Tag: long Covid

Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation

Abstract:

Inflammation-driven fatigue is a clinically significant feature of several chronic inflammatory conditions, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-COVID condition, autoimmune disease, and cancer-related fatigue. Across these conditions, partially overlapping disturbances in immune regulation, cellular metabolism, and neuroimmune signaling may contribute to persistent fatigue, despite important differences in initiating context and biological substrate. Current evidence implicates mitochondrial dysfunction, altered glycolysis and fatty acid utilization, lactate- and succinate-associated signaling, metabolite-sensing G protein-coupled receptor (GPCR) pathways, epigenetic acylation, and immune remodeling in the maintenance of fatigue.

This narrative review synthesizes both shared and disease-context-specific mechanisms underlying inflammation-associated fatigue, with particular emphasis on immunometabolism, peripheral-central neuroimmune crosstalk, metabolite-GPCR signaling, and epigenetic regulation.

We highlight GPCR signaling as a potentially important regulatory interface in inflammatory and metabolic pathways relevant to fatigue, while recognizing that direct causal evidence in human fatigue syndromes remains limited.

The review also examines how metabolite-mediated epigenetic acylation may influence immune cell function and fatigue-related biology, although this association remains incompletely validated in fatigue-specific settings. By integrating metabolic dysregulation, neuroimmune signaling, and immune dysfunction, this review consolidates current knowledge on candidate biomarkers, mechanistic pathways, and emerging therapeutic targets in chronic inflammation-driven fatigue.

Overall, this review provides a multidimensional framework for understanding fatigue across inflammatory disorders and for guiding future mechanistic and translational research.

Source: Hu Z, Wang J, Ma S, Zhuang J, Shi J, Zhu Y. Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation. Front Immunol. 2026 May 15;17:1806420. doi: 10.3389/fimmu.2026.1806420. PMID: 42220511; PMCID: PMC13218923. https://pmc.ncbi.nlm.nih.gov/articles/PMC13218923/ (Full text)

Omics-based computational approaches for biomarker identification, prediction, and treatment of Long COVID

Abstract:

Long COVID, or post-acute sequelae of COVID-19 (PASC), is a major global health problem, with cumulative estimates suggesting that around 400 million people worldwide have been affected. It is characterized by persistent or new symptoms such as fatigue, cognitive impairment, and breathlessness lasting beyond four weeks after acute infection. Diverse clinical manifestations, chronic course, and incompletely understood pathophysiology-including hypotheses involving viral persistence, immune dysregulation, autoimmunity, endothelial dysfunction, and metabolic reprogramming-impede the development of diagnostic criteria, biomarkers, and targeted therapies. We conducted a critical review of 101 Long COVID omics studies, focusing on the computational methods used and their methodological quality.

Using standardized criteria, we evaluated study design, statistical rigor, reproducibility, and clinical relevance across genomics, epigenomics, transcriptomics, proteomics, metabolomics, and multiomics integration, and mapped these findings onto regulatory and translational frameworks. Despite substantial methodological heterogeneity, convergent biological signals emerged.

Genomic studies implicate risk loci in immune and cardiopulmonary pathways. Epigenomic analyses identify differentially methylated regions in immune and circadian genes. Transcriptomic studies reveal persistent dysregulation of innate immune and coagulation pathways, as well as reproducible molecular endotypes. Proteomic studies consistently show abnormalities in the complement cascade and coagulation, with a small panel of complement proteins showing highly reproducible changes across independent cohorts. Metabolomic studies demonstrate sustained mitochondrial dysfunction and altered cellular bioenergetics for up to two years after infection.

Multiomics integration supports at least two major endotypes, characterized by predominant inflammatory versus metabolic dysregulation, and provides a basis for patient stratification and computational treatment discovery. Machine learning models frequently achieve high classification performance, but are rarely externally validated. Critical limitations restrict clinical translation. Most studies are underpowered relative to analytical complexity, use heterogeneous case definitions and controls, and report platform-specific signatures with limited overlap. External validation, preregistered analysis plans, and regulatory-aligned assay development are uncommon. To date, no regulatory-approved diagnostic assay or evidence-based therapeutic intervention has directly emerged from these computational findings.

Future progress requires harmonized phenotyping protocols, adequately powered longitudinal cohorts with external validation, integration of spatial omics and explainable artificial intelligence, and early engagement with regulatory and health-technology assessment pathways. This review provides a critical assessment and a translational roadmap, outlining how methodologically robust computational omics can be advanced toward clinically actionable tools for Long COVID.

