Risk factors for poorer respiratory outcomes in adolescents and young adults born preterm.

RATIONALE: The respiratory outcomes for adult survivors of preterm birth in the postsurfactant era are wide-ranging with prognostic factors, especially those encountered after the neonatal period, poorly understood. OBJECTIVES: To obtain comprehensive 'peak' lung health data from survivors of very preterm birth and identify neonatal and life-course risk factors for poorer respiratory outcomes in adulthood. METHODS: 127 participants born ≤32 weeks gestation (64%, n=81 with bronchopulmonary dysplasia (BPD), initially recruited according to a 2 with-BPD:1 without-BPD strategy), and 41 term-born controls completed a lung health assessment at 16-23 years, including lung function, imaging and symptom review. Risk factors assessed against poor lung health included neonatal treatments, respiratory hospitalisation in childhood, atopy and tobacco smoke exposure. MEASUREMENTS AND MAIN RESULTS: Young adults born prematurely had greater airflow obstruction, gas trapping and ventilation inhomogeneity, in addition to abnormalities in gas transfer and respiratory mechanics, compared with term. Beyond lung function, we observed greater structural abnormalities, respiratory symptoms and inhaled medication use. A previous respiratory admission was associated with airway obstruction; mean forced expiratory volume in 1 s/forced vital capacity z-score was -0.561 lower after neonatal confounders were accounted for (95% CI -0.998 to -0.125; p=0.012). Similarly, respiratory symptom burden was increased in the preterm group with a respiratory admission, as was peribronchial thickening (6% vs 23%, p=0.010) and bronchodilator responsiveness (17% vs 35%, p=0.025). Atopy, maternal asthma and tobacco smoke exposure did not influence lung function or structure at 16-23 years in our preterm cohort. CONCLUSIONS: Even after accounting for the neonatal course, a respiratory admission during childhood remained significantly associated with reduced peak lung function in the preterm-born cohort, with the largest difference seen in those with BPD. A respiratory admission during childhood should, therefore, be considered a risk factor for long-term respiratory morbidity in those born preterm, especially for individuals with BPD.

Elevated leukotriene B4 and 8-isoprostane in exhaled breath condensate from preterm-born infants.

BACKGROUND: Inflammation and oxidative stress play a key role in the development of bronchopulmonary dysplasia (BPD), possibly contributing to persistent respiratory morbidity after preterm birth. We aimed to assess if inflammatory markers were elevated in exhaled breath condensate (EBC) of infants born very prematurely (< 32 weeks gestation) at 12-16 corrected months of age, and if increased levels were associated with BPD diagnosis and respiratory morbidity. METHODS: EBC samples and respiratory questionnaires were collected from 15 term-born infants and 33 preterm-born infants, 12 with a neonatal BPD diagnosis. EBC samples were analysed for leukotriene B4 (inflammation) and 8-isoprostane (oxidative stress) concentrations using enzyme-linked immune-assays. Differences between groups were analysed by Kruskal-Wallis Test with post-hoc comparisons, independent samples t-test or Mann-Whitney U test depending on normality of the data. RESULTS: Leukotriene B4 and 8-isoprostane levels were elevated in exhaled breath condensate of preterm-born infants compared to those born at term (mean difference [95% CI]; 1.52 [0.45, 2.59], p = 0.02; 0.77 [0.52, 1.02], p < 0.001, respectively). Leukotriene B4 and 8-isoprostane levels were independent of BPD diagnosis and respiratory morbidity over the first year of life. CONCLUSIONS: Infants born very prematurely exhibit elevated markers of airway neutrophilic inflammation and oxidative stress beyond the first year of life, regardless of a neonatal diagnosis of chronic lung disease or respiratory morbidity during infancy. These findings may have implications for future lung health. TRIAL REGISTRATION: N/A.

Health service utilisation for acute respiratory infections in infants graduating from the neonatal intensive care unit: a population-based cohort study.

