Ethnic benign neutropenia: A phenomenon finds an explanation

Abstract

Ethnic benign neutropenia (ENP) is the most common form of neutropenia (NP) worldwide, if an absolute blood neutrophil count (ANC) of < 1.5 G/L is used as definition. In 2009, ENP was associated with a gene variation in the ACKR1/DARC gene, the same variation that also confers the Duffy-null trait. In 2017, a novel mechanism for ENP was introduced, questioning if ENP is a true neutropenic state, when the body's total neutrophil count (TBNC) is concerned. Here, we summarize the current knowledge of ENP, asking (1) How well does the peripheral blood ANC predict the TBNC? (2) Can we improve methods for assessing TBNC? (3) Will estimates of TBNC predict infection propensity and reduce the need for further, costly workup?

The Duffy antigen receptor for chemokines, ACKR1,– ‘Jeanne DARC’ of benign neutropenia

“…These findings support the hypothesis that the relative neutropenia in benign ethnic neutropenia individuals results from ACKR1 ‐null progenitors preferentially differentiating to myeloid cells, leading to activated neutrophils migrating from the blood circulation to the tissues, particularly the spleen (Duchene et al , ; Charles et al , ; Palmblad & Hoglund, ). In order to determine whether this hypothesis explains benign ethnic neutropenia partly or completely, or to determine whether benign ethnic neutropenia is a true neutropenic state, the total number of neutrophils in the body (TBNC) needs to be evaluated, which is still lacking (Palmblad & Hoglund, ).…”

“…It should be noted that there have been reports of neutropenic individuals without the typical ACKR1 SNP (Reiner et al , ), indicating that some familial neutropenias might be due to other mutations that cause low ANC (Palmblad & Hoglund, ). In addition, the Fy(a−b−) phenotype was found to be overwhelmingly prevalent in neutropenic African Americans, but was also found in one‐third of individuals with normal/high ANC, suggesting additional ANC influences from other genetic traits (Charles et al , ; Palmblad & Hoglund, ).…”

“…African American smokers were found to exhibit lower neutrophil counts compared to Caucasian smokers (Hsieh et al , ). The ANC in benign ethnic neutropenia may also vary because of age (Ortiz et al , ) and minor infections (Palmblad & Hoglund, ). Mason et al () showed that the mean neutrophil increment after hydrocortisone administration to black control subjects was significantly lower than in white control subjects, and Phillips et al () demonstrated a reduced ability of African/Afro‐Caribbeans to mobilize neutrophils from the marginal granulocyte pool compared to healthy white subjects, in response to exercise.…”

“…No increase of infection was noted also in individuals with ethnic neutropenia who develop a clozapine‐induced decrease of the neutrophil count (Manu et al , ), leading to a change in the US Food and Drug Administration (FDA) guidelines, allowing those with benign ethnic neutropenia the opportunity to be commenced on clozapine (Sultan et al , ). A similar approach was adopted for deferiprone (Tricta et al , ), which may be relevant to other drug‐induced neutropenias as well (Palmblad & Hoglund, ).…”

When non-Whiteness becomes a condition

“…Several studies have confirmed that the Fy(a-b-) phenotype is the most robust method to identify BEN, and we know that the Fy(a-b-) phenotype has stronger diagnostic utility for BEN than self-identified race or ethnicity [Fy(a-b-) phenotype, 97.36% sensitivity, 95.65% specificity; self-identified race, 65.7% sensitivity, 48.8% specificity]. [23][24][25] In addition, other more recently identified polymorphisms, such as the lead SNP rs9131 on the CXCL2 gene seen in some people of African ancestry, are implicated as drivers of lower ANCs. 26 Although it is well known that genetic polymorphisms are much more strongly associated with lower ANCs than ethnicity, the practice of ascribing the condition of BEN to people solely based on a physician's assessment of skin tone and a comparison with current ANC reference ranges has not changed.…”