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CHAPTER 71 NEUTROPENIA AND NEUTROPHILIA

CHAPTER 71 NEUTROPENIA AND NEUTROPHILIA
Williams Hematology

CHAPTER 71 NEUTROPENIA AND NEUTROPHILIA

DAVID C. DALE

Neutropenia

Pathophysiologic Mechanisms

Causes of Neutropenia

A Clinical Approach to the Patient Presenting with Neutropenia
Neutrophilia

Mechanisms of Neutrophilia

Clinical Approach to Patients with Neutrophilia
Chapter References

Neutropenia designates a blood absolute neutrophil count that is less than two standard deviations below the normal population mean. Certain geographic areas contain population groups, such as those of African descent, in which the normal blood concentration of neutrophils is lower than in persons of European descent. Neutropenia results from diseases that decrease the normal rate of production of these cells in the marrow or from processes that accelerate neutrophil destruction, sequestration, or egress from the circulation. Some diseases spare erythrocyte and platelet production or survival and result in “isolated” neutropenia, such as chronic idiopathic neutropenia or drug-induced neutropenia. In some cases, other cell lineages are mildly affected but the neutropenia is severe, such as Felty syndrome. Neutropenia can be inherited or acquired. In some patients with either type of neutropenia, continuous cytokine therapy with granulocyte colony-stimulating factor can improve or restore the neutrophil count. Apparent neutropenia can occur as a result of a greater than normal proportion of neutrophils that are marginated in microvascular beds and not measured in the blood count; this condition does not lead to an increased risk of infection. Neutropenia may be an indicator of an underlying disease, such as early vitamin B12 deficiency or drug reaction. If severe, neutropenia increases the likelihood of contracting a bacterial or fungal infection and impairs the resolution of such infections.
Neutrophilia is an increase in the absolute neutrophil count to a concentration greater than two standard deviations above the normal population mean value. The most frequent causes of such an increase in count are inflammation or infection, but solid tumors occasionally may engender such a reaction. When the neutrophil count is very high, it may be referred to as a leukemoid reaction. The rare neutrophilic variants of chronic myeloid leukemia may also result in striking neutrophilia. Bacterial infections usually produce neutrophilia, whereas viral infections may not do so or the rise in neutrophil count may be slight. Demargination of neutrophils or rapid release of neutrophils from a large marrow pool may increase the blood neutrophil count transiently. Sustained increases require an increase in production of these cells. Neutrophilia facilitates the inflammatory response and antimicrobial action.

Acronyms and abbreviations that appear in this chapter include: CFU-GM, colony forming unit–granulocyte-monocyte; G-CSF, granulocyte colony-stimulating factor; G-CSFR, granulocyte colony-stimulating factor receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIV, human immunodeficiency virus; SCID, severe combined immunodeficiency.

NEUTROPENIA
Neutropenia refers to an absolute blood neutrophil count (total leukocyte count per microliter × percent of neutrophils) that is less than two standard deviations below the normal mean of the population. The terms leukopenia, a reduced total white blood cell count, and granulocytopenia, reduced numbers of blood granulocytes (neutrophils, eosinophils, and basophils), sometimes are imprecisely used as synonyms for neutropenia. Agranulocytosis literally means a complete absence of blood granulocytes, but this term often is used to indicate severe neutropenia, i.e., less than 0.5 × 103/µl (0.5 × 109/liter).
The concentration of neutrophils in blood is influenced by age, activity, and genetic and environmental factors (see Chap. 2). For children from 1 month to 10 years old, neutropenia is defined as a blood neutrophil count of less than 1.5 × 103/µl (1.5 × 109/liter). For individuals over age 10, neutropenia is less than about 1.8 × 103/µl (1.8 × 109/liter) (see Chap. 7 regarding newborns). Healthy older persons have the same blood neutrophil counts as younger individuals (see Chap. 8). Some racial and ethnic groups, such as Africans, African Americans, and Yemenite Jews, have lower mean neutrophil counts than Americans of European ancestry. These mean differences in neutrophils are modest (800–1000/µl) and have no recognized health consequences.1,2
Neutropenia is a predisposing factor for infections, usually with the organisms normally found on the skin, in the nasopharynx, and as part of the intestinal flora. The risk of infections is inversely related to the severity of the neutropenia (see Chap. 17). Individuals with neutrophil counts of 1.0–1.8 × 103/µl (1.0–1.8 × 109/liter) are at little risk. In general, between 0.5 × 103 and 1.0 × 103/µl (0.5–1.0 × 109/liter) neutrophils, the risk is moderate. Individuals with neutrophil counts of less than 0.5 × 103/µl (0.5 × 109/liter) are at substantially greater risk, but the frequency of infections varies considerably, depending on the cause and duration of neutropenia. Severe acute neutropenia (i.e., developing over a few hours or days) is usually associated with greater risk of infection than severe chronic neutropenia (usually present for months or years). Neutropenia due to disorders of production, affecting early hematopoietic precursor cells (e.g., aplastic anemia, severe congenital neutropenia) results in a greater susceptibility to infections than conditions with adequate neutrophil precursors in the marrow and neutropenia attributed to accelerated turnover in the blood (e.g., rheumatoid arthritis, autoimmune neutropenia). For patients made severely neutropenic by cancer chemotherapy, the risk is greater when the neutrophils are decreasing than with similar counts when neutrophils are increasing. Neutropenia accompanied by monocytopenia, lymphocytopenia, or hypogammaglobulinemia is more serious than solitary neutropenia. Other factors, e.g., the integrity of the skin and mucous membranes, the vascular supply to tissues, and the nutritional status of the patient, also influence the risk of infections.
PATHOPHYSIOLOGIC MECHANISMS
GENERAL MECHANISMS
Neutropenia occurs because of reduced or ineffective production, accelerated utilization or turnover, shifts of cells from the circulating to the marginal blood pools, or a combination of these mechanisms (Fig. 71-1). Some production disorders are due to intrinsic abnormalities of hematopoietic progenitor cells (see Chap. 14 and Chap. 91). Other disorders in cell production are caused by extrinsic factors, including changes in the marrow environment, e.g., tumor infiltration, fibrosis, or irradiation. Cytotoxic drugs usually cause more severe neutropenia earlier than anemia or thrombocytopenia because of the higher fractional turnover rate of neutrophils in the blood. Production is defined as ineffective when, under a steady state of hematopoiesis, there is a relative abundance of early neutrophil precursors and a paucity of late-maturing cells.

