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Zika virus was first detected in Asia in the 1960s.
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Zika virus has caused large epidemics in the South Pacific islands and the Americas.
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Data suggest that the current incidence rate of Zika in Asia is relatively low.
Summary
Zika virus (ZIKV) is an emerging mosquito-borne virus that was first isolated from a sentinel rhesus monkey in the Zika Forest in Uganda in 1947. In Asia, the virus was isolated in Malaysia from Aedes aegypti mosquitoes in 1966, and the first human infections were reported in 1977 in Central Java, Indonesia. In this review, all reported cases of ZIKV infection in Asia as of September 1, 2016 are summarized and some of the hypotheses that could currently explain the apparently low incidence of Zika cases in Asia are explored.
Zika virus (ZIKV) is an emerging mosquito-borne virus and member of the family Flaviviridae, which includes dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), and yellow fever virus (YFV) (Figure 1). The closest relative to ZIKV is Spondweni virus. ZIKV was first isolated from a sentinel rhesus monkey in the Zika Forest in Uganda in 1947 and from Aedes africanus mosquitoes in 1948.
ZIKV is transmitted by Aedes mosquitoes, with humans representing the amplifying host. A sylvatic cycle of transmission also exists and involves non-human primates and arboreal zoophilic Aedes mosquitoes from African and Asian forests.
Figure 1Phylogenetic tree of the NS5 gene of flaviviruses. The alignment includes 41 reference NS5 partial sequences from tick-borne and mosquito-borne flaviviruses available in GenBank. MEGA 6
was used to perform multiple sequence alignment and phylogenetic analyses using the maximum likelihood (ML) method and the GTR model with 1000 bootstrap re-sampling.
Prior to the outbreak in Yap State (part of the Federated States of Micronesia) in 2007, where an estimated 75% of the residents were infected, only 14 human cases had been confirmed.
During 2013, an epidemic in French Polynesia affected approximately 28 000 people, and the possible association between ZIKV infection and Guillain–Barré syndrome was suggested for the first time.
In the Americas alone, over 500 000 locally acquired cases had been reported up to September 1, 2016; however the real number of infections is probably closer to several million, based on almost 2000 microcephaly and/or central nervous system malformation cases, which are suggestive of congenital ZIKV infection or potentially associated with ZIKV infection.
2. The challenges of Zika diagnosis and detection by surveillance systems
In general, the clinical picture of natural human ZIKV infection is of a short duration, self-limiting, mild febrile illness that is accompanied by a maculopapular rash.
The most common clinical features reported during ZIKV infection are fever, rash, arthritis and/or arthralgia and/or myalgia, conjunctivitis, and fatigue.
Although it is difficult to clinically differentiate ZIKV infections from other arboviral diseases like dengue and chikungunya, symptoms such as oedema of the extremities, conjunctivitis, and the absence of leukopenia/thrombocytopenia are more common with Zika.
To date, the literature describing the performances of Zika diagnostic tests remains relatively limited. The routine diagnosis of ZIKV infection can be determined by either direct methods, i.e., isolation and detection of viral genome by RT-PCR in blood, saliva, urine, and other body fluids (cerebrospinal fluid, amniotic fluid, semen, vaginal fluid, breast milk, pharyngeal secretions), or by indirect methods based on the identification of Zika antibodies in the blood.
Although a confirmation of the diagnosis is easily achieved with the direct diagnostic methods, the cross-reactivity between viruses of the Flaviviridae family makes the serological results very difficult to interpret, especially in those countries where more than one flavivirus circulates. The antibodies against ZIKV are often detected by ELISA and then confirmed by plaque reduction neutralization test (PRNT). Because of the potential for cross-reactivity, antigens from DENV and JEV should be tested in parallel and the results compared to identify the most likely aetiological agent. The Centers for Disease Control and Prevention (CDC) in the USA offer guidelines for the interpretation of serology results (http://www.cdc.gov/zika/pdfs/laboratory-guidance-zika.pdf).
There is a clear lack of a laboratory network with ZIKV diagnostic capacities, and access to standardized reagents remains difficult in many countries.
Using the existing national arbovirus surveillance systems in Asia to detect the circulation of ZIKV remains extremely challenging for several reasons.
