Evidence browser

Clinical and Laboratory Characteristics of Fatigue-Dominant Long-COVID Subjects: A Cross-Sectional Study.

Lee, Jin-Seok, Choi, Yujin, Joung, Jin-Yong et al.·The American journal of medicine·2025

This study looked at 100 people with long COVID who experience significant ongoing fatigue, similar to ME/CFS. Researchers measured fatigue levels and checked blood levels of cortisol (a stress hormone) and other immune markers. They found that people with lower cortisol levels reported worse fatigue and lower quality of life, suggesting a possible connection between this hormone and fatigue severity.

E2 ModerateCohortPEM unclearObservational

Oral minocycline therapy as first-line treatment in patients with Myalgic encephalomyelitis and long COVID: A pilot study.

Miwa, Kunihisa·eNeurologicalSci·2025

This small study looked at whether a common antibiotic called minocycline might help people with ME/CFS, including those with long COVID. Fifty-five patients took minocycline for about 6 weeks, and 80% of those who completed the treatment reported meaningful improvements in their symptoms like fatigue, brain fog, and sleep problems. The treatment worked best for people early in their illness (within 6 months of symptom onset).

Understanding symptom clusters, diagnosis and healthcare experiences in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID: a cross-sectional survey in the UK.

Mansoubi, Maedeh, Richards, Thomas, Ainsworth-Wells, Martine et al.·BMJ open·2025

This large UK survey asked over 8,800 people with ME/CFS or long COVID about their symptoms and experiences with healthcare. The study found that fatigue, brain fog, pain, and sleep problems are the most common symptoms, but people often wait years for a diagnosis. Even after new healthcare guidelines were introduced, most patients said they weren't satisfied with the care they received from the NHS.

Deoxygenation Trends and Their Multivariate Association with Self-Reported Fatigue in Post-COVID Syndrome.

Ladek, Anja-Maria, Lucio, Marianna, Weiß, Andreas et al.·Biomedicines·2025

This study looked at oxygen levels in the muscles of 100 people with long COVID and 50 healthy controls while they performed light exercise (squeezing a stress ball). The researchers used a special non-invasive scan called NIRS to measure this. People with long COVID, especially those with post-exertional malaise, showed abnormal oxygen patterns in their muscles compared to healthy people, and this was linked to their fatigue levels.

E2 ModerateCohortPEM unclearCase-Control

Epstein-Barr virus (EBV) reactivation in post COVID-19.

Shady, Eslam Farid Abu, Ghallab, Abdelhakim Fouad, Shaker, Doaa Abdullah et al.·Auris, nasus, larynx·2025

This study looked at whether a virus called Epstein-Barr virus (EBV) wakes up again in people who have prolonged COVID symptoms like fatigue. Researchers compared 140 people with ongoing COVID fatigue to 80 people who fully recovered from COVID. They found that EBV was reactivated in about 29% of people with persistent fatigue compared to 11% of those who recovered, suggesting EBV reactivation might play a role in long COVID.

Wearable technology in the management of complex chronic illness: preliminary survey results on self-reported outcomes.

Sawyer, Abbey, Preston, Rory, Leeming, Harry et al.·Frontiers in digital health·2025

This study looked at whether a smartphone app with a wearable armband helps people with ME/CFS and Long COVID manage their energy and symptoms. Over 1,300 people with these conditions used the app and answered questions about whether it helped them. Most people who used the app for at least a month reported feeling like they better understood their energy limits and how to manage daily activities, though some improvements may have simply come from tracking their own experience over time.

E2 ModerateCohortPEM not requiredCross-Sectional

Medical complexity and healthcare utilization among patients attending three U.S. post-COVID clinics.

Nji, Miriam A M, Briones, Elizabeth M, Issa, Anindita et al.·BMC infectious diseases·2025

This study looked at 984 patients who visited specialized clinics for ongoing problems after COVID-19 infection. Patients commonly experienced shortness of breath, fatigue, post-exertional malaise (feeling much worse after activity), and brain fog. Most patients needed multiple medical visits and referrals to different specialists like lung, heart, and neurologists, showing that post-COVID illness is complex and requires coordinated care from many healthcare providers.

