Zika virus infection - Diagnosis Approach

Diagnosis of Zika virus infection is based on clinical suspicion along with molecular and serologic testing. Although the majority of infected people are asymptomatic, physicians should have a high index of suspicion for patients who present with fever, a maculopapular (sometimes morbilliform) rash, arthralgia/myalgia, and conjunctivitis in the correct epidemiologic context (i.e., residence in/travel from an area where there is a current outbreak or the potential for transmission).

All pregnant women in the US and US territories should be asked about possible Zika virus exposure before and during the current pregnancy, at every prenatal care visit.[148]

The clinical spectrum of disease overlaps with that caused by other arbovirus infections. As a consequence, the differential diagnosis is broad and includes dengue and chikungunya infection. It is important to differentiate between Zika, dengue, and chikungunya virus infection as the three diseases can produce similar symptoms, particularly during the acute phase. The World Health Organization (WHO) has produced a tool to help physicians differentiate between these three diseases.[149] Molecular or serologic testing is required to confirm the diagnosis.

Congenital Zika syndrome is a recognized pattern of congenital anomalies in infants (i.e., microcephaly, intracranial calcifications or other brain anomalies, or eye anomalies, among others) associated with Zika virus infection during pregnancy.[2][3][4][5][6] According to the WHO, there is strong scientific consensus that Zika virus is a cause of microcephaly and these other congenital abnormalities.[7] The Centers for Disease Control and Prevention (CDC) has also concluded that there is a causal relationship between prenatal Zika virus infections and microcephaly/other brain abnormalities.[8]

Guillain-Barre syndrome and other neurologic disorders are strongly associated with and suspected to be caused by Zika virus infection but the link is unproven and studies are ongoing, including to elucidate a possible mechanism.[9][10][11][12]

Infection prevention and control

Standard precautions (e.g., hand hygiene, use of personal protective equipment, respiratory hygiene and cough etiquette, safe injection practices, safe handling of potentially contaminated equipment or surfaces) are recommended for the protection of healthcare professionals and patients in healthcare settings and labor and delivery settings. These precautions are recommended regardless of whether the infection is suspected or confirmed.[147]

Transmission

Diagnosis should be suspected in patients who have resided in/traveled from an area where there is a current outbreak (or where the Aedes mosquito is present) in the 2 weeks prior to symptom onset. Nonvector transmission events (e.g., perinatal,[56] in utero,[57][58] sexual,[56][59] and transfusion transmission[60][61][62][64]) have also been reported.[63] Sperm donation is a theoretical concern; however, there have been no reports as yet.

Clinical presentation

The incubation period after transmission is between 3 and 14 days.[98] Approximately 80% of patients do not develop symptoms.[13] In those who do, characteristic clinical findings include fever, an itchy maculopapular (sometimes morbilliform) rash, arthralgia, and nonpurulent conjunctivitis. The characteristic rash is one of the most distinctive symptoms.[13] com.bmj.content.model.Caption@65c012c0 [Figure caption and citation for the preceding image starts]: Characteristic maculopapular rash in a pregnant woman with Zika virus infectionFrom the personal collection of Dr Geraldo Furtado, MD, MSc (used with permission) [Citation ends].

Other commonly reported symptoms include myalgia, malaise, and headache.[13][136] Less common symptoms include vomiting/diarrhea, abdominal pain, anorexia, edema of the lower limbs, and retro-orbital pain.[13] No differences in clinical presentation have been described between pregnant women and nonpregnant patients, or between adults and children. Most children have a rash, and more than half have a fever and rash.[150] Symptoms generally develop within 1 week of infection in 50% of patients, and within 2 weeks of infection in 99% of patients.[98]

Clinical illness is usually self-limited with mild symptoms lasting 2 to 7 days.[13][151] Severe disease requiring hospitalization is uncommon and the case fatality is low.[13]

Neurologic exam should be performed on all patients with suspected Guillain-Barre syndrome (GBS). Key diagnostic factors include paresthesias (usually of the hands and feet), muscle weakness, pain (usually starts in the back and legs), and paralysis. Oropharyngeal, facial, and extraocular weakness may also occur. The WHO recommends using the Brighton criteria for the case definition of GBS.[152] The Pan American Health Organization has also published a case definition for Zika-related GBS.[153] Physicians should be vigilant for early signs and symptoms of GBS as it may progress faster than usual in patients with Zika virus infection.[24] Neurologic consultation is recommended in patients with suspected GBS.[154] An association between Zika infection and transient hearing loss has been reported in a small number of cases.[155]