First, the routine diagnosis of acute ZIKV infection relies essentially on the detection of viral nucleic acid by RT-PCR and the detection of IgM antibodies by IgM antibody capture (MAC)-ELISA. The detection of viral RNA by RT-PCR is often considered as a gold standard and provides a definitive diagnosis; however, this test remains unavailable in most clinical settings due to the associated costs and lack of experienced laboratory personnel. Virus isolation is useful for diagnostic and research purposes but is time-consuming and faces the same technical limitations as molecular assays. A number of ZIKV sero-epidemiological studies have been conducted in Asia; however because of the extensive cross-reactivity of anti-flavivirus antibodies and the large number of flaviviruses circulating in the region, the interpretation of serological results is complicated.
The antibodies against ZIKV antigen may be reactive to DENV, JEV, and/or YFV antigens to the same level, or with even higher titres in MAC-ELISA and haemagglutination inhibition (HI) assays.
However, this test is labour-intensive and costly, requires handling of live virus, takes up to a week to perform, requires standardized reagents that are often not available, and is not widely performed. Due to the ‘original antigenic sin’ phenomenon, even the PRNT cannot reliably provide a diagnosis in patients who have previously been exposed to a heterologous Flavivirus,
which again poses some interpretational challenges in regions where dengue and/or other flaviviruses are co-circulating and more than 90% of the population may have had previous exposure to at least one of these flaviviruses.
In settings where PRNT is not available, specimens that test positive by ZIKV MAC-ELISA and negative by DENV and/or JEV MAC-ELISA may be interpreted as presumptive recent ZIKV infections (http://www.cdc.gov/zika/pdfs/laboratory-guidance-zika.pdf). However, the diagnostic accuracy of this approach remains to be validated.
Second, most of the surveillance programmes have a syndromic approach and they are often based on the report of hospitalized cases. Since ZIKV infection symptoms are rarely severe, poorly specific, and often misdiagnosed as dengue and chikungunya cases, the prevalence of Zika remains difficult to estimate through such surveillance systems.
3. Epidemiology of Zika in Asia
Tropical countries in Asia are believed to be endemic for many arboviral diseases including DENV, JEV, and chikungunya virus (CHIKV). In contrast to DENV, studies on ZIKV in Asia have been scarce, due to its apparent limited public health importance and the initial belief – prior to knowledge of the neurological complications – that the disease is mild in character.
Most of the survey results reported in the literature are dated in the 1950s and were based on serology using the HI test, complement fixation (CF) test, cross-neutralization test (NT), mouse protection test, haemagglutination assay (HA), and ELISA. Although these studies contain precious information regarding ZIKV infection in Asia, the specificity of these serological assays is questionable, especially when they are conducted in regions where other flaviviruses co-circulate. Prior to the outbreak in Yap in 2007 that drew some attention from the scientific community, little effort was made to describe ZIKV circulation in Asia. Now that Zika has become a public health concern, the infection is more closely monitored, and as of September 1, 2016 there have been reports of imported or autochthonous ZIKV infections in all Asian countries except Brunei, Hong Kong, Myanmar, and Nepal (Figure 2, Table 1).
Figure 2Map of Asian countries in which Zika virus circulation has been reported up to September 1, 2016.
Evidence of Japanese encephalitis virus infections in swine populations in 8 provinces of Cambodia: implications for national Japanese encephalitis vaccination policy.
The serological and virological surveillance of arboviruses in Cambodia has been conducted through the National Dengue Control Program (NDCP) since 2000. Antigens from both Flavivirus (DENV and JEV) and Alphavirus genus (CHIKV) are included in the panel for MAC-ELISA and HI tests.
A recent retrospective study detected five human serum samples positive for ZIKV by RT-PCR among patients with dengue-like symptoms; these samples were collected in 2007 (n = 1), 2008 (n = 1), 2009 (n = 2), and 2015 (n = 1). Phylogenetic analysis of partial sequences of the non-structural protein 5 (NS5) gene from human samples (one from 2008 and two from 2009) demonstrated that all strains belonged to the Asian cluster within the Asian/American lineage.
