{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T15:26:16Z","timestamp":1784215576649,"version":"3.55.0"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T00:00:00Z","timestamp":1614211200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["203930\/B\/16\/Z"],"award-info":[{"award-number":["203930\/B\/16\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010414","name":"Health Research Board","doi-asserted-by":"publisher","award":["203930\/B\/16\/Z"],"award-info":[{"award-number":["203930\/B\/16\/Z"]}],"id":[{"id":"10.13039\/100010414","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>The long-term clinical and physiological consequences of COVID-19 infection remain unclear. While fatigue has emerged as a common symptom following infection, little is known about its links with autonomic dysfunction. SARS-CoV-2 is known to infect endothelial cells in acute infection, resulting in autonomic dysfunction. Here we set out to test the hypothesis that this results in persistent autonomic dysfunction and is associated with post-COVID fatigue in convalescent patients.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Methods<\/jats:title><jats:p>We recruited 20 fatigued and 20 non-fatigued post-COVID patients (median age 44.5 years, 36\/40 (90%) female, median time to follow up 166.5 days). Fatigue was assessed using the Chalder Fatigue Scale. These underwent the Ewing\u2019s autonomic function test battery, including deep breathing, active standing, Valsalva manoeuvre and cold-pressor testing, with continuous electrocardiogram and blood pressure monitoring, as well as near-infrared spectroscopy-based cerebral oxygenation. 24-hour ambulatory blood pressure monitoring was also conducted, and patients completed the generalised anxiety disorder-7 questionnaire. We assessed between-group differences in autonomic function test results and used unadjusted and adjusted linear regression to investigate the relationship between fatigue, anxiety, and autonomic test results.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Results<\/jats:title><jats:p>We found no pathological differences between fatigued and non-fatigued patients on autonomic testing or on 24-hour blood pressure monitoring. Symptoms of orthostatic intolerance were reported by 70% of the fatigued cohort at the time of active standing, with no associated physiological abnormality detected. Fatigue was strongly associated with increased anxiety (p &lt;0.001), with no patients having a pre-existing diagnosis of anxiety.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Conclusions<\/jats:title><jats:p>These results demonstrate the significant burden of fatigue, symptoms of autonomic dysfunction and anxiety in the aftermath of COVID-19 infection, but reassuringly do not demonstrate pathological findings on autonomic testing.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0247280","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T19:00:12Z","timestamp":1614279612000},"page":"e0247280","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":83,"title":["Fatigue following COVID-19 infection is not associated with autonomic dysfunction"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7089-0665","authenticated-orcid":true,"given":"Liam","family":"Townsend","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Moloney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciaran","family":"Finucane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"McCarthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colm","family":"Bergin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciaran","family":"Bannan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose-Anne","family":"Kenny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,2,25]]},"reference":[{"key":"pone.0247280.ref001","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study","author":"F Zhou","year":"2020","journal-title":"The lancet"},{"key":"pone.0247280.ref002","article-title":"Prevalence of smell and taste dysfunction in a cohort of CoVID19 outpatients managed through remote consultation from a large urban teaching hospital in Dublin, Ireland","volume":"100076","author":"C Kerr","year":"2020","journal-title":"Infection Prevention in Practice"},{"issue":"10223","key":"pone.0247280.ref003","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S0140-6736(20)30211-7","article-title":"Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study","volume":"395","author":"N Chen","year":"2020","journal-title":"The Lancet"},{"key":"pone.0247280.ref004","article-title":"COVID-19 Coagulopathy in Caucasian patients","author":"H Fogarty","year":"2020","journal-title":"British Journal of Haematology"},{"key":"pone.0247280.ref005","article-title":"Complex immune dysregulation in COVID-19 patients with severe respiratory