Zika virus infection

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.; Serge Korjian M.D.; Nate Michalak, B.A.; Yamuna Kondapally, M.B.B.S[2]

Zika fever is an infectious disease caused by Zika virus (ZIKV), an enveloped, single-stranded, positive-sense RNA flavivirus. Zika virus is a vector-borne pathogen usually transmitted via the Aedes mosquito that also transmits the dengue and chikungunya viruses. Human-to-human transmission by blood transfusions, sexual intercourse, or vertical transmission has also been reported. Once rare, the incidence of Zika virus infection rose dramatically during the 2014-2016 outbreak that started in Brazil. Zika virus infection has a clinical presentation similar to Dengue fever, yellow fever, West Nile virus, and Japanese encephalitis, but it is distinct in its milder clinical manifestations and short length of infection. Only one-fifth of patients exposed to Zika virus will develop clinical manifestations, typically 3 to 12 days after contracting the disease. Symptoms will typically begin with a mild headache and fever, then progress to include maculopapular rash spread across the body within 24 hours, followed by conjunctivitis, malaise, and back pain. Symptoms typically last 4 to 7 days. The prognosis is usually excellent, with the majority of patients recovering fully. Complications may include neurological sequelae, particularly Guillain-Barré syndrome. It is also thought that Zika virus infection is teratogenic and may be associated with microcephaly in newborns of infected mothers; this association is strongly suspected but has not yet been confirmed. A diagnosis of Zika virus infection is usually made by either RT-PCR or ELISA. Treatment is usually supportive, and antiviral therapy is generally not recommended. There are no vaccines available to prevent Zika virus infection. Since the virus is usually transmitted through mosquitoes, effective measures to avoid mosquito bites include using insect repellent, installing mosquito bed nets and window/door screens, wearing long sleeves and long pants, and removing potential breeding sites from indoor/outdoor premises. It is also recommended that men practice sexual abstinence and/or wear condoms when Zika virus infected is suspected to prevent sexual transmission. Once infected, individuals may be re-infected in the future.

Zika virus was first isolated from a Rhesus Monkey in 1947 in Uganda. The virus was first isolated from humans in 1968 in Nigeria. Since then, viral circulation and outbreaks have been documented throughout Asia and Africa. The most recent outbreak occurred in Brazil in April 2015.

Zika virus is a vector-borne pathogen usually transmitted via the Aedes mosquito, which also transmits the dengue and chikungunya viruses. Human-to-human transmission is thought to occur via blood transfusions, sexual transmission, and vertical transmission. Zika virus initially replicates in dendritic cells near the site of inoculation before spreading to lymph nodes and then the bloodstream.

Zika virus infection is cause by Zika virus, an enveloped, single stranded positive sense RNA virus. Zika virus is a type of flavivirus and is primarily transmitted through mosquitoes.

A schema for the classification of Zika virus infection has yet to be developed.

The broad-ranging clinical symptoms characteristic of Zika virus infection often cause it to be commonly misdiagnosed with multiple similar diseases that are also from the Flaviviridae virus family. Zika virus infection has similar clinical presentation to Dengue fever, yellow fever, West Nile virus, and Japanese encephalitis. Zika virus infection is distinct in its milder clinical manifestations and short length of infection. The association between Zika virus infection and complications that include congenital anomalies and neurological syndromes is also distinctive. Of note, patients bitten by mosquitoes may be concomitantly infected with Zika virus and other mosquito-borne infections, and co-infection should always be considered.

In 2015, Zika virus infection outbreaks rose dramatically, particularly in Brazil as observed by the manifestation of a correlated complication, microcephaly, in infants born to mothers with Zika virus infection, an incidence of approximately 100 per 100,000 infants. The majority of Zika virus infection cases are reported in South Africa and Tropical Asia. As of 2014, Zika virus infection outbreaks have also become more common in South America. Cases reported in other regions of the world are attributed to travel from areas with outbreaks. Zika virus infection affects all age groups, though newborn infants are particularly vulnerable due to the risk of transmission from their mothers upon birth.

The most potent risk factor in the development of Zika virus infection is travel to endemic areas. Other risk factors include exposure to infected individuals via blood transfusion, sexual intercourse, or vertically to fetuses from infected mothers.

Patients exposed to Zika virus will develop symptoms between 3 and 12 days after contracting the disease. Symptoms will typically begin with a mild headache and progress to include a maculopapular rash that spreads across the body within 24 hours, followed by fever, malaise, and back pain. The symptoms typically last 4-7 days. The prognosis is excellent, with the majority of patients recovering fully. Complications include neurological and congenital sequelae, particularly Guillain-Barré syndrome and microcephaly. The association between Zika virus infection and microcephaly has not yet been confirmed.

