Neurological manifestations of Zika virus infection

Zika virus (ZIKV) is a flavivirus (Flaviviridae family) transmitted mainly by Aedes mosquitoes. The virus was restricted to the African continent until its spread to south-east Asia in the 1980’s, the Micronesia in 2007, the French Polynesia in 2013 and, more recently in the Americas in 2015, where, up to date, the World Health Organization (WHO) has estimated about 3-4 million total cases of ZIKV infection. During outbreaks in the French Polynesia and Brazil in 2013 and 2015, respectively, national health authorities reported potential neurological complications of ZIKV disease, chiefly an upsurge in Guillain-Barré syndrome, which coincided with ZIKV outbreaks. On the other hand, the emergence of ZIKV in Brazil has been associated with a striking increase in the number of reported cases of microcephaly in fetus and newborns, twenty times higher than in that reported in previous years. While investigations are currently assessing whether there is an actual association between neurological complications and ZIKV infections, the evidence was enough worrisome for WHO to declare a public health emergency of international concern. Here we present an updated review addressing what is currently known about the possible association between ZIKV infection and the development of severe neurological disorders.     

An updated review of Zika virus

The current outbreak of Zika virus (ZIKV) in South America is one of the most serious public health emergencies since the Ebola outbreak of West Africa [2014]. ZIKV belongs to the flaviviridae family and has two lineages (Asian and African). The virus was first discovered in Uganda [1947] and the first human infection was identified in Nigeria [1952]. The current epidemic is the third of its type after that of Yap Island, Micronesia [2007] and French Polynesia [2013]. Phylogenetic studies revealed that the current strain shares about 99.7% of nucleotides and 99.9% of amino acids with the strain of French Polynesia epidemic [2013], suggesting that it has spread across the Pacific Ocean to invade South America. Aedes Aegypti mosquito is the main vector for ZIKV and there are some reports describing possible sexual and maternal to fetal transmission. ZIKV infection is known to be self-limited. However, recent reports suggested that it can be associated with neurological manifestations as Guillan-Barrè Syndrome and microcephaly in the newborn population. Currently, vector control seems to be the most effective available preventive measure against ZIKV spread. The development of broad spectrum antivirals and ZIKV vaccines should be a priority of future research.     

The expanding arms of Zika virus: An updated review with recent Indian outbreaks

Zika virus (ZIKV) outbreaks and their adverse clinical consequences have raised concerns throughout the world. ZIKV was little known during the initial outbreaks in Yap islands and French Polynesia, but it came to attention after the series of Brazil outbreaks in which severe complications like microcephaly in newborn babies was detected. During 2018, outbreaks of ZIKV occurred in two states of India which, being a tropical country, has congenial climatic conditions, abundance of highly competent mosquito vectors such as Aedes aegypti and Aedes albopictus, and an immunologically naïve population. In this review, we will briefly discuss the history, epidemiology, evolution, transmission (vector‐borne and non‐vector borne), pathogenesis, clinical signs and unusual presentations, laboratory diagnosis, treatment, prevention and control of ZIKV. Finally, we suggest priorities for urgent research required to address unanswered questions about Zika infections and help bring this virus under control.     

Congenital Zika syndrome: Pitfalls in the placental barrier

Much progress with respect to congenital Zika virus (ZIKV) pathogenesis has been achieved after the 2015 outbreak in Brazil. It is now accepted that ZIKV is vertically transmitted, infects cells of the developing central nervous system and the placenta, yet it is unclear to what extent placental affection contributes to the development of congenital ZIKV. The association between fulminant villitis and severe fetal involvement emerges as a possibility. ZIKV is unique among the Flaviviruses in its ability to be sexually transmitted, possibly responsible for its teratogenicity. Furthermore, there is controversy over the participation of antibody dependent enhancement (ADE) in patients with non‐neutralizing anti‐Flavivirus antibodies, a phenomenon previously recognized in serious DENV infections. Our aim was to analyze information regarding the contribution of the placental barrier as an actual player in neonatal ZIKV. Therefore, we underwent a systematic review with keywords “Zika virus” and “ZIKV”. Articles were screened for relevance concerning the topics of microcephaly, transplacental transmission, sexual transmission, and ADE. We identified variables that affect the severity of congenital Zika syndrome: age of gestation at maternal infection, the extent of placental disruption (villitis), sexual transmission, initial viral replication at the uterine wall, anti‐DENV antibodies, and the possibility of antibody‐mediated transcytosis of ZIKV through the placenta. These questions may not seem relevant when Zika becomes endemic, and we are no longer witness to the extreme clinical sequelae seen when the virus moves through an immunologically naïve population; however, characterizing the pathogenesis of congenital Zika syndrome will continue to further our understanding.     

