Travel Surveillance and Genomics Uncover a Hidden Zika Outbreak during the Waning Epidemic.

The Zika epidemic in the Americas has challenged surveillance and control. As the epidemic appears to be waning, it is unclear whether transmission is still ongoing, which is exacerbated by discrepancies in reporting. To uncover locations with lingering outbreaks, we investigated travel-associated Zika cases to identify transmission not captured by reporting. We uncovered an unreported outbreak in Cuba during 2017, a year after peak transmission in neighboring islands. By sequencing Zika virus, we show that the establishment of the virus was delayed by a year and that the ensuing outbreak was sparked by long-lived lineages of Zika virus from other Caribbean islands. Our data suggest that, although mosquito control in Cuba may initially have been effective at mitigating Zika virus transmission, such measures need to be maintained to be effective. Our study highlights how Zika virus may still be "silently" spreading and provides a framework for understanding outbreak dynamics. VIDEO ABSTRACT.

From "A"IV to "Z"IKV: Attacks from Emerging and Re-emerging Pathogens.

100 years after the infamous "Spanish flu" pandemic, the 2017-2018 flu season has been severe, with numerous infections worldwide. In between, there have been continuous, relentless attacks from (re-)emerging viruses. To fully understand viral pathogenesis and develop effective medical countermeasures, we must strengthen current surveillance and basic research efforts.

Forging Collaborative Relationships in Brazil: From AIDS to ZIKV.

The Zika virus (ZIKV) outbreak has stimulated collaborations between Brazilians, researchers from other South American countries, and scientists from around the world. The Brazilian response to the HIV/AIDS epidemic demonstrates capabilities that can be applied to the study of ZIKV and provides lessons for developing effective international infectious disease research collaborations.

Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus.

Zika virus (ZIKV) was discovered in 1947 and was thought to lead to relatively mild disease. The recent explosive outbreak of ZIKV in South America has led to widespread concern, with reports of neurological sequelae ranging from Guillain Barré syndrome to microcephaly. ZIKV infection has occurred in areas previously exposed to dengue virus (DENV), a flavivirus closely related to ZIKV. Here we investigated the serological cross-reaction between the two viruses. Plasma immune to DENV showed substantial cross-reaction to ZIKV and was able to drive antibody-dependent enhancement (ADE) of ZIKV infection. Using a panel of human monoclonal antibodies (mAbs) to DENV, we showed that most antibodies that reacted to DENV envelope protein also reacted to ZIKV. Antibodies to linear epitopes, including the immunodominant fusion-loop epitope, were able to bind ZIKV but were unable to neutralize the virus and instead promoted ADE. Our data indicate that immunity to DENV might drive greater ZIKV replication and have clear implications for disease pathogenesis and future vaccine programs for ZIKV and DENV.

Clinical manifestations of dengue, Zika and chikungunya in the Pacific Islands: A systematic review and meta-analysis.

Dengue, Zika and chikungunya outbreaks pose a significant public health risk to Pacific Island communities. Differential diagnosis is challenging due to overlapping clinical features and limited availability of laboratory diagnostic facilities. There is also insufficient information regarding the complications of these arboviruses, particularly for Zika and chikungunya. We conducted a systematic review and meta-analysis to calculate pooled prevalence estimates with 95% confidence intervals (CI) for the clinical manifestations of dengue, Zika and chikungunya in the Pacific Islands. Based on pooled prevalence estimates, clinical features that may help to differentiate between the arboviruses include headache, haemorrhage and hepatomegaly in dengue; rash, conjunctivitis and peripheral oedema in Zika; and the combination of fever and arthralgia in chikungunya infections. We estimated that the hospitalisation and mortality rates in dengue were 9.90% (95% CI 7.67-12.37) and 0.23% (95% CI 0.16-0.31), respectively. Severe forms of dengue occurred in 1.92% (95% CI 0.72-3.63) of reported cases and 23.23% (95% CI 13.58-34.53) of hospitalised patients. Complications associated with Zika virus included Guillain-Barré syndrome (GBS), estimated to occur in 14.08 (95% CI 11.71-16.66) per 10,000 reported cases, and congenital brain malformations such as microcephaly, particularly with first trimester maternal infection. For chikungunya, the hospitalisation rate was 2.57% (95% CI 1.30-4.25) and the risk of GBS was estimated at 1.70 (95% CI 1.06-2.48) per 10,000 reported cases. Whilst ongoing research is required, this systematic review enhances existing knowledge on the clinical manifestations of dengue, Zika and chikungunya infections and will assist Pacific Island clinicians during future arbovirus outbreaks.

