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Zika virus: an emerging infectious threat

2016; Wiley; Volume: 46; Issue: 5 Linguagem: Inglês

10.1111/imj.13059

1445-5994

Chi Wi Ong,

Viral Infections and Vectors

Over a few months, the mosquito-borne Zika virus has transitioned from relative obscurity to worldwide hot news item. The epidemic in South and Central America has gained attention not only for the unprecedented rate and range of spread, but also for the high number of congenital microcephaly cases which appear to be associated. It is these and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, which constitute the Public Health Emergency of International Concern declared by the World Health Organization (WHO) on 1 February 2016.1 Zika is an RNA virus of the family Flaviviridae and genus Flavivirus. Other species in the genus include : yellow fever, dengue, Murray Valley encephalitis, Japanese encephalitis and West Nile.2 Primates are likely the main reservoir of Zika virus, with anthroponotic (human-to-vector-to-human) transmission occurring during outbreaks.3 The virus was first isolated from the serum of a febrile rhesus monkey in the Zika (meaning 'overgrown') Forest in Uganda in 1947 and later from a human in 1952. Since then, the virus has circulated in Africa and Southeast Asia in two geographically distinct lineages (i.e. African and Asian), causing infrequent cases of confirmed human infections.4 In 2007, however, a major epidemic occurred at Yap Island, Micronesia, the first outside Africa and Asia.5 In 2013–2014, epidemics occurred in the South Pacific – French Polynesia, New Caledonia, the Cook Islands and Easter Island.6 In May 2015, Brazil reported autochthonous (i.e. local) transmission of Zika virus. All these outbreaks represent expansion of the Asian lineage.7, 8 Since then, it has spread rapidly in South and Central America, with locally acquired cases within the past 2 months in Barbados, Bolivia, Brazil, Colombia, Costa Rica, Curaçao, Dominican Republic, Ecuador, El Salvador, French Guiana, Guadeloupe, Guatemala, Guyana, Haiti, Honduras, Jamaica, Martinique, Mexico, Nicaragua, Panama, Paraguay, Puerto Rico, Saint Martin, Suriname, US Virgin Islands and Venezuela (as of 8 February 2016).9 Outside the Americas, autochthonous transmission has been reported within the past 9 months in Thailand, Maldives, Cape Verde, Tonga, Samoa, American Samoa, Solomon Islands, New Caledonia, Fiji and Vanuatu.9 In Australia, Zika virus infection was first diagnosed in 2012, in a traveller returning from Jakarta, Indonesia.10 There have been 31 confirmed infections in total (as of 19 February 2016), all acquired overseas.11 No known transmission events have occurred within Australia to date. New Zealand has had 67 cases from 2002 to 2015, all acquired overseas.12 Zika virus is primarily transmitted through the bite of an infected Aedes aegypti mosquito, which lives in urban areas, bites in the daytime and breeds in stagnant water. Other potential vector species include Aedes albopictus, Aedes polynesiensis and Aedes hensilli. The mosquito acquires Zika during its blood meal on an infected viraemic host, but is itself unaffected by the virus, which persists lifelong in the vector.4 A. aegypti is established on the Australian mainland in northern Queensland, whereas A. albopictus is established in the Torres Strait. However, modelling has shown that the latter species, if allowed to spread in the future, may be capable of surviving as far south as Victoria due to its ability to adapt to cooler climates.13 Sporadic detections of Aedes spp. have been made at various airports and seaports outside northern Queensland, but there is no documentation of establishment in these places. Neither species is in New Zealand. Apart from mosquitoes, other modes of transmission are uncommon. Maternal–foetal transmission has been documented, both transplacentally and during parturition.14, 15 Although viral RNA is detectable in breast milk, there has been no definite evidence of transmission.15 Potential transmission through blood transfusions was previously identified as a possibility following detection of viraemia in asymptomatic blood donors in French Polynesia.16, 17 Brazil has since reported two transfusion-related transmissions.9 There have been limited reports of sexual transmission, supported by separate case reports of virus isolated from semen 9 weeks and, possibly, 10 weeks after illness onset.18-22 One case of transmission by a monkey bite in Indonesia has been reported, although a concurrent mosquito bite cannot be excluded.23 Based on data from the Yap outbreak, it is estimated that only about 18% of infected persons become symptomatic.5 The incubation period is considered to be 3–12 days,24 although this is not definite.3 Relatively more common symptoms include rash, fever, arthritis/arthralgia and conjunctivitis.5 Other less frequent symptoms include myalgia, headache, retro-orbital pain, oedema and vomiting.5 Pruritus, vertigo, mucosal ulcers, diarrhoea and constipation may occur.4, 25 Illness is generally mild, mostly lasting 2–7 days. Hospitalisation is uncommon and death rare.3 Post-infection asthenia appears frequent.25, 26 Guillain–Barré syndrome (GBS) may be a complication, as suggested by the 20-fold increase in GBS during the Zika outbreak in French Polynesia, although this link is not yet definitively proven at the time of writing.26 A case–control study which compared 42 GBS patients to 98 afebrile hospital patients matched for age, sex and residence island showed that a significantly greater proportion of GBS patients had serological evidence of prior Zika infection than controls (100 vs 56%, P < 0.0001).27 Several countries in the Americas have