Tag: 2026

Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem disorder characterized by neuroimmune, autonomic, and gastrointestinal dysfunction. Previous studies identified coherent symptom domains involving Brain, Autonomic, Gut, and Immune manifestations and demonstrated pronounced sex-specific differences in neurocognitive-sensory and autonomic symptom organization. However, whether immune-related and gastrointestinal symptoms form distinct or integrated latent structures in women and men with ME/CFS remains unclear. In addition, the potential influence of menopausal status on these symptom domains has not been systematically investigated.

Methods: Data from 748 adults with a medical diagnosis of ME/CFS were included in this cross-sectional analysis (608 women, 137 men, and 3 non-binary participants). Sex-stratified analyses were restricted to women and men. Symptoms were coded dichotomously. Sex-stratified analyses included cross-tabulations, Cramér’s V, tetrachoric correlations, logistic and linear regression models, exploratory factor analysis, and structural equation modeling (SEM). Additional subgroup analyses compared pre- and postmenopausal women. Model robustness was evaluated using a stratified training dataset.

Results: In women, Immune (flu-like symptoms, susceptibility to infections) and Gut (gastrointestinal complaints, food intolerances) symptoms formed two distinct but related clusters, characterized by moderate within-cluster correlations (tetrachoric ρ = 0.47-0.60) and weaker cross-cluster associations (ρ = 0.30-0.35). Exploratory factor analysis (EFA) supported a two-factor solution. Consistent with this result, the alternative one-factor SEM showed comparatively poor fit (CFI = 0.913; RMSEA = 0.119), whereas the specified two-factor model was just-identified and therefore not suitable for global fit evaluation. In men, all four symptoms loaded onto a single integrated Gut/Immune factor, with within- and cross-domain tetrachoric correlations ranging from 0.43 to 0.68. SEM confirmed excellent fit for a one-factor model (CFI = 0.981; RMSEA = 0.074). Susceptibility to infections emerged as the dominant predictor in regression analyses. Among women, menopausal status selectively affected immune-related symptoms. Women classified as premenopausal reported flu-like symptoms more frequently than women classified as postmenopausal, whereas gastrointestinal symptoms and food intolerances remained stable across groups. These findings suggest differential hormonal sensitivity of immune versus gastrointestinal symptom trajectories.

Conclusions: Immune and gastrointestinal symptoms in ME/CFS exhibit sex-specific latent structures. Women demonstrate two partially separable but related symptom domains, whereas men show a more integrated immune-gastrointestinal architecture. Furthermore, menopausal status appears to selectively modulate immune-related symptom expression while leaving gastrointestinal symptom patterns comparatively stable. Taken together, these results provide an exploratory framework that supports the concept of sex-dependent neuroimmune-autonomic mechanisms in ME/CFS and aligns with a dynamic, hormonally modulated immune component as well as a more persistent, gut-related process. The results highlight the importance of sex- and hormone-sensitive approaches to phenotyping, mechanistic research, and therapeutic stratification in ME/CFS.

Source: Habermann-Horstmeier L, Horstmeier LM. Sex- and menopause-related differences in immune and gastrointestinal symptom architecture in ME/CFS: evidence from factor analysis and structural equation modeling. J Transl Med. 2026 Jul 27;24(1):970. doi: 10.1186/s12967-026-08699-6. PMID: 42522006. https://link.springer.com/article/10.1186/s12967-026-08699-6 (Full text)

Risks of autoimmune and inflammatory post-acute COVID-19 conditions: a network cohort study in six European countries, the USA and Korea

Abstract:

Objectives: We aimed to assess the risk of incident autoimmune and inflammatory conditions during the post-acute period of COVID-19.

Design: Descriptive network cohort study.

Setting: Electronic health records from the UK and Dutch primary care, Norwegian linked health registry, hospital records of specialist centres in Spain, France and Korea and healthcare claims from Estonia and the USA.

