Christopher Short

Background: Pulmonary function tests (PFTs) and medical imaging in cystic fibrosis (CF) occasionally show discrepancies in severity levels, potentially due to different postures during testing (seated PFTs and supine imaging). To assess this, we utilised multiple breath washout with Short extension (MBW _ShX ) and oxygen‐enhanced MRI (OE‐MRI). MBW _ShX is a more sensitive PFT and offers novel insights into global ventilation efficiency by incorporating signal from under‐ventilated lung units (UVLU). We hypothesised there would be a significant difference in MBW _ShX parameters between seated and supine postures and aimed to compare the relationship between MBW _ShX obtained in both posture and OE‐MRI. Methods: Twenty three CF patients performed two seated and at least 1onesupine MBW, along with same day OE‐MRI. MBW _ShX outcome measures included conventional lung clearance index (LCI _2.5 ), and two novel parameters: LCI _ShX and UVLU. The primary OE‐MRI parameter was the ventilation defect percentage (VDP%). Results: We demonstrated a significant increase in LCI _ShX (median difference [IQR]:2.00[0.16; 2.61]; p < 0.01) and UVLU (0.66[0.11; 2.22]; p < 0.05) from seated to supine posture, but no significant change in LCI _2.5 (0.27 [−0.21; 0.89]; p = 0.06). Moreover, we showed strong correlation between MBW and VDP% of OE‐MRI parameters across postures ( ρ > 0.8). However, no differences were detected between seated and supine MBW correlations with OE‐MRI (LCI _2.5 , p = 0.77; LCI _ShX , p = 0.90; UVLU, p = 0.29). Conclusion: We found significant postural differences in MBW _ShX parameters, with reduced global ventilation efficiency (increased LCI _ShX ) and increased UVLU in supine posture. However, the relationship between MBW and OE‐MRI remained unaffected by posture. In conclusion, supine MBW may offer novel clinical insights but does not enhance sensitivity for comparisons with medical imaging.

Introduction: The current cystic fibrosis (CF) care era, while hugely welcome, raises new challenges, particularly the need for more sensitive pulmonary outcome measures. Seeking further optimisation, we previously developed a Short extension to multiple breath washout measure (MBW _ShX ) which captures previously overlooked, under-ventilated lung units but lacks regional information. Functional lung MRI addresses this limitation. We hypothesised these measures would be more sensitive to change in tracking CF lung disease than usual clinical respiratory function tests. Methods: Forty-six people with (pw)CF, median age 15 (range 6–55) years were recruited to a single-centre study. While clinically stable, pwCF performed OE-MRI, MBW+/- _ShX and spirometry at baseline and at 6 monthly intervals over 18 months of follow-up. A subgroup of pwCF (n=20) and age-matched healthy controls (HC, n=20) performed two repeatability visits within 6 weeks. Results: OE-MRI/MBW _ShX were well tolerated, differentiated HC and CF groups, and were repeatable with negligible differences between two visits ShX parameters worsened at 12 months (p1 + LCI _2.5 ) did not change significantly. Conclusions: OE-MRI/MBW _ShX are novel, sensitive tools to track progression of abnormalities in lung structure/function. Such progression may not be detected by conventional outcome measures. CF transmembrane conductance regulator (CFTR) modulators have been transformative for many pwCF and generally lead to substantial improvements in lung health. Stable FEV ₁ over longer time periods and, during mucoactive treatment withdrawal, may give false reassurance. OE-MRI/MBW _ShX reveal the likely less welcome reality that lung-disease progresses despite CFTR modulators. These measures could be considered in future studies when enhanced sensitivity is required.

We consider the term “trapped air” either in the use of imaging or pulmonary function testing, something of a misnomer that can lead to an inaccurate assessment of an important physiological feature. Instead, we propose the term underventilated lung units (UVLU). Of the many pulmonary function methods we used in this study, we found that the use of multiple breath washout with short extension (MBW_ShX) to be the best nonimaging method.

