1. Introduction to Benign Ethnic Neutropenia
Neutropenia, defined by an absolute neutrophil count (ANC) below 1500 cells per microliter (μL), is clinically categorized based on severity: mild (ANC 1000–1500/μL), moderate (ANC 500–1000/μL), and severe (ANC < 500/μL) [1,2]. This classification, primarily established in Caucasian populations and those undergoing immunosuppressive therapies like chemotherapy, links neutropenia severity to infection risk. The primary concern with neutropenia is the heightened susceptibility to infections, especially in moderate to severe cases [1,2].
Neutropenia can be broadly classified as congenital or acquired. Congenital neutropenias vary in severity and subsequent infection risk. Severe congenital neutropenia, often stemming from autosomal dominant ELANE gene mutations, and other genetic mutations, predisposes individuals to severe infections, frequently diagnosed in infancy [3–7]. Cyclic neutropenia, another form linked to ELANE mutations, features periodic neutropenia episodes approximately every 21 days, typically with milder symptoms like infections and oral ulcers during neutrophil nadirs [8, 9].
Acquired neutropenia has diverse etiologies, with viral infections, medications, and radiation therapy being common causes. Other causes include autoimmune disorders, malignancies, and nutritional deficiencies [10].
However, a unique condition, benign ethnic neutropenia (BEN), presents a different clinical picture. Predominantly observed in individuals of African, Caribbean, Middle Eastern, and West Indian descent, BEN is characterized by chronic neutropenia without a corresponding increase in infection risk. Differentiating BEN from congenital neutropenia is crucial because BEN is a benign condition and not typically associated with increased morbidity or mortality. BEN diagnosis should be considered in individuals from these ethnic groups exhibiting persistent, isolated low neutrophil counts (below 1500/μL) in the absence of secondary neutropenia causes. BEN is essentially a diagnosis of exclusion. The presence of recurrent infections, anemia, thrombocytopenia, splenomegaly, or lymphadenopathy warrants consideration of alternative neutropenia etiologies. Key features of BEN are summarized in Table 1.
Table 1. Salient Features of Benign Ethnic Neutropenia
| Feature | Description |
|---|---|
| Persistent Absolute Neutrophil Count (ANC) | Less than 1500/μL, typically between 1000 and 1500/μL |
| Infection Risk | No increased risk of infections |
| Secondary Causes of Neutropenia | Absence of identifiable secondary causes |
| Other Cytopenias | Absence of other blood cell deficiencies |
| Splenomegaly | Absence of enlarged spleen |
| Lymphadenopathy | Absence of enlarged lymph nodes |
| Ethnic Predisposition | More frequent in individuals of African, Yemenite Jewish, Ethiopian Jewish, Arab, Caribbean, and West Indian descent |
Genetic studies have identified a strong link between BEN and a single nucleotide polymorphism (SNP) in the DARC gene on chromosome 1 in individuals of African and Yemenite Jewish ancestry. The exact mechanism of BEN is still being investigated. Current research suggests BEN may result from either impaired release of mature granulocytes from bone marrow or increased neutrophil migration into organs and tissues.
This review provides a comprehensive overview of BEN, including its prevalence, genetic and mechanistic underpinnings, and clinical significance. It aims to equip physicians with the knowledge to recognize BEN, guide diagnostic decisions for neutropenic patients, and avoid unnecessary extensive evaluations when BEN is suspected. Furthermore, it addresses the clinical implications of BEN, particularly in oncology and medication management.
2. Prevalence of Benign Ethnic Neutropenia
Benign ethnic neutropenia is notably prevalent in specific populations, including those of African, Caribbean, Middle Eastern, and West Indian heritage. While the precise prevalence remains undefined, estimates suggest it may be as high as 25–50% in individuals of African descent [11–13], 4.5% in African-Americans, 10.7% in Arabs [14], 11.8% in Yemenite Jews, and 15.4% in Black Ethiopian Jews [12]. In contrast, the prevalence is less than 1% in US white populations [1]. Importantly, most individuals with BEN maintain ANC levels between 1000 and 1500/μL and do not exhibit an elevated risk of infections. Pediatric BEN cases often present with lower ANC values compared to adults, aligning with the naturally lower normal ANC ranges in children [15].
