Paediatrics (RCH) - Research Publications

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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 Review group, (International Global Health Society, 2022-08-22)
    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 ; ARI Review group, (International Global Health Society, 2022-08-22)
    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 ; ARI Review group, (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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    Prospective Associations of Susceptibility-Weighted Imaging Biomarkers with Fatigue Symptom Severity in Childhood Traumatic Brain Injury.
    Ryan, NP ; Catroppa, C ; Beauchamp, MH ; Beare, R ; Ditchfield, M ; Coleman, L ; Kean, M ; Crossley, L ; Hearps, SJC ; Anderson, V (Mary Ann Liebert Inc, 2022-08-22)
    Fatigue may be among the most profound and debilitating consequences of pediatric traumatic brain injury (TBI); however, neurostructural risk factors associated with post-injury fatigue remain elusive. This prospective study aimed to evaluate the independent value of susceptibility-weighted imaging (SWI) biomarkers, over-and-above known risk factors, to predict fatigue symptom severity in children with TBI. 42 children were examined with structural magnetic-resonance imaging (sMRI), including a SWI sequence, within 8-weeks post-injury. The PedsQL Multi-Dimensional Fatigue Scale (MFS) was administered 24-months post-injury. Compared to population expectations, the TBI group displayed significantly higher levels of general fatigue (Cohen's d = 0.44), cognitive fatigue (Cohen's d = 0.59), sleep/rest fatigue (Cohen's d = 0.37), and total fatigue (Cohen's d = 0.63). In multi-variate models adjusted for TBI severity, child demographic factors and depression, sub-acute volume of SWI lesions was independently associated with all fatigue symptom domains. The magnitude of the brain-behavior relationship varied by fatigue symptom domain, such that the strongest relationships were observed for the cognitive fatigue and total fatigue symptom scales. Overall, we found that total volume of SWI lesions explained up to 24% additional variance in multi-dimensional fatigue, over-and-above known risk factors. SWI has potential to improve prediction of post-injury fatigue in children with TBI. Our preliminary findings suggest that volume of SWI lesions may represent a novel, independent biomarker of post-injury fatigue scores, which could help to identify high-risk children who are likely to benefit from targeted psychoeducation and/or preventive strategies to minimize risk of persisting fatigue.
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    Obesity in young sudden cardiac death: Rates, clinical features, and insights into people with body mass index >50kg/m2.
    Paratz, ED ; Ashokkumar, S ; van Heusden, A ; Smith, K ; Zentner, D ; Morgan, N ; Parsons, S ; Thompson, T ; James, P ; Connell, V ; Pflaumer, A ; Semsarian, C ; Ingles, J ; Stub, D ; Gerche, AL (Elsevier BV, 2022-09)
    Objective: To contextualize obesity rates in young sudden cardiac death (SCD) against the age-matched national population, and identify clinical and pathologic features in WHO class II and III obesity. Methods: A prospective state-wide out-of-hospital cardiac arrest registry included all SCDs in Victoria, Australia from 2019-2021. Body mass indices (BMIs) of patients 18-50 years were compared to age-referenced general population. Characteristics of SCD patients with WHO Class II obesity (BMI ≥30kg/m2) and non-obesity (BMI<30kg/m2) were compared. Clinical characteristics of people with BMI>50kg/m2 were assessed. Results: 504 patients were included. Obesity was strongly over-represented in young SCD compared to the age-matched general population (55.0% vs 28.7%, p<0.0001). Obese SCD patients more frequently had hypertension, diabetes and obstructive sleep apnoea (p<0.0001, p=0.009 and p=0.001 respectively), ventricular fibrillation as their arrest rhythm (p=0.008) and left ventricular hypertrophy (LVH) (p<0.0001). Obese patients were less likely to have toxicology positive for illicit substances (22.0% vs 32.6%, p=0.008) or history of alcohol abuse (18.8% vs 26.9%, p=0.030). Patients with BMI>50 kg/m2 represented 8.5% of young SCD. LVH (n=26, 60.5%) was their predominant cause of death and only 10 (9.3%) patients died from coronary disease. Conclusion: Over half of young Australian SCD patients are obese, with all obesity classes over-represented compared to the general population. Obese patients had more cardiac risk factors. Almost two thirds of patients with BMI>50 kg/m2 died from LVH, with fewer than 10% dying from coronary disease.
