What is the dengue disease cycle?

Dengue Disease Cycle

Dengue virus is transmitted primarily through the bite of infected Aedes mosquitoes, particularly Aedes aegypti, in a cycle that involves humans and mosquitoes with distinct phases of infection, viremia, and transmission. 1

Transmission Cycles

• Dengue virus is transmitted by Aedes species mosquitoes, primarily Aedes aegypti, which are present throughout tropical and subtropical regions worldwide 1
• Day-biting mosquitoes of the genus Aedes act as the primary vector of dengue 1
• Dengue has been reported in more than 100 countries with an annual global incidence of 50-100 million patients per year 1

Types of Transmission Cycles

• While yellow fever virus (a related flavivirus) has three distinct transmission cycles (jungle/sylvatic, intermediate/savannah, and urban), dengue transmission is primarily urban and periurban 1
• The urban cycle involves transmission between humans and urban mosquitoes, primarily Aedes aegypti 1
• Humans infected with dengue experience high levels of viremia and are infectious to mosquitoes shortly before onset of fever and for 3-5 days thereafter 1, 2

Infection Timeline and Phases

Incubation Period

• Dengue has an incubation period of 4-8 days (range: 3-14 days) from infection until disease onset 1
• Among symptomatic persons, the incubation period is typically a few days to 2 weeks 1

Viremic Phase

• Dengue virus RNA can be detected in serum from approximately 2 days before to 1 week after illness onset 1, 3
• During the febrile phase, patients are typically viremic for approximately 3 days 3
• This viremic period is when humans can transmit the virus to mosquitoes that bite them 2

Immune Response

• IgM antibodies directed against dengue virus typically develop during the first week of illness 1
• IgM antibodies may persist for extended periods - studies show 71% of patients had detectable IgM antibodies at 6 months and 46% at 12 months after infection 1
• Dengue virus nonstructural protein-1 (NS1) antigen can be detected in serum with similar frequency and duration as dengue viral RNA 1

Clinical Manifestations

• Most dengue virus infections are asymptomatic 1, 4
• The spectrum of illness associated with dengue varies from mild febrile illness to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) 1
• Classic dengue fever is characterized by fever, headache, retro-orbital pain, myalgia, arthralgia (particularly back pain), and rash 1
• During the critical phase of dengue, hematocrit levels begin to rise due to plasma leakage, while leukocytes increase during the recovery phase 3
• A ≥20% increase in hematocrit from baseline is considered evidence of significant plasma leakage 3

Viral Replication and Host Interaction

• Dengue virus is a positive-stranded RNA virus belonging to the Flaviviridae family 5
• There are four antigenically distinct serotypes of dengue virus (DENV-1 to DENV-4) 4
• The virus modulates host metabolism to create an environment conducive to genome replication and viral dissemination 5
• Intrahost genetic diversity of dengue virus differs between human hosts and mosquito vectors, with specific mutations appearing during infection in Aedes aegypti mosquitoes 6
• Primary infection causes activation of immune responses against one dengue serotype, but secondary infection with a different serotype can lead to more severe disease through antibody-dependent enhancement (ADE) 4

Diagnostic Considerations

• For symptomatic patients, nucleic acid amplification tests (NAATs) are the preferred method of diagnosis when performed on serum collected ≤7 days after symptom onset 1
• Dengue IgM antibody testing should be performed on NAAT-negative serum specimens or serum collected >7 days after onset of symptoms 1
• Acute dengue can be confirmed with a positive PCR or, if symptoms have been present for over 5-7 days, with a positive IgM capture ELISA 1
• Cross-reaction with other flavivirus IgG is well recognized; therefore, vaccination history (yellow fever, Japanese encephalitis, tick-borne encephalitis) is useful in interpreting test results 1

Epidemiological Significance

• The incidence of dengue has doubled each decade since 1990, with an estimated 58 million symptomatic infections and 13,000 deaths worldwide in 2013 1
• Dengue is the most common arbovirus encountered in returning travelers and a common cause of fever in those returning from Asia 1
• Appropriate clinical management of severe dengue can reduce the case-fatality rate among hospitalized patients to <0.5% 1