An ambitious study of people with Long Covid, the mysterious, disabling symptoms that can trail a SARS-CoV-2 infection, has turned up a host of abnormalities in their blood. The clues add to a body of evidence hinting at drivers of the condition and potential treatments worth testing. They also suggest that, as many scientists and patients have suspected, Long Covid shares certain features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), another condition thought to follow an infection.
The new study, posted as a preprint last week, was modest in size, examining just 99 people with Long Covid. “But it went very deep, it went into granular aspects of the T cells, the antibody response,” says Eric Topol, director of the Scripps Research Translational Institute, who was not involved in the work. “This is exploratory, but it’s the foundation for much bigger studies.”
The Long Covid patients, most of them struggling with intense 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. Features of their T cells indicated their immune system was battling 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 a January Cell paper that documented low cortisol in those with long-lived respiratory symptoms, and reactivation of viruses in patients with neurological issues. Collectively, these data “make me think about what other drugs we can test,” such as virus-directed antibodies or targeted anti-inflammatories to tame the immune system, says Emma Wall at University College London and the Francis Crick Institute, who co-leads a large trial of potential Long 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 caring for affected patients. The pair wanted to compare those 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 resume. In the end, the team signed on 39 COVID-19–recovered volunteers among a total of 116 controls.
The low cortisol levels in the Long Covid patients, about half of normal levels, aren’t 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. Furthermore, note Putrino and others, 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 rises and falls on a daily cycle, and the initial research only tested it in the morning.
The Long Covid blood samples were also awash with a category of “exhausted” T cells that can be recognized by certain markers they express. Such cells surge in the ongoing presence of pathogens—suggesting “the bodies of people with Long Covid are actively fighting something,” Putrino says.
This battle would produce chronic inflammation, which matches many Long Covid symptoms. By measuring levels of antibodies against viral proteins released in the blood, the study also noted reactivation of Epstein-Barr virus and other herpesviruses whose genes can sit dormant inside infected cells for extended periods. Iwasaki was intrigued to learn that degree of T cell exhaustion appeared to track with Epstein-Barr virus reactivation, though she doesn’t consider that virus the only potential culprit. SARS-CoV-2 may linger in Long Covid patients, too, she and others say. Epstein-Barr reactivation, low cortisol, and T cell exhaustion have all turned up in some ME/CFS patients.
Long Covid is far from uniform, the new study makes clear—for example, only about 20% to 30% of the study’s patients had very high levels of exhausted T cells. But, “The level of consistency is great” among recent studies probing Long Covid biology, says James Heath, president of the Institute for Systems Biology, an author of the Cell paper that found low cortisol and virus reactivation. He notes that his group’s study examined patients about 3 months after SARS-CoV-2 infection, whereas Iwasaki and Putrino’s cohort was on average more than a year out from their COVID-19.
Putrino and Iwasaki say it’s time to forge ahead with new trials of potential therapies, which could also elucidate Long Covid’s causes and whether subsets of patients are more likely to respond to certain interventions. Iwasaki’s experimental therapy wish list is long and includes cortisol supplementation; Epstein-Barr virus–targeting therapy; the antiviral drug Paxlovid, now used for acute COVID-19; and even therapies that deplete B cells, which are used to treat autoimmune disease and calm the immune system.
“We should be trying these right now,” Iwasaki says. “As a basic scientist, of course I’d like to have all the pieces of the puzzle” before launching trials. “But the patients, they can’t wait.”
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