Publications by authors named "Stephen M Graham"

117 Publications

The incidence of acute respiratory infection in Indonesian infants and association with vitamin D deficiency.

PLoS One 2021 23;16(3):e0248722. Epub 2021 Mar 23.

Department of Paediatrics, Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Melbourne, Australia.

Background: Vitamin D deficiency has been associated with acute respiratory infection (ARI) in early life, but this has not been evaluated in Indonesia. We aimed to determine the incidence of ARI in Indonesian infants, and to evaluate the association with vitamin D deficiency.

Methods: From 23 December 2015 to 31 December 2017, we conducted a community-based prospective cohort study in Yogyakarta province. We enrolled 422 pregnant women and followed their infants from birth until 12 months of age for ARI episodes. Vitamin D status was measured at birth and at age six months. We performed Cox proportional hazard regression analysis to evaluate the association between vitamin D deficiency and pneumonia incidence.

Results: At study completion, 95% (400/422) of infants retained with a total of 412 child years of observation (CYO). The incidence of all ARI and of WHO-defined pneumonia was 3.89 (95% CI 3.70-4.08) and 0.25 (95% CI 0.21-0.30) episodes per CYO respectively. Vitamin D deficiency at birth was common (90%, 308/344) and associated with more frequent episodes of ARI non-pneumonia (adjusted odds ratio 4.48, 95% CI:1.04-19.34). Vitamin D status at birth or six months was not associated with subsequent pneumonia incidence, but greater maternal sun exposure during pregnancy was associated with a trend to less frequent ARI and pneumonia in infants.

Conclusion: ARI, pneumonia, and vitamin D deficiency at birth were common in Indonesian infants. Minimising vitamin D deficiency at birth such as by supplementation of mothers or safe sun exposure during pregnancy has the potential to reduce ARI incidence in infants in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248722PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987198PMC
March 2021

Paediatric tuberculosis - new advances to close persistent gaps.

Int J Infect Dis 2021 Mar 11. Epub 2021 Mar 11.

The Indus Hospital, Karachi, Pakistan.

Young children are most vulnerable to develop severe forms of tuberculosis (TB) and are over-represented among TB deaths. Almost all children estimated to have died from TB were never diagnosed or offered TB treatment. Improved access to TB preventive treatment (TPT) requires major upscaling of household contact investigation with allocation of adequate resources. Symptom-based screening is often discouraged in adults for fear of generating drug resistance, if TB cases are missed. However, the situation in vulnerable young children is different, as they present minimal risk of drug resistance generation. Further, the perceived need for additional diagnostic evaluation presents a major barrier to TPT access and underlies general reluctance to consider pragmatic decentralised models of care. Widespread roll-out of Xpert MTB/RIF Ultra® represents an opportunity for improved case detection in young children, but attaining full impact will require the use of non-sputum specimens. The new Fujifilm SILVAMP TB LAM® urine assay demonstrated good diagnostic accuracy in HIV-positive and malnourished children, but further validation is required. Given the limited accuracy of all available tests and the excellent tolerance of TB drugs in children, the global community may have to accept some over-treatment if we want to close the persistent case detection gap in young children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2021.02.003DOI Listing
March 2021

Community intervention for child tuberculosis active contact investigation and management: study protocol for a parallel cluster randomized controlled trial.

Trials 2021 Mar 2;22(1):180. Epub 2021 Mar 2.

French National Research Institute for Sustainable Development (IRD UMI 233 TransVIHMI- UM-INSERM U1175), Montpellier, France.

Background: There are major gaps in the management of pediatric tuberculosis (TB) contact investigation for rapid identification of active tuberculosis and initiation of preventive therapy. This study aims to evaluate the impact of a community-based intervention as compared to facility-based model for the management of children in contact with bacteriologically confirmed pulmonary TB adults in low-resource high-burden settings.

Methods/design: This multicenter parallel open-label cluster randomized controlled trial is composed of three phases: I, baseline phase in which retrospective data are collected, quality of data recording in facility registers is checked, and expected acceptability and feasibility of the intervention is assessed; II, intervention phase with enrolment of index cases and contact cases in either facility- or community-based models; and III, explanatory phase including endpoint data analysis, cost-effectiveness analysis, and post-intervention acceptability assessment by healthcare providers and beneficiaries. The study uses both quantitative and qualitative analysis methods. The community-based intervention includes identification and screening of all household contacts, referral of contacts with TB-suggestive symptoms to the facility for investigation, and household initiation of preventive therapy with follow-up of eligible child contacts by community healthcare workers, i.e., all young (< 5 years) child contacts or older (5-14 years) child contacts living with HIV, and with no evidence of TB disease. Twenty clusters representing TB diagnostic and treatment facilities with their catchment areas are randomized in a 1:1 ratio to either the community-based intervention arm or the facility-based standard of care arm in Cameroon and Uganda. Randomization was stratified by country and constrained on the number of index cases per cluster. The primary endpoint is the proportion of eligible child contacts who initiate and complete the preventive therapy. The sample size is of 1500 child contacts to identify a 10% difference between the arms with the assumption that 60% of children will complete the preventive therapy in the standard of care arm.

