Leukocytosis

LEUKOCYTOSIS. Contents: Redistributive L. and mechanism of its origin.................556 Mechanism of origin of true L. .... 557 Condition of bone marrow in L........560 Physiological L................560 Pathological L................563 Leukocytosis, temporary increase in the number of leukocytes in peripheral blood. Such a definition was already given by Virchow, to whom the word "leukocytosis" belongs. At that time, they spoke of L. when the peripheral blood on an empty stomach contained more than 10,000 leukocytes in 1 mm³. But such a purely quantitative definition of L. is insufficient, since an increase, for example, only in the number of neutrophils even without an increase in the total number of leukocytes, even with a decrease in the latter, is also called leukocytosis, in this case neutrophilic. Thus, the word "leukocytosis" denotes not only a temporary increase in the total number of all leukocytes, but also an increase in at least one form of leukocytes. An increase in the number of neutrophils, eosinophils, and basophils is called neutrophilic, eosinophilic, and basophilic L.; while an increase in lymphocytes and monocytes is called lymphocytosis and monocytosis. Often, to denote an increase in the total number of leukocytes, the term "hyperleukocytosis" is also used, and the term "hypoleukocytosis" is used to denote a decrease in the total number of leukocytes (instead of the word leukopenia-see).- To distinguish L. from leukemia, it was usually said that L. is a transient and symptomatic change in the blood, but such a distinction is fundamentally incorrect, since the change in blood in leukemia is also only a symptom, and not the disease itself. It is also incorrect to distinguish L. from leukemia by the total number of leukocytes, since if in leukemia it is not at all necessary to have a large increase in the total number of leukocytes, then on the other hand, in L., enormous quantities of leukocytes are sometimes observed-up to 100,000, even up to 250,000 in 1 mm³. Speaking of the mechanism of origin of L., it is necessary to distinguish between true (actual) L. and apparent L. The first is due to a temporary but actual increase in the number of blood leukocytes. The second, however, is due to a temporary increase in the number of leukocytes only in the blood of peripheral capillaries at the expense of a decrease in the number of leukocytes in the blood of capillaries of internal organs; this L. is therefore called redistributive (Verteilungs-leukocytose). Redistributive leukocytosis and mechanism of its origin. It should be considered as an established fact that leukocytes are unevenly distributed in the periphery and in internal organs even in the physiological state of the body. In recent years, this has been particularly clearly shown by Graff. Capillaries of internal organs, especially of the abdominal cavity, are much richer in leukocytes than peripheral capillaries, and many forms of rapidly passing and especially physiological leukocytoses are explained by the increased influx of leukocytes to the periphery. This includes static L. (see below), L. after mild thermal influences, daily fluctuations of leukocytes, L. during insulin shock, after injections of vagotrophic and sympathicotropic substances, the first phase of L. after blood loss. If not always completely, then at least partially, leukocytosis must be explained by redistribution of leukocytes after physiological work (myogenic), after convulsions, in children after crying, digestive L. (in detail-see below). The mechanism of redistributive L. must be sought in the change in the speed of blood flow in various vascular areas and in the increased flow of lymph. The change in the speed of blood flow changes the quantitative ratio of erythrocytes and leukocytes due to their different specific gravity. With an increased flow of blood through the vessels of the abdominal organs, where leukocytes are usually retained due to the slower blood flow there (occupying a marginal position), a significantly larger amount of leukocytes enters the blood vessels of the skin. In this connection, the dependence of peripheral L. on the state of the autonomic nervous system deserves special attention. This question has been carefully studied in recent years by E. Müller and his colleagues. Müller believes that a change in the tone of peripheral capillaries is always accompanied by an opposite change in the tone of capillaries of organs innervated by the vagus nerve. Therefore, with every enhancement of the skin reaction, enhancement of muscle activity, as during sweating, with a critical drop in temperature, with muscle tension, insulin shock, etc., when skin vessels dilate, at the same time the vessels of abdominal organs constrict. The dilation of skin vessels is accompanied by an increase in the number of leukocytes in the periphery and a decrease in internal organs. Conversely, in chills, after food intake, after injection of foreign substances, etc., there is a constriction of skin capillaries in certain stages, which is accompanied by the reverse ratio between the number of leukocytes in the periphery and in internal organs.