key: cord-0957209-0j9myuef authors: de Roquetaillade, Charles; Guillemin, Jérémie; Picod, Adrien; Mebazaa, Alexandre; Kimmoun, Antoine; Chousterman, Benjamin Glenn title: Single-dose tocilizumab blunts systemic inflammation in severe COVID-19 patients date: 2021-11-14 journal: J Crit Care DOI: 10.1016/j.jcrc.2021.11.001 sha: af5be2db6aa72b5734693cb991da0947428d89ef doc_id: 957209 cord_uid: 0j9myuef nan To the Editor, Interleukin-6 (IL-6) is a major pro-inflammatory cytokine whose concentration correlates with disease severity and survival during COVID-19. Blocking IL-6 pathway with tocilizumab, an anti-IL-6 receptor (IL-6R), was shown to be effective to treat COVID-19 patients and is now recommended by several societies such as NIH [1] . However, the benefits of tocilizumab seems to depend both on patient severity and its association with steroids [2] . Several important questions remain unresolved regarding 1-the impact of anti-IL-6R on systemic inflammation, and 2-the appropriateness of a second dose of tocilizumab for which there is no clear guidance or evidence of benefit [3] [4] [5] . In a previous study among patients suffering from rheumatic arthrtitis treated with tocilizumab, the authors demonstrated that a single dose was sufficient to blunt inflammatory parameters [6] . In COVID19 settings, is has been demonstrated that Tocilizumab could considerably reduces both CRP and PCT which can be used as surrogate of IL6-IL6R pathway inhibition [7] , however, it is unclear whether patients were given a single or two doses of tocilizumab. We therefore hypothesized that a single injection of tocilizumab could be sufficient to blunt systemic inflammation in severe COVID-19 patients. Journal of Critical Care xxx (xxxx) xxx We retrospectively included COVID-19 patients from 3 French centers from 20th of March 2020 to 15th of April 2021 who either received tocilizumab plus dexamethasone or dexamethasone alone. In our institutions, severe patients were treated with dexamethasone using various doses and since September 2020 with 6 mg/d for 10 days after March 2021, Tocilizumab could be administered within 24 h following ICU admission, at physician's discretion, at a single dose of 8 mg/kg intravenously, (D0). For those patients, we measured concentrations of IL-6, C-reactive Protein (CRP), absolute lymphocyte count (ALC), neutrophils, over the first week of ICU admission. Patients with no available immuno-inflammatory monitoring were excluded. Over the 3 participating centers, a total of 54 patients' could be included. Twenty-nine adult patients who received a single dose of tocilizumab plus dexamethasone were compared with 25 patients who received only dexamethasone. Baseline caracteristics were similar between groups at the notable exception of day 0 SOFA which was found superior in the dexamethasone group, mainly due to an increased rate of intubated patients upon ICU admission (4 [4] [5] vs. 3 [2] [3] [4] , p = 0.03) (Table 1) , other severity scores (SAPS II and Charlson comoribidity score) were no different between groups. Overall, tocilizumab + dexamethasone blunted systemic inflammation as compared to dexamethasone ( Fig. 1 (Fig. 1) . Our study strongly suggests that IL-6R blockade with a single dose of tocilizumab is sufficient to blunt systemic inflammation for up to 7 days following administration. The observed increase in IL-6 with the concomitant normalization of serum CRP advocates in favor of an effective shut down of the IL-6-IL-6R classic signaling on which CRP synthesis depends. Several limitations might dampen the impact of our work. First, the observational nature of our study makes it vulnerable to indication bias, indeed we observed a difference in the rate of intubaiton on Fig. 1 . Kinetic analysis of immune parameters in COVID-19 patients within first week of admission according to tocilizumab administration. Time course of immune parameters following ICU-admission between Covid-19 patients who either received dexamethasone + tocilizumab (red) or dexamethasone alone (blue). For intergroup comparison, data were compared using the Mann-Whitney U tests only when interaction was significantly different between group (linear mixed model); CRP: C-reactive protein; PCT: Procalcitonin *p < 0.05. admissin between the two groups. This difference mainly reflects the evolution of patient care during successive waves of COVID-19 and not the severity of disease (same P/F ratio). The observed similar severity scores on admission (SAPS II and Charlson), together with similar ICU-mortality advocates in favor of this hypothesis. The surprising higher occurrence of secondary infection in the dexamethasone group might be due to an higher exposure to mechanical ventilation as well. Indeed several studies have pointed out the increase'd rate of seconday infeciton in patient sexposed to both anti-IL6R antagonist and corticosteroids as compared to corticosteroids alone [2] . Another hypothseis might rely on the inability to detect secondary infection after tocilizumab exposure because of false negative biomarkers like PCT or CRP [7] . Indeed, our analysis do not provide correcion for secondayr infecitons, however, recent litterature have demonstrated that the occurrence of secondary infeciton is very low during the first 7 days of ICU amdission 8 . At last, the non-randomized comparison we provide does not allow a definite causality assumption but the major differences we observe, the strong pathophysiological rational and the longitudinal analysis makes the observed immune alterations most likely the consequence of tocilizumab administration. On the basis of our findings, a second injection within the first 48 h seems not necessary. Serum CRP monitoring appears an excellent marker to assess the efficacy of tocilizumab. The positive impact on ALC could partly explain the benefits of tocilizumab observed in reported studies [3, 4] . CdR, JG, AK, AP and TM collected the data; CdR and BGC conceived the study; AK, CdR, AP and TM make data analysis; AM, BL, YC, CdR, BGC, JG, AK and TM drafted the manuscript. All authors approved the final version of the manuscript. No funding. The dataset used and analyzed for the current study is available from the corresponding author on motivated request. This study was conducted in accordance with the amended Declaration of Helsinki and was approved by the Institutional Review Board (IRB 00006477 HUPNVS, Paris 7, AP-HP). Not applicable. BC served as an advisory board member for Roche diagnostics. All other authors declare no conflict of interest with the present study. Dr. Mebazaa reports personal fees from Orion, Servier, Otsuka, Philips, Sanofi, Adrenomed, Epygon and Fire 1 and grants and personal fees from 4TEEN4, Abbott, Roche and Sphyngotec. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: A meta-analysis Interleukin-6 receptor antagonists in critically Ill patients with Covid-19 Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, openlabel, platform trial. The Lancet Tocilizumab in patients hospitalized with Covid-19 pneumonia Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease Dexamethasone and tocilizumab treatment considerably reduces the value of C-reactive protein and procalcitonin to detect secondary bacterial infections in COVID-19 patients ⁎Corresponding author at: Charles de Roquetaillade, Inserm U942 MASCOT E-mail address: charles.de-roquetaillade@aphp The authors are particurlarly gratefull for all the investigators. Other members of the Toci-Covid study group encomprise Pr. Alexandre Mebazaa (AP-HP, Hôpital Lariboisière, France), Pr. Bruno Levy, Dr. Thomas Merckling (CHU Nancy, Hôpital Brabois, Vandoeuvre-les-Nancy, France) and Pr. Yves Cohen (APHP, Hôpital Avicenne, Bobigny, France).