This week, the U.S. National Institutes of Health (NIH) starts a new phase of RECOVER, its flagship, $1.6-billion Long COVID research program. RECOVER has convened leading scientists in a three-day meeting to advance new clinical trials.
Following the program’s launch in 2021, RECOVER has drawn criticism for moving slowly and failing to support promising clinical trials. Researchers and patient-advocates have said the NIH selected scientists without appropriate expertise to lead the program and did not meaningfully incorporate people with Long COVID and related diseases into its leadership.
The NIH has responded to this criticism with a new initiative called RECOVER-Treating Long COVID (RECOVER-TLC), which will support a new round of trials utilizing an additional $515 million in funding allocated to the program earlier this year. In an interview with The Sick Times last month, institute director Dr. Monica Bertagnolli said the new trials would build on prior research and incorporate ideas from scientists and advocates outside the existing RECOVER infrastructure.
RECOVER-TLC kicks off this week in Bethesda, Maryland with a meeting of leading researchers, clinicians, and people with Long COVID and related diseases. It includes presentations about pathobiology research and trials already underway, followed by discussion about how to design new trials and which potential treatments to test.
The Sick Times’ team is closely following the event virtually. Check this article and our social media pages throughout the three-day event to find our takeaways from the sessions.
— Betsy Ladyzhets
Closing statement from Dr. Jeanne Marrazzo
Wednesday, 12:00 PM: National Institute of Allergy and Infectious Diseases director, Dr. Jeanne Marrazzo, closed RECOVER-TLC with a presentation and summary of the past three days, offering steps of what the NIH will implement in the future based on what they’ve heard from from participants of the event.
She said they will use approaches from ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) to treat the problem of Long COVID with urgency and yield faster results.
She also said that patients will be included in all aspects of clinical trial conduct, “from review of the evidence to design and onward.” She also committed to ensuring that pediatric patients will be able to participate in Long COVID clinical trials.
“We are here to build on what RECOVER has already done,” Marrazzo said. She added that a summary of the event will be available in the near future.
— Miles Griffis
The path to the next patient-centered Long COVID trials
Wednesday, 11:30 AM: Over the past few days, people with Long COVID and patient-researchers have shared their thoughts and criticisms of RECOVER, including its failures to prioritize patient partnership. They’ve offered a wealth of ideas about how to improve research in presentations, panels, audience questions, and social media commentary.
Lisa McCorkell of the Patient-Led Research Collaborative presented a summary of the ways Long COVID clinical trials can treat patients as partners, and thus improve Long COVID research.
“They should reflect the urgency and collaboration of ACTIV and meaningful patient engagement of HIV/AIDS Clinical Trials Network,” McCorkell said, explaining a need for interventions that are both curative and accessible to patients, including new and repurposed drugs. In designing trials, McCorkell recommended using disability justice principles as well as measuring for post-exertionnal malaise. “We [patients] can’t ignore it, neither can you.”
McCorkell gathered many other recommendations and cited a recent Life Sciences paper, “Designing and optimizing clinical trials for Long COVID,” that she co-authored in August.
A panel discussion followed with McCorkell, Dr. Laurie Gutmann of Indiana University School of Medicine, Dr. Clint Wright of National Institute of Neurological Disorders and Stroke, Dr. Yves Rosenberg of the National Heart, Lung, and Blood Institute, and Dr. Eldrin Lewis of Stanford Universty School of Medicine.
Many commenters focused on the role of patient navigators, or people who help manage and center patients throughout the entire clinical trial process. As one person with Long COVID said, “These should be required.”
— Miles Griffis
Regulatory perspectives on Long COVID treatments
Wednesday, 10:10 AM: Dr. John Farley from the Food & Drug Administration (FDA) and Dr. Marco Cavaleri from the European Medicines Agency (EMA) spoke about the regulatory challenges in approving treatments for Long COVID.
Farley highlighted the FDA’s work providing advice to drug developers prior to and during human trials. He said patient-focused drug development for Long COVID treatments is the way forward, with a statement from former FDA principal deputy commissioner Dr. Janet Woodcock: “Patients are true experts in their disease.”
“We have heard this loud and clear over the last few days,” Farley said.
He also recapped the FDA’s public meeting last April for patient-focused drug development with regard to Long COVID, noting that it created a channel for feedback on questions like, “If we conduct a trial this way, what do you think?” Farley focused on patient-reported outcomes and said ongoing clinical research is helpful in determining performance characteristics of endpoints, which should directly measure clinical benefits in patients.
Farley and Cavaleri both urged research collaboration to ensure that participants’ time isn’t being wasted and to avoid small, underpowered trials.
