Category: Overlapping Illnesses

Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles

Abstract:

While there are many postulates for the etiology of post-viral chronic fatigue and other symptomatology, little is known. We draw on our past experience of these syndromes to devise means which can expose the primary players of this malady in terms of a panoply participating biomolecules and the state of the stool microbiome.
Using databases established from a large dataset of patients at risk of colorectal cancer who were followed longitudinally over 3 decades, and a smaller database dedicated to building a Long PASC cohort (Post-Acute Sequelae of COVID-19), we were able to ascertain factors that predisposed patients to (and resulted in) significant changes in various biomarkers, i.e., the stool microbiome and serum cytokine levels, which we verified by collecting stool and serum samples.
There were significant changes in the stool microbiome with an inversion from the usual Bacillota and Bacteroidota species. Serum cytokines showed significant differences in MIP-1β versus TARC (CC chemokine ligand 17) in patients with either PASC or COVID-19 (p < 0.02); IL10 versus IL-12p70a (p < 0.02); IL-1b versus IL-6 (p < 0.01); MCP1 versus TARC (p < 0.03); IL-8 versus TARC (p < 0.002); and Eotaxin3 versus TARC (p < 0.004) in PASC. Some changes were seen solely in COVID-19, including MDC versus MIP-1α (p < 0.01); TNF-α versus IL-1-β (p < 0.06); MCP4 versus TARC (p < 0.0001). We also show correlates with chronic fatigue where an etiology was not identified.
These findings in patients with positive criteria for PASC show profound changes in the microbiome and serum cytokine expression. Patients with chronic fatigue without clear viral etiologies also have common associations, including a history of tonsillectomy, which evokes a likely immune etiology.
Source: Tobi, M., Chaudhari, D., Ryan, E. P., Rossi, N. F., Koka, O., Baxter, B., Tipton, M., Dutt, T. S., Tobi, Y., McVicker, B., & Angoa-Perez, M. (2025). Immune Signatures in Post-Acute Sequelae of COVID-19 (PASC) and Myalgia/Chronic Fatigue Syndrome (ME/CFS): Insights from the Fecal Microbiome and Serum Cytokine Profiles. Biomolecules, 15(7), 928. https://doi.org/10.3390/biom15070928 https://www.mdpi.com/2218-273X/15/7/928 (Full text)

Advancing research on regulatory autoantibodies targeting GPCRs: Insights from the 5th international symposium

Abstract:

The 5th International Symposium on Regulatory Autoantibodies Targeting GPCR (RAB-GPCRs) advanced the understanding of the significant role played by autoantibodies targeting G-protein-coupled receptors (GPCRs) in various human diseases. Once considered passive markers, RAB-GPCRs are now recognized as active modulators of cellular signaling, immune regulation, and inflammation.

The symposium highlighted their involvement in multiple prominent pathologies, including autoimmune diseases, cardio- and cerebrovascular diseases, and neuroimmunologic disorders such as myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 syndrome (ME/CFS/PCS), as well as solid organ and hematopoietic stem cell transplantation (SOT/HSCT). Experts from rheumatology, immunology, and neurology presented interdisciplinary discussions on the potential of RAB-GPCRs as biomarkers and therapeutic targets. Advances in screening methods, biomarker identification, and therapeutic strategies were shared, emphasizing their diagnostic potential and application in novel therapeutic interventions.

This report summarizes key insights from the symposium, particularly focusing on the modulatory properties of RAB-GPCRs and their relevance in both immune-mediated diseases and other pathologies (e.g., vascular, degenerative) that are traditionally not considered primarily immune-mediated. Ongoing research is expected to further establish these autoantibodies as crucial components in disease modulation and systems biology contexts, offering new opportunities for precision medicine and improved clinical outcomes in immune-related disorders.

