Rate Of Pulmonary Exacerbations Research Articles

The Real-World Effectiveness of Antifungals in People with Cystic Fibrosis and Aspergillus-Positive Cultures.

The pathogenicity of Aspergillus in the cystic fibrosis (CF) airway is debated, leading to unclear clinical benefit of antifungal therapy for Aspergillus infection. To determine the real-world effectiveness of antifungal use in people with CF (PwCF) with Aspergillus species in the United States. We conducted a retrospective cohort study evaluating the association of antifungal use and respiratory outcomes in PwCF and Aspergillus positive cultures using the Cystic Fibrosis Foundation patient registry. Marginal structural models using inverse-probability treatment weighted estimators were used to test if antifungal exposure was associated with forced expiratory volume in one second percent predicted (FEV1pp) and pulmonary exacerbation rate, while controlling for fixed and time-varying confounders. We conducted sensitivity analyses on individuals with persistent Aspergillus and without concomitant allergic bronchopulmonary aspergillosis (ABPA). A total of 14,754 individuals with Aspergillus positive cultures between 2006 and 2019 were identified. Antifungals were prescribed to 3,575 (24.2%) unique PwCF during the study period. Antifungal use was not associated with FEV1pp (adjusted estimate -0.96 percentage points, 95% CI -2.21,0.29). Antifungal use was associated with 29% increased rate of pulmonary exacerbations requiring intravenous (IV) antibiotics (adjusted IRR=1.29, 95% CI 1.22, 1.37). In sensitivity analyses limited to individuals without ABPA< antifungals were associated with 1.88 lower FEV1pp (95% CI -3.35, -0.41) and an increased rate of pulmonary exacerbations (adjusted IRR= 1.30, 95% CI 1.21,1.40). Whereas, in patients with persistent Aspergillus and persistent Aspergillus without concomitant ABPA, antifungals were not associated with FEV1pp. Antifungal therapy in PwCF and Aspergillus positive cultures was not associated with improvements in FEV>1pp. While antifungal therapy was associated with increased risk for pulmonary exacerbations, this could reflect confounding by severity of disease. Randomized clinical trials examining the clinical efficacy of antifungals in Aspergillus infections are warranted.

Long-Term Clinical Efficacy of Elexacaftor-Tezacaftor-Ivacaftor in People With Cystic Fibrosis and Preexisting Advanced Lung Disease at Treatment Initiation

BackgroundElexacaftor-tezacaftor-ivacaftor (ETI) is associated with increased forced expiratory volume in the first second (FEV1), decreased exacerbation frequency, and increased body mass index (BMI) in people with Cystic Fibrosis (pwCF) [1, 2]. Landmark clinical trials excluded patients with advanced lung disease (ALD) as defined by FEV1<40%. We have previously reported an improvement in ppFEV1 of 7.9% after 3 months of ETI in people with CF and ALD (ACFLD)[3]. The long-term effects of ETI on this cohort are unknown. This study reports the efficacy of ETI following 24 months of treatment in people with ACFLD. Study DesignWe conducted a retrospective cohort study of adult patients with FEV1<40% and/or other high-risk features defined by the 2019 CFF lung transplant guidelines who were started on ETI between September 2019 and February 2020. Response to therapy was assessed with repeat spirometry measured at 12 and 24 months. All measurements were taken outside of an acute exacerbation. Demographics and clinical data including BMI and pulmonary exacerbation frequency were extracted from the medical record. Results57 of 64 people with ACFLD showed improved lung function with a mean change in ppFEV1 of 6.74% (p = <0.001, 95% CI 4.25 – 9.23%) between baseline and 24 months of treatment. BMI increased by a mean change of 1.55 kg/m2 (p = <0.001, 95% CI 0.93 – 2.18 kg/m2) during this interval. The annual exacerbation rate between the year before ETI and 24 months on ETI declined with a median of 1 fewer per year (p = 0.0007). InterpretationPeople with ACFLD experienced a significant increase in lung function at 24 months on ETI, although less than those with higher baseline lung function compared to prior studies [1, 2]. They also had an increase in BMI and a decline in the rate of annual pulmonary exacerbations.

