key: cord-1053902-ccy8gf0k authors: Moreno Garcia, E.; Rico Caballero, V.; Albiach, L.; Aguero, D.; Ambrosioni, J.; Bodro, M.; Cardozo, C.; Chumbita, M.; De la Mora, L.; Garcia Pouton, N.; Garcia Vidal, C.; GonzalezCordon, A.; Hernandez Meneses, M.; Inciarte, A.; Laguno, M.; Leal, L.; Linares, L.; Macaya, I.; Meira, F.; Mensa, J.; Moreno, A.; Morata, L.; Puerta Alcalde, P.; Rojas, J.; Sola, M.; Torres, B.; Torres, M.; Tome, A.; Castro, P.; Fernandez, S.; Nicolas, J. M.; Almuedo Riera, A.; Munoz, J.; Fernandez, M. J.; Marcos, M. A.; Soy, D.; Martinez, J. A.; Garcia, F.; Soriano, A. title: Tocilizumab is associated with reduction of the risk of ICU admission and mortality in patients with SARS-CoV-2 infection date: 2020-06-05 journal: nan DOI: 10.1101/2020.06.05.20113738 sha: a40cd2d0ce1556dfd3347ff08265e4733bca0653 doc_id: 1053902 cord_uid: ccy8gf0k Background In some patients the immune response triggered by SARS-CoV-2 is unbalanced, presenting an acute respiratory distress syndrome which in many cases requires intensive care unit (ICU) admission. The limitation of ICU beds has been one of the major burdens in the management around the world, therefore, clinical strategies to avoid ICU admission are needed. Objective We aimed to describe the influence of tocilizumab on the need of transfer to ICU or death in non-critically ill patients. Methods A retrospective study of 171 patients with SARS-CoV-2 infection that did not qualify as requiring transfer to ICU during the first 24h after admission to a conventional ward, were included. The criteria to receive tocilizumab was radiological impairment, oxygen demand or an increasing of inflammatory parameters, however, the ultimate decision was left to the attending physician judgement. The primary outcome was the need of ICU admission or death whichever came first. Results 77 patients received tocilizumab and 94 did not. The tocilizumab group had less ICU admissions (10.3% vs. 27.6%, P= 0.005) and need of invasive ventilation (0 vs 13.8%, P=0.001). In the multivariable analysis, tocilizumab remained as a protective variable (OR: 0.03, CI 95%: 0.007-0*1, P=0.0001) of ICU admission or death. Conclusions Tocilizumab in the early stages of the inflammatory flare, could avoid an important number of ICU admissions and mechanical ventilation use. The mortality rate of 10.3% among patients receiving tocilizumab appears to be lower than other reports. on clinical criteria. Clinical criteria for defining a case of SARS-CoV-2 were the 136 presence of respiratory symptoms with uni or bilateral interstitial infiltrate in the chest-137 X ray without evidence of other potential causes (e.g. heart failure). During the study 138 period, 171 patients that did not qualify as requiring transfer to the ICU during the first 139 24h after admission to a conventional hospital ward, were included. 140 For ARDS, the Berlin definition (10) was applied. When PaO 2 was not available, 141 SpO 2 /FiO 2 ≤ 315 suggested ARDS (including in non-ventilated patients) (11). 142 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. . https://doi.org/10.1101/2020.06.05.20113738 doi: medRxiv preprint The standard protocol included antiviral treatment that consisted of lopinavir/ritonavir 143 400/100 mg BID for 7-14 days plus hydroxychloroquine 400 mg/12h on the first day, 144 followed by 200 mg/12h for the next 4 days. From the 18 th of March onwards, 145 azithromycin 500 mg the first day and 250 mg/24h for 4 additional days was added to 146 the regimen. In addition, a clinical trial with remdesivir was enrolling patients in our 147 institution during the study period. All patients with risk factors for thrombosis received 148 prophylactic doses of low molecular weight heparin (12). Intravenous 149 methylprednisolone was recommended for patients with disease progression to ARDS. 150 The local protocol suggested the use of tocilizumab for patients with pneumonia, 151 progressive respiratory failure (increasing fraction of inspired oxygen) and CRP ≥ 8 152 mg/dL or ferritin ≥800 ng/mL or lymphocyte count < 800 cells/mm 3 . The dose was 400 153 mg/24h iv for patients with ≤75 kg and 600 mg/24h iv for those with >75 kg with the 154 possibility to repeat the dose every 12h up to 3 doses in case of only partial response. 155 However, due to the lack of evidence to support its efficacy, the ultimate decision about 156 using tocilizumab was left to the judgement of the attending physician. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. . https://doi.org/10.1101/2020.06.05.20113738 doi: medRxiv preprint Categorical variables were described using the absolute number and percentage and 167 continuous variables using the mean and standard deviation (SD). Categorical variables 168 were compared using a Chi-squared test or Fisher exact test when necessary, and means 169 by using the Student-t test. For multivariable analysis, variables with a P-value ≤ 0.2 in (17%) among controls. The mean (SD) time from symptoms onset to hospital admission 191 in tocilizumab group was 6.5 (3.3) days while it was 5 (6.5) days in the control group. 192 lymphoma), the need of oxygen at day 1, a CRP > 16 mg/dL and the development of 198 cardiovascular, renal or respiratory (ARDS, invasive ventilation) complications were 199 significantly associated with the primary outcome. In contrast, tocilizumab was the only 200 one protective variable (Table 2 ). In the multivariable analysis, including the PS 201 estimate to receive tocilizumab as a potential confounder, tocilizumab remained as a 202 strong protective variable (OR: 0.03, CI 95%: 0.007-0.1, P=0.0001) of ICU admission 203 or death (Table 3) . 204 205 Monoclonal antibodies directed against key inflammatory cytokines represent a class of 207 potential adjunctive therapies for SARS-CoV-2 infected patients. The rationale for their 208 use is that the underlying pathophysiology of significant lung damage is caused by a 209 cytokine storm being IL-6 one of the main drivers. Therefore, monoclonal antibodies 210 against IL-6 or its receptor could theoretically improve clinical outcomes mainly by 211 reducing the need of ICU admission and consequently the associated mortality. 212 Tocilizumab, a monoclonal antibody IL-6 receptor antagonist, was administered to 77 213 patients admitted to a conventional ward in our hospital and the outcome was compared 214 with 94 patients also admitted in a conventional ward during the same period of time 215 that did not receive tocilizumab. Although this study was not randomized, the 216 characteristics of both groups did not differ in terms of demographics and comorbidities 217 gamma with JAK inhibitors), or a broad-spectrum inhibition with steroids with or 241 without therapeutic strategies to reduce the pro-coagulant status, could be also effective 242 (16-18). On the other hand, although in non-severe cases after one week from symptoms Department of Autoimmune diseases: 291 Espigol G, Espinona G and all the staff members. 292 293 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. . https://doi.org/10.1101/2020.06.05.20113738 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 5, 2020. . https://doi.org/10.1101/2020.06.05.20113738 doi: medRxiv preprint Table 3 . Variables significantly associated with the risk of being admitted in the ICU and/or death Clinical Course and Risk Factors for Mortality of 8