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Zika fever is a mosquito-borne illness that in humans can cause fever, malaise, and cutaneous rash. Zika virus (ZIKV) was first isolated in Uganda in 1947 and has since spread from the continent of Africa to many other areas of the world, including Oceania, and South and Central America. This course describes how the Zika virus is transmitted via the Aedes aegypti mosquito as well as clinical signs and symptoms, diagnosis, treatment, and prevention.
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Zika virus (ZIKV) was first isolated in 1947 by researchers studying Yellow Fever in the Zika Forest in Uganda. For more than 50 years it was little-studied, mainly because it was observed to cause only mild flu-like symptoms and rash in infected individuals. Zika virus was thought to be limited mostly to the continent of Africa, although some cases were reported in southeast Asia, the Phillipines, and India in the decades following its discovery in Uganda. With the increase in air travel in the second half of the 20th century, the virus has rapidly spread to other parts of the world.
ZIKV is transmitted by several different species of Aedes mosquitoes, including the Aedes aegypti and Aedes albopictus. These mosquitos transmit two other important mosquito-borne diseases—Dengue Fever and Chikungunya. In addition, Aedes aegypti transmits Yellow Fever and is sometimes referred to as the "yellow fever mosquito."
Aedes aegypti, one of the transmitters Zika virus. The mosquito is black with white bands on its legs and body. Source: Wikimedia Commons.
Aedes aegypti mosquitos are widely distributed throughout the world and thrive in urban environments. Because of this, the potential exists for ZIKV to spread to areas where Aedes aegypti is already present. This is already occuring in warmer and wetter parts of the Western Hemisphere as local mosquitoes pick up the virus from infected travelers and then spread the virus to other people.
As of July 12, 2017, CDC has reported 224 locally-acquired cases in the United States including 1 laboratory-acquired case. There have been 5,109 travel-associated cases in travelers returning from affected areas to the United States, and 46 cases in people infected through other routes, including sexual contact. As of July 12, 2017, almost 40,000 locally-acquired cases have been reported in the U.S. Territories, the vast majority in Puerto Rico (CDC, July 12, 2017). The locally-aquired cases are presumed to be from mosquito-borne transmission.
As of June 27, 2017, laboratory evidence of possible Zika virus infection has been reported in 1,997 pregnant women within the United States and the District of Columbia as well as in 4,175 pregnant women in U.S. territories (CDC, July 6, 2017a). Within the U.S. and District of Columbia, 88 infants were born with birth defects and 8 pregnancy losses with birth defects were reported. In the U.S. Territories, 122 infants were born with birth defects and 6 pregnancy losses with birth defects were reported (CDC, July 6, 2017b).
In the mid-summer of 2016 the Florida Department of Health identified an area in the Wynwood neighborhood of Miami where Zika was being spread by mosquitoes. The Department of Health issued guidance for people who live in or have traveled to this area any time after June 15, 2016 (based on the earliest time symptoms can start and the maximum 2-week incubation period for Zika virus). On September 19, 2016, the Wynwood neighborhood was declared Zika-free.
In August of 2016, the Florida Department of Health identified two areas of Miami-Dade County where Zika was spreading, including a section of Miami Beach. At that time, CDC took the unprecedented step of advising pregnant women not to travel to this part of Miami. As of June 30, 2017, CDC is recommending that pregnant women who lived in or traveled to this area between August 1, 2016 and June 2, 2017 be tested for Zika virus (CDC, June 30, 2017).
CDC is continuing to work with Florida health officials to investigate any new cases of locally transmitted Zika virus infection in Miami-Dade County. Although sporadic cases may still occur, the risk of Zika virus transmission in the Miami-Dade County is expected to remain low. On June 2, 2017, CDC removed the designation "Zika cautionary area" from Miami-Dade County, also removing any travel restrictions to the county. People living in, or traveling to, Miami-Dade County are urged to continue to protect themselves from mosquito bites (CDC, June 30, 2017).
In December of 2016, CDC issued guidance related to Zika for people living in or traveling to Brownsville, Cameron County, TX. A month earlier, the Texas Department of State Health Services reported the state’s first case of local mosquito-borne Zika virus infection in Brownsville. Additional cases of mosquito-borne Zika have been identified in the area, suggesting that there is a risk of continued spread of Zika virus in Brownsville. As a result, CDC has designated Brownsville as a Zika cautionary area.
On May 5, 2017, CDC designated Brownsville, Texas a "Zika cautionary area" meaning (1) pregnant women should consider postponing travel to the area, (2) people who live in or travel to Brownsville, TX, should remain aware of Zika virus transmission and strictly follow steps to prevent mosquito bites, (3) pregnant women and their partners who live in or travel to Brownsville, TX, should consistently and correctly use condoms each time they have sex, and (4) pregnant women who live in, traveled to, or had sex without a condom with someone who lives in or traveled to Brownsville on or after October 29, 2016, should be tested for the Zika virus (CDC, May 5, 2017).