3. Genetic Basis of Benign Ethnic Neutropenia
Extensive genetic research has aimed to elucidate the genetic underpinnings of BEN across different ethnicities. Studies have consistently demonstrated a strong association between BEN in African Americans and Yemenite Jews and a specific SNP (rs2814778). This SNP is located on chromosome 1 within the GATA box of the promoter region of the Duffy antigen receptor for chemokines (DARC) gene. The DARC gene encodes the Duffy (Fy) blood group antigens, Fya and Fyb [15–20]. The distribution of Fya and Fyb alleles varies significantly across ethnicities: Fya is present in 66% of Caucasians, 10% of Blacks, and 99% of Asians, while Fyb is found in 83% of Caucasians, 23% of Blacks, and 18.5% of Asians [21,22]. Consequently, a significant proportion of Africans (up to two-thirds) are negative for both Fya and Fyb alleles.
Admixture mapping, a technique analyzing populations of mixed ancestry like African Americans, has been instrumental in linking the rs2814778 SNP to BEN. This method identifies genetic loci contributing to phenotypic differences between ancestral populations. A genomic admixture mapping study by Reich et al. involving 6005 individuals revealed a greater than 91% difference in Fy allele frequency between Africans and Europeans, highlighting a potential genetic divergence. However, the SNP rs2814778 showed the highest differentiation. This SNP determines Duffy antigen expression and phenotype. Homozygosity for the rs2814778 polymorphism abolishes DARC gene expression by disrupting a GATA1 erythroid transcription factor binding site [16,17]. Research indicates BEN is linked to this specific SNP rather than broader ancestry variant alleles, although distinguishing them is challenging due to the SNP’s significant contribution to ancestry variance [16].
The DARC gene encodes ACKR1/Duffy antigen, a glycosylated seven-transmembrane domain receptor protein. It functions through a non-G-protein-coupled mechanism and acts as a receptor for pro-inflammatory cytokines and chemokines. Upon binding to ACKR1, chemokines are internalized into red blood cells (RBCs), where they execute their intended actions. ACKR-1/Duffy antigen expression is not limited to RBCs; it is also found on endothelial cells, brain cells, and post-capillary venules. Individuals expressing the DARC gene in erythroid cells are Duffy positive, while those lacking erythroid Duffy antigen are Duffy null.
The Duffy null phenotype in Africans is almost exclusively attributed to the rs2814778 SNP polymorphism. Duffy null individuals possess a homozygous point mutation at position -30 of the DARC promoter region, where thymine (T) is replaced by cytosine (C), resulting in a C/C genotype and Duffy null phenotype. Heterozygous alleles (T/C genotype) or homozygous wild-type genotypes (T/T) allow DARC gene expression and result in a Duffy positive phenotype. The C/C genotype accounts for two-thirds of the Duffy null phenotype in African Americans and up to 100% in West Africans [16–20]. The Duffy null phenotype is rare in whites (less than 3%) and is not associated with the same SNP polymorphism in these cases [21,22]. While the Duffy null phenotype is observed in 88–100% of Africans, only 25–50% develop BEN. Intriguingly, almost all Africans with BEN exhibit the Duffy null phenotype due to the rs2814778 polymorphism [21,22]. Reich et al. proposed the European-derived allele (T) is dominant, as homozygous wild-type (TT) individuals showed similar neutrophil counts to heterozygotes (C/T). Conversely, those with the C/C genotype had lower neutrophil counts [16]. The high frequency of the Duffy null phenotype in malaria-endemic African regions is likely due to natural selection, as it confers protection against Plasmodium vivax malaria, which utilizes the Duffy antigen receptor for erythroid cell entry [16,20–22].
