On July 9, the Patient-Led Research Collaborative (PLRC) hosted an online presentation by researchers funded by the inaugural Patient-led Research Fund (PLRF). Ms. Gina Assaf, one of the PLRC founders, started the afternoon by reviewing how the PLRC began and the PLRC’s overarching goals.
In April 2020, Gina explained, a group of people from countries all around the world and from diverse professional backgrounds banded together to document their experiences having Long COVID. This informal group grew into the PLRC, whose mission is to represent people with Long COVID and other infection-associated chronic conditions through research in which patients help conduct, through medical education, and through advocacy grounded in patients’ firsthand experiences. Even today, each PLRC team member is a patient with Long COVID or Long COVID–related condition.
Two years later, the PLRC decided to set up a research fund (the PLRF) led completely by patients. Their goal was to spur Long COVID research to substantially involve patients and to represent patients’ perspectives in meaningful ways. The PLRC team and patient volunteers raised money for the fund, reviewed submissions to choose winning projects, helped selected researchers to design projects, and helped share project results.
These PLRF-funded researchers and several patient representatives (who worked closely with researchers on some of these projects) then presented what they had discovered and to answer questions:
Researchers
- Braeden Charlton, Vrije Universiteit Amsterdam (Unraveling the pathophysiology of post-exertional malaise in Long COVID and ME/CFS)
- Caroline Dalton, Sheffield Hallam University (Understanding the relationship between fibrin amyloid microclots and Long COVID)
- David Esteban, Vassar College (Microbial metabolites as disease-modifying factors in Long COVID)
- Roshan Kumar, HiFiBio Therapeutics (Immune repertoire profiling of ME/CFS and Long COVID patients)
- Alain Moreau, Université de Montréal (Multi-omic approaches to solve post-acute COVID-19/SARS-CoV-2 Syndrome—MOSAICS)
- Janet Mullington, Harvard Medical School (Characterizing non-restorative sleep in post-viral disease to advance intervention innovations)
- Michael Peluso, University of California, San Fransico (An exploratory, randomized, double-blind placebo-controlled study to assess the safety of an anti–SARS-CoV-2 monoclonal antibody)
- Liisa Selin, University of Massachusetts (Altered T-cell responses in Long COVID and ME/CFS)
- Per Sjogren, Bragee ME Clinic, Stockholm (A pre- and postoperative study of patients with ME/CFS operated for foraminal stenosis)
- Wenzhong Xiao, Massachusetts General Hospital (Systems biology approaches to uncovering disease mechanism and drug repurposing for Long COVID)
Patient representatives
- Tess Falor (collaborating with Dr. Sjogren and Dr. Esteban)
- Megan Fitzgerald (collaborating with Dr. Esteban and Dr. Selin)
- Michael Natt (collaborating with Dr. Dalton)
- Anisha Sekar (collaborating with Dr. Peluso)
- Letícia Soares (collaborating with Dr. Mullington)
- Chimére Sweeny (collaborating with Dr. Xiao)
- Becky Taurog (collaborating with Dr. Xiao)
Watch a recording of the event here, and read the transcript here.
PLRC Vision: “…a world in which all people with Long COVID and associated conditions receive high quality care that improves their quality of life, and where research into Long COVID and associated conditions is equitable, patient-centered, efficient, and transformative.”
PLRC Mission: “…to improve the breadth, depth, and speed of global research into Long COVID and associated conditions, and to advocate for policies that improve the quality of life for Long COVID patients worldwide.”
PLRC Priorities:
- Fast Funding
- Integrated patient participation
- Open-science values
- Patient-decided research
Hannah Davis, one of the PLRC founders, then spoke more about how the PLRC created the PLRF. In only eight months, the team raised $5 million for research and assembled 15 reviewers to choose projects to fund. Reviewers were not only experts in relevant fields (like immunology, infectious diseases, neuroscience, and statistics) but also themselves patients with Long COVID or other infection-associated chronic illnesses.
The reviewers prioritized projects on topics that were most important to patients but were insufficiently studied. These included diagnostics and biomarkers, pathophysiological mechanisms, ways to repurpose drugs to help people with Long COVID (and related diseases), and clinical trials and treatments. The reviewers also prioritized projects that were well designed to ask important questions; that were performed on infection-onset illnesses; that engaged patients and planned to include patients in designing and conducting the work; that applied to diverse groups of patients worldwide; and that compared diverse infection-associated chronic conditions. And because most Long COVID studies at the time relied on surveys or only cataloged symptoms or calculated prevalence, reviewers instead prioritized more ambitious projects. Ultimately, the reviewers selected ten projects, which were presented that afternoon.
“As a patient organization comprised of people living with Long COVID and related conditions, we’re at a critical juncture. We are aiming to raise substantial funds to continue our work. We have a range of projects that require funding. We’re hoping to run PLRC again if we can raise at least $2 million. So please consider donating today and sharing our fund funding page with your network.” — Hannah Davis
Ms. Davis said that if the PLRC could raise another $2 million, they could fund another set of critical projects in the coming year. These would include critical projects on more clinical trials; coordinating endpoints for clinical trials; finding and validating biomarkers and diagnostics; advancing areas of research most important to patients; improving and sharing the PLRC’s data repositories; fostering cross-disciplinary research; enrolling more patients into the PLRC registry; and analyzing data to repurpose drugs.
Skeletal Muscle Abnormalities in Long COVID and ME/CFS: The argument against deconditioning
The first researcher to speak was Mr. Braeden Charlton, a doctoral candidate in the laboratory of Dr. Rob Wust, professor of physiology at Vrije Universiteit Amsterdam (Amsterdam, Netherlands) and Solve Ramsay Awardee. Mr. Charlton and his colleagues are researching how much muscle changes in people with Long COVID or ME/CFS are like the changes in people who experience deconditioning (physical deterioration caused by physical inactivity). The research team compared muscle tissues and exercise performance among people with Long COVID, people with ME/CFS, and people who took part in an earlier deconditioning study (conducted by the European Space Agency).
