Bustos Carrillo Fausto Andres, Ojeda Sergio, Sanchez Nery, Plazaola Miguel, Collado Damaris, Miranda Tatiana, Saborio Saira, Lopez Mercado Brenda, Carey Monterrey Jairo, Arguello Sonia, Campredon Lora, Chu Zijin, Carlson Colin J, Gordon Aubree, Balmaseda Angel, Kuan Guillermina, Harris Eva
Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, USA.
Division of Epidemiology and Biostatistics, School of Public Health, University of California, Berkeley, Berkeley, California, USA.
medRxiv. 2025 May 17:2025.01.06.25320089. doi: 10.1101/2025.01.06.25320089.
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.
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.
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.
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.
US National Institutes of Health R01AI099631, P01AI106695, U01AI153416, U19AI118610.
登革热、基孔肯雅热和寨卡病毒病是备受人类关注的疾病。儿童和青少年的鉴别诊断因临床特征（体征、症状和全血细胞计数结果）重叠而变得复杂。很少有研究直接比较这三种疾病。我们旨在确定每种疾病在儿科方面的特征。
数据来源于在尼加拉瓜马那瓜进行的一项纵向队列研究中纳入的2至未满18岁的实验室确诊病例（有症状感染），这些病例于2006年1月19日至2023年12月31日期间在一家初级卫生保健中心就诊。我们收集了发病头10天的临床记录和实验室结果。数据采用广义相加模型、特定日期和疾病的患病率估计以及机器学习模型进行分析。
我们对1405例登革热、517例基孔肯雅热和522例寨卡病毒病儿科病例进行了特征描述。我们纳入了1165例（47.7%）男性和1279例（52.3%）女性，中位年龄为10.0（四分位间距7.0 - 12.7）岁。登革热、基孔肯雅热和寨卡病毒病病例所呈现的许多临床特征的患病率在总体、年龄和发病天数方面存在显著差异。登革热病例最具鉴别性的特征是腹痛（患病率差异（PD）19.1%，95%置信区间（CI）：15.7%，22.9%）、白细胞减少（PD 41.1%，95% CI：36.2%，45.6%）、恶心（PD 15.5%，95% CI：12.2%，19.2%）、呕吐（PD 21.9%，95% CI：17.9%，26.1%）和嗜碱性粒细胞增多（PD 42.3%，95% CI：37.4%，47.0%）；基孔肯雅热病例最具鉴别性的特征是关节痛（PD 60.5%，95% CI：56.3%，64.2%）以及无白细胞减少（PD -32.0%，95% CI：-36.7%，-27.1%）和丘疹性皮疹（PD -14.9%，95% CI：-17.2%，-12.7%）；寨卡病毒病病例最具鉴别性的特征是皮疹（PD 31.8%，95% CI：27.0%，36.2%）以及无发热（PD -37.3%，95% CI：-41.7%，-33.0%）和淋巴细胞减少（PD -41.9%，95% CI：-46.6%，-37.1%）。登革热和基孔肯雅热病例在急性疾病期间表现出相似的体温动态，且它们的体温高于寨卡病毒病病例。62例实验室确诊的无热登革热病例，任何广泛使用的国际病例定义都无法涵盖这些病例，这些病例与无热寨卡病毒病病例表现非常相似，尽管有些病例表现出疾病严重程度的警示信号。关节痛的存在、嗜碱性粒细胞增多的存在以及无发热分别是基孔肯雅热、登革热和寨卡病毒病基于模型的最重要鉴别预测因素。
这些发现极大地更新了我们对儿童登革热、基孔肯雅热和寨卡病毒病的理解，同时确定了各种可改善鉴别诊断的临床特征。无热登革热的发生值得重新审视当前的指南。
美国国立卫生研究院R01AI099631、P01AI106695、U01AI153416、U19AI118610。
