Zika Virus

From EyeWiki


Zika Virus



Disease Entity

Zika is a viral infection transmitted by the Aedes aegypti mosquito.

ICD9: 066.3

ICD10: A92.5

Disease

There are several manifestations of the Zika virus, the most devastating manifestation is associated with pregnancy and fetal transmission.

While Zika virus infection acquired in children/adults is often asymptomatic or accompanied by mild symptoms, congenital infection with Zika virus can lead to damage of the brain, eye, and central nervous system.

Congenital Zika Virus Infection:

Pregnant women who become infected with Zika virus may transmit the virus to their fetus. Congenital Zika virus infection can cause microcephaly, damage to the brain and/or eye, and central nervous system dysfunction. A distinctive pattern of congenital anomalies, called congenital Zika syndrome (CZS), may be caused by Zika virus infection during pregnancy. CZS is characterized by the following: (1) severe microcephaly with partially collapsed skull; (2) brain abnormalities, including thin cerebral cortices with subcortical calcifications; (3) ophthalmologic findings, including macular scarring and focal retinal pigment mottling; (4) congenital contractures; and (5) marked early hypertonia and signs of extrapyramidal involvement.

Non-Congenital Zika Virus Infection: 

Zika virus infection can occur in infants, children, and adults and may affect ocular structures. Acute Zika virus infection is usually asymptomatic.  Symptoms if present are mild and include maculopapular rash, fever, arthralgia, and/or non-purulent conjunctivitis. In rare cases, neurological complications have occurred. About 1 in 4000 people with Zika virus infection develop Guillain-Barre Syndrome (GBS), a neurologic condition, within 5-6 days of the onset of  symptoms.  Encephalitis has also been reported following infection with Zika virus.

Etiology

The Zika virus is a single-stranded ribonucleic acid (RNA) virus of the family Flaviviridae, genus Flavivirus. Zika virus is primarily transmitted to humans through the bite of an infected Aedes species mosquito (Ae. aegypti and Ae. albopictus). Humans and nonhuman primates are likely the main reservoirs of the virus, and anthroponotic (human-to-vector-to-human) transmission occurs during outbreaks. Zika virus can be transmitted through sex and it can also be transmitted from a pregnant woman to her fetus. Perinatal transmission and transmission via blood transfusion have also been reported.

Risk Factors

Geographic risks are predominant. According to the CDC nearly every country in the Americas has been affected.

A large majority of Zika cases in the United States are travel-related. Since the outbreak began in 2015, every US state has reported travel-related cases. In the United States, only Florida and Texas have reported the spread of Zika through locally infected mosquitos. This occurred in small areas in Miami-Dade County, Florida, and Brownsville, Texas. Local mosquito-borne Zika virus transmission has also been reported in three U.S. Territories: American Samoa, US Virgin Islands, and Puerto Rico. Currently, 86 countries have noted mosquito transmitted infection, and there is no evidence of current outbreak in the United States. [1]

Risk factors for congenital Zika virus infection include maternal travel to or residence in an area with ongoing risk of Zika virus exposure during pregnancy or sex (oral, vaginal, or anal) without a condom during pregnancy with a partner who traveled to or lived in an area with ongoing risk of Zika virus exposure.

Ventura et al have identified two risk factors associated with ocular findings that include maternal infection during the first trimester and more severe microcephaly.[2] Sampaio et al found that infants with infratentorial abnormalities were more likely to have chorioretinal atrophy in the macular area as well as optic nerve abnormalities. [3]

General Pathology

In a study of 4 deceased fetuses with a diagnosis of Congenital Zika Syndrome (CZS),[4] ocular histopathologic findings included:

·      Pupillary membranes

·      Immature anterior chamber angles

·      Retina: undifferentiated nuclear layers and a thin photoreceptor layer

·      Retinal pigment epithelium: loss of pigment and thinning

·      Choroid: thinning and a perivascular inflammatory infiltrate

·      Optic nerve atrophy

On immunostaining performed with rabbit anti-ZIKV NS2B protein antibody, there was expression of the Zika virus antigen noted in the following:

·       Iris

·       Neural retina

·       Choroid

·       Optic nerve

Human iris pigment epithelium in adults has been found to be moderately susceptible to Zika virus. The cells mount a strong anti-viral response, particularly of IFN-β, although there is variation in this response across different eyes. [5]

