Prenatal cytomegalovirus, rubella, and Zika virus infections associated with developmental disabilities: past, present, and future.

Prenatal infections have long been recognized as important, preventable causes of developmental disabilities. The list of pathogens that are recognized to have deleterious effects on fetal brain development continues to grow, most recently with the association between Zika virus (ZIKV) and microcephaly. To answer clinical questions in real time about the impact of a novel infection on developmental disabilities, an historical framework is key. The lessons learned from three historically important pathogens: rubella, cytomegalovirus, and ZIKV, and how these lessons are useful to approach emerging congenital infections are discussed in this review. Congenital infections are preventable causes of developmental disabilities and several public health approaches may be used to prevent prenatal infection. When they cannot be prevented, the sequelae of prenatal infection may be treatable. WHAT THIS PAPER ADDS: The list of prenatal infections associated with developmental disabilities continues to increase. Lessons learned from rubella, cytomegalovirus, and Zika virus have implications for new pathogens. Severity of illness in the mother does not correlate with severity of sequelae in the infant.

Mapping the cryptic spread of the 2015-2016 global Zika virus epidemic.

BACKGROUND: Zika virus (ZIKV) emerged as a global epidemic in 2015-2016 from Latin America with its true geographical extent remaining unclear due to widely presumed underreporting. The identification of locations with potential and unknown spread of ZIKV is a key yet understudied component for outbreak preparedness. Here, we aim to identify locations at a high risk of cryptic ZIKV spread during 2015-2016 to further the understanding of the global ZIKV epidemiology, which is critical for the mitigation of the risk of future epidemics. METHODS: We developed an importation simulation model to estimate the weekly number of ZIKV infections imported in each susceptible spatial unit (i.e. location that did not report any autochthonous Zika cases during 2015-2016), integrating epidemiological, demographic, and travel data as model inputs. Thereafter, a global risk model was applied to estimate the weekly ZIKV transmissibility during 2015-2016 for each location. Finally, we assessed the risk of onward ZIKV spread following importation in each susceptible spatial unit to identify locations with a high potential for cryptic ZIKV spread during 2015-2016. RESULTS: We have found 24 susceptible spatial units that were likely to have experienced cryptic ZIKV spread during 2015-2016, of which 10 continue to have a high risk estimate within a highly conservative scenario, namely, Luanda in Angola, Banten in Indonesia, Maharashtra in India, Lagos in Nigeria, Taiwan and Guangdong in China, Dakar in Senegal, Maputo in Mozambique, Kinshasa in Congo DRC, and Pool in Congo. Notably, among the 24 susceptible spatial units identified, some have reported their first ZIKV outbreaks since 2017, thus adding to the credibility of our results (derived using 2015-2016 data only). CONCLUSION: Our study has provided valuable insights into the potentially high-risk locations for cryptic ZIKV circulation during the 2015-2016 pandemic and has also laid a foundation for future studies that attempt to further narrow this key knowledge gap. Our modelling framework can be adapted to identify areas with likely unknown spread of other emerging vector-borne diseases, which has important implications for public health readiness especially in resource-limited settings.

Zika Virus: A Brief History and Review of Its Pathogenesis Rediscovered.

From its discovery in Uganda in 1947, Zika virus (ZIKV) was considered a relatively innocuous viral pathogen with sporadic and infrequent occurrence of human infection. It was during an outbreak in French Polynesia in 2014 when cases of Guillain-Barré syndrome were identified as a serious complication of ZIKV infection in adults. However, in 2015, ZIKV emerged into and swept through South and Central America infecting millions of people. As part of the latter ZIKV outbreak, in Brazil, cases of microcephaly and other serious congenital complications affecting a large fraction of infants born to mothers infected during pregnancy were first identified and linked to ZIKV. This chapter reviews the history and clinical manifestations of ZIKV infection and mechanisms of immunoprotection. It is notable that, while limited, historical monographs identified most, if not all, of the precepts that are considered as newly discovered.

Preventing Sexual Transmission of Zika Virus Infection during Pregnancy, Puerto Rico, USA, 20161.

We examined condom use throughout pregnancy during the Zika outbreak in Puerto Rico during 2016. Overall, <25% of women reported consistent condom use during pregnancy. However, healthcare provider counseling was associated with a 3-fold increase in consistent use, reinforcing the value of provider counseling in Zika prevention efforts.

