ORCID Profile
0000-0001-8393-5060
Current Organisation
University of Aberdeen
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Publisher: BMJ
Date: 22-09-2021
Publisher: Wiley
Date: 18-03-2019
DOI: 10.1002/PPUL.24317
Abstract: Severe asthma is a relatively uncommon condition in children but one which causes morbidity, occasionally mortality, and is a challenging condition to manage. There are several definitions of severe asthma, which have a common theme of poor control despite high dose inhaled corticosteroid treatment. Depending on the definition chosen, the prevalence of severe childhood asthma may be up to 5% within populations with asthma. Collectively, there is some evidence that the treatments used in severe asthma are beneficial, but a solid evidence-base is lacking for many treatments and some treatments have recognized side effects. Evidence supporting the use of maintenance oral prednisolone and intramuscular triamcinolone is weak. Response to systemic corticosteroids is heterogeneous and recognizing phenotypes or endotypes may identify those most likely to gain maximal benefit from treatment. For children aged 6 to 11 years, the anti-IgE biologic omalizumab is effective and anti-IL-5 agent (mepolizumab) has recently been licenced in Europe (but not the US). Biologics, which are licenced for >11 year olds include omalizumab, mepolizumab, benralizumab, reslizumab, and dupilumab. There is plenty that the clinician can offer to the child and adolescent with severe asthma in 2019, including nontherapeutic and therapeutic interventions. To manage severe asthma, practitioners from broad specialities must establish and maintain a close therapeutic relationship with patients. Looking beyond 2019, more treatment options will emerge for severe childhood asthma, and clinical teams will need to continue weighing up benefits and harms.
Publisher: Wiley
Date: 29-03-2021
DOI: 10.1111/PAI.13494
Abstract: Some children with asthma experience exacerbations despite long‐acting beta2‐agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome‐wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. A meta‐analysis of genome‐wide association studies (meta‐GWAS) was performed in 1,425 children and young adults with asthma (age 6‐21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. Genome‐wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta‐analysed. Eight independent variants were suggestively ( P ‐value threshold ≤5 × 10 −6 ) associated with exacerbations despite LABA use. No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci ( TBX3 and EPHA7) that were previously implicated in the response to short‐acting beta2‐agonists (SABA). These loci merit further investigation in response to LABA and SABA use.
Publisher: Elsevier BV
Date: 10-2017
Publisher: Cold Spring Harbor Laboratory
Date: 06-10-2020
DOI: 10.1101/2020.10.05.20206847
Abstract: Leukotrienes play a central pathophysiological role in both pediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. To test the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically erse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). In iduals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against in iduals with no exacerbation, using logistic regression for each cohort and meta-analysis. While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset in iduals from European ancestry demonstrated the risk of experiencing asthma exacerbations in the G allele carriers’ group (AG or GG), despite montelukast treatment, was increased (odds-ratio=3.27, 95%confidence interval: 0.98–10.93, I2=69%, p=0.05) compared to those in the AA group. When meta-analyzing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR=1.69, 95% CI: 0.56-5.09, I2=84.81%, p=0.35). Our study demonstrates that genetic variation in LTA4H , together with timing of asthma onset, may contribute to variability in montelukast response. Europeans in iduals with early-onset (≤18y) carrying the rs2660845 G allele have increased risk of exacerbation under montelukast treatment, presumably due to the up-regulation of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast.
Publisher: Wiley
Date: 26-05-2023
DOI: 10.1002/PPUL.26499
Abstract: The gestation when small for gestational age (SGA) is first associated with asthma is not well understood. Here, we use routinely acquired data from 10 weeks gestation to up to 28 years of age to test the hypothesis that SGA before birth is associated with an increased risk for asthma in a large population born between 1987 and 2015. Databases were linked to produce a single database that held antenatal fetal ultrasound measurements maternal characteristics birth measurements childhood anthropometric measurements at age 5 years hospital admission data (1987–2015) and family doctor prescribing (2009–2015). Asthma admission and receipt of any asthma medications were the outcomes. Analyses related single and then multiple anthropometric measurements to asthma outcomes. Outcome data were available for 63,930 in iduals. Increased length in the first‐trimester size was associated with a reduced odds ratio (OR) for asthma admission of 0.991 [0.983, 0.998] per mm increase and also a shorter time to first admission, with a hazard ratio risk of 0.987 [0.980, 0.994] per mm increase. Independent of all earlier measurements, increased height at 5 years (available in a subset of 15,760) was associated with reduced OR for an asthma admission, with OR of 0.874 [0.790, 0.967] per z score. Longitudinal measurements of weight were not related to asthma outcomes. Longer first‐trimester length is associated with more favorable asthma outcomes, and subsequently, increased height in childhood is also independently associated with more favorable asthma outcomes. Interventions that reduce SGA and encourage healthy postnatal growth might improve asthma outcomes.
Publisher: Wiley
Date: 07-01-2020
DOI: 10.1002/PPUL.24630
Abstract: Fractional exhaled nitric oxide (F An in idual patient data analysis was performed using data from seven randomized clinical trials which used F Data were available in 1112 randomized controlled trial participants and ≥1 stable period was present for 665 in iduals. The interquartile range (IQR) and limits of agreement (LoA) for change in absolute F Over a 3-month period where F
Publisher: Wiley
Date: 04-05-2018
DOI: 10.1002/PPUL.24037
Abstract: The study of the community of microorganisms (the microbiota) in the lower airways in children is restricted to opportunistic s ling in children undergoing elective general anaesthetic. Here we tested the hypothesis that induced sputum is a valid alternative to directly s ling the lower airways to study lower airway microbiota. Children scheduled for elective operations were recruited. Pre-operatively a s le of induced sputum was obtained. After anaesthesia was induced, a bronchial brushing and swabs of the upper respiratory tract were obtained. Bacterial community analysis was performed by lification of the V3-V4 16S rRNA gene region. Twenty children were recruited, mean age 10.7 years. Induced sputum s les were obtained from 12 children, bronchial brushing from 14 and nasal, mouth, and throat s les in 15, 16, and 17 children. The profile of bacterial communities was similar in the mouth, throat, and sputum s les with the nose and bronchial s les being different. Actinobacteria species dominated the nose and mouth, Fusobacteria were the dominant species in the throat and sputum while Proteobacteria species dominated in bronchial s les. Forty-one percent of detected bacteria in bronchial s les were unclassified. Bacterial communities from the mouth, throat, and induced sputum were tightly clustered and were distinct from nose and those found in bronchial communities. Induced sputum may not be a valid surrogate for microbiome assessment of the lower airways in all in iduals. Many bacteria in bronchial s les were not recognized by standard testing, suggesting that our understanding of the lower airway microbiota in children remains rudimentary.
Publisher: Wiley
Date: 20-07-2021
DOI: 10.1111/CEA.13965
Abstract: The polymorphism Arg16 in β 2 ‐adrenergic receptor ( ADRB2 ) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long‐acting β 2 ‐agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. The study was undertaken using data from 10 independent studies ( n = 5903) participating in the multi‐ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma‐related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta‐analysed using the inverse variance weighting method assuming random‐effects. In subjects treated with ICS and LABA ( n = 832, age: 3–21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05–1.87, I 2 = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05–1.94, I 2 = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71–1.39, I 2 = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as‐required short‐acting β 2 ‐agonists ( n = 973), ICS monotherapy ( n = 2623), ICS plus leukotriene receptor antagonists (LTRA n = 338), or ICS plus LABA plus LTRA ( n = 686). The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype‐guided treatment which might improve clinical outcomes in asthmatic patients.
Publisher: European Respiratory Society (ERS)
Date: 12-2019
DOI: 10.1183/20734735.0268-2019
Abstract: Exhaled nitric oxide fraction ( F ENO ) values can be easily measured using portable analysers and are a surrogate marker of airway eosinophilia. F ENO may be useful in diagnosing and monitoring conditions characterised by airway eosinophilia, i.e. asthma and possibly COPD. Many factors other than asthma and COPD affect F ENO , especially atopy, which is associated with elevated F ENO . One guideline recommends that F ENO should be used as part of the diagnostic pathway for asthma diagnosis in adults and children aged years. The role of F ENO in monitoring asthma is even less clear, and most guidelines do not recommend its use outside of specialist asthma clinics. Currently, F ENO is not recommended for diagnosis or monitoring of COPD. Although F ENO is starting to find a place in the management of asthma in children and adults, considerably more research is required before the potential of F ENO as an objective measurement in asthma and COPD can be realised. For in iduals aged ≥12 years, F ENO is not recommended by all guidelines as a test to diagnose asthma (recommended only by the UK National Institute for Health and Care Excellence guideline for asthma symptoms, which are likely to respond to corticosteroid treatment). F ENO may be used in conjunction with other investigations to diagnose asthma in 5–16-year-olds where there is diagnostic uncertainty, but further evidence is required. F ENO is not recommended as a routine test to monitor all patients with asthma or to titrate asthma treatment. F ENO is not recommended for routine clinical testing in adults with COPD. F ENO may be useful to identify patients with COPD who could benefit from the use of inhaled corticosteroids (asthma–COPD overlap). To understand what factors other than asthma and COPD affect F ENO To understand the current controversies in the application of F ENO to diagnosis and management of asthma in children To understand the current controversies in the application of F ENO to diagnosis and management of asthma and COPD in adults
Publisher: BMJ
Date: 15-01-2021
DOI: 10.1136/ARCHDISCHILD-2020-321008
Abstract: To determine the indirect consequences of the COVID-19 pandemic on paediatric healthcare utilisation and severe disease at a national level following lockdown on 23 March 2020. National retrospective cohort study. Emergency childhood primary and secondary care providers across Scotland two national paediatric intensive care units (PICUs) statutory death records. 273 455 unscheduled primary care attendances 462 437 emergency department attendances 54 076 emergency hospital admissions 413 PICU unplanned emergency admissions requiring invasive mechanical ventilation and 415 deaths during the lockdown study period and equivalent dates in previous years. Rates of emergency care consultations, attendances and admissions clinical severity scores on presentation to PICU rates and causes of childhood death. For all data sets, rates during the lockdown period were compared with mean or aggregated rates for the equivalent dates in 2016–2019. The rates of emergency presentations to primary and secondary care fell during lockdown in comparison to previous years. Emergency PICU admissions for children requiring invasive mechanical ventilation also fell as a proportion of cases for the entire population, with an OR of 0.52 for likelihood of admission during lockdown (95% CI 0.37 to 0.73), compared with the equivalent period in previous years. Clinical severity scores did not suggest children were presenting with more advanced disease. The greatest reduction in PICU admissions was for diseases of the respiratory system those for injury, poisoning or other external causes were equivalent to previous years. Mortality during lockdown did not change significantly compared with 2016–2019. National lockdown led to a reduction in paediatric emergency care utilisation, without associated evidence of severe harm.
