Tag: 2025

Unravelling the Connection Between Energy Metabolism and Immune Senescence/Exhaustion in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease, characterized by a diverse array of symptoms including post-exertional malaise (PEM), severe fatigue, and cognitive impairments, all of which drastically diminish the patients’ quality of life. Despite its impact, no curative treatments exist, largely due to the limited understanding of the disease’s underlying pathophysiology.
Mitochondrial dysfunction, leading to impaired energy production and utilization, is believed to play a key role in the onset of fatigue and PEM, positioning it as a potential key pathophysiological mechanism underlying ME/CFS. Additionally, the disorder shows similarities to chronic viral infections, with frequent reports of immune system alterations, suggesting a critical role for immune (dys)functioning. In particular, the roles of immune senescence and immune exhaustion—two fundamental immune states—remain poorly understood in ME/CFS.
This state-of-the-art review explores how metabolic dysfunction and immune dysfunction may be interconnected in ME/CFS, proposing that energy deficits may directly impair immune function. By examining this metabolic–immune interplay, this review highlights potential pathways for developing innovative therapeutic strategies that target both energy metabolism and immune regulation, offering hope for improving patient outcomes.
Source: Van Campenhout J, Buntinx Y, Xiong H-Y, Wyns A, Polli A, Nijs J, Aerts JL, Laeremans T, Hendrix J. Unravelling the Connection Between Energy Metabolism and Immune Senescence/Exhaustion in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biomolecules. 2025; 15(3):357. https://doi.org/10.3390/biom15030357 https://www.mdpi.com/2218-273X/15/3/357 (Full text)

Direct effects of prolonged TNF-α and IL-6 exposure on neural activity in human iPSC-derived neuron-astrocyte co-cultures

Abstract:

Cognitive impairment is one of the many symptoms reported by individuals suffering from long-COVID and other post-viral infection disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A common factor among these conditions is a sustained immune response and increased levels of inflammatory cytokines. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are two such cytokines that are elevated in patients diagnosed with long-COVID and ME/CFS.

In this study, we characterized the changes in neural functionality, secreted cytokine profiles, and gene expression in co-cultures of human iPSC-derived neurons and primary astrocytes in response to prolonged exposure to TNF-α and IL-6. We found that exposure to TNF-α produced both a concentration-independent and concentration-dependent response in neural activity.

Burst duration was significantly reduced within a few days of exposure regardless of concentration (1 pg/mL – 100 ng/mL) but returned to baseline after 7 days. Treatment with low concentrations of TNF-α (e.g., 1 and 25 pg/mL) did not lead to changes in the secreted cytokine profile or gene expression but still resulted in significant changes to electrophysiological features such as interspike interval and burst duration. Conversely, treatment with high concentrations of TNF-α (e.g., 10 and 100 ng/mL) led to reduced spiking activity, which may be correlated to changes in neural health, gene expression, and increases in inflammatory cytokine secretion (e.g., IL-1β, IL-4, and CXCL-10) that were observed at higher TNF-α concentrations.

Prolonged exposure to IL-6 led to changes in bursting features, with significant reduction in the number of spikes in bursts across a wide range of treatment concentrations (i.e., 1 pg/mL-10 ng/mL). In combination, the addition of IL-6 appears to counteract the changes to neural function induced by low concentrations of TNF-α, while at high concentrations of TNF-α the addition of IL-6 had little to no effect. Conversely, the changes to electrophysiological features induced by IL-6 were lost when the cultures were co-stimulated with TNF-α regardless of the concentration, suggesting that TNF-α may play a more pronounced role in altering neural function.

These results indicate that increased concentrations of key inflammatory cytokines associated with long-COVID can directly impact neural function and may be a component of the cognitive impairment associated with long-COVID and other post-viral infection disorders.

Source: Goshi N, Lam D, Bogguri C, George VK, Sebastian A, Cadena J, Leon NF, Hum NR, Weilhammer DR, Fischer NO, Enright HA. Direct effects of prolonged TNF-α and IL-6 exposure on neural activity in human iPSC-derived neuron-astrocyte co-cultures. Front Cell Neurosci. 2025 Feb 12;19:1512591. doi: 10.3389/fncel.2025.1512591. PMID: 40012566; PMCID: PMC11860967. https://pmc.ncbi.nlm.nih.gov/articles/PMC11860967/ (Full text)

Novel Oronasal Drainage for Long COVID: Proposed Mechanisms-Case Report

Abstract:

Long COVID, potentially emerging post COVID-19 infection, involves extreme health challenges. Based on current literature in the field, we propose a novel approach to Long COVID treatment based on epipharyngeal abrasive therapy targeting ostia of the oral and nasal mucosa, having been identified for the first time. The presented case report documents the application of innovative oronasal drainage (OND), a novel treatment integrating physiological, biochemical, and fluid mechanical components simultaneously.