Underreporting of Fatal Congenital Zika Syndrome, Mexico, 2016-2017.

To determine completeness of fatal congenital Zika syndrome reporting in Mexico, we examined data from the Mexican National Institute of Statistics and Geography. We found that an estimated 50% more infants died from microcephaly attributable to congenital Zika syndrome during 2016-2017 than were reported by the existing surveillance system.

Joint Estimation of Relative Risk for Dengue and Zika Infections, Colombia, 2015-2016.

We jointly estimated relative risk for dengue and Zika virus disease (Zika) in Colombia, establishing the spatial association between them at the department and city levels for October 2015-December 2016. Cases of dengue and Zika were allocated to the 87 municipalities of 1 department and the 293 census sections of 1 city in Colombia. We fitted 8 hierarchical Bayesian Poisson joint models of relative risk for dengue and Zika, including area- and disease-specific random effects accounting for several spatial patterns of disease risk (clustered or uncorrelated heterogeneity) within and between both diseases. Most of the dengue and Zika high-risk municipalities varied in their risk distribution; those for Zika were in the northern part of the department and dengue in the southern to northeastern parts. At city level, spatially clustered patterns of dengue high-risk census sections indicated Zika high-risk areas. This information can be used to inform public health decision making.

Cross-Protection of Dengue Virus Infection against Congenital Zika Syndrome, Northeastern Brazil.

The Zika virus outbreak in Latin America resulted in congenital malformations, called congenital Zika syndrome (CZS). For unknown reasons, CZS incidence was highest in northeastern Brazil; one potential explanation is that dengue virus (DENV)-mediated immune enhancement may promote CZS development. In contrast, our analyses of historical DENV genomic data refuted the hypothesis that unique genome signatures for northeastern Brazil explain the uneven dispersion of CZS cases. To confirm our findings, we performed serotype-specific DENV neutralization tests in a case-control framework in northeastern Brazil among 29 Zika virus-seropositive mothers of neonates with CZS and 108 Zika virus-seropositive control mothers. Neutralization titers did not differ significantly between groups. In contrast, DENV seroprevalence and median number of neutralized serotypes were significantly lower among the mothers of neonates with CZS. Supported by model analyses, our results suggest that multitypic DENV infection may protect from, rather than enhance, development of CZS.

Seroprevalence of Zika and Dengue Virus Antibodies among Migrant Workers, Taiwan, 2017.

A serosurvey of 600 workers newly arrived in Taiwan from 4 Southeast Asia countries showed that 18 (3%) were positive for Zika virus IgM; 6 (1%) fulfilled the World Health Organization criteria for laboratory-confirmed recent Zika virus infection. The incidence of Zika virus infection in Southeast Asia might be underestimated.

Zika virus outbreak in Rajasthan, India in 2018 was caused by a virus endemic to Asia.

Zika virus (ZIKV) infection in human has been reported from Gujarat and Tamil Nadu states during the year 2016 and 2017 respectively. In paucity of complete genome data of ZIKV, the analysis and prediction were not possible. Zika cases were reported in Jaipur city, Rajasthan, India during the period of 21st September 2018 to 29th October 2018. In order to understand the circulating ZIKV strain in Rajasthan state about ten human serum samples from the positive cases of Jaipur city, Rajasthan state considering the locality and clustering variations were sequenced using next-generation sequencing (NGS) platform. Complete genome phylogenetic analysis of Jaipur city sequences with known GenBank ZIKV sequences revealed that the outbreak in Jaipur city was being caused by ZIKV belonging to Asian lineage. Partial genome sequencing revealed the presence of a pre-outbreak strain of ZIKV in Gujarat and current outbreak strain of Asian lineage in Tamil Nadu. Further sequence analysis of the five ZIKV positive samples of Jaipur revealed that the S139N and A188V mutations, linked to enhanced neurovirulence and transmission in animal models, were not found in the current outbreak strain. Whether this strain can cause birth defects and cause large outbreaks is not currently known, but they should be treated as such until more is known. With the identification of ZIKV in Gujarat, Tamil Nadu, and recent outbreaks of ZIKV in Rajasthan and Madhya Pradesh states alarm for India to enhance surveillance in other states and monitor the mutation and evolutionary changes in circulating Zika strains.

Zika Virus Epidemic in Pregnant Women, Dominican Republic, 2016-2017.

