219.1 🎓 醫孞生版

219.1.0.1 📌 䞀頁重點

  • Virus: ssRNA flavivirus, Flaviviridae family
  • 4 serotypes (DENV-1, 2, 3, 4) — each serotype provides homologous immunity but heterologous immunity wanes; second infection different serotype = increased severe risk
  • Vector: Aedes aegypti (peridomestic, daytime biter, classical vector) + Aedes albopictus (Asian tiger mosquito, also dengue, chikungunya, Zika)
  • Geography: tropical + subtropical worldwide; SE Asia + Pacific + Caribbean + Central + South America
  • Burden (WHO 2024): 5+ million cases/yr reported (actual estimates 100-400 million annually with ~ 40,000 deaths)
  • 2024 epidemic: largest in history (especially Americas region) — climate + travel + urbanization
  • Clinical Spectrum:
    • Asymptomatic (~ 75%)
    • Dengue fever (DF): febrile illness 3-7 days
    • Dengue with warning signs (severe dengue precursor)
    • Severe dengue (severe plasma leakage, hemorrhage, severe organ involvement) — formerly called DHF/DSS
  • WHO 2009 Classification (replaces DHF/DSS):
    • Dengue without warning signs
    • Dengue with warning signs: abdominal pain, persistent vomiting, plasma leakage signs (ascites, pleural effusion), bleeding, lethargy, hepatomegaly, increasing Hct + decreasing platelets
    • Severe dengue: severe plasma leakage (shock, fluid accumulation with respiratory distress), severe bleeding, severe organ involvement (AST/ALT > 1000, impaired consciousness, cardiac dysfunction)
  • Antibody-Dependent Enhancement (ADE):
    • Sub-neutralizing antibodies from prior infection facilitate entry of different serotype
    • → Increased viral load + cytokine cascade
    • → Severe dengue more likely on 2nd infection with different serotype
  • Diagnosis:
    • NS1 antigen (first week, sensitive)
    • PCR (first week, gold standard for acute)
    • IgM (after day 3-5, lasts 2-3 months)
    • IgG (paired sera for confirmation; lifelong)
  • Treatment:
    • Supportive (no antiviral)
    • Fluid management is critical
    • Avoid NSAIDs + aspirin (bleeding risk)
    • Plasma + platelet transfusion for severe bleeding
    • ICU for severe dengue
  • Vaccines:
    • Dengvaxia (Sanofi, 2015) — controversial; only for seropositive 9-45 yr (paradoxical risk in seronegative)
    • Qdenga (Takeda, 2022) — broader use 4-60 yr regardless of prior infection
  • Prevention: mosquito control (Aedes), insect repellent (DEET, picaridin), bed nets, eliminating breeding sites

219.1.0.2 1⃣ Virology

219.1.0.2.1 Structure
  • ssRNA, ~ 11 kb
  • Flavivirus genus
  • 3 structural proteins (capsid, prM, envelope E)
  • 7 non-structural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5)
  • NS1 secreted during infection → diagnostic
219.1.0.2.2 Serotypes + Antigenic Diversity
  • 4 serotypes (DENV-1, DENV-2, DENV-3, DENV-4)
  • Each provides homologous lifelong immunity
  • Heterologous cross-immunity transient (months)
  • After: ADE risk increased for different serotype
219.1.0.2.3 Antibody-Dependent Enhancement (ADE)
  • Sub-neutralizing IgG to one serotype binds different serotype
  • Bound virus → Fc receptor → entry into macrophages
  • Increased viral replication
  • Cytokine storm
  • Vascular leak

