Evidence browser

Genetic depletion of the early autophagy protein ATG13 impairs mitochondrial energy metabolism, augments oxidative stress, induces the polarization of macrophages to the M1 inflammatory mode, and compromises myelin integrity in skeletal muscle.

Toriola, Mubaraq A, Timlin, Emma, Bulbule, Sarojini et al.·Inflammation research : official journal of the European Histamine Research Society ... [et al.]·2026

This study examined a protein called ATG13 that helps cells clean up damaged parts, particularly in immune cells called macrophages. When ATG13 was reduced, these immune cells couldn't work properly, their energy-producing structures (mitochondria) became dysfunctional, and they created too much harmful oxidative stress. This triggered the immune cells to switch into an inflammatory state and caused muscle weakness and nerve damage in a mouse model.

E3 PreliminaryBehavioralPEM unclearObservational

Cognitive behavioural therapy for severe fatigue following COVID-19 in adolescents: a serial single-case observational study of five consecutively referred patients.

Kuut, Tanja A, Müller, Fabiola, Braamse, Annemarie M J et al.·Behavioural and cognitive psychotherapy·2025

This study tested whether cognitive behavioral therapy (CBT)—a type of talk therapy that helps people change unhelpful thinking patterns and behaviors—could help teenagers with severe fatigue after COVID-19. Five teenagers received CBT over 12 weeks. By the end, all five were no longer severely fatigued, most felt less physically limited, and all were able to return to school without absences.

E3 PreliminaryCommentaryPEM requiredEditorial

mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS.

Bar-Tana, Jacob·Journal of translational medicine·2025

This study proposes that ME/CFS, Long COVID, and similar post-infection illnesses may all be caused by the same underlying problem: excessive activity of a cellular control system called mTORC1. The authors suggest that if this overactive system is the shared driver of these conditions, it could explain why patients experience fatigue, worsening after exercise, pain, heart rate changes, and brain fog—and it might point toward new treatments.

Energy MetabolismPost-Exertional Malaise

E3 PreliminaryReviewPEM unclearReview-Narrative

Creatine and post-viral fatigue syndrome: an update.

Ostojic, Sergej M, Candow, Daren G, Tarnopolsky, Mark A·Journal of the International Society of Sports Nutrition·2025

This review examines how creatine—a natural substance that helps muscles produce energy—might help people with post-viral fatigue syndrome (the prolonged exhaustion that can follow viral infections like COVID-19). The researchers found that people with this condition often have problems with how their body produces and uses energy, particularly in the mitochondria (the cell's power centers). They suggest that taking creatine supplements could help restore energy production and reduce symptoms like fatigue and brain fog.

Energy MetabolismImmune SystemPost-Exertional Malaise

Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise in ME/CFS.

Che, Xiaoyu, Ranjan, Amit, Guo, Cheng et al.·npj metabolic health and disease·2025

This study examined blood samples and immune responses in ME/CFS patients to understand why they experience extreme fatigue and feeling worse after activity. Researchers found that patients' immune systems overreact to germs, their bodies have trouble producing energy efficiently, and they have several chemical imbalances in their blood. These problems got worse after exercise and matched how sick patients felt.

E3 PreliminaryReviewPEM requiredReview-Narrative

Tetrahydrobiopterin in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Friend or Foe?

Rahman, A F M Towheedur, Benko, Anna, Bulbule, Sarojini et al.·Biomolecules·2025

This review article examines a molecule called tetrahydrobiopterin (BH4) and its possible role in ME/CFS, particularly in patients who experience orthostatic intolerance (dizziness or fainting when standing up). The researchers found that BH4 metabolism—the way the body processes this molecule—is not working properly in ME/CFS patients with these symptoms. By understanding how BH4 goes wrong, scientists hope to explain why ME/CFS patients have problems with blood flow to the brain.

BiomarkersPost-Exertional Malaise

E3 PreliminaryReviewPEM unclearReview-Narrative

Post-COVID-19 Vaccination (or Long Vax) Syndrome: Putative Manifestation, Pathophysiology, and Therapeutic Options.

