Although sickle cell trait (SCT) has been linked to numerous adverse clinical outcomes in multiple studies, only a handful of those associations have strong supporting evidence, results of a systematic review suggest.
Venous and renal complications had the strongest evidence supporting an association with SCT, while exertion-related sudden death – perhaps the highest-profile potential complication of SCT – had moderate-strength evidence supporting a link, according to the review.
By contrast, most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link, according to Rakhi P. Naik, MD, of Johns Hopkins University, Baltimore, and coauthors of the review.
“Future rigorous studies are needed to address potential complications of SCT and to determine modifiers of risk,” they wrote. The report in the Annals of Internal Medicine.
The systematic review by Dr. Naik and colleagues focused on 41 studies, most of which were population-based cohort or case-control studies. They rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, renal, vascular, pediatric, surgery- and trauma-related outcomes, and mortality.
Exercise-related injury has received considerable attention, particularly in relation to the military and athletics.
The strength of evidence for a link between SCT and exertion-related death was low in their analysis, which included two studies evaluating the outcome. However, Dr. Naik and coauthors did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions such a highly strenuous athletic training or the military.
“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” they wrote.
Similarly, the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors, Dr. Naik and coauthors said, based on their analysis of two studies looking at this outcome.
Venous complications had a stronger body of evidence, including several studies showing high levels of procoagulants, which makes elevated venous thromboembolism risk plausible in individuals with SCT.
High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was no increased risk of isolated deep-vein thrombosis in these individuals.
“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” Dr. Naik and colleagues wrote in a discussion of the results.
Renal outcomes were often attributed to SCT, and in this review, the authors said there was evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease.
Out of six studies looking at proteinuria, the one high-quality study found a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without, according to the review.
Out of four studies looking at chronic kidney disease, the two high-quality studies found 1.57- to 1.89-fold increased risk of those outcomes in African Americans with SCT.
Support for the study came in part from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.
SOURCE: Naik RP et al. Ann Intern Med. 2018 Oct 30. doi:10.7326/M18-1161.