Possible Congenital Zika Syndrome in Older Children Due to Earlier Circulation of Zika Virus

Congenital Zika syndrome (CZS) was identified following a large Zika virus (ZIKV) outbreak in Brazil in 2015. Two children with clinical presentations consistent with CZS, ages 7 and 8 years old, are described. Both mothers lived in Cambodia, a region with known ZIKV, during their pregnancies and reported fever and rash in the second trimester. The infants were born with severe microcephaly. Testing for congenital infection at birth and genetic testing were unremarkable. In 2017, serologic testing for both mothers were consistent with prior ZIKV infection. Review of infant neuroimaging demonstrated ventriculomegaly, severe cerebral atrophy, and subcortical calcifications consistent with CZS. Given the maternal symptoms suggesting ZIKV infection during pregnancy and the combination of clinical and radiological features unique to CZS, CZS is strongly suspected in these children, suggesting that CZS occurred before the 2013–2014 French Polynesia outbreak. As such, CZS should be considered in older children with congenital microcephaly of unknown etiology and a history consistent with possible ZIKV exposure.     

First detection of autochthonous Zika virus transmission in a HIV-infected patient in Rio de Janeiro,Brazil

Since May 2015, Brazil’s Ministry of Health has reported autochthonous transmission of Zika virus (ZIKV) in some states of the country. Simultaneous circulation of Dengue, Chikungunya and ZIKV in the country hinder both the diagnosis and the therapeutic approach of patients seeking care with acute febrile illnesses especially in patients with comorbidities. The association between HIV infection and endemic diseases has been described especially in tropical regions with varying levels of complications, although there has been no report of ZIKV in HIV-infected patients. We report the first autochthonous case of laboratory confirmed ZIKV infection in a HIV-infected patient in Rio de Janeiro, Brazil. He evolved with only mild symptoms and recovered well without major laboratory abnormalities. Phylogenetic analysis of the ZIKV detected in the patient sera clustered within the Asian clade. To the best of our knowledge, this is the first time that Zika virus co-infection is reported in a HIV-infected patient.     

Detection of Zika virus in saliva

BackgroundDuring the largest Zika virus (ZIKV) outbreak ever reported that occurred from October 2013 to March 2014 in French Polynesia, we observed that several patients presenting the symptoms of acute phase Zika fever were tested negative in blood by ZIKV real-time PCR (RT-PCR).ObjectivesAs we have previously detected ZIKV RNA in the saliva of a young child, we investigated the use of saliva as an alternative sample for routine ZIKV RNA detection.Study designOver a 6 month period, 1,067 samples collected from 855 patients presenting symptoms of Zika fever (saliva only, blood only or both samples) were tested using a specific ZIKV RT-PCR. A medical questionnaire was available for most of the patients.ResultsZIKV was more frequently detected in saliva compared to blood. For the 182 patients with both samples collected, tests were positive for 35 (19.2%) in saliva while negative in blood and tests were positive for 16 (8.8%) in blood while negative in saliva; the difference in mean days after symptoms onset and the percentage of the main symptoms of Zika fever for patients only positive in saliva or in blood was not significant.ConclusionThe use of saliva sample increased the rate of molecular detection of ZIKV at the acute phase of the disease but did not enlarge the window of detection of ZIKV RNA. Saliva was of particular interest when blood was difficult to collect (children and neonates especially).     

Molecular detection of Zika virus in blood and RNA load determination during the French Polynesian outbreak

Zika virus (ZIKV) viremia is reported as low and transient; however, these estimates rely on limited data. We report RNA loads in sera collected from symptomatic patients during the 2013‐2014 French Polynesian ZIKV outbreak. We performed molecular detection of ZIKV RNA in sera from 747 patients presenting with suspected acute phase ZIKV infection. Among patients with confirmed infection, we analyzed the duration of viremia, assessed viral RNA loads and recorded the main clinical symptoms. A total of 210/747 (28.1%) sera tested positive using a ZIKV‐specific RT‐PCR. Viral RNA loads in symptomatic patients that ranged from 5 to 3.7 × 10⁶ copies/mL (mean 9.9 × 10⁴ copies/mL) were not related to a particular clinical presentation, and were significantly lower than those previously obtained from asymptomatic ZIKV infected blood donors. The rate of detection of ZIKV RNA in sera from suspected cases of acute phase ZIKV infection was low. ZIKV RNA loads were lower in symptomatic patients compared to asymptomatic blood donors and were lower than RNA loads usually reported in dengue infections. As there is no abrupt onset of symptoms in ZIKV infections, we suggest that infected patients sought for medical attention when viremia was already decreasing or had resolved.

