Multiple-breath inert gas washout test and early cystic fibrosis lung disease.

Regular spirometry measurement is an accepted component of clinical monitoring of adults and school-age children with cystic fibrosis (CF). Specifically, the forced expired volume in 1 s (FEV1), or its rate of decline, is commonly used to monitor disease progression in individuals, and as an outcome measure in clinical trials. However, as the survival of subjects with CF improves, there has been a shift towards closer monitoring and more aggressive treatment of early CF lung disease. As a consequence, two major disadvantages to the use of FEV1 in earlyCF lung disease have become apparent. Many school-age children with CF now have FEV1within thenormal range, even though they probably have lung disease. Also, reliable forced expiratory manoeuvres are difficult to obtain in children under the age of 5 years, with testing in infants being largely confined to specialist laboratories, and testing in preschool children relatively novel. There are good theoretical reasons why spirometry may be insensitive to early CF lung disease. First, airway disease in CF is known to be non-uniformly distributed. As flow measured during forced expiration is the integrated output of all airways, then it is possible that minor alterations of airway calibre in some lung regions may be masked by normal function in other regions. Secondly, airway obstruction inCF is partly due to intraluminal mucus, and thismaybedislodged by a forced expiratory manoeuvre. Thirdly, spirometry is insensitive to changes in the peripheral airways, as the large total cross-sectional area in the lung periphery prevents flow limitation in this region, even in the presence of disease. For the researcher, the relative insensitivity of FEV1 inmild diseasemandates ever larger sample sizes to demonstrate significant benefit in intervention studies. This is particularly challenging for interventions aimed at subjects with very early or mild disease, where baseline FEV1 will be within the normal range (ie, within two standard deviations of the mean of the non-CF population). For the clinician, the decision to increase or reduce treatment in subjects with mild disease may need to rely on symptoms andmicrobiology, as spirometry results may remain normal. The two most commonly cited alternative measures are high resolution CT (HRCT) scans and measures of ventilation distribution frommultiple-breath inert gas washout (MBW) tests. The potential utility ofHRCTas an outcomemeasure has been discussed extensively, and there has been important progress in standardising data acquisition and scoring systems for interpretation of these studies, However, the main limitation of HRCT as an outcome measure is the risk of radiation exposure, which limits the number of scans that can be performed each year. MBW describes the analysis of changes in exhaled tracer gas concentration over a series of tidal expirations. This can be performed using resident N2 as the marker gas, or alternatively an inhaled marker gas can be employed. In the former case, washout is performed with 100% oxygen, which can be provided via a bias flow or demand valve. In the latter case it is first necessary to ‘wash-in’ a tracer gas. Washout can then be performed with air. The most straightforward method for analysing an MBW is to study the progression of the end-tidal marker gas concentration, plotted against either time, breath number or an index of cumulative expired volume. From the last of these plots, it is possible to calculate the lung clearance index (LCI) which is the cumulative expired volume required to clear this inert gas from the lungs to 1/ 40th of the starting concentration, divided by the functional residual capacity (FRC). An increase in LCI indicates inhomogeneity of ventilation distribution, or inefficient gas mixing, and this index is therefore predicted to rise in the presence of mild CF lung disease. The potential value of LCI as an outcome measure is supported by a series of crosssectional studies, which have demonstrated that children and adults with CF have an abnormal LCI even in the presence of a normal FEV1. There ismoderate to strong correlation between LCI and the modified Brody score obtained fromHRCT, with two studies suggesting that these two measures detect abnormalities in adults and children with similar frequency. 15 In order to determine whether LCI can genuinely function as a marker for early disease, it is also necessary to demonstrate that the outcome improves in response to recognised treatments, and that it corresponds tomore establishedmarkers on longterm follow-up. The one longitudinal study reported to date was based on clinically collected data, and suggested that LCI becomes abnormal earlier than FEV1. Two studies have demonstrated that LCI in subjects with established disease responds variably to a course of intravenous antibiotics. Theflawof both of these studies is that the subjects had established lung disease, and it is possible that ventilation inhomogeneity may increase rather than decrease following treatment in subjects with established bronchiectasis, if airways that were previously completely obstructed are partly opened by treatment. This may explain why most subjects in these studies showed some improvement in LCI following treatment, but aminority showed deterioration. In this issue of Thorax (see page 379) Aminandcolleagues report a study inwhich 20 children with CF who had FEV1 $80% predicted were given hypertonic or isotonic saline in a 4 week crossover trial, separated by a 4 week washout. In addition to LCI, the investigators recorded FEV1 and the CF Questionnaire-Revised (CFQ-R) as primary outcomes. Baseline characteristics including the LCI were not significantly differentbetween studyperiods. Fourweeks of twice-daily inhalation of hypertonic saline resulted in a significant decrease (improvement) inLCI versus isotonic saline, whilst there was no significant change in FEV1 or CFQ-R. The authors point out that the absolute increase in FEV1 recorded following 4 weeks of hypertonic saline was 62 ml,which is similar to that reported from the positive trial of Elkins et al, but that in this case a relatively small sample size produced a p value >0.05. Correspondence to Dr Paul Aurora, Portex Respiratory Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK; [email protected]