2018 ME/CFS Research Summary

2018 was a pivotal year for ME/CFS research, yielding over 200 publications specifically addressing various aspects of ME/CFS. Foundational work emerged from prominent biomedical scientists around the globe, leveraging powerful novel technologies and analysis strategies to advance our understanding of the disease presentation, pathophysiology, and effective treatment modalities. From sophisticated neuroimaging to characterization of immune cell dysfunction, the body of work produced this year decidedly situates ME/CFS within the realm of neuroimmune disease.

Reports from the past year encompass a breadth of domains, illuminating the physiological and biochemical nature of the disease, and describing unique elements of the ME/CFS experience such as post-exertional malaise and social stigma. Importantly, this year has brought forth clinical trials of biochemical agents and immunomodulatory techniques, as well as substantial re-analyses debunking past trials of therapies rooted in the psychosomatic paradigm. Comprehensive molecular profiling to aid identification of biomarkers and novel therapeutic targets has moved the field closer to the prospect of objective diagnostic measures and novel clinical trials.

This post summarizes highlights from key domains in ME/CFS research and briefly describes many of the primary research articles published in the past year. An interactive graphic version of this summary is also available from SMCI.

NEUROLOGY

2018 was a particularly strong year for neuroimaging, with a multitude of studies deploying modern technologies and leveraging sophisticated analysis techniques to assess inflammatory, structural, and functional neurologic abnormalities. In the absence of access to a patient brain biorepository, researchers have delved deep into the extent to which aberrant activity can be detected through noninvasive techniques and have produced notable results conclusively implicating neurologic dysfunction in ME/CFS disease pathophysiology. Collectively, the work produced is a remarkable demonstration of altered neurological structure and function in ME/CFS patient brains, which consistently evidences a physiologic basis for patient-reported cognitive impairment and autonomic dysfunction using objective measures.

Zinn, et al. were able to discern differences in neurologic activity by electroencephalogram (EEG), a test that records electrical patterns in the brain.

Nakatomi, et al. observed widespread neuroinflammation associated with symptom severity by positron emission topography (PET) scan.

By functional MRI (fMRI), Boissoneault, et al. and Shan, et al. measured diminished functional connectivity (pattern of interactions between areas of the brain).

Barnden, et al. discovered deficits in neural conduction within the brainstems of CFS (Fukuda) patients, proposing that a compensatory increase in myelin (the “insulation” around neurons) may occur in this region and compromise cerebral function.

Staud, et al. evaluated differences in differences in cerebral blood flow patterns following a cognitive exertion task in ME/CFS subjects compared to healthy controls.

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.

Kimura, et al. measured microstructural abnormalities in patient brains by MRI, noting significant decreases in physical neurologic metrics in specific regions relative to healthy controls.

Rowe, et al. identified several ME/CFS patients whose cervical spinal stenosis (compression of the cervical spinal cord) contributed to their symptoms, as indicated by improvement following corrective surgery. The case series highlights the importance of careful neurologic examination of patients for this condition.

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 central nervous system 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.

Nilsson, et al. tested a dopamine and serotonin receptor agonist, (−)-OSU6162, in a clinical trial and found correlative but nonsignificant improvements in self-reported fatigue, especially in a subgroup receiving antidepressants.

IMMUNOLOGY & MICROBIOME

Immunologic investigations proved to be the most active area of ME/CFS research this year. Studies ranged widely in scope, from basic profiling and biomarker pursuit, to targeted follow-up evaluations of specific mechanisms, to clinical trials. Importantly, multiple efforts included stratification analyses to discern patient subgroups using objective measures and link them to specific symptoms. Building upon prior years’ groundbreaking reports of autoimmunity in ME/CFS, multiple studies focused on autoantibody detection and therapeutic removal. In-depth characterization of the distribution and functional properties of multiple immune cell types (T, B, NK and red blood cells) revealed a spectrum of abnormal phenomena at play in ME/CFS blood, including heightened susceptibility to cellular death, aberrant frequencies of certain cell subsets, and compromised abundance of proteins critical to key cellular functions. The search for differences in soluble factors circulating in the blood also yielded evidence of immune activation. High-throughput mapping of epigenetic, RNA, exosome, and microbiome signatures added to foundational profiling of the ME/CFS disease state for potential biomarker identification. The impacts of immunomodulatory events such as viral infection and vaccination on the incidence of ME/CFS were also explored.

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.

Günther, et al. utilized an unbiased approach to explore the landscape of antibody specificity in ME/CFS patients, identifying a unique signature that distinguishes patients from healthy controls.