Source: Moritz UG Kraemer, Marianne E Sinka, Kirsten A Duda, et al. http://elifesciences.org/content/4/e08347. Licensed under Creative Commons CC0 1.0 Universal Public Domain Dedication.
About seven miles northeast of the Virus Research Institute, there is a forested area called Zika. This area of forest consists of a narrow, dense belt of high but unbroken canopy growth with clumps of large trees. It lies along the edge of a long arm of Lake Victoria from which it is separated by a papyrus swamp.
The greater part of the forest runs parallel with the Entebbe-Kampala road; there is a narrow stretch of grassland between the forest and the road. The forest at no place is more than 500 yards wide. It is about one mile in length and is almost continuous with scattered forest, which in turn joins the forest at Bujuko on the Kampala–Fort Portal road.
Dick, Kitchen & Haddow, 1952
Transactions, Royal Society of Tropical Medicine and Hygiene
Location of Uganda in Africa (in green) just above Lake Victoria (in white). Source: Marcos Elias de Oliveira Júnior. Source: Wikimedia Commons.
Zika virus was unknown prior to 1947, when it was found in the blood of a rhesus monkey during a Yellow Fever study in the Zika forest of Uganda. In 1948, the virus was isolated from a pool of Aedes africanus mosquitoes collected from the same region of the Zika forest. Although the Zika virus appeared to be largely confined to forest environments, a serologic* survey conducted at that time showed that 6.1% of the residents in nearby regions of Uganda had specific antibodies to ZIKV (Lanciotti et al., 2008).
*Serologic testing: the testing of body fluids, usually blood serum, to detect the presence of antibodies against a particular organism.
Over the next twenty years, ZIKV were isolated from Aedes mosquitoes in Africa (Aedes africanus) and Malaysia (Aedes aegypti), implicating these species as likely epidemic or enzootic vectors. Several ZIKV human isolates were also obtained in the 1960s and 1970s from East and West Africa during routine arbovirus surveillance studies in the absence of epidemics (Lanciotti et al., 2008).
Additional serologic studies in the 1950s and 1960s detected Zika virus infections among humans in Egypt, Nigeria, Uganda, India, Malaysia, Indonesia, Pakistan, Thailand, North Vietnam, and the Philippines. This strongly suggests widespread occurrence of Zika viral infections from Africa to Southeast Asia west and north of the Wallace line* (Lanciotti et al., 2008).
*Wallace line: a boundary line drawn in 1859 that represents a transitional ecosystem zone between Asia and Australia. Asiatic species are found west of the line while a mixture of Asiatic and Australian species are found east of the line.
Map of Uganda showing the location of the Zika Forest near Lake Victoria. Source: M. A. Kaddumukasa, Department of Arbovirology, Uganda Virus Research Institute. http://jme.oxfordjournals.org/content/51/1/104.
In 1977 Zika viral infection was confirmed among seven patients in central Java, Indonesia, during an acute fever study. Clinical characteristics of infection included fever, headache, malaise, stomach ache, dizziness, anorexia, and maculopapular rash; in all cases infection appeared relatively mild, self-limiting, and nonlethal (Lanciotti et al., 2008).
In April 2007 an epidemic of rash, conjunctivitis, and arthralgia was noted by physicians in Yap State, Federated States of Micronesia. Laboratory testing with a rapid assay suggested that a dengue virus was the causative agent. Samples were sent for confirmatory testing to the Arbovirus Diagnostic Laboratory at the CDC, where serologic testing confirmed recent infection in several patients. Additional testing generated DNA fragments, which demonstrated about 90% nucleotide identity with ZIKV. These findings indicated that ZIKV was the causative agent of the Yap epidemic (Lanciotti et al., 2008).
The Yap Island outbreak was estimated to have infected approximately three-quarters of the island’s population (total population was 7,391 according to the 2000 census). About 900 people had mild illness attributed to Zika infection lasting several days (Duffy et al., 2009). The more severe Zika disease symptoms were not observed during the 2007 Yap Island, Micronesia, Zika outbreak, although approximately 5,000 people were infected (Malone et al., 2016).
Map of Micronesia, a cultural and geographical area in the Pacific. Yap is part of the Caroline Islands. Source: Wikipedia, public domain.
In October 2013 French Polynesia reported its first outbreak (at the time, the largest outbreak ever reported), which was estimated to affect 28,000 people (about 11% of the population) (Besnard et al., 2014).
In 2014 Zika turned up in Latin America, believed to be transmitted by tourists attending the Va’a World Sprint Championship canoe race held in Rio de Janeiro, Brazil (Musso, 2015). In May 2015 the Pan American Health Organization (PAHO) issued an alert regarding the first confirmed Zika virus infection in Brazil (CDC, 2016a).
