key: cord-0929737-1nw707dg authors: Ooi, Say Tat; Parthasarathy, Purnima; Yi, Lin; Nallakaruppan, Valliammai; Ng Jia Huey, Shereen; Tan, Teck Choon; Serena, Low; Terence, Tang title: Antivirals with Adjunctive Corticosteroids Prevent Clinical Progression of Early COVID-19 Pneumonia: A Retrospective Cohort Study date: 2020-10-14 journal: Open Forum Infect Dis DOI: 10.1093/ofid/ofaa486 sha: 672d6cf14e8e93b111f5f135979b72bc94ac726e doc_id: 929737 cord_uid: 1nw707dg This is a retrospective cohort study of hospitalized adults with COVID-19, 57 received treatment alone and 35 received treatment with adjunctive prednisolone. Combination of corticosteroids and antivirals was associated with lower risk of clinical progression and invasive MV or death in early COVID-19 pneumonia. Coronavirus disease 2019 (COVID-19) ranges from asymptomatic to severe pneumonia with respiratory failure. 1, 2, 3 Severe COVID-19 is typically marked by rapid clinical deterioration with features of hyperinflammation. 4, 5 Recent studies on use of tocilizumab and dexamethasone have shown promising results in reducing mortality in severe COVID- 19. 7,8 However, treatment approach for early infection remains unclear. At our center, treatment of COVID-19 has included interferon beta, lopinavir/ritonavir and hydroxycholoroquine (HCQ). Prednisolone and tocilizumab were added as adjunctive therapy for COVID-19 in mid-April 2020 when there were reports suggesting potential benefit with its use. 9,10,11, 12 We aim to evaluate the effect of antivirals with adjunctive corticosteroids in the management of COVID-19. This is a retrospective cohort study of hospitalized adults (≥18 years) with COVID- 19 , confirmed by PCR on nasopharyngeal swab, who received treatment from February 9, 2020 to May 31, 2020. Those who were on supportive care only, on invasive mechanical ventilation (MV) prior to treatment or those admissions not related to respiratory illness were excluded. A c c e p t e d M a n u s c r i p t 3 Decision to initiate treatment was at discretion of the treating physicians in consultation with an Infectious Diseases physician. Treatment regimens included lopinavir/ritonavir 400/100 mg twice a day or hydroxychloroquine 400mg twice on day 1, followed by 200mg three times a day on days 2-5 and prednisolone. Dose of prednisolone varied from 30mg once a day to 40mg twice a day depending on severity of illness and patient's body weight. Corticosteroids use of 3 days or more for any medical indications was considered as adjunctive corticosteroids. Patients were classified into two groups; Group A received treatment without corticosteroids and Group B received treatment with adjunctive corticosteroids. Comparison of continuous and categorical data between groups was done using Mann-Whitney U test and χ2 test or Fisher's exact test when appropriate. Changes in C-reactive protein (CRP) and daily maximal body temperature were compared between treatment groups. Data was preprocessed with entropy balancing to achieve covariate balance between the two treatment groups and reduce model dependence for estimation of treatment effects. 13 Weight derived from entropy reweighting scheme was used to generate stabilized weight for subjects in the cohort. Balanced covariate is defined by standardized mean difference of less than 0.1 and variance ratio between 0.5 - There were 1046 patients with COVID-19 admitted to our institution during the study period. Of these, 94 (9.0%) patients were initiated on treatment. Two patients were excluded as treatment was initiated following invasive MV. In total, 57 patients Table S2 ). Eight subjects received tocilizumab in our cohort. All were given post MV except two cases (one in each treatment group). Table S3 ). One death occurred in Group A following invasive MV and none in Group B. Analysis of composite outcome was the same as clinical progression. In overall cohort, weighted Cox regression analysis showed a statistically significant lower risk of clinical progression in Group B compared to Group A, however there was no statistically significant difference in risk of invasive MV or death between the two groups (Table 1 ). In subgroup with pneumonia, unweighted Kaplan-Meier estimates showed 58.8% HCQ has been shown to effectively inhibit SARS-CoV-2 infection in vitro. 18 However, its clinical efficacy has largely been reported as ineffective. The RECOVERY trial reported an increased risk of invasive MV or death with use of HCQ compared to supportive care. 19 We found that the group received antivirals without corticosteroids in our cohort had a more protracted course with a higher inflammatory response. Their CRP trended to higher level at day 5-8 post treatment despite a similar fever response in both groups. Perhaps this is a paradoxical inflammatory reaction due to treatment. The use of prednisolone during early pneumonia in our study had a significantly better outcome which may be due to the concurrent administration of antiviral agents such as HCQ or lopinavir/ritonavir. The prominent protective effect of adjunctive prednisolone observed in M a n u s c r i p t Transmission of 2019-nCoV infection from an asymptomatic contact in Germany Clinical Characteristics of Coronavirus Disease 2019 in China Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China SARS-CoV-2: a storm is raging COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal COVID-19: consider cytokine storm syndromes and immunosuppression Entropy Balancing for Causal Effects: A Multivariate Reweighting Method to Produce Balanced Samples in Observational Studies Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 Corticosteroid Domain randomized clinical trial Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multicentre, randomized A c c e p t e d M a n u s c r i p t