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Comment Early treatment with inhaled budesonide to prevent clinical deterioration in patients with COVID-19 In most individuals, infection with SARS-CoV-2 is either clinical recovery was also significantly reduced in the asymptomatic or produces mild illness (COVID-19) budesonide group.6 Based on these observations, the Molekuul/Science Photo Library that resolves spontaneously; yet, a small proportion authors concluded that early administration of inhaled of patients with COVID-19 develop severe disease, budesonide in patients infected with SARS-CoV-2 require hospitalisation (often in a critical-care setting), reduced the likelihood of needing urgent medical care and die.1 A dysregulated type I interferon response to and enhanced clinical recovery.6 SARS-CoV-2 with overproduction of proinflammatory Ramakrishnan and colleagues’ study is important Lancet Respir Med 2021 cytokines seems to be a key pathogenic mechanism because it is the first to show that an easily accessible Published Online April 9, 2021 underlying progression to severe COVID-19 and death.1 therapeutic intervention is effective to prevent https://doi.org/10.1016/ Thus, controlling this excessive inflammatory response COVID-19 clinical deterioration. However, the study S2213-2600(21)00171-5 See Online/Articles might potentially prevent disease progression. has a potentially important limitation that needs https://doi.org/10.1016/ Inhaled corticosteroids have been used for more careful consideration: it was terminated early due S2213-2600(21)00160-0 than 30 years in the treatment of several inflammatory to “the impact of the national pandemic control This online publication has been corrected. The corrected version respiratory conditions, such as asthma and chronic measures and national prioritisation rules for clinical first appeared at thelancet.com obstructive pulmonary disease (COPD), to control research trials in the UK”6 and, as a result, the number on April 14, 2021 dysregulated airway inflammation, with a good efficacy of randomised patients (n=146) was much lower than and safety track record.2,3 In the context of the current that estimated originally (n=398).6 Although logistic pandemic, it was noted that patients with asthma and conditions limiting recruitment into the study are COPD appear to be under-represented among COVID- understandable, under these circumstances it is not 19-infected individuals seeking emergency care, and possible to exclude a potential type I error, so p values it was hypothesised that the chronic use of inhaled might not be valid.7 To address this potential limitation, corticosteroids might have controlled the excessive an independent statistical assessment used bootstrap inflammatory response induced by SARS-CoV-2 in these simulations of a virtual trial with the same study design, individuals.4 Yet, a later observational study did not primary endpoint and duration, and concluded that support this possibility.5 the estimated power was more than 99% to reject the In The Lancet Respiratory Medicine, Sanjay null hypothesis.6 However, this in silico exercise is only Ramakrishnan and colleagues6 explored this hypothesis hypothesis generating,8 supporting, but not confirming, in a prospective, randomised, open-label, phase 2 trial the working hypothesis. that compared treatment with 1600 µg (two puffs of In any case, and acknowledging this important 400 µg to be taken twice per day) of inhaled budesonide, limitation, the study’s results are encouraging. Inhaled a widely used inhaled corticosteroid, versus usual budesonide is a low cost, safe (time censored), effective care in 146 adults within 7 days of the onset of mild (number needed to treat of eight), simple, and widely COVID-19 symptoms.6 The primary outcome of the available therapeutic option, which can be of great trial was urgent care visit, emergency department help around the world, particularly in low-income assessment, or hospitalisation.6 Results showed that, and middle-income countries,9 and can effectively in the per-protocol analysis, this primary outcome complement the global vaccination strategy. Several occurred in ten (14%) participants in the usual care potential mechanisms might underlie these clinical group and one (1%) participant in the budesonide group observations. First, inhaled corticosteroids (including (difference in proportions 0·131, 95% CI 0·043–0·218; budesonide) have been used successfully for decades p=0·004), indicating a relative risk reduction of 91% for to downregulate the excessive inflammation that budesonide; importantly, the number needed to treat characterises several chronic airway diseases such with budesonide to reduce COVID-19 deterioration was as asthma and COPD,2,3 so it is plausible that