Publisher: European Respiratory Society (ERS)
Date: 13-10-2022
DOI: 10.1183/13993003.00606-2022
Abstract: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients’ and carers’ views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV 1 ) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.
Publisher: Springer Science and Business Media LLC
Date: 04-10-2019
DOI: 10.1186/S13063-019-3500-7
Abstract: Childhood asthma is a common condition. Currently there is no validated objective test which can be used to guide asthma treatment in children. This study tests the hypothesis that the addition of fractional exhaled nitric oxide (F E NO) monitoring in addition to standard care reduces the number of exacerbations (or attacks) in children with asthma. This is a multi-centre, randomised controlled study. Children will be included of age 6–16 years who have a diagnosis of asthma, currently use inhaled corticosteroids (ICSs) and have had an exacerbation in the previous 12 months. Exclusion criteria include being unable to provide F E NO measurement at baseline assessment, having another chronic respiratory condition and being currently treated with maintenance oral steroids. Participants will be recruited in both primary and secondary care settings and will be randomised to either receive asthma treatment guided by F E NO plus symptoms (F E NO group) or asthma treatment guided by symptoms only (standard care group). Within the F E NO group, different treatment decisions will be made dependent on changes in F E NO. Participants will attend assessments 3, 6, 9 and 12 months post randomisation. The primary outcome is asthma exacerbation requiring prescription and/or use of an oral corticosteroid over 12 months as recorded by the participant arent or in general practitioner records. Secondary outcomes include time to first attack, number of attacks, asthma control score and quality of life. Adherence to ICS treatment is objectively measured by an electronic logging device. Participants are invited to participate in a “phenotyping” assessment where skin prick reactivity and bronchodilator response are determined and a saliva s le is collected for DNA extraction. Qualitative interviews will be held with participants and research nurses. A health economic evaluation will take place. This study will evaluate whether F E NO can provide an objective index to guide and stratify asthma treatment in children. ISRCTN, ISRCTN67875351. Registered on 12 April 2017. Prospectively registered.
Publisher: American Thoracic Society
Date: 15-12-2020
Publisher: BMJ
Date: 02-08-2022
DOI: 10.1136/ARCHDISCHILD-2021-321884
Abstract: Admission rates are rising despite no change to burden of illness, and interventions to reduce unscheduled admission to hospital safely may be justified. To systematically examine admission prevention strategies and report long-term follow-up of admission prevention initiatives. MEDLINE, Embase, OVID SP, PsychINFO, Science Citation Index Expanded/ISI Web of Science, The Cochrane Library from inception to time of writing. Reference lists were hand searched. Randomised controlled trials and before-and-after studies. In iduals aged years. Studies were independently screened by two reviewers with final screening by a third. Data extraction and the Critical Appraisals Skills Programme checklist completion (for risk of bias assessment) were performed by one reviewer and checked by a second. Twenty-eight studies were included of whom 24 were before-and-after studies and 4 were studies comparing outcomes between non-randomised groups. Interventions included referral pathways, staff reconfiguration, new healthcare facilities and telemedicine. The strongest evidence for admission prevention was seen in asthma-specific referral pathways (n=6) showing 34% (95% CI 28 to 39) reduction, but with evidence of publication bias. Other pathways showed inconsistent results or were insufficient for wider interpretation. Staffing reconfiguration showed reduced admissions in two studies, and shorter length of stay in one. Short stay admission units reduced admissions in three studies. There is little robust evidence to support interventions aimed at preventing paediatric admissions and further research is needed.
Publisher: F1000 Research Ltd
Date: 24-03-2020
DOI: 10.12688/WELLCOMEOPENRES.15751.1
Abstract: Background: Accurately diagnosing asthma can be challenging. Uncertainty about the best combination of clinical features and investigations for asthma diagnosis is reflected in conflicting recommendations from international guidelines. One solution could be a clinical prediction model to support health professionals estimate the probability of an asthma diagnosis. However, systematic review evidence identifies that existing models for asthma diagnosis are at high risk of bias and unsuitable for clinical use. Being mindful of previous limitations, this protocol describes plans to derive and validate a prediction model for use by healthcare professionals to aid diagnostic decision making during assessment of a child or young person with symptoms suggestive of asthma in primary care. Methods: A prediction model will be derived using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and linked primary care electronic health records (EHR). Data will be included from study participants up to 25 years of age where permissions exist to use their linked EHR. Participants will be identified as having asthma if they received at least three prescriptions for an inhaled corticosteroid within a one-year period and have an asthma code in their EHR. To deal with missing data we will consider conducting a complete case analysis. However, if the exclusion of cases with missing data substantially reduces the total s le size, multiple imputation will be used. A multivariable logistic regression model will be fitted with backward stepwise selection of candidate predictors. Apparent model performance will be assessed before internal validation using bootstrapping techniques. The model will be adjusted for optimism before external validation in a dataset created from the Optimum Patient Care Research Database. Discussion: This protocol describes a robust strategy for the derivation and validation of a prediction model to support the diagnosis of asthma in children and young people in primary care.
Publisher: European Respiratory Society (ERS)
Date: 12-2020
Publisher: American Thoracic Society
Date: 15-04-2022
Publisher: F1000 Research Ltd
Date: 17-05-2018
DOI: 10.12688/WELLCOMEOPENRES.14489.1
Abstract: Background. Childhood asthma is a common complex condition whose aetiology is thought to involve gene-environment interactions in early life occurring at the airway epithelium, associated with immune dysmaturation. It is not clear if abnormal airway epithelium cell (AEC) and cellular immune system functions associated with asthma are primary or secondary. To explore this, we will (i) recruit a birth cohort and observe the evolution of respiratory symptoms (ii) recruit children with and without asthma symptoms and (iii) use existing data from children in established STELAR birth cohorts. Novel pathways identified in the birth cohort will be sought in the children with established disease. Our over-arching hypothesis is that epithelium function is abnormal at birth in babies who subsequently develop asthma and progression is driven by abnormal interactions between the epithelium, genetic factors, the developing immune system, and the microbiome in the first years of life. Methods. One thousand babies will be recruited and nasal AEC collected at 5-10 days after birth for culture. Transcriptomes in AEC and blood leukocytes and the upper airway microbiome will be determined in babies and again at one and three years of age. In a subset of 100 in iduals, AEC transcriptomes and microbiomes will also be assessed at three and six months. In iduals will be assigned a wheeze category at age three years. In a cross sectional study, 300 asthmatic and healthy children aged 1 to 16 years will have nasal and bronchial AEC collected for culture and transcriptome analysis, leukocyte transcriptome analysis, and upper and lower airway microbiomes ascertained. Genetic variants associated with asthma symptoms will be confirmed in the STELAR cohorts. Conclusions. This study is the first to comprehensively study the temporal relationship between aberrant AEC and immune cell function and asthma symptoms in the context of early gene-microbiome interactions.
Publisher: American Thoracic Society
Date: 15-08-2019
Publisher: European Respiratory Society (ERS)
Date: 07-2022
DOI: 10.1183/23120541.00319-2022
Abstract: The normal range of fractional exhaled nitric oxide ( F ENO ) is influenced by demographic factors. However, single, fixed cut-off values are used for clinical interpretation in children despite rapid growth. We aimed to define the normal range of F ENO during childhood and evaluate its utility in a diagnostic setting. F ENO percentile charts were developed using data from nonasthmatic children in a population-based birth cohort (Manchester Asthma and Allergy Study). Children were skin prick tested, F ENO measured at the ages of 8, 11, 13–16 and 18 years and clinical information collected. This chart was externally validated in the Study of Eczema and Asthma to Observe the Influence of Nutrition (SEATON) cohort before being prospectively tested in symptomatic, treatment-naïve patients with suspected asthma in a diagnostic setting (Rapid Access Diagnostics for Asthma study). Height, weight, body mass index and age were predictive of F ENO in univariate analysis using 1220 F ENO measurements. Only height remained significant after adjustment in the overall, nonatopic and atopic populations, and was included in the predictive equations for 50th, 75th 90th and 98th percentiles. The proposed percentile lines corresponded to the 57th (95% CI 53rd–61st), 80th (76th–83rd), 90th (87th–92nd) and 98th (96th–99th) percentiles in the SEATON cohort (660 measurements). When tested in 73 symptomatic treatment-naïve children and young adults (median (interquartile range) age: 11 (8–14) years), an F ENO th percentile gave a 96% specificity and positive predictive value of 97%, identifying 59% of children who were subsequently diagnosed with asthma after extensive testing. We developed a height-based F ENO percentile chart which quantifies the probability of asthma in symptomatic children and merits further validation towards clinical implementation.
Publisher: Wiley
Date: 09-07-2018
DOI: 10.1111/ALL.13499
Publisher: Wiley
Date: 06-2022
DOI: 10.1111/PAI.13802
Abstract: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi‐ancestry meta‐analysis of genome‐wide association studies (meta‐GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across erse populations and to assess their functional role in regulating DNA methylation and gene expression. A meta‐GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants ( p ≤ 5 × 10 −5 ) were assessed for replication in 36,477 European and 1078 non‐European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. One hundred and twenty‐six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule‐1/exostosin like glycosyltransferase‐2 ( VCAM1 / EXTL2 ) (discovery: odds ratio (OR T allele ) = 0.82, p = 9.05 × 10 −6 and replication: OR T allele = 0.89, p = 5.35 × 10 −3 ) and rs943126 from pantothenate kinase 1 ( PANK1 ) (discovery: OR C allele = 0.85, p = 3.10 × 10 −5 and replication: OR C allele = 0.89, p = 1.30 × 10 −2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. This multi‐ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.