Sex Differences After Treatment With Ivacaftor in People With Cystic Fibrosis

Historically, studies show that females with cystic fibrosis (CF) have worse pulmonary outcomes than males, including decreased life expectancy. It is unknown whether this disparity persists in the new era of highly effective modulator therapies (HEMTs). Ivacaftor has been available in the United States for over ten years, allowing for the opportunity to understand the impact this therapy may have on sex disparities in CF. We hypothesize that females will continue to have worse outcomes as we suspect the disparity is not solely driven by ion channel dysfunction. Does a male female difference in outcomes persist after the initiation of ivacaftor in people with CF? We conducted a retrospective cohort study using the CF Foundation Patient Registry (CFFPR) comparing changes in pulmonary exacerbation rate, lung function (ppFEV1), and presence of Pseudomonas aeruginosa among males versus females pre- and post- initiation of treatment with the highly effective modulator, ivacaftor. Our cohort consisted of 1900 people with CF who were treated with ivacaftor between 2010-2017; 928 (48.84%) were male and 972 (51.16%) were female with a mean age of 33.09 years. Males had a significant decrease in pulmonary exacerbations post-ivacaftor (0.38 to 0.34, adjusted rate ratio of 0.89, p = 0.028) while females did not (0.48 to 0.45, adjusted rate ratio 0.95, p = 0.174). ppFEV1 similarly decreased in both males and females pre- vs post-ivacaftor. P. aeruginosa prevalence decreased to a similar extent in both males and females post-ivacaftor. Our findings demonstrate that sex disparities in CF persist in those treated with ivacaftor due to differences in pulmonary exacerbations. More research is needed to determine the specific pathophysiologic drivers of this disparity.

Biomarkers associated with pulmonary exacerbations in a randomized trial of nintedanib for radiation pneumonitis

Background and purposeRadiation pneumonitis (RP) is a common side effect of thoracic radiotherapy and often has a long course characterized by acute exacerbations and progression to permanent lung fibrosis. There are no validated biomarkers of prognosis in patients diagnosed with RP. Materials and methodsWe analyzed a time course of serum chemokines, cytokines, and other proteins from patients with grade 2+ RP in a randomized clinical trial of a steroid taper plus nintedanib, a multiple tyrosine kinase inhibitor, versus placebo plus a steroid taper for the treatment of RP. Weighted gene correlation network analysis (WGCNA) and univariable zero inflated Poisson models were used to identify groups of correlated analytes and their associations with clinical outcomes. ResultsThirty enrolled patients had biomarker data available, and 17 patients had enough analytes tested for network analysis. WGNCA identified ten analytes, including transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), and platelet-derived growth factor (PDGF), that in aggregate were correlated with the occurrence of pulmonary exacerbations (p = 0.008), the total number of acute pulmonary exacerbations (p = 0.002), and treatment arm (p = 0.036). By univariable analysis, an increase in rate of change of two components of the RP module were associated with an increased incidence rate of pulmonary exacerbations: interleukin 5 (IL-5, incidence rate ratio (IRR) 1.02, 95% CI 1.01–1.04, p = 0.002), and tumor necrosis factor superfamily 12 (TNFSF12, IRR 1.06, CI 1–1.11, p = 0.036). An increased slope of epidermal growth factor (EGF) was associated with a decreased incidence rate of exacerbations (IRR 0.94, CI 0.89–1, p = 0.036). ConclusionWe identified a panel of serum biomarkers that showed association with nintedanib treatment and acute pulmonary exacerbations in patients with RP. A confirmatory study will be needed to validate this panel for use as a prognostic tool in patients with RP.

Clinical outcomes of functional endoscopic sinus surgery in cystic fibrosis patients - a single centre experience.

