This quarter’s summaries highlight several studies examining the biological mechanisms of ME/CFS and Long Covid, including the roles of specific autoantibodies and persisting viral components in driving distinct symptoms. Several of the studies were led by Solve-funded researchers and collaborators, including Dr. Akiko Iwasaki, Dr. Amy Proal, Dr. Carmen Scheibenbogen, Dr. David Putrino, and Dr. Jonas Bergquist.
Measuring how much Long Covid impairs learning and socialization for children and adolescents
Dr. Rachel Gross (professor of pediatrics at New York University School of Medicine) and Dr. Harrison Reeder (instructor in biostatistics at Harvard Medical School) recently led a study of the NIH RECOVER pediatric cohort to understand how Long Covid affects school-related functioning in children (aged 6–11 years) and adolescents (12–17 years).
Earlier research on pandemic-era schooling emphasized how isolation led to learning loss and reduced social development. But less is known about how Long Covid may affect learning and socialization. The researchers studied outcomes for ~400 children and ~1,600 adolescents (~one-third with Long Covid and ~two-thirds without). For both age groups, those with Long Covid did worse in school and had less enjoyable interactions with peers. For children with Long Covid, the relative risk for having worse grades than before the pandemic was about twice as high as for those without Long Covid (about one in five children with Long Covid reported worse grades). The risk of having moderate or severe difficulty paying attention was 2.5 times as high (about two in five children with Long Covid reported this difficulty). And the risk for only sometimes, rarely, or never having fun with peers was almost three times as high (about one in three children with Long Covid reported low enjoyment).
For adolescents with Long Covid, the relative risk for having worse grades than before the pandemic was about 2.5 times as high (about one in three adolescents with Long Covid having worse grades). The risk of having moderate or severe difficulty paying attention was over three times as high (almost two in five adolescents with Long Covid reported this difficulty). And the risk for only sometimes, rarely, or never having fun with peers was twice as high (over two in five adolescents with Long Covid reported low enjoyment). Children and adolescents with Long Covid were also more likely to receive or be considered for special educational support, like that offered to students with autism, developmental delays, or disabilities.
These results matter because school performance and peer relationships are critical for overall life trajectories. Given the size of these effects and the number of young people with Long Covid, elementary, middle, and high schools must develop effective services that support students with Long Covid and help them reach their potential. This paper appeared in Academic Pediatrics.
Wearable biometric monitor helps predict fluctuating symptoms of ME/CFS, Long Covid, and other energy-limiting diseases
Solve Collaborator Dr. David Putrino (Mount Sinai School of Medicine), Solve Catalyst Award winner Dr. Akiko Iwasaki, and Solve Ramsay Award winner Dr. Amy Proal recently teamed up to study whether mobile and wearable devices can help predict daily symptom fluctuations in people with Long Covid, ME/CFS, and other energy‑limiting complex chronic conditions.
The team analyzed data from well over 4,200 participants who had used the Visible app, which lets people with these conditions track biometrics with a wristband. Each morning, participants recorded their heart rate, heart rate variability, and breathing rate. Each evening, they reported severity of symptoms of brain fog, crashes, and fatigue. The researchers found that the severity of a person’s symptoms on one evening strongly predicted their symptoms the following evening. Also, incorporating certain biometric patterns, captured either in the morning or throughout the week, significantly improved prediction of evening symptoms.
Biometric trends associated with more severe brain fog, crashes, and fatigue included higher morning heart rate; lower morning heart rate variability; and more stable breathing rates, heart rates, and heart rate variabilities throughout the week. These results show that data from wearable devices can significantly improve prediction of Long Covid– and ME/CFS-associated symptoms, helping people better manage these diseases and improve their quality of life. This article appeared in npj Digital Medicine.
Altered levels of cellular proteins released into blood circulation in people with ME/CFS suggests systemic and chronic dysregulation
Dr. Karl Tronstad, professor of biomedicine at the University of Bergen (Norway), recently compared circulating blood proteins in 50 people with ME/CFS with those in 29 healthy people. He found widespread differences in protein levels. Patterns suggested ME/CFS dysregulates specific types of cells, tissues, and processes. People with ME/CFS had higher levels of cell-secreted proteins (e.g., signaling proteins that travel from one tissue to other tissues) and lower levels of intracellular proteins. This was true across diverse tissues, like brain, intestines, liver, lymphoid cells, and skeletal muscle.
