Pathophysiology of Flushing in Dengue
Flushing in dengue results from virus-induced endothelial activation and cytokine-mediated vasodilation, driven primarily by the host immune response rather than direct viral cytopathic effects.
Primary Mechanism: Immune-Mediated Vascular Changes
The pathophysiology of flushing in dengue is fundamentally a manifestation of endothelial dysfunction triggered by an aberrant immune response 1, 2. The mechanism unfolds through the following cascade:
Viral Infection and Immune Activation
- Dengue virus primarily infects monocytes, macrophages, and dendritic cells, which become the main source of inflammatory mediators 3, 4
- The endothelium itself can be directly infected by dengue virus, contributing to both viremia and immune activation 5
- This dual targeting—both immune cells and endothelial cells—creates a "cytokine storm" characterized by an imbalance between pro-inflammatory and anti-inflammatory mediators 1, 2
Endothelial Activation and Vasodilation
- Elevated vasoactive cytokines and chemokines induce permeability changes in endothelial cells lining the vasculature 3
- The endothelium becomes a "battlefield" where immune responses target vascular integrity, leading to functional changes without necessarily causing morphological damage 4
- These inflammatory mediators cause vasodilation of cutaneous blood vessels, manifesting clinically as flushing 2
Clinical Correlation
- Flushing typically appears during the febrile phase of dengue, coinciding with peak viremia and cytokine production 6, 7
- The transient nature of flushing reflects the short-lived effects of biological mediators rather than permanent vascular damage 1
- Flushing may be accompanied by other cutaneous manifestations including generalized erythematous rash 7
Key Pathophysiologic Mediators
- Cytokines: The cytokine storm includes both pro-inflammatory mediators that drive vasodilation and anti-inflammatory factors that attempt to restore homeostasis 1, 2
- Viral NS1 protein: Dengue non-structural protein-1 (NS1) and antibodies against it contribute to endothelial cell dysfunction and may play a role in vascular changes 5
- Sphingosine kinase-1 and microRNAs: These factors regulate normal vascular function and inflammatory responses, and their dysregulation during dengue infection may affect endothelial cell function 3
Important Clinical Distinction
- Flushing represents a relatively benign manifestation of endothelial activation, distinct from the more severe vascular permeability changes that characterize dengue hemorrhagic fever or dengue shock syndrome 4, 5
- While flushing involves vasodilation, severe dengue involves increased vascular permeability with plasma leakage—both mediated by endothelial dysfunction but with different clinical consequences 1, 4
Critical Pitfall to Avoid
Do not confuse flushing with the warning signs of severe dengue progression. While flushing is common and generally benign, persistent vomiting, abdominal pain, mucosal bleeding, lethargy, or restlessness indicate potential progression to severe disease and require immediate medical attention 8.