Treatment of Cytokine Release Syndrome
For Grade 1 CRS, provide supportive care with antipyretics and IV hydration; for Grade 2, administer tocilizumab 8 mg/kg IV; for Grade 3, add dexamethasone 10 mg IV every 6 hours to tocilizumab; and for Grade 4, escalate to high-dose methylprednisolone 500 mg IV every 12 hours with tocilizumab and ICU-level care. 1, 2
CRS Grading System
The American Society for Transplantation and Cellular Therapy (ASTCT) defines CRS severity based on fever, hypotension, and hypoxia requirements 2, 3:
- Grade 1: Temperature ≥38°C without hypotension or hypoxia 1, 2
- Grade 2: Temperature ≥38°C with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen (≤6 L/min) 1, 2
- Grade 3: Temperature ≥38°C with hypotension requiring vasopressor support and/or hypoxia requiring high-flow oxygen delivery 1, 2
- Grade 4: Temperature ≥38°C with hypotension requiring multiple vasopressors and/or hypoxia requiring positive pressure ventilation 1, 2
Critical caveat: Once antipyretics or anticytokine therapy is initiated, fever is no longer required for grading—subsequent severity is determined solely by hypotension and/or hypoxia 1, 3
Initial Evaluation and Monitoring
Before initiating treatment, obtain comprehensive laboratory workup including CBC, comprehensive metabolic panel, magnesium, phosphorus, CRP, LDH, uric acid, fibrinogen, PT/PTT, and ferritin 2. Perform blood and urine cultures with chest radiograph if fever is present to exclude infection 2, 3. For Grade 2 or higher CRS, implement continuous cardiac telemetry and pulse oximetry 2. Consider echocardiogram to assess cardiac function in severe cases 1, 2.
Grade-Specific Treatment Algorithm
Grade 1 CRS Management
Provide supportive care with antipyretics, IV hydration, and symptomatic management of organ toxicities 1, 2. Consider empiric broad-spectrum antibiotics if neutropenic 1. May use G-CSF per product guidelines, but GM-CSF is not recommended 1.
For persistent fever >3 days or patients with significant comorbidities, consider early tocilizumab 8 mg/kg IV (not exceeding 800 mg) 2, 3.
Grade 2 CRS Management
Continue supportive care and add IV fluid boluses and/or supplemental oxygen as needed 1. Administer tocilizumab 8 mg/kg IV over 1 hour (maximum 800 mg per dose) 1, 2, 4. Repeat every 8 hours if no improvement in signs and symptoms, limiting to maximum three doses in 24 hours with four doses total 1, 2.
For hypotension persisting after two fluid boluses and one to two doses of tocilizumab, consider dexamethasone 10 mg IV every 12 hours for one to two doses, then reassess 1. If no improvement within 24 hours of starting tocilizumab, escalate to Grade 3 management 1.
Grade 3 CRS Management
Admit patient to ICU and continue supportive care with vasopressors as needed 1, 2. If echocardiogram not already performed, obtain to assess cardiac function and conduct hemodynamic monitoring 1.
Administer tocilizumab as per Grade 2 protocol if maximum dose not reached within 24 hours, plus dexamethasone 10 mg IV every 6 hours 1, 2, 3. Rapidly taper dexamethasone once symptoms improve 1. If refractory, escalate to Grade 4 management 1.
Grade 4 CRS Management
Continue supportive care with mechanical ventilation as needed 1, 2. Administer tocilizumab as per Grade 2 if maximum not reached within 24 hours 1.
Initiate high-dose methylprednisolone 500 mg IV every 12 hours for 3 days, followed by structured taper: 250 mg IV every 12 hours for 2 days, then 125 mg IV every 12 hours for 2 days, then 60 mg IV every 12 hours until CRS improves to Grade 1 1, 2. If not improving, consider methylprednisolone 1,000 mg IV twice daily or alternate therapy 1.
Refractory CRS Management
For CRS refractory to tocilizumab and steroids, consider alternative agents 1, 2:
- Anakinra (IL-1 receptor antagonist) 2, 3
- Siltuximab (alternative IL-6 antagonist) 2, 3
- Other options with limited experience include ruxolitinib, cyclophosphamide, and antithymocyte globulin 1
Special Populations and Considerations
Pediatric Dosing
For pediatric patients <30 kg, tocilizumab is dosed at 12 mg/kg 2, 4. Tocilizumab is FDA-approved for CAR T cell-induced severe or life-threatening CRS in adults and pediatric patients ≥2 years 2, 4.
CAR T-Cell Therapy Context
Earlier steroid use reduces the rate of CAR T-cell treatment-related CRS and neurologic events for certain products (axicabtagene ciloleucel or brexucabtagene autoleucel) 1, 3. The decision to use immunosuppression should balance CRS severity against potential impact on CAR T-cell efficacy 1.
COVID-19-Associated CRS
For hospitalized COVID-19 patients receiving systemic corticosteroids who require supplemental oxygen or mechanical ventilation, tocilizumab is indicated 4. Initiation thresholds differ: do not start if ANC <1000/mm³, platelets <50,000/mm³, or ALT/AST >10× ULN 4.
Critical Pitfalls and Caveats
Infection versus CRS: CRS frequently mimics infection, making differentiation challenging 5. Always perform appropriate infectious workup before attributing symptoms solely to CRS 2, 3, 5. Infections occur in up to 23% of patients post-CAR T therapy 5.
Concurrent ICANS: CRS may occur with immune effector cell-associated neurotoxicity syndrome (ICANS), which requires separate management 1, 2, 3. Tocilizumab may not be effective for ICANS and may potentially contribute to it 2.
Antifungal prophylaxis: Strongly consider antifungal prophylaxis in patients receiving steroids for CRS treatment 1, 2, 3.
Organ dysfunction: CRS may be associated with cardiac, hepatic, and/or renal dysfunction that should be graded according to CTCAE v5.0, though these do not influence CRS grading itself 1, 3.
Corticosteroid timing: While short courses of corticosteroids do not appear to significantly impact CAR T-cell efficacy, delay their use when possible in Grade 1-2 CRS to maximize therapeutic benefit 2. However, do not withhold steroids in Grade 3-4 CRS due to life-threatening nature 1.