What is Cytokine Release Syndrome?
Cytokine Release Syndrome (CRS) is a systemic inflammatory response characterized by fever, hypotension, hypoxia, and multi-organ dysfunction caused by excessive release of cytokines—primarily from monocytes, macrophages, and other immune effector cells—following immune-based therapies such as CAR T-cell therapy, bispecific antibodies, and monoclonal antibodies. 1
Pathophysiology
CRS results from a supraphysiologic immune response where activated T cells and other immune effector cells trigger massive cytokine release into the circulation. 2, 3 The key mediators are:
- IL-6, IL-1, and nitric oxide derived from recipient monocytes and macrophages (not from the CAR T cells themselves) are the primary determinants of CRS severity 1
- Interferon-gamma and other pro-inflammatory cytokines contribute to the systemic inflammatory cascade 4
- The syndrome represents a non-dose-related, unpredictable Type B adverse drug reaction unrelated to the drug's pharmacological activity 1
Clinical Presentation
Core Features
CRS manifests with a constellation of symptoms that can rapidly progress from mild to life-threatening:
- Fever ≥38°C is the hallmark initial symptom 1, 2, 3
- Cardiovascular: Tachycardia, hypotension requiring vasopressors in severe cases 1
- Respiratory: Hypoxia, shortness of breath, potentially requiring mechanical ventilation 1
- Constitutional: Nausea, headache, asthenia, rash 1, 5
- Multi-organ dysfunction: Can involve cardiac, hepatic, and renal systems 3
Grading System
The American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria define four grades:
- Grade 1: Fever ≥38°C without hypotension or hypoxia 1, 2, 3
- Grade 2: Fever with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen (≤6 L/min) 1, 2, 3
- Grade 3: Fever with hypotension requiring vasopressor (with or without vasopressin) and/or hypoxia requiring high-flow oxygen 1, 2, 3
- Grade 4: Fever with hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure ventilation 1, 2, 3
Important caveat: Fever is not required to grade subsequent CRS severity in patients receiving antipyretics or anticytokine therapy; grading is then based solely on hypotension and/or hypoxia. 1, 2, 3
Timing and Risk Factors
- Onset: CRS typically occurs within hours to days after immune therapy administration, most commonly during or after the first infusion 5
- Highest risk: Patients with hematologic malignancies, high tumor burden, and those receiving CAR T-cell therapy or bispecific T-cell engagers 1, 6
- Pediatric considerations: Almost half of pediatric patients receiving tisagenlecleucel require intensive monitoring due to CRS 1
Associated Conditions and Complications
CRS can occur concurrently with or be followed by:
- CAR T cell-related encephalopathy syndrome (CRES): Characterized by encephalopathy, delirium, seizures, and rarely cerebral edema 1
- Immune effector cell-associated neurotoxicity syndrome (ICANS): Requires separate management from CRS 2
- Secondary infections: Risk elevated by both the underlying immunosuppression and CRS treatments; infections occur in up to 23-24% of patients post-CAR T or BiTE therapy 6
Diagnostic Mimics
Critical pitfall: CRS can be confused with infectious and inflammatory conditions, complicating diagnosis. 6 Key differentiators include:
- Sepsis: Requires infectious workup including blood/urine cultures and chest radiograph 1, 2
- Tumor lysis syndrome: Consider in malignancies with high tumor burden 1
- Non-infectious inflammatory syndromes: Cytokine profiling and biomarkers may aid differentiation 6
Diagnostic Evaluation
When CRS is suspected, obtain:
- Laboratory markers: CBC, comprehensive metabolic panel, magnesium, phosphorus, CRP, LDH, uric acid, fibrinogen, PT/PTT, ferritin 2, 3
- Cytokine levels: IL-6, ferritin, CRP, sIL-2Rα can support diagnosis and guide severity assessment 6
- Infectious workup: Blood and urine cultures, chest radiograph if fever present 2, 3
- Cardiac monitoring: Continuous telemetry and pulse oximetry for Grade 2+ CRS; consider echocardiogram in severe cases 2, 3
Treatment Principles
Management is graded based on severity:
Grade 1 CRS
- Supportive care with antipyretics, IV hydration, symptom management 2, 3
- Consider tocilizumab 8 mg/kg IV (max 800 mg) if symptoms persist >3 days or patient has significant comorbidities 1, 2
Grade 2 CRS
- Tocilizumab 8 mg/kg IV (max 800 mg), repeatable after 8 hours if no improvement (maximum 3 doses in 24 hours, 4 doses total) 1, 2, 3
- Empiric broad-spectrum antibiotics if neutropenic 1
Grade 3 CRS
- Tocilizumab as in Grade 2 plus dexamethasone 10 mg IV every 6 hours 1, 2, 3
- Transfer to ICU for closer monitoring 2, 7
- Supplemental oxygen to maintain saturation >92% 7
Grade 4 CRS
- Tocilizumab as in Grade 2 plus high-dose corticosteroids: methylprednisolone 1000 mg/day IV or dexamethasone 10 mg IV every 6 hours 1, 3
- ICU care with mechanical ventilation as needed 1, 2
- Vasopressor support for refractory hypotension 7
Refractory CRS
For cases not responding to tocilizumab and steroids:
- Anakinra (IL-1 receptor antagonist) 2, 3
- Siltuximab or clazakizumab (alternative IL-6 antagonists) 2, 3
FDA-Approved Treatment
Tocilizumab (ACTEMRA®) is FDA-approved for treatment of CAR T cell-induced severe or life-threatening CRS in adults and pediatric patients ≥2 years of age. 8 Dosing:
- Adults and pediatric patients ≥30 kg: 8 mg/kg IV (max 800 mg) 8
- Pediatric patients <30 kg: 12 mg/kg IV 2
Critical Management Pitfalls
- Delayed recognition: CRS can progress rapidly to life-threatening cardiorespiratory failure; early intervention is essential 1
- Infection vs. CRS: Always perform infectious workup as both can present with fever and hemodynamic instability 1, 2, 6
- Corticosteroid timing: While concerns exist about reducing CAR T-cell efficacy, short courses do not significantly impact outcomes in life-threatening situations and should not be delayed 2, 3
- Tocilizumab and neurotoxicity: Tocilizumab may not be effective for ICANS and may potentially contribute to it 2
- Antifungal prophylaxis: Consider in patients receiving steroids for CRS due to increased infection risk 2, 3