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Background: Ivacaftor is a significant innovation in the treatment of cystic fibrosis (CF) with gating mutations. A substantial percentage of patients with CF have severe lung involvement, but these patients are usually excluded from phase III clinical trials. Thus, the effectiveness of ivacaftor in this population has not been fully determined., Methods: Data were collected from Italian CF centers with patients enrolled in an ivacaftor compassionate use programme (percent predicted [pp] forced expiratory volume in 1 second [FEV 1 ] < 40%, or on lung transplant waiting list, or with a fast worsening trend of lung function). Data were collected for 1 year before and 1 year after ivacaftor commencement., Results: Thirteen patients received ivacaftor for a median of 320 days. Mean (SD) ppFEV 1 increased from 35.1% (14.3%) before treatment to 46.6% (18.8%) after 12 months of treatment (absolute increase 11.5%, relative increase 32.8%). Mean distance of the 6-minute walking test improved significantly, from 535.1 m before to 611.6 m after 12 months of treatment (P = .002). The number of pulmonary exacerbations decreased significantly, from 57 during the year before ivacaftor to 28 in the year following ivacaftor (P = .0048). Five of the 13 patients (38.5%) had no exacerbations during the 12 months after starting ivacaftor. Median weight increased significantly, from 52.7 kg to 55.6 kg (P = .0031). Mean (SD) sweat chloride concentration decreased significantly, from 99.5 (22.8) mmol/L to 39.3 (15.8) mmol/L (P < .0001). No safety concerns were registered., Conclusions: Ivacaftor was safe and effective in patients with CF with severe lung disease and non-G551D gating mutations., (© 2019 Wiley Periodicals, Inc.)

Pharmacological rescue of mutant cystic fibrosis transmembrane conductance regulator (CFTR) in cystic fibrosis (CF) depends on the specific defect caused by different mutation classes. We asked whether a patient with the rare p.Gly970Asp (c.2909G>A) mutation could benefit from CFTR pharmacotherapy since a similar missense mutant p.Gly970Arg (c.2908G>C) was previously found to be sensitive to potentiators in vitro but not in vivo. By complementary DNA transfection, we found that both mutations are associated with defective CFTR function amenable to pharmacological treatment. However, analysis of messenger RNA (mRNA) from patient's cells revealed that c.2908G>C impairs RNA splicing whereas c.2909G>A does not perturb splicing and leads to the expected p.Gly970Asp mutation. In agreement with these results, nasal epithelial cells from the p.Gly970Asp patient showed significant improvement of CFTR function upon pharmacological treatment. Our results underline the importance of controlling the effect of CF mutation at the mRNA level to determine if the pharmacotherapy of CFTR basic defect is appropriate., (© 2019 Wiley Periodicals, Inc.)