There are two types of functional methodology to assess ventilation with lung MRI:(i)observing ventilatory mechanics during the respiratory cycle as an indirect measure (α-mapping/Fourier decomposition);(ii)observing contrast gas distribution after inhalation; our group uses dynamic oxygen enhanced (OE-)MRI as a feasible alternative to hyperpolarised gas MRI. We hypothesized that OE-MRI would be more sensitive to detect PEx in pwCF than α-mapping. PwCF (n=14) performed spirometry, α-mapping & OE-MRI on the same day. PEx were pragmatically defined as a new course of anti-biotics/fungals to treat worsening symptoms of lung disease and/or unexpected drop in ppFEV1. α-mapping parameters: ventilation defect percentage (α-VDP). OE-MRI parameters: OE-VDP and ∆R₂* (ventilation signal). Data are median(range) and compared with Wilcoxon signed matched pairs. Baseline values: OE-VDP 22.6%(6.9-52.0%), ∆R₂* 0.062(0.03-0.10), α-VDP 9.7% (1.0-39.3%) and ppFEV1 88%(71-105%). PEx values were significantly worse for OE-VDP 32.3%(5.4-57.0%, P2* 0.05 (0.02-0.09, P<0.001) ppFEV1 85% (65-102%, P0.05). α-VDP was significantly lower than OE-VDP at both visits (P<0.05 and P<0.001 respectively). This sub-study suggests that OE-MRI and α-mapping measure different aspects of respiratory physiology. Assessing longitudinal disease status and detecting accute changes may require a combined approach. This ongoing project will assess repeatability, disease progression, responsiveness, and assess spatial heterogeneity. We aim ultimately to establish the utility of OE-MRI as a clinical and research outcome for the future. Funded by the CF Foundation.

Title: Reply to Migration is not the perfect answer: Optimised methodology to assess LCI agreement between corrected legacy multiple breath nitrogen washout data and that directly collected on updated software.

Recently, a cross‐talk error with commercial multiple breath nitrogen washout (MBWN₂) software was discovered, which produced an absolute over‐reading of N₂ of approximately 1%, i.e., 2% N₂ read as 3%. This caused an extended tail to the washout, and over‐estimated lung clearance index (LCI_2.5) values. Subsequently an updated and corrected software version has been released. Within the field there have been discussions on how to correct legacy data, whether to migrate or completely “rerun” raw data A‐files from the old software into the new corrected software. To our knowledge, no research has been published assessing whether either method is equivalent to directly collecting data in the new corrected software. We prospectively recruited 19 participants, 10 adult healthy controls and 9 people with cystic fibrosis (CF). MBWN₂ was performed using the Exhalyzer® D first on the old 3.1.6 software and next, directly on corrected 3.3.1 software. Multiple breath washout (MBW) data directly collected in 3.3.1 was significantly different from both migrated and rerun data. A total of 7 of the 19 participants (37%; 4 CF) had a relative difference in LCI_2.5 > 10% for both migrated and rerun data compared to 3.3.1 collected data. Our findings have implications for the Global Lung Initiative MBW project, which is accepting a combination of directly collected, A‐file reruns and migrated data to establish normative values. Further, caution must be used in clinical practice when comparing corrected legacy data versus 3.3.1 collected data for clinical interpretation. We recommend that a new baseline is collected directly on 3.3.1. before clinical interpretation and decisions are determined when comparing consecutive MBW tests.

This is an exciting time for research and novel drug development in cystic fibrosis. However, rarely has the adage, “Children are not just little adults” been more relevant. This article is divided into two main sections. In the first, we explore why it is important to involve children in research. We discuss the potential benefits of understanding a disease and its treatment in children, and we highlight that children have the same legal and ethical right to evidence-based therapy as adults. Additionally, we discuss why extrapolation from adults may be inappropriate, for example, medication pharmacokinetics may be different in children, and there may be unpredictable adverse effects. In the second part, we discuss how to involve children and their families in research. We outline the importance and the complexities of selecting appropriate outcome measures, and we discuss the role co-design may have in improving the involvement of children. We highlight the importance of appropriate staffing and resourcing, and we outline some of the common challenges and possible solutions, including practical tips on obtaining consent/assent in children and adolescents. We conclude that it is unethical to simply rely on extrapolation from adult studies because research in young children is challenging and that research should be seen as a normal part of the paediatric therapeutic journey.