Tag: review

Recognizing and managing post-exertional malaise in primary care

Abstract:

in English, French

Post-exertional malaise (PEM) is a syndrome characterized by a worsening of symptoms after physical, cognitive, or emotional exertion. It presents as increased fatigue, usually accompanied by other clinical symptoms, such as muscle pain or cognitive impairment. First described in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), PEM is now recognized as a hallmark of post-infectious syndromes that have received increasing attention through the emergence of long COVID. PEM is a distinguishing symptom of these conditions, and its early detection and appropriate management are essential to prevent long-term functional decline of affected patients. This review describes the definition and clinical impact of PEM and summarizes current recommendations for its management.

Source: Garcia S, Tzartzas K, von Plessen C, Favrat B, Kokkinakis I. Reconnaître et gérer le malaise post-effort en médecine de premier recours [Recognizing and managing post-exertional malaise in primary care]. Rev Med Suisse. 2026 Oct;22(1):17-21. French. doi: 10.53738/REVMED.2026.22.1.e48753. PMID: 42899626. https://pubmed.ncbi.nlm.nih.gov/42899626/

Measures of Overall Illness Severity and Burden for ME/CFS: A Scoping Review

Abstract:

Background and objectives: Consensus has not been established on measures of illness severity and burden for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), which is characterized by a wide range of symptoms including post-exertional malaise, unrefreshing sleep, and cognitive impairment. A scoping review was conducted to systematically evaluate the measurement of illness severity and burden in individuals with ME/CFS.

Methods: A literature search was conducted following PRISMA-ScR guidelines across five academic databases and one patient-organization-led website (with no restrictions on publication date; restricted to English language studies, and excluding review articles). Records were imported into Covidence, a systematic and scoping review data management tool, with studies retained if they evaluated an ME/CFS population and explicitly measured illness severity or illness burden. Information from each source was extracted and relevant measures were evaluated.

Results: From the reviewed literature, 190 full-text articles met the final inclusion criteria and were retained for analysis. The most frequently utilized tools for evaluating illness severity and burden in individuals with ME/CFS were the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Sickness Impact Profile (SIP). Additional prominent instruments identified across the literature include disease-specific measures such as the DePaul Symptom Questionnaire (DSQ) and generic health-related quality of life indices like the EuroQoL 5-Dimension (EQ-5D-5L).

Conclusions: Significant discrepancies persist in how illness severity and illness burden are operationalized in ME/CFS research. The reliance on generic instruments often obscures core symptom domains like post-exertional malaise (PEM), while inconsistent standards limit cross-comparability. Establishing standardized, disease-specifici illness metrics is critical to accurately capturing the true burden of illness and advancing rigorous clinical research.

Source: Cripe J, Ravichandran S, Deditz S, Jason LA. Measures of Overall Illness Severity and Burden for ME/CFS: A Scoping Review. Patient. 2026 Oct 15. doi: 10.1007/s40271-026-00849-8. Epub ahead of print. PMID: 42879116. https://pubmed.ncbi.nlm.nih.gov/42879116/

Myalgic Encephalomyelitis/chronic fatigue syndrome: a critical narrative review of modern concepts and unani perspectives

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, disabling, multisystem illness characterized by persistent fatigue, post-exertional malaise/post-exertional symptom exacerbation (PEM/PESE), unrefreshing sleep, and cognitive impairment. Classical Unani medicine does not recognize ME/CFS as a distinct disease entity. However, its descriptions of fatigue (I’yā), particularly I’yā Dhātī (spontaneous fatigue), provide a basis for examining parallels with ME/CFS.

Objective: To examine I’yā Dhātī (spontaneous fatigue) and its three simple subtypes (I’yā Qarūḥī, I’yā Tamaddudī, and I’yā Waramī) and compare them qualitatively with contemporary ME/CFS, including areas of similarity and discordance.

Methods: This critical narrative review used structured searches of PubMed, Scopus, Google Scholar, ScienceDirect, and Web of Science. Eight primary Unani sources were examined: Al-Qānūn fi al-Ṭibb, Kulliyāt al-Qānūn, Kitāb al-Ḥāwī, Kitāb al-Murshid, Kitāb al-Manṣūrī, Dhakhīrah-i Khwārazm Shāhī, Kitāb al-Kulliyāt, and Al-Mukhtārāt fi al-Ṭibb. The three subtypes were compared using predefined qualitative domains based on contemporary ME/CFS features and classical descriptions.