Source: Pinero S, Li X, Zhang J, Winter M, Lee SH, Nguyen T, Liu L, Li J, Le TD. Omics-based computational approaches for biomarker identification, prediction, and treatment of Long COVID. Crit Rev Clin Lab Sci. 2026 Jun;63(4):332-358. doi: 10.1080/10408363.2025.2583083. Epub 2025 Dec 9. PMID: 41368891. https://pubmed.ncbi.nlm.nih.gov/41368891/

Comprehensive Immunophenotyping of Monocytes and Dendritic Cells Suggests Distinct Pathophysiology in Chronic Fatigue Syndrome and Long COVID

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long Coronavirus Disease 2019 (long COVID) are complex chronic conditions that often follow infectious triggers with overlapping clinical features but poorly defined pathophysiological relationships. This study aimed to identify disease-specific immune signatures through multiparameter immunophenotyping of monocytes, dendritic cells, and T cell subsets.

A total of 207 participants were included (ME/CFS: n = 103; long COVID: n = 63; healthy controls: n = 41). Peripheral blood mononuclear cells were analyzed using multiparameter flow cytometry. Statistical analyses included non-parametric testing, age-adjusted Analysis of covariance (ANCOVA), correlation network analysis, and principal component analysis (PCA).

Long COVID was characterized by increased M2-like monocyte polarization, elevated CD80 expression across monocyte subsets, expansion of dendritic cells, and reduced expression of activation markers, indicating persistent immune activation with features of immune exhaustion.

In contrast, ME/CFS exhibited reduced costimulatory molecule expression, impaired C-C chemokine receptor type 7 (CCR7)-mediated immune cell trafficking, and less coordinated activation patterns, consistent with a state of immune suppression. Correlation network analysis revealed more extensive and integrated immune interactions in long COVID, while PCA identified distinct immunophenotypic components and enabled moderate discrimination between the two conditions.

These findings demonstrate that ME/CFS and long COVID are characterized by distinct immune profiles, supporting the concept of divergent immunopathological mechanisms. The identified signatures may contribute to biomarker development and guide targeted therapeutic approaches.

Source: Petrov S, Bozhkova M, Ivanovska M, Kalfova T, Dudova D, Todorova Y, Dimitrova R, Murdjeva M, Taskov H, Nikolova M, Maes M. Comprehensive Immunophenotyping of Monocytes and Dendritic Cells Suggests Distinct Pathophysiology in Chronic Fatigue Syndrome and Long COVID. Int J Mol Sci. 2026 May 17;27(10):4488. doi: 10.3390/ijms27104488. PMID: 42196466; PMCID: PMC13206834. https://pmc.ncbi.nlm.nih.gov/articles/PMC13206834/ (Full text)

Vascular inflammation in neuropsychiatric long COVID

Highlights:

  • Long COVID is characterized by endothelial dysfunction with dysregulated inflammatory and coagulation pathways.
  • Endothelial biomarkers are elevated in Long COVID vs acute COVID-19, supporting a distinct vascular process.
  • Vascular biomarkers correlate with key cognitive and neuropsychiatric measures (fluency, memory, depression, and anxiety).
  • Vascular inflammation is a targetable mechanism in Long COVID, informing patient stratification and therapeutic trials.
  • Results highlight need to define the short- and long-term impact of vascular inflammation on brain health after COVID-19.

Abstract

The role of vascular inflammation in neuropsychiatric Long COVID (LC) is suspected but not well understood. This study evaluated whether vascular inflammation is present in individuals with neuropsychiatric LC and how it relates to cognitive and mental health symptoms.

This cross-sectional, case-control study included individuals with acute COVID-19 (AC), neuropsychiatric LC, and recovered controls. Participants were enrolled from the COVID Mind Study and the Yale IMPACT Study (hospitalized), and an independent cohort from the Johns Hopkins University (JHU) Long COVID Study. Fifty individuals with neuropsychiatric LC (new symptoms a median of 368 days post-COVID), 28 with AC, and 29 recovered controls (>3 months post-COVID) were evaluated. All underwent blood sampling and neuropsychiatric testing. The JHU cohort included 114 individuals with late LC (median 1065 days post-COVID illness associated with LC onset) and 31 recovered controls (median 852 days).

Fourteen plasma biomarkers of vascular inflammation were measured. ANCOVA was used to compare groups, adjusting for comorbidities. Non-hospitalized participants completed the Global Neuropsychological Assessment, GAD-7, and PHQ-9. LC and recovered groups were demographically similar, while AC participants had higher obesity and hypertension rates. LC participants had elevated circulating biomarkers of endothelial, leukocyte, and platelet adhesion (sL-selectin, ADAMTS13, sP-selectin, sICAM-1) compared to recovered controls.

