The term leucocytosis indicates an increase in the number of leucocytes so that the normal range of values is exceeded. Generally speaking, leucocytosis occurs when there is an increase in the number of neutrophils or lymphocytes in the blood, which alone account for more than 80% of leucocytes. Occasionally the increase in the number of these cells is sufficient to exceed the reference limit for the respective population but not to cause an increase in the total leucocyte count. A numerical increase in the other subpopulations of white blood cells (monocytes, eosinophils, basophils) rarely causes an absolute leucocytosis (that is, an increase in the total number of white blood cells) since these populations are less abundant than the populations of neutrophils and lymphocytes (in normal conditions they do not account for more than 20-25% of the total leucocytes).
For each leucocyte population it is usually possible for there to be an increase in the number of cells such that this exceeds the reference range of values for the single population (absolute leucocytosis) or a less consistent increase such that the number of cells remains within the reference range, but the percentage of the cells of the given subpopulation increases in relation to the total number of leucocytes (relative leucocytosis). This situation is associated with decreased percentages of the other white blood cell subpopulations whose absolute counts do not, however, change. Therefore, when there is a relative leucocytosis or leucopenia, the white blood cell differential (leucogram) must be analysed in order to determine in which leucocyte subpopulation the numerical changes have occurred.
Given that there are different classes of leucocytes in the blood, the significance of increased numbers of leucocytes depends on the class involved and on any morphological changes as well as the mere numbers. An increase in the number of neutrophils, eosinophils, basophils, lymphocytes and monocytes is called neutrophilia, eosinophilia, basophilia, lymphocytosis and monocytosis, respectively.
NEUTROPHILIA
The term neutrophilia indicates a numerical increase (absolute neutrophilia) or a percentage increase (relative neutrophilia) of neutrophils with respect to the reference ranges. In the case of relative neutrophilia it must be determined whether this is associated with an absolute neutrophilia and investigate the possible causes of the increased number of neutrophils or whether the neutrophilia depends on numerical decreases in other classes of leucocytes, in particular lymphocytes. In this case it will be important to investigate the possible causes of the lymphopenia. If the neutrophilia is absolute, but is also associated with an absolute lymphopenia, the potential causes of both variations must obviously be considered.
CAUSES OF ABSOLUTE NEUTROPHILIA
The situations in which neutrophilia is most frequently observed are inflammation, stress and endogenous or exogenous hypercortisolism. There are also forms of reactive neutrophilia not related to inflammation. Finally, increases in the number of neutrophils and/or their precursors can occur in cases of haematopoietic neoplasms involving the granulocyte lineage (acute or chronic myeloid leukaemia).
Neutrophilia and inflammation
The cytokines produced during the acute phase reaction(interleukin-1, tumour necrosis factor, interleukin-6) and glucocorticoids, besides causing changes in the plasma concentrations of acute phase proteins, activate neutrophils, promoting their movement from the blood to inflamed tissues, but also the detachment of mature neutrophils of the marginal pool from the endothelium. Given that the number of neutrophils in the marginal pool is approximately the same as that in the circulating pool in the dog and about three times higher in the cat, the detachment of the marginal pool cells induces a rapid and intense neutrophilia in both species.
If this is not sufficient to counteract the pathogen (e.g. very virulent infectious agents that attract large numbers of neutrophils into the tissues), mature neutrophils are also released from the bone marrow pool, further increasing the number of circulating neutrophils. At the same time, pro-inflammatory cytokines activate the bone marrow production of growth factors, such as granulocyte monocyte-colony stimulating factor (GM-CSF), which induces the production of new neutrophils in the bone marrow. If the inflammatory stimulus is particularly intense, these newly produced neutrophils may enter the circulation before having completed their maturation. In this case “young” neutrophils, such as non-segmented neutrophils or “bands” (Fig. 1), or even metamyelocytes, myelocytes and gradually ever more immature cells, may be found in the blood.
Neutrophilia and stress
Glucocorticoids contribute to detaching the marginal pool of neutrophils from the endothelium but have less effect than the pro-inflammatory cytokines on inducing activation of bone marrow myelopoiesis. Consequently, the neutrophilia occurring during stress is mainly due to the release of mature cells into the circulation rather than to the production of new granulocytes in early stages of maturation.