Discussion: This study will provide evidence of the impact of a community-based intervention on household child contact screening and management of TB preventive therapy in order to improve care and prevention of childhood TB in low-resource high-burden settings.

Trial Registration: ClinicalTrials.gov NCT03832023 . Registered on 6 February 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-021-05124-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927252PMC
March 2021

The prevalence and determinants of vitamin D deficiency in Indonesian infants at birth and six months of age.

PLoS One 2020 5;15(10):e0239603. Epub 2020 Oct 5.

Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.

Background: Vitamin D deficiency in infants has been associated with an increased risk of a number of diseases but there are limited data on the prevalence and determinants of vitamin D deficiency from tropical settings with high infant morbidity and mortality.

Objective: To determine the prevalence and determinants of vitamin D deficiency in infants at birth and at six months of age in Yogyakarta province, Indonesia.

Design: Serum vitamin D of eligible infants was measured in cord blood at birth and at six months of age. Factors associated with vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) were collected prospectively monthly from birth and concentrations measured by liquid chromatography-tandem mass spectrometry. Independent risk factors were identified by multiple logistic regression.

Results: Between December 2015 to December 2017, 350 maternal-newborn participants were recruited and followed up. Vitamin D deficiency was detected in 90% (308/344) of cord blood samples and 13% (33/255) of venous blood samples at six months. Longer time outdoors (≥2 hours per day) and maternal multivitamin intake containing vitamin D during pregnancy were protective against vitamin D deficiency at birth (AOR: 0.10, 95% CI: 0.01-0.90 and AOR: 0.21, 95% CI: 0.06-0.68, respectively). Risk factors for vitamin D deficiency at six months included lower cumulative skin-sun exposure score (AOR: 1.12, 95% CI: 1.04-1.20), severe vitamin D deficiency at birth (AOR: 7.73, 95% CI: 1.20-49.60) and exclusive breastfeeding (AOR: 2.64, 95% CI: 1.07-6.49) until six months. Among exclusively breast fed (EBF) infants, a higher skin-sun exposure score was associated with reduced vitamin D deficiency risk.

Conclusion: In equatorial regions, the role of 'safe' morning sun exposure in infants and mothers in populations with medium to dark brown skin pigmentation and effective interventions to prevent vitamin D deficiency in newborns and EBF infants, need further consideration and evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239603PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535980PMC
November 2020

Scaling up tuberculosis preventive therapy for contacts in high transmission settings.

Lancet Glob Health 2020 05;8(5):e617-e618

Burnet Institute, Melbourne, VIC 3004, Australia; Centre for International Child Health, Department of Paediatrics University of Melbourne and Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2214-109X(20)30133-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185935PMC
May 2020

European guidance on drug-resistant tuberculosis in children and adolescents.

Lancet Child Adolesc Health 2020 01 30;4(1):9-11. Epub 2019 Oct 30.

Joint TB, HIV and Viral Hepatitis Programme, Division of Health Emergencies and Communicable Diseases, WHO Regional Office for Europe, UN City, 2100 Copenhagen Ø, Denmark. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-4642(19)30332-3DOI Listing
January 2020

Explaining variation in the burden of child and adolescent tuberculosis.

Eur Respir J 2019 Jun 27;53(6). Epub 2019 Jun 27.

Centre for International Child Health, Dept of Paediatrics, University of Melbourne, Melbourne, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.01007-2019DOI Listing
June 2019

Predictors of Unlikely Bacterial Pneumonia and Adverse Pneumonia Outcome in Children Admitted to a Hospital in Central Vietnam.

Clin Infect Dis 2020 04;70(8):1733-1741

Discipline of Child and Adolescent Health, Sydney Medical School, the Children's Hospital at Westmead, University of Sydney, Australia.

Background: Pneumonia is the leading cause of antibiotic use and hospitalization in Vietnam. There is a need for better prediction of unlikely bacterial pneumonia and adverse pneumonia outcome in order to guide hospital admission and improve rational antibiotic use.

Methods: All children under 5 admitted with pneumonia (per clinician assessment) to the Da Nang Hospital for Women and Children were prospectively enrolled. Children were classified as having likely or unlikely bacterial pneumonia and followed for outcome assessment. A Bayesian model averaging approach was used to identify predictors of unlikely bacterial pneumonia and adverse pneumonia outcome, which guided the development of a pragmatic management algorithm.

Results: Of 3817 patients assessed, 2199 (57.6%) met World Health Organization (WHO) pneumonia criteria. In total, 1594 (41.7%) children were classified as having unlikely and 129 (3.4%) as having likely bacterial pneumonia. The remainder (2399; 62.9%) were considered to have disease of uncertain etiology. Factors predictive of unlikely bacterial pneumonia were no fever, no consolidation on chest radiograph, and absolute neutrophil count <5 × 109/L at presentation, which had a negative predictive value (NPV) for likely bacterial pneumonia of 99.0%. Among those who met WHO pneumonia criteria, 8.6% (189/2199) experienced an adverse outcome. Not having any WHO danger sign or consolidation on chest radiograph had an NPV of 96.8% for adverse pneumonia outcome.

