The problem of leucocytosis is one of the most keenly debated questions of modern medicine. An exhaustive account of the various works devoted to it, of the methods and results, could fill by itself a whole volume, and would widely exceed the limits of an account of the histology of the blood. We can only deal fully therefore with the purely hÆmatological side of the subject.

Virchow designated by the name "Leucocytosis," a transient increase in the number of the leucocytes in the blood; and taught that it occurred in many physiological and pathological conditions. In the period that followed particular attention was paid to the leucocytosis in infectious diseases, and to the investigators of the last 15 years in this province we owe very important conclusions as to the biological meaning of this symptom. Above all Metschnikoff has done pioneer service in this direction by his theory of phagocytes, and though his theory has been shaken in many essential points, yet it has exercised a stimulating and fruitful influence on the whole field of investigation.

To sketch Metschnikoff's doctrine in a few strokes is only possible by a paraphrase of the very pregnant words "Phagocytes, digestive cells." These words express the view, that the leucocytes defend the organism against bacteria by imprisoning them by the aid of their pseudopodia, taking them up into their substance, and so depriving them of the power of external influence. The issue of an infectious disease would chiefly depend on whether the number of leucocytes in the blood is sufficient for this purpose.

This engaging theory of Metschnikoff has undergone important limitations as the result of further investigation. Denys, Buchner, Martin Hahn, Goldscheider and Jacob, LÖwy and Richter, and many others have demonstrated, that the most important weapon of the leucocytes is not the mechanical one of their pseudopodia, but their chemical products ("Alexine," Bucher). By the aid of bactericidal or antitoxic substances which they secrete, they neutralise the toxines produced by the bacteria, and thus render the foe harmless by destroying his weapon of offence, even if they do not exterminate him.

An explanation of the almost constant increase of the leucocytes of the blood in bacterial diseases is given by the chemiotactic as well as by the phagocytic theory of leucocytosis. The principle of chemiotaxis discovered by Pfeffer asserts that bacteria, or rather their metabolic products, are able to attract by chemical stimulus the cells stored up in the blood-forming organs ("positive chemiotaxis"). In the cases in which a diminution of the leucocytes in the blood is found, it is the result of a repulsion of the leucocytes by the bodies mentioned, negative chemiotaxis.

As the experimental investigation of leucocytosis was carried further, it was found that leucocytosis, quite similar to that occurring in infectious diseases, could also be brought about by the injection of various chemical substances (bacterio-proteins, albumoses, organic extracts and so forth); and it became evident that the explanation of the process by chemiotaxis must be supplemented in many respects. LÖwit for instance found that when substances of this kind are injected, two different stages can be distinguished in the behaviour of the leucocytes. First came a stage in which they were diminished ("leukopenia," LÖwit) and in such a way that only the polynuclear cells were concerned in the diminution, whilst the number of the lymphocytes was unchanged. After this came the phase of increase of the white blood corpuscles; and here too exclusively of the polynuclear cells; the polynuclear leucocytosis. This behaviour seemed to indicate that during the first period a destruction of white blood corpuscles brought about by the foreign substances took place, and that it was only the dissolved products of the latter which caused the emigration of fresh leucocytes by chemiotaxis. But new objections were raised against this view. Goldscheider and Jacob, in particular, shewed by exact experiments that the transient leukopenia of the blood was not true but merely apparent; and was caused by an altered distribution of the white blood corpuscles within the vascular system. For whilst in the peripheral vessels from which the blood for investigation was usually obtained, there was in fact a diminution of the leucocytes, "hypoleucocytosis," in the capillaries of the internal organs, especially of the lungs, a marked increase of the leucocytes, "hyperleucocytosis," was found.

There are other objections to the great importance that LÖwit has given to leukopenia. A priori it is quite incomprehensible that the various substances, which in the fundamental test-tube experiment are able to exercise a distinct chemiotactic influence on the leucocytes, should under other circumstances need the intervention of the products of decomposition of the white blood corpuscles. Moreover clinical experience speaks in general against LÖwit's theory. For in infectious diseases hyperleucocytosis is very common; and a transient leukopenia is equally rare.

This contradiction to the experimental results obtained by LÖwit is easily explained when one reflects how different from the natural processes of disease are the circumstances of experiment. In this case the animal is by intravenous injection flooded at once with the morbid substance, and a violent acute reaction of the vascular and blood systems is the natural consequence. In natural infection, insidious and increasing amounts of poison come quite gradually into play, and for this reason, perhaps, hypoleucocytosis in the normal course of infectious diseases is much rarer than in the brusque conditions of experiment.

Upon the clinical importance of leucocytosis, particularly for the infectious diseases and their various stages, an enormous mass of observations has accumulated. Selecting pneumonia as the best studied example, in the typical course of this disease the constant occurrence of leucocytosis is undisputed; the increase usually continues up to the crisis, and then gives place to a diminution of the leucocytes until a subnormal number is reached.

Of special importance are the observations on an absence of leucocytosis in particularly severe or lethally ending cases (Kikodse, Sadler, v. Jaksch, Tschistowitch, TÜrk and others).

In many other diseases as well, the observation has been made that hyperleucocytosis as a rule is only absent in specially severe, or in some way atypical cases. Several observers (LÖwy and Richter, M. Hahn, Jacob), have been able to demonstrate experimentally for various infections, that artificial hyperleucocytosis influences the course of an artificial infection most favourably. The question, in what way does this process contribute to the protection of the body, is at the present time under discussion, and introduces the most difficult problems of biology.

The morphological character of leucocytosis is certainly not simple, and we must sharply separate various groups, according to the kind of leucocyte increased.