Coagulation markers (D-dimer, fibrinogen) did not differ. Most biomarkers were highest in AC and lower in LC; however, fetuin, sL-selectin, and α-2 macroglobulin were higher in LC than AC. In LC, higher sP-selectin correlated with lower fluency and verbal learning. Lower α1-acid glycoprotein levels were strongly associated with poorer verbal memory, verbal learning, fluency, depression, and anxiety. In the JHU cohort, late LC and recovered controls showed no differences in biomarkers or demographics, suggesting normalization over time. Persistent dysregulation at the intersection of inflammation, platelet adhesion, and endothelial dysfunction is strongly linked to neuropsychiatric Long COVID.

Elevated markers of endothelial adhesion in LC suggest distinct pathophysiology from AC. These biomarkers correlate with lower fluency and verbal learning, linking vascular dysfunction to brain function. This study underscores the critical need for longitudinal, within-person investigations to elucidate how vascular inflammation evolves over time.

Source: McAlpine LS, Shorer EF, Chiarella J, Nelson A, Veenhuis R, Azola A, Lee A, Pierce R, Farhadian S, Rubin LH, Spudich SS; Yale COVID Mind; IMPACT Study Groups. Vascular inflammation in neuropsychiatric long COVID. Brain Behav Immun Health. 2026 Apr 28;54:101247. doi: 10.1016/j.bbih.2026.101247. PMID: 42099668; PMCID: PMC13147379. https://pmc.ncbi.nlm.nih.gov/articles/PMC13147379/ (Full text)

Plasma Extracellular Vesicle Surface Marker Profiling Reveals Immune Cell-Associated Mitochondrial Membrane Potential Alterations in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Long COVID (LC) is characterized by symptoms persisting at least 3 months after SARS-CoV-2 infection and affecting multiple organ systems. Diagnosis relies on subjective criteria without established biomarkers. Immune dysregulation and mitochondrial dysfunction are implicated in LC pathophysiology. Given clinical overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we investigated whether plasma extracellular vesicles (EVs) capture shared molecular signatures.

Methods: Plasma EVs from 125 individuals across pandemic-era and prepandemic cohorts were analyzed. The pandemic-era cohort included COVID-Recovered, LC with ME/CFS phenotype (LC-ME/CFS), and ME/CFS without infection (pan-ME/CFS). The prepandemic cohort included ME/CFS and matched controls. Extracellular vesicles were isolated using size-exclusion chromatography. Concentration and size were assessed by nanoparticle tracking analysis, and surface markers and mitochondrial membrane potential were evaluated by flow cytometry.

Results: Both pan-ME/CFS and LC-ME/CFS exhibited elevated EV concentrations compared with COVID-recovered controls after false discovery rate (FDR) correction (q = 0.0042 and 0.0024). Leukocyte-, monocyte/macrophage-, and platelet-derived EVs were increased, whereas B cell-derived EVs were reduced in both groups. Compared with controls, pan-ME/CFS demonstrated increased mitochondrial membrane potential in B cell-, monocyte/macrophage-, and NK cell-derived subsets after FDR correction, whereas no significant differences were observed in LC-ME/CFS. Prepandemic ME/CFS showed a nominal increase in leukocyte-derived EVs that did not persist after correction, whereas elevated mitochondrial membrane potential in B cell-derived EV subsets remained significant.

Conclusions: ME/CFS and LC-ME/CFS demonstrate partially overlapping immune cell-associated EV alterations. Mitochondrial membrane potential alterations within selected immune-derived EV subsets, particularly B cell-associated EVs, suggest immune-metabolic involvement. Plasma EV profiling may inform future biomarker development.

Source: Ikeda G, Koike-Ieki M, Inoue H, Dadhania AV, El Kamari V, Jagannathan P, Geng LN, Miglis MG, Shafer RW, Yang PC, Bonilla HF. Plasma Extracellular Vesicle Surface Marker Profiling Reveals Immune Cell-Associated Mitochondrial Membrane Potential Alterations in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Open Forum Infect Dis. 2026 May 12;13(5):ofag209. doi: 10.1093/ofid/ofag209. PMID: 42131622; PMCID: PMC13166156. https://pmc.ncbi.nlm.nih.gov/articles/PMC13166156/ (Full text)

What is the Role of “the Psyche”? Long COVID and ME/CFS as Test Cases for Evidence-Based and Patient-Centered Psychiatry and Psychotherapy

Abstract:

in English, German

The role of psychological factors in the development and course of Long Covid (LC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) remains a subject of controversial debate. We argue that psychologizing LC and ME/CFS carries significant risks: it leads to potentially harmful therapies, invalidates the patients’ experience of illness, hinders effective interventions such as pacing, diverts focus from necessary physical diagnostics and treatment, disadvantages patients in medical assessments, and places a considerable additional burden on the families of affected children or other relatives. We show that many of the arguments presented for a psychological contribution are nonspecific or insufficiently supported by empirical evidence. Our essay therefore advocates for extreme caution in attributing psychological factors to these conditions, in the interest of a specific, evidence-based, and patient-centered psychiatry and psychotherapy.

