In early 2020, Alison Sbrana watched the coronavirus skip from China across continents with a sense of impending doom. Sbrana, plagued by fatigue and brain fog since being diagnosed with mononucleosis six years earlier, was convinced that the pernicious new virus would wreak similar havoc in some of those who contracted it.
Her intuition proved prescient. Some people who had suffered even mild cases of covid-19 began complaining of problems that Sbrana knew too well, including muscle pain and drop-dead exhaustion. Now, as millions of people nationwide are suffering from long-haul covid, Sbrana and an army of patient advocates are cautiously hopeful that new research may unlock clues to other conditions that appear to crop up after infections, including myalgic encephalomyelitis/chronic fatigue syndrome, known as ME/CFS.
“I think there is potential,” said Sbrana, who suffers from ME/CFS.
Covid long-haulers inherited many of the challenges that have faced people like Sbrana for years, including a lack of understanding of the mechanisms that triggered their disabilities — leaving some doctors to view their symptoms as largely psychosomatic.
But long-haulers have also opened doors. As a new pathogen, SARS-CoV-2 offers a fresh opportunity to examine what many doctors agree is not well understood — how people recover from infections, even common ones. The National Institutes of Health earlier this year launched a $1.15 billion initiative to study long covid, and researchers and patients hope it will provide answers.
“How many people have long-term nagging or even disabling symptoms after other viral illnesses, such as flu?” asked Harlan M. Krumholz, the Harold H. Hines Jr. professor of medicine at the Yale University School of Medicine. “We don’t have a good handle on that.”
Viruses seem to lurk. Some like varicella reactivate, appearing first as chickenpox and often decades later as shingles. Others, like herpes simplex, can hide for years in neurons only to erupt suddenly without warning.
The challenge is urgent, with a recent study finding that as many as one-third of covid survivors reported symptoms ranging from breathing problems to headaches and fatigue three to six months after diagnosis. Among long-haulers are patients who have suffered after extended periods in the ICU, often with scarred lungs and sometimes with kidney or brain damage. Others who had milder cases report lingering symptoms that appear to be unique to covid, such as loss of smell and taste. Another group complains of a more familiar form of lasting fatigue that — as in ME/CFS — worsens after exercise.
The quest to find answers is increasingly important as the pandemic approaches a turning point. Now that vaccines and therapeutics have lessened the chance of severe illness and death and people are eager to return to normal life, is the threat of long covid an ongoing reason to avoid contracting the virus? Others wonder: Could endemic covid leave millions disabled with long-haul symptoms every year, creating a growing public health crisis?
Or, if researchers put the recovery process from this new disease under closer scrutiny, could they expose patterns and even find treatments common to other post-infectious conditions?
“Maybe this is a chance for us,” said Krumholz, who is working with colleagues to design rigorous, broad-based studies.
Among his fellow researchers is Akiko Iwasaki, a Yale immunologist and principal investigator at the Howard Hughes Medical Institute, who lists five hypotheses that she believes could explain the biological underpinning of long covid. Top among them is what she calls a “viral reservoir” of persistent virus or viral remnants in the body that cause chronic inflammation. Autoimmune disease could also be triggered by the coronavirus, Iwasaki believes.
Such approaches are “likely relevant to all post-viral syndromes,” Iwasaki said, and could also explain lingering symptoms after infections with bacteria or parasites. They can potentially be treated, either by targeting the virus or by suppressing the body’s immune system. One encouraging signal is that some long-haulers have said their symptoms improved after they received the coronavirus vaccine.
“We have a big dream,” Iwasaki said, describing a sweeping goal of understanding the development of long covid and other post-acute-infection syndromes.
That has involved embracing the cohort of covid survivors — many of whom share their experiences online — and others who believe that their lingering symptoms stem from other illnesses, including Epstein-Barr, the virus that causes mononucleosis; herpes viruses; or bacterial Lyme disease.
“They are equal partners,” Iwasaki said of patients, including the advocacy group Survivor Corps, which has 180,000 members and worked with the Yale researchers to design studies and recruit participants.
Survivor Corps founder Diana Zicklin Berrent, who had covid early in the pandemic, recalled how people with ME/CFS and similar conditions initially looked with envy at the attention garnered by covid long-haulers.
“It was, ‘Wait a second, we’ve been suffering all these years and nobody pays attention to us. These guys come along, and everybody pays attention,’” recalled Berrent. She soon realized it made sense to join forces.
“I think it’s an obligation of the long-covid world to pull these other communities along with us in research,” she said. “They have gotten short shrift for a long time.”
In February, NIH Director Francis S. Collins said the $1.15 billion investment in research would go beyond long covid to “improve our understanding of other chronic post-viral syndromes and autoimmune diseases, as well as other diseases with similar symptoms.”
Walter Koroshetz, director of NIH’s National Institute of Neurological Disorders and Stroke and co-chair of the new initiative, said his and other departments have been collaborating on ME/CFS for several years but with little success, in part because the initial infection was often unclear and the symptoms diffuse. Now, Koroshetz said, covid is providing scientists with a “natural experiment.”
