Autonomic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Findings from the Multi-Site Clinical Assessment of ME/CFS (MCAM) Study in the USA

Abstract:

Background/Objectives: Symptoms of autonomic dysfunction are common in infection-associated chronic conditions and illnesses (IACCIs), including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study aimed to evaluate autonomic symptoms and their impact on ME/CFS illness severity.
Methods: Data came from a multi-site study conducted in seven ME/CFS specialty clinics during 2012–2020. Autonomic dysfunction was assessed using the Composite Autonomic Symptom Scale 31 (COMPASS-31), medical history, and a lean test originally described by the National Aeronautics and Space Administration (NASA). Illness severity was assessed using Patient-Reported Outcomes Measurement Information System measures, the 36-item short-form, as well as the CDC Symptom Inventory. This analysis included 442 participants who completed the baseline COMPASS-31 assessment, comprising 301 individuals with ME/CFS and 141 healthy controls (HC).
Results: ME/CFS participants reported higher autonomic symptom burden than HC across three assessment tools (all p < 0.0001), including the COMPASS-31 total score (34.1 vs. 6.8) and medical history indicators [dizziness or vertigo (42.6% vs. 2.8%), cold extremities (38.6% vs. 5.7%), and orthostatic intolerance (OI, 33.9% vs. 0.7%)]. Among ME/CFS participants, 97% had at least one autonomic symptom. Those with symptoms in the OI, gastrointestinal, and pupillomotor domains had significantly higher illness severity than those without these symptoms.
Conclusions: ME/CFS patients exhibit a substantial autonomic symptom burden that correlates with greater illness severity. Individualized care strategies targeting dysautonomia assessment and intervention may offer meaningful improvements in symptom management and quality of life for those with ME/CFS and similar chronic conditions.
Source: Issa A, Lin J-MS, Chen Y, Attell J, Brimmer D, Bertolli J, Natelson BH, Lapp CW, Podell RN, Kogelnik AM, et al. Autonomic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Findings from the Multi-Site Clinical Assessment of ME/CFS (MCAM) Study in the USA. Journal of Clinical Medicine. 2025; 14(17):6269. https://doi.org/10.3390/jcm14176269  https://www.mdpi.com/2077-0383/14/17/6269 (Full text)

Microfluidic assessment of PO2-regulated RBC capillary velocity in ME/CFS

Key points:
1. PO2-regulated RBC capillary velocity is impaired in ME/CFS.
2. RBC velocity response to PO2 is a unique characteristic in ME/CFS.

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease of unknown etiology that affects multiple organ systems. Although there is no established treatment or diagnostic test for ME/CFS yet, studies have consistently demonstrated impaired cerebral blood flow (CBF) and blood flow regulation in ME/CFS. In this study, we measured red blood cell (RBC) velocity in microfluidic capillaries at varied oxygen tensions (PO2) and showed that, compared to RBCs from heathy controls, RBCs from ME/CFS exhibit compromised capillary velocity in response to reduced PO2.
To examine whether such PO2-regulated RBC capillary velocity could be used to assess or diagnose ME/CFS, we conducted receiver operator characteristic (ROC) analysis and used machine learning (ML) to analyze various features of PO2-regulated RBC capillary velocity. We found that velocity slope-based classifiers were highly accurate, sensitive and specific (i.e., 77.8%, 76% and 90% respectively) in ME/CFS classification.
Furthermore, we demonstrated this RBC-based microfluidic approach can be used to evaluate potential drugs (i.e., salmeterol xinafoate and xanomeline) for improving RBC capillary velocity in ME/CFS. These findings highlight previously unrecognized roles of RBCs in the pathophysiology of ME/CFS and suggest a potential RBC-based test for ME/CFS diagnosis.
Source: Yaojun Guo, Sitong Zhou, Samuel Ren, Xin Liu, Mohsen Nemat-Gorgani, Mike Gresser, Ronald W. Davis, Jiandi Wan. Microfluidic assessment of PO2-regulated RBC capillary velocity in ME/CFS, Blood Red Cells & Iron, 2025, 100019. ISSN 3050-5984. https://doi.org/10.1016/j.brci.2025.100019. https://www.sciencedirect.com/science/article/pii/S3050598425000198 (Full text)

