In a patient with confirmed dengue infection presenting with fever, thrombocytopenia, rising hematocrit and warning signs (e.g., abdominal pain, persistent vomiting, mucosal bleeding), how should serum ferritin be measured and interpreted to assess severity and guide management?

Serum Ferritin in Severe Dengue Fever

Serum ferritin is a validated prognostic biomarker for severe dengue and should be measured on admission and at defervescence (day 4–5) to stratify risk and guide intensive monitoring decisions.

Measurement Timing and Technique

• Measure serum ferritin on day 1 of admission (febrile phase) and repeat on day 4 (defervescence phase) to capture the dynamic changes that correlate with disease severity 1.
• Standard immunoassay methods are adequate; the testing method itself contributes to variability between studies but does not affect clinical utility 2.
• No special preparation is required—ferritin can be measured alongside routine dengue workup (complete blood count, liver enzymes, hematocrit) 3.

Diagnostic Thresholds and Interpretation

Day 1 (Admission) Values

• Ferritin >1,000 ng/mL on admission predicts severe dengue with good accuracy (AUC 0.863, sensitivity 76.9%, specificity 83.3%) 1, 4.
• Ferritin levels are significantly higher in severe dengue compared to non-severe dengue (standardized mean difference 4.05) 2.
• Hyperferritinemia on admission is associated with viraemia, thrombocytopenia, elevated liver enzymes, and coagulation disturbances 3.

Day 4 (Defervescence) Values

• Ferritin measured at defervescence is an excellent predictor of severe dengue (AUC 0.947, sensitivity 90%, specificity 91.6%) 1, 4.
• A steady increase in ferritin throughout the illness course indicates progression toward severe disease 4.
• Ferritin >8,613 ng/mL at defervescence has 67% sensitivity and 55% specificity for hemophagocytic lymphohistiocytosis (HLH), though this threshold is less reliable than soluble IL-2 receptor 5.

Comparison Across Disease Severity Categories

• Dengue with warning signs (DwWS) shows higher ferritin than dengue without warning signs (standardized mean difference 2.01) 2.
• Severe dengue shows higher ferritin than DwWS (standardized mean difference 2.66) and much higher than dengue without warning signs (standardized mean difference 6.65) 2.

Clinical Utility and Management Implications

Risk Stratification Algorithm

• If ferritin <1,000 ng/mL on admission: Patient likely has non-severe dengue; continue standard monitoring with daily hematocrit, platelet count, and clinical assessment for warning signs 1, 4.
• If ferritin 1,000–8,000 ng/mL on admission: Patient is at increased risk for severe dengue; escalate monitoring frequency (hematocrit every 6–12 hours), ensure IV access, prepare for fluid resuscitation, and repeat ferritin at defervescence 1, 3.
• If ferritin >8,000 ng/mL at any point: Consider dengue-associated HLH; check soluble IL-2 receptor (sIL-2R >10,345 pg/mL has 100% sensitivity/specificity for HLH), triglycerides, fibrinogen, and calculate HScore 5.

Pathophysiologic Correlation

• Hyperferritinemia in dengue reflects extensive immune activation, not iron overload 3.
• Elevated ferritin correlates with pro-inflammatory cytokine profiles (IL-6, IL-18, TNF-α) and indicates highly active disease 3.
• Ferritin elevation is associated with coagulation disturbances including prolonged PT/PTT, elevated D-dimer, and consumptive coagulopathy 3.

Critical Pitfalls to Avoid

• Do not interpret ferritin in isolation—it must be integrated with platelet count, hematocrit trend, liver enzymes, and clinical warning signs (abdominal pain, persistent vomiting, mucosal bleeding) 3.
• Do not assume ferritin elevation indicates iron overload requiring phlebotomy—in dengue, hyperferritinemia is an acute-phase reactant reflecting immune activation, not iron stores 3.
• Do not rely solely on admission ferritin—serial measurement at defervescence provides superior prognostic accuracy (AUC 0.947 vs. 0.863) 1.
• Do not use ferritin alone to diagnose HLH—soluble IL-2 receptor is far superior (AUC 1.00 vs. 0.694 for ferritin); reserve full HLH workup for patients with sIL-2R >10,345 pg/mL 5.
• Do not overlook the differential diagnosis—ferritin can distinguish dengue from other febrile illnesses, as dengue patients have significantly higher levels than non-dengue febrile controls 3.

Practical Implementation

• Order ferritin on all dengue patients with fever >5 days, thrombocytopenia, rising hematocrit, or warning signs 5.
• Repeat ferritin on day 4 or at defervescence (when fever resolves) to capture peak values that best predict severe outcomes 1, 4.
• Use ferritin trends to guide disposition decisions: rising ferritin warrants ICU-level monitoring; stable or declining ferritin after defervescence supports step-down care 1, 3.
• In resource-limited settings, ferritin is an inexpensive and accessible biomarker that can triage patients for intensive monitoring without requiring specialized assays 1.