In that earlier study, participants remained head down in bed for two months straight to induce deconditioning. Unsurprisingly, Mr. Charlton’s team found that people in all three groups had less physical endurance than healthy people. But people with either Long COVID or ME/CFS differed in critical ways from people experiencing deconditioning.
The muscles of people experiencing deconditioning wasted away, but the muscles of people with Long COVID or ME/CFS did not. Even though people with ME/CFS retained muscle mass, their retained muscles had fewer capillaries (to bring in oxygen and nutrients and to remove waste). And the hearts of people with either Long COVID or ME/CFS had to pump significantly faster than did the hearts of people who experienced deconditioning to supply muscles with the same amount of oxygen.
Finally, while people experiencing deconditioning had significantly fewer muscle mitochondria, the retained mitochondria in people with either disease functioned significantly worse. Overall, these results are compelling evidence that Long COVID and ME/CFS damage muscles and impact ability to exercise in a way that cannot be explained by mere physical inactivity. Instead, these diseases fundamentally change how muscles work.
Understanding the relationship between fibrin amyloid microclots and Long COVID
Next, Dr. Caroline Dalton, professor of neuroscience and genetics at Sheffield Hallam University (United Kingdom), spoke about using plasma levels of microclots—aggregates comprising the human protein fibrinogen and the SARS-CoV-2 protein Spike—as an biomarker of Long COVID. Fibrinogen aggregates naturally (for example, to help stop bleeding by forming blood clots), but when fibrinogen aggregates alongside Spike protein, the ensuing microclots become harder to break down. And microclot levels in people with Long COVID are higher than those in healthy people, suggesting these levels could be useful for diagnosing Long COVID.
Dr. Dalton’s team developed a microscope-based assay to measure microclot levels in blood-plasma samples quickly and accurately. Then, they analyzed samples from people recently infected by SARS-CoV-2; people infected by SARS-CoV-2 but who recovered with no Long COVID symptoms; people with Long COVID; people with ME/CFS; people recently vaccinated (for example, with mRNA to express Spike protein); and people never infected by SARS-CoV-2. Microclot concentrations in people recently infected by the virus and in those with Long COVID were significantly higher than in people never infected and in those who recovered from infection with no Long COVID symptoms. Microclot concentrations were as high in people with ME/CFS as in people with Long COVID. And microclot concentrations in vaccinated people were significantly higher than in people with Long COVID.
These results suggested that high microclot concentration is not specific to Long COVID, since any exposure to Spike (whether from recent SARS-CoV-2 infection, persisting infection, or vaccination) may increase microclot levels. Also, inflammation (the body’s response to infection or injury) may raise microclot concentrations, as may be the case for people with ME/CFS. For half of the people with Long COVID, microclot levels were the same as in people never infected by SARS-CoV-2, suggesting that microclot levels would not identify many people with this disease. (Furthermore, microclot concentrations do not necessarily correlate with symptom severity—some people have severe Long COVID symptoms but low concentrations of microclots; others have no symptoms but high concentrations. And drugs that reduce microclot concentrations do not necessarily reduce symptoms.)
“From this first experience with patient involvement, I now have a good idea what it should look like. It doesn’t always look as good as this. I know that because I’ve been involved in lots of other projects now, which haven’t done it quite as well. But [this experience] has helped me inform those [other projects]. For example, one of the tools that I take to those groups is the PLRC scorecards. They’re very useful if you’re trying to convince a research group that their research culture around patient involvement could be improved.” — Michael Natt, Patient Representative with Dr. Dalton
The research team is next studying whether microclots in people with Long COVID significantly differ from microclots in other people. For example, microclots in people with Long COVID may have specific proteins not found in microclots from other people. Alternatively, considering both microclot levels and some other marker (or panel of markers) may be more diagnostically effective than considering microclot levels alone.
Altered T-cell responses in Long COVID and ME/CFS
Dr. Liisa Selin, professor of pathology at the University of Massachusetts Medical School, is a prominent ME/CFS and Long COVID scientist who for five decades has overcome severe ME/CFS to conduct world-class research on these diseases. She presented results from her PLRC-funded project about how ME/CFS and Long COVID affect T cells (an immune-cell type) and about T cell–related biomarkers and treatments. Specifically, Dr. Selin focused on CD4+ T cells (which release chemicals that tell other immune cells how to respond to infections); CD8+ T cells (which attack infected or malignant cells); and dual CD4+/CD8+ T cells (which are not well understood but which increase in number after infections and which in some ways behave like both CD4+ and CD8+ cells).
Dr. Selin’s team found that people with ME/CFS or Long COVID have fewer CD8+ T cells, and the ones they have are usually overstimulated and exhausted. But treating patients with inspiritol (an experimental nebulized drug being tested to reduce inflammation and to inhibit viruses and bacteria) helped these T cells behave normally and significantly reduced symptoms. Most patients with ME/CFS also had significantly more double-positive T cells than healthy people (as is the case for patients after other types of infection). The double-positive T cells released a cytokine called interleukin-9, which boosts functions of the diminished CD8+ T cells. And symptoms were less severe in patients with more double-positive T cells than in patients with fewer double-positive cells.
Solve awarded Dr. Selin a Ramsay Research Grant in 2019 to fund this work and awarded both Dr. Selin and Dr. Kumar (who presented later) further funds to collaborate on this project moving forward.
“It was really inspiring to me to see how much her own experience has informed her research—not only the PLRC-funded work, but also the work that she’s done for decades before this. Before, I had a PhD and I was conducting searching on a high level. One of the big things psychologically for me was that I was afraid that this would be the end of my research career. But then I got paired with [Liisa], and it was so inspiring to see all of the work that she’s done for so many of us.” — Megan Fitzgerald, PhD, Patient Representative with Dr. Selin
Microbial metabolites as disease-modifying factors in Long COVID
Dr. David Esteban, professor at Vassar College and Solve Ramsay Awardee, presented his Solve-funded work on how gut microbes in people with ME/CFS differ from those in healthy people, and how these differences relate to symptoms and possible treatments. Gut microbes make many metabolites that may travel to other tissues, like the brain, to regulate diverse physiological functions. Dr. Estaban’s team found gut-microbe populations in people with ME/CFS are less diverse than those in healthy people and include distinct types of microorganisms.
