Nicholas Bell

Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation

Background Clinical trials in cystic fibrosis (CF) have been hindered by the paucity of well characterised and clinically relevant outcome measures. Aim To evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for a clinical trial of CFTR gene therapy. Methods A multicentre observational study of adult and paediatric patients with CF (>10 years) treated for a physician-defined exacerbation of CF pulmonary symptoms. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers. Results Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31). Discussion We identify the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with our study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.

Effects of Ivacaftor in Patients With Cystic Fibrosis Who Carry the G551D Mutation and Have Severe Lung Disease

BACKGROUND The development of ivacaftor represents a significant advance in therapeutics for patients with cystic fibrosis (CF) who carry the G551D mutation. Patients with an FEV1 < 40% predicted represent a considerable proportion of eligible patients but were excluded from phase 3 clinical trials, and the effectiveness of the drug in this population is, therefore, unknown. METHODS Data were collected from adult CF centers in the United Kingdom and Ireland with patients enrolled in an ivacaftor compassionate use program (FEV1 < 40% or on lung transplant waiting list). Clinically recorded data were collated from patient records for 1 year prior and for a period of 90 to 270 days following ivacaftor commencement. Each patient was matched to two control subjects who would have met the requirements for the compassionate use program with the exception of genotype. RESULTS Twenty-one patients received ivacaftor for a median of 237 days. Mean FEV1 improved from 26.5% to 30.7% predicted (P = .01), representing a 16.7% relative improvement. Median weight improved from 49.8 to 51.6 kg (P = .006). Median inpatient IV antibiotic days declined from 23 to 0 d/y (P = .001) and median total IV treatment days decreased from 74 to 38 d/y (P = .002) following ivacaftor. Changes in pulmonary function and IV antibiotic requirements were significant compared with control subjects. CONCLUSIONS Ivacaftor was clinically effective in patients with CF who carry the G551D mutation and have severe pulmonary disease. The reductions in treatment requirements were clinically and statistically significant and have not been described in less severe populations.

Effects of cystic fibrosis lung disease on gas mixing indices derived from alveolar slope analysis.

S(cond) and S(acin) are derived from analysis of concentration-normalized phase III slopes (Sn(III)) of a multiple breath inert gas washout. Studies in healthy and COPD subjects suggest these reflect ventilation heterogeneity in conducting and acinar airway zones respectively, but similar studies in cystic fibrosis (CF) are lacking. S(cond), S(acin) and lung clearance index (LCI, a measure of overall gas mixing efficiency) were measured in 22 adults and 18 children with CF and 17 adult and 29 child controls. Plethysmography and gas transfer measurements were performed in adults, and spirometry in all subjects. S(cond) was elevated in almost all CF patients, including children with mild disease and normal LCI. However, S(cond) did not correlate with other measurements and appeared to reach a maximum; further increase in ventilation heterogeneity being restricted to S(acin). The nature and/or severity of CF lung disease may invalidate assumptions underlying the ability to separate phase III slope analysis of ventilation heterogeneity into proximal and peripheral components, and LCI may be a better indicator of gas mixing in this population.

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.

Enhanced photoacoustic gas analyser response time and impact on accuracy at fast ventilation rates during multiple breath washout.

Background The Innocor device contains a highly sensitive photoacoustic gas analyser that has been used to perform multiple breath washout (MBW) measurements using very low concentrations of the tracer gas SF6. Use in smaller subjects has been restricted by the requirement for a gas analyser response time of <100 ms, in order to ensure accurate estimation of lung volumes at rapid ventilation rates. Methods A series of previously reported and novel enhancements were made to the gas analyser to produce a clinically practical system with a reduced response time. An enhanced lung model system, capable of delivering highly accurate ventilation rates and volumes, was used to assess in vitro accuracy of functional residual capacity (FRC) volume calculation and the effects of flow and gas signal alignment on this. Results 10–90% rise time was reduced from 154 to 88 ms. In an adult/child lung model, accuracy of volume calculation was −0.9 to 2.9% for all measurements, including those with ventilation rate of 30/min and FRC of 0.5 L; for the un-enhanced system, accuracy deteriorated at higher ventilation rates and smaller FRC. In a separate smaller lung model (ventilation rate 60/min, FRC 250 ml, tidal volume 100 ml), mean accuracy of FRC measurement for the enhanced system was minus 0.95% (range −3.8 to 2.0%). Error sensitivity to flow and gas signal alignment was increased by ventilation rate, smaller FRC and slower analyser response time. Conclusion The Innocor analyser can be enhanced to reliably generate highly accurate FRC measurements down at volumes as low as those simulating infant lung settings. Signal alignment is a critical factor. With these enhancements, the Innocor analyser exceeds key technical component recommendations for MBW apparatus.