Countries and territories with active Zika virus transmission include Mexico, Central America, South America, Samoa (Oceania/Pacific Islands), and Cape Verde (Africa). Source: CDC, 2016a.
ZIKV is expected to continue to spread to Central and North America. Infectious disease modelers estimate that about 200 million Americans—more than 60% of the U.S. population—reside in areas that might be conducive to the spread of ZIKV during warmer months, including areas along the East and West Coasts and much of the Midwest. In addition, another 22.7 million people live in humid, subtropical parts of the United States that might support the spread of ZIKV year round, including southern Texas and Florida. Already there are reports of local spread of the virus within Puerto Rico and of travelers returning to mainland United States with the Zika infection (Collins, 2016).
Countries and territories with active Zika virus transmission include Mexico, Central America, South America, Samoa (Oceania/Pacific Islands), and Cape Verde (Africa). Source: CDC, 2016a.
ZIKV is a single-stranded RNA virus of the Flaviviridae family, genus Flavivirus, closely related to Dengue. It is an arthropod-borne virus* (arbovirus), transmitted to humans primarily through the bite of an infected Aedes species mosquito, especially Aedes aegypti, which is the main vector worldwide. In forested areas of Africa, Asia, and South America ZIKV is maintained in enzootic transmission cycles, a cycle that involves mostly wild animals such as birds, rodents, and non-human primates as the reservoirs, usually in a limited region or area.
*Arthropod-borne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. Most arboviruses are maintained in transmission cycles between arthropods and vertebrate hosts (typically birds or small mammals). Human arboviral cases with laboratory evidence of recent infection are classified as neuroinvasive disease (causing encephalitis, meningitis, or acute flaccid paralysis) or non-neuroinvasive disease.
In urban and suburban areas, the virus is transmitted between people who have been bitten by Aedes mosquitoes. Aedes aegypti mosquitoes have a high vectorial capacity (effectiveness of virus transmission in nature) (CDC, 2016b).
Source: CDC, 2016c.
Unlike the Culex mosquitoes that carry West Nile virus—which are active from dusk to dawn—Aedes mosquitoes are aggressive daytime biters and feed both indoors and outdoors near dwellings. They are most active 2 hours after dawn and 2 hours before dusk but can bite throughout the day. Non-human and human primates are likely the main reservoirs of the virus, and anthroponotic (human-to-vector-to-human) transmission occurs during outbreaks (CDC, 2016a).
Aedes mosquitoes typically breed in domestic water-holding containers and thrive in urban environments where small pools of water and moist soil are readily available. They are able to find people using several complex sensory systems. Dark colors, body heat, and smells from body chemicals, such as carbon dioxide and lactic acid, all attract mosquitoes; they can smell carbon dioxide from 75 feet away. Both male and female mosquitoes feed on plant nectar for their own nourishment but only females feed on blood so they can make eggs (NIAID, 2015).
This 2006 photograph depicts a female Aedes aegypti mosquito in the process of acquiring a blood meal from her human host. The feeding apparatus consists of a sharp, orange-colored fascicle that is covered in a soft, pliant sheath called the labellum while not feeding. The labellum is shown here retracted as the sharp stylets contained within pierce the host’s skin surface, allowing the insect to obtain its blood meal. The orange color of the fascicle is due to the red color of the blood as it migrated up the thin, sharp translucent tube. Note the distended abdominal exoskeleton which, being translucent, allowed the color of the ingested blood meal to be visible. Photo credit: James Gathany, CDC, Public Health Image Library.
Zika virus is transmitted to people primarily through the bite of an infected Aedes species mosquito (A. aegypti and A. albopictus). Primates, including humans, are the best-documented Zika virus animal reservoir, with transmission to humans primarily by mosquito vectors. Based on serology, but not verified by viral isolation, many other species may support Zika virus infection, including forest-dwelling birds, horses, goats, cattle, ducks and bats. Zika virus is also present in the saliva of infected patients (Malone et al., 2016).
Prior to the current outbreak of Zika viral infection in Brazil, no cases of transmission of ZIKV from mother to fetus had been reported (Oliveira Melo et al., 2016). Perinatal transmission was documented in French Polynesia during the 2013–2014 outbreak where Zika virus sequences were identified in breast milk by polymerase chain reaction (PCR), but reports from that outbreak did not indicate microcephaly as a complication (Malone et al., 2016).
Maternal-fetal transmission of Zika virus has now been documented throughout pregnancy in the recent Brazilian outbreak (Petersen et al., 2016) and Zika virus RNA has been detected in the pathologic specimens of fetal losses. Zika virus infections have been confirmed in infants with microcephaly in the current outbreak in Brazil (Petersen et al., 2016).
