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Call for US RECOVER Initiative to include ME/CFS

RECOVER is a large, United States research programme designed to understand, treat and prevent long COVID, which is marked by long-term symptoms following infection by SARS-CoV-2, the virus that causes COVID-19. The National Institutes of Health Researching COVID to Enhance Recovery (NIH RECOVER) initiative was allocated $1.15 billion, including support through the Rescue Plan Act 2021, which seeks to identify how people recuperate from COVID-19, and who are at risk for developing post-acute sequelae of SARS-CoV-2 (PASC). According to the National Institutes of Health (NIH) the initial stage of the initiative involved launching large, observational, multi-site studies examining and following people through their experience with COVID-19 to learn why some people develop long-term symptoms while others recover completely. Studies are ongoing but more than 24,000 participants have been recruited thus far. Researchers are also analysing 60 million electronic health records and conducting more than 40 pathobiology studies on how COVID-19 affects different body tissues and organs. Data gleaned from these efforts helped shape the development of phase 2 clinical trials, which test the safety and effectiveness of treatments typically in groups of 100-300 participants.

At present the over-all scheme comprises

  • RECOVER-VITAL focussing on a treatment targeting SARS-CoV-2 persistence, which could occur if the virus stays in the body and causes the immune system to not function properly or damage to the organs.
  • RECOVER-NEURO examining accessible interventions for cognitive dysfunction related to long COVID, including brain fog, memory problems and difficulty with attention, thinking clearly and problem solving.

with the intention to add

  • RECOVER-SLEEP to test interventions for changes in sleep patterns or ability to sleep after having COVID-19. A trial for hypersomnia, or excessive daytime sleepiness, will test two wakefulness-promoting drugs compared to a placebo control.
  • RECOVER-AUTONOMIC to examine interventions to help treat symptoms associated with problems in the autonomic nervous system, which controls a range of bodily functions including heart rate, breathing and digestive system activity. The initial trial will focus on postural orthostatic tachycardia syndrome (POTS), a disorder with a number of symptoms including irregular heartbeat, dizziness and fatigue, and will have multiple study arms.
  • A fifth platform protocol, focusing on exercise intolerance and fatigue, is under development with input from the patient community and scientific experts.

What about ME/CFS?

With the symptoms of ME/CFS and long COVID exhibiting considerable similarities and sharing underlying pathophysiology (e.g. abnormalities of the central and autonomic nervous system, lungs, heart, vasculature, immune system, gut microbiome, energy metabolism and redox balance) surely there is scope to harness learnings from ME/CFS research to aid RECOVER and for the well-funded RECOVER initiative to extend to ME/CFS (bearing in mind that US federal funding of research and treatment via the NIH into ME/CFS has remained limited – an estimated $13 million in 2022, 2023, and 2024)?

It is therefore to be welcomed that the US Senate Appropriations Committee recognised

….. the economic and overall health impact that Long COVID inflicts on the Nation. It is currently estimated that between 6 percent and 19 percent of those infected with SARS–CoV–2 go on to develop Long COVID, resulting in up to 20 million Americans suffering from this set of debilitating chronic symptoms….. Further, it resembles other post-acute infection syndromes [PAISs], such as fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS] and related conditions, known as chronic overlapping pain conditions [COPCs] or nociplastic syndromes. The Committee urges NIH to rebalance its research program to prioritize clinical trials in pursuit of effective treatments and to use the NASEM Long COVID definition to guide its choice of symptoms and conditions to be address by the candidate treatments. Such trials should target key symptoms and symptom complexes associated with Long COVID including widespread pain, fatigue, non-restorative sleep, brain fog, dizziness, post-exertional malaise [PEM], postural orthostatic tachycardia syndrome [POTS] and loss of taste and smell. Further, the Committee urges NIH to prioritize the support of clinical trials evaluating therapies for Long COVID including therapies that have demonstrated efficacy in treating COPCs or nociplastic syndromes that overlap with Long COVID.