Source: Schomerus G, Nicolas ML, Fritz F, Schneider D, Büchner R. Welche Rolle spielt „die Psyche“? Long COVID und ME/CFS als Prüfsteine für eine evidenzbasierte und patient*innenorientierte Psychiatrie und Psychotherapie [What is the Role of “the Psyche”? Long COVID and ME/CFS as Test Cases for Evidence-Based and Patient-Centered Psychiatry and Psychotherapy]. Psychiatr Prax. 2026 May 12. German. doi: 10.1055/a-2866-9127. Epub ahead of print. PMID: 42119693. https://www.thieme-connect.de/products/ejournals/html/10.1055/a-2866-9127 (Full text)

Feasibility, Adherence, Acceptance and Usability of a Multimodal Telemonitoring for Pediatric Post-COVID Syndrome: A Bicentric Pilot Study

Abstract:

Existing healthcare infrastructure struggles to meet the complex care required for pediatric Post-COVID Syndrome (pPCS). Telemonitoring offers potential to enhance care access, reduce patient burden, and ensure continuity. This study introduces and evaluates a novel, multimodal telemonitoring concept for pPCS with high translational potential for broader pediatric chronic and post-infectious conditions. Telemonitoring included a patient app, digital sensors (spirometer, smartwatch), Patient Reported Outcome Measures, chat/video consultations (VC), and a medical telemonitoring platform.

Patients aged 12-17 years with diagnosed PCS were recruited from two pPCS outpatient university clinics in Bielefeld and Munich, Germany. Monitoring lasted three months. Evaluation focused on feasibility, adherence, acceptance, and usability, using monitoring data, the System Usability Scale (SUS), Technology Usage Inventory (TUI), and a custom survey completed by patients and parents. 30 patients (mean age: 15y ± 1.9; 57% female (17/30); mean Baseline Bell-Score: 36.4) and 30 parents participated.

Adherence was high, with an average of 3.4 (smartwatch) to 4.6 (spirometry) measurements/week. Questionnaire response rate was 86% (411/480) and 97% (58/60) of VCs were conducted. SUS scores indicated very high usability (patients: 81.25/100; parents: 75.42/100). TUI results showed low skepticism, and high interest. Telemonitoring supported symptom management independent of in-person visits, despite sensor connectivity issues.

This is the first study to demonstrate successful integration of telemonitoring in pPCS, with high adherence and positive feedback from all stakeholders supporting its potential. Despite occasional technical challenges and resource needs, this concept shows promise for broader hybrid telemonitoring care implementation in PCS and other post-infectious syndromes.

TRIAL REGISTRATION: German Clinical Trials Register (DRKS), trial registration number: DRKS00029354. Registered 07 February 2023 – Retrospectively registered https://drks.de/search/en/trial/DRKS00029354/entails.

Source: Oftring ZS, Schmidt J, Greenfield J, Hägele M, Farzaneh A, Hamelmann E, Behrends U, Kuhn S. Feasibility, Adherence, Acceptance and Usability of a Multimodal Telemonitoring for Pediatric Post-COVID Syndrome: A Bicentric Pilot Study. J Med Syst. 2026 May 9;50(1):76. doi: 10.1007/s10916-026-02409-x. PMID: 42105038. https://link.springer.com/article/10.1007/s10916-026-02409-x (Full text)

Interpreting hand grip strength in hospital employees with post-COVID syndrome compared to non-infected controls: a case-control study

Abstract:

Post-COVID syndrome (PCS) is characterized by a variety of persistent symptoms following SARS-CoV-2 infection, including fatigue among others. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a related neurological disorder primarily characterized by severe fatigue and post-exertional malaise. This exploratory study aimed to assess hand grip strength (HGS) in individuals with PCS to evaluate muscular performance and fatigability and to explore potential HGS-derived parameters associated with PCS.

