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Pearls and Pitfalls

Sports Medicine Pearls and Pitfalls

Benign Neutropenia in Athletes

Eichner, E. Randy

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Current Sports Medicine Reports: July 2009 - Volume 8 - Issue 4 - p 162-163
doi: 10.1249/JSR.0b013e3181ae00f0
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INTRODUCTION

Questions arise about chronic neutropenia in athletes. Example: A collegiate basketball player, an African-American female, who is healthy but for 3 yr in a row, upon routine testing, has had a white blood cell (WBC) count ranging from 2300 to 3100 cells·uL−1, with an absolute neutrophil count (ANC) from 1100 to 1500 cells·uL−1. Example: A professional baseball player, an African-American male, who is healthy but for 2 yr in a row, upon routine testing, has had a WBC from 3100 to 3600 cells·uL−1, with an ANC from 900 to 940 cells·uL−1. Example: In my years as team internist at the University of Oklahoma, I have seen chronic neutropenia like this in several African-American athletes in various sports and in runners from Jamaica, with ANC as low as 800 cells·uL−1. None of these athletes with chronic neutropenia has had any unusual problem with infections. The neutropenia is benign.

ETHNIC NEUTROPENIA

Indeed, odds are that this neutropenia in healthy athletes is not only benign, but inborn, lifelong, and beneficial. Evidence suggests that this chronic neutropenia is inherited as an autosomal dominant trait that somehow relates to protection against malaria (5,10). By this hypothesis, chronic benign neutropenia is like the erythrocyte polymorphisms that protect against death from malaria. As a result, like sickle cell trait, glucose-6-phosphate dehydrogenase deficiency, and the thalassemias, over the millennia, chronic benign neutropenia has become "ethnic" - more common in people from malarial parts of the world. Benign neutropenia thus may belong on a growing list of hematologic traits that reflect a malaria fingerprint in the human genome (4,14). In any case, ethnic neutropenia has practical implications for sports and family medicine physicians.

HOW COMMON IS IT?

Studies differ on the frequency of chronic benign neutropenia, and the difference hinges partly on the cutoff chosen to define the lower limit of normal for WBC and ANC. That WBC and ANC tend to be lower in African-American people than Caucasian people was first noted nearly 70 years ago, in sharecroppers in the cotton fields of Mississippi. Many studies have confirmed this; some have shown that ANC normally can be as low as 800 cells·uL−1 in African and Afro-Caribbean people (1). A comprehensive review in 1999 notes that approximately 25%-50% of people of African descent and some ethnic groups in the Middle East have benign ethnic neutropenia (6). This estimate, which depends partly upon definition, seems too high. A recent study from the United Arab Emirates finds that the frequency of benign neutropenia varies widely among tribes, with an average frequency of approximately 11% (5). In the 1999 to 2004 National Health and Nutrition Examination Survey, neutropenia (ANC < 1500 cells·uL−1) was found in nearly 5% of black people in the United States, but in <1% of white people in the United States and in <0.5% of Mexican-American people (8). All considered, it seems likely that the sports medicine physician will encounter benign neutropenia in up to 5% or more of athletes of African or Middle Eastern descent. This is one reason why screening for WBC has no role in the pre-participation examination (13).

MECHANISM OF NEUTROPENIA: CLUES FROM EXERCISERS AND ATHLETES

In a study of Yemenite Jewish people with and without benign neutropenia, 10 min of submaximal cycling ergometry increased mean WBC 2600 cells·uL−1 in the normal control subjects but only 700 cells·uL−1 in those with benign neutropenia. This was interpreted as subnormal release of neutrophils from bone marrow storage (reserve) in benign neutropenia (12). In a similar exercise study, volunteers of African or Afro-Caribbean heritage mobilized fewer neutrophils than did white volunteers (9). Also, the neutrophil increment to intravenous corticosteroid challenge is subnormal in benign neutropenia (6), even though bone marrow cellularity and maturation appear to be normal.

Another study of the mechanism of ethnic neutropenia investigated ANC before and after the London Marathon. Studied were 42 volunteers, about half of whom were Caucasian and half of African or Afro-Caribbean origin. Prerace ANC was lower in the African/Afro-Caribbean subjects. The absolute increment in ANC post-race also was lower in this group, although the percentage rise in ANC evoked by the marathon was similar in both groups. This was interpreted in a similar manner to the first exercise study mentioned previously: as a subnormal bone marrow reserve of neutrophils in benign neutropenia (2).