Zika virus infection during pregnancy may result in birth defects and pregnancy complications. We describe the Zika virus outbreak in pregnant women in the Dominican Republic during 2016-2017. We conducted multinomial logistic regression to identify factors associated with fetal losses and preterm birth. The Ministry of Health identified 1,282 pregnant women with suspected Zika virus infection, a substantial proportion during their first trimester. Fetal loss was reported for ≈10% of the reported pregnancies, and 3 cases of fetal microcephaly were reported. Women infected during the first trimester were more likely to have early fetal loss (adjusted odds ratio 5.9, 95% CI 3.5-10.0). Experiencing fever during infection was associated with increased odds of premature birth (adjusted odds ratio 1.65, 95% CI 1.03-2.65). There was widespread morbidity during the epidemic. Our findings strengthen the evidence for a broad range of adverse pregnancy outcomes resulting from Zika virus infection.

Expansão da circulação do vírus Zika da África à América, 1947-2018: revisão da literatura / Expansión de la circulación del virus Zika de África a América, 1947-2018: una revisión de literatura / Expansion of Zika virus circulation from Africa to the Americas, 1947-2018: a literature review

Objetivo: descrever as expansões temporal e geográfica da circulação do vírus Zika (ZIKV) em países e territórios, desde seu isolamento até 2018. Métodos: revisão não sistemática da literatura do período entre 1947 e 2018, utilizando a base MEDLINE e estimativas da Organização Mundial da Saúde. Resultados: desde seu isolamento em 1947, a circulação do ZIKV expandiu-se pela África, Ásia e Pacífico, até chegar à América em 2013, causando manifestações clínicas graves; as maiores soroprevalências foram registradas na ilha de Yap (74%) e no Brasil (63%); mutações genéticas, a ausência de imunidade e a alta susceptibilidade dos vetores podem ter influenciado sua transmissibilidade e ajudam a explicar a magnitude de sua expansão. Conclusão: a expansão da circulação do ZIKV nas Américas foi a mais ampla já registrada, possivelmente resultado de características populacionais e geográficas dos locais por onde o vírus circulou.

Objetivo: Describir las expansiones temporal y geográfica de la circulación del virus Zika en países y territorios, desde su aislamiento hasta 2018. Métodos: Revisión no sistemática de la literatura del período comprendido entre 1947 y 2018 utilizando la base MEDLINE y estimaciones de la Organización Mundial de la Salud. Resultados: Desde su aislamiento en 1947 la circulación del virus Zika se expandió por África, Asia y el Pacífico hasta llegar a América en 2013, causando manifestaciones clínicas graves. Las mayores seroprevalencias se registraron en la isla Yap (74%) y en Brasil (63%). Mutaciones genéticas, ausencia de inmunidad y alta susceptibilidad de los vectores pueden haber influenciado su transmisibilidad y ayudan a explicar la magnitud de su expansión. Conclusión: La expansión de la circulación del virus Zika en las Américas fue la más amplia ya registrada, posiblemente como resultado de características poblacionales y geográficas de los lugares por donde el virus circuló.

Objective: to describe the temporal and geographical expansion of Zika virus (ZIKV) circulation in countries and territories, from the time it was first isolated until 2018. Methods: This was a non-systematic literature review covering the period from 1947 to 2018 using the MEDLINE database and World Health Organization estimates. Results: Since its isolation in 1947, ZIKV circulation spread through Africa, Asia and the Pacific before reaching the Americas in 2013, causing serious clinical manifestations; the highest seroprevalence rates were recorded in Yap (74%) and in Brazil (63%); genetic mutations, absence of immunity and high vector susceptibility may have influenced ZIKV transmissibility and help to explain the magnitude of its expansion. Conclusion: The spread of ZIKV circulation in the Americas was the most extensive recorded thus far, possibly as a result of population and geographical characteristics of the sites where the virus circulated.

Influences of Community Interventions on Zika Prevention Behaviors of Pregnant Women, Puerto Rico, July 2016-June 20171.

