OVERVIEW: What every clinician needs to know

Virus name and classification

Zika virus, genus Flavivirus, family Flaviviridae

What is the best treatment?

No specific therapies or vaccines currently exist.Treatment is supportive. For mild disease, symptoms can be alleviated with analgesics and antipyretics.Zika infection may be associated with Guillain-Barre syndrome, microcephaly and other neurological abnormalities in neonates. If diagnosed with Guillain-Barre syndrome, the patient should be admitted to the hospital in the event that respiratory insufficiency and/or autonomic dysfunction develop. Guidelines for microcephaly are detailed below.

What are the clinical manifestations of infection with this organism?

  • Macular or papular rash

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  • Fever

  • Arthritis or arthralgia

  • Nonpurulent conjunctivitis

  • Myalgia

  • Headache

  • Retro-orbital pain

  • Edema

  • Vomiting

Do other diseases mimic its manifestations?

  • Dengue

  • Chikungunya

  • Malaria

  • Venezuelan equine encephalitis

  • Mayaro

  • West Nile

  • Epstein-Barr or cytomegalovirus infection

  • Parvovirus

  • Acute HIV

  • Influenza

  • Leptospirosis

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Peripheral WBC with differential may be normal; mild thrombocytopenia has been reported

Chemistries, including liver function tests, may be normal

Results that confirm the diagnosis

Zika-specific RT-PCR can be done on serum within the first week of symptom onset. Virus may be detectable for longer periods in urine and semen.

After 1 week onset, Zika can be diagnosed by IgM ELISA, but flavivirus crossreactivity to related flaviviruses may occur and ELISAs should be confirmed by plaque reduction neutralization testing.

Local and state health departments should be contacted to facilitate testing. Zika is a nationally notifiable condition in the U.S.

What imaging studies will be helpful in making or excluding the diagnosis of Zika?

For mild disease in a nonpregnant individual, no imaging is indicated.

If Zika exposure is suspected in a pregnant woman, serial fetal ultrasounds ($$) are recommended to assess for microcephaly and other intracranial abnormalities. According to CDC guidelines (MMWR April 1, 2016/65(12);315-322), Zika testing should be offered to pregnant women with exposure history (travel to endemic area) with or without clinical symptoms of Zika. If the test is positive, serial ultrasounds every 3-4 weeks should be considered to evaluate for brain anomalies such as microcephaly and intracranial calcifications. At delivery, histopathological examination of the placental and umbilical cord, and Zika RNA testing of the placental and cord tissue as well as cord serum is recommended.

If the woman tests negative for Zika, she should receive routine prenatal care including a fetal anatomy ultrasound at 18-20 weeks gestation. This ultrasound should be evaluated for the presence of microcephaly or intracranial calcifications, and should any doubt exist, additional fetal ultrasounds can be considered later in the pregnancy.

If fetal microcephaly or intracranial calcifications are noted on prenatal ultrasound, Zika testing of the amniotic fluid should be considered.

Referral to a maternal-fetal specialist is recommended for pregnant women testing positive or inconclusive for Zika.

What complications can be associated with Zika infection and are there additional treatments that can help to alleviate these complications?

80% of people infected are asymptomatic. Of those who are symptomatic, the vast majority have a mild self-limited illness of 2 to 7 days duration. There have been case reports of meningoencephalitis, myelitis and hematospermia. Congenital infection may be linked to microcephaly and other neurological abnormalities in the neonate. Mortality due to Zika is very rare, but has been reported in patients with sickle cell disease, congenital Zika infection and post-Zika Guillain-Barre syndrome.

The association between Guillain-Barre syndrome (GBS) and Zika infection has been shown in a case-control study in Polynesia, in which 93% of GBS cases had evidence of recent Zika infection, compared to 17% of controls. Patients developed neurological symptoms after a median of 6 days following a viral syndrome. 38% of GBS patients were admitted to the ICU, and most of them required ventilatory support. All patients received intravenous immunoglobulin (IVIG). Outcomes were favorable, with no deaths and most patients able to walk without assistance 3 months after hospital discharge. The incidence of GBS in Polynesia was estimated to be 0.24 per 1000 Zika infections.

The association between Zika virus and microcephaly was corroborated in a prospective study of pregnant women in Brazil, in which fetal abnormalities were seen in 29% of Zika-positive women (12 of 42) but in none of the Zika-negative women (0 of 16). These abnormalities included intrauterine growth restriction with and without microcephaly, cerebral calcifications, cerebral atrophy, agenesis vermis, abnormal arterial flow in cerebral or umbilical arteries, oligohydramnios and anhydramnios.

The CDC recommends the following for the management of pregnant women with a history of travel to an area with ongoing Zika transmission:

  • Test symptomatic women by RT-PCR during the first week of illness, or by Zika IgM and plaque reduction neutralization test if more than 3 days after illness onset.

  • Testing may be offered to asymptomatic women (Zika IgM and plaque reduction neutralization test) 2 to 12 weeks after travel.

  • If the woman tests negative, a fetal anatomy ultrasound is recommended. If there is evidence of microcephaly or intracranial calcifications, retest the woman for Zika and consider amniocentesis for Zika testing.

  • If the woman tests positive, consider serial fetal ultrasounds and amniocentesis for Zika testing.

The CDC recommends the following for the management of pregnant women residing in an area with ongoing Zika transmission:

  • Test symptomatic women by RT-PCR during the first week of illness, or by Zika IgM and plaque reduction neutralization test if more than 3 days after illness onset.

  • If asymptomatic, Zika virus IgM testing is recommended at the initiation of prenatal care and again mid-second trimester.

