Whole blood human transcriptome and virome analysis of ME/CFS patients experiencing post-exertional malaise following cardiopulmonary exercise testing.

Jérôme Bouquet ,Ruth R Miller ,Jennifer L Gardy ,Shoshana Parker ,Mark Vanness ,Miguel Uyaguari ,Wee‐Shian Chan ,Staci R Stevens ,Mark Mccabe ,James E Potts ,André Mattman ,Theodore S Steiner ,Tony Li ,Christopher R Snell ,Astrid-Marie De Souza ,Jared Stevens ,David M Patrick ,Patrick Tang ,Xiaoying Kang ,Muhammad Morshed ,Charles Y Chiu

doi:10.1371/journal.pone.0212193

Abstract

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a syndrome of unknown etiology characterized by profound fatigue exacerbated by physical activity, also known as post-exertional malaise (PEM). Previously, we did not detect evidence of immune dysregulation or virus reactivation outside of PEM periods. Here we sought to determine whether cardiopulmonary exercise stress testing of ME/CFS patients could trigger such changes. ME/CFS patients (n = 14) and matched sedentary controls (n = 11) were subjected to cardiopulmonary exercise on 2 consecutive days and followed up to 7 days post-exercise, and longitudinal whole blood samples analyzed by RNA-seq. Although ME/CFS patients showed significant worsening of symptoms following exercise versus controls, with 8 of 14 ME/CFS patients showing reduced oxygen consumption () on day 2, transcriptome analysis yielded only 6 differentially expressed gene (DEG) candidates when comparing ME/CFS patients to controls across all time points. None of the DEGs were related to immune signaling, and no DEGs were found in ME/CFS patients before and after exercise. Virome composition (P = 0.746 by chi-square test) and number of viral reads (P = 0.098 by paired t-test) were not significantly associated with PEM. These observations do not support transcriptionally-mediated immune cell dysregulation or viral reactivation in ME/CFS patients during symptomatic PEM episodes.

Highlights

Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) is characterized by longterm, debilitating fatigue that is characteristically exacerbated by physical and mental exertion [1,2]
The potential participants who were not enrolled included those who were lost to follow-up (n = 2), withdrew from the study prior to exercise testing (n = 2), were unable to participate due to the lack of eligible age-matched controls or cases (n = 26), declined to participate (n = 40, many who wished to avoid triggering symptoms of exercise-induced Post-exertional malaise (PEM)), or were ineligible according to Canadian Consensus Criteria because of the presence of an underlying illness precluding a diagnosis of ME/CFS (n = 41)
Seven out of the fifteen ME/CFS subjects had participated in a previous published study examining gene expression profiles in comparison to a matched control group [18]; the cardiopulmonary exercise testing (CPET) study was a separate study with its own enrollment cohort

Summary

Introduction

Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) is characterized by longterm, debilitating fatigue that is characteristically exacerbated by physical and mental exertion [1,2]. Several lines of evidence point toward a role for disordered immunity or inflammation These include disordered cytokine expression in serum [8] and cerebrospinal fluid [9], NK cell dysfunction [10] and promising response to early trials of B cell depletion [11]. These results suggest that irregularities in circulating immune cell subsets, and their gene expression, drive chonic autoimmune activation. Taken together these studies do not validate each other, but rather describe heterogeneous putative disease mechanisms [15]

Methods

Results

Conclusion