{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:05:45Z","timestamp":1791335145413,"version":"4.3.1"},"reference-count":33,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T00:00:00Z","timestamp":1647043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Dyspnea, shortness of breath, and chest pain are frequent symptoms of post-COVID syndrome (PCS). These symptoms are unrelated to organ damage in most patients after mild acute COVID infection. Hyperventilation has been identified as a cause of exercise-induced dyspnea in PCS. Since there is a broad overlap in symptomatology with myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS), causes for dyspnea and potential consequences can be deduced by a stringent application of assumptions made for ME\/CFS in our recent review papers. One of the first stimuli of respiration in exercise is caused by metabolic feedback via skeletal muscle afferents. Hyperventilation in PCS, which occurs early on during exercise, can arise from a combined disturbance of a poor skeletal muscle energetic situation and autonomic dysfunction (overshooting respiratory response), both found in ME\/CFS. The exaggerated respiratory response aggravating dyspnea does not only limit the ability to exercise but further impairs the muscular energetic situation: one of the buffering mechanisms to respiratory alkalosis is a proton shift from intracellular to extracellular space via the sodium\u2013proton-exchanger subtype 1 (NHE1), thereby loading cells with sodium. This adds to two other sodium loading mechanisms already operative, namely glycolytic metabolism (intracellular acidosis) and impaired Na+\/K+ATPase activity. High intracellular sodium has unfavorable effects on mitochondrial calcium and metabolism via sodium\u2013calcium-exchangers (NCX). Mitochondrial calcium overload by high intracellular sodium reversing the transport mode of NCX to import calcium is a key driver for fatigue and chronification. Prevention of hyperventilation has a therapeutic potential by keeping intracellular sodium below the threshold where calcium overload occurs.<\/jats:p>","DOI":"10.3390\/medicina58030419","type":"journal-article","created":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T22:29:43Z","timestamp":1647210583000},"page":"419","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Dyspnea in Post-COVID Syndrome following Mild Acute COVID-19 Infections: Potential Causes and Consequences for a Therapeutic Approach"],"prefix":"10.3390","volume":"58","author":[{"given":"Klaus J.","family":"Wirth","sequence":"first","affiliation":[{"name":"Institute of General Pharmacology and Toxicology, University Hospital Frankfurt am Main, Goethe-University, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany"},{"name":"KOSA Pharma GmbH, 60590 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8554-9638","authenticated-orcid":false,"given":"Carmen","family":"Scheibenbogen","sequence":"additional","affiliation":[{"name":"Institute of Medical Immunology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"614590","DOI":"10.3389\/fphys.2020.614590","article-title":"Hyperventilation: A Possible Explanation for Long-Lasting Exercise Intolerance in Mild COVID-19 Survivors?","volume":"11","author":"Motiejunaite","year":"2021","journal-title":"Front. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Aparisi, \u00c1., Ybarra-Falc\u00f3n, C., Garc\u00eda-G\u00f3mez, M., Tobar, J., Iglesias-Echeverr\u00eda, C., Jaurrieta-Largo, S., Ladr\u00f3n, R., Uribarri, A., Catal\u00e1, P., and Hinojosa, W. (2021). Exercise Ventilatory Inefficiency in Post-COVID-19 Syndrome: Insights from a Prospective Evaluation. J. Clin. Med., 10.","DOI":"10.3390\/jcm10122591"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/j.jchf.2021.10.002","article-title":"Use of Cardiopulmonary Stress Testing for Patients With Unexplained Dyspnea Post\u2013Coronavirus Disease","volume":"9","author":"Mancini","year":"2021","journal-title":"JACC Heart Fail."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Freitag, H., Szklarski, M., Lorenz, S., Sotzny, F., Bauer, S., Philippe, A., Kedor, C., Grabowski, P., Lange, T., and Riemekasten, G. (2021). Autoantibodies to Vasoregulative G-Protein-Coupled Receptors Correlate with Symptom Severity, Autonomic Dysfunction and Disability in Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome. J. Clin. Med., 10.","DOI":"10.3390\/jcm10163675"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1080\/21641846.2021.1922140","article-title":"COVID-19 symptoms over time: Comparing long-haulers to ME\/CFS","volume":"9","author":"Jason","year":"2021","journal-title":"Fatigue Biomed. Health Behav."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kedor, C., Freitag, H., Meyer-Arndt, L., Wittke, K., Zoller, T., Steinbeis, F., Haffke, M., Rudolf, G., Heidecker, B., and Volk, H. (2021). Chronic COVID-19 Syndrome and Chronic Fatigue Syndrome (ME\/CFS) following the first pandemic wave in Germany\u2014A first analysis of a prospective observational study. medRxiv.","DOI":"10.1101\/2021.02.06.21249256"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s13365-021-01002-x","article-title":"Chronic fatigue syndrome: An emerging sequela in COVID-19 survivors?","volume":"27","author":"Mantovani","year":"2021","journal-title":"J. NeuroVirology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"668944","DOI":"10.3389\/fmed.2021.668944","article-title":"Adolescent and Young Adult ME\/CFS After Confirmed or Probable COVID-19","volume":"8","author":"Petracek","year":"2021","journal-title":"Front. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41591-021-01292-y","article-title":"Attributes and predictors of long COVID","volume":"27","author":"Sudre","year":"2021","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wong, T.L., and Weitzer, D.J. (2021). Long COVID and Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS)\u2014A Systemic Review and Comparison of Clinical Presentation and Symptomatology. Medicina, 57.","DOI":"10.3390\/medicina57050418"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1111\/j.1365-2796.2011.02428.x","article-title":"Myalgic encephalomyelitis: International Consensus Criteria","volume":"270","author":"Carruthers","year":"2011","journal-title":"J. Intern. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3918","DOI":"10.21037\/jtd-20-2753","article-title":"High incidence of hyperventilation syndrome after COVID-19","volume":"13","author":"Taverne","year":"2021","journal-title":"J. Thorac. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"289","DOI":"10.3389\/fnins.2019.00289","article-title":"Modulation of Respiratory System by Limb Muscle Afferents in Intact and Injured Spinal Cord","volume":"13","author":"Shevtsova","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"van Campen, C.M.C., Rowe, P.C., and Visser, F.C. (2022). Orthostatic Symptoms and Reductions in Cerebral Blood Flow in Long-Haul COVID-19 Patients: Similarities with Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome. Medicina, 58.","DOI":"10.3390\/medicina58010028"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102527","DOI":"10.1016\/j.autrev.2020.102527","article-title":"A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS): Recognitions from the finding of autoantibodies against ss2-adrenergic receptors","volume":"19","author":"Wirth","year":"2020","journal-title":"Autoimmun. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s12967-021-02833-2","article-title":"Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome (ME\/CFS)","volume":"19","author":"Wirth","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1186\/s12967-021-03143-3","article-title":"An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome","volume":"19","author":"Wirth","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ijcard.2021.10.140","article-title":"In-vivo evidence of systemic endothelial vascular dysfunction in COVID-19","volume":"345","author":"Travieso","year":"2021","journal-title":"Int. J. Cardiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.3389\/fcvm.2021.745758","article-title":"Long COVID 19 Syndrome: Is It Related to Microcirculation and Endothelial Dysfunction? Insights From TUN-EndCOV Study","volume":"8","author":"Charfeddine","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107370","DOI":"10.1016\/j.carpath.2021.107370","article-title":"Cardiac pathology in COVID-19: A single center autopsy experience","volume":"54","author":"Sang","year":"2021","journal-title":"Cardiovasc. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2838","DOI":"10.1016\/j.bpj.2021.05.025","article-title":"Physical phenotype of blood cells is altered in COVID-19","volume":"120","author":"Hohberger","year":"2021","journal-title":"Biophys. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S0008-6363(01)00228-0","article-title":"Na+\/H+ exchange in ischemia, reperfusion and preconditioning","volume":"50","author":"Avkiran","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"323","DOI":"10.2174\/1568006054553417","article-title":"The Na(+)\/H(+) exchanger: A target for cardiac therapeutic intervention","volume":"5","author":"Karmazyn","year":"2005","journal-title":"Curr. Drug. Targets. Cardiovasc. Haematol. Disord."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10250","DOI":"10.1073\/pnas.1901274116","article-title":"A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis\/chronic fatigue syndrome (ME\/CFS)","volume":"116","author":"Esfandyarpour","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17303","DOI":"10.1074\/jbc.272.28.17303","article-title":"Induction of tyrosine phosphorylation and Na+\/H+ exchanger activation during shrinkage of human neutrophils","volume":"272","author":"Krump","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14042","DOI":"10.1038\/s41598-021-93546-5","article-title":"Clinical characterization of dysautonomia in long COVID-19 patients","volume":"11","author":"Barizien","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1113\/jphysiol.1992.sp019057","article-title":"Central command influences cardiorespiratory response to dynamic exercise in humans with unilateral weakness","volume":"448","author":"Innes","year":"1992","journal-title":"J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zakharycheva, T., Makhovskaya, T., Shirokova, A., and Shikina, I. (2022). Autonomic Dysregulation Syndrome in COVID-19 Convalescents: Possible Causes and Approaches to Its Correction, Springer Nature.","DOI":"10.1007\/978-3-030-85799-8_34"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Abrams, R.M.C., Simpson, D.M., Navis, A., Jette, N., Zhou, L., and Shin, S.C. (2021). Small fiber neuropathy associated with SARS-CoV-2 infection. Muscle Nerve, 1\u20134.","DOI":"10.1002\/mus.27458"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ceca.2016.01.008","article-title":"Kinetic and equilibrium properties of regulatory Ca(2+)-binding domains in sodium-calcium exchangers 2 and 3","volume":"59","author":"Tal","year":"2016","journal-title":"Cell Calcium"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1097\/00000441-200606000-00001","article-title":"Patterns of Hypocapnia on Tilt in Patients with Fibromyalgia, Chronic Fatigue Syndrome, Nonspecific Dizziness, and Neurally Mediated Syncope","volume":"331","author":"Naschitz","year":"2006","journal-title":"Am. J. Med. Sci."},{"key":"ref_32","unstructured":"Sophie, B., Alan, K.O., Jemina, F., Florian, L., Sylvain, C., Aline, S., Thomas, S., Marina, S.P., Bruno, H., and Dan, A. (2021). Virtual reality exercise to help COVID patients with refractory breathlessness. medRxiv."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1111\/dme.14315","article-title":"Hyperoxia improves autonomic function in individuals with long-duration type 1 diabetes and macroalbuminuria","volume":"37","author":"Laursen","year":"2020","journal-title":"Diabet. Med."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/3\/419\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:35:38Z","timestamp":1760135738000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/3\/419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,12]]},"references-count":33,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["medicina58030419"],"URL":"https:\/\/doi.org\/10.3390\/medicina58030419","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,12]]}}}