Paediatrics (RCH) - Research Publications

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    Magnitude and factors associated with post-tuberculosis lung disease in low- and middle-income countries: A systematic review and meta-analysis.
    Maleche-Obimbo, E ; Odhiambo, MA ; Njeri, L ; Mburu, M ; Jaoko, W ; Were, F ; Graham, SM ; Trajman, A (Public Library of Science (PLoS), 2022)
    BACKGROUND: Emerging evidence suggests that after completion of treatment for tuberculosis (TB) a significant proportion of patients experience sequelae. However, there is limited synthesized evidence on this from low-income countries, from Sub-Saharan Africa, and in HIV infected individuals. We seek to provide an updated comprehensive systematic review and meta-analysis on the magnitude and factors associated with post-TB lung disease (PTLD) in low- and middle-income countries (LMICs). METHODS: We searched PubMed, Embase and CINAHL for studies from LMICs with data on post-TB lung health in patients who had previously completed treatment for pulmonary TB. Data on study characteristics, prevalence of PTLD-specifically abnormal lung function (spirometry), persisting respiratory symptoms and radiologic abnormalities were abstracted. Statistical analysis was performed using Microsoft Excel and R version 4.1 software, and random effects meta-analysis conducted to compute pooled prevalence of PTLD, evaluate heterogeneity, and assess factors associated with PTLD. RESULTS: We identified 32 eligible studies with 6225 participants. Twenty-one studies were from Africa, 16 included HIV infected participants, spirometry was conducted in 20 studies, symptom assessment in 16 and chest imaging in eight. Pooled prevalence of abnormal lung function was 46.7%, persistent respiratory symptoms 41.0%, and radiologic abnormalities 64.6%. Magnitude of any type of PTLD varied by HIV status (HIV- 66.9%, HIV+ 32.8%, p = 0.0013), across geographic setting (SE Asia 57.5%, Southern America 50.8%, and Africa 38.2%, p = 0.0118), and across urban-rural settings (symptom prevalence: rural 68.8%, urban 39.1%, mixed settings 27.9%, p = 0.0035), but not by income settings, sex or age-group. CONCLUSIONS: There is high burden of post-TB persistent respiratory symptoms, functional lung impairment and radiologic structural abnormalities in individuals living in LMICs. Burden varies across settings and by HIV status. This evidence may be valuable to advocate for and inform implementation of structured health care specific to the needs of this vulnerable population of individuals.
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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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    Tuberculosis Infection in Children and Adolescents
    Youngui, BT ; Tchounga, BK ; Graham, SMM ; Bonnet, M (MDPI, 2022-12)
    The burden of tuberculosis (TB) in children and adolescents remains very significant. Several million children and adolescents are infected with TB each year worldwide following exposure to an infectious TB case and the risk of progression from TB infection to tuberculosis disease is higher in this group compared to adults. This review describes the risk factors for TB infection in children and adolescents. Following TB exposure, the risk of TB infection is determined by a combination of index case characteristics, contact features, and environmental determinants. We also present the recently recommended approaches to diagnose and treat TB infection as well as novel tests for infection. The tests for TB infection have limitations and diagnosis still relies on an indirect immunological assessment of cellular immune response to Mycobacterium tuberculosis antigens using immunodiagnostic testing. It is recommended that TB exposed children and adolescents and those living with HIV receive TB preventive treatment (TPT) to reduce the risk of progression to TB disease. Several TPT regimens of similar effectiveness and safety are now available and recommended by the World Health Organisation.
