Paediatrics (RCH) - Research Publications
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ItemEffect of systematic tuberculosis detection on mortality in young children with severe pneumonia in countries with high incidence of tuberculosis: a stepped-wedge cluster-randomised trial(Elsevier BV, 2022-11)Background: Tuberculosis diagnosis might be delayed or missed in children with severe pneumonia because this diagnosis is usually only considered in cases of prolonged symptoms or antibiotic failure. Systematic tuberculosis detection at hospital admission could increase case detection and reduce mortality. Methods: We did a stepped-wedge cluster-randomised trial in 16 hospitals from six countries (Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Uganda, and Zambia) with high incidence of tuberculosis. Children younger than 5 years with WHO-defined severe pneumonia received either the standard of care (control group) or standard of care plus Xpert MTB/RIF Ultra (Xpert Ultra; Cepheid, Sunnyvale, CA, USA) on nasopharyngeal aspirate and stool samples (intervention group). Clusters (hospitals) were progressively switched from control to intervention at 5-week intervals, using a computer-generated random sequence, stratified on incidence rate of tuberculosis at country level, and masked to teams until 5 weeks before switch. We assessed the effect of the intervention on primary (12-week all-cause mortality) and secondary (including tuberculosis diagnosis) outcomes, using generalised linear mixed models. The primary analysis was by intention to treat. We described outcomes in children with severe acute malnutrition in a post hoc analysis. This study is registered with ClinicalTrials.gov (NCT03831906) and the Pan African Clinical Trial Registry (PACTR202101615120643). Findings: From March 21, 2019, to March 30, 2021, we enrolled 1401 children in the control group and 1169 children in the intervention group. In the intervention group, 1140 (97·5%) children had nasopharyngeal aspirates and 942 (80·6%) had their stool collected; 24 (2·1%) had positive Xpert Ultra. At 12 weeks, 110 (7·9%) children in the control group and 91 (7·8%) children in the intervention group had died (adjusted odds ratio [OR] 0·986, 95% CI 0·597–1·630, p=0·957), and 74 (5·3%) children in the control group and 88 (7·5%) children in the intervention group had tuberculosis diagnosed (adjusted OR 1·238, 95% CI 0·696–2·202, p=0·467). In children with severe acute malnutrition, 57 (23·8%) of 240 children in the control group and 53 (17·8%) of 297 children in the intervention group died, and 36 (15·0%) of 240 children in the control group and 56 (18·9%) of 297 children in the intervention group were diagnosed with tuberculosis. The main adverse events associated with nasopharyngeal aspirates were samples with blood in 312 (27·3%) of 1147 children with nasopharyngeal aspirates attempted, dyspnoea or SpO2 less than 95% in 134 (11·4%) of children, and transient respiratory distress or SpO2 less than 90% in 59 (5·2%) children. There was no serious adverse event related to nasopharyngeal aspirates reported during the trial. Interpretation: Systematic molecular tuberculosis detection at hospital admission did not reduce mortality in children with severe pneumonia. High treatment and microbiological confirmation rates support more systematic use of Xpert Ultra in this group, notably in children with severe acute malnutrition.
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ItemSlow progress towards pneumonia control for children in low-and-middle income countries as measured by pneumonia indicators: A systematic review of the literature.(International Society of Global Health, 2022-10-25)BACKGROUND: The integrated Global Action Plan for Prevention and Control of Pneumonia and Diarrhoea (GAPPD) has the goal of ending preventable childhood deaths from pneumonia and diarrhoea by 2025 with targets and indicators to monitor progress. The aim of this systematic review is to summarise how low-and-middle income countries (LMICs) reported pneumonia-specific GAPPD indicators at national and subnational levels and whether GAPPD targets have been achieved. METHODS: We searched MEDLINE, Embase, PubMed and Global Health Databases, and the World Health Organization (WHO) website. Publications/reports between 2015 and 2020 reporting on two or more GAPPD-pneumonia indicators from LMICs were included. Data prior to 2015 were included if available in the same report series. Quality of publications was assessed with the Quality Assessment Tool for Quantitative Studies. A narrative synthesis of the literature was performed to describe which countries and WHO regions were reporting on GAPPD indicators and progress in GAPPD coverage targets. RESULTS: Our search identified 17 publications/reports meeting inclusion criteria, with six from peer-reviewed publications. Data were available from 139 LMICs between 2010 and 2020, predominantly from Africa. Immunisation coverage rates were the indicators most commonly reported, followed by exclusive breastfeeding rates and pneumonia case management. Most GAPPD indicators were reported at the national level with minimal reporting at the subnational level. Immunisation coverage (Haemophilus influenzae, measles, diphtheria-tetanus-pertussis vaccines) in the WHO Europe, Americas and South-East Asia regions were meeting 90% coverage targets, while pneumococcal conjugate vaccine coverage lagged globally. The remaining GAPPD indicators (breastfeeding, pneumonia case management, antiretroviral prophylaxis, household air pollution) were not meeting GAPPD targets in LMICs. There was a strong negative correlation between pneumonia specific GAPPD coverage rates and under-five mortality (Pearson correlation coefficient range = -0.74, -0.79). CONCLUSION: There is still substantial progress to be made in LMICs to achieve the 2025 GAPPD targets. Current GAPPD indicators along with country reporting mechanisms should be reviewed with consideration of adding undernutrition and access to oxygen therapy as important indicators which impact pneumonia outcomes. Further research on GAPPD indicators over longer time periods and at subnational levels can help identify high-risk populations for targeted pneumonia interventions.
