Matthew M. Hsieh and Harry L. Malech
Neutrophils or polymorphonuclear (PMN) cells are 5 μm in diameter with a distinctive multilobed nucleus and many small granules. Neutrophil maturation begins with myeloblasts in the bone marrow. Myeloblasts differentiate into promyelocytes, which are characterized by the appearance of primary (azurophilic) granules containing myeloperoxidase (MPO), followed by differentiation into myelocytes, characterized by the formation of secondary granules containing lactoferrin and gelatinase, and progress through metamyelocytes, band forms, and finally mature neutrophils. This process of differentiation typically occurs over 10 to 14 days but may be accelerated in the setting of infection, in some cases leading to mature forms retaining large azurophilic granules (toxic granulation). Once neutrophils exit bone marrow, they circulate for about 6 to 12 hours. At sites of infection or inflammation, neutrophils adhere to and migrate between post-venule endothelial cells in order to exit blood vessels into the tissues, where they remain for 1 to 3 days. In the absence of overt infection, most neutrophils in the circulation ultimately undergo apoptosis and are taken up by macrophages in the spleen. Even without infection, there is a baseline rate of neutrophil migration into the mouth and gastrointestinal tract where, together with the barrier function of the mucosa, they prevent entry of bacteria into tissues at local sites. In the setting of severe neutropenia, the gastrointestinal tract is often the first site of invasive bacterial infection.
Neutrophils circulate in a metabolically quiescent state. When stimulated by inflammation, infection-related cytokines, or chemotactic factors, they exit the circulation by adherence to endothelial cells and migrate to sites of inflammation. Neutrophils are among the first cells to migrate to sites of inflammation and thus represent the first line of defense against microbes. They internalize microbial particles by phagocytosis via Fc receptors and complement C3, and granule contents and reactive oxidants are released into phagosomes to kill microbes. Increased numbers of life-threatening bacterial infections occur in association with inherited or acquired disorders characterized by abnormal granule formation, poor neutrophil adherence, failure to produce microbicidal oxidants, or where there is very low production or increased destruction of neutrophils.1 Table 9.1 provide an overview of neutrophil disorders and Abbreviated List of Common Drugs Causing Neutropenia.
NEUTROPHIL DISORDERS
Leukocyte Adhesion Deficiency
The β2 integrins in neutrophils are particularly important for normal neutrophil egress from blood at postcapillary venules, for migration through tissues, and for complement-mediated phagocytosis.
There are three leukocyte β2 integrin adhesion molecules which share the CD18 protein antigen as a common subunit; CD11a/CD18 (lymphocyte function associated antigen-1), CD11b/CD18 (macrophage 1 antigen), and CD11c/CD18 (also known as p150/95). Mutations in the gene encoding CD18, leading to near absent CD18 protein expression, are responsible for a disease known as leukocyte adhesion deficiency 1 (LAD-1). LAD-2 and -3 have been described in a handful of individuals, and they are due to an abnormality of fucose glycosylation (ligand required for selectin binding) and FERMT3 protein-mediated integrin activation, respectively.3 In general, “LAD” used without the numerical identification refers to LAD-1, the defect responsible for the great majority of cases. LAD has an autosomal recessive inheritance pattern, affecting only a few individuals per million. LAD is associated with recurrent life-threatening infections and other characteristic clinical manifestations. Diagnosis is usually made by flow cytometry measurement of the amount of CD11b or CD18 on the surface of neutrophils using specific antibodies. The severity of disease manifestations, including risk of early death from infection, appears to be correlated with the amount of β2 integrins present.
