Neutropenia
Caron A. Jacobson
Nancy Berliner
INTRODUCTION
The normal range for the peripheral white blood count (WBC) is between 4.5 × 109/L and 10.0 × 109/L, with a mean of 7.5 × 109/L. The total WBC includes neutrophils and lymphocytes, as well as smaller numbers of monocytes, basophils, and eosinophils. Leukopenia, a depressed WBC, may reflect either neutropenia or lymphopenia. Neutrophils constitute about 60% of the peripheral WBC, and therefore, reduction of WBC number most commonly reflects a decreased absolute neutrophil count (ANC). Neutropenia can occur as a secondary manifestation of an underlying disease or exposure or may reflect primary hematologic disease. This chapter focuses on the primary and secondary causes of neutropenia.
NORMAL NEUTROPHIL KINETICS
The circulating neutrophil pool represents only approximately 5% of the body’s total neutrophil number. It is therefore a fairly distant reflection of the dynamics of neutrophil maturation within the bone marrow.1 Neutrophils arise in the bone marrow from a multipotent progenitor cell that also gives rise to all other formed elements of the blood. Maturation of neutrophil precursors occurs over 6 to 10 days. The majority of mature neutrophils constitute a storage pool that remains in the bone marrow poised for release as needed. The proliferating pool and storage pool together make up about 95% of the total granulocyte mass. Of the remaining 5% of neutrophils that enter the peripheral circulation, about 60% are a “marginating pool” that adheres to the vascular endothelium. These marginated neutrophils are easily mobilized into the circulation in response to stress. Circulating neutrophils survive for only 6 to 12 hours; when mobilized to sites of infection or inflammation, they can migrate into tissues where they survive for 1 to 4 days. Neutropenia can occur upon disruption of any of these processes: it may reflect decreased marrow production, increased margination (especially in the setting of splenomegaly and sequestration by the spleen), or peripheral immune destruction of mature cells.
DEFINITION AND CLASSIFICATION OF NEUTROPENIA
Neutropenia is defined by a decreased ANC, calculated by multiplying the total WBC by the percentage of neutrophils and bands noted on the differential cell count. What constitutes a low ANC differs by age, sex, race, and other factors; the normal range for the ANC for a given population, then, is defined as the mean ANC for that population +/- two standard deviations.2, 3 In general, however, an ANC less than 1.5 × 109/L is considered neutropenic in most patient populations. Neutropenia can be further classified as mild, moderate, or severe based on the degree of ANC depression: an ANC of 1.0 to 1.5 × 109/L is considered mild, 0.5 to 1.0 × 109/L is considered moderate, and less than 0.5 × 109/L is considered severe. Although this classification is useful in predicting the risk of severe bacterial infection, other features may modify the risk. The risk of infection may be modified by the neutrophil storage pool.4 Risk may also be modified by the cause of neutropenia. For instance, chemotherapyinduced neutropenia is associated with a much greater risk of serious infection than chronic immune or nonimmune neutropenia. The risk of infection is also a function of both the degree and duration of neutropenia.5
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of neutropenia includes pseudoneutropenia, primary or congenital neutropenias (Table 57.1), and acquired neutropenias (Table 57.2). Global marrow defects such as aplastic anemia, leukemia, myelodysplasia, or myeloproliferative disorders can also cause neutropenia and are discussed in other chapters. Here we outline and discuss the causes of isolated neutropenia.
Pseudoneutropenia
Neutropenia may be the result of laboratory or clerical error, an artifact due to prolonged processing time of a peripheral blood specimen, the consequence of neutrophil clumping due to the presence of a paraprotein or certain anticoagulants, or as a result of marginalization of the circulating neutrophil pool.6, 7 In each of these situations, the ANC is not actually low and these patients are not at increased risk of infection. Manual examination of the peripheral blood smear and repeated measurements can help to differentiate these causes of pseudoneutropenia from true neutropenia.
