What is the treatment for influenza with Hemophagocytic Lymphohistiocytosis (HLH) in children?

Treatment of Influenza with Hemophagocytic Lymphohistiocytosis (HLH) in Children

Treatment for influenza-associated HLH in children requires a combination of antiviral therapy with oseltamivir and immunomodulatory treatment, primarily with high-dose corticosteroids as first-line therapy. 1

Initial Assessment and Treatment

Antiviral Therapy

• Begin oseltamivir immediately upon suspicion of influenza-associated HLH 1, 2
• Administer at age-appropriate dosing
• Continue for at least 5-10 days depending on clinical response

First-Line Immunomodulatory Treatment

• High-dose pulse methylprednisolone: 15-30 mg/kg/day (maximum 1g/day) for 3-5 consecutive days 3
• Consider dexamethasone if central nervous system involvement is present 3

Second-Line Therapy for Insufficient Response

Add one or more of the following if inadequate response to corticosteroids within 24-48 hours:

1. Cyclosporine A:

   • Dosage: 2-7 mg/kg/day (oral or IV in critical settings) 4, 3
   • Monitor for renal function and drug levels

2. Anakinra (IL-1 receptor antagonist):

   • Dosage: 2-10 mg/kg/day in divided doses 4, 3
   • Higher doses than standard may be required for HLH

3. Intravenous Immunoglobulin (IVIG):

   • Dosage: 1-2 g/kg 5
   • May be particularly useful in viral-triggered HLH

Treatment Algorithm for Refractory Cases

For cases not responding to above measures within 48-72 hours:

1. Consider HLH-2004 protocol components:

   • Etoposide may be considered in severe cases, though use should be cautious due to potential side effects 4, 3
   • Consultation with hematology/immunology specialists is essential before initiating

2. Emerging therapies to consider:

   • Emapalumab (anti-IFN-γ antibody) has shown efficacy in clinical trials 3
   • JAK inhibitors such as ruxolitinib may be beneficial in refractory cases 4, 3

Supportive Care

• Frequent monitoring of vital signs and laboratory parameters (at least every 12 hours in critically ill patients) 4
• Respiratory support as needed, including potential need for intubation in severe cases 1
• Correction of coagulopathy and cytopenias
• Anti-infectious prophylaxis (anti-fungal, pneumocystis jirovecii) 4
• Regular surveillance for secondary infections or viral reactivations (EBV, CMV) 4

Special Considerations

Diagnostic Criteria to Monitor

• Persistent fever
• Cytopenias (particularly anemia and thrombocytopenia)
• Hyperferritinemia (present in 96% of cases) 5
• Elevated LDH (present in 91% of cases) 5
• Hypofibrinogenemia (present in 42% of cases) 5
• Hemophagocytosis on bone marrow examination (present in 80% of cases) 5

Prognosis and Follow-up

• Secondary HLH from viral infections like influenza has better prognosis than familial HLH 5
• Complete recovery is possible with prompt recognition and treatment 5, 1
• Close follow-up for at least 6-12 months after resolution is recommended to monitor for recurrence

Pitfalls and Caveats

• Delay in diagnosis and treatment significantly increases mortality
• Differentiation from sepsis can be challenging as HLH, multi-organ dysfunction, and sepsis can coexist 4
• Genetic testing should be considered in all children with HLH to rule out familial forms, which require different long-term management including potential HSCT 5, 6
• Familial HLH has significantly worse outcomes compared to secondary HLH, with mortality approaching 100% without HSCT 5

Early recognition and aggressive treatment of influenza-associated HLH in children is critical for improving outcomes, with case reports showing good response to the combination of antiviral therapy and immunomodulatory treatment 1, 2.