Description of Procedure or Service

1. Description
   Zika virus is a flavivirus, closely related to dengue. It is transmitted to humans primarily through the bite of certain infected Aedes species mosquitoes, and less frequently, via sexual intercourse, blood transfusion, laboratory. There is no vaccine or specific medicine for Zika virus (CDC, 2016).
2. Literature Review
   Zika virus is a mosquito-borne illness discovered in Uganda in 1947 but has since spread across Asia and to the Americas. Zika infection has been tied to several birth defects. The first human cases of Zika were detected in 1952. Prior to 2007, at least 14 cases of Zika had been documented. Symptoms of Zika are similar to those of many other diseases, therefore many cases may not have been recognized. In May 2015, the Pan American Health Organization (PAHO) issued an alert regarding the first confirmed Zika virus infection in Brazil. On February 1, 2016, the World Health Organization (WHO) declared Zika virus a Public Health Emergency of International Concern (PHEIC). The most common symptoms of Zika are fever, rash, joint pain, and conjunctivitis (CDC, 2016). The illness is usually mild with symptoms lasting for several days to a week after being bitten by an infected mosquito. Most individuals infected with Zika virus are unaware of the infection, as only 1 in 5 people infected will exhibit symptoms. Symptoms are typically mild and self-resolving, and begin 2-7 days after being bitten by an infected mosquito (Jamieson, 2016).
   
   Zika virus infection during pregnancy can cause serious birth defects, as the virus can be passed to the developing fetus. Zika can cause microcephaly as well as other severe fetal brain defects (CDC)
3. Applicable Federal Regulations
   On October 5, 2017 the FDA approved the cobas Zika for use to screen donor samples for Zika virus RNA in plasma samples from individual human donors, including donors of whole blood and blood components, and other living donors. This test is also intended for use to screen organ and tissue donors when donor samples are obtained while the donor’s heart is still beating.

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for ZIKA Virus risk assessment when it is determined to be medically necessary because the medical criteria and guidelines noted below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When ZIKA Virus risk assessment is covered

In alignment with CDC guidelines, Avalon will approve tests with blood and urine samples only.

Zika virus urine and serum RNA NAT testing and Zika virus serum IgM testing is considered medically necessary for symptomatic individuals and all pregnant women, with or without symptoms, with possible Zika virus exposure such as living in, traveling to, or having intimate contact with someone who lives in or traveled to an area with risk of Zika.

Zika virus serum and urine RNA NAT testing in asymptomatic pregnant women with ongoing possible Zika virus exposure is considered medically necessary three times during pregnancy.

Zika virus Plaque Reduction Neutralization Test (PRNT) testing is considered medically necessary in symptomatic pregnant individuals and asymptomatic pregnant individuals without ongoing exposure.

Zika virus RNA NAT testing of amniocentesis, placental and fetal tissues is considered medically necessary in pregnant women with possible exposure to Zika virus and who have a fetus with prenatal ultrasound findings consistent with congenital Zika virus infection and undergoing amniocentesis.

When ZIKA Virus risk assessment is not covered

Zika virus urine and serum RNA NAT testing and Zika virus serum IgM testing is considered not medically necessary for asymptomatic individuals, asymptomatic non-pregnant individual and for preconception screening.

Zika virus urine and serum RNA NAT testing is considered not medically necessary in all symptomatic non-pregnant individuals presenting with > 14 days after symptoms onset.

Zika virus serum IgM testing is considered not medically necessary in asymptomatic pregnant women with ongoing possible Zika virus exposure.

All other tests for diagnosing Zika virus not mentioned above in all other situations and testing of samples other than serum, urine, amniocentesis, placental and fetal tissues at this time are considered investigational.

Policy Guidelines

Guidelines and Recommendations

Centers for Disease Control and Prevention (CDC)

The CDC states that Zika testing is recommended only for certain people as follows (CDC, 2016) (CDC, 2017):

CDC Testing Guidance for Zika Virus recommends testing anyone with possible Zika virus exposure which includes living in, traveling to, or having unprotected sex with someone who lives in or traveled to an area with risk of Zika. In addition, CDC recommends testing symptomatic pregnant women with possible Zika virus exposure, asymptomatic pregnant women with ongoing possible Zika virus exposure and pregnant women with possible Zika virus exposure who have a fetus with prenatal ultrasound findings consistent with congenital Zika virus infection. The asymptomatic pregnant women with recent possible but not ongoing exposure to Zika virus population is classified as a consider for testing category. CDC does not recommend Zika virus testing for non-pregnant asymptomatic individuals and for preconception screening.

