Publications by authors named "Ricardo Ximenes"

132 Publications

Neurodevelopment in Children Exposed to Zika Virus: What Are the Consequences for Children Who Do Not Present with Microcephaly at Birth?

Viruses 2021 Jul 22;13(8). Epub 2021 Jul 22.

Pós-Graduação em Ciências da Saúde, Universidade de Pernambuco, Recife 50100-010, Brazil.

The relation of Zika virus (ZIKV) with microcephaly is well established. However, knowledge is lacking on later developmental outcomes in children with evidence of maternal ZIKV infection during pregnancy born without microcephaly. The objective of this analysis is to investigate the impact of prenatal exposure to ZIKV on neuropsychomotor development in children without microcephaly. We evaluated 274 children including 235 ZIKV exposed and 39 controls using the Bayley-III Scales of Infant and Toddler Development (BSIDIII) and neurological examination. We observed a difference in cognition with a borderline p-value ( = 0.052): 9.4% of exposed children and none of the unexposed control group had mild to moderate delays. The prevalence of delays in the language and motor domains did not differ significantly between ZIKV-exposed and unexposed children (language: 12.3% versus 12.8%; motor: 4.7% versus 2.6%). Notably, neurological examination results were predictive of neurodevelopmental delays in the BSIDIII assessments for exposed children: 46.7% of children with abnormalities on clinical neurological examination presented with delay in contrast to 17.8% among exposed children without apparent neurological abnormalities ( = 0.001). Overall, our findings suggest that relative to their unexposed peers, ZIKV-exposed children without microcephaly are not at considerably increased risk of neurodevelopmental impairment in the first 42 months of life, although a small group of children demonstrated higher frequencies of cognitive delay. It is important to highlight that in the group of exposed children, an abnormal neuroclinical examination may be a predictor of developmental delay. The article contributes to practical guidance and advances our knowledge about congenital Zika.
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http://dx.doi.org/10.3390/v13081427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8402706PMC
July 2021

Epidemic preparedness: Prenatal Zika virus screening during the next epidemic.

BMJ Glob Health 2021 06;6(6)

Health Equity Action Lab, Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK

Zika virus (ZIKV) is a vectorborne infectious agent of global public health significance due to its potential to cause severe teratogenic outcomes. The question of whether health systems should consider adopting screening programmes for ZIKV infections during pregnancy warrants consideration. In this analysis, we apply the Wilson-Jungner framework to appraise the potential utility of a prenatal ZIKV screening programme, outline potential screening strategies within the case-finding pathway, and consider other epidemiological factors that may influence the planning of such a screening programme. Our evaluation of a potential prenatal ZIKV screening programme highlights factors affirming its usefulness, including the importance of Congenital Zika Syndrome as a public health problem and the existence of analogous congenital prenatal screening programmes for STORCH agents (syphilis, toxoplasmosis, others (eg, human immunodeficiency virus, varicella-zoster virus, parvovirus B19), rubella, cytomegalovirus, and herpes simplex virus). However, our assessment also reveals key barriers to implementation, such as the need for more accurate diagnostic tests, effective antiviral treatments, increased social service capacity, and surveillance. Given that the reemergence of ZIKV is likely, we provide a guiding framework for policymakers and public health leaders that can be further elaborated and adapted to different contexts in order to reduce the burden of adverse ZIKV-related birth outcomes during future outbreaks.
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http://dx.doi.org/10.1136/bmjgh-2021-005332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202108PMC
June 2021

COVID-19 in northeast Brazil: first year of the pandemic and uncertainties to come.

Rev Saude Publica 2021 2;55:35. Epub 2021 Jun 2.

Fundação Oswaldo Cruz. Centro de Integração de Dados e Conhecimentos para Saúde Instituto Gonçalo Moniz. Salvador, BA, Brasil.

Objective: To analyze the epidemic of COVID-19 in northeastern Brazil, one of the regions most affected by the virus.

Methods: The official data for COVID-19, from March 2020 to March 2021 in the states of the Northeast Region (NE), were used. The analysis of capital cities and states for accumulated weekly cases and confirmed deaths was made using the JoinPoint Trend Analysis application.

Results: In one year, the Northeast region reported 22.9% of the cases and 21.5% of the deaths in the country due to COVID-19. At the beginning of the pandemic, all states showed a growing number of cases, first in the capitals and then in the interior. Following this wave, decreases are observed in all states and their capitals, but with many still reporting a large number of cases. In the middle of the 2nd semester of 2020 the number of cases begins to increase again simultaneously in states and their capitals-some at explosive speed-especially in late 2020 and early 2021. A similar pattern is observed in deaths, which exceed or approach the peak seen in the first wave. In the first wave, all capitals and northeastern states adopted intense isolation measures. Fortaleza, Recife and Teresina reached the highest isolation index of all capitals, close to 0.60. This index decreases, with a slight growth trend until the end of December. With the exception of Fortaleza and Salvador, the other capitals fell to less than 0.40.

Conclusion: The Brazilian NE and the country are in increasingly complicated health, social and economic situations. It is necessary to speed up vaccinations and maintain non-pharmacological measures: face masks, social distancing measures and hygiene care, in addition to policies to protect workers who have lost their incomes and to subsidize small business owners.
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http://dx.doi.org/10.11606/s1518-8787.2021055003728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139846PMC
June 2021

Zika Brazilian Cohorts (ZBC) Consortium: Protocol for an Individual Participant Data Meta-Analysis of Congenital Zika Syndrome after Maternal Exposure during Pregnancy.

Viruses 2021 04 16;13(4). Epub 2021 Apr 16.

Faculdade de Ciências Médicas, Universidade de Pernambuco, Recife 50100-130, Brazil.

Despite great advances in our knowledge of the consequences of Zika virus to human health, many questions remain unanswered, and results are often inconsistent. The small sample size of individual studies has limited inference about the spectrum of congenital Zika manifestations and the prognosis of affected children. The Brazilian Zika Cohorts Consortium addresses these limitations by bringing together and harmonizing epidemiological data from a series of prospective cohort studies of pregnant women with rash and of children with microcephaly and/or other manifestations of congenital Zika. The objective is to estimate the absolute risk of congenital Zika manifestations and to characterize the full spectrum and natural history of the manifestations of congenital Zika in children with and without microcephaly. This protocol describes the assembly of the Consortium and protocol for the Individual Participant Data Meta-analyses (IPD Meta-analyses). The findings will address knowledge gaps and inform public policies related to Zika virus. The large harmonized dataset and joint analyses will facilitate more precise estimates of the absolute risk of congenital Zika manifestations among Zika virus-infected pregnancies and more complete descriptions of its full spectrum, including rare manifestations. It will enable sensitivity analyses using different definitions of exposure and outcomes, and the investigation of the sources of heterogeneity between studies and regions.
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http://dx.doi.org/10.3390/v13040687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072625PMC
April 2021

Prevalence of hepatitis A in the capitals of the States of North, Southeast and South regions of Brazil: decrease in prevalence and some consequences.

