T cell derived HIV-1 is present in the CSF in the face of suppressive antiretroviral therapy.

HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus producing cell type and whether lowered CSF ART levels are responsible for CSF escape, we collected blood and CSF from 156 neurosymptomatic participants from Durban, South Africa. We observed that 28% of participants with an undetectable HIV blood viral load showed CSF escape. We detected host cell surface markers on the HIV envelope to determine the cellular source of HIV in participants on the first line regimen of efavirenz, emtricitabine, and tenofovir. We confirmed CD26 as a marker which could differentiate between T cells and macrophages and microglia, and quantified CD26 levels on the virion surface, comparing the result to virus from in vitro infected T cells or macrophages. The measured CD26 level was consistent with the presence of T cell produced virus. We found no significant differences in ART concentrations between CSF escape and fully suppressed individuals in CSF or blood, and did not observe a clear association with drug resistance mutations in CSF virus which would allow HIV to replicate. Hence, CSF HIV in the face of ART may at least partly originate in CD4+ T cell populations.

Maternal demographic and antenatal factors, low birth weight and preterm birth: findings from the mother and child in the environment (MACE) birth cohort, Durban, South Africa.

BACKGROUND: Low birthweight (LBW) and preterm birth (PB) remain the leading cause of morbidity and mortality in neonates worldwide. The aim of this study was to identify maternal demographic and antenatal factors associated with PB and LBW among low socio-economic communities. METHODS: Pregnant women (n = 1099) were recruited in the first trimester into the Mother and Child in the Environment (MACE) birth cohort in Durban, South Africa. Maternal factors such as demographic information, health status, residential area, occupational, personal and environmental smoking and biomass fuel use were obtained through standardised interviews, while clinical status was obtained in each trimester and antenatal information on HIV status and treatment, syphilis and conditions such as pregnancy induced hypertension, diabetes etc. was extracted from the antenatal assessments. Key outcomes of interest were preterm birth and low birthweight. The latter data was obtained from the clinical assessments performed by midwives at delivery. Logistic regression models identified factors associated with PB and LBW. RESULTS: Of the 760 live births, 16.4 and 13.5% were preterm and LBW, respectively. Mothers who delivered by caesarean section had an increased odds of having LBW babies (Adjusted odds ratio (AOR): 1.7; 95% CI: 1.1-2.7) and PB (AOR: 1.7, 95% CI: 1.1-2.7) versus normal vaginal deliveries. Mothers > 30 years (AOR: 1.8, 95% CI: 1.1-2.9) and current smokers (AOR: 2.7, 95% CI: 1.3-5.8) had an increased odds of having PB babies. Compared to younger mothers and non-smokers respectively. An effect of PB and LBW was seen among mothers with high BMI (25.0-29.9 kg/m2) (PB: AOR: 0.5, 95% CI: 0.3-0.9 and LBW: AOR: 0.5, 0.5, CI: 0.3-0.8), and obese BMI (> 30 kg/m2) (PB: AOR: 0.5, 95% CI: 0.3-0.9 and LBW: AOR: 0.4, CI: 0.2-0.7). Maternal HIV (PB AOR: 1.4 and LBW AOR: 1.2) and history of sexually transmitted infections (PB AOR: 2.7 and LBW AOR: 4.2) were not statistically significant. CONCLUSION: Maternal age, cigarette smoking and caesarean delivery were associated with LBW and PB. Findings highlight the need of maternal health interventions to improve new-born health outcomes.

Association of childhood pulmonary tuberculosis with exposure to indoor air pollution: a case control study.

