People With Sickle Cell Trait at Greater Risk of Rhabdomyolysis
Interview with Lianne Markie Kurina, PhD, and D. Alan Nelson, PhD
Exertional rhabdomyolysis is a dangerous syndrome triggered by intense physical activity. This potentially fatal condition has been linked to numerous high-profile deaths,1-3 particularly in athletes and soldiers. A new study has found that people with the sickle cell trait may be especially at risk for the condition.4
In a study of military health records, researchers found that while soldiers with the sickle cell trait may not be at a higher risk of dying from exertional rhabdomyolysis, they are at higher risk of developing the condition.4 The study found that exertional rhabdomyolysis also is associated with certain medications.
“These findings are compelling because case reports dominate the relevant literature and emphasize the presence of sickle cell trait as a risk factor for adverse outcomes, including exertional rhabdomyolysis and sudden death,” the authors noted.
The sickle cell trait consists of a single mutation in the beta-globin gene. A heterozygous genotype produces the sickle cell trait, which is not the same as the sickle cell disease, a condition in which a person must have 2 copies of the allele mutation. The sickle cell trait genotype is typically referred to as hemoglobin AS (HbAS), and usually people who have the sickle cell trait have African ancestry. An estimated 7.3% of blacks in America have the trait.5
How the Study Was Performed
Using data from the Stanford Military Data Repository (SMDR), researchers specifically looked at black soldiers who had been on active duty in the US Army anytime from January 2011 through December 2014. The intent was to only look at soldiers who had been laboratory tested for HbAS, excluding any rhabdomyolysis cases caused by a drug-toxicity event or tissue trauma.
Out of 47,944 persons, there were 391 cases of exertional rhabdomyolysis. While 7.4% of the cohort tested positive for the sickle cell trait, the soldiers’ demographics and health characteristics were “broadly similar” to those without the trait, the authors noted.
HbAS soldiers had a 54% higher adjusted risk for exertional rhabdomyolysis compared with their counterparts (hazard ratio, 1.54; 95% CI, 1.12 to 2.12; P=0.008). This did not, however, appear to be life-threatening since there was no real difference in the risk of death among soldiers with or without the sickle cell trait (hazard ratio, 0.99; 95% CI, 0.46 to 2.13, P=0.97).
In fact, out of the 96 deaths that occurred in the study population, only 1 death was caused by exertional rhabdomyolysis, and it had occurred in a soldier who did not have the sickle cell trait. The death occurred approximately 8 months after the initial emergency room diagnosis, according to Lianne Marie Kurina, PhD, from the Stanford University School of Medicine in Stanford, California.
The US Air Force screens for the sickle cell trait in all its recruits,6 and the US Army screens for the trait in the context of high-altitude deployment.7 Whether screening for the sickle cell trait, or simply employing universal precautions to prevent heat- or exercise-induced injury, has improved mortality rates is hard to say due to lack clinical studies, noted the researchers.8,9
However, it could be a “logical explanation, given the specific intent of the military’s prevention approaches,” said D. Alan Nelson, PhD, lead author of the study. “However, the methods and data used in this study cannot verify a causative relationship between prevention approaches and outcomes, which would require further study,” he told Practical Pain Management.
Role of Statins and Antipsychotic Medications
A litany of modifiable risk factors were associated with exertional rhabdomyolysis, including body mass index (BMI). Obese people (>30 BMI) had a significantly higher risk of exertional rhabdomyolysis compared with those within the reference range (18.5 to <25.0 BMI) (hazard ratio, 1.39; 95% CI, 1.04 to 1.86; P=0.03).
Any tobacco use within the past 6 months resulted in a 54% higher risk of exertional rhabdomyolysis compared with no tobacco use, a similar amount of risk as the presence of sickle cell trait, in fact. Being male and 36 years or older also appeared to increase the risk—similar to what has been seen in earlier studies in the military population.
Indeed, researchers found the greatest increases in risk actually were related to usage of certain medications, particularly statins and antipsychotic agents.10,11 “Recent statin use was associated with a near-tripling of the risk of exertional rhabdomyolysis, as compared with no statin use [HR, 2.89; 95% CI, 1.51 to 5.55; P=0.001],” noted the study. In addition, recent use of an antipsychotic tripled the risk of exertional rhabdomyolysis compared with no antipsychotic use (HR, 3.02; 95% CI, 1.34 to 6.82; P=0.008). Although these are not novel findings, the associations between medications and rhabdomyolysis are only partially understood at the moment, said Dr. Nelson. (See related article.)
The authors did note that the study could be limited by the fact that not all black soldiers are tested for sickle cell trait. And some cases of exertional rhabdomyolysis may have been excluded from the electronic health records due to clinician error or bias.
The study did not explore how alcohol or some other toxic event (use of heroin, cocaine, or methamphetamine) could have influenced the sickle cell trait and the increased risk for exertional rhabdomyolysis and/or death.
Disclosure: This research was supported by a grant from the National Heart, Lung, and Blood Institute in collaboration with the Uniformed Services University of the Health Sciences. All data used in the study were provided under a cooperative agreement with the US Army Medical Command. The views expressed in the article are those of the authors and do not reflect the views or official policies of the US government, the Department of Defense, the Defense Health Agency, the Department of the Army, the Uniformed Services University of the Health Sciences, or the US Army Medical Command.