Rev Inst Med Trop Sao Paulo 2021 26;63:e34. Epub 2021 Apr 26.

Universidade de Pernambuco, Faculdade de Ciências Médicas, Recife, Pernambuco, Brazil.

Hepatitis A virus (HAV) infection has been considered one of the leading causes of acute hepatitis. The aim of the present study was to estimate the prevalence of HAV among children and adolescents in a population-based study in the capitals of the States of the North, Southeast and South of Brazil and identify predictive factors for the infection. A multi-stage sampling was used to select subjects aged between 5-9 and 10-19 years. Individual and household levels aside from the level of variables in the areas were collected. The outcome was the total IgG antibodies to HAV levels detected using a commercial Enzyme Immuno Assay (EIA). The associations between HAV and the independent variables were assessed using the odds ratio. A multilevel analysis was performed by GLLAMM using the Stata software. The prevalence of HAV infection in the 5-9 and 10-19 age groups was 28.7% and 67.5%, respectively for the North, 20.6% and 37.7%, for the Southeast and 18.9% and 34.5% for the South Region. The prevalence of HAV increased according to age in all sites. Variables related to education at the individual level (North and South), family and area level (South and Southeast) and family income level (Southeast and South) were independently associated with HAV infection. This emphasizes the need for individualized strategies to prevent the infection.
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http://dx.doi.org/10.1590/S1678-9946202163034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075615PMC
May 2021

[Covid-19 in the Northeast of Brazil: from lockdown to the relaxation of social distancing measures].

Cien Saude Colet 2021 Apr 9;26(4):1441-1456. Epub 2021 Jan 9.

Centro de Integração de Dados e Conhecimentos para Saúde, Instituto Gonçalo Moniz, Fiocruz Bahia. Salvador BA Brasil.

Even in the period when the Covid-19 pandemic was on the rise in the Northeast of Brazil, the relaxation of social distancing measures was introduced. The scope of the study is to assess, in the light of the epidemiological-sanitary situation in the region, the suitability of relaxation of social distancing measures. Based on the WHO guidelines for relaxation of social distancing, operational indicators were created and analyzed for each guideline in the context of the Northeast. To analyze the behavior of the epidemic, according to selected indicators, Joinpoint trend analysis techniques, heat maps, rate ratios and time trends between capitals and the state interior were compared. The weekly growth peak of the epidemic occurred in May-July 2020 (epidemiological weeks 19 to 31). In most capitals, there was no simultaneous downward trend in the number of cases and deaths in the 14 days prior to flexibilization. In all states the number of tests performed was insufficient. In epidemiological week 24, the state percentages of ICU/Covid-19 bed occupancy were close to or above 70%. The epidemiological situation of the nine Northeastern state capitals analyzed here did not meet criteria and parameters recommended by the World Health Organization for the relaxation of social distancing measures.
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http://dx.doi.org/10.1590/1413-81232021264.39422020DOI Listing
April 2021

Zika-related adverse outcomes in a cohort of pregnant women with rash in Pernambuco, Brazil.

PLoS Negl Trop Dis 2021 03 8;15(3):e0009216. Epub 2021 Mar 8.

Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom.

Background: While Zika virus (ZIKV) is now widely recognized as a teratogen, the frequency and full spectrum of adverse outcomes of congenital ZIKV infection remains incompletely understood.

Methods: Participants in the MERG cohort of pregnant women with rash, recruited from the surveillance system from December/2015-June/2017. Exposure definition was based on a combination of longitudinal data from molecular, serologic (IgM and IgG3) and plaque reduction neutralization tests for ZIKV. Children were evaluated by a team of clinical specialists and by transfontanelle ultrasound and were classified as having microcephaly and/or other signs/symptoms consistent with congenital Zika syndrome (CZS). Risks of adverse outcomes were quantified according to the relative evidence of a ZIKV infection in pregnancy.

Findings: 376 women had confirmed and suspected exposure to ZIKV. Among evaluable children born to these mothers, 20% presented with an adverse outcome compatible with exposure to ZIKV during pregnancy. The absolute risk of microcephaly was 2.9% (11/376), of calcifications and/or ventriculomegaly was 7.2% (13/180), of additional neurologic alterations was 5.3% (13/245), of ophthalmologic abnormalities was 7% (15/214), and of dysphagia was 1.8% (4/226). Less than 1% of the children experienced abnormalities across all of the domains simultaneously. Interpretation: Although approximately one-fifth of children with confirmed and suspected exposure to ZIKV in pregnancy presented with at least one abnormality compatible with CZS, the manifestations presented more frequently in isolation than in combination. Due to the rare nature of some outcomes and the possibility of later manifestations, large scale individual participant data meta-analysis and the long-term evaluation of children are imperative to identify the full spectrum of this syndrome and to plan actions to reduce damages.
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http://dx.doi.org/10.1371/journal.pntd.0009216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971861PMC
March 2021

The 1G/1G+1G/2G Genotypes of rs1799750 Are Associated with Higher Levels of MMP-1 and Are Both Associated with Lipodystrophy in People Living with HIV on Antiretroviral Therapy.

AIDS Res Hum Retroviruses 2021 05 22;37(5):399-406. Epub 2021 Mar 22.

Faculty of Medical Sciences (FCM), University of Pernambuco (UPE), Recife, Brazil.