Publisher: F1000 Research Ltd
Date: 03-05-2023
DOI: 10.12688/WELLCOMEOPENRES.19078.1
Abstract: Introduction: Accurately diagnosing asthma can be challenging. We aimed to derive and validate a prediction model to support primary care clinicians assess the probability of an asthma diagnosis in children and young people. Methods: The derivation dataset was created from the Avon Longitudinal Study of Parents and Children (ALSPAC) linked to electronic health records. Participants with at least three inhaled corticosteroid prescriptions in 12-months and a coded asthma diagnosis were designated as having asthma. Demographics, symptoms, past medical/family history, exposures, investigations, and prescriptions were considered as candidate predictors. Potential candidate predictors were included if data were available in ≥60% of participants. Multiple imputation was used to handle remaining missing data. The prediction model was derived using logistic regression. Internal validation was completed using bootstrap re-s ling. External validation was conducted using health records from the Optimum Patient Care Research Database (OPCRD). Results: Predictors included in the final model were wheeze, cough, breathlessness, hay-fever, eczema, food allergy, social class, maternal asthma, childhood exposure to cigarette smoke, prescription of a short acting beta agonist and the past recording of lung function/reversibility testing. In the derivation dataset, which comprised 11,972 participants aged years (49% female, 8% asthma), model performance as indicated by the C-statistic and calibration slope was 0.86, 95% confidence interval (CI) 0.85–0.87 and 1.00, 95% CI 0.95–1.05 respectively. In the external validation dataset, which included 2,670 participants aged years (50% female, 10% asthma), the C-statistic was 0.85, 95% CI 0.83–0.88, and calibration slope 1.22, 95% CI 1.09–1.35. Conclusions: We derived and validated a prediction model for clinicians to calculate the probability of asthma diagnosis for a child or young person up to 25 years of age presenting to primary care. Following further evaluation of clinical effectiveness, the prediction model could be implemented as a decision support software.
Publisher: Wiley
Date: 19-01-2023
DOI: 10.1111/ALL.15639
Publisher: F1000 Research Ltd
Date: 07-09-2023
Publisher: BMJ
Date: 02-2021
DOI: 10.1136/BMJOPEN-2020-040528
Abstract: Asthma affects millions of children worldwide—1.1 million children in the UK. Asthma symptoms cannot be cured but can be controlled with low-dose inhaled corticosteroids (ICSs) in the majority of in iduals. Treatment with a low-dose ICS, however, fails to control asthma symptoms in around 10%–15% of children and this places the in idual at increased risk for an asthma attack. At present, there is no clear preferred treatment option for a child whose asthma is not controlled by low-dose ICS and international guidelines currently recommend at least three treatment options. Herein, we propose a systematic review and in idual participant data network meta-analysis (IPD-NMA) aiming to synthesise all available published and unpublished evidence from randomised controlled trials (RCTs) to establish the clinical effectiveness of pharmacological treatments in children and adolescents with uncontrolled asthma on ICS and help to make evidence-informed treatment choices. This will be used to parameterise a Markov-based economic model to assess the cost-effectiveness of alternative treatment options in order to inform decisions in the context of drug formularies and clinical guidelines. We will search in MEDLINE, the Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, NICE Technology Appraisals and the National Institute for Health Research (NIHR) Health Technology Assessment series for RCTs of interventions in patients with uncontrolled asthma on ICS. All studies where children and adolescents were eligible for inclusion will be considered, and authors or sponsors will be contacted to request IPD on patients aged . The reference lists of existing clinical guidelines, along with included studies and relevant reviews, will be checked to identify further relevant studies. Unpublished studies will be located by searching across a range of clinical trial registries, including internal trial registers for pharmaceutical companies. All studies will be appraised for inclusion against predefined inclusion and exclusion criteria by two independent reviewers with disagreements resolved through discussion with a third reviewer. We will perform an IPD-NMA—eventually supplemented with aggregate data for the RCTs without IPD—to establish both the probability that a treatment is best and the probability that a particular treatment is most likely to be effective for a specific profile of the patient. The IPD-NMA will be performed for each outcome variable within a Bayesian framework, using the WinBUGS software. Also, potential patient-level characteristics that may modify treatment effects will be explored, which represents one of the strengths of this study. The Committee on Research Ethics, University of Liverpool, has confirmed that ethics review is not required. The dissemination plan consists of publishing the results in an open-access medical journal, a plain-language summary available for parents and children, dissemination via local, national and international meetings and conferences and the press offices of our Higher Education Institutions (HEIs). A synopsis of results will be disseminated to NICE and British Thoracic Society/Scottish Intercollegiate Guidelines Network (SIGN) as highly relevant to future clinical guideline updates. CRD42019127599.
Publisher: European Respiratory Society (ERS)
Date: 28-07-2022
DOI: 10.1183/23120541.00174-2022
Abstract: Acute exacerbations are common in children and potentially preventable. Currently, a past exacerbation is the best predictor of a future exacerbation. We undertook a systematic review of the literature describing the relationship between past and future exacerbations. Our analysis considered whether the odds ratios for one exacerbation to predict a recurrence were different across different categories of exacerbation. Four databases were searched systematically (MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health and PsycInfo). Exacerbations were categorised by severity as: presentation to emergency department (ED) hospital admission paediatric intensive care unit (PICU) admission and “unspecified severity” ( i.e. no distinction between severity categories was made). Meta-analysis was performed for studies where sufficient data were provided for inclusion. There were 26 eligible articles from 9185 identified. There was significant heterogeneity in duration of follow-up, healthcare system and exacerbation definition between studies. For the unspecified severity definition, the odds ratio for an exacerbation after a previous exacerbation was 9.87 (95% CI 5.02–19.39 six studies, 162 583 in iduals). PICU admission was also associated with increased risk of future admission (OR 5.87, 95% CI 2.96–11.64 two studies, 730 in iduals). Meta-analysis was not possible for ED visits or hospitalisation. The median odds ratio (range) for past ED visit predicting future ED visit was 6.27 (3.3–8.26) and for past hospitalisation predicting future hospitalisation was 3.37 (1.89–5.36). The odds for a second asthma exacerbation do not necessarily increase with increasing severity of an initial exacerbation.
Publisher: European Respiratory Society (ERS)
Date: 08-01-2021
DOI: 10.1183/13993003.03599-2020
Abstract: Asthma exacerbations are major contributors to asthma morbidity and mortality. They are usually managed with bronchodilators and oral corticosteroids (OCS), but clinical trial evidence suggests that antibiotics could be beneficial. We aimed to assess whether treatment of asthma exacerbations with antibiotics in addition to OCS improved outcomes in larger, more representative routine-care populations. A retrospective comparative effectiveness study into managing asthma exacerbations with OCS alone versus OCS plus antibiotics was conducted using the Optimum Patient Care Research Database. The dataset included 28 637 patients following propensity score matching 20 024 adults and 4184 children were analysed. Antibiotics in addition to OCS were prescribed for the treatment of asthma exacerbations in 45% of adults and 32% of children. Compared to OCS alone, OCS plus antibiotics was associated with reduced risk of having an asthma/wheeze consultation in the following 2 weeks (children hazard ratio (HR) 0.84 (95% CI 0.73–0.96), p=0.012 adults HR 0.86 (95% CI 0.81–0.91), p .001), but an increase in risk of a further OCS prescription for a new/ongoing exacerbation within 6 weeks in adults (HR 1.11 (95% CI 1.01–1.21), p=0.030), but not children. Penicillins, but not macrolides, were associated with a reduction in the odds of a subsequent asthma/wheeze consultation compared to OCS alone, in both adults and children. Antibiotics were frequently prescribed in relation to asthma exacerbations, contrary to guideline recommendations. Overall, the routine addition of antibiotics to OCS in the management of asthma exacerbations appeared to confer little clinical benefit, especially when considering the risks of antibiotic overuse.
Publisher: European Respiratory Society (ERS)
Date: 06-2023
DOI: 10.1183/20734735.0048-2023
Abstract: Childhood asthma is a common condition in children. This review describes the evidence from seven asthma guidelines for using spirometry in the diagnosis and monitoring of childhood asthma. All guidelines recommend spirometry as the primary test to be performed for diagnosing asthma in children aged years. Spirometry is often normal in children with asthma. Guidelines are not consistent with respect to whether forced expiratory volume in 1 s (FEV 1 ) or FEV 1 /forced vital capacity (FVC) should be measured, or their threshold for “abnormal” spirometry, and we describe the sensitivity and specificity for these different cut-offs. The role of spirometry in monitoring asthma is less clear in the guidelines, and some do not suggest spirometry should be done. There is no consensus on what spirometric measurement should be used, how often it should be measured and what is a minimum clinically important change in spirometry. The role of spirometry in diagnosing asthma is more clearly established when compared to its role in monitoring asthma. The potential of spirometry to aid decision making for asthma diagnosis and monitoring in children remains to be fully evaluated. To provide knowledge of the commonly used guidelines for asthma diagnosis and management. To give insight into the opportunities and challenges in using spirometry to diagnose and monitor asthma in children. To provide an understanding of the precision of spirometry for diagnosing asthma.
Publisher: Cold Spring Harbor Laboratory
Date: 13-01-2020
DOI: 10.1101/2020.01.13.904037
Abstract: The culture of differentiated human airway epithelial cells allows the study of pathogen-host interactions and innate immune responses in a physiologically relevant in vitro model. As the use of primary cell culture has gained popularity the availability of the reagents needed to generate these cultures has increased. In this study we assessed two different media, Promocell and PneumaCult, during the differentiation and maintenance of well-differentiated primary nasal epithelial cell cultures (WD-PNECs). We compared and contrasted the consequences of these media on WD-PNEC morphological and physiological characteristics and their responses to respiratory syncytial virus (RSV) infection. We found that cultures generated using PneumaCult resulted in greater total numbers of smaller, tightly packed, pseudostratified cells. However, cultures from both media resulted in similar proportions of ciliated and goblet cells. There were no differences in RSV growth kinetics, although more ciliated cells were infected in the PneumaCult cultures. There was also significantly more IL-29/IFNλ1 secreted from PneumaCult compared to Promocell cultures. In conclusion, the type of medium used for the differentiation of primary human airway epithelial cells impacts experimental results.
