Millions of Americans carry the sickle cell trait, many without knowing it. Could they be at risk for severe Covid-19?

Sickle cell disease, which causes Covid-like symptoms — clotting, strokes, and severe oxygen deprivation —  is one of the medical conditions that the Centers for Disease Control and Prevention says puts people at higher risk for severe illness from the coronavirus. Now, a research team is trying to determine whether the several million people who merely carry one copy of the sickle cell mutation — but do not have the disease itself — could be more vulnerable to Covid-19, and whether that might be one reason the virus is disproportionately sickening and killing Black Americans.

About 100,000 Americans have sickle cell disease, an inherited disorder marked by sickle-shaped blood cells that can clump together, causing painful blockages of blood vessels, strokes, anemia, and early death. According to the American Society of Hematology, up to 3 million Americans may have the sickle cell trait, meaning they carry one copy of the gene — often without knowing it. (Two copies are required to have the disease.) In the U.S., both the disease and the trait largely affect African Americans.

It had long been thought that having sickle cell trait was a largely benign condition, and for many, it may be. But new research suggests that some people with the trait are more likely to suffer from higher rates of chronic kidney disease, kidney cancer, complications in pregnancy, and exercise-related deaths. Having only one copy of the gene can lead to milder, infrequent, or localized sickling, but that mild sickling can in some cases clog blood vessels and deprive tissues of oxygen.

Complications from sickle cell trait have killed nearly a dozen college football players since 2000; some NFL players with the trait routinely sit out games played in cities at high altitude, and the NCAA now strongly recommends all athletes confirm their trait status.

It was making this connection — that people with sickle cell trait can suffer from oxygen deprivation in some situations — that sparked the idea for the study now underway at Atlanta’s Grady Memorial Hospital. “Extreme, low oxygen conditions, like those at higher altitudes or during scuba diving, can trigger extreme pain, microinfarctions (tiny strokes), and even death in some people with sickle cell disease. Covid may be one of those triggering conditions,” said Deneen Vojta, a former pediatrician and executive vice president of global research and development at UnitedHealth Group who helped design the $600,000 study, which is being conducted by physicians at the Morehouse School of Medicine and funded by UnitedHealth, a managed health care and insurance company.

It is still not known whether patients with sickle cell disease fare worse when they contract Covid-19, though there are strong reasons to believe they would. Flu pandemics, for example, have led to higher death rates in patients with sickle cell disease. The Medical College of Wisconsin has created a national registry to track infected sickle cell patients, and while the data are not conclusive, they so far suggest having sickle cell disease may lead to worse outcomes and a higher risk of death. The average age of the 307 patients in the database is 25, and 16 of them, or 5%, have died. One in five has had a severe or critical case of Covid-19.

The case is less clear in patients with sickle cell trait, making the new Morehouse study of interest, said Kim Smith-Whitley, a pediatrician and hematologist who directs the Comprehensive Sickle Cell Center at Children’s Hospital of Philadelphia. “This could be really valuable,” she said.

Vojta, familiar with sickle cell disease from her training in hematology, said she saw many similarities between sickle cell and Covid. She noticed early on that X-rays of Covid-infected lungs resemble those of sickle cell patients with acute chest syndrome, a severe complication caused when sickling blocks oxygen flow in lungs. And many complications, like clotting and strokes, are common to both diseases.

“I thought, ‘Ding, ding, ding, doesn’t this sound familiar,’” Vojta said. Covid infections have triggered acute chest syndrome in some sickle cell patients.

The study is being co-led by Herman Taylor, a cardiologist who directs the cardiovascular research institute at Morehouse and was the longtime director of the Jackson Heart Study, which helped tease out why heart disease disproportionately kills African Americans. Taylor is now interested in finding out exactly why Black Americans who contract the coronavirus are dying at twice the rate of white people.

“It’s really quite an old story that African Americans suffer inordinately from poor outcomes in health care, and Covid has really brought that to the fore,” he said. “The question is why. We know African Americans are at higher risk because of what they are exposed to, where they work,

and poorer access to care, but we didn’t want to look past other factors that might be involved.”

While health care providers are largely on the alert for complications in Covid-19 patients who have sickle cell disease, said Mayowa Azeez Osundiji of Toronto’s SickKids pediatric hospital, “it is important not to overlook the potential increased risk to patients who carry the trait.” A fourth-year medical resident in the division of clinical and metabolic genetics, he wrote a recent review of sickle cell trait and Covid.

He said health care workers should be aware of the theoretical risks when assessing individuals from ethnicities with a high prevalence of sickle cell trait; these include not just African Americans, but also Latin Americans from Central and South America and people of Middle Eastern, Asian, Indian, and Mediterranean descent. Targeted interventions for those with increased risk could include anticoagulants, oxygen treatment, and blood transfusions.

Rakhi Naik, an assistant professor of medicine at Johns Hopkins University who has studied the risk of kidney disease in people with sickle cell trait, said having the trait could potentially worsen the lung and kidney disease associated with Covid because these people are already at increased risk for those issues. But she added that while it is a genetic risk factor for blood clots and kidney disease, “the vast majority of individuals with sickle cell trait will never develop these complications.”

While Naik said the new study would be useful to determine whether the trait is associated with an increased risk of severe Covid-19 infection, she said additional studies would be needed to determine if the sickle cell trait was the actual cause of the increased risk and clarify how exactly clinicians should alter care for Covid patients with the sickle cell trait.

E. Leila Jerome Clay, a pediatrician who directs the sickle cell program at Johns Hopkins All Children’s Hospital in St. Petersburg, Fla., said anyone who has the trait, or suspects they may have it because of family history of the disease, should take extra precautions to prevent exposing themselves to the virus. “We want people to know that if they have the trait they need to be careful,” she said. “They need to wear masks and make sure they are maintaining hydration.”

Study leaders plan to enroll 300 patients who have been hospitalized for Covid at Grady Memorial and who test positive for the sickle cell trait in a simple blood test. Fifty patients have already been enrolled, said Morehouse’s Taylor. The study will compare the medical records and outcomes of patients with sickle cell trait to those without the trait to see whether having the trait is correlated with poorer outcomes. They expect results in six months to one year.

The findings, Vojta believes, could have immediate clinical relevance to Covid treatment. Many Americans over the age of about 30 do not know they carry the sickle cell trait because newborn testing for the mutation has only become widespread in recent decades, she said. If a connection is found, people who have the trait would likely be more closely monitored for worsening symptoms..

“Sickle cell trait, in the absence of extreme conditions or major health problems, has negligible consequences for most people,” said Taylor. “Covid could change that dynamic — turning a silent condition into a deadly risk — and we must take a closer look.”