Using reference equations to standardise incremental shuttle walk test performance in children and young people with chronic conditions and facilitate the evaluation of exercise capacity and disease severity.

AIMS: The aim was to evaluate whether standardised exercise performance during the incremental shuttle walk test (ISWT) can be used to assess disease severity in children and young people (CYP) with chronic conditions, through (1) identifying the most appropriate paediatric normative reference equation for the ISWT, (2) assessing how well CYP with haemophilia and cystic fibrosis (CF) perform against the values predicted by the best fit reference equation and (3) evaluating the association between standardised ISWT performance and disease severity. METHODS: A cross-sectional analysis was carried out using existing data from two independent studies (2018-2019) at paediatric hospitals in London,UK. CYP with haemophilia (n=35) and CF (n=134) aged 5-18 years were included. Published reference equations for standardising ISWT were evaluated through a comparison of populations, and Bland-Altman analysis was used to assess the level of agreement between distances predicted by each equation. Associations between ISWT and disease severity were assessed with linear regression. RESULTS: Three relevant reference equations were identified for the ISWT that standardised performance based on age, sex and body mass index (Vardhan, Lanza, Pinho). A systematic proportional bias of standardised ISWT was observed in all equations, most pronounced with Vardhan and Lanza; the male Pinho equation was identified as most appropriate. On average, CYP with CF and haemophilia performed worse than predicted by the Pihno equation, although the range was wide. Standardised ISWT, and not ISWT distance alone, was significantly associated with forced expiratory volume in 1 s in CYP with CF. Standardised ISWT in CYP with haemophilia was slightly associated with haemophilia joint health score, but this was not significant. CONCLUSIONS: ISWT performance may be useful in a clinic to identify those with worsening disease, but only when performance is standardised against a healthy reference population. The development of validated global reference equations is necessary for more robust assessment.

Real-world effectiveness of airway clearance techniques in children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is commonly characterised by thick respiratory mucus. From diagnosis, people with CF are prescribed daily physiotherapy, including airway clearance techniques (ACTs). ACTs consume a large proportion of treatment time, yet the efficacy and effectiveness of ACTs are poorly understood. This study aimed to evaluate associations between the quality and quantity of ACTs and lung function in children and young people with CF. METHODS: Project Fizzyo, a longitudinal observational cohort study in the UK, used remote monitoring with electronic pressure sensors attached to four different commercial ACT devices to record real-time, breath-by-breath pressure data during usual ACTs undertaken at home over 16 months in 145 children. ACTs were categorised either as conformant or not with current ACT recommendations based on breath pressure and length measurements, or as missed treatments if not recorded. Daily, weekly and monthly associations between ACT category and lung function were investigated using linear mixed effects regression models adjusting for clinical confounders. RESULTS: After exclusions, 45 224 ACT treatments (135 individuals) and 21 069 days without treatments (141 individuals) were analysed. The mean±sd age of participants was 10.2±2.9 years. Conformant ACTs (21%) had significantly higher forced expiratory volume in 1 s (FEV1) (mean effect size 0.23 (95% CI 0.19-0.27) FEV1 % pred per treatment) than non-conformant (79%) or missed treatments. There was no benefit from non-conformant or missed treatments and no significant difference in FEV1 between them (mean effect size 0.02 (95% CI -0.01-0.05) FEV1 % pred per treatment). CONCLUSIONS: ACTs are beneficial when performed as recommended, but most people use techniques that do not improve lung function. Work is needed to monitor and improve ACT quality and to increase the proportion of people doing effective airway clearance at home.

Exploring flexible polynomial regression as a method to align routine clinical outcomes with daily data capture through remote technologies.