Participants: We followed individuals between September 2020 and the latest available data from day 91 after a SARS-CoV-2 negative test (comparator) or a COVID-19 record (exposed patients, ie assessing patients during the post-acute phase). We further established a reinfection cohort (any further COVID-19 record among the exposed patients). We followed patients until an outcome, end of study period, death, day 365 or an infection (comparator only) or reinfection (exposed patients only).

Main outcome measures: We assessed postural orthostatic tachycardia syndrome (POTS) diagnoses/symptoms, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) diagnoses/symptoms, multi-inflammatory syndrome (MIS) and several autoimmune diseases (rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) and type 1 diabetes mellitus (T1DM)). Meta-analysed crude incidence rate ratios (IRRs) of outcomes after COVID-19 versus negative testing and after reinfection versus a previous COVID-19 record yield the ratios of respective absolute risks of each assessed outcome. We performed subgroup analyses by age, sex and predominant variant periods.

Results: We included 2 521 812 individuals with a first COVID-19 record, 4 233 145 with a first negative test and 135 551 with a reinfection. Age and sex were largely comparable between exposure groups with a shorter follow-up for the reinfection cohorts. After COVID-19 compared with test-negative patients and equally after reinfection compared with previous COVID-19 patients, we did not observe increased rates for all outcomes and all subgroup analyses. Counts of MIS and JIA were too small for meta-analyses.

Conclusions: In our descriptive meta-analyses of crude IRRs among databases from various countries and settings, we did not observe increased rates of incident POTS, ME/CFS, RA, IBD, SLE and T1DM in COVID-19 versus test-negative or reinfection versus COVID-19 during the first 9 months of the post-acute phase of COVID-19 or reinfection (>90 days postinfection until month 12). Since causal interpretation cannot be made from this study, further causal research is warranted.

Source: Burkard TM, López-Güell K, Català M, Burn E, Delmestri A, Khalid S, Jödicke AM, Dedman D, Oyinlola J, Abellan A, Pérez-Crespo L, Mercadé-Besora N, Duarte-Salles T, Prieto-Alhambra D, Arinze J, Mosseveld M, Kolde R, Meléndez J, López-Blasco R, Martínez Á, Valdivieso B, Delseny D, Mercier G, Kim C, Kim JW, Kostka K, Ramírez-Anguita JM, Mayer MA, Trinh NTH, Nordeng H, Paredes R, Uusküla A, Nishimura A, Loste C, Mateu L, Xie J. Risks of autoimmune and inflammatory post-acute COVID-19 conditions: a network cohort study in six European countries, the USA and Korea. BMJ Public Health. 2026 Jul 24;4(3):e001686. doi: 10.1136/bmjph-2024-001686. PMID: 42516718; PMCID: PMC13404851. https://pmc.ncbi.nlm.nih.gov/articles/PMC13404851/ (Full text)

Low-Dose Ionizing Radiation and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Review of Recent Evidence and Future Research Directions Toward the Elucidation of a Metabolic, Immunologic, and Signaling Cascade

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an idiopathic, multisystem disorder marked by debilitating fatigue, post-exertional malaise, cognitive dysfunction and neuroinflammation. Its etiology remains unclear, yet emerging evidence implicates a complex interplay between immune dysregulation, metabolic impairment, mitochondrial bioenergetics, and environmental stressors such as viral infection or low-dose ionizing radiation (LDIR). To develop treatments for ME/CFS, it is essential to identify suitable targets for therapy.

In this narrative review, we discuss recent findings on the overlap of ME/CFS with LDIR effects and examine potential mechanistic links that may arise from LDIR-induced bystander effects (RIBEs). We highlight potential candidate biomarkers that bridge these domains: mitochondrial respiratory dysfunction, altered ornithine transport via SLC25A15 (ORNT1), possible roles of CD38 in the context of immunity and NAD+ depletion, cyclin D1-dependent metabolic reprogramming and modulation of gene expression, and α-synuclein as a potential neuroinflammatory damage-associated molecular pattern (DAMP).