Cavaleri presented on the regulatory outlook of medicines for Long COVID in the European Union. As in the U.S., there are no approved treatments or preventative medications for the disease. He presented about the main regulatory challenges to approving treatment, namely defining a patient population, inclusion/exclusion factors in clinical trials, and defining primary efficacy endpoints.
He summarized the takeaways from an EMA workshop held last year focused on generating clinical evidence for treatment and prevention options for Long COVID. Among them: The first step should be an agreed operational case definition of Long COVID, treatment of Long COVID should be prioritized over prevention (which has generally been the focus of NIH-RECOVER), and patient-reported outcomes are considered the best primary endpoint.
Instead of an industry speaker, the session on regulatory perspectives ended up including a longer audience Q&A.
Meighan Stone from the Long COVID Campaign emphasized the importance of people with Long COVID being able to get Novavax, as the updated formula still has not been approved in Europe despite being submitted for approval in June. She also asked about bringing pharmaceutical companies and the FDA onto the same page, and about which European governments are looking at Long COVID as a priority.
Farley said that “pharma is looking for good science,” and the next step is a public workshop sharing data between different fields.
“We [The FDA] often take what we learn in public workshops to write guidance,” he said. “A lot of their [pharmaceutical company’s] frustration is the scientific frustration we all feel.”
Cavaleri said many countries have been looking into how to help people with Long COVID by setting up centers that can help them, but research-wise, “We are not seeing what we want to see.” He said it’s been difficult to set up trials akin to RECOVER, and “my plea is that we find a good way of collaborating internationally.”
Jaime Seltzer from #MEAction also encouraged a public workshop, asking that there’s a “bid for genuine engagement” with people living with Long COVID and related diseases.
Other points of discussion during the Q&A included timelines to regulatory approval, the role of clinicians in the regulatory realm, developing measurable endpoints, and determining clinically meaningful results. On the last note, Farley said, “the right answer is asking patients first.”
One attendee asked whether Long COVID was a disease or syndrome, to which Farley and Cavaleri said they were not the right people to answer. Several audience members in the Q&A pushed back against characterizing a syndrome as “less severe.” NIH-RECOVER investigator Dr. Jerry Krishnan also pointed out that the NASEM definition of Long COVID defines it as a disease.
—James Salanga
Recap of Tuesday highlights
Wednesday, 9:00 AM: At the outset of the last day of the RECOVER-TLC kick-off meeting, Dr. Lindsay Baden (the vice president of clinical research at Brigham and Women’s Hospital/Harvard) rehashed the panel sessions from Tuesday. He noted that alongside provider comments highlighting clinical trial design challenges among populations, 10 people shared perspectives from their own lived experiences. Baden also reiterated the RECOVER-TLC agent submission portal will open shortly.
A prevalent message from yesterday and the broader kick-off meeting, Baden added, is that “recruitment moves at the speed of trust.”
—James Salanga
Recruitment challenges
Tuesday, 4:15 PM: During the final panel of the day, panelists Dr. Kanecia Zimmermann of Duke University School of Medicine, Dr. Jerry Krishnan of University of Illinois at Chicago, and Dr. Catherine Blish, Stanford University School of Medicine, continued conversations from an earlier panel, also moderated by Dr. Sally Hodder, on the challenges of populations in Long COVID trials.
Each panelist spoke briefly about their take on the topic before they received questions in person and online. Krishnan spoke about his study, “Participation in Clinical Trials Doesn’t Have to Be a Lousy Experience.”
Rachel Gross, a researcher at New York University, made a comment during the Q&A on the importance of reaching out to participants to better explain the research to them. For example, words and terms other than “Long COVID” may include more people in the study recruitment, as many aren’t well aware of the term Long COVID.
That’s it for today, join us tomorrow for our coverage of the third and final day of RECOVER-TLC.
— Miles Griffis
Challenges in pediatric trials
Tuesday, 3:45 PM: Dr. Melissa Stockwell of Columbia University opened the pediatric trials panel with a presentation on the enormous burden of Long COVID in children, which she spoke about with us in February in a Q&A. She said millions of children are affected by Long COVID in the United States.
The panel was moderated by Dr. Sindhu Mohandas of the Children’s Hospital Los Angeles. The panel included Stockwell, Dr. Roberta DeBiasi of Children’s National, and Dr. Gail Pearso of the National Heart, Lung, and Blood Institute.
Debiasi said many families are hoping to get their children with Long COVID into clinical trials. There are currently very few pediatric trials. She specified that Long COVID can look different in different pediatric age groups.
“The immune system is developed differently in different age groups,” she said. “So the way we collect data, the way we look at the targeted outcomes is going to be different for each of the pediatric age group. So it’s not like everyone’s the same as is, potentially an adult.”