BACKGROUND: Clinical outcomes are normally captured less frequently than data from remote technologies, leaving a disparity in volumes of data from these different sources. To align these data, flexible polynomial regression was investigated to estimate personalised trends for a continuous outcome over time. METHODS: Using electronic health records, flexible polynomial regression models inclusive of a 1st up to a 4th order were calculated to predict forced expiratory volume in 1 s (FEV1) over time in children with cystic fibrosis. The model with the lowest AIC for each individual was selected as the best fit. The optimal parameters for using flexible polynomials were investigated by comparing the measured FEV1 values to the values given by the individualised polynomial. RESULTS: There were 8,549 FEV1 measurements from 267 individuals. For individuals with > 15 measurements (n = 178), the polynomial predictions worked well; however, with < 15 measurements (n = 89), the polynomial models were conditional on the number of measurements and time between measurements. The method was validated using BMI in the same population of children. CONCLUSION: Flexible polynomials can be used to extrapolate clinical outcome measures at frequent time intervals to align with daily data captured through remote technologies.

Quantity and quality of airway clearance in children and young people with cystic fibrosis.

Children and young people with CF (CYPwCF) get advice about using positive expiratory pressure (PEP) or oscillating PEP (OPEP) devices to clear sticky mucus from their lungs. However, little is known about the quantity (number of treatments, breaths, or sets) or quality (breath pressures and lengths) of these daily airway clearance techniques (ACTs) undertaken at home. This study used electronic pressure sensors to record real time breath-by-breath data from 145 CYPwCF (6-16y) during routine ACTs over 2 months. ACT quantity and quality were benchmarked against individual prescriptions and accepted recommendations for device use. In total 742,084 breaths from 9,081 treatments were recorded. Individual CYPwCF maintained consistent patterns of ACT quantity and quality over time. Overall, 60% of CYPwCF did at least half their prescribed treatments, while 27% did fewer than a quarter. About 77% of pre-teens did the right number of daily treatments compared with only 56% of teenagers. CYPwCF usually did the right number of breaths. ACT quality (recommended breath length and pressure) varied between participants and depended on device. Breath pressures, lengths and pressure-length relationships were significantly different between ACT devices. PEP devices encouraged longer breaths with lower pressures, while OPEP devices encouraged shorter breaths with higher pressures. More breaths per treatment were within advised ranges for both pressure and length using PEP (30-31%) than OPEP devices (1-3%). Objective measures of quantity and quality may help to optimise ACT device selection and support CYPwCF to do regular effective ACTs.

Protocol for Project Fizzyo, an analytic longitudinal observational cohort study of physiotherapy for children and young people with cystic fibrosis, with interrupted time-series design.

INTRODUCTION: Daily physiotherapy is believed to mitigate the progression of cystic fibrosis (CF) lung disease. However, physiotherapy airway clearance techniques (ACTs) are burdensome and the evidence guiding practice remains weak. This paper describes the protocol for Project Fizzyo, which uses innovative technology and analysis methods to remotely capture longitudinal daily data from physiotherapy treatments to measure adherence and prospectively evaluate associations with clinical outcomes. METHODS AND ANALYSIS: A cohort of 145 children and young people with CF aged 6-16 years were recruited. Each participant will record their usual physiotherapy sessions daily for 16 months, using remote monitoring sensors: (1) a bespoke ACT sensor, inserted into their usual ACT device and (2) a Fitbit Alta HR activity tracker. Real-time breath pressure during ACTs, and heart rate and daily step counts (Fitbit) are synced using specific software applications. An interrupted time-series design will facilitate evaluation of ACT interventions (feedback and ACT-driven gaming). Baseline, mid and endpoint assessments of spirometry, exercise capacity and quality of life and longitudinal clinical record data will also be collected.This large dataset will be analysed in R using big data analytics approaches. Distinct ACT and physical activity adherence profiles will be identified, using cluster analysis to define groups of individuals based on measured characteristics and any relationships to clinical profiles assessed. Changes in adherence to physiotherapy over time or in relation to ACT interventions will be quantified and evaluated in relation to clinical outcomes. ETHICS AND DISSEMINATION: Ethical approval for this study (IRAS: 228625) was granted by the London-Brighton and Sussex NREC (18/LO/1038). Findings will be disseminated via peer-reviewed publications, at conferences and via CF clinical networks. The statistical code will be published in the Fizzyo GitHub repository and the dataset stored in the Great Ormond Street Hospital Digital Research Environment. TRIAL REGISTRATION NUMBER: ISRCTN51624752; Pre-results.

Limitations of regional ventilation inhomogeneity indices in children with cystic fibrosis.

