What are the diagnostic criteria for dengue Hemophagocytic Lymphohistiocytosis (HLH)?

Diagnosis of Dengue-Associated Hemophagocytic Lymphohistiocytosis (HLH)

Dengue-associated HLH should be diagnosed using the HLH-2004 diagnostic criteria, which requires fulfilling at least 5 of 8 criteria including: fever, splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow/spleen/lymph nodes, low/absent NK cell activity, elevated ferritin (>500 ng/mL), and elevated soluble IL-2 receptor. 1, 2, 3, 4

Key Diagnostic Criteria for Dengue HLH

Clinical Features

• Persistent fever exceeding 7 days despite resolution of dengue critical phase 2
• Hepatosplenomegaly (particularly splenomegaly) 1, 2, 3
• Neurologic dysfunction (in some cases)
• Lymphadenopathy

Laboratory Findings

1. Cytopenia affecting at least 2 cell lines:

   • Persistent or worsening thrombocytopenia
   • Neutropenia
   • Anemia

2. Biochemical markers:

   • Hyperferritinemia (>500 ng/mL, often >3,000 ng/mL) 1, 3
   • Hypertriglyceridemia (≥265 mg/dL) 5, 3
   • Hypofibrinogenemia (≤150 mg/dL) 5
   • Elevated liver enzymes (ALT, AST) 4
   • Elevated bilirubin 4

3. Specialized testing:

   • Elevated soluble IL-2 receptor (sIL-2R/sCD25) levels (>2,400 U/mL) - a crucial diagnostic marker 4
   • Low or absent NK cell activity

4. Bone marrow examination:

   • Presence of hemophagocytosis (histiocytes engulfing blood cells) 1, 3

Diagnostic Algorithm for Dengue HLH

1. Initial suspicion: Consider HLH in dengue patients with:

   • Fever persisting beyond 7 days
   • Worsening or persistent cytopenia after critical phase resolution
   • Hepatosplenomegaly
   • Disproportionately elevated ferritin levels (>3,000 ng/mL)

2. First-line investigations:

   • Complete blood count (monitor for persistent/worsening cytopenia)
   • Serum ferritin (typically markedly elevated)
   • Liver function tests
   • Triglycerides
   • Fibrinogen
   • Dengue confirmation (NS1 antigen, IgM/IgG antibodies)

3. Second-line investigations:

   • Soluble IL-2 receptor (sCD25) levels - crucial for confirmation 4
   • Bone marrow examination for hemophagocytosis
   • NK cell activity (if available)

Clinical Pearls and Pitfalls

• Key warning sign: Persistent fever and cytopenia after resolution of dengue critical phase should trigger HLH evaluation 2, 3

• Diagnostic challenge: Dengue-associated HLH is often missed as clinicians focus on treating the primary infection 5

• Laboratory pattern: The combination of extremely high ferritin (often >10,000 ng/mL) with worsening cytopenia is particularly suggestive 1, 4

• Timing: HLH typically develops during hospitalization for dengue, not at initial presentation 1, 3

• Soluble IL-2 receptor: Levels are significantly elevated in dengue HLH (mean 51,711 pg/mL in one study) and correlate with disease activity, making it an excellent confirmatory test 4

• Bone marrow findings: May show trilineage hematopoiesis with increased histiocytes and hemophagocytosis 1

• Organ dysfunction: Liver dysfunction is notably higher in dengue patients with HLH compared to those without (significantly elevated ALT, AST, and bilirubin) 4

• Mortality risk: Dengue-associated HLH has high mortality if not recognized and treated promptly 3

Early recognition and prompt treatment with appropriate immunosuppressive therapy (typically dexamethasone) can significantly improve outcomes in this potentially fatal complication of dengue infection 2, 3.