Utility of lung clearance index in CF: What we know, what we don't know and musings on how to bridge the gap

Abstract

Lung clearance index (LCI) derived from multiple breath washout (MBW) has experienced a resurgence in interest over the last decade, with almost 250 publications cited in Pubmed since 2010. The vast majority of these have focussed on paediatrics, and many specifically on the monitoring challenges of early cystic fibrosis (CF) lung disease [[1]Saunders C Bayfield K Irving S et al.Developments in multiple breath washout testing in children with cystic fibrosis.Curr Med Res Opin. 2017; : 1-8Google Scholar]. MBW involves monitoring a tracer gas as it is eliminated from the lungs during tidal breathing. Tracer gas can be exogenous, administered to the subject prior to beginning the washout, eg. sulphur hexafluoride (SF6), or endogenous, lung nitrogen (N2) being washed out with 100% O2. Various methods are in use with a widely held understanding that measurements with different equipment or gases are not interchangeable [2Stahl M. Joachim C. Wielputz M.O. Mall M.A Comparison of lung clearance index determined by washout of N2 and SF6 in infants and preschool children with cystic fibrosis.J Cyst Fibros. 2019; 18: 399-406Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 3Bayfield K.J. Horsley A. Alton E. et al.Simultaneous sulfur hexafluoride and nitrogen multiple-breath washout (MBW) to examine inherent differences in MBW outcomes.ERJ Open Res. 2019; 5 (00234-2018)Crossref PubMed Scopus (15) Google Scholar, 4Yammine S L.N. Nyilas S. Singer F. Latzin P Using the same cut-off for sulfur hexafluoride and nitrogen multiple-breath washout may not be appropriate.J Appl Physiol (Bethesda, Md.: 1985). 2015; 119: 1510-1512Crossref PubMed Scopus (23) Google Scholar]. The signal from MBW arises from the inhomogeneity of gas mixing in the lungs; healthy, patent airways allow gas to wash out of the lungs relatively rapidly and evenly. Airway obstruction (reactive, structural or lumenal, eg. excessive mucus) will lead to uneven gas mixing and a longer period required for gas clearance. The LCI is a derived index of the number of lung volume turnovers required to clear the chosen tracer gas to a pre-specified concentration, conventionally 2.5% of its starting concentration (hence, sometimes termed LCI2.5). Because the LCI signal is generated from all parts of the airway tree, and as the major contribution is made by the multiple, small, distal airways, LCI reflects disease in this region substantially better than do spirometric indices, particularly FEV1. In CF, LCI is abnormal in early life [[5]Aurora P Davies G The use of multiple breath washout for assessing cystic fibrosis in infants.Expert Rev Resp Med. 2017; 11: 21-28Crossref PubMed Scopus (8) Google Scholar], correlates with (but provides additional information to) structural abnormalities on CT scan [6Owens C.M. Aurora P. Stanojevic S. et al.Lung Clearance Index and HRCT are complementary markers of lung abnormalities in young children with CF.Thorax. 2011; 66: 481-488Crossref PubMed Scopus (156) Google Scholar, 7Gustafsson P.M. De Jong P.A. Tiddens H.A. Lindblad A Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis.Thorax. 2008; 63: 129-134Crossref PubMed Scopus (283) Google Scholar], is more abnormal in children with airway infection [8Kraemer R. Baldwin D.N. Ammann R.A. et al.Progression of pulmonary hyperinflation and trapped gas associated with genetic and environmental factors in children with cystic fibrosis.Respir Res. 2006; 7: 138Crossref PubMed Scopus (52) Google Scholar, 9Hall G.L. Logie K.M. Parsons F. et al.Air trapping on chest CT is associated with worse ventilation distribution in infants with cystic fibrosis diagnosed following newborn screening.PLoS ONE. 2011; 6: e23932Crossref PubMed Scopus (90) Google Scholar, 10Aurora P. Kozlowska W. Stocks J Gas mixing efficiency from birth to adulthood measured by multiple-breath washout.Respir Physiol Neurobiol. 2005; 148: 125-139Crossref PubMed Scopus (102) Google Scholar] and inflammation [[11]Belessis Y. Dixon B. Hawkins G. et al.Early cystic fibrosis lung disease detected by bronchoalveolar lavage and lung clearance index.Am J Respir Crit Care Med. 2012; 185: 862-873Crossref PubMed Scopus (117) Google Scholar] and tracks into later life [[12]Horsley A.R. Gustafsson P.M. Macleod K.A. et al.Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis.Thorax. 2008; 63: 135-140Crossref PubMed Scopus (106) Google Scholar]. It may be of less value in advanced lung disease where it takes a long time to perform, is subject to noise related to mucus shifts and will under-estimate disease severity in the presence of completely obstructed lung units [[13]Short C. Saunders C. Davies J.C Horses for courses: learning from functional tests of pulmonary health.Pediatr Pulmonol. 2020; 55: 1855-1858Crossref PubMed Scopus (4) Google Scholar]. LCI is a more sensitive clinical trial outcome measure than FEV1 in children and adults with milder lung disease, improving (decreasing) with therapies such as DNase [[14]Amin R. Subbarao P. Lou W. et al.The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis.Eur Respir J. 2011; 37: 806-812Crossref PubMed Scopus (158) Google Scholar], hypertonic saline [15Amin R. Subbarao P. Jabar A. et al.Hypertonic saline improves the LCI in paediatric patients with CF with normal lung function.Thorax. 2010; 65: 379-383Crossref PubMed Scopus (191) Google Scholar, 16Ratjen F. Davis S.D. Stanojevic S. et al.Inhaled hypertonic saline in preschool children with cystic fibrosis (SHIP): a multicentre, randomised, double-blind, placebo-controlled trial.Lancet Respir Med. 2019; 7: 802-809Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar] and ivacaftor [17Davies J. Sheridan H. Bell N. et al.Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial.Lancet Respir Med. 2013; 1: 630-638Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar, 18Ratjen F. Klingel M. Black P. et al.Changes in Lung Clearance Index in Preschool-aged Patients with Cystic Fibrosis Treated with Ivacaftor (GOAL): a Clinical Trial.Am J Respir Crit Care Med. 2018; 198: 526-528Crossref PubMed Scopus (29) Google Scholar] Standardisation of protocols and the implementation of quality assurance processes through a network of Core Facilities [[19]Saunders C. Jensen R. Robinson P.D. et al.Integrating the multiple breath washout test into international multicentre trials.J Cyst Fibros. 2020; 19: 602-607Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar] have led to its more frequent inclusion in recent commercially sponsored trials of CFTR modulators [20Ratjen F. Hug C. Marigowda G. et al.Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial.Lancet Respir Med. 2017; 5: 557-567Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 21Davies J.C. Sermet-Gaudelus I. Naehrlich L. et al.A phase 3, double-blind, parallel-group study to evaluate the efficacy and safety of tezacaftor in combination with ivacaftor in participants 6 through 11 years of age with cystic fibrosis homozygous for F508del or heterozygous for the F508del-CFTR mutation and a residual function mutation.J Cyst Fibros. 2020 Sep 21; (S1569-1993(20)30811-0)Google Scholar], mucus hydrating (ClinicalTrials. gov NCT04059094) and mucolytic drugs (ClinicalTrials. gov NCT03822455 & NCT00970346). Despite the body of evidence around the use of LCI in CF, major questions remain and require answering before MBW will fulfil its potential in both clinic and research space. The minimal clinically important difference (MCID) in a measure is often used for powering studies, or to determine the relevance of a given change. The MCID for LCI is not yet fully defined, although longitudinal data sets from healthy [[22]Oude Engberink E. Ratjen F. Davis S.D. et al.Inter-test reproducibility of the lung clearance index measured by multiple breath washout.Eur Respir J. 2017; : 50Google Scholar] and stable CF children, suggest variability may be as high as 15% and 17–25% respectively [23Green K. Kongstad T. Skov M. et al.Variability of monthly nitrogen multiple-breath washout during one year in children with cystic fibrosis.J Cyst Fibros. 2018; 17: 242-248Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 24Svedberg M. Gustafsson P.M. Robinson P.D. et al.Variability of lung clearance index in clinically stable cystic fibrosis lung disease in school age children.J Cyst Fibros. 2018; 17: 236-241Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. Whether the MCID is best defined in relative terms, or absolute units, and whether these would differ at different stages of CF disease also remains to be answered. The clinical utility of LCI in aiding management decisions is poorly defined to date, although it has been shown to be a useful predictor of people at risk of frequent exacerbation [[25]Vermeulen F. Proesmans M. Boon M. et al.Lung clearance index predicts pulmonary exacerbations in young patients with cystic fibrosis.Thorax. 