Immune neutropenia

INTRODUCTION — Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1500/microL. The ANC is equal to the product of the white blood cell count (WBC) and the fraction of polymorphonuclear cells (PMNs) and band forms noted on the differential analysis:

ANC = WBC (cells/microL) x percent (PMNs + bands) ÷ 100

Neutrophilic metamyelocytes and younger forms are not included in this calculation (calculator 1).

Most cases of neutropenia are acquired and are due to apoptosis of myeloid cells or increased destruction [1], usually resulting from immunologic mechanisms, which can be antibody or cytotoxic-T cell related [2]. (See "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia", section on 'Causes of neutropenia'.)

●If the cause of the neutropenia is decreased production of granulocytes, the risk of infection begins to increase at an ANC below 500/microL (table 1).

●In general, however, the risk of infection is related to the adequacy of the marrow reserve pool. Patients with normal marrow granulocyte production may have a very low ANC and be at no increased risk of infection because of the neutropenia [3-5].

This topic will review the immune neutropenias. Other causes of acquired neutropenia, such as drugs and infections, are discussed separately. (See "Drug-induced neutropenia and agranulocytosis" and "Infectious causes of neutropenia".)

OVERVIEW — Immune destruction of mature/maturing neutrophils accounts for many cases of isolated neutropenia, but most affected individuals have normal marrow reserves and little or no increased propensity to infection, regardless of the degree of neutropenia.

In addition to immune mechanisms, some individuals with isolated neutropenia have a normal variant in which mild neutropenia (eg, usually >1000/microL) is associated with the Duffy null [Fy(a-b-)] red blood cell phenotype. This condition is more common in individuals of African descent and in Sephardic Jews, West Indians, Yemenites, Greeks, and Arabs; it was formerly called constitutional neutropenia or benign ethnic neutropenia and is described separately. (See "Approach to the adult with unexplained neutropenia", section on 'Normal variants <1500/microL'.)

The true incidence of immune neutropenia is unknown; some reports estimate a prevalence of 1:100,000 in children younger than 10 years, with a slight female predominance [6]. However, the incidence has been reported to be as high as 1:6300 [7,8].

There is confusing overlap between the immune neutropenia syndromes of chronic benign neutropenia of infancy, chronic benign neutropenia (CBN), autoimmune immune neutropenia (AIN), and chronic idiopathic neutropenia (CIN). In fact, they are very similar and differ only in a few features related to the age of presentation and duration of neutropenia. The vast majority of patients have normal bone marrow reserve and little if any increased propensity to infection regardless of the degree of neutropenia. Isoimmune neonatal neutropenia and neutropenia associated with immunodeficiency are similar as well. They differ mainly in that the source of the antibody is known. The fact that assays for antineutrophil antibodies have a significant false negative rate and in fact are not routinely available [9,10] probably explains the existence of CIN, which is essentially identical to AIN except that antibody tests are negative. To add to the confusion, a small subset of each of these groups has been reported to have serious infections and have even been treated with granulocyte colony-stimulating factor (G-CSF). Careful review of some of the reports fails to uncover evidence that the illness was caused by the neutropenia, and in some reports, patients with severe forms of congenital neutropenia were included in articles about CBN.

Inherited disorders of immune regulatory genes that are associated with aberrant antibody production, cytotoxic lymphocyte activation, and inflammasomopathies are increasingly recognized [10]. Examples include dysregulated B- and T-lymphocyte functions with concomitant AIN in association with inherited gene variants of TACI, BAFFR, ACKR1/DARC, LRBA, CTLA 4. Cellular immune mechanisms may also play a prominent role in the development of immune neutropenia whether there are detectable autoantibodies, such as large granular lymphocyte syndromes of T- and NK-cell types or in chronic idiopathic neutropenia, especially in adults with clonal T-cell populations.

For these reasons, we feel it is more important to focus on factors that affect risk to the patient and may modify treatment (see "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia", section on 'Causes of neutropenia'). The fundamental issues with any neutropenia are:

●Can the patient provide neutrophils to the site of infection?

●Does the presence of neutropenia indicate some other significant disease state that may put the patient at risk for infection?

If the marrow reserve is good, neutrophils can get to the site of infection [4,5,11]. Underlying autoimmune disorders, such as systemic lupus erythematosus or polyarteritis nodosum, can cause vasculitis with mouth sores and mucositis independent of neutropenia that can put the patient at significant risk for infection. If the immune neutropenia is an autoimmune manifestation of an underlying immunodeficiency state, the patient may be at risk for infection because of the immunodeficiency, rather than the neutropenia.