Conclusions: An algorithm that screens for predictors of likely bacterial pneumonia and adverse pneumonia outcome could reduce unnecessary antibiotic use and hospital admission, but its clinical utility requires validation in a prospective study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciz445DOI Listing
April 2020

Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies.

Autism 2019 11 26;23(8):2096-2111. Epub 2019 Apr 26.

Forest Research Institute (currently Allergan plc), USA.

Three phase 2 trials were conducted to assess the efficacy and long-term safety of weight-based memantine extended release (ER) treatment in children with autism spectrum disorder. MEM-MD-91, a 50-week open-label trial, identified memantine extended-release treatment responders for enrollment into MEM-MD-68, a 12-week randomized, double-blind, placebo-controlled withdrawal trial. MEM-MD-69 was an open-label extension trial in which participants from MEM-MD-68, MEM-MD-91, and open-label trial MEM-MD-67 were treated ⩽48 weeks with memantine extended release. In MEM-MD-91, 517 (59.6%) participants were confirmed Social Responsiveness Scale responders at week 12; mean Social Responsiveness Scale total raw scores improved two to three times a minimal clinically important difference of 10 points. In MEM-MD-68, there was no difference between memantine and placebo on the primary efficacy parameter, the proportion of patients with a loss of therapeutic response (defined as ⩾10-point increase from baseline in Social Responsiveness Scale total raw score). MEM-MD-69 exploratory analyses revealed mean standard deviation improvement in Social Responsiveness Scale total raw score of 32.4 (26.4) from baseline of the first lead-in study. No new safety concerns were evident. While the a priori-defined efficacy results of the double-blind trial were not achieved, the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1362361318824103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779018PMC
November 2019

Mycobacteria-Specific Mono- and Polyfunctional CD4+ T Cell Profiles in Children With Latent and Active Tuberculosis: A Prospective Proof-of-Concept Study.

Front Immunol 2019 5;10:431. Epub 2019 Apr 5.

Department of Paediatrics, The University of Melbourne, Parkville, VIC, Australia.

Current immune-based TB tests, including the tuberculin skin test (TST) and interferon-gamma release assays (IGRA), have significant limitations, including the inability to distinguish between latent TB infection (LTBI) and active TB. Few biomarkers with the potential to discriminate between these two infection states have been identified. To determine whether functional profiling of mycobacteria-specific T cells can distinguish between TB-infected and -uninfected children, and simultaneously discriminate between LTBI and active TB. One hundred and forty-nine children with suspected active TB or risk factors for LTBI were recruited at the Royal Children's Hospital Melbourne. Whole-blood stimulation assays, using ESAT-6, CFP-10, PPD, and heat-killed as stimulants, were done, followed by intracellular cytokine staining and flow cytometric analysis. Eighty-two participants in the well-defined diagnostic categories 'uninfected individuals' (asymptomatic, TST 0 mm / IGRA-; = 61), LTBI (asymptomatic, TST ≥10 mm / IGRA+, normal chest radiograph; = 15), or active TB [microbiologically-confirmed ( = 3) or fulfilling stringent criteria ( = 3)] were included in the final analysis. The proportions of mycobacteria-specific single-positive TNF-α+ and double-positive IFN-γ+/TNF-α+ CD4+ T cells were significantly higher in participants with active TB than in those with LTBI and uninfected individuals. Additionally, the frequency of IL-17-expressing CD4+ T cells, predominately with single-positive IL-17+ and double-positive IL-2+/IL-17+ phenotypes, was higher in participants with active TB than in the other two groups. The frequencies and functional profiles of mycobacteria-specific CD4+ T cells differ significantly both between TB-infected and TB-uninfected children, and between LTBI and active TB. Although confirmation in further studies will be required, these findings indicate that functional profiling of mycobacteria-specific CD4+ T cells could potentially be exploited for novel immune-based TB assays that enable the distinction between infection states based on a blood sample alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.00431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459895PMC
September 2020

Characterisation of children hospitalised with pneumonia in central Vietnam: a prospective study.

Eur Respir J 2019 07 11;54(1). Epub 2019 Jul 11.

Discipline of Child and Adolescent Health, Sydney Medical School, The Children's Hospital at Westmead, The University of Sydney, Sydney, Australia.

