Role of Systemic and Nasal Glucocorticoid Treatment in the Regulation of the Inflammatory Response in Patients with SARS-Cov-2 Infection

Abstract

The Chinese outbreak of SARS-CoV-2 during 2019 has become pandemic and the most important concerns are the acute respiratory distress syndrome (ARDS) and hyperinflammation developed by the population at risk (elderly and/or having obesity, diabetes, and hypertension) in whom clinical evolution quickly progresses to multi-organ dysfunction and fatal outcome. Immune dysregulation is linked to uncontrolled proinflammatory response characterized by the release of cytokines (cytokines storm). A proper control of this response is mandatory to improve clinical prognosis. In this context, glucocorticoids are able to change the expression of several genes involved in the inflammatory response leading to an improvement in acute respiratory distress. Although there are contradictory data in the literature, in this report we highlight the potential benefits of glucocorticoids as adjuvant therapy for hyperinflammation control; emphasizing that adequate dosage, timing, and delivery are crucial to reduce the dysregulated peripheral-and neuro-inflammatory response with minimal adverse effects. We propose the use of the intranasal route for glucocorticoid administration, which has been shown to effectively control the neuro-and peripheral-inflammatory response using low doses without generating unwanted side effects.

Keywords: COVID-19; Glucocorticoids; Immunity; Inflammation; Intranasal delivery.

Figure 1

SARS-CoV-2 pathogenesis. SARS-CoV-2 cell entry depends on ACE2, TMPRSS2, and CTSL (A) The SARS-CoV-2 virus uses two ways to enter the host cells: (1.1) Via host membrane fusion through the binding of the viral spike proteins (S) to the ACE2 (angiotensin-converting enzyme 2) receptor, which is co-expressed with the serine protease TMPRSS2 (type II transmembrane serine protease), that allows the priming of the viral protein S, initiating the fusion of the viral membrane with the host membrane. (1.2) Via endosomes. In this pathway the endosomal protease CTSL (cathepsin L) primes the viral protein S. Then, (2) viral RNA is released into the host cell. Once (3) viral RNA transcription and replication occurred, (4) the virion assembly takes place, small vesicles are released from the Golgi apparatus containing (5) virions that are released from the infected cell through exocytosis. (B) The receptors and proteases essential for SARS-CoV-2 infective cycle are present in a wide variety of tissues and cell types: brain (glial cells and neurons), eye (corneal epithelium), nasal (globet, basal and ciliated cells), heart (myocyte, pericyte), lungs (secretory, basal and multiciliated cells), liver (cholangiocytes), pancreas (ductal epithelium), kidney (proximal tubule cells), ileum (fibroblast, endothelial, and epithelial enterocytes), bladder (fibroblast, and epithelial cells), among others. (C) SARS-CoV-2 infection can induce a host immune response that leads to exacerbated inflammation not only in the respiratory system but at the systemic level and in the central nervous system. The common mechanisms supporting such inflammatory state include enhanced cellular influx with the subsequent cytokine and chemokine secretion, which are in part due to pyroptosis induced by the pathogen. An effective anti-inflammatory treatment might comprise the administration of corticosteroids at stage 2 just before the appearance of cytokine storm. Pulmonary insufficiency is likely associated to impairment of the central respiratory system provoked by the viral-induced neuroinflammatory response. Therefore, IN administration of low GC doses may provide better therapeutic effects avoiding the undesired effects of the high GC doses typically administered parenterally, such as the increase of viral load. A clinical trial to assess this proposed therapeutic scheme is under planning.