Management Protocol for Dengue-Associated Hemophagocytic Lymphohistiocytosis (HLH)
For dengue-associated HLH, initiate high-dose corticosteroids (dexamethasone 10 mg/m²/day or methylprednisolone 1g/day for 3-5 days) as first-line therapy while providing aggressive supportive care, with treatment duration typically limited to 3-4 weeks given the self-limited nature of dengue infection. 1, 2
Diagnostic Suspicion and Confirmation
Suspect dengue-associated HLH when:
- Persistent or recurrent fever continuing beyond 7 days after dengue onset 1
- Anemia developing without evidence of intravascular hemolysis or massive bleeding 1
- Cytopenias (thrombocytopenia, neutropenia) persisting after resolution of the critical phase 2
- Hepatosplenomegaly appearing during or after the critical phase 2
Confirm diagnosis using HLH-2004 criteria (≥5 of 8 required):
- Fever, splenomegaly, cytopenias (≥2 cell lines), hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis on bone marrow, low NK cell activity, ferritin >500 ng/mL (typically >3000-9840 ng/mL in dengue-HLH), and elevated soluble CD25 3, 4, 2
Treatment Algorithm
First-Line Therapy: Corticosteroids
Initiate immediately upon diagnosis:
- Dexamethasone 10 mg/m²/day IV for 2 weeks, then taper over 6-8 weeks 2, OR
- Methylprednisolone 1g/day IV for 3-5 consecutive days 5, 6, 3
The evidence strongly supports short-course steroid therapy for dengue-associated HLH, with excellent outcomes reported in multiple case series. 1, 7 Unlike other forms of secondary HLH, dengue-associated HLH often responds favorably to steroids alone without requiring additional immunosuppressive agents. 1
Second-Line Therapy (for inadequate response after 24-48 hours)
If no clinical improvement within 48-72 hours, escalate treatment:
- Add cyclosporine A 2-7 mg/kg/day with careful drug level monitoring 5, 6
- Consider anakinra 2-10 mg/kg/day subcutaneously in divided doses 5, 6
- Intravenous immunoglobulin (IVIG) 1.6 g/kg over 2-3 days may be added 5
Third-Line Therapy (for refractory cases)
Reserve etoposide for severe, life-threatening cases only:
- Etoposide 50-100 mg/m² weekly (reduced dose in adults with comorbidities) 6
- This should be used sparingly in dengue-associated HLH due to significant toxicity and the generally self-limited nature of the trigger 5
Critical caveat: Unlike malignancy-associated or EBV-associated HLH where etoposide is often necessary, dengue-associated HLH frequently resolves with steroids alone or even supportive care in select cases. 4, 1, 7
Supportive Care Measures
Aggressive supportive management is essential:
- Fluid management: Careful monitoring for plasma leakage and vascular permeability, avoiding fluid overload 5
- Transfusion support: Platelets for severe thrombocytopenia with bleeding, packed red blood cells for symptomatic anemia 3
- Avoid aspirin and NSAIDs due to bleeding risk in dengue 5
- Antimicrobial prophylaxis: Consider antifungal prophylaxis with prolonged corticosteroid use 3
- Monitor for secondary infections: Broad-spectrum antimicrobials if bacterial superinfection suspected 5
Monitoring and Reassessment
Frequent clinical reassessment is mandatory:
- Every 12 hours for critically ill patients with organ dysfunction 5, 3
- Monitor ferritin, triglycerides, fibrinogen, complete blood counts, liver function tests 3, 2
- Track inflammatory markers (CRP, IL-6, soluble CD25) to assess treatment response 3
ICU-level care required for:
- Shock or vasopressor requirement 3
- Platelet count <30,000/μL 3
- Grade ≥2 organ dysfunction (renal, hepatic, pulmonary) 3
- Neurologic involvement (altered mental status, seizures) 3
Treatment Duration
Dengue-associated HLH typically requires shorter treatment courses:
- 3-4 weeks of steroid therapy is usually sufficient, compared to 8+ weeks for other HLH forms 1, 7
- Taper steroids gradually over 6-8 weeks after initial high-dose period 2
- Most patients show improvement within 4-5 days of initiating treatment 4, 7
Critical Pitfalls to Avoid
Do not delay treatment while awaiting all diagnostic criteria - empirical therapy should begin when clinical suspicion is high (persistent fever >7 days, cytopenias, ferritin >3000 ng/mL) 3, 1
Do not apply full HLH-94 or HLH-2004 protocols designed for primary HLH - dengue-associated HLH is self-limited and responds to less aggressive therapy 5, 1
Do not overlook the possibility of steroid-sparing management in mild cases - rare cases have resolved with supportive care alone, though this should only be considered in hemodynamically stable patients with improving trends 4
Do not miss concurrent bacterial sepsis - dengue-HLH can coexist with sepsis, and antimicrobials should be initiated if bacterial infection is suspected 5
Do not use tocilizumab as first-line therapy - while effective in CAR T-cell-associated HLH, it is not established for dengue-associated HLH and corticosteroids remain the standard 5, 3
Prognosis
Outcomes are generally favorable with prompt recognition and treatment: