Presented by the Global Virology Network, an alliance of leading virologists, the virtual conference brought together experts from various disciplines and around the world to ask and answer questions about the causes of Covid’s long illness, how to predict who gets it, how to treat it, and perhaps just how to prevent it.
Nobody has the answers, but Gallo, who co-founded the group, has put his money on the amount of viruses out there from the start. “We have definitive data that the vaccine reduces virus, so if we can take that as a conclusion that the amount of virus is necessary to predict 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.”
For one, scientists have expressed enthusiasm for better studies, better funding, and better participation, with growing urgency from specialists in cardiology, neuroscience, epidemiology, pulmonology, and immunology. However, it is still early days for long-term Covid research. Recognized since 2020, its definition is still sometimes debated, although most definitions include symptoms that persist weeks or months after an acute injury and include fatigue, headache, shortness of breath, memory problems, digestive problems, and joint and muscle pain.
We still need classification to sort people and their myriad symptoms into groups so that scientists with different experiences can speak the same language as they try to better understand what’s wrong, said Harlan Krumholz, a cardiologist at Yale University.
But when something seems to work, give it a try, the consensus was. “I don’t think we should wait just to fully understand the mechanism before trying some reasonable interventions, especially if they are low-risk interventions,” Krumholz said.
Epidemiologist Sairam Parthasarathy of the University of Arizona painted a picture of prevalence, identifying it as 43% of all COVID cases based on evidence pooled from 50 studies. He described the long-term Covid risk as greater than the risk of diabetes and asthma, citing a study from Italy that put it at 25%. And in the United States, disadvantaged populations, including Native Americans and people of Hispanic origin, are more likely to be hospitalized due to Covid. “It’s a few that may actually carry the burden of the many, and we need to address this,” Parthasarathy said.
There are lessons from another familiar disease: cancer. Michelle Monge, a neuroscientist and neuro-oncologist from Stanford, has linked Covid’s long-term effects in the brain to cognitive impairment called “chemo-brain” that follows methotrexate treatment. Now she says Long Covid is also similar to what happens in the cytokine storm that follows CAR-T cancer immunotherapy. In all three cases, inflammation disrupts immune cells in the brain called microglia, which normally maintain healthy nerve circuit function, but when inflammation occurs, they become neurotoxic. In mice, it found that depletion of microglia with a small molecule targeting the necessary growth factor receptor allows microglia to return to normal and rescue cognitive deficits after cancer treatments. “This is something we haven’t tested yet, but we are in the process of testing in the long Covid context,” she said.
Mongey also magnified a specific protein circulating in the brain at elevated levels caused by inflammation in response to a viral infection. In blood samples from patients who developed relatively mild COVID-19 in the spring of 2020 and subsequently cognitive impairment, higher levels of chemokine CCL11 persisted. It also found a lot of variation in CCL11 levels that could be explained by previous autoimmune diseases.
Inflammation causes neuroinflammation, which leads to dysregulation of multiple cell lineages. And, you know, we think this is a relatively common mechanism contributing to post-Covid cognitive impairment.” “It really raises the question of how different immune challenges that might give rise to different cytokine traits may increase the risk of overlapping distinct signs of neuropsychiatric symptoms.”
There may be other goals to explore, and other vital signs to guide the way. Here’s where some other scholars devote their attention:
James Harker of Imperial College London studies the prolonged impact of Covid on the lungs, Using CT scans and proteomics tools to see if there is permanent damage to the lungs after an acute injury, such as scarring known as fibrosis. As in other long-running Covid research, there was no strong association between disease severity and persistent changes in the lungs. The story goes beyond inflammatory responses to infection. “The proteins that we see in a post-Covid lung are largely related to things like cell death, wounds, altered oxygen status and reactive oxygen status,” he said. “So they suggest that the lungs of these individuals may have ongoing cell death and tissue repair processes, and that this is an altered metabolic state.”
James Heath of the Institute of Systems Biology in Seattle focuses his research on identifying factors that would put patients at long-term risk of contracting COVID-19. Application of multitasking tools for querying blood samples, electronic health records and questionnaires. His work has revealed evidence of higher levels of antibodies — an antibody targeted by the immune system — the body’s proteins mean when they trigger a cascade of immune responses. In the group he studied, the presence of autoantibodies was not strongly associated with disease severity, but rather was associated with gastrointestinal problems and changes in the ability to exercise. Some autoantibodies activated a specific immune pathway, a pathway targeted by the monoclonal antibody narsoplimab. Heath’s team designed and proposed to the National Institutes of Health a clinical trial to test the drug to treat long-term Covid patients, especially those who could be identified by the specific autoantibodies it identified.
Speaking about the National Institutes of Health, Janko Nikolic Ojic of the University of Arizona called for more funding Study recoveryAnd the A national observational study of the long-Covid virus. He said the $1.2 billion allocated to it was not enough. Recruitment is close to 40% of its goals, which must be met by the January deadline, but “actually falls completely short of everything that needs to be done,” he said. “Funding really needs to be tripled to extract the value of this study and mobilize the broad scientific community to participate in it in the best possible way in the scientific and medical sense.”
Brett Giroir, a four-star admiral who was previously on the White House COVID staff, Summarize the search as it is now. We have mechanisms anywhere from persistence of SARS-CoV-2 to activation of other viruses, to autoantibodies to distant infections in the brain, to fibrosis signaling in the lung. And who the hell knows what happens in the heart system, like Harlan [Krumholz] Because we really don’t have the evidence, he said. “We have a multi-year, NIH ongoing study that could be conclusive. But what can we do in the short term? We cannot wait five to ten years for patients described by Harlan who are experiencing this suffering.”
Eric Rubin, an immunologist at Harvard Medical School and editor of the New England Journal of Medicine, noted the power of big data. “We have a lot of patients and we have data,” he said. “I think we’re still looking for a collective kind of wisdom to ask this question.” In an interview before the conference, Robin told STAT “There are a lot of different symptoms and we haven’t done a very good job of figuring out the vast majority of them,” he said. “What hasn’t worked so far, at least not in the ways I’ve seen, is to describe a syndrome or come up with a list of criteria for a syndrome, which is how we usually deal with new diseases. This entity actually represents a lot of distinct entities. No one Covid is tall.”
Paul Otz of Stanford University has called for more, larger studies to explore autoimmunity and the long-running COVID-19 virus To understand who has or is developing antibodies and how they can contribute. He listed what we do not yet know: the true prevalence of autoantibodies in Covid or in long Covid; whether transient or permanent; and whether patients go on to develop autoimmunity. “Rickver won’t answer that,” he said. Asked about the effect of vaccination on new autoimmunity, he said: “We don’t know if vaccination prevents it, but we expect it does.”
Meanwhile, Krumholz urges people to put together everything they know to prevent patients from wandering in the wild for the best partial solutions to their symptoms.
“It is about this abyss of ignorance that is spreading across the entire field,” he said. “Most of our tests are insensitive to detecting abnormalities, yet we have people sitting in front of us who are not even slightly affected.”