What is cytokine release syndrome (CRS) caused by chimeric antigen receptor (CAR) T-cell therapy and how is it treated?

Updated: Dec 17, 2020
  • Author: Sameh Gaballa, MD, MS; Chief Editor: Emmanuel C Besa, MD  more...
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CRS is a potentially life-threatening complication of CAR T cell therapy. It is a systemic inflammatory response that results when the activated CAR T cells rapidly release large amounts of cytokines, including interleukin-6 (IL-6) and interferon γ, into the bloodstream. Clinically, CRS presents as flulike illness, with fever and systemic symptoms (eg, nausea, fatigue, headache, myalgias, malaise). With higher grades of CRS, patients can develop hypotension and multi-organ toxicity (eg, acute respiratory distress syndrome, renal failure, liver failure, cardiac dysfunction, disseminated intravascular coagulation, and encephalopathy). [4, 34]

ASTCT CRS grading is based on the presence and severity of fever, hypotension, and hypoxia (see Table 1, below). Organ toxicities associated with CRS may be graded according to Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0), but they do not influence CRS grading. [33]

Table 1. American Society for Transplantation and Cellular Therapy Consensus Grading of Cytokine Release Syndrome (CRS) (Open Table in a new window)



Grade 1

Fever ≥38°C

Grade 2

Fever ≥38°C with

Hypotension not requiring vasopressors and/or

Hypoxia requiring low-flow oxygen via nasal cannula or blow-by


Grade 3

Fever ≥ 38°C with

Hypotension requiring a vasopressor with or without vasopressin and/or

Hypoxia requiring high-flow oxygen via nasal cannula, facemask, nonrebreather mask, or Venturi mask


Grade 4

Fever ≥ 38°C with

Hypotension requiring multiple vasopressors (excluding vasopressin) and/or

Hypoxia requiring positive pressure ventilation (eg, CPAP, BiPAP, intubation and mechanical ventilation)

BiPAP=bilevel positive airway pressure; CPAP=continuous positive airway pressure


  • Fever must not be attributable to any other cause. In patients treated with antipyretics or anti-cytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent severity; instead, grading is driven by hypotension and/or hypoxia.
  • CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with hypotension requiring 1 vasopressor and hypoxia requiring low-flow nasal cannula is classified as having grade 3 CRS.
  • Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/min. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/min.

The onset of CRS is typically within 14 days after CAR T-cell infusion and coincides with maximal expansion of CAR T cells. The incidence and severity of CRS appear to be greater in patients with a large tumor burden and in those with an active infection at the time of CAR T infusion, presumably because those patients experience higher levels of T-cell activation. [34]

CRS is a diagnosis of exclusion. Therapy begins with symptomatic measures for mild manifestations (fluids, fever management, antibiotics). As CRS severity progresses, patients may need supplemental oxygen, mechanical ventilation, or vasopressors. [34, 33]

Tocilizumab, an antibody targeting the IL-6 receptor, has become standard therapy for CRS and is the first-line treatment for progressive CRS. Fever and hypotension often resolve within a few hours after administration of tocilizumab, allowing patients to be weaned off vasopressors and other supportive care measures. In patients whose condition does not improve or stabilize after they receive tocilizumab, an additional 1 or 2 doses of tocilizumab can be administered.

Second-line treatment options for CRS include other immunosuppressant medications such as glucocorticosteroids or siltuximab. [34, 35] Theoretically, steroids may inhibit CAR T efficacy, but judicious use is necessary to dampen the severity of CRS and to minimize toxicity.

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