Clinical spectrum of congenital Zika virus infection in Brazil: Update and issues for research development.

This review aimed to provide an update on the morphological and/or functional abnormalities related to congenital Zika virus (ZIKV) infection, based on primary data from studies conducted in Brazil since 2015. During the epidemic years (2015-2016), case series and pediatric cohort studies described several birth defects, including severe and/or disproportionate microcephaly, cranial bone overlap, skull collapse, congenital contractures (arthrogryposis and/or clubfoot), and visual and hearing abnormalities, as part of the spectrum of Congenital Zika Syndrome (CZS). Brain imaging abnormalities, mainly cortical atrophy, ventriculomegaly, and calcifications, serve as structural markers of CZS severity. Most case series and cohorts of microcephaly have reported the co-occurrence of epilepsy, dysphagia, orthopedic deformities, motor function impairment, cerebral palsy, and urological impairment. A previous large meta-analysis conducted in Brazil revealed that a confirmed ZIKV infection during pregnancy was associated with a 4% risk of microcephaly. Additionally, one-third of children showed at least one abnormality, predominantly identified in isolation. Studies examining antenatally ZIKV-exposed children without detectable abnormalities at birth reported conflicting neurodevelopmental results. Therefore, long-term follow-up studies involving pediatric cohorts with appropriate control groups are needed to address this knowledge gap. We recognize the crucial role of a national network of scientists collaborating with international research institutions in understanding the lifelong consequences of congenital ZIKV infection. Additionally, we highlight the need to provide sustainable resources for research and development to reduce the risk of future Zika outbreaks.

Clinical spectrum of congenital Zika virus infection in Brazil: Update and issues for research development

ABSTRACT This review aimed to provide an update on the morphological and/or functional abnormalities related to congenital Zika virus (ZIKV) infection, based on primary data from studies conducted in Brazil since 2015. During the epidemic years (2015-2016), case series and pediatric cohort studies described several birth defects, including severe and/or disproportionate microcephaly, cranial bone overlap, skull collapse, congenital contractures (arthrogryposis and/or clubfoot), and visual and hearing abnormalities, as part of the spectrum of Congenital Zika Syndrome (CZS). Brain imaging abnormalities, mainly cortical atrophy, ventriculomegaly, and calcifications, serve as structural markers of CZS severity. Most case series and cohorts of microcephaly have reported the co-occurrence of epilepsy, dysphagia, orthopedic deformities, motor function impairment, cerebral palsy, and urological impairment. A previous large meta-analysis conducted in Brazil revealed that a confirmed ZIKV infection during pregnancy was associated with a 4% risk of microcephaly. Additionally, one-third of children showed at least one abnormality, predominantly identified in isolation. Studies examining antenatally ZIKV-exposed children without detectable abnormalities at birth reported conflicting neurodevelopmental results. Therefore, long-term follow-up studies involving pediatric cohorts with appropriate control groups are needed to address this knowledge gap. We recognize the crucial role of a national network of scientists collaborating with international research institutions in understanding the lifelong consequences of congenital ZIKV infection. Additionally, we highlight the need to provide sustainable resources for research and development to reduce the risk of future Zika outbreaks.

Risk of adverse pregnancy and infant outcomes associated with prenatal Zika virus infection: a post-epidemic cohort in Central-West Brazil.

