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

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

Sleep in children from northeastern Brazil with congenital Zika syndrome: assessment using polysomnography.

STUDY OBJECTIVES: We performed this study to describe the characteristics of sleep in children with congenital Zika syndrome through polysomnographic assessment. METHODS: Polysomnography with neurological setup and capnography was performed. Respiratory events were scored according to American Academy of Sleep Medicine criteria. Children were classified based on neuroclinical examination as having corticospinal plus neuromuscular abnormalities or exclusively corticospinal abnormalities. Neuroradiological classification was based on imaging exams, with children classed as having supratentorial plus infratentorial abnormalities or exclusively supratentorial abnormalities. RESULTS: Of 65 children diagnosed with congenital Zika syndrome, sleep apnea was present in 23 children (35.4%), desaturation in 26 (40%), and snoring in 13 (20%). The most prevalent apnea type was central in 15 children (65.2%), followed by obstructive apnea in 5 (21.7%) and mixed type in 3 (13%). The average of the lowest saturation recorded was slightly below normal (89.1 ± 4.9%) and the mean partial pressure of end-tidal carbon dioxide value was normal. Periodic leg movements were present in 48 of 65 children. Lower ferritin levels were observed in 84.6% of children. Palatine and pharyngeal tonsils (adenoids) were small in most children and not associated with the presence of obstructive apnea. Ventriculomegaly and subcortical and nucleus calcification were the most frequent neuroimaging findings. Supratentorial and infratentorial anomalies were present in 26.7% (16 of 60) and exclusively supratentorial changes in 73.3% (44 of 60). In the neuroclinical classification, isolated corticospinal changes were more frequent and the mean peak in capnography was lower in this group. There was no difference regarding the presence of apnea for children in the neuroclinical and neuroradiological classification groups. CONCLUSIONS: Sleep disorders were frequent in children with congenital Zika syndrome, with central sleep apnea being the main finding. CITATION: Brandão Marquis V, de Oliveira Melo A, Pradella-Hallinan M, et al. Sleep in children from northeastern Brazil with congenital Zika syndrome: assessment using polysomnography. J Clin Sleep Med. 2023;19(10):1759-1767.

The impact of implementing the 10-valent pneumococcal conjugate vaccine on hospitalizations for pneumonia among children.

Pneumonia is a major cause of morbidity and mortality in children, with pneumococcus as the main etiologic agent. In Brazil, the 10-valent pneumococcal conjugate vaccine (PCV-10) was introduced into the childhood immunization schedule in 2010. The aim of this study was to assess the impact caused by implementing PCV-10 on the hospitalizations of children with pneumonia, between 2005 and 2015, in the state of Pernambuco, Brazil. An ecological time series study and a forecasting analysis were conducted. A comparison was made between the hospitalizations of children aged between seven months and four years due to pneumonia in the Brazilian Unified Health System, in the 5 years before (2005-2009) and after (2011-2015) implementation of PCV-10. Descriptive analysis included absolute and relative values, means and rates of hospitalization. The chi-square test was used to compare the annual incidence of hospitalizations and the t-Student test to compare the five-year mean values. For the temporal modeling of hospitalizations, an autoregressive integrated moving average was used, adjusted with seasonal-SARIMA (Box-Jenkins methodology), with a prediction of the monthly number of hospitalizations for 2011-2015. The predicted and observed values for 2011-2015 were then compared. The number of hospitalizations after implementing PCV-10 was reduced by 24.5 %. The monthly average of hospitalizations dropped from 681 (2005-2009) to 514 (2011-2015). The hospitalization rate dropped from 56.1 per thousand live births in the five-year period prior to PCV-10 to 43.4 in the following five-year period (a 22.7% reduction). Comparing the values predicted by the SARIMA model for a scenario without PCV-10 in the second five-year period, with those reported after implementing PCV-10, the estimated number of prevented hospitalizations was 8,682 in the five years following the introduction of the vaccine. In conclusion, in the five years following implementation of PCV-10, hospitalizations of children with pneumonia in Pernambuco decrease by 22%.

Characteristics of children of the Microcephaly Epidemic Research Group Pediatric Cohort who developed postnatal microcephaly.

