Search

BackgroundSuboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level.MethodsWe systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24andCmaxwere assessed with linear mixed-effects models.ResultsOf 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially 0–24for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24for isoniazid and pyrazinamide.N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24and slow acetylators had higher isoniazid AUC0–24than intermediate acetylators. Determinants ofCmaxwere generally similar to those for AUC0–24.ConclusionsThis study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Contains fulltext : 292759.pdf (Publisher’s version ) (Closed access) Immunological problems are increasingly acknowledged manifestations in many inherited metabolic diseases (IMDs), ranging from exaggerated inflammation, autoimmunity and abnormal cell counts to recurrent microbial infections. A subgroup of IMDs, the congenital disorders of glycosylation (CDG), includes CDG types that are even classified as primary immunodeficiencies. Here, we reviewed the list of metabolic disorders reported to be associated with various immunological defects and identified 171 IMDs accompanied by immunological manifestations. Most IMDs are accompanied by immune dysfunctions of which immunodeficiency and infections, innate immune defects, and autoimmunity are the most common abnormalities reported in 144/171 (84%), 44/171 (26%) and 33/171 (19%) of IMDs with immune system involvement, respectively, followed by autoinflammation 17/171 (10%). This article belongs to a series aiming at creating and maintaining a comprehensive list of clinical and metabolic differential diagnoses according to organ system involvement.

BackgroundBacillus Calmette-Guerin (BCG) vaccination has been hypothesised to reduce SARS-CoV-2 infection, severity, and/or duration via trained immunity induction.MethodsHealthcare workers (HCWs) in 9 Dutch hospitals were randomised to BCG or placebo vaccination (1:1) in March/April 2020 and followed for one year. They reported daily symptoms, SARS-CoV-2 test results, and healthcare-seeking behaviour via a smartphone application, and donated blood for SARS-CoV-2 serology at two time points.Results1,511 HCWs were randomised and 1,309 analysed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio=0.95; 95% confidence interval 0.76-1.21; p=0.732). Only three participants required hospitalisation for COVID-19. The proportions of participants with asymptomatic, mild, or mild-to-moderate infections, and the mean infection durations, did not differ between randomisation groups. Unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes either. The percentage of participants with seroconversion (7.8% versus 2.8%; p=0.006) and mean anti-S1 antibody concentration (13.1 versus 4.3 IU/ml; p=0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months post-vaccination.ConclusionsBCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (on a scale from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection.

Background Recent research suggests that the microbiota affects susceptibility to both respiratory tract infections (RTIs) and gastrointestinal infections (GIIs). In order to optimize global treatment options, it is important to characterize microbiota profiles across different niches and geographic/socioeconomic areas where RTI and GII prevalences are high. Methods We performed 16S sequencing of nasopharyngeal swabs from 209 Venezuelan Amerindian children aged 6 weeks–59 months who were participating in a 13-valent pneumococcal conjugate vaccine (PCV13) study. Using random forest models, differential abundance testing, and regression analysis, we determined whether specific bacteria were associated with RTIs or GIIs and variation in PCV13 response. Results Microbiota compositions differed between children with or without RTIs (P = .018) or GIIs (P = .001). Several species were associated with the absence of infections. Some of these health-associated bacteria are also observed in developed regions, such as Corynebacterium (log2(fold change [FC]) = 3.30 for RTIs and log2(FC) = 1.71 for GIIs), while others are not commonly observed in developed regions, such as Acinetobacter (log2(FC) = 2.82 and log2(FC) = 5.06, respectively). Klebsiella spp. presence was associated with both RTIs (log2(FC) = 5.48) and GIIs (log2(FC) = 7.20). Conclusions The nasopharyngeal microbiota of rural Venezuelan children included several bacteria that thrive in tropical humid climates. Interestingly, nasopharyngeal microbiota composition not only differed in children with an RTI but also in those with a GII, which suggests a reciprocal interplay between the 2 environments. Knowledge of region-specific microbiota patterns enables tailoring of preventive and therapeutic approaches., The nasopharyngeal microbiota of rural Venezuelan children included several bacteria that thrive in tropical humid climates. Nasopharyngeal microbiota composition not only differed in children with a respiratory infection but also in those with a gastrointestinal infection.

Background Almost 200 million children worldwide are either undernourished or overweight. Only a few studies have addressed the effect of variation in nutritional status on vaccine response. We previously demonstrated an association between stunting and an increased post-vaccination 13-valent pneumococcal conjugate vaccine (PCV13) response. In this prospective study, we assessed to what extent metabolic hormones may be a modifier in the association between nutritional status and PCV13 response. Methods Venezuelan children aged 6 weeks to 59 months were vaccinated with a primary series of PCV13. Nutritional status and serum levels of leptin, adiponectin and ghrelin were measured upon vaccination and their combined effect on serum post-vaccination antibody concentrations was assessed by generalized estimating equations multivariable regression analysis. Results A total of 210 children were included, of whom 80 were stunted, 81 had a normal weight and 49 were overweight. Overweight children had lower post-vaccination antibody concentrations than normal weight children (regression coefficient -1.15, 95% CI -2.22 –-0.072). Additionally, there was a significant adiponectin-nutritional status interaction. In stunted children, higher adiponectin serum concentrations were associated with lower post-PCV13 antibody concentrations (regression coefficient -0.19, 95% CI -0.24 –-0.14) while the opposite was seen in overweight children (regression coefficient 0.14, 95% CI 0.049–0.22). Conclusion Metabolic hormones, in particular adiponectin, may modify the effect of nutritional status on pneumococcal vaccine response. These findings emphasize the importance of further research to better understand the immunometabolic pathways underlying vaccine response and enable a future of optimal personalized vaccination schedules.