     

Zika virus infections imported to Italy: Clinical,immunological and virological findings,and public health implications

We report the first two cases of laboratory confirmed Zika virus (ZIKV) infections imported into Italy from French Polynesia. Both patients presented with low grade fever, malaise, conjunctivitis, myalgia, arthralgia, ankle oedema, and axillary and inguinal lymphadenopathy. One patient showed leukopenia with relative monocytosis and thrombocytopenia.The diagnosis was based on ZIKV seroconversion in both cases and on ZIKV RNA detection in one patient from acute serum sample. Sera from both patients exhibited cross-reactivity with dengue virus antigens. Our immunological analysis demonstrated that recovery from ZIKV infection is associated with restoration of normal numbers of immune cells in the periphery as well as with normal function of antigen-presenting cells. ZIKV is an emerging arbovirus, which has recently spread extensively in tourist destinations on several West Pacific islands. Returning viremic travelers may ignite autochthonous infections in countries like Italy, which are infested by Aedes albopictus, a suitable vector for ZIKV. The role of clinicians is crucial and includes early diagnosis and timely notification of public health authorities in order to quickly implement adequate focal vector control measurements.     

Zika virus: Future reproductive concerns

The pandemic spread of Zika virus (ZIKV), a member of the flavivirus genus of the Flaviviridae family, has become a major public health concern. Reproductive specialists are particularly concerned over the spread of ZIKV as it is now known to have both sexual and transplacental routes of transmission resulting in fetal congenital abnormalities. Other members of the Flaviviridae family, hepatitis C virus (HCV) and bovine viral diarrhea virus (BVDV) (which primarily affects cattle), are well known to reproductive specialists as both sexually transmitted illnesses that are capable of vertical transmission. Congenital infection with BVDV also has a predilection for neuro‐teratogenicity as has been seen with ZIKV. HCV and BVDV are also known to be capable of persistent infection in offspring. Could this be the case with ZIKV? Examining what we know about HCV and BVDV, in addition to what we have already learned about ZIKV, may answer some of the questions that remain about ZIKV. Herein, we review the current literature as it pertains to ZIKV vertical transmission and neuro‐teratogenicity and compare it to what is known about HCV and BVDV.     

Zika virus outbreak in Brazil—Lessons learned and perspectives for a safe and effective vaccine

Zika virus (ZIKV) is an emerging pathogen of public health concern, associated with a dramatic burden in places where the virus caused outbreaks between 2015 and 2017. In the Americas, the ZIKV was first reported in Brazil and rapidly spread through the Americas. Since its first report, a number of studies have been published as we continue to learn, not only about modes of transmission, but also clinical manifestations, risk of congenital anomalies, including microcephaly and neurological malformations in fetuses born from mothers infected during pregnancy. Interventions to reduce the burden of ZIKV infection are restricted to mosquito control, and for Aedes spp mosquitoes the strategies implemented to that end proved to be unsuccessful so far. Hence the lessons we can learn following the ZIKV epidemics become of paramount importance in the development of drug treatments and in search for a vaccine.     

Rapid decline of Zika virus NS1 antigen-specific antibody responses,northeastern Brazil

Virus Genes - Zika virus (ZIKV) is a positive-stranded RNA virus within the Flaviviridae family. After decades of circulation in Asia, ZIKV was introduced to Brazil in 2014–2015, associated...     

Zika virus: what we need to know?

Zika virus is one of the emerging viruses and is of significant threat to human health globally. It is a mosquito borne flavivirus similar to dengue, yellow fever, and West Nile viruses. It was reported about 5 decades ago and then it spreads to different parts of the world. Large outbreaks were reported on Yap Islands in 2007. Now it has gained wide attention globally by health communities. Major vector for virus transmission is Aedes aegypti mosquito. ZIKV infection is mostly asymptomatic but it is also responsible to cause mild influenza like illness to serious manifestations. There is no specific anti‐viral treatment is available for ZIKV infection. The virus disseminates very fast due to which it possesses a serious threat especially in those areas where there is lack of specific immunity against virus. Little knowledge is available on its transmission and pathogenicity. Although virus was discovered years ago but its genomic structure is not clearly understood yet. In this review we focus on the current knowledge of epidemiology of ZIKV, its transmission, its structural biology, different aspects of diagnosis and diagnostic challenges as well as highlighted appropriates antiviral drugs and vaccines regarding treatment.     