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    Contact screening and management in a high-transmission MDR-TB setting in Papua New Guinea: Progress, challenges and future directions
    Majumdar, SS ; Islam, S ; Huang, GKL ; Morris, L ; Bauri, M ; Chan, G ; Kama, G ; Keam, T ; Peacock-Smith, A ; Finch, S ; Marukutira, T ; Bhatt, S ; Drewett, G ; Wratten, M ; Murray, A ; Pank, N ; Masah, C ; Bala, R ; Umali, S ; Kalon, S ; Greig, J ; Chani, K ; Kal, M ; Graham, SM (Frontiers Media SA, 2022-01-01)
    Daru, South Fly District, Papua New Guinea is a high transmission setting for multidrug-resistant tuberculosis (MDR-TB). An emergency response by the Government in 2014 established a high-quality model for treatment and care. Household contact screening and management commenced in 2016 with TB preventive treatment (TPT) for well young child (<5 years) contacts of people with drug-susceptible TB and later expanded to young child contacts of MDR-TB. The model of care is community-based and led by non-specialist health workers, under supervision. An electronic medical record system supports care, reporting and operational research. Community engagement and education has been central, with a concerted focus on peer-led counselling and patient-centred services to improve TPT uptake and completion. Challenges include the application of households as the unit of intervention for detection of active TB and TPT provision. Our implementation experience in Daru has highlighted significant population mixing dynamics with most transmission likely occurring outside the household. We propose a community-wide screening approach with the provision of TPT based on testing to include older children, adolescents, and young adults. As there is the possibility of MDR-TB infection irrespective of the drug susceptibility of the household index case, a novel option is a combination TPT regimen of 6 months of daily isoniazid and levofloxacin (6HLfx). A sensitive aged-related algorithm to detect and exclude active TB is being developed. Ongoing community engagement, quality data systems with operational research to evaluate approaches are critical in high transmission MDR-TB settings.
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    Effect of systematic tuberculosis detection on mortality in young children with severe pneumonia in countries with high incidence of tuberculosis: a stepped-wedge cluster-randomised trial
    Marcy, O ; Wobudeya, E ; Font, H ; Vessière, A ; Chabala, C ; Khosa, C ; Taguebue, J-V ; Moh, R ; Mwanga-Amumpaire, J ; Lounnas, M ; Mulenga, V ; Mavale, S ; Chilundo, J ; Rego, D ; Nduna, B ; Shankalala, P ; Chirwa, U ; De Lauzanne, A ; Dim, B ; Tiogouo Ngouana, E ; Folquet Amorrissani, M ; Cisse, L ; Amon Tanoh Dick, F ; Komena, EA ; Kwedi Nolna, S ; Businge, G ; Natukunda, N ; Cumbe, S ; Mbekeka, P ; Kim, A ; Kheang, C ; Pol, S ; Maleche-Obimbo, E ; Seddon, JA ; Mao, TE ; Graham, SM ; Delacourt, C ; Borand, L ; Bonnet, M ; Marcy, O ; Serre, A ; Badrichani, A ; Razafimanantsoa, M ; Poublan, J ; Vessière, A ; Roucher, C ; Occelli, E ; Beuscart, A ; Charpin, A ; Habiyambere, G ; Mesnier, S ; Balestre, E ; Bhatta, B ; Maillard, A-L ; Orne-Gliemann, J ; Baillet, E ; Koskas, N ; D'Elbée, M ; Gabillard, D ; Font, H ; Huyen, M ; Bonnet, M ; Lounnas, M ; Espérou, H ; Couffin-Cadiergues, S ; Kuppers, A ; Hamze, B ; BORAND, L ; de LAUZANNE, A ; DIM, B ; Keang, C ; PRING, L ; YIN, S ; SARITH, C ; PHAN, C ; NHEUONG, S ; LY, S ; KAING, S ; SRENG, V ; LUN, E ; SAY, L ; SUOM, S ; FERHY, R ; SO, D ; BORN, S ; PAL, S ; NANG, B ; MAO, TE ; KIM, A ; Srey, V ; Kan, P ; Hout, L ; Ith, S ; Oum, S ; Sau, S ; Ho, KH ; Kith, D ; Nuch, N ; Horm, CL ; Sophon, C ; Roeungdeth, B ; MENG, C ; RITH, R ; PHY, S ; SOR, C ; SAO, V ; KHAT, S ; MAK, B ; UY, A ; KHAY, S ; SOM, K ; HACH, R ; SOK, H ; KUON, S ; HENG, S ; SENG, A ; NIM, S ; PAN, R ; KIM, S ; SREY LEAP, K ; NET, B ; NOUN, V ; LAY, D ; MANY, C ; Seng, S ; Ly, V ; So, S ; Oun, S ; CHEY, S ; CHHEA, R ; BAONG, L ; THOUNG, V ; KHEANG, C ; BY, B ; Nguon, V ; MEACH, E ; Tek, S ; Ngeav, S ; Lun, T ; HEM, D ; CHUT, N ; SARIK, S ; NANG, H ; MEACH, M ; SRENG, S ; SAR, D ; KIN, R ; ROS, P ; DORN, C ; KAK, C ; Sambath, SL ; Son, L ; Bin, L ; Pengong, E ; Pol, S ; Khutsorn, S ; Seang, S ; Soun, V ; Vong, V ; Khoeung, C ; Um, P ; Bou, S ; Song Pich, S ; Nim, P ; Khat, S ; Ban Si, N ; Ream, S ; Ing, S ; Chann, P ; Ngeth, S ; Sun, M ; Chhoeung, S ; Sean, S ; Prak, R ; Taguebue, J-V ; Kwedi Nolna, S ; Amboua Schouame Onambele, A ; Hycenth, N ; Melingui, B ; Nkembe Medounmga, A ; Hougnang Tatmi, L ; Etemgoua, N ; Kouesso, V ; Bugin, J ; Nzedjom, C ; Ngoya, R ; Eyike, J ; Loudjom, E ; Lonsti, R ; Dang, L ; Bintar, E ; Njayong, C ; Ngonsoa O, C ; Ndzeukap, I ; Dzoyem, P ; Dzokou, C ; Dindo, B ; Moh, R ; Komena, EA ; Aka Bony, R ; Kouadio, C ; Danho, S ; Goli, M ; Folquet, M ; Itchy, MV ; Sidibé, A ; Cissé, L ; Ouattara, J ; Konaté, M ; Amon-Tanoh Dick, F ; Cardena, M ; Adonis-Koffi, L ; Eugenie, D ; Kouamé, F ; Menan, H ; Inwoley, A ; Ouassa, T ; Nguessan, MS ; Khosa, C ; Cumbe, S ; Manhiça, E ; Zitha, A ; Chiúle, V ; Muxanga, E ; Gune, I ; Lima, Y ; Ribeiro, J ; Mavale, S ; Chilundo, J ; Maxanguana, F ; Morais, N ; Manhiça, J ; Give, J ; Atumane, J ; Lucas, G ; Thai, A ; Chave, A ; Rego, D ; Guambe, L ; Issa, F ; Carneiro, R ; Pene, N ; Florindo, N ; Machel, D ; Cumbane, C ; Mendes, H ; Kitungwa, M ; Muianga, V ; Tamele, H ; Sulude, A ; Mabota, R ; Comandante, H ; Massangaie, A ; Wobudeya, E ; Businge, GB ; Namulinda, F ; Sserunjogi, R ; Nassozi, R ; Barungi, C ; Aanyu, H ; Muwonge, D ; Kagoya, E ; Aciparu, S ; Chemutai, S ; Ntambi, S ; Wasswa, A ; Nangozi, J ; Tagoola, A ; Mbekeka, P ; Kenneth, S ; Lubega, JP ; Nassali, A ; Tagobera, J ; Agwang, C ; Kalembe, F ; Ajambo, A ; Aguti, E ; Kasibante, S ; Matende, H ; Odongo, IO ; Mwanga Amumpaire, J ; Natukunda, N ; Ngabirano, G ; Kakwenza, P ; Nuwamanya, S ; Nyangoma, M ; Nabbuto, J ; Abok, F ; Arinaitwe, R ; Birungi, D ; Mwesigwa, E ; Atwine, D ; Mbega, H ; Orikiriza, P ; Taremwa, I ; Turyashemererwa, E ; Derrick, H ; Nyehangane, D ; Kaitano, R ; Logoose, S ; Businge, S ; Ntambi, C ; Mugabi, J ; Mzee, J ; Besigye, J ; Kanzira, S ; Turyatemba, P ; Twebaze, F ; Chabala, C ; Mulenga, V ; Shankalala, P ; Hambulo, C ; Kapotwe, V ; Ngambi, M ; Kasakwa, K ; Chirwa, U ; Kapula, C ; Zulu, S ; Nawakwi, G ; Siasulingana, T ; Chilonga, J ; Chimbini, M ; Chilanga, M ; Nduna, B ; Inambao, M ; Mwambazi, M ; Halende, B ; Mumba, W ; Mankunshe, E ; Silavwe, M ; Chakopo, M ; Moono, R (Elsevier BV, 2022-11)