In people with ME/CFS, the changed gut-microbe populations made more metabolites activating the aryl hydrocarbon receptor transcription factor. Many tissues (not only gut tissues, but also brain tissues, immune cells, and other tissues) have the aryl hydrocarbon receptor transcription factor. When these metabolites travel from the gut to these distal tissues, they activate the aryl hydrocarbon receptor transcription factor in ways relevant to ME/CFS symptoms—for example, to regulate inflammation, passage of material across the gut wall into the body, development of immune cells, and brain activity. The aryl hydrocarbon receptor was more active in patients with ME/CFS cognitive symptoms than in healthy people.
Overall, this work shows that the changed gut microbiomes in people with ME/CFS produce metabolites that activate the aryl hydrocarbon receptor in diverse tissues, and that this activation correlates with poor cognition. This is important because we already have drugs that repress the aryl hydrocarbon receptor; so, these drugs may reduce cognitive symptoms in people with ME/CFS. Dr. Esteban especially thanked Solve for access to the Solve Together Patient Registry, for help recruiting patients, and for money to do this work.
“Vassar is an undergraduate liberal arts college, so I do not have grad students or postdocs. All the work here is all either done by myself directly or an undergraduate student. And one of the real benefits of doing this work at a place like Vassar is that these students go on to be doctors or researchers or other health professions; and hopefully having gone through research in my lab, they have a better understanding of the importance of really understanding diseases like ME and Long COVID.” — Dr. David Esteban
Nothing for us without us: Aligning research funding with patient priorities
Dr. Megan Fitzgerald, a member of the PLRC and a patient representative for several PLRF-funded projects, spoke about the importance of patient input in researching Long COVID. Dr. Fitzgerald recounted how early in the pandemic, the PLRC started as a group of people with severe, lasting symptoms of COVID who were communicating on Slack, just trying to survive.
At the time, the Long COVID research being done substantially differed from the Long COVID research that patients wanted. Researchers focused on less impactful projects, like those on cognitive behavioral therapy or graded exercise therapy (which can sometimes harm patients instead of helping them), instead of impactful projects, like those on disease pathobiology or clinical trials of curative treatments. Also, researchers fixated on patients hospitalized for COVID and passed over the great many patients who developed chronic symptoms after having mild acute symptoms.
Dr. Fitzgerald and other biomedical researcher-patient advocates were instrumental in changing the game. They pushed researchers to do more of the kind of work that patients wanted. They fought for studies to include people from marginalized communities and people with clear Long COVID symptoms but no positive SARS-CoV-2–test results on hand. They called for more attention to critical but poorly understood symptoms, like post-exertional malaise. And they leveraged their dual stations as researchers and patients to help design studies better.
Dr. Fitzgerald and other patient/researcher advocates were integral to better studying Long COVID and treating patients. For example, patients with both Long COVID and dysautonomia may perform worse on cognitive tests if these patients take the tests while physically positioned in ways that exasperate symptoms of dysautonomia. And patients with Long COVID may be excluded from studies (or misassigned to COVID-negative control groups) if those patients test negative for COVID, even though the tests may have been given weeks or months after their initial infections. Having experienced these challenges (as patients) and understanding how they affected research studies (as scientists), Dr. Fitzgerald and her colleagues were uniquely suited to advocate for the necessary changes.
They also challenged doctors to no longer think of Long COVID as a mainly psychological condition. Dr. Fitzgerald was proud of how the PLRC is creating a “virtuous cycle” of Long COVID research. The team is breaking the cycle of funding less important work leading to more of these same old studies; and igniting a cycle of funding more important work leading to better treatments and quality of life.
Immune repertoire profiling of ME/CFS and Long COVID patients
Dr. Roshan Kumar, head of research at HiFiBio Therapeutics, later presenting his work done in collaboration with Dr. Selin. While Dr. Selin’s team is focused on using functional assays to understand how ME/CFS and Long COVID affect populations of T cells, Dr. Kumar’s team is focused on studying how these diseases affect individual T cells.
By studying cells one by one, the team is learning critical details about the antigens that provoke ME/CFS or Long COVID and is developing more effective biomarkers and diagnostic assays. Like Dr. Selin, Dr. Kumar has long been personally affected by ME/CFS.
“I’ve been a caregiver as well for my wife who has had ME/CFS for many years. And one of the most frustrating things was going to all these doctors and—as many of you might have experienced—getting many test results back that are basically normal. And wondering How can someone so sick have all these normal test results? But these are the sorts of processes that can be happening basically under the hood. You can test for them in [a specialized] laboratory, but we don’t really have clinical tests for them right now. So being able to understand these responses at a high resolution is critical to developing biomarkers for these diseases”.—Dr. Roshan Kumar
Dr. Kumar’s team found that in some patients with ME/CFS or Long COVID, continually present antigens chronically activate T cells to clonally expand (make more copies of themselves), eventually exhausting the T cells. Interestingly, the exhausted T cells recognize antigens by using a specific protein (a specific T-cell receptor) that is associated with Multisystem Inflammatory Syndrome in Children and with more inflammatory COVID.
Next, Dr. Kumar’s team will sequence the T-cell receptors of individual, clonally expanded T cells to find which antigens continually provoke T cells in patients. This information will help reveal the mechanisms of ME/CFS and Long COVID and will uncover biomarkers to better classify patients.