Congenital Zika syndrome is a recognized pattern of congenital anomalies (i.e., microcephaly, intracranial calcifications or other brain anomalies, or eye anomalies, among others) in infants associated with Zika virus infection during pregnancy.[2][3][4][5][6] Infants may present with microcephaly or other manifestations including spasticity, seizures, craniofacial disproportion, brainstem dysfunction, ocular abnormalities, hearing loss, findings on neuroimaging (e.g., cortical disorders, calcifications, ventriculomegaly), arthrogryposis (e.g., congenital joint contractures), irritability, dysphagia,[156] and feeding difficulties. Other presentations include ocular abnormalities in infants without microcephaly or other brain abnormalities, postpartum-onset microcephaly in infants born with a normal head circumference, postpartum-onset hydrocephalus in infants born with microcephaly, sleep electroencephalogram (EEG) abnormalities, and diaphragmatic paralysis in infants born with microcephaly and arthrogryposis.[2] Features consistent with fetal immobility (e.g., dimples, feet malpositions, distal hand/finger contractures) may also be present.[157] There have been reports of these abnormalities in infants who have a normal head circumference and with mothers who do not report having a rash during pregnancy.[3][158][159][160][161] The syndrome does not appear to be associated with maternal disease severity.[162] Signs of congenital brain injury due to Zika virus infection acquired during the third trimester of pregnancy have been reported.[163] Poor head growth with microcephaly developing after birth has been reported in a small number of patients in Brazil.[164] Eye abnormalities may be the only initial finding; therefore, it is recommended that all infants with potential Zika virus exposure should undergo an eye exam regardless of the presence or absence of other symptoms.[165] Other infectious causes of microcephaly should be ruled out.[166]

Case definitions

Case definitions have been published by WHO, CDC, and PAHO:

Case definitions vary and their sensitivity has been questioned, particularly in areas where other arboviruses, such as chikungunya and dengue, circulate. One study found that the symptoms most strongly associated with Zika virus infection included rash, pruritus, conjunctival hyperemia, absence of fever (axillary temperature <99.5°F [<37.5°C]), no petechiae, and no anorexia.[167]

Investigations

Diagnosis can be confirmed with molecular or serologic testing, which includes reverse transcriptase-polymerase chain reaction (RT-PCR) for viral RNA, and IgM ELISA plus plaque-reduction neutralization testing (PRNT) for Zika virus antibodies. PRNT can be performed to measure virus-specific neutralizing antibodies and discriminate between cross-reacting antibodies in primary flavivirus infections (e.g., dengue and yellow fever viruses, yellow fever vaccine recipients);[168] however, there are currently few laboratories that perform this test. In the US, the Food and Drug Administration (FDA) has issued Emergency Use Authorizations for various RT-PCR and ELISA assays. FDA: emergency use authorizations external link opens in a new window Testing is done at the CDC Arbovirus Diagnostic Laboratory or some local/state health departments. Availability of commercial tests depends on location.

Prenatal ultrasound and amniocentesis may be recommended in some pregnant women. Head circumference measurement, CT/MRI of the head, cranial ultrasound, hearing screen, ophthalmologic screen, and neurologic exam may be recommended in infants with suspected congenital Zika syndrome.

Nerve conduction studies/electromyography and cerebrospinal fluid (CSF) exam should be performed in patients with suspected GBS if available; however, these investigations are not needed to make a clinical diagnosis and should not delay treatment.[152] Interpretation of these studies and definitive diagnosis requires consultation with a neurologist.

CDC: instructions for submitting diagnostic specimens to the DVBD Arbovirus Diagnostic Laboratory external link opens in a new window

Limitations of testing

The duration of typical IgM detectability is about 12 weeks.[169] However, data suggest that Zika virus IgM can persist beyond 12 weeks in some people; therefore, a positive IgM result may not always indicate recent infection. Therefore, IgM test results cannot always reliably distinguish between infection that occurred before or during the current pregnancy, particularly in women with possible Zika exposure before the current pregnancy. Additionally, as the prevalence of Zika virus disease declines, the likelihood of false-positive test results increases.[148] Before testing, limitations should be discussed with the patient.