-The adrenaline leukocytosis should also be discussed. Frey and Hatiegan found after injection of adrenaline a two-phase picture of peripheral L.-first with lymphocytosis (I phase), then with neutrophilia (II phase). The increased number of leukocytes with lymphocytosis (I phase) they explained by contraction of the spleen and on this basis interpreted adrenaline L. as a test reflecting the functional state of the spleen in terms of its ability to contract. Therefore, adrenaline L. some call Frey's test for spleen function. On the basis of numerous studies, this point of view must be considered incorrect and adrenaline L. must be considered as redistributive; at the same time, the increased influx of leukocytes to the periphery comes not only from the spleen, but also from the liver, lymph glands, thoracic duct, etc. Thus, redistributive L. undoubtedly deserves serious attention.-In old studies (Chistovich, Verigo, Rieder, Schultz, Goldscheider and Jakob), the mechanism of redistribution of leukocytes was explained by chemotaxis; this explanation does not correspond to modern views. The mechanism of redistributive L. must therefore be sought primarily in the regulation of vascular tone by the autonomic nervous system. Its degree will depend on the one hand on the intensity of irritants, on the other-on individual peculiarities of the organism, mainly its autonomic nervous system. It is also necessary to note that some explain redistributive L. by a change in the concentration of blood due to a change in the exchange of plasma between blood and tissues (Grawitz, Meyer u. Walterhofer). What role the factor of increased blood concentration plays in redistributive L. and in what form of it, in what connection this factor is with autonomic regulation-these questions are still unclear. Mechanism of origin of true L. If redistributive L. is mainly observed in physiological states, although, as indicated, it can also be caused by certain pathological changes in the body, then true L. is mainly observed in pathological states, although, as indicated below, it can also occur in some physiological states of the body. It is known that inflammatory diseases and generally inflammatory processes are most often accompanied by actual L. It is therefore natural that the mechanism of development of infectious, inflammatory L. has been studied the most. The mechanism of development of all true L. is based essentially on one general principle-on the altered function of hematopoietic, more precisely - leukoblastic tissue, i.e., first of all, bone marrow and lymph glands. But before this general principle became clear, the explanation of the mechanism of development of true L. underwent a great evolution. Virchow believed that every L. occurs by irritation of lymph glands. In this form, this view naturally does not correspond to the modern development of science, since true L. is often characterized by the predominance of granulocytes, which do not come from lymph glands. But Virchow's view retains its force to the present time in relation to those L. which are characterized by absolute lymphocytosis (e.g., in measles, sometimes in secondary syphilis, etc.)-Of course, the view of other authors (Rieder, Schulz), who reduced every L. to redistribution of leukocytes, is also incorrect. Such a view contradicts the often encountered in L. immature forms of leukocytes, e.g., immature neutrophils, which were absent in the blood before L. and which can appear in the blood only as a result of an abnormal functional state of the bone marrow. However, it has already been noted above that the redistribution of leukocytes is closely related to the state of the autonomic nervous system. The state of the autonomic nervous system, however, often undergoes great changes in those pathological processes that are accompanied by L. Therefore, it is quite legitimate to think that the factor of redistribution plays some role in the mechanism of development of most, and perhaps even all, pathological L. In this formulation, there is still no concrete material on this question. At present, no one also accepts the view of Römer and Buchner, who explained L. by a leukogenetic process in the blood itself.