2014; 69: 39-45Crossref PubMed Scopus (71) Google Scholar]. Against the backdrop of these outstanding questions, we welcome the publication in this month's Journal of several papers contributing further knowledge. In most of these, the work described also highlights remaining unknowns where further work is needed. Firstly, adding to the evolving evidence base building for the use of LCI in monitoring response to therapies, Shaw et al. report the changes in LCI in people aged ≥ 6 years (median 15) commencing lumacaftor/ ivacaftor in the post-approval, observational PROSPECT study [[26]Shaw M. Khan U. Clancy J.P. et al.Changes in LCI in F508del/F508del patients treated with lumacaftor/ivacaftor: results from the prospect study.J Cyst Fibros. 2020 Jun 6; (S1569-1993(20)30160-0)Abstract Full Text Full Text PDF Scopus (25) Google Scholar]. The full study manuscript has recently been published [[27]Sagel S.D. Khan U. Heltshe S.L. et al.Clinical Effectiveness of Lumacaftor/Ivacaftor in Cystic Fibrosis Patients Homozygous for F508del-CFTR.Ann Am Thorac Soc. 2020 Jul 9; https://doi.org/10.1513/AnnalsATS.202002-144OCCrossref PubMed Scopus (22) Google Scholar]. Unlike older cohorts of patients [[28]Wainwright C.E. Elborn J.S. Ramsey B.W. et al.Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.N Engl J Med. 2015; 373: 220-231Crossref PubMed Scopus (936) Google Scholar] with abnormal baseline spirometry, this group commenced drug with a mean FEV1 of 85% predicted. FEV1 did not change significantly in either the whole study cohort (n = 193) nor the subgroup reported here who also underwent LCI monitoring (n = 49). LCI did however improve significantly, by means of 0.88, 0.77 and 0.67 units at 1, 3 and 6 months respectively. In line with ‘real-world’ effectiveness outcomes often being somewhat smaller in magnitude than efficacy reported from the carefully selected and monitored context of randomised, controlled trials (RCTs), these changes were slightly smaller than those reported from the phase 3 trial in 6–11 year olds [[20]Ratjen F. Hug C. Marigowda G. et al.Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial.Lancet Respir Med. 2017; 5: 557-567Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar]. These findings, whilst perhaps not unexpected, provide further welcome support of LCI's usefulness. Somewhat more controversial were findings that certain baseline demographic features appeared to correlate with a larger change in LCI: male sex, higher LCI and younger age. The first of these has not been reported previously to our knowledge as affecting either response to modulator drugs nor LCI values. The 2nd and 3rd groups would appear to be, at least in part, mutually exclusive, LCI most commonly increasing (worsening lung disease) with age. These findings may reflect underpowering and illustrate the problems related to sample size and subgroup analyses. That said, the data add further weight to LCI being a more suitable outcome measure at early disease stages, perhaps particularly so when the impact of the intervention is expected to be modest. Further work is still needed to understand MCID. The next issue is one of clinical utility. We have watched with some concern as LCI is being adopted clinically in a number of CF centres globally [29Stahl M. Joachim C. Blessing K. et al.Multiple breath washout is feasible in the clinical setting and detects abnormal lung function in infants and young children with cystic fibrosis.Respiration. 2014; 87: 357-363Crossref PubMed Scopus (41) Google Scholar, 30Shawcross A. Murray C.S. Pike K. Horsley A A novel method for infant multiple breath washout: first report in clinical practice.Pediatr Pulmonol. 2019; 54: 1284-1290Crossref PubMed Scopus (5) Google Scholar, 31Bush A. Saglani S. Management of severe asthma in children.Lancet. 