Category: Overlapping Illnesses

Long COVID and chronic fatigue syndrome/myalgic encephalitis share similar pathophysiologic mechanisms of exercise limitation

Abstract:

Post-acute sequelae of SARS-CoV-2 (PASC or “long COVID”) and chronic fatigue syndrome/myalgic encephalitis (CFS/ME) share symptoms such as exertional dyspnea. We used exercise oxygen pathway analysis, comprising six parameters of oxygen transport and utilization, to identify limiting mechanisms in both conditions. Invasive cardiopulmonary exercise testing was performed on 15 PASC patients, 11 CFS/ME patients, and 11 controls.

We evaluated the contributions of alveolar ventilation (V̇a), lung diffusion capacity (DL ), cardiac output (Q̇), skeletal muscle diffusion capacity (DM ), hemoglobin (Hb), and mitochondrial oxidative phosphorylation (Vmax) to peak oxygen consumption (V̇O2peak). To simulate targeted interventions, each variable was sequentially normalized to assess its impact on V̇O2peak. V̇O2peak was significantly reduced in both PASC and CFS/ME compared to controls.

Skeletal muscle O2 diffusion (DM ) was the most impaired parameter in both patient groups (p = 0.01). Correcting DM alone improved V̇O2 by 66% in PASC (p = 0.008) and 34.7% in CFS/ME (p = 0.06), suggesting a dominant role for peripheral O2 extraction in exercise limitation. Impaired skeletal muscle oxygen diffusion (DM ) is a shared mechanism of exercise intolerance in PASC and CFS/ME and may represent a therapeutic target. However, our findings are limited by small sample size.

Source: Jothi S, Insel M, Claessen G, Kubba S, Howden EJ, Ruiz-Carmona S, Levine T, Rischard FP. Long COVID and chronic fatigue syndrome/myalgic encephalitis share similar pathophysiologic mechanisms of exercise limitation. Physiol Rep. 2025 Sep;13(17):e70535. doi: 10.14814/phy2.70535. PMID: 40892700. https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.70535 (Full text)

Mapping cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance: insights from a systematic review

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating condition with a large proportion of patients that experience orthostatic intolerance (OI). This systematic review aimed to assess whether cerebral blood flow (CBF) is reduced in ME/CFS and OI, and whether the presence of both conditions leads to an additional decline in CBF.

Methods: PubMed (from 1943), MEDLINE (from 1946), EMBASE (from 1947) and Cochrane were searched from inception to February 14th, 2025, using terms including “chronic fatigue syndrome”, “myalgic encephalomyelitis”, “orthostatic intolerance” and “cerebral blood flow”. Article selection required the following criteria: published in English; CBF measured in participants with either ME/CFS or OI, or both ME/CFS and OI combined. Quality assessment and risk of bias was assessed using the Newcastle-Ottawa Scale and the systematic review was conducted in accordance with the PRISMA 2020 guidelines.

Results: Of 14,928 articles, 118 were included, 26 (22.1%) of which studied CBF in ME/CFS alone, 81 (68.6%) in OI alone and 11 (9.3%) in both ME/CFS and OI. Overall, the articles included 9185 participants, with a mean age of 39.1 years (SD = 8.8), and 73.8% of participants were female. Studies found CBF was significantly reduced in 12 of the articles focused on ME/CFS and in 56 of those focused on OI; compared to controls. Additionally, in 4 out of 11 studies that examined both conditions, CBF was further reduced in participants suffering from both conditions compared to those with ME/CFS alone.

Conclusions: CBF is reduced in ME/CFS and OI alone and having both conditions comorbidly amplifies CBF reductions. Therefore, observing CBF changes in ME/CFS with and without OI may be important in monitoring disease severity. Despite this, few studies focus on the combination of ME/CFS and OI, and OI may be a confounding factor in CBF in a large portion of ME/CFS studies.