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ItemManagement of tuberculosis infection in Victorian children: A retrospective clinical audit of factors affecting treatment completion.(Public Library of Science (PLoS), 2022)BACKGROUND: Tuberculosis preventive treatment (TPT) is strongly recommended for children following infection with Mycobacterium tuberculosis because of their high risk of progression to active tuberculosis, including severe disseminated disease. We describe the implementation of TPT for children and adolescents with evidence of tuberculosis infection (TBI) at Victoria's largest children's hospital and examine factors affecting treatment completion. METHODS: We conducted a retrospective clinical audit of all children and adolescents aged <18 years diagnosed with latent TBI at the Royal Children's Hospital, Melbourne, between 2010 and 2016 inclusive. The primary outcome was treatment completion, defined as completing TPT to within one month of a target duration for the specified regimen (for instance, at least five months of a six-month isoniazid course), confirmed by the treating clinician. Factors associated with treatment adherence were evaluated by univariate and multivariate analysis. RESULTS: Of 402 participants with TBI, 296 (74%) met the criteria for treatment "complete". The most common TPT regimen was six months of daily isoniazid (377, 94%). On multivariate logistic regression analysis, treatment completion was more likely among children and adolescents who had refugee health screening performed (OR 2.31, 95%CI 1.34-4.00) or who were also treated for other medical conditions (OR 1.67 95%CI 1.0-2.85), and less likely among those who experienced side-effects (OR 0.32, 95%CI 0.11-0.94). However, TPT was generally well tolerated with side-effects reported in 15 participants (3.7%). CONCLUSION: Identification of factors associated with TPT completion and deficiencies in the existing care pathway have informed service provision changes to further improve outcomes for Victorian children and adolescents with TBI.
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ItemTowards Shorter, Child-Friendly Regimens for Treatment of Tuberculosis Disease and Infection in Children.(Ovid Technologies (Wolters Kluwer Health), 2022-10-03)
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ItemSystematic review of the clinical outcomes of pneumonia with a penicillin-group resistant pneumococcus in respiratory and blood culture specimens in children in low- and middle-income countries(INT SOC GLOBAL HEALTH, 2022-01-01)BACKGROUND: Streptococcus pneumoniae is one of the most common bacteria causing pneumonia and the World Health Organization (WHO) recommends first-line treatment of pneumonia with penicillins. Due to increases in the frequency of penicillin resistance, this systematic review aimed to determine the clinical outcomes of children with pneumonia in low- and middle-income countries (LMICs), with penicillin-group resistant pneumococci in respiratory and/or blood cultures specimens. METHODS: English-language articles from January 2000 to November 2020 were identified by searching four databases. Systematic reviews and epidemiological studies from LMICs that included children aged one month to 9 years and reported outcomes of pneumonia with a penicillin-resistant pneumococcus in respiratory and blood culture specimens with or without comparison groups were included. Risk of bias was assessed using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies. A narrative synthesis of findings based on the results of included studies was performed. RESULTS: We included 7 articles involving 2864 children. One strong- and four medium-quality studies showed no difference in clinical outcomes (duration of symptoms, length of hospital stay and mortality) between those children with penicillin non-susceptible compared to susceptible pneumococci. Two weak quality studies suggested better outcomes in the penicillin-susceptible group. CONCLUSIONS: Current evidence suggests no difference in clinical outcomes of child pneumonia due to a penicillin-resistant S. pneumoniae and as such, there is no evidence to support a change in current WHO antibiotic guidelines.