Endoscopic sinus surgery (ESS) is an established surgical option for cystic fibrosis (CF) patients with chronic rhinosinusitis that is refractory to conventional medical management. Objective and subjective evidence of benefit of ESS in this cohort of patients is currently conflicting in the literature. A single center retrospective study was undertaken of all CF patients (transplanted and non-transplanted) over the age of 16 who underwent an ESS over a six-year period from 2015 to 2021. Patients on triple-therapy CFTR modulators were excluded. Data was collected on demographics, clinical management, and outcome measures. The objective outcome measures were lung function (%predicted FEV1), pulmonary exacerbations (total number of days of IV antibiotics- both ambulatory and in hospital). The subjective outcome measure was SNOT-22 scores pre and 6 months post-operatively. A minimally clinical important difference (MCID) in SNOT-22 scores of 9 points was used. 55 patients were included in our study, with a median age of 31 and 53% females. Median Lund-Mackay scores for the cohort was 13 (3-24). There was a significant improvement in lung function at 1-year post-surgery, and a significant MCID reduction in SNOT-22 scores at 6 months post-surgery across the cohort. Sub-group analysis revealed a sustained MCID reduction in SNOT-22 scores in both lung-transplanted and native lung groups, and in patients with primary ESS or previous ESS. However, there was no post-operative pulmonary function improvement in lung transplanted patients and patients with previous ESS. There was no impact on the rate of pulmonary exacerbations across the cohort. 2 patients in the cohort died secondary to pulmonary disease. There was a demonstrated clinical and symptomatic benefit of ESS in CF patients in this study. Stricter guidelines for indications for ESS need to be established with regards to CF patients who will undergo ESS in the future.

Cystic Fibrosis Transmembrane Regulator Modulator Therapy Perspective: Findings in Clinical Outcomes in a Series of Pediatric Patients

Cystic Fibrosis (CF) is the most frequent autosomal recessive disorder in Caucasians and has reduced life expectancy. It is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene which results in impairment of production, expression, and trafficking of the CFTR protein. CF has a multifaceted clinical representation with respiratory involvement as a main cause of morbidity and mortality. The multidisciplinary approach, care in specialized centers, early diagnosis through neonatal screening, and development of symptomatic treatments improved survival in the last decades. CFTR modulators were developed based on the discovery of the CF gene in 1989 and the improvement of genetic testing and have changed the perspective of a debilitating disease. These therapies, acting more upstream in the pathogenic cascade, overcome the underlying dysfunctions caused by CFTR mutations, having the ability to enhance or restore the resulting functional effects. CFTR modulator therapies are highly effective treatments for cystic fibrosis patients as shown in many clinical trials and real-life analyses so far. Improvement of quality of life, lung function, and pulmonary exacerbation rates are indisputable targets when evaluating the efficacy and efficiency of medical interventions in such a disease as CF, and they have been substantially changed in the era of modulators. We analyzed a small group of patients who were initiated on Kaftrio as per the indicated protocol. All significant clinical and functional aspects were improved, demonstrating the disease-changing potential of this therapy. We did not observe threatening side effects, no patients were stopped from the medication. CFTR modulators are the beginning of a new era in CF, a perspective for the improvement and effectiveness of precision medicine in CF patients.

Impact of lumacaftor/ivacaftor on the bacterial and fungal respiratory pathogens in cystic fibrosis: a prospective multicenter cohort study in Sweden.

A significant decline in pulmonary exacerbation rates has been reported in CF patients homozygous for F508del treated with lumacaftor/ivacaftor. However, it is still unclear whether this reduction reflects a diminished microbiological burden. The aim of this study was to determine the impact of lumacaftor/ivacaftor on the bacterial and fungal burden. The study is a prospective multicenter cohort study including 132 CF patients homozygous for F508del treated with lumacaftor/ivacaftor. Clinical parameters as well as bacterial and fungal outcomes 1 year after initiation of lumacaftor/ivacaftor were compared to data from 2 years prior to initiation of the treatment. Changes in the slope of the outcomes before and after the onset of treatment were assessed. Lung function measured as ppFEV1 (p < 0.001), body mass index (BMI) in adults (p < 0.001), and BMI z-score in children (p = 0.007) were improved after initiation of lumacaftor/ivacaftor. In addition, the slope of the prevalence of Streptococcus pneumoniae (p = 0.007) and Stenotrophomonas maltophilia (p < 0.001) shifted from positive to negative, that is, became less prevalent, 1 year after treatment, while the slope for Candida albicans (p = 0.009), Penicillium spp (p = 0.026), and Scedosporium apiospermum (p < 0.001) shifted from negative to positive. The current study showed a significant improvement in clinical parameters and a reduction of some of CF respiratory microorganisms 1 year after starting with lumacaftor/ivacaftor. However, no significant changes were observed for Pseudomonas aeruginosa, Staphylococcus aureus, or Aspergillus fumigatus, key pathogens in the CF context.