Sensitivity and negative predictive value for all Zika investigations has not been fully established, especially for asymptomatic people. Consequently, transmission prevention precautions remain important even when a test is negative. Additionally, it is important to exclude differential diagnoses that may resemble Zika virus infection, dengue fever, and chikungunya. Other conditions such as malaria or leptospirosis may require specific and urgent treatment.

The testing recommendations in this topic are based on CDC guidance. Testing recommendations may differ between guidelines and locations, with WHO and PAHO offering different recommendations:

Testing in nonpregnant individuals

Testing is recommended in all symptomatic patients with possible exposure (including patients who have had sex with someone who lives in, or has recently traveled to, an area with Zika transmission). The CDC recommends RT-PCR on serum for specimens collected <7 days after symptom onset. Other acceptable specimen types include plasma, whole blood, CSF, or urine. If RT-PCR is positive, infection is confirmed. If RT-PCR is negative, or the specimen is collected ≥14 days after symptom onset, serologic testing is recommended. If serologic testing is negative, infection can be ruled out and no further testing is required. If positive (or equivocal), PRNT is recommended to confirm diagnosis (except in Puerto Rico). A PRNT <10 rules out infection. Dengue and chikungunya testing (RT-PCR or serology) should also be performed in patients at risk of exposure with clinically compatible illness. Testing is not recommended in asymptomatic nonpregnant people.[170]

Testing in pregnant women

All pregnant women should be asked about possible Zika virus exposure before and during the current pregnancy, at every prenatal care visit. The CDC recommendations for testing symptomatic and asymptomatic pregnant women are detailed below.[148]

Symptomatic pregnant women

Testing is recommended in all symptomatic pregnant women with possible Zika virus exposure (i.e., travel to, or residence in, an area with risk for mosquito-borne Zika virus transmission, or sex with a partner who has traveled to or resides in an area with risk for mosquito-borne Zika virus transmission).
Concurrent RT-PCR (paired serum and urine specimens) and serologic testing (serum) is recommended in pregnant women as soon as possible up to 12 weeks after symptom onset. If RT-PCR is positive, infection is confirmed, although further testing may be required if the IgM result is negative. If RT-PCR and serology are both negative, diagnosis is excluded. If RT-PCR is negative and serology is either positive or equivocal, PRNT is recommended. A PRNT <10 rules out diagnosis.
Serologic testing may be considered >12 weeks after symptom onset; however, a negative result does not rule out infection during pregnancy as IgM levels decrease over time. A positive result should be interpreted in the context of the known limitations of serologic testing.
Dengue virus IgM antibody testing is also recommended in symptomatic pregnant women.

Asymptomatic pregnant women

Asymptomatic pregnant women with ongoing possible exposure: RT-PCR (serum and urine) is recommended 3 times during pregnancy (e.g., at the initial prenatal care visit, and then at 2 nonconsecutive prenatal visits). If the result is positive, infection is confirmed. Additional testing is not recommended in women who have a positive test any time before or during the current pregnancy. IgM testing is no longer routinely recommended.
Asymptomatic pregnant women with recent possible exposure but no ongoing possible exposure (e.g., travel or sexual exposure): testing is not routinely recommended but may be considered on a case-by-case basis.

Pregnant women with possible exposure to Zika virus who have a fetus with prenatal ultrasound findings consistent with congenital Zika virus infection should be tested following the same recommendations for symptomatic pregnant women. If amniocentesis is performed as part of routine clinical care, RT-PCR should be performed on amniotic fluid as a positive result may indicate fetal infection. Testing placental and fetal tissues is not routinely recommended, but may be performed in certain situations (e.g., a woman without laboratory-confirmed infection who has a fetus or infant with possible Zika virus-associated abnormalities).[148]

Pregnant women with laboratory evidence of possible Zika virus infection should have serial ultrasounds every 3 to 4 weeks to monitor fetal anatomy and growth, and be referred to a specialist.[148] Intrauterine diagnosis of microcephaly is made when the head circumference is ≥2 standard deviations below the mean for gender and gestational age.[171]

The CDC has produced an algorithm to assist in clinical decision making about testing based on current recommendations:

CDC: pregnancy & Zika testing external link opens in a new window

Dengue and chikungunya testing (RT-PCR or serology) should also be performed in patients at risk of exposure with clinically compatible illness.