On December 2, 2015, Brazilian health officials released a statement providing guidance on Zika virus and breastfeeding. The document states that there is insufficient evidence to modify current breastfeeding practices (ECDC, 2015). Although Zika virus RNA has been detected in breast milk, transmission of Zika infection through breastfeeding has not been documented (CDC, 2016a).
On June 21, 2016 the U.S. National Institutes of Health and Fundacao Oswaldo Cruz-Fiocruz (Fiocruz), a national scientific research organization linked to the Brazilian Ministry of Health, announced they have begun a multi-country study to evaluate the magnitude of health risks that Zika virus infection poses to pregnant women and their developing fetuses and infants. The study is opening in Puerto Rico and will expand to several locations in Brazil, Colombia and other areas that are experiencing active local transmission of the virus (NIH, 2016).
The incidence of Zika virus infection in pregnant women is not currently known and data on pregnant women infected with Zika virus are limited. No evidence exists to suggest that pregnant women are more susceptible to Zika virus infection or experience more severe disease during pregnancy (Staples and Meaney-Delman et al., 2016).
In the United States, As of June 16, 2016, laboratory evidence of possible ZIKV infection has been found in 265 pregnant women in the U.S. and the District of Columbia and 216 pregnant women in Puerto Rico. Of these, 4 infants were born with birth defects and 4 pregnancy losses were reported. In the live births, defects included microcephaly, calcium deposits in the brain indicating possible brain damage, excess fluid in the brain cavities and surrounding the brain, absent or poorly formed brain structures, abnormal eye development, or other problems resulting from damage to the brain that affects nerves, muscles and bones, such as clubfoot or inflexible joints. The pregnancy losses included miscarriage, stillbirths, and terminations with evidence of the birth defects already mentioned (CDC, 2016a).
CDC has developed interim guidelines for healthcare providers in the United States who are caring for pregnant women during a Zika virus outbreak. These guidelines include recommendations for pregnant women who are considering travel to an area with Zika virus transmission, and recommendations for screening, testing, and management of returning pregnant travelers. Updates on areas with ongoing Zika virus transmission are available online (http://wwwnc.cdc.gov/travel/notices/) (Staples and Meaney-Delman et al., 2016).
Healthcare providers should ask all pregnant women about recent travel. Pregnant women with a history of travel to an area with Zika virus transmission and who report two or more symptoms consistent with Zika virus disease (acute onset of fever, maculopapular rash, arthralgia, or conjunctivitis) during or within two weeks of travel, or who have ultrasound findings of fetal microcephaly or intracranial calcifications, should be tested for Zika virus infection. Testing is not indicated for women without a travel history to an area with Zika virus transmission (Staples and Meaney-Delman et al., 2016).
In pregnant women with laboratory evidence of Zika virus infection, serial ultrasound examination should be considered to monitor fetal growth and anatomy, and referral to a maternal–fetal medicine or infectious disease specialist with expertise in pregnancy management is recommended. There is no specific antiviral treatment for Zika virus; supportive care is recommended (Staples and Meaney-Delman et al., 2016).
Zika can be passed through sex from a person who has Zika to his or her partners even if the infected person does not have symptoms at the time. Potential sexual exposure to Zika virus includes having had sex with a person who has traveled to or lives in an area with active Zika virus transmission when the sexual contact did not include a barrier to protect against infection. Such barriers include male or female condoms for vaginal or anal sex and other barriers for oral sex. Sexual exposure includes vaginal sex, anal sex, oral sex, or other activities that might expose a sex partner to genital secretions (MMWR, 2016, July 29).
Zika virus infection is of particular concern during pregnancy. Pregnant women with sex partners (male or female) who live in or who have traveled to an area with active Zika virus transmission should consistently and correctly use barriers against infection during sex or abstain from sex for the duration of the pregnancy. This reduces the risk for sexual transmission of Zika virus during pregnancy. Pregnant women should discuss with their healthcare provider their own and their sex partner’s history of having been in areas with active Zika virus transmission and history of illness consistent with Zika virus disease; providers can consult CDC’s guidance for evaluation and testing of pregnant women (MMWR, 2016, July 29).
Men and women who want to reduce the risk for sexual transmission of Zika virus should use barrier methods against infection consistently and correctly during sex or abstain from sex when one sex partner has traveled to or lives in an area with active Zika virus transmission. Based on expert opinion and on limited but evolving information about the sexual transmission of Zika virus, the recommended duration of consistent use of a barrier method against infection or abstinence from sex depends on whether the sex partner has confirmed infection or clinical illness consistent with Zika virus disease and whether the sex partner is male or female (MMWR, 2016, July 29).