  • If the woman tests negative, a fetal anatomy ultrasound is recommended. If there is evidence of microcephaly or intracranial calcifications, retest the woman for Zika and consider amniocentesis for Zika testing.

  • If the woman tests positive, consider serial fetal ultrasounds and amniocentesis for Zika testing.

What is the epidemiology of Zika?

It is thought that Zika was originally transmitted between non-human primates by sylvatic Aedes mosquitoes in central Africa. In the current epidemic in the Pacific islands and the Americas, humans are the main amplifying hosts. The primary vectors are thought to be Aedesspecies mosquitoes (Aedes aegypti, Ae. albopictus, and Ae. africanushave been found to be naturally infected), though other potential vector(s) in the Americas are still under study.

Sexual transmission of Zika has also been reported, and the virus is noted to persist for weeks to months in semen. Zika virus also is found in other body fluids such as saliva and urine, and can be detected in these fluids even after it is no longer detectable in blood.

It is likely that there will be seasonality, as seen in dengue infections, but data are not yet available.

The vector Aedes aegyptibreeds in peridomiciliary containers and tree holes. Assuming that this vector is playing an important role, lack of running water and sanitation are likely to be important environmental factors predisposing communities to Zika.

Zika virus was associated with only sporadic human cases until 2007, when it caused an outbreak on the Micronesian island of Yap. From there, it spread to French Polynesia and Easter Island (2013-4), and then the Americas in early 2015. Indigenous transmission has been reported from most countries in the Caribbean, Central and South America (Aruba, Barbados, Bonaire, Curacao, Dominican Republic, Guadaloupe, Haiti, Jamaica, Martinique, Puerto Rico, St. Maarten, St. Vincent and the Grenadines, Trinidad and Tobago, US Virgin Islands, Mexico, El Salvador, Costa Rica, Nicaragua, Panama, Honduras, Guatemala, Brazil, Venezuela, Colombia, Ecuador, Bolivia, Guyana, French Guiana, Paraguay and Suriname). In addition, Zika is circulating in Cape Verde, Samoa, American Samoa, New Caledonia, Marshall Islands and Tonga. Recent Zika infection in returning travelers from Thailand and Indonesia also has been reported.

People who have not been exposed to Zika previously are thought to be susceptible. Prior exposure to the related dengue virus does not appear to confer protection.

It appears that transmission has died down on many of the islands that were initially affected, likely due to herd immunity. In countries with much larger populations, however, it is unclear what the transmission dynamics will be.

Infection control issues:

  • No postexposure prophylaxis is available.

  • No vaccines are available, though several different candidates are in development.

  • The best strategy to prevent infection is by avoiding mosquito bites. The suspected mosquito vectors (Aedes spp.) are day biting mosquitoes. Therefore, precautions should be taken by applying insect repellant, wearing permethrin-impregnated clothing, remaining in screened or air-conditioned environments, and using mosquito netting, especially during the day time.

  • Mosquito control strategies also include eliminating larval breeding sites. This consists of emptying or covering containers around the home and applying larvicide to bodies of water that cannot be drained. Indoor residual spraying also may offer benefit.

  • Transgenic mosquitoes have been developed that render male Aedes aegyptisterile, thus reducing the total Aedes aegyptipopulation within the release area. It is unclear what role these mosquitoes may play in modifying Zika transmission.

How does this organism cause disease?

It has been recently shown that human embryonic neural progenitor cells derived from pluripotent stem cells are targets for Zika virus. Once infected, these cells experience increased cell death, cell cycle and transcription dysregulation, and are able to produce infectious viral particles. This provides a plausible mechanism for the congenital neurological abnormalities seen following in utero Zika infection.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Cao-Lormeau, VM, Blake, A, Mons, S. “Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study”. Lancet. vol. 387. 2016. pp. 1581-89. (Good epidemiological evidence of the link between Zika and Guillain-Barre syndrome, with a detailed discussion of the clinical features of GBS cases.)

Tang, H, Hammack, C, Ogden, SC. “Zika virus infects human cortical neural progenitors and attenuates their growth”. Cell Stem Cell. vol. pii. 2016 Mar 3. pp. S1934-5909. (In vitro demonstration that human neural progenitor cells, derived from pluripotent stem cells, are targets for Zika virus. Once infected, these cells experience increased cell death, cell cycle and transcription dysregulation, and are able to produce infectious viral particles)

Brasil, P, Perreira, JP, Raja Gabaglia, C. “Zika virus infection in pregnang women in Rio de Janeiro – preliminary report”. N Engl J Med.. 2016 Mar 4. (Prospective study of pregnant women in Brazil, demonstrating sonographic abnormalities in 29% of women infected with Zika during pregnancy compared to 0% in noninfected women)

Oduyebo, T, Petersen, EE, Rasmussen, SA. “Update: interim guidelines for health care providers caring for pregnant women and women of reproductive age with possible Zika virus exposure – United States 2016”. MMWR Morb Mortal Wkly Rep. vol. 65. 2016. pp. 122-27. (Algorithm for testing women with a history of travel to Zika endemic areas and women residing in an area with ongoing Zika transmission.)

Duffy, MR, Chen, TH, Hancock, WT. “Zika virus outbreak on Yap Island, Federated States of Micronesia”. N Engl J Med. vol. 360. 2009. pp. 2536-43. (Description of the first substantial outbreak and clinical features.)

Hills, SL, Russell, K, Hennessey, M. “Transmission of Zika virus through sexual contact with travelers to areas of ongoing transmission – Continental United States, 2016”. MMWR Morb Mortal Wkly Rep. vol. 65. 2016. pp. 215-16. (Details cases of sexual transmission of Zika and guidelines for prevention.)

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