FIGURE 71-1 The mechanisms of neutropenia are shown schematically. The size of each pool is represented by the size of the cross-hatched areas. The rate of flow of cells through each compartment is represented by the size of the arrows. Mi, mitotic; MSP, maturation (marrow storage) pool; MGP, marginated granulocyte (neutrophil) pool; CGP, circulating granulocyte (neutrophil) pool.

Accelerated neutrophil utilization occurs with autoimmune neutropenia and acute bacterial infections. When there is both rapid neutrophil utilization and impaired production, acute severe neutropenia often develops. This is illustrated by the abrupt and sustained fall in neutrophils when an alcoholic patient develops pneumococcal pneumonia. Alcohol suppresses the marrow, and the infection consumes the available neutrophil supply. The abrupt fall in blood neutrophils at the onset of infection in patients recently given cancer chemotherapy reflects a similar mechanism. With idiosyncratic drug-induced neutropenia, the counts may fall abruptly because both blood and marrow cells are simultaneously damaged. When acute neutropenia develops because of a shift of blood neutrophils from the circulating to the marginal pool, i.e., increased margination (for example, after injection of endotoxin, with exposure of blood to dialysis membranes, or after intravenous G-CSF or GM-CSF), it is usually a transient event.
CELLULAR AND MOLECULAR MECHANISMS OF NEUTROPENIA
Our understanding of the mechanisms of neutropenia at the cellular and molecular level is increasing rapidly, due to advances in molecular genetics and cell biology. For several diseases associated with neutropenia, such as the congenital immunodeficiency syndromes, the abnormal genetic loci have been identified, but the precise cellular mechanisms for failure to produce and maintain normal neutrophil levels is not yet known. In Kostmann syndrome, a form of congenital neutropenia, a cellular mechanism—namely, an abnormality of the G-CSFR receptor—has been identified in some, but not all, patients.3 How this mutation leads to neutropenia is still unclear. Neutropenia can develop because of a failure of cell survival, i.e., apoptotic loss, due to acquired or congenital intrinsic defects, that is, to vitamin B12 deficiency,4 myelodysplasia,5 or myelokathexis.6 Neutrophilia can be depleted from both the blood and the marrow due to extrinsic factors such as antibodies to specific neutrophil surface antigens, as in immune neutropenia. Some disorders that cause neutropenia also perturb neutrophil function, such as glycogen storage disease type 1b7 and HIV infection.8 The susceptibility to infection in these conditions relates to the combination of defects.
CAUSES OF NEUTROPENIA
Causes of neutropenia are classified physiologically as disorders of production, distribution, or turnover. Not every condition fits neatly into this scheme, but it provides a framework for understanding these diverse disorders.
DISORDERS OF PRODUCTION
Cytotoxic drugs given for cancer chemotherapy and as immunosuppressive agents regularly cause neutropenia by decreasing cell production (see Chap. 16). These drugs are probably now the most frequent cause for neutropenia in the United States. Neutropenia due to impaired production is a common feature of several diseases affecting hematopoietic stem cells, e.g., leukemia, aplastic anemia, and the myelodysplastic (preleukemic) syndromes. The selective causes for impaired production, progressing from disorders of early precursors to disorders presumed to involve defective maturation (ineffective production), are described briefly as follows.
Congenital Disorders Kostmann Syndrome and Related Disorders. In 1956, Kostmann described congenital neutropenia (agranulocytosis) as an autosomal recessive disease of families in northern Sweden.9,10 Symptoms and signs of otitis, gingivitis, pneumonia, enteritis, peritonitis, and bacteremia usually begin in the first month of life. Often the neutrophil count is less than 0.2 × 103/µl (0.2 × 109/liter). Eosinophilia, monocytosis, and splenomegaly may be present. Characteristically the marrow shows early neutrophil precursors (myeloblasts, promyelocytes) but few or no myelocytes or mature neutrophils. Marrow eosinophilia is common. In vitro marrow culture studies show that the number of colonies composed of granulocytes and monocytes (CFU-GM) and the response to some growth factors may be reduced.11 Blood lymphocyte numbers are normal, immunoglobulin levels are usually normal or increased, and lymphocyte functions are intact. Some patients have abnormalities of the receptor for G-CSF; most frequently this is a truncation of the distal portion of the cytoplasmic domain of this receptor.12 Patients’ capacity for G-CSF and GM-CSF production appears to be normal.13 Because there is no specific diagnostic test for this disorder, it may be difficult to distinguish isolated cases of Kostmann syndrome from other severe causes of neutropenia (agranulocytosis) of early childhood.
G-CSF is now recognized to be a very effective therapy in increasing the neutrophil count in patients with Kostmann syndrome.14 However, patients with Kostmann syndrome and some other congenital neutropenia, including patients on long-term G-CSF treatment, have developed acute myelogenous leukemia, frequently in association with acquired abnormalities of the G-CSF receptor, monosomy 7, and Ras mutations, at a rate of about two percent per year.15 No other cytokines are of proven efficacy; bone marrow transplantation is the alternative therapy for patients with a suitable donor.
Congenital Immunodeficiency Diseases. Neutropenia is a feature of the congenital immunodeficiency diseases and a contributing factor to susceptibility to infection in many, but not all, patients (see Chap. 88). In X-linked agammaglobulinemia, which is attributed to defective B-cell development and a mutation in a cytoplasmic (Bruton) tyrosine kinase (Btk), severe neutropenia is present in approximately 25 percent of patients.16 Children with common variable immunodeficiency often have neutropenia associated with thrombocytopenia and hemolytic anemia.17 Neutropenia occurs in almost half of the patients with the X-linked hyper-IgM syndrome, a disorder caused by a mutation in the gene that encodes the CD-40 ligand.18,19 With SCID, neutropenia is variably present.20 The neutropenia also varies over time in individual patients. Neutropenia is particularly prominent in the rarest of the immunodeficiencies, reticular dysgenesis.20,21 Neutropenia is a less common feature of adenosine deaminase deficiency, the T–B+, T–B–, and Omenn syndromes.20 Case reports indicate that G-CSF therapy is effective in patients with neutropenia associated with immunodeficiencies, except that it appears to be ineffective in reticular dysgenesis.22,23,24,25,26 and 27
Cartilage-Hair Hypoplasia Syndrome. In this rare autosomal recessive syndrome, short-limbed dwarfism is associated with hyperextensible digits, very fine hair, neutropenia, lymphopenia, and recurrent infections.28 The degree of neutropenia is variable, ranging from 0.1 to 2.0 × 103/µl. It contributes to the recurrent respiratory infections of some patients. An accompanying defect in T-cell proliferation, with a defect in the transition from the G0 to the G1 of the lymphocyte miotic cycle, makes patients susceptible to viral respiratory infections29; the mechanism for neutropenia is not yet known.