In HIV-infected patients, antiretroviral therapy (ART) is associated to adipose tissue redistribution known as lipodystrophy (LD). This study aimed at verifying the association between the polymorphism of the gene (rs1799750) (1G/2G) and the serum levels of matrix metalloproteinase 1 (MMP-1) with LD and its subtypes in people living with HIV on ART. This is a cross-secional study. LD was self-reported. The determination of the rs1799750 gene polymorphism was performed by real-time PCR, and the serum concentrations of MMP-1 were quantified by the enzyme-linked immunosorbent assay (ELISA) method. Of 404 participants, 204 (51%) were diagnosed with LD, of whom 89 (43%) had mixed lipodystrophy (ML), 72 (35%) had lipohypertrophy (LH), and 43 (22%) had lipoatrophy (LA). There was an association between the genotypes 1G/1G+1G/2G and higher serum levels of MMP-1 ( = .025). There was no association of (1G/2G) with LD. Other factors associated with LD were current CD4 ≤ 350 [odds ratio (OR) = 4.85, confidence interval (CI) = 1.78-47.99,  = .0033] and serum MMP-1 levels >6.81 (OR = 2.67, CI = 1.21-6.08,  = .0165). Factors associated with ML: current CD4 ≤ 350 (OR = 5.59, CI = 1.69-20.39,  = .006); with LH: number of antiretroviral regimens used: 2 (OR = 2.06, CI = 1.01-4.20,  = .0460) and 3+ (OR = 2.09, CI = 1.00-4.35,  = .0477), and current CD4 ≤ 350 (OR = 2.08, CI = 1.00-4.24,  = .0461); and with LA: current viral load >40 (OR = 2.52, CI = 1.03-5.91,  = .0372) and current use of zidovudine (OR = 2.97, CI = 1.32-6.54,  = .0074). Higher levels of MMP-1 were associated with genotypes 1G/2G+1G/1G and with LD. Other individual risk factors were independently associated with LD, and its subtypes, suggesting that the pathogenesis itself is differently manifested for each type of LD.
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http://dx.doi.org/10.1089/AID.2020.0237DOI Listing
May 2021

The Prevalence of Adenoid Hypertrophy among Children with Zika Related Microcephaly.

Viruses 2021 Jan 5;13(1). Epub 2021 Jan 5.

Surgery Department, Federal University of Pernambuco, Recife 50670-901, Brazil.

Upper respiratory obstruction is a common sequela in children with Zika-related microcephaly (ZRM). As a cross-sectional analysis nested in a cohort study, this study aims to investigate the prevalence of adenoid hypertrophy (AH) in children with ZRM and symptoms of respiratory obstruction. The data were collected in the first three years of life from children with ZRM who were followed in two reference centers for otorhinolaryngological care of patients with congenital Zika syndrome. Out of 92 children with confirmed ZRM, 57 were evaluated by nasopharyngoscopy after presenting with upper respiratory obstruction symptoms. In this study, 31 of the 57 (54%) children with ZRM who were evaluated had obstructive AH. Thirteen children with obstructive AH were submitted to surgery, which resulted in the complete resolution of symptoms for 11, partial resolution in 1, and no improvement in 1. No evidence of direct involvement by Zika virus (ZIKV) infection in the adenoid tissues was demonstrated by histology or immunohistochemistry. Our results suggest that there is a high prevalence and early presentation of AH in children with ZRM, with consequent upper airway obstruction causing upper airway obstructive disorder, secretory otitis media, and dysphagia.
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http://dx.doi.org/10.3390/v13010062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824820PMC
January 2021

Protective effect of exclusive breastfeeding and effectiveness of maternal vaccination in reducing pertussis-like illness.

J Pediatr (Rio J) 2021 Sep-Oct;97(5):500-507. Epub 2021 Jan 16.

Universidade de Pernambuco, Pós-Graduação em Ciências da Saúde, Recife, PE, Brazil.

Objective: To assess the protective effect of exclusive breastfeeding and the effectiveness of maternal vaccination in reducing pertussis-like illness.

Method: This was a case-control study conducted in sentinel hospitals for pertussis in Recife between July 2016 and July 2018. Cases included children aged under six months with symptoms compatible with pertussis (pertussis-like illness). Controls included children aged under six months, living in the metropolitan region of Recife with no diagnosis of pertussis-like illness and matched by the same hospital and birth date.

Results: Seventy-three cases and 194 controls were included. The diagnosis of pertussis-like illness was predominantly clinical (97,2%). Amongst the main symptoms, paroxysmal cough was observed in 95.89% of cases and vomiting in 53.4%. There were 29 hospitalized cases and no deaths. Out of the 73 cases, 47 were born to mothers vaccinated against pertussis during pregnancy, and the mothers of 144 of the 194 controls had been vaccinated. The protective effect of breastfeeding was of 74% (95% CI;38%, 89%). Children younger than six months, who were exclusively breastfed and with mothers vaccinated against pertussis during pregnancy were 5 times less likely to develop pertussis-like illness, corresponding to a protection of 79% (95% CI;31%, 94%). The effectiveness of maternal vaccination against pertussis-like illness in children under six months was low (27%) and not statistically significant (CI 95%; -34% a 60%).

Conclusions: Exclusive breastfeeding protects children under six months from pertussis-like illness and may be enhanced when associated with maternal vaccination. These strategies should be encouraged because they also protect against pertussis-like illnesses.
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http://dx.doi.org/10.1016/j.jped.2020.10.018DOI Listing
January 2021

Endocrine Dysfunction in Children with Zika-Related Microcephaly Who Were Born during the 2015 Epidemic in the State of Pernambuco, Brazil.

Viruses 2020 12 22;13(1). Epub 2020 Dec 22.

Department of Tropical Medicine, Health Sciences Center, Federal University of Pernambuco, Recife 50670-901, Brazil.

Congenital viral infections and the occurrence of septo-optic dysplasia, which is a combination of optic nerve hypoplasia, abnormal formation of structures along the midline of the brain, and pituitary hypofunction, support the biological plausibility of endocrine dysfunction in Zika-related microcephaly. In this case series we ascertained the presence and describe endocrine dysfunction in 30 children with severe Zika-related microcephaly from the MERG Pediatric Cohort, referred for endocrinological evaluation between February and August 2019. Of the 30 children, 97% had severe microcephaly. The average age at the endocrinological consultation was 41 months and 53% were female. The most frequently observed endocrine dysfunctions comprised short stature, hypothyroidism, obesity and variants early puberty. These dysfunctions occurred alone 57% or in combination 43%. We found optic nerve hypoplasia (6/21) and corpus callosum hypoplasia (20/21). Seizure crises were reported in 86% of the children. The most common-and clinically important-endocrine dysfunctions were pubertal dysfunctions, thyroid disease, growth impairment, and obesity. These dysfunctions require careful monitoring and signal the need for endocrinological evaluation in children with Zika-related microcephaly, in order to make early diagnoses and implement appropriate treatment when necessary.
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http://dx.doi.org/10.3390/v13010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821916PMC
December 2020

The first hundred days of COVID-19 in Pernambuco State, Brazil: epidemiology in historical context.