Importantly, some autoimmune disorders can cause severe depression of myeloid reserve and put the patient at great risk because of neutropenia as well as vasculitis. In general, there are four scenarios to consider with autoimmune neutropenia:

●The patient has antibody-mediated neutropenia with normal marrow reserve. The patient will generally be asymptomatic and at no increased risk of infection. This is the most common situation.

●The patient has antibody-mediated neutropenia as an autoimmune manifestation of an underlying immunodeficiency state. The marrow reserve is likely normal. The patient may be at increased risk of infection, not because of the neutropenia but because of the underlying immunodeficiency. As primary immunodeficiency is not common, this is not a common situation.

●The patient has antibody-mediated or cytotoxic T cell mediated neutropenia. The marrow reserve is normal. However, the patient is very symptomatic with gingivitis, painful mucosal ulcers, and other evidence of inflammation because of immune vasculitis. They may be at increased risk of infection because of the underlying disorder causing the mucosal symptoms. The neutropenia is a sign of the immune disorder but is likely not contributing to the symptoms.

●The patient has cytotoxic T cell or possibly antibody-mediated neutropenia. The myeloid precursors are markedly decreased in the marrow. The patient is at high risk of infection if the absolute neutrophil count (ANC) is very low. The patient is likely very symptomatic with gingivitis, painful mucosal ulcers, and other evidence of inflammation, and will be at significantly increased risk of serious infection because of the neutropenia and underlying autoimmune disorder. Such patients may have disruption of mucosal surfaces because of vasculitis, which, in combination with the decreased marrow production of granulocytes, puts them at significant risk for bacterial invasion.

Most cases of immune neutropenia fall into the first scenario. If the patient has significant symptoms suggesting mucosal invasion, frank sepsis, or unusual infection, they will likely require bone marrow aspiration to determine the degree of myeloid reserve and other evaluations to determine the nature of the underlying autoimmune disorder. Treatment is aimed at the underlying diagnosis. G-CSF may be indicated if the myeloid reserve is significantly decreased.

Neutropenia due to cytotoxic lymphocytes is seen in the so-called "lymphoproliferative disorders of large granular lymphocytes" (LDLGL). These patients are older and often have a rheumatoid arthritis-like clinical presentation and mild splenomegaly [10,12]. The myeloid reserve can be markedly reduced, and they are at significant risk of infection related to the neutropenia. This disorder is discussed separately (See "Clinical manifestations, pathologic features, and diagnosis of T cell large granular lymphocyte leukemia" and "Treatment of large granular lymphocyte leukemia".)

DETECTION OF ANTINEUTROPHIL ANTIBODIES — The presence or absence of detectable antibody in the serum is generally not helpful in the diagnosis and management of immune neutropenia, and management decisions are not based on the results of antineutrophil antibody testing [9]. Limited availability of testing and lack of standardization of assays limit the utility of such approaches.

Several tests are available for detecting antineutrophil antibodies, including agglutination, cytotoxicity, direct and indirect immunofluorescence, direct and indirect antiglobulin assays, and tests that use binding of staphylococcal protein A to immunoglobulins on the surface of cells [9,13]. Antineutrophil antibodies can be present in the absence of neutropenia (ie, false positive results) [14]. There is also a significant rate of false negative results, unless several different detection methods are used, yet few laboratories carry out all of the approaches.

NEONATAL ISOIMMUNE (ALLOIMMUNE) NEUTROPENIA — Moderate to severe neutropenia can occur in newborn infants due to the transplacental passage of IgG antibodies to neutrophil-specific antigens inherited from the father [7,15,16]. Rarely, the antibody can arise from autoimmune neutropenia in the mother [7,17,18]. The pathogenesis of the former disorder is identical to that of Rh hemolytic disease, while the latter is identical to maternal immune thrombocytopenia (ITP). The incidence has been estimated at 2 per 1000 live births [15].