BACKGROUND: Crude measures of exposure to indicate indoor air pollution have been associated with the increased risk for acquiring tuberculosis. Our study aimed to determine an association between childhood pulmonary tuberculosis (PTB) and exposure to indoor air pollution (IAP), based on crude exposure predictors and directly sampled and modelled pollutant concentrations. METHODS: In this case control study, children diagnosed with PTB were compared to children without PTB. Questionnaires about children's health; and house characteristics and activities (including household air pollution) and secondhand smoke (SHS) exposure were administered to caregivers of participants. A subset of the participants' homes was sampled for measurements of PM10 over a 24-h period (n = 105), and NO2 over a period of 2 to 3 weeks (n = 82). IAP concentrations of PM10 and NO2 were estimated in the remaining homes using predictive models. Logistic regression was used to look for association between IAP concentrations, crude measures of IAP, and PTB. RESULTS: Of the 234 participants, 107 were cases and 127 were controls. Pollutants concentrations (µg/m3) for were PM10 median: 48 (range: 6.6-241) and NO2 median: 16.7 (range: 4.5-55). Day-to-day variability within- household was large. In multivariate models adjusted for age, sex, socioeconomic status, TB contact and HIV status, the crude exposure measures of pollution viz. cooking fuel type (clean or dirty fuel) and SHS showed positive non-significant associations with PTB. Presence of dampness in the household was a significant risk factor for childhood TB acquisition with aOR of 2.4 (95% CI: 1.1-5.0). The crude exposure predictors of indoor air pollution are less influenced by day-to-day variability. No risk was observed between pollutant concentrations and PTB in children for PM10 and NO2. CONCLUSION: Our study suggests increased risk of childhood tuberculosis disease when children are exposed to SHS, dirty cooking fuel, and dampness in their homes. Yet, HIV status, age and TB contact are the most important risk factors of childhood PTB in this population.

Indoor air quality of low and middle income urban households in Durban, South Africa.

INTRODUCTION: Elevated levels of indoor air pollutants may cause cardiopulmonary disease such as lower respiratory infection, chronic obstructive lung disease and lung cancer, but the association with tuberculosis (TB) is unclear. So far the risk estimates of TB infection or/and disease due to indoor air pollution (IAP) exposure are based on self-reported exposures rather than direct measurements of IAP, and these exposures have not been validated. OBJECTIVE: The aim of this paper was to characterize and develop predictive models for concentrations of three air pollutants (PM10, NO2 and SO2) in homes of children participating in a childhood TB study. METHODS: Children younger than 15 years living within the eThekwini Municipality in South Africa were recruited for a childhood TB case control study. The homes of these children (n=246) were assessed using a walkthrough checklist, and in 114 of them monitoring of three indoor pollutants was also performed (sampling period: 24h for PM10, and 2-3 weeks for NO2 and SO2). Linear regression models were used to predict PM10 and NO2 concentrations from household characteristics, and these models were validated using leave out one cross validation (LOOCV). SO2 concentrations were not modeled as concentrations were very low. RESULTS: Mean indoor concentrations of PM10 (n=105), NO2 (n=82) and SO2 (n=82) were 64µg/m3 (range 6.6-241); 19µg/m3 (range 4.5-55) and 0.6µg/m3 (range 0.005-3.4) respectively with the distributions for all three pollutants being skewed to the right. Spearman correlations showed weak positive correlations between the three pollutants. The largest contributors to the PM10 predictive model were type of housing structure (formal or informal), number of smokers in the household, and type of primary fuel used in the household. The NO2 predictive model was influenced mostly by the primary fuel type and by distance from the major roadway. The coefficients of determination (R2) for the models were 0.41 for PM10 and 0.31 for NO2. Spearman correlations were significant between measured vs. predicted PM10 and NO2 with coefficients of 0.66 and 0.55 respectively. CONCLUSION: Indoor PM10 levels were relatively high in these households. Both PM10 and NO2 can be modeled with a reasonable validity and these predictive models can decrease the necessary number of direct measurements that are expensive and time consuming.

Lung infiltrates in antiretroviral-naive HIV-infected children with chronic lung disease: value of non-bronchoscopic bronchoalveolar lavage in the detection of Candida albicans.

