In 2021, the National Institutes of Health (NIH) launched its ambitious nearly  $2 billion RECOVER Initiative, dedicated to finding the root causes of and possible treatments for Long Covid.

Solve played a critical role in securing the preliminary $1.25 billion in funding for the program, and Solve representatives continue to serve on many advisory, authorship, and oversight committees for RECOVER.  

RECOVER has published nearly 80 papers and collected millions of data points with more work still underway, but only recently has responded to public pressure to focus on therapeutics and treatments. The launch of RECOVER-Treating Long COVID (RECOVER – TLC), a new program to develop and initiate additional Long Covid clinical trials, is backed by $500 million to find new ways to treat patients with Long Covid.

In September, the NIH held a three-day workshop at its campus in Bethesda, Maryland, to discuss the path forward for RECOVER-TLC. In this blog series, we’re summarizing the workshop in its entirety. 

RECOVER-TLC: DAY 1

PATIENT’S LIVED EXPERIENCES, HEALTH CARE PROVIDERS’ PERSPECTIVES, AND UPDATES OF RECENT FINDINGS AND ONGOING WORK

Many patients with Long Covid, ME/CFS, or other infection-associated chronic conditions and illnesses had traveled to Bethesda for the meeting, at great personal expense and physical risk. 

Also present were dozens of world-renowned experts—basic researchers; biologists; biostatisticians; clinical trial experts; immunologists; industry representatives; ME/CFS and POTS experts; neurologists, pediatricians, and regulatory representatives. And over 1,500 people attended virtually.

It was clear right away that this workshop was all about action. As NIH Director Dr. Monica Bertangnolli began thanking participants, a few people began chanting demands for Long Covid blood tests and for support for kids with Long Covid. They also proclaimed that the Long Covid pandemic now is like the HIV/AIDS pandemic of the early 1980s.

After the demands quieted, Dr. Bertagnolli said, “You know what? We’re with you. Totally.” The in-person audience stirred in agreement. This set a unique tone for the remaining three days. On one side was the devastating disease, Long Covid; on the other, the united, resolved, and powerful team of researchers, patients, and activists. Dr. Bertagnolli continued, “We’ve got a lot to do and a lot of ground to cover. We want to come out of this meeting with an action plan.”

How RECOVER-TLC is structured and how it will work

The workshop then kicked off with Dr. Joseph Breen, section chief at the National Institute for Allergies and Infectious Diseases (NIAID), explaining how RECOVER-TLC will work. 

RECOVER-TLC will not run under the original RECOVER structure. Instead, RECOVER-TLC is sponsored by NIAID, which has unparalleled experience and resources in successfully running large, complex clinical trials. RECOVER-TLC will follow two key principles: engagement and transparency, he said. 

RECOVER-TLC will engage the most critical partners to start new clinical trials. For example, RECOVER-TLC is engaging the Foundation of the NIH to structure the clinical trials; and patient communities, to prioritize interventions and form all working and oversight groups. 

Also, RECOVER-TLC is setting up an online portal through which anyone can suggest new interventions to test in clinical trials, as discussed later in the workshop; (see Box 4) 

RECOVER-TLC will be transparent about its progress at all steps. The program will present results in online seminars throughout the year and in a larger meeting once each year. Scientific working groups will also include diverse members (researcher, clinicians, patients, and people from other invested communities) to include all groups in decisions and better share findings among these groups. 

Patients with Long Covid describe what it’s like

Three patients with Long Covid described what it was like to have this disease and to note what participants should keep in mind over these three days. Ms. Christine Maughan represented patients with Long Covid (being herself a patient with Long Covid, ME/CFS, and POTS). Patients want to be a part of the discussion, she said. They want to have a voice in deciding how their disease is researched and treated. 

Ms. Maughan said she must travel over 90 miles to get medical care for Long Covid and has over $10,000 in medical expenses. She must plan every activity to get through each day. And with 18 million other Americans living with Long Covid, she said, she is not alone. Her online support group includes over 4,000 people from across the country. Patients also want researchers to act with a sense of urgency. And researchers should consider other infection-associated chronic conditions, like ME/CFS. 

