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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