OND led to remarkable improvements and even remissions of various symptoms, along with enhanced hand blood circulation. While the case suggests potential efficacy in Long COVID therapy, acknowledging inherent limitations is essential and its impact needs further validation through clinical trials.

Source: Lorenz C, Frankenberger R. Novel Oronasal Drainage for Long COVID: Proposed Mechanisms-Case Report. Viruses. 2025 Jan 31;17(2):210. doi: 10.3390/v17020210. PMID: 40006965. https://www.mdpi.com/1999-4915/17/2/210 (Full text)

Serum Spike Protein Persistence Post COVID Is Not Associated with ME/CFS

Abstract:

Background/Objectives: According to the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC), an estimated 3-6% of people suffer from post-COVID condition or syndrome (PCS). A subset meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies have reported that SARS-CoV-2 proteins or RNA can persist after acute infection in serum or tissues, but their role in PCS is unclear.

Methods: Here, SARS-CoV-2 spike protein was analyzed in the serum of 121 PCS patients with predominant fatigue and exertional intolerance, of whom 72 met diagnostic criteria for ME/CFS, 37 post-COVID recovered healthy controls, and 32 pre-pandemic healthy controls.

Results: Spike protein was detected in the serum of 11% of recovered controls, 2% of PCS patients, and 14% of ME/CFS patients between 4 and 31 months after SARS-CoV-2 infection, but not in pre-pandemic samples. The occurrence and concentration of spike protein did not correlate with infection or vaccination timepoints. In ME/CFS patients, spike protein presence was not associated with the severity of symptoms or functional disability. In 5 out of 22 patients who under-went immunoglobulin depletion, spike protein levels were reduced or undetectable after treatment, indicating binding to immunoglobulins.

Conclusions: In summary, this study identified serum spike protein in a subset of patients but found no association with ME/CFS.

Source: Fehrer A, Sotzny F, Kim L, Kedor C, Freitag H, Heindrich C, Grabowski P, Babel N, Scheibenbogen C, Wittke K. Serum Spike Protein Persistence Post COVID Is Not Associated with ME/CFS. J Clin Med. 2025 Feb 8;14(4):1086. doi: 10.3390/jcm14041086. PMID: 40004616. https://www.mdpi.com/2077-0383/14/4/1086 (Full text)

Comparative Study Between Cognitive Phenotypes of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Multiple Sclerosis

Abstract:

Objective: Cognitive impairments are one of the most common and disabling symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Here, we address the possibility of a specific cognitive profile inherent to ME/CFS. Due to the occurrence of cognitive deficits, fatigue, and pain in both pathologies, multiple sclerosis (MS) is a relevant comparison model. For this purpose, we carried out a comparative study between cognitive profiles of patients with ME/CFS and patients suffering from MS.

Methods: In total, 40 ME/CFS and 40 MS patients were included. A complete screening of all cognitive functions was carried out through an extensive battery of tests routinely used in clinical practice.

Results: ME/CFS and MS patients showed deficits in episodic memory retrieval, visual selective attention and reading speed. ME/CFS patients also elicited a lower level of performance than MS patients regarding consolidation. For both groups, levels of performance on these cognitive tests did not correlate with levels of fatigue, pain, and depression.

Conclusions: This study highlighted both similarities and differences in the cognitive profiles of ME/CFS and MS patients. While both groups exhibited deficits in episodic memory retrieval, visual selective attention, and reading speed, ME/CFS patients showed distinct impairment in consolidation processes. These cognitive deficits were not correlated with fatigue, pain, or depression, reinforcing the hypothesis of intrinsic cognitive dysfunction in ME/CFS. These findings define a specific cognitive phenotype for ME/CFS, which could improve diagnostic accuracy and therapeutic strategies. Future research, particularly in functional imaging, may elucidate the neurobiological mechanisms underlying these impairments.

Source: Aoun Sebaiti M, Oubaya N, Gounden Y, Samson C, Lechapt E, Wahab A, Creange A, Hainselin M, Authier FJ. Comparative Study Between Cognitive Phenotypes of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Multiple Sclerosis. Diagnostics (Basel). 2025 Feb 17;15(4):487. doi: 10.3390/diagnostics15040487. PMID: 40002638. https://www.mdpi.com/2075-4418/15/4/487 (Full text)

A comparison of genome-wide association analyses of persistent symptoms after Lyme disease, fibromyalgia, and myalgic encephalomyelitis – chronic fatigue syndrome

Abstract:

Background: Up to 20% of Lyme disease cases experience post-treatment Lyme disease syndrome (PTLDS). The biological basis for PTLDS is poorly understood and no evidence-based treatment has been identified. Genetic studies have the potential to elucidate PTLDS pathophysiology and identify treatment targets.

