Overlapping Clinical Presentation of Long COVID and Postacute COVID-19 Vaccination Syndrome: Phenotypes, Severity, and Biomarkers

Abstract:

Background: Postacute sequelae of COVID-19 (PASC), also known as long COVID, and postacute COVID-19 vaccination syndrome (PACVS) present overlapping but distinct clinical challenges. We hypothesize that PASC and PACVS share clinical features but differ in symptom patterns and biomarker profiles. This study aims to identify differences in presentation and distinguish immunologic biomarkers relevant to general clinical practice.

Methods: This cross-sectional study analyzed 181 patients from a PASC clinic at Columbia University Irving Medical Center. Patients were divided into PASC with myalgic encephalomyelitis/chronic fatigue syndrome (MECFS), PASC without MECFS (LC), and PACVS groups. Prevalence and severity of self-reported symptoms, as well as immunologic abnormalities, were compared across groups.

Results: Fatigue was the most common symptom (Total: 88.95%; MECFS: 100.00%; PACVS: 92.86%; LC: 78.05%). The MECFS group generally reported more symptoms across all organ systems. The PACVS group reported higher rates of atypical chief complaints such as peripheral neuropathy (17.9%), tinnitus (7.1%), and rash (10.7%) compared to the other groups (P = <.01). Functional impairment was comparable between the MECFS and PACVS groups and less severe in the LC group. All groups had high rates of autoantibody positivity and cytokine elevation. The PACVS group showed significantly higher rates of anticardiolipin IgM (PACVS 42.9%, LC 11.6%; P = .02) and anti-U1-RNP (PACVS 21.4%, LC 2.3%; P = .04) positivity compared to the LC group.

Conclusions: PASC and PACVS share symptom overlap but exhibit distinct biomarker patterns, particularly elevated autoantibody levels in PACVS. These findings suggest autoimmune involvement, warranting further investigation for targeted therapies.

Source: Purpura L, Heisler T, Palmer S, Shah J, Graham A, Seo GY, Sturiza A, Javier X, Pinto G, Rosa A, Bosco J, Reis K, Sobieszczyk ME, Yin MT. Overlapping Clinical Presentation of Long COVID and Postacute COVID-19 Vaccination Syndrome: Phenotypes, Severity, and Biomarkers. Clin Infect Dis. 2026 Jan 9:ciaf624. doi: 10.1093/cid/ciaf624. Epub ahead of print. PMID: 41510565. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf624/8417802 (Full text)

Multi-Strain Probiotic Improves Tryptophan Metabolism and Symptoms in Chronic Fatigue Syndrome Patients with Co-Occurring Irritable Bowel Syndrome: An Open-Label Pilot Study

Simple Summary:

Chronic Fatigue Syndrome (CFS) is a debilitating condition often accompanied by gut health issues, but effective treatments are scarce. Recent research suggests that an imbalance in gut bacteria (dysbiosis) may contribute to CFS symptoms by producing harmful substances that affect the nervous system. We investigated whether a specific multi-strain probiotic (CDS22-formula) could improve symptoms in women with CFS and co-occurring IBS. Over 12 weeks, patients took a high-dose probiotic supplement. We monitored their fatigue levels and analyzed urine samples to track changes in tryptophan metabolism—a key pathway linking the gut to the brain. The results showed that the probiotic intervention was associated with an improved gut bacteria profile. Importantly, this coincided with a reduction in neurotoxic metabolites and a significant decrease in fatigue severity. Our findings suggest that targeting the gut microbiome can be a valuable strategy for managing chronic fatigue, potentially by modulating the production of metabolites that affect brain function.
Abstract:

Background/Objectives: Gut dysbiosis in Chronic Fatigue Syndrome (CFS) drives low-grade inflammation and shifts tryptophan metabolism toward neurotoxic pathways. The causal link between bacterial translocation, kynurenine pathway dysregulation, and symptom severity remains under-defined. We evaluated the impact of a high-concentration multi-strain probiotic on the “gut-kynurenine axis” and clinical status in CFS patients with co-morbid IBS-U and confirmed dysbiosis.
Methods: Forty female patients with confirmed dysbiosis (GA-map™ Dysbiosis Index > 2) received the CDS22 formula (450 billion CFU/day) for 12 weeks. We compared urinary tryptophan metabolite profiles (LC-MS/MS), gut dysbiosis markers (3-indoxyl sulfate), and fatigue severity (FSS) against 40 age-matched healthy controls.
Results: Baseline analysis revealed profound metabolic perturbations: elevated bacterial proteolytic markers (3-IS), substrate depletion (low tryptophan), and a neurotoxic signature (high quinolinic acid [QA], low kynurenic acid [KYNA]). Following the intervention, fatigue scores declined by 40.3%, with 97.5% of patients reaching the remission threshold (FSS < 36). Biochemically, 3-IS levels decreased to the range observed in healthy controls and attenuated xanthurenic acid levels. Although absolute QA concentrations remained elevated compared to controls, the neuroprotective KYNA/QA ratio increased significantly (+45%). Increased systemic tryptophan availability correlated directly with clinical symptom reduction (Spearman’s rho = −0.36, p = 0.024).
Conclusions: The CDS22 formulation was associated with a restoration of intestinal eubiosis and functional tryptophan partitioning. Clinical remission coincides with a metabolic shift favoring neuroprotection (increased KYNA/QA ratio), validating the gut–kynurenine axis as a modifiable therapeutic target. Peripheral metabolic improvement relative to the healthy baseline appeared sufficient for symptom relief in this specific phenotype, despite incomplete clearance of neurotoxic metabolites.
Source:

Multi-omics identifies lipid accumulation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome cell lines: a case-control study

Abstract:

Background: In recent years, evidence has indicated a metabolic shift towards increased demand for lipids in various lymphoid cell populations from people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We previously screened the mitochondrial function and gene expression of B cell-derived lymphoblastoid cell lines (LCLs) generated from the blood of people with ME/CFS to characterise a model for hypothesis discovery and testing, observing elevated expression of gene products facilitating amino acid and fatty acid degradation for energy.

Method: In this follow-up study we have expanded this characterisation by profiling the polar metabolomes and non-polar lipidomes of an all-female cohort of 17 healthy control and 15 ME/CFS LCLs, and we integrated this new data with the previously generated proteomic and transcriptomic data.

Results: In the polar metabolome we detected no significantly altered individual features, while integrated multi-omic analysis by MetaboAnalyst indicated 15 dysregulated pathways. Next, in the non-polar lipidome, we identified that PC(O-38:4) had significantly reduced levels in ME/CFS LCLs and was almost entirely discriminative of ME/CFS status. Among all detected classes of lipids we found that triradylglycerolipids (“triglycerides”), diradylglycerolipids and fatty acids were the most significantly affected and were elevated, and that most lipids exhibited average levels higher than in healthy controls. BioPAN pathway analysis of the lipidomic data predicted a more-active gene product that we confirmed to be significantly elevated in both our proteomic and transcriptomic data, this being phosphatidylserine synthase 1 (PTDSS1), plus 7 other gene products that were concordantly altered in expression in the transcriptomic data. We also found that ME/CFS LCLs exhibited a significant tendency towards more saturated lipid content.

Conclusions: LCLs generated from circulating B cells from people with ME/CFS show accumulation of lipids, skewed lipid profiles and altered activity of related metabolic enzymes such as PTDSS1. These findings will inform future hypothesis-driven studies of primary lymphoid cell populations from people with ME/CFS to dissect specific immunometabolic mechanisms that may be involved in the syndrome, particularly relating to intersections between lipid abnormalities and potential effects on immune cell effector functions.