A pre- and postoperative study of patients with ME/CFS operated for foraminal stenosis
Dr. Per Sjogren (Braggee Myalgic Encephalomyelitis Clinic, Sweden) and Dr. Bo Bertilson (Karolinska Institutet, Sweden) then presented their study on how cervical spine operations can relieve symptoms of ME/CFS. Patient groups have long known that often people with ME/CFS have structural problems with their spinal columns. Earlier, Dr. Bertilson’s team found that of over 200 people with ME/CFS, 80% had craniocervical obstructions and half had intracranial hypertension. This suggested that problems with spinal structures can impede flow of the cerebrospinal fluid and increase intracranial pressure to drive ME/CFS symptoms.
To test this hypothesis, the team examined how spinal surgery (specifically, surgery to address foraminal stenosis, which is when a narrowed spine compresses the spinal nerves) relieved ME/CFS symptoms in two patients.
The first patient said the surgery completely changed her life, even from day one (right after waking up from anesthesia). She could do things she hadn’t done in 40 years, like walking and working in her garden without getting tired, and she no longer had post-exertional malaise. The time she spent in deep sleep increased by half; the number of steps she took each day doubled; and the time spent reclined decreased by half. She could think more clearly and felt more sociable and alive. Although spinal surgery helped the second patient much less than it helped the first, the second patient was also happy with the outcome, and she wished she had done it long ago. Most important was how much better her brain functioned. Neither patient had surgical complications.
The research team is now searching for more participants to continue this study. They especially want to recruit patients with ME/CFS with spinal stenosis, which blocks flow of cerebrospinal fluid more directly than does foraminal stenosis. However, the team is struggling to recruit the right patients and to convince review boards this treatment is safe for people with ME/CFS. Indeed, people with ME/CFS who seek surgery to correct structural problems can be refused because of their ME/CFS condition. Dr. Bertilson especially thanked Dr. Jonas Bergquist, his collaborator at Uppsala University (Sweden) and a Solve Ramsay Awardee.
(“Why is it relevant to study structural spinal conditions after infections?”)
“How long do I have? This is something I’m very passionate about. It’s a good example of a gap between patient anecdotes and what patients want to have researched and what is being done and being funding. [Many patients said they] improved from surgery or non-surgical treatments from multiple different structural abnormalities. I’m one of them. I have many of these different conditions. So, again, this is just so important to study, and it’s not being funded, and there’s so much we don’t know.” — Ms. Tess Falor, Patient Representative with Dr. Sjogren
Systems biology approaches to uncovering disease mechanism and drug repurposing for Long COVID
Dr. Wenzhong Xiao, from Harvard, then discussed how his research team analyzes large datasets to overcome unique challenges in finding treatments for people with ME/CFS or Long COVID. For example, unlike the case for most prominent diseases, we have neither well-established animal models nor extensive clinical trial datasets available to study ME/CFS and Long COVID.
So, Dr. Xiao’s team is finding other ways to get the vital information normally obtained with animal models and clinical trials. For example, his team compared ME/CFS and Long COVID datasets with other disease datasets to find which drugs can be repurposed to help people with ME/CFS or Long COVID. (Researchers normally get this information from animal model experiments and clinical trials.) They found several genes dysregulated in ME/CFS and Long COVID are also dysregulated in diseases like arthritis, diabetes, obesity, and schizophrenia. These genes relate to the central nervous system, the immune system and inflammation, and metabolism.
Now, the team is collaborating with doctors and pharmaceutical companies to test whether we can help people with ME/CFS or Long COVID by repurposing drugs targeting these systems in these other diseases. For example, the team found that people with ME/CFS or Long COVID often poorly metabolize amino acids; thus, drugs that target amino-acid metabolic pathways in patients with other diseases may also help people with ME/CFS or Long COVID. In another effort, the team is using survey data (from ~4,000 people with ME/CFS or Long COVID) to understand which drugs (of ~150 ones surveyed) work best for relieving which symptoms. In this way, the team is using people’s real-world experience to find which drug candidates to prioritize (information normally obtained through clinical trials).
“As a teacher and educator who likes to educate Black folks [with Long COVID and disabling conditions] on how to advocate for themselves, [Wenzhong’s results] are something that I would bring back to my educational cohorts. Because most of the time, if you have a fear of the hospital or a fear of medical treatment for one reason or another, most of the time it’s because I’ve been racialized so much. And for many of the people like me, it is very comforting to know that there have already been drugs that are placed on the market that your doctor can say, “Well this drug will work in addition to this [other one], for to your condition most of the time.” I felt like I could trust my doctor. My current doctor at Mount Sinai—she’ll say to me, “Chimére, this has been proven to do these four things. would you like to try it?” And it’s that precise medical care and questions that Wenzhong just talked about that that makes me more trusting of her expertise.
I know that if I were to go back to people that I educate, I’d be able to say, “This [drug] is used for this. That [other drug] is used for this [other purpose]. And it makes it so much easier and so much more likely that they will actually go to their doctors and say, “How about we try this versus this?” That gives those kinds of patients an opportunity to feel like they’re partnering with their doctor. Versus feeling like they are just being told to take this [drug] without any information.” — Ms. Chimére Sweeny, Patient Representative with Dr. Xiao
Multi-omic approaches to solve post-acute COVID-19/SARS-CoV-2 Syndrome—MOSAICS
Dr. Alain Moreau, professor of biochemistry at the Université de Montréal (Canada), discussed using epigenetic biomarkers to classify subgroups of people with distinct combinations of Long COVID symptoms, ME/CFS symptoms, and fibromyalgia symptoms and to predict which patients would eventually recover and which would not. His team examined RNA and DNA biomarkers in cells from blood and saliva.
