Transdisciplinary Expert Statement: care guide for people severely affected by ME/CFS in home-based care

Abstract:

in English, German

Background: Many of those affected by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have significant care needs. However, post-exertional malaise, the defining feature of ME/CFS, means that even minor physical, orthostatic, cognitive, or sensory stressors can trigger a disproportionate worsening of health status, condition and symptoms. This results in specific requirements and significant challenges in home care. Nursing care is still provided predominantly by family caregivers, who frequently lack adequate assistance and support. At the same time, there are significant gaps in knowledge, care infrastructure, and professional guidance for the nursing and healthcare professionals, as well as physicians, involved in providing care.

Objective: The objective of this guide is to structure care measures in a way that prevents overexertion and promotes stability.

Methods: The guide is based on a compilation of practice-oriented measures that have proven effective from the perspective of those affected and family caregivers. These were professionally categorized and further developed by experts in nursing science, physical therapy, general practice and public health.

Results: The guide describes how to adjust key dimensions of care – from nutrition and personal hygiene to communication and managing emotional stress – to disease-specific exertion thresholds. Additionally, requirements for the caregiving relationship and the planning of home visits are outlined and the possibilities of palliative care principles are discussed.

Source: Hermisson J, Schreiner C, Weichselbaumer S, Werner M, Hackl V, Roth J, Leiss S, Maukner AC, Wojczewski S, Hainzl A, Hermisson S, Thonhofer K, Pleschberger S, Hoffmann K. Transdisziplinäres Expert:innen-Statement: Pflegeleitfaden für Menschen mit schwerem ME/CFS in der häuslichen Versorgung [Transdisciplinary Expert Statement: care guide for people severely affected by ME/CFS in home-based care]. Wien Med Wochenschr. 2026 Jun 1. German. doi: 10.1007/s10354-026-01155-6. Epub ahead of print. PMID: 42223876. https://link.springer.com/article/10.1007/s10354-026-01155-6 (Full text)

Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Leading to Assisted Suicide in a Patient in Her Late 30s: A Case Report

Abstract:

A patient in her late 30s developed severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) following an Epstein-Barr virus infection. No distinct autoimmune or autoinflammatory disorder could be identified as the underlying cause of her symptoms, as the observed constellation of cytokine elevations (IL-2, IL-6, and IFN-γ) was not consistent with any known or established disease entity. Despite comprehensive multidisciplinary treatment over two years, including medical, psychological, and rehabilitative approaches, her condition deteriorated, and treatment-related hypersensitivities emerged. The severity and progressive nature of her symptoms, compounded by the absence of effective therapeutic options, ultimately led the patient to pursue assisted suicide.

Source: Opala D, Villiger E, Levenfus I. Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Leading to Assisted Suicide in a Patient in Her Late 30s: A Case Report. Cureus. 2026 May 28;18(5):e109798. doi: 10.7759/cureus.109798. PMID: 42222634; PMCID: PMC13217520. https://pmc.ncbi.nlm.nih.gov/articles/PMC13217520/ (Full text)

Comparative Gut Microbiome Alterations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome & Long COVID-19 Syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID-19 syndrome (LC) show substantial clinical overlap, but direct comparative microbiome studies remain limited.
Methods: In this cross-sectional study, we compared the fecal gut microbiome of patients with ME/CFS, LC, and healthy controls (HC) within a unified analytical framework using 16S rRNA profiling, differential abundance testing, and multivariate modeling. We also examined associations between microbiome variation and questionnaire-derived symptom-domain scores.
Results: Alpha-diversity did not differ significantly among groups, whereas beta-diversity analyses showed small but significant disease-associated community differences with broad overlap between cohorts. Differential abundance analysis identified stronger signals in disease-versus-control contrasts than in the direct ME/CFS vs. LC contrast. Both ME/CFS and LC shared enrichment of Sutterella and depletion of Terrisporobacter and Lachnospiraceae relative to HC. Predicted functional profiling showed shared disease-versus-control changes in pathways related to anaerobic acetate/H2 carbon flow, inositol/polyol degradation, phosphonate/C1-related metabolism, and lysine-derived fermentation. Regression analyses showed the strongest microbiome associations with fatigue-related and physiosomatic domains, while affective, cognitive, and gastrointestinal outcomes showed weaker signals.
Conclusions: Overall, these findings support the presence of overlapping but non-identical gut microbiome alterations in ME/CFS and LC. The results provide a basis for future longitudinal and multi-omics studies aimed at clarifying the stability, functional relevance, and clinical utility of these microbial patterns.
Source: Donchev D, Nikolova R, Vaseva K, Taskov H, Murdjeva M, Maes M, Ivanov IN. Comparative Gut Microbiome Alterations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID-19 Syndrome. Biomedicines. 2026; 14(6):1183. https://doi.org/10.3390/biomedicines14061183 https://www.mdpi.com/2227-9059/14/6/1183 (Full text available as PDF file)

Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation

Abstract:

Inflammation-driven fatigue is a clinically significant feature of several chronic inflammatory conditions, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), post-COVID condition, autoimmune disease, and cancer-related fatigue. Across these conditions, partially overlapping disturbances in immune regulation, cellular metabolism, and neuroimmune signaling may contribute to persistent fatigue, despite important differences in initiating context and biological substrate. Current evidence implicates mitochondrial dysfunction, altered glycolysis and fatty acid utilization, lactate- and succinate-associated signaling, metabolite-sensing G protein-coupled receptor (GPCR) pathways, epigenetic acylation, and immune remodeling in the maintenance of fatigue.

This narrative review synthesizes both shared and disease-context-specific mechanisms underlying inflammation-associated fatigue, with particular emphasis on immunometabolism, peripheral-central neuroimmune crosstalk, metabolite-GPCR signaling, and epigenetic regulation.

We highlight GPCR signaling as a potentially important regulatory interface in inflammatory and metabolic pathways relevant to fatigue, while recognizing that direct causal evidence in human fatigue syndromes remains limited.

The review also examines how metabolite-mediated epigenetic acylation may influence immune cell function and fatigue-related biology, although this association remains incompletely validated in fatigue-specific settings. By integrating metabolic dysregulation, neuroimmune signaling, and immune dysfunction, this review consolidates current knowledge on candidate biomarkers, mechanistic pathways, and emerging therapeutic targets in chronic inflammation-driven fatigue.

Overall, this review provides a multidimensional framework for understanding fatigue across inflammatory disorders and for guiding future mechanistic and translational research.

Source: Hu Z, Wang J, Ma S, Zhuang J, Shi J, Zhu Y. Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation. Front Immunol. 2026 May 15;17:1806420. doi: 10.3389/fimmu.2026.1806420. PMID: 42220511; PMCID: PMC13218923. https://pmc.ncbi.nlm.nih.gov/articles/PMC13218923/ (Full text)

Low-Dose Naltrexone: What is the Evidence? A Narrative Review

Abstract:

Naltrexone is prescribed off-label at low doses, typically 0.5-6.0 mg, for a variety of therapeutic indications. This review evaluates the clinical evidence for low-dose naltrexone (LDN). A literature search was conducted in February 2026 across PubMed, Embase and CINAHL for studies published from 1989 to 2026.

Title and abstract searches for “low dose naltrexone” identified peer-reviewed English-language studies using doses of ≤ 12.5 mg in humans. A total of 105 studies were reviewed, including 15 randomised controlled trials (RCTs) in chronic pain, autoimmune and neuroimmune disorders, gastrointestinal disease, dermatological conditions, post-infectious syndromes, mental health and oncology.

Across these fields, early positive findings from uncontrolled studies were rarely replicated in placebo-controlled trials. Most available evidence consists of case reports and small feasibility studies that are prone to publication bias and rely heavily on subjective outcomes. LDN is generally safe, inexpensive and well tolerated, with most studies using a daily dose of 4.5 mg.

Although these features contribute to its appeal, current evidence does not support routine clinical use. LDN may have a pragmatic role in treatment-resistant cases where standard therapies have failed, provided its experimental status and uncertain efficacy are clearly explained. Larger, well-designed RCTs with objective endpoints, along with N-of-1 approaches to identify potential responders, are needed to clarify its true clinical value.

Source: Gouda AHK, Aitcheson NEC, Steadman KJ. Low-Dose Naltrexone: What is the Evidence? A Narrative Review. Adv Ther. 2026 Apr 30. doi: 10.1007/s12325-026-03612-5. Epub ahead of print. PMID: 42060160. https://link.springer.com/article/10.1007/s12325-026-03612-5 (Full text)

Omics-based computational approaches for biomarker identification, prediction, and treatment of Long COVID

Abstract:

Long COVID, or post-acute sequelae of COVID-19 (PASC), is a major global health problem, with cumulative estimates suggesting that around 400 million people worldwide have been affected. It is characterized by persistent or new symptoms such as fatigue, cognitive impairment, and breathlessness lasting beyond four weeks after acute infection. Diverse clinical manifestations, chronic course, and incompletely understood pathophysiology-including hypotheses involving viral persistence, immune dysregulation, autoimmunity, endothelial dysfunction, and metabolic reprogramming-impede the development of diagnostic criteria, biomarkers, and targeted therapies. We conducted a critical review of 101 Long COVID omics studies, focusing on the computational methods used and their methodological quality.

