Kenneth Macleod

Consensus statement for inert gas washout measurement using multiple- and single- breath tests

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.

Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis

Background: Lung clearance index (LCI) is a sensitive marker of early lung disease in children but has not been assessed in adults. Measurement is hindered by the complexity of the equipment required. The aims of this study were to assess performance of a novel gas analyser (Innocor) and to use it as a clinical tool for the measurement of LCI in cystic fibrosis (CF). Methods: LCI was measured in 48 healthy adults, 12 healthy school-age children and 33 adults with CF by performing an inert gas washout from 0.2% sulfur hexafluoride (SF6). SF6 signal:noise ratio and 10–90% rise time of Innocor were compared with a mass spectrometer used in similar studies in children. Results: Compared with the mass spectrometer, Innocor had a superior signal:noise ratio but a slower rise time (150 ms vs 60 ms) which may limit its use in very young children. Mean (SD) LCI in healthy adults was significantly different from that in patients with CF: 6.7 (0.4) vs 13.1 (3.8), p<0.001. Ten of the patients with CF had forced expiratory volume in 1 s ⩾80% predicted but only one had a normal LCI. LCI repeats were reproducible in all three groups of subjects (mean intra-visit coefficient of variation ranged from 3.6% to 5.4%). Conclusions: Innocor can be adapted to measure LCI and affords a simpler alternative to a mass spectrometer. LCI is raised in adults with CF with normal spirometry, and may prove to be a more sensitive marker of the effects of treatment in this group.

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 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.

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.

Multiple breath washouts in children can be shortened without compromising quality

Lung clearance index (LCI) derived from multiple breath washout (MBW) is a sensitive, noninvasive measure of ventilation heterogeneity and is used for the assessment of cystic fibrosis (CF) [1], asthma [1] and primary ciliary dyskinesia (PCD) [2]. LCI is the number of lung turnovers (functional residual capacity (FRC)) required to washout an inhaled inert gas to 1/40 of its initial concentration: a historically set end-point of no physiological significance [3]. The number of lung turnovers needed to wash out the gas, and hence the LCI, increases with disease severity. It is non-effort-dependent and requires only passive cooperation. The test can be time-consuming, especially with severe airway obstruction as more time is required to wash out the tracer gas. This is a particular problem in young children, in whom a test lasting several minutes is intolerable. This could be shortened by stopping the test at a higher concentration of tracer gas. We propose that instead of 1/40 of the initial concentration being used as an end-point (“LCI standard” (LCIstd)), the concentration could be raised to 1/30 (LCI0.75), 1/20 (LCI0.5) or 1/10 (LCI0.25) of the starting concentration of tracer gas, or using a fixed time period of washout, for example 20 s, or a fixed number of breaths. Shortened LCI is quicker to perform with no loss of measurement quality and could be used in young children http://ow.ly/SyC5a

Supine posture changes lung volumes and increases ventilation heterogeneity in cystic fibrosis

Introduction Lung Clearance Index (LCI) is recognised as an early marker of cystic fibrosis (CF) lung disease. The effect of posture on LCI however is important when considering longitudinal measurements from infancy and when comparing LCI to imaging studies. Methods 35 children with CF and 28 healthy controls (HC) were assessed. Multiple breath washout (MBW) was performed both sitting and supine in triplicate and analysed for LCI, Scond, Sacin, and lung volumes. These values were also corrected for the Fowler dead-space to create ‘alveolar’ indices. Results From sitting to supine there was a significant increase in LCI and a significant decrease in FRC for both CF and HC (p<0.01). LCI, when adjusted to estimate ‘alveolar’ LCI (LCIalv), increased the magnitude of change with posture for both LCIalv and FRCalv in both groups, with a greater effect of change in lung volume in HC compared with children with CF. The % change in LCIalv for all subjects correlated significantly with lung volume % changes, most notably tidal volume/functional residual capacity (Vtalv/FRCalv (r = 0.54,p<0.001)). Conclusion There is a significant increase in LCI from sitting to supine, which we believe to be in part due to changes in lung volume and also increasing ventilation heterogeneity related to posture. This may have implications in longitudinal measurements from infancy to older childhood and for studies comparing supine imaging methods to LCI.

S22 Lung clearance index, FEV1 and CT findings in cystic fibrosis: data from the UK CF Gene Therapy Consortium run-in study

Introduction Lung Clearance Index (LCI) is a measure of lung gas mixing derived from the Multiple Breath Washout (MBW) test. We present LCI, FEV1 and CT data from the Run-In Study, a longitudinal study in preparation for a multi-dose trial of nebulised gene therapy for CF. Methods MBW, spirometry and low-dose HRCT chest were performed as part of the first Run-In Study visit. LCI was reported as the mean result from at least two technically acceptable sulphur hexafluoride MBW tests performed using a modified Innocor gas analyser. Spirometry was performed to ERS standards. CT scans were assessed by two independent radiologists for extent and severity of bronchiectasis, wall thickening, presence of small and large airway plugs, and gas trapping. Results 191 patients attended visit 1, mean (range) age 22.6 (10–59.1) years. Validated LCI, FEV1 and CT results were available for 167, 191 and 150 patients, respectively. Mean (SD) FEV1 was 72(19)% predicted. Mean (SD) LCI was 10.7 (2.7), with mean intravisit coefficient of variation of 4.9%. LCI correlated negatively with FEV1 (r=−0.68, p<0.001), but was abnormally elevated in 72% of participants with normal FEV1 (see Abstract S22 Figure 1; triangles indicate FEV1 >80% and LCI >7.5). 95% CI for LCI in normal subjects 5.9 to 7.5. Both FEV1 and LCI correlated with all CT measures (p<0.001), most strongly with extent of bronchiectasis. LCI correlated better than FEV1 with extent of bronchiectasis, r=0.72 (p<0.001) vs r=−0.61 (p<0.001), respectively.Abstract S22 Figure 1 Conclusions Results from this large cohort suggests that LCI is a more sensitive test of early CF lung disease, and correlates better with extent of bronchiectasis seen on CT, than FEV1. Validation of data from subsequent study visits is in progress and will be reported at a future date.