E2 ModerateCohortPEM unclearLongitudinal

Gastrointestinal Barrier Disruption in Post-COVID Syndrome Fatigue Patients.

Rohrhofer, Johanna, Wolflehner, Viktoria, Schweighardt, Johannes et al.·Allergy·2025

This study looked at whether problems with the digestive system might help explain why some people develop long-lasting fatigue and other symptoms after COVID-19 (post-COVID syndrome). The researchers found that people with post-COVID fatigue had signs of gut inflammation and a leaky intestinal barrier, along with changes in immune markers in their blood. This suggests that COVID-19 may damage the gut in ways that contribute to long-term fatigue and post-exertional malaise.

Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia.

Azimi, Ghazaleh, Elremaly, Wesam, Elbakry, Mohamed et al.·International journal of molecular sciences·2025

This study measured a protein called FGF-21 in the blood of people with ME/CFS, fibromyalgia, and both conditions combined, then compared how their symptoms and thinking abilities differed based on their FGF-21 levels. The researchers found that FGF-21 levels—not just the diagnosis alone—were better at predicting which symptoms and cognitive problems each person would experience. This suggests FGF-21 could become a useful blood test to help doctors understand and treat these conditions more precisely.

E2 ModerateCohortPEM requiredCase-Control

Haptoglobin phenotypes and structural variants associate with post-exertional malaise and cognitive dysfunction in myalgic encephalomyelitis.

Moezzi, Atefeh, Ushenkina, Anastasiya, Widgren, Anna et al.·Journal of translational medicine·2025

Researchers studied a protein called haptoglobin in people with ME/CFS and found it may be connected to post-exertional malaise (that worsening of symptoms after activity) and brain fog. They discovered that certain genetic variations of this protein were more common in ME/CFS patients, and those variations were linked to worse symptoms and cognitive problems. The study suggests haptoglobin could be a useful marker to help doctors understand why ME/CFS symptoms vary between patients.

BiomarkersPost-Exertional Malaise

Poor Association Between Clinical Characteristics and Seropositivity in Children With Suspected Long COVID-A Single-Centre Study.

Olsson-Åkefeldt, S, Luthander, J, Anmyr, L et al.·Acta paediatrica (Oslo, Norway : 1992)·2025

This study looked at 113 children and teenagers who visited a specialized clinic for suspected long COVID symptoms. The researchers found that about half of the children had antibodies showing they had been infected with SARS-CoV-2, while the other half did not. Most children reported multiple symptoms like fatigue, dizziness, difficulty concentrating, and nausea, and these symptoms were similar whether or not they had evidence of past COVID infection. Many children were missing school and had to stop doing activities they enjoyed.

Concentrations of uremic bacterial metabolites in patients with post-COVID-19 syndrome.

Brigo, Natascha, Mayr, Wolfram, Taenzer, Maja et al.·Frontiers in cellular and infection microbiology·2025

This small study looked at special waste products made by gut bacteria in the urine of people with long COVID, ME/CFS, and healthy people. Researchers found that people with long COVID and ME/CFS had different patterns of these bacterial products compared to healthy controls, and these patterns might be connected to their symptoms like fatigue and post-exertional malaise (feeling much worse after activity).

Putting the PASC Score to the Test: Clinical vs. Statistical Accuracy in Long COVID Diagnosis.

Azola, Alba, Dastgheyb, Raha M, Easter, Rebecca et al.·Journal of general internal medicine·2025

Researchers tested a scoring tool called the PASC score to see if it could correctly identify long COVID patients. They compared 130 long COVID patients with 60 people who recovered completely from COVID-19. The PASC score was very accurate at confirming who had long COVID, but missed about 20% of actual patients. A simpler approach using just three symptoms (loss of smell/taste, post-exertional malaise, or sexual dysfunction) worked even better at catching long COVID cases.

E2 ModerateCohortPEM unclearLongitudinal

Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID.