OBJECTIVE: To describe the etiology of lung infiltrates in HIV-infected antiretroviral-naive children with chronic persistent/recurrent lung disease in whom routine cultures were negative and were non-responders to World Health Organization standard antimicrobial therapy. METHOD: Non-bronchoscopic bronchoalveolar lavage (NBBAL) was performed on these non-responders. RESULTS: Fifty children were enrolled. Single isolates on NBBAL were seen in 28 cases, dual pathogens in 5 cases and no growth in 14 cases. Haemophilus influenzae (n = 12), Candida albicans (n = 5) and Mycobacterium spp. other than tuberculosis (n = 4) were the commonest pathogens seen. Eight cases with no growth had segmental or lobar collapse: in five cases, NBBAL was therapeutic and in two cases, a diagnosis of lymphoma was made on open lung biopsy. Thirty-two of the 38 cases (84%) had favorable outcomes on follow-up. CONCLUSION: Haemophilus influenzae, C. albicans and Mycobacterium spp. other than tuberculosis are important pathogens in children with HIV and HIV-associated chronic lung disease.

Advances in childhood immunisation in South Africa: where to now? Programme managers' views and evidence from systematic reviews.

BACKGROUND: The Expanded Programme on Immunisation (EPI) is one of the most powerful and cost-effective public health programmes to improve child survival. We assessed challenges and enablers for the programme in South Africa, as we approach the 2015 deadline for the Millennium Development Goals. METHODS: Between September 2009 and September 2010 we requested national and provincial EPI managers in South Africa to identify key challenges facing EPI, and to propose appropriate solutions. We collated their responses and searched for systematic reviews on the effectiveness of the proposed solutions; in the Health Systems Evidence, Cochrane Library, and PubMed electronic databases. We screened the search outputs, selected systematic reviews, extracted data, and assessed the quality of included reviews (using AMSTAR) and the quality of the evidence (using GRADE) in duplicate; resolving disagreements by discussion and consensus. RESULTS: Challenges identified by EPI managers were linked to healthcare workers (insufficient knowledge of vaccines and immunisation), the public (anti-immunisation rumours and reluctance from parents), and health system (insufficient financial and human resources). Strategies proposed by managers to overcome the challenges include training, supervision, and audit and feedback; strengthening advocacy and social mobilisation; and sustainable EPI funding schemes, respectively. The findings from reliable systematic reviews indicate that interactive educational meetings, audit and feedback, and supportive supervision improve healthcare worker performance. Structured and interactive communication tools probably increase parents' understanding of immunisation; and reminders and recall, use of community health workers, conditional cash transfers, and mass media interventions probably increase immunisation coverage. Finally, a national social health insurance scheme is a potential EPI financing mechanism; however, given the absence of high-quality evidence of effects, its implementation should be pilot-tested and the impacts and costs rigorously monitored. CONCLUSION: In line with the Millennium Development Goals, we have to ensure that our children's right to health, development and survival is respected, protected and promoted. EPI is central to this vision. We found numerous promising strategies for improving EPI performance in South Africa. However, their implementation would need to be tailored to local circumstances and accompanied by high-quality monitoring and evaluation. The strength of our approach comes from having a strong framework for interventions before looking for systematic reviews. Without a framework, we would have been driven by what reviews have been done and what is easily researchable; rather than the values and preferences of key immunisation stakeholders.

Derivation and validation of a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality in 20 countries.

INTRODUCTION: Existing risk assessment tools to identify children at risk of hospitalised pneumonia-related mortality have shown suboptimal discriminatory value during external validation. Our objective was to derive and validate a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality across various settings. METHODS: We used primary, baseline, patient-level data from 11 studies, including children evaluated for pneumonia in 20 low-income and middle-income countries. Patients with complete data were included in a logistic regression model to assess the association of candidate variables with the outcome hospitalised pneumonia-related mortality. Adjusted log coefficients were calculated for each candidate variable and assigned weighted points to derive the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) risk assessment tool. We used bootstrapped selection with 200 repetitions to internally validate the PREPARE risk assessment tool. RESULTS: A total of 27 388 children were included in the analysis (mean age 14.0 months, pneumonia-related case fatality ratio 3.1%). The PREPARE risk assessment tool included patient age, sex, weight-for-age z-score, body temperature, respiratory rate, unconsciousness or decreased level of consciousness, convulsions, cyanosis and hypoxaemia at baseline. The PREPARE risk assessment tool had good discriminatory value when internally validated (area under the curve 0.83, 95% CI 0.81 to 0.84). CONCLUSIONS: The PREPARE risk assessment tool had good discriminatory ability for identifying children at risk of hospitalised pneumonia-related mortality in a large, geographically diverse dataset. After external validation, this tool may be implemented in various settings to identify children at risk of hospitalised pneumonia-related mortality.