First, they measured levels of 11 microRNAs, which are small RNAs that regulate expression of genes. (Earlier, the team found that levels of specific microRNAs were extremely useful for diagnosing people with ME/CFS, so they hypothesized microRNA levels could diagnose people with Long COVID too.) Second, they measured methylation patterns in cellular DNA. The team collected samples at the start of the study, when a great many patients had the same symptoms and the same severity of symptoms. Even though the patients seemed the same, the team could predict which ones eventually recovered and which would not based on the RNA and DNA biomarkers. Interestingly, infections by distinct viruses affected the same microRNAs, or affected microRNAs that perform similar functions, possibly explaining why infection by diverse viruses (like SARS-CoV-2 and Epstein Barr Virus) can lead to the same chronic symptoms (like those of Long COVID and ME/CFS).
The team also found that at the first visit, the people who eventually improved expressed more of a key gene (called “gene X” until the team can verify these results), while people who would not eventually improve expressed normal levels. Thus, expressing gene X early on may be critical for setting a person on the road to recovery. Dr. Moreau is now testing whether treating people with drugs that boost gene X levels helps people recover from symptoms. Dr. Moreau especially thanked his collaborator Dr. Dawei Li, professor of immunology at Texas Tech University Health Sciences Center and Solve Ramsay Grant Awardee.
Characterizing non-restorative sleep in post-viral disease to advance intervention innovations
Dr. Janet Mullington, professor of neurology at Harvard Medical School, presented her work on problems that people with ME/CFS or Long COVID have with sleep. About one in three patients with Long COVID report having disturbed sleep, like trouble falling or staying asleep, trouble acting out while dreaming, trouble breathing while asleep, and irregular sleep schedules. And the risk of developing Long COVID for people with pre-existing sleep problems is higher than for people without such problems.
Dr. Mullington’s team found that people with Long COVID take longer to sleep, take longer to enter REM sleep (which may be important for cognition and mood), and have less REM sleep. They often have less “rebound” sleep—nights of good sleep after nights of poor sleep—which is essential for recovering from poor sleep. People with Long COVID also have lower blood oxygen levels and higher heart rates while sleeping.
Interestingly, brain activity during sleep for people with Long COVID or ME/CFS differs from that for healthy people, particularly activity related to deep, restorative sleep. The research team is now looking at how these diseases affect levels of sleep-related chemicals, like orexin (a marker of narcolepsy), cortisol, and melatonin. Considering their early results, Dr. Mullington thinks these analyses will yield neuroelectric and molecular biomarkers of Long COVID– and ME/CFS–related sleep symptoms.
Monoclonal antibodies in Long COVID outSMART-LC results and what we need to do next
Dr. Michael Peluso, from the University of California, San Fransico, presented results from the outsmart-LC clinical trial. This was the first placebo-controlled, randomized clinical trial to test whether a SARS-CoV-2–specific monoclonal antibody is safe and whether it reduces symptoms of Long COVID. The idea behind this trial was that the SARS-CoV-2 strains that originally infected people (up until fall of 2022) were persisting in some people and causing Long COVID; thus, a monoclonal antibody targeting these strains could reduce symptoms by clearing the persisting viral strains.
The research team gave two dozen patients the monoclonal antibody and gave a dozen patients placebo. Then, the team tracked adverse events, physical health, cognition, autonomic function, and levels of diverse biomarkers. For some patients, the team also collected gut samples and administered more extensive tests (like exercise and imaging tests). They found the monoclonal antibody was safe, but that it significantly improved no symptoms and affected no biomarkers.
Despite these negative results, Dr. Peluso thinks persisting SARS-CoV-2 drives chronic symptoms for many people with Long COVID. He thinks the team may have seen more effects if they had given more than one dose of the monoclonal antibody to patients ; included more patients whose disease was driven by persisting virus (instead of by other mechanisms); or had combined monoclonal antibody with other treatments (like other antiviral or immune-modulating drugs).
He recommended that future studies address these possibilities, and especially that future studies identify and recruit people for whom persisting virus probably drives Long COVID disease (which he estimates may be a third of patients). Dr. Peluso’s team is now analyzing these samples more thoroughly to determine whether the monoclonal antibody treatment affected persisting virus, immune dysfunction, or inflammation.
Advancing Long COVID research: The power of patient-centered science and patient-driven funding
To end the afternoon’s presentation, Dr. Julia Moore Vogel, director at the Scripps Research Institute and patient with Long COVID, led a discussion among panelists Dr. Liisa Selin, Dr. Roshan Kumar, Dr. Janet Mullington, Ms. Anisha Sekar, and Ms. Hannah Davis.
Dr. Vogel: What do you want future funders or institutions to know about your role in this process and how they could learn from this collaboration or build on it?
Ms. Anisha Sekar: That involving patients end-to-end is crucial. If patients help set the research question and design the study, then usually the study focuses more on the big, important questions that will lead to treatments. Involving patients early also ensures that studies stay on track to pursue these fundamental questions.
Dr. Liisa Selin: Patients who participate in her group meetings keep her team focused and give her team huge advantages by advocating for the team and helping recruit patients for studies. Also, the grant-review process for the PLRC is more open-minded than for other funders. Other funders may not have liked the fact that Dr. Selin proposed work that substantially differed from her earlier work—but the PLRC funded her.
“As you can imagine, after 50 years of [living with] ME/CFS and I’m still here fighting—I realize I am a glass half full person, or I wouldn’t be here.” — Dr. Liisa Selin
Dr. Janet Mullington: The PLRC patient group published excellent work, including work reporting sleep-related symptoms and experiences, which were incredibly valuable to her research team. For example, the PLRC reported how patients can act out of behavior while asleep and can have lucid dreams. These unique insights (obtainable no other way) are what led her to think ME/CFS and Long COVID affect REM sleep.
Dr. Kumar: PLRC funds exceptional research. Considering that PLRC gave $5 million to these groups for the research presented today—that was a fantastic return on investment. Also, applying for grants through the PLRC was much smoother and more transparent than applying through other funders. And the PLRC review board values researchers’ individual experiences with these diseases, like his wife having had ME/CFS for many years. Traditional funders would not value researchers’ firsthand experiences and perspectives.