The number of studies published on postnatal microcephaly in children with Congenital Zika Syndrome is small, clinical presentations vary and aspects of the evolution of these children remain unclarified. The present case series examined clinical characteristics and assessed the growth velocity of the head circumference, weight and height Z-scores in 23 children who developed postnatal microcephaly during follow-up in the Microcephaly Epidemic Research Group Pediatric Cohort. To estimate the change in the head circumference, weight and height Z-scores over time and compare the mean difference between sexes, we used multilevel mixed-effects linear regressions with child-specific random effects. Among these children, 60.9% (n = 14/23) presented with craniofacial disproportion, 60.9% (n = 14/23) with strabismus, 47.8% (n = 11/23) with early onset seizures, 47.8% (n = 11/23) with dysphagia and 43.5% (n = 10/23) with arthrogryposis. Of the 82.7% (n = 19/23) children who underwent neuroimaging, 78.9% (n = 15/19) presented with alterations in the central nervous system. Monthly growth velocity, expressed in Z-scores, of the head circumference was - 0.098 (95% CI % - 0.117 to - 0.080), of weight was: - 0.010 (95%-CI - 0.033 to 0.014) and of height was: - 0.023 (95%-CI - 0.046 to 0.0001). Postnatal microcephaly occurred mainly in children who had already presented with signs of severe brain damage at birth; there was variability in weight and height development, with no set pattern.

Cortical Auditory Evoked Potentials in Children with Prenatal Exposure to Zika Virus.

Prenatal exposure to ZIKV can cause neurologic and auditory damage. The electrophysiological responses obtained by Cortical Auditory Evoked Potentials (CAEP) may provide an objective method to investigate the function of cortical auditory pathways in children exposed to ZIKV. This case series analyzed the findings of CAEP in prenatal-period ZIKV-exposed children with and without microcephaly. The CAEP was performed in a total of 24 children. Five magnetic resonance imaging (MRI) images of the inner ear and brain of microcephalic children were analyzed and compared with CAEP measurements. Ventriculomegaly (80%), cortical/subcortical calcification (80%), and brain reduction (60%) were the most common alterations in the MRI. The P1-N1-P2 complex of the CAEP was observed in all children evaluated. The peak N2 was absent in two children. In the comparison of the CAEP measurements between the groups, children with microcephaly presented a higher amplitude of P2 (p = 0.017), which may reflect immaturity of the auditory pathways. Microcephalic and normocephalic children with prenatal exposure to ZIKV presented with the mandatory components of the CAEPs, regardless of changes in the CNS, suggesting that this population has, to some extent, the cortical ability to process sound stimuli preserved.

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

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

Pediatric neurodevelopment by prenatal Zika virus exposure: a cross-sectional study of the Microcephaly Epidemic Research Group Cohort.

BACKGROUND: The implications of congenital Zika Virus (ZIKV) infections for pediatric neurodevelopment and behavior remain inadequately studied. The aim of this study is to investigate patterns of neurodevelopment and behavior in groups of children with differening severities of ZIKV-related microcephaly and children with prenatal ZIKV exposure in the absence of microcephaly. METHODS: We conducted a cross-sectional study, nested in a cohort, of 274 children (aged 10-45 months) who were born during the peak and decline of the microcephaly epidemic in Northeast Brazil. Participants were evaluated between February 2017 and August 2019 at two tertiary care hospitals in Recife, Pernambuco, Brazil. We analyzed the children in four groups assigned based on clinical and laboratory criteria: Group 1 had severe microcephaly; Group 2 had moderate microcephaly; Group 3 had prenatal ZIKVexposure confirmed by maternal RT-PCR testing but no microcephaly; and Group 4 was a neurotypical control group. Groups were evaluated clinically for neurological abnormalities and compared using the Survey of Wellbeing of Young Children (SWYC), a neurodevelopment and behavior screening instrument validated for use in Brazil. Children with severe delays underwent further evaluation with an adapted version of the SWYC. RESULTS: Based on the SWYC screening, we observed differences between the groups for developmental milestones but not behavior. Among the 114 children with severe microcephaly of whom 98.2% presented with neurological abnormalities, 99.1% were 'at risk of development delay' according to the SWYC instrument. Among the 20 children with moderate microcephaly of whom 60% presented with neurological abnormalities, 65% were 'at risk of development delay'. For children without microcephaly, the percentages found to be 'at risk of developmental delay' were markedly lower and did not differ by prenatal ZIKV exposure status: Group 3 (N = 94), 13.8%; Group 4 (N = 46), 21.7%. CONCLUSIONS: Among children with prenatal ZIKV exposure, we found a gradient of risk of development delay according to head circumference. Children with severe microcephaly were at highest risk for delays, while normocephalic ZIKV-exposed children had similar risks to unexposed control children. We propose that ZIKV-exposed children should undergo first-line screening for neurodevelopment and behavior using the SWYC instrument. Early assessment and follow-up will enable at-risk children to be referred to a more comprehensive developmental evaluation and to multidisciplinary care management.

