Macrophage Activation Syndrome in Dengue: When to Suspect
Macrophage Activation Syndrome (MAS) should be suspected in dengue patients with persistent high fever beyond 7 days, worsening cytopenias, hepatosplenomegaly, hyperferritinemia (>10,000 ng/ml), and development of multiorgan dysfunction despite resolution of the critical phase. 1, 2, 3
Clinical Indicators for MAS in Dengue
- Persistent high fever spikes that continue beyond the expected resolution of dengue's critical phase 1, 3
- Development of hepatosplenomegaly during or after the critical phase of dengue 2, 3
- Worsening cytopenias (thrombocytopenia, neutropenia, anemia) despite resolution of the critical phase 1, 3
- Abnormal liver function tests with features of liver failure 2
- Coagulopathy that persists or worsens after critical phase 2
- Neurological complications not typical for uncomplicated dengue 2
Laboratory Parameters to Monitor
- Serum ferritin levels >3,000 ng/ml (particularly >10,000 ng/ml is highly suspicious for MAS) 4, 3
- Elevated soluble CD163 (sCD163) levels, which can differentiate severe dengue from dengue fever 5
- Elevated triglyceride levels (>265 mg/dL) 3
- Declining fibrinogen levels 2
- Persistently elevated or worsening liver enzymes 2
- Prolonged prothrombin time/international normalized ratio (PT/INR) 2
- High erythrocyte sedimentation rate (ESR) despite improvement in other dengue parameters 2
Diagnostic Approach
- Consider bone marrow evaluation in suspected cases, which can confirm hemophagocytosis 2, 3
- Apply HLH-2004 diagnostic criteria when suspecting MAS in dengue patients 3
- Monitor for multiorgan dysfunction, which commonly occurs concurrently with MAS in dengue 2
- Differentiate from prolonged dengue by looking for the constellation of persistent fever, cytopenias, and extremely elevated ferritin levels 1, 3
High-Risk Scenarios
- Patients with prolonged critical phase of dengue 1
- Cases with unusual clinical features like hepatosplenomegaly developing during dengue infection 3
- Patients showing signs of autoimmune response during dengue infection 6
- Dengue patients with multiorgan dysfunction not responding to standard supportive care 1
Management Considerations
- Early recognition and prompt treatment are crucial for good outcomes 3
- Consider immunosuppressive therapy with corticosteroids (e.g., dexamethasone 10 mg/BSA/day) for confirmed cases 3
- Intravenous immunoglobulin (IVIG) has shown good results in pediatric dengue-associated HLH/MAS 1, 2
- Monitor response to therapy with serial ferritin levels and improvement in cytopenias 3
Pitfalls and Caveats
- MAS can be easily missed as its symptoms may be attributed to severe dengue itself 1
- Delay in diagnosis and treatment significantly increases mortality 3
- The surge of pro-inflammatory cytokines in dengue-associated MAS and multiorgan dysfunction may indicate they are part of a related inflammatory spectrum 1
- Laboratory parameters of MAS may overlap with those of severe dengue, making diagnosis challenging 5