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Background: Adding a slow vital capacity (SVC) to multiple breath washout (MBW) allows quantification of otherwise overlooked signal from under/un-ventilated lung units (UVLU) and may provide a more comprehensive assessment of airway disease than conventional lung clearance index (LCI 2.5 )., Methods: We conducted a pilot study on people undergoing MBW tests: 10 healthy controls (HC) and 43 cystic fibrosis (CF) subjects performed an SVC after the standard end of test. We term the new outcome LCI with Short extension (LCI ShX ). We assessed (i) CF/ HC differences, (ii) variability (iii) effect of pulmonary exacerbation (PEx)/treatment and (iv) relationship with CF computed tomography (CFCT) scores., Results: HC/ CF group differences were larger with LCI ShX than LCI 2.5 (P<0.001). Within the CF group UVLU was highly variable and when abnormal it did not correlate with corresponding LCI 2.5 . Signal showed little variability during clinical stability (n = 11 CF; 2 visits; median inter-test variability 2.6% LCI ShX, 2.5% LCI 2.5 ). PEx signal was significantly greater for LCI ShX both for onset and resolution. Both MBW parameters correlated significantly with total lung CT scores and hyperinflation but only LCI ShX correlated with mucus plugging., Conclusions: UVLU captured within the LCI ShX varies between individuals; the lack of relationship with LCI 2.5 demonstrates that new, additional information is being captured. LCI ShX repeatability during clinical stability combined with its larger signal around episodes of PEx may lend it superior sensitivity as an outcome measure. Further studies will build on this pilot data to fully establish its utility in monitoring disease status., Competing Interests: Declaration of Competing Interest Christopher Short, Clare Saunders, Dominic Hughes, Samantha Irving, Laura Gardener, Mark Rosenthal and Paul Robinson report no conflicts of interest. Thomas Semple reports speakers fees - Vertex Pharmaceuticals. Research grants – Chiesi Pharmaceuticals. Consultancy fees - Boehringer-Ingelheim and Calyx. Prof. Jane Davies has performed clinical trial leadership roles, educational and/ or advisory activities for the following: Abbvie, Algipharma AS, Bayer AG, Boehringer Ingelheim Pharma GmbH & Co. KG, Eloxx, Enterprise, Galapagos NV, ImevaX GmbH, Ionis, Nivalis Therapeutics, Inc., Novartis, ProQR Therapeutics III B.V., Proteostasis Therapeutics, INC., Pulmocide Raptor Pharmaceuticals, Inc, Vertex Pharmaceuticals., (Copyright © 2021. Published by Elsevier B.V.)

Background: The lung clearance index (LCI), derived from the Multiple Breath Washout (MBW) test, is sensitive to treatment effects and compared with spirometry has higher feasibility in younger children and requires smaller sample sizes. As a result, the LCI has been endorsed by the European CF Society Clinical Trials Network for use as a primary outcome measure in CF clinical trials., Methods: Here we describe the implementation of standardised protocols for MBW test performance, data collection and quality control to successfully incorporate LCI as a novel outcome measure in a large multicentre phase III clinical trial., Results: Three regional (North America (NA), Europe (EU), Australia (AUS)) central over-reading centres (CORC) were established to provide a collaborative platform for MBW training, certification and quality control of data. One hundred and thirty-two naïve operators from 53 sites across NA, EU and AUS were successfully trained and certified to perform MBW testing.  Incorporation of a re-screening opportunity in the study protocol resulted a final screening feasibility rate of 93%, success remained high throughout the study resulting in an overall feasibility of MBW study data of 88.1% (1107/1257). MBW test acceptability was similar between geographical regions: NA (88%), EU (89%) and AUS (89%)., Conclusion: With this approach we achieved high MBW test feasibility and sustained collection of good quality data, demonstrating the utility of LCI as an effective primary endpoint in the first international phase III clinical trial to report LCI as the primary outcome., (Copyright © 2019. Published by Elsevier B.V.)