Source: Missailidis D, Armstrong CW, Anderson D, Allan CY, Sanislav O, Smith PK, Esmaili T, Creek DJ, Annesley SJ, Fisher PR. Multi-omics identifies lipid accumulation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome cell lines: a case-control study. J Transl Med. 2026 Jan 8. doi: 10.1186/s12967-025-07620-x. Epub ahead of print. PMID: 41508032. https://link.springer.com/article/10.1186/s12967-025-07620-x (Full text available as PDF file)

Evaluating working memory functioning in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis

Abstract:

Individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) frequently report pronounced cognitive difficulties, yet the empirical literature has not fully characterised how discrete components of working memory are affected. Given that working memory serves as a foundational system supporting complex cognitive processes, differentiating performance across verbal and visual modalities provides critical insight into which higher-order functions may be most vulnerable. This systematic review/meta-analysis aimed to synthesise current research to investigate how ME/CFS impacts working memory systems.

Using PRISMA guidelines, a systematic search of 6 databases was undertaken (MEDLINE, CINAHL, Web of Science Core Collection, PubMed, EMBASE and PsycINFO). Initially, 10 574 papers were imported and following screening 34 studies of good to strong quality met the inclusion criteria. A series of random effects models were utilised to analyse working memory.

Results indicated a significant difference and large effect size between ME/CFS individuals and controls on verbal working memory tasks; however, no significant difference in visual working memory performance was found between the groups. Following the breakdown of these subsystems into span/attentional control tasks and object/spatial tasks, these results remained consistent.

These findings contribute to the body of ME/CFS research by articulating where specific working memory deficits lie. Specifically, they show that individuals with ME/CFS have impaired verbal memory performance. This knowledge can guide future research targeting higher-order verbal cognition and underscores the importance of recognising cognitive manifestations within ME/CFS clinical care.

Source: Penson M, Kelly K. Evaluating working memory functioning in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis. Psychol Health Med. 2026 Jan 8:1-30. doi: 10.1080/13548506.2025.2606183. Epub ahead of print. PMID: 41504224. https://pubmed.ncbi.nlm.nih.gov/41504224/

Wheat and chaff in Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) in clinics and laboratory

To the Editor,

We read the contribution by Hunter et al., titled “Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling” in this journal, initially impressed for the large collection of data. They actually presented a novel, genome-wide epigenetic profiling approach using EpiSwitch® technology to identify potential diagnostic biomarkers for ME/CFS [1]. The use of 3D chromatin conformation signatures provides a fresh perspective on disease-specific gene regulation, moving beyond conventional transcriptomics and methylation analyses. In general, the diagnostic model demonstrates impressive sensitivity (92%) and specificity (98%) in distinguishing ME/CFS patients from controls, suggesting real clinical potential [1]. Moreover, the application of advanced machine learning techniques adds analytical robustness, while pathway analysis identifies biologically plausible immune-related mechanisms. This integrative approach sets a promising foundation for future biomarker-driven diagnostics and personalized therapy stratification in ME/CFS. Fundamentally, they presented a retrospective case-control analysis aiming to identify diagnostic epigenetic markers for ME/CFS using 3D chromatin conformation profiling (EpiSwitch®). However, while the authors make bold claims regarding diagnostic sensitivity and specificity, the paper suffers from multiple scientific weaknesses and methodological ambiguities that undermine its validity and translational relevance.

First, the article repeatedly asserts that “immune dysregulation” is a hallmark of ME/CFS, citing elevated pro-inflammatory cytokines and natural killer (NK) cell dysfunction. However, whereas the authors cite updated papers with a presumptive relationship with the issue, a critical omission here is the lack of citation of early foundational immunological studies in ME/CFS [2]. Notably absent is the 1994 work by Tirelli et al. in the Scandinavian Journal of Immunology, which documented, for the first time, immunological abnormalities in CFS patients and could serve as an important historical anchor for claims of immune dysregulation [2]. This omission raises concerns about reporting bias and selective citation to frame the narrative around newer, possibly more aligned findings with the current study methodology [2, 3].

Additionally, the paper refers to “ME/CFS inclusion criteria” as requiring severe CFS with patients being “housebound,” but fails to specify which diagnostic criteria were used, whether the Fukuda, Canadian Consensus, International Consensus, or IOM/NAM criteria [1]. This lack of precision is critical, as different case definitions yield different cohorts in terms of clinical features and biological signatures. Using “severe housebound” as a criterion, without reference to a validated clinical definition or stratification tool (e.g., Bell Disability Scale), introduces subjectivity and undermines the reproducibility of patient selection. The term “housebound” is not a recognized diagnostic stratifier and suggests imprecise cohort construction.

