A randomised trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment.

BACKGROUND: Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1 s (FEV1) % pred in CF pulmonary exacerbations not responding to antibiotic therapy. METHODS: This was a randomised, double-blind, placebo-controlled trial in pwCF treated with intravenous antibiotics for a pulmonary exacerbation. At day 7, those who had not returned to >90% baseline FEV1 % pred were randomised to adjuvant prednisone 1 mg·kg-1 twice daily (maximum 60 mg·day-1) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline FEV1 % pred at day 14 of i.v. antibiotic therapy. RESULTS: 173 subjects were enrolled, with 76 randomised. 50% of subjects in the prednisone group recovered baseline FEV1 on day 14 compared with 39% of subjects in the placebo group (difference of 11%, 95% CI -11-34%; p=0.34). The mean±sd change in FEV1 % pred from day 7 to day 14 was 6.8±8.8% predicted in the prednisone group and 4.6±6.9% predicted in the placebo group (mean difference 2.2% predicted, 95% CI -1.5-5.9%; p=0.24). Time to subsequent exacerbation was not prolonged in prednisone-treated subjects (hazard ratio 0.83, 95% CI 0.45-1.53; p=0.54). CONCLUSIONS: This study failed to detect a difference in FEV1 % pred recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of i.v. antibiotic therapy for pulmonary exacerbations.

Outcomes Following Surgical Lung Biopsy for Interstitial Lung Diseases: A Monocenter Experience.

BACKGROUND: Surgical lung biopsy (SLB) is considered in the investigation of interstitial lung diseases (ILDs) when a complete clinical evaluation and a multidisciplinary discussion (MDD) do not allow the clinician to make a confident diagnosis. Owing to the risk of the procedure, an appropriate assessment of the risk/benefit ratio prior to the intervention is recommended. We aimed to assess the postoperative outcomes and diagnostic yield of SLB for the investigation of ILD in a tertiary care institution. METHODS: We conducted a retrospective cohort study of consecutive subjects who underwent a SLB for the investigation of ILD in our center from 2009 to 2020. The postoperative mortality and complications rates as well as the diagnostic yield of the procedure were assessed. RESULTS: Of the 1,805 patients newly investigated for ILD in our center from 2009 to 2020, 71 (3.93%) underwent a SLB. At days 30 and 90, the mortality rates were 0 and 2.8%, whereas 4.3 and 7.6% patients experienced an acute ILD exacerbation, respectively. In addition, 4 (5.8%) patients experienced infectious complications and 5 (7.0%) presented prolonged air leaks (all within 30 days). A definite pathological diagnosis was made in 47 (66.2%) patients. Following postoperative MDD, a confident diagnosis was made in 61 patients (85.9%) and resulted in a change of therapy in 49 (69.0%) patients. CONCLUSION: SLB for the diagnosis of unclassifiable ILDs is associated with low mortality but significant morbidity. However, it results in a confident diagnosis and a change in therapy in the majority of patients.

Cystic fibrosis-related diabetes onset can be predicted using biomarkers measured at birth.

PURPOSE: Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. METHODS: Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. RESULTS: The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. CONCLUSION: We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

Asthma-COPD Overlap Phenotypes and Smoking :Comparative features of asthma in smoking or non-smoking patients with an incomplete reversibility of airway obstruction.

