Early treatment with inhaled budesonide to prevent clinical deterioration in patients with COVID-19
2021; Elsevier BV; Volume: 9; Issue: 7 Linguagem: Inglês
10.1016/s2213-2600(21)00171-5
ISSN2213-2619
AutoresÀlvar Agustí, Ferrán Torres, Rosa Faner,
Tópico(s)Respiratory Support and Mechanisms
ResumoIn most individuals, infection with SARS-CoV-2 is either asymptomatic or produces mild illness (COVID-19) that resolves spontaneously; yet, a small proportion of patients with COVID-19 develop severe disease, require hospitalisation (often in a critical-care setting), and die.1Brodin P Immune determinants of COVID-19 disease presentation and severity.Nat Med. 2021; 27: 28-33Crossref PubMed Scopus (417) Google Scholar A dysregulated type I interferon response to SARS-CoV-2 with overproduction of proinflammatory cytokines seems to be a key pathogenic mechanism underlying progression to severe COVID-19 and death.1Brodin P Immune determinants of COVID-19 disease presentation and severity.Nat Med. 2021; 27: 28-33Crossref PubMed Scopus (417) Google Scholar Thus, controlling this excessive inflammatory response might potentially prevent disease progression. Inhaled corticosteroids have been used for more than 30 years in the treatment of several inflammatory respiratory conditions, such as asthma and chronic obstructive pulmonary disease (COPD), to control dysregulated airway inflammation, with a good efficacy and safety track record.2Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonar disease (GOLD).www.goldcopd.orgDate: 2021Date accessed: March 1, 2021Google Scholar, 3Global strategy for asthma management and prevention (GINA) 2020 update.https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-full-report_-final-_wms.pdfDate: 2020Date accessed: March 1, 2021Google Scholar In the context of the current pandemic, it was noted that patients with asthma and COPD appear to be under-represented among COVID-19-infected individuals seeking emergency care, and it was hypothesised that the chronic use of inhaled corticosteroids might have controlled the excessive inflammatory response induced by SARS-CoV-2 in these individuals.4Halpin DMG Faner R Sibila O Badia JR Agusti A Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection?.Lancet Respir Med. 2020; 8: 436-438Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar Yet, a later observational study did not support this possibility.5Schultze A Walker AJ MacKenna B et al.Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform.Lancet Respir Med. 2020; 8: 1106-1120Summary Full Text Full Text PDF PubMed Scopus (185) Google Scholar In The Lancet Respiratory Medicine, Sanjay Ramakrishnan and colleagues6Ramakrishnan S Nicolau DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, randomised controlled trial.Lancet Respir Med. 2021; (published onlineApril 9.)https://doi.org/10.1016/S2213-2600(21)00160-0Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar explored this hypothesis in a prospective, randomised, open-label, phase 2 trial that compared treatment with 1600 μg (two puffs of 400 μg to be taken twice per day) of inhaled budesonide, a widely used inhaled corticosteroid, versus usual care in 146 adults within 7 days of the onset of mild COVID-19 symptoms.6Ramakrishnan S Nicolau DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, randomised controlled trial.Lancet Respir Med. 2021; (published onlineApril 9.)https://doi.org/10.1016/S2213-2600(21)00160-0Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar The primary outcome of the trial was urgent care visit, emergency department assessment, or hospitalisation.6Ramakrishnan S Nicolau DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, randomised controlled trial.Lancet Respir Med. 2021; (published onlineApril 9.)https://doi.org/10.1016/S2213-2600(21)00160-0Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar Results showed that, in the per-protocol analysis, this primary outcome occurred in ten (14%) participants in the usual care group and one (1%) participant in the budesonide group (difference in proportions 0·131, 95% CI 0·043–0·218; p=0·004), indicating a relative risk reduction of 91% for budesonide; importantly, the number needed to treat with budesonide to reduce COVID-19 deterioration was eight patients.6Ramakrishnan S Nicolau DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, randomised controlled trial.Lancet Respir Med. 2021; (published onlineApril 9.)https://doi.org/10.1016/S2213-2600(21)00160-0Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar Secondary outcome results showed that clinical recovery was also significantly reduced in the budesonide group.6Ramakrishnan S Nicolau DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, randomised controlled trial.Lancet Respir Med. 2021; (published onlineApril 9.)https://doi.org/10.1016/S2213-2600(21)00160-0Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar Based on these observations, the authors concluded that early administration of inhaled budesonide in patients infected with SARS-CoV-2 reduced the likelihood of needing urgent medical care and enhanced clinical recovery.6Ramakrishnan S Nicolau DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, randomised controlled trial.Lancet Respir Med. 2021; (published onlineApril 9.)https://doi.org/10.1016/S2213-2600(21)00160-0Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar Ramakrishnan and colleagues' study is important because it is the first to show that an easily accessible therapeutic intervention is effective to prevent COVID-19 clinical deterioration. However, the study has a potentially important limitation that needs careful consideration: it was terminated early due to "the impact of the national pandemic control measures and national prioritisation rules for clinical research trials in the UK"6Ramakrishnan S Nicolau DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, randomised controlled trial.Lancet Respir Med. 2021; (published onlineApril 9.)https://doi.org/10.1016/S2213-2600(21)00160-0Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar and, as a result, the number of randomised patients (n=146) was much lower than that estimated originally (n=398).6Ramakrishnan S Nicolau DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, randomised controlled trial.Lancet Respir Med. 2021; (published onlineApril 9.)https://doi.org/10.1016/S2213-2600(21)00160-0Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar Although logistic conditions limiting recruitment into the study are understandable, under these circumstances it is not possible to exclude a potential type I error, so p values might not be