key: cord-0858605-5oprt4j7 authors: Quartuccio, Luca; Sonaglia, Arianna; Pecori, Davide; Peghin, Maddalena; Fabris, Martina; Tascini, Carlo; De Vita, Salvatore title: Higher levels of IL‐6 early after tocilizumab distinguish survivors from non‐survivors in COVID‐19 pneumonia: a possible indication for deeper targeting IL‐6 date: 2020-06-09 journal: J Med Virol DOI: 10.1002/jmv.26149 sha: 948da0d46d594712ebfeb9a936d986fbbc325574 doc_id: 858605 cord_uid: 5oprt4j7 INTRODUCTION: The most serious COVID‐19 deriving from severe acute respiratory syndrome coronavirus 2 causes cytokine release storm and it is associated with worse outcomes. In COVID‐19 patients, Interleukin (IL)‐6 levels are significantly elevated. Blocking IL‐6 preliminary resulted in the improvement of this hyperinflammatory state. It is unknown which patients could require higher doses of tocilizumab to get out of the cytokine storm. MATERIALS AND METHODS: Twenty‐four patients affected by COVID‐19 pneumonia were included. All the patients underwent tocilizumab 8 mg/kg intravenously and were tested for serum IL‐6 24‐48 hours before and 12‐48 hours after tocilizumab infusion. Comparisons between survivors and non‐survivors were performed. RESULTS: Eighteen patients were discharged, while six patients died, with no clinical or laboratory differences between the two groups at baseline. IL‐6 was not different at baseline (p=0.41), while 24‐48h post‐tocilizumab IL‐6 serum levels were significantly higher in non‐survivors than in survivors [2398.5 (430.5‐9372) pg/mL vs 290.5 (58.5‐1305.5) pg/mL, p=0.022)]. Serum IL‐6 post‐tocilizumab showed a good predictive ability to discriminate survivors from non‐survivors (AUC 0.815 95%CI 0.63‐0.99, p=0.02). CONCLUSION: Repeated measurement of serum level of IL‐6 early after tocilizumab may distinguish non‐survivors from survivors and support the choice of deeper targeting IL‐6 in COVID‐19 pneumonia. This article is protected by copyright. All rights reserved. At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, China. It rapidly spread, resulting in an epidemic throughout China, followed by an increasing number of cases in other countries throughout the world. In February 2020, the World Health Organization designated the disease COVID-19, which stands for coronavirus disease 2019 1 . The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This article is protected by copyright. All rights reserved. COVID-19 pneumonia and all of them were tested for serum IL-6 24-48 hours before and within 48 hours after tocilizumab infusion. Only one of them received two tocilizumab infusions two days apart. Serum IL-6 was measured by CE_IVD electrochemiluminescence immunoassay (Elecsys IL6, Cobas, physiological range < 7pg/mL) 7 . Variables were reported as mean and standard deviation or median and interquartile range (IQR), as appropriate, or frequency rates and percentages if categorical; consequently, comparisons between survivors and non-survivors were made by parametric tests (t-test for two independent samples) or no parametric tests (Mann-Whitney test) for continuous variables. Proportions were compared by χ2 test, or Fisher exact test. For unadjusted comparisons, a 2-sided α of less than .05 was considered statistically significant. A receiver operating characteristic curve (ROC curve) was made to identify the optimal cut-off value for serum IL-6 post-tocilizumab that was able to distinguish survivors and non-survivors. Ethical approval for this study was given by "Comitato Etico Unico Regionale (CEUR)", with the following registration number: CEUR-2020-Os-102. The study was conducted in accordance with the ethical principles of the Helsinki Declaration. Patients' consents for using data for research purpose were obtained at the time of hospital admission. Eighteen patients recovered and were discharged, while six patients died. There were no differences between the two groups regarding sex, age, weight, time to tocilizumab infusion from onset, Charlson's index and other clinical and laboratory baseline features as reported in table 1. Notably, there was no difference between the two groups as regards baseline IL-6 levels (p=0.41) (table 1), while 24-48h post-tocilizumab IL-6 serum levels were significantly higher in non-survivors than in survivors [2398.5 (430.5-9372) pg/mL vs 290.5 (58.5-1305.5) pg/mL, p=0.022)]. In addition, C-reactive protein (CRP) level was significantly higher in non-survivors than in survivors (114.5±83.6 mg/L vs 54.5±34.9 pg/mL, p=0.04), while procalcitonin did not differ (0.69 (0.36-1.13) ng/mL vs 0.07 (0.04-0.92) ng/mL, p=0.21). Lactate dehydrogenase, total white blood cell count, lymphocyte count and platelet count did not differ between survivors and non- 130 pg/ml before tocilizumab, 433 pg/mL 24 hours after, and 51 pg/mL after one week. Recent data suggest that severe COVID-19 causes cytokine release storm and it is associated with worse clinical outcomes 10 . IL-6 plays a pivotal role in this clinical scenario. In fact, in COVID-19 patients treated with tocilizumab, IL-6 levels are significantly elevated, which are supportive of cytokine storm 11 . It is plausible that This article is protected by copyright. All rights reserved. blocking IL-6 resulted in the improvement of this hyperinflammatory state, especially in patients with baseline higher levels of IL-6 7, 9, 12 . Ongoing randomized control trials will allow for further evaluation of this promising therapy. It is known that following initiation of tocilizumab, there is an elevation in the IL-6 levels due to saturation of the IL-6 receptors by the drug 13 It may be argued that in older people there is a dysregulated innate immunity and damage from too much IL-6 15 , even if the virus is killed. However, non-survivors were not older than survivors in this study, as well as in the study by Luo et al. 15 CRP values showed similar differences between survivors and non-survivors as seen for IL-6, even if less significant. Non-survivors showed a less clear reduction in CRP levels and, interestingly, procalcitonin appeared not to decrease after tocilizumab. Tocilizumab increases the risk of secondary infections, as other biologic agents do 16 , and it could mask infections by inhibiting CRP production 17 . Importantly, procalcitonin, as well as white blood cell count, did not differ between the two groups, thus the higher levels of IL-6 or CRP in non-survivors were unlikely This article is protected by copyright. All rights reserved. This study has some limitations: first, the retrospective nature, secondly, the absence of corrections for confounding factors and the small number of patients included; therefore, it needs confirmation by larger studies, and a more precise definition of the cut-off value of serum IL-6. To conclude, though preliminary, this study may provide a useful indication for This article is protected by copyright. All rights reserved. World Health Organization. Director-General's remarks at the media briefing on Accepted Article Distress Syndrome: A Case Report Brescia International Research and Training HUB (BIRTH). Tocilizumab for the Treatment of Severe Pneumonia With Hyperinflammatory Syndrome and Acute Respiratory Failure: A Single Center Study of 100 Patients in Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: results from a single Italian Centre study on tocilizumab versus standard of care Safety and efficacy of early high-dose IV anakinra in severe COVID-19 lung disease Elevated Interleukin-6 and Severe COVID-19: A Meta-Analysis The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease The relevance of serum procalcitonin quantification for differential diagnosis of infections and rheumatic diseases Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor Tcell therapy COVID-19: Consider IL6 Receptor Antagonist for the Therapy of Cytokine Storm Syndrome in SARS-CoV-2 Infected Patients