Early Oral N-Acetylcysteine for Ambulatory Dengue Patients at Risk of Severe Disease Progression

Background

Dengue infects ~390 million people annually. No approved antiviral therapy exists. Previous clinical trials of host-directed therapies failed consistently — not because the targets were wrong, but because they enrolled the wrong patients (already hospitalised) at the wrong time (viral peak already passed). A critical gap remains: no early, low-cost intervention for ambulatory patients to prevent progression to severe dengue.

Hypothesis

In ambulatory dengue patients presenting within 72 hours of fever onset, oral N-acetylcysteine (600–1200 mg twice daily for 5–7 days) given to individuals identified by simple clinical risk scores (age >40, secondary infection by rapid NS1/IgG test, comorbidities, or warning signs) will reduce progression to severe dengue and hospitalisation by ≥40% compared to standard supportive care alone.

Mechanistic Rationale

DENV infection drives oxidative stress via mitochondrial dysfunction and NOX activation in endothelial cells, generating ROS that trigger inflammation, vascular hyperpermeability, and plasma leakage — the hallmarks of severe dengue. NAC has a dual mechanism: (1) antioxidant — scavenges ROS, restores glutathione, blocks NOX- and mitochondrial-derived ROS in endothelial models; (2) antiviral — dose-dependently reduces DENV replication, E protein expression, and infectivity while upregulating RIG-I and MDA5 innate immune sensors. In severe dengue-associated acute liver failure, IV NAC showed 97% survival vs ~50% expected mortality in a retrospective series of 30 adults.

Why Previous Trials Failed

Past trials targeted hospitalised patients with established severe disease, used virological surrogate endpoints (viral load) rather than clinical outcomes, and were statistically underpowered. The early ambulatory window — when oxidative stress and endothelial dysfunction are building but plasma leakage has not yet occurred — remains completely unexplored.

Why NAC Fits the Setting

Oral, heat-stable, no cold chain, ~$0.10–0.50/day, widely available in dengue-endemic LMIC settings. Risk-stratification via rapid NS1/IgG serology is already standard practice. Simple to implement without specialist infrastructure.

Proposed Study Design

Randomised controlled trial, ambulatory dengue patients, within 72hrs of fever onset, stratified by risk score. Primary endpoint: WHO 2009 severe dengue criteria or hospitalisation at day 14. Secondary: time to defervescence, platelet nadir, haematocrit change, safety.

Grounded via AUBRAI. Key references: PMC8454086, PMC2900558, PMC8847576, PMC7650016