What is the treatment approach for Hemophagocytic Lymphohistiocytosis (HLH) with suspected link to influenza A infection?

Treatment Approach for Influenza A-Associated Hemophagocytic Lymphohistiocytosis (HLH)

Influenza A infection can trigger severe HLH that may become refractory to standard treatments, requiring prompt initiation of antiviral therapy combined with immunomodulatory agents to control hyperinflammation and prevent mortality. 1

Pathophysiological Connection

• Influenza virus can trigger pathologic immune activation and hypercytokinemia leading to HLH development or reactivation, with viral infections being common triggers of HLH 2, 1
• Influenza A-associated HLH may present with persistent fever, unexplained cytopenias, organomegaly, and disproportionate inflammatory response despite antimicrobial therapy 1, 3

Diagnostic Approach

• Suspect HLH in influenza patients with:
  • Rapidly rising ferritin (>5000 ng/mL) with cytopenias and fever 2, 1
  • Liver dysfunction (elevated bilirubin, AST, ALT) 2
  • Renal dysfunction (oliguria, elevated creatinine) 2
  • Pulmonary edema 2
• Diagnostic workup should include:
  • Ferritin levels (often markedly elevated) 1
  • Soluble CD25 (IL-2 receptor) levels 1, 3
  • Complete blood counts 1
  • Liver function tests 3
  • Assessment of NK cell function and percentage (often reduced in influenza-associated HLH) 3

Treatment Algorithm for Influenza A-Associated HLH

First-Line Treatment

1. Antiviral Therapy

   • Initiate oseltamivir immediately to target the underlying viral trigger 4, 5

2. Corticosteroids

   • Start with prednisolone 1-2 mg/kg or dexamethasone 5-10 mg/m² to control hyperinflammation 2, 1
   • For less severe disease or improving clinical manifestations, a short course of corticosteroids may be sufficient 2

3. Intravenous Immunoglobulin (IVIG)

   • Consider IVIG 1.6 g/kg over 2-3 days for anti-inflammatory effects 2, 4
   • IVIG has shown benefit in influenza-associated HLH cases 1, 6

For Refractory Cases

1. Etoposide-Based Therapy

   • For rapidly deteriorating patients or those not responding to initial therapy, initiate etoposide according to HLH-94 protocol 2, 1
   • Perform weekly reevaluation of the need for continued etoposide therapy 2
   • Use etoposide sparingly in patients with bone marrow suppression, as immune reconstitution is crucial 2

2. Consider Biological Agents

   • Anakinra may reduce mortality in patients with MAS features and has shown benefit in refractory cases 2, 6
   • For EBV co-infection, consider adding rituximab (375 mg/m² once weekly, 2-4 times) 2

Supportive Care

1. Infection Prevention

   • Administer broad antimicrobial prophylaxis against Pneumocystis jirovecii and fungi 2
   • Consider antiviral prophylaxis due to T-cell depletion 2
   • Consider hospitalization in units with HEPA-filtered air 2

2. Monitoring

   • Regular monitoring of cell counts, ferritin, liver function tests, and viral load 1, 3
   • Monitor for secondary infections, which are a major cause of mortality 2, 1

Special Considerations

• Refractoriness in Influenza-Associated HLH

  • May be related to persistent viral replication, acquired immunodeficiency, and secondary infections 1
  • Consider plasmapheresis for severe cases not responding to standard therapy 4

• Mortality Risk

  • Mortality in adult HLH ranges from 20% to 88%, primarily due to refractory HLH, secondary infections, and progression of underlying disease 2
  • Prompt recognition and treatment are essential to improve outcomes 4, 7

• Malignancy Considerations

  • In patients with malignancy, differentiate between "malignancy-triggered HLH" and "HLH during chemotherapy" as treatment approaches differ markedly 2, 1

Pitfalls and Caveats

• Diagnostic Challenges

  • HLH symptoms may overlap with severe sepsis or cytokine release syndrome, leading to delayed diagnosis 2, 3
  • Low NK cell percentages correlate with hyperferritinemia and may contribute to pathogenesis 3

• Treatment Considerations

  • Avoid delaying etoposide in rapidly deteriorating patients 2
  • Secondary infections are a major cause of fatality during HLH treatment 2
  • Consider HLH when cytopenia is unduly prolonged after chemotherapy and fever persists despite antibiotic treatment 2