Stephen Rowan

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.

Reduced bacterial colony count of anaerobic bacteria is associated with a worsening in lung clearance index and inflammation in cystic fibrosis.

Anaerobic bacteria have been identified in abundance in the airways of cystic fibrosis (CF) subjects. The impact their presence and abundance has on lung function and inflammation is unclear. The aim of this study was to investigate the relationship between the colony count of aerobic and anaerobic bacteria, lung clearance index (LCI), spirometry and C-Reactive Protein (CRP) in patients with CF. Sputum and blood were collected from CF patients at a single cross-sectional visit when clinically stable. Community composition and bacterial colony counts were analysed using extended aerobic and anaerobic culture. Patients completed spirometry and a multiple breath washout (MBW) test to obtain LCI. An inverse correlation between colony count of aerobic bacteria (n = 41, r = -0.35; p = 0.02), anaerobic bacteria (n = 41, r = -0.44, p = 0.004) and LCI was observed. There was an inverse correlation between colony count of anaerobic bacteria and CRP (n = 25, r = -0.44, p = 0.03) only. The results of this study demonstrate that a lower colony count of aerobic and anaerobic bacteria correlated with a worse LCI. A lower colony count of anaerobic bacteria also correlated with higher CRP levels. These results indicate that lower abundance of aerobic and anaerobic bacteria may reflect microbiota disruption and disease progression in the CF lung.

Structural and Functional Lung Impairment in Adult Survivors of Bronchopulmonary Dysplasia

RATIONALE As more preterm infants recover from severe bronchopulmonary dysplasia (BPD), it is critical to understand the clinical consequences of this condition on the lung health of adult survivors. OBJECTIVES To assess structural and functional lung parameters in young adult BPD survivors and preterm and term control subjects. METHODS Young adult survivors of BPD (mean age, 24 yr) underwent spirometry, lung volume assessment, transfer factor, lung clearance index, and fractional exhaled nitric oxide measurements, together with high-resolution chest computed tomography and cardiopulmonary exercise testing. MEASUREMENTS AND MAIN RESULTS Twenty-five adult BPD survivors (mean ± SD gestational age, 26.8 ± 2.3 wk; birth weight, 866 ± 255 g), 24 adult prematurely born non-BPD control subjects (gestational age, 30.6 ± 1.9 wk; birth weight, 1,234 ± 207 g), and 25 adult term-birth control subjects (gestational age, 38.5 ± 0.9 wk; birth weight, 3,569 ± 2,979 g) were studied. Subjects with BPD were more likely to be wakened by cough (odds ratio, 9.7; 95% confidence interval, 1.8-52.6; P < 0.01) or wheeze and breathlessness (odds ratio, 12.2; 95% confidence interval; 1.3-112; P < 0.05) than term control subjects after adjusting for sex and current smoking. Preterm subjects had greater airway obstruction than term subjects. Subjects with BPD had significantly lower values for FEV1 and forced expiratory flow, midexpiratory phase (percent predicted and z-scores), than term control subjects (both P < 0.001). Although non-BPD subjects also had lower spirometric values than term control subjects, none of the differences reached statistical significance. More subjects with BPD (25%) had fixed airflow obstruction than non-BPD (12.5%) and term (0%) subjects (P = 0.004). Both BPD and non-BPD subjects had significantly greater impairment in gas transfer (Kco percent predicted) than term subjects (both P < 0.05). Eighteen (37%) preterm participants were classified as small for gestational age (birth weight below the 10th percentile for gestational age). These subjects had significantly greater impairment in FEV1 (percent predicted values and z-scores) than those born appropriate for gestational age. BPD survivors had significantly more severe radiographic structural lung impairment than non-BPD subjects. Both preterm groups had impaired exercise capacity compared with term control subjects. There was a trend for greater limitation and leg discomfort in BPD survivors. CONCLUSIONS Adult preterm birth survivors, especially those who developed BPD, continue to experience respiratory symptoms and exhibit clinically important levels of pulmonary impairment.

Reply: lung clearance index in primary ciliary dyskinesia and bronchiectasis.

