Tag: chronic inflammation

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)

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)

Immunosenescence-Driven Hemodynamic Dysregulation and Cognitive Impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Integrative Perspective

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder marked by persistent fatigue and cognitive impairments, often termed “brain fog.” Emerging evidence suggests that immunosenescence, age- or stress-related deterioration of immune function, plays a pivotal role in the pathogenesis of cognitive dysfunction in ME/CFS.

Immunosenescence induces chronic low-grade inflammation (inflammaging); alters T-, NK-, and B-cell function; and promotes the release of senescence-associated secretory phenotype (SASP) factors. These changes are proposed to cerebral blood flow (CBF) regulation, may impair endothelial nitric oxide production, and may contribute to blood-brain barrier (BBB) breakdown. Consequently, brain hypoperfusion and oxidative stress are associated with impaired neuronal energy metabolism and synaptic plasticity, particularly in memory-related networks such as the default mode and fronto-hippocampal systems. This results in reduced ATP availability, excitotoxicity, and neurotransmitter imbalance, contributing to cognitive decline.

The review proposes an “immune-vascular-cognitive axis” linking peripheral immune aging to central neural dysfunction. It further highlights therapeutic strategies-such as cytokine blockade, nitric oxide enhancement, immune modulation, and acupuncture-that may ameliorate neurovascular impairments and cognitive symptoms. Understanding this integrative mechanism may offer new pathways for targeted intervention in ME/CFS.

Source: Xu H, Luo Y, Wu X. Immunosenescence-Driven Hemodynamic Dysregulation and Cognitive Impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Integrative Perspective. Compr Physiol. 2026 Feb;16(1):e70098. doi: 10.1002/cph4.70098. PMID: 41527963. https://pubmed.ncbi.nlm.nih.gov/41527963/

Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disorder characterized by immune dysregulation, metabolic impairments, neuroendocrine disturbances, endothelial dysfunction, and gastrointestinal abnormalities.

Immune alterations include reduced natural killer cell cytotoxicity, T-cell exhaustion, abnormal B-cell subsets, and the presence of diverse autoantibodies, suggesting an autoimmune component.

Gut dysbiosis and increased intestinal permeability may promote systemic inflammation and contribute to neurocognitive symptoms via the gut-brain axis. Neuroendocrine findings such as hypothalamic-pituitary-adrenal (HPA) axis hypofunction and altered thyroid hormone metabolism further compound metabolic and immune abnormalities.

Metabolomic and mitochondrial studies identify impaired ATP generation, redox imbalance, and compensatory shifts toward alternative energy pathways underlying hallmark symptoms like post-exertional malaise.

Endothelial dysfunction driven by oxidative and nitrosative stress, along with autoantibody-mediated receptor interference, may explain orthostatic intolerance and impaired perfusion. Collectively, ME/CFS appears to arise from a self-sustaining cycle of chronic inflammation, metabolic insufficiency, and neuroimmune imbalance.

Source: Dudova D, Bozhkova M, Petrov S, Nikolova R, Kalfova T, Ivanovska M, Vaseva K, Nikolova M, Ivanov IN. Insights into the Complex Biological Network Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2025 Dec 26;27(1):268. doi: 10.3390/ijms27010268. PMID: 41516145; PMCID: PMC12785471. https://pmc.ncbi.nlm.nih.gov/articles/PMC12785471/ (Full text)

Brain MRI findings in patients with post COVID-19 condition: frequency and longitudinal changes in a nationwide cohort study

Abstract:

Background: Prolonged neurological symptoms following COVID-19 are common, yet few longitudinal studies describe brain MRI findings in this patient group. The use of contrast enhanced sequences is particularly lacking. We address this knowledge gap by reporting the frequency and longitudinal changes in brain MRI findings among patients with post COVID-19 condition exhibiting neurological symptoms.

Methods: This prospective multicenter study included 140 adult patients referred for persistent neurological symptoms following COVID-19. Brain MRI was performed at both 6 and 12 months after infection onset, reporting white matter hyperintensities, cerebral microbleeds, and additional pathological findings including contrast enhancement. White matter hyperintensities were compared with a healthy control group.