Publisher: Public Library of Science (PLoS)
Date: 11-02-2019
Publisher: American Thoracic Society
Date: 07-2019
Publisher: European Respiratory Society (ERS)
Date: 12-03-2020
DOI: 10.1183/13993003.01879-2019
Abstract: Exhaled nitric oxide fraction ( F ENO ), a biomarker of eosinophilic airway inflammation, may be useful to guide asthma treatment. F ENO -guided treatment may be more effective in certain subgroups for improving asthma outcomes compared to standard treatment. An in idual patient data analysis was performed using data from seven randomised clinical trials (RCTs) which used F ENO to guide asthma treatment. The incidence of an asthma exacerbation and loss of control, and the time to first exacerbation and loss of control were described between five subgroups of RCT participants. Data were available in 1112 RCT participants. Among those not treated with leukotriene receptor antagonists (LTRA), but not among those who were treated with LTRA, F ENO -guided treatment was associated with reduced exacerbation risk (OR 0.68, 95% CI 0.49–0.94), longer time to first exacerbation (hazard ratio (HR) 0.76, 95% CI 0.57–0.99) and borderline reduced risk for loss of control (OR 0.70, 95% CI 0.49–1.00). Nonobese children, compared to obese children, were less likely to lose asthma control when treatment was guided by F ENO (OR 0.69, 95% CI 0.48–0.99) and time to loss of control was longer (HR 0.77, 95% CI 0.61–0.99). Asthma treatment guided by F ENO may be more effective in achieving better asthma outcomes for patients who are not treated with LTRA and who are not obese, compared to standard practice.
Publisher: Springer Science and Business Media LLC
Date: 19-12-2018
Publisher: Cold Spring Harbor Laboratory
Date: 20-10-2020
DOI: 10.1101/2020.10.15.20212308
Abstract: Severe disease directly associated with SARS-CoV-2 infection in children is rare. However, the indirect consequences of the COVID-19 pandemic on paediatric health have not been fully quantified. We examined paediatric health-care utilisation, incidence of severe disease, and mortality during the lockdown period in Scotland. This national retrospective cohort study examined national data for emergency childhood primary and secondary care utilisation following national lockdown on March 23, 2020. To determine whether social distancing measures and caregiver behavioural changes were associated with delayed care-seeking and increased disease severity on presentation, unplanned, emergency admissions requiring invasive mechanical ventilation for the two national Paediatric Intensive Care Units (PICUs) were analysed. PICU admissions were grouped by diagnostic category, and disease severity on presentation calculated. National statutory death records were consulted to establish childhood mortality rates and causes of death. For all observations, the lockdown period was compared to equivalent dates in 2016-2019. We identified 273,455 unscheduled primary care attendances 462,437 emergency department attendances 54,076 emergency hospital admissions 413 PICU emergency admissions and 415 deaths during the lockdown study period and equivalent dates in previous years. The rates of emergency presentations to primary and secondary care fell during lockdown in comparison to previous years. Emergency PICU admissions for children requiring invasive mechanical ventilation also fell, with an odds ratio of 0·52 for chance of admission during lockdown (95% CI 0·37-0·73, p 0·001). Clinical severity scores did not suggest children were presenting with more advanced disease. The greatest reduction in PICU admissions was for diseases of the respiratory system those for injury, poisoning or other external causes were equivalent to previous years. Mortality during lockdown did not change significantly compared to 2016-2019. National lockdown led a reduction in paediatric emergency care utilisation, without associated evidence of severe harm. None Data on the indirect effects of the COVID-19 pandemic on children at a population level are limited. We searched PubMed and medRxiv on October 13, 2020, for studies published from Jan 1, 2020 examining the indirect effects of non-pharmaceutical interventions (NPIs), and associated changes in caregiver health-care seeking behaviour, on the risk of severe paediatric disease and death. We used the search terms COVID-19, SARS-CoV-2, non-pharmaceutical interventions, indirect, and children, as well as manually searching references in other relevant papers. Terms were searched in idually and in combination as necessary, with no language restrictions. We identified one study that modelled the indirect effects of the COVID-19 pandemic on child deaths in low- and middle-income countries. Other studies analysed in isolation the effects of NPIs and other behavioural changes on emergency department attendances, hospital admission rates, paediatric intensive care unit (PICU) admission rates, or the incidence of specific presentations, such as asthma exacerbations. Some case series described delayed care-seeking for children with non-SARS-CoV-2 disease. We did not identify any national studies examining the indirect effects of the COVID-19 pandemic on the incidence of severe paediatric disease and mortality. This national study quantified the changes following national lockdown in Scotland on March 23, 2020. We examined data for unscheduled primary care and emergency department attendances, emergency hospital admissions, emergency paediatric intensive care unit (PICU) admissions requiring invasive mechanical ventilation, and paediatric mortality. Rates were compared with previous years. We found a reduction in paediatric emergency care utilisation rates associated with national lockdown. This reduction is likely to be due to a combination of changes in health care seeking behavior, and a fall in overall burden of paediatric infectious disease. These measures did not appear to have been associated with evidence of severe harm to children in Scotland, as evidenced by severity scores on presentation to PICU or mortality. This is the first comprehensive population-based assessment at a national level of the indirect effects of the COVID-19 pandemic on severe paediatric morbidity and mortality. Despite a significant reduction in health-care utilisation rates, we did not find associated evidence of severe harm. This study will assist policy makers, health-care providers and the public in evaluating the effects of lockdown on the risk of severe paediatric disease at a population level.
Publisher: Wiley
Date: 08-06-2017
DOI: 10.1111/PAI.12725
Abstract: The use of antibiotic therapy early in life might influence the risk of developing asthma. Studies assessing the influence of early life antibiotic use on the risk of asthma exacerbations are limited, and the results are inconsistent. Therefore, the aim of this study was to assess the association between use of antibiotic during the first 3 years of life and the risk of developing childhood asthma and the occurrence of asthma exacerbations. Data from four large childhood cohorts were used two population-based cohorts to study the risk of developing asthma: Generation R (n=7393, The Netherlands) and SEATON (n=891, Scotland, UK), and two asthma cohorts to assess the risk of asthma exacerbations: PACMAN (n=668, The Netherlands) and BREATHE (n=806, Scotland, UK). Odds ratios (ORs) were derived from logistic regression analysis within each database followed by pooling the results using a fixed- or random-effect model. Antibiotic use in early life was associated with an increased risk of asthma in a meta-analysis of the Generation R and SEATON data (OR: 2.18, 95% CI: 1.04-4.60 I Children treated with antibiotic in the first 3 years of life are more likely to develop asthma, but there is no evidence that the exposure to antibiotic is associated with increased risk of asthma exacerbations.
Publisher: Research Square Platform LLC
Date: 19-01-2021
DOI: 10.21203/RS.3.RS-46907/V3
Abstract: Background. Service reconfiguration of inpatient services in a hospital includes complete and partial closure of all emergency inpatient facilities. The “natural experiment” of service reconfiguration may give insight into drivers for emergency admissions to hospital. This study addressed the question does the prevalence of emergency admission to hospital for children change after reconfiguration of inpatient services? Methods. There were five service reconfigurations in Scottish hospitals between 2004 and 2018 where emergency admissions to one “reconfigured” hospital were halted (permanently or temporarily) and directed to a second “adjacent” hospital. The number of emergency admissions (standardised to /1000 children in the regional population) per month to the “reconfigured” and “adjacent” hospitals was obtained for five years prior to reconfiguration and up to five years afterwards. An interrupted time series analysis considered the association between reconfiguration and admissions across pairs comprised of “reconfigured” and “adjacent” hospitals, with adjustment for seasonality and an overall rising trend in admissions. Results. Of the five episodes of reconfiguration, two were immediate closure, two involved closure only to overnight admissions and one with overnight closure for a period and then closure. In “reconfigured” hospitals there was an average fall of 117 admissions/month [95% CI 78, 156] in the year after reconfiguration compared to the year before, and in “adjacent” hospitals admissions rose by 82/month [32, 131]. Across paired reconfigured and adjacent hospitals, in the months post reconfiguration, the overall number of admissions to one hospital pair slowed, in another pair admissions accelerated, and admission prevalence was unchanged in three pairs. After reconfiguration in one hospital, there was a rise in admissions to a third hospital which was closer than the named “adjacent” hospital. Conclusions. There are erse outcomes for the number of emergency admissions post reconfiguration of inpatient facilities. Factors including resources placed in the community after local reconfiguration, distance to the “adjacent” hospital and local deprivation may be important drivers for admission pathways after reconfiguration. Policy makers considering reconfiguration might consider a number of factors which may be important determinants of admissions post reconfiguration.
Publisher: Research Square Platform LLC
Date: 14-12-2020
DOI: 10.21203/RS.3.RS-46907/V2
Abstract: Background. Service reconfiguration of inpatient services in a hospital includes complete and partial closure of all emergency inpatient facilities. The “natural experiment” of service reconfiguration may give insight into drivers for emergency admissions to hospital. This study addressed the question does the prevalence of emergency admission to hospital for children change after reconfiguration of inpatient services? Methods. There were five service reconfigurations in Scottish hospitals between 2004 and 2018 where emergency admissions to one “reconfigured” hospital were halted (permanently or temporarily) and directed to a second “adjacent” hospital. The number of emergency admissions (standardised to /1000 children in the regional population) per month to the “reconfigured” and “adjacent” hospitals was obtained for five years prior to reconfiguration and up to five years afterwards. An interrupted time series analysis considered the association between reconfiguration and admissions across pairs comprised of “reconfigured” and “adjacent” hospitals, with adjustment for seasonality and an overall rising trend in admissions. Results. Of the five episodes of reconfiguration, two were immediate closure, two involved closure only to overnight admissions and one with overnight closure for a period and then closure. In “reconfigured” hospitals there was an average fall of 117 admissions/month [95% CI 78, 156] in the year after reconfiguration compared to the year before, and in “adjacent” hospitals admissions rose by 82/month [32, 131]. Across paired reconfigured and adjacent hospitals, in the months post reconfiguration, the overall number of admissions to one hospital pair slowed, in another pair admissions accelerated, and admission prevalence was unchanged in three pairs. After reconfiguration in one hospital, there was a rise in admissions to a third hospital which was closer than the named “adjacent” hospital. Conclusions. There are erse outcomes for the number of emergency admissions post reconfiguration of inpatient facilities. Factors including resources placed in the community after local reconfiguration, distance to the “adjacent” hospital and local deprivation may be important drivers for admission pathways after reconfiguration. Policy makers considering reconfiguration might consider a number of factors which may be important determinants of admissions post reconfiguration.