Long-term clinical outcomes of elexacaftor/tezacaftor/ivacaftor therapy in adults with cystic fibrosis and advanced pulmonary disease

BackgroundThe combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators elexacaftor, tezacaftor and ivacaftor (ELX/TEZ/IVA) has been approved for treatment of cystic fibrosis (CF) patients (pwCF) homozygous and heterozygous for Phe508del. We aim to assess the long-term effects of ELX/TEZ/IVA therapy on clinical outcomes in severe pwCF. MethodsLung function, pulmonary exacerbation (PEx), sweat chloride concentration, body mass index (BMI) and the respiratory domain of the cystic fibrosis questionnaire-revised (CFQ-R RD) were prospectively evaluated in a cohort of pwCF who were candidates for inclusion in a compassionate program of ELX/TEZ/IVA therapy. All procedures were performed at baseline and then at 12 and 24 months after initiation of modulator therapy. The number of PExs in the year before the study enrollment was collected from our records. ResultsThirty-six adult pwCF (median age 36.7 years; BMI 19.8 kg/m2; FEV1 36.5% predicted) were recruited from 2019. At 12 and 24 months after initiation, the absolute change in ppFEV1 (percent predicted forced expiratory volume in 1 s) from baseline was +12.5% (p < 0.0001) and +13% (p < 0.0001), respectively. A median of 4.0 exacerbations per patient was reported in the preceding year, while the median number of PExs was 0.0 and 1.0 after 12 and 24 months, respectively, of modulator therapy (both p < 0.0001). After 12 and 24 months of ELX/TEZ/IVA therapy, the CFQ-R RD score improved by 22.4 points (p < 0.0001) and 16.7 points (p < 0.0001), and sweat chloride levels decreased by 65.5 mmol/L (p < 0.0001) and 60 mmol/L (p < 0.0001), respectively. BMI significantly increased. ConclusionsLong-term ELX/TEZ/IVA combination therapy markedly impacts the clinical status of patients with severe CF, showing a sustained improvement in lung function and PEx rate.

The effect of elexacaftor/tezacaftor/ivacaftor on non-pulmonary symptoms in adults with cystic fibrosis

BackgroundElexacaftor/Tezacaftor/Ivacaftor (ETI) is a CFTR modulator that has led to large benefits in lung function, pulmonary exacerbation rates, and respiratory symptoms. Less is known about the effect of ETI on non-pulmonary symptoms. The objective of this study was to examine the changes in patient reported outcomes after starting ETI in multiple non-pulmonary symptoms. MethodsThis was a prospective cohort study of adults with CF. Participants completed questionnaires prior to starting ETI and then at weeks 2, 4, 6, 8, 10, 12, and 14 after starting ETI. They completed the following validated instruments: PROMIS Pain Intensity, PROMIS Pain Interference, FACIT Fatigue, SNOT22, PAC-SYM, PHQ8, GAD7 and Pittsburgh Sleep Quality Index. Longitudinal changes for outcomes were modelled using linear regression based on general estimating equations. Results22 participants enrolled who answered questionnaires before and after starting ETI. The median age was 35.3 years (IQR 11.1) and 13 (59.1%) were male. In models adjusted for age, sex, and baseline value there were significant improvements in pain interference (β = −2.57; 95% CI -4.92, −0.23), sinus symptoms (β = −4.50; 95% CI -7.59, −1.41), and sleep disturbance (β = −1.90; 95% CI -2.71, −1.09) over 14 weeks after starting ETI. No symptom areas worsened over the study period. ConclusionsIn this prospective study we found statistically significant improvements in three different non-pulmonary symptom areas in people with CF started on ETI. While this was a small, uncontrolled study it suggests that use of highly effective CFTR modulators can result in benefits for patients beyond pulmonary symptoms.

