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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established. We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls. Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism. The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses. In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles. We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention. publishedVersion

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition associated with several negative health outcomes. A hallmark of ME/CFS is decreased exercise capacity and often profound exercise intolerance. The causes of ME/CSF and its related symptoms are unknown, but there are indications of a dysregulated metabolism with impaired glycolytic vs oxidative energy balance. In line with this, we recently demonstrated abnormal lactate accumulation among ME/CFS patients compared with healthy controls after exercise testing. Here we examined if cardiac dimensions and function were altered in ME/CFS, as this could lead to increased lactate production. Methods: We studied 16 female ME/CFS patients and 10 healthy controls with supine transthoracic echocardiography, and we assessed cardiac dimensions and function by conventional echocardiographic and Doppler analysis as well as novel tissue Doppler and strain variables. Results: A detailed analyses of key variables of cardiac dimensions and cardiac function revealed no significant differences between the two study groups. Conclusion: In this cohort of well-described ME/CFS patients, we found no significant differences in echocardiographic variables characterizing cardiac dimensions and function compared with healthy controls.

Post‐exertional malaise and delayed recovery are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME /CFS ). Studies on repeated cardiopulmonary exercise testing (CPET ) show that previous exercise negatively affects oxygen uptake (VO 2) and power output (PO ) in ME /CFS . Whether this affects arterial lactate concentrations ([Laa]) is unknown. We studied 18 female patients (18–50 years) fulfilling the Canadian Consensus Criteria for ME /CFS and 15 healthy females (18–50 years) who underwent repeated CPET s 24 h apart (CPET 1 and CPET 2) with [Laa] measured every 30th second. VO 2 at peak exercise (VO 2peak) was lower in patients than in controls on CPET 1 (P < 0.001) and decreased in patients on CPET 2 (P < 0.001). However, the difference in VO 2peak between CPET s did not differ significantly between groups. [Laa] per PO was higher in patients during both CPET s (P interaction < 0.001), but increased in patients and decreased in controls from CPET 1 to CPET 2 (P interaction < 0.001). Patients had lower VO 2 (P = 0.02) and PO (P = 0.002) at the gas exchange threshold (GET , the point where CO 2 production increases relative to VO 2), but relative intensity (%VO 2peak) and [Laa] at GET did not differ significantly from controls on CPET 1. Patients had a reduction in VO 2 (P = 0.02) and PO (P = 0.01) at GET on CPET 2, but no significant differences in %VO 2peak and [Laa] at GET between CPET s. Controls had no significant differences in VO 2, PO or %VO 2peak at GET between CPET s, but [Laa] at GET was reduced on CPET 2 (P = 0.008). In conclusion, previous exercise deteriorates physical performance and increases [Laa] during exercise in patients with ME /CFS while it lowers [Laa] in healthy subjects.

Background Previous phase 2 trials indicated benefit from B-lymphocyte depletion in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Objective To evaluate the effect of the monoclonal anti-CD20 antibody rituximab versus placebo in patients with ME/CFS. Design Randomized, placebo-controlled, double-blind, multicenter trial. (ClinicalTrials.gov: NCT02229942). Setting 4 university hospitals and 1 general hospital in Norway. Patients 151 patients aged 18 to 65 years who had ME/CFS according to Canadian consensus criteria and had had the disease for 2 to 15 years. Intervention Treatment induction with 2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months (n = 77), or placebo (n = 74). Measurements Primary outcomes were overall response rate (fatigue score ≥4.5 for ≥8 consecutive weeks) and repeated measurements of fatigue score over 24 months. Secondary outcomes included repeated measurements of self-reported function over 24 months, components of the Short Form-36 Health Survey and Fatigue Severity Scale over 24 months, and changes from baseline to 18 months in these measures and physical activity level. Between-group differences in outcome measures over time were assessed by general linear models for repeated measures. Results Overall response rates were 35.1% in the placebo group and 26.0% in the rituximab group (difference, 9.2 percentage points [95% CI, -5.5 to 23.3 percentage points]; P = 0.22). The treatment groups did not differ in fatigue score over 24 months (difference in average score, 0.02 [CI, -0.27 to 0.31]; P = 0.80) or any of the secondary end points. Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events. Limitation Self-reported primary outcome measures and possible recall bias. Conclusion B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS. Primary Funding Source The Norwegian Research Council, Norwegian Regional Health Trusts, Kavli Trust, MEandYou Foundation, and Norwegian ME Association.