The most common symptoms of Zika virus include fever and maculopapular rash. Additional symptoms include arthralgia, conjunctivitis, myalgia, headache, retro-orbital pain, and vomiting.

Physical examination of patients with Zika virus infection is usually remarkable for fever and a maculopapular rash that often includes the face, trunk, and extremities (may include the palms and soles). Other physical examination findings include non-purulent conjunctivitis and edema.

The diagnosis of Zika virus infection is usually made by detection of elevated IgM and IgG Zika virus antibodies by ELISA or viral RNA by RT-PCR. Non-specific lab findings include elevated markers of inflammation, mild neutropenia, normal leukocyte count or mild leukocytosis with normal platelet count and liver function tests.

According to the CDC, pregnant women suspected to have Zika virus infection may be advised to undergo amniocentesis and testing of histopathologic samples of the placenta and umbilical cord, frozen placental tissue and cord tissue for Zika virus RNA, and cord serum for Zika and dengue virus IgM and neutralizing antibodies.

According to the CDC, Zika virus testing is recommended among 1) infants with microcephaly or intracranial calcifications born to women who traveled to or resided in an area with Zika virus transmission while pregnant, or 2) infants born to mothers with positive or inconclusive test results for Zika virus infection. When an infant is born with microcephaly or intracranial calcifications to a mother who was potentially infected with Zika virus during pregnancy, the infant should be tested for Zika virus infection and given an ophthalmologic examination. For an infant without microcephaly or intracranial calcifications born to a mother who was potentially infected with Zika virus during pregnancy, subsequent evaluation is dependent on results from maternal Zika virus testing. Developmental monitoring and screening during the first year of life is recommended for all children with congenital Zika virus infection.

In the USA, all fetal tissue suspected to be infected with Zika virus must be collected and submitted to the Centers for Disease Control and Prevention (CDC) for testing. Histopathology, immunohistochemical staining, and reverse transcription-polymerase chain reaction (RT-PCR) will be performed on fixed tissues. RT-PCR can be performed on frozen tissues.

At present, Zika virus testing for the assessment of risk for sexual transmission is of uncertain value, because current understanding of the incidence and duration of shedding in the male genitourinary tract is limited to one case report in which Zika virus persisted longer than in blood.^[1] The CDC does not recommend testing men for the purpose of assessing risk for sexual transmission.

There are no other diagnostic studies associated with Zika virus infection.

The mainstay of therapy for Zika virus infection is supportive care. Supportive care includes includes rest, adequate fluids intake, and administration of antipyretics and analgesics. Aspirin and other NSAIDs should be avoided until Dengue fever is ruled out, as NSAIDs may increase the risk of hemorrhage in cases of Dengue fever. Antiviral treatment is not recommended for the management of Zika virus infection. The general principles of medical therapy for the management of Zika virus apply to pregnant women. Treatment of congenital Zika virus infection is supportive and should address specific medical and neurodevelopmental issues for the infant’s particular needs. Mothers are encouraged to breastfeed infants even in areas where Zika virus is found, as available evidence indicates that the benefits of breastfeeding outweigh any potential risks associated with Zika virus infection transmission through breastmilk.^[2][3]

Surgery is not recommended for the management of Zika virus infection.

There are no vaccines available to prevent Zika virus infection. Since the virus is usually transmitted through mosquitoes, effective preventive measures revolve around avoiding mosquito bites, which can be achieved by using insect repellent, installing mosquito bed nets and window/door screens, wearing long sleeves and long pants, and removing potential breeding sites from indoor/outdoor premises. Once infected, individuals may be re-infected in the future. Men who reside in or have traveled to an area of active Zika virus transmission who have a pregnant partner should abstain from sexual activity or consistently and correctly use condoms during sex (i.e., vaginal intercourse, anal intercourse, or fellatio) for the duration of the pregnancy. Men who reside in or have traveled to an area of active Zika virus transmission who are concerned about sexual transmission of Zika virus might consider abstaining from sexual activity or using condoms consistently and correctly during sex.

The CDC has issued level 2 alert (practice enhanced precautions) for travelers to Cape Verde, the Carribean, Central America, Mexico, Pacific Islands, and South America.

Zika virus may be detected in blood for a short period of time. Although rare, there have been reports of Zika virus transmission via blood transfusions. The risk of Zika virus infection in the continental USA due to blood transfusion is extremely low. The U.S. Food and Drug Administration (FDA), the Red Cross, and the British National Health Service Blood and Transplant Agency announced that individuals who traveled to Zika-affected regions would be ineligible to donate blood for at least 28 days. The Canadian Blood Agency announced that individuals who traveled to Zika-affected regions would be ineligible to donate blood for at least 3 weeks (21 days).

