Several recent studies have reported that systemic corticosteroids were effective against coronavirus disease 2019 (COVID-19) (1). Patients with severe COVID-19 present with acute respiratory distress syndrome (ARDS), also known as diffuse alveolar damage, presumably caused by an excessive immune response in the alveoli. Similar but milder alveolar inflammation may also exist in early stage patients, and systemic corticosteroids may contribute to the suppression of excessive inflammation in the alveoli, however, adverse effects such as opportunistic infections and delayed viral elimination may outweigh this advantage. This could be why the study by Horby et al. found no benefit in less severe patients who were not receiving oxygen (1). Delivering corticosteroids directly to the alveoli by inhalation should be effective and would have fewer systemic side effects. SARS-CoV-2 infection is suggested to elicit inflammatory cytokine secretion, not only from alveolar macrophages but also from alveolar epithelial type 2 cells (2). Additionally, ICS (inhaled corticosteroids) deposited in the alveoli enter the systemic circulation via the pulmonary vasculature, leading to potential anti-inflammatory effects in this region, which is also considered to be a site of inflammation during COVID-19.
Nebulized budesonide improved oxygenation and significantly reduced inflammatory markers (TNF-α, IL-1β, and IL-6) in patients with ARDS (3). There are several reviews of inhaled corticosteroids for COVID-19, and currently, there is no clear evidence on whether pre-morbid use of ICS is a factor in adverse or beneficial outcomes for COVID-19 (4,5).
ICS can reach different sites in the lungs, depending on particle size (5). As the alveoli are considered to be the main site for lung inflammation in COVID-19, steroids with smaller particle sizes that can reach the alveoli should be more promising. Among ICS, pressurized metered-dose inhalers (pMDIs) of beclomethasone and ciclesonide have the smallest particle sizes (<2 µm) and, thus, are considered to reach the alveoli more easily (6). The particles in the nebulizer are also small enough to reach the alveoli, but there is a concern that the particles that return on exhalation may contain the virus and could therefore infect medical personnel.
Apart from their anti-inflammatory effects, some ICS have been found to have antiviral effects. Ciclesonide and mometasone, which are both marketed as ICS, suppressed the replication of SARS-CoV-2 and MERS-CoV in vitro, whereas dexamethasone, cortisone, prednisolone, and fluticasone did not (7). There is a case report of three COVID-19 patients treated with inhaled ciclesonide (8). Although it might be more difficult for dry powder inhalers (DPI) to reach the alveoli, owing to their larger particle size, than for pMDIs (6), mometasone may be worth considering, as it has antiviral properties and a smaller particle size than budesonide (6). A mutant MERS-CoV that developed resistance to ciclesonide did not show resistance to mometasone (7).
ICS should be considered as a promising therapeutic candidate, and should be prioritized for clinical trials in both mildly symptomatic outpatients and severely ill inpatients. As of July 5, 2020, several clinical trials worldwide utilizing ICS for COVID-19 have been registered on ClinicalTrials.gov: four trials (one recruiting, three not yet) for ciclesonide, and four trials (three recruiting, one not yet) for budesonide (one including formoterol).
The antiviral effect of ICS as well as their particle size, which is related to the ability to reach the alveoli, should also be noted. The anti-SARS-COV-2 effect of beclomethasone in vitro has yet to be tested. We propose that clinical trials that confirm the clinical effect of beclomethasone, which has a similar particle size to ciclesonide, as well as studies that confirm its antiviral effect, should be conducted. This is because, if either or both drugs are found to be effective it may be possible to speculate whether these effects are due to the antiviral or anti-inflammatory effects. If beclomethasone is found to be clinically effective but not antiviral, the effect of particle size can be estimated by comparing it to budesonide, which also has no antiviral effect. For the same reason and in anticipation of the unique antiviral effect that is different from ciclesonide, we propose that clinical trials of mometasone, which has a smaller but similar particle size to budesonide, should also be conducted. Mometasone is also available in nasal spray form. Clinical trials could be conducted to determine the preventive effects of intranasal mometasone and its effectiveness in treating early stage COVID-19.
References
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3. Mohamed HS, Meguid MM. Effect of nebulized budesonide on respiratory mechanics and oxygenation in acute lung injury/acute respiratory distress syndrome: Randomized controlled study. Saudi J Anaesth. 2017 Jan-Mar;11(1):9-14. doi:10.4103/1658-354X.197369
4. Maes T, Bracke K, Brusselle GG. COVID-19, Asthma, and Inhaled Corticosteroids: Another Beneficial Effect of Inhaled Corticosteroids?. Am J Respir Crit Care Med. 2020 Jul;202(1):8-10. doi:10.1164/rccm.202005-1651ED
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