Experts are struggling to make sense of the lingering mystery of the long Covid

RRobert Gallo apologized for still coughing. The day before President Biden tested positive for Covid-19, the famed HIV researcher said he was still recovering from a Covid infection that left him unable to walk, put him in the hospital and had made him delusional, he said during a panel discussion on Wednesday. discussion on the long Covid.

Presented by the Global Virus Network, a coalition of leading virologists, the two-day virtual conference brought together experts from all disciplines and around the world to ask and answer questions about the causes of long Covid, how to predict who catches it, how to treat it, and perhaps how to prevent it.

No one has the answers, but Gallo, who co-founded the group, bets from the start on the amount of virus present. “We have definitive data that the vaccine reduces the virus, so if we can take that as a conclusion that the amount of virus is critical in predicting the future, you have a great biomarker,” he said. “I don’t think you can wait. I agree with those clinical people who want to move forward right away.

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To one person, scientists expressed their desire for better studies, better funding, better participation, with a seething urgency of specialists in cardiology, neuroscience, epidemiology, pulmonology and immunology. Yet these are still the early days of long Covid research. Recognized since 2020, its definition is still sometimes debated, although most definitions include symptoms that persist weeks or months after an acute infection and include fatigue, headache, shortness of breath, memory problems, gastrointestinal problems and joint and muscle pain.

We still need a taxonomy, Yale cardiologist Harlan Krumholz said, to sort people and their myriad symptoms into groups so that scientists with different expertise can speak the same language while trying to better understand what’s going on. do not go.

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But when something seems to work, try it, that was the consensus. “I don’t think we should wait just to fully understand a mechanism before trying reasonable interventions, especially if the interventions are low-risk,” Krumholz said.

Epidemiologist Sairam Parthasarathy from the University of Arizona painted the picture of the prevalence, pegging it at 43% of all Covid cases based on pooled evidence from 50 studies. He called the risk of long Covid greater than the risk of developing diabetes and asthma, citing an Italian study which put it at 25%. And in the United States, disadvantaged populations, including Native Americans and Hispanics, are disproportionately more likely to be hospitalized with Covid. “These are the few who can actually carry the burden of the many, and we have to deal with that,” Parthasarathy said.

There are lessons to be learned from another familiar disease: cancer. Michelle Monje, a Stanford neuroscientist and neuro-oncologist, previously linked the long effects of Covid in the brain to the cognitive impairment called “chemo brain” that follows methotrexate treatment. Now, she says long Covid also looks like what happens in the cytokine storm that follows CAR-T cancer immunotherapy. In all three cases, the inflammation disrupts immune cells in the brain called microglia, which usually maintain healthy neural circuitry functioning, but which, when inflammation occurs, become neurotoxic. In mice, she found that depleting microglia with a small molecule that targets a needed growth factor receptor allows microglia to return to normal and rescue cognitive deficits after cancer treatments. “It’s something we haven’t tested yet, but are testing in the context of the long Covid,” she said.

Monje also zoomed in on a particular protein circulating in the brain at high levels triggered by inflammation in response to viral infection. In blood samples taken from patients who had had relatively mild Covid in the spring of 2020 and then later cognitive impairment, higher levels of the chemokine CCL11 persisted. She also found much of the variability in CCL11 levels that could be explained by prior autoimmune disease.

“Inflammation causes neuroinflammation, which causes dysregulation of multiple cell lines. And, you know, we think that’s a relatively common mechanism contributing to post-Covid cognitive impairment,” Monje said. really raises the question of how various immune challenges that might elicit different cytokine profiles might increase the risk of overlapping but distinct constellations of neurological and psychiatric symptoms.”

There may be other targets to explore and other biomarkers to guide the way. Here is where some of the other scientists devote their attention:

James Harker of Imperial College London studies the impact of long Covid on the lungs, use CT scans and proteomics tools to see if there is lasting damage to the lungs after an acute infection, such as the scarring known as fibrosis. As in other long-running Covid research, there was no strong link between disease severity and ongoing changes in the lungs. And the story goes beyond inflammatory responses to infection. “The proteins we see in the post-Covid lung are broadly associated with things like cell death and injury and altered oxygenation status and reactive oxygen status,” he said. “They therefore suggest that the lungs of these individuals may have ongoing cell death and tissue repair processes, that this is an altered metabolic state.”

James Heath of the Institute for Systems Biology in Seattle is focusing his research on identifying factors that would put patients at long risk of Covid, apply multi-omics tools to interrogate blood samples, electronic health records and questionnaires. His work has revealed clues to what higher levels of autoantibody – an antibody that the immune system targets at the body’s own proteins – mean when they trigger a cascade of immune responses. In the cohort he studied, the presence of autoantibodies was not strongly associated with disease severity, but they were linked to gastrointestinal problems and changes in exercise capacity. Some specific autoantibodies have activated a particular immune pathway, the one that the narsoplimab monoclonal antibody targets. Heath’s team designed and proposed to the NIH a clinical trial to test the drug to treat long Covid patients, especially those who can be identified through the specific autoantibodies he identified.

Speaking from the NIH, Janko Nikolich-Žugich of the University of Arizona called for increased funding for his Retrieve the study, a nationwide observational study of long Covid. The $1.2 billion allocated to it is not enough, he said. Recruitment is approaching 40% of its targets, which should be met by the January deadline, but “it’s actually quite short of anything that needs to be done,” he said. “Funding really needs to be tripled to extract the value from this study and broadly mobilize the scientific community to participate in it in the best possible way in both a scientific and a medical sense.”

Brett Giroir, the four-star admiral formerly on the White House Covid task force, summarizes the research as it currently stands. “We have mechanisms that range from persistence of SARS-CoV-2 to activation of other viruses, from autoantibodies to remote inflammation in the brain, to profibrotic signals in the lungs. And who the hell knows what’s going on in the heart system, like Harlan [Krumholz] said, because we really have no idea,” he said. “We have a multi-year NIH study underway that may prove definitive. But what can we do in the short term? We can’t wait 5-10 years for the patients that Harlan described who are in so much pain.

Eric Rubin, an immunologist at Harvard Medical School and editor of the New England Journal of Medicine, highlighted the power of big data. “We have a lot of patients and we have data,” he said. “I think we’re still looking for some kind of collective wisdom to bring to this question.” In an interview before the conference, Rubin told STAT “there are a lot of different symptoms and we haven’t done a very good job of determining the vast majority of them,” he said. “What hasn’t worked so far, at least not the way I’ve seen it, is describing a syndrome or establishing a list of criteria for a syndrome, which is the way which we usually address new diseases. This entity actually represents a large number of separate entities. There is no one for a long time Covid.

Stanford University’s Paul Utz has called for more and larger studies to explore autoimmunity and the long Covid to understand who has or is developing autoantibodies and how they might contribute. He listed what we don’t know yet: the true prevalence of autoantibodies in Covid or long Covid; whether temporary or permanent; and whether patients develop autoimmunity. “Recover won’t respond to that,” he said. Asked about the impact of vaccination on the new autoimmunity, he replied: “we don’t know if vaccination prevents it, but we think it does”.

Meanwhile, Krumholz urges people to put together everything they know to keep patients from wandering into the wilderness of at best partial solutions to their symptoms.

“It’s about this abyss of ignorance that pervades the whole field,” he said. “Most of our tests are impervious to anomaly detection, and yet we have people sitting in front of us who are not only mildly affected.”

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