Benign Ethnic Neutropenia

Abstract

Benign ethnic neutropenia (BEN) is one of the most common causes of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent, affecting many individuals worldwide. Despite its prevalence, many physicians are not familiar with this benign condition, resulting in unnecessary evaluation and testing for neutropenia in otherwise healthy individuals. Clinically, patients with BEN are at no increased risk of infection despite their neutropenia. Implications of this condition are highlighted in those patients receiving therapies that have a known side effect of neutropenia, most commonly chemotherapy agents. Studies have suggested that disparities in survival among those patients receiving chemotherapy between patients of European decent and African decent may be attributed to measured neutropenia in these populations, questioning whether BEN could be an influential factor. This review encompasses all aspects of benign ethnic neutropenia, providing information about this condition and helping to guide clinical decision-making as to when an aggressive work up and referral are indicated and when it is appropriate to monitor. Additionally, we review the role of genetic studies in identifying the genes related to BEN, summarize the theories that offer the most accepted mechanisms behind the condition, and address the importance of pursuing larger studies to assess the implication of BEN in oncology patients as well as patients taking neutropenia-causing medications.

1. Introduction

Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1500/μL. ANC is also useful for classification of the severity of neutropenia, with mild defined as ANC between 1000/μL and 1500/μL, moderate neutropenia as an ANC between 500/μL and 1000/μL, and severe neutropenia as ANC of less than 500 /μL. This classification was developed largely in the Caucasian population and was based on individuals receiving chemotherapy or other immunosuppressive agents, who often also have more generalized immunosuppression and barrier lesions in the skin or mucosa [1,2]. The greatest clinical consequence of neutropenia is an increased risk of infection, which depends both on its severity and duration. Neutropenia is relevant clinically when the neutropenia falls in the moderate or, more significantly, in the severe range [1,2]

Neutropenia can be either congenital or acquired. Congenital neutropenias can vary in severity and, therefore, in the risk of infection. The most severe form of congenital neutropenia stems most commonly from autosomal dominant mutations in the ELANE gene, but also from autosomal dominant, autosomal recessive, and X-linked mutations in a large and expanding number of other genes [3–7]. Severe congenital neutropenia predisposes the individual to sepsis and invasive infections that are usually, but not always, first diagnosed in infancy. A rarer form, cyclic neutropenia, is also caused by autosomal dominant mutations of ELANE, but is characterized by self-limiting neutropenia that occurs close to every 21 days. These patients tend to have a mild clinical course characterized by infections and oral ulcers that correspond with nadirs of neutrophils [8, 9].

Acquired neutropenia can be due to a variety of causes, the most common of which are viral infections, medications and therapeutic radiation. Other causes of acquired neutropenia can be divided into groups including autoimmune disorders, malignant disease, nutritional deficiencies and others [10].

Whereas congenital neutropenias generally confer lifelong increased risk of infection, members of some ethnic groups, mainly African, Caribbean, Middle Eastern and West Indian, can have chronic neutropenia without any increased risk of infection, due to a condition termed benign ethnic neutropenia (BEN). BEN needs to be differentiated from congenital neutropenia for this practice-altering reason. BEN should be suspected when individuals of certain ethnicities present with a persistent absolute neutrophil count below 1500μ/L in isolation, as well as in the absence of causes of secondary neutropenia, such that BEN is largely a diagnosis of exclusion. Presence of recurrent infections, anemia, thrombocytopenia, splenomegaly or lymphadenopathy should raise the concern for other causes of neutropenia. The salient features of BEN are summarized in Table 1.

Table 1.