Evidence of Zika Virus Reinfection by Genome Diversity and Antibody Response Analysis, Brazil.

We generated 238 Zika virus (ZIKV) genomes from 135 persons in Brazil who had samples collected over 1 year to evaluate virus persistence. Phylogenetic inference clustered the genomes together with previously reported ZIKV strains from northern Brazil, showing that ZIKV has been remained relatively stable over time. Temporal phylogenetic analysis revealed limited within-host diversity among most ZIKV-persistent infected associated samples. However, we detected unusual virus temporal diversity from >5 persons, uncovering the existence of divergent genomes within the same patient. All those patients showed an increase in neutralizing antibody levels, followed by a decline at the convalescent phase of ZIKV infection. Of interest, in 3 of those patients, titers of neutralizing antibodies increased again after 6 months of ZIKV infection, concomitantly with real-time reverse transcription PCR re-positivity, supporting ZIKV reinfection events. Altogether, our findings provide evidence for the existence of ZIKV reinfection events.

Endemic viral infections in immunocompromised hosts: Dengue, Chikungunya, Zika.

PURPOSE OF REVIEW: Arbovirus infections are a challenge for immunocompromised hosts who travel to or live in endemic regions or who receive organs or tissues from donors who travel or live in such areas. This review addresses Dengue (DENV), Chikungunya (CHIKV), and Zika (ZIKV) infections in hematological patients, hematopoietic cell or solid organ transplant recipients, and people with HIV (PWH). RECENT FINDINGS: Transmission is mainly due through Aedes mosquito bite. DENV and ZIKV may also be transmitted through blood, tissues or donor grafts. Clinical manifestations are quite similar and diagnosis requires laboratory confirmation to provide appropriate management. The best diagnostic method is PCR since serology may present false negative results in immunocompromised patients, or cross-reactivity as in the case of DENV and ZIKV. There is no specific treatment for any of these infections. SUMMARY: Educational and preventive measures are the best strategy: vector control, knowledge of the vector's habits, protection against mosquito bites, avoiding travel to endemic areas or with a current epidemic, and avoiding nonvector transmission according to local recommendations for donor deferral. Vaccination, currently only available for DENV, has not yet been studied in immunocompromised patients and is not currently recommended.

Universal Difference-in-Differences for Causal Inference in Epidemiology.

Difference-in-differences is undoubtedly one of the most widely used methods for evaluating the causal effect of an intervention in observational (i.e., nonrandomized) settings. The approach is typically used when pre- and postexposure outcome measurements are available, and one can reasonably assume that the association of the unobserved confounder with the outcome has the same absolute magnitude in the two exposure arms and is constant over time; a so-called parallel trends assumption. The parallel trends assumption may not be credible in many practical settings, for example, if the outcome is binary, a count, or polytomous, as well as when an uncontrolled confounder exhibits nonadditive effects on the distribution of the outcome, even if such effects are constant over time. We introduce an alternative approach that replaces the parallel trends assumption with an odds ratio equi-confounding assumption under which an association between treatment and the potential outcome under no treatment is identified with a well-specified generalized linear model relating the pre-exposure outcome and the exposure. Because the proposed method identifies any causal effect that is conceivably identified in the absence of confounding bias, including nonlinear effects such as quantile treatment effects, the approach is aptly called universal difference-in-differences. We describe and illustrate both fully parametric and more robust semiparametric universal difference-in-differences estimators in a real-world application concerning the causal effects of a Zika virus outbreak on birth rate in Brazil. A supplementary digital video is available at: http://links.lww.com/EDE/C90.

Optimising the surveillance of Aedes aegypti in Brazil by selecting smaller representative areas within an endemic city.