Results: The prevalence of white matter hyperintensities was comparable to healthy controls, and microbleeds were found at rates comparable to population studies, with longitudinal changes being infrequent. Lesions consistent with inflammation or demyelination were present in 4% (5/120) of patients at 6 months. Cranial nerve enhancement was found in 7% (7/94) of patients, persisting up to 12 months, predominantly affecting the oculomotor nerve. However, enhancement occurred without clinically detected ocular muscle paresis.

Conclusion: Our findings indicate that brain MRI primarily serves to exclude differential diagnoses in post COVID-19 condition, with limited clinical benefit of repeated imaging in the absence of new symptoms. However, signs of long-term inflammatory processes can be observed, and detection is improved by contrast enhanced sequences.

Source: Furevik LL, Lapina O, Lindland ES, Høgestøl EA, Geier OM, Devik K, Farmen AH, Flemmen HØ, Harbo HF, Morsund ÅH, Novotny V, Ofte HK, Pedersen KO, Popperud TH, Ratajczak-Tretel B, Samsonsen C, Selnes P, Torkildsen Ø, Undseth RM, Aamodt AH, Beyer MK, Boldingh MI. Brain MRI findings in patients with post COVID-19 condition: frequency and longitudinal changes in a nationwide cohort study. Front Neurol. 2025 Nov 13;16:1662263. doi: 10.3389/fneur.2025.1662263. PMID: 41323230; PMCID: PMC12658414. https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1662263/full (Full text)

A multidimensional immunological perspective on long COVID

Highlights:

  • Inflammaging may predispose to and be amplified by Long COVID.
  • SARS-CoV-2 may trigger autoantibodies disrupting neuroimmune balance.
  • Long COVID involves persistent immune system and autonomic dysregulation.
  • Biomarkers reflect immune and autonomic imbalance in Long COVID.
  • Biological clocks may help identify Long COVID vulnerability and guide care.

Abstract

Long COVID is a chronic condition that arises after SARS-CoV-2 infection and is characterized by persistent and often debilitating symptoms, such as fatigue, cognitive dysfunction (“brain fog”), dyspnea, and autonomic disturbances. Increasing evidence suggests that Long COVID shares key immunopathological mechanisms with autoimmune diseases, primarily sustained immune dysregulation.

In individuals with genetic or immunological susceptibility, SARS-CoV-2 infection can trigger the production of autoantibodies targeting cytokines, membrane receptors, and components of the autonomic nervous system (ANS), thereby disrupting neuroimmune homeostasis. This immune imbalance may impair anti-inflammatory regulatory pathways, such as the cholinergic anti-inflammatory pathway (CAP), and may contribute to a chronic state of inflammation and autoimmunity. One proposed contributor to this process is inflammaging – a chronic, low-grade inflammation associated with aging – which may not only predispose individuals to Long COVID but may also be amplified by the persistent immune activation seen in this condition.

In this perspective, we propose a conceptual framework in which inflammaging, immune-tolerance breakdown, and autonomic dysfunctions interact to sustain the pathophysiology of Long COVID. We discuss emerging biomarkers across these axes, including inflammatory cytokines, circulating autoantibodies, immune cell phenotypes, epigenetic modifications, and heart rate variability. Advances in inflammaging-related biomarkers and biological clocks may support early identification of individuals at higher risk for persistent immune and autonomic dysregulation, ultimately informing more precise diagnostic and therapeutic strategies for Long COVID.

Source: Giunta S, Giuliani A, Sabbatinelli J, Olivieri F. A multidimensional immunological perspective on long COVID. Cytokine Growth Factor Rev. 2025 Aug;84:1-11. doi: 10.1016/j.cytogfr.2025.07.001. Epub 2025 Jul 5. PMID: 40640033. https://pubmed.ncbi.nlm.nih.gov/40640033/

Urinary Peptidomic Profiling In Post-Acute Sequelae of SARS-CoV-2 Infection: A Case-Control Study

Abstract:

