Daily Respiratory Research Analysis

RATIONALE: Elexacaftor/tezacaftor/ivacaftor, a CF transmembrane conductance regulator (CFTR) modulator, stabilizes and restores F508del-CFTR function, which is the most common CFTR variant. In multiple clinical and real-world studies, elexacaftor/tezacaftor/ivacaftor was shown to be safe and highly effective in people with CF carrying at least one F508del-CFTR (∼80% of people with CF). OBJECTIVES: To characterize the response of rare, non-F508del CFTR variants to elexacaftor/tezacaftor/ivacaftor in vitro, and in clinical and real-world studies. METHODS: We engineered Fischer rat thyroid (FRT) cells each of which express one of 620 rare exonic CFTR variants present in public databases and evaluated their in vitro response to elexacaftor/tezacaftor/ivacaftor. We evaluated efficacy and safety of elexacaftor/tezacaftor/ivacaftor in a 24-week randomized, placebo-controlled, Phase 3 trial (445-124) in participants with 1 of 18 rare variants and no F508del and in a real-world study (CFD-016) in people carrying 82 rare variants and no F508del. MEASUREMENTS AND MAIN RESULTS: In FRT cells, 518 of 620 (84%) rare variants responded to elexacaftor/tezacaftor/ivacaftor. In 445-124, mean improvements were seen in the primary endpoint of percent predicted FEV1 (9.2 percentage points [95%CI:7.2,11.3;P<0.0001]), and secondary endpoints of sweat chloride (-28.3mmol/L [95%CI:-32.1,-24.5mmol/L;P<0.0001]) and CFQ-R RD (19.5points [95%CI:15.5,23.5;P<0.0001]). In CFD-016, improvements in lung function were seen after treatment initiation. CONCLUSIONS: In vitro, clinical, and real-world data support elexacaftor/tezacaftor/ivacaftor treatment in people carrying a range of CFTR variants and no F508del. The response of 84% of rare CFTR variants that produce protein to protein-stabilizing therapy suggests variants in many regions of the protein causes disease via protein destabilization.

RATIONALE: Conventional monitoring of acute respiratory distress syndrome (ARDS) relies on global parameters, e.g., tidal volume, airway pressure, and driving pressure. These parameters do not capture regional stress heterogeneity within the lung. OBJECTIVES: To develop and validate a novel technique, lung stress mapping visualizing regional lung stress throughout the lung, and to evaluate its biological and clinical relevance. METHODS: Lung stress mapping combines esophageal pressure and plateau pressure with CT-derived pleural pressure gradients to generate spatially resolved maps of inspiratory transpulmonary pressure. Accuracy was tested in pigs by surgically inserted pleural sensors. Biological relevance was assessed in rabbits by correlating lung stress mapping-derived parameters with regional proinflammatory cytokine expression. Clinical feasibility and associations with outcome were evaluated in 20 consecutive ARDS patients enrolled in a prospective study. MEASUREMENTS AND MAIN RESULTS: Good correlation and agreement between sensor-derived and mapping-derived lung stress were confirmed. In rabbits, lung inflammation predominantly occurred in nondependent lung regions where lung stress was higher, and overall inflammation correlated with lung stress mapping-derived parameters. In ARDS patients, all received lung-protective ventilation. Non-survivors had significantly higher lung stress mapping-derived maximum and mean lung stress than survivors, despite similar global ventilatory parameters. Exploratory ROC analyses showed stronger associations of lung stress mapping-derived parameters with 90-day mortality than driving pressure. CONCLUSIONS: Lung stress mapping accurately quantified regional transpulmonary stress and revealed biologically and clinically meaningful heterogeneity. This technique may help identify patients with ARDS at increased risk of ventilator-induced lung injury who would not be recognized through conventional respiratory monitoring.

INTRODUCTION: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of rare lung diseases. Symptoms of ILD are non-specific, and diagnosis requires multiple investigations including invasive procedures. Therefore, diagnostic delay is common. Previous single-center studies showed that profiling of exhaled volatile organic compounds using non-invasive electronic nose (eNose) sensor technology has potential as diagnostic tool for ILD. We aimed to validate eNose technology to differentiate various ILDs in an international multicenter cohort. METHODS: We included patients with an ILD diagnosis established in a multidisciplinary team (MDT) discussion and pulmonary fibrosis on HRCT scan in five international ILD expert centers. An eNose (SpiroNose®) was used for exhaled breath analysis. We compared eNose breath profiles of different ILD subtypes versus all other ILDs as a group, and across six different ILD subtypes. Breath profiles were analyzed with partial least squares discriminant and receiver operating characteristic analyses. Models were trained on data from a selection of centers and externally validated in other centers. RESULTS: Breath profiles of 587 patients were analyzed. Comparing breath profiles of ILD subtypes versus all other ILDs resulted in area under the curve values (AUCs) ranging from 0.88-0.92 in the training set and 0.75-0.95 in the validation set. ILD subtypes could be discriminated with AUCs ranging from 0.95-0.98 in the training set and 0.83-0.93 in the validation set. DISCUSSION: This international study demonstrates that eNose technology accurately differentiates breath profiles from patients with various ILDs. eNose technology holds potential as easy point-of-care tool for diagnosis of fILDs.