{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:53:04Z","timestamp":1791849184756,"version":"4.3.4"},"reference-count":36,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Patients with COVID-19 present with a variety of clinical manifestations, ranging from mild or asymptomatic disease to severe illness and death. Whilst previous studies have clarified these and several other aspects of COVID-19, one of the ongoing challenges regarding COVID-19 is to determine which patients are at risk of adverse outcomes of COVID-19 infection. It is hypothesized that this is the result of insufficient inhibition of the immune response, with the vagus nerve being an important neuro-immuno-modulator of inflammation. Vagus nerve activity can be non-invasively indexed by heart-rate-variability (HRV). Therefore, we aimed to assess the prognostic value of HRV, as a surrogate marker for vagus nerve activity, in predicting mortality and intensive care unit (ICU) referral, in patients hospitalized with COVID-19.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>A retrospective cohort study including all consecutive patients (n = 271) diagnosed and hospitalized with COVID-19 between March 2020 and May 2020, without a history of cardiac arrhythmias (including atrial and ventricular premature contractions), pacemaker, or current bradycardia (heart rate &lt;50 bpm) or tachycardia (heart rate &gt;110 bpm). HRV was based on one 10s ECG recorded at admission. 3-week survival and ICU referral were examined.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>HRV indexed as standard deviation of normal to normal heartbeat intervals (SDNN) predicted survival (H.R. = 0.53 95%CI: 0.31\u20130.92). This protective role was observed only in patients aged 70 years and older, not in younger patients. HRV below median value also predicted ICU referral within the first week of hospitalization (H.R = 0.51, 95%CI: 0.29\u20130.90, P = 0.021).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Higher HRV predicts greater chances of survival, especially in patients aged 70 years and older with COVID-19, independent of major prognostic factors. Low HRV predicts ICU indication and admission in the first week after hospitalization.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0258841","type":"journal-article","created":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T17:41:33Z","timestamp":1635442893000},"page":"e0258841","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":110,"title":["Heart-rate-variability (HRV), predicts outcomes in COVID-19"],"prefix":"10.1371","volume":"16","author":[{"given":"Maartje B. A.","family":"Mol","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7116-4465","authenticated-orcid":true,"given":"Maud T. A.","family":"Strous","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frits H. M.","family":"van Osch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F. Jeroen","family":"Vogelaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7185-9491","authenticated-orcid":true,"given":"Dennis G.","family":"Barten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3041-4872","authenticated-orcid":true,"given":"Moshe","family":"Farchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert A.","family":"Foudraine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yori","family":"Gidron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"pone.0258841.ref001","doi-asserted-by":"crossref","first-page":"m1036","DOI":"10.1136\/bmj.m1036","article-title":"Covid-19: WHO declares pandemic because of \"alarming levels\" of spread, severity, and inaction","volume":"368","author":"E. Mahase","year":"2020","journal-title":"Bmj"},{"key":"pone.0258841.ref002","unstructured":"Organization WH. WHO Coronavirus Disease (COVID-19) Dashboard 2020. Available from: https:\/\/covid19.who.int\/, accessed on 27.01.2020"},{"issue":"2","key":"pone.0258841.ref003","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1111\/joim.13091","article-title":"COVID-19 diagnosis and management: a comprehensive review","volume":"288","author":"G Pascarella","year":"2020","journal-title":"J Intern Med"},{"key":"pone.0258841.ref004","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12575-020-00128-2","article-title":"A comprehensive review of COVID-19 characteristics","volume":"22","author":"H Esakandari","year":"2020","journal-title":"Biol Proced Online"},{"key":"pone.0258841.ref005","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.3389\/fimmu.2020.01441","article-title":"Immune Response, Inflammation, and the Clinical Spectrum of COVID-19","volume":"11","author":"LF Garc\u00eda","year":"2020","journal-title":"Front Immunol"},{"issue":"6","key":"pone.0258841.ref006","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.ihj.2020.11.007","article-title":"A