Description/Background
Zika virus is a flavivirus, closely related to dengue. It is transmitted to humans primarily through the bite of certain infected Aedes species mosquitoes.

Zika virus is a mosquito-borne illness discovered in Uganda in 1947 but has since spread across Asia and to the Americas. Outbreaks of Zika virus have specifically been reported in tropical Africa, Southeast Asia and the Pacific Islands. Zika infection has been tied to several birth defects. 

In 1952, the first human cases of Zika were detected, and, since then, outbreaks of Zika have been reported in tropical Africa, Southeast Asia and the Pacific Islands. Zika outbreaks have probably occurred in many locations. Before 2007, at least 14 cases of Zika had been documented, although other cases were likely to have occurred and were not reported. Because the symptoms of Zika are similar to those of many other diseases, 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 Feb. 1, 2016, the World Health Organization (WHO) declared Zika virus a Public Health Emergency of International Concern (PHEIC). Local transmission has been reported in many other countries and territories. Zika virus will likely continue to spread to new areas. 

Aedes aegypti mosquitoes are commonly found in tropical and sub-tropical regions around the world, including north Queensland and some areas in central Queensland. Another similar mosquito, Aedes albopictus, also has the potential to transmit Zika virus, but in Australia is only found in the Torres Strait. These mosquito vectors typically breed in domestic water-holding containers; they are daytime biters and feed both indoors and outdoors near dwellings. Other methods of transmission are through sexual contact and blood transfusion.

The most common symptoms of Zika are fever, rash, joint pain and conjunctivitis (red eyes). The illness is usually mild, with symptoms lasting for several days to a week after being bitten by an infected mosquito. People usually don’t get sick enough to go to the hospital, and they very rarely die of Zika. For this reason, many people might not realize they have been infected. However, Zika virus infection during pregnancy can cause a serious birth defect called microcephaly, as well as other severe fetal brain defects. Once a person has been infected, he or she is likely to be protected from future infections (CDC). The ongoing issues related to the prevention, diagnosis and treatment of the Zika virus are still emerging. The president’s recent budget includes a $1.8 billion request from Congress to respond to the Zika virus (White House 2016). 

Recent outbreaks of Zika in pregnant women have been found to be linked to very serious health conditions such as microcephaly (a birth defect resulting in tiny heads) and Guillain-Barre Syndrome  (an immune-mediated neurologic condition). The virus has been declared a pandemic, which, according to the World Health Organization, refers to the worldwide spread of a disease (WHO 2016). There is no vaccine and no treatment for Zika; there is only an antibody test to find out if you have it, which is far from perfect.

Zika Testing Guidelines:

1. CDC

What should providers consider when ordering a test for Zika virus infection?
Each clinical scenario is unique, and health care providers should consider all available information when ordering a test for Zika virus infection, including patient travel history, history of flavivirus infection, vaccination history, ultrasound findings and the presence of symptoms. They should work with their state, local and territorial health departments for assistance interpreting test results.

Diagnosis of Zika Virus

• During the first week after onset of symptoms, Zika virus disease can often be diagnosed by performing reverse transcriptase-polymerase chain reaction (RT-PCR) on serum.
• Virus-specific IgM and neutralizing antibodies typically develop toward the end of the first week of illness.
• Cross-reaction with related flaviviruses (e.g., dengue and yellow fever viruses) is common and may be difficult to discern.
• Plaque-reduction neutralization testing can be performed to measure virus-specific neutralizing antibodies and discriminate between cross-reacting antibodies in primary flavivirus infections.

Zika MAC-ELISA (CDC)

• The Zika MAC-ELISA is a laboratory test to detect proteins the human body makes to fight a Zika virus infection.  These proteins, called antibodies, appear in the blood starting 4-5 days after the start of illness and last for up to 12 weeks.  In some people, they are present for longer than 12 weeks. 
• The CDC Zika MAC-ELISA test has been authorized under the EUA for use by qualified laboratories in the U.S. designated by the CDC that are certified to perform high-complexity tests.  
• Because of the possibility of false positive results in patients who were previously infected with viruses similar to the Zika virus (i.e., flaviviruses, such as dengue), under the terms of the EUA, positive and inconclusive results must be further tested by the CDC or by authorized laboratories in consultation with the CDC to confirm the presence of antibodies to Zika virus. 

