A patient perspective on enduring symptoms – the unmet need

Abstract:

This short paper illustrates the lived experience of individuals with severe enduring symptoms: chronic, often debilitating conditions for which no clear medical explanation currently exists. Drawing on qualitative interviews, the paper highlights the profound suffering, isolation, and lack of medical support experienced by this underserved population. It examines the systemic barriers to care, including stigma, the absence of follow-up services, and the traumatising nature of some healthcare encounters, which can lead to healthcare avoidance even in the face of potentially life-threatening symptoms. It concludes with a call for improved training for clinicians, increased capacity within NHS services, and ring-fenced funding for biomedical research.
Source: Katharine Cheston. A patient perspective on enduring symptoms – the unmet need. Future Healthcare Journal: Volume 12, Issue 4, 2025, 100465. ISSN 2514-6645. https://doi.org/10.1016/j.fhj.2025.100465. https://www.sciencedirect.com/science/article/pii/S2514664525002462 (Full text)

Long COVID: a long road ahead

Abstract:

The SARS-CoV-2 pandemic caused an estimated 400 million people worldwide to experience Long COVID and post-COVID complications leading to significant chronic illness and disability with its devastating physical, societal and economic consequences. Since post-acute infectious syndromes have not been given adequate consideration prior to the pandemic, many millions of people with Long COVID worldwide have been left disabled as currently available therapies are largely symptomatic and only partially effective.

A case of a previously healthy woman with Long COVID and post-COVID autonomic dysfunction and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is presented here from the perspective of a physician-patient relationship and a broader context of medical care and public health. Immunologic and autonomic mechanistic factors and therapies as these relate to Long COVID are highlighted.

Complexities and issues pertaining to patient care, public health and education of neurologists and other specialists regarding Long COVID, dysautonomia and ME/CFS diagnosis and treatment are discussed, in conjunction with the need to develop and diversify effective therapies for people living with these highly disabling conditions.

Source: Blitshteyn S. Long COVID: a long road ahead. Oxf Open Immunol. 2025 Dec 13;6(1):iqaf010. doi: 10.1093/oxfimm/iqaf010. PMID: 41426345; PMCID: PMC12718103. https://pmc.ncbi.nlm.nih.gov/articles/PMC12718103/ Full text)

Inefficient energy consumption is related to post exertional malaise during cardiopulmonary exercise testing in long COVID

Abstract:

Background: Dyspnea, fatigue and post-exertional malaise (PEM) are hallmark features of long Covid and emerging evidence suggests that abnormal energy metabolism may contribute to these symptoms. A cardiopulmonary exercise test (CPET) provides a detailed physiologic assessment of ventilatory and cardiovascular function and can offer insights into metabolic substrate utilization energy at rest and during exertion. Our aim was to evaluate patterns of energy metabolism at rest and during exercise during a CPET in patients with long Covid.

Methods: We conducted a cross-sectional study of consecutive non-selected patients that had been referred for a CPET. We included two groups: a long COVID and a control group. The CPET was performed on a cycle ergometer and we measured standard variables including oxygen uptake (V̇O₂), respiratory exchange ratio (RER), breathing reserve, heart rate, O2 pulse, and anaerobic threshold. We used RER to calculate indirect calorimetry estimating the use of carbohydrates and fat at rest and exertion. We analyzed the association between long COVID symptom severity symptoms including fatigue and post-exertional malaise (PEM) with patterns of energy consumption. We used logistic regression and area under the receiver operating characteristic curve to determine which CPET variables were most associated with long COVID.

Results: CPET results were analyzed for 50 patients who met the definition of long COVID and 45 patients controls. Long COVID patients and controls had similar peak V̇O₂, heart rate on exertion and V̇O₂ at anaerobic threshold. Seventy-three percent of patients with long COVID had predominant energy use of carbohydrates rather than fat at rest compared to 20% of controls. In multivariable models the odds ratio of using fat as energy source at rest was 0.99; 95% CI 0.99–0.99; p = 0.04. Patients with long COVID and severe fatigue as well as severe PEM had higher usage of carbohydrates (p < 0.01) and similar use of fat.

Conclusion: Patients with long COVID use energy inefficiently and this pattern could serve as a diagnostic feature in certain presentations of long COVID.

Source: Leonardo Tamariz, Brian Garnet, Santiago Avecillas et al. Inefficient energy consumption is related to post exertional malaise during cardiopulmonary exercise testing in long COVID, 15 December 2025, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-8072121/v1] https://www.researchsquare.com/article/rs-8072121/v1 (Full text)

Altered brain tissue microstructure and neurochemical profiles in long COVID and recovered COVID-19 individuals: A multimodal MRI study

Abstract:

Background: Diverse neurological symptoms are experienced by long COVID and COVID-19 recovered individuals. However, the long-term effects of SARS-CoV-2 in the brain of both groups are underexplored. This study aimed to investigate changes in tissue microstructural and brain neurochemical levels in long COVID and recovered COVID-19 patients compared to healthy controls.