To date, confirmed ZIKV cases have only been reported in travellers returning to China and no autochthonous ZIKV infection has yet been reported. In February 2016, nine imported cases were documented in mainland China: five from Venezuela, three from Samoa, and one from Samoa/Fiji.
the NT screening was conducted on 211 serum samples tested against 15 different arboviruses. Antibodies against ZIKV were detected in 33 out of 196 samples tested (16.8%) alongside many other viruses including, among others, DENV, WNV, JEV, Murray Valley virus, and St. Louis encephalitis virus.
3.4 Indonesia
The first human ZIKV infections were reported in Central Java, Indonesia in 1977, although the identification was only based on serology and no virus isolation confirmed the diagnosis.
Up to 12.7% of sera collected tested positive by HI testing.
ZIKV was detected in 2012 in an Australian traveller returning from Jakarta on the island of Java, and in 2015 in another traveller returning from Bali.
The latter traveller reported having been bitten by a monkey before the onset of symptoms, although mosquito bites might have occurred as well. Between December 2014 and April 2015, during an outbreak of dengue fever, the first autochthonous ZIKV infection was confirmed by RT-PCR in an Indonesian resident in Sumatra.
The phylogenetic analysis indicated that this strain belonged to the Asian cluster within the Asian/American lineage and clustered closely with strains isolated in Thailand and from the Australian traveller who had visited Bali.
ZIKV was detected by RT-PCR in travellers returning from French Polynesia in December 2013 (n = 1) and January 2014 (n = 1), and from Thailand (n = 1) in August 2014.
3.6 Lao PDR
An autochthonous case of ZIKV infection was detected in Laos in March 2016.
Recently, a retrospective study investigating the presence of ZIKV in samples collected from suspected dengue cases detected the virus in a small proportion of samples (1.3%); in some cases ZIKV and DENV co-infections were detected.
in humans as well as non-human primates in Malaysia. In 2014, a German traveller returning from Peninsular Malaysia and Sabah (Malaysian Borneo) was serologically diagnosed with ZIKV infection.
A ZIKV infection was detected by RT-PCR in a 37-year-old Finnish male who had returned to his country in June 2015 after spending several months in the Maldives.
A serological study using a CF test was conducted in 1983 and investigated the presence of antibodies to eight arboviruses in 42 human, 157 rodent, and 172 domestic animal sera. Antibodies against ZIKV antigen were detected in 2.3%, 3.8%, and 1.2% of human, rodent, and domestic animal sera, respectively.
3.10 Philippines
A serological study conducted in 1953 in the Philippines detected 19 Zika-positive sera out of 153 samples tested.
A prospective cohort study of 267 acute febrile illnesses in Cebu City, Philippines, initiated in March 2012, detected one case of ZIKV infection by RT-PCR in a 15-year-old boy.
Phylogenetic analysis of the strain demonstrated that the virus belonged to the Asian cluster within the Asian/American lineage and was grouped closely with the strains isolated in 2007 in Micronesia.
The virus was detected in a Singapore Permanent Resident who had visited Sao Paulo, Brazil from March to May 2016. Subsequently, the country reported a dramatic rise in ZIKV cases after the Olympic games.
By August 31, 2016, a total of 115 ZIKV infections had been confirmed, including 41 cases that resulted from local transmission outside the original cluster.
The first imported case was confirmed in a man travelling to Taipei from northern Thailand in January 2016. The other cases were detected in travellers returning from Thailand in January (n = 1) and in May 2016 (n = 1), from St. Lucia in July 2016 (n = 1), from St. Vincent and the Grenadines in August 2016 (n = 1), and from Miami, Florida, USA in August 2016 (n = 1).
3.14 Thailand
In Thailand, a serosurvey was conducted in 1954 using an NT assay. Sixteen percent of sera tested (n = 8/50; 25 from Bangkok and 25 from Chiang Mai) were reactive to ZIKV antigen.
However, HI testing showed that 80% of the 25 samples from Bangkok were also reactive to DENV-1 antigen, suggesting some potential cross-reactivity.
In early 2013, a Canadian woman who had returned from a vacation in southern Thailand developed a dengue-like symptom and tested positive for ZIKV RNA in blood, urine, and nasopharyngeal swab specimens.