Moving forward, the PLRC model could be exceptionally helpful for launching studies that would otherwise struggle to win grants from traditional funders. These pioneer studies could generate precious preliminary data, which could later launch more traditional studies.
Question: Must we treat antivirals and immune modulators concurrently?
Dr. Selin: Absolutely. We must attack the disease on three levels: by modulating the immune system, by suppressing viral infections, and by supporting metabolism. Focusing on viral infection may be a distraction because although a virus may start the disease, it needn’t be what drives persisting symptoms.
Question: Where will the Long COVID field be in five years?
Hannah Davis: So many people have Long COVID. Long COVID rates are already higher than diabetes rates. That means more researchers will study Long COVID. In five years, we will probably have solid diagnostics and biomarkers; then, we will have treatments.
Ms. Anisha Sekar: We will have better vocabulary to use for discussing Long COVID. We will be able to describe different presentations of Long COVID and discuss how Long COVID relates to other conditions.
Dr. Janet Mullington: We will be able to apply machine learning to crunch the immense data now available. This will finally let us treat patients on a case-by-case basis—to tailor treatments to individual needs.
Attendee Q&A
Question: The internet abounds with interviews with people who have recovered from Long COVID. How can these people’s stories be analyzed and categorized into groupings/sub-groupings so their recoveries can be made scientifically useful, and then possibly applied to the right populations? Is it possible to create a scientific retrospective analysis of recovery stories that could be objectively useful for the greater public?
Letícia Soares, PLRC 01:41 PM
That’s a good point, we know and understand very little about what LC recovery looks like, and what it means when considering reinfections. Documenting these as you suggested could be a way to document hows and whys. PLRC recently launched a registry in which we embedded a research study to look into Long COVID trajectories over time. Since we ask about relevant IACC subgroups there, we hope to be able to understand the disease over time a bit better, which includes remission/recovery.
Hannah Davis 01:42 PM
This is a good question! analyzing recoveries is very hard for several reasons – here is a lot of recovery in the first six months and even first few years, but little recovery as time goes on – likelihood of recovery is different not only between demographics and phenotype, but also ability to rest and access care, and various drugs and supplements people take may factor in – so datasets on it are hard to create. We would love to do a project like this if we could find a solid dataset and funding for analysis! And we do put out case series on collected stories on particular treatments (like our recent extended Paxlovid paper).
Question: You said specifically several times that your research collaborative is ONLY for patients with this so-called “infection-associated conditions”. Do the 40% of patients with non-infectious onset ME/CFS have to create their own research collaborative to get research and funding even though they are clinically identical? What rationale was included in your decision-making process for excluding them?
Lúcia 01:16 PM
Thank you for your question. Our focus is on Long COVID, other comorbid conditions, and other infection-associated conditions. Non-infectious onset ME cases are certainly not excluded, and we fervently hope that insights and treatments will be impactful for people with non-infectious onset ME.
Question: Does PLRC also fund social scientific studies (say, in sociology or anthropology) about LC and other infection-associated chronic illnesses?
This seems particularly important for attempting to make sense of the vast amount of patient stories that exist online, as well as for developing analyses of the systemic failures that continue to make it difficult for people with LC to achieve recognition and access to care.
Letícia Soares, PLRC 01:15 PM
The Patient-Led Research Fund focused on biomedical research. However, PLRC is involved in qualitative studies that try to understand the experiences of people with Long COVID.
Hannah Davis 01:26 PM
You can see a full list of our studies here: https://patientresearchcovid19.com/publication/
Question: Other advocacy groups like OMF and Polybio use the term “Complex Chronic Conditions” in order to include those with non-infectious onset ME/CFS. This helps to not only include those patients, but prevent our research perspectives from being skewed thinking this pathology only happens with infections, prevent patients from self-trialing with dangerous experimental antivirals, allow us to have multiple pillars of research not just viral persistence, and move us closer to evidence-based diagnoses. Can you please join our other advocacy groups in being more encompassing and moving away from this IACC term?
Lúcia 01:28 PM
Speaking for myself: infectious-onset is a very interesting element for research, across multiple disease spaces. However, non-infectious ME should also be included as a patient cohort whenever possible. As you can imagine, cost is an important barrier to this. We hope to be able to continue to advocate for diverse cohorts in research (including non-infectious-onset ME).
Question: Thoughts on V-Nella or other probiotics to break down lactic acid in Long COVID patients?
Braeden Charlton 01:43 PM
Perhaps an unsatisfying answer, we unfortunately give lactic acid or lactate a bad name in exercise, however, it is a really important molecule in adapting to our environments. We unfortunately don’t fully understand what happens when lactate is chronically high or low either. That said, it may help temporarily alleviate some symptoms, but it’s something we really don’t understand fully at the moment.
Question: I’ve heard some reports where dextromethorphan has helped alleviate PEM in long covid patients, and conversely, some reports that it is pro-viral. What are your thoughts on dextromethorphan for alleviating PEM in long covid patients?
Prof. Alain Moreau 04:12 PM
Yes, it has been reported by many patients with ME. We have some ideas about the mechanism or target but this awaits validation.
Question: What drugs/supplements/therapeutics would you recommend to alleviate PEM and at what dose?
Hannah Davis 01:30 PM
We are working on a document of treatment guidance with an LC clinical care group that we will share later this summer!
Question: In patients with confirmed persistent microclots, are there any tests we should be doing to look for underlying drivers of the clotting such as genetic factors e.g. MTHFR, 4G / 5G?
Dr. Caroline Dalton 02:00 PM
MTHFR and 4G/5G polymorphisms are common, so although the risk alleles might be more common in patients they also have the same problem as a biomarker that they are not very specific. We are looking at other markers in the blood to try and see if combining a set of markers is more sensitive/specific.
Question: I’m a LC patient with confirmed microclots, and made improvements on triple anticoagulation therapy over a period of 15 months. I stopped it and quickly got worse, then on restarting a few weeks later never returned to previously high baseline. Any thoughts on what is driving persistent clotting in LC patients who have persistent improvement on triple anticoagulation therapy but deteriorated back to their previous baseline after stopping?
