Category: Overlapping Illnesses

Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia – overlap, differences, and emerging insights

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating chronic illnesses with considerable symptom overlap. Their symptoms include profound fatigue, widespread pain, post-exertional deterioration, sleep disturbance, dysautonomia, and cognitive impairment. These illnesses frequently co-occur; ME/CFS often develops first, particularly after infection. This overlap creates a diagnostic grey area and contributes to severe reductions in quality of life. Despite these shared features, key distinctions remain essential. ME/CFS is characterised by post-exertional neuroimmune exhaustion (PENE)/post-exertional malaise (PEM), a hallmark of post-exertional worsening and multisystem involvement. Contrastingly, FM centres on chronic widespread pain and symptom variability. It is not characterised by PEM/PENE or the same extent of system dysfunction as ME/CFS. Both disorders lack a definitive biomarker as of 2025. Thus, diagnosis remains clinical and supported by objective tests where available.

Main body: Although immune dysregulation is common in patients with each condition, distinct immune signatures have been observed. ME/CFS is characterised by fluctuating pro- and anti-inflammatory cytokine levels and a frequent reduction in natural killer (NK) cell function; this is consistent with immune exhaustion. Patients with FM exhibit elevated IL-6, IL-17 A, and IL-4 levels, and a broader immune imbalance linked to pain amplification rather than immune collapse. Viral infections do not directly cause either condition, but commonly act as triggers. Shared mechanisms, such as spinal reflex arc activation and microglial sensitisation, suggest a common pathway mediated by proprioceptor-induced microglial activation for chronic pain. ME/CFS causes autoimmunity-like processes, whereas evidence of autoimmune drivers for FM is limited. Gut microbiome studies have revealed reduced microbial diversity in patients with ME/CFS. Moreover, the two disorders are characterised by shared, yet distinct, microbial alterations.

Conclusion: Given the chronic and debilitating nature of ME/CFS and FM, prevention and early intervention remain crucial, but understudied. Health education, workplace adaptations, and early diagnostic pathways may substantially reduce the disease burden. Many patients are outside formal healthcare systems. Therefore, digital tools such as symptom-tracking apps, biosensors, remote testing, and assistive technologies are becoming central to disease management and monitoring. These approaches support a transdiagnostic, patient-centred model capable of addressing both conditions and reaching populations that remain underserved.

Source: Murovska M, Krumina A, Araja D, Kujawski S, Zalewski P, Nora-Krukle Z, Berkis U. Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia – overlap, differences, and emerging insights. J Transl Med. 2026 Feb 20. doi: 10.1186/s12967-026-07889-6. Epub ahead of print. PMID: 41715182. https://link.springer.com/article/10.1186/s12967-026-07889-6 (Full text available as PDF file)

Effects of Cacao Flavonoids in Long COVID-19 Patients with Chronic Fatigue: FLALOC, a Placebo-Controlled Randomized Clinical Trial

Abstract:

Background: In the context of long COVID, persistent fatigue is among the most prevalent symptoms that can develop after SARS-CoV-2 infection. Mitochondrial myopathy and endothelial dysfunction, which are triggers of inflammation, have emerged as prominent causes of long COVID-induced fatigue. Interestingly, the intake of flavanols, particularly (−)-epicatechin (EC), has been associated with the positive modulation of endothelial and mitochondrial structure and function.
Methods: In this work, we conducted a randomized, double-blind, placebo-controlled clinical trial to determine whether an EC-enriched supplement (ECES) improves plasma markers of inflammation, endothelial structure, and fatigue-related endpoints in patients with long COVID-19.
Results: The study included 46 subjects (mean age 52 years) who were instructed to consume two capsules/day for 90 days of either ECES (n = 23) or placebo (n = 23). Endpoints assessed included mean changes in plasma inflammatory markers (IL-1β, IL-6, and TNF-α) and endothelial dysfunction markers (syndecan-1), handgrip strength, fatigue scale, and quality of life (QoL). The results showed significant improvements in the ECES group for inflammatory markers, syndecan-1, and fatigue compared with the placebo group.
Conclusions: The results yield intriguing positive findings for EC and open a new avenue for treating long COVID.
Source: Munguía L, Silva S, Villarreal F, Nájera N, Ceballos G. Effects of Cacao Flavonoids in Long COVID-19 Patients with Chronic Fatigue: FLALOC, a Placebo-Controlled Randomized Clinical Trial. Journal of Clinical Medicine. 2026; 15(4):1468. https://doi.org/10.3390/jcm15041468 https://www.mdpi.com/2077-0383/15/4/1468 (Full text)

Altered Pain Perception and Modulation in Individuals With Post-COVID-Condition: Insights From Quantitative Sensory Testing

Abstract:

Introduction: Chronic pain is a significant and debilitating symptom observed in individuals with post-COVID condition (PCC), yet the underlying mechanisms remain poorly understood. This study aimed to investigate whether changes in psychophysical indicators of myofascial pain perception and modulation are present in individuals with PCC compared to symptom-free healthy controls (HC), and whether these changes correlate with the severity of clinical symptoms.

