Abstract: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained fatigue, post-exertional malaise (PEM), and cognitive dysfunction. ME/CFS patients often report a prodrome consistent with infection. We present a multi-omics analysis based on plasma metabolomic and proteomic profiling, and immune responses to microbial stimulation, before and after exercise. We report evidence of an exaggerated innate immune response after exposure to microbial antigens; impaired energy production involving the citric acid cycle, beta-oxidation of fatty acids, and urea cycle energy production from amino acids; systemic inflammation linked to lipid abnormalities; disrupted extracellular matrix homeostasis with release of endogenous ligands that promote inflammation; reduced cell-cell adhesion and associated gut dysbiosis; complement activation; redox imbalance reflected by disturbances in copper-dependent antioxidant pathways; and dysregulation of tryptophan-serotonin-kynurenine pathways. Many abnormalities were worse following exercise and correlated with the intensity of symptoms. Our findings may inform development of targeted therapeutic interventions for ME/CFS and PEM.

View the full publication in Nature.

Results: The majority of participants in both groups were female (ME/CFS: 69.8% vs. HC: 70.9%, p = 0.8048). Participants with ME/CFS were older than the HCs (51.4 vs. 47.0 years, p = 0.0012) and more likely to identify as White and non-Hispanic (ME/CFS vs. HC: White: 90.4% vs. 56.0%, p < 0.0001; non-Hispanic: 84.1% vs. 61.7%, p < 0.0001). ME/CFS participants were also more likely to have health insurance (96.3% vs. 87.2%, p = 0.0001) and reported a higher number of clinic office visits (5.1 vs. 0.7 visits, p < 0.0001). Conversely, ME/CFS participants were less likely to be employed (19.9% vs. 75.8%, p < 0.0001) or to be obese (11.3% vs. 26.2%, p < 0.0001). No statistically significant differences between ME/CFS and HC individuals were observed in terms of marital status or educational attainment. Among ME/CFS participants, the mean duration of illness was 18.4 ± 10.98 years, with 63.1% reporting a sudden onset of illness.

Conclusion: Our study revealed consistent and robust differences in dysautonomia burden between patients with ME/CFS and healthy controls, as assessed using clinical history and multiple assessment tools. Dysautonomia abnormalities, as captured by the COMPASS-31 domains, were associated with greater illness burden and functional impairment. Our results highlight the potential value of recognizing and addressing dysautonomia symptoms in ME/CFS to reduce the illness severity. Future studies are necessary to confirm whether individualized treatment strategies can effectively improve the quality of life for this population.

View the full publication in Journal of Clinical Medicine.

Results: Stage 1 was completed in September 2013, with 471 study participants completing at least 80% of each instrument and form. This exceeded target enrollment by 5%. Each of the 7 clinics contributed 10%–16% of enrolled patients. Demographic characteristics of the ME/CFS patients are shown in Table 2. Overall, the mean age of patients was 48.2 years; 73.9% were female, and 94.7% were white. Nearly all were insured (94.4%), but 74.9% were not working. Of those who were currently unemployed, 69.6% reported that they were disabled, and only 16.9% were currently receiving unemployment benefits. Regardless of current employment status, 72.6% of patients reported missing work or school because of their illness. The majority (77.0%) had a college education or more, and 56.1% were married. Patients had a mean body mass index (weight in kilograms divided by height in meters squared) of 26.6. The mean age at onset of illness was 38.4 years, and the mean duration of illness at the time of enrollment was 14.3 years. Overall, 65.4% of patients described a sudden onset of illness.

View the full publication in National Library of Medicine.

Results: We tracked 249 participants over 3 to 4 years, including 153 patients with ME/CFS (75 ‘short-term’ with disease symptoms <4 years and 78 ‘long-term’ with disease symptoms >10 years) and 96 healthy controls (Fig. 1a and Supplementary Table 1). The cohort is 68% female and 32% male, aligning with the epidemiological data showing that women are three to four times more likely to develop ME/CFS10,11. Participants ranged in age from 19 to 68 y, with body mass indexes (BMIs) from 16 to 43 kg/m2. Throughout the study, we collected detailed clinical metadata, blood samples and fecal samples. In total, 1471 biological samples were collected across all participants at 515 time points (Methods, Extended Data Fig. 1a and Supplementary Table 1).

View the full publication in Nature.

Results: No significant difference in the CFQ-measured fatigue reduction was observed between the groups. However, the OAA group showed significantly greater improvements in the DSQ-SF-measured fatigue and total symptom burden at day 21 of the trial. Cognitive performance improved significantly in the OAA group, with strong correlations between symptom response and cognitive gains. OAA was well tolerated.

Conclusion: OAA may contribute to earlier improvements in symptom burden and cognitive function in individuals with long COVID. Further studies are warranted.

View the full publication in Frontiers in Neuroscience.

