Approach

Diagnosis of Zika virus infection is based on clinical suspicion along with molecular testing and, in some circumstances, 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). The diagnostic approach is different in pregnant and nonpregnant individuals.

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.[137] Coinfection with chikungunya and/or dengue is possible.[138] The World Health Organization (WHO) has produced a tool to help physicians differentiate between these three diseases.[137] Other conditions in the differential diagnosis, such as malaria or leptospirosis, may require specific and urgent treatment.

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] Evidence to support a causal relationship has expanded in recent years; however, the total number of cases investigated in the published cohort or case-control studies remains small.[9]

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.[10][11][12][13] Evidence to support a causal relationship has expanded in recent years; however, the body of evidence is still smaller than that for congenital abnormalities.[9]

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.[92]

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, in utero,​ sexual, and transfusion transmission​) have also been reported.[58][59][60][61][62][63][64][66][65] Sperm donation is a theoretical concern; however, there have been no reports as yet.

Clinical presentation

Approximately 80% of patients do not develop symptoms.[14][98]​ In those who do, the most common clinical findings include fever, an itchy maculopapular (sometimes morbilliform) rash, arthralgia, and nonpurulent conjunctivitis. The characteristic rash is one of the most distinctive symptoms.[14][46][98]​​​[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].com.bmj.content.model.Caption@1a510c5a

Other commonly reported symptoms include myalgia, malaise, and headache.[14][98]​​[129] Less common symptoms include vomiting/diarrhea, abdominal pain, anorexia, edema of the lower limbs, and retro-orbital pain.[14]

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.[139] The most common symptoms in children and adolescents were mild and included fever, rash, conjunctivitis, and arthralgia.[140]

Symptoms generally develop within 1 week of infection in 50% of patients, and within 2 weeks of infection in 99% of patients.[97] Clinical illness is usually self-limited with mild symptoms lasting 2 to 7 days.[14][141] Severe disease requiring hospitalization is uncommon and has been estimated to be 11%, and the case fatality is low (median 0.02%).[14][46][142] 

Neurologic exam should be performed on all patients with suspected Guillain-Barre syndrome (GBS).

  • Neurologic complications are rare and have been reported in 0.3% of cases, with the most common complication being GBS.[46]

  • The clinical phenotype is generally a sensorimotor demyelinating GBS with a severe disease course. The most common features were limb weakness (97%), absent/diminished reflexes (96%), sensory symptoms (82%), and facial palsy (51%). Median time between infectious and neurologic symptoms was 5 to 12 days.[138]

  • 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.[143] The Pan American Health Organization (PAHO) has also published a case definition for Zika-related GBS.[144] 

  • Physicians should be vigilant for early signs and symptoms of GBS as it may progress faster than usual in patients with Zika virus infection.[25] Neurologic consultation is recommended in patients with suspected GBS.[145] 

  • An association between Zika infection and transient hearing loss has been reported in a small number of cases.[146]

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, hypertonia, abnormal persistence of primitive reflexes, impaired cognitive development, delayed neuropsychomotor development, seizures, craniofacial disproportion, retrognathia, brainstem dysfunction, ocular abnormalities, hearing loss, speech disorders, impaired language development, alteration in tongue frenulum, absence of stapedial reflexes, findings on neuroimaging (e.g., cortical disorders, calcifications, ventriculomegaly), arthrogryposis (e.g., congenital joint contractures), low birth weight for gestational age, irritability, dysphagia, and feeding difficulties.[147][148][149] Features consistent with fetal immobility (e.g., dimples, feet malpositions, distal hand/finger contractures) may also be present.[150] 

  • 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]

  • 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][151][152][153][154] The syndrome does not appear to be associated with maternal disease severity.[155]

  • Although the risk appears to be greatest with infection in the first or second trimester, signs of congenital brain injury due to Zika virus infection acquired during the third trimester of pregnancy have been reported.[156] Poor head growth with microcephaly developing after birth has been reported in a small number of patients in Brazil.[157]

  • 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.[158]

  • Other infectious causes of microcephaly should be ruled out.[159]

​Zika virus infection should be considered in an infant:[98]

  • Who has one or more of the following manifestations during the first 2 weeks of life:

    • Fever

    • Rash

    • Conjunctivitis

    • Arthralgia (can manifest as irritability, difficulty moving or refusing to move an extremity, pain on palpation, or pain with active or passive movement of the affected joint in infants and young children); AND

  • Whose gestational parent was potentially exposed to Zika virus within approximately 2 weeks of delivery.

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.[160]​ See Criteria.

Investigations

Diagnosis can be confirmed with molecular testing, which includes reverse transcriptase-polymerase chain reaction (RT-PCR) for viral RNA. Serologic testing, which includes immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA) plus plaque-reduction neutralization testing (PRNT) for Zika virus antibodies, may be recommended in some circumstances. 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); however, there are currently few laboratories that perform this test.[161]​ Suitable specimens include serum, plasma, whole blood, and urine.[162] Availability of commercial tests depends on location.

Prenatal ultrasound and amniocentesis may be recommended in some pregnant women. Head circumference measurement, computed tomography/magnetic resonance imaging 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.[143] Interpretation of these studies and definitive diagnosis requires consultation with a neurologist.

