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  Addressing the ‘hypoxia paradox’ in severe COVID-19: literature review and report of four cases treated with erythropoietin analogues

Begemann, M., Gross, O., Wincewicz, D., Hardeland, R., Daguano Gastaldi, V., Vieta, E., et al. (2021). Addressing the ‘hypoxia paradox’ in severe COVID-19: literature review and report of four cases treated with erythropoietin analogues. Molecular Medicine, 27: 120. doi:10.1186/s10020-021-00381-5.

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 Creators:
Begemann, M.1, Author           
Gross, O., Author
Wincewicz, D., Author
Hardeland, R., Author
Daguano Gastaldi, V.1, Author           
Vieta, E., Author
Weissenborn, K., Author
Miskowiak, K. W., Author
Moerer, O., Author
Ehrenreich, H.1, Author           
Affiliations:
1Clinical neuroscience, Max Planck Institute of Experimental Medicine, Max Planck Society, ou_2173651              

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Free keywords: Recombinant human EPO, Darbepoetin, Neuroprotection, Treatment, Signaling, Critical care, Outcome
 Abstract: Background: Since fall 2019, SARS-CoV-2 spread world-wide, causing a major pandemic with estimated ~ 220 million subjects affected as of September 2021. Severe COVID-19 is associated with multiple organ failure, particularly of lung and kidney, but also grave neuropsychiatric manifestations. Overall mortality reaches > 2%. 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 ‘long COVID’ and ‘neuroCOVID’, becomes increasingly evident. Main body of the abstract: 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 ‘hypoxia paradox’. 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 ‘hypoxia paradox’ 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. Short conclusion: Substitution of EPO may—among other beneficial EPO effects in severe COVID-19—circumvent downstream consequences of the ‘hypoxia paradox’. A double-blind, placebo-controlled, randomized clinical trial for proof-of-concept is warranted

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Language(s): eng - English
 Dates: 2021-09-262021
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1186/s10020-021-00381-5
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Title: Molecular Medicine
Source Genre: Journal
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Pages: 11 Volume / Issue: 27 Sequence Number: 120 Start / End Page: - Identifier: ISSN: 1076-1551
ISSN: 1528-3658