Evaluation of a pharmacist‐led smoking cessation service in a pulmonary clinic

AbstractIntroductionStudies have demonstrated the positive effect that pharmacist‐led smoking cessation services have on smoking cessation rates, but data regarding pharmacists' impact on smoking cessation in a pulmonary clinic are lacking.ObjectivesTo evaluate the effect of pharmacist‐led smoking cessation visits compared with routine smoking cessation counseling performed by other pulmonary practitioners on smoking cessation rates and outcomes in a population with significant pulmonary disease.MethodsThis was a single center, retrospective, observational cohort study comparing patients who were solely counseled on smoking cessation by a practitioner during their pulmonary clinic appointment to patients who received smoking cessation services from a pharmacist. The primary outcome was a comparison of the percentage of patients who self‐reported cessation at 1, 6, and at 12 months from their initial visit between both cohorts. Other outcomes included the rate of relapse, rate of asthma and chronic obstructive pulmonary disease exacerbations, and time spent counseling patients. Continuous variables were analyzed with an independent samples t‐test or Mann–Whitney U‐test as appropriate. Pearson's chi‐square or Fisher's exact test was used to analyze categorical data.ResultsIn total, 149 patients counseled by a pharmacist met the inclusion criteria for the study. A matched cohort of 88 practitioner‐managed patients was used for comparison. Patients managed by the pharmacist achieved higher cessation rates at 1 and 6 months compared with those managed by practitioners, though results were not statistically significant. Patients managed by the pharmacist had significantly higher quit rates at 12 months compared with those managed by practitioners, with 21 patients (14.1%) quitting in the pharmacist‐managed group versus 5 patients (5.7%) in the practitioner‐managed group (p = 0.045).ConclusionPatients with significant pulmonary disease had higher rates of smoking cessation at 12 months when managed by a pharmacist compared with routine counseling provided during practitioner‐led visits.

Digital technology for delivering and monitoring exercise programs for people with cystic fibrosis.

Digital technology for delivering and monitoring exercise programs for people with cystic fibrosis.

Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor inChildren Aged ⩾6 Years with Cystic Fibrosis and at Least One F508del Allele: A Phase 3, Open-Label Clinical Trial.

Rationale: A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6-11 years with cystic fibrosis (CF) and one or more F508del-CFTR alleles. Objectives: To assess long-term safety and efficacy of ELX/TEZ/IVA in children who completed the pivotal 24-week phase 3 trial. Methods: In this phase 3, two-part (part A and part B), open-label extension study, children aged ⩾6 years with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes) or homozygous for F508del (F/F genotype) who completed the 24-week parent study received ELX/TEZ/IVA based on weight. Children weighing <30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, whereas children weighing ⩾30 kg received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose). The 96-week analysis of part A of this extension study is reported here. Measurements and Main Results: Sixty-four children (F/MF genotypes, n = 36; F/F genotype, n = 28) were enrolled and received one or more doses of ELX/TEZ/IVA. Mean (SD) period of exposure to ELX/TEZ/IVA was 93.9 (11.1) weeks. The primary endpoint was safety and tolerability. Adverse events and serious adverse events were consistent with common manifestations of CF disease. Overall, exposure-adjusted rates of adverse events andserious adverse events (407.74 and 4.72 events per 100 patient-years) were lower than in the parent study (987.04and8.68 events per 100 patient-years). One child (1.6%) had an adverse event of aggression that was moderate in severity and resolved after study drug discontinuation. From parent study baseline at Week 96 of this extension study, the mean percent predicted FEV1 increased (11.2[95% confidence interval (CI), 8.3 to 14.2] percentage points), sweat chloride concentration decreased (-62.3 [95% CI, -65.9 to -58.8] mmol/L), Cystic Fibrosis Questionnaire-Revised respiratory domain score increased (13.3 [95% CI, 11.4 to 15.1] points), and lung clearance index 2.5 decreased (-2.00 [95% CI, -2.45 to -1.55] units). Increases in growth parameters were also observed. The estimated pulmonary exacerbation rate per 48 weeks was 0.04. The annualized rate of change in percent predicted FEV1 was 0.51 (95% CI, -0.73 to 1.75) percentage points per year. Conclusions: ELX/TEZ/IVA continued to be generally safe and well tolerated in children aged ⩾6 years through an additional 96 weeks of treatment. Improvements in lung function, respiratory symptoms, and CFTR function observed in the parent study were maintained. These results demonstrate the favorable long-term safety profile and durable clinical benefits of ELX/TEZ/IVA in this pediatric population. Clinical trial registered with www.clinicaltrials.gov (NCT04183790).

