Striking decreases in the stress hormone cortisol were the strongest predictor for who develops long Covid in new research that identified several potential drivers of the lingering symptoms afflicting millions of survivors.

Levels of cortisol in the blood of those with the so-called post Covid-19 condition were roughly half those found in healthy, uninfected people or individuals who fully recovered from the pandemic disease, researchers at Yale School of Medicine in Connecticut and the Icahn School of Medicine at Mount Sinai in New York found.

One avenue for research is the endocrine system, which produces hormones like cortisol that affect every part of the body, including inflammation and metabolism. Cortisol helps control mood, motivation, and fear. Low levels can cause fatigue, muscle weakness, gastrointestinal upsets and hypotension, according to the Mayo Clinic.

Low cortisol has been reported in people with myalgic encephalomyelitis, or chronic fatigue syndrome, and boosting it with hydrocortisone treatment has provided a modest improvement in symptoms, researchers Akiko Iwasaki, David Putrino and their co-authors wrote in the study, released ahead of peer-review and publication on Aug. 10.

Data from the group points to remnants of the virus persisting in the body, reactivation of latent herpesviruses and chronic inflammation as potential causes, Iwasaki, a professor of immunobiology and molecular, cellular, and developmental biology at Yale, said in a series of Twitter posts.

The study involved 215 people, including 99 with long Covid. Forty were part of a healthy, uninfected control group, while the remainder had been infected but fully recovered. Although the study was small and exploratory in nature, it will help inform the development of strategies to diagnose and treat long Covid, she said.

“Our studies still need to be validated in other cohorts, but provide many clues for therapeutic avenues, including antivirals and hormone therapy,” Iwasaki said in an email.