Evidence browser

NeuroinflammationImmune SystemPost-Exertional Malaise

Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses.

Tate, Warren, Walker, Max, Sweetman, Eiren et al.·Frontiers in neurology·2022

This study explores why ME/CFS and Long COVID symptoms persist and come and go in cycles. The researchers propose that after an initial trigger—like a viral infection, chemical exposure, or major stress—inflammation spreads to the brain through damaged blood vessels, causing ongoing brain inflammation that keeps the illness cycling. They suggest that similar mechanisms may explain why both ME/CFS (from various causes) and Long COVID (from COVID-19) produce remarkably similar symptoms despite different starting triggers.

Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Stanculescu, Dominic, Bergquist, Jonas·Frontiers in medicine·2022

This paper suggests that ME/CFS might develop through similar biological problems seen in people with severe critical illnesses. The researchers propose that four interconnected issues—reduced blood flow to tissues, damage to the gut lining, problems with pituitary gland function, and low thyroid hormone activity—could work together to create a cycle that keeps ME/CFS going. Understanding these connections could help develop better treatments.

E3 PreliminaryReviewPEM requiredReview-Narrative

Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM).

Baraniuk, James N·Brain sciences·2022

This review examines a brain region called the midbrain and how it might contribute to post-exertional malaise (PEM)—the worsening of symptoms after activity that happens in ME/CFS. When ME/CFS patients did exercise in a study, their midbrain showed increased activity during mental tasks, while Gulf War Illness patients showed the opposite pattern. The authors suggest that problems in this brain region could explain why ME/CFS patients have trouble with energy, sleep, mood, pain, and temperature control, especially after exertion.

Cognitive ImpairmentPost-Exertional Malaise

The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Dehhaghi, Mona, Panahi, Hamed Kazemi Shariat, Kavyani, Bahar et al.·Aging and disease·2022

This review examines how tryptophan, an amino acid we get from food, is processed differently in people with ME/CFS. The body normally converts tryptophan into important substances like serotonin (which affects mood) and NAD+, an energy molecule. The authors propose that this conversion process may become overactive in ME/CFS, depleting NAD+ and making fatigue worse. They suggest that NAD+ supplements might help reduce fatigue and improve quality of life.

Energy MetabolismPost-Exertional Malaise

Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach.

Wirth, Klaus J, Scheibenbogen, Carmen·Medicina (Kaunas, Lithuania)·2022

Many people with post-COVID syndrome experience shortness of breath and chest pain, even though their lungs and heart are typically healthy. This study proposes that the problem may stem from overbreathing (hyperventilation) during exercise, combined with problems in how the body regulates breathing and uses energy in muscles. The authors suggest that overbreathing creates a harmful cascade inside cells—disrupting sodium and calcium balance—which worsens fatigue and breathing difficulties. Preventing overbreathing might be a way to help these patients recover.

E3 PreliminaryCohortPEM unclearCase-Control

Stellate Ganglion Block for Long COVID Symptom Management: A Case Report.

Khan, Mashfee H, Kirkpatrick, Kennedy P, Deng, Yi et al.·Cureus·2022

This study describes one patient with long COVID who received a stellate ganglion block (SGB)—an injection that calms an overactive nervous system. The treatment helped reduce their fatigue, post-exertional malaise (worsening after activity), shortness of breath, and stomach problems. Because the nervous system controls many body functions, blocking specific nerve signals may help relieve symptoms driven by this dysregulation.

E3 PreliminaryGuidelinePEM requiredGuideline

[Recommendation for standardized medical care for children and adolescents with long COVID].

Töpfner, Nicole, Deutsche Gesellschaft für Pädiatrische Infektiologie e. V. (DGPI), Alberer, Martin et al.·Monatsschrift Kinderheilkunde : Organ der Deutschen Gesellschaft fur Kinderheilkunde·2022

This guideline provides doctors with expert recommendations for recognizing and treating long COVID in children and teenagers. It includes screening questions and step-by-step evaluation tools to help identify long COVID cases, as well as guidance on how different medical specialists should work together to care for affected young people. The recommendations are based on the best available evidence, though more research is still needed.

Immune SystemPost-Exertional Malaise

The autonomic aspects of the post-COVID19 syndrome.

Dotan, Arad, David, Paula, Arnheim, Dana et al.·Autoimmunity reviews·2022

After COVID-19 infection, many people experience long-lasting symptoms similar to ME/CFS, including fatigue, brain fog, and mood problems. Recent research suggests the immune system may attack nerve cells that control heart rate, blood pressure, and other automatic body functions, rather than just the virus itself. The authors propose that exercise therapy might be safer and more helpful than immunosuppressive drugs for treating these lingering post-COVID symptoms.

E3 PreliminaryCommentaryPEM required

Letter: Could endothelial dysfunction and vascular damage contribute to pain, inflammation and post-exertional malaise in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)?

Lubell, Jeffrey·Journal of translational medicine·2022

This editorial letter explores whether problems with blood vessel function and damage might explain some of the key symptoms of ME/CFS, including pain, inflammation, and post-exertional malaise (the exhaustion that follows physical activity). The author proposes that if blood vessels aren't working properly, they may not deliver enough oxygen and nutrients to tissues, which could trigger the symptoms many ME/CFS patients experience.

