Inhaled corticosteroids: A rapid review of the evidence for treatment or prevention of COVID-19

June 22, 2020

 Laura C Armitage and Rachel Brettell

 On behalf of the Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford

Correspondence to: laura.armitage@phc.ox.ac.uk

VERDICT
This review aimed to synthesise the current literature on the role of inhaled corticosteroids in moderating the disease course or severity of COVID-19 disease. Inhaled ciclesonide has been shown to suppress SARS-CoV-2 replication in cultured cells and it is suggested that it exhibits direct acting anti-viral activity in addition to its intrinsic anti-inflammatory function. Inhaled ciclesonide has therefore been proposed as a candidate drug for treatment of patients suffering Covid19. However, further in vitro research is required to investigate whether this finding is replicable. Furthermore, at the time of writing, there have been no clinical trials or observational studies examining the use of ICS in COVID-19. Clinical trials would be required to establish whether these drugs may be repurposed for the treatment of this disease.

BACKGROUND
This rapid review set out to

1. Explore the possible mechanism of action of any effect of inhaled corticosteroid therapy on the disease course or severity of COVID-19.
2. Synthesise any relevant proof of principle data available on the effect of inhaled corticosteroid therapy on COVID-19 or infection.
3. Synthesise any relevant clinical data available, including observational data and clinical trials investigating acute administration of inhaled corticosteroids during COVID-19

Since the identification of the Severe acute respiratory syndrome (SARS) virus in 2003, the role of steroid therapy in the management of acute respiratory illnesses has been debated. Systemic steroid administration has dominated the scientific literature, with systemic dexamethasone recently having been shown to reduce the risk of COVID-19 mortality.¹ Alongside, there has been consideration as to whether those with asthma and chronic obstructive pulmonary disease (COPD) should continue to take their usual inhaled corticosteroid medications during the COVID-19 pandemic. Information on the use of inhaled corticosteroids for the treatment of COVID-19 or its effect on the SARS-CoV-2 virus is, however, limited. The pathogenesis of SARS involves the release of pro-inflammatory cytokines by immune cells called macrophages in the lung alveoli.² Steroids inhibit the adhesion and action of cytokines and it has been hypothesised that through such moderation of the immune response, inhaled corticosteroids could prevent the development of acute respiratory distress syndrome.² We performed a rapid review of the literature to assimilate the current scientific data on this topic.

EMERGING EVIDENCE
We searched Medline, Google Scholar and MedRxive on 6 May 2020 for studies that included terms for inhaled corticosteroids and COVID-19 and other related acute coronavirus respiratory tract infections (search strategy provided below). Google Scholar citations were screened until there were 5 consistent pages of citations with no relevant results, meaning 250 citations in total were screened. After removal of duplicates, our combined database search yielded 289 citations. After screening by title and abstract, 29 were considered relevant and we were able to obtain full text articles for all but one, as this was not available online and we were unable to establish contact with the authors.³ A further 21 citations were identified from manual citation searches of relevant articles and systematic reviews and their full text articles screened. Full text articles were obtained for a total of 49 citations and screened by both reviewers; 4 articles were deemed eligible for inclusion.^4–7 These comprised 3 in vitro studies and 1 case series. Three of the articles were published as pre-prints,^4,5,7 without peer review and 1 had been peer-reviewed.⁶

In vitro research
Jeon et al screened approximately 3000 FDA-approved drugs from a drug library against SARS-CoV to identify antiviral drug candidates for therapeutic development.⁷ The authors chose the SARS-CoV drug library owing to the high degree of similarity between the SARS-CoV and SARS-CoV-2 virus, hypothesising that drugs showing antiviral activity against SARS-CoV would likely show a similar extent of antiviral activity against SARS-CoV-2. The authors selected 35 drugs for further screening, alongside 13 additional drugs that were included based on recommendations from infectious diseases specialists. The drugs were screened against SARS-CoV-2 by adding each drug to mammalian cells that are commonly used for virology research (Vero cells) and then infecting the cells with the virus. Infected cells were scored at 24hr after infection using immunofluorescence analysis with an antibody specific for the viral N protein of SARS-CoV-2. Drug effectiveness was measured using Half-maximal inhibitory concentration (IC₅₀). This indicates how much drug is needed to inhibit a biological process by half, thus providing a measure of potency of an antagonist drug in research.⁸ The authors compared the drug effectiveness of ciclesonide, an inhaled corticosteroid medication used to treat asthma and allergic rhinitis, against the drug effectiveness of chloroquine, lopinavir and remdesivir as reference drugs. They found that ciclesonide had an IC₅₀ of 4.33 μM, which was much lower than that of chloroquine (9.12 μM), lopinavir (7.28 μM) and remdesivir (11.41 μM). The authors therefore proposed that ciclesonide exhibits a direct acting anti-viral activity in addition to its intrinsic anti-inflammatory function.

Matsuyama et al also screened drugs from a chemical library and ciclesonide, fluticasone, and mometasone furoate (all inhaled corticosteroids) were included in the list of drugs screened.⁴ In this instance, the cytopathic effect caused by MERS-CoV infection was measured to evaluate viral replication when cells were treated with these four steroid compounds. Ciclesonide conferred a >95% cell survival rate, exhibited low cytotoxicity and resulted in potent suppression of viral replication. They authors investigated the antiviral effects of steroids against other respiratory viruses including HCoV-229E (one of the causes of the common cold) and SARS-CoV. Ciclesonide and mometasone suppressed replication of these viruses. The authors sought to investigate the viral drug target, by conducting 11 consecutive MERS-CoV passages in the presence of 40 μM ciclesonide or 40 μM mometasone. A mutant virus that developed resistance to ciclesonide was generated. Next-generation sequencing identified an amino acid substitution in non-structural protein (NSP-15), an endoribonuclease, in the mutant virus. A recombinant virus containing this amino acid substitution overcame the antiviral effect of ciclesonide. The authors concluded that NSP15 is the molecular target of ciclesonide. The authors also observed that the mutant virus was still inhibited by mometasone, suggesting that the antiviral target of mometasone is different to that of ciclesonide.