Further ambiguity arises when the authors discuss the control group. They state that controls had “none of the four key CFS symptoms present or in the past” and “preferably an existing history of glandular fever or COVID.” The phrase “preferably” is ambiguous and methodologically problematic [1]. Did the control group actually include individuals with prior infectious mononucleosis or COVID-19, and if so, how were these illnesses verified? The phrase “preferably” suggests either inconsistency in selection or retrospective rationalization, both of which compromise the clarity and control of variables in the study. Furthermore, it is scientifically incoherent to describe individuals as controls (i.e., free from ME/CFS) while also including those with a known post-infectious risk profile, potentially biasing the control group with latent post-viral immunogenetic changes [1].

There is further conceptual confusion when the authors state that the ME/CFS network reveals some overlap with pathways involved in multiple sclerosis (MS) and rheumatoid arthritis (RA). While such overlaps are plausible and worth exploring, the authors do not sufficiently explain the biological rationale for this claim or its relevance to ME/CFS pathophysiology [1]. They reference IL-2, IL-10, CD4, and TLR pathways as shared elements, but these are highly pleiotropic and non-specific immunological signals.

The mere presence of these markers in ME/CFS does not imply mechanistic similarity to MS or RA. Without longitudinal or functional studies, this comparison becomes speculative and possibly misleading, especially given the known heterogeneity of ME/CFS and the distinct immunopathology of autoimmune diseases like MS.

Read the rest of this letter HERE.

Source: Tirelli U, Franzini M, Chirumbolo S. Wheat and chaff in Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) in clinics and laboratory. J Transl Med. 2026 Jan 5;24(1):20. doi: 10.1186/s12967-025-07397-z. PMID: 41491817. https://link.springer.com/article/10.1186/s12967-025-07397-z (Full text)

Re-analysis: 200 treatments by 4000 Long Covid/ME patients

I ranked 200+ treatments by effect scores and got a new Top 5

In 2023, a survey was run among 3,925 ME/CFS and Long Covid patients called TREATME. It asked patients which treatments they have tried and how they responded to it. It is by far the biggest survey of its kind. I am really grateful to Martha Eckey, a PharmD and patient herself, for collecting the data and to the Open Medicine Foundation for having helped her to analyze and publish it.

At the time I wasn’t very interested in the results, but I’ve since come to appreciate the severity of publication biases. Those retrospective “we treated x patients with treatment Y without blinding and without controls” only get published if there are positive results! This survey, on the other hand, would have been published regardless of any individual treatment results, making it significantly more trustworthy (although not as good as well-designed RCTs).

Read the rest of this article here: https://viralpersistence.substack.com/p/re-analyzing-the-treatme-survey?triedRedirect=true

LOW VASOPRESSIN IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME

Abstract:

Objective: The complex clinical picture of ME/CFS includes orthostatic intolerance with symptoms and signs suggesting abnormal water homeostasis and hypovolemia. Since many ME/CFS patients report polyuria-polydipsia, we conducted an observational study based on series of plasma and urine osmolality (P-Osm and U-Osm) as well as plasma levels of vasopressin (P-VP) or copeptin in consecutive patients diagnosed with ME/CFS according to the International Consensus Criteria.

Methods: P-VP as well as P-Osm and U-Osm were measured in 111 patients after 10 hour overnight fasting and fluid deprivation. Additional 13 patients were assessed for copeptin, when P-VP measurements were no longer available. The clinical routine also included brain MRI and blood chemistry.

Results: P-Osm was abnormally high (>292 mOsm/kg) in 71/124 (57.3 %) and U-Osm below the reference interval (< 750 mOsm/kg) in 82/124 (66.1%) patients. P-VP was below the level of detection (<1.6 pg/mL) in 91/111 (82.0 %) patients. A normal P-VP level compared with their P-Osm was found in 11/111 (9.9 %) patients. Copeptin levels were all within the given reference range, albeit in the lower end in most patients. No indication of relevant pathology in either hypothalamus or hypophysis was present.