Shwachman-Diamond Syndrome. This autosomal recessive disorder combines short stature, pancreatic exocrine deficiency, and neutropenia beginning early in the neonatal period. The patients are malnourished, but the neutropenia is not corrected by improving their nutritional status. Thrombocytopenia and anemia may also be severe and evolution to myelodysplastic syndrome and acute myeloid leukemia occurs.30,31
Diamond-Blackfan Syndrome. Neutropenia is a rare complication of congenital hypoplastic anemia; other features include congenital anomalies of the head and upper limbs. The varying severity of neutropenia may reflect genetic heterogeneity among patients with this diagnosis. The mechanism for neutropenia is not known.32,33
Gracelli Syndrome. This rare autosomal recessive disorder is characterized by pigmentary dilution, variable degrees of cellular immunodeficiency, and an acute phase of uncontrolled lymphocyte and macrophage activation leading rapidly to death unless bone marrow transplantation is successful.34,35 and 36 In the skin, there is accumulation of diffuse pigmentation due to melanosome accumulation in the patient’s melanocytes. The pigmentation occurs because of an abnormal transfer of the cellular granules from the melanocytes to the keratinocytes. The mutation is in a gene on chromosome 15 at q21 that encodes a member of the myosin protein family. The neutropenia is relatively mild and associated with pancytopenia. Evolution to myelodysplasia has been reported.37
Chédiak-Higashi Syndrome. This rare autosomal recessive disorder is characterized by partial oculocutaneous albinism, abnormal giant granules in many cells (including granulocytes, monocytes, and lymphocytes), neutropenia, and recurrent infections (see Chap. 72). The neutropenia is usually mild, and susceptibility to infection is attributed to both neutropenia and defective microbicidal activity of the phagocytes38 (see Chap. 70).
Myelokathexis and Related Syndromes. Myelokathexis is a rare autosomal dominant disorder in which patients have severe neutropenia and lymphocytopenia, with total white blood cell counts less than 1.0 × 103/µl, although the marrow has abundant precursors and developing neutrophils. Morphologic abnormalities in the marrow and blood include hypersegmentation and severely pyknotic nuclei, as well as cytoplasmic vacuoles. These morphologic changes and some molecular studies suggest cell loss in the marrow and blood by accelerated apoptosis.6,39 Favorable responses to G-CSF and GM-CSF occur, as well as evolution to the myelodysplastic syndrome.40,41 A myelokathexis-like variant of myelodysplastic syndrome has also been reported.42 In the 1970s a condition called the “lazy leukocyte syndrome” was described in which the neutrophils accumulated in the marrow. The neutrophils were morphologically normal. The neutropenia was attributed to defective chemotaxis of cells in the marrow to the blood.43 No genetic or molecular mechanism has yet been identified.
Glycogen Storage Diseases. These autosomal recessive disorders are characterized by hypoglycemia, hepatosplenomegaly, seizures, and failure to thrive in infants. Neutropenia develops in glycogen storage disease type 1b, but not in other types. The marrow appears normal despite a severe reduction in blood neutrophils. The neutrophils have a reduced oxidative burst and defective chemotaxis.44 The genetic defect maps to chromosome 11q23 and is attributed to an intracellular transport protein defect for glucose.45 Treatment with G-CSF is effective for both correcting the neutropenia and improving the associated inflammatory bowel disease.46,47
Cyclic Neutropenia. Cyclic neutropenia, an autosomal dominant or sporadically occurring disease, is characterized by regularly recurring episodes of severe neutropenia, usually every 21 days. It is diagnosed in young children, especially when there is a family history of this condition.48,49 The neutropenic periods last for 3 to 6 days and are accompanied by malaise, anorexia, fever, lymphadenopathy, and ulcerations of the mucous membranes. There are also regular oscillations of other white blood cells, reticulocytes, and platelets. There is also an acquired syndrome in adults, some of whom have an associated clonal proliferation of large granular lymphocytes.48
Pathophysiologic studies in humans and in gray collie dogs, which have a very similar disorder, indicate that cycling is due to a defect in the regulation of hemopoietic stem cells.50 Serial marrow culture studies show cyclical fluctuations in the number of granulocyte colonies, generally with fewer colonies forming from samples taken during the period of maximum neutrophilia.51 Oscillations in colony-stimulating factors have been measured, but these changes probably are secondary to the recurrent inflammation which occurs with the neutropenic periods.
The diagnosis of cyclic neutropenia can be made only by serial differential counts, at least two or three times per week for a minimum of 6 weeks. Most affected children survive to adulthood; the symptoms are often milder after puberty. Fatal clostridial bacteremia has been reported in several cases, and careful observation is warranted with each neutropenic period in untreated patients. Treatment with granulocyte colony-stimulating factor is very effective.52 It does not abolish cycling, but it shortens the neutropenic periods sufficiently to avoid symptoms and infections.53
Neutropenia Due to Genetic Defects of Folate, Cobalamin, and Transcobalamin II. A variety of congenital disorders lead to disturbed function of the two cobalamin-requiring enzymes, methylmalonyl CoA mutase and methionine synthetase. Each of these disorders causes neutropenia, as well as anemia and thrombocytopenia, as a result of ineffective hematopoiesis54,55 (see Chap. 25).
Chronic Idiopathic Neutropenia Several disorders, some congenital and some acquired, cause selective neutropenia in both children and adults. Childhood cases have been called familial (severe) neutropenia (probably autosomal dominant), familial benign neutropenia (probably autosomal dominant), chronic benign neutropenia of childhood (usually a negative family history), and chronic idiopathic neutropenia in adults (usually considered to be an acquired disease or occasionally, the case of affected children escaping detection until adulthood).56,57,58 and 59
Patients with these diverse syndromes share several characteristics: normal or near-normal erythrocyte, reticulocyte, lymphocyte, and platelet counts and normal or increased blood monocyte counts and immunoglobulin levels. The spleen is normal or only minimally enlarged. They have no chromosomal abnormalities or other evidence of myelodysplasia. Marrow examinations show a spectrum of abnormalities, from normal cellularity to selective hypoplasia of the neutrophilic series.60,61 In most cases, quantitative marrow studies show that the ratio of immature to mature cells is increased, suggesting the loss of cells during the maturation process, that is, ineffective granulocytopoiesis. This suggests the presence of an intrinsic defect in the developing neutrophils or immunological mediated cell injury. In these cases, however, antineutrophil antibodies are not detected and tests for other autoantibodies, including antinuclear or antimitochondrial, are negative.62
