Results of a Zika Virus (ZIKV) Immunoglobulin M-Specific Diagnostic Assay Are Highly Correlated With Detection of Neutralizing Anti-ZIKV Antibodies in Neonates With Congenital Disease.

BACKGROUND:  Usually, immunoglobulin M (IgM) serologic analysis is not sufficiently specific to confirm Zika virus (ZIKV) infection. However, since IgM does not cross the placenta, it may be a good marker of infection in neonates. METHODS:  We tested blood from 42 mothers and neonates with microcephaly and collected cerebrospinal fluid (CSF) specimens from 30 neonates. Molecular assays were performed for detection of ZIKV, dengue virus, and chikungunya virus; IgM enzyme-linked immunosorbent assays and plaque-reduction neutralization tests (PRNTs) were performed to detect ZIKV and dengue virus. No control neonates without microcephaly were evaluated. RESULTS:  Among neonates, all 42 tested positive for ZIKV IgM: 38 of 42 serum specimens (90.5%) were positive, whereas 30 of 30 CSF specimens (100%) were positive. ZIKV IgM-specific ELISA ratios, calculated as the mean optical density (OD) of the test sample when reacted on viral antigen divided by the mean OD of the negative control when reacted with viral antigen, were higher in CSF specimens (median, 14.9 [range, 9.3-16.4]) than in serum (median, 8.9 [range, 2.1-20.6]; P = .0003). All ZIKV IgM-positive results among the neonates were confirmed by the detection of neutralizing antibodies. Mother/neonate pairs with primary ZIKV infection had neutralizing antibodies to ZIKV only, and mother/neonate pairs with ZIKV virus infection secondary to infection with another flavivirus had high titers of neutralizing antibodies to ZIKV. Among secondary infections, median titers in serum were 2072 (range, 232-12 980) for mothers and 2730 (range, 398-12 980) for neonates (P < .0001), and the median titer in CSF was 93 (range, 40-578) among neonates (P < .0001). CONCLUSIONS:  Among neonates, detection of ZIKV IgM in serum is confirmatory of congenital ZIKV infection, and detection of ZIKV IgM in CSF is confirmatory of neurologic infection. Therefore, we recommend testing for ZIKV IgM in neonates suspected of having congenital ZIKV infection and performance of PRNTs in equivocal cases

Neighbourhood-level income and Zika virus infection during pregnancy in Recife, Pernambuco, Brazil: an ecological perspective, 2015-2017.

Zika virus (ZIKV) infections during pregnancy can lead to adverse neurodevelopmental and clinical outcomes in congenitally infected offspring. As the city of Recife in Pernambuco State, Brazil-the epicentre of the Brazilian microcephaly epidemic-has considerable disparities in living conditions, this study used an ecological approach to investigate the association between income at the neighbourhood level and the risk of ZIKV infections in pregnant individuals between December 2015 and April 2017. The spatial distribution of pregnant individuals with ZIKV infection was plotted on a map of Recife stratified into four categories based on mean monthly income of household heads. Additionally, a Poisson regression model with robust variance was fitted to compare proportions of ZIKV infections among pregnant individuals in relation to the mean monthly income of household heads, based on the 2010 census data, across 94 neighbourhoods in Recife. The results provide evidence that the risk of ZIKV infection to pregnant individuals was higher among those residing in lower-income neighbourhoods: relative to neighbourhoods that had a mean monthly income of ≥5 times minimum wage, neighbourhoods with <1 and 1 to <2 times minimum wage had more than four times the risk (incidence rate ratio, 95% CI 4.08, 1.88 to 8.85 and 4.30, 2.00 to 9.20, respectively). This study provides evidence of a strong association between neighbourhood-level income and ZIKV infection risks in the pregnant population of Recife. In settings prone to arboviral outbreaks, locally targeted interventions to improve living conditions, sanitation, and mosquito control should be a key focus of governmental interventions to reduce risks associated with ZIKV infections during pregnancy

Co-circulation of Chikungunya Virus during the 2015-2017 Zika Virus Outbreak in Pernambuco, Brazil: An Analysis of the Microcephaly Epidemic Research Group Pregnancy Cohort.

