What is secondary dengue infection?

Secondary Dengue Infection

Secondary dengue infection occurs when a person who was previously infected with one dengue virus serotype (DENV1-4) becomes infected with a different serotype, resulting in a distinct immunologic response characterized by diminished IgM antibody production and rapid elevation of cross-reactive neutralizing antibodies against multiple flaviviruses. 1

Immunologic Definition

Secondary dengue infection is defined immunologically by the antibody response pattern:

• In primary infection: IgM antibodies appear 3-5 days after symptom onset and remain detectable for 2-3 months, while IgG antibodies appear 10-12 days after onset and persist for months to years 1

• In secondary infection: IgM antibodies may not be detectable at all, or appear at significantly lower levels than in primary infection, while there is a rapid and robust IgG response with high titers of cross-reactive neutralizing antibodies against multiple dengue serotypes 1

• Laboratory distinction: The IgM:IgG ratio is the key diagnostic parameter—secondary infections show a low IgM:IgG ratio due to the predominant IgG response, whereas primary infections demonstrate a high IgM:IgG ratio 2

Clinical Significance and Disease Severity

The relationship between secondary infection and severe dengue is more complex than traditionally believed:

• Traditional paradigm: Secondary dengue infections have historically been considered the primary risk factor for dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) due to antibody-dependent enhancement (ADE), where pre-existing cross-reactive antibodies facilitate viral entry into Fcγ receptor-bearing cells 3

• Recent evidence challenges this: A 2024 study from India found that primary dengue infections accounted for more than half of severe dengue cases (112 of 202) and fatalities (5 of 7), questioning the predominant association of severe disease with secondary infections 2

• Quantified risk in secondary infection: A 2024 Taiwan cohort study demonstrated that secondary infection increases the risk of severe dengue with an odds ratio of 2.13 (95% CI: 1.40-3.25), with risk of severe disease at 7.8% versus 3.8% in primary infection 4

• Time interval matters: The increased risk of severe dengue in secondary infection is most significant when the interval between first and second infections exceeds two years (OR 3.19,95% CI 2.04-5.00) 4

Mechanism of Antibody-Dependent Enhancement

The immunologic basis for increased severity involves specific antibody populations:

• Cross-reactive antibodies are the culprits: Removal of serotype cross-reactive antibodies from immune sera completely ablates enhancement of heterotypic virus infection in vitro and antibody-enhanced mortality in animal models 3

• Multiple viral targets: Both envelope (E) protein-specific and pre-membrane (prM) protein-specific antibodies contribute significantly to enhancement of heterotypic dengue infection 3

• Neutralizing antibody persistence: Neutralizing antibodies persist for multiple years after flavivirus infections and usually confer long-lived immunity to the original serotype, but can enhance infection with different serotypes 1

Diagnostic Challenges in Secondary Infection

Identifying secondary dengue infection presents specific laboratory difficulties:

• Diminished IgM response: The hallmark of secondary infection is that IgM antibodies may not be detectable, making diagnosis challenging if testing occurs during the typical IgM detection window 1

• Cross-reactivity issues: Neutralizing antibody titers in secondary infections often cannot distinguish between dengue serotypes, especially during acute illness—at 12-19 months after confirmed Zika virus infection, 27% of patients still had neutralizing antibody titers that could not differentiate between dengue and Zika viruses 1

• PRNT limitations: While plaque reduction neutralization tests (PRNTs) can identify the infecting virus in primary infections when neutralizing antibody titers are ≥4-fold higher against one serotype, this discrimination fails in secondary infections due to broadly cross-reactive antibody responses 1

Changes in T Cell Repertoire

Secondary heterologous dengue infection fundamentally alters cellular immunity:

• Conserved epitope expansion: Recognition of conserved/cross-reactive T cell epitopes is either constant or expanded in heterologous secondary infection compared to homologous infection 5

• Impaired serotype-specific responses: Previous infection with a different serotype impairs the development of T cell responses directed to serotype-specific epitopes of the newly infecting serotype, while responses to conserved epitopes remain intact 5

• Immunodominance shifts: The T cell repertoire changes substantially between primary and secondary infections, with responses to the original serotype potentially limiting the magnitude of responses against the current infecting serotype 5

Genotype-Specific Considerations

Not all secondary infections carry equal risk:

• American genotype exception: A prospective study in Peru demonstrated that secondary infection with American genotype DEN-2 following primary DEN-1 infection did not cause dengue hemorrhagic fever or dengue shock syndrome, despite 60.5% of the population experiencing secondary infections 6

• Southeast Asian genotype risk: The introduction of southeast Asian DEN-2 genotypes into the western hemisphere was associated with the first epidemics of severe dengue, suggesting genotype-specific virulence factors 6

Clinical Management Implications

Recognition of secondary infection status should guide clinical approach:

• Heightened surveillance required: Healthcare professionals should maintain increased vigilance for individuals with a history of previous dengue infection, particularly if the initial diagnosis occurred more than two years prior 4

• Testing strategy: For patients with suspected dengue and prior flavivirus exposure, NAAT testing on serum collected ≤7 days after symptom onset is preferred, as serologic testing may be unreliable due to the altered antibody response pattern 7

• Warning signs monitoring: Regardless of primary versus secondary infection status, all patients require monitoring for warning signs including persistent vomiting, abdominal pain, mucosal bleeding, lethargy, and rising hematocrit with falling platelet count 7, 8