Indication - Zika virus infection
Zika virus nucleic acid test (NAT)
First added in 2019
Changed in 2020
To diagnose acute Zika virus infection
Venous whole blood, Serum, Plasma, Urine, CSF
WHO prequalified or recommended products
WHO supporting documents
ICD11 code: 1D48
Summary of evidence evaluation
Two tests have published small evaluation studies which show agreement with confirmed PCR methods. Studies have been undertaken in small stored sample banks or spiked sera.
Summary of SAGE IVD deliberations
The importance of monitoring and controlling ZIKV transmission globally was underscored when WHO declared ZIKV infection and its associated complications a PHEIC. Several studies have shown valid results of ZIKV NAT tests in patients with acute infection, pregnant women, fetal deaths (stillbirths) and children born with neurological and other congenital clinical outcomes, as confirmed by PCR methods. Studies in selected, sometimes artificial samples provide some evidence for the accuracy of ZIKV NAT tests.
SAGE IVD recommendation
The SAGE IVD recommended inclusion on the EDL of the test for ZIKV nucleic acid for diagnosis or confirmation of early ZIKV infection, noting that it is specific for confirming infection and detecting outbreaks; its sensitivity and specificity appear to be acceptable. There is no cross-reactivity with other flaviviruses. The Group noted, however, that no studies of use in the field have been reported. Use of NAT for diagnosis of ZIKV infection is included in WHO laboratory guidance published in 2016 and in updated guidance by the WHO Regional Office for the Americas in 2018. The Group also recommended that simple NAT tests be developed for use in primary care settings or in district hospitals.
Details of submission from 2020
Disease condition and its impact on patients: By 3 August 2017, about 217 000 cases of ZIKV disease and about 3400 cases of associated congenital syndrome had been reported in Latin America and the Caribbean (1). It has been projected that about 12.3 (0.7–162.3) million cases could be expected in Latin America and the Caribbean every year, which could result in about 64 400 cases of Guillain-Barré syndrome and about 4700 cases of microcephaly (2). Although non-congenital ZIKV disease is not generally fatal, the mortality rate among 602 suspected cases of congenital microcephaly in infants in Brazil during the first week of life was 51 per 1 000 live births (3). Does the test meet a medical need? Cases of ZIKV infection have been identified in Africa and Asia since the 1950s, and outbreaks of ZIKV disease were first recognized in the Pacific islands in 2007 and 2013. The 2015–2016 outbreak in the Americas further demonstrated the epidemic potential of ZIKV, with capacity for rapid global spread and birth defects, other adverse pregnancy outcomes and Guillain-Barré syndrome. How the test is used: Diagnosis of ZIKV disease depends on the interval between symptom onset and specimen collection. Serum and/or urine specimens collected within 7 days of symptom onset are tested for the presence of viral RNA by RT-PCR. If the result is negative, specimens are tested for the presence of IgM antibodies, with possible confirmatory testing with neutralization assays. WHO guidance (4) is being updated to incorporate guidance on testing for dengue and chikungunya.
Public health relevance
Prevalence: The importance of monitoring and controlling ZIKV transmission globally was underscored when WHO declared ZIKV infection and its associated complications a PHEIC and changed the emergency response into a long-term programme with a sustained global strategy. To date, 86 countries and territories have reported mosquito-borne ZIKV transmission; and 36 have confirmed ZIKV infection-associated microcephaly and congenital Zika syndrome. Congenital Zika syndrome has been reported in the Americas, the Pacific, South and Southeast Asia and sub-Saharan Africa. Evidence from epidemiological studies and animal models of infection with African and Asian ZIKV strains, indicate a risk for maternal–fetal transmission and adverse pregnancy outcomes in all regions with ZIKV transmission. Socioeconomic impact: The prospective economic burden of the neurological sequelae of ZIKV infection in South America and the Caribbean is estimated to be US$ 2.3 (US$ 0–159.3) billion per annum (2). In a separate analysis, it was estimated that an attack rate of 0.3% across the six states of Brazil at greatest risk would result in a total cost exceeding US$ 0.5 billion, an attack rate of 1% would cost more than US $1 billion, and an attack rate of 2% would cost more than US$ 2 billion (3).