Moderate phenotype has 1% to 10% of normal levels of β2 integrins; while the severe phenotype is associated with presence of less than 1% detectable β2 integrins. On the cellular level, there is poor neutrophil adhesion to endothelial and other immune cells, and neutrophils do not egress from vasculature and migrate to sites of inflammation. Baseline peripheral blood neutrophil count, even in the absence of infection, is characteristically about 2 to 3 times normal; with infection, neutrophil counts can exceed 60 k/µL and mimic a leukemic condition. Despite the very high circulating levels of neutrophils, there may be only mild erythema or pain at sites of infection, and the patients fail to form pus (called “tissue neutropenia”). One of the hallmarks of severe LAD is delayed separation of the umbilical cord, indicating a role for neutrophils in providing the proteases and hyaluronidases required for that event. A prominent manifestation of severe LAD is recurrent infections with large non-healing ulcers of the skin, particularly over the lower abdomen, perineum, and legs. Patients also suffer recurrent infections of the oral cavity (gingivitis, periodontitis with early loss of primary and secondary teeth), respiratory tract (sinusitis, otitis media, and pneumonia), gastrointestinal tract, and genital mucosa. Infection of the wall of the small bowel or colon complicated by perforation is a particular risk that often leads to a fatal outcome. Infections are commonly caused by Staphylococcus aureus, enteric organisms, Candida, and Aspergillus species. In patients with milder forms of LAD, who are not transplanted and survive past the first decade, large non-healing ulcers of the lower extremities and groin become chronic and are very difficult to control or treat. Therapies include bacterial prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX), supportive antibiotics during acute infections, surgical debridement of skin, and skin grafting. There is a high mortality rate (∼75%) of severe LAD in the first year of life. Successful bone marrow transplant is curative and should be considered for all patients with severe LAD.4
Myeloperoxidase Deficiency
MPO is the most abundant protein in neutrophil granules. MPO resides in the primary (azurophilic) granules, and has antimicrobial functions (catalyzes the production of hypochlorous acid from chloride and the hydrogen peroxide product of the phagocyte NADPH oxidase). MPO deficiency is the most common neutrophil abnormality, with an incidence of about one per 2,000 for partial deficiency and one per 4,000 for complete deficiency.5 Most individuals with MPO deficiency do not manifest clinically though ex vivo assays of bacterial and fungal killing demonstrate a defect associated with MPO deficiency. MPO deficiency is inherited in an autosomal recessive pattern, but MPO deficiency can also appear as an acquired abnormality associated with leukemia or myelodysplasia. Specific mutations in the MPO gene have been identified, which may affect transcription, translation, and/or insertion of the heme group. Neutrophils with MPO deficiency mature, migrate, and phagocytose normally, but as noted there are defects in microbial killing. Some individuals may have a mildly increased frequency of bacterial infections, and in the setting of cofactors like diabetes there may be particular difficulty in clearance of candida species (albicans, tropicalis, stelatoidea, and krusei ) infections. Diagnosis of MPO deficiency may be made by measurement of peroxidase activity using flow cytometry or using certain types of automated blood count devices that use peroxidase activity to perform differential counts of blood leukocytes. Since most affected patients have mild disease, antimicrobial and supportive therapy is sufficient. Prophylactic antibiotics should be limited to those with recurrent infections or with another disorder predisposing to infections, such as diabetes.
Chronic Granulomatous Disease
Chronic granulomatous diseases (CGDs) are a group of closely related inherited disorders characterized by defective phagocyte NADPH oxidase manifested by a failure of stimulated neutrophils, monocytes, eosinophils, and macrophages to produce superoxide and hydrogen peroxide.6 CGD affects approximately 5 individuals per million, equally affecting all ethnic groups. CGDs are caused by mutations in any of 5 subunit components of the phagocyte NADPH oxidase. The clinically most severe is the X-linked, gp91phox subunit deficient form of CGD, usually associated with total absence of any oxidant production and affecting almost 70% of patients with CGD. The other 4 types of CGD are inherited in an autosomal recessive pattern and consist mostly of p47phox deficient CGD patients (25% of CGD patients) with the remainder comprised of the much less common p67phox, p40phox, or p22phox deficient forms of CGD. Clinical manifestations of CGDs involve both recurrent infections and formation of inflammatory granulomas, for which severity and individual manifestations can vary widely. The average age of diagnosis of X-linked CGD is 3 years, but the average age of diagnosis of females with the p47phox form of CGD is 9 years of age. Thus, some patients with no family history may reach young adulthood before the disease is recognized.
