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Zika fever

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For the 2015–16 outbreak, see Zika virus outbreak (2015–present).

Zika fever
Pronunciation
SpecialtyInfectious diseases, neonatology Edit this on Wikidata

Zika fever (also known as Zika virus disease) is an illness caused by the Zika virus.[1] Most cases have no symptoms, but when present they are usually mild and can resemble dengue fever.[1][2] Symptoms may include fever, red eyes, joint pain, headache, and a maculopapular rash.[1][3][4] Symptoms generally last less than seven days.[3] It has not caused any reported deaths during the initial infection.[2] Infection during pregnancy causes microcephaly in some babies.[5][6] Infections in adults has been linked to Guillain–Barré syndrome (GBS).[2]

Zika fever is mainly spread via the bite of mosquitoes of the Aedes type.[3] It can also be sexually transmitted from a man to his sex partners and potentially spread by blood transfusions.[3][7] Infections in pregnant women can be spread to the baby.[5][6][8] Diagnosis is by testing the blood, urine, or saliva for the presence of Zika virus RNA when the person is sick.[1][3]

Prevention involves decreasing mosquitoes bites in areas where the disease occurs and proper use of condoms.[3][7] Efforts to prevent bites include the use of insect repellent, covering much of the body with clothing, mosquito nets, and getting rid of standing water where mosquitoes reproduce.[1] There is no effective vaccine.[3] Health officials recommended that women in areas affected by the 2015–16 Zika outbreak consider putting off pregnancy and that pregnant women not travel to these areas.[3][9] While there is no specific treatment, paracetamol (acetaminophen) may help with the symptoms.[3] Admission to hospital is rarely necessary.[2]

The virus that causes the disease was first isolated in 1947.[10] The first documented outbreak among people occurred in 2007 in the Federated States of Micronesia.[3] As of January 2016, the disease was occurring in twenty regions of the Americas.[3] It is also known to occur in Africa, Asia, and the Pacific.[1] Due to an outbreak which started in Brazil in 2015, the World Health Organization declared it a Public Health Emergency of International Concern in February 2016.[11]

Signs and symptoms

A video explanation of Zika virus and Zika fever
Rash on an arm due to Zika fever

Most people who are infected have no or few symptoms.[12] Otherwise the most common signs and symptoms of Zika fever are fever, rash, conjunctivitis (red eyes), muscle and joint pain, and headache, which are similar to signs and symptoms of dengue and chikungunya fever.[13] The time from a mosquito bite to developing symptoms is not yet known, but is probably a few days to a week.[14] The disease lasts for several days to a week and is usually mild enough that people do not have to go to a hospital.[1][15]

Due to being in the same family as dengue, there has been concern that it could cause similar bleeding disorders. However that has only been documented in one case, with blood seen in semen, also known as hematospermia.[16]

Guillain-Barré syndrome

Zika virus infections have been linked with GBS, which is the rapid onset of muscle weakness that can progress to paralysis.[17] While both GBS and Zika infection can simultaneously occur in the same individual, it is difficult to definitively identify Zika virus as the cause of GBS.[18] Several countries affected by Zika outbreaks have reported increases in the rate of new cases of GBS. During the 2013–2014 outbreak in French Polynesia there were 42 reported cases of GBS over a 3-month period, compared to between 3 and 10 annually prior to the outbreak.[19] Three deaths due to Zika-linked GBS have been reported in Colombia.[20]

Pregnancy

Microcephaly

The disease spreads from mother-to-child in the womb and can cause multiple problems, most notably microcephaly in the baby. As of April 2016, the full range of birth defects caused by maternal infection was not known, but appear to be common with abnormalities seen on up to 29% of ultrasounds.[21] Observed associations include microcephaly, eye abnormalities such as chorioretinal scarring,[22] and hydrops fetalis, where there is abnormal accumulation of fluid in the fetus.[23]

