key: cord-0715357-w5yk3fx5 authors: Hofmaenner, Daniel Andrea; Wendel Garcia , Pedro David; Ganter, Christoph Camille; Brugger, Silvio D.; Buehler, Philipp Karl; David, Sascha title: What every intensivist should know about Tocilizumab date: 2021-07-27 journal: Crit Care DOI: 10.1186/s13054-021-03696-1 sha: d8f65a77528364d1a05a5d39fe35838e262626fd doc_id: 715357 cord_uid: w5yk3fx5 nan Treatment strategies against corona virus disease (COVID)-19 have been investigated since the recognition of SARS-CoV-2. Anti-viral strategies such as Remdesivir have shown effects in the early disease phase [1] . Progression is often driven by a dysregulated host response triggering a hyper-inflammatory phenotype. In this state, anti-infectives were inferior to anti-inflammatory strategies. Dexamethasone improves survival in COVID-19 patients with pneumonia requiring oxygen [2] . Tocilizumab-a humanized anti-human IL-6 receptor (IL-6R) antibody of the IgG1 subclass-has gained attention due to a potential synergistic survival benefit [3] , especially in certain subpopulations. Tocilizumab is no stranger to rheumatologists as it has widely been used to treat various disorders such as rheumatoid arthritis. Although some intensivists had experience with Tocilizumab to control CAR-T-associated cytokine release syndrome (CRS), it remains an alien in the intensivists' armamentarium. Still, many colleagues have adopted this drug in light of the recent data to treat severe COVID-19. Given its unknown biological specifics in the critical care context, we have analyzed the longitudinal course of IL-6, together with C-reactive protein (CRP), procalcitonin (PCT) and leucocyte counts in 16 COVID-19 patients (Fig. 1) . Baseline characteristics and outcomes are demonstrated in Table 1 . Tocilizumab was almost exclusively administered if there was a progression of the disease (i.e., requirement of invasive ventilation in those on high-flow oxygen or deterioration in invasively ventilated patients) despite prior steroid use. Aside from reported side effects [3] , we want to highlight the following phenomena: 1. Increase in IL-6 Circulating IL-6 serum levels increase rapidly and profoundly (up to 38×), peak around day 3-5 and stay elevated for many days after Tocilizumab administration. Comparable increases have also been described in other studies [4] . 2. Suppression of CRP In line with the previous literature [4] , IL-6R blockade leads to a sustained suppression of downstream effectors such as CRP. In our cohort, this effect was observed for approximately 14 days rendering its clinical use as a biomarker of infection useless ("CRP-blind spot"). 3. Unchanged leucocyte count and PCT Despite their limited sensitivity and specificity, leukocyte count and PCT are rather unaffected by Tocilizumab and might give additional information during the "CRPblind spot". However, the relevance of these phenomena has still not been elucidated in COVID-19 and should be seen in an individual context. Additionally, we want to highlight two aspects that are of importance when administering Tocilizumab: to cross the blood-brain-barrier but increases the circulating amount of IL-6 (a small molecule that can easily do so) up to 3800%. This phenomenon of induced encephalopathy is known from CAR-T-associated CRS and should be considered when giving Tocilizumab to awake patients (particularly in the context of delirium) [6] . Whereas it has been used in the CAR-T context according to the standard algorithm usually before steroids, in COVID-19, Tocilizumab's effect might be different after prior steroid use.Mechanistically, it has been proposed that the increase in IL-6 is the result of IL-6R blockade, inhibiting internalization of IL-6 after ligation with its receptor. In other words, the blocked IL-6R liberates the release of accumulated IL-6 into the circulation. One can speculate that a given IL-6 increase reflects its local production in the inflamed lung and that this increase might even be useful to predict a clinical Tocilizumab response. In our rather small cohort, no differences between survivors and non-survi- vors were detectable, but a controlled trial would be desirable. Remdesivir improved time to recovery in adults hospitalized with COVID-19 and lower respiratory tract involvement Dexamethasone in hospitalized patients with Covid-19 Interleukin-6 receptor antagonists in critically ill patients with Covid-19 Appropriate use of tocilizumab in COVID-19 infection Risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: a multidatabase cohort study Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Not applicable. Authors' contributions DAH, PDWG and SD analyzed the data. SDB, PKBSD, CG, SD discussed the findings and wrote the manuscript. All authors have proofread the final manuscript version. All authors read and approved the final manuscript. Not applicable. All data supports results for this comment are available with the corresponding author. The analysis was approved by the local ethics committee (Kantonale Ethikkommission Zürich: No. 2020-00646). Not applicable. All authors confirm that they have no competing conflict of interest.