This study aimed to estimate the risks of adverse infant outcomes in the first year of life related to prenatal Zika virus (ZIKV) exposure. A prospective cohort of pregnant women with rash was recruited in Central-West Brazil in a post-epidemic period (January 2017 to April 2019). We evaluated participants' medical histories and performed ZIKV diagnostic testing using molecular (reverse transcription polymerase chain reaction [RT-PCR]) and serologic (immunoglobulin [Ig]M and plaque reduction neutralization tests [PRNT90]) assays. The ZIKV-positive group included both RT-PCR-confirmed cases as well as IgM and/or PRNT90-positive probable cases. Children were evaluated at birth and in the first 12 months of life. Transfontanellar ultrasound, central nervous system computed tomography, eye fundoscopy and retinography were performed. We estimated the absolute risk and 95% confidence interval (95% CI) of adverse infant outcomes among confirmed prenatally ZIKV-exposed children. Among 81 pregnant women with rash, 43 (53.1%) were ZIKV infected. The absolute risk of microcephaly among offspring of ZIKV-infected pregnant women was 7.0% (95% CI: 1.5-19.1), including the two cases of microcephaly detected prenatally and one detected postnatally. In total, 54.5% (95% CI: 39.8-68.7) of children in the ZIKV-exposed group had at least one ophthalmic abnormality, with the most frequent abnormalities being focal pigmentary mottling and chorioretinal atrophy or scarring. Our findings reinforce the importance of long-term monitoring of prenatally ZIKV-exposed children born apparently asymptomatic for Congenital Zika Syndrome.

Risk of adverse outcomes in offspring with RT-PCR confirmed prenatal Zika virus exposure: An individual participant data meta-analysis of 13 cohorts in the Zika Brazilian Cohorts Consortium.

Background: Knowledge regarding the risks associated with Zika virus (ZIKV) infections in pregnancy has relied on individual studies with relatively small sample sizes and variable risk estimates of adverse outcomes, or on surveillance or routinely collected data. Using data from the Zika Brazilian Cohorts Consortium, this study aims, to estimate the risk of adverse outcomes among offspring of women with RT-PCR-confirmed ZIKV infection during pregnancy and to explore heterogeneity between studies. Methods: We performed an individual participant data meta-analysis of the offspring of 1548 pregnant women from 13 studies, using one and two-stage meta-analyses to estimate the absolute risks. Findings: Of the 1548 ZIKV-exposed pregnancies, the risk of miscarriage was 0.9%, while the risk of stillbirth was 0.3%. Among the pregnancies with liveborn children, the risk of prematurity was 10,5%, the risk of low birth weight was 7.7, and the risk of small for gestational age (SGA) was 16.2%. For other abnormalities, the absolute risks were: 2.6% for microcephaly at birth or first evaluation, 4.0% for microcephaly at any time during follow-up, 7.9% for neuroimaging abnormalities, 18.7% for functional neurological abnormalities, 4.0% for ophthalmic abnormalities, 6.4% for auditory abnormalities, 0.6% for arthrogryposis, and 1.5% for dysphagia. This risk was similar in all sites studied and in different socioeconomic conditions, indicating that there are not likely to be other factors modifying this association. Interpretation: This study based on prospectively collected data generates the most robust evidence to date on the risks of congenital ZIKV infections over the early life course. Overall, approximately one-third of liveborn children with prenatal ZIKV exposure presented with at least one abnormality compatible with congenital infection, while the risk to present with at least two abnormalities in combination was less than 1.0%.

Socioeconomic disparities associated with symptomatic Zika virus infections in pregnancy and congenital microcephaly: A spatiotemporal analysis from Goiânia, Brazil (2016 to 2020).