failure","author":"EJ Giamarellos-Bourboulis","year":"2020","journal-title":"Cell host & microbe"},{"key":"pone.0247280.ref006","doi-asserted-by":"crossref","first-page":"m3026","DOI":"10.1136\/bmj.m3026","article-title":"Management of post-acute covid-19 in primary care","volume":"370","author":"T Greenhalgh","year":"2020","journal-title":"BMJ"},{"key":"pone.0247280.ref007","article-title":"Persistent symptoms in patients after acute COVID-19","author":"A Carf\u00ec","year":"2020","journal-title":"JAMA"},{"issue":"11","key":"pone.0247280.ref008","doi-asserted-by":"crossref","first-page":"e0240784","DOI":"10.1371\/journal.pone.0240784","article-title":"Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection","volume":"15","author":"L Townsend","year":"2020","journal-title":"Plos one"},{"issue":"7461","key":"pone.0247280.ref009","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1136\/bmj.329.7461.336","article-title":"Neurocardiogenic syncope","volume":"329","author":"C Chen-Scarabelli","year":"2004","journal-title":"Bmj"},{"issue":"1","key":"pone.0247280.ref010","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s10286-017-0452-4","article-title":"Infectious diseases causing autonomic dysfunction","volume":"28","author":"FJ Carod-Artal","year":"2018","journal-title":"Clinical Autonomic Research"},{"issue":"8","key":"pone.0247280.ref011","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1001\/archpediatrics.2011.124","article-title":"Autonomic symptoms at baseline and following infectious mononucleosis in a prospective cohort of adolescents","volume":"165","author":"BZ Katz","year":"2011","journal-title":"Archives of pediatrics & adolescent medicine"},{"key":"pone.0247280.ref012","first-page":"1","article-title":"A case report of postural tachycardia syndrome after COVID-19","author":"MG Miglis","year":"2020","journal-title":"Clinical Autonomic Research"},{"issue":"10234","key":"pone.0247280.ref013","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/S0140-6736(20)30937-5","article-title":"Endothelial cell infection and endotheliitis in COVID-19","volume":"395","author":"Z Varga","year":"2020","journal-title":"The Lancet"},{"issue":"1","key":"pone.0247280.ref014","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13054-020-03062-7","article-title":"The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection","volume":"24","author":"S Pons","year":"2020","journal-title":"Critical care"},{"key":"pone.0247280.ref015","article-title":"Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)?","author":"A Huertas","year":"2020","journal-title":"Eur Respiratory Soc"},{"issue":"1","key":"pone.0247280.ref016","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1186\/s12985-015-0446-6","article-title":"Middle East respiratory syndrome coronavirus infection: virus-host cell interactions and implications on pathogenesis","volume":"12","author":"J Zhou","year":"2015","journal-title":"Virology journal"},{"issue":"1","key":"pone.0247280.ref017","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ijcard.2004.06.022","article-title":"Tachycardia amongst subjects recovering from severe acute respiratory syndrome (SARS)","volume":"100","author":"S-T Lau","year":"2005","journal-title":"International journal of cardiology"},{"issue":"964","key":"pone.0247280.ref018","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1136\/pgmj.2005.037515","article-title":"Cardiovascular complications of severe acute respiratory syndrome","volume":"82","author":"C Yu","year":"2006","journal-title":"Postgraduate medical journal"},{"key":"pone.0247280.ref019","article-title":"6-month consequences of COVID-19 in patients discharged from hospital: a cohort study","author":"C Huang","year":"2021","journal-title":"The Lancet"},{"issue":"3","key":"pone.0247280.ref020","doi-asserted-by":"crossref","first-page":"M146","DOI":"10.1093\/gerona\/56.3.M146","article-title":"Frailty in older adults: evidence for a phenotype","volume":"56","author":"LP Fried","year":"2001","journal-title":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences"},{"issue":"4","key":"pone.0247280.ref021","first-page":"373","article-title":"World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects","volume":"79","author":"WM Association","year":"2001","journal-title":"Bulletin of the World Health Organization"},{"issue":"2","key":"pone.0247280.ref022","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1136\/jnnp.54.2.153","article-title":"Cognitive behaviour therapy in chronic fatigue syndrome","volume":"54","author":"S Butler","year":"1991","journal-title":"Journal of Neurology, Neurosurgery & Psychiatry"},{"issue":"2","key":"pone.0247280.ref023","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0022-3999(93)90081-P","article-title":"Development of a fatigue scale","volume":"37","author":"T