Tag: long Covid

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)

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)

Therapeutic plasma exchange and immunomodulatory strategies in post-infectious syndromes: A review of immune dysregulation in PTLDS, long COVID, ME/CFS, and PANS/PANDAS

Abstract:

Post-infectious syndromes including post-treatment Lyme disease syndrome (PTLDS), long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and pediatric acute-onset neuropsychiatric syndrome (PANS)/pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) share overlapping clinical phenotypes characterized by fatigue, cognitive dysfunction, sleep disturbance, and neuropsychiatric symptoms. Increasing evidence suggests that immune dysregulation-including persistent inflammation, autoantibody production, and cellular immune dysfunction-may underlie these conditions.

This narrative review synthesizes peer-reviewed literature describing immune abnormalities across these syndromes and evaluates the rationale for immunomodulatory therapies, including intravenous immunoglobulin (IVIG), rituximab, and therapeutic plasma exchange (TPE). Evidence supporting immune-targeted treatment strategies is strongest in subsets of patients with identifiable immunologic abnormalities. Notably, the phase III RituxME trial in ME/CFS and a phase II trial of TPE in post-COVID condition both failed to demonstrate efficacy in unselected populations, reinforcing the importance of biomarker-guided patient stratification. TPE functions by removing circulating immune complexes, autoantibodies, and inflammatory mediators, and observational data suggest benefit in patients with demonstrable autoantibody burden. Further controlled studies incorporating immunologic phenotyping and early intervention are needed to define the therapeutic role of immune-directed interventions across these conditions.

Source: Kaplan G. Therapeutic plasma exchange and immunomodulatory strategies in post-infectious syndromes: A review of immune dysregulation in PTLDS, long COVID, ME/CFS, and PANS/PANDAS. Transfus Apher Sci. 2026 Jun 26;65(4):104482. doi: 10.1016/j.transci.2026.104482. Epub ahead of print. PMID: 42391726.  https://pubmed.ncbi.nlm.nih.gov/42391726/

Exploring the mechanisms of acupuncture in improving cognitive function in post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome: study protocol for a randomized controlled trial using multimodal MRI

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common sequela following COVID-19. Although cognitive dysfunction is one of the most debilitating symptoms in ME/CFS, effective therapies are limited. Acupuncture is an important complementary and alternative therapy for ME/CFS and has been shown to have positive effects on cognitive dysfunction in other diseases. However, the effect and mechanism of acupuncture in treating cognitive dysfunction in post-COVID-19 ME/CFS(PCME/CFS) remain unclear. In this study, we designed a randomized controlled trial to evaluate the efficacy of acupuncture treatment in improving cognitive function in PCME/CFS and to investigate the neural mechanisms of acupuncture using multimodal magnetic resonance imaging (MRI) techniques.

Methods: A total of 129 patients and 30 healthy controls (HCs) will be enrolled. The 129 patients with PCME/CFS will be randomly assigned in a 1:1:1 ratio to a verum acupuncture (VA), sham acupuncture (SA), or a waitlist control group. Participants in the VA and SA groups will receive three sessions of treatment per week for 8 weeks, while patients in the waitlist control group will be treated after the 8-week waiting period. The primary outcome is the change in the Symbol Digit Modalities Test (SDMT) score from baseline to week 8. The secondary outcome measures include changes from baseline to endpoint (week 8) in cognitive performance as assessed by the Digit Span Test (DST), Trail Making Test (TMT), Rey Auditory Verbal Learning Test (RAVLT), Rey-Osterrieth complex figure test (RCFT), Stroop Color and Word Test (SCWT), phonemic fluency test, category fluency test, action fluency test, and 30-item Boston Naming Test (BNT-30). In addition, changes in hippocampal metabolites and resting-state functional connectivity(RSFC) will be examined using 1H-magnetic resonance spectroscopy(1H-MRS) and functional MRI (fMRI), respectively. Moreover, the Multidimensional Fatigue Inventory (MFI-20), Pittsburgh Sleep Quality Index (PSQI), Generalized Anxiety Disorder 7-item scale (GAD-7), 24-item Hamilton Depression Scale (HAMD-24), and 36-Item Short Form Survey (SF-36) will also be assessed at baseline and week 8.

Discussion: The results of this study will provide preliminary evidence regarding the efficacy of acupuncture therapy in improving cognitive function in PCME/CFS and will explore whether acupuncture improves cognitive function in this disease by modulating metabolism and RSFC in the hippocampus.

Clinical trial registration: www.clinicaltrials.gov, identifier: NCT07357688.