Results: I’yā Tamaddudī (distensive fatigue) showed the greatest phenomenological overlap with ME/CFS, particularly spontaneous fatigue, generalized heaviness, sleep disturbances, mental dullness, reduced functional capacity, and diffuse somatic manifestations. However, no clearly documented classical equivalent of delayed PEM/PESE was identified, representing a major area of discordance.

Conclusion: I’yā Tamaddudī (distensive fatigue) showed the greatest phenomenological/conceptual overlap with ME/CFS among the subtypes examined. This represents a historical and interpretative correspondence, not biological, diagnostic, or therapeutic equivalence. Independent operationalization and prospective evaluation are required before its clinical or biological relevance can be established.

Keywords: Chronic fatigue syndrome; Integrative medicine; I‘yā; I‘yā dhātī; I‘yā tamaddudī; Myalgic encephalomyelitis; Narrative review; Unani medicine.

Source: Israr IM, Eram F, Ahmed MM. Myalgic Encephalomyelitis/chronic fatigue syndrome: a critical narrative review of modern concepts and unani perspectives. Explore (NY). 2026 Oct 10;22(6):103545. doi: 10.1016/j.explore.2026.103545. Epub ahead of print. PMID: 42874496. https://pubmed.ncbi.nlm.nih.gov/42874496/

Comprehensive review of myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, debilitating disease that is unexplained and is characterised by persistent unexplained fatigue, Post Exertional Malaise (PEM), cognitive impairment, unrefreshing sleep and multisystem impairment. Despite the high burden of symptoms and the worldwide prevalence, ME/CFS has been poorly understood, underdiagnosed and underfunded. This large-scale review summarises the available evidence regarding the epidemiology, diagnostic progress, main clinical characteristics, pathophysiological theories and therapeutic approaches for ME/CFS.

Despite problems with diagnostic consistency, the lack of validated biomarkers, and historical linkage to psychiatric illness, the recognition of this condition has been delayed and has led to patient marginalisation. The review highlights PEM as a cardinal symptom and reviews the weaknesses in earlier diagnostic criteria, as well as current changes in treatment guidelines, including the formal withdrawal of Graded Exercise Therapy, which has evidence of harm.

New pathophysiological evidence suggests mitochondrial dysfunction, immune dysregulation, autonomic imbalance, neuroinflammation, and alterations in gut microbiome. New diagnostic and therapeutic strategies, such as metabolomic and electrophysiological assays, mTOR inhibitors, and decentralised clinical trial designs, are being studied. This intersection with Long COVID offers a chance to rapidly advance studies of post-infectious chronic diseases. The paper also argues for stringent subtyping, uniform data collection, and ongoing patient participation in research as strategies to surmount challenges of heterogeneity.

Finally, it underscores the critical need for fair funding of research, so biomarker discovery and development of disease-modifying treatments can be achieved. The care of people with ME/CFS is not only a clinical obligation, but also a public health one.

Source: Jeyaraman, M., Jeyaraman, N., Ramasubramanian, S. et al. Comprehensive review of myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med (2026). https://doi.org/10.1186/s12967-026-08833-4 https://link.springer.com/article/10.1186/s12967-026-08833-4 (Full text)

Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review

Abstract:

Fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic multisystem disorders characterized by persistent fatigue, pain, cognitive dysfunction, sleep disturbances, and reduced quality of life. Increasing evidence implicates mitochondrial dysfunction, oxidative and nitrosative stress, immune dysregulation, and altered redox and nicotinamide adenine dinucleotide (NAD+) metabolism as interconnected mechanisms contributing to fatigue, although the strength of evidence varies across these pathways. Micronutrients are essential components of mitochondrial bioenergetics, antioxidant defense, and immune-metabolic regulation.

This narrative review critically examines the mechanistic and clinical evidence supporting mitochondrial-oriented micronutritional interventions in fibromyalgia and ME/CFS, including NAD+ precursors, B-complex vitamins, magnesium, coenzyme Q10, alpha-lipoic acid, GlyNAC, L-carnitine, pyrroloquinoline quinone, taurine, and creatine. Mechanistic plausibility is distinguished from clinical efficacy, as disease-specific randomized controlled evidence remains limited for several interventions. We further discuss biomarkers, metabolic phenotyping, and precision nutrition within a systems-based micronutrition framework.