Pneumonia is the most common reason for paediatric hospital admission in Vietnam. The potential value of using the World Health Organization (WHO) case management approach in Vietnam has not been documented.We performed a prospective descriptive study of all children (2-59 months) admitted with "pneumonia" (as assessed by the admitting clinician) to the Da Nang Hospital for Women and Children to characterise their disease profiles and assess risk factors for an adverse outcome. The disease profile was classified using WHO pneumonia criteria, with tachypnoea or chest indrawing as defining clinical signs. Adverse outcome was defined as death, intensive care unit admission, tertiary care transfer or hospital stay >10 days.Of 4206 admissions, 1758 (41.8%) were classified as "no pneumonia" using WHO criteria and only 252 (6.0%) met revised criteria for "severe pneumonia". The inpatient death rate was low (0.4% of admissions) with most deaths (11 out of 16; 68.8%) occurring in the "severe pneumonia" group. An adverse outcome was recorded in 18.7% of all admissions and 60.7% of the "severe pneumonia" group. Children were hospitalised for a median of 7 days at an average cost of 253 USD per admission. Risk factors for adverse outcome included WHO-classified "severe pneumonia", age <1 year, low birth weight, previous recent admission with an acute respiratory infection and recent tuberculosis exposure. Breastfeeding, day-care attendance and pre-admission antibiotic use were associated with reduced risk.Few hospital admissions met WHO criteria for "severe pneumonia", suggesting potential unnecessary hospitalisation and use of intravenous antibiotics. Better characterisation of the underlying diagnosis requires careful consideration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.02256-2018DOI Listing
July 2019

Building a tuberculosis-free world: The Lancet Commission on tuberculosis.

Lancet 2019 Mar 20;393(10178):1331-1384. Epub 2019 Mar 20.

Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Institute for Global Health Sciences, University of California San Francisco, San Francisco, CA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(19)30024-8DOI Listing
March 2019

Incidence and prevalence of bacteriologically confirmed pulmonary tuberculosis among adolescents and young adults: a systematic review.

Epidemiol Infect 2018 06 15;146(8):946-953. Epub 2018 Apr 15.

Centre for International Child Health,Department of Paediatrics,University of Melbourne,Melbourne,Victoria,Australia.

The burden of tuberculosis (TB) among adolescents and young adults in endemic settings is poorly characterised. This study aimed to review published and unpublished estimates of the incidence and prevalence of bacteriologically confirmed TB among young people aged 10-24 years. We searched PubMed and World Health Organization archives for publications and unpublished data from population-based epidemiologic studies reporting confirmed pulmonary TB among young people, conducted from January 2000 onwards. We identified 27 publications and unpublished data from two national surveys, representing a total of 26 studies in 19 countries. The prevalence of bacteriologically confirmed TB ranged from 45 to 799 per 100 000 in the Asia-Pacific region and from 160 to 462 per 100 000 in African settings. We did not identify any epidemiologic studies of confirmed TB among adolescents living with human immunodeficiency virus (HIV). Many studies were excluded due to absent or inadequately reported age-specific data. Adolescents and young adults living in many endemic settings appear to be at substantial risk of developing active TB. There is a pressing need to improve the routine reporting of age in epidemiologic studies of TB, and to generate high-quality epidemiologic data regarding TB among adolescents living with HIV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0950268818000821DOI Listing
June 2018

The upcoming UN general assembly resolution on tuberculosis must also benefit children.

Lancet Glob Health 2018 05 23;6(5):e485-e486. Epub 2018 Mar 23.

The Indus Hospital, Karachi, Sindh, Pakistan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2214-109X(18)30108-6DOI Listing
May 2018

The incidence of tuberculosis among adolescents and young adults: a global estimate.

Eur Respir J 2018 02 21;51(2). Epub 2018 Feb 21.

Centre for International Child Health, University of Melbourne Dept of Paediatrics and Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Australia.

Historical data show that the risk of tuberculosis increases dramatically during adolescence, and young people face unique challenges in terms of case detection and effective treatment. However, little is known about the burden of tuberculosis among young people in the modern era. This study aimed to provide the first estimates of the global and regional incidence of tuberculosis among young people aged 10-24 years.Using the World Health Organization (WHO) database of tuberculosis notifications for 2012, we estimated the burden of tuberculosis among young people by WHO region. Adjustments were made for incomplete age disaggregation and underreporting, using supplementary data from several countries representing diverse tuberculosis epidemics.We estimate that 1.78 million (uncertainty interval (UI) 1.23-3.00 million) young people developed tuberculosis in 2012, accounting for 17% of all new tuberculosis cases globally. Young people in the WHO South East Asian Region (721 000, UI 473 000-1.35 million) and the WHO African Region (534 000, UI 359 000-912 000) experienced the greatest number of tuberculosis episodes.Young people suffer a considerable burden of tuberculosis. Age-specific burden of disease estimation for this age group is complicated by incomplete age disaggregation of tuberculosis data, highlighting the importance of continued surveillance system strengthening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.02352-2017DOI Listing
February 2018

Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study.

PLoS Negl Trop Dis 2017 12 7;11(12):e0006027. Epub 2017 Dec 7.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Malawi.

