The 2019 novel coronavirus (2019-nCoV) outbreak is a major challenge for clinicians. The clinical course of patients remains to be fully characterised, little data are available that describe the disease pathogenesis, and no pharmacological therapies of proven efficacy yet exist. Corticosteroids were widely used during the outbreaks of severe acute respiratory syndrome (SARS)-CoV1Stockman LJ Bellamy R Garner P SARS: systematic review of treatment effects.PLoS Med. 2006; 3: e343Crossref PubMed Scopus (981) Google Scholar and Middle East respiratory syndrome (MERS)-CoV,2Arabi YM Mandourah Y Al-Hameed F et al.Corticosteroid therapy for critically ill patients with middle east respiratory syndrome.Am J Respir Crit Care Med. 2018; 197: 757-767Crossref PubMed Scopus (831) Google Scholar and are being used in patients with 2019-nCoV in addition to other therapeutics.3Huang C Wang Y Li X et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; (published online Jan 24.)https://doi.org/10.1016/S0140-6736(20)30183-5Summary Full Text Full Text PDF Scopus (32878) Google Scholar However, current interim guidance from WHO on clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected (released Jan 28, 2020) advises against the use of corticosteroids unless indicated for another reason.4WHOClinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected. World Health Organization, GenevaJan 28, 2020https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspectedDate accessed: February 2, 2020Google Scholar Understanding the evidence for harm or benefit from corticosteroids in 2019-nCoV is of immediate clinical importance. Here we discuss the clinical outcomes of corticosteroid use in coronavirus and similar outbreaks (table).TableSummary of clinical evidence to dateOutcomes of corticosteroid therapy*Hydrocortisone, methylprednisolone, dexamethasone, and prednisolone.CommentMERS-CoVDelayed clearance of viral RNA from respiratory tract2Arabi YM Mandourah Y Al-Hameed F et al.Corticosteroid therapy for critically ill patients with middle east respiratory syndrome.Am J Respir Crit Care Med. 2018; 197: 757-767Crossref PubMed Scopus (831) Google ScholarAdjusted hazard ratio 0·4 (95% CI 0·2–0·7)SARS-CoVDelayed clearance of viral RNA from blood5Lee N Allen Chan KC Hui DS et al.Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients.J Clin Virol. 2004; 31: 304-309Crossref PubMed Scopus (486) Google ScholarSignificant difference but effect size not quantifiedSARS-CoVComplication: psychosis6Lee DTS Wing YK Leung HCM et al.Factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study.Clin Infect Dis. 2004; 39: 1247-1249Crossref PubMed Scopus (110) Google ScholarAssociated with higher cumulative dose, 10 975 mg vs 6780 mg hydrocortisone equivalentSARS-CoVComplication: diabetes7Xiao JZ Ma L Gao J et al.Glucocorticoid-induced diabetes in severe acute respiratory syndrome: the impact of high dosage and duration of methylprednisolone therapy.Zhonghua Nei Ke Za Zhi. 2004; 43 (in Chinese).: 179-182PubMed Google Scholar33 (35%) of 95 patients treated with corticosteroid developed corticosteroid-induced diabetesSARS-CoVComplication: avascular necrosis in survivors8Li YM Wang SX Gao HS et al.Factors of avascular necrosis of femoral head and osteoporosis in SARS patients' convalescence.Zhonghua Yi Xue Za Zhi. 2004; 84 (in Chinese).: 1348-1353PubMed Google ScholarAmong 40 patients who survived after corticosteroid treatment, 12 (30%) had avascular necrosis and 30 (75%) had osteoporosisInfluenzaIncreased mortality9Ni Y-N Chen G Sun J Liang B-M Liang Z-A The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis.Crit Care. 2019; 23: 99Crossref PubMed Scopus (276) Google ScholarRisk ratio for mortality 1·75 (95% CI 1·3–2·4) in a meta-analysis of 6548 patients from ten studiesRSVNo clinical benefit in children10McGee S Hirschmann J Use of corticosteroids in treating infectious diseases.Arch Intern Med. 2008; 168: 1034-1046Crossref PubMed Scopus (102) Google Scholar, 11Corneli HM Zorc JJ Mahajan P et al.A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis.N Engl J Med. 2007; 357: 331-339Crossref PubMed Scopus (241) Google ScholarNo effect in largest randomised controlled trial of 600 children, of whom 305 (51%) had been treated with corticosteroidsCoV=coronavirus. MERS=Middle East respiratory syndrome. RSV=respiratory syncytial virus. SARS=severe acute respiratory syndrome.* Hydrocortisone, methylprednisolone, dexamethasone, and prednisolone. Open table in a new tab CoV=coronavirus. MERS=Middle East respiratory syndrome. RSV=respiratory syncytial virus. SARS=severe acute respiratory syndrome. Acute lung injury and acute respiratory distress syndrome are partly caused by host immune responses. Corticosteroids suppress lung inflammation but also inhibit immune responses and pathogen clearance. In SARS-CoV infection, as with influenza, systemic inflammation is associated with adverse outcomes.12Tang NL-S Chan PK-S Wong C-K et al.Early enhanced expression of interferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome.Clin Chem. 2005; 51: 2333-2340Crossref PubMed Scopus (169) Google Scholar In SARS, inflammation persists after viral clearance.13Peiris JSM Chu CM Cheng VCC et al.Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study.Lancet. 2003; 361: 1767-1772Summary Full Text Full Text PDF PubMed Scopus (1986) Google Scholar, 14Beijing Group of National Research Project for SARSDynamic changes in blood cytokine levels as clinical indicators in severe acute respiratory syndrome.Chin Med J (Engl). 2003; 116: 1283-1287PubMed Google Scholar Pulmonary histology in both SARS and MERS infections reveals inflammation and diffuse alveolar damage,15Arabi YM Balkhy HH Hayden FG et al.Middle East respiratory syndrome.N Engl J Med. 2017; 376: 584-594Crossref PubMed Scopus (315) Google Scholar with one report suggesting haemophagocytosis.16Nicholls JM Poon LLM Lee KC et al.Lung pathology of fatal severe acute respiratory syndrome.Lancet. 2003; 361: 1773-1778Summary Full Text Full Text PDF PubMed Scopus (913) Google Scholar Theoretically, corticosteroid treatment could have a role to suppress lung inflammation. In a retrospective observational study reporting on 309 adults who were critically ill with MERS,2Arabi YM Mandourah Y Al-Hameed F et al.Corticosteroid therapy for critically ill patients with middle east respiratory syndrome.Am J Respir Crit Care Med. 2018; 197: 757-767Crossref PubMed Scopus (831) Google Scholar almost half of patients (151 [49%]) were given corticosteroids (median hydrocortisone equivalent dose [ie, methylprednisolone 1:5, dexamethasone 1:25, prednisolone 1:4] of 300 mg/day). Patients who were given corticosteroids were more likely to require mechanical ventilation, vasopressors, and renal replacement therapy. After statistical adjustment for immortal time and indication biases, the authors concluded that administration of corticosteroids was not associated with a difference in 90-day mortality (adjusted odds ratio 0·8, 95% CI 0·5–1·1; p=0·12) but was associated with delayed clearance of viral RNA from respiratory tract secretions (adjusted hazard ratio 0·4, 95% CI 0·2–0·7; p=0·0005). However, these effect estimates have a high risk of error due to the probable presence of unmeasured confounders. In a meta-analysis of corticosteroid use in patients with SARS, only four studies provided conclusive data, all indicating harm.1Stockman LJ Bellamy R Garner P SARS: systematic review of treatment effects.PLoS Med. 2006; 3: e343Crossref PubMed Scopus (981) Google Scholar The first was a case-control study of SARS patients with (n=15) and without (n=30) SARS-related psychosis; all were given corticosteroid treatment, but those who developed psychosis were given a higher cumulative dose than those who did not (10 975 mg hydrocortisone equivalent vs 6780 mg; p=0·017).6Lee DTS Wing YK Leung HCM et al.Factors associated with psychosis among patients with severe acute respiratory syndrome: a case-control study.Clin Infect Dis. 2004; 39: 1247-1249Crossref PubMed Scopus (110) Google Scholar The second was a randomised controlled trial of 16 patients with SARS who were not critically ill; the nine patients who were given hydrocortisone (mean 4·8 days [95% CI 4·1–5·5] since fever onset) had greater viraemia in the second and third weeks after infection than those who were given 0·9% saline control.5Lee N Allen Chan KC Hui DS et al.Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients.J Clin Virol. 2004; 31: 304-309Crossref PubMed Scopus (486) Google Scholar The remaining two studies reported diabetes and avascular necrosis as complications associated with corticosteroid treatment.7Xiao JZ Ma L Gao J et al.Glucocorticoid-induced diabetes in severe acute respiratory syndrome: the impact of high dosage and duration of methylprednisolone therapy.Zhonghua Nei Ke Za Zhi. 2004; 43 (in Chinese).: 179-182PubMed Google Scholar, 8Li YM Wang SX Gao HS et al.Factors of avascular necrosis of femoral head and osteoporosis in SARS patients' convalescence.Zhonghua Yi Xue Za Zhi. 2004; 84 (in Chinese).: 1348-1353PubMed Google Scholar A 2019 systematic review and meta-analysis9Ni Y-N Chen G Sun J Liang B-M Liang Z-A The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis.Crit Care. 2019; 23: 99Crossref PubMed Scopus (276) Google Scholar identified ten observational studies in influenza, with a total of 6548 patients. The investigators found increased mortality in patients who were given corticosteroids (risk ratio [RR] 1·75, 95% CI 1·3–2·4; p=0·0002). Among other outcomes, length of stay in an intensive care unit was increased (mean difference 2·1, 95% CI 1·2–3·1; p<0·0001), as was the rate of secondary bacterial or fungal infection (RR 2·0, 95% CI 1·0–3·8; p=0·04). Corticosteroids have been investigated for respiratory syncytial virus (RSV) in clinical trials in children, with no conclusive evidence of benefit and are therefore not recommended.10McGee S Hirschmann J Use of corticosteroids in treating infectious diseases.Arch Intern Med. 2008; 168: 1034-1046Crossref PubMed Scopus (102) Google Scholar An observational study of 50 adults with RSV infection, in which 33 (66%) were given corticosteroids, suggested impaired antibody responses at 28 days in those given corticosteroids.17Lee FE-H Walsh EE Falsey AR The effect of steroid use in hospitalized adults with respiratory syncytial virus-related illness.Chest. 