Tag: 2025

Health-related quality of life in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition: a systematic review

Abstract:

Purpose: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post COVID-19 Condition (PCC) are debilitating, chronic multi-systemic illnesses that require multidisciplinary care. However, people with ME/CFS (pwME/CFS) and people with PCC (pwPCC) are often precluded from accessing necessary disability and social support services. These unmet care needs exacerbate the existing illness burdens experienced by pwME/CFS and pwPCC. To deliver appropriate care and optimise health outcomes for pwME/CFS and pwPCC, the development of evidence-based healthcare policies that recognise the disabling impacts of these illnesses must be prioritised. This systematic review summarises the health-related quality of life (HRQoL) of pwME/CFS and pwPCC when compared with healthy controls (HCs) to elucidate the impacts of these illnesses and guide healthcare policy reform.

Methods: CINAHL, Embase, MEDLINE, PubMed, PsycINFO and the Web of Science Core Collection were systematically searched from 1st January 2003 to 23rd July 2024. Eligible publications included observational studies capturing quantitative HRQoL data among pwME/CFS or pwPCC when compared with HCs. The use of validated patient-reported outcome measures (PROMs) was mandatory. Eligible studies were also required to employ the most stringent diagnostic criteria currently available, including the Canadian Consensus Criteria or International Consensus Criteria for ME/CFS and the World Health Organization case definition for PCC (PROSPERO ID: CRD42024501309).

Results: This review captured 16 studies, including eight studies among pwME/CFS, seven studies among pwPCC and one study among both illness cohorts. Most participants were female and middle-aged. All pwPCC had experienced prolonged COVID-19 symptoms for at least three months. When compared with HCs, all HRQoL domains were significantly impaired among pwME/CFS and pwPCC. Both illnesses had a salient impact on physical health, including pain and ability to perform daily and work activities. While direct comparisons between pwME/CFS and pwPCC were limited by inconsistencies in the PROMs employed, comparable impact trends across HRQoL domain scores were observed.

Conclusion: ME/CFS and PCC have similar, profound impacts on HRQoL that warrant access to multidisciplinary disability and social support services. Future research must harmonise HRQoL data collection and prioritise longitudinal investigations among pwME/CFS and pwPCC to characterise PCC subgroups (including those fulfilling ME/CFS criteria) and predictors of prognosis.

Source: Weigel B, Inderyas M, Eaton-Fitch N, Thapaliya K, Marshall-Gradisnik S. Health-related quality of life in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post COVID-19 Condition: a systematic review. J Transl Med. 2025 Mar 13;23(1):318. doi: 10.1186/s12967-025-06131-z. PMID: 40075382. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06131-z (Full text)

Recognizing the role of fibromyalgia in post-exertional malaise

Letter:

The recent opinion by Charlton et al. published in Trends in Endocrinology & Metabolism [] provides a thought-provoking discussion of the overlap between long coronavirus disease (long-COVID) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), emphasizing the centrality of post-exertional malaise (PEM) as a shared mechanism.

Here, we suggest that fibromyalgia should be included in the discussion, given the established role of PEM in this condition []. In addition, fibromyalgia not only shares symptomatic and mechanistic overlaps with ME/CFS, but also offers a complementary perspective on the pathophysiology of PEM. Considering that PEM is a key symptom in both fibromyalgia and long COVID, exploring skeletal muscle function in fibromyalgia could provide complementary insights into the muscle-specific alterations that contribute to this debilitating phenomenon.

Source: Giollo A, Salvato M, Doria A. Recognizing the role of fibromyalgia in post-exertional malaise. Trends Endocrinol Metab. 2025 Mar 11:S1043-2760(25)00045-1. doi: 10.1016/j.tem.2025.02.005. Epub ahead of print. PMID: 40074568. https://www.cell.com/trends/endocrinology-metabolism/abstract/S1043-2760(25)00045-1

mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS

Abstract:

Post-acute SarS-Cov2 (PASC), Myalgia encephalomyelitis/Chronic fatigue syndrome (ME/CFS) and Post-acute infection syndrome (PAIS) consist of chronic post-acute infectious syndromes, sharing exhaustive fatigue, post exertional malaise, intermittent pain, postural tachycardia and neuro-cognitive-psychiatric dysfunction. However, the concerned shared pathophysiology is still unresolved in terms of upstream drivers and transducers. Also, risk factors which may determine vulnerability/progression to the chronic phase still remain to be defined.

