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Background: Right shift of the peripheral oxyhaemoglobin saturation (SpO2) versus inspired oxygen pressure (PIO2) curve is a sensitive marker of pulmonary gas exchange. Objectives: The aim of this study was to assess the impact of prematurity and bronchopulmonary dysplasia (BPD) on gas exchange and right-to-left shunt in the neonatal period, and its evolution over the first year of life. Method: We assessed shift and shunt in extremely preterm (EP) and very preterm (VP) infants at 36 and 44 weeks’ postmenstrual age (PMA), and at 1-year corrected postnatal age (cPNA). PIO2 was decreased stepwise to achieve SpO2 between 85 and 98%. Shift and shunt were calculated from paired SpO2/PIO2 measurements using customized software. Results were examined cross-sectionally at each time point, and longitudinally using generalized linear regression. Term infants were assessed at 44 wk PMA as a comparative reference. Results: Longitudinal modelling showed continuous decline in shift in EP and VP infants during the first year of life. There was no difference in shift compared to term infants at 44 wk PMA (p = 0.094). EP infants with BPD had higher shift than infants without BPD at 36 wk PMA (p < 0.001) and 44 wk PMA (p = 0.005) but not at 1-year cPNA. Conclusions: In the absence of lung disease, prematurity per se did not result in reduced gas exchange at 1-year cPNA. We report ongoing, significant improvements in pulmonary gas exchange in all preterm infants during the first year of life, despite evidence of early deficits in gas exchange in EP infants with BPD.

Children born preterm have impaired lung function and altered lung structure. However, there are conflicting reports on how preterm birth impacts aerobic exercise capacity in childhood. We aimed to investigate how neonatal history and a diagnosis of bronchopulmonary dysplasia (BPD) impact the relationship between function and structure of the lung, and aerobic capacity in school-aged children born very preterm. Preterm children (≤ 32 w completed gestation) aged 9–12 years with (n = 38) and without (n = 35) BPD, and term-born controls (n = 31), underwent spirometry, lung volume measurements, gas transfer capacity, a high-resolution computer tomography (CT) scan of the chest, and an incremental treadmill exercise test. Children born preterm with BPD had an elevated breathing frequency to tidal volume ratio compared to term controls (76% vs 63%, p = 0.002). The majority (88%) of preterm children had structural changes on CT scan. There were no differences in peak VO2 (47.1 vs 47.7 mL/kg/min, p = 0.407) or oxygen uptake efficiency slope when corrected for body weight (67.6 vs 67.3, p = 0.5) between preterm children with BPD and term controls. There were no differences in any other exercise outcomes. The severity of structural lung disease was not associated with exercise outcomes in this preterm population. Children born preterm have impaired lung function, and a high prevalence of structural lung abnormalities. However, abnormal lung function and structure do not appear to impact on the aerobic exercise capacity of preterm children at school age.

Birth prior to term interrupts the normal development of the respiratory system and consequently results in poor respiratory outcomes that persist throughout childhood. The mechanisms underpinning these poor respiratory outcomes are not well understood, but intrinsic abnormalities within the airway epithelium may be a contributing factor. Current evidence suggests that the airway epithelium is both structurally and functionally abnormal after preterm birth, with reports of epithelial thickening and goblet cell hyperplasia in addition to increased inflammation and apoptosis in the neonatal intensive care unit. However, studies focusing on the airway epithelium are limited and many questions remain unanswered; including whether abnormalities are a direct result of interrupted development, a consequence of exposure to inflammatory stimuli in the perinatal period or a combination of the two. In addition, the difficulty of accessing airway tissue has resulted in the majority of evidence being collected in the pre-surfactant era which may not reflect contemporary preterm birth. This review examines the consequences of preterm birth on the airway epithelium and explores the clinical relevance of currently available models whilst highlighting the need to develop a clinically relevant in vitro model to help further our understanding of the airway epithelium in preterm birth.

