key: cord-292892-6gwnhkn4 authors: Liu, Bingwen; Li, Min; Zhou, Zhiguang; Guan, Xuan; Xiang, Yufei title: Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? date: 2020-04-10 journal: J Autoimmun DOI: 10.1016/j.jaut.2020.102452 sha: doc_id: 292892 cord_uid: 6gwnhkn4 Abstract The emergent outbreak of coronavirus disease 2019 (COVID-19) has caused a global pandemic. Acute respiratory distress syndrome (ARDS) and multiorgan dysfunction are among the leading causes of death in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a cytokine storm, also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19. However, the efficacy of corticosteroids, commonly utilized antiinflammatory agents, to treat COVID-19-induced CRS is controversial. There is an urgent need for novel therapies to treat COVID-19-induced CRS. Here, we discuss the pathogenesis of severe acute respiratory syndrome (SARS)-induced CRS, compare the CRS in COVID-19 with that in SARS and Middle East respiratory syndrome (MERS), and summarize the existing therapies for CRS. We propose to utilize interleukin-6 (IL-6) blockade to manage COVID-19-induced CRS and discuss several factors that should be taken into consideration for its clinical application. cytokines (interleukin-4) in addition to T helper 1 cytokines compared to those in 150 patients with SARS or MERS. There are many potential therapies targeting the host 151 immune system that may be effective for COVID-19, such as inflammatory cytokine 152 blockade (IL-6, IL-1, and IFN), stem cell therapy, immune cell depletion, transfusion of 153 convalescent plasma and artificial extracorporeal liver support [32], among which we 154 believe IL-6 blockade is a promising strategy for COVID-induced CRS. We noticed 155 that elevated IL-6 levels were consistently reported in several studies of COVID-19 156 [33 -36] and might serve as a predictive biomarker for disease severity [37] . A large 157 retrospective cohort study found that IL-6 levels were correlated with mortality in 158 patients with COVID-19 [6] . Mechanistically, IL-6 is essential for the generation of T 159 helper 17 (Th17) cells in the dendritic cell-T cell interaction [30] . The excessive IL-6 160 may explain the overly activated Th17 cells observed in COVID-19 patients, as 161 reported by Xu et al [8] . Although clinical data of IL-6 blockade in virus 162 infection-related CRS are unavailable, animal studies of SARS-CoV have 163 demonstrated that inhibiting nuclear factor kappa-B (NF-κB), a key transcription factor 164 of IL-6, or infecting animals with SARS-CoV lacking the coronavirus envelope (E) 165 protein, a strong stimulus to NF-κB signaling, increased animal survival, with reduced 166 IL-6 levels [38] . Interestingly, we noticed that the E proteins of SARS-CoV-2 ( Tocilizumab is a recombinant humanized monoclonal anti-IL-6R antibody. It 173 binds both soluble and membrane-bound IL-6R to inhibit IL-6-mediated cis-and 174 trans-signaling [41] . Tocilizumab has been approved by the U.S. Food and Drug 175 Administration for the treatment of severe CAR T cell-induced CRS (Table 2 ) [12] . 176 As mentioned earlier, CRS is the most severe adverse effect induced by CAR T cell 177 therapy, with an incidence of 50-100% [41] . It is believed that binding of the CAR T 178 cell receptor to its antigen induces the activation of bystander cells to release massive 179 amounts of interferon γ (IFN-γ) and tumor necrosis factor-α (TNF-α), which further 180 activate innate immune cells, including macrophages and endothelial cells, to secrete 181 IL-6 and other inflammatory mediators [42] . IL-6 is a central mediator of toxicity in 182 CRS, and its level correlates with the severity of CAR T cell-induced CRS [12, 43] . 183 Clinically, severe cases of CAR-T induced CRS present with fever, hypoxia, acute 184 renal failure, hypotension, and cardiac arrhythmia that often warrants ICU admission 185 [12] . Tocilizumab showed promising efficacy in severe CRS. After one or two doses of 186 tocilizumab, 69% of patients responded within 14 days, for whom fever and 187 hypotension resolved within hours, and vasopressors could be weaned quickly in 188 several days [10, 41] . The effect of tocilizumab has also been reported in CRS related to tocilizumab is safe for both pediatric and adult patients, as no adverse reactions have 191 been reported in a retrospective analysis of patients with CAR T cell-induced CRS [41] . 