The second case was reported in November 2013 in an adult German man who was diagnosed with acute ZIKV infection after visiting a number of islands in southern Thailand.
The first autochthonous cases were detected in a retrospective study of samples collected between 2012 and 2014. Seven cases of acute ZIKV infection were identified either by RT-PCR or PRNT assay in Thai residents in different provinces of central, northwest, and northeast Thailand.
The patient had no history of travel outside Thailand during the 3 months prior to his arrival in Taiwan. Another recent serosurvey reported anti-ZIKV antibodies in serum samples collected from northeast Thailand.
All together, these studies suggest that ZIKV is endemic and widespread throughout the country. Analysis of the NS5 gene and full genome sequences demonstrated that the Thai ZIKV belonged to the Asian cluster within the Asian/American lineage and was clustered closely with sequences from the Cambodian strain detected in 2010 and to the sequences of the viruses isolated during the outbreak in French Polynesia.
Little is known about ZIKV circulation in Vietnam. Historically, neutralizing antibodies against ZIKV were detected in 4% of 50 sera tested in residents of northern Vietnam in 1954.
and South Korea (see above). The first cases of autochthonous infection in Vietnam were reported in March 2016 in two women living in Ho Chi Minh City and in August 2016 in a male living in the south-central coast region.
only sporadic human cases were detected over the next 55 years. There were no documented large outbreaks in Africa or Asia, and between the 1940s and 1990s only serological evidence of ZIKV circulation was provided in those regions.
An unprecedented outbreak of ZIKV then occurred on several islands of Yap state (Micronesia), resulting in an estimated 5000 infections among the total population of 6700 (attack rate over 74%).
In stark contrast to these outbreaks, both serological and virological results from these studies suggest that ZIKV is endemically present with a low prevalence in those Asian countries.
There is a clear difference in landscape of ZIKV transmission in different regions of the world. This marked heterogeneity in epidemiology has raised two questions: (1) Why has ZIKV presently circulating in Asia never been associated with outbreaks on the same scale as those in South America? (2) Would the strain causing outbreaks in the Pacific and the Americas cause the same extent of public health concern if introduced into Asia?
To date, there is no clear evidence to explain the relatively low prevalence of ZIKV infection in Asia and why ZIKV has not been associated with similarly large outbreaks in Asia to those seen in the Pacific and the Americas. The mild character and non-specific clinical presentation of ZIKV infection, coupled with the low burden to public health prior to 2007, led to ZIKV disease being of less interest in scientific studies. Additionally, ZIKV was not recognized, was misdiagnosed, or was simply overlooked in clinical settings such as hospitals and private clinics, even during testing for arbovirus infections in the framework of national surveillance. This may explain why the circulation of ZIKV in some Asian countries is often documented based on cases in which travellers experiencing a febrile disease after returning to their home country are subsequently diagnosed following a broad investigatory panel of aetiology that includes Zika. Another challenge is in the laboratory diagnosis. The great extent of cross-reactivity between flaviviruses in the IgM and HI assays could lead to erroneous conclusions in Asian countries where DENV and JEV are predominantly circulating and where these assays are more widely available than molecular methods.
Prior to the observation of the increase in microcephaly cases in Brazil and the confirmed link of neurological complications in neonates to ZIKV infection,
the prevalence of microcephaly due to ZIKV infection was never investigated in Asian and African countries even though ZIKV was endemic. Microcephaly due to ZIKV was reported retrospectively in French Polynesia,
Since the present review was performed, further microcephaly cases linked to ZIKV infection have been reported, involving three babies in Thailand in September 2016
However, it was not reported whether these microcephaly cases were associated with the endemic Asian strain or that from the Americas. At this stage, and considering that microcephaly is still a relatively rare event, it is difficult to establish whether the low numbers of microcephaly cases detected in Asia are the result of weak surveillance systems or whether the strains of the Asian cluster within the Asian/American lineage are associated with a lower risk of such birth defects.
