The Zika Virus (ZV): Causes and Features

The Zika Virus (ZV): Causes and Features The Zika Virus (ZV) is a mosquito-borne flavivirus that is transmitted by Aedes species, specifically A. aegypti, africanus, and the albopictus mosquitoes.1,2,3 ZV has recently gained global concern as recent outbreaks have occurred in the Americas. However, the virus was first isolated in 1947 from a macaque monkey in the Zika forest located in Uganda. The virus migrated to the Southeast Asian countries in 1945; the first human case was reported in Nigeria in 1952. Multiple epidemics have been reported since its first reported case in 1952. The first large scale outbreak occurred on Yap Island, Micronesia in 2007. Between April and July 2007, there were 49 confirmed and 59 probable cases of the ZV infection.4 During this time, no deaths were reported. Of the 6,982 Yap Island residents that were at least three years of age, 5,005 (roughly 73%) were estimated to be infected with ZV during this outbreak.4 The second major outbreak occurred in the French Polynesia between October 2013 and February 2014. As of February 14, 2014, 8,510 suspected cases were reported.5 The largest and current outbreak in the Americas began in Brazil. Brazils first reported locally transmitted case in Brazil occurred May 2015. The ZV entry into Brazil is not clear; however, it is proposed that travelers from ZV-infected areas of Chile, Asia, and Africa brought it during 2014 sporting events. This outbreak brought ZV back into the news as many athletes became weary of contracting ZV while participating in the 2016 Rio de Janeiro Olympic Games. Based on rates of asymptomatic infection, an estimated 500,000 to 1.5 million people in Brazil were affected with ZV.6 As of January 18, 2017, there are 738,783 confirmed cases, with the highest number of cases reported in Brazil, Columbia, and Venezuela.6 Mexico, Central America, the United States, and the Caribbean including the U.S. Virgin Islands and Puerto Rico reported confirmed cases of the virus. Regions outside of the Americas, specifically Singapore, Thailand, and Cape Verde reported confirmed cases of ZV. In January 2016, a traveler returning from Latin America to Texas reported the first U.S. case of ZV infection. As of March 22, 2017, more than 5,100 cases of ZV were reported.7 Of those reported, 4,861 cases were travel-related, 1,617 cases occurred in pregnant women, and 45 cases were sexually transmitted.8,9,10 The first case of transmission within the U.S. was in Florida. Those who were traveling to the U.S. from other affected areas reported many of the subsequent ZV cases. Every state has reported laboratory-confirmed symptomatic ZV disease. Only Florida and Texas have reported local-transmission of ZV.9 ZV is a member of the virus family Flaviviridae. The Flaviviruses include arboviruses that are transmitted through mosquitoes to humans. Ranging from 40-50 nm in diameter, the Flaviviruses are positive-sense and single-stranded RNA. The ZV is an icosahedral capsid enveloped virus. Several small proteins surround the RNA genome; the capsid proteins cover the core, creating its icosahedral shape. The lipid bilayer envelope membrane contains both the membrane and the envelope proteins, which are glycosylated in many flaviviruses.11 Vectors, generally mosquitoes, are infected when they feed on viremic hosts. Humans are generally the accidental hosts. The mosquitoes will take a blood meal from an infected host and transmit it to another individual. In the U.S., these mosquito vectors are isolated to the southeastern states. Aerosols or contaminated food products can also transmit Flaviviruses; however, this only occurs under certain circumstances. Other diseases associated with Flaviviruses include Japanese encephalitis, yellow fever, dengue fever, chikungunya fever, and hemorrhagic fever. ZV is an arthropod-borne virus (arbovirus) that infects their vectors after ingestion of a blood meal from aviremic non-human vertebrate. Some arthropods can be infected by saliva-infected transmission. The arthropod vectors develop chronic systemic infections as the virus will penetrate the gut and spread to the salivary glands. This dissemination to the salivary glands is known as extrinsic incubation, which lasts about 1-3 weeks in mosquitoes.12 The mosquito is not harmed by the infection. The ZV pathogen has two lineages that are based on phylogenetic analysis of viral envelope proteins:13 the African and Asian lineages. The African lineage is primarily restricted to the African countries of Central African Republic, Kenya, Nigeria, Senegal, and Uganda. The Asian lineage seems to be the strand that has been seen in recent outbreaks. This lineage has been circulating in the Southeast Asian countries since the 1950s, in French Polynesia in 2013, and the Americas in 2015. ZV is primarily transmitted by a bite of an infected Aedes mosquito. Humans are the likely main reservoirs; however, during outbreaks, human-to-vector-to-human transmission is common. Other modes of transmission of ZV are sexual transmission and maternal-fetal transmission during pregnancy. The estimated reproduction number of ZV infection during the Columbia epidemic in 2015-2016 ranged 2.2-14.8.14 During the Yap Island and French Polynesia epidemics, the estimated reproduction number ranged 4.3-5.815, that is comparable to dengue and chikungunya fevers, which are from the same family as ZV. Various sexual transmission has been reported: multiple cases of male to female transmission in the U.S. between January-April 201615, one case of male-to-male anal intercourse17, one case of female-to-male transmission18, and an asymptomatic case of male-to- female transmission.19 The duration of ZV RNA persistence in semen has been monitored to determine the degree of ZV infectivity. Detection of