Using immunocompromised mice to identify mechanisms of Zika virus transmission and pathogenesis

Zika virus (ZIKV) is responsible for a recent global epidemic that has been associated with congenital brain malformations in fetuses and with Guillain–Barré syndrome in adults. Within the last 2 years, a major effort has been made to develop murine models to study the mechanism of viral transmission, pathogenesis and the host immune response. Here, we discuss the findings from these models regarding the role that the innate and adaptive immune responses have in controlling ZIKV infection and pathogenesis. Additionally, we examine how innate and adaptive immune responses influence sexual and vertical transmission of ZIKV infection as well as how these responses can influence the ability of ZIKV to cross the placenta and to induce damage in the developing brain.     

Zika and pregnancy: A comprehensive review

Zika virus (ZIKV) infection is a well‐nurtured topic for healthcare personnel nowadays. Central nervous system involvement including microcephaly and ocular involvements has already been reported in neonates of affected pregnant ladies. In this article, we have discussed these effects on the newborns of ZIKV‐infected mothers. The proposed pathogenesis, modes of transmission of this infection from mothers to the fetuses, diagnosis of the cases and precaution for the pregnant ladies have also been discussed. We have gathered the recently available data on the risk of ZIKV for expectant mothers from PubMed, https://www.gov.uk/guidance/zika-virus as well as from centers for disease control and prevention websites.     

Impact on blood safety of the last arboviruses outbreaks in French Polynesia (2012–2018)

BackgroundSeveral successive arbovirus outbreaks have affected French Polynesia (FP) in the recent past years due to different dengue serotypes (DENV) present for several decades, Zika (ZIKV) (2013–2014) and chikungunya (CHIKV) (2014–2015) viruses with a potential impact on blood safety and blood supply due to the geographical isolation of these islands. This study reports an assessment of the impact of these outbreaks on blood products supply and infectious safety in FP and discuss the effectiveness of implemented preventive measures.MethodsTo ensure the infectious safety of blood products during outbreaks, several measures have successively been introduced as the selection of donors suspected of infection, the nucleic acid testing (NAT) and the pathogen reduction of platelets and plasmas.ResultsThe donor deferral rate increased by 6% between 2012 and 2014 without changes in the number of collected donations. NAT excluded five blood donations reactive for DENV RNA, 42 for ZIKV and 34 for CHIKV. As Zika screening could not been implemented before the third month of the outbreak, 36 blood products from ZIKV-infected donors were transfused to 26 recipients. However, no transfusion-transmitted arbovirus has been reported.ConclusionThe last past arboviruses outbreaks did not have a significant impact on blood supply in FP. The measures introduced to prevent arbovirus transmission by transfusion were able to maintain infectious safety for all blood products without impairing self-sufficiency.     

Zika virus infection of Hofbauer cells

Recent studies have linked antenatal infection with Zika virus (ZIKV) with major adverse fetal and neonatal outcomes, including microcephaly. There is a growing consensus for the existence of a congenital Zika syndrome (CZS). Previous studies have indicated that non‐placental macrophages play a key role in the replication of dengue virus (DENV), a closely related flavivirus. As the placenta provides the conduit for vertical transmission of certain viruses, and placental Hofbauer cells (HBCs) are fetal—placental macrophages located adjacent to fetal capillaries, it is not surprising that several recent studies have examined infection of HBCs by ZIKV. In this review, we describe congenital abnormalities associated with ZIKV infection, the role of HBCs in the placental response to infection, and evidence for the susceptibility of HBCs to ZIKV infection. We conclude that HBCs may contribute to the spread of ZIKV in placenta and promote vertical transmission of ZIKV, ultimately compromising fetal and neonatal development and function. Current evidence strongly suggests that further studies are warranted to dissect the specific molecular mechanism through which ZIKV infects HBCs and its potential impact on the development of CZS.     

Growth of Zika virus in human reconstituted respiratory,intestinal, vaginal and neural tissues

ObjectivesZika virus (ZIKV) is mostly mosquito borne but it can also be transmitted via the sexual route and persists in semen for a prolonged time. Moreover, viral RNA has been detected in breast milk, saliva, lacrimal fluids and urine, suggesting other possible transmission routes. The aim of our research is to better define ZIKV tropism.MethodsWe investigated the tropism of Asian and African strains of ZIKV using human-derived neural, vaginal, intestinal and respiratory tissues.ResultsAsian and African strains of ZIKV were able to grow in all tissues tested, although with different efficiency (7.3 log RNA copies released apically in vaginal tissues versus 9.8 log RNA copies released in intestinal tissues), without the need for major adaptation.ConclusionsOur results underline that ZIKV tropism may be broader than expected in humans and stress the need to better explore all possible virus-shedding sites and transmission routes.