Paediatrics (RCH) - Research Publications

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    Preventive therapy in children exposed to Mycobacterium tuberculosis: problems and solutions
    Rutherford, ME ; Hill, PC ; Triasih, R ; Sinfield, R ; van Crevel, R ; Graham, SM (WILEY-BLACKWELL, 2012-10-01)
    Young children living with a tuberculosis patient are at high risk of Mycobacterium tuberculosis infection and disease. WHO guidelines promote active screening and isoniazid (INH) preventive therapy (PT) for such children under 5 years, yet this well-established intervention is seldom used in endemic countries. We review the literature regarding barriers to implementation of PT and find that they are multifactorial, including difficulties in screening, poor adherence, fear of increasing INH resistance and poor acceptability among primary caregivers and healthcare workers. These barriers are largely resolvable, and proposed solutions such as the adoption of symptom-based screening and shorter drug regimens are discussed. Integrated multicomponent and site-specific solutions need to be developed and evaluated within a public health framework to overcome the policy-practice gap and provide functional PT programmes for children in endemic settings.
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    Importance of tuberculosis control to address child survival
    Graham, SM ; Sismanidis, C ; Menzies, HJ ; Marais, BJ ; Detjen, AK ; Black, RE (ELSEVIER SCIENCE INC, 2014-05-03)
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    A Prospective Evaluation of the Symptom-Based Screening Approach to the Management of Children Who Are Contacts of Tuberculosis Cases
    Triasih, R ; Robertson, CF ; Duke, T ; Graham, SM (OXFORD UNIV PRESS INC, 2015-01-01)
    BACKGROUND: Child tuberculosis contact screening and management can enhance case finding and prevent tuberculosis disease. It is universally recommended but rarely implemented in tuberculosis-endemic settings. The World Health Organization (WHO)-recommended symptom-based screening approach could improve implementation but has not been prospectively evaluated. METHODS: We conducted a cohort study of children who were close contacts of pulmonary tuberculosis patients in Indonesia from August 2010 to December 2012. We performed clinical assessment, tuberculin skin test, and chest radiography in all eligible children irrespective of symptoms at baseline. Mycobacterial culture and Xpert MTB/RIF assay were performed on sputum from children with persistent symptoms of suspected tuberculosis. Children were managed according to WHO guidelines and were prospectively followed for 12 months. RESULTS: A total of 269 child contacts of 140 index cases were evaluated. At baseline, 21 (8%) children had tuberculosis diagnosed clinically; an additional 102 (38%) had evidence of infection without disease. Of children with any tuberculosis-related symptoms at baseline, 21% had tuberculosis diagnosed compared with none of the asymptomatic children (P < .001). After 12 months of follow-up, none of the 99 eligible young child contacts (<5 years) who received isoniazid preventive therapy (IPT) had developed disease compared with 4 of 149 (2.6%) asymptomatic older children who did not receive IPT. CONCLUSIONS: Symptom-based screening is an effective and simple approach to child tuberculosis contact management that can be implemented at the primary healthcare level.
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    Tuberculosis as a cause or comorbidity of childhood pneumonia in tuberculosis-endemic areas: a systematic review
    Oliwa, JN ; Karumbi, JM ; Marais, BJ ; Madhi, SA ; Graham, SM (ELSEVIER SCI LTD, 2015-03-01)
    Pneumonia is a major cause of morbidity and mortality in infants and children worldwide, with most cases occurring in tuberculosis-endemic settings. Studies have emphasised the potential importance of Mycobacterium tuberculosis in acute severe pneumonia in children as a primary cause or underlying comorbidity, further emphasised by the changing aetiological range with rollout of bacterial conjugate vaccines in high mortality settings. We systematically reviewed clinical and autopsy studies done in tuberculosis-endemic settings that enrolled at least 100 children aged younger than 5 years with severe pneumonia, and that prospectively included a diagnostic approach to tuberculosis in all study participants. We noted substantial heterogeneity between studies in terms of study population and diagnostic methods. Of the 3644 patients who had culture of respiratory specimens for M tuberculosis undertaken, 275 (7·5%) were culture positive, and an acute presentation was common. Inpatient case-fatality rate for pneumonia associated with tuberculosis ranged from 4% to 21% in the four clinical studies that reported pathogen-related outcomes. Prospective studies are needed in high tuberculosis-burden settings to address whether tuberculosis is a cause or comorbidity of childhood acute severe pneumonia.