Identification of SARS-CoV-2 infected individuals is imperative to prevent hospital transmission, but symptom-based screening may fail to identify asymptomatic/mildly symptomatic infectious children and their caregivers.A COVID-19 period prevalence study was conducted between 13 and 26 August 2020 at Tygerberg Hospital, testing all children and their accompanying asymptomatic caregivers after initial symptom screening. One nasopharyngeal swab was submitted for SARS-CoV-2 using real-time reverse-transcription polymerase chain reaction (rRT-PCR). An additional Respiratory Viral 16-multiplex rRT-PCR test was simultaneously done in children presenting with symptoms compatible with possible SARS-CoV-2 infection.SARS-Co-V 2 RT-PCR tests from 196 children and 116 caregivers were included in the analysis. The SARS-CoV-2 period prevalence in children was 5.6% (11/196) versus 15.5% (18/116) in asymptomatic caregivers (Given the poor correlation between SARS-CoV-2 symptoms and RT-PCR test positivity, universal testing of children and their accompanying caregivers should be considered for emergency and inpatient paediatric admissions during high COVID-19 community transmission periods. Universal PPE and optimising ventilation is likely the most effective way to control transmission of respiratory viral infections, including SARS-CoV-2, where universal testing is not feasible. In these settings, repeated point prevalence studies may be useful to inform local testing and cohorting strategies.

IntroductionRespiratory tract infections (RTIs) affect children all over the world and are associated with significant morbidity and mortality. In particular, recurrent RTIs cause a high burden of disease and lead to frequent doctor visits. Children with recurrent RTIs generally have no significant alterations or deficits in systemic immunity. In an attempt to treat the assumed bacterial component involved, they are often treated with prolonged courses of prophylactic antibiotics taken on a daily basis. Despite its common use, there is no evidence that this is beneficial. Studies assessing the clinical effectiveness of antibiotic prophylaxis as well as potential adverse effects and antibiotic resistance development, are therefore urgently needed.Methods and analysisWe present a protocol for a randomised double-blind placebo-controlled trial comparing co-trimoxazole with placebo treatment in children with recurrent RTIs. A total of 158 children (aged 6 months–10 years) with recurrent RTIs without significant comorbidity will be enrolled from a minimum of 10 Dutch hospitals. One group receives co-trimoxazole 18 mg/kg two times per day (36 mg/kg/day) and the other group receives a placebo two times per day for a period of 3 months. The main objective is to determine whether antibiotic prophylaxis is more effective than placebo to prevent/reduce respiratory symptoms in children with recurrent RTIs. Respiratory symptoms will be scored by parents on a daily basis in both study arms by the use of a mobile phone application. Our primary outcome will be the number of days with at least two respiratory symptoms during the treatment.Ethics and disseminationEthics approval was obtained from the Medical Ethics Research Committee Zuidwest Holland/LDD. A manuscript with the study results will be submitted to a peer-reviewed journal. All participants will be informed about the study results. The results of the study will inform clinical guidelines regarding the prophylactic treatment of children with recurrent RTIs.Trial registration numberNL7044.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is characterised by deficient glucose transport over the blood‐brain barrier and reduced glucose availability in the brain. This causes epilepsy, movement disorders, and cognitive impairment. Treatment with ketogenic diet provides ketones as alternative energy source. However, not all GLUT1DS patients are on dietary treatment (worldwide registry: 77/181 [43%] of patients). The current 25‐year experience allows evaluation of effects and tolerability of dietary treatment for GLUT1DS. To this end, literature was searched up to January 2019 for individual case reports and series reporting (side) effects of dietary treatment for GLUT1DS. Upon aggregation of data for analysis, we identified 270 GLUT1DS patients with dietary treatment with a mean follow‐up of 53 months. Epilepsy improved for 83% of 230 patients and remained unchanged for 17%, movement disorders improved for 82% of 127 patients and remained unchanged for 17%, and cognition improved for 59% of 58 patients and remained stable for 40%. Effects on epilepsy were seen within days/weeks and were most pronounced in patients with early treatment initiation. Effects on movement disorders were noticed within months and were strongest in patients with higher cerebrospinal fluid‐to‐blood glucose ratio. Although side effects were minimal, 18% of 270 patients reported poor compliance. In individual patients, symptoms deteriorated upon low ketosis, poor compliance, or treatment discontinuation. Based on the good tolerability and strong favourable effect of dietary treatment on GLUT1DS symptoms, we advocate dietary treatment in all GLUT1DS patients and prompt diagnosis or screening to allow early treatment.