Cad Saude Publica 2020;36(11):e00228220. Epub 2020 Dec 18.

Instituto Aggeu Magalhães, Fundação Oswaldo Cruz, Recife, Brasil.

The timeline of the COVID-19 pandemic began on December 31, 2019, in China, with SARS-CoV-2 identified as the etiological agent. This article aims to describe the COVID-19 epidemic's spatial and temporal dynamics in the first hundred days in the State of Pernambuco, Brazil. We present the evolution in cases and deaths according to epidemiological weeks. We analyzed the series of accumulated daily confirmed COVID-19 cases, with projections for the subsequent 15 days, using the JoinPoint app. This software allows identifying turning points, testing their statistical significance. We also analyze the trend in the spread of COVID-19 to the interior of the state, considering the percent distribution of cases in the state capital, Recife, municipalities in Greater Metropolitan Recife, and the state's interior, by sets of three weeks, constructing thematic maps. The first hundred days of the COVID-19 epidemic resulted in 52,213 cases and 4,235 deaths from March 12, or epidemiological week 11, until June 20, 2020 (epidemiological week 25). The peak in the epidemic curve occurred in epidemiological week 21 (May 23), followed by deceleration in the number of cases. We initially detected the spread of cases from the city center to the periphery of the state capital and Metropolitan Area, followed by rapid spread to the state's interior. There was a decrease in the mean daily growth starting in April, but with an average threshold of more than 6,000 weekly cases of COVID-19. At the end of the period, the state's case series indicates the persistence of SARS-CoV-2 circulation and community transmission. Finally, paraphrasing Gabriel Garcia Marques in One Hundred Years of Solitude, we ask whether we are facing "a pause in the storm or a sign of redoubled rain".
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http://dx.doi.org/10.1590/0102-311X00228220DOI Listing
December 2020

Zika virus infection in pregnancy: a protocol for the joint analysis of the prospective cohort studies of the ZIKAlliance, ZikaPLAN and ZIKAction consortia.

BMJ Open 2020 12 15;10(12):e035307. Epub 2020 Dec 15.

Centro Nacional de Enfermedades Tropicales, Santa Cruz de la Sierra, Santa Cruz de la Sierra, Bolivia.

Introduction: Zika virus (ZIKV) infection in pregnancy has been associated with microcephaly and severe neurological damage to the fetus. Our aim is to document the risks of adverse pregnancy and birth outcomes and the prevalence of laboratory markers of congenital infection in deliveries to women experiencing ZIKV infection during pregnancy, using data from European Commission-funded prospective cohort studies in 20 centres in 11 countries across Latin America and the Caribbean.

Methods And Analysis: We will carry out a centre-by-centre analysis of the risks of adverse pregnancy and birth outcomes, comparing women with confirmed and suspected ZIKV infection in pregnancy to those with no evidence of infection in pregnancy. We will document the proportion of deliveries in which laboratory markers of congenital infection were present. Finally, we will investigate the associations of trimester of maternal infection in pregnancy, presence or absence of maternal symptoms of acute ZIKV infection and previous flavivirus infections with adverse outcomes and with markers of congenital infection. Centre-specific estimates will be pooled using a two-stage approach.

Ethics And Dissemination: Ethical approval was obtained at each centre. Findings will be presented at international conferences and published in peer-reviewed open access journals and discussed with local public health officials and representatives of the national Ministries of Health, Pan American Health Organization and WHO involved with ZIKV prevention and control activities.
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http://dx.doi.org/10.1136/bmjopen-2019-035307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745317PMC
December 2020

Surgical findings in cryptorchidism in children with Zika-related microcephaly: a case series.

BMC Urol 2020 Nov 23;20(1):186. Epub 2020 Nov 23.

Universidade de Pernambuco, Rua Arnóbio Marques, 310 - Santo Amaro, Recife, PE, 50100-130, Brazil.

Background: Complications in the urinary tract related to congenital Zika syndrome have recently been reported. One complication, cryptorchidism, has been reported by the Microcephaly Epidemic Research Group/MERG, in Pernambuco/Brazil. The present article describes for the first time the surgical findings in a case series of boys with Zika-related microcephaly and cryptorchidism, who underwent surgical testicular exploration as a contribution to better understand the possible mechanisms involved in gonads formation and descent.

Methods: A total of 7 children (11 testicular units), aged 3 to 4 years, were submitted to inguinal or scrotal orchidopexy for the treatment of palpable cryptorchidism between August 2019 and January 2020. Characteristics of the gonads and its annexes related to appendixes, testis-epididymis dissociation, gubernacular insertion, and associated hydroceles and/or hernias were described. Measures in centimetres were taken for volume calculate.

Results: We found a low prevalence of testicular and epididymal appendix (66.7%), a high prevalence of testis-epididymis dissociation (55.6%), low mean testicular volume for their ages (lower for older boys) and ectopic gubernacular insertion in all cases. There was no evidence of associated hydroceles and/or hernias in any case. No surgical complication was registered or reported, and all explored gonads were properly placed in the scrotal sac.

Conclusions: We herein describe the surgical findings of these children's orchidopexies and discuss the possible mechanisms of viral action in embryogenesis and postnatal growth and development of the testes and annexes. These children need to be followed over time due to the higher risk of testicular atrophy and malignancy. Surgical timing seems to be relevant to avoid loss of testicular volume.
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http://dx.doi.org/10.1186/s12894-020-00721-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681962PMC
November 2020

COVID-19 in Northeast Brazil: achievements and limitations in the responses of the state governments.

Cien Saude Colet 2020 Oct 12;25(suppl 2):4099-4120. Epub 2020 Aug 12.

Centro de Integração de Dados e Conhecimentos para Saúde, Fundação Oswaldo Cruz (Fiocruz). Salvador BA Brasil.

The COVID-19 pandemic has been most severe in the poorest regions of Brazil, such as the states of the Northeast Region. The lack of national policies for pandemic control forced state and municipal authorities to implement public health measures. The aim of this study is to show the effect of these measures on the epidemic. The highest incidence of COVID-19 among the nine states in the Northeast was recorded in Sergipe, Paraíba and Ceará. Piauí, Paraíba and Ceará were the states that most tested. Factors associated with transmission included the high proportion of people in informal work. States with international airports played an important role in the entry of the virus and the initial spread, especially Ceará. All states applied social distancing measures, banned public events and closed schools. The response was a significant increase in social distancing, especially in Ceará and Pernambuco, a decline in the reproduction rate (Rt), and a separation of the curve of observed cases versus expected cases if the non-pharmacological interventions had not been implemented in all states. Poverty, inequality, and the high rates of informal work provide clues to the intensity of COVID-19 in the region. On the other hand, the measures taken early by the governments mitigated the effects of the pandemic.
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http://dx.doi.org/10.1590/1413-812320202510.2.28642020DOI Listing
October 2020

Neurological disease in adults with Zika and chikungunya virus infection in Northeast Brazil: a prospective observational study.

