Cytokine Release Syndrome: When the Emergency Department Meets Immunotherapy and Everyone Gets Nervous

Is it sepsis? Pulmonary embolism? Tumor progression? Cytokine release syndrome (CRS) can masquerade as all of these and missing it can be fatal, with reported mortality as high as 58%. For emergency clinicians, evaluating patients receiving immunotherapy is increasingly common and often intimidating, as presentations are nonspecific, and management differs from traditional critical illness. This presentation highlights high-yield pearls and common pitfalls in recognizing and managing CRS in the emergency department. CRS is defined by the National Comprehensive Cancer Network as a supraphysiologic immune response to therapies that activate or engage T cells or other immune effector cells. Symptoms are initially vague, including fever, fatigue, headache, and myalgias, but can rapidly progress to hypotension, hypoxia, and multiorgan failure. CRS should be considered in any patient recently treated with chimeric antigen receptor (CAR) T-cell therapy or bispecific T-cell engager (BiTE) therapy, commonly used in multiple myeloma, B-cell acute lymphoblastic leukemia, B-cell lymphoma, small cell lung cancer, and uveal melanoma. Onset most often occurs within 2–3 days of infusion but may be delayed up to 15 days. Decisions in CRS management are nuanced. Corticosteroids, frequently used reflexively in the emergency department, may improve symptoms but risk impairing CAR-T cell expansion and durability of remission. Steroids should be reserved for severe disease, such as immune effector cell–associated neurotoxicity syndrome (ICANS), and ideally administered in collaboration with oncology. Tocilizumab, an interleukin-6 receptor antagonist, is first-line therapy for severe CRS and does not compromise antitumor efficacy; however, it may worsen ICANS and can mask infection by suppressing fever and inflammatory markers. In patients with concern for superimposed infection, empiric broad-spectrum antibiotics similar to neutropenic sepsis regimens should be initiated. CRS belongs on the differential for any patient with recent CAR-T or BiTE therapy presenting with systemic inflammatory symptoms. Early recognition and thoughtful use of immunomodulatory therapies are critical to improving outcomes.