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Early individualized risk prediction using clinical data for children during the febrile phase of dengue in outpatient settings in Vietnam and Thailand
(2026-02-01)
Sangkaew, Sorawat
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Daniels, Bethan Cracknell
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Ming, Damien K.
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Hernandez, Bernard
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Herrero, Pau
Dengue severity prediction models are usually developed using hospitalized patient data, but triage and hospital admission are mainly evaluated in outpatient settings. This study developed models using clinical and laboratory data from patients in outpatient settings during the febrile phase. Data from two cohort studies in Vietnam and Thailand were used to develop and validate six models: logistic regression with warning signs, Lasso-selected logistic regression, random forest, extreme gradient boosted classification, support vector machine, and artificial neural network. Models predicted dengue shock syndrome (DSS) as the primary endpoint and moderate plasma leakage and/or DSS as the secondary endpoint. We assessed model performance, discrimination, and calibration, using sensitivity, specificity, accuracy, Brier score, AUROC, CITL, calibration slope, calibration plots, and decision curve analysis. The optimal model was the Lasso-selected logistic regression for predicting DSS and the combined endpoint of moderate plasma leakage and/or DSS (Brier score: 0.044 [95% CI 0.043, 0.044] and 0.104 [95% CI 0.104, 0.105]; AUROC: 0.789 [95% CI 0.787, 0.791] and 0.741 [95% CI 0.740, 0.742]). We identified hematocrit, platelet count, lymphocyte count, and aspartate aminotransferase as predictors for DSS, and abdominal pain or tenderness, vomiting, mucosal bleeding, white blood cell count, lymphocyte count, platelet count, aspartate aminotransferase, and serum albumin as predictors for the secondary endpoint. Logistic regression and machine learning models using clinical and laboratory data during the febrile phase can support early prediction of severe disease in outpatient settings. Integrating risk prediction models into a decision support system could improve triage and optimize healthcare and resource allocation in endemic and resource-limited areas.
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Linking multiple serological assays to infer dengue virus infections from paired samples using mixture models
(2025-12-20)
Hamins-Puértolas, Marco
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Buddhari, Darunee
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Salje, Henrik
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Huang, Angkana T.
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Hunsawong, Taweewun
Dengue virus (DENV) is an increasingly important human pathogen, with already half of the globe’s population living in environments with transmission potential. Since many cases are missed by direct detection methods (RT-PCR or antigen tests), serological assays play an important role in the diagnostic process. However, individual assays can suffer from low sensitivity and specificity and interpreting results from multiple assays remains challenging, particularly because interpretations from multiple assays may differ, creating uncertainty over how to generate finalized interpretations. We develop a Bayesian mixture model that can jointly model data from multiple paired serological assays, to infer infection events. We first test the performance of our model using simulated data. We then apply our model to 677 pairs of acute and convalescent serum collected as a part of illness and household investigations across two longitudinal cohort studies in Kamphaeng Phet, Thailand, including data from 232 RT-PCR confirmed infections (gold standard). We compare the classification of the new model to prior standard interpretations that independently utilize information from either the hemagglutination inhibition assay (HAI) or the enzyme-linked immunosorbent assay (EIA). We find that additional serological assays improve accuracy of infection detection for both simulated and real world data. Models incorporating paired IgG and IgM data as well as those incorporating IgG, IgM, and HAI data consistently have higher accuracy when using PCR confirmed infections as a gold standard (87–90% F1 scores, a combined metric of sensitivity and specificity) than currently implemented cut-point approaches (82–84% F1 scores). Our results provide a probabilistic framework through which multiple serological assays across different platforms can be leveraged across sequential serum samples to provide insight into whether individuals have recently experienced a DENV infection. These methods are applicable to other pathogen systems where multiple serological assays can be leveraged to quantify infection history.