Trioplex rRT-PCR (CDC)

• The CDC Trioplex rRT-PCR test has been authorized under the EUA for use by qualified laboratories in the U.S. designated by the CDC that are certified to perform high-complexity tests.  
• The assay (test) is intended for use with specimens collected from individuals meeting CDC Zika virus clinical criteria (e.g., clinical signs and symptoms associated with Zika virus infection) and/or CDC Zika virus epidemiological criteria (e.g., history of residence in or travel to a geographic region with active Zika transmission at the time of travel, or other epidemiologic criteria for which Zika virus testing may be indicated as part of a public health investigation). 

Testing for Zika virus in pregnant women (CDC Recommends)

1. During the first week of illness, Zika virus disease can often be diagnosed by performing reverse transcriptase-polymerase chain reaction (RT-PCR) on serum.
2. Serology assays can also be used to detect Zika virus-specific IgM and neutralizing antibodies, which typically develop toward the end of the first week of illness.
3. Plaque-reduction neutralization testing (PRNT) can be performed to measure virus-specific neutralizing antibodies to confirm primary flavivirus infections and differentiate from other viral illnesses. 

How is maternal Zika virus infection diagnosed?

1. Laboratory evidence of maternal Zika virus infection can include Zika virus RNA detected by RT-PCR in any clinical specimen; or
2. Positive Zika virus IgM with confirmatory neutralizing antibody titers that are ≥ 4-fold higher than dengue virus neutralizing antibody titers in serum by PRNT.
3. Testing would be considered inconclusive if Zika virus neutralizing antibody titers are < 4-fold higher than dengue virus neutralizing antibody titers. 

Limitations 

• RT-PCR test may not demonstrate Zika virus RNA in a woman with Zika virus infection if the period of viremia has passed.
• Serum serologic testing can be performed; however, cross-reactivity with related flaviviruses (e.g., dengue and yellow fever viruses) is common.
• Plaque-reduction neutralization testing (PRNT) can be performed to measure virus-specific neutralizing antibodies to Zika virus, but neutralizing antibodies may still yield cross-reactive results in persons who were previously infected with another flavivirus, such as dengue, or have been vaccinated against yellow fever or Japanese encephalitis.
• A positive IgM result can be difficult to interpret, since cross-reactivity can occur with related flaviviruses (e.g., dengue, Japanese encephalitis, West Nile, yellow fever).
• A positive Zika virus IgM result may reflect: previous vaccination against a flavivirus (e.g., yellow fever); previous infection with a related flavivirus; or current infection with a flavivirus, including Zika virus.
• During the first 7 days of symptom onset, viral RNA can often be identified in serum, and RT-PCR is the preferred test. 
• However, viremia decreases over time, and a negative RT-PCR on serum collected 5-7 days after symptom onset does not preclude Zika virus infection. Serologic testing should be performed.

Guidelines from Dept. of Health, Australia:
Testing for Zika virus infection may include IgM, IgG and PCR (positive only in early infection) of blood and urine. 

• Acute serum (taken soon after exposure or symptom appearance) and convalescent serum (2 weeks later) should be taken wherever possible. The two samples are important to rule out false positive tests due to cross reactivity with similar viruses such as dengue. 

Overseas travel history and clinical history, including the onset day of any symptoms. Onset date is extremely important to ensure that the most appropriate test is performed. Details of any previous flavivirus vaccine (e.g., Japanese encephalitis, yellow fever) or previous flavivirus illness (e.g., West Nile virus, dengue) can be useful for the pathologist in test interpretation.