Report – Departments of Labor, Health and Human Services, and Education, and Related Agencies Apporpriation Bill, 2025 pp 145 to 146

Building upon this recommendation, a letter has been sent by leading ME/CFS researchers to NIH Director Monica M. Bertagnolli, M.D., providing a roadmap for how NIH can successfully integrate ME/CFS into the RECOVER Initiative and that they were looking “… forward to a fruitful collaboration and are excited about the future this initiative promises for patients with Long COVID, the ME/CFS community, and beyond.”

To allow facilitate this ‘fruitful collaboartion’ the authors of the letter suggested there be

  • Enhanced Focus on Clinical Trials: The Senate report points out the necessity for a broader evaluation of treatments across the symptom spectra of Long COVID and ME/CFS. It is imperative that NIH champions this cause by actively supporting and prioritising the development of clinical trials focused on comprehensive symptom profiles. Trials should be designed to test both existing and novel therapies that show promise in addressing the complex nature of ME/CFS and related conditions. To enhance the impact of existing RECOVER Initiative trials, we recommend including ME/CFS with onset of disease prior to 2020 as a comparison group. This will facilitate direct comparisons between Long COVID and ME/CFS and ensure that therapies developed for one condition are evaluated for their potential benefits in the other.
  • Subject Selection: We recommend a deliberate expansion in the RECOVER Initiative’s research criteria to comprehensively cover the diverse and overlapping symptoms associated with ME/CFS. The 2024 NASEM definition emphasizes the importance of recognizing a broad array of symptoms, including, but not limited to, cognitive impairment, persistent fatigue, post-exertional malaise, autonomic dysfunction, and various forms of pain. Approximately 45% of Long COVID patients meet the case definition for ME/CFS. This overlap underscores the necessity of studying both conditions in tandem. One cannot effectively study Long COVID without also assessing each Long COVID patient for the symptoms that define ME/CFS and using instruments employed in studies of people with ME/CFS.
  • Test Selection: A literature review of more than 10,000 publications has documented and replicated underlying and similar abnormalities involving the central and autonomic nervous system, the immune system, energy metabolism, endothelial dysfunction, and the gut microbiome in both Long COVID and ME/CFS (1). Unfortunately, two studies from the NIH on laboratory abnormalities in Long COVID (2,3) have included only the standard battery of hematologic and chemistry tests used by clinicians to evaluate patients with common illnesses. Multiple past publications have found these tests uninformative in Long COVID and ME/CFS. Furthermore, the two NIH studies published have included virtually none of the studies that have been shown repeatedly to be abnormal in both people with Long COVID and ME/CFS. In its further studies, we urge NIH to expand the tests used to include those tests that other studies have already proved to be informative.
  • Utilisation of Existing Research Networks: The two NIH ME/CFS centers and other centres with expertise in ME/CFS are eager to assist in this effort. We have worked together in formal and informal collaborations for decades, sharing samples, data, and other resources. Together we have independently and collaboratively tested the validity of immunologic, metabolomic, proteomic, transcriptomic, and microbiome findings. We have found ourselves in agreement in most instances, including debunking prominent articles in Science and PNAS, respectively, wherein XMRV and pMLV were implicated in ME/CFS. We are confident that our work has yielded mechanistic insights that may be helpful in identifying targets for intervention. It is essential that the RECOVER Initiative leverage past insights and avoid duplicative efforts. This integration is crucial to accelerate the research timeline and to enhance rigor and reproducibility.
  • Integration of Patient and Expertise-Driven Insights: To truly align the RECOVER Initiative’s research objectives with the needs of those affected, we recommend the establishment of an advisory panel comprising patients, caregivers, and scientific experts with experience in ME/CFS. This panel would serve a critical role in advising on research priorities, study design, and patient engagement trategies, ensuring that the initiative remains responsive to the community it aims to serve.

In the event that this roadmap come to fruition it would be a major step forward in ME/CFS research and would benefit not only thioose diagnosed proir to 2020, those with Long-COVID but also those who are now diagnosed with ME/CFS post COVID infection.

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