Source: Cabral-Marques O, Schimke LF, Moll G, Filgueiras IS, Nóbile AL, Adri AS, do Vale FYN, Usuda JN, Corrêa YLG, Albuquerque D, Nava RG, Santos RS, Dias HD, Silva HF, Marconi PB, Catar R, Adu-Gyamfi M, Wang P, Khan TA, Hackel AM, Leheis A, Stähle A, Müller A, Schmidt C, Radunovic C, Adjailia EB, Grasshoff H, Humrich JY, Menz J, Fourlakis K, Winziers M, Jäpel M, Wegner MV, Lamprecht P, Nieberding R, Akbarzadeh R, Arnold S, Jendrek S, Klapa S, Augustin S, Biedermann S, Schinke S, Scheerer P, Endres M, Schulze-Forster K, Paul F, Yu X, Sotzny F, Sakmar TP, Banasik M, Haghikia A, Hoffmann MH, Veprintsev D, Witte T, Dalmolin RJS, Ochs HD, Heidecke H, Scheibenbogen C, Shoenfeld Y, Riemekasten G. Advancing research on regulatory autoantibodies targeting GPCRs: Insights from the 5th international symposium. Autoimmun Rev. 2025 Jun 19:103855. doi: 10.1016/j.autrev.2025.103855. Epub ahead of print. PMID: 40543860. https://www.sciencedirect.com/science/article/pii/S1568997225001156 (Full text)

A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID

Abstract:
The underlying pathologies driving post-acute infectious syndromes (e.g. myalgic encephalomyelitis / chronic fatigue syndrome, long COVID, etc) remain poorly understood. Given the extreme burden these illnesses impose on suffers, and the dramatic increase in cases following the COVID-19 pandemic, it is important to establish a deeper understanding of these pathologies.
We propose a model of how ME/CFS (and related illnesses), might emerge following a viral insult. Central to this hypothesis is the recognition that the core diagnostic features of ME/CFS involve bodily systems known to be governed by the brainstem. This is consistent with the growing literature suggesting that spinal and craniocervical pathologies are over-represented in people with ME/CFS and other post-infectious disorders.
We hypothesize that a non-trivial number of cases of ME/CFS and Long Covid (LC) may have a “mechanical basis.” We propose that an infectious insult may trigger an initial loss of connective tissue integrity in susceptible individuals (e.g. those with pre-existing hypermobility spectrum disorders), which in turn leads to instability at the craniocervical junction, and ultimately mechanical deformation of the brainstem. This ultimately causes widespread autonomic nervous system and immune system dysfunction due to aberrant signaling from the deformed nuclei.
This causal chain may also lead to a vicious cycle: if the dysregulation produced by the initial brainstem deformation leads to a deranged immune response or state of chronic hyper-inflammation, further expression of connective tissue degrading and remodeling factors such as MMPs and mast cells may be triggered. This could further degrade the connective tissues of the craniocervical junction and, in turn, increase mechanical deformation of the brainstem, leading to symptom exacerbation over time and leading to the chronic, lifelong presentation typical of ME/CFS.
Source: Wood, J., Varley, T., Hartman, J., Melia, N., Kaufman, D., & Falor, T. (2025). A Mechanical Basis: Brainstem Dysfunction as a Potential Etiology of ME/CFS and Long COVID. Preprints. https://doi.org/10.20944/preprints202506.0874.v1 https://www.preprints.org/manuscript/202506.0874/v1 (Full text)

Core features and inherent diversity of post-acute infection syndromes

Abstract:

Post-acute infection syndromes (PAIS), i.e., long-lasting pathologies subsequent to infections that do not properly resolve, have both a common core and a broad diversity of manifestations. PAIS include a group of core symptoms (pathological fatigue, cognitive problems, sleep disorders and pain) accompanied by a large set of diverse symptoms. Core and diverse additional symptoms, which can persist for years, exhibiting periods of relapses and remissions, usually start suddenly after an apparently common infection.

PAIS display highly variable clinical features depending on the nature of the initial pathogen, and to an even larger extent, on the diversity of preexisting individual terrains in which PAIS are rooted. In a first part, I discuss biological issues related to the persistence of microbial antigens, dysregulated immune responses, reactivation of latent viruses, different potential self-sustained inflammatory loops, mitochondrial dysfunction, metabolic disorders in the tryptophan- kynurenin pathway (TKP) with impact on serotonin, and consequences of a dysfunctional bidirectional microbiota-gut-brain axis.

The second part deals with the nervous system dependence of PAIS. I rely on the concept of interoception, the process by which the brain senses, integrates and interprets signals originating from within the body, and sends feebacks aimed at maintaining homeostasis. Interoception is central for understanding the origin of fatigue, dysautonomia, dysfunctioning of the hypothalamus-pituitary-adrenal (HPA) axis, and its relation with stress, inflammation or depression.