The panel discussed the excitement many families and kids have in participating in clinical trials — they are incredibly engaged, some of the panelists said.
“The goal here is to protect children through research,” Pearso said. “Not from research.”
— Miles Griffis
Note about access
Some people with severe Long COVID and ME have said that their requests for accessible accommodations were denied by RECOVER. “There are a lot of severe patients out here with important perspectives but not providing timely transcripts means we can’t participate,” Emily Fraser wrote on Twitter/X. “This is a conference about a disease that leaves huge numbers of patients unable to tolerate audio/video.”
— Miles Griffis
Considering the challenge of endpoints
Tuesday, 2:45 PM: An endpoint in a clinical trial, according to the NIH, means “a measurable outcome or event in a clinical trial that helps determine if an intervention is beneficial.”
Dr. Alison K. Cohen of University of California, San Francisco, opened with a stage setting talk about the various endpoints for Long COVID trials.
She spoke on the importance of inclusion to gather more information on the disease to produce better research outcomes, including deep patient engagement, including severe participants, taking post-exertional malaise into consideration, including gender diverse participants, and taking COVID-19 precautions so that people with Long COVID can participate more safely without the risk of reinfection, which can worsen the disease.
“Taking COVID precautions will increase the spectrum of patients who are able to participate,” Cohen said. “Rather than making patients request that people mask — just offer it across the board.” The NIH can say it will only fund studies that take COVID-19 precautions for in-person trials, she suggested.
A panel discussion began after Cohen’s talk, moderated by Dr. Adrian Hernandez of Duke University School of Medicine. It included Cohen, Dr. Seth Lederma of Tonix, Dr. Linda Geng of Stanford University School of Medicine, Dr. Todd Davenport, University of the Pacific, and Dr. Paul Lee of the U.S. Food and Drug Administration (FDA).
“This workshop so far has involved precious little specific discussion of PENE [post-exertional neuroimmune exhaustion, also known as post-exertional malaise (PEM) or post-exertional symptom exacerbation (PESE)],” Davenport said. “Even the people with Long COVID in this workshop are doing so at great sacrifice to themselves, which largely goes unseen by healthy people.”
Davenport said there are already ways to include and measure PENE in Long COVID and associated diseases as an endpoint, but they are often left out of clinical trials. “Here’s our chance to finally get this right.”
— Miles Griffis
Study designs
Tuesday, 2:00 PM: After a few in-person and online questions on populations, Dr. Prscilla Hsue or the University of California, Los Angeles, took the podium to set the stage on study design. She gave reflections on a study put together by UCSF’s LIINC (Long-term Impact of Infection with Novel Coronavirus), stressing the importance of including patients and patient researchers in study design.
The panel was moderated by Dr. Dean Follmann of the National Institute of Allergy and Infectious Diseases and included Dr. Priscilla Hsue, Dr. Christopher McAleer of AIM Immunotech Dr. Tom Patterson of University of Texas at San Antonio, JD Davids from Strategies for High Impact, and Lauren Stiles from Dysautonomia International.
Stiles stressed that Long COVID can include many other associated diagnoses and that one treatment may not cure the disease outright. Including associated diagnoses in randomized trials may help led to more specific treatments for subgroups of Long COVID.
Patterson stated that many people with more severe Long COVID are often underserved and excluded from research, as we recently reported on. He spoke on testing potential treatments like Ampligen, which has been used to treat ME in the past with some success.
Davids, who joined the panel virtually, said that the many who were not masking at the in-person meeting were contributing to a “microaggression” of people with Long COVID.
Many other Long COVID advocates have criticized the meeting for not mandating masks and participants for not masking, which they say undermines the science and reality of COVID-19 and Long COVID.
Davids also stressed the importance of including transgender people in study design and echoed calls for including severe participants.
— Miles Griffis
The challenges of defining populations for trial design
Tuesday, 1:15 PM: After a short lunch break, Dr. Sally Hodder of West Virginia University led a panel discussion on the challenge of recruiting populations in RECOVER-TLC trial designs, particularly disporportinoately affected people and those living in rural areas.
She was joined by Angela Meriquez Vazquez, Dr. Sharon Saydah from the Centers for Disease Control and Prevention, and Dr. Helen Ward of Imperial College.
“I really worry about the long term impacts that we’re seeing as a result of even the quote unquote mild infections,” Vasquez said. “What are we doing to our children by persistently infecting them with COVID?”
Much of the panel discussion touched on the stigma of Long COVID. People don’t want to come forward talking about Long COVID because of stigma, Ward said. A lack of access to treatments and public education on the disease also contributes to the stigma, Vazquez pointed out, noting that many clinicians may be hesitant to diagnose children with Long COVID because of it.