Publisher: BMJ
Date: 09-09-2022
DOI: 10.1136/ARCHDISCHILD-2022-324171
Abstract: This study identified the referral source for urgent short-stay admissions (SSAs) and compared characteristics of children with SSA stratified by different referral sources. Routinely acquired data from urgent admissions to Scottish hospitals during 2015–2017 were linked to data held by the three referral sources: emergency department (ED), out-of-hours (OOH) service and general practice (GP). There were 171 039 admissions including 92 229 (54%) SSAs. Only 171 (19%) of all of Scotland’s GP practices contributed data. Among the subgroup of 10 588 SSAs where GP data were available (11% all SSA), there was contact with the following referral source on the day of admission: only ED, 1853 (18%) only GP, 3384 (32%) and only OOH, 823 (8%). Additionally, 2165 (20%) had contact with more than one referral source, and 1037 (10%) had contact with referral source(s) on the day before the admission. When all 92 229 SSAs were considered, those with an ED referrer were more likely to be for older children, of white ethnicity, living in more deprived communities and diagnosed with asthma, convulsions or croup. The odds ratio for an SSA for a given condition differed by referral source and ranged from 0.07 to 1.9 (with reference to ED referrals). This study yielded insights and potential limitations regarding data linkage in a healthcare setting. Data coverage, particularly from primary care, needs to improve further. Evidence from data linkage studies can inform future intervention designed to provide safe integrated care pathways.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2018
DOI: 10.1038/S41533-018-0095-5
Abstract: Current understanding of risk factors for asthma attacks in children is based on studies of small but well-characterised populations or pharmaco-epidemiology studies of large but poorly characterised populations. We describe an observational study of factors linked to future asthma attacks in large number of well-characterised children. From two UK primary care databases (Clinical Practice Research Datalink and Optimum Patient Care research Database), a cohort of children was identified with asthma aged 5–12 years and where data were available for ≥2 consecutive years. In the “baseline” year, predictors included treatment step, number of attacks, blood eosinophil count, peak flow and obesity. In the “outcome” year the number of attacks was determined and related to predictors. There were 3776 children, of whom 525 (14%) had ≥1 attack in the outcome year. The odds ratio (OR) for one attack was 3.7 (95% Confidence Interval (CI) 2.9, 4.8) for children with 1 attack in the baseline year and increased to 7.7 (95% CI 5.6, 10.7) for those with ≥2 attacks, relative to no attacks. Higher treatment step, younger age, lower respiratory tract infections, reduced peak flow and eosinophil count /μL were also associated with small increases in OR for an asthma attack during the outcome year. In this large population, several factors were associated with a future asthma attack, but a past history of attacks was most strongly associated with future attacks. Interventions aimed at reducing the risk for asthma attacks could use primary care records to identify children at risk for asthma attacks.
Publisher: Research Square Platform LLC
Date: 12-08-2020
DOI: 10.21203/RS.3.RS-46907/V1
Abstract: Background . Service reconfiguration of inpatient services in a hospital includes complete and partial closure of all emergency inpatient facilities. The “natural experiment” of service reconfiguration may give insight into drivers for emergency admissions to hospital. This study addressed the question does the prevalence of emergency admission to hospital for children change after reconfiguration of inpatient services? Methods . There were five service reconfigurations in Scottish hospitals between 2004 and 2018 where emergency admissions to one “reconfigured” hospital were halted (permanently or temporarily) and directed to a second “adjacent” hospital. The number of emergency admissions per month to the “reconfigured” and “adjacent” hospitals was obtained for five years prior to reconfiguration and up to five years afterwards. An interrupted time series analysis considered the association between reconfiguration and admissions across pairs comprised of “reconfigured” and “adjacent” hospitals, with adjustment for seasonality and an overall rising trend in admissions. Results . Of the five episodes of reconfiguration, two were immediate closure, two involved closure only to overnight admissions and one with overnight closure for a period and then closure. In “reconfigured” hospitals there was an average fall of 117 admissions/month [95% CI 78, 156] in the year after reconfiguration compared to the year before, and in “adjacent” hospitals admissions rose by 82/month [32, 131]. Across paired reconfigured and adjacent hospitals, in the months post reconfiguration, the overall number of admissions to one hospital pair slowed, in another pair admissions accelerated, and admission prevalence was unchanged in three pairs. After reconfiguration in one hospital, there was a rise in admissions to a third hospital which was closer than the named “adjacent” hospital. Conclusions . There are erse outcomes for the number of emergency admissions post reconfiguration of inpatient facilities. Factors including resources placed in the community after local reconfiguration, distance to the “adjacent” hospital and local deprivation may be important drivers for admission pathways after reconfiguration. Policy makers considering reconfiguration might consider a number of factors which may be important determinants of admissions post reconfiguration.
Publisher: American Thoracic Society
Date: 15-12-2018
Publisher: BMJ
Date: 06-07-2019
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.ENVINT.2018.07.039
Abstract: To determine if low-cost air-quality monitors providing personalised feedback of household second-hand smoke (SHS) concentrations plus standard health service advice on SHS were more effective than standard advice in helping parents protect their child from SHS. A randomised controlled trial of a personalised intervention delivered to disadvantaged mothers who were exposed to SHS at home. Changes in household concentrations of fine Particulate Matter (PM Air-quality monitors measured household PM 120 mothers were recruited of whom 117 were randomised. Follow up was completed after 1-month in 102 and at 6-months in 78 participants. There was no statistically significant reduction in PM Neither standard advice nor standard advice plus personalised air-quality feedback were effective in reducing PM
Publisher: BMJ
Date: 24-02-2022
Publisher: MDPI AG
Date: 17-09-2018
DOI: 10.3390/HEALTHCARE6030117
Abstract: Background: The number of acute medical paediatric emergency admissions is rising. We undertook qualitative interviews with parents and clinicians to better understand what factors, other than the health status of the child, may influence decision making leading to emergency admission. Methods: Semi-structured interviews were conducted with parents clinicians working in general practice, out-of-hours or the emergency department (referring clinicians) and doctors working in acute medical paediatrics (receiving clinicians). Results: Ten parents, 7 referring clinicians and 10 receiving clinicians were interviewed. Parents described “erring on the side of caution” when seeking medical opinion and one mentioned anxiety. Among themes seen among referring clinicians, “erring on the side of caution” was also identified as was managing “parental anxiety” and acting on “gut instinct”. Among receiving clinicians, themes included managing parental anxiety and increasing parental expectations of the health service. Conclusions: The study of parent and referring clinician decision-making prior to a hospital admission can identify “teachable moments” where interventions might be delivered to slow or even arrest the rise in short-stay acute medical admissions in Britain and other countries. Interventions could assure parents or referring clinicians that hospital referral is not required and help clinicians understand what they perceive as “parental anxiety”.
Publisher: BMJ
Date: 29-10-2021
DOI: 10.1136/ARCHDISCHILD-2021-322636
Abstract: The General and Adolescent Paediatric Research Network in the UK and Ireland (GAPRUKI) was established in 2016. The aims of GAPRUKI are to unite general paediatricians around the UK and Ireland, to develop research ideas and protocols, and facilitate delivery of multicentre research. To undertake a research prioritisation exercise among UK and Ireland general paediatricians. This was a four-phase study using a modified Delphi survey. The first phase asked for suggested research priorities. The second phase developed ideas and ranked them in priority. In the third phase, priorities were refined and the final stage used the Hanlon Prioritisation Process to agree on the highest priorities. In phase one, there were 250 questions submitted by 61 GAPRUKI members (66% of the whole membership). For phase two, 92 priorities were scored by 62 members and the mean Likert scale (1–7) scores ranged from 3.13 to 5.77. In a face-to-face meeting (phases three and four), 17 research questions were identified and ultimately 14 priorities were identified and ranked. The four priorities with the highest ranking focused on these three respiratory conditions: asthma, bronchiolitis and acute wheeze. Other priorities were in the diagnosis or management of constipation, urinary tract infection, fever, gastro-oesophageal reflux and also new models of care for scheduled general paediatric clinics. Research priorities for child health in the UK and Ireland have been identified using a robust methodology. The next steps are for studies to be designed and funded to address these priorities.
Publisher: Public Library of Science (PLoS)
Date: 22-09-2021
DOI: 10.1371/JOURNAL.PONE.0257396
Abstract: Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically erse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). In iduals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against in iduals with no exacerbation, using logistic regression for each cohort and meta-analysis. While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset in iduals from European ancestry demonstrated the odds of experiencing asthma exacerbations by carriers of at least one G allele, despite montelukast treatment, were increased (odds-ratio = 2.92, 95%confidence interval (CI): 1.04–8.18, I2 = 62%, p = 0.0412) compared to those in the AA group. When meta-analysing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR = 1.60, 95% CI: 0.61–4.19, I2 = 85%, p = 0.342). Our study demonstrates that genetic variation in LTA4H , together with timing of asthma onset, may contribute to variability in montelukast response. European in iduals with early-onset (≤18y) carrying at least one copy of rs2660845 have increased odd of exacerbation under montelukast treatment, presumably due to the up-regulation of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast.