Co-circulation of arthropod-borne viruses, particularly those with shared mosquito vectors like Zika (ZIKV) and Chikungunya (CHIKV), is increasingly reported. An accurate differential diagnosis between ZIKV and CHIKV is of high clinical importance, especially in the context of pregnancy, but remains challenging due to limitations in the availability of specialized laboratory testing facilities. Using data collected from the prospective pregnancy cohort study of the Microcephaly Epidemic Research Group, which followed up pregnant persons with rash during the peak and decline of the 2015-2017 ZIKV epidemic in Recife, Pernambuco, Brazil, this study aims to describe the geographic and temporal distribution of ZIKV and CHIKV infections and to investigate the extent to which ZIKV and CHIKV infections may be clinically differentiable. Between December 2015 and June 2017, we observed evidence of co-circulation with laboratory confirmation of 213 ZIKV mono-infections, 55 CHIKV mono-infections, and 58 sequential ZIKV/CHIKV infections (i.e., cases with evidence of acute ZIKV infection with concomitant serological evidence of recent CHIKV infection). In logistic regressions with adjustment for maternal age, ZIKV mono-infected cases had lower odds than CHIKV mono-infected cases of presenting with arthralgia (aOR, 99% CI: 0.33, 0.15-0.74), arthritis (0.35, 0.14-0.85), fatigue (0.40, 0.17-0.96), and headache (0.44, 0.19-1.90). However, sequential ZIKV/CHIKV infections complicated discrimination, as they did not significantly differ in clinical presentation from CHIKV mono-infections. These findings suggest clinical symptoms alone may be insufficient for differentiating between ZIKV and CHIKV infections during pregnancy and therefore laboratory diagnostics continue to be a valuable tool for tailoring care in the event of arboviral co-circulation

Zika virus infection in pregnancy: Establishing a case definition for clinical research on pregnant women with rash in an active transmission setting.

Defining cases of Zika virus (ZIKV) infection is a critical challenge for epidemiological research. Due to ZIKV's overlapping clinical features and potential immunologic cross-reactivity with other flaviviruses and the current lack of an optimal ZIKV-specific diagnostic assay, varying approaches for identifying ZIKV infections have been employed to date. This paper presents the laboratory results and diagnostic criteria developed by the Microcephaly Epidemic Research Group for defining cases of maternal ZIKV infection in a cohort of pregnant women with rash (N = 694) recruited during the declining 2015-2017 epidemic in northeast Brazil. For this investigation, we tested maternal sera for ZIKV by quantitative reverse transcription polymerase chain reaction (qRT-PCR), Immunoglobulin (Ig) M and IgG3 enzyme-linked immunosorbent assays (ELISAs), and Plaque Reduction Neutralization Test (PRNT50). Overall, 23.8% of participants tested positive by qRT-PCR during pregnancy (range of detection: 0-72 days after rash onset). However, the inter-assay concordance was lower than expected. Among women with qRT-PCR-confirmed ZIKV and further testing, only 10.1% had positive IgM tests within 90 days of rash, and only 48.5% had ZIKV-specific PRNT50 titers ≥20 within 1 year of rash. Given the complexity of these data, we convened a panel of experts to propose an algorithm for identifying ZIKV infections in pregnancy based on all available lines of evidence. When the diagnostic algorithm was applied to the cohort, 26.9% of participants were classified as having robust evidence of a ZIKV infection during pregnancy, 4.0% as having moderate evidence, 13.3% as having limited evidence of a ZIKV infection but with uncertain timing, and 19.5% as having evidence of an unspecified flavivirus infection before or during pregnancy. Our findings suggest that integrating longitudinal data from nucleic acid and serologic testing may enhance diagnostic sensitivity and underscore the need for an on-going dialogue regarding the optimization of strategies for defining cases of ZIKV in research

The Microcephaly Epidemic Research Group Paediatric Cohort (MERG-PC): A Cohort Profile.

This cohort profile aims to describe the ongoing follow-up of children in the Microcephaly Epidemic Research Group Paediatric Cohort (MERG-PC). The profile details the context and aims of the study, study population, methodology including assessments, and key results and publications to date. The children that make up MERG-PC were born in Recife or within 120 km of the city, in Pernambuco/Brazil, the epicentre of the microcephaly epidemic. MERG-PC includes children from four groups recruited at different stages of the ZIKV microcephaly epidemic in Pernambuco, i.e., the Outpatient Group (OG/n = 195), the Microcephaly Case-Control Study (MCCS/n = 80), the MERG Pregnant Women Cohort (MERG-PWC/n = 336), and the Control Group (CG/n = 100). We developed a comprehensive array of clinical, laboratory, and imaging assessments that were undertaken by a 'task force' of clinical specialists in a single day at 3, 6, 12, 18 months of age, and annually from 24 months. Children from MCCS and CG had their baseline assessment at birth and children from the other groups, at the first evaluation by the task force. The baseline cohort includes 711 children born between February 2015 and February 2019. Children's characteristics at baseline, excluding CG, were as follows: 32.6% (184/565) had microcephaly, 47% (263/559) had at least one physical abnormality, 29.5% (160/543) had at least one neurological abnormality, and 46.2% (257/556) had at least one ophthalmological abnormality. This ongoing cohort has contributed to the understanding of the congenital Zika syndrome (CZS) spectrum. The cohort has provided descriptions of paediatric neurodevelopment and early epilepsy, including EEG patterns and treatment response, and information on the frequency and characteristics of oropharyngeal dysphagia; cryptorchidism and its surgical findings; endocrine dysfunction; and adenoid hypertrophy in children with Zika-related microcephaly. The study protocols and questionnaires were shared across Brazilian states to enable harmonization across the different studies investigating microcephaly and CZS, providing the opportunity for the Zika Brazilian Cohorts Consortium to be formed, uniting all the ZIKV clinical cohorts in Brazil

