Infusing hospitalized Covid-19 patients with blood plasma from people who recovered from the disease appeared to show a benefit in a nationwide study, but the study’s lack of a placebo group left several experts struggling to interpret the data.

The study, which enrolled more than 35,000 patients, found that quickly administering so-called convalescent plasma had a marked effect on mortality for patients with severe cases of Covid-19. Those who received transfusions within three days of diagnosis had a seven-day death rate of 8.7%, while patients who got plasma after four or more days had a mortality rate of 11.9%. The difference (3,2%) met the standard for statistical significance.

But without a placebo group for comparison, it’s unclear just how valuable the treatment might be. The study, run by the Mayo Clinic and sponsored by the National Institutes of Health, was meant to broaden access to convalescent plasma. It was part of what is known as an “expanded access program,” not designed to definitively test how well the treatment works but to get it to patients while collecting data.

In a statement, the Mayo Clinic said that the Food and Drug Administration has advised it that the expanded access program will continue “while planning is under way to transition smoothly to Emergency Use Authorization of convalescent plasma.”

Peter Bach, director of Memorial Sloan Kettering’s Center for Health Policy and Outcomes, said there’s no way to be sure about the ultimate benefit of convalescent plasma, but the study “checks a few boxes.” For one, it supports the overall theory that convalescent plasma might help some patients, he said. He noted that researchers also found that the quality of the plasma infusion had an effect on patient outcomes, as those who got infusions that were particularly rich with antibodies fared better overall. 

“If we had just done the randomized controlled trials, we would know the answers we are still guessing at,” Bach said, noting the authors of the study were “appropriately cautious.”

The results of the study were published Thursday on a preprint server, meaning they have not yet been peer-reviewed. 

The study enrolled a high proportion of critically ill patients, with about 52% in intensive care units and 28% requiring mechanical help to breathe. About 60% of the study participants were male. Roughly half the patients were white, while 38% were Hispanic, 19% were Black, and 4% were Asian. The study classified more than a quarter of patients as “other or unknown.”

The concept behind convalescent plasma, which dates back more than a century, is that blood from patients who have recovered from an infection will be rich with antibodies against it, making their plasma an effective treatment. A host of pharmaceutical companies are developing lab-grown Covid-19 antibodies that would work much the same way, and the many vaccines in development are meant to spur the production of similar antibodies that would prevent infection in the first place.

As doctors around the world scramble to find effective therapies for Covid-19, studies like this one present enticing data but do little to address the clinical guesswork physicians face when treating the disease.

“It raises the question of what strength of evidence is necessary to treat during a pandemic,” said Harlan Krumholz, director of the Center for Outcomes Research and Evaluation at Yale New Haven Hospital. “The problem is we have yet to resolve what is sufficient evidence to change the treatment paradigm.”

Steven Nissen, a noted clinical trialist at the Cleveland Clinic, agreed: “The lack of high-quality trials in making clinical decisions about how to treat patients with coronavirus infection is a national embarrassment. Here we have another non-randomized study, NIH-funded, and uninterpretable.”

Randomized, placebo-control studies of convalescent plasma are ongoing.