Tag: long Covid

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/

Vitamin D in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After COVID-19 or Vaccination: A Randomized Controlled Trial

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can develop as post-vaccination syndrome (PVS) or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). In our prior retrospective study, most patients with PVS who developed ME/CFS had vitamin D insufficiency or deficiency. We evaluated the efficacy of vitamin D replacement therapy guidance for ME/CFS symptom improvement in patients with vitamin D insufficiency or deficiency.

Methods: This open-label randomized controlled trial enrolled 91 participants with ME/CFS as PVS or PASC and serum 25(OH) vitamin D < 30 ng/mL across five clinical sites. Participants were randomized 1:1 to intervention (active vitamin D preparation plus vitamin D replacement therapy guidance: 25 μg daily supplementation, dietary counseling, sun exposure, and exercise) or control (active vitamin D preparation alone) for 12 weeks. The primary endpoint was the change in ME/CFS symptom count from screening to Week 12.

Results: Mean symptom change was -6.7 in the intervention group versus -1.2 in the control group (between-group difference -5.6; 95% CI: -7.2, -3.9; p < 0.001). Serum 25(OH) vitamin D improved from 18.6 to 27.1 ng/mL in the intervention group, while the control group showed a decreasing trend (between-group difference 10.2 ng/mL; 95% CI: 7.9, 12.5). Achievement of <8 symptoms (i.e., no longer meeting ME/CFS diagnostic criteria) was significantly higher in the intervention group, with 16 participants achieving this threshold compared to 1 in the control group (p < 0.001). Subgroup analyses showed consistent benefit in both PVS (n = 56) and PASC (n = 29) cohorts.

Conclusions: Vitamin D replacement therapy guidance significantly reduced ME/CFS symptoms along with improvement of serum 25(OH) vitamin D levels in patients with vitamin D insufficiency or deficiency who developed ME/CFS as PVS or PASC.

Source: Kodama S, Nakata M, Konishi N, Yoshino M, Fujisawa A, Naganuma M, Kobayashi Y, Hirai Y, Kitagawa A, Miyokawa M, Mishima R, Teramukai S, Fukushima M. Vitamin D in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After COVID-19 or Vaccination: A Randomized Controlled Trial. Nutrients. 2026 Feb 3;18(3):521. doi: 10.3390/nu18030521. PMID: 41683343. https://www.mdpi.com/2072-6643/18/3/521 (Full text)

Potential application of brain-gut axis-based treatments in Long COVID and ME/CFS: a case-based systematic review

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID share clinical features including persistent fatigue, post-exertional malaise (PEM), and gastrointestinal (GI) dysfunction. Growing evidence implicates brain-gut axis dysregulation, characterized by dysbiosis, neuroinflammation within the central nervous system (CNS), increased intestinal permeability, and microbial translocation in their pathophysiology. However, therapeutic strategies targeting these pathways remain poorly defined.

Methods: We report a case of post-COVID ME/CFS successfully treated with electroacupuncture (EA)-based deep peroneal nerve stimulation which was employed to potentiate the vagal reflex. Fatigue trajectories were assessed using the Multidimensional Fatigue Inventory over 12 weeks. Based on the case, a systematic review of randomized controlled trials (RCTs) evaluating brain-gut axis-modulating interventions in ME/CFS or Long COVID was conducted.

Results: The patient exhibited a significant reduction in total fatigue, with early improvements in motivation and mental fatigue, and delayed improvement in physical fatigue following transient systemic symptom flares. Across included RCTs (n = 8, 790 participants), four investigated gut microbiome-modulating therapies and four employed nerve stimulation. Synbiotic and herbal interventions demonstrated benefits for fatigue or PEM, accompanied by alterations in specific bacterial populations or CNS metabolisms. Regarding nerve stimulation, transcranial direct current stimulation (tDCS) combined with exercise program improved fatigue, whereas standalone tDCS, auricular or peripheral TENS showed limited efficacy.

