ICS plays an important role in controlling airway diseases such as asthma and COPD by reducing airway inflammation. However, the increased risk of infection with the use of ICS has always been a concern. Although the mechanism has not been fully elucidated, the immunosuppressive effects of ICS are speculated to be associated with the locally high concentration of ICS in the respiratory tract.  As ICS is often regarded as being immunosuppressive and associated with an increased risk of respiratory infection, many physicians are concerned about an increased risk of SARS-CoV-2 infection in patients with airway diseases taking ICS. Furthermore, whether such patients should continue using ICS during the SARS-CoV-2 pandemic is unclear. Our study showed that ICS did not increase the risk of SARS-CoV-2 infection. Furthermore, risk of SARS-CoV-2 infection was not associated with doses and types of ICS.
These effects have raised concerns about an increased risk of respiratory infection, including upper respiratory tract infection (URTI), pneumonia, and mycobacterial pulmonary disease. Two meta-analyses reported that ICS was associated with a significantly increased risk of URTI in patients with asthma or COPD. [14, 15] Only high-dose ICS increased the risk of URTI (OR = 1.19) in patients with COPD, while low-dose (OR = 1.46) and high-dose (OR = 1.20) ICS increased the risk of URTI in patients with asthma. Singanayagam et al. reported that ICS impairs innate and acquired antiviral immune responses leading to delayed virus clearance. They also found previously unrecognized adverse effects such as enhanced mucus production, impaired antimicrobial peptide secretion, and increased pulmonary bacterial load during virus-induced exacerbations, which increased risk of pneumonia after clearance of the viral infection.  Several studies and a meta-analysis have demonstrated an increased risk of pneumonia with ICS use in COPD patients, although this increased risk of pneumonia did not lead to increased mortality.  However, ICS use and pneumonia in asthma patients have shown controversial results, which might owe to the varying age range and comorbidities assessed in different studies. [7, 8, 17] ICS also increased the infection risk of both nontuberculous and tuberculous mycobacterial pulmonary diseases. [9, 10, 18] There was a strong dose-response relationship between mycobacterial infection and the cumulative ICS dose. 
Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. SARS-CoV-2 uses the angiotensin converting enzyme 2 (ACE2) for entry and the transmembrane protease serine 2 (TMPRSS2) for S protein priming. [19, 20] An increased expression in lung cells will increase susceptibility to SARS-CoV-2 infection or lead to a more severe COVID-19 disease. 
Peters et al. analysed gene expression of ACE2 in sputum cells from 330 participants in the Severe Asthma Research Program-3 and 79 healthy controls. They found that the use of ICS was associated with a decreased expression of ACE2 and TMPRSS2.  However, intramuscular triamcinolone acetonide injection did not lower expression of either genes. This discordant result between systemic corticosteroid and inhaled corticosteroid might be related to assessment of sputum cell gene expression at different time points after exposure to the corticosteroid.  They suggested that the decrease in ACE2 and TMPRSS2 gene expression provided some reassurance that ICS use will not increase the risk of SARS-CoV-2 infection or morbidity, although prospective studies are required to confirm this assumption. Moreover, the mechanism by which ICS reduces the expression of ACE2 and TMPRSS2 needs to be investigated further.
Type of ICS was not associated with risk of SARS-CoV-2. Iwabuchi et al reported cases of SARS-CoV-2 pneumonia successfully treated with ciclesonide inhalation.  However, it is not clear that whether these patients would have improved spontaneously because there was no control group. Nevertheless, there have been several reports that provide evidence for the beneficial effects of ICS in dealing with virus infections.  Matsuyama et al. showed that ICS ciclesonide blocks coronavirus RNA replication by targeting viral NSP15.  Moreover, glycopyrronium, formoterol, and a combination of glycopyrronium, formoterol, and budesonide inhibited human coronaviruses-229E replication partly by inhibiting receptor expression and/or endosomal function suggesting that these drugs may modulate infection-induced inflammation in the airway. 
Previous studies reported that fluticasone use is associated with a higher risk of pneumonia than budesonide due to its greater and more protracted immunosuppressive effects locally, in the airways and lungs. [15, 18] Local pharmacokinetic profiles (e.g. rate and extent of airway/pulmonary absorption) of ICS are strongly associated with the intrinsic physicochemical properties of corticosteroids, such as lipophilicity, aqueous solubility, and airway epithelial permeability.  However, all the types of ICS did not increase the risk of SARS-CoV-2 infection in this study. The differences in pharmacokinetics and immune modulatory effects of each type of ICS warrants further study, to investigate the relationship between different types of ICS and the risk of SARS-CoV-2 infection.
This is the first report to demonstrate the relationship between the use of ICS and risk of SARS-CoV-2 infection in a large population-based study including different types of ICS. However, this study has several limitations. The severity of primary respiratory diseases for which ICS were prescribed was not categorized. The severity of respiratory disease would affect the degree of risk for SARS-CoV-2 infection. Secondly, previous use of systemic corticosteroid was not included in the analysis. Systemic corticosteroids are more potent immune modulators than ICS; therefore, its effects on the risk for SARS-CoV-2 infection should be important. Thirdly, the risk of infection based on different types of ICS could not be fully evaluated because of the different number of each ICS prescribed. Lastly, this study included people who were suspected of or at a high risk of SARS-CoV-2 infection; therefore, asymptomatic infected persons could have been missed. Moreover, data were analysed until the middle of the pandemic period and from the administrative claims database; thus, this study does not represent the whole population who were suspected of having SARS-CoV-2, at a high risk of infection, and confirmed with SARS-CoV-2 in Korea.