Unlike patients with severe neutropenia or LAD who get infected primarily with commensal organisms (such as enteric bacteria normally found in the gastrointestinal tract), CGD patients are generally not susceptible to commensal organisms such as E. coli. Patients are particularly prone to infection by environmental organisms that are catalase positive: the usual bacterial pathogens are Staphylococcus aureus,nocardia, Burkholderia cepacia (and other Burkholderia species), and Serratia marcescens . Fungal pneumonia and other fungal infections are primarily aspergillus species, with Aspergillus nidulans being a problem particular to CGD patients. However, infections with paecilomyces, and other fungi including dematiaceous molds are an increasing problem; they need to be considered because they may be resistant to voriconazole but sensitive to posaconazole. CGD patients do not seem to be particularly susceptible to Candida albicans, though infections with other candida species such as C. glabrata occur. While infections are usually recurrent, prolonged, and episodic, CGD patients who are on appropriate effective prophylaxis may have many months or even years between severe infections.
In infancy, S. marcescens osteomyelitis or soft tissue infection is a very common first presenting infection leading to diagnosis. In older children and adults with CGD, the most common life-threatening infections are bacterial or fungal pneumonias, even if local soft tissue infections and lymph node infections are more common. Other tissues can be infected, including sites as diverse as osteomyelitis or brain abscess. After pneumonia, the most common severe infections are liver abscesses. It is noteworthy that in CGD patients taking TMP/SMX as daily prophylaxis, severe staphylococcal deep tissue infections are relatively uncommon, yet almost 90% of liver abscesses are caused by S. aureus. Methicillin-resistant S. aureus liver abscess is an increasing problem. A liver abscess is generally not an easily drained pustular lesion but often consists of a solid granulomatous mass with micro-abscesses. In the recent past, the standard of care often involved surgical extirpation of the infected granulomatous mass together with prolonged antibiotic therapy for most effective cure. More recently, a period of use of high dose corticosteroids together with prolonged antibiotic therapy directed at the liver abscess pathogen have been demonstrated to effectively treat liver abscess in CGD without the need for surgical intervention in most cases. The steroids likely reduce the granulomatous inflammation and fibrotic reaction, allowing improved penetration of antibiotic into the infected mass in the liver.
In some CGD individuals, granuloma formation in the absence of active infection may predominate over recurrent infections; in some cases the granulomatous inflammation can cause gastroesophageal junction or gastric outlet obstruction, bladder outlet obstruction, or chronic abdominal pain with diarrhea. A gastrointestinal granulomatous process may be indistinguishable from Crohn’s disease and even respond to similar treatments such as those used for Crohn’s disease. CGD granulomas are different from granulomas of autoimmune diseases, as they are responsive to tapering doses of corticosteroids and controllable in the long term by very low dose alternate day prednisone. Autoimmune disorders of the Th1 cytokine pattern type (Crohn’s disease, rheumatoid arthritis, lupus, sarcoidosis) occur with increased frequency in CGD. Whether this association is triggered by recurrent infections, by the hyperinflammation associated with CGD, or an intrinsic characteristic of CGD lymphocytes is yet to be determined.