In lack of drivers and a cohesive pathophysiology, the concerned syndromes still remain unmet therapeutic needs. ‘mTORC1 Syndrome’ (TorS) implies an exhaustive disease entity driven by sustained hyper-activation of the mammalian target of rapamycin C1 (mTORC1), and resulting in a variety of disease aspects of the Metabolic Syndrome (MetS), non-alcoholic fatty liver disease, chronic obstructive pulmonary disease, some cancers, neurodegeneration and other [Bar-Tana in Trends Endocrinol Metab 34:135-145, 2023]. TorS may offer a cohesive insight of PASC, ME/CFS and PAIS drivers, pathophysiology, vulnerability and treatment options.

Source: Bar-Tana J. mTORC1 syndrome (TorS): unifying paradigm for PASC, ME/CFS and PAIS. J Transl Med. 2025 Mar 10;23(1):297. doi: 10.1186/s12967-025-06220-z. PMID: 40059164. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06220-z (Full text)

Post-infective myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID as two puzzling faces of the same medal. Recent insights

Background:

How much is truly shared in terms of pathogenesis, symptomatology, and disease progression between the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID, and why have these two very complex conditions recently been grouped under the same umbrella terms?
The 1st International Conference on Clinical and Scientific Advances of ME/CFS/long COVID”, held in Portugal, on April 3rd and 4th 2024 [1], addressed, for the first time, this concern, shedding light onto two highly…
Source: Chirumbolo S, Franzini M, Tirelli U. Post-infective myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID as two puzzling faces of the same medal. Recent insights. Int Immunopharmacol. 2025 Mar 7:114365. doi: 10.1016/j.intimp.2025.114365. Epub ahead of print. PMID: 40057420. https://www.sciencedirect.com/science/article/abs/pii/S1567576925003558

“I still can’t forget those words”: mixed methods study of the persisting impact on patients reporting psychosomatic and psychiatric misdiagnoses

Abstract:

Objectives: This research aimed to improve understanding of persisting impacts of patient-reported psychosomatic and psychiatric misdiagnoses on patients with systemic autoimmune rheumatic diseases (SARDs).
Methods: Mixed methods data from two SARDs cohorts were analysed (N = 1,543 and N = 1,853). Validated instruments and patient-designed questions were used to measure self-reported depression, anxiety and mental wellbeing, in addition to medical relationships and healthcare behaviours. Comparative tests were used to evaluate differences between patients reporting a psychosomatic and/or psychiatric misdiagnoses and other patients.
Results: Persisting adverse outcomes of perceived psychosomatic and psychiatric misdiagnoses were identified in multiple domains. This included >80% of patients reporting that it had damaged their self-worth, and 72% reporting that it still upset them. Patients reporting psychosomatic and/or psychiatric misdiagnoses had significantly lower mental wellbeing, and higher depression and anxiety levels (all p< 0.001), and lower levels of satisfaction with every aspect of medical care, compared with patients reporting no psychosomatic or psychiatric misdiagnoses. Psychosomatic and psychiatric misdiagnoses had varying associations with healthcare behaviours, including a significantly higher likelihood of under-reporting symptoms (p< 0.001) and healthcare avoidance (p= 0.012), but not with medication adherence (p= 0.2). Thematic analysis of qualitative data revealed that symptom under-reporting and healthcare avoidance often resulted from distrust and fear that symptoms would be disbelieved and misattributed again.
Conclusion: Patient-reported psychosomatic and psychiatric (mis)diagnoses are associated with persisting adverse impacts in multiple domains including mental health, medical relationships, self-worth, and some healthcare behaviours. Health services and clinicians should consider these potential adverse impacts on patients and offer support to reduce any persisting negative impacts.