219.1.0.3 2⃣ Epidemiology

219.1.0.3.1 Geography
  • SE Asia, Pacific, Caribbean, Central + South America main
  • Vietnam, Thailand, Philippines, Indonesia historically high
  • 2024 epidemic: Americas region most severe in history
  • Climate change + travel + urbanization = expanding range
  • Mediterranean + USA southern now seeing local transmission (sporadic)
  • Taiwan: every 2-3 yr major outbreak (after 1998); 2023 outbreak ~ 40,000 cases (Taiwan record)
219.1.0.3.2 Vectors
  • Aedes aegypti (primary): peridomestic, daytime biter, prefers humans
  • Aedes albopictus (Asian tiger mosquito, secondary): also chikungunya, Zika; expanding north in Europe + USA due climate
219.1.0.3.3 Transmission
  • Mosquito bite (Aedes aegypti / albopictus)
  • Vertical (rare)
  • Transfusion (rare)
  • Organ transplant (rare)
  • Person-to-person: NOT direct (vector required)
219.1.0.3.4 Risk Factors for Severe Disease
  • Secondary infection different serotype
  • Young children + elderly
  • Pregnancy
  • Chronic diseases (DM, asthma, sickle cell)
  • DENV-2 + DENV-3 serotypes (more severe)

219.1.0.4 3⃣ Clinical

219.1.0.4.1 Incubation
  • 3-14 days (mean 4-7)
219.1.0.4.2 Phase 1: Febrile Phase (Days 1-3)
  • Sudden onset high fever 39-41°C
  • Severe headache + retro-orbital pain
  • Severe myalgia + arthralgia (“breakbone fever”)
  • Nausea, vomiting
  • Maculopapular rash (50% of cases) — trunk + extremities, blanching
  • Bone pain
  • Petechiae in some
219.1.0.4.3 Phase 2: Critical Phase (Days 4-7)
  • Around defervescence (paradoxically)
  • Plasma leakage can occur — fluid extravasation
  • Watch for warning signs
  • Most cases: spontaneous recovery during this phase
  • 1-5%: progresses to severe dengue
219.1.0.4.4 Phase 3: Recovery Phase (Days 7-10)
  • Resolution of plasma leakage
  • Reabsorption
  • Fluid overload risk (don’t over-resuscitate)
  • Itchy rash (flame-shaped) — common during recovery
219.1.0.4.5 Warning Signs (Days 3-7 Critical Phase)
  1. Abdominal pain or tenderness
  2. Persistent vomiting
  3. Clinical fluid accumulation (pleural effusion, ascites)
  4. Mucosal bleeding
  5. Lethargy / restlessness
  6. Liver enlargement > 2 cm
  7. Increase in Hct concurrent with decreasing platelets
219.1.0.4.6 Severe Dengue (3 Categories)
219.1.0.4.6.1 1. Severe Plasma Leakage
  • Shock (Dengue Shock Syndrome — DSS) — narrow pulse pressure, cold, clammy
  • Fluid accumulation with respiratory distress (ARDS-like)
219.1.0.4.6.2 2. Severe Bleeding
  • Hematemesis, melena, CNS bleed
  • Petechiae alone not severe
219.1.0.4.6.3 3. Severe Organ Involvement
  • Hepatic: AST/ALT > 1000
  • CNS: impaired consciousness
  • Cardiac: myocarditis
  • AKI
219.1.0.4.7 Special Forms
219.1.0.4.7.1 Dengue Hemorrhagic Fever (DHF) — Old Classification
  • Plasma leakage + thrombocytopenia + hemorrhage manifestations
  • Now incorporated into severe dengue
219.1.0.4.7.2 Dengue Shock Syndrome (DSS) — Old Classification
  • Profound shock from plasma leakage
  • ~ 5% mortality if untreated; < 1% with proper management
  • Now part of severe dengue category
219.1.0.4.7.3 Dengue in Pregnancy
  • Can be severe
  • Vertical transmission late pregnancy
  • Hemorrhagic complications
  • Increased preterm + fetal loss

219.1.0.5 4⃣ Diagnosis

219.1.0.5.1 NS1 Antigen
  • First 1-7 days of illness
  • Sensitive (90%+) in primary infection
  • Less sensitive in secondary
  • Rapid test available (POC)
219.1.0.5.2 PCR
  • First 5-7 days
  • Gold standard
  • Serotype identification
  • Sensitive even before NS1
219.1.0.5.3 IgM
  • After day 3-5 typically
  • Lasts 2-3 months
  • Cross-reacts with other flaviviruses (especially Zika)
219.1.0.5.4 IgG
  • Paired sera (acute + convalescent)
  • 4-fold rise diagnostic
  • Lifelong after infection
219.1.0.5.5 Lab Findings
  • Leukopenia + thrombocytopenia typical
  • Increased Hct (hemoconcentration, plasma leakage)
  • ↑ AST/ALT (modestly to severe)
  • Coagulation abnormalities in severe
  • AKI in severe
219.1.0.5.6 Imaging
  • CXR or US for pleural effusion
  • Abdominal US for ascites
  • Echocardiogram if myocarditis suspected