While the involvement of these biomarkers in ME/CFS is yet to be confirmed experimentally, evidence from in vitro studies of irradiated cells, exosome profiling, and patient samples suggests that RIBEs can, in theory, produce prominent cellular ME/CFS phenotypes through associated mechanisms, including those exhibiting oxidative stress, impaired ATP production, and immune modulation.

We propose a hypothetical, exploratory model wherein LDIR initiates or contributes to adaptive metabolic shifts (including CD38 upregulation and cyclin D1 stabilization) that, coupled with persistent bystander signaling, could potentially culminate in chronic fatigue and neurocognitive symptoms in some reported ME/CFS cases.

Finally, we outline a research agenda encompassing the establishment of standardized diagnostic criteria, multi-omics profiling of patient cohorts, exosome analysis, functional mitochondrial assays, and targeted therapeutic trials focusing on possible anti-CD38 antibodies and NAD+ precursor therapy. By integrating recent findings in low-dose radiation biology with ME/CFS pathophysiology, this review aims to promote interdisciplinary investigations that may uncover mechanistic insights and novel biomarkers for diagnosis and treatment of ME/CFS. We further review steps in a proposed model taking us from low-dose radiation exposure to a number of possible targets.

Source: Rusin A, Cocchetto A, Mothersill C. Low-Dose Ionizing Radiation and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Review of Recent Evidence and Future Research Directions Toward the Elucidation of a Metabolic, Immunologic, and Signaling Cascade. Int J Mol Sci. 2026 Jul 22;27(14):6535. doi: 10.3390/ijms27146535. PMID: 42511874; PMCID: PMC13411118. https://pmc.ncbi.nlm.nih.gov/articles/PMC13411118/ (Full text)

Pacing and energy management with digital tools for conditions with chronic fatigue: What we know so far in ME/CFS and Long COVID

Introduction:

Why pacing matters in conditions with post‑exertional symptom exacerbation

‘Pacing’, or ‘energy management’, is a structured approach to regulating one’s physical, cognitive, and emotional activities to remain within limits imposed by chronic illnesses such as fibromyalgia, cancer, ME/CFS, and Long COVID [1,2]. Pacing ostensibly prevents post‑exertional symptom exacerbation, notably post‑exertional malaise (PEM), the worsening of fatigue, pain, cognitive dysfunction, and other symptoms following even modest activity. Across the literature, pacing is heterogeneously described as strategies that include activity planning, routine‑setting, pre‑emptive rest, breaking tasks into smaller components, monitoring energy fluctuations, and intentionally avoiding activity “push‑crash” cycles that commonly drive clinical deterioration [3]. In addition to heterogenous implementation, evidence of efficacy is also varied [3–9]. In this article, we will focus on ME/CFS and Long COVID as use case examples.

Historically, pacing emerged as an energy management method encouraging individuals to do as much as they can within their limits, rather than pushing through symptoms or following externally prescribed exercise. The central principle is that of the “energy envelope” [1], which asks individuals to identify the threshold at which activity begins to provoke symptoms and then remain inside that envelope as consistently as possible.

While definitions vary across clinicians, researchers, and patient groups, a consistent theme in both our systematic review and the scoping review is that pacing is individualised and requires ongoing adjustment as symptoms fluctuate [3,7]. Importantly, pacing is now the only management strategy recommended by the 2021 NICE guidelines for ME/CFS [10], underscoring its centrality in clinical care despite the concerning lack of evidence for efficacy. As Long COVID research evolved, pacing increasingly became recognised as a pragmatic, do no harm approach for a condition characterised by varied symptomology, unpredictable recovery patterns, and vulnerability to overexertion [8,11].