HGS was measured in 19 hospital employees with PCS (mean age 47.8; 89.5% female; 7 fulfilling ME/CFS criteria) and compared with 23 healthy controls (mean age 43.7; 69.6% female). Measurements were performed in two sessions separated by 60 min, each consisting of ten consecutive HGS measurements. Linear mixed model analysis indicated that HGS tended to be lower in PCS at specific measurement points, although no consistent overall group effect was observed. HGS was reduced in the second session in PCS but not in controls, suggesting possible alterations in recovery following repeated exertion.

Exploratory analysis of 30 HGS-derived parameters using logisitic regression models in female participants identified parameters based on maximum, minimum, and mean force values as showing the most promising discriminatory patterns: however, predictive performace was moderate and should be interpreted with caution.

Overall, HGS may provide insights into funcitional impairment in PCS and could serve as a supportive adjunct in clinical assessment, although its diagnostic utility requires validation in larger cohorts.

Source: Tack M, Gruber R, Betting L, Herbrandt S, Schlang G, Mattner F. Interpreting hand grip strength in hospital employees with post-COVID syndrome compared to non-infected controls: a case-control study. Sci Rep. 2026 May 9. doi: 10.1038/s41598-026-51666-w. Epub ahead of print. PMID: 42103832. https://www.nature.com/articles/s41598-026-51666-w (Full study available as PDF file)

Erythroid-hormonal axis in long COVID

Abstract:

Long COVID may reflect a failure of coordinated physiological recovery rather than persistent infection. Emerging evidence identifies inflammation-driven disruption of erythropoiesis and hormonal balance as central mechanisms linking immune dysregulation, metabolic stress, and persistent symptoms. This framework positions erythroid-endocrine pathways as key determinants of recovery and promising therapeutic targets.

Source: Elahi S. Erythroid-hormonal axis in long COVID. Trends Mol Med. 2026 May 4:S1471-4914(26)00088-2. doi: 10.1016/j.molmed.2026.04.006. Epub ahead of print. PMID: 42086409. https://pubmed.ncbi.nlm.nih.gov/42086409/

‘I Want Everyone to Have It, and Everyone to Be on It’: A Feasibility Study of the Transforming Long Covid Intervention

Abstract:

Background: An understanding of the nature of long Covid (LC) is evolving, with recent evidence highlighting the role of increased sympathetic activation and decreased parasympathetic response. Building upon this emerging science, the ‘Transforming Long COVID’ (TLC) programme was developed to support participants in their recovery by (i) introducing education on the neuroscience underpinning persistent symptoms (with a particular focus on the autonomic nervous system) and (ii) the development of self-management strategies to support recovery. The aim of this study was to examine the feasibility of the TLC programme with a cohort of people significantly affected by LC.

Methods: Seventeen participants took part in the 8-week TLC programme which comprised of seven content sessions and one discussion (Q&A) session. Participants completed survey scales (investigating anxiety, pain-related interference, pain catastrophising, sleep disturbance and fatigue) at baseline, immediately post-programme (at 8 weeks), and retention (at 13 weeks). Participants also took part in focus group interviews to investigate their experiences of the programme.

Results: Fourteen participants (82%) attended at least six of the seven TLC content sessions. Decreases in mean values over time were observed across all measures, indicating a positive (non-significant) change. Participants reported an increase in understanding of LC, new hope for recovery, belief that they now had a realistic pathway for recovery, validation of their experiences and symptoms, meaningful improvements in function, and enhanced ability to respond to and attenuate physical symptoms. No adverse events were reported. Participants highlighted a number of programme strengths, along with some potential areas for improvement.

Conclusion: The TLC programme was shown to be feasible based on engagement, adherence, acceptable completion of surveys, and no adverse events. Study findings point to the potential for this programme to be refined, trialled and evaluated with a larger sample.

Patient or public contribution: Four people (living with LC, ME/CFS, chronic migraine and chronic Lyme, fibromyalgia, and centralised pain syndrome), who have experience of applying a recovery approach aligned with the TLC programme, acted in a PPI (Public and Patient Involvement in research) capacity on this study. In addition, the lead author has personal experience with the illness, and developing the recovery approach, which helped inform programme structure and development [1]. These individuals provided advice and guidance on the potential structure for the group programme, course duration, tool selection, and language and wording of the programme and materials. Further detail is provided in the Supplementary Materials.

Source: Belton S, Goss H, Whyte E, McCaffrey N, Gibney S, Sheridan K. ‘I Want Everyone to Have It, and Everyone to Be on It’: A Feasibility Study of the Transforming Long Covid Intervention. Health Expect. 2026 Jun;29(3):e70681. doi: 10.1111/hex.70681. PMID: 42076812. https://onlinelibrary.wiley.com/doi/10.1111/hex.70681 (Full text)