In studies with ZIKV-infected mice, only the superficial layer of vasculature was developed in the retina. Vessel density was also greatly decreased. Staining with antibody against CD45, a marker of leukocytes, showed an abundance in CD45 positive cells in ZIKV-infected retinas. These findings suggest that ZIKV causes a reduction in vascular growth of the retina as well as an increased inflammatory response.[6]

Pathophysiology

While the exact pathophysiologic mechanism in congenital Zika virus infection is not known, Zika virus is known to have a predilection for neural progenitor cells. Studies in mice have suggested that Zika virus crosses the blood retinal barrier and infects cells in the choroid and retinal layers of the eye leading to inflammatory responses and cell death.[7]

Primary prevention

Avoiding endemic areas if possible is a key to prevention. Otherwise avoiding situations that may expose to mosquito bites is advised. Also avoid using insect repellant, areas with standing water, and times when mosquitoes feed (twilight).

Strategies for prevention of Zika virus exposure :

Congenital Zika Virus Infection:

Centers for Disease Control and Prevention (CDC) recommends that pregnant women consider the risks associated with possible exposure to Zika virus. This includes avoiding areas with a Zika outbreak and considering the potential risks and possible consequences of traveling to other areas with a risk of Zika If a pregnant woman or her partner recently traveled to an area with current or past risk of Zika, they should  use condoms for the entire pregnancy, even if the traveler does not have symptoms of Zika. (Link for most up to date guidelines: [1])

Non-Congenital Zika Virus Infection:

Preventing mosquito bites is a primary prevention strategy. All people who live in or travel to an area with a risk of Zika can reduce the risk of Zika virus infection by preventing mosquito bites. It is also important to take steps to prevent mosquito bites after returning from areas with risk of Zika. An asymptomatic infected person who has returned from travel can get bitten by a mosquito, which can then spread the virus to others.

Diagnosis

Several tests exist to detect the Zika virus.

Congenital Zika Virus Infection:

Congenital Zika virus infection may be suspected based on the neonate’s clinical features and maternal history of possible Zika virus exposure, including places and dates of travel or sex with a male partner who has traveled to an area with risk of Zika. It is critical that all infants with possible congenital Zika virus infection receive recommended screening and follow-up care.

Non-Congenital Zika Virus Infection:

Persons who have symptoms consistent with Zika virus infection and who have traveled to or had sex without a condom with a person who traveled to an area with risk of Zika virus exposure are considered possibly exposed to Zika. Laboratory diagnosis of Zika virus infection is accomplished by testing various body fluids including: whole blood, serum, plasma, and urine to detect virus, viral nucleic acid, or virus-specific immunoglobulin M and neutralizing antibodies.

History

Travel history is imperative to obtain. History in Zika is endemic areas, and, though less common, risk via sexual transmission can be asked during patient interview.

Congenital Zika Virus Infection:

Travel to or residence in an area with risk of Zika virus exposure during pregnancy or the periconceptional period (the 6 weeks before last menstrual period or 8 weeks before conception) or sex (vaginal, anal, or oral sex) or sharing sex toys without a condom during pregnancy with a person who traveled to or lives in an area with risk of Zika virus exposure.

Non-Congenital Zika Virus Infection:

Living in or travel to an area with risk of possible Zika virus exposure or sex (vaginal, anal, or oral) with a person who has recently lived in or traveled to an area with risk of Zika virus.

Physical examination

As related to ophthalmology, a comprehensive ocular examination should be performed within a month of birth in all infants when Zika infection exposure during pregnancy is suspected. The ophthalmic exam is crucial regardless of neurological findings as 41.7% of children with CZS may not present with microcephaly or with other neurological manifestations.[8] Ophthalmic manifestations of CZS are present in up to 55% of babies. [2]

Congenital Zika Virus Infection:

Currently, the CDC recommends that all infants (1) with findings consistent with Congenital Zika Syndrome (CZS) or (2) without clinical findings consistent with CZS but maternal laboratory evidence of possible Zika virus infection during pregnancy be referred for a comprehensive ophthalmologic exam before 1 month of age. The initial comprehensive examination should be performed by an ophthalmologist experienced in the assessment of and intervention in infants, and should include visual acuity assessment (if able, using teller or grating acuity tests), pupillary response, external exam, slit lamp exam, intraocular pressure measurements (if indicated), and dilated fundus examination. After 3-4 months of age, ocular motility, cycloplegic refraction, and accommodation by dynamic retinoscopy should also be assessed. Follow up visits should be determined by the examining ophthalmologist.