OBJECTIVES: Arboviruses, such as dengue (DENV), zika (ZIKV), and chikungunya (CHIKV), constitute a growing urban public health threat. Focusing on Aedes aegypti mosquitoes, their primary vectors, is crucial for mitigation. While traditional immature-stage mosquito surveillance has limitations, capturing adult mosquitoes through traps yields more accurate data on disease transmission. However, deploying traps presents logistical and financial challenges, demonstrating effective temporal predictions but lacking spatial accuracy. Our goal is to identify smaller representative areas within cities to enhance the early warning system for DENV outbreaks. METHODS: We created Sentinel Geographic Units (SGUs), smaller areas of 1 km2 within each stratum, larger areas, with the aim of aligning the Trap Positivity Index (TPI) and Adult Density Index (ADI) with their respective strata. We conducted a two-step evaluation of SGUs. First, we examined the equivalence of TPI and ADI between SGUs and strata from January 2017 to July 2022. Second, we assessed the ability of SGU's TPI and ADI to predict DENV outbreaks in comparison to Foz do Iguaçu's Early-Warning System, which forecasts outbreaks up to 4 weeks ahead. Spatial and temporal analyses were carried out, including data interpolation and model selection based on Akaike information criteria (AIC). RESULTS: Entomological indicators produced in small SGUs can effectively replace larger sentinel areas to access dengue outbreaks. Based on historical data, the best predictive capability is achieved 2 weeks after infestation verification. Implementing the SGU strategy with more frequent sampling can provide more precise space-time estimates and enhance dengue control. CONCLUSIONS: The implementation of SGUs offers an efficient way to monitor mosquito populations, reducing the need for extensive resources. This approach has the potential to improve dengue transmission management and enhance the public health response in endemic cities.

Outcomes up to age 36 months after congenital Zika virus infection-U.S. states.

BACKGROUND: To characterize neurodevelopmental abnormalities in children up to 36 months of age with congenital Zika virus exposure. METHODS: From the U.S. Zika Pregnancy and Infant Registry, a national surveillance system to monitor pregnancies with laboratory evidence of Zika virus infection, pregnancy outcomes and presence of Zika associated birth defects (ZBD) were reported among infants with available information. Neurologic sequelae and developmental delay were reported among children with ≥1 follow-up exam after 14 days of age or with ≥1 visit with development reported, respectively. RESULTS: Among 2248 infants, 10.1% were born preterm, and 10.5% were small-for-gestational age. Overall, 122 (5.4%) had any ZBD; 91.8% of infants had brain abnormalities or microcephaly, 23.0% had eye abnormalities, and 14.8% had both. Of 1881 children ≥1 follow-up exam reported, neurologic sequelae were more common among children with ZBD (44.6%) vs. without ZBD (1.5%). Of children with ≥1 visit with development reported, 46.8% (51/109) of children with ZBD and 7.4% (129/1739) of children without ZBD had confirmed or possible developmental delay. CONCLUSION: Understanding the prevalence of developmental delays and healthcare needs of children with congenital Zika virus exposure can inform health systems and planning to ensure services are available for affected families. IMPACT: We characterize pregnancy and infant outcomes and describe neurodevelopmental abnormalities up to 36 months of age by presence of Zika associated birth defects (ZBD). Neurologic sequelae and developmental delays were common among children with ZBD. Children with ZBD had increased frequency of neurologic sequelae and developmental delay compared to children without ZBD. Longitudinal follow-up of infants with Zika virus exposure in utero is important to characterize neurodevelopmental delay not apparent in early infancy, but logistically challenging in surveillance models.

A Gaussian-process approximation to a spatial SIR process using moment closures and emulators.

The dynamics that govern disease spread are hard to model because infections are functions of both the underlying pathogen as well as human or animal behavior. This challenge is increased when modeling how diseases spread between different spatial locations. Many proposed spatial epidemiological models require trade-offs to fit, either by abstracting away theoretical spread dynamics, fitting a deterministic model, or by requiring large computational resources for many simulations. We propose an approach that approximates the complex spatial spread dynamics with a Gaussian process. We first propose a flexible spatial extension to the well-known SIR stochastic process, and then we derive a moment-closure approximation to this stochastic process. This moment-closure approximation yields ordinary differential equations for the evolution of the means and covariances of the susceptibles and infectious through time. Because these ODEs are a bottleneck to fitting our model by MCMC, we approximate them using a low-rank emulator. This approximation serves as the basis for our hierarchical model for noisy, underreported counts of new infections by spatial location and time. We demonstrate using our model to conduct inference on simulated infections from the underlying, true spatial SIR jump process. We then apply our method to model counts of new Zika infections in Brazil from late 2015 through early 2016.

Single proxy control.