[Post-COVID syndrome with fatigue and exercise intolerance: myalgic encephalomyelitis/chronic fatigue syndrome].

Renz-Polster, Herbert, Scheibenbogen, Carmen·Innere Medizin (Heidelberg, Germany)·2022

This article explains that ME/CFS is a serious neurological and immune system disease, often triggered by infections like COVID-19, characterized by extreme fatigue lasting at least 6 months and a unique symptom called post-exertional malaise (PEM)—where even mild activity causes symptoms to worsen hours or days later. The authors stress that ME/CFS is a distinct medical condition that should not be confused with ordinary tiredness, and while there is no cure yet, treatment focuses on managing symptoms, addressing related circulation problems, and helping patients conserve energy through pacing.

Proposed subtypes of post-COVID-19 syndrome (or long-COVID) and their respective potential therapies.

Yong, Shin Jie, Liu, Shiliang·Reviews in medical virology·2022

This review examines long COVID (persistent symptoms lasting months after COVID-19 infection) and proposes that it comes in six different subtypes, one of which is ME/CFS-like illness. The authors describe the symptoms and potential treatments for each subtype, helping doctors and patients better understand which type of long COVID a person might have. This framework could help lead to more targeted treatments since different subtypes may need different approaches.

E3 PreliminaryDiagnosticPEM not requiredMethods-Paper

Estimating total morbidity burden of COVID-19: relative importance of death and disability.

Smith, Maia P·Journal of clinical epidemiology·2022

This study looked at the total health impact of COVID-19 by measuring not just deaths, but also the years of healthy life lost due to long-COVID symptoms. The researchers found that most of the burden from COVID-19 actually comes from people who survive but live with ongoing disability—not from deaths alone. The study suggests that resources should focus on preventing and treating long-COVID, especially in younger people and women who appear to bear a larger share of this burden.

E3 PreliminaryReviewPEM not requiredReview-Narrative

Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19.

Soares, Madu N, Eggelbusch, Moritz, Naddaf, Elie et al.·Journal of cachexia, sarcopenia and muscle·2022

Many people with COVID-19 and long COVID experience muscle weakness and tiredness, especially after physical activity. This review examines what happens inside muscle cells in these patients, including muscle fiber shrinkage, changes in how muscles use energy, and immune cell buildup. The authors suggest that severe illness, lack of activity, low oxygen levels, and poor nutrition all contribute to these problems, similar to what happens in other serious conditions.

E3 PreliminaryReviewPEM requiredReview-Narrative

The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implications.

Kell, Douglas B, Pretorius, Etheresia·The Biochemical journal·2022

This paper proposes that ME/CFS, Long COVID, and some other chronic diseases may be caused by a harmful cycle involving tiny blood clots blocking small blood vessels, followed by damage when blood flow returns. The authors suggest that this process creates harmful molecules called free radicals and triggers inflammation and other problems. They review existing evidence that treatments like antioxidants, anti-inflammatory drugs, and blood thinners might help address these underlying mechanisms.

Severe MEPost-Exertional Malaise

[Facts and myths about chronic fatigue syndrome].

Fink, Per, Skjernov, Mathias, Petersen, Line Kirkeby et al.·Ugeskrift for laeger·2022

This article discusses updates to ME/CFS treatment guidelines and challenges some common beliefs about the condition. The authors argue that new guidelines recommend against intense exercise programs for severely ill patients and suggest energy management instead, but they question whether the evidence supporting these changes was properly evaluated. They raise concerns about how the new guidelines were developed and what type of evidence was considered.

E3 PreliminaryMechanismPEM requiredCross-Sectional

Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Rayhan, Rakib U, Baraniuk, James N·Frontiers in neuroscience·2021

Researchers used brain imaging to look at what happens in ME/CFS patients' brains after exercise. They found that after submaximal exercise, a specific brain region (the anterior Default Mode Network) showed increased activity in ME/CFS patients but decreased activity in healthy controls. This brain pattern may help explain why ME/CFS patients experience symptom flare-ups after physical activity.

E3 PreliminaryMechanismPEM requiredObservational

Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Results From Open-Label Cyclophosphamide Intervention Study.

Sørland, Kari, Sandvik, Miriam Kristine, Rekeland, Ingrid Gurvin et al.·Frontiers in medicine·2021

This study found that blood vessels in people with ME/CFS don't work as well as they do in healthy people. The researchers measured how blood vessels widen and respond to changes in blood flow, and found these responses were reduced in ME/CFS patients. Interestingly, when patients received a strong immune-suppressing drug called cyclophosphamide, improvements in symptoms didn't match up with improvements in blood vessel function.

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Wirth, Klaus J, Scheibenbogen, Carmen·Journal of translational medicine·2021

This study proposes that ME/CFS may be caused by a problem with how the body's nervous system controls blood vessels and muscle function. The researchers suggest that faulty beta-2 receptors (proteins that normally help regulate these systems) lead to poor blood flow in muscles, buildup of harmful substances, and damage to the energy-producing structures inside muscle cells. This creates a harmful cycle where even small amounts of activity can trigger the same problems again and again, explaining why patients experience crashes after exertion.