Ms. Angela Meriquez Vasquez is the policy director at the Children’s Partnership, which advocates for the most underserved children in California (including those severely affected by COVID). Having severe symptoms for three years, she struggled to be diagnosed by doctors but was eventually diagnosed with lupus and found an ME/CFS specialist. Ms. Vasquez said the NIH must spend more money helping patients get diagnosed more quickly than she was diagnosed and be taken more seriously than she was taken. 

The NIH must especially help disadvantaged patients with ME/CFS (low-income patients, people of color), whom the disease hits especially hard. To get by, Ms. Vasquez detailed an extensive list of antivirals she used and the need to painstakingly pace her activities. Even attending this meeting was a herculean task, she said. Because she has POTS, she had a terrible time on the flight. (Other patients who traveled to the workshop said this too.) 

Ms. Liza Fisher, a patient advocate and Solve M.E. Advocacy Week veteran, detailed a long and painful journey to be diagnosed with several severe diseases (including Long Covid, ME/CFS, and mast cell activation syndrome) and to find interventions that help. She described Long Covid as “diabolic,” “neverending,” “life-changing,” and “a thief.” 

She detailed many pharmaceutical interventions, non-pharmaceutical interventions, and lifestyle changes she tried; showing how complex and exhausting the process is for trying to live with these diseases. Ms. Fisher can no longer work, must be cared for by her mother, and receives disability from the government. That many other patients must struggle with these symptoms alone is all the more tragic.

Defining Long Covid, and how our definition affects clinical trials

Dr. Jerry Krishnan from the University of Illinois, Chicago, then spoke about how the National Academies of Sciences, Engineering, and Medicine define Long Covid. Dr. Krishnan explained that defining a disease like Long Covid is no small thing. This definition will substantially determine how we test interventions for patients in clinical trials. 

For example, with a definition in place, we will know which patients to include in trials and which to exclude; we can properly account for heterogeneity in patients’ symptoms, preexisting conditions, and responses to interventions; and we can use standardized protocols for all trials, which will help apply findings from one trial to those of others. 

To define Long Covid, the National Academies committee spoke with 1,300 patients, researchers, doctors, and public health workers; read over a hundred research papers; and asked a range of patient groups and scientific and medical experts to scrutinize the committee’s work. (Solve recently summarized the National Academies’ definition in its Science Spotlight Series. Read it here.)

To define the disease, the committee chose words carefully. They chose Long Covid because patients prefer this straightforward, easy-to-understand term. Also, patients, doctors, and researchers will communicate more clearly if they agree to use the same term than if they use different terms for the same disease. They chose “infection-associated chronic condition” to highlight that Long Covid started with an infection and persists long after that infection. And they chose “disease state” to emphasize that Long Covid affects organ systems throughout the human body.

The committee’s definition (Box 1) includes lists of key symptoms (like post-exertional malaise, fast heart rate, and difficulty concentrating) and other diagnosable conditions (like POTS, ME/CFS, and fibromyalgia) that patients may have.

During discussions, some participants worried that the committee’s definition was too simple and too vague to help clinical trials. An overly simplistic and vague definition wouldn’t represent the many subtypes and diverse symptoms of the disease. Some people asked whether we should use multiple definitions, treat patients case by case, and find biomarkers to classify distinct patient subgroups.

Dr. Krishnan agreed the disease was complicated, but he explained how we needed a standard definition to unify and organize our efforts. We must use common terms and ideas to collaborate as much as possible and to find treatments for patients as quickly as possible. And a common definition is vital for the public to register the disease and for doctors to learn about it.

Certainly, some clinical trials may need more nuanced definitions to distinguish subtypes or symptoms. But, these trials could build on the standard definition by adding inclusion and exclusion criteria needed for the tested intervention. The panel also said this definition is not set in stone. As we learn more about the disease, we should refine the definition so it better serves our goal of finding treatments for patients with Long Covid. 