Lancet Neurol 2020 10 16;19(10):826-839. Epub 2020 Sep 16.

National Institute for Health Research Health Protection Research Unit on Emerging and Zoonotic Infections, Institute of Infection, Veterinary & Ecological Sciences, University of Liverpool, Liverpool, UK; The Walton Centre NHS Foundation Trust, Liverpool, UK; Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. Electronic address:

Background: Since 2015, the arthropod-borne viruses (arboviruses) Zika and chikungunya have spread across the Americas causing outbreaks, accompanied by increases in immune-mediated and infectious neurological disease. The spectrum of neurological manifestations linked to these viruses, and the importance of dual infection, are not known fully. We aimed to investigate whether neurological presentations differed according to the infecting arbovirus, and whether patients with dual infection had a different disease spectrum or severity.

Methods: We report a prospective observational study done during epidemics of Zika and chikungunya viruses in Recife, Pernambuco, a dengue-endemic area of Brazil. We recruited adults aged 18 years or older referred to Hospital da Restauração, a secondary-level and tertiary-level hospital, with suspected acute neurological disease and a history of suspected arboviral infection. We looked for evidence of Zika, chikungunya, or dengue infection by viral RNA or specific IgM antibodies in serum or CSF. We grouped patients according to their arbovirus laboratory diagnosis and then compared demographic and clinical characteristics.

Findings: Between Dec 4, 2014, and Dec 4, 2016, 1410 patients were admitted to the hospital neurology service; 201 (14%) had symptoms consistent with arbovirus infection and sufficient samples for diagnostic testing and were included in the study. The median age was 48 years (IQR 34-60), and 106 (53%) were women. 148 (74%) of 201 patients had laboratory evidence of arboviral infection. 98 (49%) of them had a single viral infection (41 [20%] had Zika, 55 [27%] had chikungunya, and two [1%] had dengue infection), whereas 50 (25%) had evidence of dual infection, mostly with Zika and chikungunya viruses (46 [23%] patients). Patients positive for arbovirus infection presented with a broad range of CNS and peripheral nervous system (PNS) disease. Chikungunya infection was more often associated with CNS disease (26 [47%] of 55 patients with chikungunya infection vs six [15%] of 41 with Zika infection; p=0·0008), especially myelitis (12 [22%] patients). Zika infection was more often associated with PNS disease (26 [63%] of 41 patients with Zika infection vs nine [16%] of 55 with chikungunya infection; p≤0·0001), particularly Guillain-Barré syndrome (25 [61%] patients). Patients with Guillain-Barré syndrome who had Zika and chikungunya dual infection had more aggressive disease, requiring intensive care support and longer hospital stays, than those with mono-infection (median 24 days [IQR 20-30] vs 17 days [10-20]; p=0·0028). Eight (17%) of 46 patients with Zika and chikungunya dual infection had a stroke or transient ischaemic attack, compared with five (6%) of 96 patients with Zika or chikungunya mono-infection (p=0·047).

Interpretation: There is a wide and overlapping spectrum of neurological manifestations caused by Zika or chikungunya mono-infection and by dual infections. The possible increased risk of acute cerebrovascular disease in patients with dual infection merits further investigation.

Funding: Fundação do Amparo a Ciência e Tecnologia de Pernambuco (FACEPE), EU's Horizon 2020 research and innovation programme, National Institute for Health Research.

Translations: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1474-4422(20)30232-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494308PMC
October 2020

Comparison of Oropharyngeal Dysphagia in Brazilian Children with Prenatal Exposure to Zika Virus, With and Without Microcephaly.

Dysphagia 2021 Aug 4;36(4):583-594. Epub 2020 Sep 4.

Faculdade de Ciência Médicas/Hospital Universitário Oswaldo Cruz/ Universidade de Pernambuco, Setor NIR- ZIKA, Rua Arnóbio Marques, no. 310, Santo Amaro, Recife, PE, CEP 50100-130, Brazil.

Severe brain damage associated with Zika-related microcephaly (ZRM) have been reported to result in oropharyngeal dysphagia (OPD); however, it is unknown if OPD presents in children with prenatal Zika virus (ZIKV) exposure but only mild or undetectable abnormalities. The aims of this study were: to compare the frequency and characteristics of OPD in children with ZRM and in children without microcephaly born to mothers who tested polymerase chain reaction positive (PCR+) for ZIKV during pregnancy; and to investigate the concordance of caregiver reports of OPD with the diagnosis from the clinical swallowing assessment (CSA). Between Mar/2017 and May/2018, we evaluated 116 children (n = 58 with microcephaly, n = 58 children without microcephaly born to ZIKV PCR + mothers) participating in the Microcephaly Epidemic Research Group (MERG) cohort of children born during the 2015-2016 ZIKV epidemic in Pernambuco, Brazil. To assess OPD we used: a CSA; a clinical assessment of the stomatognathic system; and a questionnaire administered to caregivers. The frequency of OPD was markedly higher in children with ZRM (79.3%) than in the exposed but normocephalic group (8.6%). The children with microcephaly also presented more frequently with anatomic and functional abnormalities in the stomatognathic system. There was a high degree of agreement between the caregiver reports of OPD and the CSA (κ = 0.92). In conclusion, our findings confirm that OPD is a feature of Congenital Zika Syndrome that primarily occurs in children with microcephaly and provide support for policies in which children are referred for rehabilitation with an OPD diagnosis based on caregiver report.
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http://dx.doi.org/10.1007/s00455-020-10173-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289769PMC
August 2021

The need for fast-track, high-quality and low-cost studies about the role of the BCG vaccine in the fight against COVID-19.

Respir Res 2020 Jul 11;21(1):178. Epub 2020 Jul 11.

Institute of Collective Health, Federal University of Bahia, Salvador, Brazil.

Bacillus Calmette-Guérin (BCG) vaccination is routine and near-universal in many low- and middle-income countries (LMIC). It has been suggested that BCG can have a protective effect on COVID-19 morbidity and mortality. This commentary discusses the limitations of the evidence around BCG and COVID-19. We argue that higher-quality evidence is necessary to understand the protective effect of the BCG vaccine from existing, secondary data, while we await results from clinical trials currently conducted in different settings.
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http://dx.doi.org/10.1186/s12931-020-01439-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351640PMC
July 2020

The frequency and clinical presentation of Zika virus coinfections: a systematic review.

