Tag: 2026

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)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Successful Therapeutic Plasma Exchange Treatment After SARS-CoV-2 Infection-A Case Report

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex neuroimmunological disorder characterized by disabling symptoms that are often difficult to manage. More recently, in the context of SARS-CoV-2 infection, potential pathophysiological overlaps and disease modulation have been hypothesized. Our successful case highlights the need to investigate novel therapeutic approaches, including plasma exchange.

Source: Ciobanu G, Arn N. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Successful Therapeutic Plasma Exchange Treatment After SARS-CoV-2 Infection-A Case Report. Clin Case Rep. 2026 May 17;14:e72725. doi: 10.1002/ccr3.72725. PMID: 42158223; PMCID: PMC13180788. https://pmc.ncbi.nlm.nih.gov/articles/PMC13180788/ (Full text)

Vascular inflammation in neuropsychiatric long COVID

Highlights:

  • Long COVID is characterized by endothelial dysfunction with dysregulated inflammatory and coagulation pathways.
  • Endothelial biomarkers are elevated in Long COVID vs acute COVID-19, supporting a distinct vascular process.
  • Vascular biomarkers correlate with key cognitive and neuropsychiatric measures (fluency, memory, depression, and anxiety).
  • Vascular inflammation is a targetable mechanism in Long COVID, informing patient stratification and therapeutic trials.
  • Results highlight need to define the short- and long-term impact of vascular inflammation on brain health after COVID-19.

Abstract

The role of vascular inflammation in neuropsychiatric Long COVID (LC) is suspected but not well understood. This study evaluated whether vascular inflammation is present in individuals with neuropsychiatric LC and how it relates to cognitive and mental health symptoms.

This cross-sectional, case-control study included individuals with acute COVID-19 (AC), neuropsychiatric LC, and recovered controls. Participants were enrolled from the COVID Mind Study and the Yale IMPACT Study (hospitalized), and an independent cohort from the Johns Hopkins University (JHU) Long COVID Study. Fifty individuals with neuropsychiatric LC (new symptoms a median of 368 days post-COVID), 28 with AC, and 29 recovered controls (>3 months post-COVID) were evaluated. All underwent blood sampling and neuropsychiatric testing. The JHU cohort included 114 individuals with late LC (median 1065 days post-COVID illness associated with LC onset) and 31 recovered controls (median 852 days).

Fourteen plasma biomarkers of vascular inflammation were measured. ANCOVA was used to compare groups, adjusting for comorbidities. Non-hospitalized participants completed the Global Neuropsychological Assessment, GAD-7, and PHQ-9. LC and recovered groups were demographically similar, while AC participants had higher obesity and hypertension rates. LC participants had elevated circulating biomarkers of endothelial, leukocyte, and platelet adhesion (sL-selectin, ADAMTS13, sP-selectin, sICAM-1) compared to recovered controls.

Coagulation markers (D-dimer, fibrinogen) did not differ. Most biomarkers were highest in AC and lower in LC; however, fetuin, sL-selectin, and α-2 macroglobulin were higher in LC than AC. In LC, higher sP-selectin correlated with lower fluency and verbal learning. Lower α1-acid glycoprotein levels were strongly associated with poorer verbal memory, verbal learning, fluency, depression, and anxiety. In the JHU cohort, late LC and recovered controls showed no differences in biomarkers or demographics, suggesting normalization over time. Persistent dysregulation at the intersection of inflammation, platelet adhesion, and endothelial dysfunction is strongly linked to neuropsychiatric Long COVID.

Elevated markers of endothelial adhesion in LC suggest distinct pathophysiology from AC. These biomarkers correlate with lower fluency and verbal learning, linking vascular dysfunction to brain function. This study underscores the critical need for longitudinal, within-person investigations to elucidate how vascular inflammation evolves over time.