The development of COPD features, such as an incomplete reversibility of airway obstruction (IRAO), in smoking or non-smoking asthmatic patients, a condition often named Asthma-COPD Overlap (ACO), has been recognized for decades. However, there is a need to know more about the sub-phenotypes of this condition according to smoking. This study aimed at comparing the clinical, physiological and inflammatory features of smoking and non-smoking asthmatic patients exhibiting IRAO. In this cross-sectional study, patients with an IRAO with (ACO, ≥20 pack-years) or without (NS-IRAO, <5 pack-years) significant smoking history completed questionnaires about asthma control (ACQ, score 0-6, 6 = better score) and quality of life (AQLQ, score 1-7, 1 = better score) and performed expiratory flows, lung volume and carbon monoxide diffusion capacity measurements. Blood sampling and induced sputum were obtained for systemic and lower airway inflammation assessment. A total of 115 asthmatic patients were included (75 ACO: age 61 ± 10 years, 60% women and 40 NS-IRAO: age 64 ± 9 years, 38% women). ACO patients had worse asthma control scores (1.8 ± 0.9 vs 1.4 ± 0.9, P = 0.02) and poorer asthma quality of life (5.3 ± 1.0 vs 5.9 ± 1.0, P = 0.003). In addition, ACO had higher residual volume (145 ± 45 vs 121 ± 29% predicted, P = 0.008) and a lower carbon monoxide diffusing capacity corrected for alveolar volume (90 ± 22 vs 108 ± 20% predicted, P = 0.0008). No significant differences were observed in systemic or lower airway inflammation. In conclusion, in smokers and non-smokers, the presence of IRAO in asthmatics is associated with different phenotypes that reflect the addition of smoking-induced changes to asthma physiopathology.

Efficacy and safety of LAU-7b in a Phase 2 trial in adults with cystic fibrosis.

BACKGROUND: Lung inflammation is associated with tissue damage in cystic fibrosis (CF). LAU-7b, a novel oral drug candidate, was shown to control inflammation and stabilize CFTR protein in the epithelial membrane during inflammatory stress in preclinical models of CF. METHODS: A double-blind, randomized, placebo-controlled Phase 2 study was conducted to evaluate efficacy and safety of LAU-7b in adults with CF. LAU-7b or placebo was administered over 24 weeks as six 21-day treatment cycles each separated by 7 days. The primary efficacy endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) at 24 weeks. RESULTS: A total of 166 subjects received at least one dose of study drug (Intent-To-Treat population, ITT), of which 122 received ≥5 treatment cycles (Per-Protocol population, PP). Both treatment arms showed a mean lung function loss at 24 weeks of 1.18 ppFEV1 points with LAU-7b and 1.95 ppFEV1 with placebo, a 0.77 ppFEV1 (40 s) difference, p=0.345, and a 0.95 ppFEV1 (49 %) difference in the same direction in PP population, p=0.263. Primary analysis of mean ppFEV1 through 24 weeks showed differences of 1.01 and 1.23 ppFEV1, in the ITT (65 % less loss, p=0.067) and PP populations (78 % less loss, reaching statistical significance p=0.049), respectively. LAU-7b had an acceptable safety profile. CONCLUSION: Although the study did not meet its primary efficacy endpoint in the ITT population, LAU-7b was generally well tolerated and showed evidence of preservation of lung function to support further development.

Automated O2 Titration Alone or With High-Flow Nasal Cannula During Walking Exercise in Chronic Lung Diseases.

BACKGROUND: Exercise-induced O2 desaturation contributes to dyspnea and exercise intolerance in various respiratory diseases. This study assessed whether automated O2 titration was superior to fixed-flow O2 to improve exertional dyspnea and walking exercise endurance. We also aimed at evaluating possible additive effects of high-flow nasal cannula coupled with automated O2 titration on these outcomes. METHODS: Subjects with chronic respiratory diseases and exercise-induced desaturation performed a 3-min constant-speed shuttle test (CSST) and an endurance shuttle walking test (ESWT) with either (1) fixed-flow O2, (2) automated O2 titration targeting an SpO2 of 94% (± 2%), and (3) automated O2 titration + high-flow nasal cannula according to a randomized sequence. The main outcome was Borg dyspnea score at the end of the 3-min CSST. Secondary outcomes included endurance time and dyspnea during ESWT and oxygenation status during exercise. RESULTS: Ten subjects with COPD, 10 with interstitial lung disease, 5 with pulmonary hypertension, and 3 with cystic fibrosis completed the study. Compared to fixed-flow O2, automated O2 titration did not reduce dyspnea at the end of the 3-min CSST. Endurance time during the ESWT was prolonged with automated O2 titration (mean difference 298 [95% CI 205-391] s, P < .001), and dyspnea at isotime was reduced. No further improvement was noted when high-flow nasal cannula was added to automated O2 titration. Compared to fixed-flow O2, O2 flows were higher with automated O2 titration, resulting in better oxygenation. CONCLUSIONS: Automated O2 titration was superior to fixed-flow O2 to alleviate dyspnea and improve exercise endurance during the ESWT in subjects with a variety of chronic respiratory diseases. Adding high-flow nasal cannula to automated O2 titration provided no further benefits.