Methods: We used electronic health record data (EHR) and genetic data from a linked biorepository to conduct a genome-wide association study (GWAS) for PTLDS among patients from a Pennsylvania health system. We evaluated the validity of the GWAS results in two separate conditions that have hypothesized overlapping pathophysiology, fibromyalgia and myalgic encephalomyelitis – chronic fatigue syndrome (ME/CFS). GWAS analyses were performed using logistic regression in SUGEN, assuming an additive genetic model, and adjusting for age, sex, array, and the first 10 principal components calculated from whole genome genotyping to adjust for ancestry, and accounting for relatedness including all 1st degree relationships. The functional mapping and annotation analysis (FUMA) tool was used to explore top findings from our GWAS.

Results: Among the 161,875 eligible MyCode participants with genotyping, there were 3,585 who met the criteria for treated Lyme disease. A subset of 695 (19.4%) of these patients met the criteria for PTLDS and the remaining 2890 were classified as controls. We identified two PTLDS loci that reached the suggestive significance threshold (P < 5 × 10– 7), with lead variants rs77857587, near IRX1, and rs10833979, near GAS2. Our top index single nucleotide polymorphism (SNP), rs77857587, is in high linkage disequilibrium with a long-range protein quantitative locus SNP, rs111774530, for the MARC2 (Mitochondrial Amidoxime Reducing Component 2) protein. We identified 5,041 cases of fibromyalgia (150,599 controls) and 2,268 cases of ME/CFS (151,594 controls) among the MyCode participants. Neither of the two suggestively significant loci were associated with fibromyalgia or ME/CFS.

Conclusion: We identified two PTLDS loci that reached a suggestive significance threshold. Our top index SNP is associated with the MARC2 protein, a protein that has been linked to multiple immune checkpoints. Further study is needed in a larger population to evaluate whether there is genetic evidence of the role of immune response in the occurrence of PTLDS.

Source: Hirsch AG, Justice AE, Poissant A, Nordberg CM, Josyula NS, Aucott J, Rebman AW, Schwartz BS. A comparison of genome-wide association analyses of persistent symptoms after Lyme disease, fibromyalgia, and myalgic encephalomyelitis – chronic fatigue syndrome. BMC Infect Dis. 2025 Feb 24;25(1):265. doi: 10.1186/s12879-024-10238-x. PMID: 39994562; PMCID: PMC11853495. https://pmc.ncbi.nlm.nih.gov/articles/PMC11853495/ (Full text)

Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination

Summary:

COVID-19 vaccines have prevented millions of COVID-19 deaths. Yet, a small fraction of the population reports a chronic debilitating condition after COVID-19 vaccination, often referred to as post-vaccination syndrome (PVS). To explore potential pathobiological features associated with PVS, we conducted a decentralized, cross-sectional study involving 42 PVS participants and 22 healthy controls enrolled in the Yale LISTEN study.

Compared with controls, PVS participants exhibited differences in immune profiles, including reduced circulating memory and effector CD4 T cells (type 1 and type 2) and an increase in TNFα+ CD8 T cells. PVS participants also had lower anti-spike antibody titers, primarily due to fewer vaccine doses. Serological evidence of recent Epstein-Barr virus (EBV) reactivation was observed more frequently in PVS participants. Further, individuals with PVS exhibited elevated levels of circulating spike protein compared to healthy controls.

These findings reveal potential immune differences in individuals with PVS that merit further investigation to better understand this condition and inform future research into diagnostic and therapeutic approaches.

Source: Bornali Bhattacharjee, Peiwen Lu, Valter Silva Monteiro, Alexandra Tabachnikova, Kexin Wang, William B. Hooper, Victoria Bastos, Kerrie Greene, Mitsuaki Sawano, Christian Guirgis, Tiffany J. Tzeng, Frederick Warner, Pavlina Baevova, Kathy Kamath, Jack Reifert, Danice Hertz, Brianne Dressen, Laura Tabacof, Jamie Wood, Lily Cooke, Mackenzie Doerstling, Shadan Nolasco, Amer Ahmed, Amy Proal, David Putrino, Leying Guan, Harlan M. Krumholz, Akiko Iwasaki. Immunological and Antigenic Signatures Associated with Chronic Illnesses after COVID-19 Vaccination medRxiv 2025.02.18.25322379; doi: https://doi.org/10.1101/2025.02.18.25322379 https://www.medrxiv.org/content/10.1101/2025.02.18.25322379v1.full-text (Full text)