Results: Anhydrous enol-oxaloacetate (oxaloacetate) was well tolerated at the tested doses. Oxaloacetate significantly reduced fatigue by more than 25% from baseline, while the control group showed a non-significant reduction of approximately 10%. Intergroup analysis showed a significant decrease in fatigue levels in the oxaloacetate group (p = 0.0039) with no notable change in the control group. A greater proportion of subjects in the oxaloacetate group achieved a reduction in fatigue greater than 25% compared to the control group (p < 0.05). Additionally, 40.5% of the oxaloacetate group were classified as “enhanced responders,” with an average fatigue reduction of 63%. Both physical and mental fatigue improved with oxaloacetate supplementation.

Conclusion: Oxaloacetate is well tolerated and effectively helps reduce fatigue in ME/CFS patients.

View the full publication in Frontiers in Neuroscience.

Description: RECOVER-Adult is a longitudinal observational cohort study conducted across the U.S. We included participants who had a study visit at least 6 months after infection and had no pre-existing ME/CFS, grouped as (1) acute infected, enrolled within 30 days of infection or enrolled as uninfected who became infected (n=4515); (2) post-acute infected, enrolled greater than 30 days after infection (n=7270); and (3) uninfected (1439). View the full publication in Journal of General Internal Medicine. 

Importance: For PASC patients, both their disease state and hemodynamic changes during orthostatic challenge were associated with slower reaction time and decreased response accuracy during cognitive testing. Reduced cognitive efficiency in <4 year ME/CFS patients was associated with higher heart rate in response to orthostatic stress. Hemodynamic changes did not correlate with cognitive impairment for >10 year ME/CFS patients, but cognitive impairment remained. These findings underscore the need for early diagnosis to mitigate direct hemodynamic and other physiological effects on symptoms of cognitive impairment. View the full publication in Frontiers in Neuroscience. 

Importance: All but one Long COVID respondent reported having PEM. There were many significant differences in the types of PEM triggers, symptoms experienced during PEM, and ways to recover and prevent PEM between Long COVID and ME/CFS. Similarities between Long COVID and ME/CFS included low and medium physical and cognitive exertion to trigger PEM, symptoms of fatigue, pain, immune reaction, neurologic, orthostatic intolerance, and gastrointestinal symptoms during PEM, rest to recover from PEM, and pacing to prevent PEM.

View the full publication in the journal of WORK. 

Importance:  In this study, we employed shotgun metagenomics and metabolomics to assess dysbiosis in the largest prospective case-control study to date, consisting of 106 ME/CFS subjects and 91 matched healthy controls. Our findings provide insights into disturbances in the microbiome and their relationship with fatigue symptoms in ME/CFS.

View the full publication in the journal of Cell Host & Microbe. 

Importance:  The etiology of chronic fatigue syndrome (CFS) is largely unknown. In this issue of Cell Host and Microbe, Guo et al. and Xiong et al. report CFS-associated gut microbiome and metabolomic datasets-implicating dysregulation of immune-modulating molecules. This may provide a framework for new therapeutic paradigms and disease origins.

View the full publication in the journal of Cell Host & Microbe. 

View the full publication in the journal of Frontiers in Medicine. 

Background: Some patients with acute COVID-19 are left with persistent, debilitating fatigue, cognitive impairment (“brain fog”), orthostatic intolerance (OI) and other symptoms (“Long COVID”). Many of the symptoms are like those of other post-infectious fatigue syndromes and may meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Common diagnostic laboratory tests are often unrevealing.

View the full publication in the journal of Frontiers in Medicine: Family and Primary Care

Background:  Post-exertional malaise (PEM) is a defining characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) but there is insufficient research dissecting the nature of PEM from the patients’ perspective. 

View the full publication in the journal of Fatigue : Biomedicine, Health & Behavior. 

Background:  Approximately 2.5 million people in the U.S. suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This disease negatively impacts patients’ ability to function, often resulting in difficulty maintaining employment, sustaining financial independence, engaging socially with others, and in particularly severe cases, consistently and adequately performing activities of daily living. The focus of this research was to develop a sensor-based method to measure upright activity defined as time with feet on the floor and referred to as UpTime, as an indicator of ME/CFS disease severity.

View the full publication in the Journal of Translational Medicine.

Background:  Lightheadedness, fatigue, weakness, heart palpitations, cognitive dysfunction, muscle pain, and exercise intolerance are some of the symptoms of orthostatic intolerance (OI). There is substantial comorbidity of OI in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). The 10-minute NASA Lean Test (NLT) is a simple, point-of-care method that can aid ME/CFS diagnosis and guide management and treatment of OI. The objective of this study was to understand the hemodynamic changes that occur in ME/CFS patients during the 10-minute NLT.

View the full publication in the Journal of Translational Medicine.

Background: Clinical observations have indicated that hours of upright activity (HUA) reported by Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients correlated with orthostatic symptoms and impaired physical function. This study examined the relationship between HUA and orthostatic intolerance (OI).

View the full publication in Work.