BACKGROUND: Scond is a multiple breath washout (MBW) index that measures convection-dependent ventilation inhomogeneity (CDI) arising within conductive airways, but the calculation method is unreliable in subjects with advanced cystic fibrosis (CF) lung disease. A new CDI index, Scond *, has been proposed for use in adults with CF and moderate to severe ventilation inhomogeneity. We aimed to evaluate the most appropriate CDI index in children and adolescents with CF and various degrees of inhomogeneity, and from that the most appropriate diffusion-convection-interaction index (Sacin or Sacin *). METHODS: Scond , Sacin  and the alternative indices, Scond *, and Sacin * were retrospectively calculated in subjects with CF aged 3 to 18 years and age-matched controls, who underwent sulfur hexafluoride MBW between 2003 and 2015. The upper limit of normal was based on 95th percentile of the control population. RESULTS: One hundred and twenty-seven subjects with CF (44% male; mean age ± SD: 7.5 years ± 4.9) and 94 controls (53% male; 7.9 years ± 5.1) were included in the final analysis. All measures of ventilation inhomogeneity were significantly higher in children with CF. As predicted, Scond reached a maximum value at lung clearance index (LCI) values of approximately 9. In subjects with LCI ≥ 9 Scond * showed good correlation with LCI, whilst Scond had no relationship with LCI (Spearman rank correlation Scond */LCI, 0.49; P < .01; Scond /LCI, -0.068; P = .46). In subjects with mild disease (LCI < 9) Scond was more frequently abnormal than Scond * (37% vs 16%; P = .01). CONCLUSIONS: Scond and Sacin are sensitive indices of early regional inhomogeneity, but are of no value when LCI ≥ 9. In these subjects, Scond * & Sacin * are potential alternatives.

Differences in lung function between children with sickle cell anaemia from West Africa and Europe.

INTRODUCTION: Lung function abnormalities are common in sickle cell anaemia (SCA) but data from sub-Saharan Africa are limited. We hypothesised that children with SCA from West Africa had worse lung function than their counterparts from Europe. METHODS: This prospective cross-sectional study evaluated spirometry and anthropometry in black African individuals with SCA (haemoglobin phenotype SS) aged 6-18 years from Nigeria and the UK, when clinically stable. Age-matched controls were also included in Nigeria to validate the Global Lung Initiative spirometry reference values. RESULTS: Nigerian SCA patients (n=154) had significant reductions in both FEV1 and FVC of ~1 z-score compared with local controls (n=364) and ~0.5 z-scores compared with the UK patients (n=101). Wasting (body mass index z-score<-2) had a prevalence of 27% in Nigerian patients and 7% in the UK ones (p<0.001). Among children with SCA, being resident in Nigeria (OR 2.4, 95% CI 1.1 to 4.9), wasting (OR 2.3, 95% CI 1.1 to 5.0) and each additional year of age (OR 1.2, 95% CI 1.1 to 1.4) were independently associated with increased risk of restrictive spirometry (FVC z-score<-1.64+FEV1/FVC≥-1.64). CONCLUSIONS: This study showed that chronic respiratory impairment is more severe in children with SCA from West Africa than Europe. Our findings suggest the utility of implementing respiratory assessment in African children with SCA to early identify those with chronic lung injury, eligible for closer follow-up and more aggressive therapies.

The bronchodilator response in preschool children: A systematic review.