Source: Luo T, Luo Y, Huang L, Jin H, An Y, Huang J, Luo K, Guo Y, Wang D, Liu D, Wu X. Exploring the mechanisms of acupuncture in improving cognitive function in post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome: study protocol for a randomized controlled trial using multimodal MRI. Front Neurol. 2026 Jun 3;17:1793397. doi: 10.3389/fneur.2026.1793397. PMID: 42383026; PMCID: PMC13318089. https://pmc.ncbi.nlm.nih.gov/articles/PMC13318089/ (Full text)

Redefining pandemic resilience: a roadmap for post-infectious syndrome preparedness and health system transformation

Abstract:

Post-infectious syndromes like Long COVID and ME/CFS lead to disability and economic losses globally, especially in lower-income countries. These involve complex multisystem issues such as immune disturbances, inflammation, autonomic dysregulation, vascular problems, altered metabolism, and tissue damage. Re-infections increase the risk of disability and complications. Healthcare delays diagnosis and neglects long-term effects.

We propose a three-part healthcare approach: primary care screening with digital tools, regional testing centers, and specialized Centers of Excellence for complex cases. An integrated infrastructure with registries, patient data, and wearables supports personalized care and surveillance. Policies should include disability benefits, rehab, infection control, and innovative funding. Healthcare must be accessible via mobile and community efforts, integrated into pandemic plans. The goal is to reduce morbidity and improve socioeconomic resilience.

Source: Schieffer B. Redefining pandemic resilience: a roadmap for post-infectious syndrome preparedness and health system transformation. Front Health Serv. 2026 Jun 10;6:1779647. doi: 10.3389/frhs.2026.1779647. PMID: 42358486; PMCID: PMC13290723. https://pmc.ncbi.nlm.nih.gov/articles/PMC13290723/ (Full text)

Systems neuroendocrinology in ME/CFS and long COVID: a chronobiological framework for hormone-based research

Abstract:

Hormonal dysregulation is increasingly reported in ME/CFS and Long COVID, yet the broader role of neuroendocrine disruption in these conditions remains underexplored. While changes in steroid, peptide, and neuropeptide hormones have been identified, these findings are often considered in isolation and without attention to their timing or integration within broader physiological systems. The hypothalamic-pituitary axes regulate endocrine, immune, autonomic, nervous, and metabolic functions, systems commonly affected in both conditions, yet their circadian and menstrual dynamics are rarely investigated.

In this review, we examine the evidence for neuroendocrine dysfunction in ME/CFS and Long COVID, focusing on hormone output, functional assays, receptor expression, and the coordination of endocrine biorhythms. Sex hormone signalling emerges as a key area of vulnerability, particularly given the female predominance in both conditions and the complexity of reproductive hormone regulation.

We argue that accurate hormone measurement and time-structured sampling, including circadian and menstrual rhythms, are essential for detecting meaningful biological differences. By embedding chronobiology-aware, dense-sampling strategies and integrating multi-omic analyses into multi-system study designs, we outline a framework for investigating dynamic endocrine mechanisms underlying symptom variability and multisystem dysfunction, which may ultimately support the development of more targeted, personalised interventions.

Source: Thomas N, Huang K, Schneider-Futschik EK, Pollack B, Tal MC, Fineberg D, Wang X, Gurvich C, Pretorius R, Bergquist J, Armstrong CW. Systems neuroendocrinology in ME/CFS and long COVID: a chronobiological framework for hormone-based research. Front Neuroendocrinol. 2026 Jun 19:101268. doi: 10.1016/j.yfrne.2026.101268. Epub ahead of print. PMID: 42320559. https://www.sciencedirect.com/science/article/abs/pii/S0091302226000385 (Full text)

Two-timepoint multidomain follow-up of post-COVID condition and ME/CFS: overlapping autonomic, small-fiber, and cognitive changes

Abstract:

Background: Post-COVID condition (PCC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) show marked clinical overlap, suggesting a shared post-infectious pathophysiology. This study aims to characterize the longitudinal change of autonomic function, small-fiber integrity, cognitive performance, and clinical symptoms in PCC and ME/CFS, and to determine whether trajectories differ between diagnostic groups.

Methods: Thirty-eight participants (21 PCC, 17 ME/CFS) underwent two standardized evaluations separated by a median of 31 months. Assessments included comprehensive autonomic testing, small-fiber evaluation, and an extensive neuropsychological battery.

