What is the pathophysiology of Dengue phases in patients with and without underlying medical conditions?

Pathophysiology of Dengue Phases

Dengue infection progresses through three distinct clinical phases—febrile, critical, and recovery—driven by viral replication, immune activation, and plasma leakage, with the critical phase (days 3-7) representing the period of greatest risk for vascular permeability and shock. 1

Viral Transmission and Initial Infection

• The dengue virus (DENV) is transmitted by Aedes aegypti mosquitoes with an incubation period of 4-8 days before symptom onset 1
• Viral RNA becomes detectable in serum approximately 2 days before symptoms appear and persists for up to 1 week after illness onset, with peak viremia occurring during the acute febrile phase 2, 1
• Four distinct serotypes (dengue-1, dengue-2, dengue-3, and dengue-4) exist, and sequential infection with different serotypes significantly alters disease pathogenesis 3

Phase 1: Febrile Phase (Days 1-3)

• Fever, headache, retro-orbital pain, myalgia, and arthralgia result from the cytokine storm triggered by viral infection and immune activation 1
• During this phase, viral replication is at its peak, with dengue virus NS1 antigen detectable from day 1 to day 10 after symptom onset 4
• Leukopenia develops as a characteristic finding during the febrile phase 3

Phase 2: Critical Phase (Days 3-7)

This is the most dangerous period when plasma leakage occurs, typically coinciding with defervescence when fever subsides. 1, 4

Vascular Endothelial Dysfunction

• Increased vascular permeability without morphological damage to the capillary endothelium is the cardinal feature of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) 5
• The vascular endothelium becomes the "battlefield" where immune-mediated damage occurs, leading to severe dengue disease 5
• Fcγ receptor-mediated antibody-dependent enhancement (ADE) results in cytokine release from immune cells, causing vascular endothelial cell dysfunction and increased vascular permeability 6

Immune-Mediated Mechanisms

• In secondary infections with different DENV serotypes, memory cross-reactive T cells produce altered cytokine responses, leading to elevated pro-inflammatory cytokines that contribute to detrimental immune responses 6
• Anti-DENV NS1 antibodies can cross-react with self-antigens such as plasminogen, integrin, and platelet cells, contributing to thrombocytopenia and bleeding manifestations 6
• The combination of secondary infection and viral virulence factors, rather than either alone, explains the mechanism of severe dengue 7

Clinical Manifestations of Critical Phase

• Warning signs appear during days 3-7, including persistent vomiting, abdominal pain/tenderness, clinical fluid accumulation, mucosal bleeding, lethargy/restlessness, hepatomegaly, and hematocrit rise with concurrent thrombocytopenia 4
• Thrombocytopenia combined with rising hematocrit represents a critical warning sign of progression to severe dengue 1
• Extensive plasma leakage into tissue spaces and serous cavities (pleural, pericardial, peritoneal) can result in profound shock 5

Dengue Shock Syndrome (DSS)

• DSS occurs when plasma leakage becomes severe enough to cause hypovolemia, leading to hypotension (systolic BP <90 mmHg) or narrow pulse pressure (<20 mmHg) 1
• The case fatality rate in patients with dengue shock syndrome can be as high as 44% without appropriate management 7
• Early recognition and appropriate supportive management can reduce case-fatality rates to <0.5% in hospitalized patients 1

Phase 3: Recovery Phase (Days 7-10)

• The characteristic dengue rash typically appears during days 3-7 of illness, coinciding with the defervescence period when fever subsides 1
• Reabsorption of extravasated fluids occurs during the recovery phase
• Laboratory parameters begin returning to normal ranges during this period 8

Pathophysiologic Differences in Special Populations

• Approximately 15% of pregnant women develop dengue shock syndrome compared to 5% of non-pregnant individuals, likely due to pregnancy-related immune and hemodynamic changes 1
• Pregnant women face increased risk of maternal death, hemorrhage, preeclampsia/eclampsia, and vertical transmission 8

Critical Pathophysiologic Distinctions

Dengue shock behaves differently from bacterial septic shock—the underlying plasma leakage pathophysiology requires careful fluid management to avoid over-resuscitation, as excessive fluids can worsen outcomes. 1, 4

• The pathogenesis involves complex interplay between virus, host genes, and host immune response, with antibody-dependent enhancement, memory cross-reactive T cells, anti-DENV NS1 antibodies, autoimmunity, and genetic factors as major determinants of disease susceptibility 6
• Subgenomic flavivirus RNA (sfRNA) suppresses host immune response, representing a viral determinant of disease severity 6