Zika virus disease (ZVD) is an emerging infectious disease transmitted by Aedes mosquitoes. Although ZVD usually causes only mild illness, at most, the virus can survive in the body and be sexually transmitted. It also can infect a developing fetus, leading to congenital Zika syndrome, including microcephaly, an abnormally small head and severe brain damage.
Zika virus is one of about 500 known arboviruses with single-stranded RNA as their genetic material and complex life cycles in which they reproduce (replicate) in both arthropod—usually mosquito—and vertebrate hosts. Zika virus is believed to be maintained in nonhuman primate reservoirs and possibly non-primate reservoirs. ZVD is similar to other diseases, including dengue and yellow fever, caused by closely related viruses in the Flavivirus genus of the Flaviviridae family and transmitted primarily by Aedes aegypti mosquitoes.
Zika virus was discovered in 1947 in a rhesus monkey in the Zika Forest of Uganda. The following year, it was isolated from Aedes africanus mosquitoes and subsequently from other Aedes species. The first ZVD case was reported in 1952. Two years later, the virus was isolated from human blood. Over subsequent decades, sporadic outbreaks of mild illness occurred across Africa and Southeast Asia, but ZVD was generally unrecognized or mistaken for dengue. Nevertheless, early studies reported that 40% of tested Nigerians had antibodies against Zika virus indicating past infection.
The first report of ZVD outside Africa and Asia occurred in 2007, when an epidemic of mild illness erupted on the Pacific island of Yap. In 2013–2014, an epidemic struck French Polynesia. Although most of the estimated 30,000 illnesses were mild, a few cases led to Guillain-Barrésyndrome (GBS), a rare paralytic condition triggered by infection. Cases of microcephaly were identified in the islands retrospectively.
Travel rapidly spread ZVD to populations lacking immunity. By early 2014, it had become established in northeast Brazil, but it was months before reports of unexplained fever and skin rashes reached health authorities and May 2015 before Zika virus was recognized as the culprit. By then, it had spread to neighboring countries, the Caribbean, and Florida, with imported cases in travelers worldwide. Panic ensued when, in early 2016, a northern Brazilian state reported up to 26 times the expected number of newborns with microcephaly.
There are significant genetic differences between the African Zika strain and the Asian strain that spread to the Western Hemisphere. Chinese researchers have reported that microcephaly is caused by a single amino-acid change (mutation) in a viral protein that probably occurred in May 2013, just before the Polynesian epidemic.
As of 2018, the primary risk factor for ZVD is the bite of an Aedes mosquito where the virus is endemic or new outbreaks were occurring. The mosquitoes are common indoors and outdoors in urban areas, and they bite day and night but are especially aggressive during the day. They lay eggs in or near standing water. Homes without window and door screens or air-conditioning increase the risk to inhabitants.
Zika virus can be transmitted between people via semen, vaginal fluids, blood, or urine and across the placenta of pregnant women to their fetus. The virus can persist in semen for at least six months following infection. Blood transfusions and organ and tissue transplants are risk factors. Laboratory and healthcare workers are at risk.
Previous dengue or West Nile virus (WNV) infection may be a risk factor for more serious ZVD. Dengue and WNV are endemic in many regions that have or are at risk for Zika, and the presence of antibodies against the coat proteins of these related viruses appears to increase ZVD severity by a mechanism called antibody-dependent enhancement.
ZVD is endemic to and widely distributed throughout Africa and Southeast Asia. By 2017, some 70 countries had reported local transmission of mosquito-borne ZVD, including in Brownsville, Texas and Miami-Dade County, Florida. At least 27 countries had reported congenital Zika syndrome and/or GBS. As of 2018, reported ZVD cases included:
Thousands of infants in Central and South America and the Caribbean were born with congenital Zika syndrome in 2015 and 2016. In the second half of 2016, 15 U.S. states and territories with local Zika transmission or travel-associated infections saw a 21% increase in birth defects potentially linked to the virus—three out of every 1,000 newborns. However, the incidence of congenital Zika syndrome was likely to have been underestimated, since only about one-quarter of potentially exposed newborns had brain imaging, and some apparently healthy infants later exhibit Zika-associated developmental problems.