Finally, we present the rationale for a future randomized, double-blind, placebo-controlled trial in fibromyalgia patients with clinically significant fatigue, which is planned for 2027, subject to ethics approval and prospective registration, as a strategy for future clinical validation.

Source: Abanades S, Fernández I, Capdevila N, Cardona F. Micronutrition as a Therapeutic Strategy for Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Narrative Review. Nutrients. 2026 Aug 19;18(16):2702. doi: 10.3390/nu18162702. PMID: 42654282. https://www.mdpi.com/2072-6643/18/16/2702 (Full text)

Association between myalgic encephalomyelitis/chronic fatigue syndrome and irritable bowel syndrome: a systematic review and meta-analysis

Abstract:

Background: Irritable bowel syndrome (IBS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic, debilitating disorders characterized by substantial symptom burden, impaired quality of life, and high healthcare utilization. IBS is a disorder of gut-brain interaction with a global prevalence ranging from 3.8% to 9.2%, while ME/CFS is defined by persistent, exertion-intolerant fatigue and multisystem dysfunction. Growing evidence suggests frequent co-occurrence of these conditions, implicating shared mechanisms such as immune dysregulation, autonomic imbalance, and altered gut-brain signaling. However, the magnitude of their association has not been comprehensively quantified.

Methods: We conducted a systematic review and meta-analysis by searching Embase, PubMed, Scopus, and Google Scholar databases from inception through February 2026. Eligible observational studies reporting associations or prevalence between IBS and ME/CFS were included. Random-effects meta-analyses were performed to pool odds ratios (ORs) and prevalence estimates. Heterogeneity was assessed using I2 statistics. We evaluated for publication bias and assessed for risk of bias.

Results: Twenty-two studies were included in the systematic review and 18 in the meta-analysis. Individuals with ME/CFS had significantly higher odds of IBS compared with controls (OR = 7.20; 95% CI: 2.77-18.76; I2 = 72.1%). The pooled prevalence of IBS among individuals with ME/CFS was 37% (95% CI: 23-54%), with substantial heterogeneity (I2 = 99.5%). Subgroup analysis revealed that diagnostic criteria significantly influenced prevalence (p < 0.0001), while meta-regression identified ME/CFS diagnostic criteria as a significant moderator.

Conclusion: IBS and ME/CFS are strongly associated, suggesting shared underlying mechanisms. These findings support integrated screening approaches and coordinated, multidisciplinary management to improve outcomes in affected patients.

Source: Rajabi N, Ramdass PVAK. Association between myalgic encephalomyelitis/chronic fatigue syndrome and irritable bowel syndrome: a systematic review and meta-analysis. Front Med (Lausanne). 2026 Jul 27;13:1881784. doi: 10.3389/fmed.2026.1881784. PMID: 42577233; PMCID: PMC13453825. https://pmc.ncbi.nlm.nih.gov/articles/PMC13453825/ (Full text)

Low-Dose Ionizing Radiation and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Review of Recent Evidence and Future Research Directions Toward the Elucidation of a Metabolic, Immunologic, and Signaling Cascade

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an idiopathic, multisystem disorder marked by debilitating fatigue, post-exertional malaise, cognitive dysfunction and neuroinflammation. Its etiology remains unclear, yet emerging evidence implicates a complex interplay between immune dysregulation, metabolic impairment, mitochondrial bioenergetics, and environmental stressors such as viral infection or low-dose ionizing radiation (LDIR). To develop treatments for ME/CFS, it is essential to identify suitable targets for therapy.

In this narrative review, we discuss recent findings on the overlap of ME/CFS with LDIR effects and examine potential mechanistic links that may arise from LDIR-induced bystander effects (RIBEs). We highlight potential candidate biomarkers that bridge these domains: mitochondrial respiratory dysfunction, altered ornithine transport via SLC25A15 (ORNT1), possible roles of CD38 in the context of immunity and NAD+ depletion, cyclin D1-dependent metabolic reprogramming and modulation of gene expression, and α-synuclein as a potential neuroinflammatory damage-associated molecular pattern (DAMP).

