What is the pathophysiology of dengue hemorrhagic fever (DHF)?

Pathophysiology of Dengue Hemorrhagic Fever

Core Pathophysiological Mechanism

The defining pathophysiological hallmark of dengue hemorrhagic fever (DHF) is increased vascular permeability leading to plasma leakage, which distinguishes it from uncomplicated dengue fever and can progress to hypovolemic shock when critical plasma volume is lost. 1, 2

Viral Infection and Immune Response

• Dengue virus (DENV) is transmitted by Aedes aegypti mosquitoes with a 4-8 day incubation period before symptom onset 1
• Viral RNA becomes detectable in serum approximately 2 days before to 1 week after illness onset, with peak viremia occurring during the acute febrile phase 1
• An enhanced immune response during secondary dengue infection is the central feature driving DHF pathogenesis, particularly through antibody-dependent enhancement and memory T-cell activation 2, 3

The Cytokine Storm and Vascular Endothelium

• The cytokine storm triggered by viral infection and immune activation produces fever, headache, retro-orbital pain, myalgia, and arthralgia 1
• The vascular endothelium becomes the primary battlefield in DHF, with increased permeability occurring without morphological damage to capillary endothelium 3
• Multiple mechanisms target the vascular endothelium including immune complex formation, complement activation with anaphylatoxin release, and massive cytokine release into circulation 2, 4
• Excessive production of prostacyclin (PGI2), the most potent vasodilator and platelet aggregation inhibitor, contributes to vascular dysfunction 4

Hematological Abnormalities

Thrombocytopenia Mechanisms

• Bone marrow suppression with hypocellularity shows increased megakaryocytes in all forms, but particularly vacuolated and disintegrated ones 2, 4
• Platelet destruction occurs through multiple pathways: hepatic and splenic sequestration, immune-mediated injury with dengue antibody complexes on platelet surfaces, and spontaneous aggregation to dengue-infected vascular endothelial cells causing platelet lysis 4
• Thrombocytopenia combined with rising hematocrit represents a critical warning sign of progression to severe dengue 1

Platelet Dysfunction

• Beyond low counts, platelets demonstrate functional abnormalities including increased release of beta-thromboglobulin, platelet factor 4 (PF4), and PGI2 4
• In vitro studies show hypoaggregation when stimulated by ADP and defects in ADP-releasing ability 4

Coagulopathy and Bleeding

• The mechanisms underlying bleeding in DHF are threefold: vasculopathy, thrombopathy (thrombocytopenia plus platelet dysfunction), and disseminated intravascular coagulation (DIC) 2
• Prothrombin complex deficiency develops due to liver damage 4
• Consumptive coagulopathy results from activation by mononuclear phagocytes and platelet factor 3 (PF3) released from platelet aggregation 4
• DIC becomes prominent in patients with shock, and the most severe DIC with massive bleeding occurs in prolonged shock cases, leading to fatal outcomes 2

Plasma Leakage and Shock Progression

• Extensive plasma leakage into tissue spaces and serous cavities (pleural, pericardial, peritoneal) occurs without visible endothelial damage 3
• Dengue shock syndrome (DSS) develops when plasma leakage becomes severe enough to cause hypovolemia, manifesting as hypotension (systolic BP <90 mmHg) or narrow pulse pressure (<20 mmHg) 1
• Approximately 15% of pregnant women develop DSS compared to 5% of non-pregnant individuals, likely due to pregnancy-related immune and hemodynamic changes 1

Critical Phase Timing

• The characteristic dengue rash appears during days 3-7 of illness, coinciding with the defervescence period when fever subsides 1
• Warning signs typically emerge around day 3-7, marking the critical phase when plasma leakage intensifies 5

Clinical Implications

• Understanding that dengue shock behaves differently from bacterial septic shock is crucial—the underlying plasma leakage pathophysiology requires careful fluid management to avoid over-resuscitation 1
• Early recognition of warning signs (persistent vomiting, abdominal pain, clinical fluid accumulation, mucosal bleeding, lethargy/restlessness, hepatomegaly, hematocrit rise with concurrent thrombocytopenia) and appropriate supportive management can reduce case-fatality rates to <0.5% in hospitalized patients 1, 5