Observational Studies–critical for designing interventional clinical trials

Dr. Leora Horwitz from New York University then spoke about why observational clinical trials are so critical to finding treatments and cures for patients. While interventional clinical trials test how treatments affect patients (like clinical benefits or adverse effects); observational trials describe things (like symptoms). Dr. Horwitz explained that without observations trials, interventional trials would be impossible. We need observational trials to precisely define the disease, to even know what we’re talking about when we say Long Covid. We need observational trials to count how many people develop Long Covid; and to know of the people who develop it, how many improve without a treatment.

These numbers are critical for calculating how many patients to include in interventional clinical trials. If we enroll too few patients, we won’t be able tell whether an intervention works, and we might throw out good medicines. (Without these numbers, we also might enroll more patients than we need, wasting precious funds.) We also need observational trials to figure out patient subgroups that might respond differently to interventions. Finally, we need observational trials to know how Long Covid affects patients’ bodies.

Dr. Horwitz gave three examples of observational trials done by researchers with money from RECOVER. Dr. Akiko Iwasaki (Yale) did a ground-breaking observational study that showed patients with Long Covid have an overly intense immune response to the SARS-CoV-2 virus. Dr. Michael Peluso (University of California, San Francisco) did an observational study that showed the virus sticks around for a long time in the bodies of the patients with Long Covid. Dr. Michael VanElzakker—a Solve Ramsay Research Grant awardee—did a fantastic observational study that showed inflammation in the brains of patients with Long Covid.

Dr. Horwitz explained that RECOVER-TLC observational clinical trials are carefully designed to extract the most important information for interventional trials. RECOVER observational trials consistently measure a set of symptoms in a large group of patients, one as diverse as the nation’s population. These observational trials have at hand electronic health records from 60 million patients and samples from over 14,000 adult patients and over 14,000 children.

(Dr. Michael Sneller, from the National Institute of Allergy and Infectious Diseases, was scheduled to speak after Dr. Horwitz but could not attend as planned. A substitute presented his slides, which also showed how observational clinical trials must secure key information for interventional trials (like how many people naturally recover from Long Covid without treatment). Dr. Sneller’s slides also showed how Long Covid symptoms in adults may differ from those in children, and that we must confirm biomarkers work by testing them in multiple trials.)

Dr. Ziyad Al-Aly is a clinical epidemic at Veteran’s Association St. Louis Health Care System and a preeminent Long Covid researcher and adviser for Long Covid policies. Reviewing lessons he learned, Dr. Al-Aly said the number one thing for people to remember is that pandemics disable people. If we don’t understand Long Covid, then we will be unprepared for the next pandemic. Long Covid devastates patients and communities, he said. Over 400 million people have Long Covid, and the disease already costs the world over $1 trillion each year. Dr. Al-Aly worried what will happen in the coming years. Will patients with Long Covid have greater risk for early onset dementia or Alzheimer’s? Will children with Long Covid have lasting effects on development and have shorter lives? 

Dr. Melissa Stockwell (Columbia University) especially agreed about studying children with Long Covid. “They are just beginning their lives,” she said. “We must fight for them and for their interventions, so they can go back to doing all the things they should be doing as kids.”

Most strikingly, we have zero approved treatment for patients with Long Covid, said Dr. Al-Aly. This number must change soon.

Dr. Al-Aly reviewed other valuable lessons. We must listen to patients. We must not oversimplify Long Covid because it is not a simple disease. (Dr. Al-Aly said even he must resist urges to oversimplify Long Covid to produce short-and-sweet sound bites for newspaper or television interviews.) Finally, we must learn from the decades of unheralded research on ME/CFS and other chronic infection-associated conditions and illnesses (Box 2).

Patients and panels then discussed details. People spoke about needing to make observational clinical trials easy to participate in for people from rural areas or for children and their families. Dr. Stockwell said their clinical trial has a visiting nurse who visits patients in their homes. Dr. Horwitz added that RECOVER clinical trials have mobile vans that visit patients in rural areas. And if patients must travel over 150 miles to a clinical site, then RECOVER pays for their hotel rooms. Although RECOVER must recruit more patients from rural areas (about 5 in 100 RECOVER patients are from rural areas, still below the national rate), we have been improving, she said. Participants also discussed the need to include all sorts of people in observational studies. Dr. Helen Ward (Imperial College) said this was her primary concern. If observational clinical include only patients from specialized clinics or those properly diagnosed, then these trials will leave out the great majority of patients. Fewer than one in five patients with Long Covid is recognized as having the disease. 

