Treatment of Cytokine Release Syndrome (CRS)
The primary treatment for cytokine release syndrome is tocilizumab (anti-IL-6 receptor antibody), with corticosteroids added for refractory cases, while providing appropriate supportive care based on CRS severity. 1
CRS Definition and Grading
CRS is a systemic inflammatory response characterized by fever, tachycardia, hypoxia, hypotension, and potential multi-organ dysfunction caused by the release of cytokines from activated immune cells. It commonly occurs following CAR T-cell therapy, bispecific antibodies, and other immunotherapies.
The American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system classifies CRS into four grades:
| Grade | Characteristics |
|---|---|
| Grade 1 | Fever ≥38°C without hypotension or hypoxia |
| Grade 2 | Fever with hypotension responsive to fluids/low-dose vasopressors OR hypoxia requiring low-flow oxygen |
| Grade 3 | Fever with hypotension requiring vasopressors OR hypoxia requiring high-flow oxygen |
| Grade 4 | Fever with hypotension requiring multiple vasopressors OR hypoxia requiring mechanical ventilation |
Management Algorithm
Initial Evaluation and Monitoring
- Complete blood count, comprehensive metabolic panel, magnesium, phosphorus, CRP, LDH, uric acid, fibrinogen, PT/PTT, and ferritin 2
- Blood and urine cultures, chest radiograph if fever present
- Continuous cardiac telemetry and pulse oximetry for grade ≥2 CRS
- Consider echocardiogram for severe CRS to assess cardiac function 2
Grade 1 CRS Management
- Antipyretics, IV hydration, and symptomatic management
- Consider tocilizumab 8 mg/kg IV (not exceeding 800 mg) for prolonged symptoms >24 hours or in high-risk patients 2, 1
- Consider empiric broad-spectrum antibiotics if neutropenic 2
Grade 2 CRS Management
- Continue supportive care plus IV fluid boluses and supplemental oxygen
- Administer tocilizumab 8 mg/kg IV (not exceeding 800 mg) 2
- Repeat tocilizumab every 8 hours if no improvement, maximum 3 doses in 24 hours or 4 doses total
- For persistent hypotension after 1-2 doses of tocilizumab, add dexamethasone 10 mg IV every 12 hours 2
- Escalate to Grade 3 management if no improvement within 24 hours 2
Grade 3 CRS Management
- Transfer to ICU
- Continue tocilizumab as in Grade 2
- Add dexamethasone 10 mg IV every 6 hours 2
- Vasopressors as needed
- Obtain echocardiogram and perform hemodynamic monitoring
- Escalate to Grade 4 management if refractory 2
Grade 4 CRS Management
- Continue ICU care with mechanical ventilation as needed
- Continue tocilizumab as in Grade 2
- Initiate high-dose methylprednisolone 500-1000 mg IV every 12 hours for 3 days, followed by a taper 2
- For refractory cases, consider alternative therapies such as anakinra (IL-1 receptor antagonist), siltuximab, ruxolitinib, or other immunosuppressants 2, 1
Special Considerations
Pediatric Dosing
- For children <30 kg, administer tocilizumab at 12 mg/kg IV 1
Steroid Use Caution
- While necessary for severe CRS, corticosteroids may potentially impact the efficacy of immunotherapy 1
- Strongly consider antifungal prophylaxis in patients receiving steroids for CRS 2
Concurrent Conditions
- Monitor for concurrent immune effector cell-associated neurotoxicity syndrome (ICANS), which may require additional management 2, 1
- Avoid medications that cause CNS depression in patients with neurological symptoms 1
Refractory CRS
- For cases not responding to tocilizumab and steroids, consider:
- Anakinra (IL-1 receptor antagonist)
- Siltuximab (alternative IL-6 antagonist)
- Continuous renal replacement therapy (CRRT) for cytokine removal in severe cases 3
Common Pitfalls and Caveats
Delayed recognition: Early identification of CRS is critical for timely intervention. Fever is typically the first sign.
Underestimating progression: CRS can rapidly progress from mild to severe; close monitoring is essential even with mild symptoms.
Infection vs. CRS: Symptoms of CRS can mimic infection. Always perform infection workup but don't delay CRS treatment while awaiting results.
Tocilizumab timing: Delaying tocilizumab administration in moderate-severe CRS can lead to worse outcomes. Don't hesitate to administer for grade ≥2 CRS.
Steroid concerns: While there are concerns about steroids potentially reducing CAR T-cell efficacy, the benefit of treating life-threatening CRS outweighs this risk in severe cases.
Overlooking organ dysfunction: CRS can affect multiple organ systems; comprehensive monitoring of cardiac, renal, hepatic, and pulmonary function is essential.
Forgetting that fever may be masked: In patients receiving antipyretics, CRS grading is driven by hypotension and/or hypoxia rather than fever 2.