CGDs should be suspected in patients with a family history of unexplained deaths in infant or young boys, or in boys or girls infected with specific organisms characteristic of CGD infections (serratia osteomyelitis in an infant is almost diagnostic of CGD), and in children with pneumonia that does not rapidly resolve with conventional therapy. Diagnosis is made by a dihydrorhodamine flow cytometry, demonstrating defective oxidase activity in neutrophils, and confirmed by quantitative assays of superoxide production. Acute infections are managed with antibiotics and supportive therapy. Because of the propensity of CGD patients to infections with unusual organisms such as nocardia or aspergillus, aggressively seeking a pathogenic organism is essential to achieve correct antimicrobial therapy. When infections resolve, prophylaxis is implemented with good oral hygiene using chlorhexidine and/ or peroxide based mouthwash, daily oral TMP/SMX (5–6 mg/kg/day TMP equivalent), daily oral itraconazole (4–5 mg/kg/day), and three-times-a-week subcutaneous injections of recombinant interferon gamma (0.05 mg/m2). Surgical intervention may be necessary to identify pathogens, debride devitalized tissues, or accelerate recovery and response to therapy. Granulomatous processes can occur with or without infections, so appropriate microbial cultures are an important part of the evaluation. Gastrointestinal or genitourinary granulomas not associated with any pathogen can be treated with 0.5 to 1 mg/kg of prednisone for 2 weeks, followed by gradual taper, though some patients require 0.1 to 0.25 mg/kg prednisone long term for control of (GI) and/or (GU) lesions. Some CGD patients may have difficulty with dehiscence of surgical wounds, particularly on the abdomen or neck, and paradoxically they may require a course of low-dose corticosteroid to suppress granuloma formation in the wound to allow healing. Bone marrow or other source hematopoietic stem cell transplant may be considered for some patients with severe disease and/or many recurrent infections who have an HLA-matched sibling donor.7 Gene therapy appears to be a promising alternative for those who are not eligible for stem cell transplantation.8
Chédiak-Higashi Syndrome
Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive disorder caused by LYST gene mutations, leading to abnormal intracytoplasmic protein transport and vacuole formation.8,9 The genetic defect results in the fusion of intracellular granules and uneven distribution of giant granules in the cytoplasm of neutrophils and many other cells, such as platelets, melanocytes, renal tubular cells, Schwann cells, thyroid follicular cells, and mast cells. Cells containing giant granules have impaired function and manifest as recurrent bacterial infections; bleeding or easy bruising; hypopigmentation of skin, eyes, and hair; recurrent infections; peripheral nerve defects (neuropathy, nystagmus); or abnormal natural killer cell functions. Diagnosis is made by detecting large granules in neutrophils on the peripheral blood smear. Treatment includes supportive therapy and bacterial prophylaxis with TMP/SMX. Not all patients appear to have recurrent infections; major problems include a progressive peripheral neuropathy that manifests during the third decade of life and the risk of developing a lymphoma-like condition, which can be fatal. Vitamin C was shown to partially reverse some of the cellular defect observed in vitro, leading to its use in patients, but whether it reduces infection or alters the course of the disease is not clear. Bone marrow transplantation, immunosuppression, or rituximab can be considered for those who develop an “accelerated phase” with lympho-proliferative lymphoma-like syndrome.
Specific Granule Deficiency
Neutrophil secondary (or specific) granules contain a variety of proteases and other antimicrobial molecules. These proteins perform important normal functions in infection control and possibly also in wound healing. Specific granule deficiency (SGD) occurs as a very rare inherited disorder, or more commonly appears associated with leukemia or myelodysplasia.10 Acute burn injury has also been noted to result in neutrophils deficient in specific granules, perhaps secondary to degranulation. Inherited SGD can result from a mutation in the gene encoding a key regulatory factor required for late events during myeloid differentiation (CCAAT/enhancer binding protein ε). Failure of function of this DNA-binding differentiation factor protein results in the inability to produce the specific granule itself, the contents of the specific granule, as well as the inability to produce other proteins normally made during the late phase of myeloid differentiation. Clinically, SGD patients have recurrent bacterial infections starting in early childhood. Common sites of infections are skin (cellulitis) and respiratory tract (sinusitis, pneumonia, otitis media). Similar to LAD, there is no erythema or pus at the site of infections, and recurrent large non-healing ulcers are a chronic problem. The presence of non-healing ulcers in both SGD and in LAD probably points to an important role of neutrophils not only for infection control but possibly also in wound healing. Treatment includes antibiotics for acute infections and prophylaxis with daily TMP/ SMX and itraconazole.
NEUTROPENIAS
Neutropenia is typically defined as an absolute neutrophil count (ANC) less than 1.5 × 109/L (or <1,500/µL). Neutropenia is characteristic of some specific hereditary syndromes, and it can result from infections, drugs or toxins, or autoimmune disorders. The risk of infection from neutropenia depends on three factors: the ANC, the neutrophil reserve in the bone marrow, and the duration of neutropenia. This risk is increased with neutrophil counts of 0.5 to 1.0 × 109/L (500–1,000/µL) and the greatest with less than 0.5 × 109/L (<500/µL). A falling neutrophil count or a significant decrease over steady-state levels, with a failure to increase neutrophil counts in the setting of infection or other bone marrow stress carries a higher risk of complication than a stable chronically low neutrophil count over many months or years that rises significantly in response to infection.