Methods: We recruited 47 participants (long COVID = 19, COVID-recovered healthy controls = 12, and healthy controls without COVID-19 infection = 16) who underwent 3T MRI scans. We acquired T1 and T2 weighted images to assess myelin signal, diffusion weighted images to assess tissue microstructure, and magnetic resonance spectroscopy data to estimate brain neurochemical levels.

Findings: Our multimodal MRI study showed altered T1w/T2w signal between long COVID vs COVID-recovered-healthy controls, long COVID vs healthy controls, and COVID-recovered-healthy controls vs healthy controls. Furthermore, T1w/T2w signal intensity was significantly correlated with physical and cognitive function. Diffusion weighted imaging also showed altered tissue microstructure in these three group comparisons. However, brain neurochemicals were only significantly different between long COVID vs COVID-recovered-healthy controls.

Interpretation: This is one of the first studies to report different myelin signal and brain neurochemical changes between long COVID, COVID-recovered-healthy controls, and healthy controls without SARS-CoV-2 infection. These brain changes provide compelling evidence for the long-term effects of SARS-CoV-2 on brain function.

Source: Thapaliya K, Marshall-Gradisnik S, Inderyas M, Barnden L. Altered brain tissue microstructure and neurochemical profiles in long COVID and recovered COVID-19 individuals: A multimodal MRI study. Brain Behav Immun Health. 2025 Nov 25;50:101142. doi: 10.1016/j.bbih.2025.101142. PMID: 41404601; PMCID: PMC12704066. https://pmc.ncbi.nlm.nih.gov/articles/PMC12704066/ (Full text)

Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile, and vascular dysfunction

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder with undefined mechanisms, no diagnostic tools and treatments. To investigate concurrent system dysfunctions, we recruited age- and sex-matched ME/CFS patients and healthy controls for a multimodal analysis of energy metabolism, immune profiles, and plasma proteomics.

Immune cells from ME/CFS patients show elevated adenosine monophosphate (AMP) and adenosine diphosphate (ADP) with a reduced ATP/ADP ratio, indicating decreased ATP generation and cellular energy stress. Immune profiling reveals skewing toward less mature effector subsets of CD4+, CD8+, and γδ T cells, with reduced CD1c+CD141– conventional DC type 2 and CD56lowCD16+ terminal natural killer cells.

Elevated levels of plasma proteins associated with thrombus formation and vascular reactivity may contribute to the endothelial dysfunction observed in ME/CFS patients. Classification and regression tree modeling identifies variables with strong predictive potential for ME/CFS. Together, this study provides insights into the somatic symptoms and underlying biology of ME/CFS.

Source: Heng B, Gunasegaran B, Krishnamurthy S, Bustamante S, Pires AS, Chow S, Ahn SB, Paul-Heng M, Maciver Y, Smith K, Tran DP, Howley PP, Bilgin AA, Sharland A, Schloeffel R, Guillemin GJ. Mapping the complexity of ME/CFS: Evidence for abnormal energy metabolism, altered immune profile, and vascular dysfunction. Cell Rep Med. 2025 Dec 16;6(12):102514. doi: 10.1016/j.xcrm.2025.102514. PMID: 41406947. https://www.sciencedirect.com/science/article/pii/S2666379125005877 (Full text)

Association of Autonomic Dysfunction With Long COVID: Evaluation Using Quantitative Autonomic Testing

Abstract:

Background: Persistent symptoms (eg, heart palpitations, lightheadedness, fatigue) despite resolution of acute COVID-19 infection is termed “long COVID syndrome” or simply “long COVID.” Long COVID is believed to be associated with autonomic dysfunction, but the nature and severity of any autonomic disturbances are not well understood.

Objective: This study sought to compare autonomic function measures in patients with long COVID, control subjects, and individuals with pure autonomic failure.

Methods: Patients referred for autonomic testing were classified into 3 groups: long COVID (acute COVID-19 infection ≥12 weeks before testing), control subjects (COVID-19 negative, normal autonomic tests), and pure autonomic failure (COVID-19 negative, abnormal autonomic testing). Heart rate and blood pressure were recorded during active standing, Valsalva maneuver, respiratory sinus arrhythmia, and tilt-table testing.