However, their interpretation of our different findings may not be quite correct. Two papers (2, 3), with cohorts of 38 and 27, respectively, have now shown that the relationship between FEV1 and LCI was very different in PCD compared with CF, and thus a different relationship between LCI and HRCT findings in the two diseases is highly likely to be real, and not due to lack of power as Rowan and colleagues suggested. Rather, we believe that the difference is because CF is a patchy disease of secondary ciliary dyskinesia as against a diffuse disease where ciliary dyskinesia is primary. To test this we studied children with non-CF, non-PCD bronchiectasis, a disease also characterized by patchy secondary ciliary dyskinesia. There was a correlation between FEV1 and LCI, similar to that described in CF, even with small numbers (n = 16, P = 0.009, r = –0.6, nonparametric Spearman’s test) (Figure 1). Furthermore, there were correlations between LCI and HRCT extent and severity of bronchiectasis (P = 0.002, r = 0.8 and P = 0.01, r = 0.7, respectively), airway wall thickening (P = 0.01, r = 0.7), and air trapping (P = 0.0006, r = 0.8) even in this small sample, although only air trapping correlates with FEV1 (P= 0.03, r= –0.6), confirming the findings of Rowan and colleagues (1). We conclude that the differences between their results and ours are real (2) and reflect the different pathophysiology of PCD and non-CF bronchiectasis. We caution against extrapolating uncritically between airway diseases when considering structure–function relationships. n

Training in Multiple Breath Washout testing for respiratory physiotherapists

INTRODUCTION The development of multiple breath washout (MBW) testing in respiratory disease highlights the need for increased awareness amongst respiratory physiotherapists and a potential opportunity for professional development in the use of an important outcome measure for clinical trials. OBJECTIVES To rationalise how MBW may be a useful assessment tool for respiratory physiotherapists and to describe a local MBW training and certification programme for physiotherapists. RESULTS The respiratory Multidisciplinary Team in the Belfast Health and Social Care Trust (BHSCT) identified a need for MBW testing to be available to facilitate clinical research and assessment. A 2day training programme consisting of prereading preparation, self-directed learning, theory presentations, practical demonstrations and hands-on practice was developed and delivered. All participants underwent a certification process. CONCLUSION We have demonstrated the successful training and certification of clinical and research physiotherapists and encourage other respiratory physiotherapists to consider MBW test training.

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

P106 Lung Clearance Index is a Repeatable Test of Lung Function and Superior Predictor of CT Scan Abnormalities in Bronchiectasis

Introduction In cystic fibrosis, lung clearance index (LCI) is a sensitive predictor of CT scan determined lung pathology. In bronchiectasis (BE) there is a need for improved markers of lung function to gauge disease severity and response to interventions in clinical trials. Aims To assess if LCI is a repeatable and superior predictor of CT scan abnormalities compared with FEV1 in BE. Methods 60 patients with stable BE were recruited. LCI (using SF6 multiple breath washout), spirometry and CT scores were collected. Health related quality of life (HRQoL) was measured using the St. George’s Respiratory Questionnaire. A separate group of 30 BE patients were recruited and LCI, spirometry and HRQoL were assessed when clinically stable on 2 occasions, 2 weeks apart. Results Mean (SD) age was 62 (10) years, FEV1 76.5 (18.9)% predicted, LCI 9.1 (2.0) and total CT score 14.1 (10.2)%. FEV1 negatively correlated with LCI (r = -0.51, p < 0.0001.) Across all CT score subscales, there was clear evidence of a relationship with LCI, with no or very weak evidence of any additional effect of FEV1. The strongest correlations of subgroup CT scores with LCI were seen in),% parenchymal score (r = 0.56, p < 0.001),% mucus plugging (r = 0.49, p < 0.001),% total score (r = 0.55, p < 0.001)% bronchiectasis (r = 0.41, p < 0.01. There was no association for either FEV1 or LCI with% airway thickening and for % bronchiectasis score and FEV1. There were no significant associations between LCI or FEV1 and HRQoL. The inter-visit ICC for LCI was 0.94 (95% CI 0.89 to 0.97, p < 0.001). Conclusions LCI is a valid and repeatable test of lung function in BE. It is a superior predictor of lung function than FEV1 in the detection of abnormalities demonstrated on CT scan. LCI is a useful test in patients with early lung disease or those with preserved spirometric scores. LCI also has the potential to be an alternative outcome measure to spirometry in clinical trials.