valid.7Emerson SS Kittelson JM Gillen DL Frequentist evaluation of group sequential clinical trial designs.Stat Med. 2007; 26: 5047-5080Crossref PubMed Scopus (58) Google Scholar To address this potential limitation, an independent statistical assessment used bootstrap simulations of a virtual trial with the same study design, primary endpoint and duration, and concluded that the estimated power was more than 99% to reject the null hypothesis.6Ramakrishnan S Nicolau DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, randomised controlled trial.Lancet Respir Med. 2021; (published onlineApril 9.)https://doi.org/10.1016/S2213-2600(21)00160-0Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar However, this in silico exercise is only hypothesis generating,8Sankoh AJ Interim analyses: an update of an FDA reviewer's experience and perspective.Drug Info J. 1999; 33: 165-176Crossref Scopus (12) Google Scholar supporting, but not confirming, the working hypothesis. In any case, and acknowledging this important limitation, the study's results are encouraging. Inhaled budesonide is a low cost, safe (time censored), effective (number needed to treat of eight), simple, and widely available therapeutic option, which can be of great help around the world, particularly in low-income and middle-income countries,9Meghji J Mortimer K Agusti A et al.Improving lung health in low-income and middle-income countries: from challenges to solutions.Lancet. 2021; 397: 928-940Summary Full Text Full Text PDF PubMed Scopus (144) Google Scholar and can effectively complement the global vaccination strategy. Several potential mechanisms might underlie these clinical observations. First, inhaled corticosteroids (including budesonide) have been used successfully for decades to downregulate the excessive inflammation that characterises several chronic airway diseases such as asthma and COPD,2Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonar disease (GOLD).www.goldcopd.orgDate: 2021Date accessed: March 1, 2021Google Scholar, 3Global strategy for asthma management and prevention (GINA) 2020 update.https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-full-report_-final-_wms.pdfDate: 2020Date accessed: March 1, 2021Google Scholar so it is plausible that inhaled budesonide might have contributed to control the inflammatory response in early COVID-19,4Halpin DMG Faner R Sibila O Badia JR Agusti A Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection?.Lancet Respir Med. 2020; 8: 436-438Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar as systemic dexamethasone seems to do in patients with severe COVID-19.10The RECOVERY Collaborative GroupDexamethasone in hospitalized patients with COVID-19.N Engl J Med. 2021; 384: 693-704Crossref PubMed Scopus (6947) Google Scholar Second, in patients with asthma and COPD, inhaled corticosteroids reduce the pulmonary expression of the SARS-CoV-2 viral entry receptor, angiotensin-converting enzyme 2.11Peters 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; 202: 83-90Crossref PubMed Scopus (352) Google Scholar, 12Finney LJ Glanville N Farne H et al.Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon.J Allergy Clin Immunol. 2021; 147: 510-519Summary Full Text Full Text PDF PubMed Scopus (105) Google Scholar Finally, some inhaled corticosteroids (including budesonide) reduce or block SARS-CoV-2 replication in vitro.13Yamaya 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; 58: 155-168Crossref PubMed Scopus (199) Google Scholar, 14Matsuyama S Kawase M Nao N et al.The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15.J Virol. 2020; 95: e01648-e01650Crossref PubMed Scopus (142) Google Scholar Future research will have to explore if the observations in the study by Ramakrishnan and colleagues6Ramakrishnan S Nicolau DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, randomised controlled trial.Lancet Respir Med. 2021; (published onlineApril 9.)https://doi.org/10.1016/S2213-2600(21)00160-0Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar are exclusive to budesonide, or represent a class effect of inhaled corticosteroids. In this context, it is worth mentioning that there are other ongoing randomised clinical trials using other inhaled corticosteroids or exploring the effects of budesonide in more severe (hospitalised) COVID-19 patients. Likewise, the observation that clinical recovery was accelerated in patients treated with budesonide6Ramakrishnan S Nicolau DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 illness (STOIC): a phase 2, open-label, randomised controlled trial.Lancet Respir Med. 2021; (published onlineApril 9.)https://doi.org/10.1016/S2213-2600(21)00160-0Summary Full Text Full Text PDF PubMed Scopus (282) Google Scholar might suggest that it can prevent or reduce COVID-19 sequelae,15Sibila O Albacar N Perea L et al.Lung function sequelae in COVID-19 patients 3 months after hospital discharge.Arch Bronconeumol. 2021; (published Feb 24)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903150/Date accessed: March 1, 2021Crossref Scopus (30) Google Scholar but this also requires specific research. A final lesson from this study is the importance of doing well designed randomised clinical trials during a pandemic situation. Under these tragic circumstances, compassioned care is understandable but unable to produce the scientific evidence needed to guide best patient care. This online publication has been corrected. The corrected version first appeared at thelancet.com on April 14, 2021 This online publication has been corrected. The corrected version first appeared at thelancet.com on April 14, 2021 AA and RF are the leading investigators of a multicentre, randomised clinical trial supported by AstraZeneca, which is currently exploring the effects of inhaled budesonide in hospitalised patients with COVID-19 pneumonia (NCT04355637). Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trialEarly administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery after early COVID-19. Full-Text PDF Correction to Lancet Respir Med 2021; published online April 9. https://doi. org/10.1016/S2213-2600(21)00171-5Agusti A, Torres F, Faner R. Early treatment with inhaled budesonide to prevent clinical deterioration in patients with COVID-19. Lancet Respir Med 2021; published online April 9. https://doi.org/10.1016/S2213-2600(21)00171-5—In this Comment, the dose of budesonide should have been 400 μg per actuation, to a total dose (two puffs to be taken twice per day) of 1600 μg. This correction has been made to the online version as of April 14, 2021, and the printed version is correct. Full-Text PDF
Referência(s)