In the past three weeks, local, state, national and international news networks have been covering a “new” virus called Zika. Sensational news reports have concentrated on the precipitous rise in microcephalic cases primarily in Brazil. Along the way, some news agencies have mentioned other Central and South American countries. The signs and symptoms have been glossed over, but the mode of transmission by mosquitoes has been stressed. Two weeks ago, the Brazilian army was shown fanning out around Rio de Janiero to spray insecticides on water containing vesicles for prevention of transmission during the 2016 Carnival. Only on BBC World News was there a mention of Guillain-Barré Syndrome where a young man was shown relearning to walk while another older gentleman lay unmoving in a hospital bed.
The impression given by the news media is that this illness belongs solely to poverty-stricken third-world countries. Travel-imported cases in the United States have been covered by the state only and only regarding numbers. Essentially, this coverage has led the United States citizenry to believe that the illness is benign except in the case of pregnancy. Young women who are pregnant seem to be the most at risk while men have nothing to worry about. The news agencies have covered the Centers for Disease Control and Prevention guidelines regarding travel restrictions for pregnant women. Little to no coverage has focused on other complications which can affect all ages, races and sexes.
Learning more unbiased information about the Zika epidemic should lead to better prevention strategies on the part of individuals and countries in order to control this outbreak. Better assessment and management of individuals who have Zika virus infection should lead to better outcomes and fewer complications. So onwards…..
After completing this course, the learner will be able to meet the following objectives:
The Zika virus (ZIKV) is a member of the Flaviviridae virus family and the Flavivirus genus.
In humans, ZIKV causes a mild illness known as Zika virus infection, Zika fever, Zika or Zika disease. Since the 1950s, it had been known to occur within a narrow equatorial belt from Africa to Asia. In 2007, the virus spread eastward across the Pacific Ocean to Micronesia, French Polynesia then to Easter Island. In 2015 it spread to South and Central America where the Zika outbreak has reached pandemic levels and then spread to the Caribbean and Puerto Rico. Travel-related cases have been reported worldwide in countries including the United States, Great Britain, Ireland and France to name just a few.
Zika virus infection is similar to a mild form of dengue fever. Treatment is supportive in nature and currently cannot be prevented by medications or vaccines.
Zika virus infection is related to yellow fever and West Nile disease, which are caused by other arthropod-borne flaviviruses. Possible complications from Zika virus infection include Guillain-Barré syndrome and microcephaly.
In January 2016, the United States Centers for Disease Control and Prevention (CDC) issued travel guidance on affected countries, including the use of enhanced precautions, considering postponing travel and guidelines for pregnant women. Other governments or health agencies soon issued similar travel warnings, while Colombia, Ecuador, El Salvador and Jamaica advised women to postpone getting pregnant until more was known about the risks.
ZIKV is an RNA virus containing 10,794 nucleotides encoding 3,419 amino acids. Along with other viruses in the Flaviviridae family, the Zika virus is enveloped with a nonsegmented, single-stranded, positive-sense RNA ((+)ssRNA) genome (Table 1). It is closely related to the Spondweni virus. The two viruses are the only members of their clade within the mosquito-borne cluster of flaviviruses.
|Group:||Group IV ((+)ssRNA)|
The next nearest relatives include Ilheus, Rocio and St. Louis encephalitis viruses. Yellow fever virus is the prototype of the family which also includes dengue, Japanese encephalitis and West Nile viruses.
Mosquito-borne flaviviruses are thought to initially replicate in dendritic cells near the site of inoculation followed by spread to the lymph nodes and bloodstream although information regarding the pathogenesis of ZIKV is scarce. Although flaviviral replication is thought to occur in cellular cytoplasm, one study suggested that ZIKV antigens could be found in infected cell nuclei. As of today, infectious ZIKV has been detected in human blood as early as the day of illness onset. Viral nucleic acid has been detected as late as 11 days after illness onset.
1947 - Scientists researching yellow fever placed a rhesus monkey in a cage on a tree platform in the Zika Forest (zika meaning "overgrown" in the Luganda language), near the East African Virus Research Institute in Entebbe, Uganda. The rhesus monkey developed a fever and researchers isolated a transmissible agent from its serum which was first described as the Zika virus (ZIKV) in 1952.
1948 – ZIKV was isolated from Aedes africanus mosquitoes trapped in the Zika Forest. Serologic studies indicated that humans could also be infected.
From 1951 through 1981 - Serologic evidence of human ZIKV infection was reported in other African countries such as Tanzania, Egypt, Central African Republic, Sierra Leone and Gabon and in parts of Asia including India, Malaysia, the Philippines, Thailand, Vietnam and Indonesia. In additional investigations, the virus was isolated from Aedes aegypti mosquitoes in Malaysia, a human in Senegal and mosquitoes in Côte d’Ivoire.
1968 and during 1971 – 1975, ZIKV was isolated from humans in Nigeria. In one study, 40% of the individuals tested had neutralizing antibody to ZIKV. Human isolates were obtained from febrile children 10 months, 2 years (2 cases) and 3 years of age, all without other clinical details and from a 10 year-old boy with fever, headache and body pains.