“This is our best chance to figure out ME/CFS,” Koroshetz said, “with the resources and an army of people.”
The NIH initiative, known as RECOVER, announced its first major awards in June, to support infrastructure and the development of core resources. In September, it awarded an additional $470 million to develop a national population of research volunteers and support large-scale studies, with a goal of enrolling tens of thousands of participants, including pregnant and pediatric populations, across dozens of U.S. research institutions. Researchers will evaluate tissue samples, analyze data from electronic health records, and employ apps and wearable devices to gather real-time data.
While patient advocacy groups were involved in the development of protocols, some fear that the research will be cumbersome and take on a life of its own in the rarefied world of academic medicine.
“A lot of us feel as if they are saying, ‘Thank you very much, you’ve done your part. We’ll take it from here.’ And they don’t want to listen to us anymore,” said Sbrana, now a board member of Body Politic, a feminist collective that launched a support group for long covid after several members developed the disease.
The Body Politic support group, which now hosts more than 10,000 members from around the world, operates over Slack channels, allowing not only for conversations about shared symptoms but also for data gathering.
One member, Hannah Davis, whose background is in machine learning and who came down with covid in March 2020, said she met others in a “data nerds channel,” and now works in the Patient-Led Research Collaborative, which is collecting information from the disability community about post-infectious conditions and communicating it to long-covid researchers.
“I see a lot of researchers ignoring all these fields, all the work that has already been done,” Davis said. “They are starting from scratch. It’s a huge waste of resources.”
Another group, the Long Covid Alliance, shares one of its key tenets with the broader disability community: “Nothing about us, without us.” The network of patient-advocates, scientists, disease experts and drug developers is dedicated to accelerating “understanding of post-viral illness.” Amy Proal, a microbiologist with the PolyBio Research Foundation who has studied ME/CFS, joined the alliance after noticing parallels with long covid, determined to bring “cutting-edge tools and technologies” as to any other disease process. She co-authored a recent paper on the biological factors that may contribute to long covid.
The grass-roots groups have already proved their value in citizen-scientist collaborations, according to Survivor Corps’ Berrent, who is now free of symptoms. After noticing a tweet from a Columbia University doctor suggesting that vaccines appeared to offer relief to some people with long covid, Berrent followed up through Survivor Corps and found that 45 percent of respondents reported some form of symptom resolution after vaccination — results that she took to Iwasaki at Yale, who launched a joint study.
The studies so far are small, but the possibility that stimulating the immune system through vaccination could relieve symptoms is intriguing to researchers and a potential clue to the underlying mechanism.
“It would be interesting if [ME/CFS sufferers] get the flu vaccine and feel better,” Koroshetz said, alluding to the kind of research that may lie ahead.
For now, though, it remains unclear exactly what causes long covid — or ME/CFS.
Michael Sneller, an infectious-disease specialist at the National Institutes of Health who has studied the lingering impacts of Ebola and immune-based treatments for HIV, began to work with covid patients in April 2020. He said the battery of tests he has administered to the 225 post-acute covid patients has failed — so far — to show solid evidence of persistent viral infection or excessive activation of the immune system.
Sneller remains vigilant. But when doctors cannot offer a cure, there is a real danger that patients turn to other sources for relief.
“There’s a lucrative market out there for the snake-oil salesmen,” Sneller said.
There is also a lack of understanding of the psychological toll that covid has taken and what role that may be playing in how people perceive fatigue. Stress and anxiety — common responses to the isolation and uncertainty of the pandemic — exacerbate almost any illness. Talk therapy has shown benefits in treating ailments from cancer to chronic physical complaints.
“One should not neglect the mental health aspects of this pandemic,” Sneller said. “There is clearly a stigma about mental health that there should not be.”
Joanna Hellmuth, a cognitive neurologist at the University of California at San Francisco’s Memory and Aging Center, said she is seeing cognitive impairment in people who had covid and who measure well in mood testing, suggesting they are not depressed or anxious. She sees parallels with earlier work she did on HIV in which she identified changes that she said are “clinically indistinguishable from covid-associated cognitive changes.” Other research suggests that people who recovered from the coronaviruses SARS and MERS in 2003 and 2013 also experienced cognitive shifts.
“I am trying to be a data-driven voice for people who feel unheard by doctors,” Hellmuth said.
Viewing long covid purely as a psychogenic illness will do little to counter the public health threat the country now faces, Krumholz said, or to address the lingering suffering from other potentially post-infectious conditions.
“To be dismissive when the story is not yet told is shortsighted at best, cruel at worst,” Krumholz said. “We are far too ignorant of the long-term effects of viruses to come to that conclusion.”
Like others, he expressed a commitment to the opportunity that long covid offers.
“I really feel a kinship with these other groups,” Berrent said. “We are in touch with all of these people because it is so important that we don’t leave people behind, that we end up with a net benefit for humanity.”