Diagnosing and Treating HLH in Dengue Fever
In dengue-associated HLH, use the HLH-2004 diagnostic criteria (requiring 5 of 8 parameters) and initiate high-dose corticosteroids (methylprednisolone 1g IV daily for 3-5 days) immediately upon diagnosis, though some cases may resolve with supportive care alone if clinical improvement occurs rapidly. 1
Diagnostic Criteria for HLH in Dengue
The diagnosis requires meeting at least 5 of the following 8 HLH-2004 criteria 1:
- Fever (persistent, high-grade, unremitting) 1
- Splenomegaly 1
- Cytopenias affecting ≥2 cell lines: hemoglobin <9 g/dL, platelets <100,000/μL, neutrophils <1,000/μL 1
- Hypertriglyceridemia (≥265 mg/dL) and/or hypofibrinogenemia (≤150 mg/dL) 1
- Hemophagocytosis in bone marrow, spleen, or lymph nodes 1
- Low or absent NK cell activity 1
- Ferritin ≥500 ng/mL (typically >5,000 ng/mL in HLH) 1
- Soluble CD25 (sIL-2Rα) ≥2,400 U/mL 1
Key Clinical Clues Specific to Dengue-HLH
Suspect HLH when dengue patients exhibit these red flags 2, 3:
- Prolonged fever beyond 7 days (persisting after the expected critical phase resolution) 2, 3
- Persistent or worsening cytopenias despite resolution of plasma leakage phase 3
- Hepatosplenomegaly (particularly splenomegaly, which is not typical of uncomplicated dengue) 2, 3
- Markedly elevated ferritin (>3,000-9,840 ng/mL reported in dengue-HLH cases) 4, 3
- Ongoing fever spikes during or after the critical phase when defervescence is expected 3
Diagnostic Workup
Perform the following investigations immediately when HLH is suspected 1:
- Complete blood count with differential (assess cytopenias) 1
- Ferritin level (expect >5,000 ng/mL in HLH) 1
- Triglycerides and fibrinogen 1
- Liver function tests (transaminases, bilirubin) 1
- Coagulation profile 1
- Soluble CD25 (if available) 1
- Bone marrow aspiration to document hemophagocytosis 1, 3
Critical pitfall: Do not delay empirical treatment while awaiting all diagnostic criteria if clinical suspicion is high with ferritin >10,000 μg/L and progressive cytopenias 1. Hemophagocytosis on bone marrow is neither sensitive nor specific and may be absent early in disease 5.
Treatment Algorithm for Dengue-Associated HLH
First-Line Treatment
Initiate high-dose corticosteroids immediately upon diagnosis 1, 2, 3:
- Methylprednisolone 1g IV daily for 3-5 consecutive days (pulse dosing) 5, 1
- Alternative: Dexamethasone 10 mg/m²/day for 2 weeks, then taper over 8 weeks 2, 3
The evidence shows excellent response to corticosteroids in dengue-HLH, with dramatic defervescence and improvement in cytopenias, hypofibrinogenemia, and hyperferritinemia 2, 6.
Supportive Care Considerations
A unique aspect of dengue-HLH: Some cases may resolve with supportive care alone if rapid clinical improvement occurs within 24-48 hours 4. One case report documented complete resolution without steroids when symptoms improved by day 4 4. However, this approach should only be considered if:
- Fever resolves within 3-4 days of HLH diagnosis 4
- Cytopenias begin improving rapidly 4
- No evidence of shock or multiorgan failure 4
- Close monitoring (every 12 hours) is feasible 5, 1
This is the exception, not the rule—most cases require immunosuppressive therapy 2, 3, 7.
Second-Line Therapies
If inadequate response to corticosteroids within 48-72 hours, add 5, 1:
- Intravenous immunoglobulin (IVIG) 2 g/kg over 2-5 days 2, 7
- Cyclosporine A 2-7 mg/kg/day (particularly effective in refractory cases) 5, 1
- Anakinra (IL-1 blockade) 2-10 mg/kg/day subcutaneously in divided doses 5, 1
Refractory Cases
For cases refractory to corticosteroids and IVIG 5, 1:
- Etoposide may be considered as last resort, though it carries significant T-cell toxicity and should be used with extreme caution in dengue-HLH 5, 1
- Contact an HLH reference center for guidance 5
Critical Care Management
Transfer to ICU if any of the following are present 5, 1:
- Shock or hypotension requiring vasopressors 5, 1
- Platelet count <30,000/μL 1
- Grade ≥3 neurotoxicity (altered mental status, seizures) 5
- Multiorgan dysfunction 5, 1
Reassess clinical status every 12 hours to determine if additional HLH-directed therapy is needed 5, 1.
Provide aggressive supportive care 1:
- Mechanical ventilation if respiratory failure 1
- Vasopressor support for shock 1
- Renal replacement therapy if needed 1
- Platelet and blood product transfusions 1
Antifungal prophylaxis should be strongly considered in patients receiving prolonged corticosteroids 5, 1.
Monitoring Response to Treatment
Track these parameters every 12-24 hours 1:
- Fever curve (expect defervescence within 24-72 hours of treatment) 2, 6
- Complete blood counts (cytopenias should improve) 1, 2
- Ferritin levels (should decline) 1, 2
- Triglycerides and fibrinogen (should normalize) 1, 2
- Liver function tests 1
Common Pitfalls to Avoid
Do not miss the diagnosis: HLH should be suspected in any dengue patient with prolonged fever beyond 7 days, persistent cytopenias after the critical phase, and hepatosplenomegaly 2, 3. Delayed diagnosis significantly increases mortality 1, 7.
Do not wait for all HLH-2004 criteria: Empirical treatment should begin when clinical suspicion is high, even if only 4 criteria are met initially 1.
Do not over-resuscitate with fluids: Dengue-HLH patients have underlying plasma leakage pathophysiology; excessive fluid administration can worsen outcomes 5, 1.
Do not apply pediatric HLH protocols directly to adults: Dose adjustments and different considerations are required 1.
Do not ignore underlying dengue-specific complications: Continue monitoring for dengue shock syndrome, hemorrhage, and organ dysfunction even while treating HLH 3, 7.
Prognosis
Dengue-associated HLH has high mortality if untreated or if diagnosis is delayed 1, 7. However, early recognition and prompt corticosteroid therapy result in excellent outcomes, with most patients showing dramatic improvement within days 2, 3, 6. Factors associated with poor prognosis include shock at presentation, platelet count <30,000/μL, and development of complications like retroperitoneal hematoma 1, 7.