1981 - Olson et al. reported seven individuals with serologic evidence of Zika virus infection in Indonesia. A subsequent serologic study indicated that 13% (9/71) of human volunteers in Lombok, Indonesia, had neutralizing antibody to ZIKV.
From 1947 until 2007, confirmed cases of Zika virus infection from Africa and Southeast Asia were rare.
April 2007 - The first Zika virus outbreak outside of Africa and Asia occurred on the island of Yap in the Federated States of Micronesia. This outbreak was characterized by rash, arthralgia and conjunctivitis which was initially thought to be dengue, Chikungunya or Ross River disease. Serum samples from patients in the acute phase of the illness contained the RNA of ZIKV. There were 49 confirmed cases, 59 unconfirmed cases, no hospitalizations and no deaths.
2013 through 2014 - A large outbreak (8,750 suspected cases and an estimated 32,000 infected individuals) occurred in French Polynesia where public health officials estimated infection rates of 70% on some islands. There have been 74 cases of neurological and autoimmune complications of which 41 cases were Guillain-Barré syndrome.
February 2014 – In New Caledonia 140 confirmed cases of Zika virus infection were reported of which 32 were travel-related cases.
February until June 2014 – Chile notified the Pan American Health Organization (PAHO) and the World Health Organization (WHO) that it had confirmed a case of autochthonous (i.e., native to the place where it is found) transmission of the Zika virus on Easter Island. Cases were reported there up to June 2014.
March 2014 – A travel-related case of Zika virus infection reached the Cook Islands with 175 individuals displaying symptoms.
April 2015 - A large, ongoing outbreak of Zika virus infection that began in Brazil had spread to much of South and Central America and the Caribbean.
May 2015 – The first autochthonous Zika virus infection in Brazil was confirmed.
October 2015 – The Columbia health authorities reported the first autochthonous case of Zika virus infection. To date, 26 out of 36 territorial entities have reported autochthonous circulation of the Zika virus.
November 2015 – El Salvador, Guatemala, Mexico, Paraguay, Suriname and Venezuela each confirmed autochthonous circulation of the Zika virus.
Between October 2015 and January 2016 - Brazilian health authorities reported more than 3,500 microcephalic cases, according to the CDC. Some of the affected infants have had a severe type of microcephaly and some have died.
December 2015 – Ten Member States in the Americas reported confirmed autochthonous circulation of the Zika virus: Brazil (a total of 18 states), Chile (on Easter Island), Columbia, El Salvador, Guatemala, Mexico, Panama, Paraguay, Suriname and Venezuela. Zika virus infection was detected in Puerto Rico. Local transmission of Zika virus infection has not been reported in the continental United States but cases of travel-related Zika virus infection have been reported.
January 13, 2016 – A case of Zika was confirmed in Houston, Texas in a woman who had recently traveled to El Salvador thus importing the disease.
On January 15, 2016 - Hawaii's Department of Health (DOH) confirmed that a baby born in Oahu with microcephaly tested positive for the Zika virus. The DOH believes the mother contracted the infection while living in Brazil in May 2015.
January 20, 2016 – Three cases of travel-related Zika virus infection were reported in Florida. Two cases involved travel to Columbia in December 2015 (both in Miami-Dade County) and one case to Venezuela in December 2015 (Hillsborough County). All three are not pregnant. Illinois reported cases of two pregnant women who had traveled to South America.
January 22, 2016 – Three individuals in New York were reported to have contracted the Zika virus while traveling out of country.
January 28, 2016: Countries and Territories with Active Autochthonous Zika Virus Transmission (Table 2) per the CDC
U.S. Virgin Islands
January 29, 2016 – reported cases of Zika virus infection in the United States were acquired abroad and detected once the traveler returned to the United States.?
Countries and Territories with Documented Autochthonous Transmission of Zika Virus Infection Reported to PAHO - Region of the Americas, 2015–2016
Through Mosquito Bites
The Zika virus is transmitted by daytime-active mosquitoes and has been isolated from a number of species in the genus Aedes. Zika virus is a mosquito-borne flavivirus primarily transmitted by Aedes aegypti mosquitoes. Aedes albopictus mosquitoes also might transmit the virus. A. aegypti and A. albopictus mosquitoes are found throughout much of the Region of the Americas, including parts of the United States, and also transmit dengue, chikungunya, yellow fever and West Nile viruses.
Studies show that the extrinsic incubation period for ZIKV in mosquitoes is about 10 days. Nonhuman (monkeys) and human primates are likely the main reservoirs of the virus and anthroponotic (human-to-vector-to-human) transmission occurs during outbreaks.
The Zika virus is transmitted to humans primarily via the bite of an infected Aedes species mosquito. Aedes mosquitoes become infected when they bite an already infected individual, draw blood and contract the Zika virus. The Zika virus then spreads when the infected mosquito then goes and bites another individual.
Aedes mosquitoes typically breed and lay eggs in or near domestic water-holding containers (i.e., buckets, bowls, animal dishes, flower pots, vases etc.). They are aggressive daytime biters, prefer to bite humans and live indoors and outdoors near humans.
