Background. Dengue, chikungunya, and Zika are mosquito-borne 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 assessed clinical features of cases aged 2-17 years experiencing these diseases. Methods. We characterized 1,405 dengue, 517 chikungunya, and 522 Zika pediatric cases occurring from January 2006 through December 2023 in a Nicaraguan cohort study. Clinical records and laboratory results across the first 10 days of illness were examined from a primary care health center. All cases were laboratory-confirmed. Data were analyzed with generalized additive models, generalized mixed models, and machine learning models. Findings. 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, leukopenia, nausea/vomiting, and basophilia; chikungunya cases were differentiated most by arthralgia and the absence of leukopenia and papular rash; and Zika cases were differentiated most by rash and lack of fever and lymphocytopenia. 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 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 case definitions. Funding. US National Institutes of Health R01AI099631, P01AI106695, U01AI153416, U19AI118610.

The authors have declared no competing interest.

This study was supported by grants R01 AI099631 (AB), P01 AI106695 (EH), U01 AI153416 (EH), and U19 AI118610 (EH) from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Additional support for the PDCS (2004-2015) was obtained from grant VE-1 from the Pediatric Dengue Vaccine Initiative and the FIRST grant from the Bill and Melinda Gates Foundation and the Instituto Carlos Slim de la Salud. CJC was supported by the US National Science Foundation (NSF DBI 2213854).

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Institutional Review Boards of the University of California, Berkeley, the University of Michigan, and the Nicaraguan Ministry of Health approved the Pediatric Dengue Cohort Study (PDCS) protocol.

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Individual-level data may be shared with outside investigators following UC Berkeley IRB approval. Data will be available by request, as is required by the IRB-approved protocols for the PDCS. Please contact the UC Berkeley Center for the Protection of Human Subjects (ophs@berkeley.edu) and Eva Harris (eharris@berkeley.edu) to arrange for data access. Databases without names and other identifiable information were used for all analyses. Collaborating research groups and institutions will be sent coded data with all personal identifiers unlinked as well as data dictionaries and the accompanying R code.