Oxygen saturation targets in infants with bronchiolitis (BIDS): a double-blind, randomised, equivalence trial.

BACKGROUND: The American Academy of Pediatrics recommends a permissive hypoxaemic target for an oxygen saturation of 90% for children with bronchiolitis, which is consistent with the WHO recommendations for targets in children with lower respiratory tract infections. No evidence exists to support this threshold. We aimed to assess whether the 90% or higher target for management of oxygen supplementation was equivalent to a normoxic 94% or higher target for infants admitted to hospital with viral bronchiolitis. METHODS: We did a parallel-group, randomised, controlled, equivalence trial of infants aged 6 weeks to 12 months of age with physician-diagnosed bronchiolitis newly admitted into eight paediatric hospital units in the UK (the Bronchiolitis of Infancy Discharge Study [BIDS]). A central computer randomly allocated (1:1) infants, in varying length blocks of four and six and without stratification, to be clipped to standard oximeters (patients treated with oxygen if pulse oxygen saturation [SpO2] <94%) or modified oximeters (displayed a measured value of 90% as 94%, therefore oxygen not given until SpO2 <90%). All parents, clinical staff, and outcome assessors were masked to allocation. The primary outcome was time to resolution of cough (prespecified equivalence limits of plus or minus 2 days) in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN28405428. FINDINGS: Between Oct 3, and March 30, 2012, and Oct 1, and March 29, 2013, we randomly assigned 308 infants to standard oximeters and 307 infants to modified oximeters. Cough resolved by 15·0 days (median) in both groups (95% CI for difference -1 to 2) and so oxygen thresholds were equivalent. We recorded 35 serious adverse events in 32 infants in the standard care group and 25 serious adverse events in 24 infants in the modified care group. In the standard care group, eight infants transferred to a high-dependency unit, 23 were readmitted, and one had a prolonged hospital stay. In the modified care group, 12 infants were transferred to a high-dependency unit and 12 were readmitted to hospital. Recorded adverse events did not differ significantly. INTERPRETATION: Management of infants with bronchiolitis to an oxygen saturation target of 90% or higher is as safe and clinically effective as one of 94% or higher. Future research should assess the benefits and risks of different oxygen saturation targets in acute respiratory infection in older children, particularly in developing nations where resources are scarce. FUNDING: National Institute for Health Research, Health Technology Assessment programme.

Unsupervised home spirometry is not equivalent to supervised clinic spirometry in children and young people with cystic fibrosis: Results from the CLIMB-CF study.

BACKGROUND: Handheld spirometry allows monitoring of lung function at home, of particular importance during the COVID-19 pandemic. Pediatric studies are unclear on whether values are interchangeable with traditional, clinic-based spirometry. We aimed to assess differences between contemporaneous, home (unsupervised) and clinic (supervised) spirometry and the variability of the former. The accuracy of the commercially available spirometer used in the study was also tested. METHODS: Data from participants in the Clinical Monitoring and Biomarkers to stratify severity and predict outcomes in children with cystic fibrosisc (CLIMB-CF) Study aged ≥ 6 years who had paired (±1 day) clinic and home forced expiratory volume in 1 s (FEV1 ) readings were analyzed. Variability during clinical stability over 6-months was assessed. Four devices from Vitalograph were tested using 1 and 3 L calibration syringes. RESULTS: Sixty-seven participants (median [interquartile range] age 10.7 [7.6-13.9] years) provided home and clinic FEV1 data pairs. The mean (SD) FEV1 % bias was 6.5% [±8.2%]) with wide limits of agreement (-9.6% to +22.7%); 76.2% of participants recorded lower results at home. Coefficient of variation of home FEV1 % during stable periods was 9.9%. Data from the testing of the handheld device used in CLIMB-CF showed a potential underread. CONCLUSION: In children and adolescents, home spirometry using hand-held equipment cannot be used interchangeably with clinic spirometry. Home spirometry is moderately variable during clinical stability. New handheld devices underread, particularly at lower volumes of potential clinical significance for smaller patients; this suggests that supervision does not account fully for the discrepancy. Opportunities should be taken to obtain dual device measurements in clinic, so that trend data from home can be utilized more accurately.

Comparative demographics of the European cystic fibrosis population: a cross-sectional database analysis.