Source: Sanal-Hayes NEM, Hayes LD, Mclaughlin M, Sculthorpe NF (2026) Pacing and energy management with digital tools for conditions with chronic fatigue: What we know so far in ME/CFS and Long COVID. PLOS Digit Health 5(7): e0001586. https://doi.org/10.1371/journal.pdig.0001586 https://journals.plos.org/digitalhealth/article?id=10.1371/journal.pdig.0001586 (Full text)

Overcoming barriers in myalgic encephalomyelitis/chronic fatigue syndrome research: the CureME participatory model

Abstract:

Research into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents unique challenges. These stem from the logistical difficulties created by the degree of disability experienced and heterogeneous diagnostic criteria driven by etiological uncertainty. This is compounded by distrust of research institutions within the ME/CFS community, due to historical mischaracterization of ME/CFS as a psychosomatic disease. This commentary proposes a framework to address the resulting methodological and practical barriers.

The CureME Framework draws on the UK ME/CFS Biobank’s extensive experience of participatory research and incorporates strategies for effective recruitment and data collection. It is informed by collaborations with individuals with lived experience of ME/CFS including severely affected individuals. This is achieved by integrating co-produced study design, community-engaged recruitment, and adaptations that minimize the cognitive and physical burden of participation.

This increases access to research participation, reduces selection bias, and strengthens cohort representativeness. Adopting this approach may enhance methodological rigor, accessibility, trust, cohort representativeness, statistical power, and ethical integrity in ME/CFS research.

Source: Abken E, Tyson S, Kingdon C. Overcoming barriers in myalgic encephalomyelitis/chronic fatigue syndrome research: the CureME participatory model. Front Hum Neurosci. 2026 Jul 7;20:1826525. doi: 10.3389/fnhum.2026.1826525. PMID: 42483535; PMCID: PMC13385095. https://pmc.ncbi.nlm.nih.gov/articles/PMC13385095/ (Full text)

Inflammatory and neuroinjury blood biomarkers across COVID-19 severity groups in individuals with persistent neurological symptoms

Abstract:

Persistent neurological symptoms such as cognitive impairment, fatigue, and neuropsychiatric disturbances are increasingly reported in patients with long COVID, with chronic neuroinflammation and neuronal injury proposed as potential contributors. To characterize inflammatory and neuroinjury-related biomarker patterns, we conducted a case-control study including 325 participants recruited at King Chulalongkorn Memorial Hospital between January 2022 and December 2023, comprising 265 individuals with persistent neurological symptoms following COVID-19 infection and 60 asymptomatic COVID-19 participants who did not develop long COVID symptoms.

Blood samples were analysed for inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α, IFN-α, IL-4) using multiplex immunoassays, and for neuroinflammatory and neurodegenerative biomarkers, including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau181, and beta-amyloid peptides (Aβ40, Aβ42) using SIMOA and ELISA platforms. Among 265 participants with complete data (critical = 7, severe = 22, moderate = 79, mild = 157), patients with severe and critical COVID-19 exhibited significantly higher concentrations of IL-6, IL-1β, TNF-α, and IL-8, together with elevated NfL, GFAP, and phosphorylated tau181 levels, and reduced Aβ42/40 ratios.

Strong positive correlations between neurodegenerative biomarkers and pro-inflammatory cytokines were observed in critically ill patients, whereas these associations were weak or absent in mild and moderate cases. Older age was also associated with greater disease severity and increased risk of persistent neurological complications.

These findings indicate that individuals with persistent neurological symptoms following COVID-19, particularly those with a history of severe or critical disease, exhibited higher inflammatory and neuroinjury-related biomarker levels, while blood-based biomarkers such as NfL, GFAP, and phosphorylated tau181 may serve as minimally invasive tools for characterizing neurological involvement and identifying patients at risk of long-term neurological sequelae.