Methods: The study involved 84 individuals with PCC and 50 HC, assessing pain detection and tolerance thresholds (PDT and PTT), spatial and temporal summation of pain (SSP and TSP), and conditioned pain modulation (CPM) using phasic cuff pressure on the legs.

Results: Results indicated that individuals with PCC exhibited lower PDT and PPT (PDT: d = -0.557, p = 0.0022; PTT: d = -0.575, p = 0.0016), increased TSP (d = 0.424, p = 0.02) and decreased SSPPTT (d = -0.532, p = 0.0038) compared to HC CPM effects (CPMPDT: p = 0.058; CPMPTT: p = 0.43) did not differ significantly between groups but post hoc analysis revealed a significantly higher proportion of inhibitory responders among HC. Subgroup analyses highlighted that these effects were particularly pronounced in participants that reported chronic pain among their PCC symptoms, as well as those with more severe PCC symptomatology.

Conclusion: The findings suggest that individuals with PCC demonstrate altered myofascial pain perception, indicative of central sensitization. These results underscore the need for further research into targeted therapeutic strategies for managing chronic pain in PCC.

Significance statement: Individuals with post-COVID condition (PCC) often experience persistent pain. Using quantitative sensory testing of deep tissue pain, we found that individuals with PCC had lower pain detection and tolerance thresholds, stronger spatial and temporal summation, and a higher proportion of facilitatory conditioned pain modulation compared to healthy controls. This pattern is consistent with nociplastic pain, suggesting altered central pain processing in PCC. Understanding these mechanisms is essential for developing targeted treatments of chronic pain in this growing patient population.

Source: Lange H, Reichert J, Vock S, Hermes M, Beiner E, Eich W, Friederich HC, Treede RD, Tesarz J. Altered Pain Perception and Modulation in Individuals With Post-COVID-Condition: Insights From Quantitative Sensory Testing. Eur J Pain. 2026 Feb;30(2):e70203. doi: 10.1002/ejp.70203. PMID: 41699921. https://pubmed.ncbi.nlm.nih.gov/41699921/

Forced isolation by invisible barriers: international survey on the effects of fragrances on the quality of life

Abstract:

Background: Previous cross-sectional surveys showed that between 20 to 35% of the adult population report health effects in contact with fragrances. The present international survey with 3152 self-reported fragrance sensitive persons addresses the situation in more detail, gathered reported symptoms, underlying diseases, strategies to cope with fragrance sensitivity, and the impact on participation in social life and on quality of life.

Results: On average, every fragrance sensitive person in this survey associates almost ten health symptoms with fragrance exposure, the most frequent ones being cognitive problems, migraine/headaches, mucous membrane problems and breathing problems. More than a third (37.47%) of the survey participants indicate that they have experienced a physical breakdown due to heavy exposure to fragrances. Almost half of the respondents (48.92%) report that their fragrance sensitivity was the reason why they lost their job. Nearly 70% (68,31%) of survey participants indicate that they are excluded from social life almost completely or very strongly, and nearly two thirds (62.53%) indicate that they are forced into increasing isolation almost completely or very strongly. Around three quarters (76.84%) of survey participants state that fragrance exposure affects their quality of life strongly or takes away any quality of life completely.

Conclusions: Fragrance exposure is an invisible barrier that leads to isolation of fragrance sensitive persons in society. General avoidance of fragrances does not heal their sensitivity, but prevents the manifestation of the symptoms, so that fragrance sensitive persons would be able to participate in and contribute to society. Fragrance-free regulations for important areas, such as those implemented partially in Canada and the USA, would be an important improvement.

Many fragrance substances are hazardous with effects for the human health and the environment, but they are not essential for human health, safety or for the functioning of society. Therefore, hazardous fragrances are obvious candidates for a prompt phase out according to the European essential use concept. A responsible use of fragrances would not only help fragrance vulnerable individuals, but also the general population and the environment.