Conclusions: Our findings suggest that chronic down-regulation of VP mimicking central diabetes insipidus is an important measurable part of the disease mechanism that potentially contributes to criterial symptoms of ME/CFS.

Source: Huhmar HM, Soinne LS, Bertilson BC, Ghatan PH, Bragée BA, Polo OJ. LOW VASOPRESSIN IN MYALGIC ENCEPHALOMYELITIS/CHRONIC FATIGUE SYNDROME. Endocr Pract. 2025 Dec 29:S1530-891X(25)01349-7. doi: 10.1016/j.eprac.2025.12.020. Epub ahead of print. PMID: 41475665. https://www.endocrinepractice.org/article/S1530-891X(25)01349-7/fulltext (Full text)

Post-translational modifications within fibrinaloid microclot complexes distinguish Pre-COVID-19 Postural Orthostatic Tachycardia Syndrome, Long COVID, and Long COVID-POTS and reveal disease-specific molecular pathways

Abstract:

Background: Pre-COVID-19 Postural orthostatic tachycardia syndrome (PC-POTS), Long COVID, and their overlap (LC-POTS) are chronic post-viral conditions marked by debilitating symptoms despite frequently normal routine laboratory results. We have previously identified insoluble fibrinaloid microclot complexes (FMCs) in Long COVID. It is not known whether FMCs are also present in PC-POTS, or whether post-translational modifications (PTMs) within FMC-entrapped proteins contribute to disease mechanisms.

Methods: Platelet-poor plasma from healthy controls, PC-POTS patients (collected prior to the COVID-19 pandemic), Long COVID (without POTS) and LC-POTS patients underwent fluorescence imaging flow cytometry to quantify FMCs. Proteomic analyses were performed on insoluble protein fractions using a double trypsin digestion strategy and data-independent liquid chromatography-tandem mass spectrometry (LC-MS/MS). Differential protein abundance, PTMs, and amyloidogenicity were compared across groups.

Results: Measured with imaging flow cytometry in objects/mL, higher levels of FMCs were present in disease groups compared to controls, although not statistically significant. Statistically significant differences potentially lay within FMC sizes and composition. Furthermore, despite only a few dysregulated proteins, FMC proteomics revealed extensive and disease-specific peptides with PTM dysregulation across coagulation, immune, and metabolic pathways. Long COVID displayed FMCs with PTMs of coagulation proteins including prominent advanced glycation end-products (AGE)- and oxidation-based modifications of fibrinogen subunits, particularly fibrinogen subunit A (FIBA), resembling diabetic glycation profiles. FMCs in PC-POTS showed fewer fibrinogen PTMs but markedly increased modifications in metabolic proteins, including oxidised apoA1 and apoB, and immune patterns with complement-related proteins (C3, C4A/B, IC1), immunoglobulin G1 (IGG1) and alpha 2 macroglobulin (A2MG). LC-POTS shared coagulation pathology with Long COVID and immune pathology with PC-POTS. Many dysregulated peptides were determined by in silco methods to be highly amyloidogenic, consistent with FMCs as beta-sheet-rich aggregates. Protein-level differences were minimal compared with PTM changes.

Conclusions: This study provides the first evidence that post-translational modifications (PTMs) within fibrinaloid microclots complexes (FMCs) uniquely distinguish pre-COVID-19 POTS, Long COVID, and Long COVID-POTS. Because PC-POTS samples were collected before SARS-CoV-2, their PTM patterns reflect intrinsic disease biology, allowing a clear separation from Long COVID-related changes. PTM profiling revealed pro-coagulant fibrinogen modifications in Long COVID and LC-POTS, metabolic-oxidative disruptions in Long COVID and PC-POTS, and immune dysregulation in PC-POTS and LC-POTS. None of these is detectable with routine assays, and all are independent of protein abundance. The consistent presence of amyloidogenic peptides suggests a contribution to microvascular dysfunction. These findings define disease-specific PTM landscapes and support new diagnostic and therapeutic avenues across autonomic and post-viral disorders.