Question: Testing for microclots is hard to find. What is the best way to pursue this issue?
Dr. Caroline Dalton 02:02 PM
It’s quite a fussy assay, amyloid is hard to work with so it needs a specialist lab, looking out for research labs that are trying it out is the best way, you are unlikely to find a mainstream clinical lab with the expertise
Question: Hi. I have a neurological sleep disorder named Idiopathic Hypersomnia (IH) and in March 2020 my family and I got Covid. While my cousin passed away, my parents and I survived. However, my body didn’t develop antibodies until almost four months later. Meanwhile, I had all the symptoms. Not too long after I started developing weird symptoms that have labeled as part of Long COVID, but they haven’t given me another name for it, nor were more studies done. Unfortunately, I haven’t been able to find out more because there doesn’t seem to be more funding for Long COVID here so there are no doctors in my area who specializes in it.
That’s one part of it. Is there anything I can do to find out what I might have due to Long-Covid?
The second part, that I find fascinating, is that ever since Covid, more and more people have been diagnosed with IH and I believe there’s a correlation.
Hannah Davis 01:54 PM
Hi, I’m so sorry you’re dealing with this! For care, this is the most recent clinic list – https://docs.google.com/spreadsheets/d/1d0wd0obKUVUWQgCR5ZwX8TsvX1T3VbYC3anuOa09L94/htmlview#
If you have ME/CFS and dysautonomia, you can also see if there are providers in your area here : https://www.meaction.net/resources/find-your-doctor/
https://www.dysautonomiainternational.org/page.php?ID=14
Question: To clear persistent covid virus in LC patients, do we need both an antibody response and a T cell response, or would just one of these be sufficient for clearance?
Dr. Liisa Selin 02:45 PM
Generally for viruses you need both a T cell and antibody response. Cd8 T cell responses are particularly important to control persistent viruses that live in our body after the infection is over. There is evidence that COVID may persist.
Question: In long covid patients, could a CD4/CD8 ratio test influence treatment or would it be for interest only?
Rivka 02:21 PM
The Selin Lab hopes that their findings that show dysregulation in the immune system of ME and LC patients (e.g. T cell exhaustion and CD4/CD8 ratio findings) can be used to track treatment response. That is, is a patient responding to a treatment? They found that to be true in a few patients and published that as a retrospective case study: https://pmc.ncbi.nlm.nih.gov/articles/PMC10847863/
Question: Thank you so much for talking about this T-cell response! I’m covered in over 200 lesions/spots from my T-cells attacking me from the inside out. My T-cell specialist was stumped, so this research is clearly needed. Is this information available for me to share with him and my pcp? Again, thank you!
Rivka 02:02 PM
Here are some links that may give your T cell specialist and PCP to access more info on the Selin Lab’s work and in collaboration with Roshan Kumar’s HiFiBio lab:
Selin Lab: https://www.umassmed.edu/selinlab/
Solve M.E. Webinar “Investigating Immune Dysfunction & T-Cell Exhaustion Via Single Cell Immune Profiling in ME/CFS & Long Covid” with Dr. Selin, Dr. Gil, Roshan Kumar, Megan L. Fitzgerald, PhD, Rivka Solomon, and Emily Taylor: https://youtu.be/2DQZp48fyek
Question:
Why do the antioxidants have to be nebulized?
Lúcia 02:05 PM
Hello, nebulization can allow for targeted treatment of respiratory symptoms (in the lungs) as well as oxidative stress.
Rivka 02:17 PM
Many people take antioxidant supplements that are not nebulized. It is just that the Selin Lab’s retrospective study was with ME and LC folks who used a nebulized treatment called Inspiritol. More info here: https://inspiritol.com/ They are looking for funding for a larger clinical trial.
Dr. Liisa Selin 02:28 PM
Taking antioxidants nebulized is more efficient than even intravenous, so you get high concentrations with very low doses. So no side effects. It also gives better access to enter the brain and CNS. Some antioxidants such as GSH cannot be given orally as they are metabolized. Inspiritol also allows combining complementary 5 antioxidants that treat oxidative stress but also are antiviral.
Question:
It sounds like if a patient is a responder to Inspiritol does it follow that they likely would also be a jak stat inhibitor responder – is that a correct interpretation?
Dr. Liisa Selin 03:03 PM
No, not necessarily. It appears to be much more complex than that. There are many kinds of immumodulators. Inspiritol and JAKstat inhibitors are very different mechanistically. Studies need to be done to see what effect JAKstat inhibitors have on T cell responses.
Question:
Are you aware of Dr Shoon Siong treatment for T cells called Bioshield? It sounds like it could help L.C./ME. I think he is planning a trial for this summer. Has anyone reached out to him?
Rivka 02:44 PM
Liisa Selin says she is not familiar with this treatment and will look into it.
Question:
I am reminded of a presentation I attended years ago on the role of engaged patients. Worth a listen as it shows how this has been an issue for some time.
Question:
I have long covid can I be part of the research? I’m based in the north west of England.
Dr. Caroline Dalton 02:40 PM
email me c.f.dalton@shu.ac.uk if you think you can make it to Sheffield
Question:
I have had long covid for three years. In all that time, I have had difficulty finding and joining studies. I don’t have the energy or brain function to search regularly.
Megan 02:41 PM
It is difficult work and understandable that many will not be able to! Part of the role of every patient who is able to participate in research is to give a voice to those who are too unwell to do so. Please don’t hesitate to share your story in support groups, advocacy settings, etc., and those of us who are well enough will do our best to ensure that your experience is represented too.
Letícia Soares, PLRC 02:57 PM
Hi Helen, PLRC recently launched a registry with the coal to connect patients to studies they may be eligible for participating. https://patientresearchcovid19.com/plrc-registry/
Question:
I do not have the energy to sort through all the info to find and join studies. My doctors do not follow up on studies, even if they are aware of them. Can we create a registry of some kind that will help patients connect with studies? Possibly geographic or symptomatic? A clearinghouse of sorts.
