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)

Plasma cell targeting with the anti-CD38 antibody daratumumab in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) -a clinical pilot study

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) entails low quality of life for patients and massive societal costs. There is an urgent need for elucidation of disease mechanisms and for rational treatment. Our working hypothesis is that ME/CFS in a subgroup of patients is associated with functional autoantibodies emerging after an infection, and that plasma-cell depletion with transient reductions in serum immunoglobulins will have a beneficial effect on symptoms.

Objective: To evaluate feasibility and toxicity of plasma-cell targeting treatment using subcutaneous anti-CD38 antibody daratumumab (Darzalex) in moderate to severe ME/CFS, and to assess the clinical course through 12-24 months follow-up. Methods: We performed an open-label pilot trial (EudraCT 2022-000281-18). Ten female patients were enrolled. Following 12 weeks run-in, six patients received four daratumumab injections. The next four patients received four, followed by three additional injections from week 20.

Results: All planned treatments were administered, and there were no serious adverse events. Four patients had no significant clinical changes. Six patients experienced marked improvement. For all ten patients, mean SF-36 Physical Function (SF-36 PF) increased from 25.9 to 55.0 at eight to nine months (p=0.002). In six responders, mean SF-36 PF increased from 32.2 to 78.3. Five of these had major and sustained improvement with a mean SF-36 PF of 88 (range 80 to 95) toward end of follow-up. Mean steps per 24 hours was 3359 (range 1493 to 6277) at baseline. At eight to nine months, the mean number of steps was 5862, and 7392 in the six responders. All five patients with sustained improvement reached a mean step count above 10000/24h for some weeks, and above 15000 on individual days. Relative reduction of serum IgG levels was 54% in patients with clinical improvement, and 40% in those with no benefit. Low baseline NK-cell count in blood was associated with lack of clinical response.

Conclusion: Subcutaneous daratumumab was well tolerated. In six ME/CFS patients, treatment was associated with clinical improvement and concurrent transient reduction of serum IgG levels, indicating pathomechanistic roles for long-lived plasma cells and functional autoantibodies. No definite conclusions should be drawn before a randomized study has been performed.

See: Correction

Source: Øystein Fluge, Ingrid Gurvin Rekeland, Kari Sørland, Kine Alme. Kristin Risa, Ove Bruland, Karl Johan Tronstad, Olav Mella. Plasma cell targeting with the anti-CD38 antibody daratumumab in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) -a clinical pilot study.
Front. Med., Sec. Infectious Diseases: Pathogenesis and Therapy, Volume 12 – 2025 | doi: 10.3389/fmed.2025.1607353  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2025.1607353/abstract

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)

Medication use and symptomology in North American women with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: There are no known curative treatments for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and current therapeutic regimens often yield inconsistent results. Despite the profound physical and mental burden experienced by those living with ME/CFS, patients often face a trial-and-error process in finding medications that offer some relief.

Method: The current study surveyed 135 North American women diagnosed with ME/CFS to characterize medication use in relation to disease features, symptomology, and function. Medications were classified into 9 categories according to their primary mechanism of action and therapeutic use.

Results: Participants were primarily middle-aged (47.1 ± 15.3 years) and were diagnosed for a mean duration of 8.4 ± 9.5 years (mean ± SD). Responses showed 68.6% of participants reported taking medications specifically for ME/CFS. Of those taking ME/CFS-related symptom medications, the average use was 3.0 medications per patient, with higher use in US compared to Canadian participants. Analgesic medications (31.7%) were the most frequently used, followed by psychotropic (26.4%), and immune-related medications (10.6%). These trends persisted across different symptom profiles, apart from gastrointestinal associated medication use replacing immune-related medications in those with gastrointestinal, neurological, and psychiatric symptoms. There was no significant correlation found between the number of medications used with disease duration, age, or age at diagnosis. However, a U-shaped relationship between ME/CFS-related symptom medication use and functional capacity as assessed by self-reported physical movement (hours/week) was evident.

Conclusion: Our study highlights the diverse and complex patterns in pharmacological treatment regimens for ME/CFS in women, while also underscoring the need for more tailored and evidence-based therapeutic strategies to address the varied symptom profiles.

Source: Pochakom A, MacNevin G, Madden RF, Moss AC, Martin JM, Lalonde-Bester S, Parnell JA, Stein E, Shearer J. Medication use and symptomology in North American women with myalgic encephalomyelitis/chronic fatigue syndrome. Front Med (Lausanne). 2025 Jun 6;12:1543158. doi: 10.3389/fmed.2025.1543158. PMID: 40547918; PMCID: PMC12179203. https://pmc.ncbi.nlm.nih.gov/articles/PMC12179203/ (Full text)

Differential diagnosis between “chronic fatigue” and “chronic fatigue syndrome”

Introduction:

Fatigue is a common complaint experienced by most of subjects during lifetime, which affects approximately 30–50% of general population as point prevalence. According to the fatigue-lasting duration, it is classified as acute (<1 month), prolonged (>1 month, <6 months), and chronic fatigue (≥6 months), respectively. Acute fatigue is generally disappears after taking a rest or treating the causative diseases, while uncontrolled prolonged and chronic fatigue limit the physical and social activities. Especially, medically unexplained chronic fatigue is a debilitating status, such as idiopathic chronic fatigue (ICF) and chronic fatigue syndrome (CFS).