Zika Virus Laboratory Testing

The definitive laboratory diagnosis of Zika virus requires multiple assays and sample types. There are several types of Zika Virus tests available such as RNA NAT (nucleic acid testing), Trioplex Real-time RT-PCR Assay, Serologic test for Zika Virus, Zika MAC-ELISA and Plaque Reduction Neutralization Test (PRNT). They all have their limitations and are recommended or not recommended to use depending on population tested.

Laboratory testing for Zika virus has a number of limitations. Zika virus RNA is only transiently present in body fluids; thus, negative nucleic acid testing (NAT) does not rule out infection.

Serologic testing is affected by timing of sample collection: a negative immunoglobulin M (IgM) serologic test result does not rule out infection because the serum specimen might have been collected before the development of IgM antibodies, or after these antibodies have waned. Conversely, IgM antibodies might be detectable for months after the initial infection; for pregnant women, this can make it difficult to determine if infection occurred before or during a current pregnancy. In addition, cross-reactivity of the Zika virus IgM antibody tests with other flaviviruses can result in a false-positive test result, especially in persons previously infected with or vaccinated against a related flavivirus, further complicating interpretation. Limitations of Zika virus IgM antibody assays that were approved under an Emergency Use Authorization have been recognized; both false-positive and false-negative test results have occurred.

Updated Guidance for Testing of Symptomatic Pregnant Women with Possible Zika virus Exposure

Given the decreasing prevalence of Zika virus infection cases in the Americas and emerging data regarding Zika virus laboratory testing, on July 24, 2017, CDC published updated guidance for testing of pregnant women with possible Zika virus exposure (2). Zika virus NAT testing should be offered as part of routine obstetric care to asymptomatic pregnant women with ongoing possible Zika virus exposure (residing in or frequently traveling to an area with risk for Zika virus transmission); serologic testing is no longer routinely recommended because of the limitations of IgM tests, specifically the potential persistence of IgM antibodies from an infection before conception and the potential for false-positive results. Zika virus testing is not routinely recommended for asymptomatic pregnant women who have possible recent, but not ongoing, Zika virus exposure; however, guidance might vary among jurisdictions (2).

Updated Recommendations for Diagnosis, Clinical Evaluation, and Management of Infants with Clinical Findings Consistent with Congenital Zika Syndrome Born to Mothers with Possible Zika

Virus Exposure in Pregnancy

Zika virus testing is recommended for infants with clinical findings consistent with congenital Zika syndrome and possible maternal Zika virus exposure during pregnancy, regardless of maternal testing results. Testing CSF for Zika virus RNA and Zika virus IgM antibodies should be considered, especially if serum and urine testing are negative and another etiology has not been identified.

Updated Recommendations for Diagnosis, Clinical Evaluation, and Management of Infants without Clinical Findings Consistent with Congenital Zika Syndrome Born to Mothers with Laboratory Evidence of Possible Zika Virus Infection During Pregnancy Laboratory testing. Zika virus testing is recommended for infants without clinical findings consistent with congenital Zika syndrome born to mothers with laboratory evidence of possible Zika virus infection during pregnancy

Updated Recommendations for Diagnosis, Clinical Evaluation, and Management of Infants without Clinical Findings Consistent with Congenital Zika Syndrome Born to Mothers with Possible Zika Virus Exposure in Pregnancy but without Laboratory Evidence of Possible Zika

Virus Infection During Pregnancy

This heterogeneous group includes mothers who were never tested during pregnancy as well as those whose test result could have been negative because of issues related to timing or sensitivity and specificity of the test. Because the latter issues are not easily discerned, all mothers with possible exposure to Zika virus during pregnancy who do not have laboratory evidence of possible Zika virus infection, including those who tested negative with currently available technology, should be considered in this group.

Laboratory testing. Laboratory testing for congenital Zika virus infection is not routinely recommended for infants born to mothers in this category based on the unknown risk for infection; the lower likelihood of congenital Zika virus infection as a result of the declining prevalence of Zika virus infection; and limitations of infant laboratory testing. If abnormal findings are identified, these infants should receive further evaluation, including evaluation and testing for congenital Zika virus infection.