Confirmed ZVD cases declined dramatically throughout the Western Hemisphere in 2017, possibly because populations had developed immunity, but also because of precautions and stepped-up mosquito control. Nevertheless, nearly half of the global population resides in regions with Aedes mosquitoes capable of transmitting Zika. Furthermore, with a warming climate, the mosquitoes' geographic range is expected to continue to grow, and increased virulence is possible as the virus adapts to larger human populations.
Zika virus infects mosquitoes that feed on the blood of infected people. The mosquitoes transmit the virus in their saliva when they bite other people. Mosquito-borne flaviviruses such as Zika are believed to replicate in immune-system dendritic cells near the site of the bite. From there, the virus spreads to the lymph nodes and bloodstream. ZVD symptoms are caused by the immune system's response to the virus.
Sexual partners can transmit Zika virus before, during, and after symptoms of infection and in the absence of symptoms. The virus can be transmitted through vaginal, anal, and oral sex or the sharing of sex toys. Men are infectious longer than women, because the virus survives in semen longer than in other body fluids.
Zika virus can infect, reproduce, and persist in the placenta and fetal brain during at least the first trimester of pregnancy, even in women with no symptoms of infection, and is associated with miscarriage. The virus infects and destroys neural stem and progenitor cells in the developing fetal brain, preventing neurons from maturing and often leading to an abnormally small brain and microcephaly. The virus also can be transmitted perinatally, that is, at or near the time of birth. As of 2018, there were no reports of Zika transmission through breast milk, and the virus is not absorbed through the gastrointestinal tract.
Only about 20% of people infected with Zika virus develop symptoms. Symptoms, if present, are thought to appear within a few days of infection and are usually mild, lasting a few days to a week. Common symptoms include:
Other symptoms can include:
Some patients develop cardiac problems, including heart rhythm disorders and heart failure, beginning about ten days after the appearance of ZVD symptoms. Rarely, patients develop Guillain-Barŕ syndrome (GBS), usually within one month of infection. GBS is an autoimmune reaction that causes muscle weakness or paralysis.
Signs and symptoms of congenital Zika syndrome can include:
ZVD diagnosis is often based on symptoms and either exposure to mosquito bites in Zika-endemic regions or a sexual partner with a current or previous Zika infection. However, ZVD symptoms are similar to those of other mosquito-borne illnesses such as dengue and chikungunya.
Serology testing for anti-Zika antibodies in the blood is complicated by cross-reactivity with antibodies against other flaviviruses such as dengue, WNV, and yellow fever. However, as of 2018, testing for Zika virus RNA in blood or other body fluids by reverse-transcription polymerase chain reaction (RT-PCR) was becoming more available. The virus can also be isolated from blood samples.
Some researchers recommend electrocardiograms for all Zika-infected patients to detect developing heart problems. Babies at risk for prenatal Zika exposure should have brain imaging and ongoing developmental monitoring.
ZVD is usually mild, and there is no specific treatment. People with symptoms should get plenty of rest and fluids to prevent dehydration. Acetaminophen can reduce fever, pain, and headache.
There are no specific treatments for ZVD complications such as GBS or congenital Zika syndrome. Children with microcephaly or other congenital complications will require various therapies and special education.
In February 2016, the World Health Organization (WHO) declared ZVD a Public Health Emergency of International Concern and strongly advised pregnant women to avoid travel to countries with Zika transmission. Women in some countries were advised to avoid pregnancy altogether. However, in many regions hard hit by ZVD, even basic contraception is unavailable to many women, and abortion is illegal even for women carrying severely affected fetuses.
By November 2016, WHO had declared an end to the international emergency. Emphasis shifted to research, prevention, and tailoring interventions at the community level. For example, a study in Singapore, which in 2016 experienced one of the largest Southeast Asian ZVD outbreaks, reported that Facebook was an effective tool for rapid community outreach and management. WHO also developed a Zika app for providing essential information to healthcare workers and the public.