Benign ethnic neutropenia is also common among Yemenite Jews. Genetic studies in this population also linked BEN to the rs2814778 SNP and Duffy null phenotype. A study of 50 Yemenite Jews found half exhibited neutropenia. A strong correlation was observed between homozygous C/C SNP genotype and neutropenia. 80% of neutropenic individuals had homozygous C/C genotype with a Duffy null phenotype, compared to only 8% of non-neutropenic individuals [17].
While rs2814778 SNP is strongly associated with BEN in Africans and Yemenite Jews, further research is needed to determine if this correlation extends to other ethnicities. A study from the United Arab Emirates indicated a high BEN prevalence among Arabs, suggesting autosomal dominant inheritance in this population [14].
Beyond the DARC gene polymorphism, other genetic variants have been linked to lower white blood cell counts in African Americans. These include variants in CXCL2 on chromosome 4, near CDK6 on chromosome 7, and CSF3 on chromosome 17. The SNP in CXCL2 is specifically associated with BEN in African Americans, while CDK6 and CSF3 SNPs are linked in both African Americans and other ethnicities. Although CSF3 encodes granulocyte colony-stimulating factor (G-CSF), which regulates neutrophil production and release, the mechanism of its association with BEN in African Americans remains unclear [20,23]. Additionally, loci on chromosomes 6, 12, 17, and 20 have been shown to influence leukocyte counts in European and Japanese populations [20,24].
4. Etiology and Pathophysiology of Benign Ethnic Neutropenia
The underlying mechanism of neutropenia in BEN is not fully understood. Several leading theories exist, which are summarized in Table 2.
Table 2. Theories Explaining BEN Pathophysiology Due to Duffy Null Phenotype
| Theory | Description |
|---|---|
| Disturbance of Pro-inflammatory Cytokine Balance | Affects neutrophil recruitment and migration from bone marrow granulocyte reserve due to altered chemokine levels caused by lack of Duffy antigen. |
| Alteration of Hematopoietic Stem Cell Phenotype | Increased expression of CD16 and CD15 on neutrophils leads to enhanced neutrophil migration into tissues like gut, spleen, and skin, reducing circulating neutrophil counts. |
| Increased Expression of Neutrophil Migration Genes | Elevated expression of genes governing neutrophil migration promotes neutrophil egress from peripheral blood into organs, leading to a relative decrease in circulating neutrophils. |
| Defect in Mature Granulocyte Release from Bone Marrow | Impaired release of mature neutrophils from bone marrow reserve into circulation, resulting in lower peripheral blood neutrophil counts. |
| Increased Neutrophil Margination | Enhanced adhesion of neutrophils to blood vessel walls (margination), reducing the number of circulating neutrophils measured in blood samples. |
These proposed mechanisms are interconnected and may coexist in BEN etiology.
Several studies indicate individuals with BEN have normal bone marrow cellularity and myeloid maturation, suggesting the neutropenia is likely due to impaired release of mature granulocytes from the bone marrow. This theory is supported by a study by Mason et al., where hydrocortisone administration to BEN subjects (both Black and White) resulted in a neutrophil count increase. White participants showed a greater mean neutrophil count increase post-hydrocortisone. However, excluding four Black participants with baseline neutrophil counts below 2000/μL, the mean neutrophil count increase became comparable between groups. Bone marrow smears revealed similar cellularity and myeloid maturation across all participants. This suggests the diminished neutrophil response to steroids in these four Black individuals was likely due to fewer neutrophils being released from the bone marrow [25].
Another study by Shoenfield et al. compared neutrophil count increases post-hydrocortisone injection in Yemenite Jews. Control subjects showed a significantly higher mean neutrophil count increase compared to the study population, while monocyte, eosinophil, and lymphocyte decreases were similar in both groups. These findings suggest a reduced bone marrow response in Yemenite Jews, potentially due to decreased granulocyte release into circulation [26]. This observation is corroborated by Mitz et al., who demonstrated normal granulocyte colony-forming cell numbers in the bone marrow of Yemenite Jews with BEN. This supports the hypothesis that BEN reflects a defect in neutrophil release rather than in neutrophil precursor production [27].
