Co-circulation and misdiagnosis led to underestimation of the 2015-2017 Zika epidemic in the Americas

During the 2015-2017 Zika epidemic, dengue and chikungunya-two other viral diseases with the same vector as Zika-were also in circulation. Clinical presentation of these diseases can vary from person to person in terms of symptoms and severity, making it difficult to differentially diagnose them. Under these circumstances, it is possible that numerous cases of Zika could have been misdiagnosed as dengue or chikungunya, or vice versa. Given the importance of surveillance data for informing epidemiological analyses, our aim was to quantify the potential extent of misdiagnosis during this epidemic. Using basic principles of probability and empirical estimates of diagnostic sensitivity and specificity, we generated revised estimates of reported cases of Zika that accounted for the accuracy of diagnoses made on the basis of clinical presentation with or without laboratory confirmation. Applying this method to weekly reported case data from 43 countries throughout Latin America and the Caribbean, we estimated that 944,700 (95% CrI: 884,900-996,400) Zika cases occurred when assuming all confirmed cases were diagnosed using molecular methods versus 608,400 (95% CrI: 442,000-821,800) Zika cases that occurred when assuming all confirmed cases were diagnosed using serological methods. Our results imply that misdiagnosis was more common in countries with proportionally higher reported cases of dengue and chikungunya, such as Brazil. Given that Zika, dengue, and chikungunya appear likely to co-circulate in the Americas and elsewhere for years to come, our methodology has the potential to enhance the interpretation of passive surveillance data for these diseases going forward. Likewise, our methodology could also be used to help resolve transmission dynamics of other co-circulating diseases with similarities in symptomatology and potential for misdiagnosis. Author summary In 2016, the Zika epidemic in the Americas was declared a Public Health Emergency of International Concern by the World Health Organization, due to the finding that Zika virus infection was associated with microcephaly. In total, nearly 700,000 cases of Zika were reported to the Pan American Health Organization between 2015 and 2017. During this time, there were also nearly 4 million cases of dengue and chikungunya, diseases that share a common mosquito vector, and similar symptomatology, with Zika. In a region with co-circulation of these diseases, high potential for clinical misdiagnosis among these diseases has been found. This raises the question of how misdiagnosis could have affected reports of the overall size of the Zika epidemic. We addressed this question by leveraging passive surveillance data and empirical estimates of misdiagnosis to quantify the spatial and temporal extent of misdiagnosis between Zika, dengue, and chikungunya. Our results suggest that, across the Americas, the Zika epidemic was likely larger than indicated by passive surveillance data taken at face value, but that conclusions about the overall size of the epidemic depend on assumptions made about sensitivities and specificities of laboratory diagnostic tests. We estimated that many misdiagnosed Zika cases occurred in 2015, prior to the start of reporting of Zika in most countries.