What we know about Long Covid pathobiology, what else we must know, and how this information informs upcoming clinical trials.

Later that afternoon, several researchers spoke about their work on the pathology of Long Covid, describing how we can use this information to design upcoming clinical trials.

Activating inflammation and the immune response in the brains of patients with Long Covid. First, Dr. Michael VanElzakker from Massachusetts General Hospital and Harvard University explained how problems in the blood (like improper coagulation) can cause neuroinflammation (the nervous system’s response to infection) in patients with Long Covid. 

Dr. VanElzakker showed how the levels of two key blood molecules, fibrinogen (needed to form blood clots) and sL-selectin (which sticks to immune cells and brings them to inflamed sites), significantly correlate with neuroinflammation in these patients. Fibrinogen and immune cells bind the SARS-CoV-2 Spike protein, which is part of the outer wall of the viral particle. 

Persistently elevated levels of Spike protein in the blood of patients create nets of fibrinogen and immune cells. These nets stick to the blood–brain barrier and cause neuroinflammation. Scanning brains of patients, Dr. VanElzakker found many regions more inflamed than they were in the brains of healthy participants. 

Future clinical trials should test how much treatments that break up these nets lower neuroinflammation. Dr. VanElzakker recommended that we focus on small, agile clinical trials to test many varied interventions (like interventions that reduce fibrinogen or break up fibrinogen from Spike), instead of focusing on larger trials of a few “magic-bullet drugs.”

Blood clots and other blood-related problems for patients with Long Covid

Next, Dr. Resia Pretorius (from Stellenbosch University, in South Africa) spoke about how tiny blood clots (microclots) form in patients with Long Covid and the potential of using these blood clots as biomarkers to predict how distinct groups of patients will respond to different types of treatment. Patients with Long Covid have significantly more microclots than do healthy participants; and, as Dr. VanElzakker said, the viral Spike protein helps form microclots.

But Dr. Pretorius explained that patients with any inflammatory disease have microclots, so the degree to which microclots contribute to Long Covid is still unclear and, a critical gap in our knowledge. Dr. Pretorius is leading clinical trials to test whether these microclots cause neurological symptoms of Long Covid. For example, she is now testing the extent to which microclots in patients with Long Covid differ from microclots in patients with other inflammatory diseases.

Still, Dr. Pretorius predicts microclots will be a useful biomarker to use in clinical trials. In both children and adults with Long Covid, microclots are both more abundant and larger than they are in healthy participants. Microclots in patients with Long Covid also have unique molecules and unique properties. Upcoming clinical trials should take advantage of these differences to study patients and treatment effects (for example, by seeing how interventions reduce the number or change the composition of microclots).

Dr. Pretorius thinks microclots damage endothelial cells in patients, and a much-heralded recent study found that antibody against fibrin, a component of microclots, protects against SARS-CoV-2. Moving forward, microclots may be an important biomarker and therapeutic target.

SARS-CoV-2 persists in patients with Long Covid. Next, Dr. Michael Peluso from the University of California, San Francisco, spoke about how the SARS-CoV-2 virus can persist in patients with Long Covid; how persisting virus relates to patients’ symptoms; and whether we can reduce symptoms by getting rid of the persisting virus. 

SARS-CoV-2 persists in patients by laying low in tissues and by changing its appearance (mutating) to escape from the immune system. Also, the immune systems of patients with Long Covid often don’t work properly, so patients’ immune systems may not properly detect and clear the virus in the first place. These factors are also true for patients with other infection-associated chronic conditions (like ME/CFS and Post Lyme).