BACKGROUND: The bronchodilator response (BDR) is frequently used to support diagnostic and therapeutic decision-making for children who wheeze. However, there is little evidence-based guidance describing the role of BDR testing in preschool children and it is unclear whether published cut-off values, which are derived from adult data, can be applied to this population. METHODS: We searched MEDLINE, EMBASE, Web of Science, and Cochrane databases (inception-September 2015) for studies reporting response to a bronchodilator in healthy preschool children, response following placebo inhalation, and the diagnostic efficacy of BDR compared with a clinical diagnosis of asthma/recurrent wheezing. FINDINGS: We included 14 studies. Thirteen studies provided BDR data from healthy preschool children. Two studies reported response to placebo in preschool children with asthma/recurrent wheezing. Twelve studies compared BDR measurements from preschool children with asthma/recurrent wheeze to those from healthy children and seven of these studies reported diagnostic efficacy. Significant differences between the BDR measured in healthy preschool children compared with that in children with asthma/recurrent wheeze were demonstrated in some, but not all studies. Techniques such as interrupter resistance, oscillometry, and plethysmography were more consistently successfully completed than spirometry. Between study heterogeneity precluded determination of an optimum technique. INTERPRETATION: There is little evidence to suggest spirometry-based BDR can be used in the clinical assessment of preschool children who wheeze. Further evaluation of simple alternative techniques is required. Future studies should recruit children in whom airways disease is suspected and should evaluate the ability of BDR testing to predict treatment response. Pediatr Pulmonol. 2016;51:1242-1250. © 2016 Wiley Periodicals, Inc.

Lung function in children in relation to ethnicity, physique and socioeconomic factors.

Can ethnic differences in spirometry be attributed to differences in physique and socioeconomic factors?Assessments were undertaken in 2171 London primary schoolchildren on two occasions 1 year apart, whenever possible, as part of the Size and Lung function In Children (SLIC) study. Measurements included spirometry, detailed anthropometry, three-dimensional photonic scanning for regional body shape, body composition, information on ethnic ancestry, birth and respiratory history, socioeconomic circumstances, and tobacco smoke exposure.Technically acceptable spirometry was obtained from 1901 children (mean (range) age 8.3 (5.2-11.8) years, 46% boys, 35% White, 29% Black-African origin, 24% South-Asian, 12% Other/mixed) on 2767 test occasions. After adjusting for sex, age and height, forced expiratory volume in 1 s was 1.32, 0.89 and 0.51 z-score units lower in Black-African origin, South-Asian and Other/mixed ethnicity children, respectively, when compared with White children, with similar decrements for forced vital capacity (p<0.001 for all). Although further adjustment for sitting height and chest width reduced differences attributable to ethnicity by up to 16%, significant differences persisted after adjusting for all potential determinants, including socioeconomic circumstances.Ethnic differences in spirometric lung function persist despite adjusting for a wide range of potential determinants, including body physique and socioeconomic circumstances, emphasising the need to use ethnic-specific equations when interpreting results.

Acceptability, Precision and Accuracy of 3D Photonic Scanning for Measurement of Body Shape in a Multi-Ethnic Sample of Children Aged 5-11 Years: The SLIC Study.

BACKGROUND: Information on body size and shape is used to interpret many aspects of physiology, including nutritional status, cardio-metabolic risk and lung function. Such data have traditionally been obtained through manual anthropometry, which becomes time-consuming when many measurements are required. 3D photonic scanning (3D-PS) of body surface topography represents an alternative digital technique, previously applied successfully in large studies of adults. The acceptability, precision and accuracy of 3D-PS in young children have not been assessed. METHODS: We attempted to obtain data on girth, width and depth of the chest and waist, and girth of the knee and calf, manually and by 3D-PS in a multi-ethnic sample of 1484 children aged 5-11 years. The rate of 3D-PS success, and reasons for failure, were documented. Precision and accuracy of 3D-PS were assessed relative to manual measurements using the methods of Bland and Altman. RESULTS: Manual measurements were successful in all cases. Although 97.4% of children agreed to undergo 3D-PS, successful scans were only obtained in 70.7% of these. Unsuccessful scans were primarily due to body movement, or inability of the software to extract shape outputs. The odds of scan failure, and the underlying reason, differed by age, size and ethnicity. 3D-PS measurements tended to be greater than those obtained manually (p < 0.05), however ranking consistency was high (r2 > 0.90 for most outcomes). CONCLUSIONS: 3D-PS is acceptable in children aged ≥ 5 years, though with current hardware/software, and body movement artefacts, approximately one third of scans may be unsuccessful. The technique had poorer technical success than manual measurements, and had poorer precision when the measurements were viable. Compared to manual measurements, 3D-PS showed modest average biases but acceptable limits of agreement for large surveys, and little evidence that bias varied substantially with size. Most of the issues we identified could be addressed through further technological development.