the viral RNA in semen was found up to 188 days after symptom onset in an Italian man who contracted ZV infection while traveling in Haiti.20 Additionally, it was found that ZV was found in semen up to 92 days after the illness onset.21 Various reports regarding vaginal secretions and bodily fluids have been monitored for ZV infectivity as well. Viral RNA in vaginal secretions were found up to 14 days after symptom onset.22 Viral RNA has been detected in urine and saliva in 54 days and serum up to 67 days.23 These findings were monitored in an infant whose mother displayed ZV infection symptoms during week 26 of her pregnancy and tested positive for ZV after birth. No reports of ZV in other bodily fluids of the reproductive tracts, specifically the follicular fluid, have been identified. There are potential modes of transmission that have been explored and discussed. Blood transfusion or blood products and breast-feeding have been linked to possible transmission.2 Viral RNA has been detected in the breast milk of those women who have been infected. There was a detection of ZV and viral RNA in breast milk collected 4 days postpartum from a woman who developed ZV symptoms during prenatal period.24 Breast-feeding is not a confirmed route of transmission, as it has not yet been thoroughly evaluated. Kissing is not a confirmed route of transmission. However, one case of transmission was reported from an elderly patient with a high viral load to a family member who reported kissing and hugging an infected patient, but had no known direct contact with infected bodily fluids.25 Saliva, urine, and conjunctival fluid have been detected sources, but transmission has not been confirmed. The incubation period of the ZV is usually 3-12 days. About 75-80% of ZV infections are asymptomatic.1 If ZV becomes symptomatic, disease is generally mild. Common symptoms include rash, fever, joint pain (known as arthralgia), and conjunctivitis. Symptoms generally resolve within a week. Pathogenesis of the ZV is not well studied; early data indicates that ZV will infect and replicate in dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells.26 Infected epidermal keratinocytes will undergo apoptotic cell death. The viral replication prompts an innate immune response. As a result, type I interferons in infected cells are produced. The risk factors that put an individual at a greater risk for contracting ZV are those who live or travel to endemic or epidemic areas, mosquito exposure, and unprotected sexual contact with someone who has recently traveled to areas with active transmission. To determine if an individual is at risk, asking patients about travel history to ZV-infected areas, noting specific dates and location of travel, and discussing risk factors for transmission are important. The Centers for Disease Control and Prevention (CDC) concluded that ZV is a cause of microcephaly and other severe fatal neural defects, such as Guillain-Barrà © Syndrome. This is a complication associated with pregnancy. The CDC has determined this based on epidemiologic evidence showing an increase number of infants born with microcephaly during the French Polynesian and Brazilian outbreaks.3 Through cohort and case series studies, the CDC has found a cause and effect between the ZV and various brain defects, such as microcephaly, cerebral malformation, intracranial calcifications, neurologic dysfunction, and ophthalmologic abnormalities.3 Various studies have detected ZV in brain tissue of affected fetuses. Brain tissue was collected from infants with microcephaly who later died and in the placenta of mothers who suffered a miscarriage. As of result of these findings, the CDC has established two surveillance systems to monitor pregnancies and congenital outcomes in women with ZV infection: The U.S. Zika Pregnancy Registry and Zika Active Pregnancy Surveillance System (ZAPSS) for women in Puerto Rico. Due to the CDC findings regarding malformations of embryos, ZV is considered teratogenic. Microcephaly is a common defect of infants that have contracted ZV from their mothers. Microcephaly is a condition where a baby is born with a smaller than normal head or the head stops growing after birth.27 Because there is a delay in the growth of a head, there are neural developmental abnormalities. Babies born with microcephaly typically have physical and learning disabilities as they continue to grow and age. During ZV outbreaks, there was an increased incidence of microcephaly reported. During the 2013 French Polynesia outbreak, 8,750 suspected ZV cases were reported.28 Estimated risk of microcephaly reported 95 cases per 10,000 women who contracted ZV in the first trimester, while the baseline microcephaly prevalence for that area was two per 10,000 neonates.28 In 2015, an annual rate of microcephaly in Brazil increased from 5.7 cases per 100,000 live birth in 2014 to 99.7 cases per 100,000 in 2015.29 For diagnosing ZV, polymerase chain reaction, specifically quantitative or qualitative real-time reverse transcription polymerase chain reaction (RT-PCR) is considered the gold standard. RT-PCR distinguishes ZV from other flaviviruses such as dengue and chikungunya fevers. This test can be performed on serum, urine, or blood; however, serum and urine are commonly used. Sensitivity of RT-PCR can vary within 14 days of symptom onset. If symptoms are less than 14 days from onset, it is recommended that RT-PCR of urine or serum samples be performed. Cohort studies have found that RT-PCR of plasma samples appear more sensitive than RT-PCR of urine samples within the first 5 days of symptomatic ZV infection.30 In addition to performing RT-PCR, a physical examination must be done to diagnosis ZV. During physical examination, a clinician should examine a patient for fever, maculopapular rash, arthralgia, and