The potential societal risk of the Zika virus can be delimited by the distribution of the mosquito species that transmit it (its vectors). The global distribution of the most cited carrier of Zika virus, A. aegypti, is expanding due to global trade and travel . A. aegypti distribution is now the most extensive ever recorded – across all continents including North America and even the European periphery.
The map depicts the probability of occurrence:
blue = none
red = highest occurrence
Evidence on perinatal transmission of the Zika virus during pregnancy or childbirth is limited. Pregnant women can be infected with the Zika virus in any trimester. The incidence of Zika virus infection in pregnant women is currently unknown. Data on pregnant women infected with the 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.
It is possible that the Zika virus could be passed from a mother already infected with the Zika virus to the fetus during pregnancy. Perinatal transmission has been reported with other vector-borne viruses such as dengue and chikungunya. Studies are now being conducted on possible perinatal transmission of the virus and its possible effects on the fetus.
So far, there are no documented reports of Zika virus transmission via breastfeeding. Zika virus RNA has been detected in breast milk but Zika virus transmission through breastfeeding has not been documented. Because of the benefits of breastfeeding, mothers are encouraged to breastfeed even in areas where the Zika virus is found. Mothers in areas with Zika circulation should follow PAHO/WHO recommendations on breastfeeding (exclusive breastfeeding for the first 6 months, followed by continued breastfeeding with complementary foods up to 2 years and beyond).
Possibly Through Infected Blood or Sexual Contact
ZIKV can be transmitted through blood but this is an infrequent mechanism. Zika virus RNA has been identified in asymptomatic blood donors during an ongoing outbreak. Standard precautions that are already in place for ensuring safe blood donations and transfusions should be followed.
ZIKV has been isolated in human semen and one case of possible person-to-person sexual transmission has been described. In 2009 Brian Foy, a biologist from the Arthropod-borne and Infectious Diseases Laboratory at Colorado State University, sexually transmitted the Zika virus to his wife. He visited Senegal to study mosquitoes and was bitten on a number of occasions. A few days after returning to the United States, he fell ill with Zika virus infection but not before having had unprotected intercourse with his wife. She subsequently showed symptoms of Zika virus infection with extreme sensitivity to light. Foy is the first individual known to have passed on an insect-borne virus to another human by sexual contact. However, more evidence is needed to confirm whether sexual contact is a means of ZIKV transmission.
Causes of Rapid Transmission of the Zika Virus
Given the increase in congenital anomalies, Guillain-Barré syndrome (GBS), and other neurological and autoimmune syndromes in areas where the Zika virus is circulating, the PAHO and WHO recommends its Member States:
Guillain-Barré Syndrome (GBS)
GBS in its typical form is an acute polyradiculoneuropathy that produces a lower, bilateral and symmetrical sensorimotor development deficit, associated with generalized areflexia. In many cases, there is a history of infection that causes the immune response in the nerves. Between 3.5 and 12% of patients die from complications during the acute phase. The annual incidence of GBS is estimated to be between 0.4 and 4.0 cases per 100,000 inhabitants per year. In North America and Europe, GBS is more common in adults and increases steadily with age. Several studies indicate that men tend to be more affected than women.
GBS occurs when an individual’s immune system attacks itself particularly affecting the cells of the nervous system. This process can be initiated by infection with various viruses or bacteria. The main symptoms include muscular weakness and tingling (paresthesia) in the arms and legs. Severe complications can occur if the respiratory muscles are affected. The most seriously ill individuals need care in intensive care units.
2013 through 2014 - In the French Polynesian Zika virus epidemic in which 8,750 suspected cases were detected, 74 individuals presented with neurologic syndromes or autoimmune syndromes following an illness compatible with the Zika virus infection in the previous days. Of these, 42 were confirmed as GBS, 37 of which had presented with a previous viral syndrome.
In July 2015, Brazil reported the detection of patients with neurological syndromes who had a recent history of Zika virus infection in the state of Bahia. There were 76 patients with neurological syndromes identified, of which 55% (42/76) were confirmed as GBS, 5/76 were confirmed with other neurological syndromes, 4/76 were discarded and 25/76 were still under investigation. Among the confirmed GBS, 62% (26/42) had a history of symptoms consistent with Zika virus infection.
On 25 November 2015, the Aggeu Magalhães Research Center of the Oswaldo Cruz Foundation in Rio de Janeiro, Brazil reported that Zika virus infection was found in 10 of the 224 suspected dengue patients whose samples were analyzed for Zika virus infection. Seven of the 10 samples analyzed corresponded to patients with neurological syndrome.
In January 2016, El Salvador reported the detection of an unusual increase of GBS since early December 2015. On average, El Salvador recorded 14 cases of GBS per month (169 cases per year). However, between 1 December 2015 and 6 January 2016, there were 46 GBS recorded, two of which died. Twenty-five (54%) were male and 35 (76%) were over 30 years old. All were hospitalized and treated with plasmapheresis or immunoglobulin. Of the deceased patients, one had a history of multiple underlying chronic diseases. In 22 patients whose information was available, 12 (54%) had febrile rash illness between 7 and 15 days prior to the onset of GBS.
