ZIKA VIRUS DISEASE
Zika virus is an emerging mosquito-borne flavivirus. In 1947 researchers at the East African Research Institute in Entebbe, Uganda, were studying yellow fever and placed a caged rhesus macaque in the nearby Zika Forest. The monkey developed a fever and from its serum was isolated a transmissible agent first described as Zika virus in 1952. Initially, Zika virus, borne by arboreal mosquitoes such as Aedes africanus, infected wild primates and rarely infected humans, even in highly enzootic areas. The Zika virus appears to have mutated in character while expanding its geographical range, transforming from a localized endemic, mosquito-borne infection producing only a mild illness to an infection causing explosive outbreaks linked with neurological disorders including Guillain-Barré syndrome and microcephaly.
From January 1, 2015, through January 7, 2016, three of the poorest states of Brazil—Paraiba, Pernambuco, and Bahia—reported births of microcephalic infants 20 standard deviations above their historical average. The strain of Zika virus most closely related to the one that emerged in Brazil was originally isolated from patient samples in French Polynesia. In all probability, Zika virus arrived in Brazil in 2014 during the Confederation Cup, when Tahiti’s soccer team and its supporters visited a variety of Brazilian venues.
Zika virus is transmitted by the Aedes aegypti mosquito. Excepting West Nile virus, which is predominantly spread by culex-species mosquitoes, the arboviruses recently reaching the Western Hemisphere have all been transmitted by Aedes mosquitoes. Millennia ago North African villagers began storing water in their dwellings, giving arboreal A. aegypti a new medium for depositing their eggs— domestic water-containing vessels. The hatched mosquitoes then fed on humans, evolving into an entirely new maintenance cycle of human–A. aegypti–human transmission. Now, thousands of years later, the worst effects of this evolutionary cascade are being seen in the repeated emergence of arboviruses in human ecosystems. The distribution of A. aegypti is now the most extensive ever recorded, extending across all continents including North America.
Another Zika virus vector is Aedes albopictus, commonly known as the Asian tiger mosquito, named for its white striped legs. A. albopictus is of medical importance due to its aggressive daytime human-biting behavior and ability to vector many viruses, including dengue, La Crosse, and West Nile. Figure 1 shows the estimated range of the Aedes aegypti and Aedes albopictus mosquitoes in the United States.
FIGURE 1 Range of Zika-transmitting mosquitoes in the United States. (Source: www.cdc.gov/zika/vector/index.html)
Most significantly, pregnant mothers may vertically transmit the virus to the developing fetus, potentially resulting in microcephaly. Zika virus has been isolated in semen and vaginal secretions. Male to female as well as female to male sexual transmission of the Zika virus has been reported. Blood transfusions have been a source of transmission outside of the United States. The blood supply in the U.S is tested for Zika virus. Although Zika virus has been detected in breast milk, there are no reports of infants being infected with Zika virus through breastfeeding.
From its discovery until 2007, there were only 14 confirmed human cases of Zika virus infection. Zika has followed a pattern of dispersion analogous to chikungunya and has spread pandemically from west to east. Zika has now circled the globe.
The risk of Zika virus infection for pregnant women is more pronounced because of the potential link to microcephaly of the infant. There is no evidence that pregnant women are more susceptible to Zika virus infection or have more severe disease during pregnancy. While the virus generally clears from the blood in seven days, it has been detected in the blood of pregnancy women for at least 70 days. Based on what is known about similar arbovirus infections, once a person has been infected and developed antibodies to Zika virus, he or she is likely to be protected from a future Zika infection. Based on currently available evidence, once the virus has cleared from the blood of a Zika-infected woman, she is not felt to be at risk of having a future child with a Zika-related birth defect.
The Zika virus is a member of the Flaviviridae virus family, which includes dengue, yellow fever, West Nile, and Japanese encephalitis viruses. Zika is a single-stranded, positive-sense RNA virus that has been fully sequenced. It is one of many arthropod-borne arboviruses. Monkeys are the common vertebrate host of the virus. Arboviruses oftentimes have complex natural transmission cycles involving mammals, birds, and blood-feeding arthropod vectors.
Until recently, only a few arboviruses have caused clinically significant human diseases. These include mosquito-borne alphaviruses such as chikungunya and flaviviruses such as dengue and West Nile. The most historically important of these is yellow- fever virus, the first recognized viral cause of deadly epidemic hemorrhagic fever.
Population-based mosquito control measures are recommended to prevent the spread of Zika virus. Although yellow fever has historically been prevented entirely by aggressive mosquito control, in the modern era vector control has been problematic because of expense, logistics, public resistance, the development of resistance to the pesticides used and their collateral adverse effects on humans.