2010; 376: 814-825Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar], whilst several crucial facts are not known: (a) how frequently should LCI be monitored to best detect deterioration? (b) what additional information does LCI provide if a pulmonary deterioration or acute exacerbation is already clinically apparent (symptoms, change in spirometry or imaging)? (c) what is the change in LCI that should trigger concern, and is this best measured in absolute or relative terms? (d) what does such a change reflect in pathophysiological terms? Raised LCI has been associated with infection, inflammation, mucus plugging and structural lung changes. Targeting each of these therapeutically would require very different approaches: anti-infectives+/- anti-inflammatory drugs, changes to airway clearance (physiotherapy techniques, mucoactive agents, adherence to both). With these questions in mind, we read with interest the study by Voldby et al. of their RCT assessing the impacts of an LCI-triggered clinical intervention [[32]Voldby C. Green K. Kongstad T. et al.Lung clearance index-triggered intervention in children with cystic fibrosis - A randomised pilot study.J Cyst Fibros. 2020 Jun 20; (S1569-1993–1994)Abstract Full Text Full Text PDF Scopus (9) Google Scholar]. Children and young people aged 5–18 years undertook quarterly MBW measurements during a 2 year period. At the start and end (whilst clinically stable) they also underwent bronchoalveolar lavage (BAL). The group randomly assigned to intervention had further BALs triggered by any increase in LCI (from the single baseline measurement) of ≥1 unit. BAL culture results (bacterial or fungal growths) were then treated as appropriate. LCI was effectively ‘ignored’ in the control group. Primary outcome was change in slope of LCI over the two years, with an a priori hypothesis that the control group would reflect the natural history of CF (increasing LCI) whereas the intervention group would demonstrate an improvement (reduction) in LCI. Multiple secondary outcomes were explored with a similar approach. The trial did not meet any of its outcomes, neither LCI slope nor any others differing between intervention and control groups. There are some very commendable aspects of this study design including the random group allocation and the clinical team being completely blind to the actual LCI results for all participants- they could not therefore impact clinical behaviour and bias the results. However, there are several issues which may have reduced the team's potential for a positive outcome: Was the threshold of 1 unit for the LCI trigger optimal? We don't know the answer to this, but published variability data [22Oude Engberink E. Ratjen F. Davis S.D. et al.Inter-test reproducibility of the lung clearance index measured by multiple breath washout.Eur Respir J. 2017; : 50Google Scholar, 23Green K. Kongstad T. Skov M. et al.Variability of monthly nitrogen multiple-breath washout during one year in children with cystic fibrosis.J Cyst Fibros. 2018; 17: 242-248Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 24Svedberg M. Gustafsson P.M. Robinson P.D. et al.Variability of lung clearance index in clinically stable cystic fibrosis lung disease in school age children.J Cyst Fibros. 2018; 17: 236-241Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] may suggest not, or that a relative change would have been more appropriate. As the authors themselves point out, it would almost certainly have been better if more than one time point was used to establish an individual's baseline. The powering of the study was an acknowledged weakness, in particular an over-ambitious effect size and the use of data from a different MBW methodology; we need no further evidence to state categorically that data obtained with different equipment and washout gases are not interchangeable. Here again, a fully evidence-based MCID would have been invaluable. Food for thought for those wishing to design similar protocols to assess LCI's role in clinical decision making (which we would strongly endorse) is whether the intervention was optimal? Whilst seeking evidence of infection (here, with gold-standard BAL) and treating it appropriately is entirely logical, sadly, the results of this study undermined the approach, at least on a group basis; the yield of positive microbiology from the LCI-triggered BALs was no greater than that at study start and end when participants were, per protocol, clinically stable. It is unlikely that the trigger for an LCI increase is a single pathophysiological process. Rather than a one-size-fits all approach, perhaps the ‘intervention’ in future such studies should be a detailed multidisciplinary assessment of the patient, seeking to define the underlying cause on an individual basis. Included in this should perhaps not only be tests such as airway culture or imaging but also an objective look at treatment adherence and possible environmental triggers. We personally were wrong-footed by a child with CF failing to respond to multiple interventions for worsening pulmonary symptoms, until stumbling across the fact that the family had acquired a cat; specific IgE was sky-high in the child and symptoms completely resolved following its removal from the household. Such an assessment, which is the unbiased approach taken by our centre's ‘Difficult asthma’ service [[31]Bush A. Saglani S. Management of severe asthma in children.Lancet. 