Joseph, Phillip, Arevalo, Carlo, Oliveira, Rudolf K F et al. · Chest · 2021 · DOI
This study used specialized heart and lung testing during exercise to understand why people with ME/CFS struggle with physical activity. Researchers found that ME/CFS patients had two different problems during exercise: some had reduced blood flow returning to the heart, while others couldn't efficiently extract oxygen from their blood. About 31% of patients also showed evidence of small nerve fiber damage in their skin biopsies.
This research provides objective physiological evidence for two distinct mechanisms of exercise intolerance in ME/CFS, moving beyond functional descriptions to identify measurable abnormalities in cardiac output and oxygen utilization. The identification of a subgroup with small fiber pathology suggests potential neuropathic contributions to exertional dysfunction, opening avenues for mechanistically targeted interventions. These findings validate that ME/CFS exertional intolerance has biological underpinnings rather than purely psychological causes.
This study does not establish causation between small fiber neuropathy and exertional intolerance, as the severity of nerve fiber denervation did not correlate with exercise limitation measures. It does not determine whether the observed neurovascular abnormalities cause ME/CFS or result from it, nor does it prove these mechanisms apply to all ME/CFS patients. The study population was selected from those undergoing clinical iCPET, which may not represent the broader ME/CFS patient population.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
The first block is for the primary paper and is the citation you should use in research work. The atlas-snapshot line only applies if you are specifically referring to this atlas’s reading of the paper on the date shown.
Primary citation
Joseph, Phillip, Arevalo, Carlo, Oliveira, Rudolf K F, Faria-Urbina, Mariana, Felsenstein, Donna, Oaklander, Anne Louise, et al. (2021). Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.. Chest. https://doi.org/10.1016/j.chest.2021.01.082
BibTeX
@article{mecfsatlas-joseph-2021-insights-invasive,
author = {Joseph, Phillip and Arevalo, Carlo and Oliveira, Rudolf K F and Faria-Urbina, Mariana and Felsenstein, Donna and Oaklander, Anne Louise and Systrom, David M},
title = {Insights From Invasive Cardiopulmonary Exercise Testing of Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.},
journal = {Chest},
year = {2021},
doi = {10.1016/j.chest.2021.01.082},
note = {PubMed: 33577778},
url = {https://www.mecfsatlas.com/evidence/joseph-2021-insights-invasive},
}Atlas snapshot reference
ME/CFS Atlas. Generator v1 / Scanner v1.4 / policy v0.1. Accessed 2026-05-26. https://www.mecfsatlas.com/evidence/joseph-2021-insights-invasive
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