Although a chemical war against the vector can have short-term effects, programs for improving urban infrastructure and environmental sanitation with a stable supply of potable water would have lasting results. Among the best preventive measures against Zika virus are house screens, air-conditioning, and removal of yard and household debris and containers that provide mosquito-breeding sites, luxuries often unavailable to impoverished residents of crowded urban locales where such epidemics take their greatest toll. Releasing mosquitoes that are sterile or genetically modified to die before they can reproduce is being investigated. Researchers funded by the Bill and Melinda Gates Foundation have proposed infecting mosquitoes with the Wolbachia bacteria, which seem to inhibit the transmission of dengue and other viruses by the mosquito.
Because of the association between Zika virus infection and microcephaly in fetuses, pregnant women and those considering pregnancy should reference the CDC website at http://www.nc.cdc.gov/travel/page/zika-travel-information for travel alerts and consider postponing travel plans to regions at risk. Women who are considering becoming pregnant should consult with their physicians for preconception counseling.
The CDC recommends that women who have had Zika virus exposure through travel or sexual contact and do not have ongoing risks for exposure should wait at least 8 weeks from date of diagnosis, symptom onset (if symptomatic), or last possible exposure before attempting to conceive. During this waiting period, either abstinence should be practiced or barrier contraception with condoms should be used. The 8 week waiting period may decrease the risk of maternal- fetal transmission of the Zika virus.
For men, the CDC recommends waiting at least 6 months from date of diagnosis, symptom onset (if symptomatic), or after the last possible exposure before attempting conception with their partner.
During this waiting period, either abstinence should be practiced or barrier contraception with condoms should be used. The recommendation to wait at least 6 months for asymptomatic men is based on the length of time the Zika virus RNA has been detected in semen of symptomatic men and the lack of evidence that the risk of sexual transmission differs in symptomatic and asymptomatic men. Zika virus typically remains in the semen for longer periods of time than other body fluids.
Pregnant women and men and women who are considering parenthood and who live in, have travelled to, must travel to or are considering travel to areas at risk should consult their physician and reference the CDC website for travel alerts and pregnancy counseling recommendations.
Avoiding mosquito bites is important for disease control. There are hundreds of insect repellants sold in the United States. These insect repellants have different ingredients, different concentrations of ingredients and different combinations of ingredients. Furthermore, different species of mosquitoes may be differentially repelled by different repellants. Though research is limited, the Aedes aegypti and Aedes albopictus mosquitoes seem to be most effectively repelled by products that contain at least 25% DEET (N,N-diethyl-m-toluamide), 30% Oil of Lemon Eucalyptus or 20% picaridin. When applied appropriately, these ingredients may repel mosquitoes for approximately 7 hours and seem to be safe when used during pregnancy. Products with lower concentrations of DEET, Oil of Lemon Eucalyptus and picaridin are less effective. Products containing IR3535, 2-undecanone and products made from natural plant oils such as citronella, lemongrass oil, cedar oil, rosemary oil, cinnamon oil, and geraniol seem to be ineffective against Zika-transmitting mosquitoes. Insect repellents can be used with sunscreen, but the sunscreen should be applied first.
Additional protection from mosquito bites can be achieved by treating outer clothing with permethrin. Permethrin is an insect repellent and insecticide. Though it is poorly absorbed, permethrin should not be applied directly to the skin and it should not be used on underclothing. The EPA recommends that clothes treated with permethrin should be washed separately from clothes that are not treated. If washed together, underclothing may absorb permethrin into the fabric which may increase the risk of absorption. Permethrin- treated clothing will retain repellent activity through multiple washes. The EPA indicates there is no evidence that exposure to permethrin results in adverse effects for pregnant or nursing mothers or adverse developmental effects in their children. It can be used on the outer clothing of children older than 2 months of age.
Prevention of Mosquito Bites
There are no Zika vaccines in advanced development, although a number of existing flavivirus vaccine platforms could presumably be adapted.
The incubation period is estimated to be 3 to 12 days. Serosurvey results from the Yap Islands indicate that only 19% of persons who were infected had symptoms that were attributable to Zika virus.
Common symptoms were macular or papular rash (90% of patients), fever (65%), arthritis or arthralgia (65%), nonpurulent conjunctivitis (55%), myalgia (48%), headache (45%), retro-orbital pain (39%), edema (19%), and vomiting (10%). The rash is generally maculopapular and pruritic, and fever, when present, is generally short-term and low- grade. In more than 60 years of observation, severe disease requiring hospitalization is uncommon and case fatality is low. Rarely, immune thrombocytopenia purpura has been linked to Zika.
In a “pure” Zika epidemic, a diagnosis can be ascertained on clinical grounds. However, dengue and chikungunya have similar clinical presentations and have been epidemic in the Americas, confounding a clinical diagnosis.
The CDC website should be consulted for Zika virus testing of women who are symptomatic or asymptomatic during pregnancy. Instructions for submitting laboratory specimens can be found at https://www.cdc.gov/zika/hc-providers/testing-guidance.html.
