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 Mueller 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 _a 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 Mueller and Rieder. Were the hypothesis true,
transitional stages ought to be found with ease in every sample of
normal blood. Rieder and Mueller 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, Mueller 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
depot, 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. Mueller 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 anaemic conditions," we believe we may content
ourselves with the above objections to the Mueller-Rieder theory,
although it has even quite recently found supporters (_e.g._ B.
Lenhartz). H. F. Mueller 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 Duehring's disease.
The bullae 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
bullae, 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 bullae 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 depot 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 Mueller-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 leukaemia, 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 leukaemia 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
leukaemia, 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. Michaelis
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 Michaelis' 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 Duehring's disease, that the eosinophil cells,
which are also present in the cutaneous tissue in large numbers, apart
from the contents of the bullae, 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. Mueller, 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 anaemic 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
faeces; 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[32]. 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 anaemia, 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 anaemia. Many observations, the
absence, for example, of eosinophilia in Bothriocephalus anaemia
(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 anaemic condition is due.
Leukaemia.
("Mixed leucocytosis.")
In spite of the enormous extent of the haematological observations of the
last decennia, of which a very considerable portion deals with the
problem of leukaemia, 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 leukaemia.
From the purely clinical standpoint it is usual to describe a lienal, a
lienomedullary, and a pure medullary (myelogenic) form of leukaemia. But
the distinguishing characteristics in this classification are crude and
purely external, and they find no place in haematology.