Systematic review and meta-analysis: Associations of vitamin D with pulmonary function in children and young people with cystic fibrosis

Increasing evidence suggests that vitamin D is associated with pulmonary health, which may benefit children and young people diagnosed with Cystic Fibrosis (cypCF). Therefore, the aim of this systematic review was to evaluate primary research to establish associations between 25OHD and pulmonary health in cypCF. Electronic databases were searched with keywords related to CF, vitamin D, children/young people and pulmonary function. Included studies were cypCF (aged ≤21 years) treated in a paediatric setting. The primary outcome was lung function [forced expiratory volume in 1s (FEV1% predicted)] and secondary outcomes were rate of pulmonary exacerbations, 25OHD status and growth. Evidence was appraised for risk of bias using the CASP tool, and quality using the EPHPP tool. A Meta-analysis was performed. Twenty-one studies were included with mixed quality ratings and heterogeneity of reported outcomes. The Meta-analysis including 5 studies showed a significantly higher FEV1% predicted in the 25OHD sufficiency compared to the deficiency group [FEV1% predicted mean difference (95% CI) was 7.71 (1.69-13.74) %; p=0.01]. The mean±SD FEV1% predicted for the sufficient (≥75nmol/L) vs. deficient (<50nmol/L) group was 94.7±31.9% vs. 86.9±13.2%; I2=0%; χ2=0.5; df=4). Five studies (5/21) found significantly higher rate of pulmonary exacerbations in those who were 25OHD deficient when compared to the sufficient group and negative associations between 25OHD and FEV% predicted. The effects of vitamin D supplementation dosages on 25OHD status (10/21) varied across studies and no study (12/21) showed associations between 25OHD concentration and growth. This systematic review suggests that 25OHD concentration is positively associated with lung function and a concentration of >75nmol/L is associated with reduced frequency of pulmonary exacerbations, which may slow lung function decline in cypCF. Future randomised clinical trials and mechanistic studies are warranted.

Long-term tezacaftor/ivacaftor safety and efficacy in people with cystic fibrosis and an F508del-CFTR mutation: 96-week, open-label extension of the EXTEND trial

BackgroundStudy 661-110 (EXTEND) is a phase 3, open-label, three-part rollover study designed to assess the long-term safety and efficacy of tezacaftor/ivacaftor (TEZ/IVA) in participants aged ≥12 years homozygous for F508del (F/F) or heterozygous for F508del and a residual function mutation (F/RF). TEZ/IVA was shown to be safe and efficacious for up to 120 weeks in Part A. Here we report results from Part B, which evaluated safety and efficacy for an additional 96 weeks. MethodsPart B enrolled participants aged ≥12 years with CF and F/F or F/RF genotypes who completed TEZ/IVA treatment in either Study 661-110 Part A, Study 661-112 (F/F), or Study 661-114 (F/F). Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination once daily (morning) and IVA 150 mg once daily (evening) for 96 weeks. Safety endpoints included adverse events (AEs) and serum liver function tests. Efficacy endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and pulmonary exacerbation (PEx) rate. Results464 participants were enrolled from Part A (n=377) and other eligible studies (n=87); 463 received ≥1 dose of TEZ/IVA. Overall, 92.2% had ≥1 AE, 0.9% had AEs leading to treatment discontinuation, and 29.4% reported serious AEs. The most common AEs, which were generally consistent with common manifestations of CF, included infective PEx of CF, cough, nasopharyngitis, hemoptysis, and headache. Lung function was maintained over 96 weeks in both genotype groups. PEx rates per year were comparable with Part A. ConclusionsTEZ/IVA was generally safe and well tolerated over a further 96 weeks; safety data were consistent with Part A. Improvements in ppFEV1 and PEx rates were maintained for an additional 96 weeks in Part B.

CFTR Modulators: Current Status and Evolving Knowledge.