Yamaya et al performed a further in vitro study.⁶ They obtained human nasal epithelial cells and human tracheal epithelial cells from 50 patients with chronic rhinosinusitis who were undergoing endoscopic surgery. The researchers infected these cells with coronavirus 229E (HCoV-229E), and examined the viral titres, and the levels of several infection induced inflammatory cytokines at 24, 48, 72 and 120 hours after infection. The cells were pre-treated with one of the following drugs or drug combinations: (i) glycopyrronium (a long acting muscarinic antagonist) alone, (ii) formoterol (long acting beta agonist) alone, (ii) glycopyrronium with formoterol and budesonide (GFB) or (vi) budesonide (an inhaled corticosteroid) alone. The results showed that treatments (i), (ii), and (iii) decreased the viral titre and viral RNA expression, but treatment with budesonide alone (iv) did not decrease the viral titres or RNA levels. Cells pre-treated with treatments i, ii and iii were also less susceptible to viral infection. Pre-treatment with budesonide did reduce infection-induced secretion of the inflammatory cytokines IL-6, IL-8, IFN-β, IFN-λ₁, and IFN-γ. Concentrations of IL-6 and IL-8 were lower in the GFB-treated cells than those treated with budesonide alone.

Clinical research
Iwabuchi et al present the case histories of three patients admitted to hospital in China who were positive for SARS-CoV-2 virus and who showed clinical deterioration during their stay.⁵ All three patients had poor oxygenation and CT findings and were treated with inhaled ciclesonide part way through their hospital admission. The authors describe the disease severity for these three patients as mild-to-mid-stage. Case 1 was admitted to hospital on day 8 from the onset of symptoms. On day 11 the patient was commenced on oxygen therapy and lopinavir/ritonavir. On day 16, the lopinavir/ritonavir therapy was stopped due to diarrhoea and liver damage and nasogastric (NG) feeding was commenced due to poor appetite. On day 17 ciclesonide was commenced at 200 μg twice daily. On day 19, the patient became afebrile and oxygenation and appetite improved such that oxygen therapy and NG feeding were stopped. No data on the patient’s outcomes after this point are provided but the patient was discharged from hospital on day 25. Case 2 commenced nasal oxygen on day 14 from the onset of symptoms followed by ciclesonide 200 μg twice daily from day 15. On day 17, oxygen therapy was stopped and the patient’s tolerance of physical exertion improved. On day 27, the patient’s daily ciclesonide dose was increased to 1200 μg/day in three divided doses. No data on the patient’s outcomes after this point are provided but the patient was discharged from hospital on day 37. Case 3 commenced oxygen and inhaled ciclesonide (200 μg twice daily) on day 16 from the onset of symptoms and on day 28 the dose was increased to 1200 μg/day in three divided doses. No data are provided on the patient’s outcomes after day 28 but the patient was discharged from hospital on day 37. The authors go on to discuss that inhaled ciclesonide is considered a safe drug that is simple and inexpensive to administer. They recommend frequent high dose administration and deep inhalation to ensure sufficient drug reaches the alveoli and 14 days or longer treatment to avoid reactivation of residual virus and appearance of resistant virus. They recognise the small number and observational nature of these three cases and suggest further, larger studies are warranted. The interpretation of these cases should be treated with caution as the authors do not report whether there were additional patients treated with inhaled ciclesonide who did not experience favourable outcomes.

CONCLUSIONS

• We identified three studies that investigated the antiviral potential of the inhaled corticosteroid ciclesonide.
• One study investigated the antiviral potential of ciclesonide against the SARS-CoV-2 virus in vitro, one against the MERS-CoV, HCoV-229E and SARS-CoV viruses in vitro and one was a case series of three patients admitted to hospital with COVID-19 who were treated with inhaled ciclesonide.
• Both in vitro studies indicated that ciclesonide has anti-viral properties against these respiratory viruses and the clinical study showed favourable outcomes in the three patients presented, however these clinical results should be treated with caution.
• Inhaled ciclesonide is expected to reduce viral replication and pulmonary inflammation, whilst having lower immunosuppressive effects when compared to systematic corticosteroids.
• A single in vitro study that investigated the antiviral potential of budesonide observed no reduction in viral replication in cells treated with budesonide and no reduction in inflammatory cytokine release.
• Additional data is required both in vitro and in vivo to help consider whether inhaled corticosteroids may be used for the treatment of COVID-19 pneumonia; at the time of writing there is one study underway investigating the safety and efficacy of inhaled ciclesonide for the treatment of COVID-19 in the US and three further studies due to start recruiting (one each in Sweden, Canada and South Korea).⁹

Disclaimer:  the article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.

AUTHORS
Dr Laura Armitage is a General Practitioner and Clinical Researcher based at the Nuffield Department of Primary Care Health Sciences, University of Oxford.
Dr Rachel Brettell is a General Practitioner and Honorary Clinical Researcher at the Nuffield Department of Primary Care Health Sciences, University of Oxford.

ACKNOWLEDGEMENTS
We would like to thank Nia Roberts, Medical Information Specialist at the Bodleian Library, University of Oxford for her help in designing the search strategy for the database searches.

SEARCH TERMS

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