Testing in infants with suspected congenital Zike syndrome

Both molecular and serologic testing are recommended in:[2]

Infants with clinical findings consistent with congenital Zika syndrome born to mothers with possible Zika virus exposure in pregnancy, regardless of maternal testing results
Infants without clinical findings consistent with congenital Zika syndrome who were born to mothers with laboratory evidence of possible Zika virus infection.

Laboratory testing is not routinely recommended for infants without clinical findings consistent with congenital Zika syndrome born to mothers with possible Zika exposure during pregnancy but without laboratory evidence of maternal infection.

Initial samples for testing (i.e., infant serum and urine; whole blood; cord blood is no longer recommended) should be collected directly from the infant in the first 2 days of life for simultaneous RT-PCR (on serum and urine) and IgM ELISA testing (note: specimens collected within the first few weeks to months after birth still may be useful, especially in infants born in areas without risk of Zika). CSF testing can be considered if CSF is obtained for other purposes.[2] A positive RT-PCR on serum or urine confirms congenital infection. A negative RT-PCR result with a positive IgM result suggests probable congenital infection.[2] PRNT can be used to help identify false-positive results, and confirm or rule out congenital Zika virus infection in children ages ≥18 months. com.bmj.content.model.Caption@1d4e8c00 [Figure caption and citation for the preceding image starts]: Interpretation of results of laboratory testing for evidence of congenital Zika virus infectionCenters for Disease Control and Prevention (CDC) [Citation ends].

A standard evaluation is recommended in all infants born to mothers with possible or confirmed infection, regardless of whether the infant has clinical findings consistent with congenital Zika syndrome. The evaluation should include:[2]

Comprehensive physical exam including growth parameters

Developmental monitoring and screening using validated tools

Vision screening

Newborn hearing screen at birth, with automated auditory brainstem response (ABR) if possible.

In addition to this, infants with clinical findings consistent with congenital Zika syndrome, and infants without clinical findings born to mothers with laboratory evidence of possible Zika virus infection should have the following investigations:[2]

Head ultrasound

Comprehensive ophthalmologic exam by 1 month of age

Automated ABR by 1 month of age (if not already done as part of standard newborn evaluation).

Infants with clinical findings consistent with congenital Zika syndrome should also have the following:[2]

Referral to a development specialist, early intervention service programs, and family support services

Consultation with infectious disease, clinical genetics, and neurology specialists, as well as any other clinical specialists based on the infant’s clinical findings (e.g., endocrinologist, lactation specialist, gastroenterologist, speech or occupational therapist, orthopedist, physical therapist, pulmonologist).

Infants who do not have clinical findings consistent with congenital Zika syndrome should be referred to an appropriate specialist if any clinical findings are noted at follow-up visits.

Follow-up care requires a multidisciplinary team to facilitate coordination of care and will depend on the clinical findings in the infant. Healthcare providers should be vigilant for other clinical findings (e.g., difficulty swallowing, hydrocephaly) or new clinical findings. A standard evaluation should be performed at subsequent well-child visits in all infants, along with routine pediatric care. Automated ABR testing is no longer recommended in infants at 4 to 6 months of age if they passed the initial hearing screen with ABR.[2]

The WHO offers specific guidance for the screening, assessment, and management of neonates and infants with congenital Zika syndrome.

WHO: screening, assessment and management of neonates and infants with complications associated with Zika virus exposure in utero external link opens in a new window

com.bmj.content.model.Caption@2b68273 [Figure caption and citation for the preceding image starts]: Recommended Zika virus testing and evaluation of infants born to mothers with laboratory evidence of Zika virus infection during pregnancyCenters for Disease Control and Prevention (CDC) [Citation ends].

Patients at risk of both dengue and Zika virus infection

The CDC recommend the following tests in people with symptoms who live in or travel to areas where there is a risk for infection with both dengue and Zika viruses:[173]

Symptomatic nonpregnant women
- Nucleic acid amplification tests (NAATs) such as RT-PCR for dengue and Zika viruses performed on serum collected in the first 7 days after symptom onset.
- Serologic testing (IgM antibody testing for dengue and Zika viruses) on serum collected >7 days after symptom onset, or in patients with a negative NAAT result.
Symptomatic pregnant women
- Simultaneous NAATs and IgM antibody testing for both dengue and Zika viruses on serum and urine specimens as soon as possible within 12 weeks of symptom onset.
- A positive IgM antibody test result with a negative NAAT result should be confirmed by neutralizing antibody tests.

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