Dengue

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Dengue

Overview

Dengue is a mosquito-borne viral illness caused by four closely related RNA flaviviruses (DENV-1, -2, -3, -4), transmitted primarily by Aedes aegypti and less commonly A. albopictus. It infects an estimated 400 million people annually, with ~100 million symptomatic cases and ~40,000 deaths from severe disease. 2024 was a historic peak with over 14 million cases globally; outbreaks are currently active in Sri Lanka (44,000+ cases in 2026) and other tropical regions. Cases in the US reached a 359% increase in 2024 vs. prior averages.

Virology & Transmission

Family: Flaviviridae, genus Flavivirus
Four serotypes: DENV-1, 2, 3, 4 - each can cause illness independently
Primary vector: Aedes aegypti (peridomestic, daytime biting)
Incubation: 3-14 days (human); 8-12 days in mosquito (extrinsic)
Viremic window: 1-2 days before symptoms through ~7 days of illness (patients can infect mosquitoes during this period)
Other routes: Vertical (20% risk, higher near delivery), blood/organ transplant, rarely breastfeeding or sexual contact

Red Book 2021, p. 521

Immunity & Pathogenesis - Antibody-Dependent Enhancement (ADE)

This is the key concept explaining severe dengue:

First infection with any serotype → lifelong immunity against that serotype + cross-protection against the others (lasting 1-3 years)
After cross-protection wanes, a second infection with a different serotype triggers ADE: prior cross-reactive antibodies bind the new virus but cannot neutralize it; instead they promote Fc receptor-mediated uptake into macrophages, amplifying viral replication and cytokine release
This massive cytokine storm increases vascular permeability → plasma leakage → hemorrhage and shock
DENV-2 is most commonly associated with severe secondary disease
Infants with maternal dengue antibodies are also at risk (passive ADE)

Robbins & Cotran Pathologic Basis of Disease, p. 336; Harrison's 22E, p. 3901

Clinical Phases

Phase 1 - Febrile (Days 1-3)

Sudden high fever (39-40°C)
Severe myalgia, arthralgia, bone pain ("breakbone fever")
Retro-orbital pain, headache
Facial flushing, injected oropharynx
Macular or maculopapular rash (appears days 3-5 as fever defervesces in ~50% of patients)
Leukopenia, thrombocytopenia, mildly elevated LFTs

Phase 2 - Critical (Days 3-7, around defervescence)

24-48 hour window of significant plasma leakage
Hematocrit rises (hemoconcentration) as intravascular fluid leaks
Warning signs (require hospital monitoring):
- Abdominal pain or tenderness
- Persistent vomiting
- Clinical fluid accumulation (ascites, pleural effusion)
- Mucosal bleeding
- Lethargy/restlessness
- Liver enlargement >2 cm
- Rapid platelet decline with rising hematocrit

Phase 3 - Convalescent

Gradual hemodynamic stabilization and clinical improvement
Reabsorption of leaked fluid (risk of fluid overload if over-resuscitated)
Bradycardia common

Red Book 2021, pp. 519-520

WHO 2009 Severity Classification

Category	Criteria
Dengue without warning signs	Fever + ≥2 of: nausea/vomiting, rash, aches/pains, leukopenia, positive tourniquet test
Dengue with warning signs	Above + any warning sign (see Phase 2 above)
Severe dengue	Severe plasma leakage with shock or respiratory distress; severe bleeding; severe organ involvement (AST/ALT ≥1000 IU/L, impaired consciousness, cardiac/organ failure)

The Dengue Rash

The characteristic rash appears in about 50% of patients, typically days 3-5:

Dengue fever rash - "islands of white in a sea of red" morbilliform eruption

Dengue rash showing the pathognomonic "islands of white in a sea of red" - confluent morbilliform erythema with scattered islands of spared normal skin. Linear bleeding points can appear after blood pressure cuff application (positive tourniquet test). - Andrews' Diseases of the Skin

Tourniquet test: Inflate BP cuff to midpoint between systolic/diastolic for 5 min, wait 2 min, count petechiae - ≥10/sq inch = positive (suggestive of dengue).