Currently, similar situations are being investigated in other countries of the Americas. These findings are consistent with a temporal and spatial link between Zika virus circulation and the increase of GBS. Although the etiopathogenesis and associated risk factors have not yet been well established, Member States should implement surveillance systems to detect unusual increases in cases and prepare health services for care of patients with neurological conditions.
Other Neurological Syndromes
Zika virus can cause other neurological syndromes (meningitis, meningoencephalitis and myelitis), as described in the French Polynesian outbreak (2013 - 2014). The French Polynesian Health Authorities also reported an unusual increase in central nervous system abnormalities in fetuses and newborns registered during 2013 – 2014. This finding coincided with the Zika virus outbreak in the islands. None of the pregnant women described clinical signs of the Zika virus but four women were found positive by IgM serology assays for flavivirus suggesting a possible asymptomatic Zika virus infection.
17 malformations were registered:
The French Polynesian Health Authorities hypothesize that Zika virus infection may be associated with these abnormalities if mothers are infected during the first or second trimester of pregnancy.
PAHO/WHO advises its Member States to implement or intensify surveillance of neurological and autoimmune complications in all age groups particularly in situations of possible ZIKV circulation. This surveillance can be established as hospital-based, syndromic surveillance or surveillance of cases. If case surveillance is implemented, a case definition should include GBS, Fisher syndrome, encephalitis, meningitis, and meningoencephalitis.
Fisher syndrome (or Miller Fisher syndrome) is characterized by impairment of eye movements, abnormal coordination and loss of tendon reflexes. While the clinical triad (ataxia, ophthalmoplegia and areflexia) is easily recognizable, sometimes it overlaps with GBS so some authors consider it as a variant of GBS and it is associated with an autoimmune inflammation of nerves after an infection.
While in the Region of the Americas such syndromes have not yet been reported, health services and practitioners should be alert to their possible occurrence to properly prepare health facilities for rapid detection and appropriate treatment of cases.
Microcephaly is a neurological disorder in which the occipitofrontal circumference is smaller than that of other children of the same age, race and sex. Maternal-fetal transmission of the Zika virus has been documented throughout pregnancy. Zika virus infection has been confirmed in several infants with congenital microcephaly and in fetal losses among women infected during pregnancy. The spectrum of outcomes that may be associated with infection during pregnancy is not yet fully understood nor are the factors that may increase fetal risk.
A large number of Brazilian newborns with microcephaly has been observed in parallel with the current Zika outbreak. It is not known how many of the microcephaly cases are associated with Zika virus infection. Studies are being conducted to investigate the association of Zika virus infection and microcephaly, including the role of other contributory factors (e.g., prior or concurrent infection with other organisms, nutrition and environment). The full spectrum of outcomes that might be associated with Zika virus infections during pregnancy is unknown and requires further investigation.
Data collected by the Brazilian Health Authorities suggests that newborns of mothers who had a Zika virus infection during the first trimester of pregnancy are at an increased risk of microcephaly and/or other congenital anomalies. The Brazilian Ministry of Health has since confirmed the relationship between the Zika virus and microcephaly.
Between March 2015 and January 2016, more than 3,500 cases of microcephaly have been reported among newborns born to Brazilian mothers with Zika virus infection including 46 deaths, in 20 states and the Federal District. This represented a 20-fold increase in microcephaly compared with previous years. In 2000, the prevalence of microcephaly in newborns in Brazil was 5.5 case/100,000 live births and in 2010 it was 5.7 cases/100,000 live births. Macular atrophy has also been observed among children with microcephaly born after the onset of the Zika virus outbreak in Brazil.
On 17 November 2015, the Flavivirus Laboratory at the Osvaldo Cruz Institute in Brazil indicated that the Zika virus genome was detected through RT-PCR testing in the amniotic fluid samples of two pregnant women whose fetuses had been diagnosed with microcephaly by ultrasound exams.
On 18 November 2015, the Brazilian Ministry of Health established the relationship between the increase in occurrence of microcephaly and Zika virus infection through the detection of the Zika virus genome in the blood and tissue samples of a newborn from the state of Para. The newborn presented with microcephaly and other congenital anomalies and died within five minutes of birth.
In December 2015, it was suspected that a transplacental infection of the fetus may lead to microcephaly and brain damage.
In 2015, Zika virus RNA was detected in the amniotic fluid of two fetuses, indicating that it had crossed the placenta and could cause a fetal infection.
On 13 January 2016, the Brazil Ministry of Health reported the detection of Zika virus genome, through the RT-PCR technique in four cases of congenital malformation in the state of Rio Grande do Norte. The cases correspond to two miscarriages and two full-term newborns (37 and 42 weeks respectively) who died in the first 24 hours of life. Tissue samples from both newborns were positive for the Zika virus by immunohistochemistry.
On 20 January 2016, scientists from the state of Paraná, Brazil, detected genetic material of the Zika virus in the placenta of a woman who had undergone an abortion due to the fetus's microcephaly, which confirmed that the virus is able to pass the placenta.