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    Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis.
    Martinez, L ; Cords, O ; Liu, Q ; Acuna-Villaorduna, C ; Bonnet, M ; Fox, GJ ; Carvalho, ACC ; Chan, P-C ; Croda, J ; Hill, PC ; Lopez-Varela, E ; Donkor, S ; Fielding, K ; Graham, SM ; Espinal, MA ; Kampmann, B ; Reingold, A ; Huerga, H ; Villalba, JA ; Grandjean, L ; Sotgiu, G ; Egere, U ; Singh, S ; Zhu, L ; Lienhardt, C ; Denholm, JT ; Seddon, JA ; Whalen, CC ; García-Basteiro, AL ; Triasih, R ; Chen, C ; Singh, J ; Huang, L-M ; Sharma, S ; Hannoun, D ; Del Corral, H ; Mandalakas, AM ; Malone, LL ; Ling, D-L ; Kritski, A ; Stein, CM ; Vashishtha, R ; Boulahbal, F ; Fang, C-T ; Boom, WH ; Netto, EM ; Lemos, AC ; Hesseling, AC ; Kay, A ; Jones-López, EC ; Horsburgh, CR ; Lange, C ; Andrews, JR (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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    Aetiology of childhood pneumonia in low- and middle-income countries in the era of vaccination: a systematic review.
    von Mollendorf, C ; Berger, D ; Gwee, A ; Duke, T ; Graham, SM ; Russell, FM ; Mulholland, EK ; ARI review group, (International Global Health Society, 2022-07-23)
    Background: This systematic review aimed to describe common aetiologies of severe and non-severe community acquired pneumonia among children aged 1 month to 9 years in low- and middle-income countries. Methods: We searched the MEDLINE, EMBASE, and PubMed online databases for studies published from January 2010 to August 30, 2020. We included studies on acute community-acquired pneumonia or acute lower respiratory tract infection with ≥1 year of continuous data collection; clear consistent case definition for pneumonia; >1 specimen type (except empyema studies where only pleural fluid was required); testing for >1 pathogen including both viruses and bacteria. Two researchers reviewed the studies independently. Results were presented as a narrative summary. Quality of evidence was assessed with the Quality Assessment Tool for Quantitative Studies. The study was registered on PROSPERO [CRD42020206830]. Results: We screened 5184 records; 1305 duplicates were removed. The remaining 3879 titles and abstracts were screened. Of these, 557 articles were identified for full-text review, and 55 met the inclusion criteria - 10 case-control studies, three post-mortem studies, 11 surveillance studies, eight cohort studies, five cross-sectional studies, 12 studies with another design and six studies that included patients with pleural effusions or empyema. Studies which described disease by severity showed higher bacterial detection (Streptococcus pneumoniae, Staphylococcus aureus) in severe vs non-severe cases. The most common virus causing severe disease was respiratory syncytial virus (RSV). Pathogens varied by age, with RSV and adenovirus more common in younger children. Influenza and atypical bacteria were more common in children 5-14 years than younger children. Malnourished and HIV-infected children had higher rates of pneumonia due to bacteria or tuberculosis. Conclusions: Several viral and bacterial pathogens were identified as important targets for prevention and treatment. Bacterial pathogens remain an important cause of moderate to severe disease, particularly in children with comorbidities despite widespread PCV and Hib vaccination.
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    Taking Paediatrics Abroad: Working with low- and middle-income countries in a global pandemic.