Background Within Europe, the Netherlands has one of the lowest antibiotic consumption rates. We aimed to gain insight into attitudes of Dutch physicians and parents towards information provided during discharge conversations in the emergency department (ED) and towards antibiotic use in children, in order to obtain information on the assumptions and beliefs that underlie a practice of low prescription rates. Methods Discharge conversations of 70 children presenting with an infectious disease at the ED were observed. After 7–10 days, 55 parents were called for a semi-structured interview. In addition, 29 pediatricians and pediatric residents completed a questionnaire on their prescription behaviour. Results Concerns about (recognizing) the severity of their child’s infection was parents’ main motivation to seek help. Both pediatricians and parents reported a general reluctance towards antibiotic use. While pediatricians took appropriateness based on indication and the risk of antimicrobial resistance development into account when considering antibiotic treatment, a thorough medical assessment was deemed more important for Dutch parents than any type of therapeutic treatment, including antibiotics. The topic most often discussed during the discharge conversations was safety netting instructions (in 86%), which were discussed more often during discharge conversations with parents of children that did not receive antibiotic treatment (91% versus 69%). Conclusion Dutch pediatricians and parents are both reluctant to use antibiotics for uncomplicated infections in children, but for different reasons. The emphasis of discharge conversations was on safety netting instructions, which seems to be an alternative for (early) antibiotic use in our setting and may guide overuse prevention strategies in settings where antibiotic overuse is more common.

Objectives While physicians are often confronted with immunoglobulin A (IgA) deficiency in children with recurrent infections, the clinical relevance of this finding is unclear. Large‐scale studies examining the significance of IgA deficiency in children are hampered by differences in techniques for measuring IgA and the physiological increase of IgA with age. Both result in a variety of reference values used for diagnosing IgA deficiency. We propose a new laboratory‐independent method to accurately compare IgA measurements in children of varying ages. Methods We present a method to standardise IgA values for age and laboratory differences. We applied this method to a multicentre case–control study of children under the age of seven suffering from recurrent respiratory tract infections (rRTI, cases) and children who had IgA measured as part of coeliac disease screening (controls). We defined IgA deficiency as serum IgA measurements, With our method to standardize IgA values for laboratory and age differences, we show that IgA deficiency is more prevalent in children less than 7 years of age with recurrent respiratory infections compared with controls, implicating the clinical relevance.

Background Children seem relatively protected from serious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–related disease, but little is known about children living in settings with high tuberculosis and human immunodeficiency virus (HIV) burden. This study reflects clinical data on South African children with SARS-CoV-2. Methods We collected clinical data of children aged Results One hundred fifty-nine children (median age, 48.0 months [interquartile range {IQR}, 12.0–106.0 months]) were included. Hospitalized children (n = 62), with a median age of 13.5 months (IQR, 1.8–43.5 months) were younger than children not admitted (n = 97; median age, 81.0 months [IQR, 34.5–120.5 months]; P Conclusions Children

Contains fulltext : 177354.pdf (Publisher’s version ) (Open Access) Vaccination has been one of the most successful strategies to reduce morbidity and mortality caused by respiratory infections. Recent evidence suggests that differences in the host genetic background and environmental factors may contribute to heterogeneity in the immune response to vaccination. During pre-clinical testing, vaccines are often evaluated in a single mouse inbred strain, which may not translate well to the heterogeneous human population. Here, we examined the influence of host genetic background on vaccine-induced protection against pneumococcal colonization in two commonly used inbred mouse strains, i.e. C57BL/6 and BALB/cas well as the F1 cross of these two strains. Groups of mice were vaccinated intranasally with a vaccine formulation containing a model pneumococcal antigen, i.e. pneumococcal surface protein A (PspA), adjuvanted with cholera toxin subunit B (CTB). Even in the absence of vaccination, differences in colonization density were observed between mouse strains. Although vaccination significantly reduced pneumococcal density in all mouse strains, differences were observed in the magnitude of protection. We therefore examined immunological parameters known to be involved in vaccine-induced mucosal clearance of S. pneumoniae. We found that PspA-specific IgG levels in nasal tissue differed between mouse strains, but in all cases it correlated significantly with a reduction in colonization. Furthermore, increased mucosal IL17A, but not IFNgamma, IL10, or IL4, was found to be mouse strain specific. This suggests that the reduction of bacterial load may be accompanied by a Th17 response in all genetic backgrounds, although the cytokine dynamics may differ. Increased insight into the different immune mechanisms that affect pneumococcal carriage will contribute to development of future vaccines against S. pneumoniae.

Item does not contain fulltext OBJECTIVE: To assess risk factors for nasopharyngeal carriage of potential pathogens in geographically isolated Warao Amerindians in Venezuela. METHODS: In this point prevalence survey, nasopharyngeal swabs were obtained from 1064 Warao Amerindians: 504 children aged 0-4 years, 227 children aged 5-10 years and 333 caregivers. Written questionnaires were completed to obtain information on demographics and environmental risk factors. Anthropometric measurements were performed in children aged 0-4 years. RESULTS: Carriage rates of Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis were 51%, 7%, 1% and 13%, respectively. Crowding index, method of cooking and tobacco exposure were not associated with increased carriage. In multivariable analysis, an increase in height-for-age Z score (i.e. improved chronic nutritional status) was associated with decreased odds of S. pneumoniae colonisation (OR 0.76, 95% CI 0.70-0.83) in children aged 0-4 years. CONCLUSIONS: Better knowledge of demographic and environmental risk factors facilitates better understanding of the dynamics of colonisation with respiratory bacteria in an Amerindian population. Poor chronic nutritional status was associated with increased pathogen carriage in children

Immunoglobulin A (IgA) is the principal antibody in secretions that bathe the gastrointestinal and respiratory mucosal surfaces and acts as an important first line of defense against invasion of pathogenic micro-organisms. The reported prevalence rate of complete IgA deficiency in healthy children ranges from 1:170 to 1:400, and as a solitary condition, it is often considered of limited clinical importance. However, patients with IgA deficiency can develop recurrent respiratory and gastrointestinal infections, as well as allergic and autoimmune diseases. In children referred for recurrent respiratory tract infections, the observed prevalence rate increases more than tenfold. This review discusses several aspects of IgA deficiency in children, including immunologic and microbiome changes in early childhood and the potential consequences of this condition in later life. It illustrates the importance of early identification of children with impaired IgA production who deserve appropriate clinical care and follow-up.