conjunctivitis. Most symptomatic patients will present with rash and conjunctivitis.1,2 Clinicians should access the patients risk of exposure, such as travel history to an area of active transmission and unprotected sexual contact with someone who recently traveled to an affected area. Bloodwork should be completed. Generally bloodwork results are normal, but mild leukopenia (low white blood cell count), thrombocytopenia (low platelet count) and hepatic transaminitis (elevated liver enzymes) have been reported with ZV infection.31 Patients with suspected ZV should be evaluated for dengue and chikungunya virus infections as they all cause symptoms that overlap. The same mosquito vector transmits ZV, dengue fever, and chikungunya fever. Other illnesses to differentiate are malaria, influenza, infectious mononucleosis, and acute HIV infection. Other ZV testing options include serum virus-specific immunoglobulin M (IgM) and culture. IgM testing has a greater sensitivity at the end of the first week of illness. IgM has the potential to cross-react with other flaviviruses.2 The FDA approved the CDC IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA) as the first antibody test for emergency evaluation in selected laboratories.32 In addition to the Zika MAC-ELISA, Trioplex Real-Time RT-PCR assay can be used for ZV diagnosis. Culture is generally not used as a tool, but rather an aid to determine if any additional infections are present. If a patient is symptomatic or thought to have contracted the infection due to recent ZV exposure, these diagnostic tools are used to diagnose ZV. Coinfection with other viral illnesses transmitted by the same infected Aedes mosquito can occur. Dengue and chikungunya fever are the common illnesses that are associated with ZV. These coinfections were found in Nicaragua. Between September 2015 and April 2016, 356 patients in Nicaragua with suspected arboviral illnesses provided serum samples for ZV, dengue, and chikungunya fevers.33 A real-time RT-PCR confirmed the presence of a virus. Of those that provided serum samples, 263 had at least one of these viruses, 71 of these cases had a coinfection with 2-3 viruses. Suspected cases should be reported to local health departments in the U.S. for coordination of testing, care, and spread prevention. The CDC and selected state health departments perform more testing to confirm the diagnosis of ZV. The CDC provides instruction for sending ZV samples for testing. There are specific considerations for pregnant women. In 2016, the CDC provided guidelines for evaluation and management for pregnant women and infants with suspected ZV infections (Appendices 1 and 2). Possible Zika virus exposure should be discussed with all pregnant women during each prenatal visit. Testing symptomatic pregnant women should be based on the time of potential exposure. Additional testing is needed to rule out other illnesses, such as dengue, chikungunya, and yellow fever. Other illnesses to consider include malaria, rubella, measles, parvovirus B19 infection, influenza, rickettsial illnesses, enterovirus illnesses, acute HIV infection, and group A streptococcal infection.34 If asymptomatic pregnant women have an ongoing risk for exposure, routine ZV IgM testing should be performed at visits during the first and second trimesters. Offering RT-PCR testing for asymptomatic women with possible infection is recommended for those who have had exposure within the past two weeks of their prenatal visits. Positive results from RT-PCR testing confirm infection. However, a negative result does not exclude infection; IgM testing should be performed for further analysis. In addition to testing, if ZV is suspected or confirmed, serial ultrasounds are necessary every 3-4 weeks to monitor fetal growth and anatomy. Decisions on amniocentesis should be discussed as it is considered a high-risk procedure. Amniocentesis is a medical procedure where a small sample from the amniotic sac surrounding a fetus is sampled and examined for genetic abnormalities. The optimal time to perform this procedure to accurately diagnose ZV is unknown. Amniocentesis is generally performed after 15 weeks of gestation. Because of the uncertainty surrounding the accuracy of this test, amniocentesis should be discussed on an individualized basis. Currently there is no specific antiviral treatment available for ZV. The recommended treatment is supportive with a focus primarily on rest, hydration, and fever and pain control. Acetaminophen is preferred to address fever and pain. Until dengue fever can be excluded, aspirin and other nonsteroidal anti-inflammatory (NSAIDS), such ibuprofen and naproxen, should be avoided to reduce the risk of hemorrhage. Most infected individuals recover within a week. Hospitalization or severe disease is not common. Those individuals infected with ZV are encouraged to avoid mosquito exposure during the first week of symptom onset to reduce the risk of continued transmission.2,3 While infected, individuals should isolate themselves, refrain from sexual contact, and avoid mosquito exposure. Mosquito avoidance is the main option for prevention and further spread of ZV. This is the key to preventing illness while traveling to endemic or epidemic affected regions. Eliminating mosquito habitat is also recommended. Mosquitoes can breed in small amounts of water. Individuals traveling in affected locations should wear light-colored clothing that completely cover the body, use mosquito repellents with DEET, and utilize mosquito nets. There are additional precautions for pregnant women and women trying to become pregnant. Women should avoid traveling to areas of active transmission. Consulting healthcare providers before traveling is recommended. The CDC instructs pregnant women to avoid traveling to elevations less than