While the involvement of these biomarkers in ME/CFS is yet to be confirmed experimentally, evidence from in vitro studies of irradiated cells, exosome profiling, and patient samples suggests that RIBEs can, in theory, produce prominent cellular ME/CFS phenotypes through associated mechanisms, including those exhibiting oxidative stress, impaired ATP production, and immune modulation.

We propose a hypothetical, exploratory model wherein LDIR initiates or contributes to adaptive metabolic shifts (including CD38 upregulation and cyclin D1 stabilization) that, coupled with persistent bystander signaling, could potentially culminate in chronic fatigue and neurocognitive symptoms in some reported ME/CFS cases.

Finally, we outline a research agenda encompassing the establishment of standardized diagnostic criteria, multi-omics profiling of patient cohorts, exosome analysis, functional mitochondrial assays, and targeted therapeutic trials focusing on possible anti-CD38 antibodies and NAD+ precursor therapy. By integrating recent findings in low-dose radiation biology with ME/CFS pathophysiology, this review aims to promote interdisciplinary investigations that may uncover mechanistic insights and novel biomarkers for diagnosis and treatment of ME/CFS. We further review steps in a proposed model taking us from low-dose radiation exposure to a number of possible targets.

Source: Rusin A, Cocchetto A, Mothersill C. Low-Dose Ionizing Radiation and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Review of Recent Evidence and Future Research Directions Toward the Elucidation of a Metabolic, Immunologic, and Signaling Cascade. Int J Mol Sci. 2026 Jul 22;27(14):6535. doi: 10.3390/ijms27146535. PMID: 42511874; PMCID: PMC13411118. https://pmc.ncbi.nlm.nih.gov/articles/PMC13411118/ (Full text)

Pacing and energy management with digital tools for conditions with chronic fatigue: What we know so far in ME/CFS and Long COVID

Introduction:

Why pacing matters in conditions with post‑exertional symptom exacerbation

‘Pacing’, or ‘energy management’, is a structured approach to regulating one’s physical, cognitive, and emotional activities to remain within limits imposed by chronic illnesses such as fibromyalgia, cancer, ME/CFS, and Long COVID [1,2]. Pacing ostensibly prevents post‑exertional symptom exacerbation, notably post‑exertional malaise (PEM), the worsening of fatigue, pain, cognitive dysfunction, and other symptoms following even modest activity. Across the literature, pacing is heterogeneously described as strategies that include activity planning, routine‑setting, pre‑emptive rest, breaking tasks into smaller components, monitoring energy fluctuations, and intentionally avoiding activity “push‑crash” cycles that commonly drive clinical deterioration [3]. In addition to heterogenous implementation, evidence of efficacy is also varied [3–9]. In this article, we will focus on ME/CFS and Long COVID as use case examples.

Historically, pacing emerged as an energy management method encouraging individuals to do as much as they can within their limits, rather than pushing through symptoms or following externally prescribed exercise. The central principle is that of the “energy envelope” [1], which asks individuals to identify the threshold at which activity begins to provoke symptoms and then remain inside that envelope as consistently as possible.

While definitions vary across clinicians, researchers, and patient groups, a consistent theme in both our systematic review and the scoping review is that pacing is individualised and requires ongoing adjustment as symptoms fluctuate [3,7]. Importantly, pacing is now the only management strategy recommended by the 2021 NICE guidelines for ME/CFS [10], underscoring its centrality in clinical care despite the concerning lack of evidence for efficacy. As Long COVID research evolved, pacing increasingly became recognised as a pragmatic, do no harm approach for a condition characterised by varied symptomology, unpredictable recovery patterns, and vulnerability to overexertion [8,11].

Source: Sanal-Hayes NEM, Hayes LD, Mclaughlin M, Sculthorpe NF (2026) Pacing and energy management with digital tools for conditions with chronic fatigue: What we know so far in ME/CFS and Long COVID. PLOS Digit Health 5(7): e0001586. https://doi.org/10.1371/journal.pdig.0001586 https://journals.plos.org/digitalhealth/article?id=10.1371/journal.pdig.0001586 (Full text)

Biomarkers of post-acute infection syndrome: a systematic literature review

Abstract:

Background: Post-acute infection syndrome (PAIS) remained underrecognized before the COVID-19 pandemic, which further increased exposure by introducing a novel global cause. The global burden of post-acute COVID syndrome (PACS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) alone is estimated at several tens of millions affected worldwide. Biomarker discovery is central to improving PAIS diagnosis and may provide therapeutic targets. This review summarizes current knowledge on biomarkers for PAIS, including PACS and ME/CFS.

