Part 21

In agreement with Kurloff's researches, Ehrlich formulated ("On severe anæmic conditions" 1892) his views on this subject as follows: "The bone-marrow is a breeding place in which polynuclear cells are produced in large numbers from mononuclear pre-existing forms. These polynuclear cells possess above all other elements the power of emigration. So soon as chemiotactic substances circulate in the blood, which attract the white elements, this power comes into play. This readily explains the rapid and sudden appearance of large numbers of leucocytes, which so many substances bring about, and particularly the bacterio-proteins, recognised by Buchner as leucocytic stimuli. I regard leucocytosis therefore, in agreement with Kurloff, as a function of the bone-marrow."

Of great theoretical interest is the contrast between eosinophil and neutrophil cells. At the height of ordinary leucocytosis, the number of eosinophil cells is diminished often to disappearance; whilst during its decline they occur in abnormally high numbers. Hence it follows that the eosinophil and neutrophil cells must react towards stimulating substances completely differently, and in a certain sense oppositely.

It seems, generally speaking, that the bacterial =metabolic products formed in human diseases which are positively chemiotactic for the polynuclear neutrophil cells are negatively chemiotactic= for the eosinophils, and vice versâ.

The explanation of the individual clinical forms of leucocytosis is self-evident from the above description. The occurrence of physiological and inflammatory leucocytosis is exclusively to be explained by chemiotaxis. In the other forms, however, other factors also come into play, in particular the increased activity of the bone-marrow, or the extensive transformation of fatty to red marrow, causing a large fresh formation of leucocytes.

Our knowledge of eosinophil leucocytosis is still of comparatively recent date. After Ehrlich demonstrated the constant increase of the eosinophil cells in leukæmia a considerable time elapsed before an eosinophilia was found in other diseases, an eosinophilia however that differs in its essential traits from the leukæmic type. To Friedrich Müller we owe the first researches in this direction, at whose suggestion Gollasch investigated the blood of persons suffering from asthma; in which he was able to demonstrate a considerable increase of the eosinophil cells. This was followed by the researches of H. F. Müller and Rieder, who discovered the frequency of eosinophilia in children, and its presence in chronic splenic tumours; further by the well-known work of Ed. Neusser, who observed a quite astounding increase of the oxyphil elements in pemphigus, and by the almost simultaneous analogous observations of Canon in chronic skin diseases. From amongst the flood of further papers upon this condition we will only mention the comprehensive account of the subject by Zappert.

By =eosinophilia= we understand an =increase only of the polynuclear eosinophil cells in the blood=. Confusion of this form of leucocytosis with leukæmia is quite impossible, because a good number of characteristic signs are necessary for the diagnosis of the latter, as we shall have to explain in the next section. The presence of mononuclear eosinophil cells in the blood should not be regarded, as is the case in many quarters, as an absolute proof of leukæmia, for they are also found in isolated cases of ordinary leucocytosis.

The increase of eosinophil cells is not always relative, but may be absolute. The relative number, normally 2 to 4% of all leucocytes, rises in eosinophilia to 10, 20, 30% and over; in a case described by Grawitz 90% indeed was found. The thorough researches of Zappert, carried out on moist preparations by a suitable method, are particularly instructive with regard to their absolute number. As the lowest normal value he gives 50-100 eosinophil cells per mm.^{3}, as mean value 100 to 200, as a high normal value 200-250. The highest absolute number he has ever found was 29,000 per mm.^{3} in leukæmia, the highest number in simple eosinophil leucocytosis 4800 (in a case of pemphigus). Reinbach indeed once found about 60,000 eosinophil cells per mm.^{3} in a case of lymphosarcoma of the neck with metastases in the bone-marrow.

Polynuclear eosinophil leucocytosis, apart from the form observed in healthy children, occurs in varied conditions, and for comprehensiveness we divide them into several groups. We distinguish eosinophilia:

1. =In bronchial asthma.= Increase of the eosinophil cells of the blood, often considerable, amounting to 10 and 20% and more has been regularly found, first by Gollasch, later by many other observers. (For the special clinical course of the eosinophilia in asthma see below.)

2. =In pemphigus.= Neusser first recorded that an extraordinarily great, indeed a specific eosinophilia was found in many cases of pemphigus. This interesting observation has been confirmed on many sides, in particular by Zappert, who once observed 4800 oxyphil per mm.^{3}

3. In acute and chronic =skin-diseases=. Canon was the first to notice that in a fairly large number of skin-diseases, especially in prurigo and psoriasis, the eosinophil cells are increased up to 17%. The observation of Canon is worthy of attention, that the increase of the eosinophils is connected with the degree of extension of the disease, rather than with its nature or local intensity. In a case of acute widely distributed urticaria, A. Lazarus found the eosinophils increased to 60% of the leucocytes, a number which after the course of a few days again sank to normal.