Children born preterm have impaired lung function and altered lung structure. However, there are conflicting reports on how preterm birth impacts aerobic exercise capacity in childhood. We aimed to investigate how neonatal history and a diagnosis of bronchopulmonary dysplasia (BPD) impact the relationship between function and structure of the lung, and aerobic capacity in school-aged children born very preterm.Preterm children (≤ 32 w completed gestation) aged 9-12 years with (n = 38) and without (n = 35) BPD, and term-born controls (n = 31), underwent spirometry, lung volume measurements, gas transfer capacity, a high-resolution computer tomography (CT) scan of the chest, and an incremental treadmill exercise test.Children born preterm with BPD had an elevated breathing frequency to tidal volume ratio compared to term controls (76% vs 63%, p = 0.002). The majority (88%) of preterm children had structural changes on CT scan. There were no differences in peak V̇OChildren born preterm have impaired lung function, and a high prevalence of structural lung abnormalities. However, abnormal lung function and structure do not appear to impact on the aerobic exercise capacity of preterm children at school age.

Preterm birth accounts for approximately 11% of births globally, with rates increasing across many countries. Concurrent advances in neonatal care have led to increased survival of infants of lower gestational age (GA). However, infants born

Rationale Survivors of preterm birth are at risk of chronic and lifelong pulmonary disease. Follow-up data describing lung structure and function are scarce in children born preterm during the surfactant era. Objectives To obtain comprehensive data on lung structure and function in mid-childhood from survivors of preterm birth. We aimed to explore relationships between lung structure, lung function and respiratory morbidity as well as early life contributors to poorer childhood respiratory outcomes. Methods Lung function was tested at 9–11 years in children born at term (controls) and at ≤32 weeks gestation. Tests included spirometry, oscillatory mechanics, multiple breath nitrogen washout and diffusing capacity of the lung for carbon monoxide. Preterm children had CT of the chest and completed a respiratory symptoms questionnaire. Main results 58 controls and 163 preterm children (99 with bronchopulmonary dysplasia) participated. Preterm children exhibited pulmonary obstruction and hyperinflation as well as abnormal peripheral lung mechanics compared with term controls. FEV 1 was improved by 0.10 z-scores for every additional week of gestation (95% CI 0.028 to 0.182; p=0.008) and by 0.34 z-scores per z-score increase in birth weight (0.124 to 0.548; p=0.002). Structural lung changes were present in 92% of preterm children, with total CT score decreased by 0.64 (−0.99 to −0.29; p Conclusions Abnormal lung structure in mid-childhood resulting from preterm birth in the contemporary era has important functional consequences.

To evaluate the role of upper airway dysfunction, indicated by altered vocal quality (dysphonia), on the respiratory symptoms of children surviving very preterm birth.Children born32 weeks of gestation participated in 2 separate assessments during midchildhood. The first visit assessed voice quality by a subjective evaluation using the Consensus Auditory-Perceptual Evaluation of Voice and a computerized analysis of the properties of the voice via the Acoustic Voice Quality Index. The second assessment recorded parentally reported respiratory symptoms and measures of lung function, including spirometry, lung volumes, oscillatory mechanics, and a cardiopulmonary exercise test.Preterm children (n = 35; median gestation 24.3 weeks) underwent paired voice and lung assessments at approximately 11 years of age. Preterm children with dysphonia (n = 25) reported significantly more respiratory symptoms than those with normal voices (n = 10) including wheeze (92% vs 40%; P = .001) and asthma diagnosed by a physician (60% vs 10%; P = .007). Lung function outcomes were generally not different between the dysphonic group and the group with normal voice (P .05), except for the oscillatory mechanics measures, which were all at least 0.5 z score lower in the dysphonic group (XrsThe upper airway may play a role in the respiratory symptoms experienced by some very preterm children and should be considered by clinicians, especially when symptoms are in the presence of normal lung function and are refractory to treatment.

