Carrillo Fausto Andres Bustos, Ojeda Sergio, Sanchez Nery, Plazaola Miguel, Collado Damaris, Miranda Tatiana, Saborio Saira, Mercado Brenda Lopez, Monterrey Jairo Carey, 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, CA, USA; Division of Epidemiology and Biostatistics, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
Sustainable Sciences Institute, Managua, Nicaragua.
Lancet Child Adolesc Health. 2025 Sep;9(9):622-633. doi: 10.1016/S2352-4642(25)00168-3.
Dengue, chikungunya, and Zika are diseases of major human concern. Differential diagnosis of these three diseases is complicated in children and adolescents due to overlapping clinical features (signs, symptoms, and complete blood count results). Few studies have directly compared these three diseases. We aimed to use 18 years of primary care observations from a paediatric cohort to characterise the distinguishing features of dengue, chikungunya, and Zika.
This single-centre prospective cohort study was based on the ongoing Pediatric Dengue Cohort Study (PDCS), which started on Aug 30, 2004, in District II of Managua, Nicaragua. The PDCS was initiated to study dengue virus infections in children who attended the Health Center Sócrates Flores Vivas (HCSFV) for their medical needs; over the years, the PDCS expanded the age range (2 to <10 years expanded to 2 to <18 years). The PDCS also expanded eligibility criteria to include chikungunya virus and Zika virus before they entered the geographical study area in August, 2014 and January, 2016, respectively. For this study, we included laboratory confirmed cases of dengue, chikungunya, and Zika enrolled in the PDCS between Jan 19, 2006, and Dec 31, 2023, and evaluated at the HCSFV. We assessed clinical features (clinical records and laboratory results) during the first 10 days of illness using generalised additive models, day-specific and disease-specific prevalence estimates, and machine learning models.
We characterised 1405 dengue, 517 chikungunya, and 522 Zika cases. The median age was 10·0 years (IQR 7·0-12·7); 1165 (47·7%) cases were male and 1279 (52·3%) were female. The prevalence of many clinical features shown by dengue, chikungunya, and Zika cases differed substantially overall, by age, and by day of illness. The presence of basophilia (prevalence difference 42·3% [95% CI 37·4 to 47·0]), monocytopenia (13·0% [10·0 to 16·4]), abdominal pain (19·1% [15·7 to 22·9]), and leukopenia (41·1% [36·2 to 45·6]) best distinguished dengue; the presence of arthralgia (60·5% [56·3 to 64·2]) and absence of papular rash (-14·9% [-17·2 to -12·7]), leukopenia (-32·0% [-36·7 to -27·1]), and conjunctival injection (-4·9% [-6·6 to -3·3]) best distinguished chikungunya; and the presence of generalised rash (35·0% [30·1 to 39·7]) and absence of fever (-37·3% [-41·7 to -33·0]), headache (-36·2% [-41·1 to -31·2]), myalgia (-30·1% [-33·9 to -26·2]), and lymphocytopenia (-41·9% [-46·6 to -37·1]) best distinguished Zika. Dengue and chikungunya cases showed similar temperature dynamics during acute illness, and their mean temperatures were higher than Zika cases. 62 laboratory confirmed afebrile dengue cases, which would not be captured by any widely used international case definition, presented most similarly to afebrile Zika cases, but five (8·1%) had warning signs of dengue disease severity. Based on boosted regression tree models, the presence of arthralgia and absence of basophilia and leukopenia most distinguished chikungunya, the presence of basophilia and leukopenia most distinguished dengue, and the absence of fever most distinguished Zika.
These findings substantially update the understanding of dengue, chikungunya, and Zika in a paediatric population and identify various clinical features that could improve differential diagnoses. The occurrence of afebrile dengue warrants reconsideration of current guidance.
US National Institutes of Health.
For the Spanish translation of the abstract see Supplementary Materials section.
登革热、基孔肯雅热和寨卡病毒病是引起人类重大关注的疾病。由于临床特征（体征、症状和全血细胞计数结果）重叠，儿童和青少年这三种疾病的鉴别诊断较为复杂。很少有研究直接比较这三种疾病。我们旨在利用一个儿科队列18年的初级保健观察数据，来描述登革热、基孔肯雅热和寨卡病毒病的区别特征。
这项单中心前瞻性队列研究基于正在进行的儿科登革热队列研究（PDCS），该研究于2004年8月30日在尼加拉瓜马那瓜第二区启动。启动PDCS是为了研究因医疗需求前往索克拉特斯·弗洛雷斯·比瓦斯健康中心（HCSFV）的儿童中的登革热病毒感染情况；多年来，PDCS扩大了年龄范围（从2至<10岁扩大到2至<18岁）。PDCS还扩大了纳入标准，分别在2014年8月和2016年1月基孔肯雅病毒和寨卡病毒进入地理研究区域之前，将其纳入研究范围。对于本研究，我们纳入了2006年1月19日至2023年12月31日期间在PDCS中登记并在HCSFV接受评估的登革热、基孔肯雅热和寨卡病毒病实验室确诊病例。我们使用广义相加模型、特定日期和特定疾病的患病率估计以及机器学习模型，评估了发病后前10天的临床特征（临床记录和实验室结果）。
我们对1405例登革热、517例基孔肯雅热和522例寨卡病毒病病例进行了特征描述。中位年龄为10.0岁（IQR 7.0 - 12.7）；1165例（47.7%）为男性，1279例（52.3%）为女性。登革热、基孔肯雅热和寨卡病毒病病例所表现出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。嗜碱性粒细胞增多（患病率差异42.3% [95% CI 37.4至47.0]）、单核细胞减少（13.0% [10.0至16.4]）、腹痛（19.1% [15.7至22.9]）和白细胞减少（41.1% [36.2至45.6]）最能区分登革热；关节痛（60.5% [56.3至64.2]）、无丘疹性皮疹（-14.9% [-17.2至-12.7]）、白细胞减少（-32.0% [-36.7至-27.1]）和结膜充血（-4.9% [-6.6至-3.3]）最能区分基孔肯雅热；全身性皮疹（35.0% [30.1至39.7]）、无发热（-37.3% [-41.7至-33.0]）、无头痛（-36.2% [-41.1至-31.2]）、无肌痛（-30.1% [-33.9至-26.2]）和淋巴细胞减少（-41.9% [-46.6至-37.1]）最能区分寨卡病毒病。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，且它们的平均体温高于寨卡病毒病病例。62例实验室确诊无发热的登革热病例，任何广泛使用的国际病例定义均无法识别，其表现与无发热的寨卡病毒病病例最为相似，但其中5例（8.1%）有登革热疾病严重程度的警示体征。基于增强回归树模型，关节痛、无嗜碱性粒细胞增多和白细胞减少最能区分基孔肯雅热，嗜碱性粒细胞增多和白细胞减少最能区分登革热，无发热最能区分寨卡病毒病。
这些发现极大地更新了对儿科人群中登革热、基孔肯雅热和寨卡病毒病的认识，并确定了各种可改善鉴别诊断的临床特征。无发热登革热的出现值得重新审视当前的指南。
美国国立卫生研究院。
如需获取摘要的西班牙语译文，请参阅补充材料部分。
