Sickle Cell Disease, Trait May Up Risk for Poor COVID Outcomes

Diana Swift

July 21, 2021

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Sickle cell disease (SCD) was associated with a greater than fourfold excess risk for COVID-19–related hospitalization and a greater than twofold risk for COVID-19–related death, according to a big-data analysis from the United Kingdom.

Dr Ashley Clift

SCD was associated with an adjusted hazard ratio (HR) of 4.11 (95% CI, 2.98 – 5.66) for admission to hospital and an HR of 2.55 (95% CI, 1.36 – 4.75) for death, report Ashley K. Clift, MBBS, a clinical research fellow at the University of Oxford, Oxford, United Kingdom, and colleagues. The results were published online July 20 in Annals of Internal Medicine.

Even those who carry just one copy of the sickle cell gene ― the carrier status for sickle cell disease ― appeared to be at heightened risk for these outcomes (HR for hospitalization, 1.38; 95% CI, 1.12 – 1.70; HR for death, 1.51; 95% CI, 1.13 – 2.00).

"Given the well-known ethnic patterning of sickle cell disorders, the predisposition they pose to other infections, and early evidence from smaller registries, we thought this would be an important analysis to run at the population level," Clift told Medscape Medical News.

Dr Enrico Novelli

"Our data suggest that people living with sickle cell disorders are a group at higher risk from this infection, and this is important from a public health perspective in terms of vaccination strategies and advice on nonpharmacological interventions," he said.

"The best course of action for managing risk in this group is vaccination," said Enrico M. Novelli, MD, director of the adult sickle cell program at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Novelli, who is also section chief of benign hematology in the university's School of Medicine, was not involved in the study. "To date, there are no specific studies of the effect of COVID-19 vaccination in patients with SCD, but there is no reason to believe it would be less effective or more risky in this patient population," he said.

In addition, common-sense measures, such as masking and physical distancing, particularly at large, indoor gatherings, should be encouraged, Novelli added. Keeping SCD under good control with available treatments is also important. "Any patient with SCD who contracts COVID-19 should undergo close, outpatient monitoring with pulse oxygen measurements. If sick, they should be hospitalized in a center familiar with the care of SCD patients."

The UK results are in line with and expand on earlier evidence from specialist centers and registries, but the association with sickle cell trait has been unclear and is notable in these findings, Clift said.

Dr Rabi Hanna

"The finding of the association with sickle cell trait is somewhat unexpected," pediatric hematologist/oncologist Rabi Hanna, MD, director of pediatric bone marrow transplantation at Cleveland Clinic Children's, in Cleveland, Ohio, told Medscape Medical News. "But I would question the accuracy of the numbers, since not all people with the trait realize they have it. In other respects, the study confirms earlier hypotheses and data from single-center studies." Hanna did not participate in the UK study.

Study Details

The SCD cohort consisted of 5059 persons with SCD and 25,682 carriers, those with just one copy of the trait. Data were drawn from the UK's large primary-care QResearch database. Follow-up for hospitalizations was conducted from January 24, 2020, to September 30, 2020; follow-up for deaths was conducted from January 24, 2020, to January 18, 2021. Among adults with SCD, there were 40 hospitalizations and 10 deaths. Among those with sickle cell trait, there were 98 hospitalizations and 50 deaths. No children died, and only a few (<5) required hospitalization.

Previous registry research showed similarly elevated risks for severe disease and fatality among patients with SCD who were infected with SARS-CoV-2.

Because SCD affects 8 to 12 million people globally ― 100,000 in the United States ― the authors say their results are important for policymakers and for prioritizing vaccination. They also note that trait carriers may be underdiagnosed.

"While SCD is part of newborn screening, there may be undiagnosed older people with the trait in the general population, but it's difficult to quantify how much this is undiagnosed," Clift said. "But now we have these results, it's not that surprising that sickle cell trait is also associated with increased risk, albeit to a lower extent. This could suggest an almost dose-like effect of the sickle mutations on COVID hospitalization risk."

Neonatal screening for the most common form of SCD is currently mandatory in the United States, but the Centers for Disease Control and Prevention has no clear data on how many people are aware they are carriers, Hanna said. "The states didn't all begin screening at the same time ― some started in the 1990s, others started in the 2000s ― so many young adults may be unaware they have the trait," he said.

Clift said the multiorgan complications of SCD, such as cardiac and immune problems, may be contributing to the heightened risk in individuals infected with SARS-CoV-2. "For example, we know that people with sickle cell disease are more susceptible to other viral infections. There is also some pathophysiological overlap between SCD disease and severe COVID, such as clotting dysfunction, so that may be worth further exploration," he said.

The overlapping clotting problems associated with both COVID-19 and SCD could increase the risk for severe venous thromboembolism. In addition, experts noted that patients with SCD often have pre-COVID endothelial damage and baseline inflammation and are very sensitive to hypoxia; as well, a sizable proportion have lung disease.

The message to patients and physicians counseling patients is twofold, said Hanna: "SCD patients are at higher risk of COVID complications, and these are preventable with vaccination."

The study was supported by the UK Medical Research Council. Clift is supported by Cancer Research UK. Co-author Hippisley-Cox has received fees from ClinRisk Ltd and nonfinancial support from QResearch outside of the submitted work. Hanna has disclosed no relevant financial relationships. Novelli is a consultant for Novartis.

Ann Intern Med. Published online July 20, 2021. Full text

Diana Swift is medical journalist based in Toronto.

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