Finally, there was also the localist viewpoint, which amounted to the idea that leukocytes from local inflammatory foci enter the blood retrogradely; This viewpoint was defended by Shur and Levi, Marchand and Weidenreich (Schur and Lowy, Weidenreich) and is partially admitted by Gravitz and Kryukov. This view must also be rejected. The main objections are as follows. 1) In inflammatory foci, it is very rarely possible to observe figures of karyokinetic division; here leukocytes are mostly degeneratively altered. 2) Too often one can observe a huge discrepancy between a sharply expressed L. and a slightly expressed local inflammatory focus (such a discrepancy can often be observed in some patients with appendicitis; there is also the reverse discrepancy, when a very extensive purulent process is accompanied by a normal number of leukocytes and even leukopenia-often in empyemas, especially in the elderly). Thus, from the criticism of all the above theories, which are untenable from the point of view of modern knowledge, it follows that the mechanism of development of true L. must be sought in the altered function of the hematopoietic system. This viewpoint must be considered at present generally recognized. It is undoubtedly confirmed by the morphol. changes in the bone marrow in L. (see below). Some uncertainties still exist regarding the mechanism of alteration of bone marrow function. There are three theories of this mechanism: the leukolytic theory of Levit (Lovvit), the chemotactic theory of Ehrlich (Ehrlich) and the theory of Nägeli about the direct irritation of the hematopoietic system. But according to Levit, every L. is preceded by leukopenia as a result of destruction of leukocytes; at the same time, the breakdown products of leukocytes irritate the leukoblastic tissue. But first of all, the often preceding L. leukopenia is the result of redistribution of leukocytes, their increased accumulation in the liver, lungs, spleen (Verigo, Goldscheider and Jacob, Timofeevsky, Ewing), and secondly, Goldscheider and Jacob succeeded in causing experimental L. without preceding leukopenia. Thus, this theory must be considered refuted. Ehrlich's view that the basis of L. is chemotaxis is still very widespread. However, there are also substantial objections to the chemotactic theory. The doctrine of Pfeffer (Preffer) on the chemotaxis of protozoa is transferred by this theory to leukocytes. According to this theory, leukocytosis is explained by the presence in the blood of positive chemotactic substances, which attract neutrophils from the bone marrow, and only after this reparative regeneration of new neutrophils occurs in the bone marrow. Mechnikov writes that 'leukocytes have chemotactic properties similar to those of other lower organisms.'- Such a transfer of the laws of protozoa to L. is fundamentally incorrect. A whole series of experimental and clinical facts relating to L. cannot be explained at all by the chemotactic theory. It is known that when certain bacteria enter the blood, L. is often preceded by leukopenia. This leukopenia is explained by this theory by the circulation in the blood of bacteria or toxins, which have negative chemotaxis with respect to leukocytes. But soon (sometimes after several hours) leukopenia is replaced by L. and therefore according to this theory bacteria (or toxins) that had negative chemotaxis very recently now have positive chemotaxis. This is obviously an arbitrary interpretation. The well-known clinical fact that in the elderly lobar pneumonia caused by the diplococcus of Fränkel can from the very beginning proceed without L., whereas pneumonia caused by the same diplococci in a young subject usually proceeds with a large L. cannot be explained by this theory. Many more such examples, inexplicable by chemotaxis, can be cited. It should be noted that it is precisely from the chemotactic theory that vitalistic views grow, such as the view of Birch-Hirschfeld (Birch-Hirschfeld) 'about the purposeful movement of leukocytes that have emerged toward a goal.' It is more likely that one should think that certain irritants (whether the bacteria themselves or, as Nägeli thinks, the toxic products of bacterial life activity, other toxic substances, products of cell breakdown, etc.) act on the hematopoietic tissue, primarily on the bone marrow, as a result of which certain (regenerative or degenerative) functional changes occur in it. From the point of view of this view, it is easy to understand the above facts, inexplicable from the chemotactic point of view. The same can be said with respect to a number of other facts. For example. the frequent presence in the blood during infectious processes of nuclear erythrocytes, which indicates increased function not only of the leukopoietic, but also of the erythropoietic apparatus, cannot be explained by chemotaxis at all, but it becomes easily understandable from the point of view of irritation of the hematopoietic system by toxic products. Also, the often encountered in infections extramedullary leukopoiesis, which of course is related to leukocytosis, cannot be explained by chemotaxis at