Source: Wagner, H., Klaschka, U. Forced isolation by invisible barriers: international survey on the effects of fragrances on the quality of life. Environ Sci Eur 38, 2 (2026). https://doi.org/10.1186/s12302-025-01259-7 https://link.springer.com/article/10.1186/s12302-025-01259-7 (Full text)

Activation of the Lectin Pathway Drives Persistent Complement Dysregulation in Long COVID

Abstract:

Long COVID affects a substantial proportion of survivors of acute infection with severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), who suffer a variety of symptoms that limit their quality of life and economic activity. Although the aetiology of long COVID is obscure, it appears to be a chronic inflammatory condition. Complement dysregulation is a prevalent feature of long COVID. Specifically, markers of classical, alternative, and terminal pathway activation are often elevated in patients with this condition.

Here, we used a sensitive assay for mannan-binding lectin-associated serine protease-2 (MASP-2)/C1Inh complexes to analyse lectin pathway activation in a previously characterised cohort of patients with long COVID (n = 159) and healthy convalescent individuals with no persistent symptoms after infection with SARS-CoV-2 (n = 76). The data were combined with those from the most predictive complement analytes identified previously to delineate potential biomarkers of long COVID. MASP-2/C1Inh complexes were significantly elevated in patients with long COVID (p = 0.0003). Generalised linear modelling further identified an optimal set of four markers, namely iC3b (alternative pathway), TCC (terminal pathway), MASP-2/C1Inh (lectin pathway), and the complement regulator properdin, which had a receiver operating characteristic predictive power of 0.796 (95% confidence interval = 0.664-0.905). Combinations of the classical pathway markers C4, C1q, and C1s/C1Inh were poorly predictive of long COVID.

These findings demonstrate that activation of the lectin complement pathway, which occurs upstream of the alternative and terminal pathways and can be inhibited therapeutically, is a salient feature of long COVID.

Source: Keat SBK, Khatri P, Ali YM, Arachchilage CH, Demopulos G, Baillie K, Miners KL, Ladell K, Jones SA, Davies HE, Price DA, Zelek WM, Morgan BP, Schwaeble WJ, Lynch NJ. Activation of the Lectin Pathway Drives Persistent Complement Dysregulation in Long COVID. Immunology. 2026 Jan 25. doi: 10.1111/imm.70110. Epub ahead of print. PMID: 41581925. https://onlinelibrary.wiley.com/doi/10.1111/imm.70110?af=R (Full text)

Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID

Abstract:

Background: Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with SARS-CoV-2. The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID.

Methods: We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/sex/infection/vaccine-matched patients with long COVID.

Findings: Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785.

Conclusions: These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID.

Source:Baillie K, Davies HE, Keat SBK, Ladell K, Miners KL, Jones SA, Mellou E, Toonen EJM, Price DA, Morgan BP, Zelek WM. Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID. Med. 2024 Mar 8;5(3):239-253.e5. doi: 10.1016/j.medj.2024.01.011. Epub 2024 Feb 15. PMID: 38359836. https://www.sciencedirect.com/science/article/pii/S2666634024000412 (Full text)

Immunoglobulin G complexes from post-infectious ME/CFS, including post-COVID ME/CFS disrupt cellular energetics and alter inflammatory marker secretion

Highlights:

  • This study addresses a critical gap in understanding the role of autoimmunity in ME/CFS and PASC, two debilitating conditions with overlapping features and few effective treatments.
  • By demonstrating that IgG antibodies from ME/CFS patients can directly alter mitochondrial structure and function in human endothelial cells, specifically inducing mitochondrial fragmentation and metabolic reprogramming, this study provides a mechanistic link between autoantibodies and endothelial cell dysfunction.
  • Furthermore, proteomic analyses reveal unique immune complex signatures in ME/CFS and PASC, highlighting disease-specific IgG activity and supporting the idea of antibody-mediated metabolic dysregulation.
  • These insights are especially important because they establish a foundation for novel, targeted therapies that modulate antibody activity or protect mitochondrial function.

Abstract:

Background: Autoimmunity is a key clinical feature in both post-infectious Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Post-Acute Sequelae of COVID (PASC). Passive transfer of immunoglobulins from patients’ sera into mice induces some clinical features of PASC. However, the physiological effects of immunoglobulins on cellular alterations remain elusive. In this study, we tested the potential effects of immunoglobulins from ME/CFS patients on endothelial cell dysfunction.

Methods: We have isolated immunoglobulins from 106 individuals, including ME/CFS (n = 39), PCS-CFS (n = 15), MS (n = 20) patients, and healthy controls (n = 41). Protein composition of the isolated immune complexes was studied using mass spectrometry. The effect of isolated immune complexes on mitochondria was evaluated using confocal microscopy and a Seahorse XFe96 Extracellular Flux Analyzer, and the impact on inflammatory cytokine secretion was studied using a multiplex bead-based assay.