Similarly, the panel discussion also focused on the lack of public awareness of Long COVID – many may not realize they have the disease. These many issues, including an inability to access the internet and a lack of in-home visits for people disabled by the disease, make it difficult to get a diverse set of populations in the research without more effort and intentional recruiting from researchers.
— Miles Griffis
Let’s get moving on possible interventions
Tuesday, 12:45 PM: With only fifteen minutes left in the planned 75-minute session on selecting and prioritizing Long COVID interventions, the moderator handed the floor to Meighan Stone, the executive director of Long COVID Campaign. She pointed out that while the audience had spent an hour listening to researchers, the floor still had not been opened up for patient questions and experiences.
“This is still a DIY project for patients,” Stone said. “We are flying blind. So this is a really important discussion for us.”
After taking in the presentations from Dr. Julia Moore Vogel of Scripps Research, Heather Stone of the U.S. Food and Drug Administration, Dr. Timothy G. Buchman of Emory University School of Medicine, and Dr. Stacey Adam of the Foundation for National Institutes of Health, Meighan Stone had one message that received a loud cheer and round of applause from in-person attendees: “Please, no over the counter medicines and supplements. No exercise, no CBT, no video games. We don’t have the time or resources to wait.”
Plenty of optimism from researchers led up to Stone’s call to action.
Dr. Vogel advocated for patients to be able to balance risk and reward by making their own informed choices about how risky they want their interventions to be. Doing nothing, she said, is doing harm. She shared three full slides of intervention options that had been sourced from patients, with special thanks to Hannah Davis from Patient-Led Research Collaborative. Heather Stone from the FDA focused on CURE ID, a program that began as a treatment registry for clinicians but that has now been expanded to Long COVID patients. Dr. Timothy G. Buchman urged a moonshot approach to drug interventions, as opposed to searching for a “magic silver bullet.” And Dr. Stacey Adam demonstrated RECOVER-TLC’s forthcoming Therapeutic Intervention Submission Portal, an online portal where clinicians, caregivers, and patients will be able to register the interventions they’re trying and make suggestions to the NIH.
After the call out from Meighan Stone, 15 minutes were added for more patient questions, both in-person and online.
“I’m hopeful for the first time in a long time,” Stone said. “We just need to get moving.”
— Heather Hogan
The past and future of clinical trials
Tuesday, 11:00 AM: Tuesday’s sessions continued with a look at Long COVID clinical trials, both those that have concluded and those that are still in the planning and recruiting stages.
Dr. Kanecia Zimmerman from Duke University School of Medicine presented data on RECOVER’s clinical trials. She noted that one of the most important results of early trials is that NIH’s teams have learned to prioritize “how patients are feeling and how they are functioning, rather than how they are testing.” Patient reported outcomes were the primary measures of the earliest RECOVER trials. RECOVER is now enrolling three new trials: RECOVER-Autonomic, which will include up to 380 patients and focus on POTS; RECOVER-Sleep, which will include up to 1,074 patients and focus on regulating sleep-wake patterns; and RECOVER-Energize, which will include up to 660 patients and focus on fatigue.
Dr. Upinder Singh of Iowa Carver College of Medicine spoke about non-RECOVER clinical trials. She drilled down on some of the challenges her team has faced. The was no precedent or literature from the FDA. There was no known biomarker. There were multiple clinical presentations and it was unclear if those presentations were stemming from the same disease. One of the things that caused “substantial and understandable community frustration,” she noted, was the fact that many first wave Long COVID patients do not have documented positive COVID-19 tests, and were therefore being excluded from trials. Her team adapted to accommodate those who were unable to access COVID-19 tests in the spring of 2020.
Much of the conversation during the panel discussion and audience Q&A centered on the patient burden of being involved in clinical trials. Several researchers mentioned labor-intensive studies that require in-person, hours-long visits can be extremely prohibitive. “That level of investment from an individual is not something that everybody can do,” Dr. Singh said. They agreed they must find a balance between patients who can visit clinics for blood samples, stool samples, imaging, etc. and those who are confined to their homes. They also agreed more work was needed to include patients from more rural areas.
One audience member asked about the ethics of placebo trials, wondering why someone might participate in a nine-month study in which they could be given a placebo that provided no symptom relief, when they could be actively pursuing treatments that could potentially work, or even resting for symptom management. Dr. Singh agreed with that concern and advocated for all studies to include ethicists in their design phases.
In terms of placebos working, Dr. Singh said, “We have lots of individuals who felt much better soon after starting placebo. And listen, I think, for four years when you’ve had symptoms and nobody’s believed you and nobody’s listened to you, when you come in and to have staff and others be so caring about your situation, it makes a difference, right? We all are humans. We need human interactions and human support. So I think there’s definitely some of that, but there are individuals who did feel much better.”