all. Thus, true L. is the morphol. expression of functional changes in the leukoblastic tissue and primarily of the bone marrow. These functional changes result from the action of one or another irritant. The question of the mechanism of alteration of the leukopoietic system's activity still remains unclear. The main factor should be considered the irritation of the hematopoietic system, leading to enhanced production of formed elements-normal or pathological. Irritants can be various toxic substances (bacterial endo- and exotoxins, parenterally introduced substances, etc.) as well as products of tissue breakdown and products of blood breakdown, primarily of leukocytes themselves, occurring in organs, in the bloodstream or in inflammatory foci. Whether these irritants act directly on the hematopoietic tissue or through the nervous system or in some other way, cannot yet be said. The leukocytic reaction, its degree and character will depend on the amount of irritating products, their quality and individual peculiarities of the organism.- especially its leukoblastic tissue. State of the bone marrow in L. is subject to various changes. In animals, already after ^1/2-1 ^hour after bacterial intoxications, Timofeevsky observed dilation of the bone marrow vessels and their filling with blood, depletion of the bone marrow of mature neutrophils-'bone marrow leukopenia'. Then followed the stage of myelocytic hyperplasia-'myelocytosis of the bone marrow'. Further, a significant increase in polymorphonuclear neutrophils was found in the bone marrow-'neutrophilic hyperleukocytosis of the bone marrow'. In humans, in infectious diseases and purulent processes, the transformation of fatty bone marrow into lymphoid is often observed. In severe chronic infections, this occurs to an even greater extent, but here it is necessary to take into account the factors of anemic order. L. is also related to the fact that in infectious diseases and inflammatory processes, leukocytic proliferation often occurs not only in the bone marrow but also in many other organs. This extramedullary proliferation of leukocytes occurs as a result of myeloid metaplasia primarily in the spleen, in lymphatic glands, sometimes in the liver (see Hematopoiesis).- From an etiological point of view, physiological and pathological leukocytoses are distinguished. Physiological leukocytoses. Physiological L. should include the digestive L., myogenic L., L. of newborns, L. of pregnant women, static L.'-The digestive L. amounts to the fact that 2-3 hours after food intake, an increase in the number of leukocytes is observed on average by 33% (Reider). Syrensky after a protein-rich food observed an increase on average by 60%. At this time, purely protein food gives a predominant increase in neutrophils, while fatty and carbohydrate'-lymphocytes (Keuthe, Syrensky). Digestive L. is often preceded by leukopenia occurring soon after food intake. Many researchers deny the existence of digestive L. They pointed to the absence of digestive L. in animals (K-Penberger, Karl); in infants after food intake, one can observe quite significant fluctuations in the number of leukocytes-from 6 to 19 thousand, and when feeding with maternal milk, a significant and lasting about 1 hour leukopenia often occurs, which is replaced by leukocytosis, and when giving cow's milk, leukopenia occurs after the initial wave of leukocytosis. However, daily blood examination in the same infant under the same conditions can give completely different leukocytic curves (Schippers and Lange, Stransky, Sokolov, Kononova and Grigorieva). All this allows (at least with respect to the infant) to abandon the term 'digestive L.'. And with respect to adults, Yafa, observing an increase in the number of leukocytes only after dinner, pointed out that this L. occurs at lunchtime even in the absence of dinner, which is why he reduced the post-lunch L. to the periodic daily fluctuation of the number of leukocytes, which is not necessarily associated with food intake.

In recent times, Kobryner and the staff of Zavadsky (Vorony and Ryskin) have described in healthy people wave-like fluctuations in the number of leukocytes during the day. Since these fluctuations are not related to food intake, these authors doubt the existence of digestive L. in the old understanding of this phenomenon, i.e., in the sense of the connection of L. with the processes of digestion. However, the fact that fasting leads very quickly to a decrease in the number of leukocytes, that one-sided food undoubtedly changes the percentage relationships of leukocytes (Keuthe, Syrensky), speaks in favor of the influence of food intake on the quantity and composition of blood leukocytes. The origin of digestive L. is also unclear. A very long time ago (Reader), digestive L. was explained by the redistribution of leukocytes. In recent times, Miller, Glaser, explaining digestive L. by the redistribution of leukocytes, connect it with the altered during digestion vegetative regulation of the vascular system. Other researchers consider digestive L. to be true; in favor of this view, one could cite the research of a