Direct and indirect effects of age on dengue severity: The mediating role of secondary infection

Abstract

Severe dengue occurrence has been attributed to increasing age and different dengue virus (DENV) serotypes that cause secondary infections and immune-enhancing phenomena. Therefore, we examined if the effect of age on dengue severity was mediated by infectivity status while controlling for sex and region. Further, we assessed the spatial clustering of dengue severity for individuals with primary and secondary infection across Mexican municipalities. Health data from 2012 to 2017 was retrieved from Mexico’s Ministry of Health. A mediation analysis was performed using multiple logistic regression models based on a directed acyclic graph. The models were explored for the direct effect of age on dengue severity and its indirect impact through secondary infection. In addition, severe dengue clusters were determined in some Northeastern and Southeastern municipalities through spatial analysis. We observed a nonlinear trend between age and severe dengue. There was a downward trend of severe dengue for individuals between 0 and 10 years and an upward trend above 10 years. The effect of age on dengue severity was no longer significant for individuals between 10 and 60 years after introducing infectivity status into the model. The mediating role of infectivity status in the causal model was 17%. Clustering of severe dengue among individuals with primary infection in the Northeastern region may point to the high prevalence of DENV-3 in the region. Public health efforts may prevent secondary infection among infants and the aged. In addition, there should be a further investigation into the effect of DENV-3 in individuals with primary disease.

Serotype-Specific Epidemiological Patterns of Inapparent versus Symptomatic Primary Dengue Virus Infections: A 17-year cohort study in Nicaragua

“…[32][33][34] Substantial morbidity and mortality can be attributed to primary infections, for example, ≥50% of severe cases and fatalities in a study in India 35 and 23% of hospitalized dengue patients in a study in Mexico. 36 Here, we also found a sizable amount of severe infections among primary cases, being the highest for DENV3. All together these studies show that primary infections contribute significantly to disease burden.…”

Epidemiological Characterization of Dengue Virus Serotypes in Mexico: Implications for Disease Severity

“…[20,21] In Mexico, it has been documented that there are higher probabilities of secondary infection in the Southeast [2,19 (95%CI: 1.76, 2.73)] and Northwest [3,10 (95%CI: 2.30,4.51)] regions compared to the Central region. [22] However, the probability of severe dengue is higher for the Central region compared to all others, suggesting that an epidemic in the central part of the country would lead to high demand for healthcare services and a high fatality rate. This was reflected in this study, particularly in Morelos, a state located in the central part of the country with a higher clinical severity risk.…”

“…A study conducted in Mexico from 2012 to 2017 revealed that 60% of dengue cases were in women with an average age of 33 years; however, men have 0.91 (95% CI: 0.86, 0.97) times more chances than women of having a secondary infection, and they tend to have higher odds [1.40 (95% CI: 1.35, 1.46)] of severe infection. [22] Regarding clinical presentation, DNV-3 was mainly identified, being higher in non-severe dengue; this was probably due to the predominant circulation of this serotype, after years without circulation in Mexico, which clinically manifested as an increase in cases of dengue with warning signs compared to the previous four years. [23] The cycles (Ct) for RT-qPCR for dengue were 26, except for DNV-4, which was 25.97, corresponding to approximately 1x105 copies, according to published data.…”

“…49 of 2023 was 38.81 confirmed cases, with Yucatan reporting the highest incidence at 444.31 cases, followed by Quintana Roo (261.79), Morelos (194.84), Campeche (176. 22), and Veracruz (117.85). [4] The circulation of all four serotypes has been observed in Mexico from 2016 to 2023, exhibiting cyclic behavior, primarily driven by DENV-1 and DENV-2.…”

Interplay between vaccines and treatment for dengue control: An epidemic model

“…However, it's important to acknowledge the limitations of our current model, such as the omission of seasonality effects, the impact of age on vaccine efficacy, and the consideration of only one dengue serotype. To enhance the robustness of our findings and provide a more comprehensive understanding of dengue control strategies, future work will delve into incorporating seasonality into the model [27,28] and exploring the interplay of age [29,30] and vaccine interventions [11]. Additionally, we have used a single-serotype dengue model that does not take into account the effects of secondary infections.…”