Salient features of benign ethnic neutropenia

Persistent absolute neutrophil count of less than 1500/μL, usually

between 1000 μL and 1500 μL

No increased risk of infections

Absence of secondary causes of neutropenia

Absence of other cytopenia

Absence of splenomegaly

Absence of lymphadenopathy

Occurs more frequently in individuals of African, Yemenite Jewish, Ethiopian Jewish, Arab, Caribbean and West Indian descent

Genetic studies show a strong association with a single nucleotide polymorphism (SNP) in the DARC gene on chromosome 1 in those exhibiting features of BEN in populations of African and Yemenite Jewish ancestry. The pathophysiology of BEN is not completely understood. Most studies suggest that BEN results from a defect in the release of mature granulocytes from the bone marrow; however newer studies favor an increase in the egress and migration of neutrophils into the organs and tissues as the cause.

This review addresses multiple aspects of BEN, including prevalence, best-supported theories behind its mechanism and genetics, and the clinical importance of this benign condition. We seek to familiarize physicians with BEN, guide them in their decisions regarding the need for further investigations in neutropenic patients, help them avoid aggressive evaluation when BEN is highly likely, and provide a framework for the clinical implications of this condition.

2. Prevalence

BEN has been reported to occur commonly in certain ethnicities, including individuals of African, Caribbean, Middle Eastern and West Indian descent. The exact prevalence of BEN is unknown; however, it has been estimated to be as high as 25–50% in Africans [11–13], 4.5% in African-Americans, 10.7% of Arabs [14], 11.8% in Yemenite Jews and 15.4% in Black Ethiopian Jews [12], but less than 1% in the white population living in the US [1]. Most individuals with BEN have an ANC between 1000 and 1500 and are not at any increased risk of infection. Children who have BEN tend to have lower ANCs when compared to adults with BEN, consistent with the slightly lower range of normal ANCs in children [15].

3. Genetics

Multiple genetic studies have been conducted to help understand the etiology of BEN in certain ethnicities. Studies showed a strong correlation between BEN in African Americans and Yemenite Jews with a specific SNP (rs2814778) located in the long arm of chromosome 1 at the GATA box in the promoter region of the Duffy antigen receptor for chemokines (DARC) gene, encoding the codominant Duffy (Fy) alleles Fy^a and Fy^b [15–20]. Fy^a is found in 66% of Caucasians, 10% of Blacks and 99% of Asians, while Fy^b is present in 83% of Caucasians, 23% Blacks and 18.5% of Asians [21,22]. Thus, up to two thirds of Africans have both Fy^a and Fy^b negative alleles. Admixture mapping played an important role in linking the SNP rs2814778 to BEN in African Americans. This method of gene mapping uses a population of mixed ancestry (an admixed population), such as African American, to find the genetic loci that contribute to differences in phenotypes found between the different ancestral populations. Reich et al. in their genomic admixture mapping study involving 6005 individuals demonstrated that the frequency of the F_y allele differs by greater than 91% between Africans and Europeans, possibly contributing to the genetic difference; however, the highest differentiation was at the SNP rs2814778, which determines the expression and phenotype of the Duffy antigen. A homozygous polymorphism at the SNP rs2814778 abolishes expression of the DARC gene by disrupting a binding site for the GATA1 erythroid transcription factor [16,17]. It was also demonstrated that BEN is linked to the SNP rather than the whole ancestry variant allele, though they are difficult to differentiate, as the SNP has the highest contribution to the ancestry variance [16].

The DARC gene codes for the ACKR1/Duffy antigen, which is a glycosylated seven-transmembrane domain receptor protein that functions via a non-G-protein-coupled mechanism and acts as a receptor for pro-inflammatory cytokines and chemokines. Once bound to ACKR1, chemokines become internalized into the RBC, where they implement their intended action. ACKR-1/Duffy antigen is not only expressed on RBCs, but also on endothelial cells, brain cells and post capillary venules. Those who have the DARC gene expressed in erythroid cells have the Duffy positive phenotype, while those who lack the erythroid Duffy antigen have the Duffy null phenotype.

