In a recent study published in Nature Communications, researchers explored the pathophysiological mechanisms of post-infectious (PI) myalgic encephalitis/chronic fatigue syndrome (ME/CFS).
Study: Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Image Credit: TORWAISTUDIO/Shutterstock.com
Background
ME/CFS is the term used commonly for a disorder of persistent disabling fatigue, malaise, exercise intolerance, physical symptoms, and cognitive complaints.
The physiological mechanisms underlying the persistence of fatigue and other symptoms remain undefined. Although physiological, immunological, and bioenergetic alterations have been described, most findings are inconsistent, and their clinical relevance is unknown.
As such, ME/CFS has no effective disease-modifying treatment; notably, developing/testing new treatments is impeded by the difficulty in defining cases and tracking responses through biomarkers or symptoms.
Further, symptoms are usually non-specific and overlap with other diseases. ME/CFS often follows an acute infection, i.e., PI-ME/CFS, with an estimated incidence of 10% to 12%.
The study and findings
The present study investigated the pathophysiological mechanisms underlying PI-ME/CFS. Seventeen PI-ME/CFS subjects and 21 healthy volunteers (HVs) were recruited. No group differences in sex, age, or body mass index (BMI) were observed.
Physical, psychological, and laboratory examinations found no clinically relevant findings. A 24-hour ambulatory electrocardiogram (ECG) revealed diminished heart rate variability in PI-ME/CFS subjects.
The increased heart rate in PI-ME/CFS subjects throughout the day suggested higher sympathetic activity. Besides, the diminished drop in their nighttime heart rate indicated reduced parasympathetic activity.
Reducing baroslope and prolonged blood pressure recovery following the Valsalva maneuver in PI-ME/CFS suggested reduced baroreflex-cardiovagal function. Overall, data indicated alterations in the autonomic tone.
Further, the proportion of hard-task choices (PHTC) metric was used to evaluate effort preference. There were no group differences in the probability of completing easy tasks. However, button-pressing speed declined over time in the PI-ME/CFS group.
Notably, HVs had higher odds of completing hard tasks, albeit the temporal decline in button-press rate was not different between groups for hard tasks.
Nine HVs and eight PI-ME/CFS subjects underwent cardiopulmonary exercise testing (CPET). Except for one PI-ME/CFS subject, all others reached the peak respiratory exchange ratio (≥ 1.1).
Gross mechanical efficiency and oxygen saturation levels in quadricep muscles were not different between groups. Peak heart rate, respiratory rate, and power were lower in PI-ME/CFS subjects by approximately 3.3 metabolic equivalent of task units.
One HV and five PI-ME/CFS subjects showed chronotropic incompetence. Resting salivary cortisol levels were not different between groups; however, cortisol levels were significantly reduced an hour after CPET in PI-ME/CFS participants, suggesting they were less likely to attain their maximal predicted output. In addition, there was evidence of muscular deconditioning in the PI-ME/CFS group.
Notably, no clinically meaningful between-group differences were observed in energy intake, total body energy use, respiratory quotient, and sleeping energy use pre- or post-CPET.
Furthermore, PI-ME/CFS subjects self-reported more cognitive complaints across all five domains tested. By contrast, no group differences were noted in the performance of any neuropsychological tests.
Additionally, PI-ME/CFS subjects showed significantly reduced levels of dihydroxyphenylglycine (DHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), and dihydroxyphenylalanine (DOPA) in the cerebrospinal fluid (CSF). Dopamine, cys-DOPA, and norepinephrine levels were not different between groups.
Dopamine correlated with time to failure, while norepinephrine correlated with effort preference and time to failure in PI-ME/CFS subjects.
DHPG correlated with effort preference in HVs. Metabolomic analysis of CSF revealed group differences, with tryptophan metabolites among the top 15 differentially expressed (DE).
Principal component analysis (PCA) of gene expression in peripheral blood mononuclear cells (PBMCs) revealed 614 DE genes, clustering by disease status. Further exploration indicated clustering based on sex.
The interactions between disease status and sex were insignificant. PCA of DE genes in female and male cohorts clustered samples into distinct PI-ME/CFS and HV groups.
Upregulated DE genes in male PI-ME/CFS subjects were related to the signal transducer and activator of transcription 4 (STAT4)–toll-like receptor 9 (TLR9) protein-protein interactome. DE genes in the B-cell interactome were upregulated in females with PI-ME/CFS.
PCA of serum and CSF aptamers did not identify differential features by disease status. However, within each sex, a subset of aptamers predicted PI-ME/CFS status.
PCA of muscle gene expression also revealed clustering by sex. In PI-ME/CFS males, upregulated genes were enriched in RNA processing and epigenetic changes, and downregulated genes were enriched in mitochondrial processes and hexose metabolism.
PI-ME/CFS females showed upregulation of genes enriched in ubiquitin transferase function, growth hormone receptor signaling, and downregulation of genes involved in mitochondrial processes and fatty acid oxidation.
No significant differences between HVs and PI-ME/CFS subjects were observed in plasma lipidomic data. There were differences in alpha diversity measured in stool samples; HVs showed higher taxa but without differences in the average proportional abundance.
Further, beta diversity showed significant differences in the composition of microbial communities between groups. Four PI-ME/CFS participants achieved spontaneous, full recovery within four years.
Conclusions
The study described a more extensive set of biological measures in PI-ME/CFS subjects than prior studies. PI-ME/CFS is characterized by centrally mediated somatic and cognitive perturbations, with fatigue defined by central autonomic dysfunction and effort preferences.
Additionally, distinct sex signatures of metabolic and immune dysregulation were observed, which suggested persistent antigenic stimulation. Overall, these findings will aid the discovery of potential therapeutic targets.
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