Tag: review

Toward a Molecular Reclassification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Integrating Multi-Omics, Machine Learning, and Precision Medicine

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease characterized by a multitude of symptoms across various organ systems. Diagnosis has relied heavily on heterogeneous clinical symptom presentation and evolving case definitions, with treatment focused on addressing presenting symptoms due to the paucity of validated biomarkers. Meanwhile, advances have been made in understanding the underlying pathophysiology through strong epidemiologic, clinical, and basic science studies. This narrative review synthesizes recent advances that are likely to drive a shift in understanding from symptom-based classification toward a molecularly defined understanding of the disease.

This shift in understanding will likely provide the foundation for future research efforts focused on targeting diagnosis and treatment more effectively. Specifically, we reference the identification of rare genetic risk variants through the HEAL2 deep learning framework, the large-scale DecodeME genome-wide association study, and dynamic epigenetic markers of disease state.

In addition, the findings revealed the downstream consequences of this genetic and epigenetic priming: chronic innate immune activation, CD8+ T cell exhaustion characterized by upregulation of the exhaustion-driving transcription factors Thymocyte Selection-Associated HMG Box (TOX) and Eomesodermin (EOMES), and a cellular energy crisis centered on mitochondrial dysfunction. Furthermore, results of recent studies have revealed sex-specific transcriptomic and proteomic signatures of maladaptive recovery.

We also highlight the role of machine learning and artificial intelligence integrations in translating high-dimensional multi-omics data into actionable biological insights, including the identification of monocyte subsets via Positive Unlabeled Learning, circulating cell-free RNA diagnostic signatures, and integrated multi-modal disease models such as BioMapAI.

The combination of these findings, which highlight multiple identifiable mechanisms of molecular activity, support the feasibility of molecular subtyping, precision diagnostics, and targeted therapeutic strategies for ME/CFS.

Source: Frank J, Nesterovitch N, Movva C, Klimas NG, Nathanson L. Toward a Molecular Reclassification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Integrating Multi-Omics, Machine Learning, and Precision Medicine. Int J Mol Sci. 2026 May 15;27(10):4436. doi: 10.3390/ijms27104436. PMID: 42196410; PMCID: PMC13207433. https://pmc.ncbi.nlm.nih.gov/articles/PMC13207433/ (Full text)

Reframing ME/CFS: toward a unified mechanistic model of chronic post-infectious diseases

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystem illness marked by post-exertional malaise (PEM), cognitive dysfunction, autonomic disturbance, and impaired physiological resilience. Historically, the absence of validated biomarkers, heterogeneous definitions, and limited investigative capacity have complicated mechanistic interpretation and contributed to the use of psychosocial and rehabilitative frameworks in clinical practice and in parts of the literature.

Main body: Advances in systems biology, accelerated by Long-COVID research, have transformed our understanding of post-infectious syndromes, implicating persistent immune dysregulation, mitochondrial and metabolic reprogramming, endothelial and microvascular dysfunction, abnormal coagulation, lipid-mediated signalling, extracellular vesicle communication, and viral protein-associated immune activation. This review charts the shift from early post-infectious observations through psychosocial dominance to contemporary biological frameworks, emphasising that pathology is state-dependent and revealed under physiological stress.

Conclusion: ME/CFS is thus reframed here as a disorder of impaired adaptive capacity within post-infectious disease biology.

Source: Watton P, Prusty BK. Reframing ME/CFS: toward a unified mechanistic model of chronic post-infectious diseases. J Transl Med. 2026 May 22. doi: 10.1186/s12967-026-08319-3. Epub ahead of print. PMID: 42174604. https://link.springer.com/article/10.1186/s12967-026-08319-3 (Full text available as PDF file)

Designing studies for post-treatment Lyme disease and other infection-associated chronic illnesses

Abstract:

Infection-associated chronic illnesses (IACIs) encompass a spectrum of poorly understood syndromes often marked by significant neurologic and multisystem symptoms following an infectious event. This review focuses on several diseases representative of the IACI spectrum. These are post-treatment Lyme disease syndrome (PTLDS), long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS). Their clinical and biological complexity, combined with a lack of clear diagnostic criteria and objective available laboratory biomarkers, makes them difficult to distinguish from conditions with overlapping features.

This presents challenges for research studies, as well as diagnosis and clinical management. This diagnostic ambiguity, coupled with heterogeneous patient presentations, has led to challenges in research, including misclassification of study participants and inconsistent or irreproducible findings. Some PTLDS research exemplifies these issues, which also extend to other IACIs.

