Treatment of Dengue Fever

WHO Classification of Dengue Severity

• Red Book 2021, p. 520

Phases of Illness

• Febrile phase (days 1-7): Fever, myalgia, headache, retro-orbital pain, rash, leukopenia
• Critical phase (days 3-7, around defervescence): Risk of plasma leakage, hemoconcentration - lasts 24-48 hours
• Convalescent phase: Gradual improvement; watch for fluid reabsorption and overload

1. Uncomplicated Dengue Fever (Outpatient)

• Fluids: Oral rehydration solution (ORS), fruit juices, electrolyte-containing drinks. Adequate oral hydration reduces hospitalizations.
• Antipyretics: Paracetamol (acetaminophen) to keep temperature below 39°C; interval no less than 6 hours.
• Avoid: Aspirin, ibuprofen, and all NSAIDs - these increase bleeding risk and aspirin is associated with Reye's syndrome in children.
• Return precautions: Patients should return immediately if they develop severe abdominal pain, persistent vomiting, cold/clammy extremities, altered sensorium, bleeding, or no urine for >4-6 hours.
• Park's Textbook of Preventive and Social Medicine, p. 295; Red Book 2021, p. 523

2. Dengue Hemorrhagic Fever (DHF) Grades I & II - Hospitalized

• Continue paracetamol for fever control
• Oral fluids as tolerated; IV fluids if vomiting persistently
• Monitor haematocrit daily from day 3 onwards - rising Hct signals plasma leakage and need for IV fluids
• IV fluids if Hct rises ≥20%: Start crystalloid (e.g., Lactated Ringer's) at 6 ml/kg/h for 1-2 hours, then reassess

• If improvement (Hct falls, BP stable, urine output rises): taper IV fluids 6 → 3 → 1.5 ml/kg/h, discontinue after 24-48 hours
• If no improvement and Hct rises further: increase to 10 ml/kg/h crystalloid for 2 hours
• If no improvement and Hct falls: suspect internal haemorrhage - blood transfusion (10 ml/kg whole blood or 5 ml/kg packed RBCs)
• Park's Textbook of Preventive and Social Medicine, pp. 295-296

3. Severe Dengue / DHF Grades III & IV / Dengue Shock Syndrome (DSS)

• ICU admission required
• Immediate haematocrit, platelet count, and vital signs on arrival
• IV fluid resuscitation promptly
• If >1000 ml of IV crystalloid already given with ongoing shock: switch to colloid (Dextran 40 or haemaccel)
• If Hct is declining: fresh whole blood 10-20 ml/kg/h
• Oxygen for all patients in shock
• In refractory shock with declining Hct: suspect occult internal bleeding; give fresh whole blood as a routine precaution (10 ml/kg/h)

1. Overt blood loss ≥10% of total blood volume
2. Refractory shock with declining Hct despite adequate fluids
3. 10 ml/kg body weight at a time; check coagulogram
4. If fluid overload present: use packed RBCs instead of whole blood

• Park's Textbook of Preventive and Social Medicine, p. 296

4. Monitoring Parameters

• Temperature pattern
• Fluid intake and output (urine volume and frequency)
• Warning signs (any of the above)
• Serial haematocrit (the key guide to fluid therapy)
• Platelet count and WBC
• Signs of plasma leakage (rising Hct, pleural effusion, ascites)
• Watch for fluid overload during convalescence - reabsorption of extravascular fluid causes Hct to fall; diuresis may be needed

5. What to Avoid

• Rosen's Emergency Medicine, p. 2630; Red Book 2021, p. 523

6. Disposition

• Outpatient: Uncomplicated dengue with adequate oral intake and no warning signs
• Hospital ward: DHF, dehydration, warning signs present, need for IV rehydration
• ICU: Dengue shock syndrome (DSS), Grade III/IV DHF

7. Vaccine (Prevention)

Recent Research on Dengue Antiviral Drug Candidates

1. The State of Play - What the Evidence Says

• Of 10 antiviral trials identified, none demonstrated statistically significant virological or clinical benefit
• All published antiviral RCTs tested repurposed drugs, not dengue-specific compounds
• 45% of published trials had high or critical risk of bias
• Non-standardized endpoints across trials have made meta-analysis impossible
• The authors conclude that dengue-specific direct-acting antivirals are the most promising path forward, rather than repurposing

"Progress in this field will likely depend on the development of dengue-specific direct-acting antivirals, rather than relying on repurposed treatments." - Huyen et al., PLoS NTDs, 2026 [PMID: 42247469]

2. Repurposed Drugs That Have Been Clinically Tested

3. Direct-Acting Antivirals in Clinical Development (2024-2026)

EYU688 (Novartis) - Phase 2 ONGOING

• Target: NS4B protein (viral replication complex)
• Status: Phase 2 dose-ranging trial (ClinicalTrials.gov: NCT060066559) - currently ongoing as of mid-2026
• Significance: One of the only dengue-specific small-molecule inhibitors currently in active Phase 2 trials
• Listed in the INTREPID Alliance 5th Edition Landscape (May 2026)

Mosnodenvir (KU Leuven, Belgium) - Phase 2

• Target: NS3/4B replication complex
• Status: Phase 2 clinical trial active as of January 2026 (INTREPID 5th Edition)
• Developed at Katholieke Universiteit Leuven

Molnupiravir (Brazil trial) - Phase 2 ONGOING

• Target: Viral RNA polymerase (broad-spectrum nucleoside analogue, originally for COVID-19/influenza)
• Status: Phase 2 trial for dengue and chikungunya ongoing in Brazil (Brazilian Clinical Trials Registry: U1111-1306-1425)
• A repurposing effort leveraging its broad-spectrum mechanism

Dengue Monoclonal Antibody - SII (Serum Institute of India) - Phase 2 COMPLETED

• Target: Dengue virus envelope protein (passive immunotherapy)
• Phase 2 dose-ranging trial completed; results pending publication (CTRI/2021/07/035290)

4. Drugs That Were Terminated

• AT-752 (Atea Pharmaceuticals) - nucleotide prodrug inhibitor of DENV NS5 polymerase (NCT05466240) - terminated, recruitment challenges + sponsor deprioritization
• JNJ-64281802 (Janssen/J&J) - NS3-NS4B inhibitor (NCT04906980) - terminated October 2024 as part of J&J's "strategic reprioritization" of infectious disease programs

5. Preclinical Pipeline Highlights (from Molecules Review, 2024)

6. Novel Approaches in Early Discovery (INTREPID 5th Edition, 2026)

• MLT201 (Meletios Therapeutics) - exploits defective viral genome (DVG) biology; novel mechanism; hit-stage
• Protinhi viral protease inhibitors (Protinhi) - two pan-flavivirus broad-spectrum candidates; hit-stage
• Pan-flavivirus broad-spectrum antivirals - targeting dengue alongside Zika, WNV, yellow fever

7. The Key Challenge: Narrow Treatment Window

• Human challenge models (controlled infection studies) to rapidly screen antiviral activity
• Viral clearance rate studies as surrogate endpoints before large Phase 3 trials
• Factorial randomization designs to test multiple drugs simultaneously
• Europe's DG HERA committing EUR 20 million to advance at least two new dengue medicines

Summary