A refrain that was echoed throughout the panel was also one mentioned several times yesterday: the need for more funding and pharmaceutical partnerships. There are pathobiological samples sitting around that can’t be studied because there’s no money for it. There are drugs that researchers want to test, but pharmaceutical companies aren’t willing to partner with them. Only 2/3 of patients can access the expensive wearable technology that helps bridge the gap between patient reported outcomes and biomarkers. More funding, from a variety of sources, is vital if real progress is going to be made in Long COVID clinical trials.
— Heather Hogan
Public comments express urgency and hope
Tuesday, 10:00 AM: The Tuesday sessions opened with a period of public comments. Audience members, including people with Long COVID, caregivers, and clinicians, shared their experiences with the disease and reflections on the meeting.
“My story isn’t unique, but everybody I meet thinks it is,” said Josh Porter, one speaker with Long COVID. Like other speakers, Porter described how Long COVID symptoms had changed his life, yet doctors were dismissive. “I’ve given up on medical care, because no physician has ever offered me any treatment other than an SSRI,” said Ezra Spier. Spier also noted that he had spent all of his savings on rent and medical bills over the last two years, while waiting for novel treatments.
Speakers also identified connections between Long COVID and other diseases. Jermaine Greaves, founder of Black Disabled Lives Matter, shared how he’s faced dismissals from medical providers as he seeks treatment for Long COVID, cerebral palsy, and other chronic illnesses. “People don’t think people with Long COVID are people because the system has allowed them to think we don’t exist,” he said.
Rivka Solomon, a long-time advocate for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), spoke about her decades of debilitating symptoms. “Advocates from these various infection-associated chronic conditions [IACCs] are working together as a coalition,” she said. One central goal of that effort is for the NIH to establish a new office for IACC research, to make the research “more coordinated and cost-effective.”
Overall, speakers shared that they have a lot of hope for future Long COVID treatments, but that much work remains to be done. “We must work harder, smarter, and more collaboratively than ever before,” Spier said.
— Betsy Ladyzhets
Balancing novel research with pressing need
Monday, 5:15 PM: Day one of the TLC meeting concluded with a panel discussion about how research into the underlying biology of Long COVID and related diseases may inform successful clinical trials. The panel included an esteemed group of scientists: Dr. Cliff Lane from NIAID, Hannah Davis from the Patient-Led Research Collaborative, Jaime Seltzer from #MEAction, Dr. Alba Azola from Johns Hopkins University, Dr. Ian Lipkin from Columbia University, and Dr. Steve Deeks from UCSF.
The discussion centered on a central challenge for Long COVID trials: how to strike a balance between designing novel drugs specific to Long COVID and repurposing drugs from other diseases. Novel, experimental work may be more likely to provide cures, Deeks suggested. But developing new drugs is time- and resource-intensive, and people with Long COVID can’t afford to wait; they need strategies for managing their symptoms in the meantime. There “needs to be a pathway” for repurposed drugs in parallel to designing new ones, Azola said.
Another major theme from the session was a push to include people with ME/CFS and other related diseases in Long COVID trials. “I’m thinking about not just who has Long COVID today, but who has the ME/CFS picture from other infections, and who will have the ME/CFS picture from future infections,” Seltzer said. She, as well as Lipkin, recommended that people who had ME/CFS prior to the pandemic should be included as cohorts in Long COVID trials. In addition, panelists recommended other trial design lessons from the ME/CFS field, such as stratifying patients based on the duration of their symptoms and including people who have more severe symptoms.
This panel, surprisingly to some participants, also included the first mention of post-exertional malaise (PEM) at the three-day meeting. As a unique state specific to Long COVID and ME/CFS, PEM should be a central outcome in trials and focus of pathobiology research, several panelists said. While PEM can be challenging to measure, ME/CFS researchers can offer decades of experience in this area.
During the Q&A, one audience member speaking from pharmaceutical industry experience suggested that more creativity is needed in testing antiviral drugs for Long COVID. “We need combination antiviral treatments,” she said, and treatments should be tested for longer periods of time than the current studies looking at Paxlovid for a couple of weeks at most.
NIAID director Jeanne Marrazzo closed out the day by thanking presenters and audience members for their “stamina” in engaging with these complex topics. “I think we’re going to come out of this [meeting] with some fantastic plans,” she said.