Nontyphoidal Salmonellae commonly cause invasive disease in African children that is often fatal. The clinical diagnosis of these infections is hampered by the absence of a clear clinical syndrome. Drug resistance means that empirical antibiotic therapy is often ineffective and currently no vaccine is available. The study objective was to identify risk factors for mortality among children presenting to hospital with invasive Salmonella disease in Africa. We conducted a prospective study enrolling consecutive children with microbiologically-confirmed invasive Salmonella disease admitted to Queen Elizabeth Central Hospital, Blantyre, in 2006. Data on clinical presentation, co-morbidities and outcome were used to identify children at risk of inpatient mortality through logistic-regression modeling. Over one calendar year, 263 consecutive children presented with invasive Salmonella disease. Median age was 16 months (range 0-15 years) and 52/256 children (20%; 95%CI 15-25%) died. Nontyphoidal serovars caused 248/263 (94%) of cases. 211/259 (81%) of isolates were multi-drug resistant. 251/263 children presented with bacteremia, 6 with meningitis and 6 with both. Respiratory symptoms were present in 184/240 (77%; 95%CI 71-82%), 123/240 (51%; 95%CI 45-58%) had gastrointestinal symptoms and 101/240 (42%; 95%CI 36-49%) had an overlapping clinical syndrome. Presentation at <7 months (OR 10.0; 95%CI 2.8-35.1), dyspnea (OR 4.2; 95%CI 1.5-12.0) and HIV infection (OR 3.3; 95%CI 1.1-10.2) were independent risk factors for inpatient mortality. Invasive Salmonella disease in Malawi is characterized by high mortality and prevalence of multi-drug resistant isolates, along with non-specific presentation. Young infants, children with dyspnea and HIV-infected children bear a disproportionate burden of the Salmonella-associated mortality in Malawi. Strategies to improve prevention, diagnosis and management of invasive Salmonella disease should be targeted at these children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pntd.0006027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745124PMC
December 2017

Encouraging rational antibiotic use in childhood pneumonia: a focus on Vietnam and the Western Pacific Region.

Pneumonia (Nathan) 2017 25;9. Epub 2017 Apr 25.

Infectious Disease Team, The Children's Hospital at Westmead and Discipline of Paediatrics and Adolescent Medicine, University of Sydney, Sydney, NSW Australia.

Globally, pneumonia is considered to be the biggest killer of infants and young children (aged <5 years) outside the neonatal period, with the greatest disease burden in low- and middle-income countries. Optimal management of childhood pneumonia is challenging in settings where clinicians have limited information regarding the local pathogen and drug resistance profiles. This frequently results in unnecessary and poorly targeted antibiotic use. Restricting antibiotic use is a global priority, particularly in Asia and the Western Pacific Region where excessive use is driving high rates of antimicrobial resistance. The authors conducted a comprehensive literature review to explore the antibiotic resistance profile of bacteria associated with pneumonia in the Western Pacific Region, with a focus on Vietnam. Current management practices were also considered, along with the diagnostic dilemmas faced by doctors and other factors that increase unnecessary antibiotic use. This review offers some suggestions on how these issues may be addressed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s41479-017-0031-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471677PMC
April 2017

Symptom-based screening of child TB contacts: defining 'symptomatic'.

Int J Tuberc Lung Dis 2017 07;21(7):832-833

Centre for Research Excellence in Tuberculosis (TB-CRE), University of Sydney, Sydney, NSW, Centre for International Child Health, University of Melbourne Department of Paediatrics and Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia, International Unon Against Tuberculosis and Lung Disease, Paris, France , Email:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5588/ijtld.17.0155DOI Listing
July 2017

The management of infection with Mycobacterium tuberculosis in young children post-2015: an opportunity to close the policy-practice gap.

Authors:
Stephen M Graham

Expert Rev Respir Med 2017 01 10;11(1):41-49. Epub 2016 Dec 10.

a Centre for International Child Health, University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute , Royal Children's Hospital , Melbourne , Australia.

Introduction: The treatment of infection with Mycobacterium tuberculosis in young children is supported by universal policy based on strong rationale and evidence of effectiveness, but has rarely been implemented in tuberculosis endemic countries. Areas covered: This review highlights a number of important recent developments that provide an unprecedented opportunity to close the policy-practice gap, as well as ongoing needs to facilitate implementation under programmatic conditions and scale-up. Expert commentary: The WHO's End TB Strategy and Stop TB Partnership's Plan to End TB provide ambitious targets for prevention at a time when National Tuberculosis Programs in tuberculosis endemic countries are increasing attention to the challenges of management and prevention of tuberculosis disease in children. This opportunity is greatly enhanced by recent evidence of the effectiveness of shorter, simpler and safer regimens to treat tuberculosis infection. The scale of the challenge for implementation will require a decentralized, integrated, community-based approach. An accurate and low-cost point-of-care test for tuberculous infection would be a major advance to support such implementation. Specific guidance for the treatment of infection in young child contacts of multidrug-resistant tuberculosis cases is a major current need while awaiting further evidence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17476348.2016.1267572DOI Listing
January 2017

New and Repurposed Drugs for Pediatric Multidrug-Resistant Tuberculosis. Practice-based Recommendations.