The seroprevalence of ZIKV infection in the general population of Asian countries has not been assessed to estimate the burden of the disease; the large majority of studies conducted so far have included only symptomatic patients seeking medical care. Although the precise incidence and prevalence are not yet known, ZIKV infections may have occurred in many Asian peoples, and especially the youngest ones, and likely provided long-lasting natural immunity (although this remains to be explored). In French Polynesia and Micronesia,
paucisymptomatic and asymptomatic infections were frequent. Among blood donors, 73.8% of the ZIKV infections were asymptomatic and the ratio of symptomatic to asymptomatic patients observed in Micronesia was approximately 1:5 to 1:6. It is therefore possible that in Asia a significant number of ZIKV infections do actually occur, but they are under-reported because of the absence of symptoms or the mild characteristics of the symptoms associated with this viral disease, while the clinically apparent infections are often wrongly classified as DENV or JEV infections, even after laboratory testing. In addition, although this may not necessarily be the case in Asia, recent studies in Latin America have reported that the frequency of ZIKV co-infections with DENV and CHIKV is even higher than that of mono-infections.
Considering the little attention that Asian countries have paid to Zika until recently, it is unlikely that patients who tested positive for DENV or CHIKV by first-line RT-PCR were further investigated for ZIKV as well.
The role of cross-protective immunity is also not well understood. We do not really know whether previous exposure to other flavivirus(es) may or may not be protective against ZIKV infection. DENV and JEV infections may play a role in the epidemiological dynamics of ZIKV by either providing protection or conversely enhancing the severity of ZIKV infection. The first concrete study on cross-reactivity between DENV and ZIKV demonstrated that plasma from DENV patients provided substantial cross-reaction to ZIKV and could not completely neutralize ZIKV; hence induced antibody-dependent enhancement (ADE) of ZIKV infection.
However, they also observed that some plasma from DENV-infected patients was able to neutralize ZIKV. They suggested that these patients might have high concentrations of cross-reactive neutralizing antibodies to DENV and ZIKV, such as those that recognize the EDE1 epitope.
Interestingly, South American and Southeast Asian countries are endemic for dengue. If the hypothesis of ADE applies, Asia should experience similar or even larger outbreaks of ZIKV with severe infection and neurological complications. As of September 2016, only sporadic ZIKV cases have been reported throughout Asia. One potentially important difference between Asia and South America is that ZIKV has been endemic in Asia for at least several decades, while the population in the Americas was certainly fully naïve to Zika, providing the virus many opportunities to spread rapidly.
However, this does not mean that Asian populations do not face any risk of a Zika epidemic. Based on the volume of travellers arriving from airports in countries where ZIKV is circulating, the resident population at risk for ZIKV exposure, and health expenditure per capita, a recent model has suggested that India, the Philippines, Indonesia, Pakistan, and Bangladesh are at a high risk of ZIKV importation with a possible significant health impact on the population.
For example, in India, an estimated 1.2 billion people are susceptible to ZIKV exposure during the peak seasonal risk (August). Combined with the continuous growth of the population, globalization, urbanization, climate change, and the lack of effective vector control measures, Asian countries may well be exposed to Zika outbreaks in the near future.
ZIKV strains are divided into two major lineages: the African lineage and the Asian/American lineage. These two lineages differ in approximately 90% of their nucleotide sequence.
Strains belonging to the Asian/American lineage have been isolated in Southeast Asia, in the Pacific Islands, and in the Americas. Within the Asian/American lineage, the strains from the Americas have formed a new American cluster.
Molecular analysis of strains isolated in Brazil has suggested that there was a single introduction of the virus into the Americas between May and December 2013, but the study did not identify specific molecular markers associated with microcephaly.
Whether the rapid spread of ZIKV in the Americas is associated with some specific mutations remains to be determined. Considering the extremely complex interplay between virus, vector, and host, which characterizes such vector-borne diseases, it may take years before we really understand the differences in epidemic situations between Asia and the Americas.
Acknowledgements
We thank Stephen Griffiths (GSK Vaccines, Asia-Pacific) for his editorial assistance.
Conflict of interest: Philippe Buchy is an employee of GSK vaccines Asia-Pacific.
References
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Evidence of Japanese encephalitis virus infections in swine populations in 8 provinces of Cambodia: implications for national Japanese encephalitis vaccination policy.
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