BACKGROUND: Country-specific patients' registries are rarely used to make international comparisons because of protocol discrepancies in data collation. We present data from a European cystic fibrosis registry that is dedicated to collection of demographic data, and assess whether the resources available in countries with and without European Union (EU) membership affects care and survival of patients. METHODS: Data for demographic indicators-age, age at diagnosis, sex, and genotype-for patients with cystic fibrosis from 35 European countries were combined, and used to establish the differences in demographic indicators between EU and non-EU countries. EU membership status in 2003 was used to divide countries. We modelled demographic indicators of EU countries on non-EU countries to estimate the size of the cystic fibrosis population if non-EU countries had had the same resources available for patients as did EU countries. FINDINGS: Data were gathered for 29 025 patients, who had a median age of 16.3 years (IQR 8.9-24.8), with a difference of 4.9 years (95% CI 4.4-5.1; p<0.0001) between EU (median 17.0 years, IQR 9.5-25.6) and non-EU countries (12.1 years, 6.0-19.2). The proportion of patients older than 40 years was higher in EU countries (1205 [5%]) than in non-EU countries (76 [2%]), with an odds ratio of 2.4 (95% CI 1.9-3.0, p<0.0001). We estimated that the cystic fibrosis population in non-EU countries would increase by 84% if patients had a demographic profile comparable to that of patients in EU countries. INTERPRETATION: Future studies need to establish the reasons for the lower proportion of patients with cystic fibrosis in non-EU countries than in EU countries, such as underdiagnosis and premature childhood mortality. FUNDING: European Community's Sixth Framework Programme for Research, and Czech Ministry of Health.

A methodology to establish a database to study gene environment interactions for childhood asthma.

BACKGROUND: Gene-environment interactions are likely to explain some of the heterogeneity in childhood asthma. Here, we describe the methodology and experiences in establishing a database for childhood asthma designed to study gene-environment interactions (PAGES--Paediatric Asthma Gene Environment Study). METHODS: Children with asthma and under the care of a respiratory paediatrician are being recruited from 15 hospitals between 2008 and 2011. An asthma questionnaire is completed and returned by post. At a routine clinic visit saliva is collected for DNA extraction. Detailed phenotyping in a proportion of children includes spirometry, bronchodilator response (BDR), skin prick reactivity, exhaled nitric oxide and salivary cotinine. Dietary and quality of life questionnaires are completed. Data are entered onto a purpose-built database. RESULTS: To date 1045 children have been invited to participate and data collected in 501 (48%). The mean age (SD) of participants is 8.6 (3.9) years, 57% male. DNA has been collected in 436 children. Spirometry has been obtained in 172 children, mean % predicted (SD) FEV1 97% (15) and median (IQR) BDR is 5% (2, 9). There were differences in age, socioeconomic status, severity and %FEV1 between the different centres (p≤0.024). Reasons for non-participation included parents not having time to take part, children not attending clinics and, in a small proportion, refusal to take part. CONCLUSIONS: It is feasible to establish a national database to study gene-environment interactions within an asthmatic paediatric population; there are barriers to participation and some different characteristics in individuals recruited from different centres. Recruitment to our study continues and is anticipated to extend current understanding of asthma heterogeneity.

Economic implications of newborn screening for cystic fibrosis: a cost of illness retrospective cohort study.

BACKGROUND: Newborn screening for cystic fibrosis might not be introduced if implementation and running costs are perceived as prohibitive. Compared with clinical diagnosis, newborn screening is associated with clinical benefit and reduced treatment needs. We estimate the potential savings in treatment costs attributable to newborn screening. METHODS: Using the UK Cystic Fibrosis Database, we used a prevalence strategy to undertake a cost of illness retrospective snapshot cohort study. We estimated yearly costs of long-term therapies and intravenous antibiotics for 184 patients who were diagnosed as a result of screening as newborn babies, and 950 patients who were clinically diagnosed aged 1-9 years in 2002. Costs of adding cystic fibrosis screening to an established newborn screening service in Scotland were adjusted to 2002 prices and applied to the UK as a whole. Costs were recalculated in US$. FINDINGS: Cost of therapy for patients diagnosed by newborn screening was significantly lower than equivalent therapies for clinically diagnosed patients: mean ($7228 vs $12 008, 95% CI of difference -6736 to -2028, p<0.0001) and median ($352 vs $2442, -1916 to -180, p<0.0001). When we limited the clinically diagnosed group to only those diagnosable with a 31 cystic fibrosis transmembrane regulator mutation assay and assumed similar disease progression in the clinically diagnosed group as in the newborn screening group, we showed that mean ($3,397,344) or median ($947,032) drug cost savings could have offset the estimated cost of adding cystic fibrosis to a UK national newborn screening service ($2,971,551). INTERPRETATION: Including indirect costs savings, newborn screening for cystic fibrosis might have even greater financial benefits to society than our estimate shows. Clinical, social, and now economic evidence suggests that universal newborn screening programmes for cystic fibrosis should be adopted internationally.