It is also not well understood whether the stage of pregnancy at which the mother becomes infected affects the risk to the fetus, nor if other risk factors might exist that affect outcomes.[5][6][8]

Cause

Reservoir

Zika virus is a mosquito-borne flavivirus closely related to the dengue virus. While mosquitoes are the vector, the reservoir species remains unknown, though serological evidence has been found in West African monkeys and rodents.[24][25]

Transmission

Transmission is via the bite of mosquitoes from the Aedes genus, primarily Aedes aegypti in tropical regions. It has also been isolated from Ae. africanus, Ae. apicoargenteus, Ae. luteocephalus,[26] Ae. vittatus and Ae. furcifer.[24] During the 2007 outbreak on Yap Island in the South Pacific, Aedes hensilli was the vector, while Aedes polynesiensis spread the virus in French Polynesia in 2013.[27]

Sexual transmission of Zika virus from men to women has been documented in at least 4 cases with several more under investigation by the CDC.[28][29][30] Zika virus has also been isolated from semen samples, with one person having 100,000 times more virus in semen than blood or urine, two weeks after being infected.[31] It is unclear why levels in semen can be higher than other body fluids, and it is also unclear how long infectious virus can remain in semen. The CDC has recommended that men with Zika fever should wait at least 6 months before trying to attempt conception.[32] To date there have been no reported sexual transmissions from women to their sexual partners.[30]

Cases of vertical perinatal transmission have been reported.[33] The CDC recommends that women with Zika fever should wait at least 8 weeks after they start having symptoms of disease before attempting to conceive.[32] There have been no reported cases of transmission from breastfeeding, but infectious virus has been found in breast milk.[34]

Like other flaviviruses it could potentially be transmitted by blood transfusion and several affected countries have developed strategies to screen blood donors.[15][35] The virus is detected in 3% of asymptomatic blood donors in French Polynesia.[36]

Diagnosis

It is difficult to diagnose Zika virus infection based on clinical signs and symptoms alone due to overlaps with other arboviruses that are endemic to similar areas.[15][37] The US Centers for Disease Control and Prevention (CDC) advises that "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, and parvovirus, enterovirus, adenovirus, and alphavirus infections (e.g., chikungunya, Mayaro, Ross River, Barmah Forest, O'nyong'nyong, and Sindbis viruses)."[38]

In small case series, routine chemistry and complete blood counts have been normal in most patients. A few have been reported to have mild leukopenia, thrombocytopenia, and elevated liver transaminases.[39]

Zika virus can be identified by reverse transcriptase PCR (RT-PCR) in acutely ill patients. However, the period of viremia can be short[2] and the World Health Organization (WHO) recommends RT-PCR testing be done on serum collected within 1 to 3 days of symptom onset or on saliva or urine samples collected during the first 3 to 5 days.[27] When evaluating paired samples, Zika virus was detected more frequently in saliva than serum.[39] The longest period of detectable virus has been 11 days and Zika virus does not appear to establish latency.[24]

Later on, serology for the detection of specific IgM and IgG antibodies to Zika virus can be used. IgM antibodies can be detectable within 3 days of the onset of illness.[24] Serological cross-reactions with closely related flaviviruses such as dengue and West Nile virus as well as vaccines to flaviviruses are possible.[2][40][41] Commercial assays for Zika antibodies are now available but have not yet been FDA approved.[37][42]

Screening in pregnancy

The CDC recommends screening some pregnant women even if they do not have symptoms of infection. Pregnant women who have travelled to affected areas should be tested between two and twelve weeks after their return from travel.[43] Due to the difficulties with ordering and interpreting tests for Zika virus, the CDC also recommends that healthcare providers contact their local health department for assistance.[43] For women living in affected areas, the CDC has recommended testing at the first prenatal visit with a doctor as well as in the mid-second trimester, though this may be adjusted based on local resources and the local burden of Zika virus.[43] Additional testing should be done if there are any signs of Zika virus disease. Women with positive test results for Zika virus infection should have their fetus monitored by ultrasound every three to four weeks to monitor fetal anatomy and growth.[43]