Association of low-density neutrophils with lung function and disease progression in adult cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) neutrophils fail to eradicate infection despite their massive recruitment into the lung. While studies mostly focus on pathogen clearance by normal density neutrophils in CF, the contribution of low-density neutrophil (LDNs) subpopulations to disease pathogenesis remains unclear. METHODS: LDNs were isolated from whole blood donations of clinically stable adult CF patients and from healthy donors. LDN proportion and immunophenotype was assessed by flow cytometry. Associations of LDNs with clinical parameters were determined. RESULTS: LDN proportion was increased in CF patients' circulation compared with healthy donors. LDNs are a heterogeneous population of both mature and immature cells in CF and in healthy individuals. Moreover, a higher proportion of mature LDN correlates with a gradual decline in lung function and repeated pulmonary exacerbations in CF patients. CONCLUSIONS: Collectively, our observations suggest that low-density neutrophils are linked to CF pathogenesis and underscore the potential clinical relevance of neutrophil subpopulations in CF.

Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease.

Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10-44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants.

Trikafta, a triple-combination drug, consisting of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor) and the gating potentiator VX-770 (ivacaftor) provided unprecedented clinical benefits for patients with the most common cystic fibrosis (CF) mutation, F508del. Trikafta indications were recently expanded to additional 177 mutations in the CF transmembrane conductance regulator (CFTR). To minimize life-long pharmacological and financial burden of drug administration, if possible, we determined the necessary and sufficient modulator combination that can achieve maximal benefit in preclinical setting for selected mutants. To this end, the biochemical and functional rescue of single corrector-responsive rare mutants were investigated in a bronchial epithelial cell line and patient-derived human primary nasal epithelia (HNE), respectively. The plasma membrane density of P67L-, L206W- or S549R-CFTR corrected by VX-661 or other type I correctors was moderately increased by VX-445. Short-circuit current measurements of HNE, however, uncovered that correction comparable to Trikafta was achieved for S549R-CFTR by VX-661 + VX-770 and for P67L- and L206W-CFTR by the VX-661 + VX-445 combination. Thus, introduction of a third modulator may not provide additional benefit for patients with a subset of rare CFTR missense mutations. These results also underscore that HNE, as a precision medicine model, enable the optimization of mutation-specific modulator combinations to maximize their efficacy and minimize life-long drug exposure of CF patients.

Comparative clinical and airway inflammatory features of asthmatics with or without polyps.

BACKGROUND: Nasal polyposis (NP) is associated with a more severe and steroid-resistant asthma. OBJECTIVE: To compare clinical and airway inflammatory features of asthmatics with or without NP. METHODS: Two groups of asthmatic patients were studied: group 1; n=39, with NP; group 2; n=40, without NP. Asthma control was assessed according to the Asthma Control Scoring System (ACSS). Expiratory flows, induced sputum, and blood eosinophils were also measured. RESULTS: ACSS score was lower (poorer control) in group 1 (meanA+-SEM = 73A+-3%) compared with group 2 (82A+-2%, p=0.01). FEV1 (mean of predicted value A+- SEM) was 81A+-3 for group 1 and 96A+-3 for group 2 (p=0.001), and the FEV1/FVC ratio was lower in group 1 (70A+-2%) compared with group 2 (76A+-1%, p=0.01). Blood and induced sputum eosinophils, as well as fibronectin and eosinophil cationic protein levels, were higher in group 1. CONCLUSION: Asthmatic subjects with NP have increased airway obstruction, increased inflammatory cells and reduced asthma control compared to those without NP. This may suggest a contribution of nasal polyps to the severity of asthma or a common susceptibility to develop upper and lower airways mucosal inflammation.