Cross-reaction with related flaviviruses (e.g., dengue and yellow- fever viruses) is common, complicating the immunologic interpretation of infection. Physicians who deliver an infant suspected of suffering the effects of maternal Zika virus infection should consult the CDC to discuss blood, placental and umbilical cord sampling. Zika virus infection is a nationally notifiable disease.
Differential diagnosis encompasses a wide variety of other viral diseases such as dengue, chikungunya, Mayaro virus disease, Ross River fever, Barmah Forest disease, o’nyong-nyong disease, and Sindbis fever. In addition, the CDC lists group A streptococcus, leptospirosis, malaria, rickettsia, rubella, measles, parvovirus, enterovirus, and adenovirus in the differential diagnosis.
At present, there is no treatment or vaccine for Zika virus disease. Because symptoms are usually absent or mild, most acutely infected patients do not access the medical system and treat themselves symptomatically. Antiviral medication is ineffective. The mainstays of management are bed rest and supportive care. When multiple arboviruses are co-circulating, testing for a specific viral diagnosis, if available, can be important in anticipating, preventing, and managing complications.
Although the Zika virus has not been associated with hemorrhagic fever, it is probably best to avoid aspirin and nonsteroidal medications due to their association with hemorrhagic fever syndromes and death when taken for the treatment of similar viruses. The use of aspirin should be avoided in children because of the risk of Reye syndrome. Guidelines for pregnant women during a Zika virus outbreak can be accessed at the CDC website www.cdc.gov/zika.
Because of the rapidly evolving knowledge about the Zika virus, clinicians are encouraged to freely consult the CDC and WHO websites for clinical guidance.
Pregnant women should be asked about their travel history. Currently the WHO recommends anomaly ultrasound investigations at 18 to 20 weeks’ gestation to identify, monitor, or exclude fetal brain abnormalities, particularly microcephaly, for all pregnant women living in areas with ongoing Zika virus transmission.
International monitoring of Zika virus infection is important. Each year, nearly 10 million international travelers depart from Brazilian airports favorable to year-round transmission of the Zika virus, and over one-quarter of these travelers are headed to the United States.
Travel-related Zika virus infection has been diagnosed from coast to coast in the continental United States, resulting in the potential for local human–mosquito–human transmission. In 2016, symptomatic and asymptomatic locally acquired Zika infection was reported in Miami.
The major complication of Zika virus disease is the potential risk of microcephaly as a result of vertical transmission. Amniocentesis has been used to detect the presence of Zika virus in amniotic fluid of women who had ultrasound confirmation of microcephalic fetuses. The virus has been isolated in the brains of newborns and miscarried fetuses. It is unclear whether there may be contributory factors to the development of microcephaly such as nutritional and environmental factors or concomitant infection with other micro-organisms. Other fetal findings have included intracranial calcifications, orbital calcifications, and microphthalmia.
The gestational age of pregnancy when Zika virus infection may affect fetal development is uncertain. The proportion of fetuses who develop microcephaly after their mothers contract Zika virus infection during pregnancy is currently unknown. The microcephaly may be subtle. Children may have a general appearance of craniofacial disproportion and abnormal cranial shape. The fontanelles may be closed or very small and the sutures may be uneven or overlapping.
In addition to microcephaly, a phenotypic spectrum has been identified in congenital Zika syndrome. Neurologically, there may be changes in motor activity, severe muscle hypertonia, feeding difficulties, and excessive and inconsolable crying. Musculoskeletal problems include joint immobility, hand and finger contractures, feet contractures and malposition, deep and multiple dimples over joints, abnormal palmar creases and generalized arthrogryposis. Skin on the scalp and other areas of the body may be redundant. Brain imaging may show calcifications, abnormal gyral patterns, enlarged ventricles and marked decreases in the volume of gray and white matter. The corpus callosum may be thin or absent. The brain stem and cerebellum and be underdeveloped. Seizures, especially between 3 and 6 months of age, may develop and children may exhibit visual problems, hearing loss and impaired growth. The viruses strong affinity for neural cells may cause neurologic damage that only becomes apparent as children age. It is unclear if infants and children who contract Zika in infancy or early childhood may develop neurologic complications.
Retrospective data from the French Polynesia Zika virus outbreak from October 2013 to April 2014 indicate that an increase in patients suffering from Guillain-Barré syndrome was closely associated. Of the 42 patients diagnosed with Guillain-Barré syndrome, 41 (98%) had anti-Zika virus IgM or IgG, and all (100%) had neutralizing antibodies against Zika virus compared with 54 (56%) of 98 in the control group.
Zika virus is a pandemic in progress and uncertainty remains regarding its teratogenicity and long-term complications. A larger issue still to be elucidated in the emergence of Zika and other novel infectious diseases is the role played by urban crowding, ease of international travel, and human encroachments into complex ecosystems.
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