Abstract
The effects of cytokine inhibition in the different phases of the severe coronavirus disease 2019 (COVID-19) are currently at the center of intense debate, and preliminary results from observational studies and case reports offer conflicting results thus far. The identification of the correct timing of administration of anti-cytokine therapies and other immunosuppressants in COVID-19 should take into account the intricate relationship between the viral burden, the hyperactivation of the innate immune system and the adaptive immune dysfunction. The main challenge for effective administration of anti-cytokine therapy in COVID-19 will be therefore to better define a precise “window of therapeutic opportunity.” Only considering a more specific set of criteria able to integrate information on direct viral damage, the cytokine burden, and the patient’s immune vulnerability, it will be possible to decide, carefully balancing both benefits and risks, the appropriateness of using immunosuppressive drugs even in patients affected primarily by an infectious disease.
Highlights
The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a wide spectrum of clinical expressiveness ranging from asymptomatic or paucisymptomatic infection to life-threating multiple organ failure
In most severe forms, SARS-CoV-2 infection leads to fulminant pneumonia and acute respiratory distress syndrome (ARDS) with a mortality rate approaching 40–50% [1]
Clinical deterioration generally occurs several days after the onset of symptoms, in association with declining viral titers [2], suggesting that part of pathophysiology may be driven by dysregulated immune responses rather than by direct viral damage
Summary
The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a wide spectrum of clinical expressiveness ranging from asymptomatic or paucisymptomatic infection to life-threating multiple organ failure. Longitudinal immune profiling of hospitalized COVID-19 cases with different outcomes has recently shown that, despite similar levels of inflammatory cytokines in the first 10 days from symptom onset, patients with less severe disease evolution express mediators of wound healing and tissue repair [41] In this phase, the therapeutic strategy should include the use of antiviral drugs and of treatments aimed at cautiously enhance immune responses. The clinical picture suddenly and unexpectedly changes with fever, respiratory failure, and ARDS associated with increased levels of acute phase reactants, neutrophilia, thrombocytosis, anemia, signs of coagulopathy, and cell lysis These acute inflammatory mechanisms may precipitate tissue damage both locally (especially at the lung level) [47] and systemically, playing an even greater pathogenetic role than that played by direct viral damage, and significantly affecting mortality. The clinical picture of the cytokine storm in COVID-19, especially when it is not associated with multi-organ damage secondary to Frontiers in Immunology | www.frontiersin.org
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