Limitations of testing

Molecular assays are the preferred detection method. However, the period of viral RNA detectability following infection is limited, with RNA less likely to be detectable after the first week following symptom onset.[162] Serologic testing is not generally recommended to confirm the diagnosis. The duration of typical IgM detectability is about 12 weeks. However, data suggest that Zika virus IgM can persist beyond 12 weeks (for months or even years) in some people, and so 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.[163] Serologic testing is also complicated by cross-reactivity with other flaviviruses, which may make conclusive determination of which flavivirus is responsible for the person’s recent infection difficult.[161]​ If used, it should be done with careful consideration of the epidemiologic and clinical context.[162]

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.

Testing a person’s blood, urine, or genital secretions to determine their risk of sexually transmitting Zika virus is not recommended.[164]

Testing recommendations

Testing recommendations may vary between countries, and depend on the current epidemiologic situation. Consult your local guidance. The testing recommendations in this topic are mainly based on CDC guidance. Testing recommendations may differ between guidelines and locations, with WHO and PAHO also offering recommendations:

Zika and dengue virus infections have a similar global geographic distribution, and the clinical presentation is similar. Therefore, patients with suspected Zika virus infection should always be evaluated for possible dengue virus infection.[161][165]

Testing in nonpregnant individuals

Asymptomatic individuals

  • Testing for Zika and dengue virus infection is not currently recommended for asymptomatic nonpregnant individuals.[161]

Symptomatic individuals

  • Testing for Zika and dengue virus infection is not currently recommended for people living in or with recent travel to the US and its territories. However, testing is recommended in people living in or with recent travel to an area with an active CDC Zika travel health notice, or to an area with current or past Zika transmission outside of the US and its territories.[161]

  • If testing is recommended, Zika and dengue RT-PCR should be performed on serum collected ≤7 days after symptom onset. A positive result typically provides evidence of acute infection. Zika and dengue IgM antibody testing should be performed on RT-PCR-negative serum specimens and serum collected >7 days after onset of symptoms. If either Zika or dengue IgM antibody testing is positive, PRNT testing should be performed against Zika, dengue, and other flaviviruses endemic to the region where exposure occurred to confirm the diagnosis (if confirmation is required).

Testing in pregnant women

The current CDC recommendations for testing pregnant women in the context of low to no Zika virus transmission globally are detailed below.[161]

Asymptomatic pregnant women

  • Routine testing is not currently recommended for asymptomatic pregnant women living in or with recent travel to the US and its territories.

  • Routine testing is also not recommended for pregnant women who have traveled to an area with current or past Zika virus transmission outside the US and its territories during pregnancy.

  • However, RT-PCR may be considered in pregnant women with recent travel to an area with an active Zika travel health notice during pregnancy, up to 12 weeks after travel.

Symptomatic pregnant women

  • Testing is recommended in symptomatic pregnant women who have:

    • (1) Lived in or traveled to an area with an active CDC Zika travel health notice during pregnancy

    • (2) Had sex during pregnancy with someone living in or with recent travel to an area with an active CDC Zika travel health notice

    • (3) Lived in or traveled to an area with current or past Zika virus transmission during pregnancy.

  • Specimens should be collected as soon as possible after the onset of symptoms, up to 12 weeks after symptom onset.

  • Zika and dengue RT-PCR on a serum specimen and Zika RT-PCR on a urine specimen should be performed at the same time in all patients.

    • If the Zika RT-PCR is positive, the test should be repeated on newly extracted RNA from the same specimen to rule out a false-positive result.

    • Women who are part of groups (1) and (2) above should also undergo Zika and dengue IgM antibody testing at the same time as RT-PCR. If both Zika and dengue RT-PCR is negative, but either antibody test is positive, PRNT testing should be performed against Zika, dengue, and other flaviviruses endemic to the region where exposure.

    • Women who are part of group (3) should undergo IgM antibody testing for dengue only. If the dengue RT-PCR or IgM antibody test is positive, this provides adequate evidence of dengue infection, and no further testing is required.

Pregnant women with prenatal ultrasound findings consistent with congenital Zika virus infection

  • Women who lived in or traveled to an area with an active CDC Zika travel health notice or current or past Zika virus transmission during pregnancy, or had sex with someone who lived in or travel to an area with an active CDC Zika travel health notice or current or past Zika virus transmission during pregnancy should have Zika virus RT-PCR and serology performed on maternal serum, and RT-PCR on maternal urine. If Zika RT-PCR results are negative and the serology is positive, confirmatory PRNT testing should be performed for Zika and dengue.

  • If amniocentesis is performed as part of routine clinical care, Zika RT-PCR should be performed on amniocentesis specimens and results interpreted in the context of the limitations of amniotic fluid testing. Testing placental and fetal tissues may also be considered.

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.[163] Intrauterine diagnosis of microcephaly is made when the head circumference is ≥2 standard deviations below the mean for gender and gestational age.[166]

The CDC provide the following resources to help determine whether patients meet the epidemiologic criteria required for testing:

Testing in infants with suspected congenital Zika syndrome

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] 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 EEG abnormalities, and diaphragmatic paralysis in infants born with microcephaly and arthrogryposis.[2][167] Suspected cases should be referred to a pediatrician.

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. [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 [Citation ends].com.bmj.content.model.Caption@3ec360dd

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 Opens in new window

[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 [Citation ends].com.bmj.content.model.Caption@603c2bfd

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