Conversely, genetic studies investigating neutrophil migration genes support an alternative theory. These studies highlight subtle gene expression differences between neutrophils of individuals with and without BEN. Differences are observed in genes related to hematopoietic stem cell mobilization and leukocyte migration, suggesting BEN could stem from defects in leukocyte migration or granulocyte mobilization from bone marrow reserves. Charles et al. presented evidence for increased expression of neutrophil migration-related genes in BEN individuals [24]. Duchenne et al. demonstrated the rs2814778 SNP is associated with phenotypically distinct myeloid hematopoietic cells, specifically overexpression of CD16/CD45 in neutrophils of BEN individuals. This leads to enhanced neutrophil egress from peripheral blood into various organs [28,29]. Thus, Duchenne et al. and Charles et al. support increased leukocyte migration as a BEN cause. Leukocyte migration into organs like the spleen may induce relative neutropenia. This suggests BEN may not represent true neutropenia, which could explain the lack of increased infection risk in these individuals [24,28,29].
Another theory links the Duffy null phenotype to neutropenia through disruption of pro-inflammatory cytokine balance, misregulating leukocyte migration and trafficking. As discussed, the Duffy erythroid antigen binds and internalizes chemokines, maintaining plasma and bone marrow pro-inflammatory chemokine concentrations [30]. Chemokines known to interact with the Duffy antigen receptor include CXC class acute inflammation chemokines, CC chronic inflammation chemokines, interleukin 8, and RANTES [31]. Lack of the Duffy receptor may disrupt chemokine sinks, altering leukocyte trafficking and affecting neutrophil recruitment and migration from bone marrow granulocyte reserves [30].
In contrast, some studies suggest BEN is associated with a decreased bone marrow granulocyte reserve [32,33]. Bain et al. showed that African ancestry individuals undergoing endurance exercise had a lower median increase in ANC compared to non-Africans, suggesting a reduced granulocyte reserve in bone marrow rather than altered granulocyte release kinetics [32]. Philips et al. found no greater mobilization of marginated neutrophils in African ancestry individuals compared to Caucasians during exercise-induced catecholamine release, indicating BEN is likely not related to an increased marginated neutrophil pool [33].
It is well-established that individuals with BEN do not have an increased infection risk compared to the general population. Genetic studies show minimal gene expression differences between African Americans with and without BEN [23]. Cytokine levels are also similar between African Americans homozygous for the rs2814778 SNP allele and other African Americans [24]. Neutrophils in BEN individuals exhibit normal morphology and expression of infection-fighting genes, indicating intact function [13,24]. As previously mentioned, Duchenne et al. and Charles et al. propose BEN may result from neutrophil egress into organs, representing a pseudo-neutropenic state. Mant et al.‘s study on neutrophil mobilization, using endotoxin injection in BEN individuals, showed normal-to-subnormal basal ANCs, consistent with reduced granulocyte mobilization from bone marrow reserves. However, under stress, bone marrow response was adequate [34]. This normal bone marrow neutrophil release under stress, coupled with mild neutropenia, may explain why BEN patients do not exhibit increased serious infection risk.
5. Benign Ethnic Neutropenia and Other Diseases
The Duffy null phenotype has implications in the pathogenesis of several other diseases. Its protective effect against Plasmodium vivax malaria, due to the parasite using Duffy antigen as a receptor, offers a positive selective advantage in malaria-endemic regions. One theory posits that the high Duffy null phenotype frequency in these regions reflects selection for malaria resistance and potentially better outcomes in malarial infections due to neutropenia. Hyper-activation of neutrophils may contribute to malaria pathogenesis [35–40]. However, this is not the case for P. falciparum malaria. Duffy antigen is required for platelet-mediated killing of P. falciparum, so Duffy null individuals may have worse outcomes with P. falciparum infections [41].
Duffy null status may also influence human immunodeficiency virus (HIV) infection. Studies suggest it can enhance HIV acquisition. Duffy antigen binds pro-inflammatory chemokine ligands for CCR5, a crucial HIV co-receptor. These ligands typically suppress HIV replication. Absence of Duffy antigen may increase HIV acquisition risk by disrupting HIV-chemokine interactions mediating trans-infection. Conversely, it’s suggested BEN might lead to a more indolent HIV course, as studies in African populations link activated neutrophils to increased tissue damage [42–44].