also reported increases in GBS cases during the current outbreak.9 Based on clinical features, the differential diagnosis for Zika virus infection is broad. Zika virus has been described as a 'dengue-like illness'. However, in addition to dengue, other considerations include alphavirus infections (e.g. chikungunya, Ross River, Barmah Forest), leptospirosis, malaria, rickettsial infection, Group A streptococcus disease, rubella, measles, parvovirus, enterovirus and adenovirus.3 Compared to dengue and chikungunya, conjunctivitis is more likely in Zika infection, but lymphadenopathy, hepatomegaly, leukopenia and thrombocytopenia are less likely to be present.4 It is important to note that concurrent circulation of Zika, dengue and chikungunya viruses has been reported in the Pacific region and also in South and Central America. Individual person Zika co-infection with another virus, such as dengue, has been demonstrated.28 Due to similar geographic distribution and symptoms, patients with suspected Zika virus infection should also be evaluated for possible dengue or chikungunya infection.25 Clinical diagnosis alone is unreliable, so patients with compatible symptoms within 2 weeks of travel to affected areas should undergo Zika virus testing. In Australia and New Zealand, analysis is performed at designated public health laboratories. If Zika virus is suspected, clinicians should discuss testing with their local pathology provider. Travel history, symptom onset date and prior flavivirus illness or vaccination history should be provided to enable optimal test strategies and results interpretation. The WHO has recently issued an interim case definition, including clinical, epidemiological and laboratory parameters.29 Specific testing for Zika infection generally includes blood sampling for serology (IgM, IgG) and reverse-transcription polymerase chain reaction (RT-PCR).25 Urine and a range of other samples may also be tested by RT-PCR where indicated.30-32 Acute serum (as early as possible or within 5 days of symptom onset) and convalescent serum (2 weeks later and at least 4 weeks after the last exposure) should be collected in order to demonstrate seroconversion.29 Due to extensive cross-reactivity between flaviviruses, serology results can be difficult to interpret (especially in the setting of prior flavivirus illness or vaccination),35 with Zika infection causing positive results in other flavivirus antibody tests and vice versa. Zika infection can cause false-positive dengue IgM and IgG results.10, 30 Although dengue NS1 antigen testing would usually be expected to be negative in Zika virus infection, at least one case of a false-positive result has been reported.30 Antibodies detected by enzyme immunoassay or immunofluorescence should ideally be confirmed by plaque reduction neutralisation testing.4, 29 Zika virus-specific RT-PCR may be positive early in infection,35 whereas dengue-specific RT-PCR would be negative.10, 31 (Diagnostic tests are summarised in Table S1, Supporting information.) No specific antiviral treatment exists for Zika infection. Treatment is generally supportive, comprising rest, fluids, analgesics and antipyretics. Aspirin and other non-steroidal anti-inflammatory drugs should be avoided until dengue can be ruled out (to reduce the risk of haemorrhage).25, 32 Zika virus infection during pregnancy is of concern because of mounting evidence suggesting an association with congenital microcephaly and also miscarriage. In October 2015, the Brazilian Ministry of Health announced an increase in birth prevalence of microcephaly in Zika virus affected areas. The background incidence of microcephaly in Brazil, reportedly 0.5 cases per 10 000 live births, had risen to approximately 20 cases per 10 000 live births in the latter half of 2015.33 Zika virus RNA has since been detected in amniotic fluid from pregnant women whose foetuses had microcephaly diagnosed by prenatal ultrasound, and from body tissues (including the brain) of neonates with microcephaly who died.14, 33, 34 In November 2015, health authorities in French Polynesia retrospectively reported an increase from an average of 1 reported case annually to 17 cases of central nervous system (CNS) malformations in foetuses and infants during 2014–2015. A wide range of CNS malformations was observed, including microcephaly.9 Zika virus RNA has been detected in the tissue of foetal losses, but it is unclear if Zika virus causes miscarriage.32, 34 A cohort study involving ultrasound follow up of 88 pregnant women with rash showed a significantly larger proportion of women with adverse pregnancy outcomes (including foetal death, placental insufficiency, foetal growth restriction and CNS injury) among those infected with Zika virus compared with those without evidence of Zika infection (29 vs 0%).35 A small case series of nine pregnant women infected with Zika virus appeared to suggest that infection in the first trimester is more likely to be associated with adverse foetal outcomes than infection later in pregnancy.36 Doubts have been raised concerning the magnitude of the Brazilian microcephaly rise due to the application of less stringent criteria in defining microcephaly at different stages of the epidemic, the lack of a uniformly applied definition of microcephaly, the likelihood that actual background rates of microcephaly were significantly higher than quoted (due to prior under-reporting), the probable effect of increased surveillance and case ascertainment following media publicity, and over-diagnosis in general.37, 38 For example, only 404 (36.2%) of 1103 reported microcephaly cases were confirmed after full scrutiny of clinical, laboratory and radiological data, with the rest being rejected.37 To