Delayed diagnosis of females with respiratory presentation of cystic fibrosis did not segregate with poorer clinical outcome.

OBJECTIVE: Does a delay in diagnosis exist in females with cystic fibrosis (CF) presenting with respiratory symptoms alone. Does it segregate with poorer clinical outcomes? STUDY DESIGN AND SETTING: A set of 3,851 patients registered with the UK CF Database (diagnosed 1986-2003) were divided into four mutually exclusive categories by mode of presentation: meconium ileus or distal intestinal obstruction syndrome (MI/DIOS); positive family history; newborn screening; and symptoms excluding MI/DIOS. The last symptom category was subdivided to create a group for respiratory symptoms alone. RESULTS: Females presenting with respiratory symptoms alone were diagnosed 9 months later than males (median age of diagnosis in males 22 months, n = 325; females, 31 months, n = 322; P = .028). No gender differences were observed for anthropometric, lung function, microbiological, supplemental feeding, or time since diagnosis using discriminant analysis applied to all patients (n = 461, Wilks' lambda = .97, P = .15) or to patients divided by genotype: DeltaF508/DeltaF508 (n = 168, Wilks' lambda = .97, P = .69), class I-III genotype (n = 251, Wilks' lambda = .96, P = .41), or class IV-V genotype (n = 73, Wilks' lambda = .90, P = .50) presenting with respiratory symptoms alone. CONCLUSIONS: A relative delay in diagnosis exists in female patients presenting with respiratory symptoms alone compared with males. This does not, however, segregate with a significantly poorer clinical phenotype in the UK.

Asians with cystic fibrosis in the UK have worse disease outcomes than clinic matched white homozygous delta F508 controls.

BACKGROUND: We tested the hypothesis that the Asian cystic fibrosis (CF) phenotype is comparable to the commonest genetic form of CF found in 50% of the white UK CF population using the UK CF Database, a national disease-specific patient registry. METHODS: 50 Asian CF patients were matched by Centre with 143 white homozygous delta F508 patients for gender, age and chronic Pseudomonas aeruginosa status (a marker of morbidity). The authors compared FEV1 and FVC% predicted, mean height, weight and BMI Z scores. RESULTS: FVC% predicted, weight and BMI Z scores were significantly worse in the Asians. Asian male/female FVC% predicted (p-value, 95% CI) -15.1 (p=0.001, -24.0, -8.8)/-15.2 (p=0.014, -27.1, -3.3) compared with white controls. Asian females also had significantly worse FEV1% predicted compared with controls (-14.9, p=0.025, 95% CI: -27.8, -2.0). Asians had significantly lower raw Z scores for weight (males p=0.002, females p=0.013) and BMI (males p=0.002, females p=0.008). CONCLUSIONS: These data suggest that the Asian CF phenotype is as severe as the white controls with the homozygous delta F508 phenotype but is worse in some outcomes, especially in Asian females. Socio-cultural factors and rare CF genotypes may contribute to the severity of CF in this vulnerable group.

Comparative analysis of Cystic Fibrosis Registry data from the UK with USA, France and Australasia.

BACKGROUND: Using the UK Cystic Fibrosis Database, we analysed the health of the UK CF paediatric population (UKPP) in terms of their biographical, clinical and infection status and compared outcomes with the US, French and Australasian CF Registries. METHODS: UKPP data were collected for 2,673 patients aged less than 18 years in 2001 and used as a reference base for comparison with the most recent equivalent CF Registry reports. RESULTS: Although differences exist between National CF Registries, all record similar demographic factors and key outcomes. Where plausible comparisons can be made, we report that the UKPP had the oldest median age (15.0 years), the Australasian population had the lowest median age at diagnosis (1.8 months). Approximately, double the expected number of UKPP patients (23% and 19%, respectively) fall below the 10th centile for height and weight with similar outcomes in Australasia. UKPP and French populations had similar proportions with FEV1 >80% predicted (53% and 54%, respectively). CONCLUSION: Each Registry's data systems have developed independently providing a first step towards international comparisons. Standardisation of data collection criteria and definition for national CF Registries is required and we propose a standardised minimum data set, which would facilitate data integration as part of a global Registry for CF.