In January 2016, ophthalmological findings were reported in three children with microcephaly and cerebral calcifications detected by CT scans and presumable intrauterine ZIKV infection. The three infants had unilateral ocular findings involving the macular region and loss of foveal reflex. In one child a well-defined macular neuroretinal atrophy was detected.
In January 2016, the United States CDC advised that pregnant women consider postponing travel to any area where Zika virus transmission is ongoing.
Zika virus infections have been confirmed in infants with microcephaly, although it is not known how many of the microcephaly cases are associated with Zika virus infection. Furthermore, Zika virus RNA has been detected in the pathologic specimens of fetal losses, although it is not known whether the Zika virus caused the fetal losses. Pregnant women can be infected with the Zika virus in any trimester.
The Brazil Ministry of Health continues to investigate the possible association between the Zika virus and a reported increase in the number of babies born with microcephaly. Due to concerns of microcephaly associated with maternal Zika virus infection, fetuses and infants of women infected with the Zika virus during pregnancy should be evaluated for possible congenital Zika virus infection and neurologic abnormalities.
The diagnosis of Zika virus infection should be suspected in individuals:
Signs and Symptoms
The first well-documented case of human ZIKV disease was in 1964 when Simpson described his own occupationally acquired ZIKV illness at age 28. It began with mild headache. The next day, a maculopapular rash covered his face, neck, trunk and upper arms and spread to his palms and soles. Transient fever, malaise and back pain developed. By the evening of the second day of illness he was afebrile, the rash had started fading and he felt better. By day three, he felt well and had only the rash, which disappeared over the next 2 days. ZIKV was isolated from serum collected while he was febrile.
The incubation period (the time from exposure to onset of symptoms) of Zika virus infection is not clear, but is typically 2 to 12 days after the mosquito vector bite. One out of four infected individuals (20 – 25%) develops symptoms of the disease. Among those who do, the symptoms/infection are usually mild and usually resolves within 2 to 7 days. Symptoms are similar to those of dengue or chikungunya which are transmitted by the same type of mosquito. An estimated 80% of individuals infected with the Zika virus are asymptomatic. The Zika virus usually remains in the blood of an infected individual for a few days but it can be found longer in some individuals.
Symptoms of infection with the Zika virus typically include:
Maculopapular rash - wikipedia.org
More rarely observed signs and symptoms include:
The differential diagnosis of Zika virus infection includes:
Dengue virus and Zika virus infections present with similar clinical manifestations and are transmitted by the same mosquito vector. They differ clinically in that dengue infection usually presents with higher fever and more severe muscle pain, which may also be associated with hemorrhage. Coinfection with Zika, chikungunya and dengue viruses has been described. The diagnosis of dengue virus infection is established via serology.
Chikungunya virus and Zika virus infections present with similar signs and symptoms and are transmitted by the same mosquito vector. They differ clinically in that chikungunya usually presents with higher fever and more intense joint pain, affecting the hands, feet, knees and back. The infection can be disabling, causing patients to bend over such that they cannot walk or rendering individuals unable to perform simple manual tasks such as opening a water bottle. Coinfection with Zika, chikungunya and dengue viruses has been described. The diagnosis of chikungunya virus infection is established via serology.
Parvovirus infection can present with acute and symmetric arthritis or arthralgia, most frequently involving the small joints of the hands, wrists, knees and feet. Rash may or may not be present. The diagnosis is established via serology.
Clinical manifestations of rubella include low-grade fever and coryza. A macular rash begins on the face and spreads to the trunk. Arthritis may be present. The diagnosis is established via serology.
A number of other viruses may also cause arthritis, including enterovirus, adenovirus and alphaviruses.
Clinical manifestations of measles include fever, cough, sore throat, coryza, conjunctivitis and lymphadenitis. Koplik spots may precede a generalized rash. The diagnosis is established via serology.
Leptospirosis is characterized by fever, rigors, myalgia, conjunctival suffusion and headache. Less common signs and symptoms include cough, nausea, vomiting, diarrhea, abdominal pain and arthralgia. It may be distinguished from Zika virus infection by the presence of jaundice. The diagnosis is established via serology.
Malaria is characterized by fever, malaise, nausea, vomiting, abdominal pain, diarrhea, myalgia and anemia. The diagnosis of malaria is established by visualization of parasites on peripheral smear.
Rickettsial infections with similar manifestations as Zika virus infection include African tick bite fever and relapsing fever. African tick bite fever is observed among travelers to Africa and is characterized by headache, fever, myalgia, solitary or multiple eschars with regional lymphadenopathy and generalized rash. The diagnosis is established via serology. Relapsing fever is characterized by fever, headache, neck stiffness, arthralgia, myalgia and nausea. Diagnostic tools include direct smear and polymerase chain reaction.
The 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 the Zika virus, viral nucleic acid or virus-specific immunoglobulin M and neutralizing antibodies.
The diagnosis is definitively established via reverse-transcription polymerase chain reaction (RT-PCR) or serology. These tests are performed at the United States CDC Arboviral Diagnostic Laboratory and some state health departments or the PAHO/WHO.