systematic review of ECG findings in patients with COVID-19","volume":"72","author":"E Mehraeen","year":"2020","journal-title":"Indian Heart Journal"},{"issue":"12","key":"pone.0258841.ref007","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/nrendo.2012.189","article-title":"The vagus nerve and the inflammatory reflex\u2014linking immunity and metabolism","volume":"8","author":"VA Pavlov","year":"2012","journal-title":"Nat Rev Endocrinol"},{"issue":"22","key":"pone.0258841.ref008","doi-asserted-by":"crossref","first-page":"9471","DOI":"10.1523\/JNEUROSCI.18-22-09471.1998","article-title":"Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins","volume":"18","author":"M Ek","year":"1998","journal-title":"J Neurosci"},{"issue":"6052","key":"pone.0258841.ref009","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1126\/science.1209985","article-title":"Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit","volume":"334","author":"M Rosas-Ballina","year":"2011","journal-title":"Science"},{"issue":"1","key":"pone.0258841.ref010","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1111\/j.1600-065X.2012.01138.x","article-title":"Rethinking inflammation: neural circuits in the regulation of immunity","volume":"248","author":"PS Olofsson","year":"2012","journal-title":"Immunol Rev"},{"issue":"1\u20132","key":"pone.0258841.ref011","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jneuroim.2013.04.011","article-title":"Vagal nerve activity as a moderator of brain-immune relationships","volume":"260","author":"H Ohira","year":"2013","journal-title":"J Neuroimmunol"},{"issue":"6","key":"pone.0258841.ref012","article-title":"Laboratory Diagnosis of COVID-19: Current Issues and Challenges","volume":"58","author":"YW Tang","year":"2020","journal-title":"J Clin Microbiol"},{"issue":"3","key":"pone.0258841.ref013","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.stem.2014.02.008","article-title":"Dietary and metabolic control of stem cell function in physiology and cancer","volume":"14","author":"MM Mihaylova","year":"2014","journal-title":"Cell Stem Cell"},{"issue":"1","key":"pone.0258841.ref014","doi-asserted-by":"crossref","first-page":"46","DOI":"10.7453\/gahmj.2014.073","article-title":"Heart Rate Variability: New Perspectives on Physiological Mechanisms, Assessment of Self-regulatory Capacity, and Health risk","volume":"4","author":"R McCraty","year":"2015","journal-title":"Glob Adv Health Med"},{"key":"pone.0258841.ref015","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.3389\/fpsyg.2014.01040","article-title":"A healthy heart is not a metronome: an integrative review of the heart\u2019s anatomy and heart rate variability","volume":"5","author":"F Shaffer","year":"2014","journal-title":"Front Psychol"},{"issue":"2","key":"pone.0258841.ref016","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1177\/1751143719853744","article-title":"Heart rate variability: Measurement and emerging use in critical care medicine","volume":"21","author":"BW Johnston","year":"2020","journal-title":"J Intensive Care Soc"},{"issue":"1","key":"pone.0258841.ref017","doi-asserted-by":"crossref","first-page":"10233","DOI":"10.1038\/s41598-021-88882-5","article-title":"Author Correction: Direct measurement of vagal tone in rats does not show correlation to HRV.","volume":"11","author":"JT Marmerstein","year":"2021","journal-title":"Scientific Reports."},{"issue":"8","key":"pone.0258841.ref018","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1111\/j.1540-8167.2005.40656.x","article-title":"Regression analysis between heart rate variability and baroreflex-related vagus nerve activity in rats","volume":"16","author":"TB Kuo","year":"2005","journal-title":"J Cardiovasc Electrophysiol"},{"key":"pone.0258841.ref019","doi-asserted-by":"crossref","first-page":"258","DOI":"10.3389\/fpubh.2017.00258","article-title":"An Overview of Heart Rate Variability Metrics and Norms","volume":"5","author":"F Shaffer","year":"2017","journal-title":"Front Public Health"},{"issue":"7","key":"pone.0258841.ref020","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1042\/CS20110299","article-title":"You may need the vagus nerve to understand pathophysiology and to treat diseases","volume":"122","author":"M De Couck","year":"2012","journal-title":"Clin Sci (Lond)."},{"issue":"1\u20132","key":"pone.0258841.ref021","doi-asserted-by":"crossref","first-page":"e34","DOI":"10.1093\/milmed\/usaa405","article-title":"Heart Rate Variability as a Possible Predictive Marker for Acute Inflammatory Response in COVID-19 Patients","volume":"186","author":"F Hasty","year":"2021","journal-title":"Military Medicine."