I propose that all individual predispositions leading to self-sustained vicious circles constitute building blocks that can self-assemble in many possible ways, to give rise to both core and diverse features of PAIS. A useful discrimination between different PAIS subtypes should be obtained with a composite profiling including biomarkers, questionnaires and functional tests so as to take into account PAIS multidimensionality.

Source: Trautmann A. Core features and inherent diversity of post-acute infection syndromes. Front Immunol. 2025 Jun 3;16:1509131. doi: 10.3389/fimmu.2025.1509131. PMID: 40529374; PMCID: PMC12170329. https://pmc.ncbi.nlm.nih.gov/articles/PMC12170329/ (Full text)

Long-term neurological and cognitive impact of COVID-19: a systematic review and meta-analysis in over 4 million patients

Abstract:

Background: Neuropsychiatric symptoms emerged early in the COVID-19 pandemic as a key feature of the virus, with research confirming a range of neuropsychiatric manifestations linked to acute SARS-CoV-2 infection. However, the persistence of neurological symptoms in the post-acute and chronic phases remains unclear. This meta-analysis assesses the long-term neurological effects of COVID-19 in recovered patients, providing insights for mental health service planning.

Methods: A comprehensive literature search was conducted across five electronic databases: PubMed, Scopus, Web of Science, EBSCO, and CENTRAL, up to March 22, 2024. Studies evaluating the prevalence of long-term neurological symptoms in COVID-19 survivors with at least six months of follow-up were included. Pooled prevalence estimates, subgroup analyses, and meta-regression were performed, and publication bias was assessed.

Results: The prevalence rates for the different symptoms were as follows: fatigue 43.3% (95% CI [36.1-50.9%]), memory disorders 27.8% (95% CI [20.1-37.1%]), cognitive impairment 27.1% (95% CI [20.4-34.9%]), sleep disorders 24.4% (95% CI [18.1-32.1%]), concentration impairment 23.8% (95% CI [17.2-31.9%]), headache 20.3% (95% CI [15-26.9%]), dizziness 16% (95% CI [9.5-25.7%]), stress 15.9% (95% CI [10.2-24%]), depression 14.0% (95% CI [10.1-19.2%]), anxiety 13.2% (95% CI [9.6-17.9%]), and migraine 13% (95% CI [2.2-49.8%]). Significant heterogeneity was observed across all symptoms. Meta-regression analysis showed higher stress, fatigue, and headache in females, and increased stress and concentration impairment with higher BMI.

Conclusions: Neurological symptoms are common and persistent in COVID-19 survivors. This meta-analysis highlights the significant burden these symptoms place on individuals, emphasizing the need for well-resourced multidisciplinary healthcare services to support post-COVID recovery.

Source: Elboraay T, Ebada MA, Elsayed M, Aboeldahab HA, Salamah HM, Rageh O, Elmallahy M, AboElfarh HE, Mansour LS, Nabil Y, Eltawab AKA, Atwan H, Alkanj S. Long-term neurological and cognitive impact of COVID-19: a systematic review and meta-analysis in over 4 million patients. BMC Neurol. 2025 Jun 14;25(1):250. doi: 10.1186/s12883-025-04174-9. PMID: 40514644; PMCID: PMC12166599. https://pmc.ncbi.nlm.nih.gov/articles/PMC12166599/ (Full text)

Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection

Abstract:

SARS-CoV-2 can cause a variety of post-acute sequelae including Long COVID19 (LC), a complex, multisystem disease characterized by a broad range of symptoms including fatigue, cognitive impairment, and post-exertional malaise. The pathogenesis of LC is incompletely understood.

In this study, we performed comprehensive cellular and transcriptional immunometabolic profiling within a cohort that included SARS-CoV-2-naïve controls (NC, N=30) and individuals with prior COVID-19 (~4-months) who fully recovered (RC, N=38) or went on to experience Long COVID symptoms (N=58).

Compared to the naïve controls, those with prior COVID-19 demonstrated profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level. Specifically, there was an enrichment in immature monocytes with sustained inflammasome activation and oxidative stress, elevated arachidonic acid levels, decreased tryptophan, and variation in the frequency and phenotype of peripheral T-cells. Those with LC had increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes by single cell RNA sequencing. Our findings support a profound and persistent immunometabolic dysfunction that follows SARS-CoV-2 which may form the pathophysiologic substrate for LC.

