What is the treatment for a cytokine storm?

Treatment of Cytokine Storm

Corticosteroids are the first-line treatment for cytokine storm, with methylprednisolone 1g/day for 3-5 consecutive days recommended as the initial approach for immune effector cell-associated cytokine storm. 1

Diagnostic Considerations

• Cytokine storm is characterized by excessive production of proinflammatory cytokines (IL-1, IL-2, IL-6, TNF-α, IFN-γ) causing a hyperinflammatory state 2
• Diagnostic criteria include elevated ferritin, organ dysfunction, fever, and cytopenias 1
• Laboratory monitoring should include complete blood counts, comprehensive metabolic panels, coagulation testing, serum ferritin and C-reactive protein measurements 3
• Early detection is crucial as delayed recognition significantly increases mortality 1

First-Line Treatment

• High-dose corticosteroids are the mainstay of initial treatment 1
  • Methylprednisolone 1g/day for 3-5 consecutive days is the recommended starting approach 3
  • For COVID-19-associated cytokine storm, systematic corticosteroids (methylprednisolone, <1–2 mg per kg body weight, for 3–5 days) are recommended 3
• Frequent reassessment (at least every 12 hours) of clinical status and laboratory parameters is essential to evaluate treatment response 1

Second-Line Treatments

• For patients not responding adequately to corticosteroids within 24-48 hours, consider adding:
  • Cyclosporine A (2-7 mg/kg per day) 3
  • IL-1 receptor antagonist (anakinra) at 2-10 mg/kg per day subcutaneously in divided doses 3
  • Tocilizumab (IL-6 inhibitor) for severe cases without significant neurologic involvement 1, 4
• Tocilizumab is FDA-approved for treatment of severe or life-threatening Cytokine Release Syndrome following CAR T cell treatment 4

Treatment Algorithm Based on Etiology

1. CAR T cell-induced cytokine storm:

   • Begin with high-dose corticosteroids 1
   • Add tocilizumab if no improvement within 24 hours 4
   • Monitor ferritin, sCD25, cell counts every 12 hours 1

2. COVID-19-associated cytokine storm:

   • Start with methylprednisolone (<1-2 mg/kg for 3-5 days) 3
   • Consider early use of steroids to prevent progression to severe disease 3
   • Add tocilizumab for hospitalized patients requiring supplemental oxygen or mechanical ventilation 4

3. Rheumatic disease-associated MAS-HLH:

   • High-dose pulse methylprednisolone (1 g/day for 3-5 consecutive days) 3
   • Add cyclosporine A (2-7 mg/kg per day) for insufficient response 3
   • Consider IL-1 blockade with anakinra as adjunctive therapy 3

Supportive Care

• Management of cytopenias with transfusion support 1
• Vasopressor support for hypotension 1
• Appropriate antimicrobial therapy if infection is identified as a trigger 1
• Continuous cardiac monitoring beginning on the day of treatment initiation 3

Monitoring Response

• Monitor ferritin, sCD25, complete blood counts, liver function, and renal function to assess treatment response 1
• Improvement in organ dysfunction and decreasing inflammatory markers indicate treatment success 1
• Reassess at least every 12 hours to determine whether additional therapy is needed 3

Emerging Therapies

• JAK inhibitors (ruxolitinib) are being investigated in clinical trials 3, 1
• Anti-IFN-γ monoclonal antibody (emapalumab) shows promise in treatment-resistant cases 1
• Blood purification strategies may be beneficial in critically ill patients 5

Pitfalls and Caveats

• Distinguishing between cytokine release syndrome and HLH can be challenging as they share clinical features 1
• Tocilizumab should be used cautiously when concurrent neurologic involvement is present 1
• Avoid immunosuppression in cases where infection is the primary driver until appropriate antimicrobial therapy is initiated 1
• Early intervention is critical - corticosteroids may be effective in early stages but less effective in later stages of disease with ARDS and multiorgan failure 3