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Severe COVID-19 is associated with multiple organ failure, particularly of lung and kidney, but also grave neuropsychiatric manifestations. Overall mortality reaches\u2009&gt;\u20092%. Vaccine development has thrived in thus far unreached dimensions and will be one prerequisite to terminate the pandemic. Despite intensive research, however, few treatment options for modifying COVID-19 course\/outcome have emerged since the pandemic outbreak. Additionally, the substantial threat of serious downstream sequelae, called \u2018long COVID\u2019 and \u2018neuroCOVID\u2019, becomes increasingly evident.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main body of the abstract<\/jats:title>\n                    <jats:p>Among candidates that were suggested but did not yet receive appropriate funding for clinical trials is recombinant human erythropoietin. Based on accumulating experimental and clinical evidence, erythropoietin is expected to (1) improve respiration\/organ function, (2) counteract overshooting inflammation, (3) act sustainably neuroprotective\/neuroregenerative. Recent counterintuitive findings of decreased serum erythropoietin levels in severe COVID-19 not only support a relative deficiency of erythropoietin in this condition, which can be therapeutically addressed, but also made us coin the term \u2018hypoxia paradox\u2019. As we review here, this paradox is likely due to uncoupling of physiological hypoxia signaling circuits, mediated by detrimental gene products of SARS-CoV-2 or unfavorable host responses, including microRNAs or dysfunctional mitochondria. Substitution of erythropoietin might overcome this \u2018hypoxia paradox\u2019 caused by deranged signaling and improve survival\/functional status of COVID-19 patients and their long-term outcome. As supporting hints, embedded in this review, we present 4 male patients with severe COVID-19 and unfavorable prognosis, including predicted high lethality, who all profoundly improved upon treatment which included erythropoietin analogues.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Short conclusion<\/jats:title>\n                    <jats:p>Substitution of EPO may\u2014among other beneficial EPO effects in severe COVID-19\u2014circumvent downstream consequences of the \u2018hypoxia paradox\u2019. A double-blind, placebo-controlled, randomized clinical trial for proof-of-concept is warranted.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-021-00381-5","type":"journal-article","created":{"date-parts":[[2021,9,26]],"date-time":"2021-09-26T13:06:53Z","timestamp":1632661613000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Addressing the \u2018hypoxia paradox\u2019 in severe COVID-19: literature review and report of four cases treated with erythropoietin analogues"],"prefix":"10.1186","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0493-7370","authenticated-orcid":false,"given":"Martin","family":"Begemann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8390-8852","authenticated-orcid":false,"given":"Oliver","family":"Gross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0747-6306","authenticated-orcid":false,"given":"Dominik","family":"Wincewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0178-6378","authenticated-orcid":false,"given":"R\u00fcdiger","family":"Hardeland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6249-6035","authenticated-orcid":false,"given":"Vinicius","family":"Daguano Gastaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0548-0053","authenticated-orcid":false,"given":"Eduard","family":"Vieta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1157-8938","authenticated-orcid":false,"given":"Karin","family":"Weissenborn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2572-1384","authenticated-orcid":false,"given":"Kamilla W.","family":"Miskowiak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4210-388X","authenticated-orcid":false,"given":"Onnen","family":"Moerer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8371-5711","authenticated-orcid":false,"given":"Hannelore","family":"Ehrenreich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,26]]},"reference":[{"key":"381_CR1","doi-asserted-by":"publisher","first-page":"102","DOI":"10.3390\/neurolint13010010","volume":"13","author":"A Al-Ramadan","year":"2021","unstructured":"Al-Ramadan A, Rabab\u2019h O, Shah J, Gharaibeh A. 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