Demographics of the UK cystic fibrosis population: implications for neonatal screening.

The objective was to determine the composition of the Cystic Fibrosis (CF) Population attending specialist UK CF centres in terms of age, gender, age at diagnosis, genotype and ethnicity. With the planned introduction of the national CF screening programme in the UK, cystic fibrosis transmembrane regulator (CFTR) mutations were compared between different ethnic groups enabling a UK-specific frequency of mutations to be defined. Data were analysed from the patient biographies held in the UK CF Database (see www.cystic-fibrosis.org.uk). The currently registered population of 5,274 CF patients is 96.3% Caucasian with a male preponderance that significantly increases with age. The majority of the 196 non-Caucasian CF patients are from the Indian Subcontinent (ISC), of which one in 84 UK CF patients are of Pakistani origin. The commonest CFTR mutation, deltaF508, is found in 74.1% of all CF chromosomes. In the Caucasian CF population, 57.5% are deltaF508 homozygotes but the UK ISC CF population with only 24.7%, has significantly fewer deltaF508 homozygotes patients (95% confidence interval (CI) 0.2-0.4). The distribution of Caucasian patients with deltaF508/deltaF508, deltaF508/Other and Other/Other does not fit the expected distribution with a Hardy-Weinberg model unless those patients without a detected mutation are excluded (P<0.001). The UK CF Database has shown the UK CF population to have distinct characteristics separate from the North American and European CF Registries. The ISC group contains many mutations not recognised by current genetic analysis, and one in four ISC patients have no CFTR mutations identified. The CFTR analysis proposed for the screening programme would detect 96% of patients registered in the database, but is unlikely to achieve the desired >80% detection rates in the ethnic minority groups. Screen-positive, non-Caucasian infants without an identifiable CFTR mutation should be referred for a sweat test and genetic counselling when serum trypsinogen concentrations remain elevated after birth.

Readmission with respiratory syncytial virus (RSV) infection among graduates from a neonatal intensive care unit.

We evaluated the incidence of readmission with respiratory syncytial virus (RSV) infection among the graduates of a regional Neonatal Intensive Care Unit (NICU), and characterized those who were rehospitalized. These data were used as a predictive tool to estimate the number of babies likely to suffer readmission with RSV for the year 2000 cohort. Using the published efficacies of palivizumab, the costs and benefits of protecting this cohort were assessed. Retrospective analysis of 2,507 NICU inpatient records from January 1, 1994-December 31, 1999 from the Royal Maternity Hospital, Belfast, were compared with data on positive RSV samples from 1,790 patients between January 1, 1995-December 31, 1999 from the Northern Ireland Regional Virus Laboratory. The analysis yielded 136 (7.6%) ex-NICU patients among the positive RSV samples over this 5-year period. Characteristic seasonal peaks of RSV infection with interseasonal variability were observed. Of those readmitted, 86.9% were hospitalized with RSV before their first birthday. A calculated readmission rate of 5.4% for all NICU graduates, and 6.4% for those

An observational study of matrix metalloproteinase (MMP)-9 in cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF), cross-sectional studies have reported sputum matrix metalloproteinase (MMP)-9 to be elevated and negatively correlated with FEV1. This longitudinal study examined the association between MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) to prognostic parameters in CF. METHOD: A cross-sectional survey of CF and control subjects; CF patients were followed up for a median of 49 months. MMP-9 and TIMP-1 and TIMP-2 were quantified in sputum and plasma. RESULTS: Seventy-three patients with CF, median age 22 years, and 40 controls were recruited. Fifty-three of these CF patients were followed up. Prospectively, in CF subjects, plasma MMP-9 activity was adversely associated with FEV1 (ß -1.15 (95% CI -2.10, -0.20), p = 0.019) and rate of FEV1 decline, and plasma TIMP-1 was adversely associated with mortality: hazard ratio 3.66 (1.91-7.04), p < 0.001. CONCLUSIONS: These associations further justify investigation of MMP-9 and TIMP-1 as biomarkers for short- to medium-term FEV1 decline and mortality in patients with CF.

Cystic fibrosis diagnosed after 2 months of age leads to worse outcomes and requires more therapy.

