Possible harm from glucocorticoid drugs misuse in the early phase of SARS-CoV-2 infection: a narrative review of the evidence

Riccardo Sarzani, Francesco Spannella, Federico Giulietti, Chiara Di Pentima, Piero Giordano, Andrea Giacometti, Riccardo Sarzani, Francesco Spannella, Federico Giulietti, Chiara Di Pentima, Piero Giordano, Andrea Giacometti

Abstract

Since the publication of the RECOVERY trial, the use of glucocorticoid drugs (GC) has spread for the treatment of severe COVID-19 worldwide. However, the benefit of dexamethasone was largest in patients who received mechanical ventilation or supplemental oxygen therapy, while no benefit was found among patients without hypoxemia. In addition, a positive outcome was found in patients who received dexamethasone after several days of symptoms, while possible harm could exist if administered early. The right time interval for GC administration is still a matter of debate. Previous studies showed that an early GC use during the first phase of the disease, when viral replication peaks, may negatively affect the innate immune response through several mechanisms, such as the inhibition of pro-inflammatory and antiviral cytokine production and signaling pathway, including type I interferon, that is fundamental to counteract the virus and that was found to be impaired in several patients with life-threatening COVID-19. The GC misuse can lead to a more severe disease even in patients who do not have the established risk factors, such as obesity and cardiovascular diseases. In our focused review, we describe the role of immune response in viral infections, especially SARS-CoV-2, and discuss the potential harms of GC misuse in COVID-19.

Keywords: Cytokine; Glucocorticoid; Innate immunity; Interferon; SARS-CoV-2; Viral infection.

Conflict of interest statement

The authors declare that they have no conflict of interest.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Impairment of the innate immune response against SARS-CoV-2 infection by early glucocorticoid therapy. At the top of the figure (blue part), the physiological innate immune response to viral infection (SARS-CoV-2) is summarized. Infected cells as well as macrophages and dendritic cells recognize the viral single-stranded RNA mainly through intracellular TLR7, inducing the transcription and subsequent secretion of inflammatory cytokines and type I interferon (IFN-I). They enhance antigen presentation and activate the adaptive immune system (antibody production, increased effector T-cell responses, production of type II interferon by activated T-cells and natural killer cells, etc.), counteracting viral replication. At the bottom of the figure (red part), the possible negative effects of early glucocorticoid therapy on immune response is described. Glucocorticoid therapy inhibits pro-inflammatory (IL-6 and IL-8) and antiviral (IFN-I) cytokine production and signaling pathway, decreasing the expression of the interferon-stimulated genes, suppress antigen-stimulated inflammation mediated by macrophages and dendritic cells. Glucocorticoid therapy also induces lymphopenia or can worsen a preexisting lymphopenia, hindering the T-lymphocyte immunity. Moreover, it can further downregulate membrane-bound angiotensin-converting enzyme 2 (ACE2). All these actions may contribute to viral replication and more severe lung injury. ACE2: angiotensin converting enzyme 2; TLR7: toll-like receptor 7; IFN: interferon; GC: glucocorticoid

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