— Betsy Ladyzhets
Learning from ME/CFS, POTS, MIS-C trials
Monday, 4:00 PM: Three researchers of common comorbidities with Long COVID — namely, ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome), POTS (postural tachycardia syndrome), and MIS-C (multisystem inflammatory syndrome in children) — spoke about their research and how it can inform future Long COVID clinical trials and trials that study those comorbidities.
Dr. Avi Nath, from the National Institute of Neurological Disorders and Stroke (NINDS), talked about some placebo-controlled trials looking at Long COVID treatments that failed, including a Stanford Medicine trial examining Paxlovid and another targeting macrophage activation that failed to meet any primary or secondary endpoints. He cited Long COVID and ME/CFS being heterogeneous diseases with multiple overlapping syndromes, phenotypes, and pathogenic processes; common misdiagnoses and comorbidities; and a lack of interest from “big pharma” as among the reasons these studies are difficult to develop.
After selecting a 17-person post-infectious ME/CFS cohort, Nath and several other researchers were able to perform deep phenotyping showing antigenic — not viral — persistence, with the central abnormality being a decreased ability to switch B cells from different antibody isotypes, specifically IgM to IgG. His recommendations for trials include clinical outcome endpoints, a clearer definition of post-exertional malaise, stratified patients based on predominant immune dysfunction, and placebo-controlled cross-over studies or platform studies. Ongoing clinical trials at NIH include looking at intravenous immunoglobulin in treating Long COVID, which is now recruiting. (Editor’s note: Many in the ME/CFS community have criticized this intramural study. Read our coverage here.)
Dr. Peter Rowe from Johns Hopkins University talked about lessons learned from two clinical trials of POTS patients. He also suggested stratifyng participant groups to address differing duration and severity of illness, along with run-in periods into studies for treating comorbidities or providing salt and fluid treatment.
Those run-in periods, Rowe said, could also be used to identify those who have no chance at responding to medication, but could respond to other types of treatment. He also suggested randomized trials of withdrawing ostensibly effective therapies, and similarly suggested running cross-over trials.
Dr. Adrienne Randolph, a pediatric critical care physician at Boston’s Children Hospital, recapped initial research on MIS-C from 2020 and a Nature study published last month about molecular mimicry in MIS-C. The study looked at antigen exposure and autoimmunity, and found three proteins explaining a “significant portion” of MIS-C. She suggested that opens up new questions for MIS-C and other IACCs developed after SARS-CoV-2 infection around enigmatic forms of autoimmune dysregulation, distinct from traditional autoimmune diseases.
—James Salanga
Long COVID pathobiology
Monday, 3:30 PM: Four Long COVID researchers presented their findings about the pathobiology of Long COVID before opening up a larger panel discussion and short audience Q&A.
Dr. Mike VanElzakker from Mass General Research Institute and Harvard University spoke about neural inflammation and immune activation. His research suggests that targeted therapies could potentially disrupt the interactions between fibrin and the SARS-CoV-2 spike protein.
Dr. Resia Pretorius of Stellenbosch University focused on endothelial injury, thrombosis, and complement activation. Dr. Pretorius believes microclots could be used as one of the key diagnostic markers to include before and after Long COVID treatment, as evidence of microclots has been found in many Long COVID patients, including pediatric Long COVID patients.
Dr. Michael Peluso of the University of California, San Francisco presented research on viral persistence. He noted that SARS-CoV-2 protein and RNA can persist post-COVID-19, and that there is a precedent for that with other viruses. Three questions he’s working to answer are: What causes viral persistence? Can it be prevented? Does viral persistence cause Long COVID? He believes we need intensive biomarker development and validation, as well as proof of concept trials. He mentioned the recent study that suggested Paxlovid does not prevent Long COVID, noting that a two-week course of the antiviral is “almost certainly too short.” Cats who have persistent SARS-COV-2, for example, often need 12 weeks of anti-viral treatment.
Dr. Paul J. Utz from Stanford University School of Medicine was excited to talk about biorepositories. He mentioned that he is now a RECOVER patient. He enrolled as a control patient prior to his second SARS-CoV-2 infection, and has now re-enrolled after being infected on an international vacation. NIH has collected all kinds of different materials: stool, nasal swabs, saliva, and whole blood. They have around 1,000 patients who, like him, had not been infected with SARS-COV-2, and have now been infected and re-enrolled.
When the panel discussion began, Dr. Amy Proal of the PolyBio Research Foundation piggybacked off of Dr. Utz’s enthusiasm, saying, “Long COVID is not a mystery. There are hundreds of papers, some of the top teams in the world working on this. We have clear leads, especially on viral persistence, which is potentially upstream of everything else. We can design really good trials. And we have NIH’s large biorepository.”
