An ambitious study of people with Long Covid, the mysterious, disabling symptoms that follow SARS-CoV-2 infection, has identified a series of abnormalities in their blood. The evidence adds to the growing body of evidence that hints at drivers’ conditions and potential treatments that should be tested. They also suggest that Long, as suspected by many scientists and patients, shares some characteristics with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), another post-infectious condition of Covid.
The new study, published as a preprint last week, was modest in size, examining only 99 people with Long Covid. “But it went much deeper, it got into the granular aspects of the T cells, the antibody responses,” says Eric Topol, director of the Scripps Translational Research Institute, who was not involved in the work. “It’s exploratory, but it’s the basis for much larger studies.”
Long Covid patients, many of whom struggle with severe fatigue, brain fog and other symptoms, had lower levels of cortisol, the stress hormone that helps the body control glucose, sleep cycles and more. The characteristics of their T cells indicated that their immune system was fighting an unknown invader, possibly a reactivated pathogen such as the SARS-CoV-2 reservoir or the Epstein-Barr virus.
Other groups studying Long Covid patients have reported similar results this year, including in January cell paper on low cortisol in people with prolonged respiratory symptoms and viral reactivation in patients with neurological disease. Overall, the data “makes me think about what other drugs we can try,” such as antibodies that target the virus or anti-inflammatory drugs that suppress the immune system, says Emma Wall and the Francis Crick Institute at University College London. Leads large trial of potential Long Covid therapies.
The new Long Covid project began in late 2020, when Akiko Iwasaki, an immunologist at Yale University, and David Putrino, a neurophysiologist at the Icahn School of Medicine at Mount Sinai, took care of affected patients. The pair wanted to compare people who had never been infected and people who had recovered. To Putrino’s surprise, “It’s been very difficult to find people who have fully recovered from COVID.” Many post-COVID-19 volunteers described themselves as healthy, but later admitted, for example, that they were too tired to resume their once-regular gym workouts. Ultimately, the team enrolled 39 volunteers who had recovered from COVID-19, including 116 controls.
The low levels of cortisol in Long Covid patients, about half the normal level, are not surprising: symptoms such as fatigue and muscle weakness are associated with lower levels of the hormone. The reason for this remains a mystery. ACTH, a hormone produced by the pituitary gland that controls cortisol production, was at normal levels in the Long Covid group. Additionally, Putrino et al., outside of the study, say some Long Covid patients tried short courses of steroids to treat low cortisol, but they didn’t help. Next, the researchers plan to monitor cortisol levels throughout the Long Covid day; The steroid rises and falls on a daily cycle, and early studies only tested it in the morning.
Long Covid blood samples were also flushed with a category of “tired” T cells that can be recognized by specific markers they display. Such cells appear in the constant presence of pathogens – “In people with chronic Covid, their bodies are actively fighting something,” says Putrino.
This battle causes chronic inflammation, which matches many of the symptoms of Chronic Covid. By measuring levels of antibodies against viral proteins secreted in the blood, the study also noted reactivation of the Epstein-Barr virus and other herpesviruses, whose genes can lie dormant for long periods of time during infection. Iwasaki was interested in whether reactivation of the Epstein-Barr virus causes T-cell exhaustion, but he doesn’t think the virus is the only potential culprit. SARS-CoV-2 may also be present in Long Covid patients, he and others say. Epstein-Barr reactivation, low cortisol, and T-cell exhaustion have been reported in some ME/CFS patients.
Long-term Covid is not uniform, the new study makes clear – for example, only 20% to 30% of the study’s patients had very high levels of tired T cells. However, among recent studies examining Long’s Covid biology, “the level of consistency is enormous,” says James Heath, president of the Institute for Systems Biology. cell paper that found low cortisol and viral reactivation. He noted that his group’s study infected and tested patients 3 months after contracting SARS-CoV-2, while Iwasaki Putrino’s cohort followed them more than a year after contracting COVID-19.
Putrino and Iwasaki say it’s time to move on to new trials of potential therapies that will also shed light on the causes of Long Covid and whether subgroups of patients may respond to certain interventions. Iwasaki’s experimental therapy wish list is long and includes cortisol supplementation; Epstein-Barr virus – targeted therapy; the antiviral drug Paxlovid, now used for acute COVID-19; and even B-cell-depleting therapies used to treat autoimmune diseases and quiet the immune system.
“We have to try these now,” says Iwasaki. “As a basic scientist, of course I want to have all the pieces of the puzzle.” “But the patients, they can’t wait.”