Detection in Urine
Kinetics of Zika virus (ZIKV) detection in serum and urine samples were studied by Ann-Claire Gourinat et al.² Urine samples were positive for ZIKV >10 days after onset of disease, which was a notably longer period than for serum samples. This finding supports the conclusion that urine samples are useful for diagnosis of ZIKV infections.

Detection of Zika virus in saliva
The use of saliva sample increased the rate of molecular detection of ZIKV at the acute phase of the disease but did not enlarge the window of detection of ZIKV RNA. Saliva was of particular interest when blood was difficult to collect (children and neonates especially).³ 

ACOG Guideline 

• Antibody testing for Zika virus is now recommended for all pregnant women who have traveled to an affected area, regardless of the presence of clinical illness.
• Antibody testing for Zika virus is now recommended for all pregnant women living in an affected area, regardless of the presence of clinical illness 
• Health care providers should discuss reproductive life plans, including pregnancy intention and timing, with women of reproductive age in the context of the potential risks associated with Zika virus infection. 
• Women of reproductive age with current or previous laboratory-confirmed Zika virus infection should be counseled that there currently is no evidence that prior Zika virus infection poses a risk of birth defects in future pregnancies. 

This includes fetal remains and placental tissue, which can be examined using Zika virus RT-PCR, histopathologic examination and immune-histochemical staining. This testing is recommended to advance the understanding of Zika infection in pregnancy and provide insight to patient counseling in the setting of fetal loss. 

Regulatory Status 
There are no commercially available diagnostic tests cleared by FDA for the detection of Zika virus. FDA encourages commercial diagnostic developers and researchers developing laboratory developed tests for Zika virus to submit an EUA request. FDA will work interactively with developers to support such requests (FDA).

Policy

1. Zika virus urine and serum RNA NAT testing and Zika virus serum IgM testing is considered MEDICALLY NECESSARY for symptomatic individuals  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.
2. Zika virus urine, serum, and CSF RNA NAT testing and IgM testing in infants is considered MEDICALLY NECESSARY in the following situations:
   1. infants with clinical findings consistent with congenital Zika syndrome and possible maternal Zika virus exposure during pregnancy, regardless of maternal testing results
   2. infants without clinical findings consistent with congenital Zika syndrome born to mothers with laboratory evidence of possible Zika virus infection during pregnancy
3. 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.
4. Zika virus serum and urine RNA NAT testing in asymptomatic pregnant women with ongoing possible Zika virus exposure is considered MEDICAL NECESSARY three times during pregnancy. 
5. Zika virus serum IgM testing is considered NOT MEDICALLY NECESSARY in asymptomatic pregnant women with ongoing possible Zika virus exposure.
6. Zika virus Plaque Reduction Neutralization Test (PRNT) testing is considered MEDICALLY NECESSARY in symptomatic pregnant individuals and asymptomatic pregnant individuals without ongoing exposure.
7. 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.
8. 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

References 

1. Ann-Claire Gourinat,¹ Olivia O’Connor,¹ Elodie Calvez, Cyrille Goarant, and Myrielle Dupont-Rouzeyrol^; Detection of Zika Virus in Urine; Emerg Infect Dis. 2015 Jan; 21(1): 84–86. (NIH cdc publication)
2. CDC; Zika  virus http://www.cdc.gov/zika/
3. FDA, FDA support for Zika virus diagnostic development and Emergency Use Authorization(EUA);
4. Guilherme Calvet, PhD^*, Renato S Aguiar, PhD^, Adriana S O Melo, PhD,  Simone A Sampaio, BSc, Ivano de Filippis, PhD, Allison Fabri, BSc, Eliane S M Araujo, BSc, Patricia C de Sequeira, PhD, Marcos C L de Mendonça, PhD, Louisi de Oliveira, PhD, Diogo A Tschoeke, PhD, Carlos G Schrago, PhD, Fabiano L Thompson, PhD, Patricia Brasil, PhD, Flavia B dos Santos, PhD, Rita M R Nogueira, PhD, Prof Amilcar Tanuri, PhD^†, Dr Ana M B de Filippis, P;  Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study; Lancet Infectious disease Feb 17, 2016
5. Ioos S, Mallet HP, Leparc Goffart I, Gauthier V, Cardoso T, Herida M.Med Mal Infect. 2014 Jul; 44(7):302-7. Epub 2014 Jul 4
6. White House; FACT SHEET: Preparing for and Responding to the Zika Virus at Home and Abroad; February, 2016.  
7. World Health Organization (WHO); Emergency Preparedness Response, February 2016;  

