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Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study

BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1985 (Published 22 May 2020) Cite this as: BMJ 2020;369:m1985

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Covid-19 care before, during, and beyond the hospital

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Inhaled corticosteroids and COVID-19 outcomes in airways disease

Dear Editor

Docherty et al should be congratulated on drilling down into the UK database of COVID-19 hospital related outcomes and comorbidities [1]. They reported a 14.5% UK prevalence of asthma and 17.7% prevalence of non asthmatic chronic pulmonary disease in hospitalised patients with COVID-19. Pointedly the presence of chronic pulmonary disease conferred a 17% greater likelihood of death.

Crucially this does not tell us whether the use of inhaled corticosteroids (ICS) might have influenced outcomes in COVID-19. This might clinically be relevant because in theory ICS might promote viral replication and predispose to secondary bacterial infections possibly leading to worse outcomes especially in COPD [2]. For example, the use of ICS in asthma was associated with a 45% increased bacterial pneumonia risk, while in COPD, taking fluticasone furoate as dual or triple combination therapy exhibited a 57% relative increase in pneumonia risk [3].

In converse, taking ICS as a class effect results in reduced ex vivo gene expression of COVID related cell entry receptors--namely, angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) in airway epithelial cells [4]. Moreover, ICS may also inhibit local and systemic production of cytokines including interleukin-6 (IL6) [5 6]. This is relevant as circulating levels of IL6 are the strongest predictor of the need for mechanical ventilation in hospitalised patients with severe COVID-19 [7]. Finally, a more ICS specific effect is described whereby ciclesonide and mometasone furoate but not fluticasone propionate, beclomethasone dipripionate or budesonide suppresses in vitro replication of SARS-CoV-2 [8].

In particular we would be interested to know if those patients with COPD taking ICS as dual or triple therapy in conjunction with long acting bronchodilators compared to those taking long acting bronchodilators alone might have an altered risk of COVID-19 outcomes. In this regard use of ICS in COPD might be more relevant than in asthma in relation to COVID-19 as the former patients tend to be older, be smokers [9] with attendant comorbidities such as chronic cardiovascular disease [10], as well as having attenuated lung reserve, altered lung microbiome and impaired mucociliary clearance, all of which are likely risk factors for worse outcomes in relation to severe SARS-CoV-2 infection.

References

1. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 2020;369:m1985. doi: 10.1136/bmj.m1985
2. Singanayagam A, Johnston SL. Long-term impact of inhaled corticosteroid use in asthma and chronic obstructive pulmonary disease (COPD): Review of mechanisms that underlie risks. J Allergy Clin Immunol 2020 doi: 10.1016/j.jaci.2019.12.907 [published Online First: 2020/01/19]
3. Qian CJ, Coulombe J, Suissa S, et al. Pneumonia risk in asthma patients using inhaled corticosteroids: a quasi-cohort study. Br J Clin Pharmacol 2017;83(9):2077-86. doi: 10.1111/bcp.13295 [published Online First: 2017/04/21]
4. Peters MC, Sajuthi S, Deford P, et al. COVID-19 Related Genes in Sputum Cells in Asthma: Relationship to Demographic Features and Corticosteroids. Am J Respir Crit Care Med 2020 doi: 10.1164/rccm.202003-0821OC [published Online First: 2020/04/30]
5. Suda K, Tsuruta M, Eom J, et al. Acute lung injury induces cardiovascular dysfunction: effects of IL-6 and budesonide/formoterol. American journal of respiratory cell and molecular biology 2011;45(3):510-6. doi: 10.1165/rcmb.2010-0169OC [published Online First: 2010/12/21]
6. Yamaya M, Nishimura H, Deng X, et al. Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells. Respir Investig 2020 doi: 10.1016/j.resinv.2019.12.005 [published Online First: 2020/02/26]
7. Herold T, Jurinovic V, Arnreich C, et al. Elevated levels of interleukin-6 and CRP predict the need for mechanical ventilation in COVID-19. Journal of Allergy and Clinical Immunology doi: 10.1016/j.jaci.2020.05.008
8. Matsuyama S, Kawase M, Nao N, et al. The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15. bioRxiv 2020:2020.03.11.987016. doi: 10.1101/2020.03.11.987016
9. Leung JM, Yang CX, Tam A, et al. ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19. Eur Respir J 2020 doi: 10.1183/13993003.00688-2020 [published Online First: 2020/04/10]
10. Mehra MR, Desai SS, Kuy S, et al. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med 2020 doi: 10.1056/NEJMoa2007621 [published Online First: 2020/05/02]

Competing interests: BJL has received funding from companies who make inhaled steroids including AstraZeneca (research grants, giving talks, advisory boards, consulting, attending ATS and ERS ), Chiesi (research grants ,giving talks, advisory boards, consulting, attending BTS), Teva (research grants, advisory boards, giving talks, attending ERS), Novartis (advisory boards), Glenmark (consulting),Cipla (consulting), Vectura (consulting), Dr Reddys (consulting), Lupin (consulting). Son of BJL is an employee of AstraZeneca.

22 May 2020
Brian J Lipworth
Professor of Pulmonology
Samuel Lipworth, Chris RuiWen Kuo, Rory Chan
Scottish Centre for Respiratory Research
Ninewells Hospital and Medical School ,Dundee