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Household immunity and individual risk of infection with dengue virus in a prospective, longitudinal cohort study
(2024-01-01)
Hamins-Puértolas, Marco
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Buddhari, Darunee
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Salje, Henrik
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Cummings, Derek A.T.
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Fernandez, Stefan
Although it is known that household infections drive the transmission of dengue virus (DENV), it is unclear how household composition and the immune status of inhabitants affect the individual risk of infection. Most population-based studies to date have focused on paediatric cohorts because more severe forms of dengue mainly occur in children, and the role of adults in dengue transmission is understudied. Here we analysed data from a multigenerational cohort study of 470 households, comprising 2,860 individuals, in Kamphaeng Phet, Thailand, to evaluate risk factors for DENV infection. Using a gradient-boosted regression model trained on annual haemagglutination inhibition antibody titre inputs, we identified 1,049 infections, 90% of which were subclinical. By analysing imputed infections, we found that individual antibody titres, household composition and antibody titres of other members in the same household affect an individual’s risk of DENV infection. Those individuals living in households with high average antibody titres, or households with more adults, had a reduced risk of infection. We propose that herd immunity to dengue acts at the household level and may provide insight into the drivers of the recent change in the shifting age distribution of dengue cases in Thailand.
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Maternally derived antibody titer dynamics and risk of hospitalized infant dengue disease
(2023-10-03)
Driscoll, Megan O.
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Buddhari, Darunee
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Huang, Angkana T.
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Waickman, Adam
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Kaewhirun, Surachai
Infants less than 1 y of age experience high rates of dengue disease in dengue virus (DENV) endemic countries. This burden is commonly attributed to antibody-dependent enhancement (ADE), whereby concentrations of maternally derived DENV antibodies become subneutralizing, and infection-enhancing. Understanding antibody-related mechanisms of enhanced infant dengue disease risk represents a significant challenge due to the dynamic nature of antibodies and their imperfect measurement processes. Further, key uncertainties exist regarding the impact of long-term shifts in birth rates, population-level infection risks, and maternal ages on the DENV immune landscape of newborns and their subsequent risks of severe dengue disease in infancy. Here, we analyze DENV antibody data from two infant cohorts (N = 142 infants with 605 blood draws) and 40 y of infant dengue hospitalization data from Thailand. We use mathematical models to reconstruct maternally derived antibody dynamics, accounting for discretized measurement processes and limits of assay detection. We then explore possible antibody-related mechanisms of enhanced infant dengue disease risk and their ability to reconstruct the observed age distribution of hospitalized infant dengue cases. We find that ADE mechanisms are best able to reconstruct the observed data. Finally, we describe how the shifting epidemiology of dengue in Thailand, combined with declining birth rates, have decreased the absolute risk of infant dengue disease by 88% over a 40-y period while having minimal impact on the mean age of infant hospitalized dengue disease.
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Individual, Household, and Community Drivers of Dengue Virus Infection Risk in Kamphaeng Phet Province, Thailand
(2022-10-15)
Ribeiro Dos Santos, Gabriel
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Buddhari, Darunee
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Iamsirithaworn, Sopon
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Khampaen, Direk
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Ponlawat, Alongkot
Background: Dengue virus (DENV) often circulates endemically. In such settings with high levels of transmission, it remains unclear whether there are risk factors that alter individual infection risk. Methods: We tested blood taken from individuals living in multigenerational households in Kamphaeng Phet province, Thailand for DENV antibodies (N = 2364, mean age 31 years). Seropositivity ranged from 45.4% among those 1-5 years old to 99.5% for those >30 years. Using spatially explicit catalytic models, we estimated that 11.8% of the susceptible population gets infected annually. Results: We found that 37.5% of the variance in seropositivity was explained by unmeasured household-level effects with only 4.2% explained by spatial differences between households. The serostatus of individuals from the same household remained significantly correlated even when separated by up to 15 years in age. Conclusions: These findings show that despite highly endemic transmission, persistent differences in infection risk exist across households, the reasons for which remain unclear.