Acquired Neutropenias
Drug-Induced Neutropenia
Drugs can cause neutropenia by one or more of the following mechanisms: direct cytotoxic effect to rapidly dividing bone marrow cells, immune mediated, or other non-immune mediated neutrophil destruction. A recent review indicated that the duration of drug exposure to onset of neutropenia can vary from less than 1 week to 60 days.11 The degree of neutropenia can be severe (ANC less than 0.1 ×109/L or 100/µL) but usually requires only that the sensitizing drug be discontinued. Neutrophil counts usually begin to recover within 5 to 10 days after the offending drug is stopped. Re-administration of the sensitizing drug may decrease neutrophil counts abruptly. While some drugs (Table 9.2) have more often been cited as a cause of drug-related neutropenia, severe immune-mediated, drug-induced neutropenia can occur with any drug, including unlikely agents such as aspirin or acetaminophen.
Infection-Related Neutropenia
Neutropenia following infections is common, from one or more of the following mechanisms: destruction, margination, sequestration, or marrow suppression. Neutropenia from viral infections can be seen as early as a few days, and can persist for the duration of viremia. The degree and duration of virus-induced neutropenia is usually mild and short, but neutropenia from Epstein-Barr virus, hepatitis, and HIV can be severe and protracted. Gram-negative bacterial infections can cause neutropenia in those with impaired marrow neutrophil reserve, such as neonates, the elderly, and the chronically immunosuppressed. Protozoal (Leishmania) and rickettsial (RMSF and Ehrlichia) infections can also cause neutropenia, often with accompanying anemia and/or thrombocytopenia.
Immune-Related Neutropenia
This form of neutropenia is typically associated with specific antibodies directed to neutrophil antigens (not to be confused with anti-nuclear antibodies). These antibodies may occur with or without autoimmune disorders. Many syndromes are clinically similar and will be briefly discussed below.
In alloimmune (or isoimmune) neonatal neutropenia,12 maternal IgG antibodies are directed toward paternal antigens on fetal neutrophils causing moderate neutropenia that is self-limiting, lasting only a few weeks to a few months. These neonates have an increased risk of infections and can develop pulmonary, skin, or urinary tract infections from gram-positive or -negative organisms. The treatment is supportive with antibiotics, IVIg, and sometimes G-CSF.
Table 9.2 Abbreviated List of Common Drugs Causing Neutropenia
Antiplatelet agents: ticlodipine
Sulfa-containing drugs: sulfasalazine, dapsone
Anti-thyroid agents: methimazole, propylthiouracil
Calcium dobesilate
Antimicrobials: particularly penicillins, cephalosporins, carbapenems
NSAIDs: dipyrone, indomethacin
Tricyclic antidepressants: clomipramine
Cardiac medications: antiarrhythmics agents, digoxin, diuretics, ACE inhibitors
Reflux/ulcer agents: cimetidine, ranitidine
Antipsychotic agents: clozapine, chlorpromazine
Antiviral agents (against HIV, HSV, CMV)
Rheumatoid arthritis agents: penicillamine, gold compounds
Chemotherapy
ACE, angiotensin converting enzyme; CMV, cytomegalovirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; NSAIDs, non-steroidal anti-inflammatory drugs.
From Palmblad JE, von dem Borne AE. Idiopathic, immune, infectious, and idiosyncratic neutropenias. Semin Hematol. 2002;39:113-120.
Autoimmune neutropenia of infancy/childhood13 is typically seen in those less than 2 years of age. The degree of neutropenia is variable, and infections in the oropharynx, ear, sinus, and upper respiratory tract can occur. The neutropenia may resolve spontaneously over many months or years, and typically does not require treatment. Antibiotics and G-CSF are given during acute infections, and TMP/SMX is often given for prophylaxis.