Reverse-Transcription Polymerase Chain Reaction (RT-PCR)
Within the first week (usually the first 3 – 5 days) after the onset of symptoms, the diagnosis of Zika virus infection may be established via RT-PCR tests on acute-phase serum for detection of Zika virus RNA.
Acute serum should be obtained to compare with convalescent serum obtained 2 – 3 weeks later.
RT-PCR testing for dengue virus and chikungunya virus should also be ordered.
Serologic Testing (Immunoglobulin M (IgM) and Confirmatory Neutralizing Antibody Titers)
Virus-specific IgM and confirmatory neutralizing antibody titers detect specific antibodies against ZIKV in the serum which typically develop toward the end of the first week of illness.
Four days or more following the onset of symptoms, the diagnosis may be established by Zika virus serologic testing IgM and confirmatory neutralizing antibody titers.
Acute and convalescent sera should be obtained to detect an increased antibody titer in the paired samples with an interval of two to three weeks between both draws.
Serologic testing for dengue virus infection and chikungunya virus infection should also be ordered.
All serologic results should be interpreted with caution since there can be cross-reactivity with other flaviviruses including dengue virus, West Nile virus and yellow fever.
Plaque-Reduction Neutralization Testing (PRNT)
Plaque-reduction neutralization testing can be performed to measure virus-specific neutralizing antibodies and discriminate between cross-reacting antibodies in primary flavivirus infections.
In 2016, Zika virus infection 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 the CDC through ArboNET, the national surveillance system for arboviral disease.
Laboratory specimens may be sent directly to the CDC Arboviral Diagnostic Laboratory. Instructions are available online. Communication should be initiated with the laboratory via telephone (1-970-221-6400) prior to shipment of specimens.
Test results are normally available 4 to 14 days after the receipt of the specimen. Reporting times for test results may be longer during summer months when arbovirus activity increases. Receipt of a hard copy of the results takes at least 2 weeks after testing is completed. All results will be sent to the appropriate state health department. All healthcare providers should notify their state health department of any direct submissions to the CDC.
Healthcare providers should question all pregnant women about recent travel. Pregnant women with a history of travel to an area with ongoing Zika virus transmission should be evaluated for Zika virus infection in accordance with CDC Interim guidance protocols. Because of the similar geographic distribution and clinical presentation of Zika, dengue and chikungunya virus infection, pregnant women with symptoms consistent with Zika virus infection should also be evaluated for dengue and chikungunya virus infections, in accordance with existing guidelines. Referral to a maternal-fetal medicine or infectious disease specialist with expertise in pregnancy management is recommended.
Laboratory testing of maternal serum for Zika virus infection including RT-PCR, IgM and neutralizing antibody testing is warranted for pregnant women:
Laboratory testing for Zika virus infection is not indicated for pregnant women in the following categories:
It is possible that a pregnant woman with relevant travel history and no clinical symptoms or positive ultrasound findings may have a fetus affected by the Zika virus infection in that asymptomatic Zika virus infection is common. The above interim guidance has been issued based on limited laboratory testing capacities and it is possible these criteria may be revised.
Zika virus testing of maternal serum includes:
Laboratory evidence of maternal Zika virus infection includes:
Fetuses and Infants
Zika virus infections have been documented through both intrauterine transmission resulting in congenital Zika virus infection and intrapartum transmission from a viremic mother to her newborn.
Zika virus RNA by RT-PCR testing of amniotic fluid can be performed for detection of intrauterine Zika virus infection. However, the sensitivity and specificity of this approach for diagnosis of congenital infection is unknown. It is reasonable to offer amniocentesis to women at 15 weeks or greater gestational age with a history of travel to an area with Zika virus transmission and either positive/inconclusive laboratory testing for Zika virus infection or relevant ultrasound findings (fetal microcephaly or intracranial calcifications).
Amniocentesis is associated with an overall 0.1% risk of pregnancy loss when performed at less than 24 weeks of gestation. Amniocentesis performed at 15 weeks or later gestational age is associated with lower rates of complications than those performed at earlier gestational ages. Amniocentesis performed at 14 weeks or less of gestational age is not recommended. Healthcare providers should discuss the risks and benefits of amniocentesis with their patients. It is unknown whether a positive amniotic fluid RT-PCR result is predictive of a subsequent fetal abnormality, and, if so, what proportion of infants born after infection will have abnormalities. A positive RT-PCR result on amniotic fluid should be considered suggestive of intrauterine Zika virus infection and potentially useful to pregnant women and their healthcare providers.
Serial ultrasound examinations (every three to four weeks) are appropriate to monitor fetal growth and anatomy in pregnant women with laboratory evidence of Zika virus infection in serum or amniotic fluid. Data on fetal ultrasound findings in infected pregnant women is limited. One small study reported variable fetal ultrasound findings that may include lower-than-expected head circumference for time of gestation (e.g., more than two standard deviations below the mean), focal brain abnormalities in areas such as the cerebellum and intraocular and brain calcifications.
