What are the guidelines for monitoring Cytokine Release Syndrome (CRS)?

Guidelines for Monitoring Cytokine Release Syndrome (CRS)

CRS monitoring should be performed at least once every 12 hours and more frequently if there is a change in the patient's clinical status or reasons for concern, as early detection and prompt management can significantly mitigate the risks of life-threatening sequelae. 1

Definition and Clinical Presentation of CRS

• CRS is a systemic inflammatory response driven by rapid and excessive secretion of cytokines (cytokine storm) associated with symptoms ranging from fever to multi-organ dysfunction 1
• CRS affects 30-100% of patients after cellular therapies, with grade 3 CRS reported in 10-30% of cases 2
• High-risk patients for severe CRS include those with early symptom onset (within 3 days of CAR T cell infusion), high disease burden, and/or pre-existing comorbidities 1

Monitoring Parameters and Frequency

Vital Signs and Clinical Assessment

• CRS grading should be performed at least once every 12 hours and more frequently if clinical status changes 1
• Monitor for fever ≥38°C, which is often the first sign of CRS 1
• Assess for hypotension: SBP <(70 + (2 × age in years)) mmHg for patients aged 1–10 years or <90 mmHg for those aged >10 years 1
• Monitor for hypoxia with arterial oxygen saturation <90% on room air 1
• Evaluate for organ toxicity using CTCAE v5.0 grading system 1

Laboratory Monitoring

• Frequent monitoring of complete blood count, coagulation profile, and chemistry panels 1
• Monitor liver enzymes, C-reactive protein, ferritin, and lactate dehydrogenase levels 1
• Consider procalcitonin monitoring, noting that levels may be elevated in severe CRS even without bacterial infection 2

Monitoring Process and Personnel

• CRS grading should be performed primarily by physicians, advanced practice providers, and bedside nurses 1
• Assessments should be reviewed by interdisciplinary team members immediately after each evaluation 1
• When possible, include patient and/or parent/caregiver participation at the bedside 1
• Nurses should perform assessments mid-shift and jointly with incoming nurses during handoff 1
• In outpatient settings, properly trained caregivers could potentially perform CRS assessment, though this approach has not been validated 1

Differential Diagnosis Considerations

• Evaluate for infectious etiologies with blood and urine cultures and chest radiography 1
• Consider broad-spectrum antibiotics and filgrastim if the patient is neutropenic 1
• Differentiate CRS from neutropenic sepsis, which necessitates empiric broad-spectrum IV antibiotics while investigating for infection 2, 3

Special Monitoring Considerations

Pediatric Patients

• Parent/caregiver concerns should be thoroughly investigated as early signs of CRS can be subtle 1
• Define baseline blood pressure range before CAR T cell infusion to detect relative hypotension 1
• For gastrointestinal symptoms, monitor changes in food intake, frequency/consistency of bowel movements, and expressions of nausea 1
• In infants, assessment of diapers is critical to evaluate urine output and detect diarrhea 1

Hemodynamic Monitoring

• Carefully monitor for early signs of hemodynamic shock 1
• Watch for symptoms such as malaise, lethargy, weakness, oliguria, irritability, and reduced appetite, which may not be self-reported by younger children 1
• Any patient requiring rapid increase in vasopressor dose or showing evidence of end-organ hypoperfusion should be treated intensively 1

Management Approach Based on Monitoring

• Patients who show signs of CRS and/or CRES should be admitted for observation 1
• For grade 1 CRS: provide supportive care with acetaminophen for fever 1
• For grade 2-4 CRS: consider anti-IL-6 therapy (tocilizumab) and/or corticosteroids based on severity 1, 4
• The recommended dose of tocilizumab for treatment of CRS is 8 mg/kg for patients ≥30 kg or 12 mg/kg for patients <30 kg 4
• If no clinical improvement occurs after the first dose of tocilizumab, up to 3 additional doses may be administered with at least 8 hours between consecutive doses 4

Pitfalls and Caveats

• Early signs of CRS can be subtle and might be best recognized by those who know the patient well 1
• Some symptoms can be caused by concurrent conditions, requiring clinical judgment to determine CRS attribution 1
• Empiric antibiotic therapy should not be delayed in critically ill patients while awaiting test results if bacterial infection is clinically suspected 2
• The sensitivity and specificity of inflammatory markers like procalcitonin may be altered in the setting of severe CRS 2
• Post-treatment patients are often neutropenic and at high risk for infections, making interpretation of inflammatory markers challenging 2