Duffy Antigen Phenotyping Is a Useful and Clinically Available Test for Benign Ethnic Neutropenia

Abstract Introduction: Benign Ethnic Neutropenia (BEN) is the most common form of neutropenia worldwide and is usually defined as a neutrophil count under 1.5x103/uL without increased infection risk. BEN has been observed predominantly in individuals of African ancestry as well as in certain Middle Eastern ethnic groups. The discovery of neutropenia during routine laboratory testing, however, may prompt extensive workup for infectious, autoimmune, and hematologic disorders. Identifying a readily available test to diagnose BEN in the appropriate ethnic and clinical setting could preempt unnecessary and invasive testing such as a bone marrow aspiration and biopsy and minimize patient anxiety. The absence of the red blood cell (RBC) Duffy antigen, Fy (a- b-), is thought to be responsible for BEN. As the Duffy antigen is utilized by the parasite Plasmodium vivax to enter the RBC, it has been hypothesized that in West Africa, positive selection for the null allele enabled individuals to be protected against infection and have a survival advantage. Aim: Our study examined whether testing for the Fy phenotype could reliably be used as a clinical assay to identify patients with BEN. Methods: Our cases included patients at the VA CT Healthcare System clinically diagnosed with BEN and controls that were chosen randomly from the pools of patients for whom a CBC and type and screen were checked for any other reason. Both probable BEN cases and controls were tested for the Fy phenotype using standard serologic methods in the blood bank. The Fy phenotype, absolute neutrophil count (ANC), white blood cell count (WBC), hemoglobin level, platelet count, and medical diagnoses were extracted from the medical record. Applicable data were compared statistically using the Mann-Whitney U Test with significance set at p < 0.05. Results: Our study included 32 patients (mean age 54, range 21 to 90) who were clinically identified as probable BEN cases and 50 patients (mean age 68, range 38 to 97) chosen as controls. In the probable BEN group, 28 patients self-identified as African American or Black and 3 declined self-identification. In the control group, 11 patients self-identified as African American or Black, 34 self-identified as White, 2 self-identified as Hispanic, 2 declined self-identification, and 1 self-identified as Native Hawaiian. The majority of probable BEN patients (31 of 32) and only a minority of control patients (6 of 50) were Fy (a- b-). Most study patients were male: 30 of 32 probable BEN patients and all control patients were male. The mean ANC count for Fy(a- b-) probable BEN patients was significantly lower than controls (1.68x103/uL versus 5.46x103/uL, p < 0.0001). Similarly, the mean WBC count for Fy (a- b-) probable BEN patients was significantly lower than the mean WBC for controls (3.72 x 103/uL versus 8.14 x 103/uL, p < 0.0001). Hemoglobin was comparable between Fy(a- b-) probable BEN patients and controls (12.91 g/dL versus 11.68 g/dL, p = 0.0673) as were platelets between Fy(a- b-) probable BEN patients and controls (194x103/uL versus 213x103/uL, p = 0.4354). The only African American patient presumed to have BEN that was not confirmed by Fy testing was found to have concurrent diagnoses that could otherwise explain his neutropenia (HIV/HCV). The remaining confirmed BEN cases did not have an accompanying marrow suppressive hematologic disorder. Five control group patients had potentially marrow suppressive hematologic disorders including myelodysplastic syndrome and acute myeloid leukemia. Conclusions: Readily available serologic testing in the blood bank for Duffy antigen phenotyping can be used to confirm suspected BEN in patients with high clinical suspicion. Further testing is in progress of Fy phenotyping comparing controls with neutropenia for any reason to our proposed BEN population to better determine the positive predictive value. Fy phenotyping to confirm BEN suspicion may help avoid unnecessary and invasive neutropenia testing. In addition, since BEN affects certain ethnic groups (primarily those of African ancestry), these individuals may be unfairly excluded from possible treatment including cytopenia-inducing psychiatric medications like clozapine, myelosuppressive chemotherapy, and clinical trials due to ANC eligibility requirements. Fy phenotyping to confirm clinical suspicion of BEN could be a useful tool to help develop modified guidelines for neutropenia-inducing medication. Disclosures No relevant conflicts of interest to declare.

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