As of July 20, 2016, 15 cases of Zika virus infection transmitted by sexual contact had been reported in the United States. Sexually transmitted Zika virus infection has also been reported in other countries. In published reports, the longest interval after symptom onset that sexual transmission from a man might have occurred was 32–41 days. Using real-time reverse transcription–polymerase chain reaction (rRT-PCR), Zika virus RNA has been detected in semen up to 93 days after symptom onset. In addition, one report describes an asymptomatically infected man with Zika virus RNA detected by rRT-PCR in his semen 39 days following departure from a Zika virus-affected area and who might have sexually transmitted Zika virus to his partner. In most cases, serial semen specimens were not collected until Zika virus RNA was no longer detectable so that the precise duration and pattern of infectious Zika virus in semen remain unknown (MMWR, 2016, July 29).
Zika virus also has been transmitted from a symptomatically infected woman to a male sex partner, and Zika virus RNA has been detected in vaginal fluids 3 days after symptom onset and in cervical mucus up to 11 days after symptom onset. For sex partners of infected women, Zika virus might be transmitted through exposure to vaginal secretions or menstrual blood. Sexual transmission of infections, including those caused by other viruses, is reduced by consistent and correct use of barriers to protect against infection (MMWR, 2016, July 29).
On September 30, 2016, CDC updated its interim guidance for persons with possible Zika virus exposure who are planning to conceive and interim guidance to prevent transmission of Zika virus through sexual contact, now combined into a single document. CDC now recommends that men with possible Zika virus exposure, regardless of symptom status, wait at least 6 months from symptom onset (if symptomatic) or last possible exposure (if asymptomatic) before attempting conception with their partner. They should also wait at least 6 months before having condomless sex to minimize their risk for sexual transmission of Zika virus to partners. The updated guidelines are available from Morbidity and Mortality Weekly Report, 2016, October 7.
During the first week of infection, Zika virus in the blood of an infected person can be passed through a mosquito bite to another mosquito. An infected mosquito can then spread the virus to other people. Zika virus RNA has been identified in asymptomatic blood donors during an ongoing outbreak and transfusion-transmission events have been reported (CDC, 2016a).
Other flaviviruses, such as Dengue and West Nile can be detected in urine samples for a longer time than in serum samples. A 2015 study at the Institut Pasteur in New Caledonia (a subtropical island west of Australia and north of New Zealand) detected strongly positive results for ZIKV RNA in the urine of 6 Zika patients. ZIKV RNA was detected ≤15 days (range 10 days to >20 days) after onset of symptoms, which was >7 days after it was no longer detected in serum samples (Gourinat et al., 2015).
It is now clear the CDC has concluded that Zika does cause Microcephaly. This confirmation is based on a thorough review of the best scientific evidence conducted by CDC and other experts in maternal and fetal health and mosquito-borne diseases. We continue to do everything possible to protect pregnant women and we're undertaking further studies to determine the broader range of birth defects beyond Microcephaly that could occur from Zika infection in pregnancy. We believe that Microcephaly is likely to be a part of a range of birth defects that may affect women at a particular time or at any time in pregnancy.
There is still a lot that we don't know, but there is no longer any doubt that Zika causes Microcephaly. We're undertaking further studies to look at the spectrum of disorders that the virus may cause, and as with much of scientific research, there is no single piece of evidence that provides conclusive proof of this connection, rather, mounting evidence from many studies and careful review of causal criteria was needed to determine that Zika causes Microcephaly and other birth defects.
Dr. Tom Frieden, Director of the Centers for Disease Control and Prevention
Press Briefing Transcript, April 13, 2016
In humans, Zika virus infection is characterized by mild fever (37.8°C–38.5°C); arthralgia, notably of small joints of hands and feet; myalgia, headache; retro-orbital pain; non-purulent conjunctivitis; and cutaneous maculopapular rash. Zika virus infection is believed to be asymptomatic or mildly symptomatic in most cases. Other rarely observed symptoms include digestive problems (abdominal pain, diarrhea, constipation), mucous membrane ulcerations (aphthae), and pruritus (Gourinat et al., 2015).
Maculopapular rash on patient infected with Zika virus, Colorado, USA. Source: Foy et al., 2011.
An estimated 80% of persons infected with Zika virus are asymptomatic (Petersen et al., 2016). Clinical illness is usually mild, with symptoms lasting for 2 to 7 days. Severe disease requiring hospitalization is uncommon and case fatality is low (CDC, 2016a).
Infection may go unrecognized or be misdiagnosed as Dengue, Chikungunya, or other viral infections with fever and rash. An association with Guillain-Barré syndrome (GBS) and other autoimmune neurologic complications was suspected during the 2013–2014 outbreak in French Polynesia and remains under investigation (ECDC, 2015). A possible association with microcephaly in infants was noted in Brazil in September of 2015, although public health officials remained uncertain, largely because for more than 50 years, no flavivirus has ever been shown definitively to cause birth defects in humans, and no reports of adverse pregnancy or birth outcomes were noted during previous outbreaks of Zika virus disease in the Pacific Islands (NEJM, 2016).
