Assessing Sensitivity and Specificity of Surveillance Case Definitions for Zika Virus Disease

We evaluated performance of 5 case definitions for Zika virus disease surveillance in a human cohort during an outbreak in Singapore, August 26–September 5, 2016. Because laboratory tests are largely inaccessible, use of case definitions that include rash as a required clinical feature are useful in identifying this disease.

Unlike dengue virus (a related flavivirus), Zika virus was not considered to be a major pathogen until recent reports of its association with Guillain-Barré syndrome and microcephaly (6). Thus, there is little information on the performance of surveillance case definitions for detection of Zika virus disease.
Responding to the rapidly evolving Zika virus epidemic to guide surveillance for Zika virus disease, the US Centers for Disease Control and Prevention worked with the Council of State and Territorial Epidemiologists (CSTE) to approve an interim definition in February 2016 and a final case definition in June 2016 for noncongenital Zika virus disease as >1 of the following signs or symptoms: acute onset of fever, maculopapular rash, arthralgia, and conjunctivitis (7). The interim case definition (February 2016) of the World Health Organization (WHO) for suspected Zika virus disease includes rash or fever and >1 of the following signs or symptoms: arthralgia, arthritis, and conjunctivitis (nonpurulent/ hyperemic) (8). The case definition of the European Centre for Disease Prevention and Control (ECDC) includes rash and optional symptoms in the WHO definition plus myalgia (9). The case definition of the Pan American Health Organization (PAHO) includes rash and >2 of the following signs or symptoms: fever, conjunctivitis (nonpurulent/hyperemic), arthralgia, myalgia, and periarticular edema (10).
The first outbreak of Zika virus disease in Singapore occurred in August 2016 (11). Singapore is a densely populated tropical country to which dengue fever is endemic. With the identification of the first local case of Zika virus disease, the Singapore Ministry of Health (MOH) initiated active case finding (12,13). The MOH recommended Zika virus screening for persons with fever and maculopapular rash, and 1 of the following: arthralgia, myalgia, headache, and nonpurulent conjunctivitis.
Clinical criteria for disease surveillance are a balancing act for satisfying 2 potentially conflicting needs: sensitivity and specificity. A more sensitive case definition will identify a larger proportion of true cases, but at the cost of finding a large number of cases from other causes. In comparison, a more specific case definition will provide a more accurate description of true cases, but at the expense of missing true cases (14).

The Study
We evaluated the performance of surveillance case definitions for Zika virus disease recommended by the CSTE, WHO, PAHO, ECDC, and the Singapore MOH by using a cohort of 359 adult patients with suspected Zika virus disease who came to the Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore, the national referral center for Zika virus disease during the containment phase of the Zika virus outbreak during August 26-September 5, 2016. All adults living or working in the outbreak area who were sick and had symptoms that partially or fully met the MOH definition were screened for Zika virus disease.
At their first visit to the hospital, all patients had their signs and symptoms documented, and blood and urine samples were obtained for detection of Zika virus nucleic acids by reverse transcription PCR (RT-PCR) (15). Parallel testing in the hospital laboratory and at the National Public Health Laboratory (Singapore) was conducted to maximize sensitivity and negative predictive values to rule out Zika virus infection.

Conclusions
Despite increasing incidence of Zika virus disease and its spread across the Americas and Asia, there is no internationally adopted common clinical criteria for the surveillance of this disease. We report a large outbreak  The main limitation of this study is that it included only adults. However, the small number of children infected with Zika virus during the containment phase of the outbreak in Singapore had symptoms similar to those for adults (A. Chow et al., unpub. data). Some Zika virus infections could have been misclassified as noninfections because RT-PCR could have missed infections late in the illness course or after development of antibodies against Zika virus.
In conclusion, we evaluated the performance of 5 case definitions for Zika virus disease surveillance. In the current effort to halt transmission of this virus worldwide, and with laboratory tests being largely inaccessible, use of surveillance case definitions that include rash as a required clinical criteria would provide a high yield in identifying Zika virus disease.