4. =In helminthiasis.= The first observations on the occurrence of eosinophilia in helminthiasis we owe to Müller and Rieder, who obtained fairly high values (8.2 and 9.7%) in two men suffering from Ankylostomum duodenale. Shortly afterwards Zappert stated that he had found a considerable increase of the eosinophil cells in the blood, reaching 17% in two cases of the same disease; at the same time he demonstrated Charcot's crystals in the fæces. In a third case of Ankylostomiasis Zappert found no increase of eosinophil cells in the blood, nor the crystals in the fæces. Almost simultaneously, Siege made similar observations.

For a detailed working out of this important branch we are greatly indebted to Leichtenstern. Under his direction Bücklers established the interesting fact that Ankylostomiasis in its relation to eosinophilia does not occupy a special place in diseases caused by worms. All kinds of Helminthides, from the harmless Oxyuris to the pernicious Ankylostoma, may bring about an increase of the eosinophil cells in the blood, often to an enormous extent. Bücklers reports an observation of 16% eosinophils in Oxyurides, of 19% in Ascarides; and Prof. Leichtenstern, as we learn from a private communication, has quite recently found 72% eosinophil cells in a case of Ankylostomiasis, and 34% in a case of Tænia mediocanellata.

It is well worthy of note that Leichtenstern was able to observe numerous eosinophil cells in the blood in those cases where Charcot's crystals were abundantly contained in the fæces. Since eosinophil cells and Charcot's crystals have elsewhere been observed to be interconnected phenomena (for example in bronchial asthma, in nasal polypi, in myelæmic blood and bone-marrow) one must fall in with Leichtenstern's supposition that eosinophil cells ought also to be found in the intestinal mucus in cases of Ankylostomiasis. Positive observations on this point as yet are wanting.

T. R. Brown, who worked under direction of Thayer, has lately communicated the interesting observation that in =trichinosis= there is constantly an extraordinary relative increase in the oxyphil leucocytes in the blood, up to 68%. The absolute figures were also much raised, and attained values (20,400 for example) which are by no means frequent even in leukæmia.

Brown regards this astonishing phenomenon as pathognomic for trichinosis, so much so, that in a case that was clinically obscure, he made, from the marked eosinophilia, the diagnosis of trichinosis which was later fully confirmed.

5. =Post-febrile form of eosinophilia= (after the termination of various infectious diseases). In the section on polynuclear neutrophil leucocytosis we have already mentioned that at the height of most of the acute infectious diseases, with the single exception of scarlet fever, the eosinophils undergo a relative decrease and may even entirely disappear. In the post-febrile period, however, abnormally high values for the eosinophil cells are often found, or even a well-marked eosinophil leucocytosis, which generally attains but moderate degree. Türk for example in pneumonia found a post-critical eosinophilia of 5.67% (430 absolute), after acute articular rheumatism 9.37% (970 absolute); Zappert in malaria, one day after the last attack 20.34% (1486 per mm.^{3}).

The eosinophilia observed as the result of tuberculin injections, we include, in agreement with Zappert, in the group of post-febrile leucocytosis. For it appears only after considerable rises of temperature. During the real reaction period the number of eosinophil cells sinks, and only goes up again after the termination of the fever. The rise may be very considerable. In one case of Zappert's the number of the oxyphils increased to 26.9%; in another of his cases the highest absolute figure formed after tuberculin injections was 3220 per mm.^{3} In a case of Grawitz' the eosinophilia was quite extraordinary. The most marked changes in the blood occurred some three weeks after cessation of the tuberculin injections, of which eight altogether (from 5 mg. to 38 mg.) were given. Investigation shewed 4,000,000 red blood corpuscles per mm.^{3}, 45,000 white. Amongst the latter there were ten eosinophils to one non-eosinophil. The total number of eosinophil cells amounted to some 41,000 per mm.^{3}, whilst the other cells as a whole made up some 4000. Inasmuch as the latter contained polynuclears, lymphocytes and other forms, it follows that in this case the polynuclear neutrophils must have been very much decreased, not only relatively but also absolutely; so that this case represents precisely the contrary condition to ordinary leucocytosis and the infectious form in particular.