Source: Melanie Sloan, Michael Bosley, Caroline Gordon, Thomas A Pollak, Farhana Mann, Efthalia Massou, Stephen Morris, Lynn Holloway, Rupert Harwood, Kate Middleton, Wendy Diment, James Brimicombe, Elliott Lever, Lucy Calderwood, Ellie Dalby, Elaine Dunbar, David D’Cruz, Felix Naughton, “I still can’t forget those words”: mixed methods study of the persisting impact on patients reporting psychosomatic and psychiatric misdiagnoses, Rheumatology, 2025;, keaf115, https://doi.org/10.1093/rheumatology/keaf115 https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keaf115/8042899 (Full text available as PDF file)

Deep sequencing of BCR heavy chain repertoires in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common and debilitating chronic illness of unknown aetiology. Chronic infection and autoimmune responses have been proposed as two mechanisms that potentially underlie the pathogenesis of ME/CFS. To explore these disease hypotheses, we characterised the antigen-specific receptors of B cells using adaptive immune receptor repertoire sequencing.

We compared the B-cell receptor (BCR) repertoires of 25 patients with mild/moderate ME/CFS, 36 patients with severe ME/CFS, 21 healthy controls, and 28 patients with multiple sclerosis (MS) to identify signatures of infection or autoimmune responses. ME/CFS patients did not display increased clonality or differential somatic hypermutation compared to healthy controls and patients with MS.

One of two immunoglobulin heavy variable (IGHV) genes, IGHV3-30, reported to be increased in ME/CFS patients in a previous study, was replicated in patients with mild/moderate disease in our cohort. However, there was no evidence of ongoing adaptive responses in IGHV3-30 repertoires from mild/moderate ME/CFS patients with increased IGHV3-30 usage.

There were no detectable repertoire signatures associated with infection or autoimmunity in repertoires from ME/CFS patients, but we observed skewing of the ratio of IgM to IgG BCRs in patients with mild/moderate ME/CFS, a preliminary finding that presents an opportunity for follow-up work.

Source: Ryback AA, Cowan GJM. Deep sequencing of BCR heavy chain repertoires in myalgic encephalomyelitis/chronic fatigue syndrome. Front Immunol. 2025 Feb 17;16:1489312. doi: 10.3389/fimmu.2025.1489312. PMID: 40034707; PMCID: PMC11872726. https://pmc.ncbi.nlm.nih.gov/articles/PMC11872726/ (Full text)

Cerebrospinal fluid metabolomics, lipidomics and serine pathway dysfunction in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS)

Abstract:

We proposed that cerebrospinal fluid would provide objective evidence for disrupted brain metabolism in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS). The concept of postexertional malaise (PEM) with disabling symptom exacerbation after limited exertion that does not respond to rest is a diagnostic criterion for ME/CFS. We proposed that submaximal exercise provocation would cause additional metabolic perturbations.

The metabolomic and lipidomic constituents of cerebrospinal fluid from separate nonexercise and postexercise cohorts of ME/CFS and sedentary control subjects were contrasted using targeted mass spectrometry (Biocrates) and frequentist multivariate general linear regression analysis with diagnosis, exercise, gender, age and body mass index as independent variables. ME/CFS diagnosis was associated with elevated serine but reduced 5-methyltetrahydrofolate (5MTHF).

One carbon pathways were disrupted. Methylation of glycine led to elevated sarcosine but further methylation to dimethylglycine and choline was decreased. Creatine and purine intermediates were elevated. Transaconitate from the tricarboxylic acid cycle was elevated in ME/CFS along with essential aromatic amino acids, lysine, purine, pyrimidine and microbiome metabolites. Serine is a precursor of phospholipids and sphingomyelins that were also elevated in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls.

The findings differ from prior hypometabolic findings in ME/CFS plasma. The novel findings generate new hypotheses regarding serine-folate-glycine one carbon and serine-phospholipid metabolism, elevation of end products of catabolic pathways, shifts in folate, thiamine and other vitamins with exercise, and changes in sphingomyelins that may indicate myelin and white matter dysfunction in ME/CFS.

Source: Baraniuk JN. Cerebrospinal fluid metabolomics, lipidomics and serine pathway dysfunction in myalgic encephalomyelitis/chronic fatigue syndroome (ME/CFS). Sci Rep. 2025 Mar 3;15(1):7381. doi: 10.1038/s41598-025-91324-1. PMID: 40025157. https://www.nature.com/articles/s41598-025-91324-1 (Full text)

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)