as the result of further investigation. Denys, Buchner, Martin Hahn,
Goldscheider and Jacob, Loewy 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. Loewit
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," Loewit) 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 Loewit 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 Loewit'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 Loewit 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, Tuerk 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 (Loewy 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
lymphaemia, including that of leukaemia. 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:
([alpha]) =polynuclear leucocytoses=:
1. =polynuclear neutrophil leucocytosis=,
2. =polynuclear eosinophil leucocytosis=;
([beta]) =mixed leucocytoses= in which the granulated mononuclear
elements take part; "=myelaemia=."
[alpha] 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 Tuerk 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 [Greek: kat'
exochen]--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 aetiology,
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 Tuerk. Of Tuerk'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). Stienon, 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 haemoglobinuria (sulphonal poisoning?) as
well as after protracted chloroform narcosis.
3. The =leucocytosis= which accompanies acute and chronic anaemic
conditions, especially posthaemorrhagic.
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 Tuerk. In this
place we will only touch on the most weighty points.
[alpha]. 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.
[beta]. 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
anaemic 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 versa_.
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.
[alpha] 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 leukaemia a considerable time elapsed before an
eosinophilia was found in other diseases, an eosinophilia however that
differs in its essential traits from the leukaemic type. To Friedrich
Mueller 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.
Mueller 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 leukaemia 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 leukaemia, 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 leukaemia, 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 Mueller 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 faeces. In a third case of Ankylostomiasis
Zappert found no increase of eosinophil cells in the blood, nor the
crystals in the faeces. Almost simultaneously, Siege made similar
observations.
For a detailed working out of this important branch we are greatly
indebted to Leichtenstern. Under his direction Buecklers 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]. Buecklers 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 Taenia 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 faeces. Since eosinophil cells
and Charcot's crystals have elsewhere been observed to be interconnected
phenomena (for example in bronchial asthma, in nasal polypi, in myelaemic
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 leukaemia.
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.
Tuerk 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 leukaemia 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.