To advance the field, we highlight key methodological refinements and approaches for studying IACIs, including rigorous participant selection, standardized sample collection protocols, and the use of appropriate control groups, including those with microbiologic proof of the initial infection when known and technologically feasible. We also address broader influences on research quality, such as stigma, historical neglect, and the urgency to find treatments, which have contributed to the proliferation of poorly controlled studies and questionable practices. Drawing lessons from past challenges, we propose a path forward grounded in fit-for-purpose methodological rigour to improve scientific understanding and support evidence-based therapeutic development for IACIs.

Source: Arnaboldi PM, Becker J, Nath A, Coyle PK, Handel A, Sellati TJ, Gomes-Solecki M, Garcet S, Henderson MK, Mullins P, Cowan E, McCombie WR, Wellins AM, Allegretta M, Bergquist J, Schutzer SE. Designing studies for post-treatment Lyme disease and other infection-associated chronic illnesses. Brain. 2026 May 18:awag016. doi: 10.1093/brain/awag016. Epub ahead of print. PMID: 42148664. https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awag016/8586348 (Full text)

Imbalance of Excitatory and Inhibitory Neurotransmitter Systems in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-COVID-19 syndrome share a symptom profile, including severe fatigue, cognitive dysfunction, exertional intolerance, sleep disturbances, hypervigilance, and the paradoxical state of being “wired but tired.” A well-established finding is sympathetic hyperactivity with reduced vagal tone, typically interpreted as autonomic nervous system dysfunction. Emerging evidence, however, suggests a broader disturbance across multiple neurotransmitter systems.

This paper reviews current knowledge on neurotransmitter systems implicated in ME/CFS and Long COVID, focusing on potential mechanisms of dysregulation and their roles in disease pathology and symptom generation, as well as implications for treatment. In addition to abnormalities of the noradrenergic system, disturbances in serotonergic, GABAergic, and glutamatergic signaling have been reported. Contributing factors may include autoimmunity, neuroinflammation, gut dysbiosis, epigenetic influences, and stressors such as orthostatic intolerance, metabolic strain, and pain.

A shift favoring excitatory over inhibitory neurotransmission can lead to excessive neural activation, autonomic dysfunction, sensory hypersensitivities, sleep disturbances, and cognitive impairment. Reduced GABAergic tone combined with increased glutamatergic and noradrenergic activity may elevate skeletal muscle tone, contributing to calcium overload, mitochondrial dysfunction, exertional intolerance, and post-exertional malaise. Various pharmacological treatments may partially rebalance these neurotransmitter systems, but limited efficacy highlights the need for systematic investigation and individualized strategies.

Source: Wirth KJ, Scheibenbogen C. Imbalance of Excitatory and Inhibitory Neurotransmitter Systems in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Int J Mol Sci. 2026 Apr 30;27(9):4041. doi: 10.3390/ijms27094041. PMID: 42123618. https://www.mdpi.com/1422-0067/27/9/4041 (Full text)

Digital Approaches for Managing Brain Fog in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Interventions, Monitoring, and Future Directions

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a high-burden, under-researched condition characterized by heterogeneous and fluctuating symptoms, including cognitive dysfunction commonly described by patients as “brain fog”. Despite growing interest in digital health technologies for symptom monitoring and personalized care, their application to the assessment and management of cognitive dysfunction in ME/CFS remains unclear. This descriptive review aimed to examine the current scientific evidence on digital approaches related to brain fog in ME/CFS.

A structured literature search following PRISMA guidance was conducted to identify relevant studies. The available literature remains limited in scope and methodological maturity. During synthesizing across studies, three main functional domains of digital application become apparent: (1) digital tools for cognitive assessment, which have the strongest evidence base; (2) digital platforms for longitudinal monitoring; and (3) digitally mediated interventions or rehabilitation approaches, both of which are less well studied.

Simultaneously, the findings suggest that patient-reported brain fog may represent a visible component of the broader ME/CFS disease spectrum and could serve as an early clinical indicator guiding diagnosis and management. Interpreting these symptoms within a biopsychosocial framework may facilitate understanding of the complex nature of the disease and optimize the use of digital technologies for monitoring cognitive dysfunction and supporting patient-centered care in ME/CFS.

Source: Araja D, Murovska M, Krumina A, Eory A, Berkis U. Digital Approaches for Managing Brain Fog in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Interventions, Monitoring, and Future Directions. Life (Basel). 2026 Apr 1;16(4):571. doi: 10.3390/life16040571. PMID: 42073381. https://www.mdpi.com/2075-1729/16/4/571 (Full text)

Regulatory Cycles of Orexin and Glucagon-Like Peptide-1 in Post-Viral Syndromes

Abstract:

Post-viral syndromes are heterogeneous multisystem diseases without a uniform etiology that occur as a result of acute viral infections. During the COVID-19 pandemic, the number of patients increased dramatically due to infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This is known as post-acute sequelae of COVID-19 (PASC), with many cases also meeting the criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the most severe form of a post-viral disease, characterized by severe fatigue, post-exertional malaise (PEM), unrefreshing sleep, neurocognitive impairment, and autonomic and immune dysregulation.