The clinical course of individual patients usually can be predicted based on the level of the blood neutrophils, marrow examination, and the prior history of fevers and infections.63 In general, patients with the lowest levels of blood neutrophils and the fewest neutrophil precursors in the marrow will have the most frequent problems. Long-term observations have shown, however, that some patients can have very low blood neutrophil levels with few or no infections. Evolution to acute leukemia or aplastic anemia generally does not occur. G-CSF will increase neutrophils in most patients and is a useful therapy for those with recurrent fever and infections.64
Acquired Disorders of Neutrophil Production Neutropenia in Neonates of Hypertensive Mothers. Hypertensive women often have low–birth weight infants with low neutrophil counts, attributed to decreased production.65,66 The neutropenia is often severe with a high risk of infection, particularly during the first few weeks of life. The neutropenia usually resolves within a few weeks. G-CSF will elevate the neutrophils in this form of neonatal neutropenia, but the clinical benefit of treatment remains to be determined.67
Neutropenia Due to Nutritional Deficiencies. Neutropenia is an early and consistent feature of megaloblastic anemias due to vitamin B12 or folate deficiency, although when present it is usually accompanied by macrocytic anemia and mild thrombocytopenia (see Chap. 25). Copper deficiency can cause neutropenia in patients on total parenteral nutrition68 and in malnourished children.69 Mild neutropenia can occur in some patients with anorexia nervosa but is generally not a feature of kwashiorkor or marasmus.70
Neutropenia Due to Immune Suppression of Production. Pure white cell aplasia is a rare acquired disorder with severe selective neutropenia and a marrow devoid or nearly devoid of neutrophils and their precursors.71 Some cases have been attributed to ibuprofen, chlorpropamide, excessive zinc, and various infectious and inflammatory diseases.72,73,74 and 75 An autoimmune mechanism is suggested by presence of antibodies in the plasma of patients that bind to the human promyelocytic cell line HL-60.76 Immunosuppressive therapy with antithymocyte globulin, corticosteroids, and cyclosporine has been used in individual cases.
DISORDERS AFFECTING NEUTROPHIL UTILIZATION AND TURNOVER
Mechanisms of Immune Neutropenia Neutropenia due to alterations of the distribution of cells in the blood and accelerated turnover is usually attributable to immunologic mechanisms. Antineutrophil antibodies are known to cause transfusion reactions, alloimmune neonatal neutropenia, and autoimmune neutropenia. Antigen-antibody complexes and autoantibodies are thought to be involved in the neutropenia of systemic lupus erythematosus and Felty syndrome. The association of neutropenia with increased numbers of circulating large granular lymphocytes has suggested that cellular as well as humoral immune mechanisms may be involved (see Chap. 85).
Neutrophils share surface antigens with other tissues including the i-I antigens and HLA antigens. They also have some specific antigens, including NA-1, NA-2 (now recognized as isotypes of Fcg RIII or CD-16), NB-1, NC-1, and 9a.77,78 A number of other antigens can be identified on neutrophils and neutrophil precursors with monoclonal antibodies. The clearest associations of autoantibodies and neutropenia are with NA-1 and NA-2.77,78
Several tests are available for detecting antineutrophil antibodies, including agglutination and microagglutination, cytotoxicity, direct and indirect immunofluorescence, direct and indirect antiglobulin assays, and tests involving the binding of staphylococcal protein A to immunoglobulins on the surface of cells.78 The agglutination tests are the oldest methods and depend on the propensity of immunoglobulin-coated cells to aggregate. Immunofluorescence tests utilize anti–human gamma globulin tagged with a fluorescein label. These tests can be adapted for quantitative studies with a flow cytometer. Immunofluorescence and staphylococcal protein A–binding tests also can be adapted for examining immunoglobulins bound to single cells, including marrow cells. Direct methods are used to detect the antibodies on the patient’s neutrophils. Indirect methods are used to test the patient’s plasma or serum against panels of normal cells. The use of paraformaldehyde to expose antigens and to preserve the neutrophils for multiple tests has been especially helpful. Appropriate controls are essential for proper interpretation of these studies.
Causes of Immune Mediated Neutropenia Alloimmune (Isoimmune) Neonatal Neutropenia. Newborn infants may have neutropenia for a variety of reasons. In some cases it is due to the transplacental passage of maternal IgG antibodies that bind to the infant’s neutrophil-specific antigens, usually the Fcg RIII isotype inherited from the infant’s father.78,79 This disorder occurs in approximately one in 2000 neonates. It usually lasts for 2 to 4 months.
Alloimmune (isoimmune) neonatal neutropenia may be severe or relatively mild. It is often not recognized until bacterial infections occur in an otherwise healthy infant. The hematologic picture usually consists of severe neutropenia with normal to increased lymphocytes and normal monocytes, erythrocytes, and platelets. Marrow cellularity is normal or increased, with reduced numbers of mature neutrophils. Alloimmune neonatal neutropenia may be confused with neonatal sepsis, since the latter condition also causes severe neutropenia. The diagnosis of alloimmune neutropenia is usually made with neutrophil agglutination or immunofluorescence tests. Treatment should be conservative; antibiotics are used only when necessary. Exchange transfusions to decrease antibody titers or neutrophil transfusions from the patient’s mother are rarely needed.
Autoimmune Neutropenia. It has been thought for years that neutrophil autoantibodies can decrease neutrophil survival and impair neutrophil production. It has proved difficult, however, to distinguish cases of autoimmune neutropenia unequivocally from cases of chronic idiopathic neutropenia.80,81 Patients diagnosed as having autoimmune neutropenia usually have one or more positive tests for antineutrophil antibodies. They also usually have normal numbers of erythrocytes, platelets, and other leukocytes. Marrow morphology, colony-forming cells, and other tests are similar to those in cases of chronic idiopathic neutropenia. In general, therapy should be conservative and expectant. Intravenous gamma globulin may increase neutrophils but is generally not a satisfactory therapy. The response to glucocorticoid therapy is unpredictable. Daily or alternate day G-CSF is effective but should be reserved for patients with recurrent infections. Spontaneous remissions sometimes occur.
Systemic Lupus Erythematosus. Total leukocyte counts between 2 and 5 × 103/µl (2–5 × 109/liter) occur in about 60 percent of patients with systemic lupus erythematosus.82,83 Mild neutropenia is often accompanied by monocytopenia and lymphocytopenia, anemia, thrombocytopenia, and mild degrees of splenomegaly. There is an increased amount of IgG on the surface of neutrophils, and immune complexes are increased within the neutrophils.84 The marrow cellularity and maturation of cells is usually normal. Most patients with lupus do not have neutropenia severe enough to increase their susceptibility to infections, unless they are treated with immunosuppressive drugs (glucocorticoids, cytotoxic agents). G-CSF and GM-CSF have now been used to elevate neutrophils in many patients with SLE, including patients on immunosuppressive therapies.85