Background: Clinical and prognostic value of preschool Multiple Breath Washout (MBW) remains unclear., Methods: Initial MBW results (Exhalyzer® D, EcoMedics AG) in preschool Cystic Fibrosis (CF) subjects (age 2-6 years) at a time of clinical stability were compared to (1) concurrent clinical status measures and (2) later spirometry outcomes. Abnormal Lung Clearance Index (LCI) was defined using published reference data (ULN for LCI 8.0)., Results: LCI was abnormal in 56% (28/50), with mean (SD) LCI 8.61(1.85) at age 4.71(1.3) years. Abnormal LCI was associated with higher dornase alfa use, previous positive bacterial cultures and pF508.del homozygous genotype. Later spirometry (n = 44; mean (SD) 2.3(0.5) years after MBW) demonstrated that abnormal initial preschool LCI was a strong predictor of lower later spirometry outcomes., Conclusion: Abnormal preschool LCI was associated with concurrent measures of clinical status and later spirometry deficits, suggesting early prognostic utility of MBW testing in this age range., (Copyright © 2019. Published by Elsevier B.V.)

Background: Obstructive airway disease is nonuniformly distributed throughout the bronchial tree, although the extent to which this occurs can vary among conditions. The multiple-breath washout (MBW) test offers important insights into pediatric lung disease, not available through spirometry or resistance measurements. The European Respiratory Society/American Thoracic Society inert gas washout consensus statement led to the emergence of validated commercial equipment for the age group 6 years and above; specific recommendations for preschool children were beyond the scope of the document. Subsequently, the focus has shifted to MBW applications within preschool subjects (aged 2-6 yr), where a "window of opportunity" exists for early diagnosis of obstructive lung disease and intervention., Methods: This preschool-specific technical standards document was developed by an international group of experts, with expertise in both custom-built and commercial MBW equipment. A comprehensive review of published evidence was performed., Results: Recommendations were devised across areas that place specific age-related demands on MBW systems. Citing evidence where available in the literature, recommendations are made regarding procedures that should be used to achieve robust MBW results in the preschool age range. The present work also highlights the important unanswered questions that need to be addressed in future work., Conclusions: Consensus recommendations are outlined to direct interested groups of manufacturers, researchers, and clinicians in preschool device design, test performance, and data analysis for the MBW technique.

Background: Accurate estimates of multiple breath washout (MBW) outcomes require correct operation of the device, appropriate distraction of the subject to ensure they breathe in a manner representative of their relaxed tidal breathing pattern, and appropriate interpretation of the acquired data. Based on available recommendations for an acceptable MBW test, we aimed to develop a protocol to systematically evaluate MBW measurements based on these criteria., Methods: 50 MBW test occasions were systematically reviewed for technical elements and whether the breathing pattern was representative of relaxed tidal breathing by an experienced MBW operator. The impact of qualitative and quantitative criteria on inter-observer agreement was assessed across eight MBW operators (n = 20 test occasions, compared using a Kappa statistic)., Results: Using qualitative criteria, 46/168 trials were rejected: 16.6% were technically unacceptable and 10.7% were excluded due to inappropriate breathing pattern. Reviewer agreement was good using qualitative criteria and further improved with quantitative criteria from (κ = 0.53-0.83%) to (κ 0.73-0.97%), but at the cost of exclusion of further test occasions in this retrospective data analysis., Conclusions: The application of the systematic review improved inter-observer agreement but did not affect reported MBW outcomes.

The lung clearance index (LCI) is a lung function parameter derived from the multiple-breath washout (MBW) test. Although first developed 60 years ago, the technique was not widely used for many years. Recent technological advances in equipment design have produced gains in popularity for this test among cystic fibrosis (CF) researchers and clinicians, particularly for testing preschool-aged children. LCI has been shown to be feasible and sensitive to early CF lung disease in patients of all ages from infancy to adulthood. A workshop was convened in January 2014 by the North American Cystic Fibrosis Foundation to determine the readiness of the LCI for use in multicenter clinical trials as well as clinical care. The workshop concluded that the MBW text is a valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older patients with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas, and standardization across systems are key issues precluding its use as a clinical trial end point in infants. Based on the current evidence, there are insufficient data to support the use of LCI or MBW parameters in the routine clinical management of patients with CF.