Non-Congenital Zika Virus Infection:

Comprehensive ophthalmologic examination should be performed for any ocular signs or concerns. Ocular manifestations during acute disease include conjunctivitis, uveitis, maculopathy, and acute hypertensive anterior uveitis.[2]

Signs

Congenital Zika Virus Infection:

The spectrum of ocular anomalies in those congenitally infected with Zika virus is still evolving. The most commonly reported ocular abnormalities associated with congenital Zika virus infection include:[2][9]

  • macular abnormalities including
    • focal pigmentary mottling and
    • chorioretinal atrophy
  • optic nerve abnormalities including
    • optic nerve hypoplasia,
    • increased cup to disk ratio, and
    • pallor
  • Other reported ocular findings include
    • microphthalmia,
    • posterior synechia,
    • buphthalmia,
    • iris colobomas,
    • intraocular calcifications,
    • cataracts,
    • lens subluxation,
    • congenital glaucoma,
    • strabismus,
    • nystagmus, and
    • other retinal findings including
      • pigmentary clumping and chorioretinal atrophy outside of the macula,
      • subretinal hemorrhages,
      • coloboma,
      • abnormal termination of the retinal vessels,
      • focal areas of vascular dilation, and vascular tortuosity, straightening, and attenuation.

Non-Congenital Zika Virus Infection:

In children and adults infected with Zika virus, the most commonly reported ocular signs are:[10]

  • retro-orbital pain and
  • non-purulent conjunctivitis

Among adults, there have been case reports of

  • non-granulomatous anterior uveitis,
  • increased intraocular pressure,
  • acute hypertensive iridocyclitis,
  • multifocal non-necrotizing chorioretinal lesions,
  • posterior uveitis with vitritis and lesions in the choroid and outer retina,
  • multifocal choroiditis,
  • neuroretinitis (with afferent pupillary defect, disc edema, and macular hard exudates arranged in a star-like pattern), and
  • an acute bull’s eye maculopathy.

Symptoms

Congenital Zika Virus Infection:

In neonates infected with Zika virus in the perinatal period: The range of symptoms is currently unknown. Perinatal transmission of Zika virus infection to infants from mothers infected near the time of delivery has been reported in two cases and no symptoms were described in either case.

Non-Congenital Zika Virus Infection:

In older children/adults: Many people infected with Zika virus are asymptomatic. The most commonly reported symptoms are acute onset of fever, arthralgia, myalgia, and headache. Those with conjunctivitis may report tearing, non-purulent discharge, and eye discomfort or pain. Other ocular symptoms may include conjunctival hyperemia, decreased vision, photopsias, and pain with extraocular movements. Clinical illness is usually mild with symptoms lasting for several days to a week. Severe disease requiring hospitalization is uncommon and case fatality is low.

Clinical diagnosis

Congenital Zika Virus Infection:  

Clinical suspicion for Zika virus infection should be based on the maternal risk factors and clinical signs and symptoms. Because Zika virus is confirmed by laboratory testing, it cannot be surely diagnosed clinically.

The most common ophthalmic signs seen in congenital zika virus infection are retinal (e.g. chorioretinal atrophy, pigment mottling) and optic nerve abnormalities (eg, increased cup:disk ratio, optic nerve pallor, optic nerve hypoplasia).[9]

Non-Congenital Zika Virus Infection:  

Clinical suspicion for Zika virus infection should be based on the patient’s risk factors and clinical signs and symptoms. Characteristic clinical findings include acute onset of fever with maculopapular rash, arthralgia, or conjunctivitis lasting several days to a week. Other commonly reported symptoms include myalgia and headache. Because Zika virus is confirmed by laboratory testing, it cannot be purely diagnosed clinically.

The ophthalmic signs most commonly reported in acute non-congenital infection include non-purulent conjunctivitis and anterior uveitis.[10]

Diagnostic procedures

Diagnostic procedures include serum, urine, and cerebral spinal fluid (CSF) testing and, in select situations, testing of the placenta, umbilical cord, and amniotic fluid.