The Zika virus (ZIKV) epidemic, which was followed by an unprecedented outbreak of congenital microcephaly, emerged in Brazil unevenly, with apparent pockets of susceptibility. The present study aimed to detect high-risk areas for ZIKV infection and microcephaly in Goiania, a large city of 1.5 million inhabitants in Central-West Brazil. Using geocoded surveillance data from the Brazilian Information System for Notifiable Diseases (SINAN) and from the Public Health Event Registry (RESP-microcefalia), we analyzed the spatiotemporal distribution and socioeconomic indicators of laboratory confirmed (RT-PCR and/or anti-ZIKV IgM ELISA) symptomatic ZIKV infections among pregnant women and clinically confirmed microcephaly in neonates, from 2016 to 2020. We investigated temporal patterns by estimating the risk of symptomatic maternal ZIKV infections and microcephaly per 1000 live births per month. We examined the spatial distribution of maternal ZIKV infections and microcephaly cases across the 63 subdistricts of Goiania by manually plotting the geographical coordinates. We used spatial scan statistics estimated by discrete Poisson models to detect high clusters of maternal ZIKV infection and microcephaly and compared the distributions by socioeconomic indicators measured at the subdistrict level. In total, 382 lab-confirmed cases of maternal ZIKV infections, and 31 cases of microcephaly were registered in the city of Goiania. More than 90% of maternal cases were reported between 2016 and 2017. The highest incidence of ZIKV cases among pregnant women occurred between February and April 2016. A similar pattern was observed in the following year, although with a lower number of cases, indicating seasonality for ZIKV infection, during the local rainy season. Most congenital microcephaly cases occurred with a time-lag of 6 to 7 months after the peak of maternal ZIKV infection. The highest estimated incidence of maternal ZIKV infections and microcephaly were 39.3 and 2.5 cases per 1000 livebirths, respectively. Districts with better socioeconomic indicators and with higher proportions of self-identified white inhabitants were associated with lower risks of maternal ZIKV infection. Overall, the findings indicate heterogeneity in the spatiotemporal patterns of maternal ZIKV infections and microcephaly, which were correlated with seasonality and included a high-risk geographic cluster. Our findings identified geographically and socio-economically underprivileged groups that would benefit from targeted interventions to reduce exposure to vector-borne infections.

Clinical practice in COVID-19: The most frequently asked questions to infectious diseases specialists.

Since the emergence of the disease caused by the severe respiratory syndrome coronavirus 2 (SARS-CoV-2) - COVID-19 - in late December 2019, a vast number of publications on the subject appeared in peer-reviewed journals and preprints. Despite the significant amount of available information, infectious disease physicians are requested to solve questions from colleagues, patients, and relatives on a daily basis. Here, we aim to describe the evidence supporting the answers for frequently asked questions, based on a literature review. We created a web-based questionnaire which was distributed to a group of 70 infectious disease specialists and medical residents, asking what questions and issues they most frequently faced. The 10 most frequent questions guided the topics for a narrative review. We provide evidence and consensus-based information on subjects such as infection and transmission, isolation, management of COVID-19 confirmed cases, reinfection, clinical-therapeutic management, vaccination, and antibodies post-infection/vaccination. Correctly clarifying doubts and providing clear information to physicians, patients, and family members helps to better manage COVID-19 in the community and the hospital settings.

Zika virus infection and microcephaly: spatial analysis and socio-environmental determinants in a region of high Aedes aegypti infestation in the Central-West Region of Brazil.

BACKGROUND: More than 5 years after the Zika virus (ZIKV) epidemic, Zika infection remains a major concern in regions with high Aedes infestation. The objectives of this study were (i) to identify clusters of ZIKV infection and microcephaly, and/or central nervous system (CNS) alterations associated with congenital infection during the epidemic peak in 2016 and subsequently, in 2017 and 2018; (ii) to measure the non-spatial correlation between ZIKV infection and microcephaly and/or CNS alterations associated with congenital infection; and (iii) to analyse the sociodemographic/economic, health, and environmental determinants associated with the incidence of ZIKV in a region of high infestation by Aedes aegypti in the Central-West Region of Brazil. METHODS: This ecological study analysed 246 municipalities in the state of Goiás (6.9 million inhabitants). The data were obtained from the Information System for Notifiable Diseases (ZIKV cases) and the Public Health Event Registry (microcephaly and/or CNS alterations associated with congenital infection). Incidence rates and prevalence of ZIKA infection were smoothed by an empirical Bayesian estimator (LEbayes), producing the local empirical Bayesian rate (LEBR). In the spatial analysis, ZIKV infection and microcephaly cases were georeferenced by the municipality of residence for 2016 and grouped for 2017 and 2018. Global Moran's I and the Hot Spot Analysis tool (Getis-Ord Gi* statistics) were used to analyse the spatial autocorrelation and clusters of ZIKV infection and microcephaly, respectively. A generalised linear model from the Poisson family was used to assess the association between ecological determinants and the smoothing incidence rate of ZIKV infection. RESULTS: A total of 9892 cases of acute ZIKV infection and 121 cases of microcephaly were confirmed. The mean LEBR of the ZIKV infection in the 246 municipalities was 22.3 cases/100,000 inhabitants in 2016, and 10.3 cases/100,000 inhabitants in 2017 and 2018. The LEBR of the prevalence rate of microcephaly and/or CNS alterations associated with congenital infection was 7 cases/10,000 live births in 2016 and 2 cases/10,000 live births during 2017-2018. Hotspots of ZIKV infection and microcephaly cases were identified in the capital and neighbouring municipalities in 2016, with new clusters in the following years. In a multiple regression Poisson analysis, ZIKV infection was associated with higher population density, the incidence of dengue, Aedes larvae infestation index, and average rainfall. The important determinant of ZIKV infection incidence reduction was the increase in households attended by endemic disease control agents. CONCLUSIONS: Our analyses were able to capture, in a more granular way, aspects that make it possible to inform public managers of the sentinel areas identified in the post-epidemic hotspots.

