Indication - Zika virus infection
IgM antibodies to Zika virus
First added in 2019
Changed in 2020
Aid to diagnosis
To aid in the diagnosis of suspected Zika virus infection
Serum (Not to be used with CSF)
WHO prequalified or recommended products
WHO supporting documents
ICD11 code: 1D48
Summary of evidence evaluation
There is no evidence base for these tests. They have not been extensively validated, and the existing studies have not been published. The evidence base for ZIKV anti-IgM tests is unclear. At least one of the tests has poor performance in patients who are not infected with ZIKV, posing a risk of misdiagnosing dengue.
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. The tests are currently available under an FDA Emergency Use Authorization. Reliable diagnostic testing is still limited, especially in resource-constrained settings. The availability of simple, affordable tests will improve detection of outbreaks, accurate diagnosis and appropriate strategies for prevention, patient care and disease control.
SAGE IVD recommendation
The SAGE IVD recommended conditional inclusion on the EDL of the ELISA for ZIKV anti-IgM, pending provision within 1 year of further evidence, including a clear recommendation in guidelines and an updated review of the available data. The Group noted that caution should be used in interpreting the results of ZIKV anti-IgM tests, particularly for pregnant women, in the absence of prior NAT testing. The Group noted the high level of cross-reactivity of anti-IgM with ZIKV, DENV and other flaviviruses, the wide range of specificity and the persistence of Zika IgM antibody, which might reflect infection before pregnancy. False-negative and false-positive results are found. The test should be used only as an aid to diagnosis, with confirmation of positive tests, and should not be used on cerebrospinal fluid samples. 3rd EDL Edition: Additional evidence to support this listing was provided and reviewed by SAGE IVD. During their third annual meeting (held as a series of remote sessions from June to July 2020), SAGE IVD accepted the evidence provided for an updated review of the available data but noted that the WHO guidelines are still pending and so recommended maintaining the Zika virus IgM test as a conditional listing in EDL 3.
Details of submission from 2020
Disease condition and 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 1000 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, which 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 indicates 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
Discrimination between ZIKV and DENV infections is critical, as pregnant women with ZIKV infection should be managed for possible adverse outcomes, including fetal microcephaly, while those who test positive for DENV should be managed to reduce their risk for severe morbidity and mortality from acute DENV infection.
Evidence for economic impact and/or cost–effectiveness
The activities that will require resources and budgetary commitment are: purchase of equipment and reagents; training in use of the selected 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 indications for use of tests and interpretation of results.
Ethical issues, equity and human rights issues
Consent is required for collection of a serum or cerebrospinal fluid sample. ZIKV infection may have serious implications in certain populations. For example, given the association with microcephaly and other poor pregnancy outcomes, a positive test is a serious, challenging situation for pregnant women. False- positive results may prompt unnecessary medical interventions or follow-up and exacerbate maternal anxiety, and false negative results may fail to identify high- risk pregnancies or proper diagnosis of congenital Zika syndrome. False-positive results may also incur use of limited public health resources for outbreak response and the economic loss associated with travel deferral if an area is identified as having active autochthonous ZIKV transmission. In addition to issues of clinical management, the absence of laboratory methods for detecting ZIKV infection may leave populations and public health programmes vulnerable to emergence and re-emergence of ZIKV transmission and adverse sequelae of congenital malformations and Guillain-Barré syndrome. Reliable ZIKV diagnostic testing is still very limited, especially in resource-constrained settings. The availability of simple, affordable tests will improve detection of outbreaks, accurate diagnosis and appropriate strategies for prevention, patient care and disease control. Better-resourced settings have greater access to diagnostic tests and to maternal and child health care, including pregnancy and antenatal medical services (with prenatal ultrasound and other mechanisms to monitor pregnancies), thus differentially affecting the management of women with ZIKV infection. All commercially available ZIKV antibody tests for use in a laboratory or at points of care and those in the pipeline should be evaluated systematically for specificity, particularly in populations with a high prevalence of diseases caused by other flaviviruses, especially DENV.
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).