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Entomological risk assessment for dengue virus transmission during 2016–2020 in kamphaeng phet, thailand
(2021-10-01)
Fansiri, Thanyalak
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Buddhari, Darunee
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Pathawong, Nattaphol
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Pongsiri, Arissara
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Klungthong, Chonticha
Individual houses with high risks of dengue virus (DENV) transmission might be a source of virus transmission within the neighborhood. We conducted an entomological risk assessment for DENV transmission at the household level, comprising family cohort members residing in the same location, to assess the risk for dengue virus transmitted by mosquito vectors. The studies were conducted in Kamphaeng Phet Province, Thailand, during 2016–2020. Entomological investigations were performed in 35 cohort families on day 1 and day 14 after receiving dengue case reports. DENV was found in 22 Aedes samples (4.9%) out of 451 tested samples. A significantly higher DENV infection rate was detected in vectors collected on day 1 (6.64%) compared to those collected on day 14 (1.82%). Annual vector surveillance was carried out in 732 houses, with 1002 traps catching 3653 Aedes females. The majority of the 13,228 water containers examined were made from plastic and clay, with used tires serving as a primary container, with 59.55% larval abundance. Larval indices, as indicators of dengue epidemics and to evaluate disease and vector control approaches, were calculated. As a result, high values of larval indices indicated the considerably high risk of dengue transmission in these communities.
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Evaluation of the extended efficacy of the Dengvaxia vaccine against symptomatic and subclinical dengue infection
(2021-08-01)
Salje, Henrik
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Alera, Maria Theresa
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Chua, Mary Noreen
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Hunsawong, Taweewun
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Ellison, Damon
More than half of the world’s population lives in areas at risk for dengue virus infection. A vaccine will be pivotal to controlling spread, however, the only licensed vaccine, Dengvaxia, has been shown to increase the risk of severe disease in a subset of individuals. Vaccine efforts are hampered by a poor understanding of antibody responses, including those generated by vaccines, and whether antibody titers can be used as a marker of protection from infection or disease. Here we present the results of an ancillary study to a phase III vaccine study (n = 611). All participants received three doses of either Dengvaxia or placebo and were followed for 6 years. We performed neutralization tests on annual samples and during confirmed dengue episodes (n = 16,508 total measurements). We use mathematical models to reconstruct long-term antibody responses to vaccination and natural infection, and to identify subclinical infections. There were 87 symptomatic infections reported, and we estimated that there were a further 351 subclinical infections. Cumulative vaccine efficacy was positive for both subclinical and symptomatic infection, although the protective effect of the vaccine was concentrated in the first 3 years following vaccination. Among individuals with the same antibody titer, we found no difference between the risk of subsequent infection or disease between placebo and vaccine recipients, suggesting that antibody titers are a good predictor of both protection and disease risk.
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Longitudinal Analysis of Dengue Virus–Specific Memory T Cell Responses and Their Association With Clinical Outcome in Subsequent DENV Infection
(2021-07-28)
Sanchez-Vargas, Luis Alberto
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Anderson, Kathryn B.
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Srikiatkhachorn, Anon
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Currier, Jeffrey R.
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Friberg, Heather
Memory T cells resulting from primary dengue virus (DENV) infection are hypothesized to influence the clinical outcome of subsequent DENV infection. However, the few studies involving prospectively collected blood samples have found weak and inconsistent associations with outcome and variable temporal trends in DENV-specific memory T cell responses between subjects. This study used both ex-vivo and cultured ELISPOT assays to further evaluate the associations between DENV serotype-cross-reactive memory T cells and severity of secondary infection. Using ex-vivo ELISPOT assays, frequencies of memory T cells secreting IFN-γ in response to DENV structural and non-structural peptide pools were low in PBMC from multiple time points prior to symptomatic secondary DENV infection and showed a variable response to infection. There were no differences in responses between subjects who were not hospitalized (NH, n=6) and those who were hospitalized with dengue hemorrhagic fever (hDHF, n=4). In contrast, responses in cultured ELISPOT assays were more reliably detectable prior to secondary infection and showed more consistent increases after infection. Responses in cultured ELISPOT assays were higher in individuals with hDHF (n=8) compared to NH (n=9) individuals before the secondary infection, with no difference between these groups after infection. These data demonstrate an association of pre-existing DENV-specific memory responses with the severity of illness in subsequent DENV infection, and suggest that frequencies of DENV-reactive T cells measured after short-term culture may be of particular importance for assessing the risk for more severe dengue disease.
