Cytokine release syndrome after treatment with immune checkpoint inhibitors: an observational cohort study of 2672 patients from Karolinska University Hospital in Sweden

Immune checkpoint inhibitors (ICIs) are linked to diverse immune-related adverse events (irAEs). Rare irAEs surface first in clinical practice. Here, we systematically studied the rare irAE, cytokine-release syndrome (CRS), in a cohort of 2672 patients treated with ICIs at Karolinska University Hospital in Stockholm, Sweden. We find that the risk of ICI-induced CRS, defined as fever, negative microbiological findings and absence of other probable causes within 30 days after ICI treatment, is approximately 1%, higher than previously reported. ICI-induced CRS was often mild and ICI rechallenge was generally safe. Two out of 28 patients experienced high-grade CRS, and one was fatal. While C-reactive protein and procalcitonin were not discriminative of fatal CRS, our data suggest that the quick Sequential Organ Failure Assessment (qSOFA) score might identify high-risk patients. These data provide a framework for CRS risk assessment and motivate multicenter studies to improve early CRS diagnosis. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement LLL is supported by Clas Groschinsky foundation, the Swedish Cancer Society and Region Stockholm (ALF FoUI-974888). MG is supported by The Swedish Research Council, project 2018-02023. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the national Ethical Review Board (etikprovningsmyndigheten, ethical approval Dnr 2022-05600-01). Informed consent for this study was waived by the Ethical Review Board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors; access may require a new application for ethical approval.