Am J Respir Crit Care Med 2017 05;195(10):1300-1310

17 Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts.

It is estimated that 33,000 children develop multidrug-resistant tuberculosis (MDR-TB) each year. In spite of these numbers, children and adolescents have limited access to the new and repurposed MDR-TB drugs. There is also little clinical guidance for the use of these drugs and for the shorter MDR-TB regimen in the pediatric population. This is despite the fact that these drugs and regimens are associated with improved interim outcomes and acceptable safety profiles in adults. This review fills a gap in the pediatric MDR-TB literature by providing practice-based recommendations for the use of the new (delamanid and bedaquiline) and repurposed (linezolid and clofazimine) MDR-TB drugs and the new shorter MDR-TB regimen in children and adolescents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201606-1227CIDOI Listing
May 2017

Cytokine Profiles during Invasive Nontyphoidal Salmonella Disease Predict Outcome in African Children.

Clin Vaccine Immunol 2016 07 5;23(7):601-9. Epub 2016 Jul 5.

School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom

Nontyphoidal Salmonella is a leading cause of sepsis in African children. Cytokine responses are central to the pathophysiology of sepsis and predict sepsis outcome in other settings. In this study, we investigated cytokine responses to invasive nontyphoidal Salmonella (iNTS) disease in Malawian children. We determined serum concentrations of 48 cytokines with multiplexed immunoassays in Malawian children during acute iNTS disease (n = 111) and in convalescence (n = 77). Principal component analysis and logistic regression were used to identify cytokine signatures of acute iNTS disease. We further investigated whether these responses are altered by HIV coinfection or severe malnutrition and whether cytokine responses predict inpatient mortality. Cytokine changes in acute iNTS disease were associated with two distinct cytokine signatures. The first is characterized by increased concentrations of mediators known to be associated with macrophage function, and the second is characterized by raised pro- and anti-inflammatory cytokines typical of responses reported in sepsis secondary to diverse pathogens. These cytokine responses were largely unaltered by either severe malnutrition or HIV coinfection. Children with fatal disease had a distinctive cytokine profile, characterized by raised mediators known to be associated with neutrophil function. In conclusion, cytokine responses to acute iNTS infection in Malawian children are reflective of both the cytokine storm typical of sepsis secondary to diverse pathogens and the intramacrophage replicative niche of NTS. The cytokine profile predictive of fatal disease supports a key role of neutrophils in the pathogenesis of NTS sepsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/CVI.00128-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933780PMC
July 2016

Interrupted BCG vaccination is a major threat to global child health.

Lancet Respir Med 2016 04 23;4(4):251-3. Epub 2016 Mar 23.

The University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(16)00099-0DOI Listing
April 2016

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension.

J Child Adolesc Psychopharmacol 2017 Jun 15;27(5):403-412. Epub 2016 Mar 15.

6 Forest Research Institute, (now Allergan) Jersey City, New Jersey.

Objective: Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension.

Methods: A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day.

Results: There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks.

Conclusions: This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/cap.2015.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510039PMC
June 2017

Childhood TB: can the End TB Strategy deliver?

Trans R Soc Trop Med Hyg 2016 Mar;110(3):155-7

Centre for International Child Health, University of Melbourne Department of Paediatrics and Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia International Union Against Tuberculosis and Lung Disease, Paris, France The Burnet Institute, Melbourne, Australia.

The accelerated reductions in global TB incidence required to achieve the End TB Strategy goal will result in reductions in the burden of childhood TB. Contact screening and preventive therapy have emerged as important components of TB burden reduction, and family-centered approaches could be an effective route in delivering these activities. Lack of accurate diagnostics for children remains a critical barrier and a need remains for better collaborative and supportive links between the child health and TB control sectors. Irrespective of whether the ambitious targets can be achieved, the unprecedented opportunities provided by the End TB Strategy must be embraced.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/trstmh/trw007DOI Listing
March 2016

The epidemiology of tuberculosis in children in Australia, 2003-2012.

Med J Aust 2015 Dec;203(11):440

University of Melbourne, Melbourne, VIC.

Objective: To describe the burden of and trends in paediatric tuberculosis (TB) in Australia between 2003 and 2012.

Design: A retrospective analysis of TB data from the National Notifiable Diseases Surveillance System (NNDSS) on TB in children (under 15 years of age) during the 10-year period, 2003-2012.