The Duffy null phenotype in Africans is almost entirely explained by the SNP polymorphism at rs2814778. Individuals with the Duffy null phenotype harbor a homozygous point mutation in the SNP at position −30 of the DARC promoter region in which thymine (T) is replaced by cytosine (C), resulting in C/C genotype and a Duffy null phenotype. Those who have heterozygous alleles, in which only one of the allele variants has the point mutation (genotype T/C), or those with the homozygous wild type genotype T/T, can express the DARC gene and so have the Duffy positive phenotype. The CC genotype explains two thirds of the Duffy null phenotype in African Americans and up to 100% of that seen in West Africans [16–20]. The Duffy null phenotype has been reported in less than 3% of whites and in those instances is not attributed to the same SNP polymorphism [21,22]. Although Duffy null phenotype is observed in 88–100% of Africans, only 25–50% of Africans have BEN. Interestingly, almost all Africans with BEN have the Duffy null phenotype due to the rs2814778 polymorphism [21,22]. Reich et al suggested that the European-derived allele (T) is the dominant allele, as those who have the homozygous wild type (TT) had a similar neutrophil count compared to those who had the C/T heterozygote phenotype. However, those who had C/C genotype had a lower neutrophil count [16]. The high frequency of the Duffy null phenotype in African countries where malaria is endemic most likely derives from natural selection for this mutation, as it is protective against Plasmodium vivax, which utilizes the Duffy antigen receptor to enter the erythroid cell [16,20–22].

Benign ethnic neutropenia is also commonly seen in Yemenite Jews. Genetic studies also related BEN in this population to SNP rs2814778 and the Duffy null phenotype. A study involving 50 Yemenite Jews showed that half of them have neutropenia. There was a strong correlation between homozygosity C/C in the SNP and the observed neutropenia. Results showed that 80 % of those who had neutropenia had homozygous C/C genotype with a Duffy null phenotype while only 8% of those without neutropenia had the C/C genotype [17].

Although SNP rs2814778 has been linked to BEN in Africans and Yemenite Jews, further genetic studies are still needed to explore if there is any correlation of the SNP and Duffy antigen phenotype with BEN in other ethnicities. A study from the United Arab Emirates suggested that Arabs have a high prevalence of BEN, with autosomal dominant being the most likely mode of inheritance in this population. [14]

In addition to the DARC gene polymorphism on chromosome 1, additional genetic variants in CXCL2 on chromosome 4, near CDK6 on chromosome 7, and CSF3 on chromosome 17, are associated with low white blood cell counts in African Americans. The SNP located in the CXCL2 gene has been specifically linked to BEN in African Americans, while the SNPs located in CDK6 and CSF3 have been linked in both African Americans and other ethnicities. Although CSF3 encodes for the cytokine granulocyte colony-stimulating factor (G-CSF) which regulates the production, differentiation, survival, and bone marrow release of neutrophil, the mechanism for its association with BEN in African Americans has not yet been established [20,23]. Additionally, loci on chromosomes 6, 12, 17 and 20 have been shown to influence the leukocyte count in Europeans and Japanese populations [20,24]

4. Etiology

The mechanism of neutropenia in BEN remains unclear. The leading theories, discussed below, are summarized in Table 2.

Table 2.

Theories to explain the pathophysiology of BEN due to the Duffy null phenotype

Disturbance of proinflammatory cytokines affecting recruitment and migration of neutrophils from the bone marrow granulocyte reserve

Alteration of hematopoietic stem cells, such as increased of CD16 and CD15, leading to a neutrophil phenotype with greater tendency for egress into gut, spleen and skin

Increased expression of genes related to neutrophil migration leading to egress of neutrophils from peripheral blood into organs

Defect in the release of mature granulocytes from the bone marrow

Increased neutrophil margination

These proposed mechanisms are related and not mutually exclusive.