Unfortunately, studies done so far have included too few patients and finished too soon to tell whether persisting SARS-CoV-2 causes Long Covid. Dr. Peluso said future clinical trials must include more patients and compare more patient subgroups (especially by including patients infected with SARS-CoV-2 but who never developed symptoms, he felt). Future trials must also watch patients for longer; better focus on key phenotypes; and better leverage useful biomarkers. Echoing other panelists, Dr. Peluso especially emphasized how much clinical trials need good biomarkers. With good biomarkers, we could more sensitively and easily discriminate among patients and measure improvements. Thus, he agreed with launching more small and nimble interventional trials, especially those validating biomarkers.

Dr. Peluso went on to describe why the RECOVER-VITAL clinical trial (testing Paxlovid) is so important. The number of patients in the RECOVER-VITAL trial (900 patients) is substantially more than the number of patients in the original Paxlovid trial (STOP-PASC trail; 155 patients). The RECOVER-VITAL trial will also search for virus-hiding in distinct types of tissues; will follow patients for much longer; will focus on well-established symptoms (post-exertional malaise, cognitive dysfunction, and autonomic dysfunction); and will use promising biomarkers to study how persisting virus affects symptoms. Dr. Peluso agreed that the best way forward is with many small interventional clinical trials, adding that each trial should test how a treatment affects key endpoints in 50–150 patients. 

One audience member from the industry asked to speak further with Dr. Peluso about these ideas—an example of the extended discussion and chance at partnership critical for these trials to succeed. 

Biorepositories and biomarkers

Next, Dr. Paul Utz from Stanford University spoke about Long Covid biorepositories (facilities that collect and handle samples from patients for research) and about potential biomarkers found by using biorepository samples. The RECOVER clinical trials have collected and are storing about a million samples—about 90,000 samples from children and teens and about 900,000 from adults.

These samples are from diverse tissues (like blood, nasal, saliva, stool, urine) and different time points (quarter year, half year, one year, two years, and three years after acute infection). The samples are valuable sources for all types of clinical and genetic data and are especially unique because they include samples from people before the pandemic. No other biorepository in the world includes such samples. The RECOVER biorepository also stores much electronic data from patients (like data collected through Apple watches or Fitbits) and survey data. 

To best use the biorepository samples, Dr. Utz explained, we must carefully plan what we want to do. Distinct approaches to analyzing data have distinct strengths and weaknesses. We must also plan how to process samples because some are delicate. But because of the substantial strengths of the RECOVER program—the many samples in the RECOVER biorepository, the incredible expertise of RECOVER researchers, the powerful technologies at hand, and the vast amount we’ve learned so far—Dr. Utz was enthusiastic that the upcoming clinical trials will extract the most information from samples to find biomarkers, treatments, and cures.

The discussion that followed centered on confidence, but also on humility. Participants were confident that we have everything we need to find cures. Dr. Amy Proal (chief executive officer at PolyBio Research Foundation) said we should appreciate how much experience and know-how the scientific community has to offer patients with Long Covid. Scientists have long studied how other viral viruses (like HIV and Ebola) persist in tissues and how to treat improper coagulation in patients with other diseases. They are now using this information to build models for what is happening with patients with Long Covid.

Dr. VanElzakker added that efforts by RECOVER and other groups are improving the educational infrastructure. Patients, doctors, researchers, pharmaceutical companies, and regulatory agencies are starting to think in the same way about this disease. 

But participants spoke of the need for humility about mistakes made along the way. Dr. VanElzakker said we still have a way to go with convincing many healthcare providers to take patients seriously. One patient lamented that too few neurologists want to keep up with the latest findings about neurological symptoms of Long Covid. Panelists said that we’ve learned too much to simply dismiss patients’ symptoms as too difficult to explain. Clinicians must start applying information from clinical trials to better care for their patients. 

The participants returned repeatedly to key recommendations:

• We urgently need biomarkers for subtypes of Long Covid (with distinct causes and symptoms) and for subgroups of patients (who respond differently to distinct interventions).
• Running small, nimble clinical trials to quickly test new ideas or interventions is critical.
• Doctors, researchers, and industry must collaborate to share resources and ideas.

Take-home points from studies on ME/CFS, POTS, MIS-C, and related syndromes to help design Long Covid clinical trials

Three researchers then spoke about what we can learn from studies of Long Covid–related syndromes (ME/CFS, POTS, and MIS-C) to design better clinical trials on Long Covid.