In silico children and the glass mouse model: clinical trial simulations to identify and individualize optimal isoniazid doses in children with tuberculosis.

Children with tuberculosis present with high rates of disseminated disease and tuberculous (TB) meningitis due to poor cell-mediated immunity. Recommended isoniazid doses vary from 5 mg/kg/day to 15 mg/kg/day. Antimicrobial pharmacokinetic/pharmacodynamic studies have demonstrated that the ratio of the 0- to 24-h area under the concentration-time curve (AUC(0-24)) to the MIC best explains isoniazid microbial kill. The AUC(0-24)/MIC ratio associated with 80% of maximal kill (80% effective concentration [EC(80)]), considered the optimal effect, is 287.2. Given the pharmacokinetics of isoniazid encountered in children 10 years old or younger, with infants as a special group, and given the differences in penetration of isoniazid into phagocytic cells, epithelial lining fluid, and subarachnoid space during TB meningitis, we performed 10,000 patient Monte Carlo simulations to determine how well isoniazid doses of between 2.5 and 40 mg/kg/day would achieve or exceed the EC(80). None of the doses examined achieved the EC(80) in ≥90% of children. Doses of 5 mg/kg were universally inferior; doses of 10 to 15 mg/kg/day were adequate only under the very limited circumstances of children who were slow acetylators and had disease limited to pneumonia. Each of the three disease syndromes, acetylation phenotype, and being an infant required different doses to achieve adequate AUC(0-24)/MIC exposures in an acceptable proportion of children. We conclude that current recommended doses for children are likely suboptimal and that isoniazid doses in children are best individualized based on disease process, age, and acetylation status.

Validation of visual estimation of neonatal jaundice in low-income and middle-income countries: a multicentre observational cohort study.

OBJECTIVE: Determine the sensitivity and specificity of neonatal jaundice visual estimation by primary healthcare workers (PHWs) and physicians as predictors of hyperbilirubinaemia. DESIGN: Multicentre observational cohort study. SETTING: Hospitals in Chandigarh and Delhi, India; Dhaka, Bangladesh; Durban, South Africa; Kumasi, Ghana; La Paz, Bolivia. PARTICIPANTS: Neonates aged 1-20 days (n=2642) who presented to hospitals for evaluation of acute illness. Infants referred for any reason from another health facility or those needing immediate cardiopulmonary resuscitation were excluded. OUTCOME MEASURES: Infants were evaluated for distribution (head, trunk, distal extremities) and degree (mild, moderate, severe) of jaundice by PHWs and physicians. Serum bilirubin level was determined for infants with jaundice, and analyses of sensitivity and specificity of visual estimations of jaundice used bilirubin thresholds of >260 µmol/L (need for phototherapy) and >340 µmol/L (need for emergency intervention in at-risk and preterm babies). RESULTS: 1241 (47.0%) neonates had jaundice. High sensitivity for detecting neonates with serum bilirubin >340 µmol/L was found for 'any jaundice of the distal extremities (palms or soles) OR deep jaundice of the trunk or head' for both PHWs (89%-100%) and physicians (81%-100%) across study sites; specificity was more variable. 'Any jaundice of the distal extremities' identified by PHWs and physicians had sensitivity of 71%-100% and specificity of 55%-95%, excluding La Paz. For the bilirubin threshold >260 µmol/L, 'any jaundice of the distal extremities OR deep jaundice of the trunk or head' had the highest sensitivity across sites (PHWs: 58%-93%, physicians: 55%-98%). CONCLUSIONS: In settings where serum bilirubin cannot be measured, neonates with any jaundice on the distal extremities should be referred to a hospital for evaluation and management, where delays in serum bilirubin measurement and appropriate treatment are anticipated following referral, the higher sensitivity sign, any jaundice on the distal extremities or deep jaundice of the trunk or head, may be preferred.