On April 13, 2016, the Centers for Disease Control and Prevention (CDC) announced a definitive link between Zika infection and congenital birth defects, particularly microcephaly (CDC Newsroom, 2016). According to the CDC briefing, there is no longer any doubt that ZIKV causes microcephaly and other birth defects. Work by the Brazilian Ministry of Health and scientists have demonstrated Zika virus genomic DNA in the blood and tissues of a baby with microcephaly, and detection in the amniotic fluid of two pregnant women whose fetus was diagnosed through ultrasonography with microcephaly (Hotez & Askoy, 2016).
Microcephaly occurs when a baby’s brain fails to develop during pregnancy. It is a lifelong condition and, depending on the severity, microcephaly has been linked to seizures, developmental delays, vision and hearing problems, movement and balance deficits, and cognitive difficulties. It can sometimes be seen on ultrasound at the end of the second trimester or the beginning of the third trimester. Otherwise, a diagnosis is made after the birth of the child.
In November (2015), health authorities in French Polynesia reported an unusual increase of central nervous system malformations in fetuses and infants that seemed to coincide with the Zika outbreak there. At the end of January (2016), came news reports of the first child born in the United States with microcephaly possibly linked to Zika. The child’s mother had lived in Brazil during her pregnancy before moving to Oahu, Hawaii (Collins, 2016).
Top: Baby with microcephaly. Bottom: Baby with normal head size. Source: CDC, National Center on Birth Defects and Developmental Disabilities.
Based on the typical clinical features, the differential diagnosis for Zika virus infection is broad. In addition to Dengue, other considerations include leptospirosis, malaria, rickettsia, group A streptococcus, rubella, measles, parvovirus, enterovirus, adenovirus, and alphavirus infections (eg, Chikungunya, Mayaro, Ross River, Barmah Forest, O’nyong-nyong, and Sindbis viruses) (CDC, 2016a).
Preliminary diagnosis is based on the patient’s clinical features, places and dates of travel, and activities. Laboratory diagnosis is generally accomplished by testing serum or plasma to detect virus, viral nucleic acid, or virus-specific immunoglobulin M (IgM) and neutralizing antibodies (CDC, 2016a).
A suspected case of Zika requires the presence of rash and/or fever with either arthralgia, arthritis, or non-purulent conjunctivitis. A probable case requires these symptoms in conjunction with the presence of anti-Zika IgM antibodies and an epidemiologic link within two weeks prior to symptom onset to a region with local transmission (Malone et al., 2016).
A confirmed case of Zika virus disease requires laboratory confirmation of recent Zika virus infection by either the presence of Zika virus RNA or antigen in serum or other samples (e.g. saliva, tissues, urine, whole blood); or IgM antibody against Zika virus positive and PRNT90 for Zika virus with titre ≥20 and Zika virus PRNT90 titre ratio ≥ 4 compared to other flaviviruses; and exclusion of other flaviviruses (Malone et al., 2016). The PRNT90 is considered the "gold standard" for detecting and measuring antibodies that can neutralize a virus.
Microcephaly is defined as occipitofrontal circumference less than the third percentile, based on standard growth charts for sex, age, and gestational age at birth. The occipitofrontal circumference should be disproportionately small in comparison with the length of the infant and not explained by other etiologies or congenital disorders. If an infant’s occipitofrontal circumference is equal to or greater than the third percentile but is notably disproportionate to the length of the infant, or if the infant has deficits that are related to the central nervous system, additional evaluation for Zika virus infection might be considered (Staples et al., 2016).
In 2016 Zika virus disease became a nationally notifiable condition. Healthcare providers are encouraged to report suspected cases to their state or local health departments to facilitate diagnosis and mitigate the risk of local transmission. State health departments are encouraged to report laboratory-confirmed cases to CDC through ArboNET, the national surveillance system for arboviral disease (CDC, 2016a).
Many countries in the Americas now have local transmission of multiple arboviruses that can cause febrile illness with rash, myalgia, or arthralgia. Therefore, laboratory testing has become even more important to confirm the etiology of these diseases. Zika, chikungunya, and dengue virus infections should all be considered for patients with acute fever, rash, myalgia, or arthralgia who have traveled within the previous 2 weeks to an area with ongoing transmission or are living in an area with ongoing transmission (CDC Memorandum, 2016).
The Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for two diagnostic tools for Zika virus, the Zika MAC-ELISA and Trioplex Real-Time RT-PCR Assay, which are being distributed to qualified laboratories that are certified to perform high-complexity tests in the United States (CDC, 2016a). If a patient is suspected of having a Zika, chikungunya, or dengue infection, a serum specimen must be collected. Other specimens may also be collected for testing in addition to the serum specimen including CSF, urine, amniotic fluid and tissues (CDC Memorandum, 2016).