ME/CFS

Dr. Avindra Nath, from the National Institute of Neurological Disorders and Stroke, described long-standing challenges in designing clinical trials on ME/CFS. Knowing which patients to include in these trials and which to exclude is difficult because these patients are easily misdiagnosed. ME/CFS may involve any number of heterogeneous symptoms that also occur with other diseases. 

For example, of 500 patients considered for an NIH clinical trial on ME/CFS, only 27 were eligible; and of those, more than one-third had other diseases that explained their symptoms. Also challenging is that clinical trials must often measure subjective symptoms because we lack reliable, objective biomarkers.

Because of these challenges, large pharmaceutical companies have long avoided investing in clinical trials on ME/CFS. This has been a disaster for progress because no other entity has the resources that pharmaceutical companies have. Dr. Nath said the challenges that have hindered clinical trials on ME/CFS also hinder trials on Long Covid, since ME/CFS and Long Covid have so much in common. He highlighted several placebo-controlled trials on Long Covid that reached no endpoints, showed strong placebo responses, or associated with companies declaring bankruptcy.

For better trials on ME/CFS and Long Covid, Dr. Nath said we need to be measuring firmer outcomes. For example, we cannot continue to rely on patients’ subjective impressions (like whether an intervention lowers post-exertional malaise). Instead, we must properly define post-exertional malaise and set up a way to measure it objectively and fairly. (Such a scale, the Hinxton scale, is now being developed, he said.) We must also separately consider subgroups of patients with distinct immunological problems.

Finally, we should launch more placebo-controlled clinical trials (where some participants receive interventions and others receive placebo); crossover studies (where participants receive placebos for one part of the study, and intervention for another part); and platform studies (which can evaluate multiple interventions at once). These are fantastic trials for quickly getting high-quality information.

Turning to his own research on ME/CFS, Dr. Nath spoke of how his studies about viral persistence differed from other such studies discussed at the workshop. Studying 17 patients with ME/CFS, Dr. Nath found that symptoms were caused by persisting viral antigens (viral molecules that continue to irritate the immune system), not by persisting virus itself.

Dr. Nath found the main problem with these patients was that their antibody-producing cells (B cells) do not properly develop during infection. Specifically, their B cells do not properly switch from making one type of antibody (for example, IgM antibody, usually made by unprovoked B cells) to another (for example, IgG antibody, made by activated B cells).

Failure of B cells to make the right kinds of antibody lets viral antigens stick around. It also exhausts T cells (whose job it is to seek and destroy pathogens, like viruses) and overly activates the innate immune system (which involves general responses, like inflammation, complement, and coagulation). Dr. Nath suggested that future clinical trials of ME/CFS and Long Covid should better distinguish among patients with aberrantly activated B cells, with exhausted T cells, or with overly activated innate immune systems.

Postural Orthostatic Tachycardia Syndrome (POTS)

Next, Dr. Peter Rowe, a Solve Research Advisory Council member from Johns Hopkins University, spoke about what we can learn from clinical trials of postural orthostatic tachycardia syndrome (POTS) to better design clinical trials of Long Covid. Dr. Rowe explained how clinical trials on POTS can work only if we are mindful of the details of the disease. For example, a clinical trial should exclude patients with POTS who are not good candidates for that intervention. Patients may have had too severe symptoms for too long or may have complicated comorbidities. 

For exploratory clinical trials on POTS, it is better to include patients with more recent and less severe symptoms because these patients have the best chance for responding to a new candidate intervention. Patients with more severe POTS should be considered for potent and more established interventions. Dr. Rowe suggested designing trials with run-in periods, during which all patients receive no treatment or salt and fluid treatments to check baseline symptoms (are they severe or mild?).

Patients with overly severe and long-standing symptoms could then be included in other studies, giving trials a better chance to detect responses to fledgling interventions. Another important detail with POTS is the time of appointments. 

Clinical trials that measure symptoms like orthostatic imbalance should assess patients at the same time each day because the intensity of orthostatic imbalance can change throughout the day. A third key detail is diet. Of the children with POTS whom Dr. Rowe treats, one-third cannot tolerate milk protein. And if these patients change their diets while participating in a study, then their symptoms may also change, complicating the study results. Thus, clinical trials must consider patients’ diets.