219 Prevalence of cystic fibrosis related liver disease in Northern Ireland

This survey was designed to assess the amount of variation around the UK in the investigation and management of CF related liver disease (CFLRD). Questionnaires were devised by a group of adult and paediatric CF physicians and also hepatologists and were sent to all major CF centres in the UK. 16 adult and 24 paediatric centres replied. The number of new CFLD cases ranged from 0−5 per year per centre. No centre carried out routine diagnostic liver biopsy and most centres did not use a severity scoring system. Non-invasive imaging other than ultrasound was mentioned by only 5 centres. In established CFLD, all centres monitored platelets, prothrombin time and albumin. Ultrasound monitoring varied between 6 monthly, annually or ad hoc. There was wide variation in screening for varices. Only 16 centres ran a joint clinic with a hepatologist but 38 centres had access to a hepatologist with a special interest in CFLD. Nearly all centres used lifelong URSO treatment for patients with, doses of 10−30mg/kg/day but only 5 centres used taurine. All adult centres advocated primary prophylaxis for grade 2+ varices and the majority preferred banding to beta blockade. Most centres considered triggers for referral for liver transplant to be one or more of: ascites, bleeding varices and impaired synthetic function but there was less consensus on proximal muscle wasting. 15 out of 40 centres felt that they did not have an adequate forum to discuss liver transplant issues. In summary, our survey showed wide variation in the assessment and management of CFLD in the UK with some differences compared to recent European guidance [1].

P133 Lung clearance index is a reproducible and sensitive measure of airways disease in bronchiectasis

Introduction Lung clearance index (LCI) is a measure of ventilation in homogeneity derived from multiple breath washout (MBW). Although FEV1 is commonly used to assess severity of airway disease and response to therapy, it is insensitive to small airways disease and is often within normal range in bronchiectasis (BE) not caused by Cystic Fibrosis (CF) until disease is well established. In CF, LCI is more sensitive than FEV1 in detecting airways abnormalities and is currently used as an outcome measure in clinical trials. In BE, there is a need to find a sensitive outcome measure that is responsive to interventions, particularly in those with mild disease. Objective To assess within and between visit repeatability of LCI and determine the relationship between FEV1 and LCI in stable BE. Methods Inclusion criteria: HRCT diagnosis of BE within the last 5 years; clinically stable (no infective symptoms for >4 weeks); no genetic or clinical features of CF. Participants attended for two visits, 2 weeks apart. At each visit they performed MBW in triplicate, using 0.2% sulphur hexafluoride and a modified Innocor device. LCI was derived from the mean of at least 2 acceptable washouts. Spirometry was performed to ATS/ERS standards. Results 14 patients (8M/6F) attended for two visits. The mean (SD) age was 60.5 (15.4) yrs. Mean (SD) FEV1 % predicted was 87.1 (18.6), range (44–117). Mean (SD) LCI was 9.4 (2.0) on visit 1 and 9.4 (1.9) on visit 2 (normal <7.5). The intra-visit coefficient of variation (CV) was 4.7 % (3 measures). Between visit repeatability of LCI was 0.54 (SD of variance between visits). LCI negatively correlated with FEV1 (r=−0.69, p<0.001). Sensitivity of LCI and FEV1 for the diagnosis of bronchiectasis by CT was 71% and 29% respectively. Conclusions This is the first report of LCI in non-CF BE. LCI is a more sensitive test of lung function than FEV1 and is abnormal in the majority of people with BE who have a normal FEV1. LCI has good intra-visit and between visit repeatability. Across a range of FEV1 there is a strong relationship between LCI and FEV1.