Other causes of neutrophilia
Neutrophilia may also be seen in the absence of particularly intense inflammatory stimuli in the case of some hereditary disorders of leucocytes, which affect the function of neutrophils. The body reacts by introducing ever more neutrophils into the circulation.
Physiological neutrophilia
A series of physiological events such as eating a meal, intense physical exercise, pregnancy and delivery can induce neutrophilia, above all by mobilisation of the marginal pool, through a mechanism similar to that described in relation to stressful situations.
Granulocytic leukaemias
Granulocytic leukaemias are types of myeloid leukaemia and are, therefore, due to a clonal proliferation of precursors of neutrophils. In chronic forms the neutrophils reach the final stages of maturation (giving rise, therefore, to a mature neutrophilia, which is usually marked) whereas in the acute forms the cells are released into the circulation in immature stages (myelocytic leukaemias), in some cases in common with those of the monocyte line (myelomonocytic leukaemias).
HAEMATOLOGICAL PICTURES ASSOCIATED WITH NEUTROPHILIA
- Stress leucogram: the white blood cell differential is characterized by mature neutrophils, associated reductions in lymphocytes and eosinophils and, in the dog monocytosis. This picture is seen in the case of stress or hyperadrenocorticism, whether spontaneous or induced by the administration of exogenous steroids.
- Mature neutrophilia (with right shift): this occurs in cases of pathological white blood cell adherence in which mature neutrophils cannot migrate out of the vessels and, therefore, age within the circulation (with an increase in the number of nuclear lobes).
- Mature neutrophilia (without right shift): this is characterized by a modest to marked increase in neutrophils without particular morphological anomalies: it is seen in cases of moderate, acute inflammation and in conditions of chronic inflammation, when the movement of neutrophils into the site of the inflammation is not so intense as to exhaust the marginal pool or the bone marrow pool. Although the bone marrow can meet the needs of the peripheral blood, to do so it introduces part of the medullary reserve pool into the circulation: the bone marrow therefore shows myeloid hyperplasia and a decrease of mature neutrophils.
- Neutrophilia with regenerative left shift: the neutrophilia in such cases is usually intense and characterized by low numbers of band neutrophils or metamyelocytes (fewer of these cells than mature cells). Both the immature cells and the mature ones can show signs of toxicity (toxic neutrophils). This picture is seen following severe, acute inflammation in which the attraction of mature neutrophils into the tissues is marked: this exhausts the reserves of the circulating, marginal and bone marrow pools.
- Neutrophilia with degenerative left shift: this is characterized by intense neutrophilia with a high number of immature cells, including cells in very early stages of development, sometimes exceeding the number of mature cells. In the past this form of neutrophilia was called a leukemoid reaction, because it is difficult to distinguish from a real myeloid leukaemia. It is an unfavourable prognostic sign since it indicates that the attraction of mature cells to the site of inflammation and their destruction are particularly intense.
LYMPHOCYTOSIS
The term lymphocytosis indicates a numerical increase (absolute lymphocytosis) or percentage increase (relative lymphocytosis) of lymphocytes with respect to the reference ranges. In normal conditions lymphocytes are the second most numerous white blood cell population. The most relevant changes in the number and morphology of lymphocytes occur in cases of lymphocytic leukaemias but non-neoplastic and even physiopathological cases of lymphocytosis occur with a certain frequency in both dogs and cats.
Physiopathological lymphocytosis
All conditions that cause adrenaline to enter the circulation can lead to lymphocytosis through an effect of contraction of the spleen, which results in lymphocytosis, erythrocytosis and neutrophilia. The most common of these conditions is the acute stress occurring during blood sampling, particularly in the cat, but a similar picture can be seen after acute traumatic events or, more simply, after intense exercise, transport, etc. In these cases the lymphocytosis is no longer present in a blood sample taken a few hours later.
