Real-world assessment of LCI following lumacaftor-ivacaftor initiation in adolescents and adults with cystic fibrosis.

Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV1 was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0]. At both M6 and M12, no statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV1 were observed in one-third of the patients. In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease.

Altered pulmonary gas transfer capacity and capillary blood volume in pediatric Crohn's disease.

OBJECTIVES: To describe diffusing capacity for carbon monoxide (DLCO) and its components, that is, membrane diffusing capacity (DmCO) and pulmonary capillary blood volume (Vc) in children with Crohn's disease (CD), and to investigate the correlation between these parameters and disease activity. WORKING HYPOTHESIS: The most common lung function abnormalities are a reduced pulmonary DLCO and small airways disorders which are in many instances, clinically silent. No valid explanations have been proposed regarding the modifications in gas transfer capacity in active CD. METHODS: DLCO, DmCO, and Vc were measured in 25 CD children by the simultaneous single breath lung diffusing capacity method using nitric oxide (NO) and carbon monoxide (CO) transfer. These parameters were analyzed in relation to the CD disease activity index. RESULTS: DLCO (90.7 ± 4.5% vs 128.5 ± 4.7%; P < 0.001), Dm (92.4 ± 5.9% vs 125.6 ± 6.3%; P < 0.001), and Vc (72.6 ± 3.7% vs 104.4 ± 4.0%; P < 0.001) were significantly decreased in the active CD group in comparison with the inactive CD group. DLCO (r = -0.60; P < 0.01), DmCO (r = -0.45; P < 0.01), and Vc (r = -0.60; P < 0.01) were inversely correlated to the PCDAI. In 8 patients who participated to the study at initial diagnosis then during remission, DmCO and Vc increased significantly between the active and the inactive period of the disease. CONCLUSION: Pulmonary diffusing capacity is impaired in children with active CD, mainly because of a decrease of the pulmonary capillary volume.

Pulmonary outcome and its correlates in school-aged children born with a gestational age ≤ 32 weeks.

BACKGROUND: There is limited data regarding factors influencing the respiratory outcome at school age of ex-preterms born since the introduction of antenatal steroids, surfactant replacement together with less aggressive ventilation. OBJECTIVES: To establish the main antenatal, neonatal and early childhood respiratory correlates of respiratory status in school-aged children born at ≤ 32 weeks of gestation. METHODS: Ex-preterm children born at ≤ 32 weeks of gestation between 1997 and 2001 at Bordeaux University Hospital were evaluated at school age, using a respiratory questionnaire and lung function tests (spirometry, plethysmography, exercise challenge test and CO lung diffusing capacity DLCO measurements). Factors associated with lung function were investigated using polynomial regression analyses. RESULTS: Of the 151 included children [mean age: 8.6 ± 0.8 years; mean gestational age, 30.1 ± 1.7 weeks; mean birth weight = 1310 ± 380 g; 68.2% ventilated at birth; 46.4% treated with surfactant; 36.4% with prior bronchopulmonary dysplasia (BPD)], 47% presented obstructive lung abnormalities, 11% restrictive or mixed lung abnormalities, 41% exercise-induced bronchoconstriction, and 15.5% reduced DLCO. Surfactant therapy was independently associated with a lower risk of lung abnormalities (p < 0.05). The association between BPD and lung abnormalities at school age was not significant, but prior BPD increased the risk of restrictive or mixed abnormalities (odds ratio: 6.11, confidence interval [1.1; 33.99]). Early childhood respiratory events were not associated with the occurrence of lung abnormalities. CONCLUSION: Children born at ≤ 32 weeks of gestation remain at risk for impaired lung function at school age in particular when they did not receive surfactant. Restrictive or mixed lung defects are mainly associated with prior BPD.

Efficacy and tolerance of high-dose inhaled ipratropium bromide vs. terbutaline in intubated premature human neonates.