Yong, Shin Jie, Kenny, Tiff-Annie, Halim, Alice et al.·Reviews in medical virology·2025

This review describes a condition called post-COVID-19 vaccination syndrome (PCVS), where some people develop long-lasting symptoms similar to long COVID after receiving a vaccine. Symptoms typically start within days to weeks after vaccination and can last for months or years, including fatigue, brain fog, and nerve tingling. The study examines what might cause PCVS and discusses possible treatments, though researchers emphasize that much remains unknown about this condition.

E3 PreliminaryMechanismPEM not requiredMechanistic

Long COVID and chronic fatigue syndrome/myalgic encephalitis share similar pathophysiologic mechanisms of exercise limitation.

Jothi, Swathi, Insel, Michael, Claessen, Guido et al.·Physiological reports·2025

This study compared how bodies use oxygen during exercise in people with long COVID, ME/CFS, and healthy controls. Researchers found that both long COVID and ME/CFS patients had trouble getting oxygen into their muscles during exercise, which was the main reason they couldn't exercise as much as healthy people. If this muscle oxygen problem could be fixed, it might significantly improve exercise ability in both conditions.

E3 PreliminaryMechanismPEM not requiredObservational

Cytokine profiles associated with persisting symptoms of post-acute sequelae of COVID-19.

Kwon, Ji-Soo, Chang, Euijin, Jang, Hyeon Mu et al.·The Korean journal of internal medicine·2025

After COVID-19, some people develop long-lasting symptoms like fatigue, brain fog, and difficulty exercising—a condition called long COVID or PASC. This study measured immune system markers (called cytokines) in the blood of 79 people and found that certain symptoms were linked to higher levels of specific immune proteins, suggesting the immune system may stay overactive in some long COVID patients.

E3 PreliminaryCohortPEM requiredObservational

Two-day cardiopulmonary exercise testing in long COVID post-exertional malaise diagnosis.

Gattoni, Chiara, Abbasi, Asghar, Ferguson, Carrie et al.·Respiratory physiology & neurobiology·2025

This study tested whether Long COVID patients experience a measurable drop in exercise capacity after 24 hours, which would suggest their bodies aren't recovering properly from exercise. Researchers had 15 Long COVID patients do exercise tests on two consecutive days and found no significant difference in performance between day 1 and day 2. Surprisingly, this was true even though 80% of patients reported post-exertional malaise (PEM) symptoms over the previous six months.

E3 PreliminaryCohortPEM unclearCross-Sectional

Patient Perspectives on the Care in a Long COVID Outpatient Clinic-A Regional Qualitative Analysis from Germany.

Gölz, Lea Alexandra, Poß-Doering, Regina, Merle, Uta et al.·Healthcare (Basel, Switzerland)·2025

Researchers interviewed 14 patients attending a specialized Long COVID clinic in Germany to understand their experiences with care. Patients reported that while the clinic staff were knowledgeable and compassionate, many experienced a worsening of symptoms after their visit (a pattern called post-exertional malaise), and most wanted more follow-up appointments to manage their condition.

Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics-Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Baraniuk, James N·International journal of molecular sciences·2025

This study examined fluid from around the brain and spinal cord in ME/CFS patients and healthy controls, measuring chemical substances before and after exercise. Researchers found that ME/CFS patients have abnormal levels of certain chemicals related to energy production and brain function, especially after exercise. The study suggests that exercise may trigger harmful changes in brain chemistry in ME/CFS patients that don't happen in healthy people, which could explain post-exertional malaise (the worsening of symptoms after activity).

E3 PreliminaryPEM unclear

Perspectives of Rehabilitation Professionals on Long COVID Interventions to Facilitate Return-to-Work.

MacKinnon, Cassandra, Castro-Barquero, Cassandra, Kontis, Alexandra et al.·Canadian journal of occupational therapy. Revue canadienne d'ergotherapie·2025

This study asked rehabilitation professionals in Quebec about their experiences helping people with long COVID return to work. The professionals emphasized that education, gradually increasing activity, and self-management are the most helpful approaches, but they noted that returning to work is very difficult without workplace accommodations and proper support for managing post-exertional malaise (when symptoms worsen after activity).

E3 PreliminaryDiagnosticPEM requiredMethods-Paper

Stress-Induced Changes in Immune Signatures in ME/CFS Patients Determined by Transcriptome Analysis.

