Assessing Surveillance Case Definitions for Zika Virus

In This Article

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.

A total of 42.0% of the cohort had Zika virus infection confirmed in blood (4%), urine (36%), or both (60%) samples (Table 1). Most (80%) infected and noninfected patients were tested ≤5 days after illness onset (infected patients, mean 3.6 days; noninfected patients, mean 4.6 days). Infected and noninfected patients were similar in age and sex. No female patients were pregnant. Among Zika virus–infected patients, rash (93.3%) was the most common symptom, followed by fever (79.2%) and myalgia (42.3%). Headache, arthralgia, and conjunctivitis were reported in <25% patients with Zika virus disease. Pruritus (11.4%) and gastrointestinal symptoms (6.7%) were relatively uncommon. For patients not infected with Zika virus, fever (86.2%) was the most common symptom, followed by myalgia (59.1%) and rash (44.8%).

The case definition recommended by CSTE for use in the United States (US definition) had a sensitivity of 100% and a specificity of 2% in detecting Zika virus in the cohort (Table 2). The WHO case definition had the lowest sensitivity (38%). The Singapore MOH case definition had a sensitivity of 54% and a high specificity of 76%, and performed well in diagnosing Zika virus disease (positive likelihood ratio [LR+] 2.2, 95% CI 1.7–3.0). The performances of PAHO (LR+ 2.1, 95% CI 1.5–2.8) and ECDC (LR+ 2.1, 95 % CI 1.6–2.8) case definitions were similar.

Table 1. Clinical characteristics of an adult cohort with suspected Zika virus disease, Singapore, August 26–September 5, 2016*
Characteristic	Zika virus positive, n = 149	Zika virus negative, n = 210
Demographic data
Mean age, y (SD)	38.1 (14.2)	34.2 (12.1)
Sex
M	92 (61.7)	129 (61.4)
F	57 (38.3)	81 (38.6)
Ethnicity
Chinese	109 (73.2)	122 (58.1)
Malay	15 (10.1)	17 (8.1)
Indian	9 (6.0)	24 (11.4)
Other	16 (10.7)	47 (22.4)
Singapore residents	113 (75.8)	131 (62.4)
Signs and symptoms at presentation
Rash	139 (93.3)	94 (44.8)
Fever	118 (79.2)	181 (86.2)
Myalgia	63 (42.3)	124 (59.1)
Headache	35 (23.5)	75 (35.7)
Conjunctivitis	35 (23.5)	32 (15.2)
Arthralgia	34 (22.8)	50 (23.8)
Pruritis	17 (11.4)	17 (8.1)
Any gastrointestinal symptom†	10 (6.7)	25 (11.9)
Fulfilled case definition
United States‡	149 (100.0)	206 (98.1)
World Health Organization§	57 (38.3)	64 (30.5)
PAHO¶	73 (49.0)	50 (23.8)
ECDC#	83 (55.7)	55 (26.2)
Singapore Ministry of Health**	81 (54.4)	51 (24.3)

*Values are no. (%) except as indicated. ECDC, European Centre for Disease Prevention and Control; PAHO, Pan American Health Organization.
†Nausea, vomiting, diarrhea, or abdominal pain.
‡Definition used in the United States (interim, February 2016; confirmed, June 2016) states that clinical criteria for noncongenital Zika virus disease are defined as >1 of the following: acute onset of fever, maculopapular rash, arthralgia, and conjunctivitis.
§Interim case definition (February 12, 2016) includes rash or fever and >1 of the following signs or symptoms: arthralgia or arthritis, or conjunctivitis (nonpurulent/hyperemic).
¶Interim case definition (April 1, 2016) includes rash with >2 of the following signs or symptoms: fever, conjunctivitis (nonpurulent/hyperemic), arthralgia, myalgia, or periarticular edema.
#Interim case definition (March 17, 2016) includes rash with or without fever and >1 of the following signs or symptoms: arthralgia, myalgia, or conjunctivitis (nonpurulent/hyperemic).
**Case definition (August 2016) includes fever and rash and >1 of the following symptoms: headache, myalgia, arthralgia, or nonpurulent conjunctivitis.

Table 2. Performance of case definitions for diagnosing Zika virus infection in a human cohort during an outbreak, Singapore, August 26–September 5, 2016*
Case definition	Sensitivity, %	Specificity, %	PPV, %	NPV, %	LR+ (95% CI)	LR– (95% CI)
United States	100	2	42	100	1.02 (1.00–1.04)	0
WHO	38	70	47	61	1.3 (0.9–1.7)	0.9 (0.8–1.0)
PAHO	49	76	59	68	2.1 (1.5–2.8)	0.7 (0.6–0.8)
ECDC	56	74	60	70	2.1 (1.6–2.8)	0.6 (0.5–0.7)
Singapore MOH	54	76	61	70	2.2 (1.7–3.0)	0.6 (0.5–0.7)

*ECDC, European Centre for Disease Prevention and Control; LR, likelihood ratio; MOH, Ministry of Health; NPV, negative predictive value; PAHO, Pan American Health Organization; PPV, positive predictive value; WHO, World Health Organization; +, positive; –, negative.