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ItemReview of the role of additional treatments including oseltamivir, oral steroids, macrolides, and vitamin supplementation for children with severe pneumonia in low- and middle-income countries(INT SOC GLOBAL HEALTH, 2022-01-01)BACKGROUND: Pneumonia is a major cause of death in children aged under five years. As children with severe pneumonia have the highest risk of morbidity and mortality, previous studies have evaluated the additional benefit of adjunctive treatments such as oseltamivir, oral steroids, macrolides, and vitamin supplementation that can be added to standard antibiotic management to improve clinical outcomes. The study reviewed the evidence for the role of these additional treatments for children with severe pneumonia in low- and middle-income countries (LMICs). METHODS: Four electronic databases were searched for English-language articles between 2000 to 2020. Systematic reviews (SRs) with meta-analyses, comparative cohort studies, and randomised controlled trials (RCTs) from LMICs that reported clinical outcomes for children with severe pneumonia aged between one month to 9 years who received adjunct treatment in addition to standard care were included. Risk of bias of included SRs was assessed using AMSTAR 2, and of individual studies using the Effective Public Health Practice Project (EPHPP) quality assessment tool for quantitative studies. RESULTS: Overall, the search identified 2147 articles, 32 of which were eligible, including 7 SRs and 25 RCTs. These studies evaluated zinc (4 SRs, 17 RCTs), Vitamin D (1 SR, 4 RCTs), Vitamin A (3 SRs, 1 RCT), Vitamin C (1 SR, 2 RCTs) and micronutrients (1 RCT). Most studies reported clinical outcomes of time to improvement, length of stay, and treatment failure (including mortality). No studies of oseltamivir, steroids, or macrolides fulfilling the inclusion criteria were identified. For zinc, pooled analyses from SRs showed no evidence of benefit. Similarly, a Cochrane review and one RCT found that Vitamin A did not improve clinical outcomes. For Vitamin D, an RCT evaluating a single high dose of 100 000 international units (IU) of vitamin D found a reduction in time to improvement, with 38%-40% documented vitamin D deficiency at baseline. However, two other studies of 1000 IU daily did not show any effect, but vitamin D status was not measured. For vitamin C, two studies found a reduction in time to symptom resolution in those with severe disease, with one reporting a shorter length of hospital stay. However, both studies were of weak quality. Most studies excluded malnourished children, and studies which included these children did not report specifically on the effect of micronutrients. CONCLUSIONS: This review found that adjunctive zinc and vitamin A, in addition to standard care, does not improve clinical outcomes in children with severe pneumonia in LMICs (strong evidence). However, a reduction in time to symptom resolution was reported with high dose vitamin D supplementation in children with documented vitamin D deficiency (strong evidence from one study) and vitamin C (weak evidence), although further research is needed, especially in underweight children.
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ItemWhich children with chest-indrawing pneumonia can be safely treated at home, and under what conditions is it safe to do so? A systematic review of evidence from low- and middle-income countries.(International Global Health Society, 2022-08-31)BACKGROUND: WHO pneumonia guidelines recommend that children (aged 2-59 months) with chest indrawing pneumonia and without any "general danger sign" can be treated with oral amoxicillin without hospital admission. This recommendation was based on trial data from limited contexts whose generalisability is unclear. This review aimed to identify which children with chest-indrawing pneumonia in low- and middle-income countries can be safely treated at home, and under what conditions is it safe to do so. METHODS: We searched MEDLINE, EMBASE, and PubMed for observational and interventional studies of home-based management of children (aged 28 days to four years) with chest-indrawing pneumonia in low- or middle-income countries. RESULTS: We included 14 studies, including seven randomised trials, from a variety of urban and rural contexts in 11 countries. Two community-based and two hospital-based trials in Pakistan and India found that home treatment of chest-indrawing pneumonia was associated with similar or superior treatment outcomes to hospital admission. Evidence from trials (n = 3) and observational (n = 6) studies in these and other countries confirms the acceptability and feasibility of home management of chest-indrawing pneumonia in low-risk cases, so long as safeguards are in place. Risk assessment includes clinical danger signs, oxygen saturation, and the presence of comorbidities such as undernutrition, anaemia, or HIV. Pulse oximetry is a critical risk-assessment tool that is currently not widely available and can identify severely ill patients with hypoxaemia otherwise possibly missed by clinical assessment alone. Additional safeguards include caregiver understanding and ability to return for review. CONCLUSIONS: Home treatment of chest-indrawing pneumonia can be safe but should only be recommended for children confirmed to be low-risk and in contexts where appropriate care and safety measures are in place.
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ItemDetecting Mycobacterium tuberculosis Infection in Children Migrating to Australia.(Centers for Disease Control and Prevention (CDC), 2022-09)In 2015, Australia updated premigration screening for tuberculosis (TB) disease in children 2-10 years of age to include testing for infection with Mycobacterium tuberculosis and enable detection of latent TB infection (LTBI). We analyzed TB screening results in children <15 years of age during November 2015-June 2017. We found 45,060 child applicants were tested with interferon-gamma release assay (IGRA) (57.7% of tests) or tuberculin skin test (TST) (42.3% of tests). A total of 21 cases of TB were diagnosed: 4 without IGRA or TST, 10 with positive IGRA or TST, and 7 with negative results. LTBI was detected in 3.3% (1,473/44,709) of children, for 30 applicants screened per LTBI case detected. LTBI-associated factors included increasing age, TB contact, origin from a higher TB prevalence region, and testing by TST. Detection of TB and LTBI benefit children, but the updated screening program's effect on TB in Australia is likely to be limited.