Source: Ruchisrisarod C, Kaewpom T, Wanthong P, Luechaipanit W, Bunprakob S, Ampoot W, Yomrat S, Hemachudha P, Supharatpariyakorn T, Thanapornsangsuth P, Tammachote R, Saraya AW. Inflammatory and neuroinjury blood biomarkers across COVID-19 severity groups in individuals with persistent neurological symptoms. Int J Immunopathol Pharmacol. 2026 Jan-Dec;40:3946320261465568. doi: 10.1177/03946320261465568. Epub 2026 Jul 16. PMID: 42460883; PMCID: PMC13376473. https://pmc.ncbi.nlm.nih.gov/articles/PMC13376473/ (Full text)

Multimodal approach to identify neuropsychophysiological subgroups in myalgic encephalomyelitis/chronic fatigue syndrome and their relevance for rehabilitation: protocol for a mechanistic cross-sectional and longitudinal study

Abstract:

Introduction: Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a debilitating condition characterized by severe fatigue and post-exertional malaise (PEM). Reported neuropsychophysiological abnormalities suggest ME/CFS is multifactorial, but current knowledge remains fragmented. This study protocol outlines a multimodal investigation designed to (1) compare neuropsychophysiological mechanisms between ME/CFS patients and healthy participants, (2) test an integrative model of ME/CFS, (3) identify neuropsychophysiological subgroups within the patient population, and (4) identify predictors of symptom response during rehabilitation.

Methods and analysis: This study will enroll 115 ME/CFS patients and 55 healthy participants. Groups will be comparable in age, sex, and education level, with a larger patient sample enabling subgroup and longitudinal analyses. A cross-sectional assessment at baseline will be carried out in both groups. Patients will then be evaluated longitudinally throughout a standardized cognitive-behavioral therapy rehabilitation program delivered as routine care.

Baseline measures include systemic inflammation and general health biomarkers, measures of autonomic and central nervous system function, neuroinflammation (magnetic resonance spectroscopy, [18F]DPA714 PET in a subsample), serum short-chain fatty acid levels, gut microbiota composition and function, and neuroendocrine and self-reported responses to psychosocial stress. Fatigue severity (physical and cognitive) and PEM will be assessed through validated questionnaires, ecological momentary assessment, and laboratory tasks.

These will be re-evaluated during therapy, and all non-neuroimaging measures will be repeated after the rehabilitation program. Statistical analyses will comprise multivariate analysis of variance, general linear models, classification algorithms, structural equation models, least absolute shrinkage selection operator principal component regression (LASSO-PCR), cluster analysis and latent class growth analysis (LCGA).

Source: Dooms Y, Qiu L, Coppieters I, Vergaelen E, Claes S, Dupont P, Hehl M, Cuypers K, Engler H, Dombrowski K, Verbeke K, Van den Bergh O, Raes J, Van Oudenhove L, Van Den Houte M, Bogaerts K. Multimodal approach to identify neuropsychophysiological subgroups in myalgic encephalomyelitis/chronic fatigue syndrome and their relevance for rehabilitation: protocol for a mechanistic cross-sectional and longitudinal study. Brain Behav Immun Health. 2026 Jul 6;56:101299. doi: 10.1016/j.bbih.2026.101299. PMID: 42472232; PMCID: PMC13380062. https://pmc.ncbi.nlm.nih.gov/articles/PMC13380062/ (Full text)

Perioperative outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome undergoing general anesthesia: a retrospective matched-pair study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem disease characterized by profound fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Despite features with potential relevance for anesthesia and perioperative care, empirical data on perioperative outcomes in patients with ME/CFS remains limited. We therefore performed a retrospective matched-pair analysis to generate clinical data on perioperative responses and identify areas for future research.

Methods: We conducted a retrospective matched-pair analysis at a single tertiary center. All patients with ME/CFS undergoing general anesthesia from 2015 to 2026 were identified using ICD-10-GM codes with additional manual verification and matched 1:1 to controls for comparison. Patients with confounding diagnoses or American Society of Anesthesiologists physical status above III were excluded. The analysis focused on intraoperative hemodynamic parameters, including baseline, post-induction, median, and lowest recorded systolic blood pressure and heart rate, as well as early postoperative outcomes in the post-anesthesia care unit (PACU), including maximum pain scores and requirement for rescue analgesia.