Results: Compared with control subjects, patients with long COVID exhibited both a greater heart rate increase and blood pressure drop with active standing and tilt-table testing (all P < 0.05). They also had lower Valsalva ratios and respiratory sinus arrhythmia values than did control subjects (both P < 0.05). Compared with pure autonomic failure patients, patients with long COVID had a greater heart rate increase but a lower drop in blood pressure with active standing and tilt-table testing and lesser respiratory sinus arrhythmia values and Valsalva ratios (all P < 0.001). After age and sex adjustment, autonomic dysfunction measures in patients with long COVID were comparable with those in the pure autonomic failure group. Further, autonomic testing abnormalities were observed in patients referred up to 40 months after infection.

Conclusions: When adjusted for age and sex, patients with long COVID may demonstrate persistent autonomic dysfunction that is similar to patients with pure autonomic failure.

Source: Keller C, Mascarenhas L, Reyes JL, Duval S, Benditt DG. Association of Autonomic Dysfunction With Long COVID: Evaluation Using Quantitative Autonomic Testing. J Am Coll Cardiol. 2025 Nov 21:S0735-1097(25)09919-X. doi: 10.1016/j.jacc.2025.09.1608. Epub ahead of print. PMID: 41369621. https://pubmed.ncbi.nlm.nih.gov/41369621/

Alterations in gut microbiota and associated metabolites in patients with chronic fatigue syndrome

Abstract:

To investigate differences in gut microbiota composition and short-chain fatty acids (SCFAs) metabolism between patients with Chronic Fatigue Syndrome (CFS) and Healthy Controls (HC), and to explore their associations with the CFS pathogenesis. This case-control study included 80 subjects, comprising 40 patients with CFS and 40 age- and sex-matched HC.

Fecal microbial community structure was analyzed using 16S rRNA gene high-throughput sequencing. Fecal SCFAs concentrations were quantified using Gas Chromatography-Mass Spectrometry (GC-MS). Spearman correlation analysis with false discovery rate (FDR) adjustment was performed to elucidate associations among gut microbiota, SCFAs, and clinical scores.

Compared to the HC group, the CFS group exhibited reduced gut microbiota α-diversity (e.g., ACE, Chao1, Shannon indices, all P < 0.01) and significantly altered β-diversity (ADONIS, P = 0.006). After FDR adjustment, fecal levels of acetate, butyrate, isobutyrate, and isovalerate remained significantly lower in the CFS group (all q < 0.05). Differential abundance analysis revealed a significant reduction in key taxa including the phylum Firmicutes (q = 0.010), class Verrucomicrobiae (q = 0.038), order Clostridiales (q = 0.043), and families Rikenellaceae (q = 0.011) and Ruminococcaceae (q = 0.049). Spearman correlation analysis solidified functional connections: key SCFA-producing taxa (e.g., Faecalibacterium, Subdoligranulum, Ruminococcaceae) were positively correlated with butyrate levels (r = 0.52-0.56, all q < 0.05).

Furthermore, reduced abundances of Rikenellaceae and Alistipes were associated with lower SF-36 scores (r = 0.26, q = 0.032) and higher fatigue scores (FSS/FS-14, r = – 0.28 to – 0.30, q < 0.05). Isovalerate levels were negatively correlated with FS-14 scores (r = – 0.307, q = 0.014). Among CFS patients, those with higher dietary fiber intake had significantly higher levels of acetate and isovalerate than those with lower intake (both q < 0.05).

Patients with CFS exhibit significant gut dysbiosis and abnormal SCFA metabolism. The reduction in key SCFA-producing taxa, their positive correlations with SCFAs levels, and the negative correlations of both with fatigue severity solidify a functional link between gut microbial depletion, reduced SCFAs, and clinical symptoms in CFS. Higher dietary fiber intake may partially ameliorate SCFAs metabolic disturbances in CFS patients.

Source: Cheng X, Wang W, Xu T, Wang Y, Zhen X, Man W, Gao S, Yin Y. Alterations in gut microbiota and associated metabolites in patients with chronic fatigue syndrome. Sci Rep. 2025 Dec 12;15(1):43681. doi: 10.1038/s41598-025-27564-y. PMID: 41387992; PMCID: PMC12700865. https://pmc.ncbi.nlm.nih.gov/articles/PMC12700865/ (Full text)

Brain MRI findings in patients with post COVID-19 condition: frequency and longitudinal changes in a nationwide cohort study

Abstract:

Background: Prolonged neurological symptoms following COVID-19 are common, yet few longitudinal studies describe brain MRI findings in this patient group. The use of contrast enhanced sequences is particularly lacking. We address this knowledge gap by reporting the frequency and longitudinal changes in brain MRI findings among patients with post COVID-19 condition exhibiting neurological symptoms.

Methods: This prospective multicenter study included 140 adult patients referred for persistent neurological symptoms following COVID-19. Brain MRI was performed at both 6 and 12 months after infection onset, reporting white matter hyperintensities, cerebral microbleeds, and additional pathological findings including contrast enhancement. White matter hyperintensities were compared with a healthy control group.