Reviewing the therapeutic management of leprosy in primary care: demand case series referred to a University Hospital in the Midwest region of Brazil

Abstract Background: Leprosy still represents a negleted public health problem in Brazil. Early and adequate treatment of leprosy, carried out in a primary health network is essential to reduce morbidity and sequelae. Objective: To analyze the therapeutic management of leprosy patients referred from primary healthy services to a specialized service. Methods: An analytical retrospective study using medical records and the Notifiable Diseases Information System. Patients diagnosed with leprosy, referred to a specialized outpatient clinic, between 2016 and 2017, in Goiás state, were included. The treatment carried out in the primary health services was compared to the Ministry of Health guidelines. Results: Two-hundred twenty-five leprosy patients were included, of whom 33.3% were referred by leprosy reactions, 27.1% by sequelae, and 10.2% by suspected recurrence or reinfection. Reviewing the therapeutic management, 123 (54.7%) were considered inadequate, 92 (40.9%) adequate, and 10 (4.4%) inconclusive. Of the 200 multibacillary patients, 39.5% had adequate management. In contrast, 12 (85.1%) out of 14 paucibacillary patients had adequate management (χ2= 11.43 and p < 0.001). Regarding the leprosy reactions and sequelae management, 56.9% and 19.5% were considered inadequate, respectively. There was no difference between the percentage of adequate or inadequate management when considering the Goiás health macroregions (χ2= 7.23; 4 degrees of freedom; p = 0.12). Study limitations: Use of recorded data, with incomplete medical records and lack of patient follow-up. Conclusions: The study demonstrated the equivocal multibacillaryleprosy management conducted in healthy primary care, with an emphasis on leprosy reactions and sequelae. Training and monitoring the medical staff in the primary healthy services could reduce the morbidity and sequelae of leprosy.

Reviewing the therapeutic management of leprosy in primary care: demand case series referred to a University Hospital in the Midwest region of Brazil.

BACKGROUND: Leprosy still represents a negleted public health problem in Brazil. Early and adequate treatment of leprosy, carried out in a primary health network is essential to reduce morbidity and sequelae. OBJECTIVE: To analyze the therapeutic management of leprosy patients referred from primary healthy services to a specialized service. METHODS: An analytical retrospective study using medical records and the Notifiable Diseases Information System. Patients diagnosed with leprosy, referred to a specialized outpatient clinic, between 2016 and 2017, in Goiás state, were included. The treatment carried out in the primary health services was compared to the Ministry of Health guidelines. RESULTS: Two-hundred twenty-five leprosy patients were included, of whom 33.3% were referred by leprosy reactions, 27.1% by sequelae, and 10.2% by suspected recurrence or reinfection. Reviewing the therapeutic management, 123 (54.7%) were considered inadequate, 92 (40.9%) adequate, and 10 (4.4%) inconclusive. Of the 200 multibacillary patients, 39.5% had adequate management. In contrast, 12 (85.1%) out of 14 paucibacillary patients had adequate management (χ2 = 11.43 and p < 0.001). Regarding the leprosy reactions and sequelae management, 56.9% and 19.5% were considered inadequate, respectively. There was no difference between the percentage of adequate or inadequate management when considering the Goiás health macroregions (χ2 = 7.23; 4 degrees of freedom; p = 0.12). STUDY LIMITATIONS: Use of recorded data, with incomplete medical records and lack of patient follow-up. CONCLUSIONS: The study demonstrated the equivocal multibacillaryleprosy management conducted in healthy primary care, with an emphasis on leprosy reactions and sequelae. Training and monitoring the medical staff in the primary healthy services could reduce the morbidity and sequelae of leprosy.

