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

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.

Research In Context: Evidence before this study: Dengue, chikungunya, and Zika are mosquito-borne diseases that co-occur in tropical and subtropical settings and give rise to fever, rash, and a variety of other clinical features. We reviewed the most widely used international case definitions for the three diseases - established by either the World Health Organization (WHO) or the Pan American Health Organization (PAHO); PAHO's 2022 report on differential diagnosis and treatment options for dengue, chikungunya, and Zika; and the 80 studies underlying PAHO's diagnostic recommendations. The available evidence suggests that dengue, chikungunya, and Zika have a broad and overlapping set of clinical manifestations that hamper differential diagnosis, and hence case management, in the absence of definitive laboratory testing. This similarity in disease presentation is believed to be especially characteristic of the first few days of illness. Most of the studies on the diseases' clinical manifestations are in adult populations, and these studies constitute the main evidence base for the existing case definitions. For example, only one of the 80 studies summarized in PAHO's recent report provided direct comparisons of the clinical features across cases experiencing dengue, chikungunya, and Zika, and that study mainly focused on adults. Disease presentation is more non-specific in children and adolescents than in adults, further impeding differential diagnoses in pediatric populations. Current guidelines suggest that the presence of thrombocytopenia, progressive increases in hematocrit, and leukopenia tend to distinguish dengue from chikungunya and Zika; that arthralgia is more common in chikungunya; and that pruritis is more common in Zika. Fever is considered a defining feature of dengue, such that all case definitions in widespread use for the disease require that patients exhibit fever. However, existing but limited evidence suggests that dengue cases can very rarely present without fever.Added value of this study: This study follows a cohort of Nicaraguan children through multiple dengue epidemics, two large chikungunya epidemics, and one explosive Zika epidemic. By synthesizing 18 years' worth of primary care medical records, we find clinically meaningful differences in the prevalence of many clinical features, including by day of illness and across age, but not by sex. In addition to verifying the clinical features PAHO identified as key distinguishing features, we also identified others, including papular rash, nausea, hemorrhagic manifestations, abdominal pain, and basophilia, that could aid differential diagnoses. As the PAHO report is based on a multitude of studies with varied age ranges, health care accessibility, overall research quality, and patient populations, this study is a complementary and important counterpart that draws from a single, well-characterized source population.Further, we identified 62 laboratory-confirmed cases of afebrile dengue (7·2% of all dengue cases since we started testing any suspected case exhibiting afebrile rash). The disease manifestations of afebrile dengue cases were generally clinically indistinguishable from afebrile Zika, although several displayed warning signs of severity. We found that cases of the three diseases exhibited different temperature dynamics across the acute period of illness. Machine learning models were best able to distinguish chikungunya (an alphaviral disease) from dengue and Zika (flaviviral diseases) based on clinical features alone. Our dengue model performed well, especially in classifying febrile dengue cases. However, our Zika model struggled to properly distinguish afebrile dengue cases from afebrile Zika cases, likely due to their very similar and minimal disease presentation.Implications of all the available evidence: Despite clinical overlap in the pediatric manifestations of dengue, chikungunya, and Zika, we identify meaningful differences in their presentation and in laboratory markers that can be leveraged to improve diagnoses in the absence of definitive laboratory-based diagnostic testing. Afebrile dengue should be studied more and incorporated into future case definitions, as not accounting for its existence can impede surveillance, laboratory testing strategies, clinical management, and research efforts.