Re‐Evaluating the Role of Inhaled Corticosteroids in COVID‐19 Management

The coronavirus disease 2019 (COVID-19) pandemic has compelled medical professionals worldwide to continually reassess and modify treatment protocols as new evidence emerges. Systemic corticosteroids such as dexamethasone significantly reduce mortality in patients with severe or critical COVID-19 who require supplemental oxygen or mechanical ventilation, as demonstrated in large randomised controlled trials (RCTs) and meta-analyses [1, 2]. In contrast, evidence does not support the role of systemic corticosteroid use in patients with mild COVID-19 who do not require oxygen therapy [1, 2]. The benefits and mechanisms of inhaled corticosteroids (ICS) in asthma and eosinophilic chronic obstructive pulmonary disease (COPD) are well recognised and widely supported by international guidelines. ICS suppress eosinophil-driven airway inflammation by inhibiting pro-inflammatory cytokines and reducing the recruitment of inflammatory cells, thereby decreasing airway hyperresponsiveness and mucosal edema [3]. In asthma, this leads to improved symptom control and fewer exacerbations [3], while in eosinophilic COPD, ICS effectively reduce exacerbation frequency in patients with elevated blood eosinophils [4]. Among studies of possible therapies for COVID-19, ICS have attracted considerable interest for their potential to mitigate respiratory symptoms in COVID-19 patients. The rationale for utilising ICS is grounded on their anti-inflammatory properties, which theoretically may attenuate the hyper-inflammatory response of acute SARS-CoV-2 infection. An in vitro study demonstrated that ICS could inhibit the replication of coronaviruses, including SARS-CoV-2, and suppress cytokine production in infected epithelial cells [5]. In COPD patients, ICS could lower the expression of genes encoding angiotensin-converting enzyme 2 (ACE-2) functional receptor and A disintegrin and metalloprotease 17 (ADAM17), which are involved in the process of SARS-CoV-2 entering the host bronchial epithelial cells, and might explain the protective role of ICS on the severity of COVID-19 [6]. Another study in asthma patients showed that ICS could also reduce the expression of ACE-2 receptors as well as transmembrane protease serine 2 (TMPRSS2), the main protein that enables SARS-CoV-2 to enter airway cells [7]. These studies demonstrated that ICS might lower the likelihood of the coronavirus infecting the airways in patients with underlying chronic airway diseases. This is supported by early epidemiologic data which showed that asthma and COPD were less commonly found among the comorbid diseases of patients with COVID-19 [8]. Thus, ICS were initially believed to have a protective effect for COVID-19. However, their effects on immune function might reduce the host antiviral defences and raise the chance of secondary lung infections. An early large-scale observational study reported that the long-term use of ICS, particularly at high doses, in patients with asthma and COPD was associated with high COVID-19 mortality [9]. However, this study did not classify patients according to the severity of COVID-19. In addition, the use of high-dose ICS indirectly indicated that the underlying asthma or COPD in this study was severe. Therefore, the potentially harmful effect of high-dose ICS in patients with COVID-19 in this study might be inconclusive, particularly if ICS use is temporary. The early pre-vaccination open-label RCTs to explore the potential benefits of short-term high-dose ICS (800 μg twice daily of inhaled budesonide) for acute COVID-19 management demonstrated a significantly shorter duration of self-reported symptoms [10, 11]. The meta-analysis of these two open-label RCTs by Wark et al. showed there was a significant symptom benefit [12]. As the pandemic progressed and new variants emerged, additional high-quality placebo-controlled studies were conducted. In a recent publication in Respirology, Wark et al. conducted a two-arm, double-blind, placebo-controlled, community-based RCT evaluating 320 μg/day of inhaled ciclesonide (n = 95) versus placebo (n = 94) for 14 days in outpatients with mild-to-moderate COVID-19 [12]. Most of the participants were fully immunised with SARS-CoV-2 vaccines. The primary outcome was the time to absence of any COVID-19 symptoms. Their findings indicated no significant difference in recovery time between the groups, with a recovery rate ratio of 1.04 (95% CI; 0.77, 1.40) [12]. This study concluded that in fully vaccinated populations, treatment with ICS such as inhaled ciclesonide did not significantly improve outcomes in COVID-19 [12]. Correspondingly, an earlier larger RCT also demonstrated that treatment with inhaled fluticasone furoate (200 μg once daily for 14 days) in outpatients with mild-to-moderate COVID-19 did not result in a shorter time to recovery than placebo [13]. Again, two-thirds of the subjects in this trial were fully vaccinated before enrolment. The results of this study led to the early termination of the Wark et al. trial. To strengthen their outcome, Wark et al. also performed an elaborate meta-analysis, including the placebo-controlled trials spanning both pre-vaccination and post-vaccination periods, which confirmed that ICS use was not associated with significantly improved recovery of COVID-19 symptoms [12]. This result aligned with a comprehensive systematic review and meta-analysis of 11 RCTs by Hsu et al., which concluded that ICS did not reduce the risk of urgent care, emergency visits, hospitalisation, or death, but might provide some symptomatic relief in patients with COVID-19 [14]. Importantly, variation in recovery outcomes observed between studies could be attributable to differences in vaccination rates during the periods when these trials were conducted. These findings underscore that ICS does not shorten the duration of COVID-19 illness, particularly in vaccinated patients. In conclusion, ICS initially appeared promising as a treatment strategy for COVID-19 due to their anti-inflammatory mechanisms. However, emerging evidence from high-quality RCTs and meta-analyses suggests that ICS do not confer significant benefits in reducing illness duration or severity in acute COVID-19 cases, particularly in vaccinated populations. Therefore, despite a good overall safety profile with short-term prescription, they have no role for routine use in patients with COVID-19 in the post-vaccination era. However, ICS are essential in managing chronic respiratory diseases such as asthma and eosinophilic COPD and should be logically continued if these patients become infected with COVID-19. The authors declare no conflicts of interest.