The most important consideration is, whether cells capable of spontaneous movement, and of active emigration into the blood, are increased ("active leucocytosis"); or whether the number of those cells is raised, to which an independent mobility cannot be ascribed, which therefore are only passively washed into the blood-stream by mechanical forces ("passive leucocytosis").

The passive form of leucocytosis corresponds to the different kinds of lymphÆmia, including that of leukÆmia. In the section on the lymphatic glands, we have established this view in detail, and we have particularly insisted that a suppuration, consisting of lymph cells, does not occur.

In sharp contrast to this form there are for every specific kind of active leucocytosis, analogous products of inflammation (pus, exudations), composed of the same kind of cell.

We divide active leucocytosis into the following groups:

(a) polynuclear leucocytoses:

1. polynuclear neutrophil leucocytosis,
2. polynuclear eosinophil leucocytosis;

() mixed leucocytoses in which the granulated mononuclear elements take part; "myelÆmia."

a 1. Polynuclear neutrophil leucocytosis, is the most frequent of all forms of active leucocytoses.

Virchow, the discoverer of leucocytosis, advocated the view, that it resulted from an increased stimulation of the lymph glands. The stimulation of the lymph glands consists in "that they are engaged in an increased formation of cells, that their follicles enlarge, and after a time contain many more cells than before." The swelling of the lymphatic glands has as a consequence an increase of the lymph corpuscles in the lymph, and through this an increase again of the colourless blood corpuscles.

This standpoint had to be abandoned, when Ehrlich shewed that it is chiefly the emigration of the polynuclear neutrophil cells, which brings about leucocytosis. Exact figures on this point were first given by Einhorn, who worked under Ehrlich, and were later generally confirmed. Corresponding with the increase of neutrophil blood corpuscles alone, there is always a relative decrease of lymphocytes, often to 2% and even lower. It must here be borne in mind, that the percentage of the lymph cells may be much diminished, without change in their absolute number. It has however been conclusively demonstrated that occasionally in polynuclear leucocytosis, the absolute number of the lymphocytes may decrease. Einhorn had already described a case of this kind, and recently TÜrk has for the first time established the fact by an abundance of numerical estimations[25].

The eosinophil cells are as a rule diminished in ordinary polynuclear leucocytosis, as Ehrlich had already mentioned in his first communication. The diminution is often considerable, often indeed absolute.

A few diseases shew, besides the neutrophil leucocytosis, an increase of the eosinophils as well, as we shall describe in detail in the next section.

Polynuclear neutrophil leucocytosis—leucocytosis ?at' e?????—may be divided into several groups according to their clinical occurrence. We distinguish:

A. physiological leucocytosis,

which appears in health as an expression of changes in the physiological state. To this group belongs the leucocytosis of digestion, the leucocytosis from bodily exertion (Schumburg and Zuntz) or from cold baths, and further the leucocytosis of pregnancy.

B. pathological leucocytosis.

1. The increase of polynuclear cells occurring in infectious processes, often called inflammatory, after the principle "a potiori fit denominatio." The majority of febrile infectious diseases, pneumonia, erysipelas, diphtheria, septic conditions of the most varied Ætiology, parotitis, acute articular rheumatism, etc. are accompanied by a leucocytosis of greater or less extent. In this connection uncomplicated typhoid fever and measles occupy a peculiar position. In them the absolute number of white blood corpuscles is diminished, and chiefly at the expense of the polynuclear neutrophil cells.

For the details we have quoted, and for the course and variations of leucocytosis in infectious diseases we refer to the thorough monograph of TÜrk. Of TÜrk's observations we will mention only that in the final stage of the process of leucocytosis, which occurs at the time of the crisis in diseases which run their course critically, mononuclear neutrophil cells and stimulation forms as well often make their appearance in the blood. In still later stages, in which the blood has once more a nearly normal composition, a moderate increase of the eosinophils—gradually waxing and again waning—is very frequently found (Zappert and others). StiÉnon, who has likewise devoted special researches to the occurrence of leucocytosis in infectious diseases, shews this point very well in his curves.

2. Toxic leucocytosis occurring in intoxications with the so-called blood poisons. This important group has not yet received adequate treatment in the literature. In general the majority of blood poisons, potassium chlorate, the derivatives of phenyl hydrazin, pyrodin, phenacetin call forth even in man a considerable increase of the leucocytes besides the destruction of the red blood corpuscles. This has been observed experimentally by Rieder.

We observed marked increase of the white blood corpuscles after poisoning from arsenurietted hydrogen, from potassium chlorate, further in a fatally ending case of hÆmoglobinuria (sulphonal poisoning?) as well as after protracted chloroform narcosis.

3. The leucocytosis which accompanies acute and chronic anÆmic conditions, especially posthÆmorrhagic.

4. Cachectic leucocytosis in malignant tumours, phthisis, etc.[26]

To enter here more precisely into the special clinical importance of blood investigation in different forms of disease would lead us too far, and we refer for this subject to the excellent and thorough monograph on leucocytosis by Rieder and to the papers of Zappert and TÜrk. In this place we will only touch on the most weighty points.

a. The importance for differential diagnosis of the leukopenic blood condition in typhoid fever as compared with other infectious diseases, and in measles as against scarlet fever.

. The prognostic importance of the enumeration of the white blood corpuscles. Thus for example the absence of leucocytosis influences the prognosis of pneumonia unfavourably (Kikodse and others); and the appearance of numerous myelocytes in diphtheria is ominous, as demonstrated by C. S. Engel (see page 78).

Finally, we may dismiss in a few words the origin of polynuclear neutrophil leucocytosis, and refer to what has been said in another place on the function of the bone-marrow.

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[27].

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.

a 2. Polynuclear eosinophil leucocytosis. Mast cells.

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[28]. 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.

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[29]; 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[30].

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[31].

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%."