Evidence browser

Overlapping Clinical Presentation of Long COVID and Postacute COVID-19 Vaccination Syndrome: Phenotypes, Severity, and Biomarkers.

Purpura, Lawrence, Heisler, Thomas, Palmer, Steven et al.·Clinical infectious diseases : an official publication of the Infectious Diseases Society of America·2026

This study compared three groups of people dealing with long-term effects from COVID-19: those with long COVID and ME/CFS, those with long COVID without ME/CFS, and those with symptoms after COVID-19 vaccination. While all three groups shared common symptoms like fatigue, the ME/CFS group experienced more widespread symptoms across their body. Interestingly, people in the vaccination-related group had higher rates of unusual symptoms like nerve pain and rashes, and their blood tests showed different patterns of autoimmune markers—substances that suggest the immune system may be attacking the body's own tissues.

Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile, and vascular dysfunction.

Heng, Benjamin, Gunasegaran, Bavani, Krishnamurthy, Shivani et al.·Cell reports. Medicine·2025

This study examined blood samples from ME/CFS patients and healthy people to understand what goes wrong in the body. Researchers found that immune cells in ME/CFS patients are struggling to make energy (ATP), the fuel that powers our cells. The immune system also showed signs of being immature or worn out, and blood proteins related to clotting and blood vessel problems were elevated, suggesting blood vessel dysfunction may contribute to ME/CFS symptoms.

Cerebrospinal fluid immune phenotyping reveals distinct immunotypes of myalgic encephalomyelitis/chronic fatigue syndrome.

Bastos, Victoria C, Greene, Kerrie A, Tabachnikova, Alexandra et al.·Journal of immunology (Baltimore, Md. : 1950)·2025

Researchers studied cerebrospinal fluid (the fluid around the brain and spinal cord) from people with ME/CFS and found that the immune system appears to work differently in different patients. They discovered two distinct patient groups with different immune patterns and pathogen exposure histories, even though both groups had similar symptoms. This suggests that ME/CFS may not be a single disease, but rather several related conditions with different underlying causes.

HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity.

Giménez-Orenga, Karen, Martín-Martínez, Eva, Nathanson, Lubov et al.·eLife·2025

This study looked at special genetic materials called human endogenous retroviruses (HERVs) in the blood cells of women with ME/CFS, fibromyalgia, both conditions, or neither. The researchers found that the pattern of which HERVs were active could perfectly distinguish between these four groups—suggesting this could become a reliable blood test to diagnose these conditions. The study also found that ME/CFS patients had specific changes in immune cells that matched how severe their symptoms were.

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.

Immune SystemLong COVID Overlap

Comparable Immune Alterations and Inflammatory Signatures in ME/CFS and Long COVID.

Petrov, Steliyan, Bozhkova, Martina, Ivanovska, Mariya et al.·Biomedicines·2025

This study compared immune system markers in people with ME/CFS and Long COVID to those of healthy individuals. Both patient groups showed similar immune problems: lower levels of protective immune cells and higher levels of inflammatory substances in their blood. The findings suggest that ME/CFS and Long COVID may involve very similar underlying immune dysfunction.

E2 ModerateCohortPEM not requiredCase-Control

Affective and chronic fatigue symptoms are associated with serum neuronal damage markers in Parkinson's disease.

Al-Hakeim, Hussein Kadhem, Khudhair, Hayder Naji, Ranaei-Siadat, Sayed-Omid et al.·Scientific reports·2025

This study looked at people with Parkinson's disease who also experienced depression and extreme fatigue, similar to ME/CFS. Researchers found that certain proteins in the blood that signal brain cell damage were elevated in these patients, and these proteins were connected to inflammation, blood sugar problems, and the mood and fatigue symptoms they experienced.

Immune SystemNeuroinflammation

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 unclearCase-Control

SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis.