Reactive lymphocytoses
Reactive lymphocytoses are associated with stimulation of the specific immune system. The stimulation may be induced (e.g. by vaccination) or spontaneous (e.g. in advanced stages of viral diseases, in the presence of intracellular pathogens). The finding of lymphocytosis is, therefore, associated with chronic diseases in which non-specific stimulation of the immune system is followed by activation of an immune response. Reactive lymphocytoses caused by viruses constitute the exception in that, apart from a first phase usually characterized by lymphopenia, viruses induce lymphocytosis relatively quickly.
In all these cases the lymphocytosis may be the only haematological finding or may be associated with neutrophilia and signs of activation of other blood cell populations (e.g. toxic neutrophils, activated monocytes). The lymphocytes in reactive lymphocytoses are usually small to medium-sized without particular morphological alterations. In the case of particularly intense stimulation, activated lymphocytes or granular lymphocytes may be found in the circulation; these are probably cytotoxic cells.
EOSINOPHILIA
The term eosinophilia indicates an increase in the number (absolute eosinophilia) or percentage (relative eosinophilia) of eosinophils. The most common causes of eosinophilia are parasitic diseases and allergies, particularly of the skin and respiratory system. Eosinophilia may also be found in some endocrine disorders such as hypoadrenocorticism and in association with some tumours (e.g. lymphomas) able to produce interleukin-5 (paraneoplastic eosinophilia). There are also some eosinophilic inflammations (eosinophilic enteritis, eosinophilic granuloma) characterized by a large infiltration of eosinophils into tissues during which it is sometimes possible to find eosinophilia. Finally, a very marked increase in the number of eosinophils may be an indicator of an eosinophilic leukaemia or a non-neoplastic form of eosinophilia, of still unclear aetiopathogenesis, called hypereosinophilic syndrome.
MONOCYTOSIS
The term monocytosis indicates an increase in the number (absolute monocytosis) or percentage (relative monocytosis) of monocytes with respect to the reference ranges. Given the role of monocytes in the innate defence system of the body, the most common cause of monocytosis in all species of animals is subacute-chronic inflammation, particularly if caused by intracellular pathogens (e.g. protozoa) or requiring a more intense phagocytic response than that which can be provided by the neutrophils (e.g. mycoses, diseases characterized by extensive necrosis). In all these cases the monocytosis is often associated with lymphocytosis and neutrophilia and activated monocytes can frequently be found in the circulation. In contrast, monocytosis, sometimes intense, not associated with morphological changes and accompanied by neutrophilia and reductions in lymphocytes and eosinophils may be seen in the so-called stress leucogram. Finally a very marked increase in the number of monocytes may be found in those forms of myeloid leukaemia involving this cell line.
BASOPHILIA
The term basophilia indicates an increase in the number (absolute basophilia) or percentage (relative basophilia) of basophils with respect to the reference ranges. An increase in basophils, which is a rare occurrence, has little clinical relevance. It may be found, usually in association with eosinophilia, in some allergies and in the extremely rare forms of myeloid leukaemia involving the basophil cell line.
Suggested readings
- Feldman B.F., Zinkl J.G., Jain N.C.: Schalm’s Veterinary Hematology, 5a edizione. Philadelphia: Lippincott Williams & Wilkins, 2000.
- Stockham S.L., Scott M.A.: Fundamentals of Veterinary Clinical Pathology, 2a edizione. Blackwell Publishing, 2008.
- Comazzi S, Pieralisi C, Bertazzolo W. Haematological and biochemical abnormalities in canine blood: frequency and associations in 1022 samples. J Small Anim Pract. 2004 Jul;45(7):343-9.
- Raskin RE. Myelopoiesis and myeloproliferative disorders. Vet Clin North Am Small Anim Pract. 1996 Sep;26(5):1023-42.
- Segev G, Klement E, Aroch I. Toxic neutrophils in cats: clinical and clinicopathologic features, and disease prevalence and outcome--a retrospective case control study. J Vet Intern Med. 2006 Jan-Feb;20(1):20-31.
- Paltrinieri S., Bertazzolo W., Giordano A. Patologia Clinica del Cane e del gatto. Approccio pratico alla diagnostica di laboratorio. ISBN: 978-88-2143-159-3. Elsevier Masson, 2010.