Sickle Cell Trait Not Associated With Increased Mortality in Military Population Interview with:
D. Alan Nelson, MPAS, PhD
Postdoctoral research fellow
Stanford Medicine What is the background for this study?

Response: The study was inspired by the uncertainty surrounding sickle cell trait (SCT) and its association with serious exertional collapse events and mortality in active populations. I conducted initial, exploratory analyses on these topics in 2014-15 while examining a range of military readiness predictors and outcomes. The early work indicated that the risk of mortality, rhabdomyolysis and other exertional events arising from SCT might be substantially lower than that suggested by prior work in the research literature.

Dr. Lianne Kurina and I decided to conduct further, focused study at the Stanford University School of Medicine to confirm or refute these findings. In considering best approaches, we noted that there was an absence of prior research in which the  sickle cell trait status of an entire, large, physically-active study population was known. This limitation could introduce bias to inflate the apparent impact of a theorized predictive factor.

Aside from the challenges in studying the impact of SCT on exertional outcomes, with respect to prevention, a further concern is that  sickle cell trait is a non-modifiable trait. If it were a serious risk factor for rhabdomyolysis and/or mortality, despite careful exertional injury precautions such as those employed by the Army, this might present great challenges for prevention efforts. To maximize the potential for new research to provide actionable prevention information, our interests included examining a range of modifiable risk factors for rhabdomyolysis.

Dr. Kurina and I have employed large, longitudinal military datasets for about five years to examine critical military health outcomes, making this study a natural progression of our joint work. The research proceeded with the support of the Uniformed Services University of the Health Sciences, and in cooperation with a distinguished group of experts who co-authored the paper and advised the project. The study was conducted using de-identified records of all SCT-tested African American US Army soldiers on active duty during 2011 – 2014 (N = 47,944). What are the main findings?

Response: Perhaps the most important finding, and a cautiously reassuring one, was the absence of an association between sickle cell trait and mortality in the studied population.

In terms of modifiable risk factors for rhabdomyolysis, the strongest associations were with recent statin use (hazard ratio [HR] = 2.89, 95% confidence interval [CI] = 1.51 to 5.55, P-value = 0.001) and recent antipsychotic medication use (HR = 3.02, 95% CI = 1.34 to 6.82. P = 0.008).

However, there was a much less impressive association between  sickle cell trait and rhabdomyolysis (HR = 1.54, 95% CI = 1.12 to 2.12, P = 0.008). This finding was effectively identical to that of being a tobacco user (HR = 1.54, 95% CI = 1.23 to 1.94, P < 0.001), another modifiable factor. Body Mass Index of 30 or greater represented a further modifiable risk factor for rhabdomyolysis with a modest effect in the studied population (HR = 1.39, 95% CI = 1.04 – 1.86, P = 0.03). What should readers take away from your report?

Response: Further study is needed to determine whether these findings generalize to other active populations. However, the work provides cautious evidence that, in one setting of universal precautions against exertional outcomes,sickle cell trait does not appear to confer an increased risk of all-causes death, nor a large increase in the hazard of rhabdomyolysis.

The non-modifiable nature of SCT, and the risk of stigmatization that may accompany measures targeting those with sickle cell trait, should provoke some discussion in light of our findings. Careful consideration of whether it plays an actionable or appropriate role in preventive programs or selection for activity appears prudent. Policies and programs targeting modifiable risk factors for rhabdomyolysis may provide greater preventive benefit. What recommendations do you have for future research as a result of this study?

Response: As mentioned above, similar research on SCT-tested, active populations is needed to assess the external validity of this work. Further, our study was not designed to assess the individual or population impact of exertional collapse prevention programs, but instead took place in the context of one such program. These programs require dedicated study to determine their impact.

Also, heat injuries among active individuals constitute important, distinct outcomes that can be fatal, and that can coincide with rhabdomyolysis. We have a growing body of research on heat injuries and SCT, medications and other potential risk factors, which will be forthcoming. Is there anything else you would like to add?

Response: We will be happy to discuss the project with any interested parties, given the importance of developing robust evidence regarding these critical topics. Thank you for your contribution to the community.


Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers
D. Alan Nelson, Ph.D., Patricia A. Deuster, Ph.D., Robert Carter, III, Ph.D., Owen T. Hill, Ph.D., Vickee L. Wolcott, Ph.D., and Lianne M. Kurina, Ph.D.
N Engl J Med 2016; 375:435-442
August 4, 2016
DOI: 10.1056/NEJMoa1516257

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on August 8, 2016 by Marie Benz MD FAAD