Bronchopulmonary dysplasia (BPD), also known as Chronic Lung Disease (CLD), is a chronic respiratory condition of prematurity with potential life-long consequences for respiratory well-being. BPD was first described by Northway in 1967, when the mean gestation of preterm infants with BPD was 34 weeks’ postmenstrual age (PMA). Survival of preterm infants at lower gestational ages has increased steadily since 1967 associated with marked improvements in respiratory management of respiratory distress syndrome. Currently, BPD develops in approximately 45 % of all infants born extremely preterm (Stoll et al., 2015). These smaller and more immature babies are born during the late canalicular or early saccular period of lung development. Not surprisingly, the pathophysiology of BPD also evolved since classical BPD was described. As the nature and our understanding of BPD evolved, so too the definitions and classification of BPD changed over time. These differing and ever-changing definitions hamper clinical benchmarking as they are interpreted and applied inconsistently, and define BPD and its severity by non-standardised treatments rather than independent evaluations of structure or function. A standardised, unambiguous definition and classification of BPD is essential for evaluation and improvement in clinical practice, both within an individual unit, as well as across and between neonatal networks. The determination and implementation of diagnostic criteria and severity classification that is standardised, globally applicable, and that has prognostic utility for clinical outcomes and guidance of ongoing respiratory management remain of utmost importance. This review describes the evolution of BPD definitions, evaluates the benefits and limitations of each approach, and discusses alternative approaches that may improve the functional assessment of BPD severity.

Evidence regarding the prevalence of expiratory flow limitation (EFL) during exercise and the ventilatory response to exercise in children born preterm is limited. This study aimed to determine the prevalence of EFL as well as contributing factors to EFL and the ventilatory response to exercise in preterm children with and without bronchopulmonary dysplasia (BPD). Preterm children (≤32 weeks gestational age) aged 9–12 years with (n=64) and without (n=42) BPD and term controls (n=43), performed an incremental treadmill exercise test with exercise tidal flow–volume loops. More preterm children with BPD (53%) had EFL compared with preterm children without BPD (26%) or term controls (28%) (p, Children born preterm have an increased prevalence of expiratory limitation during exercise associated with reduced lung function and lower gestational age http://ow.ly/jLsk30leOVI

Children born preterm, less than 37 weeks’ gestation, are at increased risk of viral respiratory infections and associated complications both during their initial birth hospitalisation and in their first years following discharge. This increased burden of viral respiratory infections is likely to have long term implications for lung health and function in individuals born preterm, particularly those with bronchopulmonary dysplasia. Several hypotheses have been put forward to explain the association between early life viral respiratory infection and development of suboptimal lung health and function later in life following preterm birth. Although preterm infants with diminished lung function, particularly small airways, might be particularly susceptible to asthma and wheezing disorders following viral infection, there is evidence that respiratory viruses can activate number of inflammatory and airway re-modelling pathways. Therefore, the aim of this review is to highlight the perinatal and early life risk factors that may contribute to increased susceptibility to viral respiratory infections among preterm infants during early life and to understand how respiratory viral infection may influence the development of abnormal lung health and function later in life.

Summary 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 (FEV 1 ), forced expiratory flow at 25–75% of the pulmonary volume, and FEV 1 /forced vital capacity all declined by at least 0·1 z-score per year in children with bronchopulmonary dysplasia (all p 1 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.

One of the most significant complications of preterm birth is bronchopulmonary dysplasia (BPD). The pathophysiology of BPD has changed in recent years as advances in neonatal care have led to increased survival of smaller, more preterm, infants who display alterations to alveolar and pulmonary microvascular development. It is becoming clear that infants with 'new' BPD experience lung disease that persists into later childhood, however, the oldest of these children are just now entering young adulthood and therefore the longer term pulmonary implications remain unknown. The role of lung function testing in the identification and subsequent management of patients with lung disease resulting from a neonatal classification of BPD is reviewed based on the underlying pathophysiology of the disease.