Several studies have shown that individuals with BEN have normal bone marrow cellularity and normal myeloid maturation, implying the neutropenia is likely related to a defect in the release of mature granulocytes from the bone marrow. This theory was supported by the study by Mason et al, in which 30 subjects with BEN, 16 white and 14 black, received hydrocortisone, and the increase in neutrophil count was observed. White participants had a greater increase in the mean neutrophil count measured in blood after receiving hydrocortisone. Only 4 out of the 14 black individuals involved in the study had a neutrophil count below 2000; if those 4 individuals were excluded from the study, then the mean rise in neutrophil count in both groups would have been the same, implying that the lower value in the mean increase in neutrophil count in the black population was attributed to those 4 individuals having low neutrophil count at baseline. Bone marrow smears showed similar cellularity and myeloid maturation in all individuals, suggesting that the smaller increase in ANC in response to steroids in those four individuals was likely due to fewer neutrophils being released from the bone marrow [25].

In another study, Shoenfield et al compared the mean increase in neutrophil count in 34 Yemenite Jews after an injection of hydrocortisone succinate. They found the mean increase in neutrophil count in the control subjects was significantly higher than in the study population, while there was a similar decrease in monocytes, eosinophils and lymphocytes in both groups. These findings suggest a decreased bone marrow response in the study population measured by a difference in the circulating neutrophil count, possibly from a decrease in the release of granulocytes from the bone marrow into circulation [26]. This observation is supported by Mitz et al., who showed that Yemenite Jews who have BEN have a normal number of granulocyte colony-forming cells in the bone marrow, supporting the hypothesis that BEN is reflective of a defect in neutrophil release from the bone marrow, rather than a defect in neutrophil precursors [27].

Other genetic studies that investigated genes related to neutrophil migration support a different theory for BEN. These studies highlight the minimal difference in gene expression between the neutrophils of individuals with BEN and those of the general population. A difference in gene expression does exist, however, in the genes related to mobilization of hematopoietic stem cells and leukocyte migration, suggesting that BEN could be due to a defect in leukocyte migration or mobilization of granulocytes in the bone marrow reserve. Charles et al showed evidence that individuals with BEN express more genes related to neutrophil migration than previously understood [24]. Duchenne et al showed that the rs2814778 SNP is associated with phenotypically different myeloid hematopoietic cells. This difference was illustrated in the overexpression of CD16/CD 45 in neutrophils of individuals having BEN, causing enhanced egress of neutrophils from peripheral blood into various organs [28,29] Thus; Duchenne et al and Charles et al support the theory of increased leukocytes migration as a cause of BEN. Leukocyte migration may lead to the egress of leukocytes into the spleen and other organs causing a relative neutropenia. This suggests that BEN does not represent a true neutropenic state, explaining why these individuals are not at increased risk for infection [24,28,29].

Another proposed theory of how the Duffy null phenotype in Africans and Yemenite Jews is related to neutropenia proposes that disturbance of the pro-inflammatory cytokine environment misregulates leukocyte migration and trafficking. As previously discussed, the Duffy erythroid antigen binds to and internalizes chemokines into the erythrocyte. This process helps maintain the concentration of pro-inflammatory chemokines in the plasma and bone marrow [30]. The chemokines most known to interact with the Duffy antigen receptor are the CXR class of acute inflammation chemokines, the CC chronic inflammation chemokines, and chemoattractants interleukin 8, and RANTES [31]. Lack of the Duffy receptor is thus hypothesized to affect the chemokine sink and thereby alter leukocyte trafficking, including the recruitment and migration of neutrophils from the bone marrow granulocyte reserve [30].

As an alternative to this theory, other studies have shown contrary evidence and attributed BEN to a decrease in the bone marrow granulocyte reserve [32,33]. Bain et al showed that individuals of African ancestry who participated in endurance exercise had a lower median increase in absolute neutrophil count in response to prolonged vigorous activity when compared to non-African participants, while lymphocytes and eosinophils decreased equally in both groups, suggesting that BEN could be due to a decrease in the granulocyte reserve in the bone marrow rather than due to the kinetics of granulocyte release from the bone marrow [32]. Philips et al showed that individuals of African ancestry had no greater increase in mobilization of marginated neutrophils when compared to Caucasians as a response to catecholamines during a brief period of vigorous exercise, indicating that BEN is likely not related to an increase in the marginated pool of neutrophils [33].