The introduction of pneumococcal conjugate vaccines (PCVs) has the greatest impact in populations that are most affected by pneumococcal carriage and disease, such as indigenous children [1]. Although ∼10% of the South American population consists of indigenous people living in remote settings, to our knowledge PCVs have not been evaluated in native South American children. The Warao people are an Amerindian population residing in wooden houses along the Orinoco River delta in Venezuela. Almost one-third of Warao children die during childhood and respiratory tract infections are a major cause of death [2]. This study is the first to evaluate the impact of 13-valent (PCV13) vaccination on nasopharyngeal colonisation rates and antibody response in PCV-naive indigenous South American children. PCV13 catch-up regimens for children aged ≥ 24 months may need to include more than one vaccine dose The authors thank the participating families and the field workers involved in the recruitment and sampling of children, in particular the medical students of the Escuela de Medicina Jose Maria Vargas of the Universidad Central de Venezuela and Thor Kuchler, Marcella Overeem and Stephan Kraai (Laboratorio de Tuberculosis, Instituto de Biomedicina, Universidad Central de Venezuela, Caracas, Venezuela and Laboratory of Paediatric Infectious Diseases, Dept of Paediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands). Furthermore, we thank Jochem Burghouts (Laboratorio de Tuberculosis, Instituto de Biomedicina, Universidad Central de Venezuela and Laboratory of Paediatric Infectious Diseases, Dept of Paediatrics, Radboud Institute for Molecular Life Sciences) for facilitation of study logistics. At the RIVM (National Institute for Health and Environment, Bilthoven, the Netherlands), we thank Irina Tcherniaeva for technical support. We are grateful to the personnel of the Laboratorio de Tuberculosis, Instituto de Biomedicina (Universidad Central de Venezuela, Caracas, Venezuela), and we acknowledge Rogier Donders (Dept of Health Evidence, Radboud University Medical Centre) for statistics support.

Item does not contain fulltext OBJECTIVE: To determine the impact of pre-vaccination nutritional status on vaccine responses in Venezuelan Warao Amerindian children vaccinated with the 13-valent pneumococcal conjugate vaccine (PCV13) and to investigate whether saliva can be used as read-out for these vaccine responses. METHODS: A cross-sectional cohort of 504 Venezuelan Warao children aged 6 weeks - 59 months residing in nine geographically isolated Warao communities were vaccinated with a primary series of PCV13 according to Centers for Disease Control and Prevention (CDC)-recommended age-related schedules. Post-vaccination antibody concentrations in serum and saliva of 411 children were measured by multiplex immunoassay. The influence of malnutrition present upon vaccination on post-vaccination antibody levels was assessed by univariate and multivariable generalized estimating equations linear regression analysis. RESULTS: In both stunted (38%) and non-stunted (62%) children, salivary antibody concentrations correlated well with serum levels for all serotypes with coefficients varying from 0.61 for serotype 3-0.80 for serotypes 5, 6A and 23F (all p

Contains fulltext : 170058.pdf (Publisher’s version ) (Open Access) OBJECTIVES: Acceptance of childhood vaccination varies between societies, affecting worldwide vaccination coverage. Low coverage rates are common in indigenous populations where parents often choose not to vaccinate their children. We aimed to gain insight into reasons for vaccine acceptance or rejection among Warao Amerindians in Venezuela. METHODS: Based on records of vaccine acceptance or refusal, in-depth interviews with 20 vaccine-accepting and 11 vaccine-declining caregivers were performed. Parents' attitudes were explored using a qualitative approach. RESULTS: Although Warao caregivers were generally in favor of vaccination, fear of side effects and the idea that young and sick children are too vulnerable to be vaccinated negatively affected vaccine acceptance. The importance assigned to side effects was related to the perception that these resembled symptoms/diseases of another origin and could thus harm the child. Religious beliefs or traditional healers did not influence the decision-making process. CONCLUSIONS: Parental vaccine acceptance requires educational programs on the preventive nature of vaccines in relation to local beliefs about health and disease. Attention needs to be directed at population-specific concerns, including explanation on the nature of and therapeutic options for side effects.

Introduction:E xtraordinarily high tuberculosis (TB) prevalence rates have been reported in Venezuelan Amerindians. Amerindian populations often live in geographically isolated villages where they receive little medical attention and live under precarious sanitary conditions. TB prevalence varies by ethnicity and geographic location and is generally higher in Amerindians than in non-indigenous (Creole) people. Methodology: Between January 1, 1998 and December 31, 2009, the tuberculin skin test (TST) was administered during field operations to 9,538 Amerindian and Creole people between 0 and 94 years of age living in Venezuela. In 6,979 individuals (73%), Bacille Calmette-Guérin (BCG) vaccination status, age, and ethnicity were recorded.Univariate and multivariate analyses were performed to determine the influence of previous BCG vaccination, age, and ethnicity on TST outcomes. Results: Age, ethnicity, and the number of BCG vaccinations administered each had a significant influence on TST outcomes (p < 0.001). The influence of BCG vaccination on TST outcomes varied by ethnicity and was only significant in children aged between 0 and 3 years. Conclusions: The utility of TST in the diagnosis of TB infection in high TB burden settings with widespread BCG vaccination should be evaluated locally and individually as this depends on ethnicity, age, and the number of BCG vaccinations administered. In Venezuelan children 4 years of age and older, the TST remains a useful tool for the detection of TB infection, independent of BCG vaccination status.

