What is the pathophysiology of dengue?

Pathophysiology of Dengue

Overview of Disease Mechanism

Dengue pathogenesis involves a complex interplay between viral factors, immune dysregulation, vascular endothelial dysfunction, and coagulation abnormalities that ultimately lead to increased vascular permeability and plasma leakage—the hallmark of severe dengue. 1

Viral Entry and Initial Infection

• Dengue virus (DENV) is transmitted primarily by Aedes aegypti mosquitoes and has four distinct serotypes (DENV-1 through DENV-4). 2, 3
• The virus infects a wide variety of immune cells including monocytes, macrophages, dendritic cells, mast cells, and T and B cells, which facilitates viral dissemination throughout the body. 4
• DENV also directly infects vascular endothelial cells and hepatocytes, causing cellular apoptosis and dysfunction. 5
• The incubation period ranges from a few days to 2 weeks, with viral RNA detectable in serum from approximately 2 days before to 1 week after illness onset. 2

Immune Response and Antibody-Dependent Enhancement (ADE)

• In secondary infections with a different DENV serotype, pre-existing non-neutralizing antibodies from the first infection bind to the new virus but fail to neutralize it, instead facilitating viral entry into Fcγ receptor-bearing cells—a phenomenon called antibody-dependent enhancement (ADE). 6, 4
• This ADE mechanism results in higher viral loads and more severe disease manifestations, particularly dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). 7
• Memory cross-reactive CD4+ T cells from prior infection produce altered cytokine responses during secondary infection, contributing to a detrimental "cytokine tsunami" with elevated pro-inflammatory mediators. 6, 4
• In secondary infections, the rapid anamnestic IgG response can suppress or delay IgM production, and neutralizing antibodies develop against multiple flaviviruses simultaneously. 8

Cytokine Storm and Immune Dysregulation

• Dengue infection induces aberrant immune activation characterized by CD4/CD8 ratio inversion and massive cytokine overproduction, including IL-6, IL-8, TNF-α, and IFN-γ. 5, 2
• IL-6 plays a crucial role in enhancing production of anti-platelet and anti-endothelial cell autoantibodies, elevated tissue plasminogen activator (tPA) levels, and coagulation deficiencies. 5
• This cytokine surge impairs normal immune function to clear the virus while simultaneously causing widespread cellular dysfunction. 5
• In pregnant women, elevated cytokines (IL-6, IL-8, TNF) contribute to increased maternal morbidity and mortality risk. 2

Vascular Endothelial Dysfunction

• Increased vascular permeability without morphological damage to the capillary endothelium is the cardinal feature of DHF/DSS. 1
• The vascular endothelium becomes the primary "battlefield" where viral infection, immune responses, and inflammatory mediators converge to cause dysfunction. 1
• Mechanisms targeting endothelial cells include: direct viral infection, immune complex deposition, cross-reactive antibodies against endothelial cells, complement activation, and cytokine-mediated damage. 1
• This endothelial dysfunction leads to extensive plasma leakage into tissue spaces and serous cavities (pleural, pericardial, peritoneal), which can result in profound shock. 1
• Increased vascular permeability and plasma leakage are triggered by the dengue virus itself or by antibodies to its antigens. 5

Thrombocytopenia and Coagulopathy

• Platelets are destroyed by cross-reactive anti-platelet autoantibodies generated during infection. 5
• Both coagulation and fibrinolysis systems are activated after dengue infection, creating an imbalance that increases the likelihood of severe hemorrhage. 5
• Hemostasis is maintained unless dysregulation of coagulation and fibrinolysis persists, at which point severe bleeding complications develop. 5
• Thrombocytopenia, along with cell stress and liver damage, accounts for the severe clinical course in pregnant women, who face a 15% risk of dengue shock syndrome compared to 5% in non-pregnant populations. 2

NS1 Protein and Autoimmunity

• Dengue virus nonstructural protein-1 (NS1) antigen is detectable in serum with similar frequency and duration as dengue viral RNA. 2
• Anti-DENV NS1 antibodies are believed to contribute to pathogenesis of severe dengue through cross-reactivity with host tissues. 6
• Dengue infection generates autoantibodies against NS1 antigen, prM, and E proteins that cross-react with self-antigens including plasminogen, integrin, and platelet cells. 6

Critical Phase and Plasma Leakage

• Days 4-6 after symptom onset represent the critical phase when plasma leakage and severe complications typically develop, particularly in secondary infections. 8
• Rising hematocrit (>20% increase) indicates plasma leakage and impending severe dengue. 8
• Warning signs requiring immediate intervention include: abdominal pain/tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleeding, lethargy/restlessness, and liver enlargement. 8

Pregnancy-Specific Pathophysiology

• Vertical transmission of dengue from mother to child occurs, though transmission rates vary significantly between studies. 2
• Placental infection and fetal transmission may account for adverse perinatal outcomes including stillbirth and neonatal mortality. 2
• The inflammatory surge during dengue infection in pregnancy may cause insufficient placental perfusion due to increased vascular permeability and plasma leakage. 2

Viral and Host Genetic Factors

• Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) can suppress host immune responses, contributing to disease severity. 6
• Host genetic factors and gene polymorphisms play a role in determining susceptibility to severe disease outcomes. 6
• The selection of virulent viral strains influences disease severity, though immune-mediated mechanisms remain the primary determinants. 1