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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.

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.

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.

Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles.

Tobi, Martin, Chaudhari, Diptaraj, Ryan, Elizabeth P et al.·Biomolecules·2025

Researchers compared gut bacteria and immune molecules in the blood of people with long COVID and chronic fatigue syndrome. They found that people with these conditions have unusual patterns of gut bacteria and different levels of immune signaling molecules compared to healthy controls. These differences suggest the immune system and gut health may play a role in why some people develop long-lasting fatigue after infection.

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.

NeuroinflammationBiomarkersImmune System

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.

Effect of immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS.

Anft, Moritz, Wiemers, Lea, Rosiewicz, Kamil S et al.·Molecular therapy : the journal of the American Society of Gene Therapy·2025

This small study tested whether a blood-cleaning treatment called immunoadsorption could help people with ME/CFS symptoms that developed or worsened after COVID-19. The treatment removed harmful antibodies (immune proteins) from patients' blood, and researchers found it temporarily reduced inflammation markers and improved some brain function tests. However, patients' main ME/CFS symptoms and fatigue scores did not significantly improve, and the harmful antibodies came back within a month.

Abnormal T-Cell activation and cytotoxic T-Cell frequency discriminate symptom severity in myalgic encephalomyelitis/chronic fatigue syndrome.

Lee, Ji-Sook, Lacerda, Eliana, Kingdon, Caroline et al.·Journal of translational medicine·2025

This study compared immune system profiles in 96 ME/CFS patients with either mild/moderate or severe disease. Researchers found that people with severe ME/CFS had more activated immune cells and higher levels of inflammatory chemicals, while those with milder disease showed different patterns suggesting their bodies were responding to chronic viral infection. These findings suggest that mild and severe ME/CFS may involve different underlying immune problems, which could eventually help doctors predict disease severity and develop targeted treatments.

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.

E2 ModerateCohortPEM not requiredObservational

Single-Center Study of Therapeutic Apheresis in 24 Male Patients from the MENA Region: Reduction of Lipids, Inflammatory Markers, Autoantibodies, and Implications for Fatigue, Genetics, and Aging.

Steenblock, Charlotte, Walther, Romy, Kok, Yannick et al.·Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme·2025

This study tested a blood-cleaning procedure called apheresis in 24 men from the Middle East and North Africa who had chronic fatigue and metabolic problems like diabetes or high cholesterol. The procedure removed harmful fats and immune molecules from their blood. After treatment, patients showed improvements in their blood work, with reduced inflammatory markers and autoantibodies that may contribute to fatigue.

NeuroinflammationEnergy MetabolismImmune System

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.

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 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.

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.

Blood parameters differentiate post COVID-19 condition from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia.

Giménez-Orenga, Karen, Pierquin, Justine, Brunel, Joanna et al.·Brain, behavior, & immunity - health·2025

Researchers measured specific proteins and immune markers in the blood of people with post-COVID-19 condition, ME/CFS, and fibromyalgia to see if they could tell these conditions apart. They found that certain blood markers could distinguish post-COVID-19 condition from the other two conditions with very high accuracy, suggesting these illnesses may involve different immune patterns even though their symptoms overlap significantly.

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.

BiomarkersGut MicrobiomeEnergy MetabolismImmune System

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.

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.

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.

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.