A final key detail about clinical trials on POTS is knowing when established protocols are ill-suited for the goals of the trial. For example, studies of POTS may use the COMPASS-31 questionnaire to measure orthostatic imbalance (or other symptoms affecting the autonomic nervous system). But this questionnaire may not help in finding important clinical differences among patients. Dr. Rowe ended by recommending that researchers pay attention to these details for clinical trials on Long Covid as well.

Multisystem inflammatory syndrome in children. Dr. Adrienne Randolph, from Harvard Medical School, then spoke about recent research on multisystem inflammatory syndrome in children (MIS-C) relevant to designing upcoming clinical trials. Dr. Randolph’s colleagues at Boston Children’s Hospital recently showed that the genetic makeup of children helps determine whether the children recover from COVID or whether they develop MIS-C.

The researchers sequenced the genomes (in whole or the expressed parts) of over 400 patients with MIS-C, 400 patients with COVID, and 400 healthy participants. Comparing these sequences, the researchers found genetic variants that may explain why some children are predisposed to developing MIS-C. Thus, Dr. Randolph was happy that RECOVER researchers are sequencing genomes of patients with Long Covid as part of the RECOVER clinical trials—these data will probably show genetic variants that predispose patients (both adults and children) to developing Long Covid, as was done for MIS-C.

Dr. Randolph also spoke about own her landmark study, which she published last month in the prestigious journal Nature, showing how children can develop autoimmune disorders after being infected by the SARS-CoV-2 virus. She found that for many patients with MIS-C, the immune system generates antibodies that bind not only the viral nucleocapid protein (which packages the viral genome), but also a human protein called SNX8 (which regulates one of the body’s antiviral pathways); thus, we may effectively treat patients with MIS-C by using drugs that modulate the immune system. Future clinical trials should test whether a similar autoimmune reaction contributes to Long Covid or other post-viral inflammatory diseases, recommended Dr. Randolph. 

Panel discussion—How do we use all this information to better design Long Covid clinical trials?

At the end of the first day, participants asked how we may use the information discussed so far (about observational studies, pathobiological research, ME/CFS studies, POTS studies, and MIS-C studies) to better design upcoming clinical trials on Long Covid.

One of the main points from this discussion was to use what we’ve learned about other infection-associated chronic conditions. First, clinical trials should focus on and measure post-exertional malaise—one of the main symptoms of both Long Covid and ME/CFS. Particularly useful for this will be methods developed over many decades in studies on ME/CFS (for example, the FUNCAP questionnaire for measuring functional ability). But, as Dr. Rowe pointed out, clinical trials should not rely on well-worn measures like questionnaires but also use newer, more appropriate tests whenever possible (like exercise challenges, a follow-up tilt-table test for post-exertional malaise, and a soon-to-be-introduced test by Illumina to measure blood flow in the brain).

Clinical trials on Long Covid should also include patients with ME/CFS, Gulf War illness, and other infection-associated chronic conditions since these diseases often look the same (especially regarding post-exertional malaise and brain fog). Clinical trials should measure the key variables that researchers think are important (like blood flow in the brain, as Dr. VanElzakker showed) and collect samples from all patients in a standardized way to compare results more fairly.

For the best chance at detecting intervention effects, trials should distinguish between patients with mild symptoms and those with severe ones; and between patients with recently developed symptoms and those with long-standing ones (as Dr. Rowe does for patients with POTS). Clinical trials must especially focus on finding solid biomarkers, which would cast how we treat patients with Long Covid in a new light. 

Participants also summarized the need to better engage pharmaceutical companies. We should launch many small clinical trials to get proof-of-concept data on biomarkers and new interventions; these would give pharmaceutical companies better foundations on which to build. And the NIH should set aside more funding for Long Covid, as it did for COVID or for AIDS. Dr. Marrazzo was hopeful after the day’s discussion, thinking the proceedings were already laying a solid roadmap for clinical trials ahead.