capable of an internal secretion, by means of which substances are produced that are specifically chemiotactic for the eosinophil cells. When the external secretion of milk is disturbed, the internal secretion is abnormally increased. The fact too that in Michælis' researches no eosinophil cells passed into the true secretion of the gland may be thus explained.

Exactly similar observations have been made on pathological material, first recorded in the brilliant and fundamental work of Goldmann. In a case of malignant lymphoma Goldmann found a considerable accumulation of eosinophil cells within the tumour, and demonstrated anatomically, that it was brought about by an emigration of the cells from the vascular system. Hence Goldmann concluded that the eosinophil cells pass over into the tissue in question, at the call of certain chemiotactic products. Goldmann, and later Kauter, shewed that these eosinophil cells were not merely due to an ordinary inflammation; for in a large number of other diseases of the lymph glands--particularly the tuberculous, they were entirely absent. Similarly Leredde and Perrin have shewn in their investigations of Dühring's disease, that the eosinophil cells, which are also present in the cutaneous tissue in large numbers, apart from the contents of the bullæ, are due to an emigration from the blood-stream.

Thus it is evident from a number of various facts, that the eosinophil cells found in the tissues are not formed there, but have immigrated from the blood-stream. It naturally often happens that this appearance is not preserved equally distinctly in all cases. For, as has been seen in the ordinary polynuclear leucocytes, the immigrated polynuclear eosinophils may similarly change to mononuclear cells; they may perhaps settle down, and approximate to the character of fixed connective tissue cells. Such appearances may readily give rise to the view that in this case the reverse nuclear metamorphosis has occurred; that is a progressive development from mononuclear eosinophil to polynuclear cells.

In agreement with Goldmann, Jadassohn and H. F. Müller, we believe that the only admissible explanation for the facts mentioned above is that the eosinophil cells obey specific chemiotactic stimuli. By this hypothesis we can easily understand eosinophil leucocytosis, the presence of eosinophil cells in exudations and secretions, and the local accumulation of this kind of cell.

As to the nature of these chemiotactically active substances, we can so far only surmise. From amongst the clinical phenomena capable of throwing light on this subject we mention once more the fact, that the metabolic products of bacteria repel the eosinophil cells.

The opposed behaviour of eosinophil and neutrophil cells is very well illustrated by a case of Leichtenstern:

"In a very anæmic almost moribund patient with Ankylostomias there were found 72% eosinophil cells in the blood in 1897. The patient contracted a croupous pneumonia, and in the high febrile period of the disease the number of eosinophils sank to 6-7%, and rose again after the termination of the pneumonia to 54%. After removal of the worm the number at once fell to 11%. In the year 1898 the patient harboured but a very few Ankylostomata; Charcot's crystals were no longer present in the fæces; the number of the eosinophils amounted to 8%."

The question, what cells produce on their destruction actively chemiotactic substances, is of very great importance; but cannot be answered with the material at present available. The breaking up of ordinary pus cells or lymphocytes does not appear to give rise to any such substances; but there is much evidence that the decomposition products of epithelial and epithelioid cells act chemiotactically. Thus we can explain the frequent occurrence of eosinophilia in all kinds of skin-diseases. Again, in all atrophic conditions of the gastric, intestinal and bronchial mucous membrane there occurs a local accumulation of eosinophil cells; further, this kind of cell is increased in the neighbourhood of carcinoma. Additional support for this view is seen in the fact that in bronchitis and asthma the less the suppurative element of the secretion is developed, the more numerous are the eosinophil cells. An observation of Jadassohn is worthy of mention in this connection. He observed abundant eosinophil cells in foci of lupus after injection of tuberculin. In these foci then, by the destruction of the epithelioid cells brought about by the tuberculin, substances must have been produced which act chemiotactically on the eosinophil cells.

The specific substances are absorbed and reach the blood, and impart to it also the chemiotactic power. =The direct cause then of most forms of eosinophilia seems actually to lie in a destruction of tissue, and in the products thus produced.=

On the other hand, it cannot be doubted that substances foreign to the organism, circulating in the body, may act chemiotactically on the eosinophil cells. The observations quoted above, of the well-marked eosinophilia in the different forms of Helminthiasis, may here be specially mentioned. The action of the Helminthides was formerly regarded as purely local, but the indications that they act also by the production of poisonous substances continue to increase. Thus Linstow has pointed out that the general typhoid state, and the fatty degeneration of liver and kidneys, that is of organs which the Trichina does not reach, necessitate the assumption of a poisonous substance. And in several varieties of Ankylostoma as well, there is distinct evidence of the production of a poison. We gather from Husemann's article on "animal poisons" (Eulenberg's Realenencyclopoedie 1867) that just as Ankylostomum in man produces the well-known severe anæmia, so Ankylostomum trigonocephalum in the dog, and Ankylostomum perniciosum in the tiger, causes analogous general effects.

Bothriocephalus latus too is now generally accredited with the production of a definite toxic substance; and the common tapeworm even, by no means infrequently brings about injuries to the body which are to be referred to the action of a poison.

So much follows from these observations, that the tapeworms can not only absorb but also can give out substances that are absorbed from the intestine of the host, and are able to bring about distant effects. One expression of these distant actions is, as Leichtenstern insists, the eosinophilia of the blood. We do not think we should assume on the evidence before us, that the substance which attracts the eosinophil cells is identical with the cause of the anæmia. Many observations, the absence, for example, of eosinophilia in Bothriocephalus anæmia (Schauman), render probable the existence of two different functions. In any case the substance causing the eosinophilia is more widely distributed than that to which the anæmic condition is due.

Leukæmia.

("Mixed leucocytosis.")

In spite of the enormous extent of the hæmatological observations of the last decennia, of which a very considerable portion deals with the problem of leukæmia, the literature shews many obscurities and misconceptions, even on important fundamental ideas. This is especially the case with the weighty question of the distinction between various forms of leukæmia.

From the purely clinical standpoint it is usual to describe a lienal, a lienomedullary, and a pure medullary (myelogenic) form of leukæmia. But the distinguishing characteristics in this classification are crude and purely external, and they find no place in hæmatology.

Neumann first shewed that the lymphoid proliferation in lymphatic anæmia is not confined to the lymph glands, but may extend to the spleen and bone-marrow. These proliferative processes may give rise to a considerable enlargement, for example, of the spleen, without any change in the specific character of the leukæmia, or the condition of the blood. In spite of the splenic tumour we have to deal then with a pure lymphatic leukæmia. In customary clinical language, a case of this kind would be described as lieno-lymphatic leukæmia. The unreliability and incorrectness of this terminology is best illustrated by another form of leukæmic metastasis. In lymphatic leukæmia the liver may swell by lymphomatous growth, to a large tumour, and we ought then to speak of a "hepato-lymphatic" form of leukæmia. This term is by no means so misleading as lieno-lymphatic; for no one would conclude from the former that any liver-cells passed into the blood, whilst the latter implies the idea, that specific splenic cells take part in the blood changes.

Further, the assumption of a pure =lienal= variety of leukæmia is totally unwarranted from hæmatological investigations. The possibility of a specific blood change, depending solely upon disease of the spleen, appears à priori almost excluded, after what has been said on the physiological participation of the spleen in the formation of the blood.