Source: Christopoulos EM, Tantanis D, Huang K, Schneider-Futschik EK, Gooley PR, Moneghetti KJ, Armstrong CW. Mapping cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance: insights from a systematic review. J Transl Med. 2025 Aug 26;23(1):963. doi: 10.1186/s12967-025-06954-w. PMID: 40859389. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06954-w (Full text)

Accelerated vascular ageing after COVID-19 infection: the CARTESIAN study

Abstract:

Background and Aims: Increasing evidence suggests that COVID-19 survivors experience long-term cardiovascular complications possibly through development of vascular damage. The study aimed to investigate whether accelerated vascular ageing occurs after COVID-19 infection, and if so, identify its determinants.
Methods: This prospective, multicentric, cohort study, included 34 centres in 16 countries worldwide, in 4 groups of participants—COVID-19-negative controls (ⅰ) and three groups of individuals with recent (6 ± 3 months) exposure to SARS-CoV-2: not hospitalized (ⅱ), hospitalized in general wards (ⅲ), and hospitalized in intensive care units (ⅳ). The main outcome was carotid-femoral pulse wave velocity (PWV), an established biomarker of large artery stiffness.
Results: 2390 individuals (age 50 ± 15 years, 49.2% women) were recruited. After adjustment for confounders, all COVID-19-positive groups showed higher PWV (+0.41, +0.37, and +0.40 m/s for groups 2–4, P < .001, P = .001 and P = .003) vs. controls [PWV 7.53 (7.09; 7.97) m/s adjusted mean (95% CI)]. In sex-stratified analyses, PWV differences were significant in women [PWV (+0.55, +0.60, and +1.09 m/s for groups 2–4, P < .001 for all)], but not in men. Among COVID-19 positive women, persistent symptoms were associated with higher PWV, regardless of disease severity and cardiovascular confounders [adjusted PWV 7.52 (95% CI 7.09; 7.96) vs. 7.13 (95% CI 6.67; 7.59) m/s, P < .001]. A stable or improved PWV after 12 months was found in the COVID+ groups, whereas a progression was observed in the COVID− group.
Conclusions: COVID-19 is associated with early vascular ageing in the long term, especially in women.

Source: Rosa Maria Bruno, Smriti Badhwar, Leila Abid, Mohsen Agharazii, Fabio Anastasio, Jeremy Bellien, Otto Burghuber, Luca Faconti, Jan Filipovsky, Lorenzo Ghiadoni, Cristina Giannattasio, Bernhard Hametner, Alun D Hughes, Ana Jeroncic, Ignatios Ikonomidis, Mai Tone Lonnebakken, Alessandro Maloberti, Christopher C Mayer, Maria Lorenza Muiesan, Anna Paini, Andrie Panayiotou, Chloe Park, Chakravarthi Rajkumar, Carlos Ramos Becerra, Bart Spronck, Dimitrios Terentes-Printzios, Yesim Tuncok, Thomas Weber, Pierre Boutouyrie, the CARTESIAN Investigators , Accelerated vascular ageing after COVID-19 infection: the CARTESIAN study, European Heart Journal, 2025;, ehaf430, https://doi.org/10.1093/eurheartj/ehaf430 https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaf430/8236450 (Full text)

Mitochondrial function is impaired in long COVID patients

Abstract:

Background: The Long COVID syndrome is a major global health problem, affecting approximately 10–20% of individuals infected with SARS-CoV-2 virus with many remaining symptomatic beyond one year. Fatigue, reduced exercise tolerance and hyperlactataemia on minimal exertion have led to the suggestion of a bioenergetic defect. We hypothesised that mitochondrial dysfunction is a pathological feature in Long COVID cases and would correlate with clinical outcome.

Methods: This prospective, case-controlled, observational study recruited 27 participants with an established diagnosis of Long COVID syndrome from a single tertiary clinic together with 16 age-matched controls aged 25–65 years. Seahorse-based mitochondrial flux analysis and bioenergetics profile of isolated peripheral blood mononuclear cells (PBMCs) was performed and correlated with clinical phenotype.

Findings: Long COVID cases had an increased baseline and ATP-induced oxygen consumption rate with a significant attenuation in tetramethylrhodamine methyl ester perchlorate fluorescence response to oligomycin. Correlations were observed between mitochondrial function and autonomic health, quality of life and time from index infection. Sex-specific differences were also observed.