Effectiveness of four antiretroviral regimens for treating people living with HIV.

The aim of this study was to compare 4 different ARV regimens in a clinical cohort in Brazil, with regard to the virologic and immunologic responses, clinical failure and reasons for changing. To compare the virologic response and clinical failure between groups we used the Cox and Kaplan Meier proportional hazard models. To analyze the immunologic outcome, we used multilevel GLLAMM and mixed effect linear regression models. To compare regimen change outcomes we used the Pearson's chi-square test. We included 840 participants distributed across the groups according to the initial ART regimen. The mean follow-up period was 27.8 months. Almost half the sample initiated ART with AIDS-related signs/symptoms. Virologic response was effective in 79.6% of participants within 12 months. The tenofovir/lamivudine/efavirenz group presented a higher proportion of virologic response (VL<50 at 6 months) when compared to the zidovudine/lamivudine/efavirenz group. There was no difference between the regimens regarding the immunologic response. A total of 17.3% of individuals changed regimen because of failure and 46.5% due to adverse events. Changes due to adverse events were more frequent in the group using zidovudine/lamivudine/efavirenz. The proportion of hospitalizations at 1 year was higher in the zidovudine/lamivudine/efavirenz group when compared to the tenofovir/lamivudine/efavirenz group. The effectiveness outcomes between the regimens were similar. Some differences may be due to the individual characteristics of patients, toxicity and acceptability of drugs. Studies are needed that compare similarly effective regimens and their respective treatment costs and financial impacts on SUS (Integrated Healthcare System).

Association of the polymorphisms of the genes APOC3 (rs2854116), ESR2 (rs3020450), HFE (rs1799945), MMP1 (rs1799750) and PPARG (rs1801282) with lipodystrophy in people living with HIV on antiretroviral therapy: a systematic review.

The aim of this study was to perform a systematic review to identify data reported in the literature concerning the association of APOC3 (rs2854116), ESR2 (rs3020450), HFE (rs1799945), MMP1 (rs1799750) and PPARG (rs1801282) polymorphisms with lipodystrophy in people living with HIV (PLWHIV) on antirretroviral therapy. The research was conducted in six databases and the studies were selected in two steps. First, a search was undertaken in the following electronic databases: PubMed, Science Direct, Medline, World Wide Science, Directory of Open Access Journals, Scielo, Lilacs and Medcarib. The titles and abstracts of 24,859 articles were read to select those that match the elegibilty criteria. Five papers that addressed the association of HAART, lipodystrophy and polymorphisms were selected for the review. There was no association between the polymorphisms of the genes APOC3 and PPARG and lipodystrophy. Another study described an association between the variant allele (G) of HFE and protection concerning the development of lipoatrophy (0.02) when compared with the reference allele (C). On the other hand, the variant allele (T) of the ESR2 gene was associated with the development of lipoatrophy (p = 0.007) when compared with the reference allele (C). In addition, the genotype and the variant allele of the gene MMP1 (2G) were associated with lipodystrophy in PLWHIV on HAART (p = 0.0002 and p = 0.0008, respectively). Therefore, further studies with other populations, involving PLWHIV on HAART are necessary to better understand the role of genetic markers, which may be involved in a predisposition to lipodystrophy.

Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: preliminary report of a case-control study.

BACKGROUND: The microcephaly epidemic, which started in Brazil in 2015, was declared a Public Health Emergency of International Concern by WHO in 2016. We report the preliminary results of a case-control study investigating the association between microcephaly and Zika virus infection during pregnancy. METHODS: We did this case-control study in eight public hospitals in Recife, Brazil. Cases were neonates with microcephaly. Two controls (neonates without microcephaly), matched by expected date of delivery and area of residence, were selected for each case. Serum samples of cases and controls and cerebrospinal fluid samples of cases were tested for Zika virus-specific IgM and by quantitative RT-PCR. Laboratory-confirmed Zika virus infection during pregnancy was defined as detection of Zika virus-specific IgM or a positive RT-PCR result in neonates. Maternal serum samples were tested by plaque reduction neutralisation assay for Zika virus and dengue virus. We estimated crude odds ratios (ORs) and 95% CIs using a median unbiased estimator for binary data in an unconditional logistic regression model. We estimated ORs separately for cases with and without radiological evidence of brain abnormalities. FINDINGS: Between Jan 15, 2016, and May 2, 2016, we prospectively recruited 32 cases and 62 controls. 24 (80%) of 30 mothers of cases had Zika virus infection compared with 39 (64%) of 61 mothers of controls (p=0·12). 13 (41%) of 32 cases and none of 62 controls had laboratory-confirmed Zika virus infection; crude overall OR 55·5 (95% CI 8·6-∞); OR 113·3 (95% CI 14·5-∞) for seven cases with brain abnormalities; and OR 24·7 (95% CI 2·9-∞) for four cases without brain abnormalities. INTERPRETATION: Our data suggest that the microcephaly epidemic is a result of congenital Zika virus infection. We await further data from this ongoing study to assess other potential risk factors and to confirm the strength of association in a larger sample size. FUNDING: Brazilian Ministry of Health, Pan American Health Organization, and Enhancing Research Activity in Epidemic Situations.

Risk Factors for Acute Symptomatic Seizure in Bacterial Meningitis in Children.

The aim of this study was to investigate the association between clinical and laboratory parameters at admission and the occurrence of in-hospital symptomatic seizures in children with acute bacterial meningitis in Brazil. A retrospective case-control study in 270 children with confirmed bacterial meningitis, aged from 1 month to 14 years, was conducted between January 2004 and December 2008. Associations with the occurrence of in-hospital epileptic seizures were adjusted using stepwise multiple logistic regression analysis. Sixty-seven children suffered at least one in-hospital epileptic seizure. After multivariate analysis, the independent predictors considered for in-hospital epileptic seizures were as follows: age less than 2 years (odds ratio = 0.97; 95% confidence interval 0.97-0.98), pneumococcal etiology (odds ratio = 4.55; 95% confidence interval 1.88-11.0); altered mental status (odds ratio = 3.47; 95% confidence interval 1.66-7.26) and cerebrospinal fluid leukocyte count below 1000 cells (odds ratio = 2.14; 95% confidence interval 0.99-4.60). Mortality was higher in patients with intrahospital epileptic seizures compared to those without (25/67 [37.3%] vs 9/203 [4.43%], P < .001].

Prognostic indicators in bacterial meningitis: a case-control study.

This was a case-control study to identify prognostic indicators of bacterial meningitis in a reference hospital in Pernambuco/Brazil. The data were collected from charts of 294 patients with bacterial meningitis between January 2000 and December 2004. Variables were grouped in biological, clinical, laboratory and etiologic agent/treatment. Variables selected in each step were grouped and adjusted for age. Two models were created: one containing clinical variables (clinical model) and other containing laboratory variables (laboratory model). In the clinical model the variables associated with death due to bacterial meningitis were dyspnea (p=0.006), evidence of shock (p=0.051), evidence of altered mental state (p=0.000), absence of headache (p=0.008), absence of vomiting (p=0.052), and age ≥40 years old (p=0.013). In the laboratory model, the variables associated with death due to bacterial meningitis were positive blood cultures (p=0.073) and thrombocytopenia (p=0.019). Identification of prognostic indicators soon after admission may allow early specific measures, like admission of patients with higher risk of death to Intensive Care Units.