Source: McAlpine LS, Shorer EF, Chiarella J, Nelson A, Veenhuis R, Azola A, Lee A, Pierce R, Farhadian S, Rubin LH, Spudich SS; Yale COVID Mind; IMPACT Study Groups. Vascular inflammation in neuropsychiatric long COVID. Brain Behav Immun Health. 2026 Apr 28;54:101247. doi: 10.1016/j.bbih.2026.101247. PMID: 42099668; PMCID: PMC13147379. https://pmc.ncbi.nlm.nih.gov/articles/PMC13147379/ (Full text)

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)

A Perspective on Observation as Intervention in Chronic Diagnostic Complexity

Abstract:

This patient perspective article advances observation as an intentional, rigorous form of clinical care rather than a passive absence of intervention. The recommendations arise from the lived experience of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), informed by clinical training as a mobile equine veterinarian.

Over a nine-year diagnostic course, early clinical curiosity gave way to prolonged skepticism in the context of normal examinations and laboratory findings, ultimately shifting responsibility for daily functioning and symptom interpretation onto the patient. Across repeated encounters, subtle but consistent indicators of impaired energy regulation and exertional intolerance were present yet remained clinically unintegrated. When viewed longitudinally, these findings revealed a coherent physiological pattern that was not apparent at any single time point.

Modern medical training emphasizes action. However complex, relapsing, and poorly understood conditions often demand sustained clinical attention before diagnostic clarity emerges. In the absence of immediate abnormalities, discomfort with uncertainty may prompt premature intervention or disengagement, eroding trust and obscuring evolving signals.

Structured observation offers an alternative. As a clinical strategy, it preserves diagnostic curiosity, strengthens the physician-patient relationship, and allows for the observation of physiology without confounding influences. Such observation can yield meaningful insight and guide precise, compassionate care.

Source: Niederman CN. A Perspective on Observation as Intervention in Chronic Diagnostic Complexity. J Patient Exp. 2026 May 11;13:23743735261449971. doi: 10.1177/23743735261449971. PMID: 42137851; PMCID: PMC13168711. https://pmc.ncbi.nlm.nih.gov/articles/PMC13168711/ (Full text)

Plasma Extracellular Vesicle Surface Marker Profiling Reveals Immune Cell-Associated Mitochondrial Membrane Potential Alterations in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Long COVID (LC) is characterized by symptoms persisting at least 3 months after SARS-CoV-2 infection and affecting multiple organ systems. Diagnosis relies on subjective criteria without established biomarkers. Immune dysregulation and mitochondrial dysfunction are implicated in LC pathophysiology. Given clinical overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we investigated whether plasma extracellular vesicles (EVs) capture shared molecular signatures.

Methods: Plasma EVs from 125 individuals across pandemic-era and prepandemic cohorts were analyzed. The pandemic-era cohort included COVID-Recovered, LC with ME/CFS phenotype (LC-ME/CFS), and ME/CFS without infection (pan-ME/CFS). The prepandemic cohort included ME/CFS and matched controls. Extracellular vesicles were isolated using size-exclusion chromatography. Concentration and size were assessed by nanoparticle tracking analysis, and surface markers and mitochondrial membrane potential were evaluated by flow cytometry.

Results: Both pan-ME/CFS and LC-ME/CFS exhibited elevated EV concentrations compared with COVID-recovered controls after false discovery rate (FDR) correction (q = 0.0042 and 0.0024). Leukocyte-, monocyte/macrophage-, and platelet-derived EVs were increased, whereas B cell-derived EVs were reduced in both groups. Compared with controls, pan-ME/CFS demonstrated increased mitochondrial membrane potential in B cell-, monocyte/macrophage-, and NK cell-derived subsets after FDR correction, whereas no significant differences were observed in LC-ME/CFS. Prepandemic ME/CFS showed a nominal increase in leukocyte-derived EVs that did not persist after correction, whereas elevated mitochondrial membrane potential in B cell-derived EV subsets remained significant.