Long COVID and chronic fatigue syndrome/myalgic encephalitis share similar pathophysiologic mechanisms of exercise limitation

Abstract:

Post-acute sequelae of SARS-CoV-2 (PASC or “long COVID”) and chronic fatigue syndrome/myalgic encephalitis (CFS/ME) share symptoms such as exertional dyspnea. We used exercise oxygen pathway analysis, comprising six parameters of oxygen transport and utilization, to identify limiting mechanisms in both conditions. Invasive cardiopulmonary exercise testing was performed on 15 PASC patients, 11 CFS/ME patients, and 11 controls.

We evaluated the contributions of alveolar ventilation (V̇a), lung diffusion capacity (DL ), cardiac output (Q̇), skeletal muscle diffusion capacity (DM ), hemoglobin (Hb), and mitochondrial oxidative phosphorylation (Vmax) to peak oxygen consumption (V̇O2peak). To simulate targeted interventions, each variable was sequentially normalized to assess its impact on V̇O2peak. V̇O2peak was significantly reduced in both PASC and CFS/ME compared to controls.

Skeletal muscle O2 diffusion (DM ) was the most impaired parameter in both patient groups (p = 0.01). Correcting DM alone improved V̇O2 by 66% in PASC (p = 0.008) and 34.7% in CFS/ME (p = 0.06), suggesting a dominant role for peripheral O2 extraction in exercise limitation. Impaired skeletal muscle oxygen diffusion (DM ) is a shared mechanism of exercise intolerance in PASC and CFS/ME and may represent a therapeutic target. However, our findings are limited by small sample size.

Source: Jothi S, Insel M, Claessen G, Kubba S, Howden EJ, Ruiz-Carmona S, Levine T, Rischard FP. Long COVID and chronic fatigue syndrome/myalgic encephalitis share similar pathophysiologic mechanisms of exercise limitation. Physiol Rep. 2025 Sep;13(17):e70535. doi: 10.14814/phy2.70535. PMID: 40892700. https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.70535 (Full text)

Killer cell immunoglobulin-like receptor (KIR) alleles suggested to be associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease with unknown cause. Involvement of infection and immune dysregulation has been suggested, including changes in immune cell subsets and abnormal functions of natural killer (NK) cells.

The regulatory NK cell receptors, killer cell immunoglobulin-like receptors (KIR) have previously been investigated in small cohorts of ME/CFS patients with conflicting results regarding gene content. Here, we studied KIR genes also at the allelic level using high-resolution sequencing, in 418 ME/CFS patients and 473 healthy controls.

Human leukocyte antigen (HLA) class I genotype data were included for KIR ligand annotation. Our healthy control data represent KIR frequencies for a Norwegian population, which have not previously been reported. We found no association between ME/CFS and KIR gene content or copy number variations. However, our data suggested that specific KIR alleles at loci encoding inhibitory receptors were associated with ME/CFS, which was further supported by allelic haplotype analyses.

Three alleles were more frequent in patients, i.e. KIR3DL3*002 (OR = 1.43, 95 %CI (1.09-1.86), p = 0.009), KIR3DL1*020 (OR = 2.20, 95 %CI (1.19-4.06), p = 0.01) and KIR3DL2*009 (OR = 1.56, 95 %CI (1.09-2.23), p = 0.01), while two alleles had a reduced patient frequency, i.e. KIR3DL3*013 (OR = 0.60, 95 %CI (0.42-0.86), p = 0.005) and KIR3DL2*010 (OR = 0.46, 95 %CI (0.30-0.71), p = 0.0005). Our data support an involvement of NK cells in ME/CFS.