Risk factors for subclinical atherosclerosis in HIV-infected patients under and over 40 years: a case-control study.

BACKGROUND: Cardiovascular diseases (CVD) are a major cause of death in people with AIDS. Factors contributing to atherosclerosis include traditional risk factors, antiretrovirals and inflammatory factors related to HIV infection. This study set out to compare risk factors associated with subclinical atherosclerosis in individuals under and over 40 years of age. METHODS: Case-control study with 697 HIV/AIDS individuals without HAART or who remain on their first antiretroviral regimen. Of the total, 351 individuals under 40 years and 346 over 40 years were analyzed separately. Subclinical atherosclerosis was assessed by carotid intima-media thickness, using B-mode ultrasound. Multivariate logistic regression was performed to find predictors of subclinical atherosclerosis in the entire group. Subsequent analysis excluded patients with major risk factors for CVD. Magnitudes of associations were expressed by odds ratio (OR) statistical significance, using a 95% confidence interval and p-value <0.05. RESULTS: In the <40 years group subclinical atherosclerosis was associated with male gender (OR: 2.77, 95% CI: 1.43-5.34), nonwhite race (OR: 3.01, 95% CI: 1.23-6.53), obesity (OR: 5.13, 95% CI: 1.79-14.7) and metabolic syndrome (OR: 3.30, 95% CI: 1.44-7.58). In the group ≥40 years predictors of subclinical atherosclerosis were overweight and obesity (OR = 2.53, 95% CI, 0.85-7.54), current CD4 ≥350 cells/mL (OR: 2.81, 95% CI: 1.22-6.47) and NNRTI use ≥ 5 years (OR: 2.65, 95% CI: 1.10-6.37) or PI use >5 years (OR: 1.81, 95% CI: 0.38-8.59). In the multivariate model excluding patients with major risk factors for CVD, age, male sex and nonwhite race were associated with subclinical atherosclerosis in the <40 y group, while in the ≥40 y group, age, HIV viral load >10,000 copies and the use of NNRTI (OR: 7.60, 95% CI: 1.61-35.8) or PI ≥5 years (OR: 3.62, 95% CI: 0.48-26.8) were associated with subclinical atherosclerosis. CONCLUSIONS: In young people the fight against obesity and metabolic syndrome is the main aim in the prevention of CVD. In individuals aged ≥40 y, the prevention of obesity is also of great importance. Moreover, the effects of uncontrolled viremia and the prolonged use of HAART appear to be more harmful in the older group.

Incidence and risk factors for tuberculosis in people living with HIV: cohort from HIV referral health centers in Recife, Brazil.

OBJECTIVE: To identify the incidence of and risk factors for tuberculosis in people living with HIV (PLHIV). DESIGN: Observational, prospective cohort study. METHODS: A total of 2069 HIV-infected patients was observed between July 2007 and December 2010. The Kaplan-Meier method was used to estimate the probability of survival free of tuberculosis, and Cox regression analysis to identify risk factors associated with the development of tuberculosis. RESULTS: Survival free of tuberculosis (TB) was 91%. The incidence rate of tuberculosis was 2.8 per 100 persons/years. Incidence of tuberculosis was higher when subjects had CD4 cell count <200 cells/mm(3); were not on antiretroviral therapy; in those who had, a body mass index <18.5 kg/m(2), anemia (or were not tested for it), were illiterate or referred previous tuberculosis treatment at entry into the cohort. Those not treated for latent TB infection had a much higher risk (HR = 7.9) of tuberculosis than those with a negative tuberculin skin test (TST). Having a TST≥5 mm but not being treated for latent TB infection increased the risk of incident tuberculosis even in those with a history of previous tuberculosis. CONCLUSIONS: Preventive actions to reduce the risk of TB in people living with HIV should include an appropriate HAART and treatment for latent TB infection in those with TST≥5 mm. The actions towards enabling rigorous implementation of treatment of latent TB infection and targeting of PLHIV drug users both at the individual and in public health level can reduce substantially the incidence of TB in PLHIV.