Conclusions: ME/CFS and LC-ME/CFS demonstrate partially overlapping immune cell-associated EV alterations. Mitochondrial membrane potential alterations within selected immune-derived EV subsets, particularly B cell-associated EVs, suggest immune-metabolic involvement. Plasma EV profiling may inform future biomarker development.

Source: Ikeda G, Koike-Ieki M, Inoue H, Dadhania AV, El Kamari V, Jagannathan P, Geng LN, Miglis MG, Shafer RW, Yang PC, Bonilla HF. Plasma Extracellular Vesicle Surface Marker Profiling Reveals Immune Cell-Associated Mitochondrial Membrane Potential Alterations in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Open Forum Infect Dis. 2026 May 12;13(5):ofag209. doi: 10.1093/ofid/ofag209. PMID: 42131622; PMCID: PMC13166156. https://pmc.ncbi.nlm.nih.gov/articles/PMC13166156/ (Full text)

Sleep in myalgic encephalomyelitis/chronic fatigue syndrome shows marked night-to-night fluctuation under free-living conditions-results from a matched case-control study

Abstract:

Purpose: Unrefreshing and non-restorative sleep is a hallmark complaint in people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, little is known about their habitual sleep and night-to-night fluctuations under real-life conditions. This study aimed to characterize sleep, and the intraindividual variability (IIV) of sleep in people living with ME/CFS compared with matched controls.

Methods: In this case-control study, 38 ME/CFS and 38 controls wore a wrist accelerometer continuously for 7 days and completed concurrent sleep diaries, the Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS). Within the ME/CFS group, participants were also stratified by symptom severity using the Bell Disability Scale. Sleep IIV was quantified using the coefficient of variation, the root mean square of successive differences, and the Bayesian variability model, respectively.

Results: Compared with controls, individuals with ME/CFS spent significantly more time in bed and exhibited poorer sleep efficiency (SE) (all p < 0.05). Despite a longer time in bed, total sleep time did not differ between groups. ME/CFS participants also displayed significantly greater IIV in SE. By contrast, sleep timing (bedtime) was more regular among ME/CFS. Exploratory analyses did not detect clear differences across ME/CFS severity subgroups for mean sleep variables or variability indices.

Conclusion: Under real-life conditions, people with ME/CFS exhibit poor sleep quality and unstable SE. These findings highlight sleep IIV as a clinically relevant dimension of sleep health in ME/CFS.

Current knowledge/study rationale: Unrefreshing sleep is a core symptom of ME/CFS, yet most evidence relies on single- or two-night laboratory assessments that may not reflect habitual sleep under real-life conditions. Moreover, night-to-night sleep variability, a potentially critical dimension of sleep health, has not been systematically examined in ME/CFS.

Study impact: Using week-long wrist accelerometry, this study shows that under free-living conditions sleep in ME/CFS is characterized not only by impaired sleep efficiency but also by pronounced night-to-night variability, despite relatively stable bedtime compared to controls. These findings highlight sleep efficiency variability as a clinically relevant feature of ME/CFS and underscore the need for multi-night assessment and targeted strategies addressing sleep variability.

Source: Saurel M, Fornasieri I, Del Sordo GC, Chatain C, Fantini ML, Gruet M, Saidi O. Sleep in myalgic encephalomyelitis/chronic fatigue syndrome shows marked night-to-night fluctuation under free-living conditions-results from a matched case-control study. J Clin Sleep Med. 2026 May 13;22(1):77. doi: 10.1007/s44470-026-00079-7. PMID: 42129014. https://link.springer.com/article/10.1007/s44470-026-00079-7 (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)

What is the Role of “the Psyche”? Long COVID and ME/CFS as Test Cases for Evidence-Based and Patient-Centered Psychiatry and Psychotherapy

Abstract:

in English, German

The role of psychological factors in the development and course of Long Covid (LC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) remains a subject of controversial debate. We argue that psychologizing LC and ME/CFS carries significant risks: it leads to potentially harmful therapies, invalidates the patients’ experience of illness, hinders effective interventions such as pacing, diverts focus from necessary physical diagnostics and treatment, disadvantages patients in medical assessments, and places a considerable additional burden on the families of affected children or other relatives. We show that many of the arguments presented for a psychological contribution are nonspecific or insufficiently supported by empirical evidence. Our essay therefore advocates for extreme caution in attributing psychological factors to these conditions, in the interest of a specific, evidence-based, and patient-centered psychiatry and psychotherapy.