Infants with isoimmune neutropenia can present with sepsis or be asymptomatic. Since neutropenia is frequently induced by sepsis in infants [19-22], it may be difficult to determine whether the neutropenia resulted in sepsis or vice versa. Bone marrow examination shows normal cellularity with a late myeloid arrest, although antibody-mediated early arrests have been seen. Antinuclear antibody can be detected in infant and maternal serum and may show specificity for the father's neutrophils, rather than the mother's [15]. The decision to treat a severely neutropenic, possibly septic infant is never dependent on bone marrow findings or antibody tests. It is not unreasonable to treat with granulocyte colony-stimulating factor (G-CSF) and complete the evaluation once the patient has been stabilized. A decision to continue G-CSF does require establishing a diagnosis of severe congenital neutropenia. (See "Overview of neutropenia in children and adolescents" and "Management of children with non-chemotherapy-induced neutropenia and fever" and "Congenital neutropenia".)

This type of neutropenia is usually noted in an otherwise normal infant. Antibiotics are usually given, because of the possibility of neonatal sepsis. Most of these children typically do well, with no culture proof of infection. We usually observe the peripheral blood counts in this setting and do not proceed with marrow aspiration. The role of G-CSF is uncertain, although some patients have responded to treatment with this agent [18,23,24]. Little benefit of G-CSF was noted in a controlled trial of neonates with neutropenia and early-onset sepsis [25].

Recovery is usually uneventful, with no episodes of serious infection. The neutropenia resolves within 12 to 15 weeks, although prolonged neutropenia for 24 weeks has been seen.

AUTOIMMUNE NEUTROPENIA — Autoimmune neutropenia (AIN) is caused by granulocyte-specific antibodies and has been associated with a variety of underlying diseases including infection (eg, hepatitis B), collagen vascular disease, primary abnormalities of B or T lymphocytes or natural killer (NK) cells (eg, autoimmune lymphoproliferative syndrome, ALPS), a deficiency of regulatory T cells, immune thrombocytopenia (ITP), and autoimmune hemolytic anemia [26-29].

In most cases, however, AIN is not associated with other illness or underlying disease and is referred to as chronic benign neutropenia (CBN/AIN) [30,31]. In pediatrics, this syndrome typically occurs in infants between the ages of 5 and 15 months but the range extends from one month to adulthood. In one registry series, the median age at onset was eight months, the median age of recovery was 25 months, and 90 percent recovered by five years of age, with the remainder recovering by 11 years [8]. Earlier age at diagnosis and absence of monocytosis were associated with earlier recovery. In contrast, secondary AIN is more common in adults, most often occurring between the ages of 40 and 60 [32].

Pathogenesis — Antineutrophil antibodies are detected in 98 to 100 percent of patients with AIN if several testing methods are used [7,8]. If only a single modality is used, the positive rate is lower [30,31,33]. The serum concentration can vary over time and may not be detectable if the patient is entering remission [30]. The antibodies are directed against a variety of neutrophil-specific antigens. In one large series, for example, most antibodies were directed against Fc gamma RIIIb or the adhesion molecule CD11b/CD18 (also called complement receptor type 3) [30]. In addition, 31 percent of autoantibodies showed preferential binding to PMN from NA1 homozygous donors; the NA1 antigen is located on Fc gamma RIIIb. The antibodies are usually IgG but are occasionally IgM.

Although an association between specific autoantibodies and HLA-DR or HLA-DQ alleles has been described [34], AIN is unlikely to be strictly a genetic disease [30]. Increased levels of soluble Fas ligand suggest an apoptotic mechanism in this disorder, as is the case with many neutropenias [35].

Clinical presentation — Most patients are diagnosed when a blood count is done during the evaluation of infection or as an incidental finding on a blood count done for other reasons. In one study of 240 infants, upper respiratory infection and otitis media accounted for 36 percent of infections at presentation; severe infections, such as pneumonia, meningitis, and sepsis occurred in 12 percent [30]. The propensity to infection correlates poorly with the severity of the neutropenia [4,5,27].

The absolute neutrophil count (ANC) is typically between 500 and 1000/microL and, in approximately one-fourth of patients, the monocyte count is above 1000/microL [30]. The bone marrow is typically normocellular or hypercellular, with a late maturational arrest at the band stage, consistent with a normal marrow reserve pool.

Diagnosis and differential diagnosis — The differential diagnosis of autoimmune neutropenia includes cyclic neutropenia and severe congenital neutropenia.

●Cyclic neutropenia classically occurs as neutropenic periods lasting three to six days and occurring approximately every 21 days. The patients often have symptoms every 21 days. This syndrome is very rare. (See "Cyclic neutropenia".)