Infant testing

For infants with suspected congenital Zika virus disease, the CDC recommends testing with both serologic and molecular assays such as RT-PCR, IgM ELISA and plaque reduction neutralization test (PRNT).[44] Newborns with a mother who was potentially exposed and who have positive blood tests, microcephaly or intracranial calcifications should have further testing including a thorough physical investigation for neurologic abnormalities, dysmorphic features, splenomegaly, hepatomegaly, and rash or other skin lesions.[44] Other recommended tests are cranial ultrasound, hearing evaluation, and eye examination.[44] Testing should be done for any abnormalities encountered as well as for other congenital infections such as syphilis, toxoplasmosis, rubella, cytomegalovirus infection, lymphocytic choriomeningitis virus infection, and herpes simplex virus.[44]

Prevention

The virus is spread by mosquitoes, making mosquito avoidance an important element to disease control. The CDC recommends that individuals:[45]

  • Cover exposed skin by wearing long-sleeved shirts and long pants
  • Use an insect repellent containing DEET, picaridin, oil of lemon eucalyptus (OLE), or IR3535
  • Always follow product directions and reapply as directed
  • If you are also using sunscreen, apply sunscreen first, let it dry, then apply insect repellent
  • Follow package directions when applying repellent on children. Avoid applying repellent to their hands, eyes, or mouth
  • Stay and sleep in screened-in or air-conditioned rooms
  • Use a bed net if the area where you are sleeping is exposed to the outdoors

The CDC also recommends strategies for controlling mosquitoes such as eliminating standing water, repairing septic tanks and using screens on doors and windows.[46][47] Spraying insecticide is used to kill flying mosquitoes and larvicide can be used in water containers.[1]

Because Zika virus may be sexually transmitted, men who have gone to an area where Zika fever is occurring should be counseled to either abstain from sex or use condoms for 6 months after travel if their partner is pregnant or could potentially become pregnant.[15][28][32] Breastfeeding is still recommended by the WHO, even by women who have had Zika fever. There have been no recorded cases of Zika transmission to infants through breastfeeding, though the replicative virus has been detected in breast milk.[34][48]

Vaccine

There is currently no vaccine. Development is a priority of the US National Institutes of Health (NIH), but officials warn that development of a vaccine could take years.[2][15][37][49] However, at least one company has publicly stated that a vaccine could be available for emergency use by the end of 2016.[50]

CDC travel alert

Because of the "growing evidence of a link between Zika and microcephaly", in January 2016, the CDC issued a travel alert advising pregnant women to consider postponing travel to countries and territories with ongoing local transmission of Zika virus.[51] Later, the advice was updated to caution pregnant women to avoid these areas entirely if possible and, if travel is unavoidable, to protect themselves from mosquito bites.[52] Male partners of pregnant women and couples contemplating pregnancy who must travel to areas where Zika is active are advised to use condoms or abstain from sex entirely.[52] The agency also suggested that women thinking about becoming pregnant should consult with their physicians before traveling.[51][53]

Areas of active Zika Virus transmission, April 2016

As of April 2016, the CDC travel advisories include:[54]

  • Cape Verde
  • Many parts of the Caribbean: Aruba, Barbados, Bonaire, Cuba, Curaçao, Dominica, Dominican Republic, Guadeloupe, Haiti, Jamaica, Martinique, Puerto Rico, Saint Lucia, Saint Martin, Saint Vincent and the Grenadines, Sint Maarten, Trinidad and Tobago, and the U.S. Virgin Islands
  • Most of Central America: Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama
  • Mexico
  • Several Pacific Islands: American Samoa, Fiji, Kosrae, Marshall Islands, New Caldonia, Samoa, and Tonga
  • Most of South America: Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana, Paraguay, Suriname, and Venezuela