For symptomatic persons with Zika virus infection, Zika virus RNA can sometimes be detected early in the course of illness. Real-time reverse transcription-polymerase chain reaction (rRT-PCR) testing should be performed on serum collected during the first two weeks after symptom onset. rRT-PCR should also be conducted on urine samples collected less than 14 days after symptom onset. Urine should always be collected with a patient-matched serum specimen. A positive rRT-PCR result on any sample confirms Zika virus infection and no additional testing is indicated. A negative rRT-PCR result does not exclude Zika virus infection and serum should be analyzed by IgM antibody (serological) testing (CDC, 2016, August 9).
For asymptomatic pregnant women who have traveled to areas with active ZIKV transmission, rRT-PCR testing is recommended on serum and urine within 2 weeks of the date of last possible exposure. rRT-PCR testing is also indicated for pregnant women who present for care ≥ 2 weeks after exposure and have been found to be IgM positive. In areas with active ZIKV transmission, asymptomatic pregnant women should undergo IgM testing as part of routine obstetric care in the 1st and 2nd trimester. Reflex rRT-PCR testing is included as a subsequent test for women who are IgM positive (CDC, 2016, August 9).
Zika virus-specific IgM and neutralizing antibodies typically develop toward the end of the first week of illness. IgM levels are variable, but generally are positive starting near day four post onset of symptoms and continuing for 12 weeks Therefore, if rRT-PCR is negative on serum and urine, serum IgM antibody testing for Zika, dengue, and chikungunya virus infections should be performed. In addition, serum samples collected >=14 days after symptom onset, with no earlier samples collected, should be tested for anti-Zika virus, anti-dengue virus, and anti-chikungunya virus IgM antibodies (CDC, 2016, August 9).
The Zika IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA) is used for the qualitative detection of Zika virus IgM antibodies in serum or cerebrospinal fluid; however, due to cross-reaction with other flaviviruses and possible nonspecific reactivity, results may be difficult to interpret. Consequently, presumed positive, equivocal, or inconclusive tests must be forwarded for confirmation by plaque-reduction neutralization testing (PRNT). PRNT is performed by CDC or a CDC-designated confirmatory testing laboratory to confirm presumed positive, equivocal, or inconclusive IgM results (CDC, 2016, August 9).
Laboratory testing for congenital Zika virus infection is recommended for infants born to mothers with laboratory evidence of Zika virus infection during pregnancy, and for infants who have abnormal clinical findings suggestive of congenital Zika virus syndrome and a maternal epidemiologic link suggesting possible transmission, regardless of maternal Zika virus test results (CDC, March 16, 2017).
For infants born to mothers with risk factors for maternal Zika virus infection (travel to or residence in an area of Zika virus transmission or sex with a partner with travel to or residence in such an area) for whom maternal testing was not performed before delivery, assessment of the infant, including comprehensive physical exam and careful measurement of head circumference should be performed. Maternal diagnostic testing should be performed and testing of the placenta for Zika virus PCR should be considered. If an infant appears clinically well, further evaluation and infant testing can be deferred until maternal test results are available. However, if there is concern about infant follow-up, infant testing should be performed before hospital discharge (CDC, March 16, 2017).
No specific antiviral treatment is available for Zika virus disease. Treatment is generally supportive and can include rest, fluids, and use of analgesics and antipyretics. Because of similar geographic distribution and symptoms, patients with suspected Zika virus infections also should be evaluated and managed for possible Dengue or Chikungunya virus infection (CDC, May 1, 2017).
Aspirin and other non-steroidal anti-inflammatory drugs should be avoided until Dengue can be ruled out to reduce the risk of hemorrhage. People infected with Zika, Chikungunya, or Dengue virus should be protected from further mosquito exposure during the first few days of illness to prevent other mosquitoes from becoming infected and reduce the risk of local transmission (CDC, May 1, 2017).
The main mosquito that transmits Zika virus—and also Dengue, Chikungunya and Yellow Fever—is Aedes aegypti, a particularly wily foe.
It prefers urban areas and bites mainly people, making it very efficient at spreading disease. It bites in the day, so bed nets, a common way to protect people against the night-biting malaria mosquitoes, have little effect. It breeds in small containers of water, such as flower pots, cans, and tires that collect rainwater.
“I’ve seen Aedes aegypti merrily breeding in discarded soda caps,” said Joseph M. Conlon, technical adviser to the American Mosquito Control Association.
The New York Times, January 30, 2016
Understanding the mosquito lifecycle is the first step in designing effective prevention measures. Aedes aegypti and other mosquitoes have a complex life-cycle with dramatic changes in shape, function, and habitat. This makes it difficult for infection prevention specialists to determine all the places they reproduce.
