From the Guidelines
Dengue fever is a complex disease caused by the dengue virus, transmitted primarily through the bite of infected Aedes mosquitoes, and its pathophysiology involves multiple mechanisms leading to increased vascular permeability, plasma leakage, and potentially life-threatening complications. The pathophysiology begins when the virus enters the bloodstream and infects various cells, particularly monocytes, macrophages, and dendritic cells 1. The virus replicates within these cells, leading to viremia and triggering an immune response. This initial infection typically causes dengue fever, characterized by high fever, severe headache, muscle and joint pain, and rash. The pathophysiology becomes more complex in severe cases, where increased vascular permeability leads to plasma leakage, resulting in dengue hemorrhagic fever or dengue shock syndrome, defined by minor or major bleeding phenomena, thrombocytopenia, and evidence of plasma leakage 1.
Key Mechanisms
- Direct viral effects on endothelial cells
- Production of inflammatory cytokines
- Complement activation
- Cross-reactive antibodies from previous dengue infections (antibody-dependent enhancement) These processes cause capillary leakage, thrombocytopenia, and coagulation abnormalities, which can lead to hemorrhage, shock, and organ failure 1. The critical phase typically occurs as fever subsides, when plasma leakage becomes most pronounced. Understanding this pathophysiology is crucial for clinical management, which focuses on fluid replacement therapy, monitoring for warning signs of severe disease, and supportive care, as no specific antiviral treatment exists for dengue.
Clinical Management
- Fluid replacement therapy
- Monitoring for warning signs of severe disease
- Supportive care In resource-limited settings, recommendations for sepsis management, including the use of crystalloids and/or colloids for fluid resuscitation, and the administration of dopamine or epinephrine in patients with persistent tissue hypoperfusion, can be applied to dengue shock syndrome 1.
From the Research
Pathophysiology of Dengue Fever
The pathophysiology of dengue fever is a complex process involving the interplay of viral and host factors.
- Viral factors include the NS1 antigen and genomic factors 2, 3.
- Host factors include antibody-dependent enhancement, anti-NS1 antibodies, cytokines, cross-reactive T-cell response, HLA allele variation, and non-HLA mediated polymorphisms 2, 3.
Clinical Manifestations
Dengue virus infection can cause a spectrum of clinical manifestations, ranging from asymptomatic or mild illness to more severe and potentially life-threatening complications 3.
- The clinical picture of dengue is described on the basis of WHO 1997 and 2009 criteria, and is classified into dengue fever, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) 3, 4.
- Life-threatening complications can develop in severe cases, including renal complications, hepatic complications, neurological complications, cardiac complications, and respiratory distress syndrome 3.
Disease Severity
The mechanisms governing the pathogenesis of severe disease are not clear, but high amounts of virus in the blood are believed to cause vascular fragility, which, together with infection of endothelial cells and high levels of cytokines and other soluble mediators, may result in bleeding 5.
- The aberrant immune response to infection is believed to result in a cytokine storm, defined as an imbalance between cytokines driving an inflammation (pro-inflammatory) and those silencing an inflammation (anti-inflammatory) 5, 6.
- Several cytokines are known to induce apoptosis, a form of cell suicide, and/or affect adherens junctions, causing permeability in vitro 5.
Host and Viral Determinants
The pathogenesis of severe dengue is thought to be immune-mediated due to the timing of the clinical manifestations and higher incidence in secondary infections with a heterologous serotype 6.
- Recent evidence has provided further information on neutralizing versus enhancing monoclonal antibodies and their target epitopes on the dengue virion, which has major implications for vaccine design 6.
- The role of T-cell immunopathology has also been advanced with recent evidence of cross-reactive high pro-inflammatory cytokine producing T cells predominating in severe dengue 6.