Longitudinal comparison of outcomes in patients with smoking-related asthma-COPD overlap and in non-smoking asthmatics with incomplete reversibility of airway obstruction.

BACKGROUND: There is a need to characterize the impact of the smoking status on the clinical course of asthmatics with incomplete reversibility of airway obstruction (IRAO). OBJECTIVE: To compare longitudinal health care use, symptom control, and medication needs between smoking and non-smoking asthmatics with IRAO. MATERIALS AND METHODS: This was a 12-month follow-up of a cross-sectional study comparing asthmatics with IRAO according to their tobacco exposure. One group had a tobacco exposure ≥20 pack-years and was considered to have asthma-COPD overlap (ACO) and the second with a past tobacco exposure <5 pack-years was considered as non-smokers with IRAO (NS-IRAO). Study participants were contacted by telephone every 3 months to document exacerbation events and symptom control. RESULTS: A total of 111 patients completed all follow-up telephone calls: 71 ACO and 40 NS-IRAO. The number of exacerbations per patient over the 12-month follow-up was similar in both groups. However, ACO reported worse symptom control throughout the follow-up as compared to NS-IRAO, although no significant variations within a group were observed over the study period. CONCLUSION: Although asthma control scores were poorer in ACO patients over 1 year compared to NS-IRAO, exacerbation rate was similar and low in both groups of asthmatics. These observations suggest that poorer asthma control in ACO was not driven by the number of exacerbations but may reflect the influence of chronic airway changes related to the COPD component.

Comparative prevalence of co-morbidities in smoking and non-smoking asthma patients with incomplete reversibility of airway obstruction, non-smoking asthma patients with complete reversibility of airway obstruction and COPD patients.

BACKGROUND: Asthma with incomplete reversibility of airway obstruction (IRAO) may often be associated to smoking-induced changes. Nevertheless, a high proportion of patients showing IRAO have never smoked. These patients with IRAO often share features of patients with chronic obstructive pulmonary disease (COPD). Although IRAO is still a poorly defined condition, it has been associated with a higher morbidity and mortality than asthma with complete reversibility of airway obstruction (CRAO) or even COPD alone. A high prevalence of comorbidities could contribute to the reported poorer clinical outcome in IRAO, in comparison to CRAO or COPD alone. AIM: To determine the prevalence of past and current comorbidities in IRAO patients compared to patients with CRAO or COPD. METHODS: This was a retrospective, cross-sectional study. Demographic data, clinical characteristics and 36 predetermined comorbidities documented from self-report and chart review, were recorded from smoking-associated IRAO (S-IRAO), non-smoking IRAO (NS-IRAO), CRAO and COPD patients. RESULTS: A total of 199 patients were included in the final analysis (111F/88M, mean (±SD) age of 63 ± 10 years). The CRAO group had more comorbidities than the three other groups, but this difference was significant only with the NS-IRAO group (P = 0.04). For most comorbidities, the prevalence of comorbidities in both IRAO sub-groups was intermediate between CRAO and COPD, with significant differences between S-IRAO and NS-IRAO only for hypertension (P = 0.03), nasal polyps (P = 0.002) and pneumonia (P = 0.04). Typical asthma-associated comorbidities tended to be more prevalent in NS-IRAO patients and COPD-associated comorbidities in S-IRAO patients. CONCLUSION: In this study, the prevalence of comorbidities was not superior in patients with IRAO, compared to those with CRAO or COPD alone. The prevalence of comorbidities in the two main types of IRAO patients reflects exposure to cigarette smoke and asthma-related mechanisms.