An ambitious study of people with Long Covid, the mysterious, debilitating symptoms that can follow a SARS-CoV-2 infection, has revealed multiple abnormalities in their blood. The clues add to a body of evidence hinting at the causes of the condition and potential treatments worth testing. They also suggest that, as many scientists and patients suspect, Long Covid shares some characteristics with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), another condition thought to follow an infection.
The new study, published as a preprint last week, was modest in size, examining just 99 people with Long Covid. “But it was very deep, it got into the granular aspects of the T cell, the antibody response,” said Eric Topol, director of the Scripps Research Translational Institute, who was not involved in the work. “It’s exploratory, but it’s the basis for much larger studies.”
Long Covid patients, most of whom struggle with severe fatigue, brain fog and other symptoms, had low levels of cortisol, a stress hormone that helps the body control inflammation, glucose, sleep cycles and more. The characteristics of their T cells indicate that their immune systems are fighting unidentified invaders, perhaps a reservoir of SARS-CoV-2 or a reactivated pathogen such as the Epstein-Barr virus.
Other groups studying patients with Long Covid have reported similar results this year, including in January cell paper that documented low cortisol in those with long-standing respiratory symptoms and viral reactivation in patients with neurological problems. Taken together, these data “make me think about what other drugs we can test,” such as antibodies that target viruses or targeted anti-inflammatories to tame the immune system, says Emma Wall of University College London and the Francis Crick Institute, who co-led a large trial of potential therapies for Long Covid.
The new Long Covid project began in late 2020, when Yale University immunologist Akiko Iwasaki teamed up with David Putrino, a neurophysiologist at the Icahn School of Medicine at Mount Sinai who cared for affected patients. The pair wanted to compare these patients with people who had never been infected — and those who had recovered. To Putrino’s surprise, “it was quite challenging to find people who were fully recovered from COVID.” Many post-COVID-19 volunteers described themselves as healthy, but then admitted, for example, that their once-normal gym workouts were too exhausting to renew them. Ultimately, the team enrolled 39 volunteers recovered from COVID-19 among a total of 116 controls.
The low cortisol levels in Long Covid patients, about half of normal levels, aren’t a complete surprise: Symptoms like fatigue and muscle weakness are associated with less of the hormone. The reason remains a mystery. ACTH, a hormone produced by the pituitary gland that controls cortisol production, was at normal levels in the Long Covid group. Also, note that Putrino and others, some Long Covid patients outside of the study tried short courses of steroids that can treat low cortisol, but say they didn’t help. The researchers then plan to track cortisol levels throughout the day in Long Covid; the steroid rises and falls on a diurnal cycle and the original study only tested it in the morning.
Blood samples from Long Covid were also flooded with a category of “exhausted” T cells that can be recognized by certain markers they express. Such cells grow in the continued presence of pathogens—suggesting that “the bodies of people with Long Covid are actively fighting something,” Putrino says.
This battle will result in chronic inflammation that matches many symptoms of Long Covid. By measuring levels of antibodies against viral proteins released into the blood, the study also noted reactivation of the Epstein-Barr virus and other herpesviruses, whose genes can remain latent in infected cells for extended periods. Iwazaki was intrigued to learn that the extent of T cell depletion seemed to track with reactivation of the Epstein-Barr virus, although she did not consider this virus the only potential culprit. SARS-CoV-2 can also remain in patients with Long Covid, she and others say. Epstein-Barr reactivation, low cortisol, and T cell depletion occur in some patients with ME/CFS.
Long Covid is far from uniform, the new study makes clear – for example, only about 20% to 30% of patients in the study had very high levels of exhausted T cells. But “The level of consistency is great” among recent studies investigating the biology of Long Covid, says James Heath, president of the Institute for Systems Biology, author of cell paper that found low cortisol and reactivation of the virus. He notes that his group’s study examined patients about 3 months after infection with SARS-CoV-2, while Iwazaki and Putrino’s cohort was on average more than a year after contracting COVID-19.
Putrino and Iwasaki say it’s time to move forward with new trials of potential therapies that could also clarify the causes of Long Covid and whether subgroups of patients are more likely to respond to certain interventions. Iwasaki’s wish list for experimental therapy is long and includes adding cortisol; Epstein-Barr virus-targeted therapy; the antiviral drug Paxlovid, now used for acute COVID-19; and even therapies that deplete B cells, which are used to treat autoimmune diseases and quiet the immune system.
“We have to try these right now,” Iwasaki says. “As a basic scientist, of course I’d like to have all the pieces of the puzzle” before I start trials. “But patients can’t wait.”