6. =In malignant tumours.= In the cachexia from tumours an increase of the eosinophil cells has been observed by various authors. It is however of moderate degree and does not exceed 7-10%. Out of 40 decided cases Reinbach found the eosinophils increased only in four, in a case of sarcoma of the forearm he found 7.8%; of the thigh 8.4%; malignant tumour of the abdomen 11.6%. Besides these he describes a case of lymphosarcoma of the neck with metastases in the bone-marrow, in which an unexampled increase of the white blood corpuscles, and especially of the eosinophil cells was found. The absolute number of the latter amounted on one day to some 60,000! This is an increase of 300 fold the normal, which apart from leukæmia has doubtless never before been found.

7. =Compensatory eosinophilia= (after exclusion of the spleen). We have entered in detail into this form in the chapter on splenic function; and have there already mentioned that the increase of the eosinophils found in chronic splenic tumours by Rieder, Weiss and others, must also be referred to the exclusion of the splenic function.

8. =Medicinal eosinophilia.= Under this group occurs only a single observation of v. Noorden's, who observed the appearance of an eosinophilia up to 9% in two chlorotic girls after internal administration of camphor. In other patients this occurrence did not repeat itself. But probably researches specially directed to this province of pharmacology would bring to our knowledge many interesting facts.

On the origin of ~polynuclear eosinophil leucocytosis~ authors have put forward various theories, which we will here critically discuss in succession.

An experiment frequently quoted as explanatory is that of Müller and Rieder's; these authors do not derive the eosinophil cells of the blood from the bone-marrow, but assume, as very probable, that the finely granular cells grow into eosinophils within the blood-stream. This developmental process seems very improbable for many reasons. Since the polynuclear cells circulating in the blood are all under the same conditions of nutrition, it is à priori inconceivable why only a relatively small portion of them should undergo the transformation in question. And it is quite inexplicable why in infectious leucocytosis, where the number of the polynuclears is increased so enormously, their ripening to the eosinophils should remain completely interrupted.

But the fact, that a transition from neutrophil to oxyphil cells has never really been observed in the blood, is decisive evidence against the hypothesis of Müller and Rieder. Were the hypothesis true, transitional stages ought to be found with ease in every sample of normal blood. Rieder and Müller themselves are unable to bring forward any positive result of this kind, else they would hardly have been contented to fall back on the authority of Max Schultze, who professed to shew the transitional forms between the finely and coarsely granular leucocytes in the circulating blood. The authority of Max Schultze in morphological questions stands high, and very rightly; but one ought not to rely upon it for support in problems that are really histo-chemical, and which should be solved by their appropriate methods.

As a logical consequence of their view, and in decided opposition to Ehrlich, Müller and Rieder assume that the eosinophil cells of the bone-marrow "are far rather the expression of a storage than of a fresh formation there. =The bone-marrow therefore should be regarded in reference to the coarsely granular cells of the blood more as a storage depôt, where these cells serve other purposes, which for the present cannot be more closely defined.="

The chief reason for this assumption, these authors see in the fact, that the majority of the eosinophils in the bone-marrow are mononuclear, whilst those of normal blood possess a polymorphous nucleus. Müller and Rieder should themselves have raised the obvious objection that the same holds good for the nucleus of the neutrophils. They would then have seen the fault in their theory; for according to it the most important blood preparing organ constitutes as it were, not the cradle of the blood cells, but their grave. The simplest and readiest explanation, based too upon histological observation, is surely this: that the mononuclear eosinophil cells grow into polynuclear in the bone-marrow, but that the latter only reach the blood by means of their power of emigration. As this view has been accepted by the great majority of authors since Ehrlich's paper "On severe anæmic conditions," we believe we may content ourselves with the above objections to the Müller-Rieder theory, although it has even quite recently found supporters (e.g. B. Lenhartz). H. F. Müller moreover in his paper on bronchial asthma (1893) takes a position different from his earlier, and approaching that of Ehrlich.

In considering the production of polynuclear eosinophilia we may best start from an experiment of E. Neusser's. Neusser found in a pemphigus patient, whose blood shewed a considerable increase of the eosinophils, that the contents of the pemphigus bulla consisted almost entirely of eosinophil cells. Neusser now produced a non-specific inflammatory bulla in the skin by a vesicant, and found that the cellular elements in it were exclusively the polynuclear neutrophil concerned in all ordinary inflammations.

Exactly analogous conditions, occurring spontaneously, have been demonstrated by Leredde and Perrin in the so-called Dühring's disease. The bullæ which appear in this dermatosis contain, so long as their contents are clear, chiefly polynuclear eosinophil cells. In a later stage, as is usually the case, bacteria effect an entrance into the bullæ, which now become filled with neutrophils.