    Background: Tuberculosis diagnosis might be delayed or missed in children with severe pneumonia because this diagnosis is usually only considered in cases of prolonged symptoms or antibiotic failure. Systematic tuberculosis detection at hospital admission could increase case detection and reduce mortality. Methods: We did a stepped-wedge cluster-randomised trial in 16 hospitals from six countries (Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Uganda, and Zambia) with high incidence of tuberculosis. Children younger than 5 years with WHO-defined severe pneumonia received either the standard of care (control group) or standard of care plus Xpert MTB/RIF Ultra (Xpert Ultra; Cepheid, Sunnyvale, CA, USA) on nasopharyngeal aspirate and stool samples (intervention group). Clusters (hospitals) were progressively switched from control to intervention at 5-week intervals, using a computer-generated random sequence, stratified on incidence rate of tuberculosis at country level, and masked to teams until 5 weeks before switch. We assessed the effect of the intervention on primary (12-week all-cause mortality) and secondary (including tuberculosis diagnosis) outcomes, using generalised linear mixed models. The primary analysis was by intention to treat. We described outcomes in children with severe acute malnutrition in a post hoc analysis. This study is registered with ClinicalTrials.gov (NCT03831906) and the Pan African Clinical Trial Registry (PACTR202101615120643). Findings: From March 21, 2019, to March 30, 2021, we enrolled 1401 children in the control group and 1169 children in the intervention group. In the intervention group, 1140 (97·5%) children had nasopharyngeal aspirates and 942 (80·6%) had their stool collected; 24 (2·1%) had positive Xpert Ultra. At 12 weeks, 110 (7·9%) children in the control group and 91 (7·8%) children in the intervention group had died (adjusted odds ratio [OR] 0·986, 95% CI 0·597–1·630, p=0·957), and 74 (5·3%) children in the control group and 88 (7·5%) children in the intervention group had tuberculosis diagnosed (adjusted OR 1·238, 95% CI 0·696–2·202, p=0·467). In children with severe acute malnutrition, 57 (23·8%) of 240 children in the control group and 53 (17·8%) of 297 children in the intervention group died, and 36 (15·0%) of 240 children in the control group and 56 (18·9%) of 297 children in the intervention group were diagnosed with tuberculosis. The main adverse events associated with nasopharyngeal aspirates were samples with blood in 312 (27·3%) of 1147 children with nasopharyngeal aspirates attempted, dyspnoea or SpO2 less than 95% in 134 (11·4%) of children, and transient respiratory distress or SpO2 less than 90% in 59 (5·2%) children. There was no serious adverse event related to nasopharyngeal aspirates reported during the trial. Interpretation: Systematic molecular tuberculosis detection at hospital admission did not reduce mortality in children with severe pneumonia. High treatment and microbiological confirmation rates support more systematic use of Xpert Ultra in this group, notably in children with severe acute malnutrition.