Possible Racial Disparities in the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis (ME/CFS) a chronic, disabling illness with no established etiopathology. It has been indicated in some population-based studies that Black and ethnic minority populations are underdiagnosed with ME/CFS. The aims of the present study were to (1) identify the agreement between receiving an ME/CFS diagnosis and meeting diagnostic criteria, (2) identify the demographic characteristics associated with receiving a diagnosis, and (3) explore patient satisfaction with healthcare.
Self-reported medical history and symptoms were collected via online survey from respondents with and without fatigue. The agreement between self-reporting an ME/CFS diagnosis and meeting the Center for Disease Control’s (CDC) ME/CFS criteria or Institute of Medicine (IOM) criteria was assessed with Cohen’s kappa. Patient characteristics predicting a physician diagnosis were analyzed with logistic regression. Associations between diagnosis, demographics, and healthcare satisfaction were assessed with chi-square tests of independence. There were 1110 responses. The agreement between meeting ME/CFS criteria and reporting an ME/CFS diagnosis was fair (CDC: κ = 0.29; SE = 0.02; IOM: κ = 0.28, SE = 0.03).
White respondents had 2.94 greater odds of being diagnosed with ME/CFS than non-White respondents. Having an ME/CFS diagnosis was associated with dissatisfaction with healthcare (χ2 (3, N = 1063) = 14.17, p = 0.003). The findings suggest racial disparities in the diagnostic processes for ME/CFS.
Source: Jones CL, Younger J. Possible Racial Disparities in the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). International Journal of Environmental Research and Public Health. 2025; 22(2):280. https://doi.org/10.3390/ijerph22020280 https://www.mdpi.com/1660-4601/22/2/280 (Full text)

Managing Energy, and Shaping Care: Insights from Adults with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Through Co-Production Workshops

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating condition characterised by severe fatigue that is not relieved by rest and is often exacerbated by physical or mental activity. A key challenge for individuals with ME/CFS is energy management and to date, the only recommended strategy is “activity pacing.” This approach involves balancing activity and rest to avoid overexertion and minimise the risk of symptom exacerbation, commonly known as “post-exertional malaise”(PEM). A recent systematic review highlighted significant shortcomings in activity pacing interventions for ME/CFS, noting that they lacked rigour, were brief, and did not follow guidelines or integrate recommended technology, limiting their relevance for modern energy management. To address these gaps, the present study aimed to explore ME/CFS patients’ and health practitioners’ perspectives on approaches to energy management, how their understanding of energy management has evolved over time, and their recommendations for future interventions concerning energy management.

Method: Eight individuals with ME/CFS participated in six one-hour long online co-production workshops with two researchers, with the option to provide input through written responses. Additionally, three health practitioners shared their perspectives via email. Thematic analysis of the data identified several key recommendations for improving ME/CFS care.

Results and conclusions: Workshops highlighted the need for early support, healthcare provider training, and public education to combat stigma and misconceptions around ME/CFS. Participants emphasised patient collaboration, research-informed practices, rigorous research, multidisciplinary teams, and the integration of technologies like mHealth, along with a comprehensive approach including sleep, diet, and psychological support for better symptom management and activity pacing.

Source: Thornton EJ, Hayes LD, Goodwin DS, Sculthorpe N, Prior Y, Sanal-Hayes NEM. Managing Energy, and Shaping Care: Insights from Adults with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Through Co-Production Workshops. Am J Med. 2025 Feb 15:S0002-9343(25)00093-2. doi: 10.1016/j.amjmed.2025.02.008. Epub ahead of print. PMID: 39961545. https://www.amjmed.com/article/S0002-9343(25)00093-2/fulltext (Full text)

Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

ME/CFS is a debilitating multisystem disorder of unclear etiology that affects many individuals worldwide. One of its hallmark symptoms is prolonged fatigue following exertion, a feature also observed in long COVID, suggesting an underlying dysfunction in energy production in both conditions. Here, mitochondrial dysfunction and its potential pathogenetic role in these disorders are reviewed.

Source: Syed AM, Karius AK, Ma J, Wang PY, Hwang PM. Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Physiology (Bethesda). 2025 Feb 17. doi: 10.1152/physiol.00056.2024. Epub ahead of print. PMID: 39960432. https://journals.physiology.org/doi/abs/10.1152/physiol.00056.2024 (Full text available as PDF file)