Chalder","year":"1993","journal-title":"Journal of psychosomatic research"},{"issue":"1","key":"pone.0247280.ref024","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1093\/occmed\/kqu168","article-title":"The Chalder fatigue scale (CFQ 11)","volume":"65","author":"C Jackson","year":"2015","journal-title":"Occupational Medicine"},{"issue":"5","key":"pone.0247280.ref025","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S0022-3999(98)00022-1","article-title":"Exploring the validity of the Chalder Fatigue scale in chronic fatigue syndrome","volume":"45","author":"R Morriss","year":"1998","journal-title":"Journal of psychosomatic research"},{"issue":"1","key":"pone.0247280.ref026","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0022-3999(97)00291-2","article-title":"Fatigue in the general Norwegian population: normative data and associations","volume":"45","author":"JH Loge","year":"1998","journal-title":"Journal of psychosomatic research"},{"issue":"1","key":"pone.0247280.ref027","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1093\/occmed\/kql169","article-title":"The general health questionnaire","volume":"57","author":"C Jackson","year":"2007","journal-title":"Occupational medicine"},{"issue":"10","key":"pone.0247280.ref028","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1001\/archinte.166.10.1092","article-title":"A brief measure for assessing generalized anxiety disorder: the GAD-7","volume":"166","author":"RL Spitzer","year":"2006","journal-title":"Archives of internal medicine"},{"issue":"5","key":"pone.0247280.ref029","doi-asserted-by":"crossref","first-page":"317","DOI":"10.7326\/0003-4819-146-5-200703060-00004","article-title":"Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection","volume":"146","author":"K Kroenke","year":"2007","journal-title":"Annals of internal medicine"},{"issue":"3","key":"pone.0247280.ref030","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.jad.2010.07.010","article-title":"Validity of the GAD-7 scale as an outcome measure of disability in patients with generalized anxiety disorders in primary care","volume":"128","author":"MA Ruiz","year":"2011","journal-title":"Journal of affective disorders"},{"issue":"5","key":"pone.0247280.ref031","doi-asserted-by":"crossref","first-page":"491","DOI":"10.2337\/diacare.8.5.491","article-title":"The value of cardiovascular autonomic function tests: 10 years experience in diabetes","volume":"8","author":"DJ Ewing","year":"1985","journal-title":"Diabetes care"},{"key":"pone.0247280.ref032","first-page":"1","article-title":"A practical guide to active stand testing and analysis using continuous beat-to-beat non-invasive blood pressure monitoring","author":"C Finucane","year":"2019","journal-title":"Clinical Autonomic Research"},{"key":"pone.0247280.ref033","doi-asserted-by":"crossref","unstructured":"Soraghan CJ, Fan CW, Hayakawa T, Cronin H, Foran T, Boyle G, et al., editors. TILDA Signal Processing Framework (SPF) for the analysis of BP responses to standing in epidemiological and clinical studies. IEEE-EMBS international conference on biomedical and health informatics (BHI); 2014: IEEE.","DOI":"10.1109\/BHI.2014.6864483"},{"issue":"5","key":"pone.0247280.ref034","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1161\/CIRCRESAHA.116.308577","article-title":"Speed of heart rate recovery in response to orthostatic challenge","volume":"119","author":"C McCrory","year":"2016","journal-title":"Circulation research"},{"issue":"7","key":"pone.0247280.ref035","doi-asserted-by":"crossref","first-page":"e014688","DOI":"10.1161\/JAHA.119.014688","article-title":"Blood pressure drop rate after standing up is associated with frailty and number of falls in geriatric outpatients","volume":"9","author":"A Mol","year":"2020","journal-title":"Journal of the American Heart Association"},{"issue":"6","key":"pone.0247280.ref036","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s10286-013-0214-x","article-title":"Cognitive function is associated with impaired heart rate variability in ageing adults: the Irish longitudinal study on ageing wave one results","volume":"23","author":"J Frewen","year":"2013","journal-title":"Clinical Autonomic Research"},{"issue":"4","key":"pone.0247280.ref037","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1093\/gerona\/glt111","article-title":"Impaired systolic blood pressure recovery directly after standing predicts mortality in older falls clinic patients","volume":"69","author":"J Lagro","year":"2014","journal-title":"Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences"},{"issue":"8","key":"pone.0247280.ref038","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1093\/qjmed\/hcm057","article-title":"Symptoms of autonomic dysfunction in chronic fatigue syndrome","volume":"100","author":"J Newton","year":"2007","journal-title":"QJM: An International Journal of Medicine"},{"issue":"1","key":"pone.0247280.ref039","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12967-019-02184-z","article-title":"Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome\/myalgic encephalomyelitis","volume":"18","author":"RM Escorihuela","year":"2020","journal-title":"Journal of translational medicine"},{"issue":"9","key":"pone.0247280.ref040","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s11910-015-0583-8","article-title":"Postural tachycardia syndrome: beyond orthostatic intolerance","volume":"15","author":"EM Garland","year":"2015","journal-title":"Current neurology and neuroscience reports"},{"key":"pone.0247280.ref041","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.autneu.2018.02.005","article-title":"Postural tachycardia syndrome\u2013diagnosis, physiology, and prognosis","volume":"215","author":"AC Arnold","year":"2018","journal-title":"Autonomic Neuroscience"},{"key":"pone.0247280.ref042","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.cnp.2020.01.003","article-title":"Cerebral blood flow is reduced in ME\/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography","volume":"5","author":"CLM van Campen","year":"2020","journal-title":"Clinical Neurophysiology Practice"},{"issue":"4","key":"pone.0247280.ref043","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1067\/mpd.2002.122725","article-title":"Impaired postural cerebral hemodynamics in young patients with chronic fatigue with and without orthostatic intolerance","volume":"140","author":"H Tanaka","year":"2002","journal-title":"The Journal of pediatrics"},{"key":"pone.0247280.ref044","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/B978-0-323-44733-1.00136-X","volume-title":"Cardiac Electrophysiology: From Cell to Bedside","author":"GG Gino Seravalle","year":"2018","edition":"7"},{"key":"pone.0247280.ref045","doi-asserted-by":"crossref","DOI":"10.1007\/s00134-008-1294-2","volume-title":"Valsalva, Valsalva, may you give me a clue, who needs fluids in my ICU?","author":"S Rehberg","year":"2009"},{"key":"pone.0247280.ref046","unstructured":"Townsend L, Dowds J, O\u2019Brien K, Sheill G, Dyer AH, O\u2019Kelly B, et al. Persistent Poor Health Post-COVID-19 Is Not Associated with Respiratory Complications or Initial Disease Severity. Annals of the American Thoracic Society. (ja)."},{"key":"pone.0247280.ref047","doi-asserted-by":"crossref","unstructured":"Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, et al. Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App. medRxiv. 2020.","DOI":"10.1101\/2020.10.19.20214494"},{"issue":"3","key":"pone.0247280.ref048","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/papt.12118","article-title":"Anxiety and depression in chronic fatigue syndrome\/myalgic encephalomyelitis (CFS\/ME): examining the incidence of health anxiety in CFS\/ME","volume":"90","author":"J Daniels","year":"2017","journal-title":"Psychology and Psychotherapy: Theory, Research and Practice"},{"issue":"1","key":"pone.0247280.ref049","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ijchp.2019.11.003","article-title":"Prevalence and treatment of Chronic Fatigue Syndrome\/Myalgic Encephalomyelitis and co-morbid severe health anxiety","volume":"20","author":"J Daniels","year":"2020","journal-title":"International Journal of Clinical and Health Psychology"},{"key":"pone.0247280.ref050","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.autneu.2016.10.004","article-title":"The genesis and presentation of anxiety in disorders of autonomic overexcitation","volume":"203","author":"AP Owens","year":"2017","journal-title":"Autonomic Neuroscience"},{"issue":"6","key":"pone.0247280.ref051","doi-asserted-by":"crossref","first-page":"e0198594","DOI":"10.1371\/journal.pone.0198594","article-title":"Fatigue symptoms in relation to neuroticism, anxiety-depression, and musculoskeletal pain. A longitudinal twin study","volume":"13","author":"O Vassend","year":"2018","journal-title":"PloS one"},{"key":"pone.0247280.ref052","doi-asserted-by":"crossref","first-page":"420","DOI":"10.3389\/fpubh.2020.00420","article-title":"The Economic Impacts of Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome in an Australian Cohort","volume":"8","author":"S Close","year":"2020","journal-title":"Frontiers in Public Health"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247280","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T00:44:59Z","timestamp":1671410699000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247280"}},"subtitle":[],"editor":[{"given":"Antonio","family":"Palaz\u00f3n-Bru","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,2,25]]},"references-count":52,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0247280","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,25]]}}}