Rekeland, et al. retrospectively analyzed serum of patients from a rituximab trial to measure levels of the drug and anti-drug antibodies (which would block its activity) in patients who responded to the treatment and those who did not in order to determine if these factors influenced outcomes. The concentration of rituximab in the blood of patients did not differ between responders and non-responders, and no anti-drug antibodies were found. Additionally, patients did show reduced B-cell numbers, indicating the drug was effective.

Recapitulating observations dating back to 1987 using modern techniques, Saha, et al. demonstrated a decreased ability of erythrocytes (red blood cells, which deliver oxygen to tissues) from ME/CFS patients to be flexible and remain intact when passing through small spaces. This phenomenon of decreased deformability is also observed in sepsis and in diseases with vascular dysfunction such as diabetes. While total oxygen saturation and hemoglobin appear adequate in patients, this study suggests their erythrocytes may be more susceptible to damage as they pass thorough small capillaries in peripheral tissues.

Eaton, et al. provided evidence of the inhibitory effect of rituximab 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.

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.

Cabanas, et al. observed reduced TRPM3 ion channel function in NK cells from ME/CFS patients, demonstrating functional impairment of these cells.

Building upon their prior work showing elevated expression of CD24, a signaling protein expressed on B cells, in B cells of ME/CFS patients, Mensah, et al. established that CD24-expressing B cells were more abundant in patients than controls and were more prone to die rapidly upon exposure to an immunologic challenge.

De Meirleir, et al. performed a retrospective analysis of ME patient laboratory tests, identifying serum levels of immune markers CD14, PGE2, and IL-8 as factors which distinguish patients from healthy controls.

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 Lyme patients.

Nguyen, et al. identified two subgroups of ME/CFS patients stratified by norepinephrine levels, noting that those with lower levels experienced greater fatigue and had higher levels of immune genes C-reactive protein and TGF-β, whereas those with higher norepinephrine showed modulation in autonomic gene sets.

Roerink, et al. attempted to replicate findings of elevated TGF-β in patient blood, but discovered that differences in the technical processing of samples alters this measurement, a factor potentially explaining discrepant findings in prior cytokine studies.

Castro-Marrero, et al. identified consistently low omega-3 fatty acid levels in ME/CFS patients, suggesting a proinflammatory state and cardiovascular risk.

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.

Trivedi, et al. performed an epigenetic study which identified DNA methylation patterns in ME/CFS reflecting expression of genes involved in immune system activation.

Yang, et al. found expression of three noncoding RNAs that are also known to be induced by innate immune activation to be elevated in the blood of patients, two of which correlated with disease severity.

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.

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.

Wang, et al. identified differences in the oral microbiome profiles of CFS patients versus healthy controls.

Rajeevan, et al. reported results from a large CDC surveillance study showing that cells in the blood of ME/CFS patients, and especially in women over 45, have significantly shorter telomeres (sections of DNA at the ends of chromosomes), a measure of premature aging.

In a prospective study of adolescents following acute EBV infection, Pedersen et al. found that fatigue 6 months post-infection associates with sensory sensitivity, pain, and diminished steps per day.

In an expansive retrospective analysis of outcomes following HPV vaccination in adolescent girls, Schurink-Van’t Klooster, et al. found no significant increase in rates of persistent fatigue or CFS following vaccination.

POST EXERTIONAL MALAISE

Work generated this year brought PEM into clear focus as a critically defining feature of ME/CFS. A comprehensive characterization of the patient-reported PEM experience led to development of novel instrumentation to measure its features, providing a critically needed resource for research cohort selection methods and patient-reported outcomes in future clinical trials. Attempts to measure differences in objective biologic factors following exertion yielded evidence of immunologic activation corresponding to patient reports of PEM.

Moneghetti, et al. identified elevated levels of several inflammatory cytokines which distinguish patients from matched sedentary controls 18 hours after an exercise challenge, implicating an inflammatory process that is independent of deconditioning.

Polli, et al. found associations between an indicator of immune system activation and patient reported pain after exercise testing in patients and not in healthy controls.

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.

Jason, et al. undertook a survey of patients’ experience of PEM and developed a new questionnaire to assess the breadth, severity and triggers of these symptoms. They found that the time of PEM onset following exertion, the type of trigger, and the number and duration of symptoms all correlated with overall physical functioning, demonstrating that more severely disabled patients experience more severe PEM.

A meta-analysis by Brown, et al. revealed that PEM is unique to ME/CFS patients versus study controls, and is therefore a defining feature of the disease.

METABOLIC

Recent research shows an emerging consensus on perturbations in various metabolic pathways in individuals with ME/CFS, indicating a hypometabolic state. Newer evidence points to irregularities in lipid and amino acid pathways, in addition to disruptions in energy, oxidative stress, nucleotide, nitrogen, and hormone metabolism. Researchers have also probed the hypothesis that metabolic dysfunction in immune cells could be driving problems with immune system functioning in ME/CFS patients.