Local, state, and territorial responses to Zika cases or an outbreak will differ in jurisdictions where Aedes species mosquitoes (Ae. aegypti and Ae. albopictus) are endemic, and, therefore, local mosquito populations could become infected with Zika virus. In the USA, the Centers for Disease Control and Prevention (CDC) has developed resources to help state, local, and territorial public health officials prepare for potential Zika virus cases.

All states need to provide public health information, particularly to pregnant women, and to assess returning travelers who may have contracted Zika virus infection. States with known Aedes aegypti mosquitoes need to intensively monitor for cases in returning travelers and prepare to find and stop clusters of Zika before they become widespread. States with Aedes albopictus mosquitos need to presume transmission is possible and be ready to prevent, detect, and respond to cases and possible clusters of Zika infection. The objective of a phased, risk-based response using Zika virus surveillance data is to implement public health interventions appropriate to the level of Zika virus risk in a community, county, or state.

There is currently no vaccine in advanced development to prevent Zika virus infection.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D., Nate Michalak, B.A., Serge Korjian M.D., Yamuna Kondapally, M.B.B.S[2]

Zika virus is a vector-borne pathogen transmitted via the Aedes mosquito, which also transmits the dengue and chikungunya viruses. Human-to-human transmission by sexual intercourse has been confirmed. Zika virus is thought to initially replicate in dendritic cells near the site of inoculation before spreading to lymph nodes and then the bloodstream.

Through mosquito bites

Zika virus is primarily transmitted to humans via the bite of an infected Aedes mosquito. These mosquitoes are also vectors for dengue and chikungunya viruses.^[1][2]

From mother to child

• Infected pregnant women can transmit the Zika virus during the pregnancy or around the time of birth.^[2]
  • Intrauterine
  • Perinatal
• Prolonged circulation of ZIKV RNA is demonstrated in serum of pregnant women.^[3][4]
• There are no reports of infants acquiring Zika virus through breastfeeding. Due to the nutritional benefits of breastmilk, mothers are encouraged to breastfeed even in areas where Zika virus is endemic.

Sexual transmission

Zika virus has also been suspected to be sexually transmitted between humans.

• Asymptomatic males to their female partners
• Symptomatic female to her male partner
• Symptomatic or asymptomatic males to males
• Longer shedding of Zika virus is detected in semen
• The maximum documented time of Zika virus RNA detection in semen after onset of symptoms is 188 days (potentially for up to 6 months)
• Zika virus has been detected for up to 11 days in vaginal fluid^[5]

Blood transfusion

• Transmission through blood transfusion is possible (very likely but not confirmed) as Zika virus has been identified in asymptomatic donors during an ongoing outbreak.^[2][6][7][8]
• In non-pregnant individuals, the viremia with ZIKV may produce 8.1 million copies/ml in serum, which can last for 1-2 weeks.^[9][10][11]
• Whole blood has a longer period of viremia than serum.
• ZIKV has been detected in whole blood as late as 58 days after onset of symptoms.^[12]

Laboratory exposure

• There has been one reported laboratory-acquired Zika virus disease in United States.^[2]

• Mosquito-borne Zika virus is thought to initially replicate in dendritic cells near the site of inoculation before spreading to lymph nodes and then the bloodstream.
• One study indicates that Zika virus replicates in cellular nuclei, as opposed to other flaviviruses that do so in the cytoplasm.^[13]
• Virus is detectable in blood with in 3 to 4 days of symptom onset.
• The virus can be detected in blood, urine, cerebrospinal fluid, amniotic fluid, semen, and saliva.
• The maximum documented time of Zika virus RNA detection in semen after onset of symptoms is 188 days.
• Once a person has been infected with Zika, they are likely to be protected from future infections.
• Zika virus can be killed by potassium permanganate, ether, temperatures >60°C, but is not effectively neutralized by 10% ethanol.^[1]

Fetus

• The exact pathogenesis of Zika virus infection in the fetus is not fully understood.^[14]
• The crucial period for brain development is the first trimester of pregnancy. ZIKV infection during this period is more strongly associated with microcephaly than infections later in the pregnancy.
• Based on in vitro investigational studies, Zika virus infects the human embryonic cortical neural progenitor cells (hNPCs) which lead to disruption of cell cycle, increased cell death (via caspase-3-mediated apoptosis), and gene dysregulation resulting in cortical thinning and microcephaly.^[15]
• Infected hNPCs also produce infectious Zika particles.

