Paediatrics (RCH) - Research Publications

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    The utility of chest x-ray and lung ultrasound in the management of infants and children presenting with severe pneumonia in low-and middle-income countries: A pragmatic scoping review
    Kazi, S ; Hernstadt, H ; Abo, Y-N ; Graham, H ; Palmer, M ; Graham, SM (INT SOC GLOBAL HEALTH, 2022)
    BACKGROUND: Chest x-ray (CXR) is commonly used (when available) to support clinical management decisions for child pneumonia and provide a reference standard for diagnosis in research studies. However, its diagnostic and technical limitations for both purposes are well recognised. Recent evidence suggests that lung ultrasound (LUS) may have diagnostic utility in pneumonia. This systematic scoping review of research on the utility of CXR and LUS in the management of severe childhood pneumonia aims to inform pragmatic guidelines for low- and middle-income countries (LMICs) and identify gaps in knowledge. METHODS: We included peer-reviewed studies published between 2000 and 2020 in infants and children aged from one month to nine years, presenting with severe pneumonia. CXR studies were limited to those from LMICs, while LUS studies included any geographic region. LUS and CXR articles were mapped into the following themes: indications, role in diagnosis, role in management, impact on outcomes, and practical considerations for LMIC settings. RESULTS: 85 articles met all eligibility criteria, including 27 CXR studies and 58 LUS studies. CXR studies were primarily observational and examined associations between radiographic abnormalities and pneumonia aetiology or outcomes. The most consistent finding was an association between CXR consolidation and risk of mortality. Difficulty obtaining quality CXR images and inter-reader variability in interpretation were commonly reported challenges. Research evaluating indications for CXR, role in management, and impact on patient outcomes was very limited. LUS studies primarily focused on diagnostic accuracy. LUS had higher sensitivity for identification of consolidation than CXR. There are gaps in knowledge regarding diagnostic criteria, as well as the practical utility of LUS in the diagnosis and management of pneumonia. Most LUS studies were conducted in HIC settings with experienced operators; however, small feasibility studies indicate that good inter-operator reliability may be achieved by training of novice clinicians in LMIC settings. CONCLUSIONS: The available evidence does not support the routine use of CXR or LUS as essential tools in the diagnosis and initial management of severe pneumonia. Further evaluation is required to determine the clinical utility and feasibility of both imaging modalities in low-resource settings.
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    Management of tuberculosis infection in Victorian children: A retrospective clinical audit of factors affecting treatment completion
    Holmes, RH ; Sun, S ; Kazi, S ; Ranganathan, S ; Tosif, S ; Graham, SM ; Graham, HR ; Williams, M (PUBLIC LIBRARY SCIENCE, 2022-10-13)
    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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    Systematic 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
    Hume-Nixon, M ; Lim, R ; Russell, F ; Graham, H ; von Mollendorf, C ; Mulholland, K ; Gwee, A ; ARI, RG (INT SOC GLOBAL HEALTH, 2022)
    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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    Review 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
    Hume-Nixon, M ; Graham, H ; Russell, F ; Mulholland, K ; Gwee, A ; Group, ARIR (INT SOC GLOBAL HEALTH, 2022)
    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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    Which 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
    Wilkes, C ; Graham, H ; Walker, P ; Duke, T (INT SOC GLOBAL HEALTH, 2022)
    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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    A systematic review of clinical, epidemiological and demographic predictors of tuberculosis in children with pneumonia.
    Kazi, S ; Corcoran, H ; Abo, Y-N ; Graham, H ; Oliwa, J ; Graham, SM ; ARI Review group, (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.
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    Childhood pneumonia in humanitarian emergencies in low- and middle-income countries: A systematic scoping review
    Chen, SJ ; Walker, PJB ; Mulholland, K ; Graham, HR (INT SOC GLOBAL HEALTH, 2022)
    BACKGROUND: Humanitarian emergencies increase many risk factors for pneumonia, including disruption to food, water and sanitation, and basic health services. This review describes pneumonia morbidity and mortality among children and adolescents affected by humanitarian emergencies. METHODS: We searched MEDLINE, EMBASE, and PubMed databases for publications reporting pneumonia morbidity or mortality among children aged 1 month to 17 years in humanitarian emergencies (eg, natural disaster, armed conflict, displacement) in low- and middle-income countries (LMICs). RESULTS: We included 22 papers published between January 2000 and July 2021 from 33 countries, involving refugee/displaced persons camps (n = 5), other conflict settings (n = 14), and natural disaster (n = 3). Population pneumonia incidence was high for children under 5 years of age (73 to 146 episodes per 100 patient-years); 6%-29% met World Health Organization (WHO) criteria for severe pneumonia requiring admission. Pneumonia accounted for 13%-34% of child and adolescent presentations to camp health facilities, 7%-48% of presentations and admissions to health facilities in other conflict settings, and 12%-22% of admissions to hospitals following natural disasters. Pneumonia related deaths accounted for 7%-30% of child and adolescent deaths in hospital, though case-fatality rates varied greatly (0.5%-17.2%). The risk for pneumonia was greater for children who are: recently displaced, living in crowded settings (particularly large camps), with deficient water and sanitation facilities, and those who are malnourished. CONCLUSION: Pneumonia is a leading cause of morbidity and mortality in children and adolescents affected by humanitarian emergencies. Future research should address population-based pneumonia burden, particularly for older children and adolescents, and describe contextual factors to allow for more meaningful interpretation and guide interventions.