challenge further the hypothesis that Zika maternal infection causes congenital microcephaly, a study involving over 16 000 newborns has shown that rates of microcephaly have been much higher since 2012, pre-dating the known introduction of the virus into the country.39 Moreover, there is also a distinct lack of microcephaly reports coming out of Columbia, the second most affected country, just as there was an absence of microcephaly reports from Yap in 2007. The question of whether Zika virus causes microcephaly remains unresolved at the time of writing, although the evidence for causality is mounting. In January 2016, the US Centers for Disease Control and Prevention (CDC) advised pregnant women to consider postponing travel to areas with ongoing Zika virus transmission or, if they must travel, to take precautions to avoid mosquito bites.32 Similar travel advice has been provided by the Australian and New Zealand Governments. US CDC issued guidelines providing detailed information to healthcare providers on the evaluation of pregnant women who have travelled to such areas. These covered indications for Zika testing, ultrasound evaluation of the foetus and the role of amniocentesis.32 These were revised shortly thereafter, advocating Zika virus testing for all pregnant women returning from affected regions, regardless of the presence or absence of symptoms, as asymptomatic infection is common.40 This reflects the difficulty in providing an optimal testing algorithm as the outbreak evolves. The US CDC also issued guidelines for evaluating infants for congenital infection.41 Their guidelines concerning sexual transmission advise men who reside in or have travelled to an area of active Zika virus transmission and who have a pregnant partner to abstain from sexual activity or consistently use condoms during sex throughout the pregnancy.19 Subsequently, Australian and New Zealand guidelines relating to pregnant women and sexual transmission have been released.42-44 For the assessment of pregnant women, differences exist between guidelines from the United Kingdom,45 United States,40 Australia34 and New Zealand,44 reflecting the complexities of guideline development. Differences in testing type and availability, healthcare resource utilisation patterns and local expert opinion contribute to these discrepancies. Clinicians should refer to the relevant documents for more information or consult any published local guidelines. There is currently no vaccine available to prevent Zika virus infection. Travellers to affected areas should take precautions to avoid mosquito bites, including appropriate attire, accommodation and use of insect repellent.25, 46 Control of vector mosquito populations by identifying and eliminating breeding sites is important. A novel method of vector manipulation is of particular interest. In Australia, the successful establishment of Wolbachia bacteria in A. aegypti populations in order to suppress dengue transmission has been reported. Wolbachia spp. introduced into mosquitoes can interfere with pathogen transmission. Such modified vectors, when released, can invade areas occupied by native Aedes mosquitoes and suppress viral transmission.47 Perhaps this may find future application in outbreak control in affected countries. A myriad unanswered questions remain regarding Zika virus. For example, the number of persons infected worldwide and the extent of transmission in affected countries are not accurately known, due largely to undiagnosed cases and incomplete surveillance data. The role of asymptomatically infected versus symptomatic persons in transmitting virus to vectors is unclear. Even if Zika virus is subsequently shown definitely to cause either congenital microcephaly or miscarriage (or both) or GBS, the mechanisms have yet to be elucidated. The absolute risk of Zika transmission from an infected pregnant woman to her foetus has not been clearly quantified, nor has the risk of development of microcephaly or miscarriage if foetal infection occurs. Variations in risk with gestational age remain unclear. There is no international consensus on the optimal diagnostic algorithm that best utilises laboratory testing and prenatal ultrasound resources while minimising missed cases and harms from unnecessary investigations. Even the most appropriate timing for amniocentesis in infected pregnant women is uncertain, with concerns that testing too early may result in false negatives. With regard to sexual transmission, it is unclear whether infected women or asymptomatically infected men transmit virus to their partners. Even the magnitude of risk of sexual transmission from an infected male with symptoms is not known. Concerning Zika infection of vectors, the vector competence of local A. aegypti in many areas has not been accurately quantified. In North Queensland, for example, how much lower is the risk to human populations since Wolbachia-infected mosquitoes, which are considered relatively 'arbovirus-resistant', are established in some zones? Many other gaps in knowledge exist in multiple dimensions relating to this Zika virus epidemic. Zika virus has spread rapidly into new regions in a short timeframe, facilitated by the transfer of infected humans or mosquitos across borders and oceans. Although the disease itself is not severe, the possible connections with adverse pregnancy outcomes and GBS warrant intensive research. Zika virus is a potential threat to northern Queensland because transmission to local Aedes mosquitoes from infected returned travellers is a risk. Health professionals and authorities should be alert to the threat posed and continually keep up with latest guidelines and emerging new evidence. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.