Millions of people in the U.S. suffer from long COVID, the mysterious collection of symptoms that sometimes persist long after coronavirus infections. Many live with fatigue, brain fog, shortness of breath and other problems that doctors struggle to treat and explain.

A new study on the possible causes of long COVID points to a number of underlying signs observed in people with the condition. It may help researchers develop better screening tools and approaches to treating those who have not been able to find relief.

The study, published this week in the journal Nature, found an apparent drop in cortisol levels among people with long COVID. The stress hormone helps regulate alertness and usually spikes in the morning to help people wake up. People with long COVID had lower levels of cortisol in the morning than healthy people. 

Hormonal changes in cortisol levels could help explain why many people with long COVID suffer from fatigue or feel unusually tired after physical exertion.

“(It) tells us that their body isn’t producing this chemical that keeps them awake and gets them moving,” David Putrino, the study’s senior author and the director of rehabilitation innovation at Mount Sinai Health System in New York, told CNN.

The researchers also found that people with long COVID appeared to have compromised immune systems. In some patients, elevated levels of certain immune cells hinted that they had never fully cleared the virus and that their bodies had been fighting it for extended periods. Some even showed indications that other dormant viruses had been reactivated in their bodies.

One theory is that the immune system’s prolonged response to fighting COVID-19 infections may allow “sleeping” viruses to resurface. About 95% of adults are thought to carry a latent form of Epstein Barr virus, which often causes severe fatigue.

Another significant finding is that most of the people with long COVID symptoms had only had mild initial cases of COVID-19. The most common lingering symptoms they noted were fatigue, brain fog, memory deficits, and a racing heart and dizziness when standing after lying down.

Although the study didn’t conclusively identify a single biomarker for long COVID, it could help doctors narrow down which diagnostic tests to use as they evaluate their patients. And for people who have faced skepticism about their chronic conditions after having COVID-19, the study helps validate that there are clear clusters of symptoms linked to different changes in the body long after an infection.

“Everyone wants a single biomarker, everyone wants a single treatment,” Putrino told the Washington Post. “That’s not realistic for long COVID.”

An annual health survey conducted last year by the U.S. Centers for Disease Control and Prevention found that about 18 million people had reported having long COVID since the start of the pandemic. About 8.8 million currently are suffering from some form the condition, including about 360,000 children. Adults between ages 35-49 were most likely to report having symptoms, and long COVID affected more women than men, the survey found.

The long COVID study used a series of medical tests to compare differences between people with long COVID and others who were healthy. Those in the healthy group either had mild infections that they recovered from or never had COVID-19. The study excluded people who were hospitalized with serious cases, since their lingering symptoms may have been caused by invasive procedures like intubation to go on a ventilator.

Notably, the researchers said they had to turn down about 50% of people who had volunteered to be part of the healthy control group. Many of them thought they had fully recovered from COVID-19, but reported symptoms linked to long COVID during the screening process.