BMJ Glob Health 2020 05;5(5)

Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK

Background: There is limited knowledge on the influence of concurrent coinfections on the clinical presentation of Zika virus (ZIKV) disease.

Methods: To better understand the types, frequencies and clinical manifestations of ZIKV coinfections, we did a systematic review of four databases (PubMed, Embase, Web of Science, LILACS) without restrictions for studies on ZIKV coinfections confirmed by nucleic acid (quantitative real-time-PCR) testing of ZIKV and coinfecting pathogens. The review aimed to identify cohort, cross-sectional, case series and case report studies that described frequencies and/or clinical signs and symptoms of ZIKV coinfections. Conference abstracts, reviews, commentaries and studies with imprecise pathogen diagnoses and/or no clinical evaluations were excluded.

Results: The search identified 34 articles from 10 countries, comprising 2 cohort, 10 cross-sectional, 8 case series and 14 case report studies. Coinfections were most frequently reported to have occurred with other arthropod-borne viruses (arboviruses); out of the 213 coinfections described, ZIKV infections co-occurred with chikungunya in 115 cases, with dengue in 68 cases and with both viruses in 19 cases. Other coinfecting agents included human immunodeficiency, Epstein-Barr, human herpes and Mayaro viruses, spp, and . ZIKV-coinfected cases primarily presented with mild clinical features, typical of ZIKV monoinfection; however, 9% of cases in cohort and cross-sectional studies were reported to experience complications.

Conclusion: Based on the evidence collated in this review, coinfections do not appear to strongly influence the clinical manifestations of uncomplicated ZIKV infections. Further research is needed to confirm whether risk of severe complications is altered when ZIKV infection co-occurs with other infections.

Prospero Registration Number: CRD42018111023.
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http://dx.doi.org/10.1136/bmjgh-2020-002350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228501PMC
May 2020

Cryptorchidism in Children with Zika-Related Microcephaly.

Am J Trop Med Hyg 2020 05;102(5):982-984

Universidade de Pernambuco, Recife, Brazil.

The genitourinary tract was recently identified as a potential site of complications related to the congenital Zika syndrome (CZS). We provide the first report of a series of cryptorchidism cases in 3-year-old children with Zika-related microcephaly who underwent consultations between October 2018 and April 2019 as part of the follow-up of the children cohort of the Microcephaly Epidemic Research Group, Pernambuco, Brazil. Of the 22 males examined, eight (36.4%) presented with cryptorchidism. Among 14 undescended testis cases, 11 (78.6%) could be palpated in the inguinal region. Seven of the eight children had severe microcephaly. Conventional risk factors for cryptorchidism were relatively infrequent in these children. We hypothesize that cryptorchidism is an additional manifestation of CZS present in children with severe microcephaly. As in our cases, for most of the children, the testes were located in the inguinal region, and the possible mechanisms for cryptorchidism were gubernaculum disturbance or cremasteric abnormality.
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http://dx.doi.org/10.4269/ajtmh.19-0753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204599PMC
May 2020

Early epilepsy in children with Zika-related microcephaly in a cohort in Recife, Brazil: Characteristics, electroencephalographic findings, and treatment response.

Epilepsia 2020 03 17;61(3):509-518. Epub 2020 Feb 17.

University of Pernambuco, Recife, Brazil.

Objective: To estimate the incidence of epilepsy in children with Zika-related microcephaly in the first 24 months of life; to characterize the associated clinical and electrographic findings; and to summarize the treatment responses.

Methods: We followed a cohort of children, born during the 2015-2016 Zika virus (ZIKV) epidemic in Brazil, with congenital microcephaly and evidence of congenital ZIKV infection on neuroimaging and/or laboratory testing. Neurological assessments were performed at ≤3, 6, 12, 15, 18, 21, and 24 months of life. Serial electroencephalograms were performed over the first 24 months.

Results: We evaluated 91 children, of whom 48 were female. In this study sample, the cumulative incidence of epilepsy was 71.4% in the first 24 months, and the main type of seizure was infantile spasms (83.1%). The highest incidence of seizures occurred between 3 and 9 months of age, and the risk remained high until 15 months of age. The incidence of infantile spasms peaked between 4 and 7 months and was followed by an increased incidence of focal epilepsy cases after 12 months of age. Neuroimaging results were available for all children, and 100% were abnormal. Cortical abnormalities were identified in 78.4% of the 74 children evaluated by computed tomography and 100% of the 53 children evaluated by magnetic resonance imaging. Overall, only 46.1% of the 65 children with epilepsy responded to treatment. The most commonly used medication was sodium valproate with or without benzodiazepines, levetiracetam, phenobarbital, and vigabatrin.

Significance: Zika-related microcephaly was associated with high risk of early epilepsy. Seizures typically began after the third month of life, usually as infantile spasms, with atypical electroencephalographic abnormalities. The seizure control rate was low. The onset of seizures in the second year was less frequent and, when it occurred, presented as focal epilepsy.
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http://dx.doi.org/10.1111/epi.16444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155083PMC
March 2020

Factors associated to modification of first-line antiretroviral therapy due to adverse events in people living with HIV/AIDS.

Braz J Infect Dis 2020 Jan - Feb;24(1):65-72. Epub 2019 Dec 10.

Universidade de Pernambuco, Programa de Pós-graduação em Ciências da Saúde, Recife, PE, Brazil.

Antiretroviral therapy (ART) has modified the outcome of patients with HIV infection, providing virological control and reducing mortality. However, there are several reasons as to why patients may discontinue their antiretroviral therapy, with adverse events being one of the main reasons reported in the literature. This is a case-control nested in a cohort of people living with HIV/AIDS, conducted to identify the incidence of ART modification due to adverse events and the associated factors, in two referral services in Recife, Brazil, between 2011 and 2014. Of the modifications occurred in the first year of ART, 25.7% were driven by adverse events. The median time elapsed between initiating ART and the first modification due to adverse events was 70.5 days (95% CI: 26-161 days). The main adverse events were dermatological, neuropsychiatric and gastrointestinal. Dermatological events were the earliest to appear after initiating ART. Efavirenz was the most prescribed and most modified drug during the study period. The group of participants who used zidovudine, lamivudine, and efavirenz had a 2-fold greater chance (adjusted OR: 2.16 95% CI: 1.28-3.65) of switching ART due to adverse events when compared to the group that used tenofovir with lamivudine and efavirenz.
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http://dx.doi.org/10.1016/j.bjid.2019.11.002DOI Listing
April 2020

Hepatotoxicity during TB treatment in people with HIV/AIDS related to NAT2 polymorphisms in Pernambuco, Northeast Brazil.