Negative control variables are sometimes used in nonexperimental studies to detect the presence of confounding by hidden factors. A negative control outcome (NCO) is an outcome that is influenced by unobserved confounders of the exposure effects on the outcome in view, but is not causally impacted by the exposure. Tchetgen Tchetgen (2013) introduced the Control Outcome Calibration Approach (COCA) as a formal NCO counterfactual method to detect and correct for residual confounding bias. For identification, COCA treats the NCO as an error-prone proxy of the treatment-free counterfactual outcome of interest, and involves regressing the NCO on the treatment-free counterfactual, together with a rank-preserving structural model, which assumes a constant individual-level causal effect. In this work, we establish nonparametric COCA identification for the average causal effect for the treated, without requiring rank-preservation, therefore accommodating unrestricted effect heterogeneity across units. This nonparametric identification result has important practical implications, as it provides single-proxy confounding control, in contrast to recently proposed proximal causal inference, which relies for identification on a pair of confounding proxies. For COCA estimation we propose 3 separate strategies: (i) an extended propensity score approach, (ii) an outcome bridge function approach, and (iii) a doubly-robust approach. Finally, we illustrate the proposed methods in an application evaluating the causal impact of a Zika virus outbreak on birth rate in Brazil.

Emerging and re-emerging infectious diseases in pregnant women in an amazonian region: a large retrospective study from French Guiana.

PURPOSE: Over the past decade, the Amazon basin has faced numerous infectious epidemics. Our comprehension of the actual extent of these infections during pregnancy remains limited. This study aimed to clarify the clinical and epidemiological features of emerging and re-emerging infectious diseases during pregnancy in western French Guiana and along the Maroni River over the previous nine years. METHODS: This retrospective cohort study enrolled pregnant women living in west French Guiana territory and giving birth in the only local referral center after 22 weeks of gestation between 2013 and 2021. Data on symptomatic or asymptomatic biologically confirmed emerging or re-emerging diseases during pregnancy was collected. RESULTS: Six epidemic waves were experienced during the study period, including 498 confirmed Zika virus infections (2016), 363 SARS-CoV-2 infections (2020-2021), 87 chikungunya virus infections (2014), 76 syphilis infections (2013-2021), and 60 dengue virus infections (2013-2021) at different gestational ages. Furthermore, 1.1% (n = 287) and 1.4% (n = 350) of pregnant women in west French Guiana were living with HIV and HTLV, respectively. During the study period, at least 5.5% (n = 1,371) faced an emerging or re-emerging infection during pregnancy. CONCLUSION: These results highlight the diversity, abundance, and dynamism of emerging and re-emerging infectious agents faced by pregnant women in the Amazon basin. Considering the maternal and neonatal adverse outcomes associated with these infections, increased efforts are required to enhance diagnosis, reporting, and treatment of these conditions.

Utilizing non-human primate models to combat recent COVID-19/SARS-CoV-2 and viral infectious disease outbreaks.

In recent times, global viral outbreaks and diseases, such as COVID-19 (SARS-CoV-2), Zika (ZIKV), monkeypox (MPOX), Ebola (EBOV), and Marburg (MARV), have been extensively documented. Swiftly deciphering the mechanisms underlying disease pathogenesis and devising vaccines or therapeutic interventions to curtail these outbreaks stand as paramount imperatives. Amidst these endeavors, animal models emerge as pivotal tools. Among these models, non-human primates (NHPs) hold a position of particular importance. Their proximity in evolutionary lineage and physiological resemblances to humans render them a primary model for comprehending human viral infections. This review encapsulates the pivotal role of various NHP species-such as rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), african green monkeys (Chlorocebus sabaeus/aethiops), pigtailed macaques (Macaca nemestrina/Macaca leonina), baboons (Papio hamadryas/Papio anubis), and common marmosets (Callithrix jacchus)-in investigations pertaining to the abovementioned viral outbreaks. These NHP models play a pivotal role in illuminating key aspects of disease dynamics, facilitating the development of effective countermeasures, and contributing significantly to our overall understanding of viral pathogenesis.

The emergence of Zika virus and its new clinical syndromes.

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that has emerged as a global health threat because of its potential to generate explosive epidemics and ability to cause congenital disease in the context of infection during pregnancy. Whereas much is known about the biology of related flaviviruses, the unique features of ZIKV pathogenesis, including infection of the fetus, persistence in immune-privileged sites and sexual transmission, have presented new challenges. The rapid development of cell culture and animal models has facilitated a new appreciation of ZIKV biology. This knowledge has created opportunities for the development of countermeasures, including multiple ZIKV vaccine candidates, which are advancing through clinical trials. Here we describe the recent advances that have led to a new understanding of the causes and consequences of the ZIKV epidemic.

Continuation of Reversible Contraception Following Enrollment in the Zika Contraception Access Network (Z-CAN) in Puerto Rico, 2016-2020.