inhaled eight patients.6 Secondary outcome results showed that budesonide might have contributed to control the www.thelancet.com/respiratory Published online April 9, 2021 https://doi.org/10.1016/S2213-2600(21)00171-5 1 Comment inflammatory response in early COVID-19,4 as systemic Biomèdiques August Pi i Sunyer, Barcelona, Spain (AA, FT, RF); CIBER Enfermedades Respiratorias, Spain (AA, RF); Biostatistics Unit, Faculty of dexamethasone seems to do in patients with severe Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain (FT) COVID-19.10 Second, in patients with asthma and 1 Brodin P. Immune determinants of COVID-19 disease presentation and COPD, inhaled corticosteroids reduce the pulmonary severity. Nat Med 2021; 27: 28–33. 2 Global strategy for the diagnosis, management and prevention of chronic expression of the SARS-CoV-2 viral entry receptor, obstructive pulmonar disease (GOLD). 2021. www.goldcopd.org (accessed angiotensin-converting enzyme 2.11,12 Finally, some March 1, 2021). 3 Global strategy for asthma management and prevention (GINA) 2020 inhaled corticosteroids (including budesonide) reduce or update. 2020. https://ginasthma.org/wp-content/uploads/2020/04/GINA- 2020-full-report_-final-_wms.pdf (accessed March 1, 2021). block SARS-CoV-2 replication in vitro.13,14 4 Halpin DMG, Faner R, Sibila O, Badia JR, Agusti A. Do chronic respiratory Future research will have to explore if the observations diseases or their treatment affect the risk of SARS-CoV-2 infection? Lancet Respir Med 2020; 8: 436–38. in the study by Ramakrishnan and colleagues6 are 5 Schultze A, Walker AJ, MacKenna B, et al. Risk of COVID-19-related death exclusive to budesonide, or represent a class effect among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the of inhaled corticosteroids. In this context, it is worth OpenSAFELY platform. Lancet Respir Med 2020; 8: 1106–20. mentioning that there are other ongoing randomised 6 Ramakrishnan S, Nicolau DV, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, clinical trials using other inhaled corticosteroids or randomised controlled trial. Lancet Respir Med 2021; published online exploring the effects of budesonide in more severe April 9. https://doi.org/10.1016/S2213-2600(21)00160-0 7 Emerson SS, Kittelson JM, Gillen DL. Frequentist evaluation of group (hospitalised) COVID-19 patients. Likewise, the sequential clinical trial designs. Stat Med 2007; 26: 5047–80. observation that clinical recovery was accelerated 8 Sankoh AJ. Interim analyses: an update of an FDA reviewer’s experience and perspective. Drug Info J 1999; 33: 165–76. in patients treated with budesonide6 might suggest 9 Meghji J, Mortimer K, Agusti A, et al. Improving lung health in low-income and middle-income countries: from challenges to solutions. Lancet 2021; that it can prevent or reduce COVID-19 sequelae,15 but 397: 928–40. this also requires specific research. A final lesson from 10 The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med 2021; 384: 693–704. this study is the importance of doing well designed 11 Peters MC, Sajuthi S, Deford P, et al. COVID-19-related genes in sputum randomised clinical trials during a pandemic situation. cells in asthma. Relationship to demographic features and corticosteroids. Am J Respir Crit Care Med 2020; 202: 83–90. Under these tragic circumstances, compassioned care 12 Finney LJ, Glanville N, Farne H, et al. Inhaled corticosteroids downregulate is understandable but unable to produce the scientific the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon. J Allergy Clin Immunol 2021; 147: 510–519. evidence needed to guide best patient care. 13 Yamaya M, Nishimura H, Deng X, et al. Inhibitory effects of AA and RF are the leading investigators of a multicentre, randomised clinical glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal trial supported by AstraZeneca, which is currently exploring the effects of and tracheal epithelial cells. Respir Investig 2020; 58: 155–68. inhaled budesonide in hospitalised patients with COVID-19 pneumonia 14 Matsuyama S, Kawase M, Nao N, et al. The inhaled corticosteroid (NCT04355637). ciclesonide blocks coronavirus RNA replication by targeting viral NSP15. J Virol 2020; 95: e01648-20. *Alvar Agusti, Ferran Torres, Rosa Faner 15 Sibila O, Albacar N, Perea L, et al. Lung function sequelae in COVID-19 aagusti@clinic.cat patients 3 months after hospital discharge. Arch Bronconeumol 2021; Càtedra Salut Respiratòria, Universitat Barcelona, Spain (AA); Respiratory published Feb 24 https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC7903150/ (accessed March 1, 2021). Institute, Hospital Clinic, 08036 Barcelona, Spain (AA); Institut d’Investigacions 2 www.thelancet.com/respiratory Published online April 9, 2021 https://doi.org/10.1016/S2213-2600(21)00171-5