In the past decade, the medical management of people with cystic fibrosis (pwCF) has changed with the development of small molecules that partially restore the function of the defective CF transmembrane conductance regulator (CFTR) protein and are called CFTR modulators. Ivacaftor (IVA), a CFTR potentiator with a large effect on epithelial ion transport, was the first modulator approved in pwCF carrying gating mutations. Because IVA was unable to restore sufficient CFTR function in pwCF with other mutations, two CFTR correctors (lumacaftor and tezacaftor) were developed and used in combination with IVA in pwCF homozygous for F508del, the most common CFTR variant. However, LUM/IVA and TEZ/IVA were only moderately effective in F508del homozygous pwCF and had no efficacy in those with F508del and minimal function mutations. Elexacaftor, a second-generation corrector, was thus developed and combined to tezacaftor and ivacaftor (ELX/TEZ/IVA) to target pwCF with at least one F508del variant, corresponding to approximately 85% of pwCF. Both IVA and ELX/TEZ/IVA are considered highly effective modulator therapies (HEMTs) in eligible pwCF and are now approved for nearly 90% of the CF population over 6 years of age. HEMTs are responsible for rapid improvement in respiratory manifestations, including improvement in symptoms and lung function, and reduction in the rate of pulmonary exacerbations. The impact of HEMT on extrapulmonary manifestations of CF is less well established, although significant weight gain and improvement in quality of life have been demonstrated. Recent clinical trials and real-world studies suggest that benefits of HEMT could even prove greater when used earlier in life (i.e., in younger children and infants). This article shortly reviews the past 10 years of development and use of CFTR modulators. Effects of HEMT on extrapulmonary manifestations and on CF demographics are also discussed.

The BATTLE study: Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis. Study protocol of a double blind, randomized, placebo-controlled trial: study protocol

BackgroundPatients with bronchiectasis typically suffer from chronic symptoms such as a productive cough with or without exacerbations leading to hospitalization, causing reduced quality of life (QoL) and mortality. Long-term inhaled antibiotics to treat chronic bronchial infection is registered for use in cystic fibrosis (CF) bronchiectasis. However, in patients with non-CF bronchiectasis data on long-term antibiotics are limited. ObjectiveTo investigate the effectiveness of maintenance tobramycin inhalation solution (TIS) in bronchiectasis patients without cystic fibrosis. Study designThe BATTLE study is a randomized, double blind placebo controlled, multicenter study in the Netherlands performed in patients aged ≥18-year-old with confirmed bronchiectasis, at least two exacerbations in the preceding year, and minimal one positive sputum culture with gram negative pathogens or Staphylococcus aureus, sensitive to tobramycin in the preceding year and at baseline. Patients will be treated with TIS once daily (OD) or placebo (saline 0.9%) OD for 52 weeks followed by a run-out period of 4 weeks after the last dose. The primary outcome is the yearly rate of pulmonary exacerbations. Among secondary outcome parameters are time to exacerbation, lung function, QoL, microbiological evaluation and safety. DiscussionThe BATTLE study is designed to determine the efficacy and safety of maintenance TIS OD in bronchiectasis patients colonized by different pathogens and could lead to important new evidence for TIS therapy in this population.The BATTLE study is registered in Clinical trials.gov with registration number: NCT02657473.

Treatment effects of Elexacaftor/Tezacaftor/Ivacaftor in people with CF carrying non-F508del mutations

BackgroundIn vitro studies have demonstrated rescue of CFTR function with Elexacaftor/Tezacaftor/Ivacaftor (ETI) in several mutations other than F508del. However, clinical efficacy was not tested in vivo in people with CF (pwCF) carrying mutations other than F508del. We report effects of treatment with ETI in pwCF with non-F508del mutations. MethodsWe retrospectively analyzed pwCF with non-F508del mutations who received treatment with ETI. We evaluated sweat chloride, nutritional status, spirometry, antibiotic treatment, and pulmonary exacerbations (PEx), at baseline and 3-6 months after commencing treatment with ETI. ResultsWe included 16 pwCF, including eight without previous use of CFTR modulators. Median time on treatment was 5.3 (range, 1.8-7.7) months. Compared to baseline, in the “naïve” group sweat chloride concentration was reduced from 113.0 (98-129) to 64.0 (32-97) mEq/L (n=7; median (IQR), p=0.018), and rate of pulmonary exacerbations declined from a median of 1.5 (IQR 1, 2.75) in the previous year to 0 (0,0) (p= 0.019) with a significant decline in annualized days with antibiotics (oral + parenteral) per year: 36 (17.5; 42) in the year before to 0 (0,0) (median (IQR), p= 0.027). Mean FEV1% changed from 66.3±25 to 72.4±29 % (mean ± SD, p=0.058). In the group of patients previously treated with Ivacaftor or Tezacaftor/Ivacaftor, we didn't observe significant improvements in any of the parameters. ConclusionsWe demonstrate the clinical efficacy of ETI in pwCF carrying CFTR processing non-F508del mutations which are predicted to respond by in vitro studies. Our results support routine clinical use of ETI in this patient group.