Orexin (OX) neuropeptides, which regulate arousal, metabolism, and neuroendocrine functions, may serve as a central link between stress, immune activation, and metabolic changes in these syndromes. Notable phenotypic similarities between OX system dysfunction and core features of PASC and ME/CFS, including fatigue, sleep issues, impaired glucose metabolism, and neuropsychiatric symptoms, support a mechanistic model in which impaired OX signaling contributes to post-viral endocrine and metabolic dysfunction.

This review examines the role of OX in regulating glucose metabolism, HPA axis activity, and systemic homeostasis, with a specific focus on sexually dimorphic expression and function in relation to post-viral syndromes. We also highlight the effect of glucagon-like peptide-1 (GLP-1), another key player in metabolism, which also has neuroprotective, anti-inflammatory, vasoprotective, and immunomodulatory effects. We further emphasize emerging therapeutic strategies, such as GLP-1 receptor agonists (GLP-1RAs) and drugs targeting the OX system.

Together, these insights provide an integrated framework for understanding and targeting the neuroendocrine-metabolic underpinnings of PASC, ME/CFS, and other post-viral syndromes.

Source: Ruhrländer J, Schieffer E, Schieffer B. Regulatory Cycles of Orexin and Glucagon-Like Peptide-1 in Post-Viral Syndromes. Endocr Rev. 2026 Apr 27:bnag009. doi: 10.1210/endrev/bnag009. Epub ahead of print. PMID: 42037238. https://pubmed.ncbi.nlm.nih.gov/42037238/

Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a major clinical challenge as a complex multisystemic disorder with no well-established pathophysiological mechanism, characterized by persistent fatigue and post-exertional malaise, along with unrefreshing sleep, cognitive impairment, and impaired stress recovery. Despite decades of investigation into the hypothalamic-pituitary-adrenal (HPA) axis, a definitive neuroendocrine hallmark has remained elusive due to inconsistent findings across various cortisol matrices. Therefore, this systematic review and meta-analysis aimed to provide an integrated understanding of HPA-axis regulation in ME/CFS.

We identified 46 case-control studies (comprising 46 independent datasets, including 12 pharmacological challenge studies), involving 1388 ME/CFS patients (71.9% female; mean age 37.3 ± 6.2 years) and 1349 matched healthy controls. Meta-analyses showed lower salivary cortisol at awakening and in the morning. Reductions were also observed in 24-h urinary cortisol and hair cortisol. In pharmacological challenge tests, patients exhibited impaired cortisol release in response to adrenocorticotropic hormone (ACTH) stimulation and exaggerated suppression following glucocorticoid administration.

Collectively, these alterations indicate reduced free cortisol availability and enhanced HPA-axis negative feedback sensitivity, consistent with a hyporeactive endocrine state in ME/CFS. This neuroendocrine hypo-reactivity may underlie hallmark clinical features such as unrefreshing sleep, post-exertional malaise, and severe fatigue, as well as cognitive slowing, emotional blunting, and diminished stress resilience frequently observed in ME/CFS and related functional disorders. Integrating neuroendocrine and psychological perspectives may help clarify mechanisms of chronic stress maladaptation and inform psychobiological interventions for fatigue syndromes.

Source: Woo TW, Choi YJ, Kim JY, Lee JS, Son CG. Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity. Mol Psychiatry. 2026 Apr 23. doi: 10.1038/s41380-026-03608-1. Epub ahead of print. PMID: 42026257. https://pubmed.ncbi.nlm.nih.gov/42026257/

Pathophysiological, Translational, and Diagnostic Aspects of ME/CFS: A Focus on Skeletal Muscle Involvement

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, multisystemic disorder characterized by severe, persistent fatigue not alleviated by rest and worsened by minimal exertion, often accompanied by post-exertional malaise (PEM), unrefreshing sleep, cognitive dysfunction, and autonomic disturbances. Despite decades of research, its pathophysiology remains incompletely understood, and skeletal muscle involvement has only recently gained attention.

This review aims to provide a historical and pathophysiological synthesis of ME/CFS, emphasizing the pivotal role of skeletal muscle in the onset and persistence of symptoms, and to integrate molecular, cellular, and pathophysiological evidence into a coherent explanatory framework.

This is a narrative review of published literature (1990-2025) with critical integration of clinical, biochemical, and experimental data on oxidative stress, mitochondrial dysfunction, Excitation-Contraction (E-C coupling) dysregulation, and muscle secretome alterations in ME/CFS also in relation to post-viral syndromes (e.g., Long COVID).