Rheumatoid Arthritis, Sjögren Syndrome, and Felty Syndrome. Leukopenia is unusual in association with rheumatoid arthritis, occurring in less than three percent of large series of patients. About one percent of patients with rheumatoid arthritis develop additional features of Felty syndrome (splenomegaly, deforming rheumatoid arthritis, and leukopenia).86 Usually, these patients have had active, deforming arthritis and very high rheumatoid factor titers. The neutropenia may be moderate to severe; occasionally patients are seen with no circulating neutrophils. The incidence of bacterial infections in patients with Felty syndrome is low until the neutrophil count is under 0.2 × 103/µl (0.2 × 109/liter), which suggests that neutrophils are made but that their blood kinetics are altered. There is no clear relationship between spleen size and the neutrophil count. High levels of circulating and intracellular immune complexes and IgG on the surface of neutrophils have been observed. The marrow is usually normal or hypercellular, but occasionally it is hypocellular. Granulopoiesis is usually marked by sufficient precursors but few band or segmented neutrophils.
In Sjögren syndrome about 30 percent of patients have moderate leukopenia; the total leukocyte count is usually 2 to 5 × 103/µl (2–5 × 109/liter) with a normal differential count.87,88 Rarely, severe neutropenia occurs associated with recurrent bacterial infections.
Therapeutic options include methotrexate, glucocorticoids, G-CSF, GM-CSF, and splenectomy. Results with these therapies are unpredictable.89,90 Weekly methotrexate is preferred by many rheumatologists. G-CSF or GM-CSF can increase neutrophils but also may exacerbate arthralgias.85 Splenectomy is followed by a rapid increase in counts in about two-thirds of cases, but about two-thirds of those who respond to splenectomy have a recurrence of neutropenia. A subset of patients with Felty syndrome has a high blood concentration of large granular lymphocytes with a phenotype characteristic of immature natural killer cells. These patients tend to respond poorly to all therapies directed toward increasing neutrophil levels.91 Several factors in addition to neutropenia predispose these patients to infections, including monocytopenia, hypocomplementemia, circulating immune complexes, and treatment with glucocorticoids or cytotoxic drugs. In general, treatments to correct neutropenia should be reserved for patients with documented infections.
Other Causes of Neutropenia Associated With Spleno-megaly In 1942 Wiseman and Doan described a disorder that they called primary splenic neutropenia.92 Since that time it has been recognized that a variety of diseases also may cause this type of neutropenia, or pseudoneutropenia. Diseases associated with splenomegaly and neutropenia include sarcoidosis, lymphoma, tuberculosis, malaria, kala-azar, and Gaucher disease. Usually there is thrombocytopenia and anemia as well. In patients with inflammatory diseases, immune mechanisms similar to those observed in patients with lupus erythematosus and Felty syndrome may be operative. In others, the sluggish blood flow through the spleen with passive trapping of neutrophils in the congested red pulp probably is the primary cause. For the most part the neutropenia in these patients is not sufficiently severe to be of clinical consequence. Removal of the spleen to raise the neutrophil count is rarely indicated.
DRUG-INDUCED NEUTROPENIA
Idiosyncratic drug reactions cause neutropenia with an estimated annual frequency of three cases per million population.93 In 1922 Schultz reported six cases of severe sore throat and prostration with absent blood neutrophils, which led rapidly to sepsis and death.94 A few years later this syndrome was associated with the coal tar-derived drug aminopyrine.95 Over the past 50 years scores of other drugs have been recognized to cause this syndrome.
Two main types of idiosyncratic drug-induced neutropenia are recognized.96,97 One type is a dose-related toxicity due to interference of the drug with protein synthesis or cell replication. This effect is often nonselective. It can involve the pluripotential hematopoietic stem cells and highly proliferative cells in other organs such as the epithelial cells of the gastrointestinal tract. Prototype drugs for this type of reaction include phenothiazines, antithyroid drugs, chloramphenicol, and clozapine.98,99 Similar effects on marrow cells may also be mediated through free radicals and drug metabolites. Patients receiving multiple drugs and patients having high plasma concentration of drugs due, for example, to the dose administered, to slow metabolism, or to renal impairment are more prone to develop these reactions.100
A second type of drug-induced neutropenia may not be dose related. It is thought to be allergic or immunologic in origin, similar to drug-induced skin reactions and drug-initiated, antibody-mediated erythrocyte destruction. These reactions occur with an even broader array of drugs.101,102 and 103 Large studies suggest that women are affected more often than men, that older patients are affected more frequently than younger ones, and that patients with a history of allergies, including allergies to other drugs, are affected more often than individuals without the allergies. Neutropenia may occur at any time but tends to occur relatively early in the course of treatment with drugs to which the patient has been previously exposed.
Our basic understanding of drug-induced neutropenia is limited, in part because of the unpredictable occurrence of cases, the myriad agents involved, and the lack of good animal models for research. Clinical studies suggest that the rate of recovery can be roughly predicted from the degree of marrow hypoplasia found when neutropenia is discovered. Once the offending drug is stopped, patients with sparse marrow neutrophils but normal-appearing precursor cells (promyelocytes and myelocytes) will have neutrophils reappear in the blood in about 4 to 7 days. Often an increase in the blood monocyte count heralds marrow recovery, and an “overshoot” with marked neutrophilia will follow. When early precursor cells are severely depleted, recovery may take considerably longer.
Patients with drug-induced neutropenia usually present with fever, myalgia, and sore throat; they usually do not have a rash or evidence of allergy elsewhere. The blood examination shows few or absent neutrophils. There may be mild lymphopenia, but other cell counts are usually normal. A high level of suspicion and careful clinical history are critical to identifying the offending drug. The differential diagnosis includes acute viral infections, particularly infectious mononucleosis and infectious hepatitis, and acute bacterial sepsis. If other hematologic abnormalities are also present, acute leukemia and aplastic anemia should be considered. Treatment usually consists of supportive care, including broad spectrum antibiotics for febrile patients. The benefit of hematopoietic growth factors in this setting has not been established in randomized trials.104,105
Table 71-1 lists some of the drugs frequently implicated in neutropenia. With the rapidity of introduction of new agents, when questions arise it is often useful to consult the manufacturer, a drug information center, or a poison control center to learn if a drug may cause neutropenia.