Source: Ramadan DJ, Kichula KM, Tao S, Porfilio T, Lande A, Fluge Ø, Mella O, Strand EB, Saugstad OD, Norman PJ, Lie BA, Viken MK. Killer cell immunoglobulin-like receptor (KIR) alleles suggested to be associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Brain Behav Immun. 2025 Aug 31:106098. doi: 10.1016/j.bbi.2025.106098. Epub ahead of print. PMID: 40897283. https://www.sciencedirect.com/science/article/pii/S0889159125003332 (Full text)

Effects of recumbent isometric yoga on the orthostatic cardiovascular response of patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Our previous studies demonstrated that the regular practice of recumbent isometric yoga reduced the fatigue of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Some patients with ME/CFS have postural orthostatic tachycardia syndrome (POTS); however, the effects of recumbent isometric yoga on orthostatic cardiovascular responses and whether recumbent isometric yoga improves POTS remain unknown. This pilot study was done to investigate the effect of recumbent isometric yoga on the orthostatic cardiovascular response of patients with ME/CFS.

Main body: Ten adult female patients with ME/CFS performed recumbent isometric yoga for 12 weeks. Changes in their systolic blood pressure (SBP), diastolic blood pressure (DBP), and the pulse rate (PR) during an active standing test were compared before and after the 12-week regimen. Among the 10 patients, 8 manifested a normal orthostatic response and 2 manifested POTS before the yoga intervention. Patients who manifested a normal orthostatic response before yoga also manifested the normal orthostatic pattern after the yoga intervention. In contrast, the two patients who manifested POTS before the regimen showed a normal orthostatic response after completing the yoga intervention.

Conclusions: This study found that the patients who manifested POTS and performed recumbent isometric yoga for 12 weeks had a reduced increase in PR after standing up. This pilot study suggests that recumbent isometric yoga would be useful as an adjunctive nonpharmacological intervention for improving POTS in patients with ME/CFS. This finding should be confirmed in a larger number of cases.

Source: Oka T, Lkhagvasuren B. Effects of recumbent isometric yoga on the orthostatic cardiovascular response of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Biopsychosoc Med. 2025 Sep 1;19(1):16. doi: 10.1186/s13030-025-00336-w. PMID: 40890788. https://bpsmedicine.biomedcentral.com/articles/10.1186/s13030-025-00336-w (Full text)

The emerging role of exosomal LncRNAs in chronic fatigue syndrome: from intercellular communication to disease biomarkers

Abstract:

Chronic fatigue syndrome (CFS) is a complex disease involving multiple systems throughout the body with unknown pathogenesis and is characterized by chronic fatigue. To date, no effective treatment for CFS has been found, as well as biomarkers for early identification of diagnosis. However, exosomes, a subpopulation of extracellular vesicles (EVs), are membranous vesicles secreted by cells into the surrounding environment, and long noncoding RNAs (LncRNAs) in EVs can mediate inter-organ and inter-cellular communication, which maybe associate with CFS.

Therefore, this study aims to review the association between EV-LncRNAs and CFS, and to explore whether LncRNAs can be used as potential biomarkers for early identification and diagnosis of CFS, which put forward new ideas and a theoretical basis for the pathogenesis of CFS, as well as the identification of novel targeted therapies.

Source: Wang Lei , Xu Yujia , Zhong Xiang , Wang Guiping , Shi Zijun , Mei Can , Chen Linwanyue , Zhan Jianbo , Cheng Jing. The emerging role of exosomal LncRNAs in chronic fatigue syndrome: from intercellular communication to disease biomarkers. Frontiers in Molecular Biosciences. Volume 12 – 2025 https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2025.1653627/full (Full text)

Haptoglobin phenotypes and structural variants associate with post-exertional malaise and cognitive dysfunction in myalgic encephalomyelitis

Abstract:

Background: Myalgic encephalomyelitis (ME) is a chronic, multisystem illness characterized by post-exertional malaise (PEM) and cognitive dysfunction, yet the molecular mechanisms driving these hallmark symptoms remain unclear. This study investigated haptoglobin (Hp) as a potential biomarker of PEM severity and cognitive impairment in ME, with a focus on Hp phenotypes and structural proteoforms.