Results: Out of 189 individuals identified through ICD-10 codes, 15 matched pairs were included after application of exclusion criteria. Patients with ME/CFS exhibited lower minimum intraoperative systolic blood pressure (90.0 [82.5-95.0] vs. 100.0 [90.0-110.0] mmHg, p = 0.044) and lower minimum heart rate (50.0 [40.0-57.5] vs. 60.0 [50.0-65.0] bpm, p = 0.012). Vasopressor use and fluid administration did not differ, and no episodes of severe hypotension or perioperative adverse events were observed. Postoperative pain was higher in ME/CFS, with higher maximum pain scores (NRS 5.0 [4.0-6.0] vs. 1.0 [0.0-4.0], p = 0.008) and more frequent opioid rescue analgesia (80% vs. 33%, p = 0.039). Postoperative nausea or vomiting, oxygen supplementation, and PACU length of stay were similar between groups.

Conclusions: In this small exploratory cohort, general anesthesia was not associated with clinically relevant hemodynamic instability in patients with ME/CFS. Postoperative pain scores and opioid rescue requirements were higher in the ME/CFS group. Post-exertional malaise, a key disease feature with potentially delayed onset and significant impact, was not captured and remains an important target for future research. These findings should be considered hypothesis-generating and support prospective studies evaluating perioperative management and patient-relevant outcomes in ME/CFS.

Source: Steinkirchner FM, Kaufmann CK, Kraus RF, Käss M, Schieffer E, Graf BM, Lassen C, Kimmerling V, Dejaco A. Perioperative outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome undergoing general anesthesia: a retrospective matched-pair study. BMC Anesthesiol. 2026 Jul 16;26(1):426. doi: 10.1186/s12871-026-04102-5. PMID: 42464211. https://link.springer.com/article/10.1186/s12871-026-04102-5 (Full text available as PDF file)

Handgrip strength in children, adolescents, and young adults with suspected myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in children, young people (CYP) lacks validated diagnostic biomarkers. Post-exertional malaise (PEM) is central to case definitions and is usually assessed by patient report. We evaluated the feasibility and clinical value of handgrip strength (HGS) testing in PEM-reporting CYP referred for suspected ME/CFS.

Methods: In this prospective observational study at the Munich Chronic Fatigue Center for Young People (November 2022-November 2024), 147 patients (10-25 years) referred for the assessment of ME/CFS with positive DSQ-PEM screening and 83 healthy controls (HC) completed two HGS sessions (10 maximal grips/session; 3-s contraction/5-s rest; 60-minute inter-session break) using a digital dynamometer. We derived maximal force (Fmax), mean force (Fmean), fatigue ratio (FR = Fmax/Fmean), and recovery ratio (RR = Fmean session 2 / session 1). Analyses used repeated-measures ANCOVA, linear regression, partial Spearman correlations (adjusted for sex, age, and BMI), and proportional odds models for group membership (HC, noME/CFS, ME/CFS), reporting accuracy, and the C-statistic. Sensitivity analyses compared noME/CFS with confirmed CCC-ME/CFS.

Results: After clinical work-up, 84/147 (57%) patients were classified as ME/CFS (confirmed or probable) and 63/147 (43%) as noME/CFS. HGS test completion rate was high (session 1: 146/147, 99.3%; session 2: 142/147, 96.6%). Compared with HC, patients had substantially lower HGS (mean difference -9.93 kg, 95% CI: -12.00 to -7.85), and HGS indices correlated modestly with physical functioning (SF-12 PCS), but not with PEM duration. Both noME/CFS and ME/CFS groups differed from HC in absolute strength indices (Fmean, Fmax) and FR. RR differed between ME/CFS and HC, whereas no HGS index significantly separated noME/CFS from ME/CFS. In proportional odds models, each HGS index improved fit (all p < 0.001), but discrimination across HC, noME/CFS, and ME/CFS patients was moderate (accuracy 49.2-57.3% vs no-information rate 36.5%, with best performance for Fmean in session 2). In the CCC-restricted sensitivity analysis, discrimination between confirmed CCC-ME/CFS and noME/CFS was moderate (accuracy 62.8-70.7%; C-statistic 0.63-0.73), with best performance for absolute strength indices and RR.