Source: Schomerus G, Nicolas ML, Fritz F, Schneider D, Büchner R. Welche Rolle spielt „die Psyche“? Long COVID und ME/CFS als Prüfsteine für eine evidenzbasierte und patient*innenorientierte Psychiatrie und Psychotherapie [What is the Role of “the Psyche”? Long COVID and ME/CFS as Test Cases for Evidence-Based and Patient-Centered Psychiatry and Psychotherapy]. Psychiatr Prax. 2026 May 12. German. doi: 10.1055/a-2866-9127. Epub ahead of print. PMID: 42119693. https://www.thieme-connect.de/products/ejournals/html/10.1055/a-2866-9127 (Full text)

Feasibility, Adherence, Acceptance and Usability of a Multimodal Telemonitoring for Pediatric Post-COVID Syndrome: A Bicentric Pilot Study

Abstract:

Existing healthcare infrastructure struggles to meet the complex care required for pediatric Post-COVID Syndrome (pPCS). Telemonitoring offers potential to enhance care access, reduce patient burden, and ensure continuity. This study introduces and evaluates a novel, multimodal telemonitoring concept for pPCS with high translational potential for broader pediatric chronic and post-infectious conditions. Telemonitoring included a patient app, digital sensors (spirometer, smartwatch), Patient Reported Outcome Measures, chat/video consultations (VC), and a medical telemonitoring platform.

Patients aged 12-17 years with diagnosed PCS were recruited from two pPCS outpatient university clinics in Bielefeld and Munich, Germany. Monitoring lasted three months. Evaluation focused on feasibility, adherence, acceptance, and usability, using monitoring data, the System Usability Scale (SUS), Technology Usage Inventory (TUI), and a custom survey completed by patients and parents. 30 patients (mean age: 15y ± 1.9; 57% female (17/30); mean Baseline Bell-Score: 36.4) and 30 parents participated.

Adherence was high, with an average of 3.4 (smartwatch) to 4.6 (spirometry) measurements/week. Questionnaire response rate was 86% (411/480) and 97% (58/60) of VCs were conducted. SUS scores indicated very high usability (patients: 81.25/100; parents: 75.42/100). TUI results showed low skepticism, and high interest. Telemonitoring supported symptom management independent of in-person visits, despite sensor connectivity issues.

This is the first study to demonstrate successful integration of telemonitoring in pPCS, with high adherence and positive feedback from all stakeholders supporting its potential. Despite occasional technical challenges and resource needs, this concept shows promise for broader hybrid telemonitoring care implementation in PCS and other post-infectious syndromes.

TRIAL REGISTRATION: German Clinical Trials Register (DRKS), trial registration number: DRKS00029354. Registered 07 February 2023 – Retrospectively registered https://drks.de/search/en/trial/DRKS00029354/entails.

Source: Oftring ZS, Schmidt J, Greenfield J, Hägele M, Farzaneh A, Hamelmann E, Behrends U, Kuhn S. Feasibility, Adherence, Acceptance and Usability of a Multimodal Telemonitoring for Pediatric Post-COVID Syndrome: A Bicentric Pilot Study. J Med Syst. 2026 May 9;50(1):76. doi: 10.1007/s10916-026-02409-x. PMID: 42105038. https://link.springer.com/article/10.1007/s10916-026-02409-x (Full text)