●Severe congenital neutropenia is characterized by severe infections in the first month of life, the absence of spontaneous remission (as occurs in AIN), and maturational arrest of myelopoiesis at the promyelocyte stage. (See "Congenital neutropenia".)

The diagnosis of autoimmune neutropenia can be assumed if the patient has isolated neutropenia, no dysmorphic features, no hepatosplenomegaly, no bone pain, no chronic diarrhea, no severe or unusual infections, and no other signs of other significant underlying disorders. The presence of an elevated sedimentation rate in the absence of clinical infection can indicate inflammation and may suggest a more serious type of neutropenia. Bone marrow aspiration is not critical unless there is evidence of deep tissue inflammation or chronic mucosal infection. Older children or adults should be screened for the presence of a collagen vascular disease. (See "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia", section on 'Other initial laboratory testing'.)

Treatment and clinical course — Autoimmune neutropenia is typically characterized by spontaneous remission with disappearance of autoantibodies [30,36]. In one series of 34 infants who were followed for up to six years, neutropenia spontaneously disappeared in 30 after a median of 17 months (range 1 to 38 months); neutropenia lasted 7 to 24 months in 80 percent [30]. The mean time to recovery may be longer in those with a demonstrable autoantibody, and may be longest in those with the highest antibody "strength" [37].

Specific treatment of neutropenia is usually not required and observation with serial blood counts is the most common practice. Most patients remain free of infections and require no or minimal medical intervention. If the marrow cellularity is normal with sufficient late myeloid precursors, treatment of any kind simply to raise the ANC is not indicated.

Granulocyte colony-stimulating factor — Granulocyte colony-stimulating factor (G-CSF) has dramatically improved the outcome for patients with more severe forms of congenital neutropenia, and has been effective in raising the neutrophil counts in small numbers of patients with autoimmune neutropenia [30,38,39]. In one report, for example, all eight patients treated with G-CSF (3 to 10 mcg/kg per day) attained an ANC above 1500/microL [30]. The increase in cell production induced by G-CSF in this setting presumably exceeds the effect of antibody binding.

Interpretation of the recommendations for use of G-CSF in the literature in neutropenia with normal marrow reserve is questionable, since these patients are able to deliver granulocytes to the tissues [11].

●Some authors have seen pyogenic granuloma in infants with CBN/AIN and report neutrophils in biopsies of the edge of the lesions yet recommended G-CSF [40].

●Similarly, a CBN/AIN infant with a fistula-in-ano that was draining purulent material, a clear sign of tissue delivery of granulocytes, was treated with G-CSF [41].

●A small subset of patients has CBN/AIN and are symptomatic with mucosal ulcerations that can be quite bothersome in spite of normal marrow findings. Two of the patients reported by Bernini [42] (the others had early myeloid arrest consistent with Kostmann syndrome) clinically improved with low dose G-CSF treatment.

●A very small number of patients with AIN/CBN [30] do have maturation arrests at the myelocyte or metamyelocyte stage and may benefit from G-CSF.

In general, neutrophil production and tissue delivery of granulocytes is normal in these patients and use of G-CSF is rarely, if ever, indicated [4,5,43]. Interestingly, when it is administered, the ANC corrects within approximately 12 hours, indicating release of neutrophils already present in the bone marrow into the circulation, rather than production of new neutrophils, which takes several days. (See "Regulation of myelopoiesis".)

Other agents — High dose intravenous immune globulin (IVIG, for a total of 1 to 3 grams/kg over two to five days) and/or corticosteroids (1 mg/kg per day of prednisone or its equivalent) also have been effective in 50 to 60 percent of patients [30,44,45]. Potential side effects remain a concern with both of these drugs. Again, therapy to raise the ANC is not indicated if the marrow reserve is normal. (See "Overview of intravenous immune globulin (IVIG) therapy".)

If patients are clinically ill with recurrent infections or other symptoms related to their autoimmune disorder, it might be necessary to treat them aggressively. Again, we would caution against attributing infections to neutropenia if the marrow is normal. However, such complex immune cytopenias may warrant treatment with drugs such as rituximab or alemtuzumab. The response to treatment with rituximab in patients with refractory autoimmune neutropenia has been generally disappointing, while anecdotal reports indicate a better response to treatment with alemtuzumab. (See 'Pure white cell aplasia' below.)