TABLE 71-1 CLASSIFICATION OF WIDELY USED DRUGS ASSOCIATED WITH IDIOSYNCRATIC NEUTROPENIA

NEUTROPENIA WITH INFECTIOUS DISEASES
Neutropenia can result from acute or chronic bacterial, viral, parasitic, or rickettsial diseases. Several mechanisms are involved. Certain viral infections, e.g., infectious mononucleosis, infectious hepatitis, parvovirus B-19, Kawasaki disease, and human immunodeficiency virus (HIV) infection, may cause severe or protracted neutropenia and pancytopenia due to infection of hematopoietic precursor cells. Other agents, e.g., Rickettsia and Bartonella, can infect endothelial cells. They may cause leukopenia, neutropenia, thrombocytopenia, and anemia as part of a generalized vasculitic process. In dengue, measles, and other viral infections, increased neutrophil adherence to altered endothelial cells may occur. With severe gram-negative bacterial infections, neutropenia is probably due to increased adherence to the endothelium as well as increased utilization at the site of infection. Some chronic infections causing splenomegaly, e.g., tuberculosis, brucellosis, typhoid fever, malaria, and kala-azar, probably cause neutropenia because of splenic sequestration and marrow suppression.
A CLINICAL APPROACH TO THE PATIENT PRESENTING WITH NEUTROPENIA
Ordinarily, patients with the acute onset of severe neutropenia present with fever, sore throat, and evidence of inflammation beneath the skin or mucous membranes. This is an urgent clinical situation requiring prompt microbial cultures, the institution of intravenous fluids, antibiotics, and other supportive measures. In the absence of recent hospitalization and antibiotic exposure, infections in this situation usually are caused by surface bacteria sensitive to numerous agents. Immediate investigation should include a careful history with particular attention to drugs and a physical examination with careful attention to the presence of bone tenderness and the size of the lymph nodes and spleen. The blood and marrow film should be studied thoroughly for atypical lymphocytes and abnormal cells. The marrow may show fibrosis, selective or nonselective hypoplasia, excessive blasts, or atypical cells. With this information in hand and supportive care started, further diagnostic tests can be considered, including measurements of antineutrophil antibodies, studies of in vitro marrow progenitor cell-proliferative activity, and studies of possible mechanisms for drug-induced neutropenia.
Chronic neutropenia usually is discovered as a chance finding with a routine examination or during the course of investigation of a patient with recurrent fevers and infections. It is useful to know if the neutropenia is chronic or cyclic and the mean level of the blood cell counts when the patient is afebrile and relatively well. Other hematologic and immunologic data that are important include the absolute monocyte, lymphocyte, eosinophil, and platelet counts; hematocrit or hemoglobin determination; and immunoglobulin levels. Patients with hypergammaglobulinemia usually have chronic and recurrent inflammation; patients with hypogammaglobulinemia and neutropenia usually are very susceptible to recurrent infections. Morphologic examination of the blood and marrow can identify some causes of benign neutropenia in children, the Chédiak-Higashi syndrome, and myelokathexis. The marrow examination is most useful to rule out leukemia and myelodysplastic disorders and to assess the severity of the marrow defect.
In patients with chronic neutropenia, it may be useful to measure antinuclear antibodies (ANA) and rheumatoid factor titers and to perform other serologic tests for autoimmune diseases. Usually, neutropenia associated with these disorders occurs in patients with obvious and severe disease, but occasionally patients are seen with occult splenomegaly, high ANA and rheumatoid factor titers, and a few other symptoms. Examination of the blood and marrow for large granular lymphocytes also may be helpful. Infectious and nutritional causes for chronic neutropenia are rare and rarely difficult to recognize. In adults, the most difficult differentiation may be between chronic idiopathic neutropenia and the myelodysplastic syndromes. Abnormalities in other cell lines (e.g., anemia, poikilocytosis and thrombocytopenia, pseudo-Pelger-Huët cells), atypical cells in the marrow, and chromosomal abnormalities suggest myelodysplasia, particularly in older patients. Investigations of the mechanism of neutropenia with marrow and blood kinetic studies, in vitro marrow cultures, measurements of marrow granulocyte reserves, and indirect measurements of marrow-proliferative activity may be useful to define mechanisms of neutropenia but are not widely available.
NEUTROPHILIA
Neutrophilia is defined as an increase in the absolute blood neutrophil count to a level greater than two standard deviations above the mean value for normal individuals. For children 1 month or older and adults of all ages this level is about 7.5 × 103/µl (7.5 × 109/liter) bands and mature neutrophils (see Chap. 2). At birth the mean neutrophil count is 12 × 103/µl (12 × 109/liter), and counts as high as 26 × 103 µl/liter (26 × 109/liter) are regarded as normal (see Chap. 7).
Several terms are used almost synonymously with neutrophilia, including neutrophilic leukocytosis, polymorphonuclear leukocytosis, and granulocytosis. Leukocytosis is used because an elevation of the number of neutrophils is the most frequent cause for an increase in the total white cell count. Granulocytosis is less specific than neutrophilia, since granulocytes include eosinophils and basophils as well as neutrophils. Extreme neutrophilia is often referred to as a leukemoid reaction because the height of the white cell count may suggest leukemia. This exaggerated reaction may be the result of segmented neutrophils or may be associated with band neutrophils, metamyelocytes, and myelocytes in smaller proportions.
In normal individuals, neutrophil counts follow a diurnal pattern of variation, with peak counts in the late afternoon. Neutrophil counts also rise slightly after meals, with erect posture, and with emotional stimuli. Ordinarily these changes are not sufficient to cause neutrophilia.108
MECHANISMS OF NEUTROPHILIA
Under normal circumstances neutrophils follow an orderly progression from the marrow through the blood to tissue sites of utilization.1,2 Neutrophilia may occur by several mechanisms: increased cell production, accelerated release of cells from the marrow into the blood, shift within the circulation from the marginal to the circulating pool, reduced egress of neutrophils from the blood to tissues, or a combination of these mechanisms. The time required for these events varies substantially. Shifts between the marginal and circulating pools take only a few minutes. Shifts of neutrophils from the marrow to the blood occur within a few hours. Increases in the production of neutrophils, even with intense stimulation, may take at least a few days (Fig. 71-2).

