Maureen Verheggen’s research while affiliated with Royal Perth Hospital and other places

on behalf of the contributing GLI Network members 9 @ERSpublications The GLI Network has developed all-ages reference equations for lung volumes for populations of European ancestry. The unification of GLI lung function reference equations will improve the interpretation of lung function in patients with lung disease. https://bit.ly/3hHZR1N ABSTRACT Background: Measurement of lung volumes across the life course is critical to the diagnosis and management of lung disease. The aim of the study was to use the Global Lung Function Initiative methodology to develop all-age multi-ethnic reference equations for lung volume indices determined using body plethysmography and gas dilution techniques. Methods: Static lung volume data from body plethysmography and gas dilution techniques from individual, healthy participants were collated. Reference equations were derived using the LMS (lambda-mu-sigma) method and the generalised additive models of location shape and scale programme in R. The impact of measurement technique, equipment type and being overweight or obese on the derived lung volume reference ranges was assessed. Results: Data from 17 centres were submitted and reference equations were derived from 7190 observations from participants of European ancestry between the ages of 5 and 80 years. Data from non-European ancestry populations were insufficient to develop multi-ethnic equations. Measurements of functional residual capacity (FRC) collected using plethysmography and dilution techniques showed physiologically insignificant differences and were combined. Sex-specific reference equations including height and age were developed for total lung capacity (TLC), FRC, residual volume (RV), inspiratory capacity, vital capacity, expiratory reserve volume and RV/TLC. The derived equations were similar to previously published equations for FRC and TLC, with closer agreement during childhood and adolescence than in adulthood. Conclusions: Global Lung Function Initiative reference equations for lung volumes provide a generalisable standard for reporting and interpretation of lung volumes measurements in individuals of European ancestry.

Objective Survival rates for congenital diaphragmatic hernia (CDH) are increasing. The long-term outcomes of CDH survivors were compared with a healthy control group to assess the morbidity for guidance of antenatal counselling and long-term follow-up programmes. Participants and design Participants born with CDH in Western Australia 1993–2008 were eligible with matched controls from the general population. Participants had comprehensive lung function tests, echocardiogram, low-dose chest CT scan and completed a Strengths and Difficulties Questionnaire (SDQ) and quality of life (QOL) questionnaire. Results 34 matched case–control pairs were recruited. Demographic data between groups were similar. Cases were smaller at follow-up (weight Z-score of −0.2vs0.3; p=0.03; height Z-score of −0.3vs0.6; p=0.01). Cases had lower mean Z-scores for forced expiratory volume in 1 s (FEV 1 ) (−1.49 vs −0.01; p=0.004), FEV 1 /forced vital capacity (−1.92 vs −1.2; p=0.009) and forced expiratory flow at 25-75% (FEF25-75) (−1.18vs0.23; p=0.007). Cases had significantly worse respiratory mechanics using forced oscillation technique. Subpleural triangles architectural distortion, linear opacities and scoliosis on chest CT were significantly higher in cases. Prosthetic patch requirement was associated with worse lung mechanics and peak cough flow. Cases had significantly higher rates of gastro-oesophageal reflux disease (GORD) and GORD medication usage. Developmental delay was significantly higher in cases. More cases had a total difficulties score in the high to very high range (25% vs 0%, p=0.03) on the SDQ and reported lower objective QOL scores (70.2 vs 79.8, p=0.02). Conclusion Survivors of CDH may have significant adverse long-term medical and psychosocial issues that would be better recognised and managed in a multidisciplinary clinic.

Rationale Increasing evidence suggests the forced oscillation technique (FOT) has the capacity to provide non‐invasive monitoring and diagnosis of respiratory disease in young children. However, which FOT outcomes provide the most pertinent clinical information is currently unknown. The aim of this study was to determine which FOT outcomes were most sensitive for differentiating between health and specific childhood respiratory disease. Methods Respiratory impedance was measured using a commercial device (i2M, Chess Medical, Belgium) in children aged between 3 and 7 years, who had been diagnosed with either cystic fibrosis (N = 84), asthma (N = 99) or were born very preterm (N = 114). Z‐scores were calculated for respiratory system resistance (Rrs) and reactance (Xrs) at 6, 8, and 10 Hz, the resonance frequency (Fres), frequency dependence (Fdep4‐24), and area under the reactance curve (AX). Pairwise comparisons of the area under the receiver operating characteristic (ROC) curve were used to determine the most relevant FOT variables. Results and Conclusions The FOT outcomes best able to discern between health and disease were Fres (P < 0.0001) in cystic fibrosis, Fres (P < 0.0001) in asthma and Xrs8 (P < 0.0001) in children born preterm. These findings suggest the utility of specific FOT outcomes is dependent on the respiratory disease being assessed. It is hoped that a disease‐specific approach to interpreting FOT data can help further refine the FOT technique to aid in the diagnosis of children with pediatric respiratory disease.