Source: Renata Madre Booyens, Mare Vlok, Cecile Bester, Rashmin Hira, M Asad Khan, Douglas B Kell, Satish R Raj, Etheresia Pretorius. Post-translational modifications within fibrinaloid microclot complexes distinguish Pre-COVID-19 Postural Orthostatic Tachycardia Syndrome, Long COVID, and Long COVID-POTS and reveal disease-specific molecular pathways.
bioRxiv 2025.12.29.696828; doi: https://doi.org/10.64898/2025.12.29.696828 https://www.biorxiv.org/content/10.64898/2025.12.29.696828v1 (Full text available as PDF file)

Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease?

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness with unknown etiology. An estimated 17-24 million people representing approximately 1% of the population are afflicted worldwide. In over half of cases, ME/CFS onset is associated with acute “flu-like” symptoms, suggesting a role for viruses. However, no single virus has been identified as the only etiological agent.

This may reflect the approach employed or more strongly the central dogma associated with herpesviruses replication, which states that a herpesvirus exists in two states, either lytic or latent. The purpose of this review is to address the role that abortive lytic replication may have in the pathogenesis of ME/CFS and other post-acute viral infections and also to raise awareness that these syndromes might be poly-herpesviruses mediated diseases.

Source: Ariza ME, Mena Palomo I, Williams MV. Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease? Viruses. 2025 Dec 16;17(12):1624. doi: 10.3390/v17121624. PMID: 41472292. https://www.mdpi.com/1999-4915/17/12/1624 (Full text)

Complex chronic adverse events following immunization: a systemic critique and reform proposal for vaccine pharmacovigilance

Abstract:

The COVID-19 pandemic has renewed attention to complex chronic health conditions that challenge conventional biomedical paradigms. Syndromes such as postural orthostatic tachycardia syndrome and myalgic encephalomyelitis/chronic fatigue syndrome have gained broader visibility through the lens of Long COVID. As global vaccination campaigns expanded, a subset of individuals began reporting similarly persistent, multisystem symptoms following COVID-19 immunization-informally referred to as post-COVID-19 vaccination syndrome.

These presentations, which include dysautonomia, neuropathic pain, post-exertional malaise, and cognitive dysfunction, resemble post-infectious syndromes and may involve shared immune-related mechanisms. Although no causal relationship to vaccination has been established, these cases-together with comparable reports following other vaccines-highlight limitations in current vaccine safety systems for detecting and evaluating complex chronic outcomes.

This article introduces the concept of complex chronic adverse events following immunization (CC-AEFIs) as a pragmatic, surveillance-oriented framework to support the systematic identification and investigation of such cases. CC-AEFIs are not syndromic diagnoses but a higher-order category encompassing persistent, multifactorial conditions that may follow immunization yet challenge existing pharmacovigilance definitions and tools.

These conditions often involve multiple organ systems, delayed onset, fluctuating trajectories, diagnostic ambiguity, and symptom heterogeneity. Drawing on the author’s lived experience as an affected patient and integrating clinical, regulatory, and experiential evidence, the analysis examines structural and epistemic limitations across the pharmacovigilance continuum-from underrecognition in clinical settings to analytic exclusion and constrained governance.

It concludes by proposing reforms to strengthen safety-system responsiveness, including enhanced diagnostic training, longitudinal surveillance, patient-reported outcome integration, and analytic transparency. Addressing these limitations is essential to sustain public trust, ensure equitable care, and uphold the scientific integrity of immunization programs.

Source: Kenny TA. Complex chronic adverse events following immunization: a systemic critique and reform proposal for vaccine pharmacovigilance. Ther Adv Drug Saf. 2025 Dec 24;16:20420986251395925. doi: 10.1177/20420986251395925. PMID: 41466718; PMCID: PMC12743803. https://pmc.ncbi.nlm.nih.gov/articles/PMC12743803/ (Full text)