Publisher: BMJ
Date: 12-05-2023
Publisher: Public Library of Science (PLoS)
Date: 26-03-2020
Publisher: Wiley
Date: 02-08-2017
DOI: 10.1111/PPE.12386
Abstract: Maternal smoking during pregnancy is associated with increased childhood body mass index (BMI), but the relationship may be due to confounding by maternal factors. This study tested the hypothesis that siblings born to mothers who begin to smoke between pregnancies will have higher BMI than older unexposed siblings. Maternal details from the Aberdeen Maternity and Neonatal Databank were linked to the Study of Trends in Obesity in North East Scotland which holds offspring BMI at 5 years of age. Change in maternal smoking status between pregnancies was linked to offspring BMI and also to the difference in BMI between siblings. Maternal smoking status in successive pregnancies was linked to child BMI at age 5 years in 6581 mother-child pairs of whom 718 included sibling pars. Children whose mothers had quit, started smoking or smoked in consecutive pregnancies had higher BMI compared with those not exposed to maternal smoking. Siblings born after onset of maternal smoking had higher mean BMI z score (0.19, 95% confidence interval (CI) 0.01, 0.36) compared with unexposed older siblings. Mean BMI z score was also higher by mean of 0.10 (95% CI 0.01, 0.20) in younger sibling compared with older siblings born to mothers who smoked in both pregnancies. BMI z score was not significantly different between siblings whose mothers quit between pregnancies. In utero exposure to maternal smoking during pregnancy may increase the likelihood of increased BMI in childhood.
Publisher: BMJ
Date: 16-03-2023
Publisher: Wiley
Date: 11-10-2022
DOI: 10.1111/PAI.13672
Publisher: BMJ
Date: 12-04-2022
Abstract: The age at onset of the association between poverty and poor health is not understood. Our hypothesis was that in iduals from highest household income (HI), compared to those with lowest HI, will have increased fetal size in the second and third trimester and birth. Second and third trimester fetal ultrasound measurements and birth measurements were obtained from eight cohorts. Results were analysed in cross-sectional two-stage in idual patient data (IPD) analyses and also a longitudinal one-stage IPD analysis. The eight cohorts included 21 714 in iduals. In the two-stage (cross-sectional) IPD analysis, in iduals from the highest HI category compared with those from the lowest HI category had larger head size at birth (mean difference 0.22 z score (0.07, 0.36)), in the third trimester (0.25 (0.16, 0.33)) and second trimester (0.11 (0.02, 0.19)). Weight was higher at birth in the highest HI category. In the one-stage (longitudinal) IPD analysis which included data from six cohorts (n=11 062), head size was larger (mean difference 0.13 (0.03, 0.23)) for in iduals in the highest HI compared with lowest category, and this difference became greater between the second trimester and birth. Similarly, in the one-stage IPD, weight was heavier in second highest HI category compared with the lowest (mean difference 0.10 (0 .00, 0.20)) and the difference widened as pregnancy progressed. Length was not linked to HI category in the longitudinal model. The association between HI, an index of poverty, and fetal size is already present in the second trimester.
Publisher: Springer Science and Business Media LLC
Date: 20-09-2023
Publisher: European Respiratory Society (ERS)
Date: 16-04-2021
DOI: 10.1183/13993003.04173-2020
Abstract: Diagnosing asthma in children represents an important clinical challenge. There is no single gold-standard test to confirm the diagnosis. Consequently, over- and under-diagnosis of asthma is frequent in children. A task force supported by the European Respiratory Society has developed these evidence-based clinical practice guidelines for the diagnosis of asthma in children aged 5–16 years using nine Population, Intervention, Comparator and Outcome (PICO) questions. The task force conducted systematic literature searches for all PICO questions and screened the outputs from these, including relevant full-text articles. All task force members approved the final decision for inclusion of research papers. The task force assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The task force then developed a diagnostic algorithm based on the critical appraisal of the PICO questions, preferences expressed by lay members and test availability. Proposed cut-offs were determined based on the best available evidence. The task force formulated recommendations using the GRADE Evidence to Decision framework. Based on the critical appraisal of the evidence and the Evidence to Decision framework, the task force recommends spirometry, bronchodilator reversibility testing and exhaled nitric oxide fraction as first-line diagnostic tests in children under investigation for asthma. The task force recommends against diagnosing asthma in children based on clinical history alone or following a single abnormal objective test. Finally, this guideline also proposes a set of research priorities to improve asthma diagnosis in children in the future.
Publisher: Public Library of Science (PLoS)
Date: 16-12-2022
DOI: 10.1371/JOURNAL.PONE.0278777
Abstract: Numbers of urgent short stay admissions (SSAs) of children to UK hospitals are rising rapidly. This paper reports on experiences of SSAs from the perspective of parents accessing urgent care for their acutely unwell child and of health professionals referring, caring for, or admitting children. A qualitative interview study was conducted by a multi-disciplinary team with patient and public involvement (PPI) to explore contextual factors relating to SSAs and better understand pre-hospital urgent care pathways. Purposive s ling of Health Board areas in Scotland, health professionals with experience of paediatric urgent care pathways and parents with experience of a SSA for their acutely unwell child was undertaken to ensure maximal variation in characteristics such as deprivation, urban-rural and hospital structure. Interviews took place between Dec 2019 and Mar 2021 and thematic framework analysis was applied. Twenty-one parents and forty-eight health professionals were interviewed. In the context of an urgent SSA, the themes were centred around shared outcomes of care that matter. The main outcome which was common to both parents and health professionals was the importance of preserving the child’s safety. Additional shared outcomes by parents and health professionals were a desire to reduce worries and uncertainty about the illness trajectory, and provide reassurance with sufficient time, space and personnel to undertake a period of skilled observation to assess and manage the acutely unwell child. Parents wanted easy access to urgent care and, preferably, with input from paediatric-trained staff. Healthcare professionals considered that it was important to reduce the number of children admitted to hospital where safe and appropriate to do so. The shared outcomes of care between parents and health professionals emphasises the potential merit of adopting a partnership approach in identifying, developing and testing interventions to improve the acceptability, safety, efficiency, and cost-effectiveness of urgent care pathways between home and hospital.
Publisher: Informa UK Limited
Date: 08-2018
DOI: 10.2147/JAA.S170285
Publisher: BMJ
Date: 09-2023
Publisher: Wiley
Date: 29-03-2021
DOI: 10.1111/PAI.13503
Abstract: There are limited data describing lung function changes in children after an asthma exacerbation. Our hypothesis was that lung function does not fully recover in children in the months following an asthma exacerbation. We used a data set of children with asthma where lung function (including FEV 1 , FEV 1 /FVC ratio and FEF 25‐75 ) was measured at 3‐month intervals over a year. Mixed‐level models compared spirometry measured on two occasions 3 months apart before a single exacerbation (assessments 1 and 2) with measurements made on two occasions after the exacerbation (assessments 3 and 4), with adjustment for covariates. Changes in spirometry over a year were also analysed across those with exacerbations in no, one or more than one 3‐month periods. For the 113 children who had a single exacerbation, spirometry measured at assessments 1 or 2 did not differ from measurements at assessments 3 or 4 when the whole population was considered. When stratified into tertiles by change in %FEV 1 between assessments 2 and 3, those with the greater reduction were more likely to be treated with long‐acting beta‐agonist, but in this category, %FEV 1 at assessment 4 had returned to the value at assessment 1. %FEV 1 did not change over a 12‐month period within and between the three exacerbation categories (n = 809). One or more asthma exacerbation was not associated with a fall in lung function for the whole population. In a subset of in iduals, lung function does fall after an exacerbation but returns to pre‐exacerbation values after a period of months.
Publisher: Wiley
Date: 28-11-2022
DOI: 10.1111/ALL.15577
Publisher: Wiley
Date: 14-11-2018
DOI: 10.1002/PPUL.23915
Abstract: Airway epithelial cell (AEC) function differs between children with and without asthma. Here, we associated neonatal AEC function with asthma symptoms at 4 years of age. Nasal AEC were collected from neonates within 48 h of birth. Cells were cultured and stimulated with tumor necrosis factor alpha/interleukin-1 beta (TNFα/IL-1β), lipopolysaccharide (LPS), or house dust mite (HDM). Absolute concentrations of pro-inflammatory mediators in the culture supernatant were quantified and expressed as median [interquartile range] in pg/mg protein. A parent-completed respiratory questionnaire was returned when the child was 4 years old. AEC were successfully cultured in 139 neonates, of whom 120 were contacted at 4 years and 91 (76%) questionnaires were returned. Sixteen children had wheezed ever and 11 had recent wheeze. At birth, when compared to those with no recent wheeze, supernatants from cultured neonatal AEC from the children with recent wheeze had reduced median IL-8 (CXCL8) release after treatment with culture medium alone (P = 0.049), with TNFα/IL-1β (P < 0.001) and LPS (P = 0.004). Additionally, and when compared to those with no recent wheeze, 4 year olds with recent wheeze had reduced neonatal AEC release of IL-6 (P = 0.013), GMCSF (P = 0.012), and ICAM-1 (P = 0.017) after treatment with TNFα/IL-1β and reduced release of ICAM-1 (P = 0.038) and RANTES (P = 0.042) after treatment with HDM. Abnormalities in AEC function are present at birth before the onset of childhood wheeze. The relationship between reduced AEC function at birth and wheeze at 4 years was not exclusive, suggesting that post-natal factors are required for the AEC abnormality to translate into symptoms.
Publisher: MDPI AG
Date: 28-07-2021
DOI: 10.3390/JPM11080733
Abstract: Inhaled corticosteroids (ICS) are the most common asthma controller medication. An important contribution of genetic factors in ICS response has been evidenced. Here, we aimed to identify novel genetic markers involved in ICS response in asthma. A genome-wide association study (GWAS) of the change in lung function after 6 weeks of ICS treatment was performed in 166 asthma patients from the SLOVENIA study. Patients with an improvement in lung function ≥8% were considered as ICS responders. Suggestively associated variants (p-value ≤ 5 × 10−6) were evaluated in an independent study (n = 175). Validation of the association with asthma exacerbations despite ICS use was attempted in European (n = 2681) and admixed (n = 1347) populations. Variants previously associated with ICS response were also assessed for replication. As a result, the SNP rs1166980 from the ROBO2 gene was suggestively associated with the change in lung function (OR for G allele: 7.01, 95% CI: 3.29–14.93, p = 4.61 × 10−7), although this was not validated in CAMP. ROBO2 showed gene-level evidence of replication with asthma exacerbations despite ICS use in Europeans (minimum p-value = 1.44 × 10−5), but not in admixed in iduals. The association of PDE10A-T with ICS response described by a previous study was validated. This study suggests that ROBO2 could be a potential novel locus for ICS response in Europeans.