Using standardized criteria, we evaluated study design, statistical rigor, reproducibility, and clinical relevance across genomics, epigenomics, transcriptomics, proteomics, metabolomics, and multiomics integration, and mapped these findings onto regulatory and translational frameworks. Despite substantial methodological heterogeneity, convergent biological signals emerged.

Genomic studies implicate risk loci in immune and cardiopulmonary pathways. Epigenomic analyses identify differentially methylated regions in immune and circadian genes. Transcriptomic studies reveal persistent dysregulation of innate immune and coagulation pathways, as well as reproducible molecular endotypes. Proteomic studies consistently show abnormalities in the complement cascade and coagulation, with a small panel of complement proteins showing highly reproducible changes across independent cohorts. Metabolomic studies demonstrate sustained mitochondrial dysfunction and altered cellular bioenergetics for up to two years after infection.

Multiomics integration supports at least two major endotypes, characterized by predominant inflammatory versus metabolic dysregulation, and provides a basis for patient stratification and computational treatment discovery. Machine learning models frequently achieve high classification performance, but are rarely externally validated. Critical limitations restrict clinical translation. Most studies are underpowered relative to analytical complexity, use heterogeneous case definitions and controls, and report platform-specific signatures with limited overlap. External validation, preregistered analysis plans, and regulatory-aligned assay development are uncommon. To date, no regulatory-approved diagnostic assay or evidence-based therapeutic intervention has directly emerged from these computational findings.

Future progress requires harmonized phenotyping protocols, adequately powered longitudinal cohorts with external validation, integration of spatial omics and explainable artificial intelligence, and early engagement with regulatory and health-technology assessment pathways. This review provides a critical assessment and a translational roadmap, outlining how methodologically robust computational omics can be advanced toward clinically actionable tools for Long COVID.

Source: Pinero S, Li X, Zhang J, Winter M, Lee SH, Nguyen T, Liu L, Li J, Le TD. Omics-based computational approaches for biomarker identification, prediction, and treatment of Long COVID. Crit Rev Clin Lab Sci. 2026 Jun;63(4):332-358. doi: 10.1080/10408363.2025.2583083. Epub 2025 Dec 9. PMID: 41368891. https://pubmed.ncbi.nlm.nih.gov/41368891/

Cardiopulmonary exercise test results do not change over two sequential days in patients with chronic fatigue syndrome

Abstract:

Background: Two consecutive cardiopulmonary exercise tests (CPETs) performed 24 hours apart are increasingly used to determine post-exertional malaise (PEM) and disability in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Declines in functional capacity on Day 2 reflect impaired recovery and PEM. However, reports have variably described a reduction in peak oxygen consumption (VO2) and/or VO2 at the anaerobic ventilatory threshold (VT). Given the inconsistent findings, we sought to replicate the studies by performing sequential 2-day CPETs in ME/CFS and age- and sex-matched sedentary controls.

Methods: Accordingly, maximal bicycle ergometer CPETs were performed on two consecutive days in 58 patients with ME/CFS (mean age 38.6 ± 9.6 years, Body Mass Index (BMI) 24.1 ± 3.3 kg/m2, 11 men and 47 women) and 25 age-matched sedentary control (CON) subjects (age 38.2 ± 9.9 years, BMI 24.2 ± 3.4 kg/m2, 5 men and 20 women). Peak VO2 was reported as the highest 30-sec average; VT was selected as the nadir of the VE/VO2 and PETCO2 curves, and VE/VCO2 as the slope throughout exercise.

Findings: For ME/CFS and CON subjects, there were no significant changes in Peak VO2 between Day 1 and Day 2 studies (ME/CFS Day 1, 22.3 ± 5.4; Day 2, 22.5 ± 5.4 mL·kg-1·min-1; CON Day 1, 23.4 ± 3.5; Day 2, 22.8 ± 3.6 mL·kg-1·min-1; NS). Similarly, VO2VT and VE/VCO2 slopes were not significantly different between the ME/CFS patients and CON, and on Day 2, they did not show any differences within or between groups. Peak heart rate was significantly higher in CON versus ME/CFS. The level of perceived exertion was significantly greater at all levels of exercise on the Day 1 and Day 2 tests for ME/CFS patients versus CON.

Interpretation: Our data indicate that 2-day CPET provides exercise-related results that are the same in ME/CFS patients and CON subjects. ME/CFS patients have a greater perception of exertion throughout exercise and a lower maximum heart rate than CON. The data do not support using the 2-day CPET protocol to define PEM or disability.