Ann Hepatol 2020 Mar - Apr;19(2):153-160. Epub 2019 Oct 24.

Laboratório de Virologia, Centro de Pesquisas Aggeu Magalhães/FIOCRUZ, Recife, PE, Brazil.

Introduction And Objective: Hepatotoxicity during tuberculosis (TB) treatment is frequent and may be related to the Arylamine N-Acetyltransferase (NAT2) acetylator profile, in which allele frequencies differ according to the population. The aim of this study was to investigate functional polymorphisms in NAT2 associated with the development of hepatotoxicity after initiating treatment for TB in people living with HIV/AIDS (PLWHA) in Pernambuco, Northeast Brazil.

Material And Methods: This was a prospective cohort study that investigated seven single nucleotide polymorphisms located in the NAT2 coding region in 173 PLWHA undergoing TB treatment. Hepatotoxicity was defined as elevated aminotransferase levels and identified as being three times higher than it was before initiating TB treatment, with associated symptoms of hepatitis. A further 80 healthy subjects, without HIV infection or TB were used as a control group. All individuals were genotyped by direct sequencing.

Results: The NAT2*13A and NAT2*6B variant alleles were significantly associated with the development of hepatotoxicity during TB treatment in PLWHA (p<0.05). Individual comparisons between the wild type and each variant genotype revealed that PLWHA with signatures NAT2*13A/NAT2*13A (OR 4.4; CI95% 1.1-18.8; p 0.037) and NAT2*13A/NAT2*6B (OR 4.4; CI95% 1.5-12.7; p 0.005) significantly increased the risk of hepatotoxicity.

Conclusion: This study suggests that NAT2*13A and NAT2*6B variant alleles are risk factors for developing hepatotoxicity, and PLWHA with genotypes NAT2*13A/NAT2*13A and NAT2*13A/NAT2*6B should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis.
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http://dx.doi.org/10.1016/j.aohep.2019.09.008DOI Listing
February 2021

ZikaPLAN: addressing the knowledge gaps and working towards a research preparedness network in the Americas.

Glob Health Action 2019 ;12(1):1666566

Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla , CA , USA.

Zika Preparedness Latin American Network (ZikaPLAN) is a research consortium funded by the European Commission to address the research gaps in combating Zika and to establish a sustainable network with research capacity building in the Americas. Here we present a report on ZikaPLAN`s mid-term achievements since its initiation in October 2016 to June 2019, illustrating the research objectives of the 15 work packages ranging from virology, diagnostics, entomology and vector control, modelling to clinical cohort studies in pregnant women and neonates, as well as studies on the neurological complications of Zika infections in adolescents and adults. For example, the Neuroviruses Emerging in the Americas Study (NEAS) has set up more than 10 clinical sites in Colombia. Through the Butantan Phase 3 dengue vaccine trial, we have access to samples of 17,000 subjects in 14 different geographic locations in Brazil. To address the lack of access to clinical samples for diagnostic evaluation, ZikaPLAN set up a network of quality sites with access to well-characterized clinical specimens and capacity for independent evaluations. The International Committee for Congenital Anomaly Surveillance Tools was formed with global representation from regional networks conducting birth defects surveillance. We have collated a comprehensive inventory of resources and tools for birth defects surveillance, and developed an App for low resource regions facilitating the coding and description of all major externally visible congenital anomalies including congenital Zika syndrome. Research Capacity Network (REDe) is a shared and open resource centre where researchers and health workers can access tools, resources and support, enabling better and more research in the region. Addressing the gap in research capacity in LMICs is pivotal in ensuring broad-based systems to be prepared for the next outbreak. Our shared and open research space through REDe will be used to maximize the transfer of research into practice by summarizing the research output and by hosting the tools, resources, guidance and recommendations generated by these studies. Leveraging on the research from this consortium, we are working towards a research preparedness network.
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http://dx.doi.org/10.1080/16549716.2019.1666566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818126PMC
March 2020

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

PLoS Negl Trop Dis 2019 10 7;13(10):e0007763. Epub 2019 Oct 7.

Instituto Aggeu Magalhães, Fundação Oswaldo Cruz, Recife, PE, Brasil.

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.
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http://dx.doi.org/10.1371/journal.pntd.0007763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797234PMC
October 2019

International prospective observational cohort study of Zika in infants and pregnancy (ZIP study): study protocol.

BMC Pregnancy Childbirth 2019 Aug 7;19(1):282. Epub 2019 Aug 7.

Maternal-Infant Studies Center (CEMI), San Juan, Puerto Rico.

Background: Until recently, Zika virus (ZIKV) infections were considered mild and self-limiting. Since 2015, they have been associated with an increase in microcephaly and other birth defects in newborns. While this association has been observed in case reports and epidemiological studies, the nature and extent of the relationship between ZIKV and adverse pregnancy and pediatric health outcomes is not well understood. With the unique opportunity to prospectively explore the full spectrum of issues related to ZIKV exposure during pregnancy, we undertook a multi-country, prospective cohort study to evaluate the association between ZIKV and pregnancy, neonatal, and infant outcomes.

Methods: At research sites in ZIKV endemic regions of Brazil (4 sites), Colombia, Guatemala, Nicaragua, Puerto Rico (2 sites), and Peru, up to 10,000 pregnant women will be recruited and consented in the first and early second trimesters of pregnancy and then followed through delivery up to 6 weeks post-partum; their infants will be followed until at least 1 year of age. Pregnant women with symptomatic ZIKV infection confirmed by presence of ZIKV RNA and/or IgM for ZIKV will also be enrolled, regardless of gestational age. Participants will be tested monthly for ZIKV infection; additional demographic, physical, laboratory and environmental data will be collected to assess the potential interaction of these variables with ZIKV infection. Delivery outcomes and detailed infant assessments, including physical and neurological outcomes, will be obtained.

