key: cord-352914-jccxzit1
authors: Sanz Herrero, Francisco; Puchades Gimeno, Francesc; Ortega García, Pilar; Ferrer Gómez, Carolina; Ocete Mochón, María Dolores; García Deltoro, Miguel
title: Methylprednisolone added to tocilizumab reduces mortality in SARS‐CoV‐2 pneumonia: An observational study
date: 2020-06-30
journal: J Intern Med
DOI: 10.1111/joim.13145
sha: 
doc_id: 352914
cord_uid: jccxzit1

Although there are few randomized controlled trials (RCTs) evaluating the efficacy of drugs to treat COVID‐19, different molecules have been used empirically and with great interest in those intended to control the excessive inflammatory response produced by SARS‐CoV‐2. By blocking the IL‐6 receptor, tocilizumab has a role in controlling the inflammatory response. Clinical improvement of respiratory parameters and hospital stay have been described in small series in a series of patients without a control group [1]. There are currently numerous ongoing clinical trials aimed to clarifying the role of this molecule in COVID‐19. The guidelines for the treatment of SARS‐CoV‐2 pneumonia from the Spanish Ministry of Health contemplate the use of tocilizumab as a therapeutic tool for those patients with severe respiratory failure or rapid respiratory deterioration with criteria for admission to the intensive care unit (ICU).

Although there are few randomized controlled trials (RCTs) evaluating the efficacy of drugs to treat COVID-19, different molecules have been used empirically and with great interest in those intended to control the excessive inflammatory response produced by SARS-CoV-2. By blocking the IL-6 receptor, tocilizumab has a role in controlling the inflammatory response. Clinical improvement of respiratory parameters and hospital stay have been described in small series in a series of patients without a control group [1] . There are currently numerous ongoing clinical trials aimed to clarifying the role of this molecule in COVID-19. The guidelines for the treatment of SARS-CoV-2 pneumonia from the Spanish Ministry of Health contemplate the use of tocilizumab as a therapeutic tool for those patients with severe respiratory failure or rapid respiratory deterioration with criteria for admission to the intensive care unit (ICU). However, in clinical practice there are patients who despite treatment with tocilizumab have a torpid evolution with persistent inflammatory response. For this reason, we included methylprednisolone treatment in the local guidelines of our center based on the study by Wu et al [2] . Our work aims to analyze the influence on survival of those patients treated with tocilizumab where methylprednisolone was also added.

Methylprednisolone treatment was introduced in our local treatment protocol on March 27, 2020 in addition to tocilizumab (administered as a single 400 mg dose) for those patients who display one of the following criteria: PaO 2 /FiO 2 <300, SpO 2 <92 (room air), tachypnea, and high ferritin levels. The dosage regimen was methylprednisolone 250 mg administered intravenously daily on the first day followed by 40 mg every 12 hours for 4 more days and stopped without tapering. We compared those patients' treatment consecutively with or without methylprednisolone in two different periods of time (before and after the new treatment protocol began). The primary endpoint was in-hospital all-cause mortality. A bivariate analysis was performed to identify the characteristics of the population receiving treatment with methylprednisolone versus those who were not. For this, the χ 2 test was used with the Yates correction when required, or the Fisher test. Cox proportional hazard regression models were used to calculate between treatments and death. The regression model included demographic

This article is protected by copyright. All rights reserved factors, comorbidities, radiological and laboratory test, and medications. For survival analysis, Kaplan-Meier curves were performed comparing the two treatment arms with and without methylprednisolone using the Log-rank test. Statistical significance was considered for a value of p <0.05. Statistical analysis was performed with SPSS version 23 software (IBM Corp., Armonk, NY). All retrospective analyses were conducted in accordance with the local institutional review board (Project number 58/2020).

We analyzed a population of 72 patients diagnosed with SARS-CoV-2 pneumonia using real-time reverse transcriptase-polymerase chain reaction who were treated with tocilizumab, of whom 77.8% (56 cases) also received treatment with methylprednisolone. Clinical characteristics are described in Table 1 . Both groups did not present differences regarding comorbidities, radiological characteristics, or laboratory data. The main treatment received by the patients was the combination of hydroxychloroquine and azithromycin (94.4%). We did not observe differences regarding the days from admission to treatment with tocilizumab. Regarding the evolution of the patients, we observed that 59.7% were admitted to the ICU. The overall mortality of the series was 29.2%. Methylprednisolone administered in patients treated with tocilizumab reduces the risk of death (risk ratio 0.20, 95% CI 0.08-0.47, p <0.01) (Figure 1 ).

In patients with maximized treatment, who are also especially severe and some with distress criteria, the administration of corticosteroids improved survival in our series.

The role of corticosteroids in reducing host inflammation in response to infection, especially that caused by viruses, is controversial.

A recent meta-analysis assessed the effect of corticosteroids on influenza pneumonia and found that the group treated with corticosteroids had more mortality, a longer ICU stay and more secondary bacterial infections compared to placebo [3] . However, this meta-analysis did not include RCTs, and there is no information in most studies regarding the dose and duration of treatment. On the other hand, pneumonia due to influenza would not be comparable to that produced by SARS-CoV-2, where the pulmonary hyper-inflammation seems to be more relevant

This article is protected by copyright. All rights reserved [4] . A reduction of the viral clearance without differences in the clinical outcomes was observed with the administration of high doses of methylprednisolone in a small RCT during SARS infection [5] . Mortality was not influenced by corticosteroid treatment in MERS patients, but delayed virus clearance and adverse effects were observed [6] . However, this study was carried out only in patients admitted to the ICU with very severe respiratory failure.

On the other hand, in an observational study, Wu et al. recently reported a decrease in mortality in those patients with SARS-CoV-2 acute respiratory distress syndrome (ARDS) who were treated with methylprednisolone, although it is not possible to rule out a selection bias [2] . A recentpublished study has observed that an early short course of methylprednisolone in patients with moderate to severe COVID-19 improved clinical outcomes preventing the development of complications and improving survival [7] .Our study has serious limitations since it is an observational single-center study and it is not a randomized trial. However, we observed an effect on survival without notable adverse effects attributed to the dose and duration of treatment. On the other hand, the precocity in its establishment is one of the facts that we consider key when it comes to impacting the evolution of the patients. We cannot rule out a deleterious effect of interferon in our series.

Our work offers modestly encouraging signs concerning this open question and how important it would be to confirm these data in large randomized controlled trials.

The authors declare that there is no conflict of interest regarding the publication of this article. 

Effective treatment of severe COVID-19 patients with tocilizumab

Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease

The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Effects of early corticosteroid treatment on plasma SARSassociated Coronavirus RNA concentrations in adult patients

Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome

Early Short Course Corticosteroids in Hospitalized Patients with COVID-19

This article is protected by copyright. All rights reserved