Katherine O'Neill

Lung clearance index: Evidence for use in clinical trials in cystic fibrosis

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the groups work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.

Lung Clearance Index Is a Repeatable and Sensitive Indicator of Radiological Changes in Bronchiectasis

RATIONALE In bronchiectasis there is a need for improved markers of lung function to determine disease severity and response to therapy. OBJECTIVES To assess whether the lung clearance index is a repeatable and more sensitive indicator of computed tomography (CT) scan abnormalities than spirometry in bronchiectasis. METHODS Thirty patients with stable bronchiectasis were recruited and lung clearance index, spirometry, and health-related quality of life measures were assessed on two occasions, 2 weeks apart when stable (study 1). A separate group of 60 patients with stable bronchiectasis was studied on a single visit with the same measurements and a CT scan (study 2). MEASUREMENTS AND MAIN RESULTS In study 1, the intervisit intraclass correlation coefficient for the lung clearance index was 0.94 (95% confidence interval, 0.89 to 0.97; P < 0.001). In study 2, the mean age was 62 (10) years, FEV1 76.5% predicted (18.9), lung clearance index 9.1 (2.0), and total CT score 14.1 (10.2)%. The lung clearance index was abnormal in 53 of 60 patients (88%) and FEV1 was abnormal in 37 of 60 patients (62%). FEV1 negatively correlated with the lung clearance index (r = -0.51, P < 0.0001). Across CT scores, there was a relationship with the lung clearance index, with little evidence of an effect of FEV1. There were no significant associations between the lung clearance index or FEV1 and health-related quality of life. CONCLUSIONS The lung clearance index is repeatable and a more sensitive measure than FEV1 in the detection of abnormalities demonstrated on CT scan. The lung clearance index has the potential to be a useful clinical and research tool in patients with bronchiectasis.

Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations

Pulmonary exacerbations are important clinical events for cystic fibrosis (CF) patients. Studies assessing the ability of the lung clearance index (LCI) to detect treatment response for pulmonary exacerbations have yielded heterogeneous results. Here, we conduct a retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations and to understand factors explaining the heterogeneous response. A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering. Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI −0.60– −0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: −0.9%, 95% CI −1.0– −0.4%). LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1. Lung clearance index response to therapy for pulmonary exacerbations is heterogeneous in cystic fibrosis patients http://ow.ly/Mnvtd

Shortened Lung Clearance Index is a repeatable and sensitive test in children and adults with cystic fibrosis

Background Lung clearance index (LCI) derived from sulfur hexafluoride (SF6) multiple breath washout (MBW) is a sensitive measure of lung disease in people with cystic fibrosis (CF). However, it can be time-consuming, limiting its use clinically. Aim To compare the repeatability, sensitivity and test duration of LCI derived from washout to 1/30th (LCI1/30), 1/20th (LCI1/20) and 1/10th (LCI1/10) to ‘standard’ LCI derived from washout to 1/40th initial concentration (LCI1/40). Methods Triplicate MBW test results from 30 clinically stable people with CF and 30 healthy controls were analysed retrospectively. MBW tests were performed using 0.2% SF6 and a modified Innocor device. All LCI end points were calculated using SimpleWashout software. Repeatability was assessed using coefficient of variation (CV%). The proportion of people with CF with and without abnormal LCI and forced expiratory volume in 1 s (FEV1) % predicted was compared. Receiver operating characteristic (ROC) curve statistics were calculated. Test duration of all LCI end points was compared using paired t tests. Results In people with CF, LCI1/40 CV% (p=0.16), LCI1/30 CV%, (p=0.53), LCI1/20 CV% (p=0.14) and LCI1/10 CV% (p=0.25) was not significantly different to controls. The sensitivity of LCI1/40, LCI1/30 and LCI1/20 to the presence of CF was equal (67%). The sensitivity of LCI1/10 and FEV1% predicted was lower (53% and 47% respectively). Area under the ROC curve (95% CI) for LCI1/40, LCI1/30, LCI1/20, LCI1/10 and FEV1% predicted was 0.89 (0.80 to 0.97), 0.87 (0.77 to 0.96), 0.87 (0.78 to 0.96), 0.83 (0.72 to 0.94) and 0.73 (0.60 to 0.86), respectively. Test duration of LCI1/30, LCI1/20 and LCI1/10 was significantly shorter compared with the test duration of LCI1/40 in people with CF (p<0.0001) equating to a 5%, 9% and 15% time saving, respectively. Conclusions In this study, LCI1/20 was a repeatable and sensitive measure with equal diagnostic performance to LCI1/40. LCI1/20 was shorter, potentially offering a more feasible research and clinical measure.