BACKGROUND: Despite advances in neonatal intensive care, babies admitted to Neonatal Intensive Care Units (NICU) suffer from adverse outcomes. We aim to describe the longer-term respiratory infectious morbidity of infants discharged from NICU using state-wide population-based linked data in Western Australia. STUDY DESIGN: We used probabilistically linked population-based administrative data to analyse respiratory infection morbidity in a cohort of 23,784 infants admitted to the sole tertiary NICU, born 2002-2013 with follow up to 2015. We analysed incidence rates of secondary care episodes (emergency department presentations and hospitalisations) by acute respiratory infection (ARI) diagnosis, age, gestational age and presence of chronic lung disease (CLD). Poisson regression was used to investigate the differences in rates of ARI hospital admission between gestational age groups and those with CLD, after adjusting for age at hospital admission. RESULTS: From 177,367 child-years at risk (i.e., time that a child could experience an ARI outcome), the overall ARI hospitalisation rate for infants and children aged 0-8 years was 71.4/1000 (95% confidence interval, CI: 70.1, 72.6), with the highest rates in infants aged 0-5 months (242.9/1000). For ARI presentations to emergency departments, equivalent rates were 114/1000 (95% CI: 112.4, 115.5) and 337.6/1000, respectively. Bronchiolitis was the most common diagnosis among both types of secondary care, followed by upper respiratory tract infections. Extremely preterm infants (< 28 weeks gestation at birth) were 6.5 (95% CI: 6.0, 7.0) times more likely and those with CLD were 5.0 (95% CI: 4.7, 5.4) times more likely to be subsequently admitted for ARI than those in NICU who were not preterm or had CLD after adjusting for age at hospital admission. CONCLUSIONS: There is an ongoing burden of ARI in children who graduate from the NICU, especially those born extremely preterm, that persists into early childhood. Early life interventions to prevent respiratory infections in these children and understanding the lifelong impact of early ARI on later lung health are urgent priorities.

Living with lung disease: experimental models to assess the long-term effects of prematurity.

Laboratory models provide an important tool in helping to understand the cellular and molecular drivers of respiratory disease. Many animal models exist that model the neonatal outcomes of preterm birth. Discoveries at the laboratory bench from examination of both human tissue and tissues from animal models have informed the life-saving technologies and clinical care used today. Yet animal laboratory models of preterm birth have rarely been utilized beyond the neonatal period, despite growing reports of respiratory symptoms and subnormal lung function throughout childhood. Elucidation of the driving factors and physiological explanations underpinning poor outcomes in survivors of preterm birth are crucial to optimize clinical care and identify therapeutic targets. Can existing neonatal models be utilized to study respiratory outcomes beyond infancy? This review answers the question by highlighting the clinical evidence underpinning an active respiratory disease process after preterm birth and exploring the benefits and drawbacks of existing models to conduct research into the long-term respiratory outcomes of preterm birth.

Lung abnormalities do not influence aerobic capacity in school children born preterm.

PURPOSE: 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. METHODS: 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. RESULTS: 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 V̇O2 (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. CONCLUSION: 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.

Technical standards for respiratory oscillometry.

Oscillometry (also known as the forced oscillation technique) measures the mechanical properties of the respiratory system (upper and intrathoracic airways, lung tissue and chest wall) during quiet tidal breathing, by the application of an oscillating pressure signal (input or forcing signal), most commonly at the mouth. With increased clinical and research use, it is critical that all technical details of the hardware design, signal processing and analyses, and testing protocols are transparent and clearly reported to allow standardisation, comparison and replication of clinical and research studies. Because of this need, an update of the 2003 European Respiratory Society (ERS) technical standards document was produced by an ERS task force of experts who are active in clinical oscillometry research.The aim of the task force was to provide technical recommendations regarding oscillometry measurement including hardware, software, testing protocols and quality control.The main changes in this update, compared with the 2003 ERS task force document are 1) new quality control procedures which reflect use of "within-breath" analysis, and methods of handling artefacts; 2) recommendation to disclose signal processing, quality control, artefact handling and breathing protocols (e.g. number and duration of acquisitions) in reports and publications to allow comparability and replication between devices and laboratories; 3) a summary review of new data to support threshold values for bronchodilator and bronchial challenge tests; and 4) updated list of predicted impedance values in adults and children.

Upper Airway Pathology Contributes to Respiratory Symptoms in Children Born Very Preterm.

OBJECTIVE: To evaluate the role of upper airway dysfunction, indicated by altered vocal quality (dysphonia), on the respiratory symptoms of children surviving very preterm birth. STUDY DESIGN: Children born <32 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. RESULTS: 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 (Xrs8 mean difference = -0.91 z scores, P = .003; fres = 1.06 z scores, P = .019; AX = -0.87 z scores, P = .010; Rrs8 = 0.63 z scores, P = .068). CONCLUSIONS: The 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: Rationale for a pathophysiological rather than treatment based approach to diagnosis.