CHRONIC IDIOPATHIC NEUTROPENIA — The term chronic idiopathic neutropenia (CIN), also known as benign chronic neutropenia, is used to describe patients with chronic neutropenia for which there is no obvious cause. In contrast to the usual occurrence of autoimmune neutropenia in infancy, CIN tends to occur in late childhood or adulthood and does not undergo spontaneous remission [46].

CIN is essentially a diagnosis of exclusion. The absolute neutrophil count (ANC) is typically 500 to 1000/microL and is often accompanied by a monocytosis. Both the number and activity of natural killer cells may be reduced [47]. Bone marrow examination in CIN is nondiagnostic; cellularity is usually normal, although some patients show moderate hypocellularity, and approximately 25 percent demonstrate a myeloid maturation arrest [48]. Bone marrow cytogenetic studies and the serum G-CSF concentration are normal [43,48].

In the original description of CIN, 14 of 15 patients were female and none experienced unexpected infectious complications with median follow-up of 15 years [49,50]. Subsequent studies from other referral centers reported another 70 patients and confirmed the female predominance, the absence of serious infections, the occasional presence of anemia, and the absence of splenomegaly [48,51].

Pathogenesis — The pathogenesis of CIN is uncertain, but immunologic factors appear to be involved in at least some patients. In one of the early studies, antineutrophil antibodies were found in only 4 of 35 patients, one of whom had received multiple transfusions for autoimmune hemolytic anemia [48]. Later reports using more sensitive assays, however, have provided evidence to include at least some patients with this disorder in the immune neutropenias:

●In a series of 121 adults with CIN, 36 percent had IgG and/or IgM antineutrophil antibodies [52].

●In another report, sera from 8 of 14 patients had inhibitory activity for myeloid colony formation in vitro (CFU-GM) [53]. The inhibitory activity correlated with myeloid hypoplasia and the presence of recurrent infections.

A possible explanation of the latter finding is that impaired granulocytopoiesis in CIN is due to overproduction of inflammatory cytokines (eg, Fas-ligand, interferon gamma) by activated T-lymphocytes within the bone marrow environment, leading to inhibition of myelopoiesis [10,54,55].

Treatment — Patients with CIN usually follow a benign course despite the degree of neutropenia. This may be because they have some marrow reserve, as demonstrated by an elevation in the ANC in response to a corticosteroid stimulation test [48]. These patients are also able to mobilize more neutrophils to tissues than can those with acute drug-induced suppression of equal degree [11], and most have a monocytosis that may be protective against infection.

For these reasons, treatment to increase the neutrophil count should be reserved for those patients with significant recurrent infectious complications. Corticosteroids, splenectomy, and cytotoxic agents have been of variable benefit in increasing neutrophil counts [48], while G-CSF has been used successfully to treat small numbers of adults and children [42,56-59]. In one study, for example, seven adults received a starting G-CSF dose of 3 mcg/kg per day and a maintenance dose that ranged from 0.1 to 8 mcg/kg per day [59]. All had a rapid increase in the ANC and maintenance therapy was associated with absence of severe infections at follow-up of up to 4.5 years. The discussion regarding use of G-CSF in AIN applies with CIN as well.

PURE WHITE CELL APLASIA — Pure white cell aplasia (PWCA) is a rare disorder characterized by complete disappearance of granulocytopoietic tissue from the bone marrow, while erythropoiesis and megakaryocytopoiesis are normal [60]. The peripheral blood shows severe neutropenia (ANC <500/microL).

Pure white cell aplasia is most often associated with thymoma, particularly the spindle cell type [61-63]; in other patients, thymoma has been associated with pure red cell aplasia (see "Acquired pure red cell aplasia in adults"). PWCA has also been reported as an idiosyncratic drug reaction due to ibuprofen and chlorpropamide (no longer available in most settings), in association with antiglomerular basement membrane antibody disease (Goodpasture's syndrome) and as a primary idiopathic condition [64-67]. It occurs more frequently in women and presents with the typical clinical picture of agranulocytosis with severe, recurrent infections. Unlike other immune neutropenias, the myeloid reserve is very low or absent. These patients are at significant risk of bacterial infections because of the neutropenia.

Pathogenesis — Immunologic mechanisms can be demonstrated in virtually all patients with PWCA [60]. In vitro studies indicate lymphocyte or serum-mediated inhibition of normal marrow growth. Most cases appear to be due to the presence of antibodies, and GM-CFU inhibitory activity has been demonstrated in the sera of all patients with thymoma-associated disease [60-63].