Primary Causes of Neutropenia
Ethnic and Benign Familial Neutropenia
A number of racial and ethnic groups have neutrophil counts that fall below the published normal range, which is largely based on Caucasian populations. These include African Americans, Yemenite Jews, Falasha Jews, and African Bedouins.8, 9, 10, 11 The occurrence of ethnic neutropenia has been linked to single nucleotide polymorphisms in the gene encoding the Duffy antigen receptor for chemokine (DARC), which is also the receptor for the malarial parasite. Loss of expression of the Duffy blood group is prevalent in the areas where malaria is endemic, which are also areas where ethnic neutropenia has been described.12 There is also an autosomal dominantly inherited condition called benign familial neutropenia characterized by neutrophil counts in the 800 to 1,400/µl range, for which the responsible gene is not known.
Ethnic and benign familial neutropenias are not associated with an increased risk of infection.13, 14 Bone marrow biopsies have normal cellularity but a reduction in mature granulocytes and neutrophil kinetic studies reveal a reduced myeloid precursor pool in the marrow, reduced mitotic pool size, and reduced concentration of colony-forming unit culture (CFU-C) consistent with the faulty release of mature neutrophils from the bone marrow.15, 16
Nonfamilial Chronic Benign and Idiopathic Chronic Severe Neutropenia
Nonfamilial chronic benign neutropenia is a condition defined by neutropenia in the absence of a familial pattern and without an increased risk of infection. There is often a compensatory monocytosis and eosinophilia and bone marrow biopsies show hypercellularity and myeloid hyperplasia with maturation arrest at the band stage of myeloid ontogeny. Neutrophil counts do rise, however, under conditions of stress such as infection or exogenous epinephrine or corticosteroid administration, perhaps explaining the absence of risk for infection.17 Some cases are associated with the presence of autoantibodies pointing toward an immune mechanism in the pathophysiology of this condition.18, 19 Other cases seem to be the result of abnormal phagocytosis of normal marrow neutrophils by macrophages or the result of T-cell and cytokine-mediated suppression of granulopoiesis in the bone marrow.20, 21 Included in this diagnosis is chronic benign granulocytopenia of infancy and childhood which typically resolves spontaneously around age 4 years.17 Although neutrophil counts do rise in response to G-CSF administration, G-CSF therapy is not recommended given the relatively benign clinical course associated with this condition.22, 23
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TABLE 57.1 DIFFERENTIAL DIAGNOSIS AND FEATURES OF CONGENITAL NEUTROPENIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Idiopathic chronic severe neutropenia is distinguished from this benign condition in that it typically affects patients in their late childhood or as adults and has a more severe clinical course with increased risk and number of infections.24 There is evidence of myeloid hypoplasia, maturation arrest, or abnormal myeloid morphology on bone marrow biopsy; the form associated with severe myeloid hypoplasia is called chronic hypoplastic neutropenia.25, 26 To diagnose patients with idiopathic chronic severe neutropenia, other causes of neutropenia must be ruled out, including autoimmune etiologies. The pathogenesis of this form of severe neutropenia is completely unknown. Despite ANCs that may be in the 100 to 250 cells/µl range, these patients have a remarkably benign course, although some have recurrent infections requiring chronic cytokine support with G-CSF.
A large body of literature has focused on chronic neutropenia in Greece. The incidence of neutropenia on the island of Crete is quite high. This should be distinguished from chronic severe neutropenia, in that nearly all these patients have an ANC in the 0.8 to 1.4 × 109/L range, and an ANC of <0.5 × 109/L rarely if ever occurs. There is evidence that these patients may have a cytokine-mediated, inflammatory component to their illness.21 It is unknown whether these patients have an increased prevalence of the DARC polymorphism associated with neutropenia.