Diagnosis

Timing determines which test to use:

Timing	Preferred Tests
Days 1-7 (febrile phase)	RT-PCR for viral RNA or NS1 antigen ELISA
Day 3 onward	Anti-dengue IgM (positive in 99% by day 10)
Days 1-10 (combined)	NS1 antigen + IgM together identifies ≥90% of cases
Convalescent	4-fold rise in IgG confirms recent infection

Caveats:

IgM can cross-react with Zika, West Nile, Japanese encephalitis, yellow fever
IgG may be falsely positive in those previously vaccinated against other flaviviruses
A 2025 Lancet Microbe meta-analysis (PMID 40209729) evaluated RT-PCR, NS1 ELISA, and IgM ELISA performance

Other labs: Leukopenia, thrombocytopenia (<100,000 in 50%), elevated transaminases (~3x normal)

Red Book 2021, pp. 521-522

Treatment

No specific antiviral exists. Management is entirely supportive.

Febrile Phase

Oral hydration - encourage fluids
Paracetamol/acetaminophen for fever and pain
Avoid: aspirin, NSAIDs (ibuprofen), and salicylate-containing products - risk of bleeding

Critical Phase (hospitalized patients with warning signs/severe dengue)

IV fluid resuscitation with crystalloids (normal saline or Ringer's lactate) - titrated carefully
Monitor hematocrit every 4-6 hours
Watch for: occult bleeding, shock, fluid overload
Platelet transfusion: generally not given unless active severe bleeding or pre-procedure with platelets <50,000; prophylactic platelet transfusions are not routinely recommended
With intensive supportive care: mortality drops from ~5-10% to <1%
Refractory shock may require colloids or vasopressors

Convalescent Phase

Caution with fluid administration - risk of overload as plasma re-enters intravascular space
Monitor for pulmonary edema

Red Book 2021, pp. 522-523

High-Risk Groups

Infants (maternal ADE antibodies)
Pregnant women
Second dengue infection (different serotype)
Chronic illness: asthma, sickle cell disease, diabetes
Persons with prior flavivirus vaccination (cross-reactive serology complications)

Rare/Atypical Manifestations

Myocarditis, pancreatitis, hepatitis
Hemophagocytic lymphohistiocytosis (HLH)
Acute meningoencephalitis
Post-dengue ADEM (acute disseminated encephalomyelitis)

Vaccines

Dengvaxia (CYD-TDV): FDA-approved in the US for children 9-16 in dengue-endemic areas who have laboratory-confirmed prior infection only; can worsen disease in seronegative individuals (paradoxical ADE concern)
Qdenga (TAK-003): Approved in several countries, studied in seronegative individuals with a better safety profile - newer option
Fear remains that vaccines could potentiate severe disease in naive recipients

Prevention & Vector Control

Eliminate standing water (breeding sites for Aedes)
Window screens, air conditioning, insect repellents (DEET)
Aedes mosquitoes bite during the day (unlike malaria-vector anophelines which bite at night)
Novel: release of Wolbachia-infected Aedes mosquitoes has reduced dengue cases by 95-97% in dense urban areas in Colombia - a promising public health tool
Military drones now being used in Sri Lanka (2026) to scan rooftops for mosquito breeding sites

Current Epidemiology (2025-2026)

2024 was a historic global peak: >14 million cases (WHO)
Sri Lanka (2026): 44,000+ cases, 28 deaths as of June - worst outbreak in years, exacerbated by post-cyclone conditions
Panama (2025): All 4 serotypes co-circulating (DENV-3 and -4 predominating), increasing severe case risk
United States: 3,798 cases in 2024 - a 359% increase over the prior annual average of 828; local transmission documented in southern states

Sources: Harrison's Principles of Internal Medicine 22E (2025) | Robbins & Cotran Pathologic Basis of Disease | Red Book 2021 | Andrews' Diseases of the Skin | Recent: Yang ZS et al. systematic review, J Infect Public Health 2025 (PMID 41037858)

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