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ItemInfant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis.(Elsevier BV, 2022-09)BACKGROUND: BCG vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults. We therefore aimed to investigate the age-specific impact of infant BCG vaccination on tuberculosis (pulmonary and extrapulmonary) development and mortality. METHODS: In this systematic review and individual participant data meta-analysis, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for case-contact cohort studies of tuberculosis contacts published between Jan 1, 1998, and April 7, 2018. Search terms included "mycobacterium tuberculosis", "TB", "tuberculosis", and "contact". We excluded cohort studies that did not provide information on BCG vaccination or were done in countries that did not recommend BCG vaccination at birth. Individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies. Our primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We derived adjusted odds ratios (aORs) using mixed-effects, binary, multivariable logistic regression analyses with study-level random effects, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. We stratified our results by contact age and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512. FINDINGS: We identified 14 927 original records from our database searches. We included participant-level data from 26 cohort studies done in 17 countries in our meta-analysis. Among 68 552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49 686 BCG-vaccinated participants vs 473 [2·5%] of 18 866 unvaccinated participants). The overall effectiveness of BCG vaccination against all tuberculosis was 18% (aOR 0·82, 95% CI 0·74-0·91). When stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0·63, 95% CI 0·49-0·81). Among contacts with a positive tuberculin skin test or IFNγ release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR 0·81, 95% CI 0·69-0·96), participants younger than 5 years (0·68, 0·47-0·97), and participants aged 5-9 years (0·62, 0·38-0·99). There was no protective effect among those with negative tests, unless they were younger than 5 years (0·54, 0·32-0·90). 14 cohorts reported on whether tuberculosis was pulmonary or extrapulmonary (n=57 421). BCG vaccination significantly protected against pulmonary tuberculosis among all participants (916 [2·2%] in 41 119 vaccinated participants vs 334 [2·1%] in 16 161 unvaccinated participants; aOR 0·81, 0·70-0·94) but not against extrapulmonary tuberculosis (106 [0·3%] in 40 318 vaccinated participants vs 38 [0·2%] in 15 865 unvaccinated participants; 0·96, 0·65-1·41). In the four studies with mortality data, BCG vaccination was significantly protective against death (0·25, 0·13-0·49). INTERPRETATION: Our results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is ineffective in adolescents and adults. Immunoprotection therefore needs to be boosted in older populations. FUNDING: National Institutes of Health.
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ItemA systematic review of clinical, epidemiological and demographic predictors of tuberculosis in children with pneumonia.(International Global Health Society, 2022-08-09)BACKGROUND: Tuberculosis (TB) can present as acute, severe pneumonia in children, but features which distinguish TB from other causes of pneumonia are not well understood. We conducted a systematic review to determine the prevalence and to explore clinical and demographic predictors of TB in children presenting with pneumonia over three decades. METHODS: We searched for peer-reviewed, English language studies published between 1990 and 2020 that included children aged between 1 month and 17 years with pneumonia and prospectively evaluated for TB. There were 895 abstracts and titles screened, and 72 full text articles assessed for eligibility. RESULTS: Thirteen clinical studies, two autopsy studies and one systematic review were included in analyses. Majority of studies were from Africa (12/15) and included children less than five years age. Prevalence of bacteriologically confirmed TB in children with pneumonia ranged from 0.2% to 14.8% (median = 3.7%, interquartile range (IQR) = 5.95) and remained stable over the three decades. TB may be more likely in children with pneumonia if they have a history of close TB contact, HIV infection, malnutrition, age less than one year or failure to respond to empirical antibiotics. However, these features have limited discriminatory value as TB commonly presents as acute severe pneumonia - with a short duration of cough, and clinical and radiographic features indistinguishable from other causes of pneumonia. Approximately half of patients with TB respond to initial empirical antibiotics, presumably due to bacterial co-infection, and follow-up may be critical to detect and treat TB. CONCLUSION: TB should be considered as a potential cause or comorbidity in all children presenting with pneumonia in high burden settings. Clinicians should be alert to the presence of known risk factors for TB and bacteriological confirmation sought whenever possible. Quality data regarding clinical predictors of TB in childhood pneumonia are lacking. Further, prospective research is needed to better understand predictors and prevalence of TB in childhood pneumonia, particularly in TB endemic settings outside of Africa and in older children. Children of all ages with pneumonia should be included in research on improved, point-of-care TB diagnostics to support early case detection and treatment.