What are the diagnosis and management steps for suspected Cytokine Release Syndrome (CRS)?

Diagnosis and Management of Cytokine Release Syndrome

For suspected CRS, immediately grade severity using fever, hypotension, and hypoxia criteria, then initiate tocilizumab 8 mg/kg IV (max 800 mg) for Grade 2 or higher CRS while simultaneously ruling out infection with blood cultures and broad-spectrum antibiotics. 1

Diagnostic Criteria and Grading

CRS is graded based on three cardinal features: fever (≥38°C), hypotension, and hypoxia. 1, 2

Grading system:

• Grade 1: Fever ≥38°C without hypotension or hypoxia 1, 2
• Grade 2: Fever ≥38°C with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen (≤6 L/min) 1, 2
• Grade 3: Fever ≥38°C with hypotension requiring vasopressor support and/or hypoxia requiring high-flow oxygen (>6 L/min, face mask, or non-rebreather) 1, 2
• Grade 4: Fever ≥38°C and/or hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure ventilation (CPAP, BiPAP, intubation) 1, 2

Critical diagnostic steps:

• Monitor CRS grading at least every 12 hours, more frequently if clinical status changes 3
• Obtain blood cultures and initiate preemptive broad-spectrum antibiotics immediately, as infection mimics CRS and must be excluded 1, 4
• Perform baseline laboratory workup including CBC, comprehensive metabolic panel, CRP, ferritin, fibrinogen, LDH, and coagulation studies 5, 2
• Conduct neurological evaluation using ICE score (adults) or CAPD score (children) to assess for concurrent immune effector cell-associated neurotoxicity syndrome (ICANS) 1

Management Algorithm by Grade

Grade 1 CRS

• Provide supportive care with acetaminophen for fever and IV hydration 3, 2
• Continue close monitoring every 12 hours or more frequently 3
• Alert ICU team for potential escalation 1

Grade 2 CRS

Administer tocilizumab 8 mg/kg IV (maximum 800 mg; 12 mg/kg for children <30 kg) immediately. 1, 2, 6

• Transfer to ICU, especially in centers with limited experience 1
• If no improvement within 3 days and infection excluded, repeat tocilizumab 8 mg/kg IV (maximum 1 additional dose) 1
• Consider adding dexamethasone 10 mg IV every 6 hours concurrently with second tocilizumab dose if deterioration occurs 1

Grade 3 CRS

Administer tocilizumab 8 mg/kg IV (maximum 800 mg) AND dexamethasone 10 mg IV every 6 hours for 1-3 days. 1, 2

• Transfer to ICU immediately 1, 5
• If deterioration occurs, escalate to dexamethasone 20 mg IV every 6 hours for 3 days with progressive tapering over 3-7 days 1
• Repeat tocilizumab if no improvement within 3 days (maximum 1 additional dose in absence of ICANS) 1

Grade 4 CRS

Administer tocilizumab 8 mg/kg IV (maximum 800 mg) AND dexamethasone 20 mg IV every 6 hours for 3 days. 1, 2

• Immediate ICU transfer with mechanical ventilation support as needed 1, 2
• If no improvement, switch to methylprednisolone 1000 mg/day IV for 3 days, then taper: 250 mg twice daily for 2 days, 125 mg twice daily for 2 days, 60 mg twice daily for 2 days 1
• Consider repeating tocilizumab (maximum 1 additional dose) in absence of ICANS 1

Refractory CRS Management

For patients not responding to tocilizumab and corticosteroids, consider alternative IL-6 pathway inhibitors or IL-1 blockade with anakinra. 2 Siltuximab and clazakizumab are alternative IL-6 antagonists that may be used. 2

Critical Pitfalls and Caveats

Infection versus CRS differentiation: CRS mimics sepsis with fever, hypotension, and organ dysfunction. 4, 7 Always obtain blood cultures and initiate empiric broad-spectrum antibiotics before or concurrent with tocilizumab administration. 1 Up to 23% of CAR T-cell patients develop infections, including bacterial, viral (CMV, HSV), fungal (Candida, Aspergillus), and parasitic pathogens. 4

ICANS overlap: CRS frequently occurs with ICANS, presenting with tremor, confusion, dysphasia, hesitant speech, deterioration in handwriting, agitation, or seizures. 1 Tocilizumab does not treat ICANS and may potentially worsen it. 2 High fever (≥38.9°C) and hemodynamic instability within 36 hours of CAR T-cell infusion predicts severe ICANS. 1

Corticosteroid timing: While short courses of corticosteroids do not significantly impact CAR T-cell efficacy in life-threatening situations, they should not be used prematurely in Grade 1-2 CRS as they may reduce therapeutic benefit. 5, 2 Reserve corticosteroids for Grade 3-4 CRS or refractory Grade 2 CRS. 1

Tocilizumab dosing: The FDA-approved dose is 8 mg/kg (maximum 800 mg) for adults and children ≥30 kg, and 12 mg/kg for children <30 kg. 1, 6 A median of 1 dose (range 1-4) is typically administered. 6

Monitoring during treatment: Perform daily laboratory tests including CBC, comprehensive metabolic panel, CRP, ferritin, and fibrinogen. 5 Monitor for neutropenia (<1000 cells/mcL), thrombocytopenia (<50,000 cells/mcL), and hepatic transaminase elevations (≥5× ULN), which occur in 3.4%, 3.2%, and 11.7% of tocilizumab-treated patients respectively. 6

Infection prophylaxis: Consider antifungal prophylaxis in patients receiving corticosteroids for CRS treatment due to increased infection risk. 5, 2