HLH after dengue: clinical presentation

Key points

• What it is: Secondary (acquired) HLH is an uncontrolled immune activation. Cytotoxic T-cell and NK-cell failure leads to a cytokine storm, macrophage activation and hemophagocytosis. Dengue is a recognised viral trigger. (Goldman-Cecil Medicine, HLH chapter; Harrison's 22E, HLH section)
• How common: A 2024 meta-analysis found HLH in about 3% of dengue fever and about 22% of severe dengue. Pooled mortality was about 20%.
• Who gets it: An individual patient data meta-analysis of 133 cases had a median age of 18 years. Fever was present in 97%, and 19.3% died.
• Poor prognosis: ALT elevation, jaundice, hypofibrinogenemia, shock and organ failure were associated with death.

Clinical presentation

Diagnosis

1. Fever
2. Splenomegaly
3. Cytopenias in 2 or more lineages
4. Triglycerides ≥3 mmol/L and/or fibrinogen ≤1.5 g/L
5. Ferritin >500 mcg/L
6. Soluble CD25 (sIL-2R) ≥2400 U/mL
7. Low or absent NK-cell activity
8. Hemophagocytosis in bone marrow, spleen or lymph node

• Limits of the criteria: Dengue alone can meet fever, cytopenia, raised ferritin and sometimes low fibrinogen. Many centres cannot test sCD25 or NK activity, so the maximum achievable score is 6.
• HScore: It is a useful supplement. A Singapore series of dengue HLH patients reported median scores of about 235, which puts HLH probability above 98%.
• Bone marrow: Do it when HLH is suspected. Hemophagocytosis is supportive but not specific, because it also occurs in sepsis.
• Work-up: Look for co-infection before starting immunosuppression. Bacterial co-infection was reported in about a third of cases in the narrative review. Also check for malignancy, autoimmune disease and other viral triggers such as EBV and CMV.

Management

• Corticosteroids: Steroids are the mainstay. Typical regimens are dexamethasone 10 mg/m² daily for 3-4 days, then a taper over 2-8 weeks. Methylprednisolone 1 g/day for 3-5 days is another option. Outcomes were often good with steroids alone, and no excess secondary infection was reported with steroids alone.
• IVIG: Doses of 1 g/kg/day for 2 days have been used with steroids, or alone when steroids cannot be given.
• Etoposide, anakinra and similar: Reserve them for refractory or severe disease. The full HLH-94/2004 protocol, chemotherapy and HSCT are generally not needed in dengue-triggered HLH. This contrasts with familial HLH, where HSCT is the only cure (Harrison's 22E).
• Monitoring: Follow the CBC, ferritin, fibrinogen, triglycerides and liver enzymes. Treat any bacterial co-infection promptly.

Caveats

• Almost all dengue-HLH evidence is case reports, case series and pooled reviews. There are no randomized trials, so the steroid-first approach rests on low-level evidence.
• The pooled prevalence estimates have very wide confidence intervals (for example, 8-48% in severe dengue).
• My search for newer meta-analyses (last 2 years) found nothing that contradicts the textbook picture.