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Correlation between reported dengue illness history and seropositivity in rural Thailand
(2021-06-01)
Buddhari, Darunee
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Anderson, Kathryn B.
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Gromowski, Gregory D.
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Jarman, Richard G.
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Iamsirithaworn, Sopon
In the latest World Health Organization (WHO) recommendation for Dengvaxia implementation, either serological testing or a person’s history of prior dengue illness may be used as supporting evidence to identify dengue virus (DENV)-immune individuals eligible for vaccination, in areas with limited capacity for laboratory confirmation. This analysis aimed to estimate the concordance between self-reported dengue illness histories and seropositivity in a prospective cohort study for dengue virus infection in Kamphaeng Phet province, a dengue-endemic area in northern Thailand. The study enrolled 2,076 subjects from 516 multigenerational families, with a median age of 30.6 years (range 0–90 years). Individual and family member dengue illness histories were obtained by questionnaire. Seropositivity was defined based on hemagglutination inhibition (HAI) assays. Overall seropositivity for DENV was 86.5% among those aged 9–45 years, which increased with age. 18.5% of participants reported a history of dengue illness prior to enrollment; 30.1% reported a previous DENV infection in the family, and 40.1% reported DENV infection in either themselves or a family member. Relative to seropositivity by HAI in the vaccine candidate group, the sensitivity and specificity of individual prior dengue illness history were 18.5% and 81.6%, respectively; sensitivity and specificity of reported dengue illness in a family member were 29.8% and 68.0%, and of either the individual or a family member were 40.1% and 60.5%. Notably, 13.4% of individuals reporting prior dengue illness were seronegative. Given the high occurrence of asymptomatic and mild DENV infection, self-reported dengue illness history is poorly sensitive for prior exposure and may misclassify individuals as ‘exposed’ when they were not. This analysis highlights that a simple, highly sensitive, and highly specific test for determining serostatus prior to Dengvaxia vaccination is urgently needed.
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Temporally integrated single cell RNA sequencing analysis of PBMC from experimental and natural primary human DENV-1 infections
(2021-01-29)
Waickman, Adam T.
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Friberg, Heather
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Gromowski, Gregory D.
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Rutvisuttinunt, Wiriya
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Li, Tao
Dengue human infection studies present an opportunity to address many longstanding questions in the field of flavivirus biology. However, limited data are available on how the immunological and transcriptional response elicited by an attenuated challenge virus compares to that associated with a wild-type DENV infection. To determine the kinetic transcriptional signature associated with experimental primary DENV-1 infection and to assess how closely this profile correlates with the transcriptional signature accompanying natural primary DENV-1 infection, we utilized scRNAseq to analyze PBMC from individuals enrolled in a DENV-1 human challenge study and from individuals experiencing a natural primary DENV-1 infection. While both experimental and natural primary DENV-1 infection resulted in overlapping patterns of inflammatory gene upregulation, natural primary DENV-1 infection was accompanied with a more pronounced suppression in gene products associated with protein translation and mitochondrial function, principally in monocytes. This suggests that the immune response elicited by experimental and natural primary DENV infection are similar, but that natural primary DENV-1 infection has a more pronounced impact on basic cellular processes to induce a multi-layered anti-viral state.

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