},{"issue":"3","key":"pone.0258841.ref022","doi-asserted-by":"crossref","first-page":"e0249128","DOI":"10.1371\/journal.pone.0249128","article-title":"Is the heart rate variability monitoring using the analgesia nociception index a predictor of illness severity and mortality in critically ill patients with COVID-19? A pilot study","volume":"16","author":"C Arag\u00f3n-Bened\u00ed","year":"2021","journal-title":"PLOS ONE"},{"key":"pone.0258841.ref023","unstructured":"WHO. Global COVID-19 Clinical Platform: Rapid core case report form (CRF) 2020. Available from: https:\/\/www.who.int\/publications\/i\/item\/WHO-2019-nCoV-Clinical_CRF-2020.4, accessed on 02.03.2020."},{"key":"pone.0258841.ref024","doi-asserted-by":"crossref","DOI":"10.1109\/CIC.2015.7410984","article-title":"Simple and Reliable Measure of Heart Rate Variability using Relative RR Intervals","author":"M. Vollmer","year":"2015"},{"key":"pone.0258841.ref025","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.autneu.2016.11.003","article-title":"Effects of short and prolonged transcutaneous vagus nerve stimulation on heart rate variability in healthy subjects","volume":"203","author":"M De Couck","year":"2017","journal-title":"Auton Neurosci"},{"issue":"2","key":"pone.0258841.ref026","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/j.1542-474X.2011.00417.x","article-title":"Reliability of Ultra-Short ECG Indices for Heart Rate Variability","volume":"16","author":"U Nussinovitch","year":"2011","journal-title":"Annals of Noninvasive Electrocardiology"},{"key":"pone.0258841.ref027","doi-asserted-by":"crossref","first-page":"424","DOI":"10.3389\/fphys.2018.00424","article-title":"Normal Values of Corrected Heart-Rate Variability in 10-Second Electrocardiograms for All Ages","volume":"9","author":"ME van den Berg","year":"2018","journal-title":"Front Physiol."},{"issue":"5","key":"pone.0258841.ref028","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.3892\/or.2013.2725","article-title":"The relationship between vagal nerve activity and clinical outcomes in prostate and non-small cell lung cancer patients","volume":"30","author":"M De Couck","year":"2013","journal-title":"Oncol Rep"},{"issue":"9","key":"pone.0258841.ref029","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1590\/S0100-879X2005000900007","article-title":"Effects of age and physical activity on the autonomic control of heart rate in healthy men","volume":"38","author":"RC Melo","year":"2005","journal-title":"Braz J Med Biol Res"},{"issue":"5","key":"pone.0258841.ref030","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1197\/j.aem.2006.12.015","article-title":"Characteristics of heart rate variability can predict impending septic shock in emergency department patients with sepsis","volume":"14","author":"WL Chen","year":"2007","journal-title":"Acad Emerg Med"},{"issue":"15","key":"pone.0258841.ref031","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/cid\/ciaa248","article-title":"Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China","volume":"71","author":"C Qin","year":"2020","journal-title":"Clin Infect Dis"},{"issue":"5","key":"pone.0258841.ref032","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1038\/s41418-020-0530-3","article-title":"COVID-19 infection: the perspectives on immune responses","volume":"27","author":"Y Shi","year":"2020","journal-title":"Cell Death Differ"},{"issue":"2313","key":"pone.0258841.ref033","article-title":"COVID-19: In the Eye of the Cytokine Storm","volume":"11","author":"R de la Rica","year":"2020","journal-title":"Frontiers in Immunology"},{"key":"pone.0258841.ref034","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.canep.2015.11.007","article-title":"Vagal nerve activity predicts overall survival in metastatic pancreatic cancer, mediated by inflammation","volume":"40","author":"M De Couck","year":"2016","journal-title":"Cancer Epidemiol."},{"issue":"3","key":"pone.0258841.ref035","first-page":"H946","article-title":"Dynamic heart rate variability: a tool for exploring sympathovagal balance continuously during sleep in men","volume":"275","author":"H Otzenberger","year":"1998","journal-title":"Am J Physiol"},{"issue":"3","key":"pone.0258841.ref036","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1111\/head.12649","article-title":"Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part III","volume":"56","author":"H Yuan","year":"2016","journal-title":"Headache"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0258841","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T17:42:00Z","timestamp":1635442920000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0258841"}},"subtitle":[],"editor":[{"given":"Elena G.","family":"Tolkacheva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,10,28]]},"references-count":36,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0258841","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,28]]}}}