Interpretation: PBMCs from Long COVID subjects exhibit an exceptional and distinctive change in ATP synthase, as it contributes to the mitochondrial membrane potential rather than using it exclusively to generate ATP. The findings suggest that the enzyme runs both forward and reverse reactions, synthesising and hydrolysing ATP. The correlation of mitochondrial function with clinical phenotype in Long COVID may indicate a causal relationship and warrants further validation in larger scale studies.

Source: Macnaughtan, J., Chau, K. Y., Brennan, E., Toffoli, M., Spinazzola, A., Hillman, T., … Schapira, A. H. V. (2025). Mitochondrial function is impaired in long COVID patients. Annals of Medicine, 57(1). https://doi.org/10.1080/07853890.2025.2528167 https://www.tandfonline.com/doi/full/10.1080/07853890.2025.2528167 (Full text)

Biomarkers over Time: From Visual Contrast Sensitivity to Transcriptomics in Differentiating Chronic Inflammatory Response Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Chronic inflammatory response syndrome (CIRS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are debilitating multisystem illnesses that share overlapping symptoms and molecular patterns, including immune dysregulation, mitochondrial impairment, and vascular dysfunction. This review provides a chronological synthesis of biomarker development in CIRS, tracing its evolution from early functional tests such as visual contrast sensitivity (VCS) to advanced transcriptomic profiling.

Drawing on peer-reviewed studies spanning two decades, we examine the layered integration of neuroendocrine, immunologic, metabolic, and genomic markers that collectively support a multisystem model of innate immune activation specific to environmentally acquired illness. Particular focus is given to the Gene Expression: Inflammation Explained (GENIE) platform’s use of transcriptomics to classify disease stages and distinguish CIRS from other fatiguing conditions.

While ME/CFS research continues to explore overlapping pathophysiologic features, it has yet to establish a unified diagnostic model with validated biomarkers or exposure-linked mechanisms. As a result, many patients labeled with ME/CFS may, in fact, represent unrecognized CIRS cases.

This review underscores the importance of structured biomarker timelines in improving differential diagnosis and guiding treatment in complex chronic illness and highlights the reproducibility of the CIRS framework in contrast to the diagnostic ambiguity surrounding ME/CFS.

Source: Dooley M. Biomarkers over Time: From Visual Contrast Sensitivity to Transcriptomics in Differentiating Chronic Inflammatory Response Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2025 Jul 28;26(15):7284. doi: 10.3390/ijms26157284. PMID: 40806417. https://www.mdpi.com/1422-0067/26/15/7284 (Full text)

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

Abstract:

Background: Functional disorders share familial risk with internalizing disorders such as generalized anxiety disorder and depression, and are comorbid with cardiometabolic and immune-related diseases. We investigated whether functional and internalizing disorders co-aggregate with these diseases in families to gain insight into the aetiology of functional and internalizing disorders.

Methods: We included 166,774 subjects (aged 3-94), from the population-based Lifelines Cohort Study, a Dutch general population cohort. We defined cases for three functional disorders (myalgic encephalomyelitis/chronic fatigue syndrome; ME/CFS, fibromyalgia, and irritable bowel syndrome; IBS), two internalizing disorders (major depressive disorder; MDD and generalized anxiety disorder; GAD), cardiometabolic diseases (obesity, metabolic associated steatotic liver disease, type 2 diabetes, hypertension and cardiovascular disease) and immune-related diseases (composite measures of auto-immune disease and atopy). We used logistic regression to model the prevalence of these disorders in the general population and in participants with affected relatives. Using these prevalence estimates, we assessed familial co-aggregation with (1) recurrence risk ratios (λR), and (2) familial correlations (rf).

Results: All functional and internalizing disorders co-aggregated with immune-related diseases (λR range 1.06-1.24). ME/CFS, FM, and MDD co-aggregated with most cardiometabolic diseases (λR range 1.00-1.23). MDD, fibromyalgia, and ME/CFS showed similar familial correlation patterns with both disease groups (rf range 0.12-0.44), while patterns of IBS and GAD were more variable.