FIGURE 71-2 The mechanisms of neutrophilia are shown schematically. The rate of flow of cells through each compartment is represented by the size of the arrows. M.P., mitotic pool; MaP, maturation (postmitotic) pool; SP, storage pool (marrow reserves); MP, marginated neutrophil pool; CP, circulating neutrophil pool.

ACUTE NEUTROPHILIA
Pseudoneutrophilia (Demargination) Vigorous exercise and acute physical and emotional stress can substantially increase the number of blood neutrophils within a few minutes.109,110 This response is mimicked by the infusion of epinephrine and other catecholamines that increase heart rate and cardiac output.111 It is caused by a shift of cells from the marginal to the circulating pool; hence it is frequently referred to as demargination. In humans this response is dependent partially on release of neutrophils from the spleen,112 but redistribution from other vascular beds, particularly the pulmonary capillaries,113 is quantitatively more important. The increase in lymphocytes and monocytes, in addition to neutrophils, that occurs with demargination may be helpful in distinguishing this type of neutrophilia from the response to infections, protracted stress, or glucocorticoid administration. With these conditions, neutrophil counts are elevated but lymphocyte and monocyte counts generally are depressed.
Marrow Storage Pool Shift Acute neutrophilia also occurs as a consequence of release of neutrophils from the marrow storage pool, the marrow neutrophil reserves.114 This mechanism produces acute neutrophilia in response to inflammation and infections. The marrow reserve pool consists principally of segmented neutrophils and bands; metamyelocytes are not released to the blood except under extreme circumstances. The postmitotic marrow neutrophil pool is approximately ten times the size of the blood neutrophil pool, and about one-half of these cells are band and segmented neutrophils.107 In neutrophil production disorders, in chronic inflammatory diseases and malignancies, and with cancer chemotherapy, the size of this pool is reduced and the capacity to develop neutrophilia is impaired. Exposure of blood to foreign surfaces, such as hemodialysis membranes, activates the complement system and causes transient neutropenia followed by neutrophilia due to release of marrow neutrophils.115 Colony-stimulating factors (i.e., G-CSF and GM-CSF), cause acute and chronic neutrophilia by mobilizing cells from the marrow reserves and stimulate neutrophil production.116,117
CHRONIC NEUTROPHILIA
Chronic neutrophilia follows a prolonged stimulus to proliferation of neutrophil precursors. It can be studied experimentally with repeated doses of endotoxin, glucocorticoids, or colony-stimulating factors. Although the details of the mediators and mechanisms for the development of chronic neutrophilia are not understood fully, a general scheme for this response is now widely accepted (see Fig. 71-2). Expansion of cell production follows stimulation of cell divisions within the mitotic precursor pool, that is, divisions of promyelocytes and myelocytes. Subsequently, the size of the postmitotic pool increases. These changes cause an increase in the marrow granulocytic-to-erythroid ratio. In humans the neutrophil production rate increases severalfold with chronic infections; even greater increases may occur in polycythemia vera, chronic myelogenous leukemia, and leukemoid reactions in response to nonhematologic malignancies118 and in response to exogenously administered hematopoietic growth factors such as G-CSF,116,117 with a maximum response taking at least a week to develop.
Neutrophilia due to decreased egress from the vascular compartment occurs infrequently. A prototype disorder illustrating this mechanism occurs in patients with the neutrophil cell membrane defect CD11a/CD18 deficiency.119 The neutrophils do not adhere to the capillary endothelium normally, but cell production and marrow release are apparently normal. Because these patients cannot mobilize neutrophils to sites of inflammation when they develop infections, extreme neutrophilia is observed (see Chap. 72). Glucocorticoids may produce a functionally similar state, with neutrophils accumulating in the blood, at least transiently, after each dose is administered.120,121 In patients recovering from infections, as the “tissue demand” for neutrophils diminishes, the persistence of neutrophilia may be attributed to this same mechanism. In chronic myelogenous leukemia, accumulation of neutrophils with a longer than normal half-life in the blood is a partial explanation for the extreme neutrophilia.122
DISORDERS ASSOCIATED WITH NEUTROPHILIA
Neutrophilia in Response to Inflammation and Stress The categories and causes of acute and chronic neutrophilia are listed in Table 71-2. Probably the most frequent causes for acute neutrophilia are exercise, emotional stress, or any other circumstance that raises endogenous epinephrine, norepinephrine, or cortisol levels. Acute neutrophilia also occurs in pregnant patients and may be especially notable at the time of entering labor; with induction of general or epidural anesthesia; with all types of surgery; and with other acute events such as seizures, gastrointestinal hemorrhage, subarachnoid hemorrhage, or other internal bleeding.