Results: Here, we demonstrate that IgG isolated from post-infectious ME/CFS patients selectively induces mitochondrial fragmentation in human endothelial cells and alters cellular energetics. This effect is lost upon cleavage of IgG into its Fab and Fc fragments. The digested Fab fragment from ME/CFS alone was able to alter the cellular energetics, resembling the effect of intact IgG. IgG from post-infectious ME/CFS, including post-COVID ME/CFS patients, induced distinct but separate cytokine secretion profiles in healthy PBMCs. Proteomics analysis of IgG-bound immune complexes revealed significant changes in immune complexes from ME/CFS patients, affecting extracellular matrix organization, whereas those from post-COVID ME/CFS patients pointed to alterations in hemostasis and blood clot regulation.

Conclusions: We demonstrate that IgGs from ME/CFS patients carry a chronic protective stress response that promotes mitochondrial adaptation via fragmentation, without altering mitochondrial ATP generation capacity in endothelial cells. Together, these results highlight a potential pathogenic role of IgG in post-infectious ME/CFS and point to novel therapeutic strategies targeting antibody-mediated metabolic dysregulation.

Source: Zheng Liu, Claudia Hollmann, Sharada Kalanidhi, Stephanie Lamer, Andreas Schlosser, Emils Edgars Basens, Georgy Nikolayshvili, Liba Sokolovska, Gabriela Riemekasten, Rebekka Rust, Judith Bellmann-Strobl, Friedemann Paul, Robert K. Naviaux, Zaiga Nora-Krukle, Franziska Sotzny, Carmen Scheibenbogen, Bhupesh K. Prusty. Immunoglobulin G complexes from post-infectious ME/CFS, including post-COVID ME/CFS disrupt cellular energetics and alter inflammatory marker secretion. Brain, Behavior, & Immunity – Health, Volume 52, 2026, 101187 ISSN 2666-3546,
https://doi.org/10.1016/j.bbih.2026.101187. https://www.sciencedirect.com/science/article/pii/S2666354626000207 (Full text)

The fatigue spectrum in a community-based long haul COVID cohort

Abstract:

Introduction: In a Long Haul COVID referral clinic we describe the primary presentations of fatigue according to the CDC 2015 criteria for myalgic encephalitis/chronic fatigue syndrome (ME/CFS).

Methods: Between September 2021 and April 2022, 277 patients (61% women, 54 yrs: range 18-90 yrs) presented an average of 10 months after an acute COVID-19 infection (22% hospitalized). The clinical data were analyzed to conpare those with or without a primary or co-primary complaint of fatigue, subdivided as meeting ME/CFS criteria or not.

Results: 209 (73.5%) people (64% women) presented with fatigue. The Fatigue Severity Score was 5.33 (out 7) in those with 5.31 (SD1.54) vs. without 4.43 (SD1.65) a primary fatigue complaint (p > 0.001). Anxiety (58% vs. 38%, p < 0.02) and any psychiatric diagnosis (66% vs. 44%%, p < 0.01), but not depression itself, were overrepresented in those with Fatigue and ME/CFS. Those with prior managed sleep conditions did not increase risk for fatigue presentation. Of those with fatigue and an elevated FSS, 45/209 (21.9%) met criteria for ME/CFS. In those not meeting these criteria, associated ME/CFS symptoms were less consistent. Physical functioning by ECOG (1.88 (0.78) and 26% >2) did correlate with fatigue status. Depression was present (PHQ9 12.34 (5.95) with 63% >10) to a moderate or higher degree and was different with fatigue complaints. Brain fog (51.9%) was similar among the three categories, and correlated with FSS > 4, ECOG, and depression.

Conclusions: The fatigue phenotype in those presenting with it as a primary complaint comprises 21% meeting ME/CFS criteria and 79% which do not. In all the Long Haul COVID presentations. brain fog had separate, distinguishing features. Post-COVID fatigue is a spectrum which will confound clinical trials.

Source: Carter IV, May A, Hsieh IC, Torer J, Rosenberg D, Strohl KP. The fatigue spectrum in a community-based long haul COVID cohort. Sleep Breath. 2026 Jan 31;30(1):27. doi: 10.1007/s11325-025-03512-y. PMID: 41620575. https://link.springer.com/article/10.1007/s11325-025-03512-y (Full text)

ME/CFS and Long COVID Demonstrate Similar Bioenergetic Impairment and Recovery Failure on Two-Day Cardiopulmonary Exercise Testing

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Covid are characterized by post-exertional malaise (PEM). Similarities in disease presentation suggest important commonalities in bioenergetic impairment, but this hypothesis has not been demonstrated. The metabolic underpinnings of each disease can be elucidated by two cardiopulmonary exercise tests (CPET) administered 24 hours apart. This retrospective study examined physiological responses on two-day CPET in people with ME/CFS (63 females and 21 males), Long Covid (52 females and 27 males), and matched non-disabled control participants (51 females and 20 males).

