What is the pathophysiology of dengue?

Pathophysiology of Dengue

Dengue infection involves complex pathophysiological mechanisms centered around viral replication, immune system activation, and vascular damage that ultimately lead to plasma leakage, thrombocytopenia, and potentially life-threatening complications.

Viral Infection and Initial Response

• Dengue virus (DENV) is primarily transmitted by Aedes aegypti mosquitoes 1
• After inoculation, the virus infects:
  • Dendritic cells
  • Monocytes/macrophages
  • Hematopoietic progenitor cells
  • Bone marrow stromal cells 2
• Initial viral replication occurs in local tissues before spreading through the bloodstream
• The incubation period ranges from a few days to 2 weeks 1
• Viral RNA is typically detectable in serum from approximately 2 days before to 1 week after illness onset 1

Immune Response and Cytokine Production

• Primary infection triggers both innate and adaptive immune responses
• IgM antibodies develop during the first week of illness 1
• IgG neutralizing antibodies develop shortly after IgM antibodies and can persist for years 1
• In secondary infections (with different DENV serotypes), several key pathological processes occur:
  1. Antibody-dependent enhancement (ADE): Pre-existing antibodies from primary infection bind but fail to neutralize the new serotype, facilitating viral entry into Fc receptor-bearing cells 3
  2. Memory cross-reactive T cells: Altered cytokine response leads to elevation of pro-inflammatory cytokines 3
  3. "Cytokine tsunami": Excessive release of cytokines (including IL-6, IL-8, TNF) contributes to vascular damage 4, 3

Vascular Endothelial Damage

• Vascular endothelium is the primary "battlefield" of dengue infection 5
• Multiple mechanisms contribute to endothelial dysfunction:
  • Direct viral infection of endothelial cells
  • Immune complex deposition
  • Complement activation and release of anaphylatoxins
  • Cross-reactive antibodies against NS1 protein binding to endothelial cells
  • Inflammatory cytokines disrupting endothelial cell junctions 4, 5
• The result is increased vascular permeability without morphological damage to capillary endothelium - the hallmark of severe dengue 5

Thrombocytopenia and Coagulopathy

• Thrombocytopenia is a consistent feature of dengue infection through multiple mechanisms:
  1. Suppression of bone marrow production of platelets
  2. Direct infection of hematopoietic progenitors
  3. Peripheral destruction of platelets via:
     • Anti-platelet antibodies
     • Platelet-endothelial cell interactions
     • Platelet-immune cell interactions
     • Direct DENV-platelet binding 2, 6
• Platelets become activated through:
  • Binding of complement and antibody-coated virus
  • Direct binding of virus to DC-SIGN receptors 4
• Activated platelets release inflammatory microparticles and cytokines 4
• Coagulopathy involves complex interactions between procoagulant and anticoagulant pathways 6

Clinical Manifestations and Disease Progression

• Most dengue infections are asymptomatic or cause mild illness 1
• Symptomatic infection typically presents as an acute febrile illness with:
  • Frontal headache
  • Retro-ocular pain
  • Muscle and joint pain
  • Rash 1
• In severe cases, a critical phase occurs 4-7 days after symptom onset, characterized by:
  • Plasma leakage
  • Hemoconcentration (hematocrit increased by ≥20%)
  • Thrombocytopenia (≤100,000/mm³)
  • Bleeding manifestations 1
• Dengue shock syndrome represents the most severe form, with hypotension or narrow pulse pressure (≤20 mm Hg) 1

Special Considerations in Pregnancy

• Pregnant women are at higher risk of developing dengue shock syndrome (15% vs. 5% in non-pregnant population) 1, 7
• Pathophysiological mechanisms in pregnancy include:
  • Thrombocytopenia
  • Cellular stress
  • Liver damage 1
  • Inflammatory response with elevated IL-8, IL-6, and TNF 1
• Vertical transmission from mother to child can occur, though transmission rates vary 1, 7
• Potential mechanisms for adverse perinatal outcomes include:
  • Placental infection
  • Inflammatory cytokine surge
  • Increased vascular permeability and plasma leakage affecting placental perfusion 1

Immunopathology in Secondary Infection

• Secondary infection with a different DENV serotype is a major risk factor for severe disease
• The immunological memory from primary infection can be detrimental through:
  • Antibody-dependent enhancement
  • Original antigenic sin (immune response biased toward previous serotype)
  • Cross-reactive T-cell activation with suboptimal viral clearance 3
• NS1 protein plays a significant role in pathogenesis through:
  • Direct endothelial damage
  • Complement activation
  • Induction of autoantibodies that cross-react with host tissues 3

Understanding these complex pathophysiological mechanisms is crucial for developing effective prevention strategies, diagnostic approaches, and therapeutic interventions for dengue infection.