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.

Preterm birth: Born too soon for the developing airway epithelium?

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.

Persistent and progressive long-term lung disease in survivors of preterm birth.

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 <32 weeks of GA experience adverse respiratory outcomes, manifesting with increased respiratory symptoms, hospitalisation and health care utilisation into early childhood. The development of bronchopulmonary dysplasia (BPD) - the chronic lung disease of prematurity - further increases the risk of poor respiratory outcomes throughout childhood, into adolescence and adulthood. Indeed, survivors of preterm birth have shown increased respiratory symptoms, altered lung structure, persistent and even declining lung function throughout childhood. The mechanisms behind this persistent and sometimes progressive lung disease are unclear, and the implications place those born preterm at increased risk of respiratory morbidity into adulthood. This review aims to summarise what is known about the long-term pulmonary outcomes of contemporary preterm birth, examine the possible mechanisms of long-term respiratory morbidity in those born preterm and discuss addressing the unknowns and potentials for targeted treatments.

Altered lung structure and function in mid-childhood survivors of very preterm birth.

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. FEV1 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<0.001) for each additional week of gestation. Obstruction was associated with increased subpleural opacities, bronchial wall thickening and hypoattenuated lung areas on inspiratory chest CT scans (p<0.05). CONCLUSIONS: Abnormal lung structure in mid-childhood resulting from preterm birth in the contemporary era has important functional consequences.

Lung Clearance Index and Structural Lung Disease on Computed Tomography in Early Cystic Fibrosis.

RATIONALE: The lung clearance index is a measure of ventilation distribution derived from the multiple-breath washout technique. It has been suggested as a surrogate for chest computed tomography to detect structural lung abnormalities in individuals with cystic fibrosis (CF); however, the associations between lung clearance index and early structural lung disease are unclear. OBJECTIVES: We assessed the ability of the lung clearance index to reflect structural lung disease on the basis of chest computed tomography across the entire pediatric age range. METHODS: Lung clearance index was assessed in 42 infants (ages 0-2 yr), 39 preschool children (ages 3-6 yr), and 38 school-age children (7-16 yr) with CF before chest computed tomography and in 72 healthy control subjects. Scans were evaluated for CF-related structural lung disease using the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis quantitative outcome measure. MEASUREMENTS AND MAIN RESULTS: In infants with CF, lung clearance index is insensitive to structural disease (κ = -0.03 [95% confidence interval, -0.05 to 0.16]). In preschool children with CF, lung clearance index correlates with total disease extent. In school-age children, lung clearance index correlates with extent of total disease, bronchiectasis, and air trapping. In preschool and school-age children, lung clearance index has a good positive predictive value (83-86%) but a poor negative predictive value (50-55%) to detect the presence of bronchiectasis. CONCLUSIONS: These data suggest that lung clearance index may be a useful surveillance tool to monitor structural lung disease in preschool and school-age children with CF. However, lung clearance index cannot replace chest computed tomography to screen for bronchiectasis in this population.

Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection.

Measures of ventilation distribution are promising for monitoring early lung disease in cystic fibrosis (CF). This study describes the cross-sectional and longitudinal impacts of pulmonary inflammation and infection on ventilation homogeneity in infants with CF.Infants diagnosed with CF underwent multiple breath washout (MBW) testing and bronchoalveolar lavage at three time points during the first 2 years of life.Measures were obtained for 108 infants on 156 occasions. Infants with a significant pulmonary infection at the time of MBW showed increases in lung clearance index (LCI) of 0.400 units (95% CI 0.150-0.648; p=0.002). The impact was long lasting, with previous pulmonary infection leading to increased ventilation inhomogeneity over time compared to those who remained free of infection (p<0.05). Infection with Haemophilus influenzae was particularly detrimental to the longitudinal lung function in young children with CF where LCI was increased by 1.069 units for each year of life (95% CI 0.484-1.612; p<0.001).Pulmonary infection during the first year of life is detrimental to later lung function. Therefore, strategies aimed at prevention, surveillance and eradication of pulmonary pathogens are paramount to preserve lung function in infants with CF.

Lung function following very preterm birth in the era of 'new' bronchopulmonary dysplasia.

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.

Early respiratory infection is associated with reduced spirometry in children with cystic fibrosis.