Results: TB notifications in Australia during the study period included 538 children (range, 37-66 cases per year), representing 4.6% of the total TB case load during the period (range, 3.8%-5.8% each year). Place of birth was recorded for 524 patients (97.4%); of these, 230 (43.9%) were born in Australia, 294 (56.1%) overseas. The average annual notification rate was 1.31 (95% CI, 1.20-1.43) cases per 100 000 child population. The rate was higher for overseas-born than for Australian-born children (9.57 [95% CI, 8.51-10.73] v 0.61 [95% CI, 0.53-0.69] cases per 100 000 children. The overall rate was highest among those aged 0-4 years. The annual notification rate was three times higher for Indigenous children than for non-Indigenous Australian-born children. Of 427 patients (79.4% of total) for whom the method of case detection was recorded, 37.0% were detected by contact screening, 8.7% by post-arrival immigration screening, and 54.3% by passive case detection. Pulmonary TB was the most common diagnostic classification (64.7% of patients). The most common risk factors were close contact with a TB case and recent residence in a country with a high incidence of TB. Treatment outcomes were satisfactory; 89.4% of children had completed treatment or were cured.

Conclusions: The burden of paediatric TB in Australia is low but has not changed over the past decade. The highest rates are among children born overseas, emphasising the important role of immigration screening as Australia aspires to eliminate TB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5694/mja15.00717DOI Listing
December 2015

Lymphocyte Perturbations in Malawian Children with Severe and Uncomplicated Malaria.

Clin Vaccine Immunol 2015 Nov 18;23(2):95-103. Epub 2015 Nov 18.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Wellcome Trust Sanger Institute, Cambridge, United Kingdom

Lymphocytes are implicated in immunity and pathogenesis of severe malaria. Since lymphocyte subsets vary with age, assessment of their contribution to different etiologies can be difficult. We immunophenotyped peripheral blood from Malawian children presenting with cerebral malaria, severe malarial anemia, and uncomplicated malaria (n = 113) and healthy aparasitemic children (n = 42) in Blantyre, Malawi, and investigated lymphocyte subset counts, activation, and memory status. Children with cerebral malaria were older than those with severe malarial anemia. We found panlymphopenia in children presenting with cerebral malaria (median lymphocyte count, 2,100/μl) and uncomplicated malaria (3,700/μl), which was corrected in convalescence and was absent in severe malarial anemia (5,950/μl). Median percentages of activated CD69(+) NK (73%) and γδ T (60%) cells were higher in cerebral malaria than in other malaria types. Median ratios of memory to naive CD4(+) lymphocytes were higher in cerebral malaria than in uncomplicated malaria and low in severe malarial anemia. The polarized lymphocyte subset profiles of different forms of severe malaria are independent of age. In conclusion, among Malawian children cerebral malaria is characterized by lymphocyte activation and increased memory cells, consistent with immune priming. In contrast, there are reduced memory cells and less activation in severe malaria anemia. Further studies are required to understand whether these immunological profiles indicate predisposition of some children to one or another form of severe malaria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/CVI.00564-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744922PMC
November 2015

Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children: An Update.

Clin Infect Dis 2015 Oct;61Suppl 3:S179-87

Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, MRC Unit on Child and Adolescent Health, University of Cape Town, South Africa.

Consensus case definitions for childhood tuberculosis have been proposed by an international expert panel, aiming to standardize the reporting of cases in research focusing on the diagnosis of intrathoracic tuberculosis in children. These definitions are intended for tuberculosis diagnostic evaluation studies of symptomatic children with clinical suspicion of intrathoracic tuberculosis, and were not intended to predefine inclusion criteria into such studies. Feedback from researchers suggested that further clarification was required and that these case definitions could be further improved. Particular concerns were the perceived complexity and overlap of some case definitions, as well as the potential exclusion of children with acute onset of symptoms or less severe disease. The updated case definitions proposed here incorporate a number of key changes that aim to reduce complexity and improve research performance, while maintaining the original focus on symptomatic children suspected of having intrathoracic tuberculosis. The changes proposed should enhance harmonized classification for intrathoracic tuberculosis disease in children across studies, resulting in greater comparability and the much-needed ability to pool study results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/civ581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583568PMC
October 2015

Resistance of Bacterial Isolates from Neonates with Suspected Sepsis to Recommended First-Line Antibiotics in Fiji.

Pediatr Infect Dis J 2015 Aug;34(8):915-6

Department of Health Sciences, College of Medicine, Nursing & Health Sciences, Fiji National University, Fiji Department of Paediatrics, Centre for International Child Health, University of Melbourne, Melbourne, Australia, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia, International Union Against Tuberculosis and Lung Disease, Paris, France Department of Health Economics, College of Engineering, Science & Technology, Fiji National University, Fiji Paediatrics Department, Colonial War Memorial Hospital, Ministry of Health, Fiji Secretariat of the Pacific Community, Noumea, New Caledonia, National Centre for Epidemiology and Population Health, Australian National University, Canberra, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/INF.0000000000000764DOI Listing
August 2015

Bubble continuous positive airway pressure for children with severe pneumonia and hypoxaemia in Bangladesh: an open, randomised controlled trial.

Lancet 2015 Sep 19;386(9998):1057-65. Epub 2015 Aug 19.