Severe Congenital Neutropenia
Severe congenital neutropenia (SCN) is a disorder of severe neutropenia first described in 1956 by Rolf Kostmann. He postulated that this was the first described congenital disorder of neutrophil number, presenting as an autosomal recessive disorder in neonates and infants with neutrophil counts <500 cells/µl associated with recurrent bacterial infections, most commonly due to Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa.27, 28 His original report described this syndrome in nine families from a remote region in northern Sweden where consanguinity was common, explaining the increased incidence of this rare autosomal recessive syndrome.27 The syndrome was named infantile genetic agranulocytosis, which later was renamed SCN or Kostmann syndrome. Afflicted children suffer from infections that can occur as early as the first months of life and often include omphalitis and perirectal abscesses; otitis media, pneumonia, gingivitis, and urinary tract infections are also common. The diagnosis is usually apparent within the first 3 months of life. Death may occur as a result of septicemia, peritonitis, and enteritis, with fatal infections common in infancy and early childhood. All patients have severe neutropenia with an ANC <0.5 × 109/L, but often <0.2 × 109/L, and there is often an increase in other myeloid cell lines including monocytes and eosinophils. SCN was previously hypothesized to be a result of a deficiency in G-CSF or its receptor but further studies have demonstrated that G-CSF production is not impaired in patients with SCN, G-CSF receptor number and function are normal in patients with SCN, and the administration of G-CSF results in correction of neutropenia and improved clinical outcomes.29, 30, 31, 32, 33 Kostmann’s early studies suggested that intramedullary apoptosis of myeloid precursors was a prominent feature of SCN, and more recent studies have confirmed that accelerated apoptosis is a central defect of this disorder, suggesting that G-CSF functions to correct the phenotype in part through its activity as an antiapoptotic agent.34, 35, 36, 37
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TABLE 57.2 DIFFERENTIAL DIAGNOSIS AND FEATURES OF ACQUIRED NEUTROPENIAS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Since the initial description in 1956, SCN has come to be recognized as a syndrome resulting from a heterogeneous mix of genetic mutations with different patterns of inheritance. SCN can follow autosomal dominant, autosomal recessive, and X-linked patterns of inheritance and has been shown to be associated with mutations in a variety of genes including those for neutrophil elastase, HAX-1, WAS (WASP), GFI1, SBDS, and G6PC3.38, 39, 40, 41, 42 Neutrophil elastase (ELANE) is a serine protease that is synthesized predominantly at the promyelocyte stage of neutrophil maturation and stored in primary granules. It has been hypothesized that ELANE mutations lead to cytoplasmic accumulation of defective protein, subsequently triggering apoptosis. Evidence supports activation of the unfolded protein response as the driver of apoptosis in ELANE-associated SCN.43, 44 SCN due to ELANE mutations is inherited in an autosomal dominant fashion. It was the first SCN gene to be identified and is responsible for the majority of cases of SCN. It is not the mutation found in the original Swedish cohort described by Kostmann, however, which is an autosomal recessive disorder that results from mutations in HAX-1.45 “Kostmann’s syndrome” now refers only to SCN with mutant HAX-1.41 HAX-1 is a mitochondrial protein with weak homology to BCL-2 and its absence results in mitochondrialdependent apoptosis. WASP regulates actin polymerization in hematopoietic cells. Absolute deficiency in this protein resulting from gene-inactivating mutations results in the Wiskott-Aldrich syndrome, characterized by thrombocytopenia, small platelets, sinopulmonary infections, and eczema. WASP mutations resulting in hypomorphic alleles, however, may lead to X-linked thrombocytopenia and neutropenia.40, 42 GFI1 encodes a transcription factor, growth factor independent-1, that regulates the expression of genes involved in granulopoiesis, Shwachman-Bodian-Diamond syndrome gene (SBDS) encodes a gene involved in ribosomal RNA regulation and is responsible for Shwachman-Diamond syndrome (SDS) (which is discussed in a later section), and G6PC3 encodes the catalytic subunit 3 of glucose-6-phosphatase. Mutations in each of these three genes have been associated with SCN.46, 47, 48 The gene(s) responsible for approximately 40% of SCN, however, remains unknown.40