Gamer, Jackson, Van Booven, Derek, Zarnowski, Oskar et al.·Methods in molecular biology (Clifton, N.J.)·2025

Researchers studied how the immune system of ME/CFS patients responds to exercise by examining blood cells before, during, and after a physical challenge. They compared these responses in ME/CFS patients to healthy people using advanced genetic testing. This study is part of ongoing efforts to understand what makes ME/CFS different at a biological level and why exercise can make symptoms worse.

E3 PreliminaryMechanismPEM requiredPreprintPreprint

Dissecting the genetic complexity of myalgic encephalomyelitis/chronic fatigue syndrome via deep learning-powered genome analysis.

Zhang, Sai, Jahanbani, Fereshteh, Chander, Varuna et al.·medRxiv : the preprint server for health sciences·2025

Researchers used advanced artificial intelligence to analyze the genes of ME/CFS patients and discovered 115 genes that may contribute to the disease. They found that people with ME/CFS have lower levels of these risk genes active in their immune cells and nervous system. This genetic analysis could eventually help doctors diagnose ME/CFS more accurately and identify new treatment targets.

BiomarkersImmune SystemCognitive ImpairmentPost-Exertional Malaise

E3 PreliminaryGuidelinePEM requiredGuideline

Multidisciplinary collaborative guidance on the assessment and treatment of patients with Long COVID: A compendium statement.

Cheng, Abby L, Herman, Eric, Abramoff, Benjamin et al.·PM & R : the journal of injury, function, and rehabilitation·2025

This is a comprehensive clinical guide created by over 40 Long COVID treatment centers to help doctors evaluate and care for Long COVID patients. The guide covers how to assess symptoms, manage common problems like fatigue and brain fog, and help patients return to work or daily activities. It emphasizes that Long COVID is real, takes it seriously, and recommends treatments based on what doctors currently know while acknowledging many unknowns remain.

BiomarkersImmune SystemPost-Exertional Malaise

Gulf War Illness Induced Sex-Specific Transcriptional Differences Under Stressful Conditions.

Frank, Joshua, Tehrani, Lily, Gamer, Jackson et al.·International journal of molecular sciences·2025

Researchers studied how the immune system responds to physical stress in Gulf War veterans with Gulf War Illness (GWI), a condition similar to ME/CFS with fatigue, brain fog, and exhaustion. They found that men and women with GWI have different patterns of immune system activation during and after exercise, suggesting their bodies handle stress differently. These differences could help doctors develop better tests and treatments tailored to each person's sex.

E3 PreliminaryReviewPEM unclearReview-Narrative

Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Syed, Abu Mohammad, Karius, Alexander K, Ma, Jin et al.·Physiology (Bethesda, Md.)·2025

This review examines how mitochondria—the parts of cells that produce energy—may not be working properly in ME/CFS patients. The authors suggest that problems with energy production in cells could explain why people with ME/CFS feel severely exhausted after physical activity. They also note that similar energy problems appear in long COVID, which suggests both conditions may share a common underlying cause.

Severe MELong COVID OverlapPost-Exertional Malaise

E3 PreliminaryBehavioralPEM requiredCase-Control

Recovery from Myalgic Encephalomyelitis/Chronic Fatigue syndrome developed after severe acute respiratory syndrome coronavirus 2 vaccination: A case report.

Kurotori, Isaku, Sasao, Wataru, Abe, Masahiko·PCN reports : psychiatry and clinical neurosciences·2025

This case report describes a 65-year-old woman who developed ME/CFS symptoms after receiving her third COVID-19 vaccine, including severe tiredness, worsening after activity, and dizziness. After 30 months of symptoms, she recovered using a combination approach that included careful activity management, medications, and mental health support. This is the first documented case showing full recovery from vaccine-associated ME/CFS.

E3 PreliminaryDiagnosticPEM unclearMethods-Paper

Developing a minimum dataset for a national patient registry on Long COVID in Canada: a Delphi consensus-based study.

Mazurik, Kathrina, Amah, Adelaide, Dumitrescu, Donna Ioana et al.·BMJ open·2025

Researchers in Canada wanted to create a standard list of questions for a national registry to collect information about Long COVID from patients. They asked 52 experts—including patients, caregivers, doctors, and researchers—to vote on which questions were most important across three rounds of surveys. The final list includes 48 key questions focused on fatigue, post-exertional malaise, heart problems, breathing issues, brain fog, quality of life, and healthcare access.