Our findings suggest that trials of therapeutics that help restore immune and metabolic homeostasis may be warranted to prevent, reduce, or resolve LC symptoms.

Source: Lage SL, Bricker-Holt K, Rocco JM, Rupert A, Donovan FX, Abramzon YA, Chandrasekharappa SC, McNinch C, Cook L, Amaral EP, Rosenfeld G, Dalhuisen T, Eun A, Hoh R, Fehrman E, Martin JN, Deeks SG, Henrich TJ, Peluso MJ, Sereti I. Persistent immune dysregulation and metabolic alterations following SARS-CoV-2 infection. medRxiv [Preprint]. 2025 Apr 17:2025.04.16.25325949. doi: 10.1101/2025.04.16.25325949. PMID: 40321289; PMCID: PMC12047922. https://pmc.ncbi.nlm.nih.gov/articles/PMC12047922/ (Full text)

The pivotal role of central sensitization in long COVID, fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Introduction: Long COVID is a condition characterized by persistent unexplained symptoms following COVID-19 infection. These symptoms are not related to another disease or organ damage and are similar to those in fibromyalgia and myslgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Areas covered: The similar clinical and pathophysiological features and management of long COVID, fibromyalgia and ME/CFS are explored from the unifying framework of central sensitivity syndromes. The article is based on a literature search utilizing PubMed for content published between 2021 and 1 May 2025, using search terms: long COVID, long COVID syndrome, post-COVID-19, post-acute SARS-CoV-2, fibromyalgia, ME/CFS, post-exertional malaise and central sensitization.

Expert opinion: Once long COVID is redefined to exclude patients with well-defined organ disease, it fits best as a model of central sensitization. Long COVID is a single syndrome, rather than many distinct diseases. Optimal management of long COVID and similar central sensitivity

Source: Goldenberg DL. The pivotal role of central sensitization in long COVID, fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. Expert Rev Neurother. 2025 Jun 13:1-17. doi: 10.1080/14737175.2025.2516097. Epub ahead of print. PMID: 40512228. https://www.tandfonline.com/doi/full/10.1080/14737175.2025.2516097

Concentrations of uremic bacterial metabolites in patients with post-COVID-19 syndrome

Abstract:

Post-COVID-19 syndrome (PCS) is characterized by persistent symptoms and reduced mental and physical performance following the acute phase of COVID-19. The underlying mechanisms remain unclear but may involve gut microbiota dysbiosis and immune-related changes in amino acid metabolism. This pilot study aimed to investigate whether specific bacterial uremic metabolites (BUM) are altered in patients with post-infectious syndromes and whether these alterations are associated with PCS symptoms.

We examined BUM in 25 PCS patients, 8 Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients, and 8 healthy controls (Ctrls). Concentrations of BUM were determined in second morning urine samples using mass spectrometry (Biovis Diagnostik, Limburg, Germany). Standardized questionnaires assesed physical, cognitive, psychological, and somatic symptoms and mental health status.

PCS and ME/CFS patients exhibited significantly higher scores for post-exertional malaise (PEM) and somatic symptom severity compared to healthy controls (p<0.001). Elevated BUM concentrations were found in 64% of PCS patients, compared to 37.5% of both healthy controls and ME/CFS patients. While overall BUM levels did not significantly differ between groups, heatmap clustering revealed distinct metabolic patterns.

Elevated tryptamine and 4-hydroxyphenylpropionic acid (HPHPA) and higher hippuric acid and trimethylamine concentrations, were exclusively analysed in patients with post-infectious syndromes. Our pilot study suggests that urine metabolomic analysis may be a useful approach for investigating the role of gut dysbiosis and BUM in patients with PCS.