Conclusion: Brain-gut axis-based interventions may alleviate fatigue in ME/CFS and Long COVID by potentially modulating neuroinflammation, restoring microbiome balance, and improving epithelial barrier function. EA-based vagal stimulation represents a feasible option for patients with severe or treatment-resistant symptoms. Larger mechanistic studies and rigorously designed RCTs are needed to establish therapeutic targets and optimize intervention strategies.

Source: Kim DY, Youn J, Kang N, Cho SI, Ha IH. Potential application of brain-gut axis-based treatments in Long COVID and ME/CFS: a case-based systematic review. J Transl Med. 2026 Feb 10. doi: 10.1186/s12967-026-07807-w. Epub ahead of print. PMID: 41668172. https://link.springer.com/article/10.1186/s12967-026-07807-w (Full text available as PDF file)

The origin of autoimmune diseases: is there a role for ancestral HLA-II haplotypes in immune hyperactivity

Abstract:

The prevalence of autoimmune diseases in contemporary human populations poses a challenge for both medicine and evolutionary biology. This review explores how the ancestral human leukocyte antigen class II (HLA-II) haplotypes DR2-DQ6, DR4-DQ8 and DR3-DQ2 could play a central role in susceptibility to these diseases.

We propose that these haplotypes, selected in historical contexts of high infectious pressure, may have been maintained because of their ability to elicit strong T-cell responses against pathogens; however, that antigenic promiscuity may be associated with an increased tendency toward immune hyperreactivity in modern environments. This hyperreactivity, involving proinflammatory cytokines including interferon-gamma (IFN-γ), could contribute to the breakdown of tolerance and the emergence of autoimmunity and related clinical phenomena (e.g., Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome and post-vaccination syndromes), although the evidence for the latter remains limited.

Finally, we discuss how chronic infections, immunotherapies, vaccination, obesity and chronic physical stressors may exacerbate this susceptibility and consider the therapeutic implications of integrating HLA-II profiling into clinical practice.

Source: Ruiz-Pablos M, Paiva B, Zabaleta A. The origin of autoimmune diseases: is there a role for ancestral HLA-II haplotypes in immune hyperactivity. Front Immunol. 2025 Dec 4;16:1710571. doi: 10.3389/fimmu.2025.1710571. PMID: 41425584; PMCID: PMC12711860. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1710571/full (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)

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)

Associations between heart rate and physical activity in people with post-COVID-19 condition accounting for myalgic encephalomyelitis/chronic fatigue syndrome symptoms

Abstract:

Background: Tachycardia after mild activity or during rest is a common complaint among people with post-COVID-19 condition (PCC). Understanding the relationships between heart rate (HR) and physical activity (PA) in this population is crucial for developing appropriate rehabilitation protocols.

Objective: To investigate the associations between HR and PA in individuals with PCC, accounting for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) symptoms.

Design: Observational study.

Subjects: Sixteen adults with PCC (81% females, mean age 51 ± 12 years).

Methods: Participants were instructed to use 2 wearable devices (Garmin smartwatch and ActiGraph accelerometer) during waking hours over 4 days while performing daily activities. Average HR, percentage of time in tachycardia (time with HR > 100 bpm), and daily step count were assessed. The accelerometer counts per minute was used to categorize daily PA as sedentary, light intensity, and moderate-to-vigorous (MVPA).

Results: Participants wore the watches and accelerometers for a mean of 11.36 ± 2.60 and 12.51 ± 1.94 h per day, respectively. Average daily HR increased with increasing PA levels from sedentary to MVPA. However, the percentage of time in tachycardia was significantly lower during periods of MVPA compared with sedentary periods, even after adjusting for ME/CFS symptoms.

Conclusion: Individuals with PCC in our study experienced more tachycardia during periods of minimal physical activity compared with periods categorized as MVPA.

Source: Adodo R, Sarmento Da Nobrega A, Villar R, Webber SC, Sanchez-Ramirez DC. Associations between heart rate and physical activity in people with post-COVID-19 condition accounting for myalgic encephalomyelitis/chronic fatigue syndrome symptoms. J Rehabil Med. 2026 Jan 27;58:jrm43340. doi: 10.2340/jrm.v58.43340. PMID: 41601198. https://medicaljournalssweden.se/jrm/article/view/43340 (Full study available as PDF file)