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2-infection (PASC) is challenging to diagnose and treat, and its molecular pathophysiology remains unclear. Urinary peptidomics can provide valuable information on urine peptides that may enable improved and specified PASC diagnosis.
Using standardized capillary electrophoresis-MS, we examined the urinary peptidomes of 50 patients with PASC 10 months after COVID-19 and 50 controls, including healthy individuals (n = 42) and patients with non-COVID-19-associated myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (n = 8).Based on peptide abundance differences between cases and controls, we developed a diagnostic model using a support vector machine. The abundance of 195 urine peptides among PASC patients significantly differed from that in controls, with a predominant abundance of collagen alpha chains. This molecular signature (PASC195) effectively distinguished PASC cases from controls in the training set (AUC of 0.949 [95% CI 0.900–0.998; p < 0.0001]) and independent validation set (AUC of 0.962 [95% CI 0.897–1.00]; p < 0.0001]). In silico assessment suggested exercise, GLP-1RAs and mineralocorticoid receptor antagonists (MRAs) as potentially efficacious interventions. We present a novel and non-invasive diagnostic model for PASC. Reflecting its molecular pathophysiology, PASC195 has the potential to advance diagnostics and inform therapeutic interventions.

Statement of Significance of the Study

Despite the recent emergence of omics-derived candidates for post-acute sequelae of SARS-CoV-2 infection (PASC), the pending validation of proposed markers and lack of consensus result in the continuous reliance on symptom-based criteria, being subject to diagnostic uncertainties and potential recall bias. Building upon prior findings of renal involvement in acute COVID-19 pathophysiology and PASC-associated alterations, we hypothesized that the use of urinary peptides for PASC-specific biomarker discovery, unlike conventional specimens that have been utilized thus far, may offer complementary information on putative disease mechanisms.

In the present study, 195 significantly expressed peptides were used to form a classifier termed PASC195, which effectively discriminated PASC from non-PASC (p < 0.0001), including healthy individuals and non-COVID-19-associated myalgic encephalomyelitis/chronic fatigue syndrome, in both the derivation (n = 60) and an independent validation set (n = 40). The peptidome profile associated with PASC was consistent with a shift in collagen turnover, with most PASC195 peptides derived from alpha chains. Ongoing inflammatory responses, hemostatic imbalances, and endothelial damage were indicated by cross-sectional variations in endogenous peptide excretion.

Source: Gülmez D, Siwy J, Kurz K, Wendt R, Banasik M, Peters B, Dudoignon E, Depret F, Salgueira M, Nowacki E, Kurnikowski A, Mussnig S, Krenn S, Gonos S, Löffler-Ragg J, Weiss G, Mischak H, Hecking M, Schernhammer E, Beige J; UriCoV Working Group. Urinary Peptidomic Profiling In Post-Acute Sequelae of SARS-CoV-2 Infection: A Case-Control Study. Proteomics. 2025 Nov 21:e70074. doi: 10.1002/pmic.70074. Epub ahead of print. PMID: 41273049. https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/pmic.70074 (Full text)

Leveraging Explainable Automated Machine Learning (AutoML) and Metabolomics for Robust Diagnosis and Pathophysiological Insights in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Background/Objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating complex disease with an elusive etiology, lacking objective diagnostic biomarkers. This study leverages advanced Automated Machine Learning (AutoML) to analyze plasma metabolomic and lipidomic profiles for the purpose of ME/CFS detection.

Methods: We utilized a publicly available dataset comprising 888 metabolic features from 106 ME/CFS patients and 91 matched controls. Three AutoML frameworks-TPOT, Auto-Sklearn, and H2O AutoML-were benchmarked under identical time constraints. Univariate ROC and PLS-DA analyses with cross-validation, permutation testing, and VIP-based feature selection were applied to standardized, log-transformed omics data to identify significant discriminatory metabolites/lipids and assess their intercorrelations.

Results: TPOT significantly outperformed its counterparts, achieving an area under the curve (AUC) of 92.1%, accuracy of 87.3%, sensitivity of 85.8%, and specificity of 89.0%. The PLS-DA model revealed a moderate but statistically significant discrimination between ME/CFS and controls. Explainable artificial intelligence (XAI) via SHAP analysis of the optimal TPOT model identified key metabolites implicating dysregulated pathways in mitochondrial energy metabolism (succinic acid, pyruvic acid, leucine), chronic inflammation (prostaglandin D2, 11,12-EET), gut-brain axis communication (glycocholic acid), and cell membrane integrity (pc(35:2)a).