Large granular lymphocytosis or leukemia (LGL)14 is caused by abnormally expanded T or NK cells infiltrating the bone marrow, spleen, and liver, resulting in variable degrees of pancytopenia and splenomegaly. LGL may be an oligoclonal or monoclonal disease, and in its more aggressive form is considered a form of leukemia. LGL is usually diagnosed in individuals about 60 years old. Laboratory evaluation shows multiple abnormalities: 80% of affected individuals will have lymphocytosis >2 × 109/L, 80% with ANC <1.5 × 109/L, 50% with hemoglobin <11 g/dL, 20% with platelet <150 × 109/L. LGL can also occur with other autoimmune disorders (rheumatoid arthritis most commonly), myeloid and B cell malignancies, or solid tumors. Bone marrow examinations are also variable, but the majority will have hypercellular marrow. No treatment is necessary until there are recurrent infections, severe neutropenia, or symptomatic anemia.15 Corticosteroids, methotrexate, cyclophosphamide, and other immunosuppressive therapy have been used with generally good response rates. However, aggressive monoclonal LGL disease should be considered a form of leukemia requiring specific chemotherapies appropriate to control the disease.
Congenital Neutropenias
Severe Congenital Neutropenia (Kostmann Syndrome and Autosomal Dominant Forms)
Dr. Kostmann in 1956 described severe neutropenia associated with recurrent bacterial infections in several families in northern Sweden. This syndrome was later observed in other geographic locations. Kostmann syndrome is an autosomal recessive form of severe congenital neutropenia that is a rare clinical entity with an incidence rate of about 1 to 2 per million.16 Neutrophil elastase (ELA 2 or ELANE) mutations are responsible for almost half of the individuals with the autosomal dominant or sporadic forms of severe congenital neutropenia. Mutations in ELA 2 have been hypothesized to cause defective signal transduction and to cause programmed cell death (apoptosis) at the myelocyte level.17 These effects may be a result of cellular mechanisms that detect protein misfolding. There are additional abnormalities that can be acquired, which may lead to myelodysplasia and/or acute myeloid leukemia: G-CSF receptor mutation, RAS oncogene mutation, or chromosome 7 monosomy. An autosomal dominant form of neutropenia has been reported to result from heterozygous mutations in the GFI1 gene that may affect ELA 2.18 Recent studies have shown that Kostmann syndrome can also be caused by mutations in the HAX1,19 G6PC3,20 or other genes.
Clinically, individuals are infected as early as 2 to 3 months of age by gram-positive or gram-negative bacteria in one or more of the following sites: skin, ears, oral or gastrointestinal mucosa, upper or lower respiratory tract, urinary tract, or blood. Blood counts usually reveal neutrophils less than 500/µL (<0.5 × 109/L) with compensatory monocytosis and eosinophilia. Bone marrow biopsies show maturation arrest at the promyelocyte-myelocyte level and absent band forms or mature neutrophils. Treatment includes supportive therapy and antibiotics for acute infections. G-CSF between 3 and 10 µg/ kg increases the neutrophil count and reduces the frequency of infections. A minority of individuals will require a dose in excess of 30 µg/kg/day. G-CSF is not currently thought to be associated with acquisition of G-CSF mutations and is not itself thought to be a cause of the leukemia associated with this disorder. However, individuals requiring longer duration or high cumulative doses of G-CSF may have a more severe form of the disorder, and therefore a higher risk of malignant transformation to leukemia. Toxicities of chronic G-CSF administration include bone pain from marrow expansion, osteopenia or osteoporosis, and splenomegaly. Bone marrow transplant is a curative option for those with HLA-matched sibling donors.