Centre for International Child Health, The University of Melbourne Department of Paediatrics, Murdoch Children's Research Institute and Intensive Care Unit, Royal Children's Hospital, Melbourne, VIC, Australia. Electronic address:

Background: In developing countries, mortality in children with very severe pneumonia is high, even with the provision of appropriate antibiotics, standard oxygen therapy, and other supportive care. We assessed whether oxygen therapy delivered by bubble continuous positive airway pressure (CPAP) improved outcomes compared with standard low-flow and high-flow oxygen therapies.

Methods: This open, randomised, controlled trial took place in Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh. We randomly assigned children younger than 5 years with severe pneumonia and hypoxaemia to receive oxygen therapy by either bubble CPAP (5 L/min starting at a CPAP level of 5 cm H2O), standard low-flow nasal cannula (2 L/min), or high-flow nasal cannula (2 L/kg per min up to the maximum of 12 L/min). Randomisation was done with use of the permuted block methods (block size of 15 patients) and Fisher and Yates tables of random permutations. The primary outcome was treatment failure (ie, clinical failure, intubation and mechanical ventilation, death, or termination of hospital stay against medical advice) after more than 1 h of treatment. Primary and safety analyses were by intention to treat. We did two interim analyses and stopped the trial after the second interim analysis on Aug 3, 2013, as directed by the data safety and monitoring board. This trial is registered at ClinicalTrials.gov, number NCT01396759.

Findings: Between Aug 4, 2011, and July 17, 2013, 225 eligible children were recruited. We randomly allocated 79 (35%) children to receive oxygen therapy by bubble CPAP, 67 (30%) to low-flow oxygen therapy, and 79 (35%) to high-flow oxygen therapy. Treatment failed for 31 (14%) children, of whom five (6%) had received bubble CPAP, 16 (24%) had received low-flow oxygen therapy, and ten (13%) had received high-flow oxygen therapy. Significantly fewer children in the bubble CPAP group had treatment failure than in the low-flow oxygen therapy group (relative risk [RR] 0·27, 99·7% CI 0·07-0·99; p=0·0026). No difference in treatment failure was noted between patients in the bubble CPAP and those in the high-flow oxygen therapy group (RR 0·50, 99·7% 0·11-2·29; p=0·175). 23 (10%) children died. Three (4%) children died in the bubble CPAP group, ten (15%) children died in the low-flow oxygen therapy group, and ten (13%) children died in the high-flow oxygen therapy group. Children who received oxygen by bubble CPAP had significantly lower rates of death than the children who received oxygen by low-flow oxygen therapy (RR 0·25, 95% CI 0·07-0·89; p=0·022).

Interpretation: Oxygen therapy delivered by bubble CPAP improved outcomes in Bangladeshi children with very severe pneumonia and hypoxaemia compared with standard low-flow oxygen therapy. Use of bubble CPAP oxygen therapy could have a large effect in hospitals in developing countries where the only respiratory support for severe childhood pneumonia and hypoxaemia is low-flow oxygen therapy. The trial was stopped early because of higher mortality in the low-flow oxygen group than in the bubble CPAP group, and we acknowledge that the early cessation of the trial reduces the certainty of the findings. Further research is needed to test the feasibility of scaling up bubble CPAP in district hospitals and to improve bubble CPAP delivery technology.

Funding: International Centre for Diarrhoeal Disease Research, Bangladesh, and Centre for International Child Health, University of Melbourne.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(15)60249-5DOI Listing
September 2015

Potentially Modifiable Factors Associated with Death of Infants and Children with Severe Pneumonia Routinely Managed in District Hospitals in Malawi.

PLoS One 2015 3;10(8):e0133365. Epub 2015 Aug 3.

International Union Against Tuberculosis and Lung Disease, Paris, France; Centre for International Child Health, University of Melbourne Department of Paediatrics and Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.

Objective: To investigate recognised co-morbidities and clinical management associated with inpatient pneumonia mortality in Malawian district hospitals.

Methods: Prospective cohort study, of patient records, carried out in Malawi between 1st October 2000 and 30th June 2003. The study included all children aged 0-59 months admitted to the paediatric wards in sixteen district hospitals throughout Malawi with severe and very severe pneumonia. We compared individual factors between those that survived (n = 14 076) and those that died (n = 1 633).

Results: From logistic regression analysis, predictors of death in hospital, adjusted for age, sex and severity grade included comorbid conditions of meningitis (OR =2.49, 95% CI 1.50-4.15), malnutrition (OR =2.37, 95% CI 1.94-2.88) and severe anaemia (OR =1.41, 95% CI 1.03-1.92). Requiring supplementary oxygen (OR =2.16, 95% CI 1.85-2.51) and intravenous fluids (OR =3.02, 95% CI 2.13-4.28) were associated with death while blood transfusion was no longer significant (OR =1.10, 95% CI 0.77-1.57) when the model included severe anaemia.

Conclusions: This study identified a number of challenges to improve outcome for Malawian infants and children hospitalised with pneumonia. These included improved assessment of co-morbidities and more rigorous application of standard case management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133365PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523211PMC
May 2016