Item does not contain fulltext Children with primary immunodeficiencies, sickle cell disease and cystic fibrosis are at risk to develop invasive bacterial infections caused by respiratory tract pathogens, in particular Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus. This review article evaluates the role of nasopharyngeal colonization by these pathogens in the high prevalence of respiratory and invasive infections in children with inherited disorders affecting the immune system or the respiratory tract. We conclude that respiratory and invasive diseases that occur in children with primary immunodeficiencies or sickle cell disease are probably a result of increased nasopharyngeal colonization rates compared with healthy children. However, when the inherited disorder is characterized by local airway abnormalities such as in cystic fibrosis, enhanced nasopharyngeal colonization does not seem to play a major role in invasive disease risk. As the evidence for the role of nasopharyngeal colonization in disease risk in these specific patient groups partly comes from experimental studies and animal models, longitudinal studies in children are needed. Detailed understanding of the effect of colonization on the development of respiratory and invasive infections in children with primary immunodeficiencies, sickle cell disease or cystic fibrosis provides a justification for the selective introduction of vaccination and prophylactic antibiotic treatment. Recommendations for the use of (preventive) therapeutic strategies in these patient groups taking into account disease-specific immunologic mechanisms underlying colonization and disease are described.

objectives The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela. methods Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1‐15 years. The effects of dose in mg ⁄kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined. results 25 patients (83%) had an isoniazid Cmax below 3 mg ⁄l and 23 patients (77%) had a rifampicin Cmax below 8 mg ⁄l. One patient (3%) had a pyrazinamide Cmax below 20 mg ⁄l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1‐4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5‐15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01). conclusion We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.

BACKGROUND: Tuberculosis (TB) transmission is associated with patient-related risk factors. However, DNA fingerprint analysis has provided anecdotal evidence suggesting a role for bacteriological factors. METHODS: To examine the importance of the bacteriological component in TB transmission, we investigated the number of tuberculin skin test-positive (TST induration, >/= 10 mm) contacts and secondary cases observed in contact investigations around TB cases in relation to the size of the genotype cluster the patient belonged to at the time of diagnosis. We also compared the number of TST-positive contacts and secondary cases of patients with drug-resistant and drug-susceptible TB. RESULTS: Larger clusters were independently associated with an increased number of positive contacts. The mean number of positive contacts ranged from 3.8 for clusters of 2 cases, to 4.7 for clusters of 3-10 cases, to 6.0 for cases in clusters of >10 cases (mean increase in number of positive contacts for every extra case in the cluster, 0.21; 95% confidence interval, 0.09-0.26). The mean number of positive contacts was significantly lower among index cases with isoniazid-monoresistant TB (1.6) than among index cases with pan-susceptible TB (4.6; relative number, 0.45; 95% confidence interval, 0.22-0.92). CONCLUSION: These results suggest that spread of tuberculosis also depends on bacteriological factors.

Contains fulltext : 88285.pdf (Publisher’s version ) (Closed access) The burden of childhood tuberculosis (TB) is influenced by the human immunodeficiency virus (HIV) epidemic and this dangerous synergy affects various aspects of both diseases; from pathogenesis and the epidemiologic profile to clinical presentation, diagnosis, treatment, and prevention. HIV-infected infants and children are at increased risk of developing severe forms of TB. The TB diagnosis is complicated by diminished sensitivity and specificity of clinical features and diagnostic tools like the tuberculin skin test and chest x-ray. Although alternative ways of pulmonary sampling and the development of interferon-gamma assays have shown to lead to some improvement of TB diagnosis in HIV-infected children, new diagnostic tools are urgently needed. Coadministration of anti-TB treatment and antiretroviral drugs induces severe complications, and this highlights the need to define optimal treatment regimens. Practical implementation of these regimens in TB control programs should be combined with isoniazid preventive therapy in TB-exposed HIV-infected children. The risk of severe complications after Bacille Calmette-Guerin vaccination of HIV-infected children emphasizes the need for new nonviable vaccines. This article reviews the current status of pediatric HIV-TB coinfection with specific emphasis on the diagnosis and treatment. 01 oktober 2010

Contains fulltext : 153830.pdf (Publisher’s version ) (Closed access) Community-acquired pneumonia is a potentially life-threatening disease affecting children worldwide. Recurrent pneumonia episodes can lead to the development of chronic respiratory morbidity. Chronic wet cough, a common pediatric complaint, is defined as a wet cough indicating excessive airway mucus that lasts for a minimum of 4 weeks. Most children with a chronic wet cough do not suffer from underlying debilitating pulmonary disorders. Rather, chronic wet cough is generally associated with neutrophilic airway inflammation and bacterial infections of the conducting airways. Failure to characterize endobronchial infections has led to under-recognition of chronic wet cough as an important clinical entity in children. Under-recognition and under-treatment of protracted bacterial bronchitis (PBB), a diagnosis made by the presence of isolated cough >4 weeks that resolves with appropriate antibiotic treatment, may lead to the development of chronic suppurative lung disease (CSLD) and bronchiectasis. The burden of bronchiectasis is highest in developing countries and in specifically vulnerable populations in developed countries, in particular indigenous children living in remote communities. The incidence, hospitalization rates and risk of long term sequelae of childhood pneumonia in indigenous children are higher than in non-indigenous children residing in the same area. The overlapping clinical and pathophysiological characteristics of PBB, CSLD and bronchiectasis are the presence of a chronic wet cough, impaired mucociliary clearance of the conducting airways, the presence of endobronchial bacterial infection (mainly non-typeable Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis) and neutrophilic airway inflammation. The principles of managing PBB, CSLD and bronchiectasis are the same. More research and public health interventions are required to improve the awareness, diagnosis and management of these causes of chronic wet cough in children.