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    Slow progress towards pneumonia control for children in low-and-middle income countries as measured by pneumonia indicators: A systematic review of the literature
    Quach, A ; Spence, H ; Nguyen, C ; Graham, SM ; von Mollendorf, C ; Mulholland, K ; Russell, FM (INT SOC GLOBAL HEALTH, 2022)
    BACKGROUND: The integrated Global Action Plan for Prevention and Control of Pneumonia and Diarrhoea (GAPPD) has the goal of ending preventable childhood deaths from pneumonia and diarrhoea by 2025 with targets and indicators to monitor progress. The aim of this systematic review is to summarise how low-and-middle income countries (LMICs) reported pneumonia-specific GAPPD indicators at national and subnational levels and whether GAPPD targets have been achieved. METHODS: We searched MEDLINE, Embase, PubMed and Global Health Databases, and the World Health Organization (WHO) website. Publications/reports between 2015 and 2020 reporting on two or more GAPPD-pneumonia indicators from LMICs were included. Data prior to 2015 were included if available in the same report series. Quality of publications was assessed with the Quality Assessment Tool for Quantitative Studies. A narrative synthesis of the literature was performed to describe which countries and WHO regions were reporting on GAPPD indicators and progress in GAPPD coverage targets. RESULTS: Our search identified 17 publications/reports meeting inclusion criteria, with six from peer-reviewed publications. Data were available from 139 LMICs between 2010 and 2020, predominantly from Africa. Immunisation coverage rates were the indicators most commonly reported, followed by exclusive breastfeeding rates and pneumonia case management. Most GAPPD indicators were reported at the national level with minimal reporting at the subnational level. Immunisation coverage (Haemophilus influenzae, measles, diphtheria-tetanus-pertussis vaccines) in the WHO Europe, Americas and South-East Asia regions were meeting 90% coverage targets, while pneumococcal conjugate vaccine coverage lagged globally. The remaining GAPPD indicators (breastfeeding, pneumonia case management, antiretroviral prophylaxis, household air pollution) were not meeting GAPPD targets in LMICs. There was a strong negative correlation between pneumonia specific GAPPD coverage rates and under-five mortality (Pearson correlation coefficient range = -0.74, -0.79). CONCLUSION: There is still substantial progress to be made in LMICs to achieve the 2025 GAPPD targets. Current GAPPD indicators along with country reporting mechanisms should be reviewed with consideration of adding undernutrition and access to oxygen therapy as important indicators which impact pneumonia outcomes. Further research on GAPPD indicators over longer time periods and at subnational levels can help identify high-risk populations for targeted pneumonia interventions.
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    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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    Impacts of tuberculosis services strengthening and the COVID-19 pandemic on case detection and treatment outcomes in Mimika District, Papua, Indonesia: 2014-2021.
    Lestari, T ; Kamaludin, ; Lowbridge, C ; Kenangalem, E ; Poespoprodjo, JR ; Graham, SM ; Ralph, AP ; Eslava-Schmalbach, JH (Public Library of Science (PLoS), 2022)
    Indonesia is a high-burden tuberculosis (TB) country with a wide case detection gap, exacerbated by the COVID-19 pandemic. We aimed to review the epidemiology of TB in a high-endemic setting of Indonesia before and during the implementation of health system strengthening activities for TB, including during the first two years of the COVID-19 pandemic. We analysed TB program data from Mimika District, Papua, Indonesia from 2014 to 2021. Health system strengthening activities to improve the programmatic management of TB were implemented from 2017 onwards. Activities included decentralization of TB services, training and mentoring of healthcare workers, improved screening for co-morbidities, and introduction and optimisation of Xpert testing in 2018. A total of 11,803 TB cases were notified to the Mimika District Health Office over eight years (2014-21). Between 2015 and 2019, there was a 67% increase in annual case notifications, an 89% increase in bacteriologically confirmed cases and the proportion of TB cases detected in primary care increased from 26% to 46%. In 2020, coinciding with the COVID-19 pandemic, investigation of people with presumptive TB fell by 38%, but the proportion of those tested with Xpert increased. TB case notifications decreased by 19% from 1,796 in 2019 to 1,461 in 2020, but then increased by 17% to 1,716 in 2021. Routine screening for co-morbidities (HIV, diabetes) among TB patients improved over time and was not affected by the pandemic. Treatment success overall was 71% and remained relatively unchanged. Loss to follow-up and death were 18% and 3.7% respectively. Improvements in TB case finding were observed over a period in which a range of health system strengthening activities were implemented. While COVID-19 had a negative impact on the TB program in Mimika District, there are encouraging signs of recovery. Further work is needed to improve TB treatment outcomes.
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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.