During the Q&A, an audience member with Long COVID said she had been diagnosed with functional neurological disorder after encountering “a disturbing lack of intellectual curiosity from many neurologists and neuropsychologists.” The audience broke out in applause when one of the researchers said, “Functional neurological disorder should not mean ‘I don’t know.’ It’s a diagnosis of positive neurological criteria.”
He followed that by saying, “The last four years have been humbling and have made me rethink how I approached some situations before the pandemic. I hope that through advocacy and through efforts like RECOVER there can be more robust educational infrastructure to get everybody onto the same page. I think I’ve seen I’ve seen firsthand improvements In the last couple of years, but we still have a long way to go — and, as you said, so many clinicians who still need convincing. Hopefully it will help to show them the data. Efforts like RECOVER will be really important in generating robust data to convince the skeptics.”
— Heather Hogan
Observational studies’ implication for clinical trial design
Monday, 2:32 PM: This session focused on examining how observational studies and data can lay the groundwork for future clinical trial designs studying Long COVID treatment, subtypes, and presentation. Before a panel discussion, Dr. Leora Horowitz from New York University presented on the importance of observational data for clinical trials.
Dr. Ziyad Al-Aly from the U.S. Department of Veterans Affairs/Washington University in St. Louis discussed the lessons he’s learned from researching Long COVID, emphasizing that the illness is “not a small problem” nor a monolith. Al-Aly also underscored the importance of listening to patients, who he said “were right all along.” He also uplifted feedback received from people living with Long COVID on X, as he had previously asked for advice on what to cover in the RECOVER session. Preventative care, COVID-safe environments for clinical trials, and studying ME/CFS and other IACCs were among the topics Al-Aly mentioned.
Dr. Clifford Lane, the deputy director for clinical research at the National Institute of Allergy and Infectious Diseases (NIAID), also recapped the cohort details for two intramural NIAID studies, one focused on adults and another on pediatrics.
After their presentations, Horowitz, Al-Aly, and Lane talked with Dr. Igor J. Koralnik (the chair of neuro-infectious disease at Northwestern University), Dr. Melissa Stockwell (chief of division of child and adolescent health at Columbia University); Dr. Helen Ward (co-lead of the REACT Long COVID study), and Dr. Simon Pollett (associate science director of the Infectious Diseases Clinical Research Program from Uniformed Services University of the Health Sciences).
Each discussed various perspectives from their fields of study; Koralnik mentioned the difficulty of securing funding for clinical research, Stockwell emphasized the importance of pediatrics cohorts for trials, Ward talked about the lack of health records for Long COVID cases and that people may not realize they are living with the illness, and Pollett, who has studied SARS-Cov-2-associated myocarditis in the military health system, mentioned the use of pre-COVID samples to help with targeting Long COVID biomarkers to look for in studies.
One audience question focused on flexibility in Long COVID clinical trials when reaching more rural areas. Travel has been a main barrier to having people with severe Long COVID participate in trials and research. RECOVER has added three additional strategies, Horowitz said: a rural-exclusive network with sites in different communities, mobile vans that drive out to areas in Arizona and Ohio, and reimbursement for participants if they have to stay overnight and live more than 150 miles away.
Other questions focused on looking at recovery from Long COVID and how research can address different subtypes experiencing different levels of recovery, though Al-Aly provided the caveat that studies on recovery show mixed results. Ward urged asking about symptoms over periods of time and offering cognitive tests to have both self-reported and more objective data. Other challenges for clinical trials Pollett mentioned: Identifying control groups in observational studies “because COVID is now so prevalent” and measuring other intervening exposures during the study that may lead to Long COVID manifestations.
—James Salanga
Discussing the NASEM Long COVID definition
Monday, 12:10 PM: The first research-focused session discussed how to define Long COVID in clinical trials. Dr. Jerry Krishnan, from the University of Illinois at Chicago, kicked off the session by presenting findings from the recent National Academies of Sciences, Engineering, and Medicine (NASEM) report offering a working definition of the disease; Krishnan was a member of the 16-person committee that developed it.
NASEM’s definition of Long COVID includes a wide range of symptoms and diagnoses that occur after COVID-19. Some Long COVID researchers and advocates have critiqued the definition’s inclusivity, suggesting that it is too broad to be used in clinical trials. Krishnan suggested that, rather than using the overall definition, researchers should “use study-specific inclusion and exclusion criteria” to ensure that trials appropriately include people who may be assisted by a given treatment.
“We could be studying any number of subtypes of Long COVID with any number of interventions,” Krishnan said, though he added that one “master protocol” should be established to ensure consistency across trials.