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

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.

Temporal trend and spatial distribution of syphilis in pregnancy and congenital syphilis in Goiás, Brazil, 2007-2017: an ecological study. / Tendência temporal e distribuição espacial da sífilis gestacional e congênita em Goiás, 2007-2017: um estudo ecológico.

OBJECTIVE: To analyze temporal trend and spatial distribution of syphilis in pregnancy and congenital syphilis in Goiás State, Brazil, between 2007 and 2017. METHODS: This was an ecological time series and spatial distribution study with data obtained from the Notifiable Health Conditions Information System. Prais-Winsten Regression was used to analyze indicator trends by health macro-region. Descriptive spatial analysis was performed to verify case distribution in three different years in the period. RESULTS: Between 2007 and 2017, 7,679 cases of syphilis in pregnancy and 1,554 congenital syphilis cases were reported. A rising trend was found in the rates of syphilis in pregnancy (annual percent change [APC] = 18.0 - 95% confidence interval [95%CI] 15.3;20.8) as well as in congenital syphilis rates (APC=16.8 - 95%CI 20.1;33.8); and a 326% increase in the number of municipalities with a congenital syphilis incidence rate >0.5/1,000 live births. CONCLUSION: Growth in syphilis in pregnancy and congenital syphilis detection rates was identified, as was growth in the number of municipalities reporting cases.

AIDS-related progressive multifocal leukoencephalopathy

Abstract INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of JC virus (JCV). METHODS: We described the profile of laboratory-confirmed PML cases among AIDS patients. RESULTS: A total of 43 HIV patients with clinical conditions compatible with PML were obtained; 5 cases were confirmed by JCV testing. The main clinical finding was mental confusion. Median CD4 count was 54 cells/mm³. CONCLUSIONS: Three of the five confirmed PML cases died; the time between diagnosis and death was 2, 5, and 6 months. It is important to consider JCV infection as a differential diagnosis.

Tendência temporal e distribuição espacial da sífilis gestacional e congênita em Goiás, 2007-2017: um estudo ecológico / Tendencia temporal y distribución espacial de la sífilis gestacional y congénita en Goiás, Brasil, 2007-2017: un estudio ecológico / Temporal trend and spatial distribution of syphilis in pregnancy and congenital syphilis in Goiás, Brazil, 2007-2017: an ecological study

Objetivo: Analisar a tendência temporal e a distribuição espacial de sífilis gestacional (SG) e sífilis congênita (SC) em Goiás, Brasil, no período 2007-2017. Métodos: Estudo ecológico de série temporal com dados do Sistema de Informação de Agravos de Notificação. Utilizou-se a regressão de Prais-Winsten para analisar a tendência dos indicadores, por macrorregião de saúde. Realizou-se análise espacial descritiva para verificar a distribuição espacial dos casos, em três anos da série. Resultados: Foram registrados 7.679 casos de SG e 1.554 de SC no período. Observou-se tendência crescente das taxas de detecção de SG (variação percentual anual [VPA] de 18,0 ­ intervalo de confiança de 95% [IC95%] de 15,3 a 20,8) e de SC (VPA=16,8 ­ IC95% 20,1;33,8); e um acréscimo de 326% no número de municípios com taxa de incidência de SC >0,5/1 mil nascidos vivos. Conclusão: Foi identificado crescimento das taxas de detecção da sífilis gestacional e congênita e do número de municípios notificantes.