The aim of this study was to determine if mycobacterial lineages affect infection risk, clustering, and disease progression among Mycobacterium tuberculosis cases in The Netherlands. Multivariate negative binomial regression models adjusted for patient-related factors and stratified by patient ethnicity were used to determine the association between phylogenetic lineages and infectivity (mean number of positive contacts around each patient) and clustering (as defined by number of secondary cases within 2 years after diagnosis of an index case sharing the same fingerprint) indices. An estimate of progression to disease by each risk factor was calculated as a bootstrapped risk ratio of the clustering index by the infectivity index. Compared to the Euro-American reference, Mycobacterium africanum showed significantly lower infectivity and clustering indices in the foreign-born population, while Mycobacterium bovis showed significantly lower infectivity and clustering indices in the native population. Significantly lower infectivity was also observed for the East African Indian lineage in the foreign-born population. Smear positivity was a significant risk factor for increased infectivity and increased clustering. Estimates of progression to disease were significantly associated with age, sputum-smear status, and behavioral risk factors, such as alcohol and intravenous drug abuse, but not with phylogenetic lineages. In conclusion, we found evidence of a bacteriological factor influencing indicators of a strain's transmissibility, namely, a decreased ability to infect and a lower clustering index in ancient phylogenetic lineages compared to their modern counterparts. Confirmation of these findings via follow-up studies using tuberculin skin test conversion data should have important implications on M. tuberculosis control efforts., This study was supported by the Portuguese Foundation for Science and Technology (FCT) (reference SFRH/BD/33902/2009 to H.N.-G)

Item does not contain fulltext Dengue is a mosquito-borne viral disease of expanding geographical range and increasing incidence. The vast majority of dengue cases are children less than 15 years of age. Dengue causes a spectrum of illness from mild fever to severe disease with plasma leakage and shock. Infants and children with secondary heterologous dengue infections are most at risk for severe dengue disease. Laboratory diagnosis of dengue can be established within five days of disease onset by direct detection of viral components in serum. After day five, serologic diagnosis provides indirect evidence of dengue. Currently, no effective antiviral agents are available to treat dengue infection. Therefore, treatment remains supportive, with emphasis on close hematological monitoring, recognition of warning signs of severe disease and fluid-replacement therapy and/or blood transfusions when required. Development of a dengue vaccine is considered a high public health priority. A safe and efficacious dengue vaccine would also be important for travelers. This review highlights the current understanding of dengue in children, including its clinical manifestations, pathogenesis, diagnostic tests, management and prevention.

Contains fulltext : 137375.pdf (Publisher’s version ) (Open Access) BACKGROUND: Interferon-gamma release assays have emerged as a more specific alternative to the tuberculin skin test (TST) for detection of tuberculosis (TB) infection, especially in Bacille Calmette-Guerin (BCG) vaccinated people. We determined the prevalence of Mycobacterium tuberculosis infection by TST and QuantiFERON(R)-TB Gold In-Tube (QFT-GIT) and assessed agreement between the two test methods and factors associated with positivity in either test in Warao Amerindian children in Venezuela. Furthermore, progression to active TB disease was evaluated for up to 12 months. METHODS: 163 HIV-negative childhood household contacts under 16 years of age were enrolled for TST, QFT-GIT and chest X-ray (CXR). Follow-up was performed at six and 12 months. Factors associated with TST and QFT-GIT positivity were studied using generalized estimation equations logistic regression models. RESULTS: At baseline, the proportion of TST positive children was similar to the proportion of children with a positive QFT-GIT (47% vs. 42%, p = 0.12). Overall concordance between QFT-GIT and TST was substantial (kappa 0.76, 95% CI 0.46-1.06). Previous BCG vaccination was not associated with significantly increased positivity in either test (OR 0.68, 95% CI 0.32-1.5 for TST and OR 0.51, 95% CI 0.14-1.9 for QFT-GIT). Eleven children were diagnosed with active TB at baseline. QFT-GIT had a higher sensitivity for active TB (88%, 95% CI 47-98%) than TST (55%, 95% CI 24-83%) while specificities were similar (respectively 58% and 55%). Five initially asymptomatic childhood contacts progressed to active TB disease during follow-up. CONCLUSION: Replacement of TST by the QFT-GIT for detection of M. tuberculosis infection is not recommended in this resource-constrained setting as test results showed substantial concordance and TST positivity was not affected by previous BCG vaccination. The QFT-GIT had a higher sensitivity than the TST for the detection of TB disease. However, the value of the QFT-GIT as an adjunct in diagnosing TB disease is limited by a high variability in QFT-GIT results over time.

