Blood abnormalities found in people with Long Covid | science

An ambitious study of people with Long Covid, the mysterious and disabling symptoms that can follow a SARS-CoV-2 infection, has detected a series of abnormalities in the blood. The clues add to a body of evidence that hints at drivers of the disease and potential treatments worth trying. They also suggest that, as many scientists and patients have suspected, Long Covid shares certain 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 went much deeper, it got into granular aspects of the T cells, the antibody response,” says Eric Topol, director of the Scripps Institute for Translational Research, who was not involved in the work. “This is exploratory, but it is the basis for much larger studies.”

Long Covid patients, most 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 his T cells indicated that his immune system was fighting unidentified invaders, perhaps a reservoir of SARS-CoV-2 or a reactivated pathogen such as Epstein-Barr virus.

Other groups studying Long Covid patients have reported similar results this year, including in January cell paper that documented low cortisol levels in those with long-lived respiratory symptoms and virus reactivation in patients with neurological problems. Collectively, these data “make me think about what other drugs we can try,” such as antibodies that target viruses or anti-inflammatories that target the immune system, says Emma Wall of University College London and the Francis Crick Institute, who co- is leading a large trial of possible long-term Covid therapies.

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 was treating affected patients. The pair wanted to compare those patients with people who had never been infected and with those who had recovered. To Putrino’s surprise, “it was quite difficult to find people who fully recovered from COVID.” Many post-COVID-19 volunteers described themselves as healthy, but later admitted, for example, that their previously normal gym workouts were too exhausting to resume. In the end, the team enrolled 39 volunteers recovered from COVID-19 among a total of 116 controls.

The low cortisol levels of Long Covid patients, about half of normal levels, are not a total surprise: symptoms such as fatigue and muscle weakness are associated with less of the hormone. The cause remains a mystery. ACTH, a hormone made by the pituitary gland that controls cortisol production, was at normal levels in the Long Covid group. Also, Putrino and others note, some Long Covid patients outside the study have tried short courses of steroids, which can treat low cortisol, but say they haven’t helped. Next, the researchers plan to track cortisol levels throughout the day in Long Covid; the steroid goes up and down in a daily cycle, and the initial research only tested it in the morning.

Covid Long’s blood samples were also flooded with a category of “exhausted” T cells that can be recognized by certain markers they express. These cells increase in the continued presence of pathogens, suggesting that “the bodies of people with Long Covid are actively fighting something,” Putrino says.

This battle would produce chronic inflammation, which coincides with many symptoms of Long Covid. By measuring the levels of antibodies against viral proteins released into the blood, the study also pointed to the reactivation of Epstein-Barr virus and other herpesviruses whose genes can lie dormant inside cells infected for prolonged periods. Iwasaki was intrigued to learn that the degree of T-cell depletion seemed to follow the reactivation of the Epstein-Barr virus, although he does not consider this virus to be the only potential culprit. SARS-CoV-2 can also persist in Long Covid patients, she and others say. Epstein-Barr reactivation, low cortisol, and T-cell depletion have been reported in some patients with ME/CFS.

The new study makes it clear that the long Covid is far from uniform; for example, only 20% to 30% of patients in the study had very high levels of exhausted T cells. But, “The level of consistency is excellent” among recent studies probing the biology of Long Covid, says James Heath, president of the Institute for Systems Biology, author of the cell paper that found low cortisol and reactivation of the virus. He notes that his group’s study examined patients about 3 months after their SARS-CoV-2 infection, while Iwasaki and Putrino’s cohort was on average more than a year out of their COVID-19.

Putrino and Iwasaki say it’s time to move forward with new trials of potential therapies, which could also elucidate the causes of Long Covid and whether subsets of patients are more likely to respond to certain interventions. Iwasaki’s wish list for experimental therapy is long and includes cortisol supplements; 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 should try them right now,” Iwasaki says. “As a basic scientist, of course I would like to have all the pieces of the puzzle” before launching the tests. “But patients, they can’t wait.”

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