Characterizing benign ethnic neutropenia using a real-world national model: Evidence from national health and nutrition examination survey 2015–2018 Free

Introduction: Benign Ethnic Neutropenia (BEN) is a physiologically distinct hematologic phenotype characterized by chronically reduced absolute neutrophil counts (ANC) without an associated increase in infection risk. It occurs more frequently in individuals of African, Yemeni Jewish, Ethiopian Jewish, Arab, Caribbean, and West Indian descent. Among these, Non-Hispanic Black (NHB) individuals in the U.S. are particularly well-suited for modeling BEN due to their high prevalence of the Duffy-null genotype, which has been genetically linked to lower baseline neutrophil counts. The salient clinical criteria for BEN include: persistent ANC <1500/μL (often between 1000–1500/μL), no increased infection risk, absence of secondary causes of neutropenia, no other cytopenias, and no splenomegaly or lymphadenopathy. Despite these features being well-described, there is no validated, population-based model that reflects the BEN phenotype in real-world clinical or epidemiologic data. We developed a reproducible national model using strict criteria to simulate BEN in NHANES, creating a framework for comparative characterization and mortality analysis.

Methods: We analyzed pooled data from the National Health and Nutrition Examination Survey (NHANES) 2015–2018, focusing on NHB adults. We defined BEN as ANC <1500 cells/μL with preserved hemoglobin (>13 g/dL in males, >12 g/dL in females), normal platelet counts (≥150×10³/μL), low C-reactive protein (CRP <5 mg/L), and no self-reported cancer. A comparator group of Non-BEN Black adults met the same inclusion criteria except for ANC ≥1500. Demographic and hematologic parameters were compared using t-tests and chi-square analysis. This model excluded confounding factors such as inflammation and cytopenia to isolate the BEN phenotype.

Results: Out of 1679 eligible NHB adults, 123 (7.3%) met criteria for BEN. Compared to Non-BEN individuals (n=1556), BEN participants were significantly younger (mean age 24.6 vs. 37.4 years, p<0.0001) and had lower mean CRP (0.74 vs. 1.48 mg/L, p<0.0001), supporting the exclusion of subclinical inflammation. As expected, mean ANC in the BEN group was markedly lower (1244 vs. 3443 cells/μL, p<0.0001). White blood cell count (3.99 vs. 6.62 ×10³/μL, p<0.0001) and neutrophil percentage (32.2% vs. 51.0%, p<0.0001) were also significantly reduced. There were no significant differences in hemoglobin (13.69 vs. 13.84 g/dL, p=0.12) or platelet counts (242 vs. 252 ×10³/μL, p=0.10), supporting the absence of concurrent cytopenias. Among individuals meeting strict BEN or Non-BEN criteria, no statistically significant difference in mortality was observed between groups. This supports the conclusion that BEN is not associated with increased mortality.

Conclusions: This is the first validated real-world model of Benign Ethnic Neutropenia using a U.S. national dataset. Our findings suggest that BEN is a distinct hematologic phenotype characterized by isolated neutropenia in otherwise healthy individuals, with no associated inflammatory markers or other cytopenias. These results provide a foundation for future research into the clinical implications, genetic determinants, and health system consequences of BEN. Moreover, this model offers a reproducible approach for reevaluating race-based laboratory cutoffs in hematology and redefining ANC thresholds for clinical trials.