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.

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.

Oscillometry and spirometry are not interchangeable when assessing the bronchodilator response in children and young adults born preterm.

INTRODUCTION: The European Respiratory Society Oscillometry Taskforce identified that clinical correlates of bronchodilator responses are needed to advance oscillometry in clinical practice. The understanding of bronchodilator-induced oscillometry changes in preterm lung disease is poor. Here we describe a comparison of bronchodilator assessments performed using oscillometry and spirometry in a population born very preterm and explore the relationship between bronchodilator-induced changes in respiratory function and clinical outcomes. METHODS: Participants aged 6-23 born ≤32 (N = 288; 132 with bronchopulmonary dysplasia) and ≥37 weeks' gestation (N = 76, term-born controls) performed spirometry and oscillometry. A significant bronchodilator response (BDR) to 400 µg salbutamol was classified according to published criteria. RESULTS: A BDR was identified in 30.9% (n = 85) of preterm-born individuals via spirometry and/or oscillometry, with poor agreement between spirometry and oscillometry definitions (k = 0.26; 95% confidence interval [CI] 0.18-0.40, p < .001). Those born preterm with a BDR by oscillometry but not spirometry had increased wheeze (33% vs. 11%, p = .010) and baseline resistance (Rrs5 z-score mean difference (MD) = 0.86, 95% CI 0.07-1.65, p = .025), but similar baseline spirometry to the group without a BDR (forced expiratory volume in 1 s [FEV1 ] z-score MD = -0.01, 95% CI -0.66 to 0.68, p > .999). Oscillometry was more feasible than spirometry (95% success rate vs. 85% (FEV1 ), 69% (forced vital capacity) success rate, p < .001), however being born preterm did not affect test feasibility. CONCLUSION: In the preterm population, oscillometry is a feasible and clinically useful supportive test to assess the airway response to inhaled salbutamol. Changes measured by oscillometry reflect related but distinct physiological changes to those measured by spirometry, and thus these tests should not be used interchangeably.

Inhaled corticosteroids to improve lung function in children (aged 6-12 years) who were born very preterm (PICSI): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Despite the substantial burden of lung disease throughout childhood in children who were born very preterm, there are no evidence-based interventions to improve lung health beyond the neonatal period. We tested the hypothesis that inhaled corticosteroid improves lung function in this population. METHODS: PICSI was a randomised, double-blind, placebo-controlled trial at Perth Children's Hospital (Perth, WA, Australia) to assess whether fluticasone propionate, an inhaled corticosteroid, improves lung function in children who had been born very preterm (<32 weeks of gestation). Eligible children were aged 6-12 years and did not have severe congenital abnormalities, cardiopulmonary defects, neurodevelopmental impairment, diabetes, or any glucocorticoid use within the preceding 3 months. Participants were randomly assigned (1:1) to receive 125 µg fluticasone propionate or placebo twice daily for 12 weeks. Participants were stratified for sex, age, bronchopulmonary dysplasia diagnosis, and recent respiratory symptoms using the biased-coin minimisation technique. The primary outcome was change in pre-bronchodilator forced expiratory volume in 1 s (FEV1) after 12 weeks of treatment. Data were analysed by intention-to-treat (ie, all participants who were randomly assigned and took at least the tolerance dose of the drug). All participants were included in the safety analyses. This trial is registered at the Australian and New Zealand Clinical Trials Registry, number 12618000781246. FINDINGS: Between Oct 23, 2018, and Feb 4, 2022, 170 participants were randomly assigned and received at least the tolerance dose (83 received placebo and 87 received inhaled corticosteroid). 92 (54%) participants were male and 78 (46%) were female. 31 participants discontinued treatment before 12 weeks (14 in the placebo group and 17 in the inhaled corticosteroid group), mostly due to the impact of the COVID-19 pandemic. When analysed by intention-to-treat, the change in pre-bronchodilator FEV1 Z score over 12 weeks was -0·11 (95% CI -0·21 to 0·00) in the placebo group and 0·20 (0·11 to 0·30) in the inhaled corticosteroid group (imputed mean difference 0·30, 0·15-0·45). Three of 83 participants in the inhaled corticosteroid group had adverse events requiring treatment discontinuation (exacerbation of asthma-like symptoms). One of 87 participants in the placebo group had an adverse event requiring treatment discontinuation (inability to tolerate the treatment with dizziness, headaches, stomach pains, and worsening of a skin condition). INTERPRETATION: As a group, children born very preterm have only modestly improved lung function when treated with inhaled corticosteroid for 12 weeks. Future studies should consider individual phenotypes of lung disease after preterm birth and other agents to improve management of prematurity-associated lung disease. FUNDING: Australian National Health and Medical Research Council, Telethon Kids Institute, and Curtin University.