Results: The prevalence of white matter hyperintensities was comparable to healthy controls, and microbleeds were found at rates comparable to population studies, with longitudinal changes being infrequent. Lesions consistent with inflammation or demyelination were present in 4% (5/120) of patients at 6 months. Cranial nerve enhancement was found in 7% (7/94) of patients, persisting up to 12 months, predominantly affecting the oculomotor nerve. However, enhancement occurred without clinically detected ocular muscle paresis.

Conclusion: Our findings indicate that brain MRI primarily serves to exclude differential diagnoses in post COVID-19 condition, with limited clinical benefit of repeated imaging in the absence of new symptoms. However, signs of long-term inflammatory processes can be observed, and detection is improved by contrast enhanced sequences.

Source: Furevik LL, Lapina O, Lindland ES, Høgestøl EA, Geier OM, Devik K, Farmen AH, Flemmen HØ, Harbo HF, Morsund ÅH, Novotny V, Ofte HK, Pedersen KO, Popperud TH, Ratajczak-Tretel B, Samsonsen C, Selnes P, Torkildsen Ø, Undseth RM, Aamodt AH, Beyer MK, Boldingh MI. Brain MRI findings in patients with post COVID-19 condition: frequency and longitudinal changes in a nationwide cohort study. Front Neurol. 2025 Nov 13;16:1662263. doi: 10.3389/fneur.2025.1662263. PMID: 41323230; PMCID: PMC12658414. https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1662263/full (Full text)

Glymphatic System Dysregulation as a Key Contributor to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Defined by the World Health Organization as a neurological disorder, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling illness, affecting millions of people worldwide. First reported in the early nineteenth century, ME/CFS is uniquely characterized by a wide array of symptoms, including fatigue, brain fog, post-exertional malaise (PEM), sleep dysfunction, and orthostatic intolerance (OI). Despite decades of extensive research, there are no effective medical treatments or simple diagnostics for ME/CFS, with an estimated 90% of patients remaining undiagnosed.

The recently discovered glymphatic system, a lymphatic analog of the brain, is believed to be responsible for the removal of toxic metabolic wastes accumulated in the course of daily activities, primarily during sleep. A link between glymphatic dysfunction and some neurological disorders such as Alzheimer’s disease has already been established, raising the possibility of its involvement in ME/CFS. Accordingly, we believe the ME/CFS medical/scientific community will be interested in seriously considering GD an important contributor to its pathophysiology. If so, therapeutics that modulate glymphatic function may also benefit patients with ME/CFS.

Source: Nemat-Gorgani M, Jensen MA, Davis RW. Glymphatic System Dysregulation as a Key Contributor to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2025 Nov 27;26(23):11524. doi: 10.3390/ijms262311524. PMID: 41373677. https://www.mdpi.com/1422-0067/26/23/11524 (Full text)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): diagnosis and management

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has garnered substantial scientific and clinical interest, due to its rising global prevalence and significant pathophysiological overlap with post-acute COVID-19 syndrome (PACS). This review systematically elucidates the prevailing diagnostic criteria, summarizes recent advances in understanding the potential pathophysiological mechanisms, and evaluates pharmacological and non-pharmacological interventions, and symptom-based assessment and management strategies.

Methods: A comprehensive literature search was conducted across PubMed, Web of Science, Embase, and the Cochrane Library for articles published from inception to August 2025.

Results: Current diagnostic frameworks for ME/CFS rely primarily on clinical symptomatology and lack definitive biomarkers. Immune dysregulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation are central to its pathology. Pharmacological management includes immunomodulatory treatments, antioxidant therapies, mitochondrial support, and neuroinflammation intervention. Non-pharmacological strategies such as cognitive behavioral therapy (CBT), graded exercise therapy (GET), activity pacing, and traditional Chinese medicine (TCM) complement biomedical approaches by alleviating symptom severity and promoting energy conservation.

Conclusion: Among these approaches, CBT serves as an adjunctive therapy for symptom management rather than a curative one, whereas GET is contraindicated due to its potential for harm. Comprehensive clinical assessment and management of ME/CFS requires being symptom oriented and the recognition of individual differences. Recommended directions for future research include developing biomarker-based diagnostic tools, optimizing combination therapies that target multiple pathophysiological pathways simultaneously, and integrating real-world data and digital health technologies for precise monitoring and management of ME/CFS.

Source: Fan J, Jiao J, Chang HQ, Zhong DL, Liu XB, Li J, Chen LM, Jin RJ, Wu X. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): diagnosis and management. J Transl Med. 2025 Dec 9. doi: 10.1186/s12967-025-07506-y. Epub ahead of print. PMID: 41366804. https://link.springer.com/article/10.1186/s12967-025-07506-y