Sickle Cell Trait Not Associated With Increased Risk of Death in African-American U.S. Army Soldiers

Research has suggested that sickle cell trait (SCT) contributes to elevated risks of exertional rhabdomyolysis (muscle deterioration due to extreme physical exertion) and death, particularly among people who engage in strenuous physical activities, such as professional athletes and military personnel. Results from a retrospective, longitudinal study of nearly 48,000 African-American U.S. Army soldiers found that SCT was not associated with a higher overall risk of death, though it was associated with a higher risk of exertional rhabdomyolysis, compared with soldiers without SCT.

The study, published in The New England Journal of Medicine, was conducted by D. Alan Nelson, PhD, from the Department of Medicine at Stanford University School of Medicine, and colleagues.

“Many organizations proceed with caution regarding the potential for exertion-related events among persons with SCT who are exposed to demanding physical training,” Dr. Nelson and colleagues wrote, with some using universal screening for SCT. However, organizations like the American Society of Hematology have raised concerns that mandatory SCT screening could lead to stigmatization and discrimination. “These concerns warrant consideration, especially given the absence of published evidence that such screening is effective in preventing exertion-related events.”

Using data from the Stanford Military Data Repository, which comprises all digitally recorded medical and administrative data for military personnel, Dr. Nelson and co-authors identified 47,944 African-American soldiers who had undergone hemoglobin AS (HbAS) testing (either before or during the study period) and were on active duty between January 2011 and December 2014: 3,564 had SCT (of whom 69.8% were men) and 44,380 did not have SCT (71.7% of whom were men).

The authors chose to study this population because the prevalence of SCT is highest among African Americans (7.3%, compared with 0.7% of Hispanics and 1.6% of the overall U.S. population). Soldiers in the National Guard and Army Reserve were excluded from the study, as were soldiers with exertional rhabdomyolysis or any duty restrictions due to related exertion-related issues during initial six-month study period.

During the study period, the authors recorded instances of exertional rhabdomyolysis and deaths among the study population. Deaths were categorized as:

  • overall mortality
  • battle-related mortality
  • non–battle-related mortality

Other variables considered in the analyses included the participants’ level of physical fitness (using the Army Physical Fitness Test, with scores ranging from 0-300), body mass index (BMI), tobacco use, and recent prescription medication use (including statins, anti-psychotic agents, and stimulants).

Three-hundred and ninety-one exertional rhabdomyolysis events occurred during the 1.61 million person-months of follow-up. Soldiers with SCT were 54 percent more likely to experience exertional rhabdomyolysis than soldiers without SCT (HR=1.54; 95% CI 1.12-2.12; p=0.008). Women were at lower risk for exertional rhabdomyolysis than men (HR=0.51; 95% CI 0.38-0.67; p<0.001). “Other factors [than SCT] were of similar or greater concern in the assessments of the risk of exertional rhabdomyolysis,” the authors observed, such as obesity and tobacco use (TABLE). Older age, for instance, was associated with a greater risk of exertional rhabdomyolysis than SCT: soldiers 36 years or older had a 57 percent higher risk than those 17 to 23 years-old (HR=1.57; 95% CI 1.06-2.32; p=0.02).

Ninety-six deaths occurred in the study population, with no significant differences in risk of death between those with and without SCT (HR=0.99; 95% CI 0.46-2.13; p=0.97). Seven deaths occurred among participants with SCT; one was classified as battle-related and the other six were considered non–battle-related. These deaths were attributed to medical histories, including cancer, substance abuse, mental disorders, heart disease, and post-operative complications.

One death was related to exertional rhabdomyolysis, though this occurred in a soldier without SCT. Hazard ratios for deaths were:

  • death from any cause: 0.99 (95% CI 0.46-2.13; p=0.97)
  • battle-related death: 0.96 (95% CI 0.13-7.37; p=0.97)
  • non–battle-related death: 0.99 (95% CI 0.43-2.27; p=0.98)

“These findings are compelling because case reports dominate the relevant literature and emphasize the presence of SCT as a risk for adverse outcomes,” Dr. Nelson and co-authors concluded. “A large, longitudinal study involving a population fully tested for HbAS that has formally investigated the relationship between the presence of SCT and exertional rhabdomyolysis or death [in a population protected by exertional-injury precautions] has been lacking.”

The study has limitations, including that not all African-American soldiers in the total Army population were tested for SCT, and some participants may have had an exertional rhabdomyolysis event prior to the study start date. It is also not clear to what extent the precautionary measures taken to prevent exertional injury might have influenced the occurrence of these events. In addition, the use of ICD-9-CM coding may have been subject to clinician error and bias, and chart audits were not conducted to examine coding fidelity.


Reference

Nelson DA, Deuster PA, Carter R, et al. Sickle cell trait, rhabdomyolysis, and mortality among U.S. army soldiers. N Engl J Med. 2016;375:435-42.

TABLE. Risk of Exertional Rhabdomyolysis
Characteristic HR (95% CI) p Value
Sickle cell traitNegative

Positive

Reference

1.54 (1.12-2.12)

 

0.008

SexMale

Female

Reference

0.51 (0.38-0.67)

 

<0.001

Age category17-23 years

24-28 years

29-35 years

≥36 years

Reference

1.10 (0.08-1.49)

1.27 (0.91-1.77)

1.57 (1.06-2.32)

 

0.56

0.16

0.02

Modified BMI category*<25

25-29.9

≥30

Reference

1.21 (0.95-1.54)

1.39 (1.04-1.47)

 

0.13

0.03

APFT score<270 or no score

≥270

Reference

1.13 (0.87-1.47)

 

0.37

Tobacco use in the previous 6 monthsNo

Yes

 

Reference

1.54 (1.223-1.94)

 

 

<0.001

SHARE