Elexacaftor/Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation and Advanced Lung Disease: A 48-Week Observational Study.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) is the newest cystic fibrosis transmembrane conductance regulator (CFTR) modulator drug approved for the treatment of patients with cystic fibrosis (pwCF) aged ≥6 years with at least one copy of the F508del mutation (F) in the CFTR gene or another mutation that is responsive to treatment with ETI. This study determined the effectiveness and safety of ETI in a cohort of severely affected pwCF with an F/F genotype. METHODS: Retrospective observational study in F/F pwCF treated for 48 weeks, enrolled in an ETI managed access program available to subjects with advanced lung disease (ppFEV1 < 40). Twenty-six patients from three centres were included. The main outcomes included lung function, sweat chloride concentration (SCC), nutrition, frequency of pulmonary exacerbations (PEx), CFQ-R, and safety. RESULTS: ppFEV1 improved by 12.06 (95%CI 8.54, 15.57) from baseline after 4 weeks of treatment with ETI, 15.32 (11.3, 19.34) after 24 weeks, and 14.48 (10.64, 18.32) after 48 weeks. The increase in FEV1 was accompanied by a decrease in SCC, improvement of BMI, and noticeable reduction in PEx. An overall good safety profile was observed. CONCLUSIONS: In F/F pwCF with advanced lung disease with an F/F genotype, ETI was safe and associated with clinical improvement.

Elexacaftor/tezacaftor/ivacaftor as rescue therapy in a patient with the cystic fibrosis genotype F508DEL/G1244E.

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane regulator (CFTR) modulator. It is known to be efficacious in stable patients with severe pneumopathy, but there are few data concerning its effectiveness during acute exacerbations. We here describe its use in a woman with CF and respiratory failure.

Comparison of an expiratory flow accelerator device versus positive expiratory pressure for tracheobronchial airway clearance after lung cancer lobectomy: a preliminary study.

OBJECTIVE: A new type of device has recently been introduced in chest physiotherapy as an aid to tracheo-bronchial airway clearance: expiratory flow accelerator (EFA). It promotes mucus clearance without generating any pressure gradient, allowing patients to breathe at tidal volume against no resistance. DESIGN: Pilot randomized controlled study. SETTING: Tertiary hospital. PARTICIPANTS: Fifty adult patients who underwent lung cancer lobectomy were randomized to undergo chest physiotherapy with EFA (n=26) or PEP (n=24). INTERVENTIONS: EFA; PEP bottle. MAIN OUTCOMES: Incidence of postoperative pulmonary complications (PPC) and length of stay. SECONDARY OUTCOMES: trends in inspiratory capacity, respiratory rate, oxygen saturation, and dyspnoea. Patients rated user-friendliness of the two devices on a 5-point Likert scale. RESULTS: A slightly different incidence of PPCs was observed between the EFA and PEP group. Nevertheless, the length of stay was similar in the two groups. No substantial differences were seen in trends of inspiratory capacity, respiratory rate, oxygen saturation, dyspnoea between the two groups. Patient-reported user-friendliness of the two devices did not differ significantly, although the use of the EFA device appeared less strenuous. CONCLUSIONS: Results of this pilot study point to the use of EFA as an alternative treatment option rather than as a replacement for the PEP bottle in chest physiotherapy following lung cancer lobectomy. EFA may be preferable for weaker patients and/or with airway leakages in whom PEP has limited indications. Further investigation in a larger sample is required to statistically confirm the findings. Clinical Trial Registration Number ChiCTR-ONC-17013255.

Effectiveness and safety of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease with the Phe508del/minimal function genotype.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (E/T/I) is a cystic fibrosis transmembrane conductance regulator (CFTR) triple combination therapy used for the treatment of cystic fibrosis (CF) in patients aged ≥12 years who have at least one copy of the Phe508del mutation (F) in the CFTR gene or another mutation that is responsive to treatment with E/T/I. This study determined the effectiveness and safety of E/T/I treatment in a cohort of CF patients. METHODS: This retrospective cohort study collected data from the first 6 months of treatment of patients with CF, compound heterozygotes for the F and a minimal function (MF) mutations, enrolled in an E/T/I compassionate use program only available to patients having ppFEV1<40 or who are considered for lung transplantation. Forty-seven patients were included. Follow-up was performed after 1, 3, and 6 months from the beginning of therapy, assessing lung function, body mass index (BMI), sweat chloride concentration (SCC), quality of life (QoL), and safety. RESULTS: After 6 months of treatment, the mean (standard deviation (SD)) SCC decreased from 91.1 (19.3) mmol/L to 46.2 (24.2) mmol/L. The decrease of SCC was accompanied by improvement of lung function (mean (95% Confidence Interval (CI) absolute increase in ppFEV1 was 10.69 (8.05,13.33) after 1 month and 14.16 (11.43, 16.89) after 6 months of treatment), nutrition (mean (SD) BMI increased from 20.7 (3.0) kg/m2 at baseline to 22.6 (3.1) after 6 months), and QoL. No safety concerns were observed. CONCLUSIONS: E/T/I was clinically effective and safe in patients with advanced CF lung disease with an F/MF genotype.

Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor Therapy in Three Subjects with the Cystic Fibrosis Genotype Phe508del/Unknown and Advanced Lung Disease.