WHO or other clinical guidelines relevant to the test
WHO guidelines: laboratory testing for Zika virus infection. Interim guidance. 23 March 2016 (4)
Evidence for clinical usefulness and impact
Limited data are available from clinical settings. ZIKV persists in serum and plasma for only 5–7 days after symptoms appear, although it may persist for up to 14 days in urine and whole blood and up to 3 months in semen. Diagnosis of ZIKV infection is critical for tracking its emergence, re-emergence and global spread as a basis for recommendations to women of reproductive age and the potential population-level risk to pregnant women. Diagnosis of ZIKV infection in pregnancy is important for clinical management in areas where there is ZIKV transmission, because of the risks for microcephaly and other complications, including preterm birth, stillbirth and the spectrum of malformations characterized as congenital ZIKV syndrome. As the symptoms of ZIKV infections tend to be mild and nonspecific, diagnostic testing is important for determining infection of pregnant women and monitoring transmission in the general population. No published studies with quantitative data are available. Cohort studies are in progress to address these issues.
Evidence for economic impact and/or cost–effectiveness
Studies of the cost–effectiveness of testing are not available, except for assessment during blood product screening. Activities that will require resources and budgetary commitment are purchase of equipment and reagents; training in use of the assays; appropriate storage conditions for reagents; collection, transport and storage of clinical specimens in optimal conditions for testing; maintenance of diagnostic equipment; and training of health care providers and public health programme managers in appropriate use of the test, interpretation of results and appropriate counselling of patients.
Ethical issues, equity and human rights issues
Consent is required for taking samples. There are no vaccines or therapeutics for ZIKV infection and no treatments to reduce the risk of exposing fetuses. Positive maternal test results do not necessarily reflect fetal infection. Pregnant women are tested to provide information for clinicians and for the women to anticipate potential adverse outcomes, to decide whether more intensive monitoring of the pregnancy is needed and to guide decision-making. In areas with low or no transmission, false-positive results may prompt unnecessary medical interventions, such as elective termination of pregnancy, or exacerbate maternal anxiety. False-negative results might fail to identify high-risk pregnancies or might result in subsequent misdiagnosis of the cause of congenital malformations. NAT is expensive and technically complex and is therefore limited to relatively sophisticated laboratories with well-trained, skilled technicians. Therefore, the test will not be widely available in many settings. Research and public health programmes are under way to develop simple, affordable point- of-care tests. Access to maternal and child health care, including pregnancy and antenatal medical services (with prenatal ultrasound or other means to monitoring of pregnancies), differs by region and socioeconomic status and thus differentially affects management of women with evidence of infection.
1. Zika cumulative cases. Washington DC: WHO Regional Office for the Americas; 2016 (http://www. paho.org/hq/index.php?option=com_content&view=article&id=12390&Itemid=42090&lang=en, accessed April 2018). 2. Colón-González FJ, Peres CA, Steiner São Bernardo C, Hunter PR, Lake IR. After the epidemic: Zika virus projections for Latin America and the Caribbean. PLoS Negl Trop Dis. 2017;11(11):e0006007. 3. França GV, Schuler-Faccini L, Oliveira WK, Henriques CM, Carmo EH, Pedi VD, et al. Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet. 2016; 388: 891–7. 4. WHO guidelines: laboratory testing for Zika virus infection. Interim guidance. 23 March 2016 (http://apps.who.int/iris/bitstream/handle/10665/204671/WHO_ZIKV_LAB_16.1_eng.pdf;jsessio nid=8BF6EDD420F9BEDD723CA4B1C2EB9566?sequence=1, accessed April 2019).