Source: Son CG. Differential diagnosis between “chronic fatigue” and “chronic fatigue syndrome”. Integr Med Res. 2019 Jun;8(2):89-91. doi: 10.1016/j.imr.2019.04.005. Epub 2019 Apr 12. PMID: 31193269; PMCID: PMC6522773. https://pmc.ncbi.nlm.nih.gov/articles/PMC6522773/ (Full text)

Neurodevelopment Genes Encoding Olduvai Domains Link Myalgic Encephalomyelitis to Neuropsychiatric Disorders

Abstract:

Background/Objectives: The aetiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a chronic and severe debilitating disease with a complex phenotype, remains elusive. Associations with infectious diseases and autoimmune and neuropsychiatric disorders have been observed, without the identification of mechanisms. Previous studies suggest that genetic predisposition plays a role, but results are difficult to replicate, with Genome-Wide Association Studies of ME/CFS being challenging due to the relative rareness and heterogeneity of the disorder.
Methods: We studied a well-defined Australian patient cohort diagnosed via the International Consensus Criteria, recruited by a specialist ME/CFS clinic. The whole-exome sequences of 77 patients were contrasted against genome variation in the 1000 Genome Project’s genome-matched population.
Results: Significant associations with ME/CFS were harboured in genes that belong to the Neuroblastoma Breakpoint Family encoding Olduvai (DUF1220) domains, namely NBPF1 (rs3897177, p-value = 3.15 × 10−8), NBPF10 (rs1553120233, p-value = 9.262 × 10−13), and NBPF16 (rs200632836, p-value = 1.04 × 10−6). Other significantly associated variants were detected in the ATR, RSPH10B, ADGRE5-CD97, and NTRK2 genes, among others. Replication of these results was attempted via a GWAS on raw data from a US cohort, which confirmed shared significant associations with variation identified in the PTPRD, CSMD3, RAPGEF5, DCC, ALDH18A1, GALNT16, UNC79, and NCOA3 genes.
Conclusions: These genes are involved in cortical neurogenesis, brain evolution, and neuroblastoma, and have been implicated by several studies in schizophrenia and autism. The sharing of these associations by the two cohorts supports their validity and grants the necessity of future studies to evaluate the implications for ME/CFS aetiology.
Source: Arcos-Burgos, M., Arcos-Holzinger, M., Mastronardi, C., Isaza-Ruget, M. A., Vélez, J. I., Lewis, D. P., Patel, H., & Lidbury, B. A. (2025). Neurodevelopment Genes Encoding Olduvai Domains Link Myalgic Encephalomyelitis to Neuropsychiatric Disorders. Diagnostics, 15(12), 1542. https://doi.org/10.3390/diagnostics15121542 https://www.mdpi.com/2075-4418/15/12/1542 (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)

Patient experiences of remote consulting with chronic fatigue syndrome/myalgic encephalomyelitis and fibromyalgia: a qualitative study

Abstract:

Background: Remote and digital consulting in primary care has rapidly expanded since March 2020. It is important to understand patient experiences, particularly for those living with complex long-term conditions, to identify how care can best be delivered, including within the remote space.

Aim: To explore the experiences of people living with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and fibromyalgia when consulting remotely in primary care.

Design & setting: Semi-structured interviews with patients living with CFS/ME and fibromyalgia in general practice in England.

Method: Semi-structured interviews were carried out with 13 participants. The interviews were transcribed and analysed thematically according to a Foucauldian theoretical framework.

Results: All participants highlighted needing to feel believed by clinicians. Many reported difficulties with telephone and online consulting owing to the lack of physical communication. Positive outcomes were reported when there was a good relationship with a clinician. Continuity in care and recognising the complexity of these conditions were also considered important.

Conclusion: This study allowed people living with CFS/ME and fibromyalgia to describe their experiences when consulting remotely. Participants highlighted needing to feel listened to and felt they benefited from an ongoing relationship with a clinician although this was difficult to achieve when consulting remotely. Some advantages of remote consulting were reported, particularly when symptoms were troublesome. Flexible access systems, with a range of consultation modalities or preferred clinician(s) availability, could improve healthcare encounters, particularly given the increased use of remote consulting in primary care.

Source: Leach H, Eccles A, Chew-Graham CA, Atherton H. Patient experiences of remote consulting with chronic fatigue syndrome/myalgic encephalomyelitis and fibromyalgia: a qualitative study. BJGP Open. 2025 Apr 24;9(1):BJGPO.2024.0079. doi: 10.3399/BJGPO.2024.0079. PMID: 39191480; PMCID: PMC12137999. https://pmc.ncbi.nlm.nih.gov/articles/PMC12137999/ (Full text)

Reframing beliefs about their illness does not lead to recovery of tube-fed patients with very severe ME/CFS. Analysis of the BMJ article by Miller et al

Abstract:

The narrative which is presented by Miller et al. as new, has dominated the field of ME/CFS for the last 35 years. It has been tested by numerous studies and has been found to be ineffective and harmful, as concluded by for example NICE in 2021. Additionally, it does not lead to objective improvement and it has a negative instead of a positive effect on work and disability status.

What has happened over the last 35 years is that severely ill patients have been ridiculed, gaslit and ignored by the medical profession. These patients have lost hope in the part of the medical profession which has been instrumental in doing and promoting that. They have not lost hope to recover and they are all hoping to get effective pharmacological treatments sooner rather than later as changing their mindset does not lead to recovery. And if it does, then the diagnosis of ME/CFS was simply wrong.

Source: Vink, Mark and Vink-Niese, Friso, Reframing beliefs about their illness does not lead to recovery of tube-fed patients with very severe ME/CFS. Analysis of the BMJ article by Miller et al. (June 06, 2025). No., Available at SSRN: https://ssrn.com/abstract=5284667 https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5284667 (Full text available as PDF file)