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

WS7.6 UK and Ireland review of ivacaftor in severe CF: Impact on lung function and weight

E. Kerem1, M. Wilschanski1, I. Sermet-Gaudelus2, K. De Boeck3, F.J. Accurso4, M. Konstan5, S. Rowe6, N. Miller7, G. Elfring7, R. Spiegel7, S. Peltz7, J. Barth7, T. Ajayi7, Ataluren CF Study Group. 1Hadassah University Hospital, Jerusalem, Israel; 2Hopital Necker, Paris, France; 3University Hospital Leuven, Leuven, Belgium; 4Children’s Hospital Colorado, Aurora, United States; 5Rainbow Babies and Children’s Hospital, Cleveland, United States; 6University of Alabama-Birmingham, Birmingham, United States; 7PTC Therapeutics, Inc, South Plainfield, United States

108 Analysis of dry powder inhaler (DPI) antibiotics in an adult cystic fibrosis (CF) centre

Objectives DPI antibiotics have been shown to be non-inferior when compared with nebulised antibiotics in research study conditions. Analysis of local anonymous questionnaires demonstrated patient preference for DPIs. We wanted to assess the effect of DPI antibiotics on clinical outcomes in our adult CF population by analysing real world data. Methods Retrospective analysis of inhaled antibiotic therapies (continuous or alternate month regimes) prescribed between June 2012 and January 2015 identified from our CF clinical database. Patients starting DPI were divided into 2 groups: Group A – those converting from nebulised to DPI antibiotics for at least 6 months, and Group B – not on nebulised antibiotics for at least 6 months due to previous intolerance. Best FEV1 and weight, and number of days of IV antibiotic treatment in the 6 month period before and after starting DPI were compared. Paired t test and Wilcoxon signed rank test were used for statistical analysis. Results 149 patients completed successful first dose DPI trials. 70 had complete data sets (49 in group A; 21 in group B). There was no significant difference in pre-DPI versus post-DPI FEV1 or weight in either group. There was a significant reduction in the number of IV days in group B (from median 14 days to 0 days, p = 0.032) but not group A after starting DPI. Conclusion This real world data is consistent with previous studies showing that DPI antibiotics are non-inferior compared to nebulised antibiotics, and demonstrates that the use of DPI antibiotics is associated with clinically useful reduction in need for IV antibiotic therapy. Studies over a longer follow up period are required.

129 Shortened SF6 MBW is a repeatable and sensitive test in adults and children with CF

129 Shortened SF6 MBW is a repeatable and sensitive test in adults and children with CF D. Hannon1, I. Bradbury2, J.M. Bradley3, A. Reid4, N.J. Bell5, J.S. Elborn1, K. O’Neill1. 1Centre for Infection & Immunity, Queen’s University Belfast, Belfast, United Kingdom; 2Frontier Science Ltd, Scotland, United Kingdom; 3Centre for Health and Rehabilitation Technologies (CHART), University of Ulster, Belfast, United Kingdom; 4Belfast Health and Social Care Trust, Belfast, United Kingdom; 5Respiratory Medicine Department, Bristol Royal Infirmary, Bristol, United Kingdom

P75 Pulmonary physiogical tests: trainees experience and exposure

Introduction Knowledge of pulmonary function test (PFT) is essential for every respiratory physician. The level of training and exposure to PFT varies depending on the local facilities, supervisors and the respiratory trainees themselves. Moreover in recently cardio-pulmonary exercise testing (CPET) are becoming more widely available as well. Objectives To test the knowledge of UK respiratory physicians (trainees mainly) on PFT and CPET, identifying what is available locally. The level of exposure to the tests themselves in terms of how to perform, the process involved and the equipment used/ available locally. Methodology An electronic survey was distributed to the UK postgraduate deaneries for all the respiratory trainees and also to some respiratory physicians, thoracic surgeons and lung function physiologists. Feedback was collected anonymously over a period of 6 months (Dec 2012–May 2013). The questions ranged from simple spirometry, PFT, CPET and basic demographics. Results A total of 160 responses were obtained from 16 deaneries out of 20 [1 from outside the UK - OOPE]. 83 (53%) were respiratory specialist/specialty registrars and 61(39%) consultants. 2 respondents had never seen spirometry performed, and 28 (18%) have not seen a PFT performed. Only ¼ have done a PFT themselves. 70% have seen CPET, 29% have done CPET, 75% have a CPET service locally with cycle ergometer (66%) being the most common method to exercise the patient. Respiratory physiologists and respiratory physicians are the ones mainly reporting CPET results with anaesthetist a distant third. Summary Most trainees have been exposed to spirometry but based on this survey almost 20% have yet to see a PFT performed. Understanding the process of how to do a PFT and CPET, experiencing it personally could influence the number of PFT requests. This aspect of respiratory specialty training is still insufficient based on the feedback of respiratory trainees who answered this survey.