Optical coherence tomography in congenital zika syndrome shows loss of ellipsoid zone, outer retinal thinning/atrophy, hyperreflectivity of retinal pigment epithelium, choroidal thinning, and colobomatous excavation.[11]

Laboratory test

Currently both serum and urine testing is available. The following modalities have been offered: RNA Nucleic Acid Testing (NAT), Zika immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA), and Zika Plaque Reduction Neutralization Test (PRNT). Other testing that can be performed includes: 1) histopathologic examination and immunohistochemical staining of the placenta and umbilical cord, and 2) Zika virus testing of frozen placental tissue and cord tissue. Cord blood is not recommended because it can yield false positive results through contamination with maternal blood and can also yield false negative results.

Zika virus has been detected from conjunctival swabs in laboratory-confirmed infected virus cases. Zika virus RNA has also been detected in fluid collected from the anterior chamber.

Zika virus testing is performed at CDC, several state, local, and territorial health departments, and some commercial laboratories.  Current testing guidelines can be found here:[2] https://www.cdc.gov/zika/hc-providers/testing-guidance.html

Differential diagnosis

Congenital Zika Virus Infection.

Differential diagnosis for congenital Zika syndrome:

·       Other congenital infections (e.g. cytomegalovirus)

·       Other causes (e.g. genetic or environmental) of birth defects present (e.g. microcephaly).

Non-Congenital Zika Virus Infection. Differential diagnosis for symptomatic adults, children, and neonates (dictated by patient history and ocular findings):

·       Chikungunya

·       Dengue

·       Yellow-fever

·       West Nile Virus

·       Other viral infections, e.g. syphilis, Epstein Barr, Lyme disease, CMV, toxoplasmosis, tuberculosis, HIV, HSV, VZV

Management

General treatment

Congenital Zika Virus Infection:

Currently there is no treatment to prevent or mitigate congenital Zika virus infection. Infants of mothers with possible Zika virus exposure during pregnancy should be managed using the CDC’s Interim Guidance for the Diagnosis, Evaluation, and Management of Infants with Possible Congenital Zika Virus Infection, which can be found at [3] https://www.cdc.gov/pregnancy/zika/testing-follow-up/evaluation-testing.html

Infants and children who experience visual impairment or loss should be referred to a low vision specialist and developmental services early in life, known as early intervention, to help babies improve and maximize their abilities.

Non-Congenital Zika Virus Infection:

Treatment is generally supportive and can include rest, fluids, and use of analgesics and antipyretics. No vaccine is currently available.

Medical therapy

Congenital Zika Virus Infection:

No active inflammatory ocular lesions have been reported in infants with congenital Zika infection.  If congenital glaucoma is present, it should be managed initially with intraocular pressure lowering drops and likely surgery.

Non-Congenital Zika Virus Infection:

Case reports of ocular lesions in adults have been reported to be self-resolving or treated with topical corticosteroids.

No specific antiviral treatment is available for Zika virus disease. Because of its similar geographic distribution and symptoms, patients with suspected Zika virus infections also should be evaluated and managed for possible dengue or chikungunya virus infection. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue can be ruled out to reduce the risk of hemorrhage.

Medical follow up

Congenital Zika Virus Infection:

Infants should be followed-up using the CDC’s Interim Guidelines for Health Care Providers Caring for Infants and Children with Possible Zika Virus Infection, which can be found at [4] https://www.cdc.gov/pregnancy/zika/testing-follow-up/follow-up-care.html

Non-Congenital Zika Virus Infection:

Zika virus infection is usually self-limiting. Patients should be followed-up based on symptomatology.  

As an arboviral disease, Zika virus is a nationally notifiable condition. Health care providers are encouraged to report suspected cases to their state or local health departments to facilitate diagnosis and mitigate the risk of local transmission. State or local health departments are encouraged to report laboratory-confirmed cases to CDC through ArboNET, the national surveillance system for arboviral disease.

Surgery

Though it has not been documented, a vitreous biopsy might be performed if a diagnosis of intraocular Zika is suspected following a confirmatory systemic laboratory test (as discussed above).

Congenital Zika Virus Infection:

Congenital cataracts should be evaluated by pediatric ophthalmologist to determine if they should be removed. Congenital glaucoma will likely require surgical management.

Complications

Congenital Zika Virus Infections:

Cortical visual impairment may be the most common cause of blindness among children with congenital Zika syndrome.

Non-Congenital Zika Virus Infections:

Case reports of ocular lesions in adults have been reported to be self-resolving or treated with topical corticosteroids with recovery of baseline vision.

Prognosis

Congenital Zika Virus Infection:

Our knowledge of congenital Zika virus infection is still evolving. The prognosis for infants with congenital Zika virus infection is currently unknown. Studies have found that cortical visual impairment may be the most common cause of blindness among children with congenital Zika syndrome.