We evaluated the effectiveness and safety of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) in three subjects carrying the Phe508del/unknown CFTR genotype. An ex vivo analysis on nasal epithelial cells (NEC) indicated a significant improvement of CFTR gating activity after the treatment. Three patients were enrolled in an ELX/TEZ/IVA managed-access program, including subjects with the highest percent predicted Forced Expiratory Volume in the 1st second (ppFEV1) < 40 in the preceding 3 months. Data were collected at baseline and after 8, 12 and 24 weeks of follow-up during treatment. All patients showed a considerable decrease of sweat chloride (i.e., meanly about 60 mmol/L as compared to baseline), relevant improvement of ppFEV1 (i.e., >8) and six-minute walk test, and an increase in body mass index after the first 8 weeks of treatment. No pulmonary exacerbations occurred during the 24 weeks of treatment and all domains of the CF Questionnaire-Revised improved. No safety concerns related to the treatment occurred. This study demonstrates the benefit from the ELX/TEZ/IVA treatment in patients with CF with the Phe508del and one unidentified CFTR variant. The preliminary ex vivo analysis of the drug response on NEC helps to predict the in vivo therapeutic endpoints.

Airway Clearance with Expiratory Flow Accelerator Technology: Effectiveness of the "Free Aspire" Device in Patients with Severe COPD.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is associated with a higher risk of pulmonary infections. This risk not only negatively affects patients' quality of life but also increases social and health costs. Hence, there is a need for an effective rehabilitative treatment including airway clearance. The aim of this pilot study was to evaluate the efficacy of a new tool for bronchial clearance based on expiratory flow accelerator (EFA) technology compared with positive expiratory pressure (PEP) treatment. MATERIALS AND METHODS: Twenty stable patients with COPD, Global Initiative for Chronic Obstructive Lung Disease 3-4 stage, were enrolled and allocated to treatment with EFA or Bubble-PEP (BP) for 20 days during a pulmonary rehabilitation program. At baseline and the end of treatment, the following parameters were measured: arterial blood gases (ABG); respiratory function, including peak cough expiratory flow (PCEF), maximal inspiratory pressure (MIP), and maximal expiratory pressure exercise capacity using the 6-minute walk test (6MWT), dyspnea using the Medical Research Council scale, and quality of life using the St. George's Respiratory Questionnaire. RESULTS: Expiratory flow accelerator showed a significant pre- and post-improvement in ABG and a significantly greater improvement than BP in PCEF, MIP, and 6MWT post-treatment. CONCLUSION: Expiratory flow accelerator is a valid device compared with BP as an adjunctive therapy for the treatment of patients with severe COPD.

Minimum Clinically Important Difference in 30-s Sit-to-Stand Test After Pulmonary Rehabilitation in Subjects With COPD.

BACKGROUND: The sit-to-stand (STS) test is a feasible tool for measuring peripheral muscle strength of the lower limbs. There is evidence of increasing use of STS tests in patients with COPD. We sought to evaluate in subjects with COPD the minimum clinically important difference in 30-s STS test after pulmonary rehabilitation. METHODS: Stable COPD subjects undergoing a 30-s STS test and a 6-min walk test (6MWT) before and after pulmonary rehabilitation were included. Responsiveness to pulmonary rehabilitation was determined by the change in 30-s STS test results (Δ 30-s STS) before and after pulmonary rehabilitation. The minimum clinically important difference was evaluated using an anchor-based method. RESULTS: 96 subjects with moderate-to-severe COPD were included. At baseline, 30-s STS test results were significantly related to distance covered in a 6MWT (6MWD) (r = 0.65, P < .001), FVC (r = 0.46, P < .001), PaCO2 (r = -0.42, P < .001), FEV1 (r = 0.39, P < .001), and age (r = -0.31, P = .002). After pulmonary rehabilitation, a significant improvement in 30-s STS test results was observed (mean difference +2 repetitions, P < .001). The Δ30-s STS was positively related to Δ6MWD (r = 0.62, P < .001), transitional dyspnea index (r = 0.67, P < .001), and baseline residual volume (r = 0.27, P = .007). The receiver operating characteristic curves method identified a Δ 30-s STS cut-off of 2 repetitions as the best discriminating value (area under the curve: 0.892, P < .001) to identify the minimum clinically important difference for Δ6MWD (30 m). In a multivariate logistic regression model, baseline 30-s STS (odds ratio 2.63; 95% CI 1.09-6.35, P = .031) and diffusing capacity of the lung for carbon monoxide (< 53% predicted) (odds ratio 2.49, 95% CI 1.04-5.98, P = .041) predict the risk to have a Δ 30-s STS ≥ 2 repetitions. CONCLUSIONS: Our study indicates that in stable subjects with moderate-to-severe COPD, the 30-s STS test was a sensitive tool to assess the efficacy of pulmonary rehabilitation. A Δ 30-s STS of ≥ 2 repetitions represented the minimum clinically important difference, which may be predicted by the baseline ability in the 30-s STS test and lung function in terms of diffusing lung capacity (ClinicalTrials.gov registration NCT03627624).

Effects of salmeterol on arterial oxyhemoglobin saturations in patients with cystic fibrosis.

Sleep-related oxygen desaturation has been described in patients with cystic fibrosis (CF). Thus we studied the effects of inhaled Salmeterol xinafoate, a long-acting beta-2 agonist, on transcutaneous oxyhemoglobin saturation in sleeping, stable CF patients. Patients with stable CF (n = 23) were divided into responders and nonresponders to beta-2 agonists, based on an albuterol challenge during daytime testing, and then they received salmeterol before sleep, in a double-blind crossover design. Overnight oxyhemoglobin saturation measurements and spirometry on awakening were performed. Salmeterol administration before sleep resulted in statistically significant increases in mean arterial oxyhemoglobin saturation and in FEV(1) and FEF(25-75) on awakening compared to placebo values, but only in patients responding to daytime albuterol inhalation by showing improvement in lung function. We conclude that salmeterol inhalation at bedtime could prevent or reduce nocturnal hypoxemia in daytime albuterol-responsive CF patients, thus improving the long-term clinical outcome of CF lung disease.