emDOCs Podcast – Episode 77: CAR T-cell and Cytokine Release Syndrome

Today on the emDOCs cast, Brit Long, MD (@long_brit) covers Part 1 in a series on complications of CAR T-cell therapy, specifically cytokine release syndrome (CRS).

Episode 77: CAR T-cell Therapy and Cytokine Release Syndrome


  • Vast array of new cancer therapies, including chimeric antigen receptor (CAR) T-cell therapy, antibodies, cytokines, oncolytic viruses, and vaccines.
  • CAR T-cell therapy is a type of immunomodulation which uses genetically modified T-cells to attack malignant cells.
  • Primarily used for ALL, CLL, Non-Hodgkin’s, multiple myeloma. Currently under study for Hodgkin’s lymphoma and solid tumors.



  • CAR T cell therapy involves T cells attacking cancer cells.
  • Process:
    • 1. T-cells present in the blood are removed from the patient or from a donor (less common).
    • 2. T-cells are incorporated with the gene encoding specific antigen receptors.
    • 3. This results in CAR receptors on the surface of T-cells.
    • 4. The modified T-cells are harvested and grown in a laboratory setting.
    • 5. The patient undergoes chemotherapy for lymphocyte depletion, and then the engineered T-cells are finally administered to the original patient.


  • Infusion usually occurs in the outpatient setting.
  • The two major complications of CAR T-cell therapy include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), or CAR T-cell-related encephalopathy syndrome (CRES).
  • Others are infusion reaction, hypogammaglobulinemia, tumor lysis syndrome (TLS), cytopenias, cardiac toxicity, and graft-versus-host disease (GVHD).


Cytokine Release Syndrome

  • CRS is a serious complication with fever and multiorgan dysfunction (Figure 2).
    • CRS is a supraphysiologic response to CAR T-cell therapy that leads to elevated cytokine activity (interleukin (IL) 6, interferon (IFN), and tumor necrosis factor (TNF) alpha) and activation of endothelial cells, macrophages, and T-cells.
  • CRS occurs in 25%-50% of patients treated with CAR T-cell therapy for ALL, but the incidence is lower in patients with NHL, CLL, and multiple myeloma.
  • Severity is associated with the disease burden of the malignancy, molecular design, level of T-cell activation in response to CAR T-cell infusion, lymphodepletion prior to infusion, and dose of CAR T-cells
  • Onset of symptoms is 1-14 days after therapy, but severe CRS usually occurs shortly after CAR T cell therapy. Duration can be days to weeks.
  • Signs/symptoms range from mild, flu-like symptoms to severe, life-threatening inflammation and end organ injury. Fever has to be present for the diagnostic criteria.
    • Mild symptoms include rash, headache, myalgias, and fatigue.
    • Gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are common.
    • Severe, uncontrolled CRS may include circulatory collapse, vascular leakage, edema, renal failure, cardiac dysfunction, and multiorgan failure.
    • Neurologic symptoms can occur several days after the onset of CRS and include aphasia, altered mental status, weakness, seizures, and cerebral edema.
    • Grading is based on cardiopulmonary dysfunction and related treatment intervention; the most severe event noted is used to define the grade

  • Consider CRS following CAR T-cell therapy in patients with fever, hypotension, hypoxia, tachypnea, tachycardia, dyspnea, myalgias, fatigue, nausea, vomiting, and diarrhea.
  • Nonspecific presentation. Patients look like sepsis or septic shock. Must keep sepsis, heart failure, pulmonary embolism (PE), hemophagocytic lymphohistiocytosis, tumor lysis syndrome, and tumor progression on the differential.


ED Evaluation

  • History: symptoms (fever, dyspnea, pain, rash), baseline patient function, disease status, burden of illness, immunotherapy type, dose, and schedule.
  • Physical examination should focus on the skin, hearts, lungs, abdomen, and neurologic system.
  • Testing: Labs and imaging are nonspecific; diagnosis needs to be based on history and end organ injury.
    • CBC, electrolytes, magnesium/phos/Ca, renal/liver function, uric acid, coags, blood cultures, CRP.
    • ECG, BNP, troponin if cardiopulmonary symptoms present.
      • Significant risk of cardiac ischemia and arrhythmia.
    • May see leukocytosis, leukopenia, neutropenia, and/or thrombocytopenia may be present due to chemotherapy, the malignancy, or other isues
    • Elevated creatinine and liver enzymes are common, as are electrolyte abnormalities, including hypophosphatemia (75%), hypokalemia (56%), and hyponatremia (51%).
    • Coagulation panel abnormalities may occur.
    • Confirmatory tests are interferon gamma, IL-6, IL-10, and soluble IL-2R alpha levels, but not available in the ED.
    • CXR for cardiopulmonary symptoms.



  • Stabilization, evaluation for concomitant pathologies (e.g., sepsis, PE), and providing targeted therapy based upon the CRS grade.
  • Involve hematology/oncology early.
  • If the patient is critically ill, start with IV fluids, vasopressors, and broad-spectrum antibiotics. These patients will look like sepsis. Respiratory support will be needed for severe cases.
  • Targeted therapy is based on CRS severity
    • Mild CRS can typically be treated with antipyretics, intravenous fluids, antihistamines, and monitoring.
    • Other grades may need steroids plus tocilizumab, but this is best left to the heme/onc and critical care specialist.
      • Patients with severe CRS (consisting of some patients with grade 2 CRS and all patients with grades 3-4 CRS) may receive tocilizumab, an IL-6 antagonist, plus a steroid. This combination provides more rapid and complete control compared with either agent alone
      • For those with less severe manifestations meeting criteria for grade 2 CRS, tocilizumab may be used alone.
      • Options for steroids include hydrocortisone 100 mg every 8 hours, dexamethasone 10 mg up to four times per day, or methylprednisolone 1 mg/kg/day.
      • Steroids should be used alone in patients with neurologic findings.
      • Other monoclonal antibodies may be used if tocilizumab is not effective.
    • All patients should be admitted.


Stay tuned for Part 2, where we cover neurotoxicity, infusion reactions, cytopenias, and cardiac toxicity!



  1. Long B, Yoo MJ, Brady WJ, Holian A, Sudhir A, Gottlieb M. Chimeric antigen receptor T-cell therapy: An emergency medicine focused review. Am J Emerg Med. 2021 Dec;50:369-375.
  2. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018 Jun 15;6(1):56.
  3. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor Tcell therapy-assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47–62.
  4. Liu D, Zhao J. Cytokine release syndrome: grading, modeling, and new therapy. J Hematol Oncol. 2018 Sep 24;11(1):121.
  5. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638.


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