An ambitious study of people with chronic Covid, the mysterious, disabling symptoms that can follow SARS-CoV-2 infection, has revealed several abnormalities in their blood. The clues add to the body of evidence pointing to drivers 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 the infection.
The new study, posted as a preprint last week, was modest in size, examining only 99 people with chronic Covid. “But it went much deeper, it went to the 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. “It’s exploratory, but it’s the basis for much larger studies.”
Long-term Covid patients, many of whom were struggling with chronic fatigue, brain fog and other symptoms, had lower levels of cortisol, a stress hormone that helps the body regulate inflammation, glucose, sleep cycles, and more. The characteristics of their T cells indicate that their immune system is fighting unknown invaders, perhaps a reservoir of SARS-CoV-2 or a reactivated pathogen such as Epstein-Barr virus.
Other groups studying chronic Covid patients reported similar results in January this year Cell Paper that documents reactivation of viruses in patients with chronic respiratory symptoms, low cortisol, and neurological problems. Collectively, these data “make me think about what other drugs we can test,” such as virus-directed antibodies or anti-inflammatories aimed at controlling the immune system, says Emma Wall of University College London and the Francis Crick Institute. Leads to larger trials of potentially longer covid therapies.
The new Long Covid Project began in late 2020, when Akiko Iwasaki, an immunologist at Yale University, teamed up with David Putrino, a neurophysiologist at Mount Sinai’s Icahn School of Medicine who cares for affected patients. The pair wanted to compare those patients to people who had never been infected and who had recovered. To Putrino’s surprise, “it was very challenging to find people who had 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-normal gym workouts. In the end, the team enrolled 39 Covid-19-recovered volunteers among a total of 116 controls.
Low cortisol levels in chronic Covid patients, about half of normal levels, are not a complete surprise: symptoms such as fatigue and muscle weakness are associated with low levels of the hormone. The reason 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, Putrino and others note, some chronic Covid patients outside the study have tried short courses of steroids, which can treat low cortisol, but they say they haven’t helped. Next, the researchers plan to track cortisol levels throughout the day in Long Kovid; The steroid rises and falls in a daily cycle, and early research only tested it in the morning.
Long-Covid blood samples were also stained with a class of “tired” T cells that can be identified by certain markers they express. Such cells multiply in the constant presence of pathogens—”people with chronic Covid have their bodies actively fighting something,” Putrino says.
This fight will produce chronic inflammation, which corresponds to many chronic Covid symptoms. By measuring levels of antibodies against viral proteins released into the blood, the study also noted the reactivation of Epstein-Barr virus and other herpesviruses whose genes can lie dormant in infected cells for extended periods. Iwasaki was intrigued to learn that the degree of T cell exhaustion appeared to track with Epstein-Barr virus reactivation, although he did not consider that virus the only possible culprit. SARS-CoV-2 can persist in long-term Covid patients, he and others said. Epstein-Barr reactivation, low cortisol, and T cell exhaustion have all been reported in some ME/CFS patients.
Long-term covid is far from uniform, the new study makes clear — for example, only 20% to 30% of study patients had very high levels of T cells. But, in recent studies exploring long-term Covid biology, “the level of persistence is huge,” says James Heath, president of the Institute for Systems Biology, one of the authors. Cell Paper that found lower cortisol and virus reactivation. He noted that his group’s study examined patients about 3 months after SARS-CoV-2 infection, while Iwasaki and Putrino’s group were on average more than a year out from their COVID-19.
Putrino and Iwasaki say it’s time to move forward with new trials of potential therapies, which may also clarify the causes of prolonged Covid and which subgroups 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 also treatments that deplete B cells, which are used to treat autoimmune disease and calm the immune system.
“We have to keep trying these now,” says Iwasaki. “As a basic scientist, of course I want to have all the pieces of the puzzle” before starting tests. “But patients, they can’t wait.”