Background: Genetic variants in NAT2 are associated with pharmacokinetic variation of isoniazid, the cornerstone of antituberculosis treatment. We investigated the acetylator genotype and phenotype in children on antituberculosis treatment that were previously shown to have low plasma isoniazid levels. Materials & methods:NAT2 genotyping and phenotyping, represented as metabolic ratio of acetylisoniazid over isoniazid and as isoniazid half-life, were performed in 30 Venezuelan children. Results: Most children carried genotypes resulting in an intermediate or low enzyme activity (43 and 40%, respectively). Isoniazid exposure differed between genotypically slow and rapid acetylators (13.3 vs 4.5 h×mg/l, p < 0.01). Both the metabolic ratio as well as the half-life of isoniazid distinguished genotypically slow from genotypically rapid or intermediate acetylators (all p ≤ 0.01). Conclusion: In Venezuelan children a clear difference in isoniazid pharmacokinetics and acetylator phenotype between genotypically slow and genotypically intermediate or rapid acetylating children was observed. Original submitted 31 July 2013; Revision submitted 11 November 2013

Item does not contain fulltext OBJECTIVES: High acute respiratory tract infection (ARTI) rates are observed in indigenous populations. We assessed the role of viral infections and nasopharyngeal bacterial carriage in ARTIs in Enepa Amerindians from Venezuela. METHODS: In 40 children aged 0-10 years with ARTIs, healthy nearest-age sibling controls and their mothers the presence of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydophila pneumoniae/psittachi and 15 respiratory viruses was investigated. RESULTS: S. pneumoniae was the most frequently detected pathogen, with carriage rates of 75% and 38% in children and mothers respectively. In children, S. pneumoniae carriage was associated with ARTI risk in multivariate analysis (OR 14.1, 95% CI 1.4-137.7). Viral infections were not associated with ARTI risk. S. pneumoniae carriage was common in children of all ages while viral co-infections were more frequently present in children under 4 years compared to older children (46% vs. 17%, p < 0.01). An increase of one unit height-for-age Z score (i.e. improved chronic nutritional status) was associated with decreased odds of S. pneumoniae colonization in multivariate analysis (OR 0.66, 95% CI 0.44-0.99). CONCLUSIONS: In Enepa children high S. pneumoniae carriage rates associated with a poor nutritional status contribute to the development of ARTIs.

Contains fulltext : 125614.pdf (Publisher’s version ) (Open Access) BACKGROUND: Children in rural areas experience the interrelated problems of poor growth, anemia and parasitic infections. We investigated the prevalence of and associations between intestinal helminth and protozoan infections, malnutrition and anemia in school-age Venezuelan children. METHODS: This cross-sectional study was conducted in 390 children aged 4-16 years from three rural areas of Venezuela: the Amazon Region, Orinoco Delta and Carabobo State. Stool samples were collected for direct parasitic examinations. Anthropometric indicators of chronic (height-for-age Z score) and acute (weight-for-height and Body Mass Index (BMI)-for-age Z score in respectively children under 5 years of age and children aged 5 years and above) malnutrition were calculated. Multivariate linear and logistic regression models were built to determine factors associated with nutritional status and polyparasitism. RESULTS: Hookworm and Strongyloides stercoralis prevalences were highest in children from the Amazon rainforest (respectively 72% and 18%) while children from the Orinoco Delta and Carabobo State showed higher rates of Ascaris lumbricoides (respectively 28% and 37%) and Trichuris trichiura (40% in both regions). The prevalence of Giardia lamblia infection was not significantly different between regions (average: 18%). Anemia prevalence was highest in the Amazon Region (24%). Hemoglobin levels were significantly decreased in children with a hookworm infection. Malnutrition was present in respectively 84%, 30% and 13% of children from the Amazon Region, Orinoco Delta and Carabobo State. In multivariate analysis including all regions, G. lamblia and helminth infections were significantly and negatively associated with respectively height-for-age and weight-for-height/BMI-for-age Z scores. Furthermore, hemoglobin levels were positively associated with the height-for-age Z score (0.11, 95% CI 0.02 - 0.20). CONCLUSIONS: In rural populations in Venezuela helminthiasis and giardiasis were associated with acute and chronic nutritional status respectively. These data highlight the need for an integrated approach to control transmission of parasites and improve the health status of rural Venezuelan children.

Item does not contain fulltext BACKGROUND: Higher prevalence rates of acute respiratory tract infections (ARTIs) have been described in Australian and Canadian indigenous populations than in nonindigenous age-matched counterparts. Few studies on ARTIs in South American indigenous populations have been published. We performed a cross-sectional survey to describe the prevalence of upper respiratory tract infections and acute lower respiratory tract infections (ALRTIs) and associations with malnutrition and immunization status. METHODS: From December 1, 2009 to May 31, 2010, 487 Warao Amerindian children 0 to 59 months of age living in the Delta Amacuro in Venezuela were included in a cross-sectional survey. Data were obtained through parent questionnaires, vaccination cards, and physical examinations including anthropometric measurements. RESULTS: Of the 487 children, 47% presented with an ARTI. Of these, 60% had upper respiratory tract infections and 40% were ALRTI. Immunization coverage was low, with only 27% of all children presenting a vaccination card being fully immunized. The prevalence of malnutrition was high (52%), with stunting (height-for-age