Methods: A longitudinal case-control study was conducted in 140 ME patients and 44 matched sedentary healthy controls. In the discovery phase, global plasma proteomic profiling was performed in 61 ME patients and 20 controls before and after a standardized, non-invasive stress protocol in order to induce PEM. Associations between Hp levels, phenotype, and cognitive performance were assessed. In the validation phase, plasma Hp concentrations and proteoform composition were analyzed in an independent cohort of 89 ME patients and 24 controls using high-performance liquid chromatography (HPLC).

Results: ME patients demonstrated a significant reduction in Hp levels following post-exertional stress. Lower baseline Hp concentrations were associated with impaired cognitive performance. Hp phenotypes were differentially associated with symptom burden, with the Hp2-1 phenotype enriched in ME and linked to greater PEM severity and cognitive deficits compared to Hp1-1 and Hp2-2. HPLC analysis revealed altered Hp proteoform profiles in the Hp2-1 subgroup, including increased high-mass tetrameric and pentameric forms and shorter retention times indicative of structural changes. In contrast, the Hp1-1 phenotype was associated with milder symptoms and greater cognitive resilience.

Conclusions: These findings suggest that Hp phenotype and proteoform structure modulate the physiological response to post-exertion in ME, offering insight into the molecular basis of PEM and its clinical heterogeneity. Hp may serve as a translational biomarker for patient stratification and a potential therapeutic target to mitigate oxidative stress and cognitive dysfunction in ME.

Source: Moezzi A, Ushenkina A, Widgren A, Bergquist J, Li P, Xiao W, Rostami-Afshari B, Leveau C, Elremaly W, Caraus I, Franco A, Godbout C, Nepotchatykh O, Moreau A. Haptoglobin phenotypes and structural variants associate with post-exertional malaise and cognitive dysfunction in myalgic encephalomyelitis. J Transl Med. 2025 Aug 28;23(1):970. doi: 10.1186/s12967-025-07006-z. PMID: 40877900. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-07006-z (Full text)

Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia

Abstract:

Myalgic encephalomyelitis (ME) and fibromyalgia (FM) are overlapping syndromes characterized by persistent fatigue, cognitive difficulties, and post-exertional malaise (PEM), yet they lack objective biomarkers for diagnosis and treatment. Fibroblast growth factor 21 (FGF-21), a stress-responsive metabolic hormone, may offer a promising avenue to distinguish subtypes within these patient populations.

In this cross-sectional study, plasma FGF-21 levels were measured in 250 patients (FM = 47; ME = 99; ME + FM = 104) and 54 healthy controls. Participants were categorized based on FGF-21 levels into three groups: low (0-50 pg/mL), normal (51-200 pg/mL), and high (>200 pg/mL). Symptoms burden and cognitive function were assessed using validated questionnaires (SF-36, MFI-20, DSQ, DPEMQ) and the BrainCheck platform. A standardized mechanical provocation maneuver was used to induce PEM.

Results showed that elevated FGF-21 levels were frequently observed in ME and ME + FM but varied widely across all groups. Stratification by circulating FGF-21 levels, rather than diagnosis alone, revealed distinct symptom and cognitive profiles. Low FGF-21 levels were linked to worsened PEM perception in FM, increased PEM severity and immune/autonomic symptoms in ME, and poorer mental health in ME + FM. Conversely, high FGF-21 levels correlated with better cognition in ME but greater fatigue in ME + FM.

These findings suggest that FGF-21 may serve as a valuable biomarker for identifying clinically meaningful subtypes within ME and FM, supporting the development of personalized treatments. Furthermore, discrepancies between DSQ and DPEMQ highlight the need for objective PEM assessment tools. Overall, FGF-21 shows potential as a biomarker to guide precision medicine in these complex conditions.

Source: Azimi G, Elremaly W, Elbakry M, Franco A, Godbout C, Moreau A. Circulating FGF-21 as a Disease-Modifying Factor Associated with Distinct Symptoms and Cognitive Profiles in Myalgic Encephalomyelitis and Fibromyalgia. Int J Mol Sci. 2025 Aug 8;26(16):7670. doi: 10.3390/ijms26167670. PMID: 40868993. https://www.mdpi.com/1422-0067/26/16/7670 (Full text)

Mapping cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance: insights from a systematic review

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating condition with a large proportion of patients that experience orthostatic intolerance (OI). This systematic review aimed to assess whether cerebral blood flow (CBF) is reduced in ME/CFS and OI, and whether the presence of both conditions leads to an additional decline in CBF.

