A comparative analysis of dengue, chikungunya, and Zika in a pediatric cohort over 18 years.

Abstract

Background: Dengue, chikungunya, and Zika are diseases of major human concern. Differential diagnosis is complicated in children and adolescents by their overlapping clinical features (signs, symptoms, and complete blood count results). Few studies have directly compared the three diseases. We aimed to identify distinguishing pediatric characteristics of each disease.

Methods: Data were derived from laboratory-confirmed cases (symptomatic infections) aged 2-<18 years enrolled in a longitudinal cohort study in Managua, Nicaragua, and attending a primary health care center from January 19, 2006, through December 31, 2023. We collected clinical records and laboratory results across the first 10 days of illness. Data were analyzed with generalized additive models, day-and-disease-specific prevalence estimates, and machine learning models.

Findings: We characterized 1,405 dengue, 517 chikungunya, and 522 Zika pediatric cases. We included 1,165 (47·7%) males and 1,279 (52·3%) females, with a median age of 10·0 (IQR 7·0-12·7) years. The prevalence of many clinical features exhibited by dengue, chikungunya, and Zika cases differed substantially overall, by age, and by day of illness. Dengue cases were differentiated most by abdominal pain (Prevalence difference (PD) 19·1%, 95% confidence interval (CI): 15·7%, 22·9%), leukopenia (PD 41·1%, 95% CI: 36·2%, 45·6%), nausea (PD 15·5%, 95% CI: 12·2%, 19·2%), vomiting (PD 21·9%, 95% CI: 17·9%, 26·1%), and basophilia (PD 42·3%, 95% CI: 37·4%, 47·0%); chikungunya cases were differentiated most by arthralgia (PD 60·5%, 95% CI: 56·3%, 64·2%) and the absence of leukopenia (PD -32·0%, 95% CI: -36·7%, -27·1%) and papular rash (PD -14·9%, 95% CI: -17·2%, -12·7%); and Zika cases were differentiated most by rash (PD 31·8%, 95% CI: 27·0%, 36·2%) and the lack of fever (PD -37·3%, 95% CI: -41·7%, -33·0%) and lymphocytopenia (PD -41·9%, 95% CI: -46·6%, -37·1%). Dengue and chikungunya cases exhibited similar temperature dynamics during acute illness, and their temperatures were higher than Zika cases. Sixty-two laboratory-confirmed afebrile dengue cases, which would not be captured by any widely used international case definition, presented very similarly to afebrile Zika cases, though some exhibited warning signs of disease severity. The presence of arthralgia, the presence of basophilia, and the absence of fever were the most important model-based distinguishing predictors of chikungunya, dengue, and Zika, respectively.

Interpretations: These findings substantially update our understanding of dengue, chikungunya, and Zika in children while identifying various clinical features that could improve differential diagnoses. The occurrence of afebrile dengue warrants reconsideration of current guidance.

Funding: US National Institutes of Health R01AI099631, P01AI106695, U01AI153416, U19AI118610.