Dengue

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Dengue

Overview

Dengue is a mosquito-borne viral infection caused by four closely related flaviviruses (DENV-1, -2, -3, -4; some sources note a fifth serotype DENV-5). It is transmitted primarily by Aedes aegypti and less commonly by Aedes albopictus and Aedes polynesiensis. It remains one of the most significant re-emerging infectious diseases globally, with an estimated 390 million infections annually - 96 million clinically apparent, ~500,000 hospitalizations, and ~20,000 deaths per year.

Around 3.9 billion people in 128 countries are at risk, predominantly in the tropics and subtropics of Asia, the Pacific, Africa, Latin America, and the Caribbean. - Red Book 2021

Virology & Transmission

Feature	Detail
Pathogen	Flavivirus (RNA, single-stranded, positive-sense)
Serotypes	DENV-1 through DENV-4 (DENV-5 reported)
Primary vector	Aedes aegypti
Secondary vectors	Aedes albopictus, Aedes polynesiensis
Extrinsic incubation	8-12 days (in mosquito)
Intrinsic incubation	3-14 days (in human, typically 4-10 days)
Viremic window	Starts 1-2 days before symptoms; lasts ~7 days

Other (rare) transmission routes include vertical (mother-to-fetus, ~20% risk, higher near delivery), breastfeeding, blood/organ transfusion, sexual contact, and needlestick. - Red Book 2021

Immunopathogenesis

Infection with one serotype confers lifelong immunity against that serotype and 1-3 years of cross-protection against the other serotypes. After that period of cross-protection wanes, a second infection with a different serotype predisposes to severe dengue through antibody-dependent enhancement (ADE):

Cross-reactive (non-neutralizing) antibodies from the first infection enhance uptake of the new serotype into macrophages via Fc receptors
This increases viral infectivity, amplifies the cytokine response, and causes massive plasma leakage
DENV-2 secondary infections carry the highest risk for severe disease
Infants with maternal anti-dengue antibodies are also at risk for severe disease via the same mechanism
Robbins Pathologic Basis of Disease; Harrison's Principles of Internal Medicine 22E (2025)

Clinical Manifestations

The 2009 WHO classification divides dengue into three severity tiers:

1. Dengue Without Warning Signs

Fever + at least 2 of:

Nausea/vomiting
Rash (macular or maculopapular)
Aches and pains (myalgia, arthralgia, retro-orbital pain - "breakbone fever")
Leukopenia
Positive tourniquet test

2. Dengue With Warning Signs

All of the above + any of:

Abdominal pain or tenderness
Persistent vomiting
Clinical fluid accumulation (ascites, pleural effusion)
Mucosal bleeding
Lethargy or restlessness
Liver enlargement >2 cm
Rapid decline in platelet count with rising hematocrit

3. Severe Dengue

At least one of:

Severe plasma leakage leading to shock or respiratory distress
Severe bleeding (clinician-assessed)
Severe organ involvement: AST or ALT ≥1000 IU/L, impaired consciousness, heart/organ failure

Disease Phases

Phase	Timing	Key Features
Febrile	Days 1-7	High fever, myalgia, rash, leukopenia, petechiae
Critical	Days 3-7 (at defervescence)	Plasma leakage 24-48 hrs; rising hematocrit; risk of shock
Convalescent	After critical phase	Gradual hemodynamic stabilization, reabsorption of leaked fluids

The critical phase is the danger window. Patients who survive to convalescence generally recover fully.

Uncommon manifestations: myocarditis, pancreatitis, hepatitis, hemophagocytic lymphohistiocytosis (HLH), meningoencephalitis, post-dengue ADEM. - Red Book 2021

High-risk groups for severe disease: infants, pregnant women, elderly, and patients with chronic conditions (asthma, sickle cell disease, diabetes). - Red Book 2021

Diagnosis

Timing-based approach

Timing	Preferred Test
Days 1-7 (febrile phase)	RT-PCR (dengue RNA) or NS-1 antigen EIA
Days 3-10	IgM antibody (detectable day 3-5, 99% positive by day 10)
>15 days (convalescent)	Fourfold rise in IgG between acute and convalescent samples
Acute + convalescent combined	NS-1 + IgM on single sample identifies ≥90% of cases

Key points:

IgM can cross-react with Zika and other flaviviruses
IgG remains elevated for life; can be falsely positive if vaccinated against other flaviviruses (yellow fever, Japanese encephalitis, West Nile)
CBC: leukopenia and thrombocytopenia are hallmark findings; rising hematocrit signals plasma leakage
Red Book 2021; Washington Manual

Management

There is no specific antiviral therapy for dengue. Treatment is entirely supportive.

General Principles

Maintain adequate intravascular volume - this is the cornerstone of management
Avoid aspirin and NSAIDs (antiplatelet/GI bleeding risk)
Oral rehydration for mild disease; IV fluids for warning signs or shock
Monitor hematocrit, platelet count, and signs of plasma leakage closely during the critical phase

Severe Dengue / Dengue Shock

IV crystalloid resuscitation (isotonic saline or lactated Ringer's)
Careful fluid management - over-resuscitation worsens pulmonary edema when leaked fluid reabsorbs in convalescence
Blood products (platelets, packed RBCs) for significant bleeding
ICU monitoring for shock, respiratory distress, organ failure
Washington Manual of Medical Therapeutics; Red Book 2021

Prevention

Approach	Details
Vector control	Eliminate standing water, larviciding, insecticides, window screens
Personal protection	Insect repellents (DEET, picaridin), long sleeves, bed nets
Wolbachia mosquito release	Releasing Aedes infected with Wolbachia bacteria (blocks viral replication) has reduced cases by 95-97% in Colombia - a novel biocontrol strategy
Vaccines	Several vaccines developed; concern exists that vaccines in seronegative individuals could prime ADE, potentially increasing severe disease risk on natural infection

Vaccines (key note):

Dengvaxia (CYD-TDV): approved in several countries but restricted to seropositive individuals only due to ADE risk in dengue-naive recipients
TAK-003 (Qdenga): approved in some regions; shows efficacy in both seropositive and seronegative individuals
Ongoing concern that vaccinating seronegative populations could mimic "first infection" and prime for ADE

Epidemiology Highlights

Dengue has re-emerged explosively since the post-WWII period; DHF/DSS emerged in Southeast Asia after the war
Dengue transmission can be more efficient within households than influenza (Puerto Rico 1977 simultaneous outbreak study) - Harrison's 22E
Despite advanced vector control programs, even Singapore cannot prevent dengue outbreaks entirely
Local outbreaks in the continental US have occurred in Texas, Florida, and Hawaii
July-September is peak incidence period in US territories

Recent Literature

A 2025 systematic review (PMID 41037858) in Journal of Infection and Public Health covers dengue pathogenesis, diagnosis, and management comprehensively. A 2024 meta-analysis (PMID 38721675) documents HLH as a rare but high-mortality complication of dengue fever.

Summary mnemonic - "DENGUE":

D - Defervescence is the dangerous phase (critical window)
E - Enhancement (ADE) drives severe disease on second infection
N - No antivirals - supportive care only
G - Grade severity: no warning signs / warning signs / severe
U - Undetectable IgM early - use NS1/PCR in first 5-7 days
E - Eliminate mosquito breeding sites for prevention

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