2010; 376: 814-825Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar] can lead to a tailored intervention with more chance of improvement in outcomes. Finally, in any future study design, the additional benefit of the LCI, over and above all other existing evidence, should be documented: would the intervention triggered by the threshold change in LCI have happened anyway (e.g. symptom reporting), or was the deterioration otherwise ‘silent’? Only by addressing these questions will the true clinical value of LCI be demonstrated. It is after all time-consuming for both patient and team and worthwhile only if providing additional benefit. Never is this time-consuming nature more apparent than when testing infants and very young children. To date, infant MBW has only been performed by a small number of highly specialised labs and even by their strongest advocates, described as research rather than clinical tools. The London CF Collaborative (LCFC) [[33]Davies G. Thia L.P. Stocks J. et al.Minimal change in structural, functional and inflammatory markers of lung disease in newborn screened infants with cystic fibrosis at one year.J Cyst Fibros. 2020 Feb 7; (S1569–1993(20)30031–X)Crossref Google Scholar] and AREST-CF group in Australia [[34]Mott L.S. Park J. Murray C.P. et al.Progression of early structural lung disease in young children with cystic fibrosis assessed using CT.Thorax. 2012; 67: 509-516Crossref PubMed Scopus (223) Google Scholar] have contributed large datasets on LCI in early life; it is clear that as clinical care evolves, in particular with widespread newborn screening and early management, early CF disease is becoming less apparent. The latest cohort published by the LCFC reported group minimal change in the first year of life [[33]Davies G. Thia L.P. Stocks J. et al.Minimal change in structural, functional and inflammatory markers of lung disease in newborn screened infants with cystic fibrosis at one year.J Cyst Fibros. 2020 Feb 7; (S1569–1993(20)30031–X)Crossref Google Scholar]. Both the LCFC and AREST-CF have though demonstrated a significant relationship between raised LCI and airway inflammation in very early life, which has long-term consequences [[34]Mott L.S. Park J. Murray C.P. et al.Progression of early structural lung disease in young children with cystic fibrosis assessed using CT.Thorax. 2012; 67: 509-516Crossref PubMed Scopus (223) Google Scholar]. Thus, a role for such monitoring to identify any outliers early, whilst avoiding excessive treatment burden in those without abnormalities, could be made. The research letter in this volume of the Journal by Schmidt et al. describes the early stages of their new initiative to introduce MBW monitoring from 3 months of age into the Copenhagen clinical service [[35]Schmidt M.N. Sandvik R.M. Voldby C. et al.What it takes to implement regular longitudinal multiple breath washout tests in infants with cystic fibrosis.J Cyst Fibros. 2020 Apr 30; (S1569-1993–1996)Abstract Full Text Full Text PDF Scopus (4) Google Scholar]. Their choice of nasal dexmedetomidine as opposed to chloral hydrate (which is not allowed in many regions) allowed sedation and successful measurements in the majority. Babies were described as mostly asleep for a maximum of 2 h (so still fairly time-consuming). No LCI data are yet presented from this cohort, so the additional usefulness of the investigation remains to be seen. Although possibly for sedation-related safety reasons, it is something of a shame that episodes of respiratory tract infection led to a test reschedule; the opportunity to see the LCI signal from these episodes was therefore lost. One of the remaining challenges for those wishing to start longitudinal monitoring in very early life is