Ezra 02:53 PM
The most comprehensive registry in the USA is ClinicalTrials.gov.
I (a PLRC member) also created the website https://longcovidstudies.net/ which uses the same data and allows you to filter Long COVID research studies and clinical trials by state or country.
Hannah Davis 02:55 PM
PLRC has also recently launched a registry we would love patients to join, which includes various studies – the link is https://mydatahelps.org/e/PLRCRG/Welcome
Question: Is PLRC connected with Long COVID families?
Hannah Davis 03:29 PM
Yes, several PLRC members also volunteer with Long COVID families!
Question:
@Hannah … Has there been an effort to locate/access blood samples taken from individuals pre-COVID (whether in the regular course of medical treatment or as part of clinical research) to identify changes in T cell composition/activation over time? (I’m thinking of the proteomics studies that have been done looking at dementia risk/organ aging using previously collected blood plasma to trace changes over time.)
Dr. Roshan Kumar 03:12 PM
I think it would be great if there were resources and samples available to be able to do longitudinal studies over the course of disease. One of the problems here, of course, is that we don’t usually have baseline data on patients before they were sick. I hope one day that will change. Immune monitoring has a lot of potential to be a powerful component of routine medical care if it can be simplified and scaled.
Megan 03:18 PM
The study design of RECOVER allowed for this. Hoping these samples will be made available to more researchers soon.
Question:
What other ways are there to contribute/participate to advance research and understanding?
Hannah Davis 03:29 PM
If you’re a patient, you can fill in this form to volunteer with PLRC https://forms.gle/Z9d1yEtxAajbGyfK9. We would also deeply appreciate sending the fundraiser to anyone interested and sending our menu of services to anyone researching Long COVID who may want to collaborate! https://patientresearchcovid19.com/plrc-advisory-services/
Question:
My own five-year LC experience demonstrates both a consistency of symptoms as well as changes of frequency and intensity. Hypothesizing T cell changes over time seems quite sensible. Very interesting work!
Dr. Liisa Selin 03:17 PM
Yes, I think it is important to have a T cell biomarker that we can track over time or after new treatments.
Question:
I’d love to have a copy of the slide with the various treatments and effectiveness of each treatment.
Dr. Wenzhong Xiao 03:40 PM
Thank you. The paper with the results of the survey is just published online:
Question:
As a drug developer, I was taught that patient-reported outcomes can be fraught with biases but are good exploratory endpoints while we work to figure out what the drug intervention does to the condition pathology under study.
My concern is that PROs alone don’t address the known pathophysiology to know what the drug is doing in that patient. To identify responders vs non-responders. What we know e.g. poor tissue diffusion/perfusion (low VO2 on CPET, DLCO, moxy-monitor. VBG0, T ex (per L. Selin and others), dysautonomia (skin bx/ AT testing), CBF velocity, abnormal cytokines, inflammatory marker, disrupted RAAS (aldosterone: renin), Ang2 … to name a few that we need to further understand.
Hannah Davis 03:41 PM
We’d love to hear more about what tests you’re interested in, if you’d like to email us at team@patientledresearch.com!
Dr. Wenzhong Xiao 03:54 PM
Yes, PROs alone are likely not sufficient for drug development. One of the goals of the study is also to help patients to see what are potentially helpful when they speak with their physicians. Results of the PROs need to connect with results of research studies as you outlined.
Just to add that we have identified a couple of candidates from the mechanisms and are supported by RWD. I’d be happy to discuss with you (wenzhong.xiao@mgh.harvard.edu)
The results of the survey are published here: Proc. Natl. Acad. Sci. U.S.A. 122 (28) e2426874122, 2025.
The results of the analysis of muscle biopsies are available at https://doi.org/10.3390/ijms26136082.
Question:
Dr. Danielle Beckman believes the neurological impact of covid will appear in, on average, 14 years after infection. Any comment?
Prof. Alain Moreau 04:02 PM
We can find such changes much sooner using our molecular tools.
Question:
Do you think potential treatments for long covid will work for me/cfs too?
Dr. Wenzhong Xiao 03:59 PM
Good question. The physicians on the zoom are more qualified than me to answer this.
In our study, we compared the patient-reported outcomes of Long COVID vs ME/CFS, and they seem to be very consistent (Figure 3).
Question:
Was Dr. Moreau saying a therapy could help prevent development of ME if given in acute phase, or treat ME once present?
Prof. Alain Moreau 03:58 PM
Yes, if we can act at the earliest stage possible, at least in the first 6 months post-infection or sooner, we could interrupt the cycle and preventing debilitating and permanent symptoms like those associated with ME/CFS.
Question:
Thank you for this amazing forum. I am new to this today and wonder if you would be able to provide me with some information about research in Toronto, Canada. I am a Nurse Practitioner who runs a support group for Long COVID participants- happy to send my email info.
Prof. Alain Moreau 04:01 PM
You can contact the environmental clinics at the Women’s health college hospital or ICanCME research network at info@icancme.ca
Question:
First off, thank you all for the wonderful presentations and all of the incredible research. There are plenty of presentations that use both LC and ME/CFS jointly. Would this be LC that follows the diagnostic criteria of the Canadian consensus criteria? Or does this include those with LC that do not meet these criteria?
Prof. Alain Moreau 04:11 PM
LC is not per se a new disease but rather a transitory stage illustrating a post-viral syndrome. Unfortunately, some individuals with LC will develop ME symptoms matching the Canadian Consensus Criteria, while other will develop something else. Of note, 30% of LC in our cohort slowly improved overtime without specific treatment. We need to study them more closely to fully understand the underlying mechanisms.
Question:
What are glucose levels like overnight?
Dr. Janet Mullington 04:27 PM
Glucose levels have a circadian rhythm and peak around waking.