For live births, Zika virus laboratory testing is recommended for:
Because the diagnosis of Zika virus infection is made through molecular and serologic testing including RT-PCR for viral RNA and IgM and plaque reduction neutralization test (PRNT) for Zika virus antibodies, it is currently not known which type of testing most reliably establishes the diagnosis of congenital Zika virus infection. The CDC recommends both molecular and serologic testing of infants who are being evaluated for evidence of a congenital Zika virus infection.
The following Zika virus testing on infants per CDC interim guidelines includes:
Results of these assays can be falsely positive because of cross-reacting antibodies. Plaque-reduction neutralization testing (PRNT) can be performed to measure virus-specific neutralizing antibodies and discriminate between cross-reacting antibodies in primary flavivirus infections (e.g., dengue or yellow fever viruses).
Finally, histopathologic examination of the placenta and umbilical cord tissues with Zika virus immunohistochemical staining to detect Zika virus antigen on fixed tissue and Zika virus RT-PCR on fixed and frozen tissue can be considered.
An infant is considered congenitally infected if Zika virus RNA or viral antigen is identified in any of the samples submitted including testing of amniotic fluid and testing of the placenta or umbilical cord. In addition, Zika virus IgM antibodies with confirmatory neutralizing antibody titers that are 4-fold or higher than dengue virus neutralizing antibody titers in the infant serum or CSF constitute evidence of a congenital Zika virus infection. If Zika virus neutralizing antibody titers are less than 4-fold higher than dengue results, the results are considered inconclusive.
Fetal tissue testing is warranted for evaluation of fetal losses in women with a history of travel to an area of Zika virus transmission, together with either symptoms consistent with Zika virus infection during or within two weeks of travel or findings of fetal microcephaly. In such cases, Zika virus RT-PCR and immunohistochemical staining should be performed on fetal tissues, including the umbilical cord and placenta.
As of 2016[update], no vaccine or antiviral medications are available to prevent or treat Zika virus infections. Effective vaccines exist for several flaviviruses. Vaccines for yellow fever virus, Japanese encephalitis and tick-borne encephalitis were introduced in the 1930s. The vaccine for dengue fever has just recently become available for use.
Work has begun towards developing a vaccine for Zika virus, according to Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases. The researchers at the Vaccine Research Center have extensive experience from working with vaccines for other viruses such as West Nile virus, chikungunya virus and dengue fever. Nikos Vasilakis of the Center for Biodefense and Emerging Infectious Diseases has predicted that 10 to 12 years may be needed before an effective Zika virus vaccine becomes available.
The goals of clinical management, whether pregnant or not, are supportive in nature and include:
In pregnant women with laboratory evidence of Zika virus infection in serum or amniotic fluid, serial ultrasound examinations (every three to four weeks) are appropriate to monitor fetal growth and anatomy.
Because of similar geographic distribution and symptoms, individuals with suspected Zika virus infections also should be evaluated and managed for possible dengue or chikungunya virus infection.
Individuals infected with the Zika, chikungunya or dengue viruses should avoid mosquito bites during the first week of infection to prevent other mosquitoes from becoming infected and reducing the risk of local transmission by passing the viruses on to other individuals.
Special Circumstances: Evaluation
For the purpose of evaluating an infant for possible congenital Zika virus infection, microcephaly is defined as occipitofrontal circumference less than the third percentile, based on standard growth charts (e.g., Fenton, Olsen, CDC or WHO growth curves) for sex, age and gestational age at birth. For a diagnosis of microcephaly to be made, the occipitofrontal circumference should be disproportionately small in comparison with the length of the infant and not explained by other etiologies (e.g., other 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 should be considered.
For all infants with possible congenital Zika virus infection, evaluation should include:
For infants with microcephaly or intracranial calcifications detected prenatally or at birth whose mothers were possibly infected with the Zika virus during pregnancy, evaluation should include:
For infants with microcephaly or intracranial calcifications who have negative results on all Zika virus tests performed, healthcare providers should evaluate for other possible etiologies and treat as indicated. Evaluation should include:
Recommendations for long-term follow-up for infants with possible congenital Zika virus infection include:
The infant should be followed to assess for possible long-term sequelae which should include:
Severe disease requiring hospitalization is rare. Case-fatality rates are low. In the Americas Region, ZIKV is new and up until now has had a very limited geographic and demographic distribution. There is only recent evidence that it can cause death. However, sporadic cases have been reported of more serious manifestations and complications in individuals with pre-existing diseases or conditions causing death.
Mosquitoes and their breeding sites pose a significant risk factor for Zika virus infection. Prevention and control relies on reducing mosquitoes through source reduction (removal and modification of breeding sites) and reducing contact between mosquitoes and humans.
Individuals in areas of autochthonous transmission or when traveling to areas where mosquitoes carrying the Zika virus or other viruses are endemic should take measures to avoid mosquito bites. Measures include both personal preventative protection, as well as, environmental control measures.
Personal protective measures include:
Environmental control measures to eliminate or control mosquitoes include:
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.