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On gross pathology, the characteristic findings of Zika virus infection in neonates include:^[16][17]

• Microcephaly
• Widespread brain calcifications in the cortex and sub-cortical white matter
• Ventricular enlargement secondary to cerebral atrophy

• There was a significant increase in patients with Guillain-Barré syndrome and congenital microcephaly during the 2014 Zika virus outbreak in French Polynesia and the 2015 Zika virus outbreak in Brazil.
• According to WHO, ZIKV infection during pregnancy is the cause of congenital brain abnormalities including microcephaly.^[18]
• Current evidence does not show which specific environmental and host factors interact with Zika virus to increase the risk of an affected pregnancy or of GBS or whether there are specific factors that also have an effect in certain places.^[18]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D., Nate Michalak, B.A., Serge Korjian M.D., Yamuna Kondapally, M.B.B.S[2]

Zika virus infection is caused by Zika virus, an enveloped, single stranded positive sense RNA virus. Zika virus is a type of flavivirus. Mosquitoes are the primary disease vector of Zika virus.

• Zika virus, also known as ZIKV is an enveloped, icosahedral virus with a single-stranded, positive sense RNA genome. The most closely related virus is the Spondweni virus and is one of the two viruses in the Spondweni virus clade.^[1]
• The Zika virus genome consists of 10,794 nucleotides that encode 3,419 amino acids.^[2]
• Zika virus is a member of the Flaviviridae family and of the flavivirus genus.
• There are two lineages for Zika virus: African and Asian.^[2]

Transmission of Zika virus to humans is thought to occur mainly through infected mosquitoes.

• The following species have been identified as vectors for Zika virus:^[3]

The table below compares the characteristics of 2 common Aedes species: Ae. aegypti and Ae. albopictus

Table adapted from https://www.cdc.gov/

Aedes aegypti	Aedes albopictus
Bright, silvery, lyre-shaped dorsal pattern and white banded legs	Single longitudinal silvery dorsal stripe and white banded legs
Urban areas with or without vegetation	Associated with thickets and arboreal vegetation
Bites, rests, and lays eggs both indoors and outdoors	Mostly an outdoor (garden) mosquito
Sneaky biter	Aggressive biter
Blood from humans mainly, and domestic mammals to a lesser extent	Humans and domestic and wild vertebrates
Major production places are human-made containers, treeholes, and bamboo internodes holding water	Preference to treeholes and bamboo internodes with water, can also utilize human-made containers for its immature development
Most containers with water used for immature development are within or in close proximity to households	Utilizes water-filled containers around or further away from households

Table adapted from the Centers for Disease Control and Prevention (CDC)[3]

Read the CDC infographic on life cycle of Aedes aegypti mosquito here

Zika virus can be trasmitted via mother to child and sexual trasmission.

• A pregnant woman who is already infected with Zika virus can pass the virus to her fetus during the pregnancy or around the time of birth.
• Zika virus has been detected in amniotic fluid, which suggests that Zika virus may cross the placental barrier and vertical transmission is possible.^[4] Mosquito-borne ZIKV is thought to initially replicate in dendritic cells near the site of inoculation before spreading to lymph nodes and then the bloodstream. ZIKV can be killed by potassium permanganate, ether, temperatures >60°C, but is not effectively neutralized by 10% ethanol.^[2]
• There are no reported cases of Zika virus spread through breastfeeding. Due to the nutritional benefits of breastmilk, mothers are encouraged to breastfeed their infants even in areas where Zika virus is endemic.

• Zika virus can be sexually transmitted between humans.^[5][6]
• It can be transmitted even if the infected person does not have symptoms.
• Zika virus remains in semen longer than in other body fluids (vaginal fluids, urine, and blood).^[7]

• Zika virus can be transmitted via blood transfusion but there are no cases reported in United States.
• The transmission of virus through blood transfusion has been reported in Brazil. These cases are under investigation.
• On August 26, 2016, the US Food and Drug Administration (FDA) issued revised guidelines recommending universal testing of donated whole blood and blood components for Zika virus in the United States and its territories.

• There has been one reported laboratory-acquired Zika virus disease in United States.^[8]

• Following a mosquito bite, the incubation period for Zika virus in humans is approximately 3 to 12 days.
• Detection of Zika virus is primarily based on the isolation of RNA from blood serum through PCR in acutely ill patients.^[9]
• An ELISA has also been developed by the Centers for Disease Control and Prevention to detect IgM against ZIKV.^[2]
• Zika virus has a short viremic period, such that the virus may be detected in serum 3-5 days following the onset of symptoms. Zika virus can be detected in urine up to 10 days following the onset of symptoms.^[9]