It is well established that individuals with BEN are at no increased risk of infection when compared to the general population. Genetic studies have shown minimal difference in gene expression between African Americans with and without BEN [23].Cytokine levels between African American whom are homozygous for the SNP rs2814778 allele and other African Americans were also similar [24]. Neutrophils of individuals with BEN have normal morphology as well as normal expression of specific genes related to fighting infections, indicating that their function is intact [13,24]. As previously discussed, Duchenne et al and Charles et al supported the theory that BEN may be a result of egress of neutrophils into organs and therefore does not represent a true neutropenic state. Mant et al, in a study of neutrophil mobilization, injected endotoxin into 15 individuals with BEN and followed their neutrophil counts. They found normal-to-subnormal basal ANCs, a finding consistent with decreased mobilization of granulocytes from the bone marrow reserve into the periphery; however, under stress, there was an adequate bone marrow [34]. The normal BM neutrophil release in stress responses along with the mild neutropenia seen in these individuals could explain why patients with BEN are not at increased risk of serious infections.

5. Other Diseases

The Duffy null phenotype has also been implicated in the pathogenesis of several other diseases. As noted above, there is a positive selective advantage for individuals who lack the Duffy antigen due to the protective effect against malaria caused by Plasmodium vivax, which utilizes the Duffy antigen as a receptor for entry into the red blood cell. One theory suggests that the high frequency of the Duffy null phenotype in geographic regions where malaria is endemic reflects not only positive selection for resistance to Plasmodium vivax malaria, but better outcomes in malarial infections due to neutropenia, as hyper-activation of neutrophils may play a role in the pathogenesis of malarial infections [35–40]. However, this is not the case for P. falciparum malaria infections, as platelet-mediated killing of the falciparum parasite requires the Duffy antigen, so individuals who have a Duffy null phenotype have a worse outcome with falciparum malaria [41]. Additionally, the Duffy null status may influence the pathogenesis of human immunodeficiency virus (HIV) infection. Studies have shown the Duffy null phenotype can enhance acquisition of HIV. The Duffy antigen binds to several proinflammatory chemokine ligands for CCR5 which is a crucial co-receptor required by HIV for cell entry. These ligands tend to suppress replication of HIV. Absence of the Duffy antigen increases the risk of acquiring HIV by disturbing HIV-chemokine interaction mediating trans-infection of HIV. However, it has also been suggested that BEN could lead to a more indolent course for HIV as studies in African populations have shown that having more activated neutrophils is associated with more tissue damage [42–44].

6. Clinical Implications

BEN is most often identified in individuals of certain ethnicities including African, Middle Eastern and Caribbean in the setting of at least three blood samples showing neutropenia at intervals of at least two weeks and with no other identifiable causes. Further diagnostic investigations can lead to increased expense and stress on patients who otherwise do not require such testing. There is no necessity to monitor the ANC after diagnosis of BEN. There is still a debate in the literature regarding the need for further outpatient investigations to rule out secondary causes of neutropenia in individuals suspected to have BEN; and still there is no threshold value for ANC in a patient suspected to have BEN that should trigger further investigations. Current literature does not favor outpatient investigations of neutropenia for individuals of certain ethnicities who have an ANC between 1000 /μL and 1500 /μL, provided they do not suffer from recurrent infections, fever, recurrent or severe oral ulcers, lymphadenopathy, splenomegaly or other cytopenias. Individuals who have an ANC between 500 /μL and 1000 /μL are recommended to undergo further outpatient investigations to rule out secondary causes of neutropenia. Emergent hematology referral is indicated for those individuals who have an ANC below 500 /μL, recurrent or severe infections, fevers, oral ulcers, organomegaly, lymphadenopathy, or other cytopenias. [45–47] These guidelines do not translate into the pediatric population, where in general further investigations are required even for mild neutropenia. However, in depth evaluation is not recommended in children of Black South African, Afro Caribbean, Yemenite Jewish and some Arabic ethnicities who have an ANC between 500 /μL and 1000 /μL, have parents with neutropenia, and have no infections or other cytopenias [48].