Conclusions: Our results demonstrate that TPOT-derived models not only provide a highly accurate and robust diagnostic tool but also yield biologically interpretable insights into the pathophysiology of ME/CFS, highlighting its potential for clinical decision support and elucidating novel therapeutic targets.

Source: Yagin FH, Colak C, Al-Hashem F, Alzakari SA, Alhussan AA, Aghaei M. Leveraging Explainable Automated Machine Learning (AutoML) and Metabolomics for Robust Diagnosis and Pathophysiological Insights in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Diagnostics (Basel). 2025 Oct 30;15(21):2755. doi: 10.3390/diagnostics15212755. PMID: 41226047. https://www.mdpi.com/2075-4418/15/21/2755 (Full text)

Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Physical Fatigue Through the Perspective of Immunosenescence

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness marked by persistent fatigue, yet its mechanisms remain unclear. Growing evidence implicates immunosenescence-the age-related decline in immune function-in the onset and persistence of fatigue.

Methods: This review synthesizes clinical and experimental data to examine how immunosenescence contributes to ME/CFS. We focus on chronic inflammation, senescent immune phenotypes, mitochondrial dysfunction, and neuroendocrine imbalance, with emphasis on maladaptive crosstalk among immune, muscular, neuroendocrine, and vascular systems.

Results: Aging immune cells drive chronic inflammation that impairs mitochondrial ATP production and promotes muscle catabolism. Concurrently, HPA-axis suppression and β2-adrenergic dysfunction amplify immune dysregulation and energy imbalance. Together, these processes illustrate how immunosenescence sustains pathological cross-organ signaling underlying systemic fatigue.

Conclusion: Immunosenescence provides a unifying framework linking immune, metabolic, and neuroendocrine dysfunction in ME/CFS. Recognizing cross-organ communication highlights its clinical relevance, suggesting biomarkers such as cytokines and exhaustion markers, and supports integrated therapeutic strategies targeting immune and metabolic networks.

Source: Luo Y, Xu H, Xiong S, Ke J. Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Physical Fatigue Through the Perspective of Immunosenescence. Compr Physiol. 2025 Oct;15(5):e70056. doi: 10.1002/cph4.70056. PMID: 41017304. https://pubmed.ncbi.nlm.nih.gov/41017304/

Endometriosis and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review and Meta-Analysis

Abstract:

Background/Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and endometriosis are debilitating conditions that share overlapping features of chronic inflammation and immune dysregulation, yet their epidemiological relationship remains poorly characterized. The objective of this study was to investigate the association between ME/CFS and endometriosis, examining shared risk factors, clinical correlates, and epidemiological patterns.

Methods: We conducted a systematic review and meta-analysis. Two independent reviewers screened 236 records after duplicate removal, with seventeen studies undergoing full-text review and thirteen meeting inclusion criteria for meta-analysis. Data were extracted using standardized forms and analyzed using random-effects models in R, with heterogeneity assessed using I2 statistics and the risk of bias evaluated using the JBI critical appraisal tool.

Results: Our meta-analysis of five studies (n = 2261 participants) revealed that women with endometriosis had 2.79-fold higher odds (95% CI: 2.00-3.89) of developing ME/CFS compared to controls. Similarly, our fixed-effects meta-analysis of two studies assessing the association of ME/CFS and endometriosis yielded a pooled OR of 2.52 (95% CI: 2.45-2.60, p < 0.001). There was minimal statistical heterogeneity (I2 = 0.0%, p > 0.7969) for both meta-analyses.

Conclusions: This study demonstrates a significant bidirectional association between endometriosis and ME/CFS, driven by shared mechanisms of immune dysregulation and chronic inflammation. Despite high heterogeneity, the consistent effect sizes support clinical vigilance for comorbidity. Future research should prioritize standardized diagnostic criteria to elucidate causal pathways. These findings underscore the need for integrated care approaches to address overlapping symptomatology in affected patients.

Source: Compton S, Alkabalan R, Cadet J, Mastali A, Ramdass PVAK. Endometriosis and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review and Meta-Analysis. Diagnostics (Basel). 2025 Sep 15;15(18):2332. doi: 10.3390/diagnostics15182332. PMID: 41008704. https://www.mdpi.com/2075-4418/15/18/2332 (Full text)