Female mosquitoes lay their eggs on the inner, wet walls of containers with water. Eggs can withstand desiccation (extreme dryness) for several months, which means that even if all larvae, pupae, and adults are eliminated, repopulation will occur as soon as the eggs are flooded with water.
Larvae hatch (see diagram below, number 1) when water inundates the eggs as a result of rain or the addition of water by people. In the following days, the larvae (number 2) will feed on microorganisms and particulate organic matter, shedding their skins three times before metamorphosis is triggered, changing the larva into a pupa (number 3) (CDC, 2012).
Pupae do not feed; they just change in form until the body of the adult, flying mosquito is formed. Then the newly formed adult emerges from the water after breaking the pupal skin (number 4). The entire life cycle lasts 8 to 10 days at room temperature, depending on the level of feeding. Thus, there is an aquatic phase (larvae, pupae) and a terrestrial phase (eggs, adults) in the Aedes aegypti life-cycle (CDC, 2012).
Source: CDC, 2012
Public health campaigns aimed at reducing the spread of Zika virus focus on ridding communities of standing water; chemically, physically, or biologically destroying breeding mosquitoes; and encouraging the use of repellants and personal protective clothing.
Rain-filled cavities in trees, bamboo internodes, leaf-axils of plants. Source: CDC, 2012.
Aedes aegypti mosquitoes lay their eggs in areas where water collects or in water storage containers that are inadequately covered. An important step in control operations is identifying the types and abundance of containers producing mosquitoes. Different containers require specific control measures that depend on the type of container and how it is used. Disposing of unused containers, placing useful containers under a roof or protected with tight covers, and frequently changing the water of animal drinking pans and flower pots greatly reduces potential breeding sites. There are five general types of containers that serve as breeding grounds for mosquitoes:
Large discarded containers (tires, damaged appliances) and small discarded containers (paint cans). Source: CDC, 2012.
Ornamental or recreational containers (plant pots and dishes, plastic pools, rooting plants in water/ aquatic plants). Source: CDC, 2012.
Physical, biologic, and chemical control methods include:
Protective clothing and other personal protective measures against mosquitoes will reduce the risk of acquiring the diseases they transmit. Mosquito-bite prevention includes using air conditioning or window and door screens when indoors, wearing long sleeves and pants, using permethrin-treated clothing and gear, and using insect repellents. When used according to the product label, U.S. Environmental Protection Agency-registered insect repellents are safe for pregnant women. To protect yourself:
A man with Zika virus can pass it to his female or male sex partners via semen or blood. The virus can stay in semen longer than in blood, although it is not known for exactly how long. To prevent the spread of Zika during sex, use condoms correctly from start to finish during each sexual encounter; this includes vaginal, anal, and oral sex. Abstaining from sex is the only way to be sure that the Zika virus is not sexually transmitted (CDC, 2016a).
If your partner is pregnant, either use condoms correctly every time you have sex, or do not have sex during the pregnancy. Even if travelers returning to the United States from an area where Zika is present do not feel sick, they should take steps to prevent mosquito bites for 3 weeks so they do not spread Zika to mosquitoes that could spread the virus to other people (CDC, 2016a).
An eradication method already in use in Brazil to combat Dengue fever employs the release of mosquitoes infected with a bacterium called Wolbachia,* which reduces the ability of the Aedes mosquito to infect a host. In September 2014 the Brazilian government approved the release of Wolbachia mosquitoes in Rio de Janeiro to fight the spread of Dengue fever. This program will likely be expanded to combat the spread of the Zika virus.
*Wolbachia are bacteria that live within insect cells and are passed from one generation to the next through the insect’s eggs. Wolbachia is present in up to 60% of the different species of insects around us including some mosquitoes that bite people. Wolbachia is not found in Aedes aegypti—the primary mosquito species involved in the transmission of Dengue and Zika (Monash University, n.d.).
Attempts to eradicate or at least slow the spread of Zika also include the release of genetically engineered male mosquitoes that pass a lethal gene to their offspring. This is currently being done in small batches in Brazil.
The only way to prevent congenital Zika virus infection is to prevent maternal infection, either by avoiding areas where Zika virus transmission is ongoing or strictly following steps to avoid mosquito bites (Staples et al., 2016).
Men who reside in, or have traveled to, an area of active Zika virus transmission and who have a pregnant partner should abstain from sexual activity or consistently and correctly use condoms during sex (vaginal intercourse, anal intercourse, or fellatio) for the duration of the pregnancy. Pregnant women should discuss their male partner’s potential exposures to mosquitoes and history of Zika-like illness (Oster et al., 2016).
Several South and Central American countries have taken the unprecedented step of advising women to avoid becoming pregnant until the risks associated with Zika virus infection are more thoroughly understood.
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