Although G-CSF receptor signaling is intact in the vast majority of patients with SCN, rare patients have been described in which SCN arises from a congenital abnormality in the G-CSF receptor. Not surprisingly, these patients are marked by resistance to therapy with G-CSF.49, 50, 51, 52 The most important observation to emerge from the studies of the G-CSF receptor in SCN, however, is the finding of frequent somatic mutations in the G-CSF receptor arising in patients with SCN on cytokine therapy. When searching for potential constitutional mutations in the G-CSF receptor that might cause SCN, investigators identified a somatic missense mutation that appeared to be associated with transformation to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML).49 This mutation introduces a stop codon leading to truncation of the distal intracellular domain of the receptor. The distal portion of the receptor is known to be the site of JAK-STAT activation and maturation signaling.49 Some investigators have postulated that the mutation causes proliferation at the expense of maturation, explaining why patients with this mutation have a higher risk of MDS/AML.53 It has clearly been demonstrated that the mutation shifts the doseresponse curve for G-CSF, rendering the cells hyperproliferative, and permitting clonal dominance of the mutant clone in the setting of G-CSF therapy. Whether the mutation actually blocks differentiation or merely predisposes to further genetic events by virtue of increasing cell proliferation remains controversial. Regardless, these G-CSF receptor mutations have been found to confer resistance to apoptosis and enhance cell survival in patients with SCN.54
In general, patients with SCN have an increased risk of developing MDS and AML at a rate of approximately 2% to 8% per year.55, 56, 57 In patients who do develop MDS and/or AML, there appears to be a sequential gain of mutations that were not present in the subpopulation of progenitor cells in the early SCN phase such that over two thirds of patients with SCN that develop MDS or leukemia have a G-CSF receptor mutation (CSF3R).58 Increasing mutations in the G-CSF receptor gene point toward a role for aberrant G-CSF receptor signaling in leukemogenesis.58, 59 The role of G-CSF in causing or promoting these mutations remains unknown and a subject of considerable controversy.
G-CSF has revolutionized the treatment and management of SCN. Prior to the development of G-CSF as a clinical agent, SCN was almost uniformly fatal, with death from infection occurring in infancy or early childhood. Patients were treated with corticosteroids, testosterone, splenectomy, vitamin B6, and lithium, all of which were largely ineffective.60, 61, 62, 63 The use of G-CSF for this disease began in the 1980s, and has prevented infection in the vast majority of patients (80% to 90%), although some patients require higher doses.57, 64 The resultant increased life expectancy of these patients has coincided with an increased incidence of MDS and AML. This has led some to posit that G-CSF therapy facilitates the transformation to these malignant diseases, whereas others contend that prolonged survival allows for the emergence of a predisposition to MDS/AML as part of the natural history of this disease. The potential role of G-CSF in the development of MDS/AML in SCN is discussed later in this chapter. Chronic G-CSF therapy in this disease has led to other complications, including osteoporosis, vasculitis, splenomegaly, hepatomegaly, and glomerulonephritis.57, 64
Cyclic Neutropenia
Cyclic neutropenia (CN) is a periodic disorder characterized by neutropenia (ANC ≤ 0.2 × 109/L) occurring at approximately 21-day intervals, although one quarter of patients may have cycles as short as 12 days or as long as 36 days.65, 66, 67 Nadirs of the ANC last 3 to 5 days and may be associated with recurrent fevers, aphthous ulcers, and infections of the skin, upper respiratory tract, and ears. The severity of infection reflects the severity and duration of neutropenia.68 Fatal infections are uncommon, however, owing to the relatively brief period of neutropenia that is the hallmark of this disease, and as a result patients enjoy favorable overall survivals. With time, the cyclic nature of the disorder becomes less prominent, however, and patients can look more like patients with chronic neutropenia.69 It was first described in 1910 in an infant with recurrent episodes of fever, stomatitis, skin infections, and neutropenia.70 Diagnosis of CN can be demonstrated by documenting intermittent neutropenia via blood counts every 2 to 3 weeks over a course of 6 weeks, but can now be confirmed by the detection of a pathogenic mutation in the setting of a suggestive pattern of WBC fluctuation. CN is inherited as an autosomal dominant disorder, although it may arise sporadically. CN can also be acquired in association with systemic diseases such as large granular lymphocytosis.71, 72 Virtually 100% of patients with congenital CN also have point mutations in the gene for neutrophil elastase (ELANE).73 These mutations are largely distinct from those that are associated with SCN, although both syndromes have been seen arising from the same mutation within the same pedigree.74, 75