Conclusions: Standardized two-session repeated HGS testing is feasible in CYP with chronic fatigue and self-reported PEM and provides an objective marker of functional impairment that aligns with physical health status but not with PEM duration. However, HGS alone shows limited ability to discriminate ME/CFS from other fatiguing noME/CFS conditions. HGS may be useful for quantitative phenotyping, patient stratification, and longitudinal outcome assessment rather than as a standalone diagnostic biomarker.

Source: Mihatsch L, Schartner L, de Luna JL, Höhler C, Bucka L, Lovrenovic L, Eidenschink S, Schmuck B, Bienemann V, Christa C, Mittelstraß K, Hausruckinger A, Warlitz C, Michel K, Gerrer K, Freitag H, Scheibenbogen C, Pricoco R, Behrends U. Handgrip strength in children, adolescents, and young adults with suspected myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2026 Jul 15. doi: 10.1186/s12967-026-08654-5. Epub ahead of print. PMID: 42458481. https://link.springer.com/article/10.1186/s12967-026-08654-5 (Full text available as PDF file)

Biomarkers of post-acute infection syndrome: a systematic literature review

Abstract:

Background: Post-acute infection syndrome (PAIS) remained underrecognized before the COVID-19 pandemic, which further increased exposure by introducing a novel global cause. The global burden of post-acute COVID syndrome (PACS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) alone is estimated at several tens of millions affected worldwide. Biomarker discovery is central to improving PAIS diagnosis and may provide therapeutic targets. This review summarizes current knowledge on biomarkers for PAIS, including PACS and ME/CFS.

Methods: A systematic literature search was conducted in PubMed and Web of Science. Inclusion criteria were: (1) studies including PAIS patients; (2) reporting laboratory or omics biomarkers; and (3) investigating biomarkers or pathomechanisms of PAIS. Although Guillain-Barré syndrome (GBS) is not PAIS, we have included it as a separate mechanistic comparator due to its prevalence in search results and its clinical and immunological similarities to PAIS.

Results: A total of 142 studies analyzing PAIS biomarkers were included. GBS was analyzed separately and later compared with the other results. Overall, the reviewed studies employed heterogeneous approaches. While similar types of data were frequently investigated, analytical methods varied and often focused only on a subset of molecules. The results indicate that amino acid, energy, and lipid metabolism, microbiome, mitochondrial stress, and miRNA networks are affected. All pathways are connected via NF-κB.

Discussion: PAIS is a multisystem disorder rooted in persistent immune activation, metabolic reprogramming, and systemic inflammation, driven not by active viral infection, but by dysregulated host responses. The NF-κB pathway serves as a unifying hub, connecting molecular, cellular, and clinical phenotypes. Our framework enables a shift from symptom-based to mechanism-based classification, paving the way for biologically grounded interventions.

Conclusion: This review synthesizes a broad spectrum of biomarkers in PAIS, integrating findings across pathogens and molecular levels rather than restricting to individual conditions or symptom clusters. This study highlights the differences and commonalities among pathogens and diseases that lead to post-acute sequelae, fills a critical knowledge gap, and provides a foundation for future research and clinical practice. Future studies incorporating multi-omics approaches, longitudinal designs, and larger patient cohorts are needed to validate specific biomarkers and advance the understanding of PAIS.

Source: Wendt K, Schieck M, Gille C, Marschollek M, Illig T, Wolff D, Nee S. Biomarkers of post-acute infection syndrome: a systematic literature review. Front Immunol. 2026 Jun 30;17:1741761. doi: 10.3389/fimmu.2026.1741761. PMID: 42454043; PMCID: PMC13365053. https://pmc.ncbi.nlm.nih.gov/articles/PMC13365053/ (Full text)