navigating the transition from infant methods to those of preschool and school-aged children. Currently different gases, and often different interfaces are required. Future age-related Z scores need to accommodate this. In terms of new outcome measures, in addition to LCI there is a growing interest in imaging, the lower radiation burden associated with modern lung CT scans making them more acceptable for regular use. The standardisation of lung volumes and the automated PRAGMA scoring system are specifically designed to detect and quantify the earliest lung changes [[36]Oudraad M.C.J. Kuo W. Rosenow T. et al.Assessment of early lung disease in young children with CF: a comparison between pressure-controlled and free-breathing chest computed tomography.Pediatr Pulmonol. 2020; 55: 1161-1168Crossref PubMed Scopus (8) Google Scholar]. Lung MRI is also coming of age, not only with the use of hyperpolarised gases [[37]Marshall H. Horsley A. Taylor C.J. et al.Detection of early subclinical lung disease in children with cystic fibrosis by lung ventilation imaging with hyperpolarised gas MRI.Thorax. 2017; 72: 760-762Crossref PubMed Scopus (57) Google Scholar] but with novel functional techniques such as oxygen-enhancement [[38]Martini K. Gygax C.M. Benden C. et al.Volumetric dynamic oxygen-enhanced MRI (OE-MRI): comparison with CT Brody score and lung function in cystic fibrosis patients.Eur Radiol. 2018; 28: 4037-4047Crossref PubMed Scopus (17) Google Scholar]. Another paper in this month's Journal describes mucociliary clearance (MCC) scanning in children receiving nebulised hypertonic saline, with measurable improvements despite no change in spirometry [[39]Donaldson S.H. Danielle Samulski T. LaFave C. et al.A four week trial of hypertonic saline in children with mild cystic fibrosis lung disease: effect on mucociliary clearance and clinical outcomes.J Cyst Fibros. 2020 Jul 12; (S1569-1993–1998)Abstract Full Text Full Text PDF Scopus (5) Google Scholar]. LCI has also previously demonstrated a signal with this intervention [15Amin R. Subbarao P. Jabar A. et al.Hypertonic saline improves the LCI in paediatric patients with CF with normal lung function.Thorax. 2010; 65: 379-383Crossref PubMed Scopus (191) Google Scholar, 16Ratjen F. Davis S.D. Stanojevic S. et al.Inhaled hypertonic saline in preschool children with cystic fibrosis (SHIP): a multicentre, randomised, double-blind, placebo-controlled trial.Lancet Respir Med. 2019; 7: 802-809Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]; it's a shame it was not done in parallel in this group. The more we can learn about these sensitive pulmonary outcome measures and how they relate to each other the more we will be able to apply them rationally in research and the clinic. As we enter the era of highly effective CFTR modulator therapy for people with the vast majority of CFTR gene mutations [[40]Mall M.A. Mayer-Hamblett N. Rowe S.M Cystic Fibrosis: emergence of Highly Effective Targeted Therapeutics and Potential Clinical Implications.Am J Respir Crit Care Med. 2020; 201: 1193-1208Crossref PubMed Scopus (72) Google Scholar] we anticipate population-level improvements in health status of people with CF of all ages; this will be particularly apparent in people who are fortunate to have grown up receiving such drugs. Those who are not so fortunate have an extremely high treatment burden [[41]Rowbotham N.J. Smith S.J. Elliott Z.C. et al.Adapting the James Lind Alliance priority setting process to better support patient participation: an example from cystic fibrosis.Res Involv Engagem. 2019; 5: 24Crossref PubMed Scopus (12) Google Scholar], and in the coming years it is essential that we can safely guide the removal of non-essential treatments. Paediatric respiratory medicine has pioneered sensitive pulmonary outcome measures; these will soon demonstrate broadening utility for older patients as we enter the next stage in the evolving landscape of CF care. 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. Clare Saunders and Christopher Short have no disclosures of interest. The authors have been supported by a grant from the European CF Society to establish the ECFS Core Facility for LCI. The team is supported by the National Institute for Health Research through the Royal Brompton/ NHLI Clinical Research Facility, the Imperial Biomedical Research Centre and a Senior Investigator Award (JCD).