Serial measurements of other hematopoietic cells in patients with CN reveal a periodicity to the numbers of platelets, reticulocytes, monocytes, and eosinophils as well, and the condition is sometimes referred to as cyclic hematopoiesis.76 As opposed to the depression seen in the neutrophil count, these other cells are often increased in number on or around periods of neutropenia.77 Bone marrow biopsies done during times of neutropenia and times of normal neutrophil counts reveal an absence of neutrophils and neutrophil precursors immediately preceding the period of neutropenia, whereas neutrophil precursors increase in number before recovery of peripheral neutrophil counts.78 The periodicity of the cell counts is thought to be the result of variations in the rate of release of mature cells from the marrow. Although knock-in mice fail to reproduce the phenotype of either SCN or CN, a dog model of CN has provided insight into its pathogenesis.79 In grey collie dogs, the disease can be transmitted to unaffected animals following bone marrow transplantation from an affected animal and can be cured following transplantation from an unaffected animal.80 In humans, a patient with acute lymphoblastic leukemia treated with a donor stem cell transplantation from a sibling with this disorder developed the disease.81 These observations and experiments support the notion that this disease is the result of an intrinsic stem cell regulatory defect, possibly related to accelerated apoptosis.82 A comparison of bone marrow biopsies from patients with CN and SCN, and normal subjects revealed that there were no differences in the frequency of CD34, KIT, and G-CSFR expression on marrow precursor cells between CN patients and normal subjects.83 Differences emerged, however, in response to hematopoietic growth factors with impaired granulopoiesis in both CD34+/KIT+/G-CSFR+ and CD34+/KIT+/G-CSFR-cells in patients with CN; in SCN impaired granulopoiesis was only observed in the former.
Despite the impairment of granulopoiesis observed in response to hematopoietic growth factors, this disease is successfully treated with G-CSF and is not associated with an increased risk of leukemic transformation.57, 69, 84 G-CSF therapy does not prevent the cyclical depressions in neutrophil counts but does decrease the duration of neutropenia. GM-CSF therapy, on the other hand, has been noted to prevent the cycles but not to increase the neutrophil numbers to the same extent as seen with G-CSF.85 G-CSF remains the treatment of choice for this disease when therapy is required. Lower doses of G-CSF are needed for the treatment of CN than SCN, with a median dose of 2.5 µg/kg/day in one cohort.65 G-CSF is safe and well tolerated, although patients may develop a gradual asymptomatic splenic enlargement.69 The acquired, adult-onset forms of CN that are associated with systemic diseases are treated differently and are often successfully managed with immunosuppression including daily or alternatedaily corticosteroids or cyclosporine.86, 87 These therapies are not successful in the congenital forms of this disease.65, 68
Congenital Immune Defects with Associated Neutropenia
Patients with inherited immunodeficiencies of humoral and/or cellular immunity are at risk of developing neutropenia. The infectious consequences in such patients are magnified due to the co-existing immune defects. Diseases involving immunoglobulin production, including X-linked agammaglobulinemia, hyper-IgM syndrome, dysgammaglobulinemia type I, isolated IgA deficiency, and familial forms of hypogammaglobulinemia have all been associated with periodic neutropenia and in some are thought to be related to the production of autoantibodies.88, 89, 90, 91, 92 These patients should be treated with intravenous immunoglobulin, which may correct both immune defects, with growth factors reserved for patients who do not respond to immunoglobulin replacement.93 Likewise, neutropenia has been associated with defects in cellular immunity; one familial syndrome was described in 1976 in which patients manifested severe neutropenia coincident with decreased antibody production in response to tetanus and poliomyelitis vaccines with resultant infectious complications.94 Finally, reticular dysgenesis is a rare immunodeficiency marked by severe neutropenia, lymphopenia, agammaglobulinemia and absent cellular immunity believed to be due to an inherent defect in hematopoietic stem cells committed to myeloid and lymphoid development.95, 96 It is not responsive to G-CSF but can be cured with stem cell transplantation.97, 98, 99
Other Congenital Syndromes with Associated Neutropenia
Neutropenia is an important feature of several other congenital disorders. (see also Chapter 37.) These include SDS, Fanconi anemia (FA), dyskeratosis congenita (DKC), glycogen storage disease Ib, myelokathexis, Chediak-Higashi syndrome (CHS), Griscelli syndrome type II (GS2), Hermansky-Pudlak syndrome II (HPSII), and cartilage-hair hypoplasia.
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