WHO response

Both the regional Pan American Health Organization (PAHO) as well as the WHO have issued statements of concern about the widespread public health impact of the Zika virus and its links to GBS and microcephaly.[55][56] The WHO Director-General, Dr. Margaret Chan, issued a statement in February 2016 "declaring that the recent cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes a Public Health Emergency of International Concern."[11] The declaration allows the WHO to coordinate international response to the virus as well as gives its guidance the force of international law under the International Health Regulations.[57][58]

Treatment

There is currently no specific treatment for Zika virus infection. Care is supportive with treatment of pain, fever, and itching.[27] Some authorities have recommended against using aspirin and other NSAIDs as these have been associated with hemorrhagic syndrome when used for other flaviviruses.[2][15] Additionally, aspirin use is generally avoided in children when possible due to the risk of Reye syndrome.[59]

Zika virus had been relatively little studied until the major outbreak in 2015, and no specific antiviral treatments are available as yet.[15] Advice to pregnant women is to avoid any risk of infection so far as possible, as once infected there is little that can be done beyond supportive treatment.[60]

Epidemiology

Countries that have past or current evidence of Zika virus transmission (as of January 2016)[61]

The very first known case of Zika fever was in a sentinel rhesus monkey stationed on a tree platform in the Zika Forest in Uganda in 1947.[24] Population surveys at the time in Uganda found a 6.1% prevalence.[33] The first human cases were reported in Nigeria in 1954.[62] A few outbreaks have been reported in tropical Africa and in some areas in Southeast Asia.[63] There have been no documented cases of Zika virus in the Indian subcontinent. Surveys have found antibodies to Zika in healthy people in India which could indicate past exposure, though it could also be due to cross-reaction with other flaviviruses.[64]

By using phylogenetic analysis of Asian strains, it was estimated that Zika virus had moved to Southeast Asia by 1945.[33] In 1977–1978, Zika virus infection was described as a cause of fever in Indonesia.[65] Before 2007, there were only 13 reported natural infections with Zika virus, all with a mild, self-limited febrile illness.[24][66]

Yap Islands

Main article: 2007 Yap Islands Zika virus outbreak

The first major outbreak, with 185 confirmed cases, was reported in 2007 in the Yap Islands of the Federated States of Micronesia.[67] A total of 108 cases were confirmed by PCR or serology and 72 additional cases were suspected. The most common symptoms were rash, fever, arthralgia, and conjunctivitis, and no deaths were reported. The mosquito Aedes hensilli, which was the predominant species identified in Yap during the outbreak, was probably the main vector of transmission. While the way of introduction of the virus on Yap Island remains uncertain, it is likely to have happened through introduction of infected mosquitoes or a human infected with a strain related to those in Southeast Asia.[33][67] This was also the first time Zika fever had been reported outside Africa and Asia.[4] Before the Yap Island outbreak, only 14 human cases had ever been reported.[68]

Oceania

Main article: 2013–2014 Zika virus outbreaks in Oceania

In 2013–2014, several outbreaks of Zika were reported in French Polynesia, New Caledonia, Easter Island and the Cook Islands. The source of the virus was thought to be an independent introduction of the virus from Southeast Asia, unrelated to the Yap Islands outbreak.[33]

Americas

Further information: Zika virus outbreak (2015–present)

Since first appearing in the Western Hemisphere in February 2014, it has rapidly spread throughout South and Central America, reaching Mexico in November 2015.[15][33][69] It has appeared sporadically in travelers to the United States and Europe, with ten confirmed cases in Dallas, Texas[15][70] but has not established local mosquito borne spread in those areas.[69] CDC estimates 20% of persons in Puerto Rico (700,000 persons) could be infected before 2017, and note the first death in the United States due to Zika occurred in February 2016.[71] There has been suspicion of local sexual transmission in one Texas case in February 2016 from a person infected in another country.[15][28]