Timing of hypertonic saline and airway clearance techniques in adults with cystic fibrosis during pulmonary exacerbation: pilot data from a randomised crossover study

Background Streamlining the timing of treatments in cystic fibrosis (CF) is important to optimise adherence while ensuring efficacy. The optimal timing of treatment with hypertonic saline (HTS) and airway clearance techniques (ACT) is unknown. Objectives This study hypothesised that HTS before ACT would be more effective than HTS during ACT as measured by Lung Clearance Index (LCI). Methods Adults with CF providing written informed consent were randomised to a crossover trial of HTS before ACT or HTS during ACT on consecutive days. ACT treatment consisted of Acapella Duet. Patients completed LCI and spirometry at baseline and 90 min post treatment. Mean difference (MD) and 95% CIs were reported. Results 13 subjects completed the study (mean (SD) age 33 (12) years, forced expiratory volume in 1second % (FEV1%) predicted 51% (22), LCI (no. turnovers) 14 (4)). Comparing the two treatments (HTS before ACT vs HTS during ACT), the change from baseline to 90 min post treatment in LCI (MD (95% CI) −0.02 (−0.63 to 0.59)) and FEV1% predicted (MD (95% CI) −0.25 (−2.50 to 1.99)) was not significant. There was no difference in sputum weight (MD (95% CI) −3.0 (−14.9 to 8.9)), patient perceived ease of clearance (MD (95% CI) 0.4 (−0.6 to 1.3) or satisfaction (MD (95% CI) 0.4 (−0.6 to 1.5)). The time taken for HTS during ACT was significantly shorter (MD (95% CI) 14.7 (9.8 to 19.6)). Conclusions In this pilot study, HTS before ACT was no more effective than HTS during ACT as measured by LCI. Trial registration number NCT01753869; Pre-results.

Closed circuit rebreathing to achieve inert gas wash-in for multiple breath wash-out

Multiple breath wash-out (MBW) testing requires prior wash-in of inert tracer gas. Wash-in efficiency can be enhanced by a rebreathing tracer in a closed circuit. Previous attempts to deploy this did not account for the impact of CO2 accumulation on patients and were unsuccessful. We hypothesised that an effective rebreathe wash-in could be delivered and it would not alter wash-out parameters. Computer modelling was used to assess the impact of the rebreathe method on wash-in efficiency. Clinical testing of open and closed circuit wash-in–wash-out was performed in healthy controls and adult patients with cystic fibrosis (CF) using a circuit with an effective CO2 scrubber and a refined wash-in protocol. Wash-in efficiency was enhanced by rebreathing. There was no difference in mean lung clearance index between the two wash-in methods for controls (6.5 versus 6.4; p=0.2, n=12) or patients with CF (10.9 versus 10.8; p=0.2, n=19). Test time was reduced by rebreathe wash-in (156 versus 230 s for CF patients, p<0.001) and both methods were well tolerated. End wash-in CO2 was maintained below 2% in most cases. Rebreathe–wash-in is a promising development that, when correctly deployed, reduces wash-in time and facilitates portable MBW testing. For mild CF, wash-out outcomes are equivalent to an open circuit. Refinements to wash-in methods permit a faster test and allow use of portable lung clearance index testing http://ow.ly/UYHiN

S44 Lung clearance index (LCI) and FEV1 correlate equally with treatment burden as measured by cystic fibrosis questionnaire-revised (CFQ-R)