If an individual has Zika virus infection, it is imperative that other individuals be protected from acquiring the virus. Since the Zika virus can be found in the infected individual’s blood during the first week of infection, if a mosquito bites the infected individual the mosquito can then pass the Zika virus onto another individual by simply biting them. Individuals with Zika virus infection may reduce the spread of infection to others by following the same personal protective measures mentioned above to protect themselves from being bitten further by other mosquitoes and then those mosquitoes biting other individuals and so on and so on. Individuals with symptoms of Zika, dengue or chikungunya should visit a healthcare center.
Anecdotal reports of apparent sexual transmission of the Zika virus have been described, although this appears to be an infrequent mechanism for virus transmission. Information regarding the persistence of the virus at different sites following infection is not yet available. Pending further study, it may be wise for men with symptoms of Zika virus infection who have female sexual partners of childbearing age to use barrier protection and defer unprotected sex for at least a few weeks following resolution of symptoms.
On Friday, January 15, 2016, the CDC issued interim travel guidance related to the Zika virus for 14 countries and territories in Central and South America and the Caribbean. The CDC issued a travel alert (Level 2-Practice Enhanced Precautions) for individuals traveling to regions and certain countries where Zika virus transmission is ongoing. These regions and countries include: Brazil, Colombia, El Salvador, French Guiana, Guatemala, Haiti, Honduras, Martinique, Mexico, Panama, Paraguay, Suriname, Venezuela, and the Commonwealth of Puerto Rico.
Because of the potential for birth defects, the CDC issued travel guidance for pregnant American women and women of childbearing age who may become pregnant, warning them to avoid visiting places where the virus is currently circulating.
Until more is known and out of an abundance of caution, the CDC recommends special precautions for pregnant women and women trying to become pregnant:
The CDC has issued interim guidelines for healthcare providers in the United States for the evaluation of pregnant women during a Zika virus outbreak. These guidelines include recommendations for pregnant women considering travel to an area with Zika virus transmission and recommendations for screening, testing and management of the pregnant returning traveler.
Governments or health agencies of the United Kingdom, Ireland, New Zealand, Canada, and the European Union have also issued similar travel warnings. In Colombia, the Minister of Health and Social Protection, Alejandro Gaviria Uribe, recommended avoiding pregnancy for eight months, while the countries of Ecuador, El Salvador and Jamaica have issued similar warnings. Women in other countries in Latin America and the Caribbean that have been hit with Zika have been told to simply avoid getting pregnant - in some cases for two years.
PAHO/WHO is actively working with the countries of the Americas to develop or maintain their ability to detect and confirm cases of Zika virus infection, treat individuals affected by the disease and implement effective strategies to reduce the presence of the mosquito and minimize the likelihood of an outbreak.
PAHO/WHO support involves:
The WHO is supporting countries to control Zika virus infection through:
Outbreaks of Zika virus infection, caused by an emerging mosquito-borne flavivirus, have occurred in Africa, Southeast Asia and the Pacific Islands. Currently, there is an ongoing Zika virus outbreak in the Americas. Zika virus is transmitted to humans via the bite of an infected Aedes mosquito. This type of mosquito usually bites during the daytime and breeds in standing water.
Clinical manifestations of Zika virus infection include acute onset of low-grade fever with maculopapular rash, arthralgia (notably of the small joints of the hands and feet) or conjunctivitis (nonpurulent). Clinical illness is consistent with Zika virus infection if two or more of these symptoms are present. Zika virus infection has also been associated with congenital microcephaly, fetal loss and Guillain-Barré syndrome.
Signs and symptoms typically occur 2 to 12 days after the mosquito vector bite. Zika virus infection is usually mild. Clinical manifestations usually resolve within two to seven days. Asymptomatic infection up to 80% is common. Symptomatic infection develops in 20 to 25% of individuals who become infected with the Zika virus.
The diagnosis of Zika virus infection should be suspected in individuals with typical clinical manifestations and relevant epidemiologic exposure (residence in or travel to an area where the Aedes mosquito is present and where travel-related or local cases have been reported or in unprotected sexual contact with an individual who meets these criteria).
The diagnosis of Zika virus infection is established via serum RT-PCR testing or serology. Within the first seven days following onset of symptoms, the diagnosis may be established via serum RT-PCR for detection of Zika viral RNA. Four or more days after the onset of symptoms, the diagnosis may be established via Zika virus serologic testing.
Pregnant women with Zika virus exposure should undergo ultrasonography to evaluate for presence of fetal microcephaly or intracranial calcifications. Laboratory testing for Zika virus infection is warranted for pregnant women with Zika virus exposure and either of the following:
Serial ultrasonography (every three to four weeks) is appropriate (with focus on evaluation for microcephaly or intracranial calcifications) for pregnant women in either of the following categories:
Indications for Zika virus laboratory testing of infants include:
There is no specific treatment for Zika virus infection and there is no vaccine for prevention. Management consists of symptomatic treatment. Preventive measures include personal protective measures to prevent mosquito bites and institution of measures to eliminate and control mosquito breeding sites.
Pregnant women should be particularly careful regarding adherence to mosquito protective measures and about traveling to areas where transmission of the Zika virus is high. In January 2016, the United States Centers for Disease Control and Prevention and the European Centre for Prevention and Control advised that pregnant women consider postponing travel to any area where Zika virus transmission is ongoing.
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