Non-Congenital Zika Virus Infection:

Zika virus infection in infants, children, and adults is usually self-limiting and the prognosis is good.  

Additional Resources

References

  1. https://www.who.int/news-room/fact-sheets/detail/zika-virus
  2. 2.0 2.1 2.2 2.3 Ventura CV, Ventura Filho MC, Ventura LO. Ocular Manifestations and Visual Outcome in Children With Congenital Zika Syndrome. Top Magn Reson Imaging. 2019 Feb;28(1):23-27. doi: 10.1097/RMR.0000000000000192. Review. PubMed PMID:30817677.
  3. Sampaio VV, Melo ASO, Coleman AL, Yu F, Martins SR, Rabello LP, Tavares JS, Nielsen-Saines K. A Novel Radiologic Finding to Predict Ophthalmic Abnormalities in Children With Congenital Zika Syndrome. J Pediatric Infect Dis Soc. 2021 May 20:piab010. doi: 10.1093/jpids/piab010. Epub ahead of print. PMID: 34013960.
  4. Fernandez MP, Parra Saad E, Ospina Martinez M, Corchuelo S, Mercado Reyes M, Herrera MJ, Parra Saavedra M, Rico A, Fernandez AM, Lee RK, Ventura CV, Berrocal AM, Dubovy SR. Ocular Histopathologic Features of Congenital Zika Syndrome. JAMA Ophthalmol. 2017 Nov 1;135(11):1163-1169.
  5. Ryan FJ, Carr JM, Furtado JM, Ma Y, Ashander LM, Simões M, Oliver GF, Granado GB, Dawson AC, Michael MZ, Appukuttan B, Lynn DJ, Smith JR. Zika Virus Infection of Human Iris Pigment Epithelial Cells. Front Immunol. 2021 Apr 22;12:644153. doi: 10.3389/fimmu.2021.644153. PMID: 33968035; PMCID: PMC8100333.
  6. Li Y, Shi S, Xia F, Shan C, Ha Y, Zou J, Adam A, Zhang M, Wang T, Liu H, Shi PY, Zhang W. Zika virus induces neuronal and vascular degeneration in developing mouse retina. Acta Neuropathol Commun. 2021 May 25;9(1):97. doi: 10.1186/s40478-021-01195-6. PMID: 34034828; PMCID: PMC8147371.
  7. Singh PK, Guest JM, Kanwar M, et al. Zika virus infects cells lining the blood-retinal barrier and causes chorioretinal atrophy in mouse eyes. JCI Insight. 2017;2(4):e92340. Published 2017 Feb 23. doi:10.1172/jci.insight.92340
  8. Zin AA, Tsui I, Rossetto J, Vasconcelos Z, Adachi K, Valderramos S, Halai UA, Pone MVDS, Pone SM, Silveira Filho JCB, Aibe MS, da Costa ACC, Zin OA, Belfort R Jr, Brasil P, Nielsen-Saines K, Moreira MEL. Screening Criteria for Ophthalmic Manifestations of Congenital Zika Virus Infection. JAMA Pediatr. 2017 Sep 1;171(9):847-854. doi: 10.1001/jamapediatrics.2017.1474. PMID: 28715527; PMCID: PMC5710409.
  9. 9.0 9.1 Ventura CV, Zin A, Paula Freitas B, Ventura LO, Rocha C, Costa F, Nery N Jr, De Senna TCR, Lopes Moreira ME, Maia M, Belfort R Jr. Ophthalmological manifestations in congenital Zika syndrome in 469 Brazilian children. J AAPOS. 2021 Jun;25(3):158.e1-158.e8. doi: 10.1016/j.jaapos.2021.01.009.
  10. 10.0 10.1 Troumani Y, Touhami S, Jackson TL, Ventura CV, Stanescu-Segall DM, Errera MH, Rousset D, Bodaghi B, Cartry G, David T, Beral L. Association of Anterior Uveitis With Acute Zika Virus Infection in Adults. JAMA Ophthalmol. 2021 Jan 1;139(1):95-102. doi: 10.1001/jamaophthalmol.2020.5131. PMID: 33237306; PMCID: PMC7689574.
  11. Tripathy K. Optical coherence tomography in congenital Zika syndrome. Arq Bras Oftalmol. 2017;80(2):138. doi:10.5935/0004-2749.20170034
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