Rostami-Afshari, Bita, Elremaly, Wesam, Franco, Anita et al.·Journal of translational medicine·2025

Researchers in Canada and Norway studied a protein called SMPDL3B in people with ME/CFS and found it was associated with higher severity of symptoms, particularly in women. In laboratory experiments, two diabetes medications (vildagliptin and saxagliptin) showed signs of restoring normal levels of this protein in immune cells, suggesting a possible future treatment approach. However, this is early-stage research; clinical trials would be needed before these medications could be tested in ME/CFS patients.

The immune checkpoint pathophysiology of depression and chronic fatigue syndrome due to preeclampsia: focus on sCD80 and sCTLA-4.

Omar, Jangir Sami, Albarzinji, Niaz, Niu, Mengqi et al.·Acta neuropsychiatrica·2025

This study looked at immune system markers in pregnant women with preeclampsia (a serious pregnancy condition) who also experienced depression, anxiety, and fatigue. Researchers found that certain immune molecules called sCTLA-4 and sCD80, along with imbalances in minerals like zinc and magnesium, were associated with these neuropsychiatric symptoms. The study suggests that immune system activation may play a role in why preeclampsia causes mood and fatigue problems.

E2 ModerateCohortPEM requiredLongitudinal

Temporal Dynamics of the Plasma Proteomic Landscape Reveals Maladaptation in ME/CFS Following Exertion.

Germain, Arnaud, Glass, Katherine A, Eckert, Melissa A et al.·Molecular & cellular proteomics : MCP·2025

Researchers studied what happens in the blood of ME/CFS patients during and after exercise to understand post-exertional malaise (PEM)—the worsening of symptoms that occurs after physical activity. They measured over 6,000 different proteins in 79 ME/CFS patients and 53 healthy controls before exercise, immediately after, and during recovery. They found that ME/CFS patients have abnormal protein changes during recovery that suggest their immune system and energy-producing cells are not working properly after exertion.

Immune SystemPost-Exertional Malaise

Energy MetabolismImmune SystemNeuroinflammation

Increased galanin-galanin receptor 1 signaling, inflammation, and insulin resistance are associated with affective symptoms and chronic fatigue syndrome due to long COVID.

Al Masoodi, Wasim Talib Mahdi, Radhi, Sami Waheed, Abdalsada, Habiba Khdair et al.·PloS one·2025

This study looked at 90 people, some with Long COVID and some without, to understand why Long COVID patients develop depression, anxiety, and chronic fatigue. Researchers measured several substances in the blood related to inflammation and metabolism. They found that people with Long COVID had higher levels of inflammatory markers and abnormal insulin function, and these changes were linked to their mood and fatigue symptoms.

E2 ModerateCohortPEM unclearObservational

A comparison of genome-wide association analyses of persistent symptoms after Lyme disease, fibromyalgia, and myalgic encephalomyelitis - chronic fatigue syndrome.

Hirsch, Annemarie G, Justice, Anne E, Poissant, Amy et al.·BMC infectious diseases·2025

Researchers studied the genes of people who had Lyme disease to understand why some develop lasting symptoms even after treatment. They found two genetic regions that might be involved in persistent Lyme disease symptoms, with one linked to a protein called MARC2 that affects immune function. When they checked whether these same genetic changes appeared in people with fibromyalgia or ME/CFS, they did not find the same patterns, suggesting these conditions may have different genetic roots.

Chronic fatigue syndrome, depression, and anxiety symptoms due to relapsing-remitting multiple sclerosis are associated with reactivation of Epstein-Barr virus and Human Herpesvirus 6.

Maes, Michael, Almulla, Abbas F, Vojdani, Elroy et al.·Neuro endocrinology letters·2025

This study looked at whether reactivation of two common viruses—Epstein-Barr virus (EBV) and Human herpesvirus 6 (HHV-6)—are connected to fatigue, depression, and anxiety in people with a type of multiple sclerosis called RRMS. Researchers measured immune responses (antibodies) to these viruses in MS patients and healthy controls, and found that higher antibody levels were strongly linked to worse fatigue and mood symptoms. The findings suggest that when these dormant viruses become active in the body, they may trigger or worsen fatigue and psychiatric symptoms.