Publisher: Public Library of Science (PLoS)
Date: 22-02-2022
DOI: 10.1371/JOURNAL.PMED.1003916
Abstract: In 2020, the SARS-CoV-2 (COVID-19) pandemic and lockdown control measures threatened to disrupt routine childhood immunisation programmes with early reports suggesting uptake would fall. In response, public health bodies in Scotland and England collected national data for childhood immunisations on a weekly or monthly basis to allow for rapid analysis of trends. The aim of this study was to use these data to assess the impact of different phases of the pandemic on infant and preschool immunisation uptake rates. We conducted an observational study using routinely collected data for the year prior to the pandemic (2019) and immediately before (22 January to March 2020), during (23 March to 26 July), and after (27 July to 4 October) the first UK “lockdown”. Data were obtained for Scotland from the Public Health Scotland “COVID19 wider impacts on the health care system” dashboard and for England from ImmForm. Five vaccinations delivered at different ages were evaluated 3 doses of “6-in-1” diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type b, and hepatitis B vaccine (DTaP/IPV/Hib/HepB) and 2 doses of measles, mumps, and rubella (MMR) vaccine. This represented 439,754 invitations to be vaccinated in Scotland and 4.1 million for England. Uptake during the 2020 periods was compared to the previous year (2019) using binary logistic regression analysis. For Scotland, uptake within 4 weeks of a child becoming eligible by age was analysed along with geographical region and indices of deprivation. For Scotland and England, we assessed whether immunisations were up-to-date at approximately 6 months (all doses 6-in-1) and 16 to 18 months (first MMR) of age. We found that uptake within 4 weeks of eligibility in Scotland for all the 5 vaccines was higher during lockdown than in 2019. Differences ranged from 1.3% for first dose 6-in-1 vaccine (95.3 versus 94%, odds ratio [OR] compared to 2019 1.28, 95% confidence intervals [CIs] 1.18 to 1.39) to 14.3% for second MMR dose (66.1 versus 51.8%, OR compared to 2019 1.8, 95% CI 1.74 to 1.87). Significant increases in uptake were seen across all deprivation levels. In England, fewer children due to receive their immunisations during the lockdown period were up to date at 6 months (6-in-1) or 18 months (first dose MMR). The fall in percentage uptake ranged from 0.5% for first 6-in-1 (95.8 versus 96.3%, OR compared to 2019 0.89, 95% CI 0.86– to 0.91) to 2.1% for third 6-in-1 (86.6 versus 88.7%, OR compared to 2019 0.82, 95% CI 0.81 to 0.83). The use of routinely collected data used in this study was a limiting factor as detailed information on potential confounding factors were not available and we were unable to eliminate the possibility of seasonal trends in immunisation uptake. In this study, we observed that the national lockdown in Scotland was associated with an increase in timely childhood immunisation uptake however, in England, uptake fell slightly. Reasons for the improved uptake in Scotland may include active measures taken to promote immunisation at local and national levels during this period and should be explored further. Promoting immunisation uptake and addressing potential vaccine hesitancy is particularly important given the ongoing pandemic and COVID-19 vaccination c aigns.
Publisher: BMJ
Date: 29-03-2019
DOI: 10.1136/ARCHDISCHILD-2018-316228
Abstract: There was a reduction in febrile seizure admissions in Scotland after 2008. Our hypothesis was that a similar trend would be seen in other countries. We obtained the number of febrile and non-febrile seizure admissions in England and Scotland 2000–2013 and the incidence of all seizure admissions 2000–2013 in European countries. We compared the incidence of admission for febrile seizure (Scotland and England) and all seizures (all countries) between 2000–2008 and 2009–2013. The incidence of febrile seizure admissions per 1000 children in 2009–2013 was lower than 2000–2008 in Scotland (0.79 vs 1.08, p=0.001) and England (0.92 vs 1.20, p .001). The incidence of all seizure admissions (but not non-febrile seizures) was lower in 2009–2013 compared with 2000–2008 in Scotland (1.84 vs 2.20, p=0.010) and England (2.71 vs 2.91, p=0.001). Across 12 European countries (including the UK), there was no difference in all seizure admissions after 2008. We explored the possibility that the fall was related to the introduction of routine pneumococcal vaccination in 2006 but there were insufficient data. A fall in admissions for febrile (but not afebrile) seizures after 2008 in Scotland and England explains a fall in all emergency admissions for seizure. A fall in all seizure admissions has not occurred in other European countries, and more research is required to understand the different outcomes in the UK and non-UK countries.
Publisher: BMJ
Date: 12-2019
Publisher: European Respiratory Society (ERS)
Date: 10-12-2020
DOI: 10.1183/13993003.03388-2020
Abstract: Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among in iduals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies. A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 children of European descent treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed. 10 independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10 −6 ). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078 p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found. The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.
Publisher: BMJ
Date: 10-2023
Publisher: European Respiratory Society (ERS)
Date: 21-01-2021
DOI: 10.1183/13993003.04107-2020
Abstract: The A allele of rs1042713 (Arg16 amino acid) in the β 2 -adrenoreceptor is associated with poor response to long-acting β 2 -agonist (LABA) in young people with asthma. Our aim was to assess whether the prescribing of second-line controller with LABA or a leukotriene receptor antagonist according to Arg16Gly genotype would result in improvements in Pediatric Asthma-Related Quality of Life Questionnaire (PAQLQ). We performed a pragmatic randomised controlled trial (RCT) via a primary care clinical research network covering England and Scotland. We enrolled participants aged 12–18 years with asthma taking inhaled corticosteroids. 241 participants (mean± sd age 14.7±1.91 years) were randomised (1:1) to receive personalised care (genotype directed prescribing) or standard guideline care. Following a 4-week run-in participants were followed for 12 months. The primary outcome measure was change in PAQLQ. Asthma control, asthma exacerbation frequency and healthcare utilisation were secondary outcomes. Genotype-directed prescribing resulted in an improvement in PAQLQ compared to standard care (0.16, 95% CI 0.00–0.31 p=0.049), although this improvement was below the pre-determined clinical threshold of 0.25. The AA genotype was associated with a larger improvement in PAQLQ with personalised versus standard care (0.42, 95% CI 0.02–0.81 p=0.041). This is the first RCT demonstrating that genotype-driven asthma prescribing is associated with a significant improvement in a clinical outcome compared to standard care. Adolescents with the AA homozygous genotype benefited most. The potential role of such β 2 -adrenoceptor genotype directed therapy in younger and more severe childhood asthma warrants further exploration.
Publisher: National Institute for Health and Care Research
Date: 05-2022
DOI: 10.3310/AWOI5587
Abstract: The role of fractional exhaled nitric oxide in guiding asthma treatment in children is uncertain. To compare treatment guided by both fractional exhaled nitric oxide and symptoms (intervention) with treatment guided by symptoms alone (standard care) in children with asthma who are at risk of an asthma exacerbation, in terms of the number of asthma exacerbations over 12 months. This was a pragmatic, multicentre, randomised controlled trial with embedded cost-effectiveness and qualitative process evaluations. Randomisation (1 : 1) was carried out using a remote web-based system and was minimised on recruitment centre, age, sex and British Thoracic Society treatment step. Clinical teams and participants were not blind to treatment allocation. The trial took place in 35 hospitals and seven primary care practices in the UK. Children aged 6–15 years with a diagnosis of asthma who were currently prescribed inhaled corticosteroids and who had one or more parent- atient-reported asthma exacerbation treated with oral corticosteroids in the 12 months prior to recruitment. Asthma treatment guided by symptoms alone (standard care) and asthma treatment guided by symptoms plus fractional exhaled nitric oxide (intervention). Treatment recommendations in both groups were protocolised within a web-based algorithm, incorporating inhaled corticosteroid adherence (objectively measured using an electronic logging device) and current treatment. The primary outcome measure was asthma exacerbations treated with oral corticosteroids in the year post randomisation. Secondary outcomes included time to first exacerbation, number of exacerbations, lung function, fractional exhaled nitric oxide, daily dose of inhaled corticosteroid, asthma control and quality of life. In total, 509 eligible participants were recruited and the primary outcome was available for 506 participants. The primary outcome occurred in 123 out of 255 (48.2%) participants in the intervention group and 129 out of 251 (51.4%) participants in the standard-care group (adjusted odds ratio 0.88, 95% confidence interval 0.61 to 1.27). There was algorithm non-compliance on 21% of assessments. Per-protocol and complier-average causal effect analysis did not change the interpretation. This non-statistically significant estimate was consistent across predefined subgroups. There were no differences between the groups in secondary outcomes. There were no serious adverse events or deaths. No meaningful differences in health service costs, direct patient costs or indirect costs to society were identified between the groups. The economic evaluation does not provide evidence to support the cost-effectiveness of the intervention. In the qualitative process evaluation, 15 trial staff and six families were interviewed. Overall, their experiences were positive. The intervention was broadly acceptable, with caveats around clinicians using the algorithm recommendation as a guide and wariness around extreme step ups/downs in treatment in the light of contextual factors not being taken into account by the algorithm. Potential limitations included the choice of cut-off point to define uncontrolled asthma and the change in fractional exhaled nitric oxide to trigger a change in treatment. Furthermore, the treatment decisions in the two groups may not have been sufficiently different to create a difference in outcomes. The RAACENO (Reducing Asthma Attacks in Children using Exhaled Nitric Oxide) trial findings do not support the routine use of fractional exhaled nitric oxide measurements as part of asthma management in a secondary care setting. The potential for other objective markers to guide asthma management in children needs to be evaluated. This trial was registered as ISRCTN67875351. This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation Vol. 9, No. 4. See the NIHR Journals Library website for further project information.
