What is the next best step in managing a post-BMT patient with dyskeratosis congenita, fever, chills, and mild to moderate respiratory distress, currently on HFNC and treated with Tocilizumab and Anakinra?

Management of Post-BMT Patient with Dyskeratosis Congenita and Respiratory Distress

The next best step in managing this post-BMT patient with dyskeratosis congenita and grade 3 CRS is to transfer to ICU, administer high-dose corticosteroids (dexamethasone 10 mg IV every 6 hours), and consider repeating tocilizumab if no improvement occurs within 24 hours. 1, 2

Assessment of Current Status

• The patient is a 15-year-old on day 11 post-haplo HSCT for dyskeratosis congenita presenting with:

  • Fever and chills with high ferritin (suggesting cytokine release syndrome) 1
  • Mild-moderate respiratory distress on HFNC 2L/kg with FiO2 35% 1
  • Recent treatment with tocilizumab (24 hours ago) and anakinra (48 hours ago) 2, 3

• This clinical presentation is consistent with Grade 3 CRS based on ASTCT criteria:

  • Temperature ≥38°C with hypoxia requiring high-flow nasal cannula 1, 2
  • Previous treatments with IL-6 and IL-1 inhibitors have not adequately controlled symptoms 3

Management Algorithm

Immediate Actions:

1. Transfer to ICU for closer monitoring and management of respiratory distress 1

   • High-flow oxygen requirements and evidence of ongoing CRS warrant ICU-level care 2

2. Initiate high-dose corticosteroids:

   • Dexamethasone 10 mg IV every 6 hours for 1-3 days 1
   • If no improvement, escalate to dexamethasone 20 mg IV every 6 hours 1, 2

3. Consider repeat tocilizumab (8 mg/kg IV, max 800 mg) if no improvement is seen within 24 hours of the first dose 1

   • For children <30 kg, the dose is 12 mg/kg 1
   • Maximum of one additional dose is recommended 1, 2

4. Perform comprehensive infectious workup:

   • Blood cultures and other infection tests 1
   • Start preemptive broad-spectrum antibiotics 1, 3

Monitoring and Supportive Care:

• Continuous cardiac telemetry and pulse oximetry 2
• Laboratory monitoring: CBC, CMP, magnesium, phosphorus, CRP, LDH, ferritin, fibrinogen, PT/PTT 2
• Consider antifungal prophylaxis due to steroid use 1, 3
• Assess for signs of ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome) 1

Treatment Escalation if No Improvement

• If no improvement after repeat tocilizumab and dexamethasone, consider:
  • Switching to methylprednisolone 1000 mg/day for 3 days, followed by tapering doses 1
  • For refractory cases, consider alternative therapies such as siltuximab (alternative IL-6 antagonist) 3

Important Considerations

• Anakinra (IL-1 receptor antagonist) has already been administered but has shown mixed results in managing tocilizumab-refractory cases 4, 5
• Some studies suggest anakinra may be effective in severe cases, but evidence is inconsistent 4, 5
• Monitoring for hepatotoxicity is important as both tocilizumab and anakinra can cause liver injury 6
• The combination of high-dose steroids with IL-6 inhibition has shown better outcomes in severe CRS than either therapy alone 7

Pitfalls to Avoid

• Do not withhold steroids due to concerns about reducing CAR T-cell efficacy; short courses do not significantly impact outcomes in life-threatening situations 3
• Do not rely solely on tocilizumab for ICANS management, as it may not be effective and could potentially worsen neurological symptoms 1, 3
• Do not forget to rule out concurrent infections, as immunosuppressed post-BMT patients are at high risk 1, 3