In May 2015, Brazil officially reported its first 16 cases of the illness.[72] According to the Brazilian Health Ministry, as of November 2015 there was no official count of the number of people infected with the virus in Brazil, since the disease is not subject to compulsory notification. Even so, cases were reported in 14 states of the country. Mosquito-borne Zika virus is suspected to be the cause of 2,400 possible cases of microcephaly and 29 infant deaths in Brazil in 2015 (of the 2400 or so notified cases in 2015, 2165 were under investigation in December 2015, 134 were confirmed and 102 were ruled out for microcephaly).[73]

The Brazilian Health Ministry has reported at least 2,400 suspected cases of microcephaly in the country in 2015 as of 12 December, and 29 fatalities.[73][74][75][76] Before the Zika outbreak, only an average of 150 to 200 cases per year were reported in Brazil.[77] In the state of Pernambuco the reported rates of microcephaly in 2015 are 77 times higher than in the previous 5 years.[77] A model using data from a Zika outbreak in French Polynesia estimated the risk of microcephaly in children born to mothers who acquired Zika virus in the first trimester to be 1%.[78]

On 24 January 2016, the WHO warned that the virus is likely to spread to nearly all countries of the Americas, since its vector, the mosquito Aedes aegypti, is found in all countries in the region, except for Canada and continental Chile.[79][80] The mosquito and dengue fever have been detected in Chile's Easter Island, some 3,500 km (2,200 mi) away from its closest point in mainland Chile, since 2002.[81]

In February 2016, WHO declared the outbreak a Public Health Emergency of International Concern as evidence grew that Zika is a cause of birth defects and neurological problems.[15][82][83][84] In April 2016, WHO stated there is a scientific consensus, based on preliminary evidence, that Zika is a cause of microcephaly in infants and Guillain-Barré syndrome in adults.[8] Studies of this and prior outbreaks have found Zika infection during pregnancy to be associated with early pregnancy loss and other pregnancy problems.[85][86]

Research

Some experimental methods of prevention include breeding and releasing mosquitoes that have been genetically modified to prevent them from transmitting pathogens, or have been infected with the Wolbachia bacterium, believed to inhibit the spread of viruses.[15][87]

History

Microcephaly and other infant disorders

A baby with microcephaly (left) compared to a baby with a typical head size

Following the initial Zika outbreak in Northeastern Brazil, physicians observed a very large surge of reports of infants born with microcephaly, with 20 times the number of expected cases.[88][89] Many of these cases have since been confirmed, leading WHO officials to project that approximately 2,500 infants will be found to have born in Brazil with Zika-related microcephaly.[90][91] On 10 March 2016, a research group from the Faculty of Medicine, University of Ljubljana (Slovenia), led by young researcher Jernej Mlakar, M.D., published an article in The New England Journal of Medicine, connecting the Zika virus to microcephaly.[92]

Proving that Zika causes these effects is difficult and complex for several reasons.[93][94] For example, the effects on an infant might not be seen until months after the mother's initial infection, long after the time when Zika is easily detected in the body.[93] In addition, research is also needed to determine the mechanism by which Zika produces these effects.[95]

Since the initial outbreak, studies that use several different methods found evidence of a link, leading public health officials to conclude that it appears increasingly likely the virus is linked to microcephaly and miscarriage.[95][96] On 1 February 2016, the World Health Organization declared recently reported clusters of microcephaly and other neurological disorders a Public Health Emergency of International Concern (PHEIC).[97] On 8 March 2016, the WHO Committee reconfirmed that the association between Zika and neurological disorders is of global concern.[95]

The Zika virus was first linked with newborn microcephaly during the Brazil Zika virus outbreak. In 2015, there were 2,782 suspected cases of microcephaly compared with 147 in 2014 and 167 in 2013.[88] Confirmation of many of the recent cases is pending,[98] and it is difficult to estimate how many cases went unreported before the recent awareness of the risk of virus infections.[99]

Brazilian President Dilma Rousseff in a videoconference about the Zika virus at the National Center for Disaster Management.