Background: Cystic fibrosis, like other chronic diseases, is a risk factor for the development of elevated symptoms of depression and anxiety. The objective of this study was to investigate the prevalence of anxiety and depression in Italian patients with CF and their parents., Methods: The Hospital Anxiety and Depression Scale (HADS) and Center for Epidemiologic Studies Depression Scale (CES-D) questionnaires were administered to a sample of patients and their parents recruited at the cystic fibrosis centers in Italy., Results: Elevated levels of anxiety were higher in mothers than in fathers, and also higher in female patients than in male patients. A correlation between elevated levels of anxiety/depression and geographical area also emerged. Patient anxiety (OR 2.33) and depression (OR 4.09) were significantly associated with forced expiratory volume in one second (FEV1) <40% and forced vital capacity (FVC) <80% (OR 1.60 and 1.61, respectively)., Conclusions: Cystic fibrosis increases the risk of developing anxiety and depression in female patients and in mothers. Geographical differences were observed, with higher anxiety and depression in southern Italy for parents, but not for patients. Anxiety and depression levels also depend on clinical status. Pediatr Pulmonol. 2016;51:1311-1319. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The aim of our study was to compare the short-term efficacy of three different chest physiotherapy (CPT) regimens (PD, postural drainage; PEP, positive expiratory pressure physiotherapy; HFCC, high-frequency chest compression physiotherapy) on patients with cystic fibrosis (CF) hospitalized for an acute pulmonary exacerbation. Sixteen patients with CF, 8 males, 8 females, aged 15-27 years (mean, 20.3 +/- 4), met the inclusion criteria: 1) age over 14 years; 2) mild or moderate airway obstruction; 3) sputum volume > 30 mL/day; 4) being proficient in PD and PEP CPT. Patients at admission had (mean +/- SD) forced volume in 1 second (FEV1) 52.2 +/- 21.9 percent predicted; Shwachman-Kulczycki clinical score 65.1 +/- 11 points; Chrispin-Norman chest radiography score 18.6 +/- 4.3 points. The three CPT regimens and a control-treatment (CONT) were administered in a random sequence, each patient receiving each treatment twice a day (in 50 minute sessions) for 2 consecutive days. During CONT and for 30 minutes after each session only spontaneous coughing was allowed. Wet and dry weight of sputum were recorded during the 50-minute sessions and 30 minutes afterward. Lung function was measured before and 30 minutes after each session. For each treatment a score was given by the patient for efficacy, and by both the patient and the physiotherapist for tolerance. Wet and dry weights of sputum collected during the sessions were greater for all CPT regimens than for CONT (P < 0.001, P < 0.0001). No significant differences between the three CPT regimens for both wet and dry weights were found when the number of coughs was taken into account.(ABSTRACT TRUNCATED AT 250 WORDS)

Forty patients with cystic fibrosis (CF) (mean age, 13 +/- 2.5 years) were studied with transcutaneous (tc) blood gas monitoring (TCM) during sleep and exercise. By comparing arterial blood samples and TCM in 24 of them (27 samples), a mean bias of tcO2 -15.91 mmHg with a precision of 8.4 mmHg was found. The mean bias of tcCo2 was 7.21 mmHg with a precision of 3.9 mmHg. A standardized submaximal exercise test (1.7 W/kg) was performed in all 40 CF patients and in 14 healthy control subjects (mean age, 13 +/- 0.5 years). The typical tc trend during exercise for CF and healthy subjects was a slight increase of tcO2 levels and tcCO2 stability. A minor decrease of tcO2 values occurred in four CF patients (no greater than 7 mmHg). In 28 patients (mean age, 13 +/- 3 years), tcO2 and tcCO2 were recorded during sleep. In 13 of them, apparent hypoxemic episodes were noted, without relation to the degree of airway obstruction. There were simultaneous episodes of hypercapnia in ten patients. Some difficulties were encountered in analyzing long-term recordings. TcO2 drifts upward and tcCO2 decreases during the recordings over several hours. The change in electrode position after 4 h of sleep modified tcO2 and tcCO2 values. Such difficulties limit the usefulness of long-term but not short-term recordings.

We evaluated the effects of an 8-week aerobic training (1 hr, three times a week) on physical performance of ten patients with cystic fibrosis (CF) (median age, 12.5 yr; range 11.1-15.3 yr), with mild airway obstruction (FEV1 = 77 +/- 22% pred.), and ten healthy age-matched children (CONTR) (median age, 12.7 yr; range 12.2-15.2 yr). Physical performance was tested with maximal incremental (MAX) and submaximal (SMAX) (fixed workload of 1.7 W/kg during 6 min) exercise tests on a cycle ergometer. These and standard spirometric and anthropometric measurements were performed at the beginning and end of a period with usual daily activity and one with the training program. The kinetics of ventilatory parameters at the onset and end of SMAX were displayed by fitting data on oxygen uptake and minute ventilation by monoexponential curves (least-squares method). At the start and the end of the training period, all children were timed for endurance run to voluntary exhaustion and for sprinting through an obstacle course. A pattern of relative hyperventilation during SMAX and of poor performance in endurance and obstacle runs were evident at the start of the training period in patients with CF. The effects of training on MAX and SMAX were small and partial; the improvement in field test performances was significant only for CF and could be attributed to improvement of skill and motivation.