Results: ME/CFS showed longer disease duration than PCC at baseline (median 42 vs. 12 months), while the interval between evaluations was comparable (31 vs. 30 months). Baseline profiles were largely overlapping, although ME/CFS showed nominally higher QST warm detection thresholds (p = 0.034), greater autonomic symptom burden (p = 0.038), and lower hemodynamic scores (p = 0.019), none surviving FDR correction. Cross-domain analyses linked small-fiber symptoms with autonomic symptom burden (Rho = 0.65, pFDR = 0.002) and fatigue (Rho = 0.55, pFDR = 0.018), while fatigue was negatively associated with processing speed (Rho = – 0.57, pFDR = 0.004), attention (Rho = – 0.49, pFDR = 0.018), and executive function (Rho = – 0.44, pFDR = 0.047). Rank-transformed mixed-effects models identified FDR-corrected Time effects, with increases in CHEPs (pFDR < 0.001) and verbal memory (pFDR = 0.010), and decreases in processing speed (pFDR = 0.006) and QST cold thresholds (pFDR = 0.038).

Conclusions: PCC and ME/CFS showed broadly overlapping multidomain profiles, with particularly similar profiles at follow-up. This suggests that, among individuals with persistent symptoms, PCC may increasingly resemble longer-standing ME/CFS across autonomic, small-fiber/sensory, and cognitive domains. These findings are consistent with overlapping post-infectious mechanisms, but do not establish identical disease trajectories or definitive disease convergence.

Source: Azcue N, Barranco C, Tijero-Merino B, Acera M, Fernández-Valle T, Lafuente JV, Gabilondo I, Ruiz-Lopez M, Del Pino R, Gómez-Esteban JC. Two-timepoint multidomain follow-up of post-COVID condition and ME/CFS: overlapping autonomic, small-fiber, and cognitive changes. J Transl Med. 2026 Jun 12. doi: 10.1186/s12967-026-08321-9. Epub ahead of print. PMID: 42286686. https://link.springer.com/article/10.1186/s12967-026-08321-9 (Full study available as PDF file)

Multi-omics analysis of long COVID (post-COVID-19 condition) reveals persistent mitochondrial dysfunction, suppressed oxidative phosphorylation, and immune dysregulation

Abstract:

Introduction: Post-COVID Syndrome (PCS), or long-COVID, is a major public health burden, but its underlying mechanisms remain poorly understood. Because acute SARS-CoV-2 infection induces marked suppression of mitochondrial oxidative phosphorylation (OXPHOS), we investigated whether persistent immunometabolic remodeling is a recurring transcriptional, metabolic, and proteomic feature of PCS.

Methods: We performed an integrated multi-omics analysis of transcriptomic, proteomic, and metabolomic datasets across multiple tissues from Syrian hamster models and human cohorts spanning acute infection through post-acute and PCS stages extending up to 12 months post-infection.

Results: Across species and tissues, we observed overlapping signatures of mitochondrial dysfunction, including sustained suppression of OXPHOS, activation of mitochondrial stress responses, and enrichment of inflammatory pathways. Skeletal muscle exhibited the most pronounced and persistent mitochondrial repression in both hamsters and PCS patient biopsies, consistent with fatigue-associated phenotypes. Hamster heart and kidney tissues also showed persistent OXPHOS suppression, while lung tissue demonstrated prolonged inflammatory signaling despite partial metabolic recovery. In the nervous system, transcriptional profiles revealed region-specific patterns, including persistent cortical mitochondrial repression and partial recovery in sensory-associated regions. Peripheral blood mononuclear cells (PBMCs) transcriptomics and serum metabolic datasets suggested prolonged downregulation of OXPHOS-associated programs up to 12 months post-infection, potentially contributing to persistent immune dysregulation in susceptible individuals with underlying conditions. Longitudinal serum proteomics in PCS patients revealed sustained mitochondrial stress responses, increased oxidative stress signatures, and persistent immune activation at 1 and 6 months post-infection compared to recovered controls.

Discussion: Together, these multi-omics results identify persistent mitochondrial repression and immune dysregulation as recurring features across PCS-associated datasets, providing a framework linking bioenergetic dysfunction with chronic immune activation and supporting future mechanistic and therapeutic investigation.

Source: Tasoula A, Arif S, Waisberg E, Bauer L, Aslinger E, Guarnieri JW. Multi-omics analysis of long COVID (post-COVID-19 condition) reveals persistent mitochondrial dysfunction, suppressed oxidative phosphorylation, and immune dysregulation. Front Immunol. 2026 May 21;17:1776555. doi: 10.3389/fimmu.2026.1776555. PMID: 42253978; PMCID: PMC13234542. https://pmc.ncbi.nlm.nih.gov/articles/PMC13234542/ (Full text)

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/