BACKGROUND: There is insufficient data to reliably assess the benefit of bronchodilators in ventilated premature neonates. OBJECTIVES: To compare the efficacy/tolerance of inhaled ipratropium bromide (IB) vs. terbutaline (T) and to describe factors associated with their efficacy. METHODS: A cross-over randomized controlled double-blind trial including intubated neonates with respiratory distress syndrome. Two puffs of IB or T were administered at 0, 20, 40 min. Passive respiratory system resistance (Rrs) and compliance (Crs) were measured at 0, 20, 40, 60 min. A positive response was defined as a >2 individual coefficients of variation decrease in Rrs or increase in Crs. RESULTS: Twenty-one infants (gestational age (mean +/- SD): 27.3 +/- 1.6 weeks; birth weight: 947 +/- 250 g; postnatal age: 20 +/- 9 days) were included. At 60 min, no treatment effect for Rrs and Crs could be identified (cross-over analysis). Overall data (irrespective of order of administration) showed that after 6 puffs, the decrease in Rrs was greater in the IB vs. T group (-17.0 +/- 22.2% vs. -11.3 +/- 26.7%, respectively (NS)). Thirty-eight percent of infants responded to IB vs. 43% to T. However, in 19% of patients, decreased Crs was observed after 6 puffs of T. No marker of a positive or paradoxical response could be identified. Treatment was well-tolerated. CONCLUSION: High doses of bronchodilators are required in ventilated neonates, but the positive response rate was <50%. Their long-term benefit remains to be proven.

Montelukast does not protect against hyperoxia-induced inhibition of alveolarization in newborn rats.

Impaired lung development has been demonstrated in neonatal animals exposed to hyperoxia. High lung cys-leukotriene levels may be a contributing factor towards the increase in oxygen toxicity. We investigated the effect of cysteinyl-leukotriene inhibition using the receptor antagonist, montelukast (MK, Singulair), on hyperoxia-induced changes in lung parenchymal structure in neonatal rat pups. Rat pups were exposed to 21% O(2) (air) or 50% O(2) (moderate hyperoxia) from days 1-14 after birth, and were administered the cys-leukotriene receptor antagonist MK (1 mg/kg/day) or normal saline from days 4-14. Somatic growth and morphometric measurements were done on day 15. There was a significant increase in bronchoalveolar lavage fluid cysteinyl-leukotriene levels (+61.9%) when animals were exposed to hyperoxia. O(2) exposure significantly decreased the specific internal surface area by 13%. There was a nonsignificant 5.8% and 19.6% increase in mean chord length and mean alveolar diameter, respectively, as well as an 8.6% decrease in lung volume to body weight ratio. Inhibition of only one arm of the arachidonic-acid cascade by MK was not sufficient to prevent these oxygen-induced changes.

Differential effect of dexamethasone and hydrocortisone on alveolar growth in rat pups.

Glucocorticoids are widely used in perinatology, since they decrease the incidence of respiratory distress syndrome and chronic lung disease. However, evidence is now increasing that their use in this age group may result in impaired alveolar lung growth and general development. The aim of this study was to determine whether a low dose of hydrocortisone (1 mg/kg/day for 11 days) was deleterious to lung growth in rat pups, as compared to an equivalent dose of dexamethasone. While both dexamethasone and hydrocortisone increased alveolar diameter with thinning of the interairspace walls, only dexamethasone reduced the overall internal surface area of the lung available for respiratory exchange. Changes were more marked with dexamethasone as compared to hydrocortisone, which did not appear to affect alveolar septation. In conclusion, a prolonged course of low-dose hydrocortisone may be deleterious for alveolar lung growth in rat pups, but the changes are less marked than those caused by dexamethasone.

Pharmacologically induced relaxation of tracheal smooth muscle is increased in hyperoxia-exposed 15-day-old rats.

Hyperoxia increases maximum airway contractility in newborn guinea pigs and immature rats. Studies examining the mechanisms of hyperoxia-induced airway hyperresponsiveness have focused on contractile mechanisms, although excessive airway narrowing could be due to impaired relaxation. Our objective was to determine the effects of hyperoxia on airway structure and relaxing properties in juvenile rats exposed to an inspired fraction of oxygen (FiO(2)) of 0.5 within 24 hr of birth for 15 days, compared to a control group of air-exposed rats. We studied the 1) tracheal smooth muscle surface area; and 2) in vitro relaxation in precontracted (carbachol, 1.10(-3) M) isolated tracheal rings to increasing cumulative concentrations (10(-8) to 10(-4) M) of salbutamol. There was no significant difference in the amount of smooth muscle between the hyperoxia and air-exposed groups. Maximal relaxation of the isolated trachea to salbutamol was greater in the hyperoxia group than in the air-exposed group when normalized to smooth muscle surface area (-12.69 +/- 3.51 g/mm(2) vs. - 8.49 +/- 1.67 g/mm(2); P (MANOVA) < 0.05) or expressed as maximal relaxation induced by 10(-3) M theophylline (61% vs. 28%; P < 0.05). In conclusion, salbutamol-induced relaxation is enhanced (and not impaired) in newborn rats exposed to prolonged moderate hyperoxia.