key: cord-315930-1vgb2mk0
authors: Andrianopoulos, Ioannis; Papathanasiou, Athanasios; Papathanakos, Georgios; Chaidos, Aristeidis; Koulouras, Vasilios
title: Tocilizumab's efficacy in patients with Coronavirus Disease 2019 (COVID‐19) is determined by the presence of cytokine storm
date: 2020-06-29
journal: J Med Virol
DOI: 10.1002/jmv.26209
sha: 
doc_id: 315930
cord_uid: 1vgb2mk0

We read with great interest the research article written by Borku Uysal B et al which is in accordance with the so far accumulating knowledge that tocilizumab is an effective treatment for COVID-19 cytokine storm syndrome (CSS). This article is protected by copyright. All rights reserved.

On the other hand, preliminary results from the Smatteo COVID-19 registry (SMACORE) study are contradictory. 7 In this published article there was no difference between the control and the tocilizumab treatment groups in mortality and intensive care unit (ICU) hospitalization. This leads us to two hypotheses: one that tocilizumab is not effective in patients with COVID-19 as evidence from a clinical trial is stronger than observational studies or that tocilizumab is indeed effective and there are certain reasons that the clinical trial has failed to prove the primary hypothesis.

First of all in our opinion SMACORE is grossly underpowered to answer the question of death and ICU admission. A rough estimation of statistical power indicates that 250 patients are needed in each arm to show 20% reduction in deaths with p 0.05 (statistical power 80%). 8 Our limited experience on tocilizumab suggests that in the setting of acute respiratory failure where the patient has fever, bilateral infiltrates on chest x-ray, raised C-reactive protein (CRP) (above 100 mg/dL), raised interleukin-6 (IL-6) (≥80 pg/mL) and significant hypoxemia (Po 2 : FiO 2 [PFO] ratio <150) tocilizumab is indeed effective in putting breaks on the disease and potentially avoiding further deterioration, leading to intubation, prolonged mechanical ventilation, and potentially death. The above is also in accordance with the findings from the Brescia study, that early treatment with tocilizumab improves outcome in patients with well-established CSS. 4 In the SMACORE study inclusion criteria are significantly different. First of all, the mortality and ICU rate of admission of the patients in the trial was lower than the one noted in the observational studies, but comparable to the mortality and ICU admission rate of all hospitalized patients in the New York City area suggesting that the population pool of the study was all hospitalized patients rather than the sicker ones that the other studies probably included. 9 This is also deduced from the median PFO ratio which was rather high for the tocilizumab group of patients (224.8) which suggests that patients that received tocilizumab in this study did not have the severity of hypoxemia used in most studies.

If the conclusions of this preliminary analysis are confirmed by the final results of SMACORE study, then this might suggest that not all hospitalized patients benefit from tocilizumab (as it happens in all treatments), as around 80% of these patients will improve with standard care treatment anyway. Recent data show that severe COVID-19 disease is driven by a complex immune dysregulation that involves the production of inflammatory cytokines (such as IL-6) as well as immune-dysregulation through IL-6 driven human leukocyte antigen D related (HLA-DR) decreased expression. 10, 11 Immune dysregulation through an IL-6 driven mechanism appears to be more frequent than the macrophage activation syndrome in patients with severe COVID-19 disease. This immune dysregulation, that is generally referred to as COVID-19 associated CSS, appears to be present in almost all patients with acute respiratory failure. 11 The tocilizumab hypothesis of treatment is that it blocks this immune dysregulation-hyperinflammatory reaction that COVID-19 causes in patients mainly through restoration of the HLA-DR expression. 11 Hyperinflammation syndrome is clinically well defined and associated with the combined presence of high fever, raised CRP, hyperferritinemia, hypertriglyceridemia, low platelets, and raised IL-6 levels and all these criteria need to be taken into account, as well as hypoxemia, when tocilizumab treatment is considered in patients with COVID-19. 12 

Tociluzumab challenge: a series of cytokine storm therapy experience in hospitalized COVID-19 pneumonia patients

Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia

Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients

Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia

Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19

Tocilizumab treatment in COVID-19: a single center experience

Tocilizumab for treatment of severe COVID-19 patients: preliminary results from Smatteo COVID-19 registry (SMACORE). Microorganisms

Sample size estimation in clinical trial

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City

Trained immunity: a tool for reducing susceptibility to and the severity of SARS-CoV-2 infection

Complex immune dysregulation in COVID-19 patients with severe respiratory failure

COVID-19: consider cytokine storm syndromes and immunosuppression