Polli, Andrea, Godderis, Lode, Martens, Dries S et al.·BMC medicine·2025

This study followed 358 people who had COVID-19 to understand why some develop Long-COVID with symptoms like extreme fatigue, sleep problems, and post-exertional malaise (feeling much worse after activity). Researchers measured biological markers in blood and found that two factors—elevated troponin T (a heart protein) and shortened telomeres (the protective caps on DNA)—were most strongly linked to Long-COVID, particularly the fatigue cluster. The study shows that Long-COVID is not a single illness but has different symptom patterns, suggesting different underlying causes may be at play.

BiomarkersPost-Exertional Malaise

Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: a 7T magnetic resonance spectroscopy study.

Godlewska, Beata R, Sylvester, Amy L, Emir, Uzay E et al.·Molecular psychiatry·2025

Researchers used advanced brain scans to look at chemical differences in the brains and muscles of people with ME/CFS, long COVID, and healthy people. They found that people with ME/CFS had higher levels of lactate (a chemical related to energy use) in specific brain areas, suggesting their brains may be working harder to produce energy. People with long COVID showed different changes - lower levels of a chemical called choline in the brain. These findings suggest that ME/CFS and long COVID may have different underlying causes, even though they produce similar symptoms.

A Cross-Sectional Study of Symptom Prevalence, Frequency, Severity, and Impact of Long COVID in Scotland: Part I.

Mclaughlin, Marie, Cerexhe, Luke, Macdonald, Eilidh et al.·The American journal of medicine·2025

Researchers surveyed 253 people living with long COVID in Scotland to understand which symptoms are most common and how severe they are. The most frequent symptoms were post-exertional malaise (when activity makes symptoms worse), extreme tiredness, and thinking problems. The study found that people living in areas with more deprivation experienced more symptoms, but factors like vaccination status and age did not significantly affect symptom patterns.

E2 ModerateCohortPEM not requiredObservational

Replicated blood-based biomarkers for myalgic encephalomyelitis not explicable by inactivity.

Beentjes, Sjoerd Viktor, Miralles Méharon, Artur, Kaczmarczyk, Julia et al.·EMBO molecular medicine·2025

Researchers found multiple blood markers that distinguish ME/CFS patients from healthy people, including signs of inflammation, insulin problems, and liver issues. Importantly, these differences were NOT caused by patients being physically inactive—they are genuine biological changes related to the disease itself. While no single blood test can diagnose ME/CFS yet, these findings suggest that a combination of blood markers could eventually provide objective diagnosis.

Fatigue, interoplastic and nociplastic distress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Illness, and chronic idiopathic fatigue.

Chen, Emily, Rudder, Tamera, Nwankwere, Charles et al.·Frontiers in neuroscience·2025

This study compared pain sensitivity and fatigue in people with ME/CFS, Gulf War Illness, and chronic fatigue to understand what causes their symptoms. Researchers found that people with ME/CFS and Gulf War Illness have increased pain sensitivity (measured by pressing on their skin), and their pain and internal body sensations are closely linked. However, pain sensitivity didn't strongly correlate with fatigue levels, suggesting that fatigue may involve different mechanisms than pain.

E2 ModerateCohortPEM requiredObservational

The Clinical Relevance of Mast Cell Activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Rohrhofer, Johanna, Ebner, Lilian, Schweighardt, Johannes et al.·Diagnostics (Basel, Switzerland)·2025

This study looked at whether mast cells—immune cells that release chemicals causing inflammation—play a role in ME/CFS. Researchers surveyed 687 ME/CFS patients and reviewed records from 383 others, finding that about 25% had signs of problematic mast cell activation. Importantly, patients with mast cell problems who received targeted treatment reported better symptom relief than those without mast cell involvement, suggesting this might be a treatable subtype of ME/CFS.

Physical activity and sedentariness levels in patients with post-exertional malaise resulting from post-COVID-19 syndrome.

Elkebir, Kamel-Eddine, Gilbert, Jo-Anne, Kugathasan, Thiffya Arabi et al.·Work (Reading, Mass.)·2025

This study looked at how physical activity changed in 154 people who developed post-exertional malaise (PEM)—extreme tiredness and pain that worsens after activity—following COVID-19. Researchers found that after COVID-19, these patients became much less active and spent more time sitting, especially at work. Women and those with more severe PEM were most affected by these changes.