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    Morbidity and mortality in hospitalised neonates in central Vietnam
    Tran, HT ; Doyle, LW ; Lee, KJ ; Dang, NM ; Graham, SM (WILEY, 2015-05-01)
    AIM: This study explored neonatal morbidity and mortality in hospitalised patients in central Vietnam and risk factors associated with mortality. METHODS: We conducted a prospective cohort study of all newborn infants (<28 days) hospitalised in a neonatal unit over a 1-year period and followed until discharge. The main outcome measures were case fatality rate and the rate of different clinical diagnoses. RESULTS: There were 2555 admissions during the study period. The leading primary causes of admissions were infections (41%), haematological problems such as jaundice (23%) and prematurity and its complications (18%). The overall case fatality rate was 8.6%, and it was 59% among very low-birthweight (<1500 g) neonates. Mortality was inversely associated with birthweight and gestational age. Of the 220 deaths, 57% occurred within the first 7 days of life. Although the causes of death were often multifactorial, the leading primary causes were infections (32%), prematurity and its complications (25%), birth defects (24%) and birth asphyxia (6%). Risk factors associated with death were being outborn, early gestational age, small for gestational age, confirmed sepsis and birth defects. CONCLUSION: Mortality rates were high among hospitalised neonates in central Vietnam, and this paper suggests interventions that might improve outcomes.
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    Bubble continuous positive airway pressure for children with severe pneumonia and hypoxaemia in Bangladesh: an open, randomised controlled trial
    Chisti, MJ ; Salam, MA ; Smith, JH ; Ahmed, T ; Pietroni, MAC ; Shahunja, KM ; Shahid, ASMSB ; Faruque, ASG ; Ashraf, H ; Bardhan, PK ; Sharifuzzaman, ; Graham, SM ; Duke, T (ELSEVIER SCIENCE INC, 2015-09-12)
    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.
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    A high burden of late-onset sepsis among newborns admitted to the largest neonatal unit in central Vietnam
    Tran, HT ; Doyle, LW ; Lee, KJ ; Dang, NM ; Graham, SM (NATURE PUBLISHING GROUP, 2015-10-01)
    OBJECTIVE: The objective of this study is to determine the prevalence, causes and outcome of sepsis in hospitalized neonates in the largest neonatal unit in central Vietnam. STUDY DESIGN: A 1-year prospective cohort study of newborns admitted to the neonatal unit in Da Nang. A sepsis work-up including blood culture was undertaken before commencing antibiotics for neonates with suspected sepsis. RESULT: Of 2555 neonatal admissions, 616 neonates had 729 episodes of suspected invasive sepsis. A pathogen was isolated from blood in 115 (16%) episodes in 106 neonates. The prevalence of early-onset sepsis (EOS) was 8 (95% confidence interval (CI): 4 to 11) per 1000 admissions, and of late-onset sepsis (LOS) was 34 (95% CI: 27 to 41) per 1000 admissions. Of 86 neonates with LOS, 69 (80%) also fulfilled the criteria for nosocomial sepsis. The commonest bacterial causes of EOS were coagulase-negative Staphylococcus (CoNS) and Staphylococcus aureus, and of LOS were Acinetobacter, CoNS and Klebsiella pneumoniae. Fungal sepsis occurred in 35 neonates of which most were nosocomial sepsis. In vitro resistance to multiple antibiotics was common among Gram-negative bacteria. Antibiotics were prescribed and given to 68% of all admissions, and 14% of all admissions received four or more different antibiotics. The case fatality rate for confirmed sepsis was 46%. CONCLUSION: Late-onset, nosocomial sepsis was common and associated with a high mortality in hospitalized newborns in the largest neonatal unit in central Vietnam. These findings highlighted the need for improved infection control measures and antibiotic stewardship, which have since been implemented.
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    Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children: An Update
    Graham, SM ; Cuevas, LE ; Jean-Philippe, P ; Browning, R ; Casenghi, M ; Detjen, AK ; Gnanashanmugam, D ; Hesseling, AC ; Kampmann, B ; Mandalakas, A ; Marais, BJ ; Schito, M ; Spiegel, HML ; Starke, JR ; Worrell, C ; Zar, HJ (OXFORD UNIV PRESS INC, 2015-10-15)
    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.
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    The background and rationale for a new fixed-dose combination for first-line treatment of tuberculosis in children
    Graham, SM ; Grzemska, M ; Gie, RP (INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D), 2015-12-01)
    In 2010, the World Health Organization revised the recommendations for the treatment of tuberculosis (TB) in children. The major revision was to increase isoniazid, rifampicin and pyrazinamide dosages according to body weight in children. The recommendations for higher dosages are based on consistent evidence from 1) pharmacokinetic studies suggesting that young children require higher dosages than adolescents and adults to achieve desired serum concentrations; and 2) observational studies reporting that the higher dosages would not be associated with increased risk of toxicity in children. However, national tuberculosis programmes faced unforeseen challenges in implementing the revised recommendations. The main difficulty was to adapt the revised dosages for the treatment of children with drug-susceptible TB using available fixed-dose combinations (FDCs). A more suitable FDC for the intensive and continuation phases of treatment has now been developed for planned implementation in 2015. This paper explains the background and rationale for the development of a new FDC tablet for children with drug-susceptible TB.