An area of clinical importance for patients with BEN is seen in the treatment of cancer. Studies have shown there is a disparity between breast cancer survival in African Americans and whites. Aside from health care discrepancies and socioeconomic factors, the difference has also been theorized to be related to the lower baseline ANC in African Americans that lead to more frequent dose reductions and discontinuations in chemotherapy treatments, and, therefore, lower survival rates [49,50]. Hershman et al, in a study of 43 African American women and 93 white women undergoing adjuvant chemotherapy for early stage breast cancer, concluded that African American patients had lower ANC at baseline and after chemotherapy when compared to white patients, although the percent decline in ANC after receiving chemotherapy was similar in both groups. Also, the total duration of treatment in African Americans was 4 weeks more than in whites, which was attributed to more frequent dose reductions and holding chemotherapy due to lower baseline ANCs [49]. There is evidence that BEN patients are not at an increased risk of developing neutropenic fever after initiation of chemotherapy when compared to other cancer patients. Smith et al, in a study of 86 white women and 19 African American women receiving adjuvant chemotherapy for early stage breast cancer, demonstrated that the leukocyte nadirs and rates of neutropenic fever were similar between both groups. Additionally, Hsieh et al concluded that cancer patients with BEN could safely receive chemotherapy if their ANC was between 500 μL and 1500 μL. Some data suggest that BEN patients have an enhanced response to filgrastim (granulocyte colony-stimulating factor (G-CSF), so giving G-CSF could be a strategy in patients with BEN when ANC is likely to decrease below 500 μL after receiving chemotherapy [50]. These studies suggest that cancer patients with BEN should have different neutrophil count thresholds for holding and discontinuing chemotherapy. This establishes an important question for the medical community: if BEN patients are not at increased risk of infection and not at increased risk for neutropenic fever, could these patients be included in clinical trials for chemotherapy or additionally have unique hold parameters during treatment for cancer? Patients with BEN may be excluded from chemotherapy clinical trials due to their baseline neutropenia but further studies may be able to show that lower ANC parameters are appropriate in this unique subset of patients.

Another area of clinical importance for those with BEN is in the administration of medications known to cause neutropenia. Clozapine is a second-generation antipsychotic with efficacy in the treatment of resistant schizophrenia, but is known to cause neutropenia and agranulocytosis. Neutropenia occurs in 3% of patients receiving clozapine while agranulocytosis occurs in 0.8% [51]. Manu et al reviewed 12 articles that described BEN patients on clozapine who developed neutropenia related to the medication. There is strong evidence that the frequency and severity of infections in BEN patients who are on clozapine were similar to others on the same medication despite this difference in ANC [52]. The United States Food and Drug Administration has adjusted the ANC threshold for holding and discontinuing clozapine in BEN patients such that clozapine is held when ANC falls below 500 μL in BEN patients, in others it is held when ANC falls below 1000 μL. This change has allowed more BEN patients with schizophrenia to be placed on clozapine, the medication of choice in resistant schizophrenia. While clozapine should be discontinued when the ANC falls below 500 μL, rechallenging with clozapine after improvement of ANC is only recommended if the risk of psychiatric illness outweighs the risk of recurrent neutropenia/agranulocytosis [51–53]. Some studies in the literature support concurrent administration of G-CSF (Filgrastim) or lithium with clozapine during rechallenge to prevent a second episode of neutropenia and also to facilitate the use of clozapine in patients who did not meet the hematological parameters to start clozapine. Although initiation or rechallenge with clozapine was successful in some reported cases of BEN who received concurrent G-CSF or lithium, it has been largely seen in the general population rather than BEN patients. The response to G-CSF is variable and unpredictable, so more frequent ANC monitoring is required for these patients. Also, G-CSF and particularly lithium have side effects, and therefore monitoring for a wide range of toxicities is required. Larger studies are required to investigate their role in clozapine and chemotherapy related neutropenia in BEN patients [53–56].