Methods: A systematic literature search was conducted in PubMed and Web of Science. Inclusion criteria were: (1) studies including PAIS patients; (2) reporting laboratory or omics biomarkers; and (3) investigating biomarkers or pathomechanisms of PAIS. Although Guillain-Barré syndrome (GBS) is not PAIS, we have included it as a separate mechanistic comparator due to its prevalence in search results and its clinical and immunological similarities to PAIS.

Results: A total of 142 studies analyzing PAIS biomarkers were included. GBS was analyzed separately and later compared with the other results. Overall, the reviewed studies employed heterogeneous approaches. While similar types of data were frequently investigated, analytical methods varied and often focused only on a subset of molecules. The results indicate that amino acid, energy, and lipid metabolism, microbiome, mitochondrial stress, and miRNA networks are affected. All pathways are connected via NF-κB.

Discussion: PAIS is a multisystem disorder rooted in persistent immune activation, metabolic reprogramming, and systemic inflammation, driven not by active viral infection, but by dysregulated host responses. The NF-κB pathway serves as a unifying hub, connecting molecular, cellular, and clinical phenotypes. Our framework enables a shift from symptom-based to mechanism-based classification, paving the way for biologically grounded interventions.

Conclusion: This review synthesizes a broad spectrum of biomarkers in PAIS, integrating findings across pathogens and molecular levels rather than restricting to individual conditions or symptom clusters. This study highlights the differences and commonalities among pathogens and diseases that lead to post-acute sequelae, fills a critical knowledge gap, and provides a foundation for future research and clinical practice. Future studies incorporating multi-omics approaches, longitudinal designs, and larger patient cohorts are needed to validate specific biomarkers and advance the understanding of PAIS.

Source: Wendt K, Schieck M, Gille C, Marschollek M, Illig T, Wolff D, Nee S. Biomarkers of post-acute infection syndrome: a systematic literature review. Front Immunol. 2026 Jun 30;17:1741761. doi: 10.3389/fimmu.2026.1741761. PMID: 42454043; PMCID: PMC13365053. https://pmc.ncbi.nlm.nih.gov/articles/PMC13365053/ (Full text)

Therapeutic plasma exchange and immunomodulatory strategies in post-infectious syndromes: A review of immune dysregulation in PTLDS, long COVID, ME/CFS, and PANS/PANDAS

Abstract:

Post-infectious syndromes including post-treatment Lyme disease syndrome (PTLDS), long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and pediatric acute-onset neuropsychiatric syndrome (PANS)/pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) share overlapping clinical phenotypes characterized by fatigue, cognitive dysfunction, sleep disturbance, and neuropsychiatric symptoms. Increasing evidence suggests that immune dysregulation-including persistent inflammation, autoantibody production, and cellular immune dysfunction-may underlie these conditions.

This narrative review synthesizes peer-reviewed literature describing immune abnormalities across these syndromes and evaluates the rationale for immunomodulatory therapies, including intravenous immunoglobulin (IVIG), rituximab, and therapeutic plasma exchange (TPE). Evidence supporting immune-targeted treatment strategies is strongest in subsets of patients with identifiable immunologic abnormalities. Notably, the phase III RituxME trial in ME/CFS and a phase II trial of TPE in post-COVID condition both failed to demonstrate efficacy in unselected populations, reinforcing the importance of biomarker-guided patient stratification. TPE functions by removing circulating immune complexes, autoantibodies, and inflammatory mediators, and observational data suggest benefit in patients with demonstrable autoantibody burden. Further controlled studies incorporating immunologic phenotyping and early intervention are needed to define the therapeutic role of immune-directed interventions across these conditions.

Source: Kaplan G. Therapeutic plasma exchange and immunomodulatory strategies in post-infectious syndromes: A review of immune dysregulation in PTLDS, long COVID, ME/CFS, and PANS/PANDAS. Transfus Apher Sci. 2026 Jun 26;65(4):104482. doi: 10.1016/j.transci.2026.104482. Epub ahead of print. PMID: 42391726.  https://pubmed.ncbi.nlm.nih.gov/42391726/