Coding Section 

Code	Number	Description
CPT	86794 (effective 1/1/2018)	Antibody; Zika virus, IgM
	87662 (effective 1/1/2018)	Qualitative or Semi-quantitative Immunoassays
ICD-10-CM	A92.5	Zika virus disease (effective 10/01/2016)
	A92.8	Other specified mosquito-borne viral fevers
	O98	Maternal infectious and parasitic diseases classifiable elsewhere but complicating pregnancy, childbirth and the puerperium
	O98.52	Other viral diseases complicating pregnancy # = 6th character for trimester (1, 2, 3, 9-unspecified), childbirth and the puerperium
	D69.6	Thrombocytopenia, unspecified
	G04.00-G04.02	Encephalitis, myelitis and encephalomyelitis
	G04.2	Bacterial meningoencephalitis and meningomyelitis, not elsewhere classified
	G04.81-G04.89	Other encephalitis, myelitis and encephalomyelitis
	G04.90-G04.91	Encephalitis, myelitis and encephalomyelitis, unspecified
	G37.3	Acute transverse myelitis in demyelinating disease of central nervous system, Acute transverse myelitis NOS
	G61.0	Guillain-Barre Syndrome
	G61.81	Chronic inflammatory demyelinating polyneuritis, Other inflammatory polyneuropathies
	ALL H10 CODES	Conjunctivitis Other specified disorders of eye and adnexa
	H57.10	Ocular pain, unspecified eye
	H57.11	Ocular pain, right eye
	H57.12	Ocular pain, left eye
	H57.13	Ocular pain, bilateral
	I51.4	Myocarditis, unspecified
	I30.8	Other forms of acute pericarditis
	I30.9	Acute pericarditis, unspecified
	I67.82	Cerebral ischemia
	M25.50-M25.579 codes	Pain in joint
	M79.1	Myalgia
	O28.3	Abnormal ultrasonic finding on antenatal screening of mother
	O35.3XX1-O35.3XX9	Maternal care for (suspected) damage to fetus from viral disease in mother
	O35.8XX0	Maternal care for other (suspected) fetal abnormality and damage, not applicable or unspecified
	R20.8	Other disturbances of skin sensation(Dysesthesia)
	R21	Rash and other nonspecific skin eruption
	R50.9	Fever, unspecified
	R53.1	Weakness, Asthenia NOS
	R90.89	Other abnormal findings on diagnostic imaging of central nervous system, (Neurologic and positional abnormalities)
	Z11.59	Encounter for screening for other viral disases
	Z20.828	Contact with and (suspected) exposure to other viral communicable diseases

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology^© American Medical Association.  All Rights Reserved" 

History From 2016 Forward     

07/12/2019	Interim review to add coverage related to the CDC recommendation for testing of infants.
01/02/2019	Interim review, updating verbiage in policy criteria number one for clarity.
07/26/2018	Annual review, updating policy verbiage with current CDC testing recommendations. Also updating coding.
12/7/2017	Updating policy with 2018 coding. No other changes.
07/18/2017	Annual review, rewriting policy criteria for expanded coverage in alignment with the CDC. No other changes made.
04/25/2017	Updated category to Laboratory. No other changes.
03/08/2017	Updated coding.
08/30/2016	Updated coding.
08/23/2016	Editing to correct error in coding section. No other changes made.
08/03/2016	New Policy