Acute Acquired Neutrophilia

Neutrophilia is usually an acquired, secondary finding associated with inflammation, infection, injury, or stress. Acute or chronic bacterial infections, trauma, and surgery are among the most common causes encountered in clinical practice. Neutrophilia may also be associated with heatstroke, burns, diabetic ketoacidosis, or any other acute stress. Drugs commonly associated with neutrophilia include epinephrine, corticosteroids, and recombinant growth factors such as recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF).

Epinephrine causes release into the circulation of a sequestered pool of neutrophils that normally marginate along the vascular endothelium. Corticosteroids accelerate the release of neutrophils and bands from a large storage pool within the bone marrow and impair the migration of neutrophils from the circulation into tissues. Acute neutrophilia in response to inflammation and infections occurs because of release of neutrophils from the marrow storage pool. The post-mitotic marrow neutrophil pools are approximately 10 times the sizes of the blood neutrophil pool, and about half of these cells are bands and segmented neutrophils. In neutrophil production disorders, such as those associated with malignancies and cancer chemotherapy, the size of this pool may be reduced and the capacity to develop neutrophilia remains impaired. Exposure of blood to foreign substances such as hemodialysis membrane activates the complement system and causes transient neutropenia followed by neutrophilia because of release of bone marrow neutrophils. The colony-stimulating factors G-CSF and GM-CSF cause acute and chronic neutrophilia by mobilizing cells from the marrow reserves and by stimulating neutrophil production (Fig. 126-1).

Figure 126-1 Cytokine control of the phagocyte production and activation by release of endotoxin during infection. Both endothelial cells and fibroblasts release substantial quantities of both granulocyte-macrophage colony–stimulating factor (GM-CSF) and granulocyte colony–stimulating factor (G-CSF) in response to tumor necrosis factor (TNF) and interleukin 1 (IL-1). Both TNF and IL-1 are released from endotoxin-activated monocytes and antigen-activated T lymphocytes. Stem cell factor (SCF), interleukin 3 (IL-3), GM-CSF, and interleukin 6 (IL-6) each influence the growth and differentiation of multilineage progenitor cells known as colony forming units (CFU)—granulocytes, eosinophils, monocytes, megakaryocytes (CFU_GEMM)—to the committed colony forming unit macrophage (CFU_M), CFU eosinophil (CFU_Eo), or CFU granulocyte (CFU_G). Platelet production can also be augmented by expansion of CFU megakaryocyte (CFU_meg). Factors that serve as growth and differentiation factors for a specific lineage also act as activation factors for the terminally differentiated forms of the same lineage. Macrophage colony–stimulating factor (M-CSF) enhances antibody-mediated cytotoxicity and phagocyte functions of monocytes. G-CSF promotes neutrophil bactericidal capacity, and interleukin 5 (IL-5) activates eosinophil function. Within hours of an infection, cytokine primed neutrophils move to the invasion site from the circulation under the influence of interleukin 8 (IL-8), which is released from endothelial cells and fibroblasts.

Chronic Acquired Neutrophilia

Chronic neutrophilia is usually associated with continued stimulation of neutrophil production resulting from persistent inflammatory reactions or chronic infections (e.g., tuberculosis), vasculitis, postsplenectomy states, Hodgkin disease, chronic myelogenous leukemia, chronic blood loss, sickle cell disease, some chronic hemolytic anemias, and prolonged administration of corticosteroids. Chronic neutrophilia can arise after expansion of cell production secondary to stimulation of cell divisions within the mitotic precursor pool, which consists of promyelocytes and myelocytes (see Fig. 126-1). Subsequently, the size of the post-mitotic pool increases. These changes lead to an increase in the marrow reserve pool, which can be readily mobilized for release of neutrophils into the circulation. The neutrophil production rate can increase greatly in response to exogenously administered hemopoietic growth factors, such as rhG-CSF, with a maximum response taking at least 1 wk to develop.

Lifelong Neutrophilia

Congenital asplenia is associated with lifelong neutrophilia. Uncommon genetic disorders that present with neutrophilia include leukocyte adhesion deficiency, familial myeloproliferative disease, Down syndrome, and Rac-2 mutation (Chapter 124). In an autosomal dominant form of hereditary neutrophilia, patients maintain an absolute neutrophil count between 1,400 and 150,000/µL, which is associated with hepatosplenomegaly, an increased alkaline phosphatase level, and Gaucher-type histiocytes in the bone marrow.

Evaluation of persistent neutrophilia requires a careful history, physical examination, and laboratory studies to search for infectious, inflammatory, and neoplastic conditions. The leukocyte alkaline phosphatase cytochemical stain of circulating neutrophils is useful to differentiate chronic myelogenous leukemia, in which the level is uniformly near zero, from reactive or secondary neutrophilia, in which normal to elevated levels are found.

Lymphocytosis

The most common cause of lymphocytosis is an acute viral illness. Lymphocytosis is a normal response to most viral infections because the majority of circulating lymphocytes are T cells. In infectious mononucleosis, the B cells are infected with the Epstein-Barr virus and the T cells react to the viral antigens present in the B cells, resulting in atypical lymphocytes with the typical large, vacuolated morphology. Other viral infections classically associated with lymphocytosis are cytomegalovirus and viral hepatitis. Chronic bacterial infections such as tuberculosis and brucellosis may lead to a sustained lymphocytosis. Pertussis is accompanied by lymphocytosis in ≈25% of infants infected before 6 mo of age. Thyrotoxicosis and Addison disease are endocrine disorders associated with lymphocytosis. Persistent or profound lymphocytosis suggests acute lymphocytic leukemia.

Basophilia

Basophilia occurs when the basophil count exceeds 100-120 cells/µL. Basophilia is a nonspecific sign of a wide variety of disorders and is usually of limited diagnostic importance. Basophilia is most often present in hypersensitivity reactions and frequently accompanies the leukocytosis of chronic myeloid leukemia.