Effect of age, polymicrobial disease, and maternal HIV status on treatment response and cause of severe pneumonia in South African children: a prospective descriptive study.

BACKGROUND: HIV-related pneumonia is the main cause of paediatric hospital admissions in southern Africa. We aimed to measure predictors of treatment failure and the cause of non-responsive pneumonia in children admitted to hospital with severe pneumonia in Durban, South Africa. METHODS: We investigated 358 children aged 1-59 months who presented with WHO-defined severe or very severe pneumonia. Children were recruited irrespective of HIV status and started on a standard antimicrobial regimen of benzylpenicillin and gentamicin. All infants also received high-dose trimethoprim-sulfamethoxazole. The primary outcome measure was treatment failure at 48 h. FINDINGS: 242 (68%) children were HIV infected, 41 (12%) HIV exposed, uninfected, and 75 (21%) HIV uninfected. Failure to respond by 48 h was predicted by age under 1 year (adjusted odds ratio 6.38, 95% CI 2.72-14.91, p<0.0001), very severe disease (2.47, 1.17-5.24, p=0.0181), HIV status (HIV infected 10.3, 3.26-32.51; HIV exposed, uninfected 6.02, 1.55-23.38; p=0.0003), and polymicrobial disease (one organism 2.06, 1.05-4.05; two organisms 10.75, 4.38-26.36; p<0.0001) on logistic regression analysis. All children with three organisms failed treatment. 72/110 treatment failures had at least two organisms isolated. Three of nine HIV-exposed, uninfected infants, 29/74 HIV-infected, but no HIV-uninfected infants who failed study therapy had Pneumocystis jirovecii pneumonia. INTERPRETATION: For children younger than 1 year, the WHO guidelines are inadequate and need to be revised since both HIV-infected and HIV-exposed, uninfected infants had more treatment failures than did HIV-uninfected infants. Polymicrobial disease is an important reason for treatment failure, and we need to identify rapid low-cost diagnostic methods to assist clinicians.

Rapid Accurate Identification of Tuberculous Meningitis Among South African Children Using a Novel Clinical Decision Tool.

BACKGROUND: Early diagnosis of tuberculous meningitis (TBM) is crucial to achieve optimum outcomes. There is no effective rapid diagnostic test for use in children. We aimed to develop a clinical decision tool to facilitate the early diagnosis of childhood TBM. METHODS: Retrospective case-control study was performed across 7 hospitals in KwaZulu-Natal, South Africa (2010-2014). We identified the variables most predictive of microbiologically confirmed TBM in children (3 months to 15 years) by univariate analysis. These variables were modelled into a clinical decision tool and performance tested on an independent sample group. RESULTS: Of 865 children with suspected TBM, 3% (25) were identified with microbiologically confirmed TBM. Clinical information was retrieved for 22 microbiologically confirmed cases of TBM and compared with 66 controls matched for age, ethnicity, sex and geographical origin. The 9 most predictive variables among the confirmed cases were used to develop a clinical decision tool (CHILD TB LP): altered Consciousness; caregiver HIV infected; Illness length >7 days; Lethargy; focal neurologic Deficit; failure to Thrive; Blood/serum sodium <132 mmol/L; CSF >10 Lymphocytes ×10/L; CSF Protein >0.65 g/L. This tool successfully classified an independent sample of 7 cases and 21 controls with a sensitivity of 100% and specificity of 90%. CONCLUSIONS: The CHILD TB LP decision tool accurately classified microbiologically confirmed TBM. We propose that CHILD TB LP is prospectively evaluated as a novel rapid diagnostic tool for use in the initial evaluation of children with suspected neurologic infection presenting to hospitals in similar settings.

Lack of association between the nasopharyngeal carriage of Streptococcus pneumoniae and Staphylococcus aureus in HIV-1-infected South African children.