Objetivo: Analizar la tendencia temporal y distribución espacial de la sífilis gestacional (SG) y la sífilis congénita (SC) en Goiás, Brasil, entre 2007 y 2017. Métodos: Estudio de series temporales y enfoque espacial con datos del Sistema de Información para Enfermedades de Notificación. Se utilizó la regresión de Prais-Winsten para analizar la tendencia de los indicadores por macroregión de salud. Fue realizado un análisis espacial para verificar la distribución espacial de los casos en tres años de la serie. Resultados:Se registraron 7.679 casos de sífilis gestacional y 1.554 casos de congénita. Hubo una tendencia creciente en las tasas de detección de SG con (Variación Porcentual Anual [VPA] de 18,0 ­ intervalo de confianza del 95% [IC95%] de 15,3 a 20,8) y de SC (VPA=16,8 ­ IC95% 20,1; 33,8); y un aumento del 326% en el número de municipios con una tasa de incidencia de sífilis congénita >0,5/1000 nacidos vivos. Conclusión: Se identificó um aumento creciente de sífilis gestacional y sífilis congénita y del número de municipios notificantes en Goiás.

Objective: To analyze temporal trend and spatial distribution of syphilis in pregnancy and congenital syphilis in Goiás State, Brazil, between 2007 and 2017. Methods: This was an ecological time series and spatial distribution study with data obtained from the Notifiable Health Conditions Information System. Prais-Winsten Regression was used to analyze indicator trends by health macro-region. Descriptive spatial analysis was performed to verify case distribution in three different years in the period. Results: Between 2007 and 2017, 7,679 cases of syphilis in pregnancy and 1,554 congenital syphilis cases were reported. A rising trend was found in the rates of syphilis in pregnancy (annual percent change [APC] = 18.0 ­ 95% confidence interval [95%CI] 15.3;20.8) as well as in congenital syphilis rates (APC=16.8 ­ 95%CI 20.1;33.8); and a 326% increase in the number of municipalities with a congenital syphilis incidence rate >0.5/1,000 live births. Conclusion: Growth in syphilis in pregnancy and congenital syphilis detection rates was identified, as was growth in the number of municipalities reporting cases.

AIDS-related progressive multifocal leukoencephalopathy.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of JC virus (JCV). METHODS: We described the profile of laboratory-confirmed PML cases among AIDS patients. RESULTS: A total of 43 HIV patients with clinical conditions compatible with PML were obtained; 5 cases were confirmed by JCV testing. The main clinical finding was mental confusion. Median CD4 count was 54 cells/mm³. CONCLUSIONS: Three of the five confirmed PML cases died; the time between diagnosis and death was 2, 5, and 6 months. It is important to consider JCV infection as a differential diagnosis.

False-negative result of serum cryptococcal antigen lateral flow assay in an HIV-infected patient with culture-proven cryptococcaemia

The detection of cryptococcal capsular antigen (CrAg) is very sensitive and specific, however false-negative results have been reported, mostly in cerebrospinal fluid. We report the case of an HIV-infected patient with CD4=42 cells/mL, asthenic, negative serum CrAg lateral flow assay (LFA) and culture-proven cryptococcaemia. Despite the high accuracy of LFA, false-negative result is possible. Careful clinical evaluation and close follow-up are relevant

False-negative result of serum cryptococcal antigen lateral flow assay in an HIV-infected patient with culture-proven cryptococcaemia.

The detection of cryptococcal capsular antigen (CrAg) is very sensitive and specific, however false-negative results have been reported, mostly in cerebrospinal fluid. We report the case of an HIV-infected patient with CD4 = 42 cells/mL, asthenic, negative serum CrAg lateral flow assay (LFA) and culture-proven cryptococcaemia. Despite the high accuracy of LFA, false-negative result is possible. Careful clinical evaluation and close follow-up are relevant.

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

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.

Prospective cohort of AIDS patients screened for cryptococcal antigenaemia, pre-emptively treated and followed in Brazil.