Source: Brigo N, Mayr W, Taenzer M, Löffler-Ragg J, Schroll A, Engl S, Schütz B, Rappl P, Heine T, Weiss G, Kurz K. Concentrations of uremic bacterial metabolites in patients with post-COVID-19 syndrome. Front Cell Infect Microbiol. 2025 May 29;15:1582972. doi: 10.3389/fcimb.2025.1582972. PMID: 40510799; PMCID: PMC12159039. https://pmc.ncbi.nlm.nih.gov/articles/PMC12159039/ (Full text)

Long COVID-19 autoantibodies and their potential effect on fertility

Abstract:

Impaired spermatogenesis has been reported in coronavirus disease 2019 (COVID-19) patients. However, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on male fertility remains unclear. The purpose of this multicenter study was to investigate the possible impact of SARS-CoV-2 infection on male fertility and determine the potential reasons leading to impaired male reproductive functions.

In silico approach identified ~60 amino acid sequences containing at least five continuous residues shared by SARS-CoV-2 Spike glycoprotein and spermatogenesis-linked proteins. Four synthetic peptides were tested with sera from independent cohorts of patients with acute and long COVID-19 syndrome (LCS), and naïve vaccinated subjects. Immunogenicity and pathogenicity studies were performed by immunizing mice with two selected peptides and testing the antigenicity of induced antibodies.

While none of four peptides were recognized by antibodies from vaccinated people, infected patients exhibited high reactivity to peptide 4, and LCS patients, especially women, showed elevated antibody levels against peptide 2. Women with LCS and chronic fatigue syndrome had higher levels of peptide 2-reacting antibodies than those with idiopathic chronic fatigue syndrome. Noteworthy, peptide 2 antibodies showed, in in vitro experiment, a specific interaction with mouse testicular tissue antigens.

These findings raise the possibility that cross-reactive epitopes between SARS-CoV-2 Spike protein and spermatogenesis-related antigens may affect infected patients’ fertility, suggesting a potential for autoimmune responses with human consequences.

Source: Talamini L, Fonseca DLM, Kanduc D, Chaloin O, Verdot C, Galmiche C, Dotan A, Filgueiras IS, Borghi MO, Meroni PL, Gavrilova NY, Ryabkova VA, Churilov LP, Halpert G, Lensch C, Thurner L, Fong SW, Ng LFP, Rénia L, Young BE, Lye DC, Lozano JM, Cabral-Marques O, Shoenfeld Y, Muller S. Long COVID-19 autoantibodies and their potential effect on fertility. Front Immunol. 2025 May 27;16:1540341. doi: 10.3389/fimmu.2025.1540341. PMID: 40496870; PMCID: PMC12149208.  https://pmc.ncbi.nlm.nih.gov/articles/PMC12149208/ (Full text)

Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest

Abstract:

Patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suffer from a reduced exercise capacity, skeletal muscle abnormalities and post-exertional malaise (PEM), where symptoms worsen with cognitive or physical exertion. PEM often results in avoidance of physical activity, resulting in a lower aerobic fitness, which may contribute to skeletal muscle abnormalities. Here, we compared whole-body exercise responses and skeletal muscle adaptations after strict 60-day bed rest in healthy people with those in patients with long COVID and ME/CFS, and healthy age- and sex-matched controls.

Bed rest altered the respiratory and cardiovascular responses to (sub)maximal exercise, while patients exhibited respiratory alterations only at submaximal exercise. Bed rest caused muscle atrophy, and the reduced oxidative phosphorylation related to reductions in maximal oxygen uptake.

Patients with long COVID and ME/CFS did not have muscle atrophy, but had less capillaries and a more glycolytic fibers, none of which were associated with maximal oxygen uptake. While the whole-body aerobic capacity is similar following bed rest compared to patients, the skeletal muscle characteristics differed, suggesting that physical inactivity alone does not explain the lower exercise capacity in long COVID and ME/CFS.

Source: Braeden T. Charlton, Anouk Slaghekke, Brent Appelman, Moritz Eggelbusch, Jelle Y. Huijts, Wendy Noort, Paul W. Hendrickse, Frank W. Bloemers, Jelle J. Posthuma, Paul van Amstel, Richie P. Goulding, Hans Degens, Richard T. Jaspers, Michèle van Vugt, Rob C.I. Wüst. Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest. medRxiv 2025.05.02.25326885; doi: https://doi.org/10.1101/2025.05.02.25326885 https://www.medrxiv.org/content/10.1101/2025.05.02.25326885v1.full?_x_tr_sl=nl&_x_tr_tl=en&_x_tr_hl=en (Full text)