Publisher: American Thoracic Society
Date: 15-10-2022
Publisher: Wiley
Date: 27-05-2018
DOI: 10.1002/PPUL.24062
Abstract: Increasing evidence suggests that poor lung function in adulthood is determined very early in life. Our study aims were: (1) identify factors associated with early infant lung function (2) quantify the link between early infant lung function and early adult lung function and (3) identify environmental and inherited factors which predict lung function throughout the post-natal growth period. In this longitudinal study, 253 in iduals were recruited antenatally. Lung function and allergy testing occurred at 1, 6, 12 months, 6, 11, 18, and 24 years of age. The relationship between lung function at 1 month (V'maxFRC) and spirometry variables at each follow-up was evaluated. Early life predictors of spirometry were assessed longitudinally using linear mixed models. V'maxFRC correlated positively with FEF25-75% at every assessment from 6 to 24 years and FEV Lung airflow measurements track from birth into early adulthood, suggesting a permanent and stable airway framework is laid down in the antenatal period. Lower infant airway function is associated with respiratory symptoms into adulthood, indicating the link is clinically important. Antenatal and early life exposures must be addressed in order to maximize airway growth and reduce lifelong respiratory compromise.
Publisher: BMJ
Date: 17-02-2023
DOI: 10.1136/ARCHDISCHILD-2022-324986
Abstract: There has been a rise in urgent paediatric hospital admissions and interventions to address this are required. To systemically review the literature describing community (or non-hospital)-based interventions designed to reduce emergency department (ED) visits or urgent hospital admissions. MEDLINE, Embase, OVIS SP, PsycINFO, Science Citation Index Expanded/ISI Web of Science (1981–present), the Cochrane Library database and the Database of Abstracts of Reviews of Effectiveness. Randomised controlled trials (RCTs) and before-and-after studies. In iduals aged years. Papers were independently reviewed by two researchers. Data extraction and the Critical Appraisals Skills Programme checklist was completed (for risk of bias assessment). Seven studies were identified. Three studies were RCTs, three were a comparison between non-randomised groups and one was a before-and-after study. Interventions were reconfiguration of staff roles (two papers), telemedicine (three papers), pathways of urgent care (one paper) and point-of-care testing (one paper). Reconfiguration of staff roles resulted in reduction in ED visits in one study (with a commensurate increase in general practitioner visits) but increased hospital admissions from ED in a second. Telemedicine was associated with a reduction in children’s admissions in one study and reduced ED admissions in two further studies. Interventions with pathways of care and point-of-care testing did not impact either ED visits or urgent admissions. New out-of-hospital models of urgent care for children need to be introduced and evaluated without delay. CRD42021274374.
Publisher: Wiley
Date: 13-11-2019
DOI: 10.1002/PPUL.24184
Abstract: This study investigated whether the previously reported associations in this birth cohort between maternal vitamin D and E intakes during pregnancy and childhood wheeze/asthma outcomes at age 5 and 10 years are still evident at age 15 years. In a prospective study of 1924 children recruited in utero, maternal vitamin D and E intakes during pregnancy were assessed by food frequency questionnaire and the children completed raespiratory questionnaire at age 15 years. Treatment for asthma at age 15 was also ascertained using healthcare data. Maternal vitamin D and E intakes were also related to combined childhood asthma data collected at 1, 2, 5, 10, and 15 years of age. Symptom data were available for 747 (39%) 15-year olds and healthcare data for 1689 (88%). There were no associations between maternal vitamin D and E intakes and childhood wheeze and asthma at age 15. Analysis of combined data collected between 1 and 15 years of age demonstrated that higher maternal vitamin D and E intakes during pregnancy were associated with a reduced likelihood of being diagnosed with asthma in the first 15 years: hazard ratio (95%CI) per quartile increase in vitamin intake of 0.87 (0.78,0.98) and 0.88 (0.78,0.98), respectively. Lower maternal vitamin D and E intakes during pregnancy are associated with increased risk of children wheezing and being diagnosed with asthma in the first 10 years but not after puberty, suggesting that post-natal exposures predominate in the etiology of incident asthma as children transition through puberty into adulthood.
Publisher: Public Library of Science (PLoS)
Date: 23-02-2017
Publisher: European Respiratory Society (ERS)
Date: 29-09-2021
DOI: 10.1183/23120541.00457-2021
Abstract: The prevalences of obstructive and restrictive spirometric phenotypes, and their relation to early-life risk factors from childhood to young adulthood remain poorly understood. The aim was to explore these phenotypes and associations with well-known respiratory risk factors across ages and populations in European cohorts. We studied 49 334 participants from 14 population-based cohorts in different age groups (≤10, –15, –20, –25 years, and overall, 5–25 years). The obstructive phenotype was defined as forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) z-score less than the lower limit of normal (LLN), whereas the restrictive phenotype was defined as FEV 1 /FVC z-score ≥LLN, and FVC z-score LLN. The prevalence of obstructive and restrictive phenotypes varied from 3.2–10.9% and 1.8–7.7%, respectively, without clear age trends. A diagnosis of asthma (adjusted odds ratio (aOR=2.55, 95% CI 2.14–3.04), preterm birth (aOR=1.84, 1.27–2.66), maternal smoking during pregnancy (aOR=1.16, 95% CI 1.01–1.35) and family history of asthma (aOR=1.44, 95% CI 1.25–1.66) were associated with a higher prevalence of obstructive, but not restrictive, phenotype across ages (5–25 years). A higher current body mass index (BMI was more often observed in those with the obstructive phenotype but less in those with the restrictive phenotype (aOR=1.05, 95% CI 1.03–1.06 and aOR=0.81, 95% CI 0.78–0.85, per kg·m −2 increase in BMI, respectively). Current smoking was associated with the obstructive phenotype in participants older than 10 years (aOR=1.24, 95% CI 1.05–1.46). Obstructive and restrictive phenotypes were found to be relatively prevalent during childhood, which supports the early origins concept. Several well-known respiratory risk factors were associated with the obstructive phenotype, whereas only low BMI was associated with the restrictive phenotype, suggesting different underlying pathobiology of these two phenotypes.
Publisher: BMJ
Date: 03-07-2020
Publisher: European Respiratory Society (ERS)
Date: 10-2020
DOI: 10.1183/23120541.00409-2020
Abstract: Early reports suggest that most children infected with severe acute respiratory syndrome coronavirus 2 (“SARS-CoV-2”) have mild symptoms. What is not known is whether children with chronic respiratory illnesses have exacerbations associated with SARS-CoV-2 virus. An expert panel created a survey, which was circulated twice (in April and May 2020) to members of the Paediatric Assembly of the European Respiratory Society (ERS) and via the social media of the ERS. The survey stratified patients by the following conditions: asthma, cystic fibrosis (CF), bronchopulmonary dysplasia (BPD) and other respiratory conditions. In total 174 centres responded to at least one survey. 80 centres reported no cases, whereas 94 entered data from 945 children with coronavirus disease 2019 (COVID-19). SARS-CoV-2 was isolated from 49 children with asthma of whom 29 required no treatment, 19 needed supplemental oxygen and four children required mechanical ventilation. Of the 14 children with CF and COVID-19, 10 required no treatment and four had only minor symptoms. Among the nine children with BPD and COVID-19, two required no treatment, five required inpatient care and oxygen and two were admitted to a paediatric intensive care unit (PICU) requiring invasive ventilation. Data were available from 33 children with other conditions and SARS-CoV-2 of whom 20 required supplemental oxygen and 11 needed noninvasive or invasive ventilation. Within the participating centres, in children with asthma and CF, infection with SARS-CoV-2 was well tolerated, but a substantial minority of children with BPD and other conditions required ventilatory support indicating that these latter groups are at risk from SARS-CoV-2 infection.
Publisher: Wiley
Date: 16-09-2020
DOI: 10.1111/ALL.14552
Publisher: Informa UK Limited
Date: 12-2018
DOI: 10.2147/JAA.S178531
Publisher: BMJ
Date: 10-12-2021
DOI: 10.1136/ARCHDISCHILD-2021-322394
Abstract: Here we describe an integrated model for scheduled care (the ‘cluster clinic’). Following a pilot in April 2018, cluster clinics were established across Aberdeen City from April 2019 but not the area surrounding Aberdeen (ie, Aberdeenshire). There were 2360 referrals in 2017/2018 (pre-cluster clinic), and 2615 in 2019/2020 (post-Aberdeen City cluster clinics). The proportions of referrals from City practices seen pre-cluster and post-cluster were 72% and 56%, respectively, and from Shire practices the corresponding proportions were 70% and 65%. The cluster clinic received positive feedback from parents and referring clinicians and was not associated with increased ‘missed diagnoses’ compared with business as usual clinic. The cluster clinic model is a realistic and effective method to deliver integrated scheduled care for children.
Publisher: Wiley
Date: 08-12-2022
DOI: 10.1111/ALL.15600
Publisher: Public Library of Science (PLoS)
Date: 21-05-2018
Publisher: Public Library of Science (PLoS)
Date: 05-01-2023
DOI: 10.1371/JOURNAL.PONE.0280086
Abstract: Healthcare technologies are becoming more commonplace, however clinical and patient perspectives regarding the use of technology in the management of childhood asthma have yet to be investigated. Within a clinical trial of asthma management in children, we conducted a qualitative process evaluation that provided insights into the experiences and perspectives of healthcare staff and families on (i) the use of smart inhalers to monitor medication adherence and (ii) the use of algorithm generated treatment recommendations. We interviewed trial staff ( n = 15) and families ( n = 6) who were involved in the trial to gauge perspectives around the use of smart inhalers to monitor adherence and the algorithm to guide clinical decision making. Staff and families indicated that there were technical issues associated with the smart inhalers. While staff suggested that the smart inhalers were good for monitoring adherence and enabling communication regarding medication use, parents and children indicated that smart inhaler use increased motivation to adhere to medication and provided the patient (child) with a sense of responsibility for the management of their asthma. Staff were open-minded about the use of the algorithm to guide treatment recommendations, but some were not familiar with its’ use in clinical care. There were some concerns expressed regarding treatment step-down decisions generated by the algorithm, and some staff highlighted the importance of using clinical judgement. Families perceived the algorithm to be a useful technology, but indicated that they felt comforted by the clinicians’ own judgements. The use of technology and in idual data within appointments was considered useful to both staff and families: closer monitoring and the educational impacts were especially highlighted. Utilising an algorithm was broadly acceptable, with caveats around clinicians using the recommendations as a guide only and wariness around extreme step-ups/downs considering contextual factors not taken into account.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Steve Turner.