7. Future Considerations

It is well established that individuals with BEN are not at an increased risk of developing infections. However, there are still only a few studies supporting the concept that cancer patients with BEN are not at an increased risk of developing neutropenic fever after starting chemotherapy, so future studies are needed to determine whether special neutrophil count thresholds are needed to avoid unnecessary dose reductions and discontinuation of medications in this population. Although genome-wide studies have been successful in linking the Duffy null phenotype to BEN especially in African Americans and Yemenite Jews, future genetic studies could focus on other genes related to BEN in Africans and other populations to help better understand the mechanisms behind BEN. Recent studies have shown that individuals with BEN have increased expression of genes related to neutrophil migration leading to increased egress into peripheral organs; performing scintigraphic studies to assess homing of neutrophils in peripheral tissues could help better understand neutrophil migration in BEN.

8. Conclusions

BEN should be highly suspected in individuals of African, Middle Eastern and Caribbean ethnicity who present with an absolute neutrophil count between 1000 μL and 1500 μL and no history of frequent or severe infections or unusually frequent or severe oral ulcers. In those individuals, in whom other secondary causes of neutropenia have been excluded and without any cytopenias, lymphadenopathy or organomegaly; no further investigations need to be performed. Duffy antigen typing can be done if there is a demand for confirmatory data, as there is strong evidence linking the Duffy null phenotype to BEN in Africans and Yemenite Jews. A decrease in the mature granulocyte reserve and release from the bone marrow is the most reported mechanism for BEN; however more recent studies support the theory of an increase in neutrophil egress into the organs as the mechanism of neutropenia.

It is well established that individuals with BEN are not at an increased risk of developing infections; however there are still only a few studies supporting the concept that cancer patients with BEN are not at an increased risk of developing neutropenic fever after starting chemotherapy. It is important to recognize the importance that this benign condition, which does not alter quality of life, can affect quality of care provided to patients, particularly those with cancer or in need of treatment with clozapine or other drugs that can cause neutropenia or agranulocytosis, or those who receive unnecessarily extensive or invasive evaluations for mild neutropenia. Providers should be aware of these implications in order to best serve this increasingly recognized population.

9. Practice Points.

• BEN should be suspected in patients of certain ethnic origins with absolute neutrophil count between 1000 and 1500 /μL in the absence of splenomegaly, lymphadenopathy, cytopenia and secondary causes of neutropenia.

• The exact mechanism of BEN is still unclear; however individuals with BEN are not at an increased risk of infections.

• Patients with BEN and schizophrenia have different ANC thresholds for holding and discontinuing clozapine. Physicians should investigate whether individuals with BEN have different ANC thresholds for holding other medications that could also cause neutropenia to prevent unnecessary discontinuations and dose reduction.

• BEN could influence the course of other diseases such as malaria and HIV.

10. Research Agenda.

• More rigorous definition of BEN in future studies.

• Determine a more consistent and precise ANC threshold to trigger further investigations in patients with BEN.

• Genetic studies on genes other than DARC that could be related to BEN in individuals of both African and non-African ethnicities.

• Scintigraphic studies could assess the migration of neutrophils into peripheral organs in BEN.

• Determine whether different neutrophil count thresholds are needed in patients with BEN who are receiving medications, including chemotherapy, known to cause neutropenia.