{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T22:17:32Z","timestamp":1778710652093,"version":"3.51.4"},"reference-count":74,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T00:00:00Z","timestamp":1647302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000030","name":"Centers for Disease Control and Prevention","doi-asserted-by":"publisher","award":["PRJ92HL"],"award-info":[{"award-number":["PRJ92HL"]}],"id":[{"id":"10.13039\/100000030","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"\nBackground<\/jats:title>\nCardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear.<\/jats:p>\n<\/jats:sec>\n\nPurpose<\/jats:title>\nTo characterize and compare exercise responses in ME\/CFS and controls with and without matching for aerobic fitness.<\/jats:p>\n<\/jats:sec>\n\nMethods<\/jats:title>\nAs part of the Multi-site Clinical Assessment of ME\/CFS (MCAM) study, 403 participants (n = 214 ME\/CFS; n = 189 controls), across six ME\/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent (V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>E<\/mml:mi>\/<\/mml:mo>V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>O<\/mml:mi>2<\/mml:mn><\/mml:msub><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula>, V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>E<\/mml:mi>\/<\/mml:mo>V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>C<\/mml:mi>O<\/mml:mi>2<\/mml:mn><\/mml:msub><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula>), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges\u2019 g<\/jats:italic> effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20\u2013100% peak V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>O<\/mml:mi>2<\/mml:mn><\/mml:msub><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula>). Subgroup analyses were conducted for 198 participants (99 ME\/CFS; 99 controls) matched for age (\u00b15 years) and peak V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>O<\/mml:mi>2<\/mml:mn><\/mml:msub><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula> (~1 ml\/kg\/min-1<\/jats:sup>).<\/jats:p>\n<\/jats:sec>\n\nResults<\/jats:title>\nNinety percent of tests (n = 194 ME\/CFS, n = 169 controls) met standard criteria for peak effort. ME\/CFS responses during exercise (20\u2013100% peak V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>O<\/mml:mi>2<\/mml:mn><\/mml:msub><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula>) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>E<\/mml:mi>\/<\/mml:mo>V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>O<\/mml:mi>2<\/mml:mn><\/mml:msub><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula>, V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>E<\/mml:mi>\/<\/mml:mo>V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>C<\/mml:mi>O<\/mml:mi>2<\/mml:mn><\/mml:msub><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula> and RPE (p<\/jats:italic><0.05adjusted<\/jats:sub>). For the fitness-matched subgroup, differences remained for breathing frequency, V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>E<\/mml:mi>\/<\/mml:mo>V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>O<\/mml:mi>2<\/mml:mn><\/mml:msub><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula>, V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>E<\/mml:mi>\/<\/mml:mo>V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>C<\/mml:mi>O<\/mml:mi>2<\/mml:mn><\/mml:msub><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula>, and RPE (p<\/jats:italic><0.05adjusted<\/jats:sub>), and higher tidal volumes were identified for ME\/CFS (p<\/jats:italic><0.05adjusted<\/jats:sub>). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>E<\/mml:mi>\/<\/mml:mo>V<\/mml:mi>\u02d9<\/mml:mo><\/mml:mover>C<\/mml:mi>O<\/mml:mi>2<\/mml:mn>n<\/mml:mi>a<\/mml:mi>d<\/mml:mi>i<\/mml:mi>r<\/mml:mi><\/mml:mrow><\/mml:msub><\/mml:mrow><\/mml:math><\/jats:alternatives><\/jats:inline-formula>) were generally reflective of those seen throughout exercise (i.e., 20\u2013100%).<\/jats:p>\n<\/jats:sec>\n\nConclusion<\/jats:title>\nCompared to fitness-matched controls, cardiopulmonary responses to exercise in ME\/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME\/CFS.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0265315","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T17:37:48Z","timestamp":1647365868000},"page":"e0265315","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS): A Multi-site Clinical Assessment of ME\/CFS (MCAM) sub-study"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3992-4820","authenticated-orcid":true,"given":"Dane B.","family":"Cook","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"VanRiper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan J.","family":"Dougherty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob B.","family":"Lindheimer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9348-6676","authenticated-orcid":true,"given":"Michael J.","family":"Falvo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin-Mann S.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth R.","family":"Unger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"The MCAM Study Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,3,15]]},"reference":[{"issue":"3","key":"pone.0265315.ref001","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1136\/jnnp.69.3.302","article-title":"Strength and physiological response to exercise in patients with chronic fatigue syndrome","volume":"69","author":"KY Fulcher","year":"2000","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"10","key":"pone.0265315.ref002","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1002\/art.22124","article-title":"The influence of aerobic fitness and fibromyalgia on cardiorespiratory and perceptual responses to exercise in patients with chronic fatigue syndrome.","volume":"54","author":"DB Cook","year":"2006","journal-title":"Arthritis & Rheumatology."},{"issue":"6","key":"pone.0265315.ref003","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1249\/MSS.0b013e3182417b9a","article-title":"Responses to exercise differ for chronic fatigue syndrome patients with fibromyalgia","volume":"44","author":"DB Cook","year":"2012","journal-title":"Medicine and science in sports and exercise"},{"issue":"9","key":"pone.0265315.ref004","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1093\/milmed\/168.9.750","article-title":"Aerobic capacity of Gulf War veterans with chronic fatigue syndrome.","volume":"168","author":"PR Nagelkirk","year":"2003","journal-title":"Military medicine."},{"issue":"21","key":"pone.0265315.ref005","doi-asserted-by":"crossref","first-page":"3270","DOI":"10.1001\/archinte.160.21.3270","article-title":"Exercise capacity in chronic fatigue syndrome","volume":"160","author":"P De Becker","year":"2000","journal-title":"Arch Intern Med"},{"issue":"9","key":"pone.0265315.ref006","first-page":"1463","article-title":"Physiological responses to incremental exercise in patients with chronic fatigue syndrome. 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