Cytokine release syndrome

Background

• Systemic inflammatory response syndrome that can be adverse effect of certain immunotherapies, such as monoclonal antibodies and CAR-T therapies (e.g. CART19 for leukemia)
• Pathophysiology and presentation similar to sepsis
• Severity ranges from mild flu-like illness to severe sepsis-like inflammatory response with shock, vascular leakage, DIC, and multi-organ system failure

Clinical Features

• Mild: flu-like illness
  • Fever, headache, and/or myalgia
• Severe: mimics septic shock
  • Fever, tachycardia, hypotension, dyspnea, hypoxia
  • Organ-specific dysfunction: encephalopathy, coagulopathy, renal failure, CHF

Differential Diagnosis

• Sepsis!
• Hemophagocytic lymphohistiocytosis

Shock

• Cardiogenic
  • Acute valvular Regurgitation/VSD
  • CHF
  • Dysrhythmia
  • ACS
  • Myocardial Contusion
  • Myocarditis
  • Drug toxicity (e.g. beta blocker, CCB, or bupropion OD)
• Obstructive
  • Air embolism
  • Aortic Stenosis
  • Cardiac Tamponade
  • PE
  • Tension pneumothorax
• Distributive
  • Adrenal crisis
  • Anaphylaxis
  • Neurogenic shock
  • Sepsis
  • Toxicologic
• Hypovolemic
  • Severe dehydration
  • Hemorrhagic shock (traumatic and non-traumatic)

Oncologic Emergencies

Related to Local Tumor Effects

• Malignant airway obstruction
• Bone metastases and pathologic fractures
• Malignant spinal cord compression
• Malignant Pericardial Effusion and Tamponade
• Superior vena cava syndrome

Related to Biochemical Derangement

• Hypercalcemia of malignancy
• Hyponatremia due to SIADH
• Adrenal insufficiency
• Tumor lysis syndrome
• Carcinoid syndrome

Related to Hematologic Derangement

• Neutropenic fever
  • Neutropenic enterocolitis (typhlitis)
• Leukostasis and hyperleukocytosis
• Hyperviscosity syndrome
• Thromboembolism

Related to Therapy

• Chemotherapy-induced nausea and vomiting
• Cytokine release syndrome
• Chemotherapeutic drug extravasation
• Differentiation syndrome (retinoic acid syndrome) in APML
• Stem cell transplant complications
• Catheter-related complications
  • Tunnel infection
  • Exit site infection
  • CVC obstruction (intraluminal or catheter tip thrombosis)
  • Catheter-related venous thrombosis
  • Fracture of catheter lumen
  • Oncologic therapy related adverse events

Evaluation

Hospitals administering CAR-T therapies will often have very specific guidelines for initial workup

• Immunocompromised infection workup: see neutropenic fever
• Evaluate for tumor lysis syndrome
• Labs to screen for organ dysfunction: CBC, BMP, LFTs, DIC labs

Management

• Strongly consider discussion with CAR-T treatment team
• Empiric antibiotics (assume sepsis until proven otherwise)
  • See immunocompromised antibiotics, sepsis
• Treat shock
• Corticosteroids for severe cases
• Consider Tocilizumab (IL-6 receptor antagonist) in consultation with oncology

Disposition

• Admit or consider transfer to hospital with oncology

External Links

• https://www.mdcalc.com/cytokine-release-syndrome-crs-grading#evidence
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003181/