ReviewBenign ethnic neutropenia
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], [4], [5], [6], [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 1500/μL 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.
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.
Section snippets
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], [12], [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
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 Fya and Fyb [[15], [16], [17], [18], [19], [20]]. Fya is found in 66% of Caucasians, 10% of
Etiology
The mechanism of neutropenia in BEN remains unclear. The leading theories, discussed below, are summarized in Table 2.
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
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
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
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
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
Practice points
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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.
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The exact mechanism of BEN is still unclear; however individuals with BEN are not at an increased risk of infections.
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Patients with BEN and schizophrenia have different ANC thresholds for holding and discontinuing clozapine. Physicians should investigate whether individuals with BEN
Research agenda
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More rigorous definition of BEN in future studies.
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Determine a more consistent and precise ANC threshold to trigger further investigations in patients with BEN.
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Genetic studies on genes other than DARC that could be related to BEN in individuals of both African and non-African ethnicities.
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Scintigraphic studies could assess the migration of neutrophils into peripheral organs in BEN.
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Determine whether different neutrophil count thresholds are needed in patients with BEN who are receiving
Declaration of Competing Interest
The authors declare no conflicts of interest.
Acknowledgements
This work was supported by the National Institutes of Health grant number R24 AI049393 (P.E.N.).
Role of the funding source
Research infrastructure for neutropenia.
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