Impact of COVID-19 on Lung Disease in People with Cystic Fibrosis: A 6-Month Follow-Up Study on Respiratory Outcomes.

The impact of COVID-19 on respiratory outcomes in people with cystic fibrosis (pwCF) has not been clearly characterized. We evaluated changes in respiratory function indicators derived from spirometry and pulmonary exacerbation rates 6 months after SARS-CoV-2 infection. This multicentre prospective study was based on pwCF enrolled between October, 2020 and June, 2021 in the DECO COVID-19 project. PwCF complaining of COVID-like symptoms were tested with real-time polymerase chain reaction (RT-PCR) for SARS-CoV-2 on nasopharyngeal swab. Mean changes in respiratory function indicators and time to first episode of pulmonary exacerbation were compared in RT-PCR-positive and RT-PCR-negative patients. Regression models were used to adjust for baseline percent predicted forced expiratory volume in one second (ppFEV1) values, number of comorbidities, and initiation of CFTR modulator therapy during the follow-up. We enrolled 26 pwCF with RT-PCR-confirmed infection and 42 with a RT-PCR-negative test. After 6 months of follow-up, mean ppFEV1 changes were not significantly different between groups (+0.3% in positive vs. +0.2% in negative patients, p = 0.19). The 6-month cumulative probabilities of a first episode of pulmonary exacerbation were: 0.425 among RT-PCR-negative patients and 0.465 among those with a positive test (adjusted hazard ratio: 0.88, 95% CI: 0.44-1.75). COVID-19 did not appear to negatively influence respiratory outcomes of pwCF at 6 months from infection.

Social determinants of health screening and intervention: A cystic fibrosis quality improvement process.

Lower socioeconomic status is associated with significantly poorer outcomes in weight, lung function, and pulmonary exacerbation rates in people with cystic fibrosis(PwCF). We aim to reduce health disparities and inequities faced by PwCF by screening for and addressing unmet social needs. We aimed to increase routine social determinants of health (SDoH) screening of eligible PwCF from 0% to 95% and follow-up within 2 weeks for those PwCF who screened positive and requested assistance from 0% to 95% by December 31, 2021. The Model for Improvement methodology was used. A process map and a simplified failure mode effects analysis chart were created for the screening and SDoH follow-up process. For those who screened positive for SDoH and requested assistance, follow-up contact was made to offer intervention. Adult PwCF who had at least oneUVAClinic encounter in 2021 were screened for SDoH. The SDoH screening tool included eight domains: housing, food, transportation, utilities, health-care access, medication access, income/employment, and education. Follow-up was completed with all PwCF who screened positive for SDoH. A total of 132 of 142(93.0%) PwCF eligible for screening completed the SDoH screening. Of the PwCF who completed screening, 56 (42.4%) screened positive for SDoH. A follow-up rate of 100% was achieved in June 2021 and maintained through December 2021. Implementing screening for SDOH and follow-up to mitigate social difficulties in adult PwCF at UVA was successful and could be reproduced at other CF care centers.

Daily versus three-times-weekly azithromycin in Chinese patients with non-cystic fibrosis bronchiectasis: protocol for a prospective, open-label and randomised controlled trial

IntroductionNon-cystic fibrosis bronchiectasis (NCFB) brought a heavy healthcare burden worldwide. Macrolide maintenance therapy was proved to be helpful in reducing exacerbation of NCFB. However, the optimal dosing regimens of macrolides...