Given the functions of these proteins, the overall effect of these ME/CFS-associated changes is predicted to create a chronically dysregulated state characterized by immune dysfunction, inflammation, blood vessel problems, and altered metabolism. Notably, these changes were not caused by deconditioning; rather, they reflected disease-driven changes in cellular functions across different tissues. This study appeared in Cell Reports Medicine.
Hamster animal model reveals how SARS-CoV-2 damages upper respiratory tract tissues over the long-term
Dr. Hin Chu, professor of microbiology at the University of Hong Kong, specializes in the mechanisms of coronavirus pathogenesis. Using the Syrian golden hamster animal model, his team recently examined the long-term effects of SARS-CoV-2 infection on the upper respiratory tract (nose, mouth, nasal cavity, sinuses, and larynx). These tissues allow air to enter the lungs and warm and humidify inhaled air. Hamsters are a valuable model for studying SARS-CoV-2 infection because their ACE2 receptor (which SARS-CoV-2 uses to enter cells) looks a lot like that of humans; thus, researchers can use these animals to learn how SARS-CoV-2 naturally infects and affects host tissues.
The study found that parts of the virus persisted in the upper respiratory tract long after acute intranasal infection, sometimes up to 120 days (equivalent to ~15 human years). In contrast, the fully infectious virus was gone after 42 days. Even without infectious virus, the persisting viral components continued to damage tissues. The tissues remained inflamed and unrepaired, and the epithelial cells lining the respiratory tract continued to die. These tissues also continually expressed higher levels of ACE2 and higher levels of entry receptors for other viruses, like respiratory syncytial virus and measles virus, suggesting that SARS-CoV-2 infection increases long-term susceptibility to infection by other viruses. When the hamsters were reinfected with SARS-CoV-2 84 days after the first infection, the virus did not replicate as well but damaged the tissues just as badly.
Overall, these results suggest that SARS-CoV-2 infection can continue to damage upper respiratory tract tissues long after the fully infectious virus is gone. This long-term damage may contribute to Long Covid respiratory symptoms and may increase vulnerability to infection by other viruses. This study appeared in npj Viruses.
A statistical model shows how people transition over time between distinct COVID-19 and Long Covid disease states
Dr. Evelina Tacconelli (professor of infectious diseases at the University of Verona, Italy) and Dr. Jan Hasenauer (professor of computational life sciences, University of Bonn, Germany) recently used a statistical method called latent transition analysis to find distinct disease states of acute COVID-19 and of Long Covid and to map how patients transition between these states over time.
From over 5,000 people (aged ≥14 years) infected by SARS-CoV-2, the researchers analyzed demographic and clinical data; health-related quality of life survey data; and nine key Long Covid symptoms (cough, fatigue, headache, joint pain, loss of smell, loss of taste, memory loss, muscle pain, and troubled breathing). Their model found seven disease states (two for acute infection, five for long-term effects) and showed how patient groups typically progressed through these states over time. For example, younger men infected during the fourth SARS-CoV-2 wave were more likely to start in chronic state no. 7 (with the most severe symptoms) but quickly transition to state no. 3 (the healthiest state). In contrast, women over 60 years old were more likely to start in acute state no. 1 (with cough, trouble breathing, fatigue, and headache) and then transition to either chronic state no. 5 (with respiratory symptoms) or no. 6 (with high fatigue), where they often remained without recovery for a long time.
A key strength of latent transition analysis is its ability to show disease states and track longitudinal transitions even without knowing underlying disease mechanisms or possible symptom combinations. Thus, this approach may be valuable for studying post-infection syndromes in future pandemics. This study appeared in Nature Communications.
An exploratory study to help people with ME/CFS live in underdeveloped health care systems that neglect their condition
Ms. Vânia Ribeiro, rehabilitation nurse specialist at the Escola Superior de Saúde Norte da Cruz Vermelha Portuguesa (Portugal), recently published her master’s thesis describing an eight-week program designed to help people with ME/CFS manage their energy. In many countries, including both highly developed countries and less developed countries like Ireland and Portugal, ME/CFS remains poorly understood by the general public and by health care providers. For example, Portugal currently has no official guidelines for diagnosing and treating ME/CFS. The Portuguese health system has allocated only limited resources to support people with ME/CFS, considering it a rheumatic disease (while the World Health Organization considers it a neurological condition).