6. Clinical Implications and Benign Ethnic Neutropenia Diagnosis
Benign ethnic neutropenia is often diagnosed in individuals of African, Middle Eastern, and Caribbean descent based on persistent neutropenia (at least three blood samples over two weeks) and exclusion of other causes. Further diagnostic investigations can lead to unnecessary costs and patient anxiety. Routine ANC monitoring is unnecessary after BEN diagnosis. Debate persists regarding outpatient investigations to rule out secondary neutropenia causes in suspected BEN cases, and no clear ANC threshold exists to trigger further investigation. Current guidelines do not favor outpatient investigations for individuals of specific ethnicities with ANC between 1000 and 1500/μL, provided they lack recurrent infections, fever, severe oral ulcers, lymphadenopathy, splenomegaly, or other cytopenias. Individuals with ANC between 500 and 1000/μL should undergo outpatient investigations to exclude secondary neutropenia causes. Emergent hematology referral is advised for ANC below 500/μL, recurrent infections, fever, oral ulcers, organomegaly, lymphadenopathy, or other cytopenias [45–47]. These guidelines may not fully apply to pediatric populations, where more extensive investigations are often required even for mild neutropenia. However, in-depth evaluation is generally not recommended for children of Black South African, Afro-Caribbean, Yemenite Jewish, and some Arabic ethnicities with ANC between 500 and 1000/μL, parental neutropenia, and no infections or other cytopenias [48].
BEN has significant implications in cancer treatment. Studies reveal breast cancer survival disparities between African Americans and whites. Beyond healthcare access and socioeconomic factors, lower baseline ANC in African Americans may lead to more frequent chemotherapy dose reductions and discontinuations, potentially affecting survival [49,50]. Hershman et al.‘s study of women undergoing adjuvant chemotherapy for early-stage breast cancer showed African American patients had lower baseline and post-chemotherapy ANC compared to white patients, although the percentage ANC decline was similar. African Americans also experienced longer treatment durations due to more frequent dose adjustments and chemotherapy holds related to lower baseline ANC [49]. Evidence suggests BEN patients do not have increased neutropenic fever risk post-chemotherapy compared to other cancer patients. Smith et al.‘s study of women receiving adjuvant chemotherapy for early-stage breast cancer demonstrated similar leukocyte nadirs and neutropenic fever rates between Black and White women. Hsieh et al. concluded cancer patients with BEN can safely receive chemotherapy if ANC is between 500 and 1500/μL. Some data suggest enhanced filgrastim (G-CSF) response in BEN patients, making G-CSF a potential strategy when ANC is likely to drop below 500/μL post-chemotherapy [50]. These studies indicate cancer patients with BEN may require different neutrophil count thresholds for chemotherapy management. This raises crucial questions: if BEN patients are not at increased infection or neutropenic fever risk, should they be included in chemotherapy clinical trials and have unique treatment hold parameters? BEN patients may be excluded from trials due to baseline neutropenia, but further research may justify lower ANC parameters for this population.
Another critical clinical area is managing medications known to cause neutropenia in BEN patients. Clozapine, an effective antipsychotic for resistant schizophrenia, can cause neutropenia and agranulocytosis. Neutropenia occurs in ~3% and agranulocytosis in ~0.8% of clozapine users [51]. Manu et al.‘s review of BEN patients on clozapine developing neutropenia found infection frequency and severity were similar to others on clozapine, despite ANC differences [52]. The FDA adjusted ANC thresholds for clozapine management in BEN patients. Clozapine is held in BEN patients below ANC 500/μL, while in others, the threshold is 1000/μL. This adjustment allows more BEN patients with schizophrenia to benefit from clozapine. While clozapine should be discontinued below ANC 500/μL, rechallenge after ANC improvement is considered if psychiatric risk outweighs recurrent neutropenia/agranulocytosis risk [51–53]. Some studies support concurrent G-CSF (Filgrastim) or lithium with clozapine rechallenge to prevent neutropenia recurrence and facilitate clozapine use in patients not meeting hematologic initiation parameters. While G-CSF or lithium co-administration has shown success in clozapine rechallenge, this is primarily studied in the general population, not BEN patients. G-CSF response is variable, requiring frequent ANC monitoring. G-CSF and lithium have side effects, necessitating toxicity monitoring. Larger studies are needed to assess their role in clozapine and chemotherapy-related neutropenia in BEN patients [53–56].