Discussion: With the emergence of ZIKV in the Americas and its association with adverse pregnancy outcomes in this region, a much better understanding of the spectrum of clinical outcomes associated with exposure to ZIKV during pregnancy is needed. This cohort study will provide information about maternal, fetal, and infant outcomes related to ZIKV infection, including congenital ZIKV syndrome, and manifestations that are not detectable at birth but may appear during the first year of life. In addition, the flexibility of the study design has provided an opportunity to modify study parameters in real time to provide rigorous research data to answer the most critical questions about the impact of congenital ZIKV exposure.

Trial Registration: NCT02856984 . Registered August 5, 2016. Retrospectively registered.
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http://dx.doi.org/10.1186/s12884-019-2430-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686399PMC
August 2019

Understanding the relation between Zika virus infection during pregnancy and adverse fetal, infant and child outcomes: a protocol for a systematic review and individual participant data meta-analysis of longitudinal studies of pregnant women and their infants and children.

BMJ Open 2019 06 18;9(6):e026092. Epub 2019 Jun 18.

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

Introduction: Zika virus (ZIKV) infection during pregnancy is a known cause of microcephaly and other congenital and developmental anomalies. In the absence of a ZIKV vaccine or prophylactics, principal investigators (PIs) and international leaders in ZIKV research have formed the ZIKV Individual Participant Data (IPD) Consortium to identify, collect and synthesise IPD from longitudinal studies of pregnant women that measure ZIKV infection during pregnancy and fetal, infant or child outcomes.

Methods And Analysis: We will identify eligible studies through the ZIKV IPD Consortium membership and a systematic review and invite study PIs to participate in the IPD meta-analysis (IPD-MA). We will use the combined dataset to estimate the relative and absolute risk of congenital Zika syndrome (CZS), including microcephaly and late symptomatic congenital infections; identify and explore sources of heterogeneity in those estimates and develop and validate a risk prediction model to identify the pregnancies at the highest risk of CZS or adverse developmental outcomes. The variable accuracy of diagnostic assays and differences in exposure and outcome definitions means that included studies will have a higher level of systematic variability, a component of measurement error, than an IPD-MA of studies of an established pathogen. We will use expert testimony, existing internal and external diagnostic accuracy validation studies and laboratory external quality assessments to inform the distribution of measurement error in our models. We will apply both Bayesian and frequentist methods to directly account for these and other sources of uncertainty.

Ethics And Dissemination: The IPD-MA was deemed exempt from ethical review. We will convene a group of patient advocates to evaluate the ethical implications and utility of the risk stratification tool. Findings from these analyses will be shared via national and international conferences and through publication in open access, peer-reviewed journals.

Trial Registration Number: PROSPERO International prospective register of systematic reviews (CRD42017068915).
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http://dx.doi.org/10.1136/bmjopen-2018-026092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588966PMC
June 2019

Perinatal analyses of Zika- and dengue virus-specific neutralizing antibodies: A microcephaly case-control study in an area of high dengue endemicity in Brazil.

PLoS Negl Trop Dis 2019 03 11;13(3):e0007246. Epub 2019 Mar 11.

Aggeu Magalhães Institute, Oswaldo Cruz Foundation (FIOCRUZ), Recife, Pernambuco, Brazil.

Laboratory confirmation of Zika virus (ZIKV) infection during pregnancy is challenging due to cross-reactivity with dengue virus (DENV) and limited knowledge about the kinetics of anti-Zika antibody responses during pregnancy. We described ZIKV and DENV serological markers and the maternal-fetal transfer of antibodies among mothers and neonates after the ZIKV microcephaly outbreak in Northeast Brazil (2016). We included 89 microcephaly cases and 173 neonate controls at time of birth and their mothers. Microcephaly cases were defined as newborns with a particular head circumference (2 SD below the mean). Two controls without microcephaly were matched by the expected date of delivery and area of residence. We tested maternal serum for recent (ZIKV genome, IgM and IgG3 anti-NS1) and previous (ZIKV and DENV neutralizing antibodies [NAbs]) markers of infection. Multiple markers of recent or previous ZIKV and DENV infection in mothers were analyzed using principal component analysis (PCA). At delivery, 5.6% of microcephaly case mothers and 1.7% of control mothers were positive for ZIKV IgM. Positivity for ZIKV IgG3 anti-NS1 was 8.0% for case mothers and 3.5% for control mothers. ZIKV NAbs was slightly higher among mothers of cases (69.6%) than that of mothers of controls (57.2%; p = 0.054). DENV exposure was detected in 85.8% of all mothers. PCA discriminated two distinct components related to recent or previous ZIKV infection and DENV exposure. ZIKV NAbs were higher in newborns than in their corresponding mothers (p<0.001). We detected a high frequency of ZIKV exposure among mothers after the first wave of the ZIKV outbreak in Northeast Brazil. However, we found low sensitivity of the serological markers to recent infection (IgM and IgG3 anti-NS1) in perinatal samples of mothers of microcephaly cases. Since the neutralization test cannot precisely determine the time of infection, testing for ZIKV immune status should be performed as early as possible and throughout pregnancy to monitor acute Zika infection in endemic areas.
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http://dx.doi.org/10.1371/journal.pntd.0007246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428350PMC
March 2019

The cost of a disease targeted for elimination in Brazil: the case of schistosomiasis mansoni.

Mem Inst Oswaldo Cruz 2019 Jan 14;114:e180347. Epub 2019 Jan 14.

Universidade de Brasília, Núcleo de Medicina Tropical, Brasília, DF, Brasil.

Background: Schistosomiasis mansoni is a poverty-related parasitic infection that has a variety of clinical manifestations. We consider the disability and deaths caused by schistosomiasis unacceptable for a tool-ready disease. Its condition in Brazil warrants an analysis that will enable better understanding of the local health losses and contribute to the complex decision-making process.

Objective: This study estimates the cost of schistosomiasis in Brazil in 2015.

Methods: We conducted a cost of illness study of schistosomiasis mansoni in Brazil in 2015 based on a prevalence approach and from a societal perspective. The study included 26,499 schistosomiasis carriers, 397 hepatosplenic cases, 48 cases with the neurological form, 284 hospitalisations, and 11,368.26 years of life lost (YLL) of which 5,187 years are attributable to economically active age groups.

Results: The total cost of schistosomiasis mansoni in Brazil was estimated to be US$ 41,7million in 2015 with 94.61% of this being indirect costs.

Conclusions: The economic burden of schistosomiasis mansoni in Brazil is high and results in the loss of productivity. Its persistence in Brazil is a challenge to public health and requires inter-sectorial interventions in areas such as indoor water supply, basic sanitation, and education.
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http://dx.doi.org/10.1590/0074-02760180347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340134PMC
January 2019
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