Is there an association between Hemophagocytic Lymphohistiocytosis (HLH) and dengue?

Association Between Hemophagocytic Lymphohistiocytosis (HLH) and Dengue

There is a definitive association between dengue infection and hemophagocytic lymphohistiocytosis (HLH), with dengue being recognized as an important infectious trigger for secondary HLH that can significantly increase morbidity and mortality if not promptly diagnosed and treated.

Understanding Dengue-Associated HLH

Dengue virus can trigger secondary HLH (also called infection-associated hemophagocytic syndrome or IAHS when caused by infections). This association is increasingly recognized as clinically significant for several reasons:

Pathophysiology and Mechanism

• Dengue infection can lead to excessive immune activation involving cytotoxic T cells, NK cells, and macrophages
• This hyperinflammatory state results in the clinical and laboratory features characteristic of HLH
• Similar to other viral triggers of HLH, dengue can induce cytokine storm and immune dysregulation

Clinical Presentation of Dengue-Associated HLH

Patients typically present with:

• Persistent high fever despite apparent resolution of initial dengue infection
• Progressive cytopenias (particularly thrombocytopenia) that fail to improve
• Hepatosplenomegaly that may worsen after initial dengue symptoms
• Liver dysfunction with elevated transaminases
• Coagulopathy
• Neurological symptoms in some cases

Diagnostic Approach

When evaluating a patient with dengue who has persistent or worsening symptoms, consider HLH if:

• Fever persists beyond the expected course of dengue
• Cytopenias worsen or fail to improve
• Ferritin levels are extremely elevated (often >10,000 ng/mL)
• Hepatosplenomegaly develops or worsens
• Liver function deteriorates significantly

Laboratory findings supporting HLH diagnosis in dengue patients:

• Markedly elevated soluble IL-2 receptor (sIL2R) levels (mean 51,711 pg/mL in confirmed cases) 1
• Hyperferritinemia (mean 34,593 ng/mL in dengue-HLH vs. 3,206 ng/mL in dengue without HLH) 1
• Significantly elevated liver enzymes (ALT mean 6,621 U/L vs. 165.6 U/L in non-HLH dengue) 1
• Hypofibrinogenemia
• Evidence of hemophagocytosis on bone marrow examination

Management Considerations

Early recognition and treatment of dengue-associated HLH is crucial for improving outcomes:

1. Corticosteroid therapy:

   • First-line treatment for dengue-associated HLH
   • Should be initiated promptly when HLH is suspected
   • Has shown effectiveness in case reports 2, 3

2. Intravenous immunoglobulin (IVIG):

   • Often used in combination with steroids
   • Particularly beneficial in severe cases 4

3. HLH-specific protocols:

   • In refractory cases, consider HLH-directed therapy with etoposide-based regimens
   • Decision should be made on a case-by-case basis depending on severity 5

4. Supportive care:

   • Blood product support for cytopenias
   • Management of organ dysfunction
   • Close monitoring for complications

Prognostic Factors and Complications

Dengue-associated HLH can lead to significant complications:

• Acute kidney injury requiring renal replacement therapy 1
• Acute respiratory distress syndrome
• Shock requiring vasopressor support
• Severe liver dysfunction
• Hemorrhagic complications including retroperitoneal hematoma 6
• Prolonged ICU and hospital stays

Special Considerations

Certain patient populations may be at higher risk:

• Patients with underlying hematological disorders (e.g., thalassemia) 4, 3
• Patients with autoimmune conditions 6
• Patients with primary immunodeficiencies 5

Clinical Pitfalls to Avoid

1. Delayed recognition: Mistaking persistent symptoms for prolonged dengue recovery
2. Inadequate monitoring: Failing to track ferritin, liver function, and blood counts in severe dengue
3. Delayed treatment: Hesitating to start immunosuppressive therapy when HLH is suspected
4. Misdiagnosis: Confusing dengue-associated HLH with severe dengue hemorrhagic fever alone

Early recognition of dengue-associated HLH and prompt initiation of appropriate therapy, particularly corticosteroids, is essential for improving outcomes in this potentially fatal complication of dengue infection.