What is the pathophysiology of dengue in individuals of all ages, particularly in young children, older adults, and those with underlying medical conditions?

Pathophysiology of Dengue Fever

Viral Transmission and Initial Infection

Dengue virus (DENV) is transmitted by Aedes aegypti mosquitoes and initiates a complex cascade of immune-mediated pathology that drives disease severity, with the host immune response—rather than direct viral cytopathic effects—being the primary determinant of clinical outcomes. 1, 2

• The incubation period ranges from 4-8 days before symptom onset, during which the virus replicates in target cells 1, 3
• Viral RNA becomes detectable in serum approximately 2 days before symptoms appear and persists for up to 1 week after illness onset, with peak viremia occurring during the acute febrile phase 4, 1
• Dengue virus NS1 antigen can be detected in serum with similar frequency and duration as viral RNA 4

Primary Target Cells and Initial Immune Activation

• Blood monocytes, dendritic cells (DCs), and tissue macrophages serve as the main target cells for DENV infection 5
• These cells recognize viral pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs), particularly Toll-like receptors (TLRs) 5
• TLR engagement with viral PAMPs triggers downstream signaling pathways leading to production of inflammatory cytokines, interferons (IFNs), and other antiviral molecules 5

The Cytokine Storm and Immune Dysregulation

The hallmark of severe dengue pathogenesis is an aberrant immune response characterized by a cytokine storm—an imbalance between pro-inflammatory and anti-inflammatory cytokines that drives vascular permeability and hemorrhagic complications. 6, 2

• Both innate and adaptive immune systems become activated in severe dengue, contributing to excessive cytokine production 6
• Monocytes, mast cells, and other immune cells, when infected with DENV (especially in the presence of poorly neutralizing antibodies), produce pro-inflammatory cytokines while simultaneously inhibiting interferon signaling pathways 7
• Production of immunosuppressive cytokines such as IL-10 further inhibits cellular antiviral responses, leading to reduced viral clearance 7
• This dysregulated immune response results in high levels of inflammatory cytokines that induce vascular leak and excessive inflammation 7

Clinical Manifestations Driven by Immune Response

Fever, headache, retro-orbital pain, myalgia, and arthralgia result from the cytokine storm triggered by viral infection and immune activation, not from direct viral tissue damage. 1

• The characteristic dengue rash typically appears during days 3-7 of illness, coinciding with the defervescence period when fever subsides 1
• Warning signs of progression to severe dengue typically appear around day 3-7 of illness, during the critical phase when plasma leakage begins 8

Mechanisms of Plasma Leakage and Vascular Permeability

• The transient period of vascular leakage is followed by rapid recovery, suggesting the effects of short-lived biological mediators rather than permanent endothelial damage 6
• Several cytokines are known to induce apoptosis (causing hemorrhage) and/or affect adherens junctions (causing permeability) in vitro 2
• Vascular fragility occurs due to high levels of cytokines and other soluble mediators, combined with potential endothelial cell infection 2

Thrombocytopenia and Hemoconcentration

Thrombocytopenia combined with rising hematocrit represents a critical warning sign of progression to severe dengue, reflecting ongoing plasma leakage and bone marrow suppression. 1, 8

• Rising hematocrit (>20% increase from baseline) indicates plasma leakage and hemoconcentration 3
• Thrombocytopenia ≤100,000/mm³, particularly when declining rapidly, signals increased risk of hemorrhagic complications 3

Antibody-Dependent Enhancement (ADE)

• Fcγ receptor-mediated antibody-dependent enhancement (ADE) occurs during secondary infection with a different DENV serotype 9
• ADE results in increased viral uptake by immune cells and release of cytokines, leading to vascular endothelial cell dysfunction and increased vascular permeability 9
• Memory cross-reactive T cells from prior DENV infection may have altered cytokine responses during sequential infection with different serotypes, contributing to detrimental immune responses 9

Autoimmune Mechanisms

• Dengue infection can generate autoantibodies against DENV NS1 antigen, prM, and E proteins 9
• These autoantibodies can cross-react with several self-antigens including plasminogen, integrin, and platelet cells, contributing to thrombocytopenia and hemorrhagic manifestations 9
• Anti-DENV NS1 antibodies are believed to play a role in the pathogenesis of severe dengue 9

Progression to Dengue Shock Syndrome (DSS)

DSS occurs when plasma leakage becomes severe enough to cause hypovolemia, leading to hypotension (systolic BP <90 mmHg) or narrow pulse pressure (<20 mmHg), and requires fundamentally different management than bacterial septic shock. 1, 8

• Approximately 15% of pregnant women develop dengue shock syndrome compared to 5% of non-pregnant individuals, likely due to pregnancy-related immune and hemodynamic changes 1
• Dengue shock behaves differently from bacterial septic shock due to the underlying plasma leakage pathophysiology, requiring careful fluid management to avoid over-resuscitation 1, 8

Severe Manifestations and Organ Dysfunction

• Profound shock leads to metabolic acidosis and development of disseminated intravascular coagulation (DIC) 2
• During DIC, multiple micro-thromboses occur, leading to organ failure 2
• High amounts of virus in the blood do not correlate directly with disease severity, supporting that the host response is the primary driver of severe disease 2

Host Genetic and Viral Factors

• Host genetic factors and gene polymorphisms play a role in determining disease severity 9
• Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) can suppress host immune responses, serving as viral determinants of disease severity 9
• Displacement of viral genotype and host genetic background are key factors driving the production of a cytokine storm 2

Comorbidities and Risk Factors

• Individuals with comorbid illnesses may be prone to more severe dengue due to low-grade endotoxemia, gut microbial dysbiosis, and an altered phenotype of innate immune cells 7
• The immunosuppressive and inflammatory lipid mediators and altered phenotype of monocytes likely further impair T cell and B cell adaptive immune responses to the virus 7

Clinical Outcomes and Prognosis

Early recognition of warning signs and appropriate supportive management can reduce case-fatality rates to <0.5% in hospitalized patients, demonstrating that timely intervention can overcome the pathophysiologic cascade. 1, 8

• Most dengue and Zika virus infections are asymptomatic, with only a minority progressing to symptomatic disease 4
• The majority of infected individuals develop only mild self-limiting illness, with severe dengue occurring in a low percentage of patients 7, 2