In March 2016, researchers published a prospective cohort study that found profound impacts in 29 percent of infants of mothers infected with Zika, some of whom were infected late in pregnancy.[21] This study did not suffer from some of the difficulties of studying Zika: the study followed women who presented to a Rio de Janeiro clinic with fever and rash within the last five days. The women were then tested for Zika using PCR, then the progess of the pregnancies were followed using ultrasound.[21][100]

In November 2015, the Zika virus was isolated in a newborn baby from the northeastern state of Ceará, Brazil, with microcephaly and other congenital disorders. The Lancet medical journal reported in January 2016 that the Brazilian Ministry of Health had confirmed 134 cases of microcephaly "believed to be associated with Zika virus infection" with an additional 2,165 cases in 549 counties in 20 states remaining under investigation.[15][101] An analysis of 574 cases of microcephaly in Brazil during 2015 and the first week of 2016, reported in March 2016, found an association with maternal illness involving rash and fever during the first trimester of pregnancy.[102] During this period, 12 Brazilian states reported increases of at least 3 standard deviations (SDs) in cases of microcephaly compared with 2000–14, with the northeastern states of Bahia, Paraíba and Pernambuco reporting increases of more than 20 SDs.[102]

In January 2016, a baby in Oahu, Hawaii, was born with microcephaly, the first case in the United States of brain damage linked to the virus. The baby and mother tested positive for a past Zika virus infection. The mother, who had probably acquired the virus while traveling in Brazil in May 2015 during the early stages of her pregnancy, had reported her bout of Zika. She recovered before relocating to Hawaii. Her pregnancy had progressed normally, and the baby's condition was not known until birth.[103]

In March 2016, first solid evidence was reported on how the virus affects the development of the brain. It appears to preferentially kill developing brain cells.[104] The first cases of birth defects linked to Zika in Colombia[105] and in Panama were reported in March 2016.[106]

Ocular disorders in newborns have also been linked to Zika virus infection.[107] In one study in Pernambuco state in Brazil, about 40 percent of babies with Zika-related microcephaly also had scarring of the retina with spots, or pigment alteration.[108]

On 20 February 2016, Brazilian scientists announced that they had successfully sequenced the Zika virus genome, and expressed hope that this would help in both developing a vaccine and in determining the nature of any link to birth defects.[109]

In February 2016, rumors that microcephaly is caused by the use of the larvicide pyriproxyfen in drinking water were refuted by scientists.[110][111][112] "It's important to state that some localities that do not use pyriproxyfen also had reported cases of microcephaly", read a Brazilian government statement.[113] The Brazilian government also refuted conspiracy theories that chickenpox and rubella vaccinations or genetically modified mosquitoes were causing increases in microcephaly.[112]

Researchers also suspected that Zika virus could be transmitted by pregnant woman to their babies ("vertical transmission"). None was proven until February 2016, when a paper by Calvet et al. was published, showing that not only Zika virus genome was found in the amniotic fluid but also IgM antibodies to those virus.[114] This means that not only can the virus cross the placental barrier, but also the antibodies produced by the mother can reach the fetus, which suggests that vertical transmission is plausible in these cases. One other study published in March 2016 by Mlakar and colleagues analysed autopsy tissues from a fetus with microcephaly that was probably related to Zika virus; researchers found ZIKV on the brain tissue and suggested that the brain injuries were probably associated with the virus, which also shed a light on the vertical transmission theory.[92]

Guillain–Barré syndrome

A high incidence of the autoimmune disease Guillain–Barré syndrome (GBS), noted in the French Polynesia outbreak, has also been found in the outbreak that began in Brazil.[101] Laboratory analysis found Zika infections in some patients with GBS in Brazil, El Salvador, Suriname and Venezuela,[115] and the WHO declared on 22 March 2016 that Zika appeared to be "implicated" in GBS infection, and that if the pattern was confirmed it would represent a global public health crisis.[116]

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