192 The most common serious adverse effect is infections in patients with rheumatoid 193 arthritis, in which chronic therapy is maintained for a longer period of time 194 jaws was reported in patients with osteoporosis [48] . 197 Given the efficacy of tocilizumab in CRS and the pivotal role of IL-6 in COVID- 19, 198 we propose to repurpose tocilizumab to treat severe cases of COVID-19. Regarding its 199 clinical use, we suggest taking the following factors into consideration and hope that 200 future clinical trials will be able to address them. 1) Diagnosis criteria. There is 201 currently no consensus in diagnosing CRS in COVID-19. Early diagnosis of CRS in 202 COVID-19 patients and prompt initiation of immunomodulatory treatment may be 203 beneficial, as suggested by the experience in HLH [49] . Prompt screening of 204 COVID-19 patients with Hscore, a diagnostic score for HLH, may help to discriminate 205 patients with CRS [50] .2) Disease severity grading system. Experience with 206 immunotherapy-triggered CRS suggests that tocilizumab is indicated only for severe 207 cases, while the risk benefit assessment favors symptomatic management for mild 208 cases [10] . This approach is rationalized by the worry that aggressive antiinflammation 209 principle is not shared in viral infections, such as COVID-19, in which timely 211 intervention in mild or moderate patients may prevent progression. A disease severity 212 grading system may provide an objective tool to assess the most appropriate timing to 213 initiate tocilizumab treatment. Currently, the Chinese guidelines for COVID-19 grade 214 patients into mild, moderate, severe and critical by vital signs, radiographic findings 215 and complications [51] . It is currently unclear which population may benefit the most should be cautious. 5) Cytokine measurement. Cytokine levels may serve as 232 biomarkers for risk stratification and prognosis. A previous cohort study suggested that 233 IL-6 levels were significantly elevated in COVID-19 patients but varied considerably 234 among both ICU and non-ICU patients [34] . This observation raises the question of 235 whether IL-6 blockade is effective only in patients with elevated serum IL-6 levels. If 236 so, IL-6 measurement may be an indispensable part of the grading system. Moreover, 237 the IL-6 level alone may not be sufficient to reflect its functional downstream effects 238 [52] . An assay that distinguishes functional IL-6 from total IL-6 may provide a refined 239 approach to guide therapeutic decisions. C-reactive protein (CRP), an acute-phase 240 inflammatory protein synthesized by IL-6-dependent hepatic biosynthesis, is a reliable 241 marker of IL-6 bioactivity and is used to predict CRS severity and monitor IL-6 242 blockade efficacy for patients with CAR T cell-induced CRS [10, 12] . The CRP level in 243 virus-induced CRS remains to be determined. Most studies suggested that elevated 244 CRP levels were associated with severe COVID-19 [37, 53, 54] , with a few exceptions 245 [35] . Nevertheless, future studies on biomarkers are needed for the purpose of risk 246 stratification and therapeutic effect monitoring. There is also a battery of biological 247 agents available that target various critical molecules in the inflammatory network 248 (Table 2) , such as IL-1, IL-18, TNF, and IFN, or Janus kinase/signal transducer and 249 activator of transcription (JAK/STAT) signaling. These agents may also be beneficial, 250 and if so, routine inflammatory cytokine measurement is warranted. 251 originated in bats, a nature reservoir of various coronavirus species with high genomic 253 diversity [55, 56] . It is unclear how many bat coronaviruses are directly or indirectly 254 transmissible to humans and how many have the potential to cause disease, especially 255 for those that share the viral spike sequence and are capable of using the human 256 ACE2 receptor for entry [55] . Thus, it is highly likely that a novel bat coronavirus 257 could cause future epidemics. For future epidemic preparedness and to reduce 258 mortality in COVID-19 patients, global effort is needed to promote novel therapy to 259 treat virus-induced CRS during the COVID-19 outbreak. Potential therapies available 260 for CRS are summarized in Table 2 . We hope that this assessment will spur future anti-inflammatory drugs, COX-2: cyclo-oxygenase 2; S1P1: sphingosine-1-phosphate receptor 1, NF-κB: nuclear factor kappa-B. 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