BACKGROUND: Cryptococcal meningitis has a high morbidity and mortality among AIDS population. Cryptococcal antigen (CrAg) detection is considered an independent predictor for meningitis and death. Since 2011, the World Health Organization recommends CrAg screening for people living with HIV/AIDS (PLHAs) with CD4 counts <100-200 cells/µl. Its implementation is still limited in low-middle-income countries. We aimed to estimate the prevalence and predictors of CrAg positivity in PLHAs. We also evaluated outcomes among those who were CrAg-positive. METHODS: Prospective cohort conducted at an infectious diseases hospital, in Brazil. Adults with CD4 <200 cells/µl, without previous cryptococcal disease and regardless of symptoms, were enrolled from 2015 to 2018. CrAg tests were performed by LFA. Lumbar puncture was done in CrAg+ individuals and pre-emptive therapy was offered for those without meningitis. RESULTS: Of 214 individuals recruited, 88% were antiretroviral experienced, of which only 11.6% with viral suppression. Overall, CrAg prevalence was 7.9% (95% CI, 4.7-12.4). In CD4 ≤100 cells/µl group it was 7.5% (95% CI, 4.1-12.6) and 9.1% (95% CI, 3.4-19.0) in the group with CD4 101 to 199 cells/µl (p = 0.17). Prevalence in asymptomatic subjects was 5.3% (95% CI, 1.4-13.1). One among 17 CrAg+ participants had documented meningoencephalitis and no subclinical meningitis was detected. Adherence to pre-emptive treatment was 68.7% (11/16). There were no statistically significant differences in sociodemographic, clinical or laboratory characteristics to predict CrAg positivity. No case of cryptococcal disease was diagnosed among CrAg + subjects, followed by a median of 12 months. CONCLUSIONS: CrAg screening for severely immunosuppressed PLHAs in Brazil yielded a prevalence of 7.9%. No difference was found in the prevalence of CrAg stratified by CD4 values (CD4 <100 versus CD4 101-199 cells/µl). No clinical nor laboratory factors predicted CrAg positivity, corroborating the need for the implementation of universal CrAg screening for PLHAs with CD4 <200 cells/µl in similar settings.

Late Onset of Antiretroviral Therapy in Adults Living with HIV in an Urban Area in Brazil: Prevalence and Risk Factors.

INTRODUCTION: Highly active antiretroviral therapy has been available since 1996. Early initiation of antiretroviral therapy (ART) leads to improved therapeutic response and reduced HIV transmission. However, a significant number of people living with HIV (PLHIV) still start treatment late. OBJECTIVE: This study aimed to analyze characteristics and factors associated with late initiation of ART among HIV-infected treatment-naïve patients. METHODS: This cross-sectional study included PLHIV older than 17 years who initiated ART at two public health facilities from 2009 to 2012, in a city located in Midwestern Brazil. Pregnant women were excluded. Data were collected from medical records, antiviral dispensing forms, and the Logistics Control of Medications System (SICLOM) of the Brazilian Ministry of Health. Late initiation of ART was defined as CD4+ cell count < 200 cells/mm3 or presence of AIDS-defining illness. Uni- and multivariate analysis were performed to evaluate associated factors for late ARV using SPSS®, version 21. The significance level was set at p<0.05. RESULTS: 1,141 individuals were included, with a median age of 41 years, and 69.1% were male. The prevalence of late initiation of ART was 55.8% (95%CI: 52.9-58.7). The more common opportunistic infections at ART initiation were pneumocystosis, cerebral toxoplasmosis, tuberculosis, and histoplasmosis. Overall, 38.8% of patients had HIV viral load equal to or greater than 100,000 copies/mL. Late onset of ART was associated with higher mortality. After logistic regression, factors shown to be associated with late initiation of ARV were low education level, sexual orientation, high baseline viral load, place of residence outside metropolitan area, and concomitant infection with hepatitis B virus. CONCLUSION: These results revealed the need to increase early treatment of HIV infection, focusing especially on groups of people who are more socially vulnerable or have lower self-perceived risk.

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

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.