Cyclic Neutropenia
The incidence of inherited cyclic neutropenia is not known,17,21 nor is the etiology completely understood, although neutrophil elastase 19p13.3 mutations are associated with this disorder and have been hypothesized to cause neutrophil apoptosis and thus to initiate the cycling. Clinically, neutrophil count oscillates predictably between very low or agranulocytic to low normal range; the average cycle length is 21 days with neutropenic duration of 3 to 6 days. The nadir neutrophil count can be zero or as low as 200/µL (0.2 × 109/L). Platelet, reticulocyte, lymphocyte, and monocyte counts may also “counter-cycle” between normal to high range, either coinciding or not coinciding with the neutrophil cycles. Serial bone marrow examinations will appear normal, when the neutrophil count is high, and show decreased myeloid precursors in the neutropenic phase. Individuals with cyclic neutropenia may be asymptomatic during periods of normal neutrophil count, and may have fever, lymphadenopathy, mild skin infections, and/or oral mucosal ulcers during periods of neutropenia. Mild skin infections and/or mouth ulcers are treated symptomatically. G-CSF, at 2 to 3 µg/kg per one or two days, appears to improve the neutrophil nadir, shorten the cycles, and thus reduce infections. GM-CSF does not effectively treat inherited cyclic neutropenia.
Other Inherited Disorders Associated with Clinically Significant Neutropenia
There are a number of inherited disorders where clinically significant neutropenia is observed, but where neutropenia is not considered the most prominent feature of the inherited syndrome. Three examples are provided. A specific mutation responsible for Wiskott-Aldrich syndrome is associated with neutropenia.22 Patients with WHIM syndrome, which is caused by inherited C-terminal truncations in CXCR4 suffer from clinically significant neutropenia that is responsive to treatment with G-CSF.23 A subset of patients with CD40 ligand deficiency (X-linked Hyper-IgM syndrome) have clinically significant neutropenia.24
Other Neutropenias
Idiopathic Neutropenia
Idiopathic neutropenia, or chronic idiopathic neutropenia, affects about 2 to 4 individuals per million, and can be seen in both children and adults.25 Clinically, it behaves very similar to autoimmune neutropenia, except anti-neutrophil antibodies are not detected and other studies are non-diagnostic. Majority of these individuals have moderate neutropenia with mild symptoms. Pro-inflammatory cytokines that promote neutrophil apoptosis and myelosuppression from activated lymphocytes have been proposed as possible mechanisms. There is a small subset of individuals that have severe neutropenia, recurrent fevers, oropharyngeal infections (mucosal ulcers, gingivitis), or severe systemic infections. Treatments are largely tailored for symptomatic relief and antibiotics dictated by sites of infection. G-CSF, 1 to 3 μg/kg per dose weekly or on alternate day, is used in those with severe clinical syndromes. Development of myelodysplastic syndrome or leukemias is very rare. Generally, patients who increase their neutrophil count with infection or with other stress do well clinically.
Benign Ethnic Neutropenia
Benign ethnic neutropenia (BEN) is a condition seen mostly in individuals of African descent, including African-Americans, Yemenite Jews, and certain populations in the Caribbean and Middle East. Prior studies showed that up to 25% of non-US individuals of African descent and about 4% of African-Americans have neutrophil counts between 1.0 and 1.5 × 109/L.26 The cause for this observation is unknown, but several investigators earlier have excluded stem cell disorder, excessive margination, and differentiation defect, suggesting that this may be a normal population-based variant. The physiologic mechanisms controlling the normal set point for circulating levels of neutrophils is unknown, but there is accumulating evidence that the Duffy antigen and receptor for chemokine (DARC) is associated with those of African descent with lower leukocyte/neutrophil counts.27,28 CXCR4 chemokine receptor for the SDF-1 chemokine may also play a role in egress of neutrophils from the marrow and, at least theoretically, differences in expression or function of this cytokine/cytokine receptor could affect this set point. Perhaps normal variants in this or other receptors may be responsible for these population differences observed in average circulating neutrophil counts. Clinically, individuals with this ethnically based neutropenia variant are asymptomatic, without recurrent oral, skin, or systemic infections. When these individuals acquire typical viral or bacterial infections, these infections are not more severe and do not need longer periods of treatment. Laboratory evaluations will show many blood counts that are abnormal over many years, and the bone marrow examinations will be normal. Other than usual symptomatic treatment and antibiotics as needed (as for a normal healthy adult), no additional treatment is required, but it is important to note this variation to avoid unnecessary medical evaluation.
References