Source: Mancini DM, Cook DB, Brunjes DL, Soto T, Blate M, Quan P, Yamazaki T, Norweg A, Natelson BH. Cardiopulmonary exercise test results do not change over two sequential days in patients with chronic fatigue syndrome. Front Physiol. 2026 May 13;17:1816082. doi: 10.3389/fphys.2026.1816082. PMID: 42212259; PMCID: PMC13213420. https://pmc.ncbi.nlm.nih.gov/articles/PMC13213420/ (Full text)

Comprehensive Immunophenotyping of Monocytes and Dendritic Cells Suggests Distinct Pathophysiology in Chronic Fatigue Syndrome and Long COVID

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long Coronavirus Disease 2019 (long COVID) are complex chronic conditions that often follow infectious triggers with overlapping clinical features but poorly defined pathophysiological relationships. This study aimed to identify disease-specific immune signatures through multiparameter immunophenotyping of monocytes, dendritic cells, and T cell subsets.

A total of 207 participants were included (ME/CFS: n = 103; long COVID: n = 63; healthy controls: n = 41). Peripheral blood mononuclear cells were analyzed using multiparameter flow cytometry. Statistical analyses included non-parametric testing, age-adjusted Analysis of covariance (ANCOVA), correlation network analysis, and principal component analysis (PCA).

Long COVID was characterized by increased M2-like monocyte polarization, elevated CD80 expression across monocyte subsets, expansion of dendritic cells, and reduced expression of activation markers, indicating persistent immune activation with features of immune exhaustion.

In contrast, ME/CFS exhibited reduced costimulatory molecule expression, impaired C-C chemokine receptor type 7 (CCR7)-mediated immune cell trafficking, and less coordinated activation patterns, consistent with a state of immune suppression. Correlation network analysis revealed more extensive and integrated immune interactions in long COVID, while PCA identified distinct immunophenotypic components and enabled moderate discrimination between the two conditions.

These findings demonstrate that ME/CFS and long COVID are characterized by distinct immune profiles, supporting the concept of divergent immunopathological mechanisms. The identified signatures may contribute to biomarker development and guide targeted therapeutic approaches.

Source: Petrov S, Bozhkova M, Ivanovska M, Kalfova T, Dudova D, Todorova Y, Dimitrova R, Murdjeva M, Taskov H, Nikolova M, Maes M. Comprehensive Immunophenotyping of Monocytes and Dendritic Cells Suggests Distinct Pathophysiology in Chronic Fatigue Syndrome and Long COVID. Int J Mol Sci. 2026 May 17;27(10):4488. doi: 10.3390/ijms27104488. PMID: 42196466; PMCID: PMC13206834. https://pmc.ncbi.nlm.nih.gov/articles/PMC13206834/ (Full text)

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)

Human Endogenous Retroviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Emerging Roles in Pathogenesis, Immunity, Biomarkers and Therapeutics

Abstract:

Human endogenous retroviruses (HERVs) are potential driving forces of the pathophysiology of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), linking post-infectious immune dysfunction to chronic inflammation and immune and neurocognitive dysfunction that are hallmark features of ME/CFS.

Accumulating evidence from related autoimmune diseases and cancers has shown that reactivated HERVs can contribute to disease pathogenesis by amplifying immune activation through viral protein-mediated innate sensing, long terminal repeat (LTR)-driven transcription, and disrupting epigenetic silencing. HERV signatures are therefore promising biomarkers for diagnosis, patient stratification for drug-repurposing trials, and therapy monitoring.

Accumulating evidence suggests a possible correlation between HERV expression and ME/CFS symptom severity, alterations in immune phenotypes, function and inflammatory gene networks. Importantly, locus-specific HERV profiling is a promising approach for distinguishing ME/CFS from overlapping or co-morbid conditions and healthy controls. Furthermore, HERV-targeted antibodies, immune modulators, epigenetic and antiviral interventions offer promise as concomitant therapeutic strategies for ME/CFS.

Additional research incorporating viromics and other-omics validation, functional assays, and HERV-stratified clinical trials is now needed to realise this potential and to transform ME/CFS from a symptom-based syndrome into a mechanism-driven, treatable condition.

Source: Perera KD, Oltra E, Carding SR. Human Endogenous Retroviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Emerging Roles in Pathogenesis, Immunity, Biomarkers and Therapeutics. Int J Mol Sci. 2026 May 12;27(10):4309. doi: 10.3390/ijms27104309. PMID: 42196290; PMCID: PMC13207908. https://pmc.ncbi.nlm.nih.gov/articles/PMC13207908/ (Full text)