A Differential Therapeutic Consideration for use of Corticosteroids According to Established COVID-19 Clinical Phenotypes in Critically Ill Patients
Authors: Moreno Gerard , Botella Manuel Ruíz- , Martin-Loeches Ignacio , Alvarez Josep Gómez , Herrera María Jiménez , Saera María Amparo Bodí , Armestar Fernando , Parra Asunción Marques - , Estella Angel , Trefler Sandra , García Ruth Jorge , Payá Josefa Murcia , Cortes Pablo Vidal , Díaz Emili , Ferrer Ricard , Moreno Antonio Albaya , Crespi Lorenzo Socias , Goytisolo Josep María Bonell , Chinesta Susana Sancho , Loza Ana , Espina Lorena Forcelledo , Laderas Juan Carlos Pozo , deAlba-Aparicio María , Montori Laura Sánchez , Perapoch Inmaculada Vallverdu , Hidalgo Virginia , Gutiérrez Virginia Fraile , Ortega Ana María Casamitjana , Serrano Fátima Martín , Nieto Mercedes , Cortes Marisa Blasco , Marín-Corral Judith , Solé-Violan Jordi , Rodriguez Alejandro 
Published: May 2021

Abstract
Background: The steroids are currently used as standard treatment for severe COVID-19. However, the evidence is weak. Our aim is to determine if the use of corticosteroids was associated with Intensive Care Unit (ICU) mortality among whole population and pre-specified clinical phenotypes.Methods: A secondary analysis derived from multicenter, observational study of adult critically ill patients with confirmed COVID-19 disease admitted to 63 ICUs in Spain. Three phenotypes were derived by non-supervised clustering analysis from whole population and classified as (A: severe, B: critical and C: life-threatening). The primary outcome was ICU mortality. We performed a Multivariate analysis after propensity score full matching (PS), Cox proportional hazards (CPH), Cox covariate time interaction (TIR), Weighted Cox Regression (WCR) and Fine-Gray analysis(sHR) to assess the impact of corticosteroids on ICU mortality according to the whole population and distinctive patient clinical phenotypes. Results: A total of 2,017 patients were analyzed, 1171(58%) with corticosteroids. After PS, corticosteroids were shown not to be associated with ICU mortality (OR:1.0,95%CI:0.98-1.15). Corticosteroids were administered in 298/537(55.5%) patients of “A” phenotype and their use was not associated with ICU mortality (HR=0.85[0.55-1.33]). A total of 338/623(54.2%) patients in “B” phenotype received corticosteroids. The CPH (HR =0.65 [0.46-0.91]) and TIR regression (1- 25 day tHR=0.56[0.39-0.82] and >25 days tHR=1.53[1.03-7.12]) showed a biphasic effect of corticosteroids due to proportional assumption violation. No effect of corticosteroids on ICU mortality was observed when WCR was performed (wHR=0.72[0.49-1.05]). Finally, 535/857(62.4%) patients in “C” phenotype received corticosteroids. The CPH (HR=0.73[0.63-0.98]) and TIR regression (1- 25 day tHR=0.69[ 0.53-0.89] and >25 days tHR=1.30[ 1.14-3.25]) showed a biphasic effect of corticosteroids and proportional assumption violation. However, wHR (0.75[0.58-0.98]) and sHR (0.79[0.63-0.98]) suggest a protective effect of corticosteroids on ICU mortality. Conclusion: Our finding warns against the widespread use of corticosteroids in all critically ill patients with COVID-19 at moderate-high dose. Only patients with the highest severity could benefit from steroid treatment although this effect on clinical outcome was minimized during ICU stay.