Evidence consistently points to mitochondrial oxidative stress, redox imbalance, impaired Ca2+ handling, and altered signaling pathways in skeletal muscle of patients with ME/CFS. Historical milestones show an evolution from psychogenic interpretations toward recognition of ME/CFS as a biological disorder with neuromuscular and metabolic underpinnings.

ME/CFS can be interpreted as a skeletal muscle-metabolic disorder characterized by oxidative distress, mitochondrial dysfunction, and impaired energy regulation, leading to the clinical picture of exercise intolerance and post-exertional malaise. Integrating basic and clinical research through a translational approach provides the foundation for new diagnostic tools, targeted therapies, and biomarkers.

Source: Fanò-Illic G, Coscia F, Gigliotti PV, Checcaglini F, Carraro U, Fulle S, Mancinelli R. Pathophysiological, Translational, and Diagnostic Aspects of ME/CFS: A Focus on Skeletal Muscle Involvement. Diagnostics (Basel). 2026 Mar 28;16(7):1019. doi: 10.3390/diagnostics16071019. PMID: 41975732. https://www.mdpi.com/2075-4418/16/7/1019 (Full text)

Expert perspectives on Myalgic encephalomyelitis/chronic fatigue syndrome – Insights from the 3rd International Conference of the Charité Fatigue Center

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystemic disorder mostly triggered by viral infections, with core symptoms including post-exertional malaise (PEM), fatigue, pain, and cognitive dysfunction. Its prevalence has increased significantly in the context of the coronavirus disease 2019 (COVID-19) pandemic. Despite its severity and impact on patients’ quality of life, ME/CFS remains poorly understood.

On May 12 and 13, 2025, the 3rd International Conference hosted by the Charité Fatigue Center brought together nearly 200 researchers from various disciplines on-site, and around 3,700 participants online to discuss recent advances in ME/CFS research, diagnostics, clinical care, and therapeutic trials. The program featured 33 lectures by international experts on key topics such as post-COVID syndrome (PCS), care structures, and pathophysiological mechanisms including cardiovascular dysregulation, immune dysregulation, autoimmune mechanisms, and metabolic dysfunction.

In addition, results from clinical trials addressing disease mechanisms, including those specifically targeting autoantibodies, were presented. While public awareness and funding opportunities have increased in the wake of the pandemic and the emergence of PCS, ME/CFS remains severely underresearched. Sustained and adequately funded research efforts are urgently required to advance understanding, identify diagnostic markers, and develop targeted therapeutic interventions.

Source: Fehrer A, Windzio L, Schoening S, Steiner S, Aschenbrenner AC, Babel N, Behrends U, Bellmann-Strobl J, Cammà G, Cash A, Doehner W, den Dunnen J, Fluge Ø, Franke C, Hoffmann K, Kedor C, Kim L, Löhden W, Mella O, Mihatsch LL, Peluso MJ, Puta C, Putrino D, Ramoji A, Sato W, Sawitzki B, Schlieper G, Schoenfeld Y, Seifert M, Sigurdsson F, Slaghekke A, Sommerfelt K, Sotzny F, Stein E, Steinacker JM, Stingl M, Systrom DM, Tronstad KJ, Wirth K, Wörmann B, Wüst RCI, Yamamura T, Scheibenbogen C. Expert perspectives on Myalgic encephalomyelitis/chronic fatigue syndrome – Insights from the 3rd International Conference of the Charité Fatigue Center. Autoimmun Rev. 2026 Mar 25:104043. doi: 10.1016/j.autrev.2026.104043. Epub ahead of print. PMID: 41895458. https://www.sciencedirect.com/science/article/pii/S1568997226000571 (Full text)

Postural Orthostatic Tachycardia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID as Neuroimmune Disorders

Abstract:

Postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID are heterogeneous disorders with overlapping complex, multi-factorial and multi-systemic pathophysiology. POTS and ME/CFS are the most common phenotypes of Long COVID that can lead to significant disability and functional impairment.

The exact pathophysiologic mechanisms of these disorders alone or in combination are still being investigated, but important mechanistic factors have been identified, such as autonomic dysfunction, immune dysregulation, autoimmunity, mitochondrial dysfunction, cerebral hypoperfusion, and neuroinflammation.

To this end, we believe that these conditions should be viewed as neuroimmune disorders and should be included in the field of neuroimmunology, with its educational curriculum, training, and clinical care pathways. Including these disorders as part of neuroimmunology subspecialty is the key to advancing the science and clinical care of this underserved patient population with these complex and disabling conditions.

Source: Blitshteyn S, Doherty TA, Steinman L. Postural Orthostatic Tachycardia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID as Neuroimmune Disorders. Immunotargets Ther. 2026 Feb 2;15:581262. doi: 10.2147/ITT.S581262. PMID: 41859298; PMCID: PMC12998959. https://pmc.ncbi.nlm.nih.gov/articles/PMC12998959/ (Full text)