2011; 140: 1155-1161Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar Life-threatening acute respiratory distress syndrome occurs in 2019-nCoV infection.18Chen N Zhou M Dong X et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020; (published online Jan 30.)https://doi.org/10.1016/S0140-6736(20)30211-7Summary Full Text Full Text PDF Scopus (14366) Google Scholar However, generalising evidence from acute respiratory distress syndrome studies to viral lung injury is problematic because these trials typically include a majority of patients with acute respiratory distress syndrome of non-pulmonary or sterile cause. A review of treatments for acute respiratory distress syndrome of any cause, based on six studies with a total of 574 patients,19Ashbaugh DG Bigelow DB Petty TL Levine BE Acute respiratory distress in adults.Lancet. 1967; 2: 319-323Summary PubMed Google Scholar concluded that insufficient evidence exists to recommend corticosteroid treatment.20Lewis SR Pritchard MW Thomas CM Smith AF Pharmacological agents for adults with acute respiratory distress syndrome.Cochrane Database Syst Rev. 2019; 7CD004477PubMed Google Scholar Septic shock has been reported in seven (5%) of 140 patients with 2019-nCoV included in published reports as of Jan 29, 2020.3Huang C Wang Y Li X et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; (published online Jan 24.)https://doi.org/10.1016/S0140-6736(20)30183-5Summary Full Text Full Text PDF Scopus (32878) Google Scholar, 18Chen N Zhou M Dong X et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020; (published online Jan 30.)https://doi.org/10.1016/S0140-6736(20)30211-7Summary Full Text Full Text PDF Scopus (14366) Google Scholar Corticosteroids are widely used in septic shock despite uncertainty over their efficacy. Most patients in septic shock trials have bacterial infection, leading to vasoplegic shock and myocardial insufficiency.21Venkatesh B Finfer S Cohen J et al.Adjunctive glucocorticoid therapy in patients with septic shock.N Engl J Med. 2018; 378: 797-808Crossref PubMed Scopus (608) Google Scholar, 22Annane D Renault A Brun-Buisson C et al.Hydrocortisone plus fludrocortisone for adults with septic shock.N Engl J Med. 2018; 378: 809-818Crossref PubMed Scopus (539) Google Scholar In this group, there is potential that net benefit might be derived from steroid treatment in severe shock.21Venkatesh B Finfer S Cohen J et al.Adjunctive glucocorticoid therapy in patients with septic shock.N Engl J Med. 2018; 378: 797-808Crossref PubMed Scopus (608) Google Scholar, 22Annane D Renault A Brun-Buisson C et al.Hydrocortisone plus fludrocortisone for adults with septic shock.N Engl J Med. 2018; 378: 809-818Crossref PubMed Scopus (539) Google Scholar However, shock in severe hypoxaemic respiratory failure is often a consequence of increased intrathoracic pressure (during invasive ventilation) impeding cardiac filling, and not vasoplegia.23Fougères E Teboul J-L Richard C Osman D Chemla D Monnet X Hemodynamic impact of a positive end-expiratory pressure setting in acute respiratory distress syndrome: importance of the volume status.Crit Care Med. 2010; 38: 802-807Crossref PubMed Scopus (136) Google Scholar In this context, steroid treatment is unlikely to provide a benefit. No clinical data exist to indicate that net benefit is derived from corticosteroids in the treatment of respiratory infection due to RSV, influenza, SARS-CoV, or MERS-CoV. The available observational data suggest increased mortality and secondary infection rates in influenza, impaired clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors. If it is present, the effect of steroids on mortality in those with septic shock is small, and is unlikely to be generalisable to shock in the context of severe respiratory failure due to 2019-nCoV. Overall, no unique reason exists to expect that patients with 2019-nCoV infection will benefit from corticosteroids, and they might be more likely to be harmed with such treatment. We conclude that corticosteroid treatment should not be used for the treatment of 2019-nCoV-induced lung injury or shock outside of a clinical trial. JKB is a member of the WHO panel on clinical management for 2019-nCoV. CDR and JEM declare no competing interests.
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