Introduction LCI derived from multiple breath washout (MBW), measures the elimination of an inert marker gas during tidal breathing and is a sensitive measure of ventilation inhomogeneity in CF. LCI is more sensitive than FEV1 and FEF25−75 in detecting airways abnormalities and does not require a forced manoeuvre. The CFQ-R is a validated patient reported outcome used to assess health related quality of life (HRQoL) and patient perception of symptoms. There is a need to better understand the relationship between LCI, HRQoL and symptoms. Objective To investigate the relationship between LCI, FEV1 % pred, HRQoL and symptoms as measured by the CFQ-R. Methods These data are part of a larger study investigating the role of LCI as a tool to monitor lung function longitudinally. Patients were recruited from the adult and paediatric CF centres in Belfast Health and Social Care Trust. Inclusion criteria: clinical diagnosis of CF; clinically stable (exacerbation free=4 weeks); informed consent. Age appropriate versions of the CFQ-R were used (patients >14 years, children aged 12 and 13, children aged 6–11). A parent questionnaire was completed in addition where appropriate (for children aged 6–13). The instrument yielded a score of 0–100 for each domain, with higher numbers indicating better function on various domains. Participants completed three MBW tests, using 0.2% sulphur hexafluoride and a modified Innocor device. LCI was reported as the mean of at least 2 acceptable tests. Spirometry was performed to ATS/ERS standards. Results Data were collected for 21 patients (15M:6F), age range 6–51 yrs, mean (SD) 26.4 (13.7). Mean (SD) FEV1 % pred was 77.1 (16.3). Mean (SD) LCI was 9.4 (2.5) (normal <7.5). LCI correlated negatively with FEV1% pred (r=−0.62 p=0.003). The domain of treatment burden was significantly correlated with LCI (r=−0.67 p=0.001) and FEV1% pred (r=0.69 p=0.001). However no correlation was observed with respiratory symptoms or any other domain of the CFQ-R. Conclusion Patients with a greater treatment burden are more likely to have more severe lung disease. The severity of CF lung disease as determined by FEV1% pred and LCI correlate equally with treatment burden. This further validates LCI as a useful measure of lung function.

Airway infection, systemic inflammation and lung clearance index in children and adults with cystic fibrosis

The lung clearance index (LCI) is a measure of ventilation distribution derived from multiple breath washout (MBW). It is a promising measure for monitoring early lung disease in cystic fibrosis (CF) [1–4] and is increasingly being used as a surrogate efficacy endpoint in CF clinical trials [5, 6]. LCI is reliable and more sensitive than forced expiratory volume in 1 s (FEV1) in detecting lung disease in infants, children and adults with CF [7–9], tracks early disease progression and symptoms [3], and predicts the onset of pulmonary exacerbations [10]. LCI has been shown to be elevated in infants and younger children with respiratory infection and correlates with airway inflammation, measured using a range of biomarkers in bronchoalveolar lavage [11–13]. However, there are few data on how LCI relates to markers of infection and inflammation in children >6 years and adults. LCI is a sensitive marker of infection and inflammation in clinically stable children and adults with cystic fibrosis http://ow.ly/vumZ30hzHL0

72 Potential for airborne bacterial contamination in an outpatient respiratory clinic

Objective Recent studies have shown that bacteria of clinical significance in respiratory infection, such as Pseudomonas aeruginosa , have potential for airborne dissemination. This study examined airborne bacteria at an outpatient respiratory clinic and to determine levels of antibiotic resistance among airborne isolates. Methods Air was sampled (Casella slit air sampler, 30litres/min) on two separate days at various locations and time points in a Belfast Respiratory Outpatient Clinic, starting before clinic, until clinic finished. Bronchiectasis (BE) patients attended morning clinic, and Cystic Fibrosis (CF) patients in the afternoon. Air samples were deposited onto Muller-Hinton agar, incubated for 24–48 hrs/37°C/O 2 , and individual colonies counted, Gram stained and identified by 16s rRNA sequencing. The antibiotic susceptibility of selected isolates (n = 11) was determined by E-test®. Results The majority of bacteria detected were Gram +ve (184/242; 76%). The most common were Micrococcus, Kocuria and Staphylococcus spp. Moraxella spp. and one Stenotrophomonas maltophilia isolate were also cultured. No apparent differences in bacterial load were observed between either the BE or CF clinics, or at sequential time points. Of the isolates tested, 8/11 (73%) were resistant to clindamycin. Discussion Although Moraxella, staphylococci and S. maltophilia were observed, the majority of bacteria isolated were those normally designated as skin commensals. Work is currently ongoing, using molecular methods to more fully describe the airborne microbiome and resistome, and to compare patient vs airborne isolates to gauge the potential for transmission within the clinic.

WS20.5 A high colony count of anaerobic bacteria is related to lung clearance index in cystic fibrosis

WS20.5 A high colony count of anaerobic bacteria is related to lung clearance index in cystic fibrosis K. O’Neill1, E. Johnston1, S.J. McGrath1, L. McIlreavey1, J.M. Bradley2, S. Rowan1, A. Reid3, I. Bradbury4, M. Tunney1, J.S. Elborn1. 1CF and Airways Microbiology Research Group, Queen’s University Belfast, Belfast, United Kingdom; 2Centre for Health and Rehabilitation Technologies (CHART), University of Ulster, Belfast, United Kingdom; 3Belfast Health and Social Care Trust, Belfast, United Kingdom; 4Frontier Science Ltd, Scotland, United Kingdom