What is the link between Hemophagocytic Lymphohistiocytosis (HLH) reactivation and refractoriness in relation to influenza infection?

Link Between HLH Reactivation, Refractoriness, and Influenza

Influenza is a common trigger of Hemophagocytic Lymphohistiocytosis (HLH) reactivation and can lead to refractory disease with significant mortality risk, requiring prompt recognition and targeted treatment. 1, 2

Pathophysiological Connection

• Influenza virus infection can trigger severe hyperinflammatory responses leading to HLH development or reactivation, characterized by pathologic immune activation and hypercytokinemia 2, 3
• The virus-induced hyperinflammation can result in reduced natural killer (NK) cell numbers and cytotoxic T lymphocyte percentages, correlating with hyperferritinemia and potentially contributing to HLH pathogenesis 4
• Persistent viral stimulation of lymphocytes and histiocytes results in hypercytokinemia, which drives the characteristic clinical manifestations of HLH 3

Clinical Presentation and Diagnosis

• HLH should be suspected in patients with influenza who develop:
  • Persistent fever despite antimicrobial therapy
  • Unexplained cytopenias
  • Organomegaly (particularly hepatomegaly)
  • Disproportionate inflammatory response 1
• Diagnostic workup should include:
  • Ferritin levels (often markedly elevated)
  • Soluble CD25 (IL-2 receptor) levels
  • Complete blood counts
  • Liver function tests (elevated alkaline phosphatase and gamma-glutamyl transferase are significant) 4, 2
• Patients with influenza-associated HLH show significantly higher peak serum concentrations of ferritin and more frequent hepatomegaly compared to those with severe influenza without HLH 4

Refractoriness in Influenza-Associated HLH

• Influenza-triggered HLH can become refractory to standard treatments, contributing to the high mortality rate (20-88%) in adult HLH 1, 5
• Refractoriness may be related to:
  • Persistent viral replication maintaining the hyperinflammatory state 2
  • Acquired immunodeficiency from the HLH itself or its treatment 1
  • Secondary infections that develop during immunosuppressive treatment 1

Management Approach

• Early recognition and prompt treatment are essential to prevent refractory disease 5, 6
• For influenza-associated HLH:
  • Initiate antiviral therapy with oseltamivir immediately 5, 6
  • Consider corticosteroids (prednisolone 1-2 mg/kg or dexamethasone 5-10 mg/m²) to control hyperinflammation 1
  • Intravenous immunoglobulin (IVIG) 1.6 g/kg over 2-3 days may be beneficial 1
• For refractory cases:
  • Etoposide-based regimens may be necessary, particularly in rapidly deteriorating patients 1
  • Dose adjustment of etoposide is required in patients with renal dysfunction 1
• Prophylactic measures to prevent secondary infections:
  • Broad antimicrobial prophylaxis against Pneumocystis jirovecii and fungi 1
  • Antiviral prophylaxis due to T-cell depletion from HLH-directed therapy 1
  • Consider hospitalization in HEPA-filtered rooms 1

Monitoring and Follow-up

• Regular monitoring of:
  • Ferritin levels
  • Cell counts
  • Viral load (when applicable)
  • Liver function tests 1, 2
• Weekly reevaluation of the need for continued etoposide therapy in patients requiring this treatment 1
• Vigilance for secondary infections, which are a major cause of mortality 1

Special Considerations

• HLH during chemotherapy ("HLH during chemotherapy") can be triggered by influenza and other infections in immunocompromised patients 1
• In patients with malignancy, differentiate between "malignancy-triggered HLH" and "HLH during chemotherapy" (often infection-induced), as treatment approaches differ markedly 1
• In critically ill patients with influenza requiring intensive care, monitor closely for signs of hyperinflammation and evaluate promptly for HLH 4