Background Data on longitudinal respiratory follow-up after preterm birth in the surfactant era are scarce and of increasing importance, with concerns that preterm survivors are destined for early onset chronic obstructive airway disease. We aimed to comprehensively assess lung function longitudinally from early childhood to mid-childhood in very preterm children (≤32 weeks gestation), and to explore factors negatively impacting on lung function trajectories. Methods Preterm children (with and without bronchopulmonary dysplasia) and healthy term children as controls were studied. All preterm participants were born at 32 weeks' gestation or earlier at King Edward Memorial Hospital, Perth, WA, Australia, between 1997 and 2003. Bronchopulmonary dysplasia was defined as at least 28 days of supplemental oxygen requirement as assessed at 36 weeks' post-menstrual age. Spirometry, oscillatory mechanics, gas exchange, lung volumes, and respiratory symptoms were assessed at three visits, two in early childhood (4–8 years) and one in mid-childhood (9–12 years). CT of the chest was done in preterm children in mid-childhood. Respiratory symptoms were documented via questionnaire at each visit. Data were analysed longitudinally using linear mixed models. Findings 200 very preterm children (126 with bronchopulmonary dysplasia and 74 without bronchopulmonary dysplasia) and 67 healthy term control children attended 458 visits between age 4 and 12 years. Chest CT was done on 133 preterm children at a mean age of 10·9 (SD 0·6) years. Preterm children, with and without bronchopulmonary dysplasia, had declines in spirometry z-scores over time compared with controls: forced expiratory volume in 1 s (FEV1), forced expiratory flow at 25–75% of the pulmonary volume, and FEV1/forced vital capacity all declined by at least 0·1 z-score per year in children with bronchopulmonary dysplasia (all p<0·001). Respiratory mechanics and gas exchange also deteriorated over time in children with bronchopulmonary dysplasia (relative to term controls, respiratory system reactance at 8 Hz decreased by −0·05 z-score per year [95% CI −0·08 to −0·01; p=0·006] and diffusing capacity of the lungs for carbon monoxide decreased by −0·03 z-score per year [95% CI −0·06 to −0·01; p=0·048]). Preterm children with bronchial wall thickening on chest CT (suggestive of inflammation) had bigger decreases in spirometry outcomes through childhood. For example, children with bronchial wall thickening on chest CT had an FEV1 z-score decline of −0·61 (95% CI −1·03 to–0·19; p=0·005) more than those without. Similarly, children exposed to tobacco smoke, those with earlier gestation, or those requiring more neonatal supplemental oxygen declined at a faster rate. Interpretation Lung function trajectories are impaired in survivors of very preterm birth. Survivors with bronchopulmonary dysplasia, ongoing respiratory symptoms, or CT changes reflecting inflammation have the poorest trajectories and might be at increased risk of lung disease in later life. Close targeted pulmonary follow-up of these individuals is necessary. Funding National Health and Medical Research Council grants APP634519, APP1073301 (to SJS), APP1077691 (to JJP), and APP1025550 (to GLH), Princess Margret Hospital Foundation, and Raine Medical Foundation.

Objective: To determine the relationships between respiratory symptoms, lung function, and neonatal events in young preterm children. Methods: Preterm children (<32 w gestation), classified as bronchopulmonary dysplasia (BPD) or non-BPD, and healthy term controls were studied. Lung function was measured by forced oscillation technique (respiratory resistance [Rrs] and reactance [Xrs]) and spirometry. Respiratory symptom questionnaires were administered. Results: One hundred and fifty children (74 BPD, 44 non-BPD, 32 controls) 4-8 years were studied. Lung function (median Z-score [10,90th centile]) was significantly impaired in preterm children compared to controls for FVC (0.00 [-1.18, 1.76], 0.69 [-0.17,1.86]), FEV1 (-0.44 [-1.94, 1.11], 0.49 [-0.83, 2.51]), Xrs (-1.26 [-3.31, 0.11], -0.11 [-0.97, 0.73]), and Rrs (0.55 [-0.48, 1.82], 0.28 [-0.99, 0.96]). Only Xrs differed between the BPD and non-BPD (-1.51 [-3.59, -0.41], -0.89 [-2.64, 0.52]). The prevalence of recent respiratory symptoms (range: 32-36%) did not differ between BPD and non-BPD children. Supplemental O2 in hospital was positively associated with worsening Xrs and FEV1 . Conclusion: Preterm children have worse lung function than healthy controls. Only respiratory reactance differentiated between preterm children with and without BPD and was influenced by days of O2 in hospital. Pediatr Pulmonol. 2016; 9999:1-9. © 2016 Wiley Periodicals, Inc.

Introduction: Bronchopulmonary dysplasia (BPD) remains the most significant pulmonary complication of preterm birth. The long term respiratory sequelae of children born very preterm are unclear. Aim: To examine how lung function tracks over the school years in children born very preterm. Methods: Term controls (N=32) and children born <32 weeks gestational age (GA) with (+BPD, N=74) and without (−BPD, N=44) a neonatal classification of BPD performed lung function at 4-7 and/or 9-11 years. Outcomes from spirometry (FEV1, FVC, FEV1/FVC, FEF25-75%) and the forced oscillation technique (area under reactance curve (AX), respiratory system resistance (R) and reactance (X) at 8 Hz)) were expressed as Z-scores. Paired t-test and Fisher's exact test were used to assess change in lung function and change in the proportion of children with lung function outside normal limits (1.64 Z-scores) between visits. Results: Compared to term controls, children born preterm had lower lung function at both visits by spirometry (FEV1, FEV1/FVC, FEF25-75) and the FOT (AX, Fres, X8) regardless of BPD classification (P<0.05). Longitudinal data (15 term; 39+BPD; 29-BPD) showed a decline (mean Z-score difference ± SD) in FEV1 (−0.47 ± 0.92; P=0.011) and FEF25-75% (−0.61 ± 0.76; P=0.001) for the +BPD group and an increased proportion of children with abnormal FEV1/FVC (32% to 52%) and FEF25-75% from (32% to 68%) between the two visits. In contrast, AX and X8 showed improvement over time in both preterm groups, though the proportion of children outside the normal limit was not different between the two time points. Conclusion: Children born <32 weeks GA with BPD experience lung function decline during childhood which may warrant intervention.