An upcoming analysis of data from four metabolomic studies (a dataset from a partnership with SMCI, Armstrong, et al. (2015), Naviaux, et al. (2016), Germain, et al. (2017)) found that differences between metabolite levels in patients and controls were highly consistent across the studies. Importantly, researchers were unable to cluster patients into subgroups from the metabolite data, suggesting that even though there might be subgroups in regard to other aspects of the disease, the lack of identifiable subgroups based on metabolite levels indicates there could be something fundamentally different in the metabolism of all individuals with ME/CFS.

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.

Nagy-Szakal, et al. compared blood metabolites with fecal microbiome profiles and clinical IBD symptoms to identify metabolic profiles that distinguish patients from healthy controls as well as patients with or without IBD.

AUTONOMIC, CIRCULATORY & ENDOCRINE

A spate of postural testing studies explored the nature of orthostatic intolerance and vascular hypotension in ME/CFS, illustrating differences that distinguish ME/CFS patients from those of other chronic conditions involving orthostatic dysfunction. Sleep studies revealed evidence of autonomic dysfunction and endocrine studies noted diminished thyroid levels and cortisol sensitivity.

Rasouli, et al. reported that CFS patients experienced difficulty comparable 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.

van Campen, et al. examined data from the first 10 minutes of 20-minute tilt table testing to determine if a shorter duration test could accurately identify POTS in ME/CFS patients, but found that abbreviated testing (less than 10 minutes) is not sufficient.

Roma, et al. determined that a full 10 minutes of standing is required in accurately diagnosing POTS, and found that an additional 2-minute post-standing heart rate measure is particularly effective in identifying the condition.

Cambras, et al. measured reduced activity and nocturnal skin temperature in ME/CFS patients, but did not observe significant differences in circadian rhythm patterns.

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. found that pain, autonomic dysfunction, poor quality of life associate with poor sleep quality in a large cohort.

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

Lynn, et al. found that blood cells from ME/CFS patients showed reduced inflammatory cytokine production and reduced sensitivity to glucocorticoid receptor signaling by steroid hormones compared to both sedentary healthy controls and Sjogren’s patients.

FUNCTION & QUALITY OF LIFE

Several studies in adults and adolescents quantitatively demonstrated the profound level of debility, poor quality of life, and impact of social stigma experienced in ME/CFS relative to other disabling diseases. New instrumentation was tested to discern reduced activity levels and the experience of stigma, and the association of various symptoms with levels of functional impairment was explored.

Kingdon, et al. found ME/CFS patients are more disabled than those with multiple sclerosis.

Knight, et al. found that adolescents with CFS have poorer quality of life, academic performance, and elevated school absence than their healthy peers.

Gleason, et al. assessed the effectiveness of several activity scales in identifying thresholds of reduced activity that discern patients from controls.

Strand, et al. demonstrated an association between pain and reduced physical functioning and quality of life in a well-characterized cohort.

McManimen, et al. demonstrated an association of suicidal ideation and depression with unsupportive social interactions, indicating that disease stigma may contribute to poor psychological health in some ME/CFS patients.

Terman, et al. generated a scale to measure the social stigma experienced by ME/CFS patients and found they experience high levels of stigma, including attribution of their disease to psychological causes, and resulting in social estrangement.

CBT & GET

2018 brought about a reckoning for the body of literature purporting efficacy of cognitive behavioral therapy (CBT) and graded exercises therapy (GET) as treatments for ME/CFS. Reanalysis of multiple CBT and GET trials identified major errors in the trial authors’ approaches, selected outcome measures, and failure to report harms, thereby undermining their claims of treatment efficacy. These reanalysis studies and the many opinion pieces that accompanied them are a critical step in balancing the scales of the literature base regarding these potentially harmful therapies and debunking the psychosomatic narrative that has dominated ME/CFS literature for decades. Their publication has also initiated ongoing review and modifications of the clinical recommendations broadcast by several major clinical education entities.

Sunnquist, et al. determined that patients meeting more stringent case definitions displayed a weaker connection between activity and impairment, suggesting inconsistency with the cognitive behavioral model that patients’ sickness beliefs and deconditioning lead to their experience of fatigue.

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 low recovery rates, contrary to what was originally reported by the trial authors.

A reanalysis of the FatigGo trial by Vink, et al. showed that study authors dismissed objective measures of activity in their results, thus illustrating that CBT was an ineffective treatment.

Broadbent, et al.’s pilot study of self-paced aquatic activity in 11 patients by showed improvements in several physical parameters and reductions in fatigue and pain without symptom exacerbation, indicating that low intensity self-paced activity may provide physical benefit.