The Zika Contraception Access Network (Z-CAN) provided access to high-quality client-centered contraceptive services across Puerto Rico during the 2016-2017 Zika virus outbreak. We sent online surveys during May 2017-August 2020 to a subset of Z-CAN patients at 6, 24, and 36 months after program enrollment (response rates: 55-60 percent). We described contraceptive method continuation, method satisfaction, and method switching, and we identified characteristics associated with discontinuation using multivariable logistic regression. Across all contraceptive methods, continuation was 82.5 percent, 64.2 percent, and 49.9 percent at 6, 24, and 36 months, respectively. Among continuing users, method satisfaction was approximately ≥90 percent. Characteristics associated with decreased likelihood of discontinuation included: using an intrauterine device or implant compared with a nonlong-acting reversible contraceptive method (shot, pills, ring, patch, or condoms alone); wanting to prevent pregnancy at follow-up; and receiving as their baseline method the same method primarily used before Z-CAN. Other associated characteristics included: receiving the method they were most interested in postcounseling (6 and 24 months) and being very satisfied with Z-CAN services at the initial visit (6 months). Among those wanting to prevent pregnancy at follow-up, about half reported switching to another method. Ongoing access to contraceptive services is essential for promoting reproductive autonomy, including supporting patients with continued use, method switching, or discontinuation.

Feeding characteristics and growth among children with prenatal exposure to Zika virus with and without microcephaly in the microcephaly epidemic research group pediatric cohort.

OBJECTIVE: To describe the feeding characteristics and growth of children with prenatal exposure to Zika virus (ZIKV) from birth to 48 months. DESIGN: Using data from the prospective Microcephaly Epidemic Research Group Pediatric Cohort (MERG-PC), children without microcephaly born to mothers with evidence of ZIKV infection during pregnancy (ZIKV-exposed children without microcephaly) and children with Zika-related microcephaly were compared using repeated cross-sectional analyses within the following age strata: birth; 1 to 12; 13 to 24; 25 to 36; and 37 to 48 months. The groups were compared in relation to prematurity, birth weight, breastfeeding, alternative feeding routes, dysphagia and anthropometric profiles based on the World Health Organization Anthro z-scores (weight-length/height, weight-age, length/height-age and BMI-age). RESULTS: The first assessment included 248 children, 77 (31.05%) with microcephaly and 171 (68.95%) without microcephaly. The final assessment was performed on 86 children. Prematurity was 2.35 times higher and low birth weight was 3.49 times higher in children with microcephaly. The frequency of breastfeeding was high (> 80%) in both groups. On discharge from the maternity hospital, the frequency of children requiring alternative feeding route in both groups was less than 5%. After 12 months of age, children with microcephaly required alternative feeding route more often than children without microcephaly. In children with microcephaly, the z-score of all growth indicators was lower than in children without microcephaly. CONCLUSIONS: Children with Zika-related microcephaly were more frequently premature and low birth weight and remained with nutritional parameters, i.e., weight-for-age, weight-for-length/height and length/height-for-age below those of the children without microcephaly.

Knowledge, Attitudes and Practices About Zika Virus Infection Among Women of Reproductive Age in Central Brooklyn, New York City, USA.

Zika virus (ZIKV) is spread by mosquitos, sexual intercourse and vertically during pregnancy. The 2015-2016 ZIKV epidemic infected millions in the Americas and resulted in thousands of infants born with malformations. Though the clusters of severe birth defects have subsided since 2017, ZIKV transmission remains a concern throughout Latin America and the Caribbean. Travel-associated and sexually-transmitted Zika, therefore, remain potential routes of transmission for women of reproductive age and their partners. This is particularly true for communities with high immigrant and foreign-born populations in Central Brooklyn, New York. Limited information has been collected on the perception by this population of ZIKV and how high-risk women engage in preventive practices. Using a survey adapted from the WHO, we assessed engagement in mosquito-related preventive practices while traveling. Data from 483 respondents on knowledge and perceived ZIKV concern, along with demographics as correlates of engagement in preventive practices were collected using a convenience sample between September 2020 and January 2021. Data were collected via a multipronged approach using social media in REDCap. Our findings show that being white/not Hispanic, pregnant, knowledgeable and concerned about ZIKV, and having enough information about ZIKV were all significantly associated with an increased likelihood of engaging in preventive practices while traveling. Multivariable logistic modeling revealed that knowledge was significantly associated with an increased likelihood of engaging in preventive practices while traveling (AOR = 1.90, 95% CI [1.28-2.83]). These findings underscore the importance of directing tailored health education efforts to vulnerable populations.