Methods: PubMed (from 1943), MEDLINE (from 1946), EMBASE (from 1947) and Cochrane were searched from inception to February 14th, 2025, using terms including “chronic fatigue syndrome”, “myalgic encephalomyelitis”, “orthostatic intolerance” and “cerebral blood flow”. Article selection required the following criteria: published in English; CBF measured in participants with either ME/CFS or OI, or both ME/CFS and OI combined. Quality assessment and risk of bias was assessed using the Newcastle-Ottawa Scale and the systematic review was conducted in accordance with the PRISMA 2020 guidelines.

Results: Of 14,928 articles, 118 were included, 26 (22.1%) of which studied CBF in ME/CFS alone, 81 (68.6%) in OI alone and 11 (9.3%) in both ME/CFS and OI. Overall, the articles included 9185 participants, with a mean age of 39.1 years (SD = 8.8), and 73.8% of participants were female. Studies found CBF was significantly reduced in 12 of the articles focused on ME/CFS and in 56 of those focused on OI; compared to controls. Additionally, in 4 out of 11 studies that examined both conditions, CBF was further reduced in participants suffering from both conditions compared to those with ME/CFS alone.

Conclusions: CBF is reduced in ME/CFS and OI alone and having both conditions comorbidly amplifies CBF reductions. Therefore, observing CBF changes in ME/CFS with and without OI may be important in monitoring disease severity. Despite this, few studies focus on the combination of ME/CFS and OI, and OI may be a confounding factor in CBF in a large portion of ME/CFS studies.

Source: Christopoulos EM, Tantanis D, Huang K, Schneider-Futschik EK, Gooley PR, Moneghetti KJ, Armstrong CW. Mapping cerebral blood flow in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and orthostatic intolerance: insights from a systematic review. J Transl Med. 2025 Aug 26;23(1):963. doi: 10.1186/s12967-025-06954-w. PMID: 40859389. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-025-06954-w (Full text)

Protocol for a qualitative study on the online connections of people with ME/CFS and the relationship between these online connections and offline lives

Abstract:

Introduction: Myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), is a debilitating chronic illness that affects the central nervous and immune systems, causing core symptoms of extreme fatigue, post-exertional malaise, cognitive issues and sleep disturbance. With reported higher online use than in other chronic illnesses, people with ME/CFS are often housebound and isolated and may struggle to maintain social relationships. Due to a lack of biomarkers, the illness is often contested, causing invalidation and stigma for those affected. This study aims to broaden the knowledge on how people with ME/CFS gain online connections and whether and how these connections integrate into and impact their everyday life.

Methods and analysis: Qualitative interviews will be conducted with adults aged over 18 years with a diagnosis or self-diagnosis of ME or CFS (n=20-25). A semi-structured topic guide will be used to interview participants and explore online connections and relationships between these and everyday life with ME/CFS. Interviews will be recorded and transcribed verbatim. Data will be thematically analysed to gain in-depth insight into this largely unexplored topic.

Ethics and dissemination: The study has ethical approval from the University of Birmingham (reference: RN_1722-Jun2024), and informed written consent will be provided by all participants. Findings will be published in peer-reviewed journals and disseminated to advocacy organisations and health professionals seeking to offer remote support for people with ME/CFS and their families. This study will provide crucial insight into online use and how it can guide the formulation of management plans for people who may currently receive no support from health professionals at all.

Source: Shortland DL, Fazil Q, Lavis A. Protocol for a qualitative study on the online connections of people with ME/CFS and the relationship between these online connections and offline lives. BMJ Open. 2025 Aug 19;15(8):e099557. doi: 10.1136/bmjopen-2025-099557. PMID: 40829849. https://bmjopen.bmj.com/content/15/8/e099557 (Full text)