number of authors (Goodall, Paton, Piro-gne) who found that the bone marrow during digestion is in a state of increased functional activity. But these are only individual studies in this direction. Little is known about changes in digestive L. in pathological conditions of the body. The change in digestive L. in stomach cancer turned out to be inconsistent (Syrensky). There were indications that the more pronounced dyspepsia is in children, the higher the digestive L., but here too these fluctuations are recently associated with a change in the tone of the autonomic nervous system (Bogdanov and Rosenthal, Speransky and others.). Digestive L. has no diagnostic or prognostic value. Myogenic L. is observed after muscular exertion. To myogenic L. should be attributed L. in children after crying, L. after convulsions (e.g., after an epileptic attack). An increase in the number of leukocytes can be detected already ten minutes after the start of muscular work, at first mainly the number of lymphocytes increases. This increase in the number of lymphocytes is apparently due to the mechanical influence of the musculature on the lymphatic apparatus and vessels in the sense of enhancing the flow of lymph, as a result of which the washing out of cells from the lymphatic glands is intensified. The same washing out of cells from the lymphatic glands and bone marrow can be facilitated by accelerated blood circulation. Apparently, the role is also played by the fact that the acceleration and intensification of breathing that occurs during muscular work, by increasing the suction action of the chest on the large lymphatic pathways, accelerates the flow of lymph into the venous system (Hirschfeld). Finally, it must be assumed that during muscular work there is also a redistribution of leukocytes from internal organs. However, all these mentioned factors are not sufficient to explain every myogenic L. Myogenic L. will differ depending on the duration of muscular work. Myogenic L., caused by light work, is characterized by the predominance of lymphocytes, and with prolonged work-neutrophilia with a shift to the left, a decrease in the number of lymphocytes and eosinophils. With severe muscular exertions, L. is characterized by a significant regenerative shift of neutrophils, sharp lymphopenia and disappearance of eosinophils. To explain these last changes, the above-mentioned factors are not sufficient, and it is necessary to assume also a functional change in the blood-forming tissue, possibly caused by toxic products (in particular lactic acid) entering the blood during intense muscular work. This form of myogenic L. is already incorrectly called physiological L. There is a dependence of the nature of myogenic L. on training and on individual reaction. L. of pregnant women. Blood leukocytes (mainly neutrophilic) clearly increase during the act of childbirth, often exceeding 20,000 in 1 mm³. This L. is probably of myogenic origin; L. during pregnancy has begun to be questioned, especially if one takes into account the daily fluctuations in the number of leukocytes (Zangemeister and Wagner and others.). Others note neutrophilic L. mainly during the first pregnancy, sometimes even with an increase in young forms (Neup). The assumption that during pregnancy, along with the intensification of many biological processes, the function of the blood-forming tissue also increases (Negeli) is very probable. Since a number of observations indicate an increase in the number of leukocytes mainly towards the end of pregnancy, its myogenic origin becomes probable, standing in connection with the onset of transient contractions (Hofbauer, Gravitz). L. of newborns. Immediately after birth, the number of blood leukocytes in newborns is always increased, reaching 15,000-20,000 in 1 mm³. Already from the first days, their number clearly falls, reaching by the 5-11th day on average 14,370 against 18,000 (on average) in the first four days. According to the data of Kononova, in the blood taken from the umbilical cord, and in the blood of the newborn 2 hours after birth, the number of leukocytes is equally high (18-19 thousand) (see table on the next page); by the 4th day leukocytosis falls to 12-13 thousand. This L. is characterized by a predominant increase in neutrophils. The origin of this L. must be sought in the changed conditions of nutrition and blood circulation. Perhaps in this L. the role is played by the thickening of the blood (Kohnstein and Zuntz), passive and active muscular activity during and after childbirth (Gravitz). Static L. is observed with a sudden change in position, a sudden transition from vertical to horizontal position (Elermann and Erlandsen); at this time the number of leukocytes can sometimes increase by 100%. These changes are apparently observed not only with a sudden change in position, but there are two different levels in the number of leukocytes: low

From the umbilical cord 2 hours after birth On the 4th day after birth Leukocytes M (average deviation) (standard deviation) S (absolute number) Total leukocytosis... 118,400 Lymphocytes...... 3,88 Total number of neutrophils...