TABLE 71-2 MAJOR CAUSES OF NEUTROPHILIA

Neutrophilia occurs with many acute bacterial infections. It occurs less predictably with infections caused by viruses, fungi, and parasites. Many aspects of the complex interactions of microbes with the infected host are not yet fully understood. Most patients with gram-positive infections, e.g., pneumococcal pneumonia, staphylococcal abscesses, or streptococcal pharyngitis, have neutrophilia. Infections caused by gram-negative bacteria, particularly those resulting in bacteremia or septic shock, may cause neutropenia or extreme neutrophilia.123 Increased circulating levels of activated complement components, G-CSF, tumor necrosis factor, and the interleukins IL-1, IL-6, and IL-8 may cause this response. Bacterial infections that have an insidious onset and cause splenomegaly, such as typhoid fever and brucellosis, characteristically do not show neutrophilia except in the initial or disseminated phases. Miliary tuberculosis is an important cause of leukemoid reactions. With viral infections, neutrophilia is far less common. In general, neutrophilia is seen in those infections producing substantial tissue injury, evoked by toxins produced by the infecting organisms. Damage to host tissues is also the presumed mechanism of neutrophilia in thermal burns, electric shock, myocardial infarction, pulmonary embolism, sickle cell crisis, and systemic vasculitis.
There are many chronic noninfectious conditions causing neutrophilia. Probably the most frequent cause is cigarette smoking.124 Neutrophil counts of smokers are increased in proportion to the amount of exposure. Neutrophil counts of smokers inhaling two packs per day are on average twice the normal levels. Chronic inflammatory diseases, including dermatitis, bronchitis, rheumatoid arthritis, ulcerative colitis, and gout, may cause a persistent neutrophilia. Sweet syndrome is an unusual dermatologic condition with intense neutrophil accumulation in the skin and persistent neutrophilia.125
Neutrophilia in Association With Cancer or Heart Disease Neutrophilia is associated with many nonhematologic malignancies, e.g., lung and gastrointestinal malignancies, particularly when they metastasize to the liver and lung.118,126 In some cases tumor cells have been found to produce colony-stimulating factors that presumably cause the neutrophilia by direct marrow stimulation.127,128 Tumor necrosis and superinfections are other possible mechanisms. Neutrophilia is unusual in brain tumors, melanoma, prostate cancer, and lymphocytic malignancies.126
Neutrophilia is a marker for both the occurrence and severity of a variety of illnesses. Neutrophilia is associated with an increased incidence and severity of coronary heart disease independent of smoking status.129,130 and 131 Similarly, elevated white cell counts have been associated with increased cancer mortality independent of smoking history.132 In patients with cancer, subarachnoid hemorrhage, and other serious inflammatory conditions, neutrophilia portends a less favorable prognosis.133
Neutrophilia as a Manifestation of an Hematologic Disorder. In addition to the myeloproliferative syndromes including chronic neutrophilic leukemia and neutrophilic chronic myelogenous leukemia (see Chap. 94), several unusual hematologic conditions may be associated with neutrophilia. The mechanisms for most of these disorders remain obscure. In Down syndrome, transient neonatal leukemoid reactions may occur that resemble chronic myelogenous leukemia.134 This type of neutrophilia may be related to a defect in regulation of neutrophil production caused by the chromosome 21 trisomy, but the precise mechanism is unknown. Idiopathic neutrophilic leukocytosis with a negative family history and a similar condition of hereditary neutrophilia with an autosomal dominant pattern of inheritance have been reported135,136 but are very rare conditions. Careful clinical examination and follow-up will almost always result in an explanation for neutrophilia.
Neutrophilia Associated With Drugs Many drugs cause neutropenia, but neutrophilia in response to drugs is uncommon except for the well-known effects of epinephrine, other catecholamines, and glucocorticoids. Lithium salts cause sustained neutrophilia.137 The counts return to normal when the drug is discontinued. The drug increases levels of colony-stimulating factor. Cases of neutrophilia have been reported with ranitidine and quinidine therapy, but such reactions are very uncommon.
CLINICAL APPROACH TO PATIENTS WITH NEUTROPHILIA
In most instances the finding of neutrophilia, band neutrophils, and toxic granules in the mature cells can be related to an obvious ongoing inflammatory condition. Often the finding of neutrophilia helps to secure the diagnosis of appendicitis, cholecystitis, or bacterial pharyngitis. When the cause of neutrophilia is not readily apparent, especially if the neutrophilia is associated with fever or other signs of inflammation, more subtle infections such as tuberculosis or osteomyelitis should be considered. In addition, a history of smoking, along with evidence for a chronic anxiety state or an occult malignancy, should be sought. If neutrophilia is accompanied by myelocytes and promyelocytes, increased basophils, and unexplained splenomegaly, the diagnosis of a myeloproliferative disease (e.g., chronic myelogenous leukemia, idiopathic myelofibrosis, or polycythemia vera) should be considered. Measurement of the leukocyte alkaline phosphatase activity can be a useful screening test in cases of moderate neutrophilia (15 to 25 × 103 neutrophils/µl [15–25 × 109 neutrophils/liter]). Ordinarily the values are elevated with inflammation of any cause and in subjects receiving glucocorticoid therapy. The values are low in chronic myelogenous leukemia and variable with other myeloproliferative disorders. Serum vitamin B12 levels and B12-binding proteins are elevated in both benign neutrophilia and chronic myelogenous leukemia. In unexplained neutrophilia, testing for the cytogenetic alterations and the BCR gene rearrangement is important in the diagnostic evaluation. The diagnosis of chronic myelogenous leukemia and of other myeloproliferative disorders with prominent neutrophilia are considered in Chapter 94.
Except for the epidemiologic associations of neutrophilia with adverse effects of smoking, coronary artery disease, and malignancies, there is no known direct adverse effect of an elevated circulating neutrophil count. In some inflammatory diseases, glucocorticoids and immunosuppressive therapies are used to reduce inflammation; a part of their mechanism is to reduce production and deployment of neutrophils and other leukocytes. For instance, glucocorticoids usually suppress the inflammation of the skin in Sweet syndrome.125 Otherwise, specific therapy to reduce the neutrophil counts generally is not indicated.
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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

 

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