Two other observations also support the hypothesis of genetically altered neutrophil kinetics in benign neutropenia. One is that a black patient with aplastic anemia was cured by a marrow transplant from a sibling with ethnic neutropenia, suggesting no abnormality of marrow progenitor cells in benign neutropenia (6). The other is the recent linking of benign neutropenia to Duffy-negative erythrocyte phenotype, which in itself is known to protect against malaria. It is thought that Duffy-negative status, common in African-American people, may alter the action of chemokines that regulate neutrophil kinetics (10). Pinpointing the mechanism of benign neutropenia, however, requires more research.

PRACTICAL PEARLS AND PITFALLS

The best approach to an isolated low WBC in a healthy athlete with a benign history is masterful inactivity. Check it once or twice to make sure it is chronic. Finding the same picture in one of the athlete's parents can cinch the diagnosis of ethnic neutropenia. Then forget it: your athlete will be fine.

Bear in mind that ethnic neutropenia can cloud clinical decisions. For example, long ago it was noted that black people with acute appendicitis are less likely than white people to have the hallmark leukocytosis (WBC > 11,000 cells·uL−1) that helps in diagnosis. Similarly, black infants with bacterial meningitis have lower WBC and ANC than do white counterparts (11).

Studies also suggest that not recognizing ethnic neutropenia is a cause of treatment delay in African-American women with early-stage breast cancer (7). This may be one unfortunate cause of ethnic differences in breast-cancer survival. Similarly, not recognizing ethnic neutropenia can lead to undertreating some schizophrenic patients with clozapine because of an unwarranted fear of the side effect of agranulocytosis (3).

Bottom line: There is no "one size fits all" for the lower limit of normal for WBC and ANC. In ethnic groups from malarial parts of the planet, an ANC as low as 800-1200 cells·uL−1 may be inborn, lifelong, and benign.

References

1. Bain BJ. Ethnic and sex differences in the total and differential white cell count and platelet count. J. Clin. Pathol. 1996; 49:664-6.
2. Bain BJ, Phillips D, Thomson K, et al. Investigation of the effect of marathon running on leukocyte counts of subjects of different ethnic origins: relevance to the aetiology of ethnic neutropenia. Br. J. Haematol. 2000; 108:483-7.
3. Blackman G. Benign ethnic neutropenia and clozapine monitoring. J. Am. Acad. Child Adolesc. Psych. 2008; 47:967-8.
4. Daily JP, Sabeti P. A malaria fingerprint in the human genome? N. Engl. J. Med. 2008; 358:1855-6.
5. Denic S, Showqi S, Klein C, et al. Prevalence, phenotype and inheritance of benign neutropenia in Arabs. BMC Blood Disorders. 2009; 9:3 doi:10.1186/1471-2326-9-3.
6. Haddy TB, Rana SR, Castro O. Benign ethnic neutropenia: what is a normal absolute neutrophil count? J. Lab. Clin. Med. 1999; 133:15-22.
7. Hershman D, Weinberg M, Rosner Z, et al. Ethnic neutropenia and treatment delay in African American women undergoing chemotherapy for early-stage breast cancer. J. Nat. Cancer Inst. 2003; 95:1545-8.
8. Hsieh MM, Everhart JE, Bryd-Holt DD, et al. Prevalence of neutropenia in the U.S. population: age, sex, smoking status, and ethnic differences. Ann. Intern. Med. 2007; 146:486-92.
9. Phillips D, Rezvani K, Bain BJ. Exercise induced mobilization of the marginated granulocyte pool in the investigation of ethnic neutropenia. J. Clin. Pathol. 2000; 53:481-3.
10. Reich D, Nalls MA, Kao WHL, et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PloS Genetics. 2009; 5(1):e1000360. Doi:10.1371/journal.pgen.1000360.
11. Sadowitz PD, Oski FA. Differences in polymorphonuclear cell counts between healthy white and black infants: Response to meningitis. Pediatrics. 1983; 72:405-7.
12. Shoenfeld Y, Aloni D, Keren G, et al. Effect of physical effort on the white blood cells in benign familial leucopenia. Acta Haemat. 1981; 65:108-13.
13. Taylor WC III, Lombardo JA. Preparticipation screening of college athletes: value of the complete blood count. Phys. Sportsmed. 1990; 18(6):106-18.
14. Weatherall DJ. Genetic variation and susceptibility to infection: the red cell and malaria. Br. J. Haematol. 2008; 141:276-86.
© 2009 American College of Sports Medicine