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.