Treatment — In some cases, PWCA resolves following thymectomy. In others, the addition of immunosuppressive therapy is necessary. Corticosteroids, high dose IVIG, alemtuzumab, cyclosporine, and cyclophosphamide have been reported as effective in the management of the neutropenia [60,68]. Transient remission has also been achieved in several patients with plasmapheresis [61] but, in other cases, it has been ineffective [64]. One patient with promyelocytic arrest and hypogammaglobulinemia, who did not respond to thymectomy, was treated successfully with G-CSF [69].

NEUTROPENIA ASSOCIATED WITH IMMUNE DEFICIENCIES — Neutropenia can occur in association with a number of immune deficiency disorders. These include hypergammaglobulinemia or hypogammaglobulinemia [67,70-72], T cell defects [73,74], and natural killer (NK) cell dysfunction [75]. Many of these patients have a positive family history of neutropenia [67,70,71]. Particularly in patients with symptoms of neutropenia (eg, gingivitis, recurring fever, mucosal infections, rheumatological issues), it is important to look for underlying immunodeficiency disorders and inflammasomopathies [10].

Affected patients usually present in childhood with frequent bacterial infections, hepatosplenomegaly, and failure to thrive. Chronic diarrhea, rash, and recurrent viral infections may also be seen. Some of the children die within the first few years of life.

It is important to distinguish these patients from those with the much more common syndromes of chronic idiopathic or chronic benign neutropenia of infants and children. In contrast to these disorders, children with global immune defects associated with neutropenia have manifestations of recurrent or unusual infections. Thus, children who fail to thrive and have pneumonia or sepsis associated with their neutropenia should undergo an immunologic evaluation. Furthermore, live-virus vaccines must be withheld and any blood product irradiated prior to administration until the possibility of a T cell defect has been eliminated. (See "Laboratory evaluation of the immune system" and "Laboratory evaluation of neutrophil disorders".)

Treatment of these disorders depends on the constellation of immunologic abnormalities present. Some patients have been treated with hematopoietic cell transplantation [73].

SUMMARY

●Definition – Neutropenia is defined as an absolute neutrophil count (ANC) <1500/microL. ANC is calculated (calculator 1) as follows:

ANC = WBC (cells/microL) x percent (PMNs + bands) ÷ 100

●Evaluation of neutropenia – The evaluation of neutropenia in adults and children is discussed separately. (See "Approach to the adult with unexplained neutropenia" and "Overview of neutropenia in children and adolescents".)

Some individuals have isolated mild neutropenia (usually >1000/microL) in association with the Duffy null [Fy(a-b-)] red blood cell phenotype. This condition is more common in individuals of African descent and in Sephardic Jews, West Indians, Yemenites, Greeks, and Arabs; it was formerly called constitutional neutropenia or benign ethnic neutropenia and is described separately. (See "Approach to the adult with unexplained neutropenia", section on 'Normal variants <1500/microL'.)

●Significance of immune neutropenia – Immune destruction of neutrophils accounts for many cases of isolated neutropenia. Most affected individuals have normal marrow reserves and little, if any, increased propensity to infection, regardless of the degree of neutropenia. (See 'Overview' above.)

●Disorders associated with immune neutropenia

•Neonatal alloimmune neutropenia – Moderate to severe neutropenia can occur in newborn infants due to the transplacental passage of IgG antibodies to neutrophil-specific antigens inherited from the father or mother. (See 'Neonatal isoimmune (alloimmune) neutropenia' above.)

•Autoimmune neutropenia – Autoimmune neutropenia (AIN) is caused by granulocyte-specific antibodies and has been associated with a variety of underlying diseases. (See 'Autoimmune neutropenia' above.)

•Chronic idiopathic neutropenia – Chronic idiopathic neutropenia (CIN; benign chronic neutropenia) describes patients for which there is no obvious cause. (See 'Chronic idiopathic neutropenia' above.)

•Pure white cell aplasia – Pure white cell aplasia (PWCA) is a rare antibody-mediated disorder characterized by complete disappearance of granulocytopoietic tissue from the bone marrow and is most often associated with thymoma. (See 'Pure white cell aplasia' above.)

•Neutropenia associated with immune deficiency – Neutropenia can occur in association with immune deficiency disorders. Such children have manifestations of recurrent or unusual infections. (See 'Neutropenia associated with immune deficiencies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges the late Laurence A Boxer, MD, for his previous role as a section editor for this topic.