Conclusions: Internalizing and functional disorders share familial risk with immune-related and cardiometabolic diseases. This suggests that risk factors relevant to immune-related and cardiometabolic diseases may also be relevant for FDs. Future studies should investigate such risk factors to identify novel treatment targets.

Source: Steen OD, Bos M, van Ockenburg SL, Zhou Y, Nolte IM, Snieder H, Kendler K, Rosmalen JGM, van Loo HM. Functional and internalizing disorders co-aggregate with cardiometabolic and immune-related diseases within families: a population-based cohort study. BMC Med. 2025 Aug 11;23(1):469. doi: 10.1186/s12916-025-04293-7. PMID: 40784894. https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-025-04293-7 (Full text)

Functional and Morphological Differences of Muscle Mitochondria in Chronic Fatigue Syndrome and Post-COVID Syndrome

Abstract:

Patients suffering from chronic fatigue syndrome (CFS) or post-COVID syndrome (PCS) exhibit a reduced physiological performance capability. Impaired mitochondrial function and morphology may play a pivotal role. Thus, we aimed to measure the muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity and assess mitochondrial morphology in CFS and PCS patients in comparison to healthy controls (HCs).

Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers using high-resolution respirometry. Mitochondrial morphology (subsarcolemmal/intermyofibrillar mitochondrial form/cristae/diameter/circumference/area) and content (number and proportion/cell) were assessed via electron microscopy. Analyses included differences in OXPHOS between HC, CFS, and PCS, whereas comparisons in morphology/content were made for CFS vs. PCS. OXPHOS capacity of complex I, which was reduced in PCS compared to HC.

While the subsarcolemmal area, volume/cell, diameter, and perimeter were higher in PCS vs. CFS, no difference was observed for these variables in intermyofibrillar mitochondria. Both the intermyofibrillar and subsarcolemmal cristae integrity was higher in PCS compared to CFS. Both CFS and PCS exhibit increased fatigue and impaired mitochondrial function, but the progressed pathological morphological changes in CFS suggest structural changes due to prolonged inactivity or unknown molecular causes. Instead, the significantly lower complex I activity in PCS suggests probably direct virus-induced alterations.

Source: Bizjak DA, Ohmayer B, Buhl JL, Schneider EM, Walther P, Calzia E, Jerg A, Matits L, Steinacker JM. Functional and Morphological Differences of Muscle Mitochondria in Chronic Fatigue Syndrome and Post-COVID Syndrome. Int J Mol Sci. 2024 Jan 30;25(3):1675. doi: 10.3390/ijms25031675. PMID: 38338957; PMCID: PMC10855807. https://pmc.ncbi.nlm.nih.gov/articles/PMC10855807/ (Full text)

Metabolic adaptation and fragility in healthy 3-D in vitro skeletal muscle tissues exposed to Chronic Fatigue Syndrome and Long COVID-19 sera

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID-19 (LC-19) are complex conditions with no diagnostic markers or consensus on disease progression. Despite extensive research, no in vitro model exists to study skeletal muscle wasting, peripheral fatigue, or potential therapies. We developed 3D in vitro skeletal muscle tissues to map muscle adaptations to patient sera over time.

Short exposures (48 hours) to patient sera led to a significant reduction in muscle contractile strength. Transcriptomic analysis revealed the upregulation of glycolytic enzymes, disturbances in calcium homeostasis, hypertrophy, and mitochondrial hyperfusion. Structural analyses confirmed myotube hypertrophy and elevated mitochondrial oxygen consumption in ME/CFS. While muscles initially adapted by increasing glycolysis, prolonged exposure (96-144 hours) caused muscle fragility and fatigue, with mitochondria fragmenting into a toroidal conformation.