We investigated the nasopharyngeal carriage of Streptococcus pneumoniae and Staphylococcus aureus in 355 children hospitalized with severe pneumonia. Of the children, 239 (67.3%) were human immunodeficiency virus (HIV)-1 positive; 169 (47.6%) carried S. pneumoniae, 91 (25.6%) carried S. aureus, and 33 (9.3%) carried both. S. pneumoniae carriage was not related to HIV-1 status. The HIV-1-positive children had a significantly higher rate of S. aureus carriage than did the HIV-1-negative children (31.4% vs. 13.8%; P<.001). The rate of S. aureus carriage in the HIV-1-negative S. pneumoniae carriers was significantly lower than that in the noncarriers (5.5% vs. 21.3%; P=.013), but the rate of S. aureus carriage in the HIV-1-positive S. pneumoniae carriers was not significantly lower than that in the noncarriers (26.3% vs. 36.0%; P=.11). We did not find a negative association between S. pneumoniae and S. aureus carriage in HIV-1-positive hospitalized children with severe pneumonia.

Provision of critical care services to HIV-infected children in an era of advanced intensive care and availability of combined antiretroviral therapy.

Intensive care facilities are always in demand in the public sector and there is constant competition for beds. Appropriate allocation of children to these resources is based on the ethical principles of distributive justice and beneficence that is determined on the presumed short-term outcome of the acute illness, long-term outcome of the underlying chronic disease and the overall demand for these facilities. At the onset of the HIV epidemic in South Africa, HIV-infected children were refused admission to the paediatric intensive care unit (PICU) on the basis of poor ICU outcomes and the lack of provision of combined antiretroviral therapy (cART) for survivors. The recent significant improvement in outcome in these patients through early recognition and treatment of HIV-related opportunistic infections, the provision of advanced organ support and the routine availability of cART suggests that the previous policy requires review. Ethical principles, the Paediatric Index of Mortality Score for each request, the quality and disability-adjusted life years and cost-effectiveness of care are all important considerations in deciding which patients should be allowed access to these limited and expensive resources. With the improved long-term outcome in HIV-infected children on cART, admission of these cases to a PICU should now be based on the prognosis of the acute illness, as with any other chronic disease such as asthma or diabetes. Withholding and withdrawing advanced life support should accord with standard protocols applied to any condition for which a child is admitted to the PICU.

Etiology of bacteremia in young infants in six countries.

BACKGROUND: Neonatal illness is a leading cause of death worldwide; sepsis is one of the main contributors. The etiologies of community-acquired neonatal bacteremia in developing countries have not been well characterized. METHODS: Infants <2 months of age brought with illness to selected health facilities in Bangladesh, Bolivia, Ghana, India, Pakistan and South Africa were evaluated, and blood cultures taken if they were considered ill enough to be admitted to hospital. Organisms were isolated using standard culture techniques. RESULTS: Eight thousand eight hundred and eighty-nine infants were recruited, including 3177 0-6 days of age and 5712 7-59 days of age; 10.7% (947/8889) had a blood culture performed. Of those requiring hospital management, 782 (54%) had blood cultures performed. Probable or definite pathogens were identified in 10.6% including 10.4% of newborns 0-6 days of age (44/424) and 10.9% of infants 7-59 days of age (39/358). Staphylococcus aureus was the most commonly isolated species (36/83, 43.4%) followed by various species of Gram-negative bacilli (39/83, 46.9%; Acinetobacter spp., Escherichia coli and Klebsiella spp. were the most common organisms). Resistance to second and third generation cephalosporins was present in more than half of isolates and 44% of the Gram-negative isolates were gentamicin-resistant. Mortality rates were similar in hospitalized infants with positive (5/71, 7.0%) and negative blood cultures (42/557, 7.5%). CONCLUSIONS: This large study of young infants aged 0-59 days demonstrated a broad array of Gram-positive and Gram-negative pathogens responsible for community-acquired bacteremia and substantial levels of antimicrobial resistance. The role of S. aureus as a pathogen is unclear and merits further investigation.

Efficacy and safety of ipratropium bromide plus fenoterol inhaled via Respimat Soft Mist Inhaler vs. a conventional metered dose inhaler plus spacer in children with asthma.