7. Future Research Directions in Benign Ethnic Neutropenia Diagnosis and Management
While it is well-established that individuals with BEN are not at an increased risk of infections, more research is needed to solidify the understanding that cancer patients with BEN also do not face an elevated risk of neutropenic fever following chemotherapy. Future studies should focus on defining specific neutrophil count thresholds for this population to prevent unnecessary chemotherapy dose reductions and treatment discontinuations. Genome-wide studies have successfully linked the Duffy null phenotype to BEN, particularly in African Americans and Yemenite Jews. However, future genetic research should explore other genes potentially involved in BEN across diverse populations, including non-African ethnicities, to gain a more comprehensive understanding of BEN mechanisms. Recent findings suggesting increased expression of neutrophil migration genes in BEN, leading to enhanced neutrophil egress into peripheral organs, warrant further investigation using scintigraphic studies to directly assess neutrophil homing patterns in peripheral tissues in individuals with BEN.
8. Conclusion: Recognizing and Managing Benign Ethnic Neutropenia
Benign ethnic neutropenia should be strongly considered in individuals of African, Middle Eastern, and Caribbean descent presenting with ANC between 1000 and 1500/μL, without a history of frequent or severe infections, or unusually frequent or severe oral ulcers. In these individuals, after excluding secondary neutropenia causes and in the absence of cytopenias, lymphadenopathy, or organomegaly, further investigations are generally unnecessary. Duffy antigen typing can be considered for confirmatory data, given the strong link between the Duffy null phenotype and BEN in Africans and Yemenite Jews. While reduced mature granulocyte reserve and release from bone marrow has been a widely reported mechanism for BEN, emerging research supports increased neutrophil egress into organs as a significant contributing factor.
It is crucial to reinforce that individuals with BEN are not at increased risk of infections; however, further studies are needed to solidify this understanding specifically in cancer patients undergoing chemotherapy. Recognizing BEN is vital to prevent unnecessary investigations and ensure optimal care for affected individuals, especially those with cancer or requiring medications like clozapine that can cause neutropenia. Healthcare providers must be aware of BEN’s implications to provide appropriate and evidence-based care to this increasingly recognized population.
9. Practice Points for Benign Ethnic Neutropenia Diagnosis and Clinical Management
- Suspect BEN in patients of African, Middle Eastern, and Caribbean descent with ANC between 1000 and 1500/μL, without splenomegaly, lymphadenopathy, cytopenia, or secondary neutropenia causes.
- While the exact mechanism of BEN remains unclear, individuals with BEN are not at increased risk of infections.
- Patients with BEN and schizophrenia have different ANC thresholds for clozapine management. Physicians should investigate if BEN patients require adjusted ANC thresholds for other neutropenia-inducing medications to avoid unnecessary treatment disruptions.
- BEN may influence the course of other diseases, such as malaria and HIV, requiring consideration in patient management.
10. Research Agenda for Benign Ethnic Neutropenia
- Develop a more rigorous and universally accepted definition of BEN for future research studies.
- Determine a more consistent and precise ANC threshold to guide further investigations in patients with suspected BEN.
- Conduct genetic studies to identify genes beyond DARC that may contribute to BEN in diverse populations, including African and non-African ethnicities.
- Utilize scintigraphic studies to further investigate neutrophil migration patterns and homing to peripheral organs in BEN.
- Determine if adjusted neutrophil count thresholds are necessary for BEN patients receiving medications, including chemotherapy, known to induce neutropenia.
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.
Footnotes
Conflict of Interest: The authors declare no conflicts of interest.
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