What is the pathophysiology of dengue fever?

Pathophysiology of Dengue Fever

Dengue pathogenesis is fundamentally driven by an aberrant host immune response that triggers a cytokine storm, leading to vascular permeability, plasma leakage, thrombocytopenia, and coagulopathy—rather than direct viral cytopathic effects alone. 1, 2

Viral Transmission and Initial Infection

• Dengue virus is transmitted by Aedes species mosquitoes, primarily Aedes aegypti, with an incubation period of 4-8 days following the bite 3, 4
• The virus replicates in target cells including monocytes, endothelial cells, and hepatocytes, with viral RNA detectable in serum from approximately 2 days before to 1 week after illness onset 3
• Most dengue infections (the majority) remain asymptomatic, but symptomatic cases range from mild febrile illness to life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) 3, 4

The Cytokine Storm: Central Pathogenic Mechanism

The hallmark of severe dengue is an imbalanced cytokine response—a "cytokine storm"—characterized by excessive pro-inflammatory cytokines overwhelming anti-inflammatory mediators. 1

• Dengue infection triggers elevated levels of IL-6, IL-8, and tumor necrosis factor (TNF), which are strongly associated with disease severity 3
• IL-8 levels during early infection are significantly elevated in patients who develop bleeding complications and hepatitis 5
• IL-6 acts synergistically with IL-8 to cause bleeding in patients with plasma leakage, and may drive production of anti-platelet autoantibodies and elevated tissue plasminogen activator (tPA) levels 5, 2
• The cytokine profile suggests a T-helper 2 (Th2) response pattern during infection 5

Vascular Permeability and Plasma Leakage

Increased vascular permeability leading to plasma leakage is the defining pathophysiologic feature that distinguishes severe dengue from uncomplicated disease. 1, 2

• Cytokines act on endothelial cells to disrupt adherens junctions, causing increased vascular permeability 1
• The dengue virus itself, along with antibodies to viral antigens (particularly NS1), can directly trigger capillary leakage 2, 6
• Endothelial cell infection and dysfunction result from both direct viral effects and immune-mediated damage 2
• Plasma leakage, if uncompensated, leads to hemoconcentration, hypovolemic shock, and ultimately dengue shock syndrome affecting 15% of pregnant women compared to 5% of non-pregnant individuals 3

Thrombocytopenia and Hemorrhagic Manifestations

• Platelets are destroyed by cross-reactive anti-platelet autoantibodies generated during infection 2, 6
• Thrombocytopenia results from immune-mediated destruction rather than direct viral effects on megakaryocytes 3, 2
• Hemorrhagic manifestations arise from the combined effects of thrombocytopenia, endothelial dysfunction, and coagulopathy 2

Coagulopathy and Hemostatic Dysfunction

• Both coagulation and fibrinolysis systems are activated following dengue infection 2
• An imbalance between coagulation and fibrinolysis activation increases the likelihood of severe hemorrhage in DHF/DSS 2
• In profound shock, disseminated intravascular coagulation (DIC) develops with multiple micro-thromboses leading to organ failure 1
• IL-6 overproduction contributes to deficiency in coagulation factors and elevated tPA levels 2

Antibody-Dependent Enhancement (ADE)

• Secondary infection with a different dengue serotype is strongly associated with more severe disease through ADE mechanisms 2, 6
• Fcγ receptor-mediated ADE results in enhanced viral replication and increased cytokine release from immune cells 6
• Pre-existing cross-reactive antibodies from prior infection facilitate viral entry into monocytes and macrophages, paradoxically increasing viral load 6

T Cell-Mediated Immunopathology

• Dengue infection induces transient immune aberrations including CD4/CD8 ratio inversion 2
• Memory cross-reactive T cells from prior heterologous dengue infection may produce altered cytokine responses, contributing to detrimental immune activation 6
• Higher frequencies of dengue-specific TNFα, IFNγ, and IL-2-producing T cells correlate with subclinical rather than symptomatic secondary infection, suggesting protective versus pathogenic immune profiles 7

Hepatocyte Involvement and Liver Damage

• Dengue virus infects hepatocytes, causing apoptosis and cellular dysfunction 2
• Cell stress and liver damage contribute to the severe clinical course, particularly in pregnant women 3
• Hepatomegaly is recognized as a danger sign requiring immediate medical attention 8

Autoimmunity

• Dengue infection generates autoantibodies against viral NS1 antigen, prM, and E proteins that cross-react with self-antigens including plasminogen, integrin, and platelet cells 6
• Anti-endothelial cell autoantibodies contribute to vascular dysfunction 2

Viral and Host Genetic Factors

• Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) can suppress host immune responses, influencing disease severity 6
• Host genetic polymorphisms and background are key factors driving cytokine storm production 1, 6
• Displacement of viral genotypes in populations affects disease patterns 1

Critical Clinical Correlation

Warning signs appear around days 3-7 of illness during defervescence and include persistent vomiting, abdominal pain/tenderness, clinical fluid accumulation, mucosal bleeding, lethargy/restlessness, hepatomegaly, and hematocrit rise with concurrent thrombocytopenia. 8, 4

• These warning signs directly reflect the underlying pathophysiology: plasma leakage (hemoconcentration), thrombocytopenia (immune destruction), bleeding (coagulopathy), and organ involvement (hepatomegaly) 8
• Early recognition and appropriate fluid management can reduce case-fatality rates to <0.5% in hospitalized patients 3, 8

Common Pitfall

The absence of correlation between viral load and disease severity underscores that host immune response, not viral burden alone, drives severe dengue pathogenesis—making immunomodulation a potential therapeutic target rather than solely antiviral approaches. 1