40,4 6,43 1)85 3,6 92 Э 4,4 5,3 10,2 when in vertical position and high-when in horizontal position (Joergensen). It is clear that static leukocytosis should be classified as redistributive. This leukocytosis is explained by changes in cardiac activity and acceleration of blood flow, depending on the position of the body. Pathological leukocytoses. Pathological leukocytoses include: inflammatory leukocytosis and leukocytosis in infectious diseases, toxic, posthemorrhagic, leukocytosis in malignant neoplasms and leukocytosis under the influence of X-rays and radium. Previously, atonal leukocytosis was also noted, which in its old understanding, i.e., in the sense of the presence of leukocytosis each time in atonal state (Litten), is now rejected. Leukocytosis sometimes observed in atonal state should be connected with the nature of the disease (see Agony). Also, the concept of 'cachectic leukocytosis' should be abandoned, since leukocytosis observed only sometimes in cachexias is probably connected with the resorption of toxic products, different depending on the disease that led to cachexia. Infectious and inflammatory leukocytoses are observed in most infectious diseases and various inflammatory processes, especially-purulent; aseptic inflammations (e.g., after turpentine) are also accompanied by leukocytosis. Leukocytosis is usually observed in lobar pneumonia, erysipelas, scarlet fever, diphtheria, cerebrospinal meningitis, cholera, smallpox, in many cases of sepsis, in phlegmonous inflammations and suppurations caused by pyogenic agents, especially-streptococcus, staphylococcus, pneumococcus and bacillus coli. In most of these cases, the number of leukocytes at the height of the disease reaches 15,000-30,000. Usually less pronounced leukocytosis in acute rheumatism, acute polyneuritis, acute encephalitis, chickenpox, typhus, malaria (during the attack), chronic sepsis, encapsulated suppurations. Many authors note significant leukocytosis (with lymphocytosis) in the catarrhal period of whooping cough and attribute diagnostic significance to this fact (Ashby, Lasch and others). In jaundice of newborns, the number of eosinophils noticeably decreases (Kononova). Infectious and inflammatory leukocytoses at the beginning and at the height of the disease are characterized by an increase in the relative and percentage of neutrophils, a decrease in m a 27,83 8,27 5,53 3,57 3,71 1,6 5,4 3,9 9,2 4,6 14,1 4,7 38,8 m 5.282 1.045 703 11.Й70 969 1.748 2.679 7.372 - 7,92 3,21 1,6 8,6 1,9 4,3 5,1 7,2 relative and absolute number of lymphocytes and eosinophils, while by the end of the disease and during the recovery period lymphocytosis and eosinophilia are usually observed in the blood. The viewpoint of Schilling, who distinguishes three phases in the course of infectious diseases: the first-neutrophilic ('phase of struggle'), the second-monocytic ('protective phase') and the third-lymphocytic ('phase of recovery'), is incorrect. This viewpoint is fundamentally incorrect because it connects the processes ('struggle with infection', 'protection from infection', 'recovery') with individual cells (neutrophils, monocytes, lymphocytes), which cannot be understood and correctly evaluated outside the connection with the whole organism. Therefore, it is clear that this scheme very often does not correspond to clinical observations (e.g., monocytosis in typhus, eosinophilia in scarlet fever, etc.) and should be abandoned. The degree and character of leukocytosis vary depending on the severity of the infection, the nature of the latter and individual peculiarities of the organism. Leukocytosis is probably caused not by bacteria as such, but by endo- or exotoxins, because 'both with killed bacteria and with soluble toxins one can achieve completely identical reactions' (Negeli). At the same time, to a small amount of toxin the organism usually reacts with insignificant leukocytosis, to medium doses-with strong leukocytosis, while to large doses the organism usually reacts with leukopenia (see). These data are now usually interpreted in such a way that in mild infection the hematopoietic system reacts with insignificant regeneration, in medium severity infection this regeneration intensifies, while in severe infection so-called degenerative changes in hematopoietic tissue occur (see in detail below, as well as Blood leukocyte formula). However, this concept has no greater significance than the scheme. Not only the quantity but also the quality of toxins has significance. Thus, it is known that some infections more often cause sharp leukocytosis, others-less sharp (see above). It is also known that some infections cause predominantly neutrophilic leukocytosis, others-predominantly lymphocytosis (see below), and scarlet fever in children-the only infection which at the height of the disease is characterized by significant eosinophilia. But all the above-mentioned reactions, depending both on quantity and quality of toxins, are of course the result of interaction with the organism, and consequently with individual peculiarities of the organism and its hematopoietic system. The leukocyte reaction to infection and inflammatory processes varies depending on the age of the patients. In young people