To begin to address these gaps, Ms. Ribeiro conducted a small exploratory study on the effects of teaching practical energy-management strategies. She recruited 13 adults with ME/CFS, and over eight online sessions, discussed ME/CFS biology and treatments; post-exertional malaise; strategies to manage energy; and ways to communicate health care needs effectively and assertively to caregivers and clinicians. She also gave participants daily diaries to record activities and symptoms and wearable heart rate monitors to help identify and prevent overexertion. Participants then planned how they would use these skills to gradually return to work or school. At the end of the program, everyone surveyed (10/13 participants) said the sessions were excellent or very helpful and fully addressed the main challenges of living with ME/CFS.
Overall, people functioned better and were less fatigued. These results suggest that even in health care systems that vastly underrecognize ME/CFS, people can gain meaningful control over their condition by understanding the disease and managing their energy. Dr. Francisco Westermeier, ME/CFS researcher at the FH JOANNEUM University of Applied Sciences (Austria) and a 2019 Solve Ramsay Grant recipient, was a coauthor on this study, which appeared in Medicina.
Further links between cerebrospinal fluid dysregulation and ME/CFS
Dr. Jonas Bergquist (at Uppsala University (Sweden) and Solve Ramsay Award winner) and Dr. Wenzhong Xiao (Harvard Medical School) recently collaborated to study cerebrospinal fluid (CSF) proteins in 31 people with ME/CFS.
Dysregulation of CSF proteins is especially interesting in ME/CFS because the disease strongly involves the central nervous system, including symptoms of cognitive impairment, autonomic dysfunction, and brain inflammation. Previous work by this group showed that many people with ME/CFS (estimated at 8 in 10 patients) have abnormalities in craniocervical structures, which can increase CSF pressure and impair its flow. In this study, the team looked for changes in CSF-protein levels associated with disease severity and with having postural orthostatic tachycardia syndrome (POTS). They found that people with more severe ME/CFS have more dysregulated complement pathway; more thromoinflammation (severe immune activation and blood clotting); more Alzheimer’s disease–related neuronal degeneration; and more problems with protein folding and with regulating extracellular structures. People both ME/CFS and POTS had dysregulated neuronal growth pathways; stronger innate immune responses; more blood platelet–mediated inflammation. These findings were published in Scientific Reports.
Autoantibodies cause neurological symptoms in some people with Long Covid
Dr. Akiko Iwasaki (Solve Catalyst Award winner at Yale University), Dr. Carmen Scheibenbogen (Solve Ramsay and Catalyst Award winner at University Hospital Charité), and Dr. David Putrino (Solve collaborator at the Mount Sinai School of Medicine) recently published an important paper showing that autoantibodies can cause neurological symptoms in a subset of people with Long Covid. Autoimmune diseases (like multiple sclerosis, rheumatoid arthritis, and systemic lupus) and Long Covid are all more prevalent in women than in men. And in addition to causing Long Covid, SARS-CoV-2 infection can trigger autoimmune diseases. These commonalities suggest that some Long Covid symptoms involve autoimmunity.
In this study, the researchers tested whether autoantibodies could cause Long Covid neurological symptoms. They studied samples from over 80 people with Long Covid–associated neurological symptoms (but no diagnosed autoimmune disease), as well as 30 people who recovered from COVID-10 and 35 healthy people. They found some people with Long Covid had higher levels and greater diversity of autoantibodies targeting central and peripheral nervous tissues than did healthy people.
Furthermore, antibodies isolated from people with Long Covid were sufficient to cause similar neurological symptoms in mice. Mice injected with antibodies from people with Long Covid–associated pain were more sensitive to pain than were mice receiving antibodies from other participants. Mice injected with antibodies from people with Long Covid–associated tinnitus or headache had less muscle strength. And mice injected with antibodies from people with Long Covid–associated dizziness were less balanced and coordinated. Additionally, mice injected with antibodies from the Long Covid group were more easily fatigued. These antibodies activated mouse brain regions associated with pain, fatigue, and emotional dysregulation. They also weakened nerves at the injected sites, reducing intraepidermal nerve fibers (consistent with small fiber neuropathy, common among people with Long Covid).
Overall, these results show that autoantibodies can directly cause neurological symptoms in some people with Long Covid. This supports use of antibody-targeting treatments, like intravenous immunoglobulin, immunoadsorption, and certain medicines including BC 007, rituximab, and Efgartigimod. This study appeared in Cell.