Risk of microcephaly after Zika virus infection in Brazil, 2015 to 2016

Submitted by Adagilson Silva ([email protected]) on 2017-06-22T13:25:56Z No. of bitstreams: 1 28250532 2017 jae-ris.oa.pdf: 485093 bytes, checksum: a3a0105d13cf4745dacbc9cbdca2dcad (MD5)Approved for entry into archive by Adagilson Silva ([email protected]) on 2017-06-22T13:26:28Z (GMT) No. of bitstreams: 1 28250532 2017 jae-ris.oa.pdf: 485093 bytes, checksum: a3a0105d13cf4745dacbc9cbdca2dcad (MD5)Made available in DSpace on 2017-06-22T13:26:28Z (GMT). No. of bitstreams: 1 28250532 2017 jae-ris.oa.pdf: 485093 bytes, checksum: a3a0105d13cf4745dacbc9cbdca2dcad (MD5) Previous issue date: 2017-03-01Heidelberg University Hospital. Section of Clinical Tropical Medicine. Department of Infectious Diseases. Heidelberg, Germany.Heidelberg University Hospital. Section of Clinical Tropical Medicine. Department of Infectious Diseases. Heidelberg, Germany.Federal University of Pernambuco. Department of Internal Medicine. Recife, PE, Brazil.London School of Hygiene & Tropical Medicine. Department of Infectious Disease Epidemiology. London, England.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Laboratório de Virologia e Terapia Experimental. Recife, PE, Brasil.OBJECTIVE: To estimate the risk of microcephaly in babies born to women infected by the Zika virus during pregnancy in Brazil in an epidemic between 2015 and 2016. METHODS: We obtained data on the number of notified and confirmed microcephaly cases in each Brazilian state between November 2015 and October 2016 from the health ministry. For Pernambuco State, one of the hardest hit, weekly data were available from August 2015 to October 2016 for different definitions of microcephaly. The absolute risk of microcephaly was calculated using the average number of live births reported in each state in the corresponding time period between 2012 and 2014 and assuming two infection rates: 10% and 50%. The relative risk was estimated using the reported background frequency of microcephaly in Brazil of 1.98 per 10 000 live births. FINDINGS: The estimated absolute risk of a notified microcephaly case varied from 0.03 to 17.1% according to geographical area, the definition of microcephaly used and the infection rate. Assuming a 50% infection rate, there was an 18-127 fold higher probability of microcephaly in children born to mothers with infection during pregnancy compared with children born to mothers without infection during pregnancy in Pernambuco State. For a 10% infection rate, the probability was 88-635 folds higher. CONCLUSION: A large variation in the estimated risk of microcephaly was found in Brazil. Research is needed into possible effect modifiers, reliable measures of Zika virus infection and clear endpoints for congenital malformations

Risk of dengue for tourists and teams during the World Cup 2014 in Brazil.

BackgroundThis year, Brazil will host about 600,000 foreign visitors during the 2014 FIFA World Cup. The concern of possible dengue transmission during this event has been raised given the high transmission rates reported in the past by this country.Methodology/principal findingsWe used dengue incidence rates reported by each host city during previous years (2001-2013) to estimate the risk of dengue during the World Cup for tourists and teams. Two statistical models were used: a percentile rank (PR) and an Empirical Bayes (EB) model. Expected IR's during the games were generally low (&lt;10/100,000) but predictions varied across locations and between models. Based on current ticket allocations, the mean number of expected symptomatic dengue cases ranged from 26 (PR, 10th-100th percentile: 5-334 cases) to 59 (EB, 95% credible interval: 30-77 cases) among foreign tourists but none are expected among teams. These numbers will highly depend on actual travel schedules and dengue immunity among visitors. Sensitivity analysis for both models indicated that the expected number of cases could be as low as 4 or 5 with 100,000 visitors and as high as 38 or 70 with 800,000 visitors (PR and EB, respectively).Conclusion/significanceThe risk of dengue among tourists during the World Cup is expected to be small due to immunity among the Brazil host population provided by last year's epidemic with the same DENV serotypes. Quantitative risk estimates by different groups and methodologies should be made routinely for mass gathering events

Prospective birth cohort in a hyperendemic dengue area in Northeast Brazil: methods and preliminary results.

Dengue cases have increased in younger age groups in Brazil. Maternal anti-dengue antibodies can have a protective effect in the first months of life, but their decline can increase the risk of severe dengue. A prospective birth cohort was established in 2011-2012 in the city of Recife, Pernambuco State, Brazil, to determine the incidence of serotype-specific dengue infection and the kinetics of transferred maternal anti-dengue antibodies in the first years of life. This article describes the design, methods and preliminary results of this cohort study. 354 children underwent clinical and laboratory monitoring for two years, with 15% losses to follow-up. The overall rate of new infections was approximately 10% in the first year of follow-up. Information on the force of serotype-specific dengue infection and the evaluation of transferred maternal antibodies can contribute to understanding dengue etiopathogenesis