We propose that skeletal muscle tissue in ME/CFS and Long COVID-19 progresses through a hypermetabolic state, leading to severe muscular and mitochondrial deterioration. This is the first study to suggest such transient metabolic adaptation

Source: Mughal S, Andújar-Sánchez F, Sabater-Arcis M, Garrabou G, Fernández-Solà J, Alegre-Martin J, Sanmartin Sentañes R, Castro-Marrero J, Esteve-Codina A, Casals E, Fernández-Costa JM, Ramón-Azcón J. Metabolic adaptation and fragility in healthy 3-D in vitro skeletal muscle tissues exposed to Chronic Fatigue Syndrome and Long COVID-19 sera. Biofabrication. 2025 Jul 31. doi: 10.1088/1758-5090/adf66c. Epub ahead of print. PMID: 40744071. https://iopscience.iop.org/article/10.1088/1758-5090/adf66c (Full text available as PDF file)

Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Debilitating symptoms for many years can follow acute COVID-19 (“long COVID”), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and various post-acute infection syndromes (PAISs). Together, long COVID and ME/CFS affect 60-400 million individuals, globally. Many similar underlying biological abnormalities have been identified in both conditions including autoantibodies against neural targets, endothelial dysfunction, acquired mitochondrial dysfunction, and a pro-inflammatory gut microbiome. Each of these abnormalities may directly cause some of the symptoms.

In addition, the symptoms also may be caused by ancient, evolutionarily conserved symptomatic and metabolic responses to vital threats-sickness behavior and torpor-responses mediated by specific, recently discovered neural circuits. These neural circuits constitute a symptom-generating pathway, activated by neuroinflammation, which may be targeted by therapeutics to quell neuroinflammation.

Many factors cause the symptoms to become chronic, including persistent infectious agents (and/or their nucleic acids and antigens) and the fact that many of the underlying biological abnormalities reinforce each other, creating ongoing physiological vicious cycles.

Source:Komaroff AL, Dantzer R. Causes of symptoms and symptom persistence in long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Cell Rep Med. 2025 Jul 25:102259. doi: 10.1016/j.xcrm.2025.102259. Epub ahead of print. PMID: 40744021. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00332-5 (Full text)

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

Abstract:

Post-COVID-19 condition, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM), are characterized by fatigue, pain, shortness of breath, sleep disturbances, cognitive dysfunction and other symptoms, heavily impacting on patients daily functioning. Moreover, over half of patients end up fulfilling ME/CFS and/or FM clinical criteria after a few months of SARS-CoV-2 infection.

Expression of the toxic human endogenous retrovirus (HERV)-W ENV protein can be induced by viral infection and HERV-W detection was correlated with acute COVID-19 severity and found significantly expressed in post-COVID-19 condition. This study shows that HERV-W ENV may also be present in prepandemic cases of ME/CFS, FM or co-diagnosed with both clinical criteria, suggesting viral participation in these chronic diseases.

To learn whether associated antiviral mechanisms may also show differing patterns of immunological responses, we measured IgM, IgG, IgA and IgE antibody isotypes against SARS-CoV-2 spike and nucleocapsid antigens, the levels of IL-6, IL-8, IL-10, IFNγ and TNFα cytokines, the level of NfL, a neural damage biomarker, as well as some blood cell markers potentially related with fatigue.

Importantly, some of the measured variables showed a capacity to discriminate post-COVID-19 condition cases from all other participants, with 100 % sensitivity and up to 71.9 % specificity providing a new tool for a differential diagnosis between diseases or syndromes with so many overlapping clinical symptoms. Interestingly, the detected markers showed moderate-to-strong correlations with patient symptoms pointing at novel therapeutic opportunities.

Source: Giménez-Orenga K, Pierquin J, Brunel J, Charvet B, Martín-Martínez E, Lemarinier M, Fried S, Lucas A, Perron H, Oltra E. Blood parameters differentiate post COVID-19 condition from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia. Brain Behav Immun Health. 2025 Jul 4;48:101058. doi: 10.1016/j.bbih.2025.101058. PMID: 40726775; PMCID: PMC12302357. https://pmc.ncbi.nlm.nih.gov/articles/PMC12302357/ (Full text)