this reaction is usually much more pronounced, while in the elderly it often completely disappears. For example, typhoid fever in children usually causes much more pronounced lymphocytosis than in adults. Scarlet fever only in children usually causes significant eosinophilia, while in adults it is barely expressed. There are numerous clinical observations indicating that during the war the tendency to react to infections with typical leukocytosis was weak (Politzer); this showed the exogenous influences on the organism and its hematopoietic tissue. From all the above it follows that infectious leukocytoses, their degree, their morphological peculiarities have in a certain combination with other clinical data great diagnostic significance. For example, combination of a certain clinical picture with leukopenia has great importance for the recognition of typhoid fever, combination with leukocytosis-for the recognition of lobar pneumonia, scarlet fever. It is clear, various complications of the main disease and mixed infection change the character of leukocytosis. Leukocytoses have great diagnostic significance in relation to local inflammatory processes. At this, rapid increase in the number of leukocytes-up to 20,000-30,000 and more-lasting more than 1-2 days, often indicates a purulent nature of the inflammatory process. But severe inflammatory processes without suppuration (e.g., perityphlitis) can proceed with very high leukocytosis, and then it indicates both a severe form of the disease and good reactive ability of the leukopoietic apparatus. On the other hand, even extensive purulent process can proceed with insignificant leukocytosis or even without leukocytosis at all, which is explained by toxic depression of bone marrow function. Encapsulated suppurations can also proceed without leukocytosis (On the diagnostic significance of individual forms of leukocytosis-see also Blood leukocyte formula.) As for the prognostic significance of infectious and inflammatory leukocytoses, it should be said that in many infectious diseases, with severe general clinical picture, insignificant leukocytosis or complete absence of it, and moreover the presence of so-called degenerative shift (see Blood leukocyte formula), usually has poor prognostic significance. At the same time, it is necessary even in cases with active leukocytic reaction to set a good prognosis with great caution only on the basis of this reaction; active leukocytic reaction indicates active, well-functioning leukoblastic tissue, but in the same infection there may be poorly functioning cardiovascular system, nervous system, etc., which can significantly worsen the prognosis. Toxic leukocytoses. These include leukocytoses after taking many medications (antifebrin, phenacetin, antipyrine, collargol, camphor, digitalis preparations), after blood poisons (berthollet salt, pyrodin, pyrogallol, salvarsan, benzene derivatives), in poisoning with mercury, acids, vitriol and in tissue breakdown. Toxic leukocytoses usually have neutrophilic character; they are caused in some cases by direct irritation of hematopoietic tissue by this toxic substance, in others-by its products of destruction of erythrocytes and leukocytes. Posthemorrhagic leukocytosis is observed after significant blood loss and usually has neutrophilic character. In internal hemorrhages posthemorrhagic leukocytosis is probably caused by irritation of myeloid tissue by products of destruction of extravasated leukocytes and erythrocytes and besides by subsequent reparative regeneration. In external hemorrhage one can only think of reparative regeneration of bone marrow (Ehrlich). In the origin of this leukocytosis acceleration of blood flow may play some role (Rieder). Finally, irritation of bone marrow may also be caused by the cause that led to the hemorrhage (Negeli). Leukocytosis in malignant neoplasms are inconsistent, usually have neutrophilic character. These leukocytoses can be caused mainly by three factors: 1) breakdown of the tumor, 2) hemorrhages, 3) metastases of tumors in bone marrow; in the presence of numerous metastases in bone marrow very sharp leukocytosis was observed in individual cases.

(even up to 100,000 in 1 mm³), sometimes with immature leukocytes, which resembles the so-called leukemoid conditions (see Leukemia). Furthermore, tumor-induced leukocytosis can be caused by toxic products of the tumor's vital activity. Leukocytosis following exposure to radiant energy (X-rays, radium) varies in both intensity and pathogenesis depending on the dose. Small doses can cause slight leukocytosis through direct irritation of hematopoietic tissue, while large doses do so through irritation of hematopoietic tissue by products of cellular breakdown. Chronic exposure to radium and X-rays usually leads to a significant decrease in the number of leukocytes, especially neutrophils. It is necessary to remember that in this form of leukocytosis, as in all previous forms, a major role belongs to the individual reactivity of the hematopoietic tissue. (For the distribution of leukocytosis according to morphological characteristics, namely: neutrophilic, eosinophilic, and basophilic leukocytosis, lymphocytosis, and monocytosis—see Blood leukocyte formula.)