The clinical impact of Lumacaftor-Ivacaftor on structural lung disease and lung function in children aged 6-11 with cystic fibrosis in a real-world setting

BACKGROUND: Data from clinical trials of lumacaftor-ivacaftor (LUM-IVA) demonstrate improvements in lung clearance index (LCI) but not in FEV1 in children with Cystic Fibrosis (CF) aged 6-11 years and homozygous for the Phe508del mutation. It is not known whether LUM/IVA use in children can impact the progression of structural lung disease. We sought to determine the real-world impact of LUM/IVA on lung structure and function in children aged 6-11 years. METHODS: This real-world observational cohort study was conducted across four paediatric sites in Ireland over 24-months using spirometry-controlled CT scores and LCI as primary outcome measures. Children commencing LUM-/IVA as part of routine care were included. CT scans were manually scored with the PRAGMA CF scoring system and analysed using the automated bronchus-artery (BA) method. Secondary outcome measures included rate of change of ppFEV1, nutritional indices and exacerbations requiring hospitalisation. RESULTS: Seventy-one participants were recruited to the study, 31 of whom had spirometry-controlled CT performed at baseline, and after one year and two years of LUM/IVA treatment. At two years there was a reduction from baseline in trapped air scores (0.13 to 0.07, p = 0.016), but an increase from baseline in the % bronchiectasis score (0.84 to 1.23, p = 0.007). There was no change in overall % disease score (2.78 to 2.25, p = 0.138). Airway lumen to pulmonary artery ratios (AlumenA ratio) were abnormal at baseline and worsened over the course of the study. In 28 participants, the mean annual change from baseline LCI2.5 (-0.055 (-0.61 to 0.50), p = 0.85) measurements over two years were not significant. Improvements from baseline in weight (0.10 (0.06 to 0.15, p < 0.0001), height (0.05 (0.02 to 0.09), p = 0.002) and BMI (0.09 (0.03 to 0.15) p = 0.005) z-scores were seen with LUM/IVA treatment. The mean annual change from baseline ppFEV1 (-2.45 (-4.44 to 2.54), p = 0.66) measurements over two years were not significant. CONCLUSION: In a real-world setting, the use of LUM/IVA over two years in children with CF aged 6-11 resulted in improvements in air trapping on CT but worsening in bronchiectasis scores. Our results suggest that LUM/IVA use in this age group improves air trapping but does not prevent progression of bronchiectasis over two years of treatment

Postnatal development of the pattern of respiratory and cardiovascular response to systemic hypoxia in the piglet: the roles of adenosine.

1. In 3-day-old and 3-week-old spontaneously breathing piglets anaesthetized with Saffan, we have studied ventilatory and cardiovascular responses evoked by 5 min periods of hypoxia (breathing 10 and 6% O2). 2. In 3-day-old piglets both 10 and 6% O2 evoked an increase followed by a secondary fall in ventilation, a gradual tachycardia and a renal vasoconstriction, with an increase in femoral blood flow that was attributable to femoral vasodilatation. Arterial blood pressure rose initially but fell towards control values by the 5th minute of hypoxia. 3. The stable adenosine analogue 2-chloroadenosine (2-CA; 30 mg kg(-1) i.v.) evoked bradycardia and renal vasoconstriction, but had no effect on femoral vasculature. These responses were blocked by the adenosine receptor antagonist 8-phenyltheophylline (8-PT; 8 mg kg(-1) i.v.). 8-PT also abolished the secondary fall in ventilation evoked by 10 and 6% O2 and the renal vasoconstriction evoked by 10% O2, but had no effect on the tachycardia, or on the femoral vascular response. 4. By contrast, in 3-week-old piglets both 10 and 6% O2 evoked a sustained increase in ventilation, tachycardia and a rise in arterial pressure with renal vasoconstriction, but no change in renal blood flow and substantial femoral vasodilatation with an increase in femoral blood flow. 2-CA evoked bradycardia and renal vasoconstriction, as in 3-day-old piglets, but also evoked pronounced femoral vasodilatation. 8-PT blocked these responses and the hypoxia-induced femoral vasodilatation, but had no significant effect on other components of the hypoxia-induced response. 5. We propose that there is postnatal development of the ventilatory and cardiovascular responses evoked by systemic hypoxia and of the role of locally released adenosine in these responses: at 3 days, adenosine released within the central nervous system and within the kidney is a major contributor to the secondary fall in ventilation and renal vasoconstriction respectively, whereas at 3 weeks, adenosine makes little contribution to the ventilatory response, or renal vasoconstriction, but is largely responsible for hypoxia-induced vaso-dilatation in skeletal muscle