Following this conversation, Krishnan, as well as Ian Simon (director of the federal Office of Long COVID Research and Practice, Karyn Bishof (founder of the COVID-19 Longhauler Advocacy Project), Sharon Saydah (from the Centers for Disease Control and Prevention, CDC), and Serena Spudich (from Yale School of Medicine), discussed how to use the NASEM definition in RECOVER trials as well as other Long COVID research.
Their conversation included looking for Long COVID biomarkers within clinical trials, how the NASEM definition may change over time, inclusion of children in Long COVID research, the importance of documentation, even before three months, and the urgency of more Long COVID education for clinicians.
“We all collectively have the responsibility of raising this awareness [around Long COVID],” Krishnan said.
— James Salanga and Betsy Ladyzhets
A quick note on access
Monday, 11:30 AM: It can be tough for people with Long COVID to attend in-person events like this one. The lived experience panel highlighted such access challenges, both through the panelist’s remarks and answers to questions. For example, panelist Angela Meriquez Vazquez said that scientists running Long COVID clinical trials should ensure that in-person appointments involve masks and other COVID-19 precautions.
Access challenges have also impacted attendees of this event. On Twitter/X this morning, Meighan Stone, executive director of the advocacy group Long COVID Campaign, posted that she was an hour late to the meeting “because NIH doesn’t know how to operate their shuttle wheelchair ramp.”
#Disabled advocacy: Missing close to an hour of @NIH @NIAIDNews #RecoverTLC meeting on #LongCOVID because NIH doesn't know how to operate their shuttle wheelchair ramp. So much for accessibility at a…medical research campus meant to serve chronically ill & disabled people ♿ pic.twitter.com/k5aj0s7bVl
— Meighan Stone | @meighanstone.bsky.social (@meighanstone) September 23, 2024
— Betsy Ladyzhets
Spotlight on lived experience
Monday, 11:00 AM: Three people with Long COVID shared their experiences with the disease, highlighting the challenges of getting medical care and the many strategies that people have tried to find relief. Christine Maughan, the first speaker, asked that research “is done with urgency” and be inclusive of people with other post-infectious chronic diseases.
Angela Meriquez Vazquez shared her experiences of dismissal from medical providers and emphasized that finding Long COVID care is harder for people “living life on the margins,” including immigrants, low-income workers, and people of color. “I am no longer interested in patient engagement,” Vazquez said. “I am here to demand that the NIH share power with patients.”
Vazquez additionally noted, in concluding her remarks, the cost for people with Long COVID to attend meetings like this one in person: “[I also] want to stop getting on a plane and traveling with POTS [Postural Orthostatic Tachycardia Syndrome], because y’all, that sucks!”
Liza Fisher, the third speaker, echoed the challenge of traveling with POTS. She shared videos and slides demonstrating her complex Long COVID symptoms and the strategies she has tried to manage them. Not only did she need to leave her former job as a flight attendant, she said, her mother left the workforce to be her full-time caregiver. Fisher now receives disability benefits from the government, which she acknowledged is a difficult program to access for many people with Long COVID.
— Betsy Ladyzhets
Opening remarks
Monday, 10:00 AM: The three-day meeting opened with remarks acknowledging the complexity of Long COVID as well as a brief protest underscoring the urgency of clinical trials. “We want to come out of today’s meeting with an action plan,” said NIH Director Dr. Monica Bertagnolli. Research on Long COVID has progressed enough that clinical trials can now take place “in parallel” to continued research to understand the disease’s underlying biology, she said.
Bertagnolli’s opening remarks were interrupted by Long COVID advocates from the group Long COVID Action Project (LCAP) chanting, “Long COVID AIDS; Long COVID Kids; Biomarkers now; Blood test now; Test viral load.” The demands align with letters that LCAP is sending to the NIH seeking research focused on viral persistence, biomarker tests, and immune deficiency.
In response to the protest, Bertagnolli said to the audience, “I don’t think anybody disagrees with what we’ve just heard.” NIH Foundation CEO Julie Gerberding, who spoke next, observed that the interruption reminded her of her experience during early years of HIV/AIDS research and acknowledged the urgency needed to find Long COVID treatments. People with Long COVID, researchers, pharmaceutical companies, and other stakeholders must “commit to true partnership,” Gerberding said, as well as to studying this disease for a long time.
Dr. Jeanne Marrazzo and Dr. Joseph Breen from the National Institute of Allergy and Infectious Diseases (NIAID) then shared an overview of the TLC initiative, which will start under NIAID’s purview rather than the existing RECOVER structure. The initiative will include new scientific working groups focused on different research areas and a new community engagement group, which seeks to learn from criticisms levied at the engagement aspects of RECOVER. More details about the TLC plans so far are forthcoming in further sessions; Breen also emphasized that the plans so far are tentative and may change based on feedback at this meeting.
— Betsy Ladyzhets
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