White Blood Cell Disorders

Background and Importance

The white blood cell (WBC) and accompanying differential count are among the most common laboratory tests ordered in the emergency department (ED) setting. Unfortunately, the WBC count has not proved to be a highly sensitive or specific test, and the absence of leukocytosis does not exclude the presence of significant infection or disease. Acute infection remains the most common nonmalignant cause of leukocytosis. In evaluation of the bacterial infectious potential in febrile children and adults, the WBC and differential counts have demonstrated limited usefulness as stand-alone biomarkers. Other tests, such as procalcitonin and C-reactive protein (CRP), may have more predictive value. ^, Thus, the WBC count should be viewed as having limited screening value in the acute care setting. However, when combined with history and physical examination findings, the WBC and differential counts can be of utility in helping determine the presence of acute infection or other processes. ^,

Anatomy and Physiology

The WBC (leukocyte) series can be divided into three basic cell types: granulocytes (neutrophils, eosinophils, and basophils), monocytes (nongranulated cells that mature into macrophages), and lymphocytes. WBCs reach their site of action through the circulation. The rate at which new cells enter the circulation is usually in equilibrium with the rate of loss in tissues. The granulocytic series is primarily involved in phagocytic activity. Its origin is the pluripotential stem cells located in the bone marrow. A subset of these cells differentiates and matures into the phagocytic cell lines, which include neutrophils, basophils, and eosinophils. Nongranulated phagocytic monocytes also develop from this same lineage. Granulocytes originate, mature, and are stored in the bone marrow, with a lifespan of days once released into the peripheral circulation. The postmitotic storage pool for neutrophils, which represents 15 to 20 times the circulating population, contains metamyelocytes, band neutrophils, and mature neutrophils (polymorphonuclear neutrophils). The pool can be drawn on as a ready reserve during rapid consumption of granulocytes. Circulating neutrophils are subdivided equally into the circulating neutrophil pool and the marginal pool, consisting of mature cells adherent to the blood vessel walls. During times of physiological stress, the marginal pool can rapidly enter the circulating pool and cause a substantial increase, even doubling, of the WBC count with neutrophilic predominance. This typically resolves within 24 to 48 hours; persistent elevation may be an indicator of leukemia or other malignancy. These patients should be referred to a primary care physician or hematologist for further evaluation.

The lymphocytic series matures in lymphoid tissues located in the bone marrow, thymus, spleen, lymph nodes, or elsewhere. They are involved in the immune response against foreign substances. There are two morphologically indistinguishable lymphocyte cell types: B cells (humoral immunity) and T cells (cellular immunity). Because lymphocytes can freely leave and return to the circulation, the storage pools are less well defined. Only a relatively small number of total body lymphocytes are in circulation at any point in time.

One unique problem in WBC disorders is the wide variability in normal values and the multiple factors influencing them. WBC counts are generally performed automatically by electrical impedance or optical diffraction techniques. Although differential counts are commonly performed by direct examination of 100 to 500 cells with the oil immersion lens of the microscope, automated techniques are becoming more popular. Normal values for the WBC count are listed in Table 110.1 . The “normal” count is age dependent and may be shifted upward by exercise, female gender, smoking, or pregnancy. Similarly, certain ethnic populations such as Blacks have a lower total WBC count and neutrophil, with a higher percentage of monocytes and lymphocytes. Laboratory errors may be due to improper sample preparation, nucleated red blood cells (RBCs), or platelet clumping. The blood smear differential count may also be influenced by small sample size, improper cell identification, and age group (children). Differential ranges are listed in Table 110.2 . One common yet easily corrected error in laboratory analysis is reporting of results in terms of the percentage of cell types. Absolute counts for each cell type are more accurate and useful in assessing the risk for infection.

Pathophysiology

Alterations in cell counts are due to changes in production, the marginal pool, or the rate of tissue destruction. The differential diagnosis of increased or decreased WBC counts can be organized by processes impacting production, destruction, loss, or sequestration. Decreased production is caused by suppression of the bone marrow secondary to chemotherapy, radiation therapy, or viral infections. Beta-lactam antibiotics, rheumatoid arthritis, and other autoimmune diseases can destroy neutrophils and reduce the WBC count. Overwhelming bacterial infections can deplete the supply of WBCs faster than the bone marrow can increase production, resulting in net loss. Finally, sequestration may occur secondary to ischemic reperfusion injury, major trauma, or other tissue insults.

Given the spectrum of anticipated values, WBC count determinations should be interpreted in the context of the overall clinical picture. A careful history and physical examination, absolute cell counts, and review of the peripheral smear differential counts are valuable in determining the origins of quantitative WBC disorders.

Leukocytosis, or elevation in WBC count, is most frequently caused by increases in the neutrophil or lymphocyte cell lines. Neutrophilic leukocytosis (neutrophilia) is defined as an absolute neutrophil count greater than 7500 cells/mm ³ and is commonly associated with infection or inflammation ( Box 110.1 ). This is manifested as a “left shift” in the differential count and represents movement of immature neutrophils from the postmitotic pool into the circulation. Because infection or inflammation is also associated with heightened peripheral neutrophil destruction, the proportion of immature (band) to mature neutrophils may increase beyond the baseline ratio of 1 band to 10 mature neutrophils.

WBC counts can also increase through demargination of neutrophils from the vessel walls, which often occurs in response to physiologic stress, endogenous or administered epinephrine, and exercise. ^,

Leukopenia is a broad definition that indicates any reduction in the circulating WBCs. The term leukopenia is often used interchangeably with neutropenia , which specifically refers to a reduction of the neutrophil cell line. Neutropenia is the most clinically significant leukopenia.

By definition, adult neutropenia is defined as an abnormally low absolute neutrophil count (ANC), calculated by multiplying the WBC count by the combined percentage of segmented and band neutrophils. An ANC below 1500 cells/mm ³ is considered mild neutropenia, less than 1000 cells/mm ³ is moderate, and less than 500 cells/mm ³ is severe. Severe neutropenia is a well-known risk factor for increased susceptibility to bacterial infection.

Clinical Features

WBC disorders often present with clinical features characteristic of the underlying cause of the WBC disorder (e.g., characteristics of inciting infection in the setting of leukocytosis). The exception is hyperleukocytosis (WBC >100,000/mm ³ ) which can result in leukostasis, a syndrome characterized by metabolic abnormalities, coagulopathy, and multiorgan failure. Although any organ system may be affected, symptoms most often arise from involvement of the cerebral, pulmonary, or renal microvasculature. Central nervous system (CNS) signs and symptoms may include headache, confusion, lethargy, dizziness, blurred vision, ataxia, papilledema, and retinal or intracranial hemorrhage. Pulmonary signs and symptoms may include dyspnea, tachypnea, hypoxia, pulmonary infiltrates, or respiratory failure. Mechanical obstruction of the capillaries also commonly results in peripheral vascular occlusion, acute renal failure, or myocardial infarction.

Differential Diagnoses

Leukocytosis can be caused by primary WBC disorders, including myeloproliferative disorders, hereditary leukocytosis, congenital anomalies, or a leukemoid reaction, which is a pronounced leukocytosis associated with acute inflammation or infection that may be mistaken for leukemia. Secondary forms of leukocytosis are more common. Box 110.1 lists common causes of primary or secondary leukocytosis, as well as lymphocytosis.