RATIONALE: Pulmonary inflammation, infection, and structural lung disease occur early in life in children with cystic fibrosis. OBJECTIVES: We hypothesized that the presence of these markers of cystic fibrosis lung disease in the first 2 years of life would be associated with reduced lung function in childhood. METHODS: Lung function (forced expiratory volume in the first three-quarters of a second [FEV0.75], FVC) was assessed in individuals with cystic fibrosis diagnosed after newborn screening and healthy subjects during infancy (0-2 yr) and again at early school age (4-8 yr). Individuals with cystic fibrosis underwent annual bronchoalveolar lavage fluid examination, and chest computed tomography. We examined which clinical outcomes (pulmonary inflammation, infection, structural lung disease, respiratory hospitalizations, antibiotic prophylaxis) measured in the first 2 years of life were associated with reduced lung function in infants and young children with cystic fibrosis, using a mixed effects model. MEASUREMENTS AND MAIN RESULTS: Children with cystic fibrosis (n = 56) had 8.3% (95% confidence interval [CI], -15.9 to -6.6; P = 0.04) lower FEV0.75 compared with healthy subjects (n = 18). Detection of proinflammatory bacterial pathogens (Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Aspergillus species, Streptococcus pneumoniae) in bronchoalveolar lavage fluid was associated with clinically significant reductions in FEV0.75 (ranging between 11.3 and 15.6%). CONCLUSIONS: The onset of lung disease in infancy, specifically the occurrence of lower respiratory tract infection, is associated with low lung function in young children with cystic fibrosis. Deficits in lung function measured in infancy persist into childhood, emphasizing the need for targeted therapeutic interventions in infancy to maximize functional outcomes later in life.

Unravelling the respiratory health path across the lifespan for survivors of preterm birth.

Many survivors of preterm birth will have abnormal lung development, reduced peak lung function and, potentially, an increased rate of physiological lung function decline, each of which places them at increased risk of chronic obstructive pulmonary disease across the lifespan. Current rates of preterm birth indicate that by the year 2040, around 50 years since the introduction of surfactant therapy, more than 700 million individuals will have been born prematurely-a number that will continue to increase by about 15 million annually. In this Personal View, we describe current understanding of the impact of preterm birth on lung function through the life course, with the aim of putting this emerging health crisis on the radar for the respiratory community. We detail the potential underlying mechanisms of prematurity-associated lung disease and review current approaches to prevention and management. Furthermore, we propose a novel way of considering lung disease after preterm birth, using a multidimensional model to determine individual phenotypes of lung disease-a first step towards optimising management approaches for prematurity-associated lung disease.

Ventilatory response and stability of oxygen saturation during a hypoxic challenge in very preterm infants.

BACKGROUND: Preterm infants have immature control of breathing and impaired pulmonary gas exchange. We hypothesized that infants with bronchopulmonary dysplasia (BPD) have a blunted ventilatory response and peripheral oxygen saturation (SpO2 ) instability during a hypoxic challenge. METHODS: We evaluated the response to hypoxia in 57 very preterm infants (38 no BPD, 10 mild BPD, 9 moderate-to-severe BPD) at 36 weeks' postmenstrual age. The fraction of inspired oxygen (FI O2 ) was reduced stepwise at 5-min intervals to achieve peripheral SpO2 between 86% and 95%. The lowest permissible FI O2 and SpO2 were 0.14% and 86%. We recorded SpO2 , FI O2 , and the respiratory signal (respiratory inductive plethysmography). We calculated respiratory rate (RR), tidal volume (VT ), minute ventilation (VE ), and respiratory drive (ratio between VT and inspiratory time, VT /TI ). SpO2 variability was expressed as the interquartile range (IQR). RESULTS: FI O2 was reduced from a median (Q1, Q3) of 0.21 (0.21, 0.21) to 0.17 (0.17, 0.18). We observed a marked individual variability in the ventilatory response to the hypoxic challenge, regardless of BPD severity. At the lowest permissible FI O2 , 37 (65%) infants reduced their VE , and 20 (35%) increased minute ventilation; 20 infants (35%) developed periodic breathing associated with increased SpO2 IQR and lower SpO2 minima, and 16 (28%) exhibited an oscillatory pattern in VE and SpO2 without end-expiratory pauses, regardless of BPD severity. CONCLUSION: In very preterm infants, a mild hypoxic challenge reduced ventilation, increased SpO2 variability and periodic breathing regardless of BPD severity.