CDC Guidelines for Diagnostic Tests for Zika Virus include (CDC, 2016):

• Molecular Test for Zika Virus – RNA NAT (nucleic acid testing) for symptomatic individuals within the first two weeks after symptom onset and for asymptomatic pregnant women who have traveled to areas with active Zika virus transmission. RNA NAT testing is also indicated for pregnant women who present for care ≥ 2 weeks after exposure and have been found to be IgM positive. A positive RNA NAT result confirms Zika virus infection and no additional testing is indicated, but a negative RNA NAT result does not exclude Zika virus infection and should be followed up with IgM antibody (serological) testing.
• Trioplex Real-time RT-PCR Assay The Trioplex rRT-PCR is a laboratory test designed to detect Zika virus, dengue virus, and chikungunya virus RNA. The Food and Drug Administration (FDA) has not cleared or approved this test. However, FDA has authorized the use of this test under an Emergency Use Authorization (EUA). Serologic Test for Zika Virus Zika virus-specific IgM and neutralizing antibodies typically develop toward the end of the first week of illness. IgM levels are variable, but generally are positive starting near day four post onset of symptoms and continuing for 12 weeks Therefore, if RNA NAT is negative on serum and urine, serum IgM antibody testing for Zika, dengue, and chikungunya virus infections should be performed. In addition, serum samples collected >=14 days after symptom onset, with no earlier samples collected, should be tested for anti-Zika virus, anti-dengue virus, and anti-chikungunya virus IgM antibodies.
• Zika MAC-ELISA The Zika IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA) is used for the qualitative detection of Zika virus IgM antibodies in serum or cerebrospinal fluid; however, due to cross-reaction with other flaviviruses and possible nonspecific reactivity, results may be difficult to interpret.
• Plaque Reduction Neutralization Test (PRNT) – Samples with presumptive positive, equivocal or inconclusive IgM antibody test result should be confirmed by PRNT, which measures virus-specific neutralizing antibodies to Zika virus and other endemic flaviviruses. PRNT must be conducted by CDC or a laboratory qualified by CDC.

The American College of Obstetricians and Gynecologists (ACOG) and Society of Maternal Fetal Medicine (SMFM)

In April 2017, ACOG and SMFM updated the practice advisory on Zika Virus. It recommends that Zika Virus testing should be done in the following situations:

• Non-pregnant women and all men with Zika virus exposure and symptoms consistent with Zika virus.
• Non-pregnant women and all men with Zika virus exposure but without symptoms consistent with Zika virus exposure.
• Pregnant women with Zika virus exposure should be tested regardless of symptom status.

ACOG and SMFM state that all pregnant women should be assessed for possible Zika virus exposure at each prenatal care visit. The practice advisory noted that “routine Zika virus testing is not currently recommended for women or men with possible Zika virus exposure without clinical illness who are attempting pregnancy”. It further stated that “testing of specimens to assess risk for sexual transmission is currently not recommended.”  

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable Diagnosis Codes - Refer to the ICD-10-CM Manual

Procedure codes appearing in policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included. 

Scientific Background and Reference Sources

American Congress of Obstetricians and Gynecologists. Practice Advisory on Zika Virus. 2016. Retrieved January 24, 2017, from http://www.acog.org/About-ACOG/News-Room/PracticeAdvisories/Practice-Advisory-Interim-Guidance-for-Care-of-Obstetric-Patients-During-a-ZikaVirus-Outbreak

Basu, R. & Tumban, E. Zika Virus on a Spreading Spree: what we now know that was unknown in the 1950’s. 2016. Retrieved January 24, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053350/

CDC. (2017). Update: Interim Guidance for the Diagnosis, Evaluation, and Management of Infants with Possible Congenital Zika Virus Infection — United States, October 2017 | MMWR. @cdcmmwr Retrieved from https://www.cdc.gov/mmwr/volumes/66/wr/mm6641a1.htm.

Centers for Disease Control and Prevention. About Zika. 2016. Retrieved January 24, 2017, from https://www.cdc.gov/zika/about/overview.html

Centers for Disease Control and Prevention. Only some people need Zika testing. 2016. Retrieved January 24, 2017, from https://www.cdc.gov/zika/pdfs/tested_for_zika_flyer.pdf

Centers for Disease Control and Prevention. Diagnostic Tests for Zika Virus. Retrieved on April 25, 2017, from https://www.cdc.gov/zika/hc-providers/types-of-tests.html

Jamieson, D. 10 Questions About Zika: The CDC Answers. 2016. Retrieved January 24, 2017, from http://www.medscape.com/viewarticle/859014

United States Food and Drug Administration. Zika virus response updates from FDA. Retrieved from http://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMIss ues/ucm485199.htm

World Health Organization. WHO statement on the first meeting of the International Health Regulations (2005) (IHR 2005) Emergency Committee on Zika virus and observed increase in neurological disorders and neonatal malformations. 2016. Retrieved from http://www.who.int/mediacentre/news/statements/2016/1st-emergency-committee-zika/en/

Policy Implementation/Update Information

1/1/19 New policy developed. BCBSNC will provide coverage for ZIKA virus risk assessment when it is determined to be medically necessary because the medical criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (sk)