ZVD's rapid spread, and recognition of congenital Zika syndrome and long-lasting sexual transmission, led to what the CDC described as the most complex public health response in its history, involving multiple centers. In addition to its January 2016 warning of the ZVD threat and its likely spread and advisories for pregnant women to avoid travel to Zika-affected regions, the CDC response included:
Following reports of Zika transmission via blood transfusions in Brazil, by December 2016, the Food and Drug Administration (FDA) mandated Zika screening at all U.S. blood centers, using emergency authorization for unlicensed tests adapted from WNV tests. As of 2018, the Biomedical Advanced Research and Development Authority and the Public Health Emergency Medical Countermeasure Enterprise were collaborating on fast-track development and FDA approval for the following:
In late 2016, Congress authorized an additional $350 million for CDC anti-Zika efforts. However, some officials in the new Trump administration questioned the science behind the indisputable association between Zika and microcephaly and the need for government-funded research. Furthermore, the Trump administration ended U.S. contributions to the United Nations Population Fund for women's reproductive health across Africa and proposed eliminating the Global Health Security programs.
The 2016 South Florida response included eliminating standing water and widespread spraying of insecticides against larval and adult mosquitoes, which significantly reduced Ae. aegypti within one week and symptomatic ZVD cases within two weeks. By mid-September, there were no new locally transmitted cases. However, aerial pesticide spraying in Miami Beach drew public protests, and aerial spraying killed millions of honeybees in South Carolina. Furthermore, current mosquito-control methods are notoriously inefficient, and Aedes mosquitoes are developing resistance to commonly used insecticides.
In 2017, Brazil began releasing billions of genetically engineered male mosquitoes (which do not bite) carrying a gene lethal to offspring. Although such releases have reduced mosquito populations in several locales, widespread releases are required since mosquitoes travel only very short distances. In 2016, residents of a Key West, Florida, community voted down a release. Gene drive methods that rapidly spread a sterilizing or lethal gene through an entire population have been criticized because of the unknown effects of eliminating entire species of insects. Brazil also released male mosquitoes infected with the bacterium Wolbachia, which reduces the likelihood of the mosquitoes becoming infected with Zika and dengue, reduces the likelihood that infected mosquitoes will transmit the viruses to humans, and kills eggs fertilized by these males. As of 2018, these and other genetically based techniques were being tested and implemented in various places around the world.
Only about 20% of Zika infections result in symptoms, and almost all cases are mild and short-lived. Zika infection probably confers protection against future ZVD. Rarely, ZVD leads to GBS or other neurological symptoms. GBS has a fatality rate of less than 5%, and most patients recover, although recovery can take up to a year. About 10% of Zika infections during pregnancy lead to congenital Zika syndrome with a grim prognosis. Microcephaly results in multiple disabilities that will probably necessitate lifelong care and dependency. Prenatal infection can also lead to other brain abnormalities and a range of additional problems. Even babies who appear healthy at birth can begin missing developmental milestones. A 2018 study reported that infant rhesus macaques infected with Zika virus after birth had abnormal brain development and behaviors.
Zika virus can persist at low levels at certain sites in monkeys, such as the cerebrospinal fluid, after its complete elimination from the blood. If such persistence is found in humans, it may have implications for long-term neurological health. Although as of 2018, the public health crisis appeared to have abated, the reprieve may be temporary. Furthermore, the long-term effects of congenital Zika syndrome will place considerable burdens on healthcare systems for decades to come.
Pregnant women must take special precautions if they live in or cannot avoid travel to areas with Zika transmission. The above repellents are safe and effective for pregnant and breastfeeding women, but they cannot be used on infants under two months of age. Oil of lemon eucalyptus cannot be used on children younger than three years of age. Women who are pregnant or could become pregnant should use latex condoms consistently and properly or abstain from all sexual activity with partners who have been to areas with Zika virus transmission. Dental dams should be used for oral sex. Sex toys should not be shared. Since about 45% of all U.S. pregnancies are unintended, precautions should be taken even by women who are not planning to become pregnant. Precautions should be continued for at least six months after a male partner has visited a region with Zika transmission and for at least eight weeks after a female partner visits such a region. Protection against infected blood and body fluids (urine, stool, and vomit), including contaminated surfaces, is very important.
See also Dengue fever ; Endemic ; West Nile virus ; Yellow fever .
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Margaret Alic, PhD