Data were analyzed within sexes using repeated measures analysis of variance. All participants met maximal effort criteria. There were significant reductions in oxygen consumption (O₂) and workload at the ventilatory anaerobic threshold (VAT) in both patient groups compared to non-disabled controls, with larger effect sizes at VAT than at peak exertion. Performance decrements were observed in both sexes.

Females exhibited more pronounced abnormalities and significant group by test effects. No significant differences were observed between patient groups. Severe disability based on impaired O₂ was prevalent in both patient groups. Hemodynamic and ventilatory measures were within normal ranges. ME/CFS and Long Covid both involve a functionally significant bioenergetic failure complicated by inadequate post-exertional recovery, which is similar between the conditions and unexplained by hemodynamic and ventilatory changes.

Findings support the utility of two-day CPET as an objective measure of PEM and functional impairment. Future studies may integrate mechanistic biomarkers with two-day CPET as trial endpoints and to establish likely responses to treatments for PEM.

Source: Todd Davenport, Staci Stevens, Jared Stevens et al. ME/CFS and Long COVID Demonstrate Similar Bioenergetic Impairment and Recovery Failure on Two-Day Cardiopulmonary Exercise Testing, 22 January 2026, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-8606329/v1] https://www.researchsquare.com/article/rs-8606329/v1 (Full text available as PDF file)

Microvascular Remodeling and Endothelial Dysfunction Across Post-COVID-19 and ME/CFS: Insights from the All Eyes on PCS Study

Abstract:

Background Post-viral diseases, including post-COVID-19 syndrome (PCS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cause substantial long-term morbidity. Persistent cardiovascular (CV) risk after acute infection highlights the need for accessible tools to quantify microvascular health.

Methods All Eyes on PCS is a prospective, observational study investigating the retinal microcirculation using retinal vessel analysis (RVA). We compared RVA parameters in 102 PCS patients with 204 age- and sex-matched healthy controls (HC, matched from n = 303). Secondary matched analyses included never infected controls (NI, n = 96), recovered individuals (n = 102), PCS patients, and ME/CFS patients (n = 62). Laboratory variables, circulating markers of endothelial dysfunction (ED) and inflammation were compared between cohorts and their associations with RVA parameters were examined.

Results Compared with HC, PCS patients showed reduced venular flicker-induced dilation (3.7 ± 2.2% vs. 4.5 ± 2.7%, p = 0.005), narrow retinal arterioles (CRAE, 178.3 ± 15.5 µm vs. 183.3 ± 15.9 µm, p = 0.009), and lower arteriolar-to-venular ratio (0.83 ± 0.06 vs. 0.86 ± 0.07, p = 0.004). Findings persisted after adjustment for CV factors and remained evident in an extended secondary matched analysis across NI, recovered, and PCS patients. ME/CFS patients showed the most pronounced alterations. PCS severity correlated with lower AVR (r = -0.21, p = 0.037) and reduced arteriolar FID (r = -0.21, p = 0.039), particularly for neurocognitive symptoms. IL-6, ICAM-1 and VCAM-1 were elevated in PCS and ME/CFS and lower AVR correlated with inflammatory and iron-related markers (all adjusted p < 0.01). A combined model discriminated ME/CFS patients with good accuracy (AUC = 0.80).

Conclusions PCS is associated with persistent ED, most pronounced in ME/CFS patients and linked to symptom severity and ongoing inflammation. RVA may provide a noninvasive, readout of ED in post-viral syndromes.

Source: Timon Wallraven, Roman Günthner, Isabelle Lethen, Andrea Ribeiro, Maciej Lech, Frederike Cosima Oertel, Lukas G. Reeß, Bernhard Haller, Lukas Streese, Henner Hanssen, Michael Wunderle, Christoph Schmaderer. Microvascular Remodeling and Endothelial Dysfunction Across Post-COVID-19 and ME/CFS: Insights from the All Eyes on PCS Study. medRxiv 2026.01.22.26344661; doi: https://doi.org/10.64898/2026.01.22.26344661 https://www.medrxiv.org/content/10.64898/2026.01.22.26344661v1.full-text (Full text)