    Parker, A ; Tek Chheng, E ; Nasi, T ; Orelly, T ; Aho, G ; Whitaker, S ; Weaver, J ; Phin, S ; Baker, R ; Woolfenden, S ; Currow, K (Wiley, 2021-07)
    Children and young people around the world face challenges to their health and wellbeing. In particular, in low- and middle-income countries they experience a higher burden of disease, exacerbated by global inequity limiting access to quality health care. According to the inverse care law, the availability of quality health care varies inversely to the need of the population, and hardworking health-care professionals in under-resourced countries may face impediments to continued education or subspecialty training. In line with the Sustainable Development Goals, collaborations have been developed between high-income and low- and-middle-income countries to address global disparities in health. These collaborations face challenges of high financial costs, difficulties creating long-term sustainable change, and with the emergence of the COVID-19 pandemic, border closures preventing fly-in volunteers. In this paper, we describe the development of an innovative, paediatric-specific model of care for training and support between high- and low-income countries - Taking Paediatrics Abroad Ltd. Taking Paediatrics Abroad supports the development of mutually beneficial relationships between Australian paediatric health-care professionals and paediatric health-care professionals in developing countries and remote, underserved Australian Aboriginal communities. Since May 2020, there have been over 100 sessions covering a vast array of paediatric specialties. This article explores Taking Paediatrics Abroad's model of care, its implementation and challenges, and opportunities for the future.
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    Community use of paracetamol and ibuprofen in children with fever
    Kloeden, B ; Tham, D ; Oakley, E ; Cheek, J (WILEY, 2021-05-26)
    OBJECTIVE: To establish, in children aged from 3 months to less than 13 years with a febrile illness, caregiver medication usage patterns and drivers. Secondary objectives assessed caregiver knowledge and concern about fever. METHODOLOGY: This was a prospective, observational study of a convenience sample of 147 children presenting to a tertiary Paediatric Emergency Department, where the caregivers reported a concern of fever within the preceding 48 h. A paper-based survey was completed by the caregivers, and the results analysed both qualitatively and quantitatively. RESULTS: Caregivers of 92.4% had administered medication for fever in the 48 h prior to presentation. Dual therapy of paracetamol and ibuprofen was used by 45.8%, with paracetamol used more frequently as monotherapy (35.4%). Almost one-third of caregivers woke their child to administer medication. Just over one-third of respondents stated that a temperature of less than 38.0°C is a fever. The majority of caregivers (67.6%) said that fever is bad for their child, with 97.9% being concerned by fever. Almost half the children (46.8%) were given medication purely to treat the degree of the temperature. General practitioners were reported as the strongest influence on medication decision (60%). CONCLUSIONS: This study provides insight into current knowledge and practices of parents regarding fever and its treatment. The results of this study may be used to direct future interventions to educate caregivers on this topic.
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    CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity
    Ernst, ME ; Baugh, EH ; Thomas, A ; Bier, L ; Lippa, N ; Stong, N ; Mulhern, MS ; Kushary, S ; Akman, CI ; Heinzen, EL ; Yeh, R ; Bi, W ; Hanchard, NA ; Burrage, LC ; Leduc, MS ; Chong, JSC ; Bend, R ; Lyons, MJ ; Lee, JA ; Suwannarat, P ; Brilstra, E ; Simon, M ; Koopmans, M ; van Binsbergen, E ; Groepper, D ; Fleischer, J ; Nava, C ; Keren, B ; Mignot, C ; Mathieu, S ; Mancini, GMS ; Madan-Khetarpal, S ; Infante, EM ; Bluvstein, J ; Seeley, A ; Bachman, K ; Klee, EW ; Schultz-Rogers, LE ; Hasadsri, L ; Barnett, S ; Ellingson, MS ; Ferber, MJ ; Narayanan, V ; Ramsey, K ; Rauch, A ; Joset, P ; Steindl, K ; Sheehan, T ; Poduri, A ; Vasquez, A ; Ruivenkamp, C ; White, SM ; Pais, L ; Monaghan, KG ; Goldstein, DB ; Sands, TT ; Aggarwal, V (WILEY, 2021-05-26)
    CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.