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    Quality of care for children with acute respiratory infections in health facilities: A comparative analysis of assessment tools
    Quach, A ; Tosif, S ; Graham, SM ; von Mollendorf, C ; Mulholland, K ; Graham, H ; Duke, T ; Russell, FM (INT SOC GLOBAL HEALTH, 2022)
    BACKGROUND: Severe childhood pneumonia requires treatment in hospital by trained health care workers. It is therefore important to determine if health facilities provide quality health services for children with acute respiratory infections (ARI), including pneumonia. Using established indicators from WHO to measure quality of care (QoC) as a reference standard, this review aims to evaluate how well existing tools assess QoC for children presenting to health facilities with ARI. METHODS: Existing assessment tools identified from a published systematic literature review that evaluated QoC assessment tools for children (<15 years) in health facilities for all health conditions were included in this ARI-specific review. 27 ARI-specific indicators or "quality measures" from the WHO "Standards for improving quality of care for children and young adolescents in health facilities" were selected for use as a reference standard to assess QoC for children presenting to health facilities with ARI symptoms. Each included assessment tool was evaluated independently by two paediatricians to determine how many of the WHO ARI quality measures were assessable by the tool. The assessment tools were then ranked in order of percentage of ARI quality measures assessable. RESULTS: Nine assessment tools that assessed QoC for children attending health facilities were included. Two hospital care tools developed by WHO had the most consistency with ARI-specific indicators, assessing 22/27 (81.5%) and 20/27 (74.1%) of the quality measures. The remaining tools were less consistent with the ARI-specific indicators, including between zero to 16 of the 27 quality measures. The most common indicators absent from the tools were assessment of appropriate use of pulse oximetry and administration of oxygen, how often oxygen supply was unavailable, and mortality rates. CONCLUSIONS: The existing WHO hospital-based QoC assessment tools are comprehensive but could be enhanced by improved data quality around oxygen availability and appropriate use of pulse oximetry and oxygen administration. Any tools, however, should be considered within broader assessments of QoC, rather than utilised in isolation. Further adaptation to local settings will improve feasibility and facilitate progress in the delivery of quality health care for children with ARI. REGISTRATION: The protocol of the original systematic review was registered in PROSPERO ID: CRD42020175652.
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    TB contact tracing for young children: an Australian cascade of care review
    Moyo, N ; Tay, EL ; Nolan, A ; Graham, HR ; Graham, SM ; Denholm, JT (International Union Against Tuberculosis and Lung Disease, 2021-06-21)
    OBJECTIVE: To evaluate care cascades for programmatic active case finding and latent TB infection (LTBI) management in young child TB contacts (aged <5 years) in Victoria, Australia. DESIGN: This was a retrospective review of public health surveillance data to identify contacts of all pulmonary TB cases notified from 2016 to 2019. RESULTS: Contact tracing identified 574 young child contacts of 251 pulmonary TB cases. Active TB was found in 28 (4.9%) contacts, none of whom had previously received bacille Calmette-Guérin vaccination, and 529 were tested for TB infection using the tuberculin skin test (TST). The overall TST positivity was 15.3% (95% CI 0.1–0.2). Among the 574 children, 150 (26.1%) were close contacts of sputum smear-positive cases and 25 (16.7%) of these were not referred to TB clinics. Of the 125 referred, 81 were considered to have LTBI, 79 agreed to commence TB preventive treatment (TPT) and 71 (89.9%) completed TPT. Following completion of TPT, no child was subsequently diagnosed with active TB. CONCLUSION: There was a high yield from active case finding and uptake of TPT. Notable losses in the cascade of care occurred around referral to tertiary clinics, but high treatment completion rates and good outcomes were found in those prescribed treatment.
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    State-of-the-art in the pneumococcal field: Proceedings of the 11th International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD-11)
    Kwambana-Adams, BA ; Mulholland, EK ; Satzke, C ; Smith-Vaughan, H ; Brueggemann, A ; Whitney, C ; Kirkham, L-A ; Sa-Leao, R ; Vidal, J ; Graham, H ; Murdoch, D ; Paranhos-Baccala, G ; Goldblatt, D ; Pomat, WS ; Best, E ; McIntyre, P ; McVernon, J ; Weinberger, D ; Dunne, E ; Scott, JA ; Cripps, AW ; Mackenzie, G ; Madhi, S ; Torzillo, P ; Graham, S ; Kartasasmita, C ; Awori, JO ; Smith, A ; Hilty, M ; Blyth, C ; Pilishvili, T ; Hammitt, L ; Andrews, R ; Crooks, K ; Hanage, WP ; Wijburg, O ; Morpeth, S ; French, N ; Cheng, A ; Trappetti, C ; Tuomanen, E ; Rosch, J ; Arora, N ; Rodgers, G ; Yoshida, LM ; Richmond, P ; Licciardi, P ; Ferreira, DM (BMC, 2020-02-05)
    The International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD) is the premier global scientific symposium dedicated to the exchange, advancement and dissemination of the latest research on the pneumococcus, one of the world's deadliest bacterial pathogens. Since the first ISPPD was held in 1998, substantial progress has been made to control pneumococcal disease, for instance, more than half of surviving infants (78.6 million) from 143 countries now have access to the life-saving pneumococcal conjugate vaccine (PCV). The 11th ISPPD (ISPPD-11) was held in Melbourne, Australia in April 2018 and the proceedings of the symposium are captured in this report. Twenty years on from the first ISPPD, there remain many challenges and unanswered questions such as the continued disparity in disease incidence in Indigenous populations, the slow roll-out of PCV in some regions such as Asia, the persisting burden of disease in adults, serotype replacement and diagnosis of pneumococcal pneumonia. ISPPD-11 also put the spotlight on cutting-edge science including metagenomic, transcriptomic, microscopy, medical imaging and mathematical modelling approaches. ISPPD-11 was highly diverse, bringing together 1184 delegates from 86 countries, representing various fields including academia, primary healthcare, pharmaceuticals, biotechnology, policymakers and public health.