Hyperbaric oxygen therapy significantly improves physical and cognitive functioning and reduces pain and fatigue in people with ME/CFS
Dr. Carmen Scheibenbogen (Solve Ramsay and Catalyst Award winner at University Hospital Charité) recently evaluated whether hyperbaric oxygen therapy improves physical functioning in people with moderate-to-severe ME/CFS. This therapy involves breathing pure oxygen in a sealed, pressurized chamber. This helps deliver more oxygen to tissues and activates metabolic pathways that can reverse ME/CFS-associated dysregulation (e.g., by stimulating energy-regulating pathways and blood-vessel growth and by reducing inflammation). Dr. Scheibenbogen’s team also evaluated effects on cognitive functioning, exercise capacity, handgrip strength, and orthostatic intolerance.
Thirty people with moderate to severe ME/CFS and 30 healthy people each completed 40 therapy sessions over two to four months. The therapy significantly improved physical and cognitive functioning, exercise capacity, and handgrip strength and significantly reduced fatigue and pain. Effects were especially strong for physical functioning and fatigue, and no one experienced serious adverse effects. Brain magnetic resonance imaging showed that regions related to fatigue, sensory overload, and motor dysfunction were significantly more connected in people with ME/CFS than in healthy people. The therapy normalized connections among these regions.
Overall, these results show that hyperbaric oxygen therapy safely and significantly improves physical and cognitive functioning while reducing fatigue and pain in people with ME/CFS. They also suggest that altered connections in key brain regions may contribute to these symptoms. This study was published in The Journal of Translational Medicine.
Recommendations to improve IACCI research
Dr. Steven Schutzer (Rutgers University) and Dr. Jonas Bergquist (Uppsala University in Sweden; Solve Ramsay Award winner) recently published recommendations to better study infection-associated chronic conditions and illnesses (IACCIs). Researching IACCIs is challenging because of their complexity; heterogeneous and often overlapping symptoms; and lack of well-defined biomarkers. As a result, earlier studies have often produced results that are difficult to interpret or replicate. To support more conclusive IACCI research and bring about more effective treatments, Schutzer, Bergquist, and colleagues recommended these guidelines:
- Include more nuanced control groups. Most IACCI studies compare people with diseases to healthy people. Future studies should also include people who experienced precipitating infections but never developed chronic symptoms. Examples would be people infected with SARS-CoV-2 but did not develop Long Covid and people infected by B. burgdorferi but did not develop post-treatment Lyme disease. This comparison would help distinguish effects of the initial infection or the acute disease from those of the chronic disease. Another control group could include people with other diseases that produce similar symptoms.
- Consider time since infection. People can live with IACCIs for months, years, or decades, and IACCI effects can change over time. Studies should account for time since infection, ideally comparing people with IACCIs to those exposed to the pathogen at the same time but who did not develop chronic symptoms.
- Standardize collection and handling of biological samples. Variability in sample collection and processing can substantially affect IACCI study outcomes. For example, cortisol levels vary by time of day, yet some studies have not accounted for this when evaluating cortisol as a Long Covid biomarker, leading to confusion among researchers. Improper processing or storage can also degrade samples. Future studies should prioritize use of IACCI biobanks, which properly collect, store, and handle samples.
- Match patient subgroups to interventions. Failure to account for disease subgroups in clinical trials may obscure breakthrough treatment effects. For example, a drug that inhibits viral replication may help people with IACCIs for whom a virus is reactivated (one subgroup) but not help those with no reactivation (another). IACCI studies should therefore select participants not only on the basis of diagnosis, but also on having relevant disease subtypes.
- Study pediatric populations separately. Results from studies of adults with IACCIs may not apply to children, who have different physiologies, metabolism, and disease presentations. Because IACCIs are especially understudied in children, future research should explicitly evaluate pediatric populations.
- Use objective, standardized measures of cognitive function. Cognitive dysfunction is a key symptom of many IACCIs but is often assessed inadequately. Studies should use comprehensive, validated neuropsychological metrics instead of brief or subjective ones (like online questionnaires). Researchers should also consider confounding factors, like comorbidities or adverse effects from medicines that could impact cognition.
The authors noted that irreproducible scientific research costs the US economy ~$28 billion each year. Also, lack of FDA-approved treatments drives many patients to untested and potentially unsafe alternatives. More rigorous and standardized IACCI research could reduce these costs and accelerate the development of safe, effective treatments. This study appeared in Brain.
For more research summaries, visit our Solve Science Spotlight archive.