Ivacaftor-induced sweat chloride reductions correlate with increases in airway surface liquid pH in cystic fibrosis.

BACKGROUND: Disruption of cystic fibrosis transmembrane conductance regulator (CFTR) anion channel function causes cystic fibrosis (CF), and lung disease produces most of the mortality. Loss of CFTR-mediated HCO3- secretion reduces the pH of airway surface liquid (ASL) in vitro and in neonatal humans and pigs in vivo. However, we previously found that, in older children and adults, ASL pH does not differ between CF and non-CF. Here, we tested whether the pH of CF ASL increases with time after birth. Finding that it did suggested that adaptations by CF airways increase ASL pH. This conjecture predicted that increasing CFTR activity in CF airways would further increase ASL pH and also that increasing CFTR activity would correlate with increases in ASL pH. METHODS: To test for longitudinal changes, we measured ASL pH in newborns and then at 3-month intervals. We also studied people with CF (bearing G551D or R117H mutations), in whom we could acutely stimulate CFTR activity with ivacaftor. To gauge changes in CFTR activity, we measured changes in sweat Cl- concentration immediately before and 48 hours after starting ivacaftor. RESULTS: Compared with that in the newborn period, ASL pH increased by 6 months of age. In people with CF bearing G551D or R117H mutations, ivacaftor did not change the average ASL pH; however reductions in sweat Cl- concentration correlated with elevations of ASL pH. Reductions in sweat Cl- concentration also correlated with improvements in pulmonary function. CONCLUSIONS: Our results suggest that CFTR-independent mechanisms increase ASL pH in people with CF. We speculate that CF airway disease, which begins soon after birth, is responsible for the adaptation. FUNDING: Vertex Inc., the NIH (P30DK089507, 1K08HL135433, HL091842, HL136813, K24HL102246), the Cystic Fibrosis Foundation (SINGH17A0 and SINGH15R0), and the Burroughs Wellcome Fund.

Sonographic evidence of abnormal tracheal cartilage ring structure in cystic fibrosis.

OBJECTIVES/HYPOTHESIS: Tracheal cartilage ring structural abnormalities have been reported in cystic fibrosis (CF) mice and pigs. Whether similar findings are present in humans with CF is unknown. We hypothesized that tracheal cartilage ring shape and size would be different in people with CF. STUDY DESIGN: Tracheal cartilage ring size and shape were measured in adults with (n = 21) and without CF (n = 18). METHODS: Ultrasonography was used in human subjects to noninvasively assess tracheal cartilage ring structure in both the sagittal and the transverse planes. Tracheal cartilage ring thickness was also determined from histological sections obtained from newborn non-CF and CF pigs. These values were compared with human data. RESULTS: Human CF tracheas had a greater width and were less circular in shape compared to non-CF subjects. CF tracheal cartilage rings had a greater midline cross-sectional area and were thicker compared to non-CF rings. Maximal tracheal cartilage ring thickness was also greater in both newborn CF pigs and human adults with CF, compared to non-CF controls. CONCLUSIONS: Our findings demonstrate that structural differences exist in tracheal cartilage rings in adults with CF. Comparison with newborn CF pig data suggests that some of these changes may be congenital in nature. LEVEL OF EVIDENCE: 3b