Research Highlights from 2018 So Far: Notable Study DevelopmentsJune 21, 2018

The first half of 2018 has yielded over 100 publications specifically addressing various aspects of ME/CFS. Reports encompass familiar domains such as neuroimaging, cytokine abnormalities and NK cell function, as well as explorations of novel technologies in biomarker identification and new findings of endocrine dysfunction, premature aging, post exertional inflammation and autoimmune activity. Here, we summarize highlights from many of the primary research articles published in the past 6 months

Central Nervous System (CNS): A spate of neuroimaging studies utilizing different technologies provided further confirmation of physical abnormalities in ME/CFS patient brains. Zinn, et al. were able to discern differences in neurologic activity by EEG and Nakatomi, et al. observed widespread neuroinflammation associated with symptom severity by PET scan. Using MRI, Boissoneault, et al. and Shan, et al. measured diminished functional connectivity, Staud, et al. evaluated differences in cerebral blood flow patterns following cognitive exertion, and Boissoneault, et al. found cerebral blood flow and heart rate variability (differences in the amount of time between heartbeats) to be inversely correlated with fatigue levels. Sevel, et al. tested the effectiveness of a machine learning platform in discerning neurologic structural abnormalities in ME/CFS. Addressing Naviaux’s hypothesis that ME/CFS may involve processes at play in autism and the fact that the two diseases share symptoms of central sensitization (changes to the CNS that produce chronic pain), Bileviciute-Ljungar, et al. measured features of autism in a CFS cohort, but did not observe an elevated rate of autistic traits. Rowe, et al. identified three ME/CFS patients whose cervical spinal stenosis (compression of the cervical spinal cord) contributed to their symptoms (indicated by improvement following corrective surgery), warranting screening of patients for this condition.

Immune System: While a formal report of the failed phase III rituximab trial has yet to be published, Eaton, et al. provided evidence of its inhibitory effect on natural killer (NK) cells at high doses in vitro, suggesting caution is warranted for its use, especially in patients with existing NK cell dysfunction. Scheibenbogen, et al. conducted a small trial in post-infectious patients with elevated autoantibodies against ß2 adrenergic receptors utilizing a technique called immunoadsorption, in which IgG antibodies are depleted from the blood. The authors measured reduced memory B cells, plasma cells and autoantibodies. 7/10 patients reported short-term and 3/10 long-term symptom improvement following the procedure. In a stringent ME/CFS cohort, Rivas, et al. documented lower frequencies of regulatory T cells (which restrain autoimmunity), lower levels of a herpes-associated proliferative receptor, NKG2C, on NK cells, and higher frequencies of a cytokine producing subset of NK cells. In an example of the power of objective measures to parse heterogenic disease groups, de Vega, et al. were able to discriminate different subtypes of ME/CFS patients by the methylation patterns (a measure of gene activation) in their immune cells, linking these profiles to specific symptoms. Uhde, et al. screened the blood of a large and stringent cohort for levels of C-reactive protein, a marker of immune activation, but found no significant differences compared to controls, in contrast to the elevated levels observed in post-Lyme patients. Rajeevan, et al. reported results from a large CDC surveillance study showing that immune cells in the blood of ME/CFS patients have significantly shorter telomeres (sections of DNA at the ends of chromosomes), a measure of premature aging. The association between ME/CFS and telomere length was particularly strong in female subjects under the age of 45.

Post Exertional Malaise (PEM): Moneghetti, et al. identified elevated levels of several inflammatory cytokines that distinguished patients from matched sedentary controls 18 hours after an exercise challenge, implicating an inflammatory process that is independent of deconditioning. Chu, et al. performed a quantitative analysis of patients’ descriptions of the symptoms experienced following exertion in an effort to further define the PEM experience.

Autonomic & Sleep: Cambras, et al. measured reduced activity and nocturnal skin temperature in ME/CFS patients against control subjects, but did not observe significant differences in circadian rhythm patterns. In a small cohort of CFS patients, Orjatsalo, et al. detected higher blood pressure and sympathetic nervous activity during sleep as well as lower parasympathetic activity during deep sleep than controls by EKG. Castro-Marrero, et al. documented correlation between ME/CFS symptoms and poor sleep quality in a large cohort.

Orthostatic Intolerance: Rasouli, et al. reported that CFS patients experienced comparable difficulty to fibromyalgia patients in maintaining a standing posture. Serrador, et al. found that balance ability was impaired relative to controls and correlated with functional but not mental status among CFS patients, and that those with comorbid fibromyalgia displayed further reduced vestibular function. Miwa, et al. observed markedly impaired performance on 10-minute sitting and standing tolerance tests in ME patients, specifically implicating disequilibrium as a more significant influence of orthostatic intolerance than POTS. Contrasting prior cardiovascular studies, Bozzini, et al. detected a significantly elevated rate of hypotension among CFS patients. Richardson, et al. demonstrated the ability of a weighted standing time test to identify ME/CFS severity.

Metabolic: Using in vitro muscle cell cultures to further investigate metabolic defects in ME/CFS, Brown, et al. found that ATP levels were unaffected by treatment with metformin to increase glucose uptake, but did find that overall ATP levels were lower in patients than controls.

Endocrine: Ruiz-Núñez, et al. observed consistently low T3 thyroid hormone activity in a large CFS cohort.

Microbiome: Mandarano, et al. found slightly reduced diversity in the gut flora and slightly increased fungal species in the intestines of a small ME/CFS cohort.

Biomarker: Castro-Marrero, et al. explored the utility of extracellular vesicles (small parcels of cellular contents circulating in the blood) to serve as a discriminatory biomarker in a small ME/CFS cohort, finding they were more numerous but smaller in size than controls.

Function & Quality of Life: Kingdon, et al. found ME/CFS patients are more disabled than those with multiple sclerosis. Gleason, et al. assessed the effectiveness of several activity scales in identifying thresholds of reduced activity that discern patients from controls.

CBT & GET: Nearly one thousand CFS patients were recruited to evaluate a cognitive behavioral model that patients’ sickness beliefs and deconditioning leads to their experience of fatigue in Sunnquist, et al. The researchers determined that patients meeting more stringent case definitions displayed a weaker connection between activity and impairment, suggesting inconsistency with a behavioral cause. In a re-analysis of original data from the PACE trial, Wilshire, et al. showed that CBT and GET therapies resulted in only modest effects by subjective reports lasting less than 2 years and with low recovery rates, contrary to what was originally reported by the trial authors.