Bronchopulmonary dysplasia (BPD) is characterised by inflammation in the developing airways and lung parenchyma. The ability of low-frequency forced oscillation technique (LFOT) to measure the impact of BPD on peripheral lung growth and function is unknown. We aimed to measure airway and pulmonary tissue mechanics in very preterm infants with/without BPD. We hypothesised that BPD alters the pulmonary mechanical properties compared to infants without BPD. LFOT (1-12 Hz) was applied to unsedated preterm infants during a short apnoea (4-7 s) provoked via the Hering-Breuer reflex (1-4 rapid manual inflations). Peak inflation pressure was 20cmH2O. Outcome variables were determined by fitting the constant phase model to the data, and analysed using t-test and multiple linear regression. 70 of 85 infants had acceptable tests: [median (range) GA 286w (234-316)] at a median (range) 355w (340-374) postmenstrual age. 25 infants had BPD (mild n=10, moderate n=7, severe n=8) according to the NICHD criteria. Newtonian resistance (R) (mean difference (SD): 3.88 (1.71); p 0.026) was significantly lower in infants with BPD than infants without BPD. Presence of BPD did not impact tissue damping, elastance, or hysteresivity. Length independently predicted all outcome variables. Duration of nCPAP was independently associated with R. In our cohort of infants, length rather than presence of BPD was the primary determinant of parenchymal mechanics: our findings may be explained by similar tissue mechanics in infants with/without BPD due to mild BPD, or that the effect size of BPD on LFOT outcome variables is low. Funding: NHMRC (1047689,1057514,1077691), MHRIF, Hungarian Scientific Research Grant #105403

Introduction: Delayed early oxygen uptake (VO2) recovery reflects disease severity in chronic lung or heart disease, linked to delayed recovery of muscle energy stores. No previous studies have investigated this in children born very preterm where altered lung structure may impair recovery Hypothesis: Children born preterm have a delayed early VO2 recovery associated with worse neonatal lung disease. Methods: Children born very preterm ( Results: 61 preterm children (27 with bronchopulmonary dysplasia) and 28 controls were assessed. There were no differences in peak VO2 of preterm compared with term children (46.4±, 6.8 vs 47.7 ±5. mL.min−1.kg−1), nor between VO2 recovery at 1 min (85 ±, 0.1 vs 86 ±, 0.1%), 2min (22.8 ± 0.07 vs 24.5 ± 0.06%) or 5min (16.5 ±0.04 vs 18.8 ± 0.07%). Time to 50% peak VO2 was similar between preterm and term children (51.0± 11.9 vs 51.8 ± 12.8s). There were no associations between VO2 recovery and GA or O2 use in the neonatal period. Conclusion: Children born preterm have normal early oxygen uptake recovery following a maximal exercise test. This is consistent with the well preserved aerobic capacity observed in this group.

Background and Aim: Pulmonary inflammation and oxidative stress contribute to the pathogenesis of bronchopulmonary dysplasia (BPD) following preterm birth. We aimed to measure inflammation and oxidative stress non-invasively, using exhaled breath condensate (EBC), in neonates with and without BPD. We also aimed to determine if markers of inflammation and oxidative stress were present later in infancy and relate biomarker levels to disease severity. Methods: EBC was collected from very preterm infants (GA Results: EBC collection is feasible in preterm infants at 36w PMA (N=5) and 12-15 months (N=20) at a volume that allows metabolomic profiling (215.0 ± 121.2 μL). Markers of inflammation and oxidative stress were detected above 3.9 pg.mL -1 and 0.8 pg.mL -1 respectively (ELISA) in all infants, regardless of BPD classification. Surprisingly, biomarker levels were higher in infants without BPD (48.8 ± 28.0 pg.mL -1 ) than in infants with BPD (17.8 ± 14.1 pg.mL -1 ; p Conclusion: EBC is a non-invasive technique capable of determining the lung metabolome in preterm infants. Preterm infants exhibit on-going inflammation and oxidative stress at 12-15 months corrected age, regardless of BPD classification.

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 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 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

One of the most significant complications of preterm birth is bronchopulmonary dysplasia (BPD). The pathophysiology of BPD has changed in recent years as advances in neonatal care have led to increased survival of smaller, more preterm, infants who display alterations to alveolar and pulmonary microvascular development. It is becoming clear that infants with 'new' BPD experience lung disease that persists into later childhood, however, the oldest of these children are just now entering young adulthood and therefore the longer term pulmonary implications remain unknown. The role of lung function testing in the identification and subsequent management of patients with lung disease resulting from a neonatal classification of BPD is reviewed based on the underlying pathophysiology of the disease.