Circulating cell-free RNA signatures for the characterization and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome.

Gardella, Anne E, Eweis-LaBolle, Daniel, Loy, Conor J et al.·Proceedings of the National Academy of Sciences of the United States of America·2025

Researchers analyzed tiny pieces of RNA floating in the blood of people with ME/CFS and compared them to healthy people. They used a computer program to identify a pattern of these RNA pieces that could help diagnose ME/CFS with 77% accuracy. The study found that people with ME/CFS have different levels of immune cells releasing material into their blood, suggesting the immune system is behaving differently.

E2 ModerateCohortPEM unclearObservational

Functional and internalizing disorders co-aggregate with cardiometabolic and immune-related diseases within families: a population-based cohort study.

Steen, Olivier D, Bos, Martje, van Ockenburg, Sonja L et al.·BMC medicine·2025

This study found that ME/CFS, fibromyalgia, and irritable bowel syndrome tend to run in families alongside conditions like depression, anxiety, autoimmune diseases, and metabolic disorders. Researchers analyzed data from over 166,000 people in a Dutch population cohort to understand whether these conditions share common inherited risk factors. The findings suggest that the causes of functional disorders like ME/CFS may overlap with the causes of immune and metabolic diseases, which could point to new treatment approaches.

E2 ModerateCohortPEM requiredCase-Control

Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling.

Hunter, Ewan, Alshaker, Heba, Bundock, Oliver et al.·Journal of translational medicine·2025

Researchers developed a new blood test called EpiSwitch®CFS that may help diagnose ME/CFS by detecting specific patterns in how DNA is organized in blood cells. When tested on stored blood samples from 47 ME/CFS patients and 61 healthy people, the test correctly identified 92% of ME/CFS patients and correctly ruled out 98% of healthy controls. This could potentially help doctors diagnose ME/CFS more reliably, since there is currently no standard blood test for the condition.

BiomarkersNeuroinflammationImmune System

Peripheral Levels of Selected Biomarkers in Patients with Post-Sarcoidosis Chronic Fatigue Syndrome.

Małujło-Balcerska, Elżbieta, Bączek, Karol, Górski, Witold et al.·Journal of inflammation research·2025

This study looked at 71 people with sarcoidosis (a disease that causes inflammation) to understand why some feel extremely tired even after their disease improves. Researchers measured inflammation markers in the blood and found that people with lingering fatigue had higher levels of a protein called IL-6 compared to those without fatigue. The findings suggest that low-grade inflammation may be keeping people fatigued even when their disease appears to be under control.

E2 ModerateCohortPEM unclearLongitudinal

AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome.

Xiong, Ruoyun, Aiken, Elizabeth, Caldwell, Ryan et al.·Nature medicine·2025

Researchers used artificial intelligence to analyze blood, gut bacteria, immune cells, and symptoms from 249 ME/CFS patients tracked over 4 years. The AI model discovered that ME/CFS involves abnormal patterns in gut bacteria products, blood fats, and immune cells that attack infections—particularly special T cells that become overactive. These findings suggest ME/CFS isn't caused by a single problem but by multiple connected systems going wrong together.

Energy MetabolismBiomarkersImmune SystemGut Microbiome

E2 ModerateCohortPEM unclearCase-Control

Killer cell immunoglobulin-like receptor (KIR) alleles suggested to be associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Ramadan, Donia Jamal, Kichula, Katherine M, Tao, Sudan et al.·Brain, behavior, and immunity·2025

This study examined specific genetic variations in natural killer (NK) cells—immune cells that help fight infections—in people with ME/CFS compared to healthy people. Researchers found that certain genetic variants were more common in ME/CFS patients while others were less common, suggesting that differences in how NK cells are regulated may play a role in ME/CFS. This supports the idea that immune system dysfunction is involved in the condition.