The objective of this study was to compare the efficacy and safety of ipratropium bromide/fenoterol hydrobromide (IB/FEN; Berodual) delivered from the novel propellant-free Respimat Soft Mist Inhaler (SMI) with that from a chlorofluorocarbon (CFC) metered-dose inhaler (MDI) plus spacer in children with asthma. The study followed a multicenter, randomized, double-blind (within Respimat SMI), parallel-group design. During the 2-week run-in period, patients received two actuations of CFC-MDI tid (IB 20 microg/FEN 50 microg per actuation) via a spacer (Aerochamber) (MDI 40/100). Patients (n=535) were then randomized to: Respimat SMI containing IB 10 microg/FEN 25 microg (Respimat SMI 10/25), IB 20 microg/FEN 50 microg (Respimat SMI 20/50), one actuation tid or CFC-MDI containing IB 20 microg/FEN 50 microg per actuation (in total 1B 40 microg/FEN 100 microg), or two actuations tid via Aerochamber (MDI 40/100), for 4 weeks. The primary endpoint was the change in forced expiratory volume in 1 second (FEV1) during the first 60 min after dosing (area under the curve from 0-1 h [AUC(0-1 h)]) on day 29. Analysis of the primary endpoint demonstrated that the efficacy of Respimat SMI 10/25 and 20/50 was equivalent to or greater than that of MDI 40/100. Similar results indicating that Respimat SMI 10/25 and 20/50 were not inferior to MDI 40/100 were also found on days 1 and 15. Analyses of other secondary endpoints supported these results. The safety profile of Respimat SMI was comparable to that of the CFC-MDI plus spacer. In conclusion, IB/FEN delivered via Respimat SMI is at least as effective as, and is as safe as, when delivered via CFC-MDI plus Aerochamber in children with asthma. Use of Respimat SMI thus enables a 2-4-fold reduction in the nominal dose of IB/FEN, and obviates the need for a spacer.

Isoniazid preventive therapy in HIV-infected and -uninfected children (0 - 14 years).

Isoniazid preventive therapy (IPT) prevents tuberculosis (TB) in immunocompetent children <5 years of age after exposure to an infectious TB source case. Routine IPT has been advocated in all HIV-infected children without TB, but has been controversial. Antiretroviral therapy markedly reduces the risk for TB in HIV-infected children, especially when started early in infancy. In HIV-infected children, as in HIV- uninfected children, we recommend post-exposure IPT after each TB exposure episode; but in HIV-infected children, this should be given irrespective of age or antiretroviral therapy. However, evidence for routine IPT without known exposure to TB in HIV-infected children is not convincing and is therefore not recommended. 

South African guideline for the diagnosis, management and prevention of acute viral bronchiolitis in children.

ENDORSEMENT: South African Thoracic Society, South African Society of Paediatric Infectious Diseases, United South African Neonatal Association. OBJECTIVE: To develop and publish a guideline for doctors managing acute viral bronchiolitis, because this condition is extremely common in South Africa, it is responsible for significant morbidity in the population, and subsequently a great deal of patient and parental distress, and the disease is costly, since many children are unnecessarily subjected to investigations and treatment strategies that are of no proven benefit. The main aims of the guideline are to promote an improved standard of treatment based on understanding of the disease and its management, and to encourage cost-effective and appropriate management. EVIDENCE: A detailed literature review was conducted and summarised into this document by a selected working group of paediatricians from around the country. Recommendations. These include the appropriate diagnostic and management strategies for acute viral bronchiolitis.

Age dependence of adenovirus-specific neutralizing antibody titers in individuals from sub-Saharan Africa.

We assessed neutralizing antibody titers to adenovirus serotype 5 (Ad5) and six rare adenovirus serotypes, serotypes 11, 35, 50, 26, 48, and 49, in pediatric populations in sub-Saharan Africa. We observed a clear age dependence of Ad5-specific neutralizing antibody titers. These data will help to guide the development of Ad vector-based vaccines for human immunodeficiency virus type 1 and other pathogens.