We assessed how community education efforts influenced pregnant women's Zika prevention behaviors during the 2016 Centers for Disease Control and Prevention-Puerto Rico Department of Health Zika virus response. Efforts included Zika virus training, distribution of Zika prevention kits, a mass media campaign, and free home mosquito spraying. We used telephone interview data from pregnant women participating in Puerto Rico's Women, Infants, and Children Program to test associations between program participation and Zika prevention behaviors. Behavior percentages ranged from 4% (wearing long-sleeved shirt) to 90% (removing standing water). Appropriate mosquito repellent use (28%) and condom use (44%) were common. Receiving a Zika prevention kit was significantly associated with larvicide application (odds ratio [OR] 8.0) and bed net use (OR 3.1), suggesting the kit's importance for lesser-known behaviors. Offer of free residential spraying was associated with spraying home for mosquitoes (OR 13.1), indicating that women supported home spraying when barriers were removed.

External Quality Assessment (EQA) for Molecular Diagnostics of Zika Virus: Experiences from an International EQA Programme, 2016⁻2018.

Quality Control for Molecular Diagnostics (QCMD), an international provider for External Quality Assessment (EQA) programmes, has introduced a programme for molecular diagnostics of Zika virus (ZIKV) in 2016, which has been continuously offered to interested laboratories since that time. The EQA schemes provided from 2016 to 2018 revealed that 86.7% (92/106), 82.4% (89/108), and 88.2% (90/102) of the participating laboratories reported correct results for all samples, respectively in 2016, 2017, and 2018. The review of results indicated a need for improvement concerning analytical sensitivity and specificity of the test methods. Comparison with the outcomes of other EQA initiatives briefly summarized here show that continuous quality assurance is important to improve laboratory performance and to increase preparedness with reliable diagnostic assays for effective patient management, infection and outbreak control.

Social responsibility and global health: lessons from the Rio Olympics Zika controversy.

The outbreak of Zika virus infection in the Americas and its possible association with microcephaly raised several concerns among global health authorities regarding the organisation of the Olympic and Paralympic Games scheduled for August and September 2016, in the city of Rio de Janeiro, Brazil. It generated an international controversy over the continuation of the Games with debates on the ethical principle of social responsibility. Based on the principles of social responsibility and health in the Universal Declaration of Bioethics and Human Rights, the present comment ponders on the application of such principles in the context of mega-events and global health.

Innovative and New Approaches to Laboratory Diagnosis of Zika and Dengue: A Meeting Report.

Epidemics of dengue, Zika, and other arboviral diseases are increasing in frequency and severity. Current efforts to rapidly identify and manage these epidemics are limited by the short diagnostic window in acute infection, the extensive serologic cross-reactivity among flaviviruses, and the lack of point-of-care diagnostic tools to detect these viral species in primary care settings. The Partnership for Dengue Control organized a workshop to review the current landscape of Flavivirus diagnostic tools, identified current gaps, and developed strategies to accelerate the adoption of promising novel technologies into national programs. The rate-limiting step to bringing new diagnostic tools to the market is access to reference materials and well-characterized clinical samples to facilitate performance evaluation. We suggest the creation of an international laboratory-response consortium for flaviviruses with a decentralized biobank of well-characterized samples to facilitate assay validation. Access to proficiency panels are needed to ensure quality control, in additional to in-country capacity building.

History and Emergence of Zika Virus.

Zika virus was discovered in East Africa in 1947 by the Rockefeller Foundation during investigations on the ecology of yellow fever. Although it was subsequently shown to have widespread distribution in Africa and Asia, it was not known to cause epidemics until 2007. This paper describes the history of the virus discovery, emergence and evolution as an epidemic virus, and the its evolving clinical spectrum.

Zika virus: History, epidemiology, transmission, and clinical presentation.

Zika virus (ZIKV), a mosquito-borne positive-stranded RNA virus of the family Flaviviridae (genus Flavivirus), is now causing an unprecedented large-scale outbreak in the Americas. Historically, ZIKV spread eastward from equatorial Africa and Asia to the Pacific Islands during the late 2000s to early 2010s, invaded the Caribbean and Central and South America in 2015, and reached North America in 2016. Although ZIKV infection generally causes no symptoms or only a mild self-limiting illness, it has recently been linked to a rising number of severe neurological diseases, including microcephaly and Guillain-Barré syndrome. Because of the continuous geographic expansion of both the virus and its mosquito vectors, ZIKV poses a serious threat to public health around the globe. However, there are no vaccines or antiviral therapies available against this pathogen. This review summarizes a fast-growing body of literature on the history, epidemiology, transmission, and clinical presentation of ZIKV and highlights the urgent need for the development of efficient control strategies for this emerging pathogen.