Contains fulltext : 136554.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 124347.pdf (Publisher’s version ) (Closed access) This study aimed to determine to what extent tuberculosis trends in the Netherlands depend on secular trend, immigration and recent transmission. Data on patients in the Netherlands Tuberculosis Register in the period 1993-2007 were matched with restriction fragment length polymorphism (RFLP) patterns of Mycobacterium tuberculosis isolates. Index patients were defined as patients with pulmonary tuberculosis whose isolates had RFLP patterns not observed in another patient in the previous 2 yrs. Among 8,330 patients with pulmonary tuberculosis the isolates of 56% of native and 50% of foreign-born patients were clustered. Of these, 5,185 were included in detailed analysis: 1,376 native index patients, 2,822 foreign-born index patients and 987 secondary cases within 2 yrs of diagnosis of the index case. The incidence of native and foreign-born index patients declined by 6% and 2% per year, respectively. The number of secondary cases per index case was 0.24. The decline of native cases contributed most to the overall decline of tuberculosis rates and was largely explained by a declining prevalence of latent infection. Tuberculosis among immigrants was associated with immigration figures. Progress towards elimination of tuberculosis would benefit from intensifying diagnosis and treatment of latent infection among immigrants and global tuberculosis control. 01 augustus 2010 2A p.

Background The International Study on Asthma and Allergies in Childhood (ISAAC) reported a prevalence of asthma symptoms in 17 centers in nine Latin American countries that was similar to prevalence rates reported in non-tropical countries. It has been proposed that the continuous exposure to infectious diseases in rural populations residing in tropical areas leads to a relatively low prevalence of asthma symptoms. As almost a quarter of Latin American people live in rural tropical areas, the encountered high prevalence of asthma symptoms is remarkable. Wood smoke exposure and environmental tobacco smoke have been identified as possible risk factors for having asthma symptoms. Methods We performed a cross-sectional observational study from June 1, 2012 to September 30, 2012 in which we interviewed parents and guardians of Warao Amerindian children from Venezuela. Asthma symptoms were defined according to the ISAAC definition as self-reported wheezing in the last 12 months. The associations between wood smoke exposure and environmental tobacco smoke and the prevalence of asthma symptoms were calculated by means of univariate and multivariable logistic regression analyses. Results We included 630 children between two and ten years of age. Asthma symptoms were recorded in 164 of these children (26%). The prevalence of asthma symptoms was associated with the cooking method. Children exposed to the smoke produced by cooking on open wood fires were at higher risk of having asthma symptoms compared to children exposed to cooking with gas (AOR 2.12, 95% CI 1.18 - 3.84). Four percent of the children lived in a household where more than ten cigarettes were smoked per day and they had a higher risk of having asthma symptoms compared to children who were not exposed to cigarette smoke (AOR 2.69, 95% CI 1.11 - 6.48). Conclusion Our findings suggest that children living in rural settings in a household where wood is used for cooking or where more than ten cigarettes are smoked daily have a higher risk of having asthma symptoms.

Background Diagnostic delay in patients with tuberculosis (TB) leads to ongoing TB transmission, higher mortality rates and increased patient and government health expenditure. Qualitative research focussed on patients’ self-perceptions of disease and their care-seeking behaviour helps to guide health education programmes by providing us with the understanding of the knowledge, attitudes and practices that underlie diagnostic delay. Patients and methods Semi-structured interviews with 28 recently diagnosed TB patients and four traditional healers were conducted. The interviews were audio-recorded and content analysis was performed. Results The median total delay was 188 days. The health provider delay (31 days) was longer than the patient delay (21 days) and the health system delay (26 days). The health system delay was longest in patients not being diagnosed at their first hospital visit and subsequently visiting other health care providers, mostly traditional healers. Conclusions A poor knowledge of TB signs and symptoms and patients’ beliefs about curses as the origin of diseases lead to delayed care-seeking at the hospital level in an area of North-Western Tanzania. Failure to identify TB cases by formal and non-formal health providers indicates that the education of both communities as well as health workers is essential in order to reduce diagnostic delays.

Contains fulltext : 136668.pdf (Publisher’s version ) (Open Access) BACKGROUND: While in developed countries the prevalence of allergic diseases is rising, inflammatory diseases are relatively uncommon in rural developing areas. High prevalence rates of helminth and protozoan infections are commonly found in children living in rural settings and several studies suggest an inverse association between helminth infections and allergies. No studies investigating the relationship between parasitic infections and atopic diseases in rural children of developing countries under the age of 2 years have been published so far. We performed a cross-sectional survey to investigate the association of helminth and protozoan infections and malnutrition with recurrent wheezing and atopic eczema in Warao Amerindian children in Venezuela. METHODS: From August to November 2012, 229 children aged 0 to 2 years residing in the Orinoco Delta in Venezuela were enrolled. Data were collected through standardized questionnaires and physical examination, including inspection of the skin and anthropometric measurements. A stool sample was requested from all participants and detection of different parasites was performed using microscopy and real time polymerase chain reaction (PCR). RESULTS: We observed high prevalence rates of atopic eczema and recurrent wheezing, respectively 19% and 23%. The prevalence of helminth infections was 26% and the prevalence of protozoan infections was 59%. Atopic eczema and recurrent wheezing were more frequently observed in stunted compared with non-stunted children in multivariable analysis (OR 4.3, 95% CI 1.3 - 13.6, p = 0.015 and OR 4.5, 95% CI 0.97 - 21.2, p = 0.055). Furthermore, recurrent wheezing was significantly more often observed in children with protozoan infections than in children without protozoan infections (OR 6.7, 95% CI 1.5 - 30.5). CONCLUSIONS: High prevalence rates of atopic eczema and recurrent wheezing in Warao Amerindian children under 2 years of age were related to stunting and intestinal protozoan infections respectively. Helminth infections were not significantly associated with either atopic eczema or recurrent wheezing.