OBJECTIVE: Newborn screening for cystic fibrosis remains controversial because improved pulmonary function has not been established. Studies to date have not accounted for differences in treatments delivered to clinically diagnosed children and newborn-screened controls. Here, we compare outcomes and treatment of patients clinically diagnosed within the newborn-screening reporting window (early-clinically diagnosed), those presenting after this period (late-clinically diagnosed), and patients diagnosed by newborn screening. PATIENTS AND METHODS: In a cross-sectional analysis of cohorts retrospectively ascertained, patients who were homozygous deltaF508 with cystic fibrosis, attending specialist cystic fibrosis centers, and 1 to 10 years of age between 2000 and 2002 were identified from the United Kingdom Cystic Fibrosis Database and stratified into newborn-screened, early-clinically diagnosed, or late-clinically diagnosed cohorts. Two analyses were performed: (1) after restricting to the most recent year of data collection, early-clinically diagnosed and late-clinically diagnosed cohorts were matched to newborn-screened patients by patient age and year of data collection (133 patients per cohort were identified); and (2) for all years of data collection, annual sets of data for early-clinically diagnosed and late-clinically diagnosed patients were matched to newborn-screened patients by patient age and year of data collection (291 data sets per cohort were identified). Median height and weight z scores, proportion of patients with height and weight <10th percentile, prevalence of chronic Pseudomonas aeruginosa infection, Shwachman-Kulczyki morbidity scores, percent predicted forced expiratory volume in 1 second, and numbers of long-term therapies were compared. RESULTS: In both analyses, newborn screening was associated with higher height z score, higher Shwachman-Kulczyki score, lower likelihood of height <10th percentile, and fewer long-term therapies compared with late-clinically diagnosed patients. No other differences were found. CONCLUSIONS: Newborn screening was associated with improved growth, reduced morbidity, and reduced therapy, yet generated equivalent pulmonary outcome compared with late clinical diagnosis, suggesting that newborn screening may slow cystic fibrosis lung disease progression.

Neonatal screening for cystic fibrosis is beneficial even in the context of modern treatment.

OBJECTIVES: To determine whether early identification of babies with cystic fibrosis (CF) improves outcome in the current environment of new improved treatments, considering the criticism that there may be only marginal benefit gained by CF newborn screening (NBS). STUDY DESIGN: We tested whether CF NBS in the setting of modern CF center care still afforded benefit using the UK CF Database (UKCFD; ) to compare clinical outcomes in infants who underwent NBS and control subjects who were clinically diagnosed (CD). With Mann-Whitney rank tests, 184 patients who underwent NBS aged 1 to 9 years in 2002 (excluding meconium ileus) were compared with matched patients who were CD in 3-year age groups (950 control subjects). RESULTS: Patients as old as 6 years who underwent NBS had significantly greater median height z-scores, less severe Northern chest radiography scores, better Shwachman-Kulczycki scores, and lower rates of chronic Pseudomonas aeruginosa infection. No difference was found for weight z-score or % predicted forced expiratory value in 1 second or forced volume capacity. Nutritional benefit was demonstrated in patients who underwent NBS and were homozygous for the DeltaF508 mutation. CONCLUSIONS: NBS segregates with better outcomes in patients as old as 6 years compared with age- and gene-matched control subjects who are CD. This cross-sectional study shows that infants who undergo screening derive nutritional benefit in improved median height and reduced morbidity.

Newborn screening for cystic fibrosis is associated with reduced treatment intensity.

OBJECTIVES: To determine whether the improved clinical status after newborn screening (NBS) for cystic fibrosis (CF) segregates with increased therapeutic intervention compared with presentation by clinical diagnosis (CD). STUDY DESIGN: In 2002, two populations (1 to 9 years of age) who presented (excluding meconium ileus) by NBS < or = 3 months of age or by CD were compared in an observational, cross-sectional design. NBS and CD populations (184 and 950 patients, respectively) were divided into 3-year age groups (1 to 3, 4 to 6, and 7 to 9 years). Therapies of duration >3 months were compared together with Pseudomonas aeruginosa infection status. RESULTS: NBS patients < or = 6 years of age received significantly fewer and less demanding therapies not explained by age, genotype, geography, or social deprivation. In 7- to 9-year-olds, significantly fewer NBS patients received intravenous antibiotics. NBS patients without P aeruginosa infection received significantly fewer therapies, but no differences were found between intermittently or chronically infected NBS and CD populations. Comparable results were found in deltaF508/deltaF508 subpopulations. CONCLUSIONS: CF populations diagnosed by NBS are associated with reduced treatment compared with age- and genotype-matched CD control subjects.