219.1.0.6 5⃣ Treatment

219.1.0.6.1 Mild Dengue (No Warning Signs)
  • Supportive: hydration, antipyretic (paracetamol only — NO NSAIDs / aspirin)
  • Oral rehydration solution
  • Rest
  • Daily monitoring CBC + warning signs
  • Outpatient OK
219.1.0.6.2 Dengue with Warning Signs
  • Hospitalization
  • IV fluid (isotonic crystalloid Ringer’s lactate or normal saline) — carefully titrated based on Hct + clinical
  • Monitor q1-2h (vital signs, urine output, Hct)
  • Continued monitoring during recovery (fluid overload risk)
219.1.0.6.3 Severe Dengue
  • ICU
  • IV fluid resuscitation (10-20 mL/kg over 15-30 min, then reassess)
  • Colloids (albumin, Hetastarch) if persistent shock after crystalloid
  • Blood products for severe bleeding (FFP, packed RBC, platelets — typically only if active bleeding, not just low platelets)
  • Inotropes for refractory shock
  • Mechanical ventilation if respiratory failure
  • AKI: dialysis if needed
219.1.0.6.4 General Principles
  • Strict fluid management is key
  • Avoid over-resuscitation (recovery phase fluid overload)
  • No NSAIDs / aspirin (bleeding + Reye syndrome)
  • Treat liver involvement, AKI, ARDS supportively
  • ICU monitoring with serial Hct + vitals
219.1.0.6.5 What NOT to Do
  • NSAIDs / aspirin — increase bleeding risk
  • Steroids routine — no benefit
  • Antibiotic empirically — no benefit (viral)
  • IVIG — no proven benefit
  • Antiviral — none approved (research)

219.1.0.7 6⃣ Prevention + Vaccines

219.1.0.7.1 Vector Control
  • Eliminate Aedes breeding sites (standing water in containers, tires, plant pots)
  • Insecticide spraying outdoor
  • Larval source reduction
  • Wolbachia infected mosquito releases (CDC + Eliminate Dengue program)
  • Sterile insect technique
219.1.0.7.2 Personal Protection
  • DEET 20-30% or picaridin 20% insect repellent
  • Long sleeves + pants
  • Bed nets (especially day-biting Aedes)
  • Window screens
219.1.0.7.3 Travel Medicine
  • Counseling for tropical travel
  • Repellent + clothing
  • Vaccine considerations (case-by-case)
219.1.0.7.4 Vaccines
219.1.0.7.4.1 Dengvaxia (Sanofi, 2015)
  • Chimeric live attenuated tetravalent yellow fever-dengue
  • 3-dose series 6 mo apart
  • Restricted use:
    • Only for prior dengue-infected (seropositive) — Philippines tragedy 2017+
    • Age 9-45 yr
    • In endemic areas
    • Screening for prior infection required (rapid serology)
  • Paradox: seronegative children vaccinated had worse outcome on infection
  • Limited deployment now
219.1.0.7.4.2 Qdenga (TAK-003, Takeda, 2022 EU approval)
  • Tetravalent live attenuated
  • 2-dose series (0 + 3 mo)
  • Broader use: 4-60 yr regardless of prior dengue infection status
  • WHO prequalified 2024
  • Efficacy: ~ 80% against any dengue, ~ 90% against hospitalization
  • Variable by serotype (better DENV-1, 2; less DENV-3, 4)
  • Mass deployment in endemic countries 2023+
219.1.0.7.4.3 Future Vaccines
  • TV003/TV005 (NIH/NIAID + Butantan + others) — live attenuated tetravalent in Phase 3
  • mRNA vaccines in development