Cystic Fibrosis Gene Therapy Research

Lung physiology and inert gas washout

One of the challenges of the gene therapy programme has been to develop methods of following changes in the lung that are non-invasive and easy for patients, but more sensitive that traditional lung function tests. The lung clearance test involves following the washout of an inert tracer gas from the lungs. This technique has been used in Sweden and at Great Ormond Street in London, and is more sensitive at detecting early lung changes in children than spirometry alone. However, until recently the technology to perform this investigation has been custom built, temperamental and very expensive.

We have adapted an Innocor device to measure lung clearance. This is a novel photoacoustic gas analyser originally produced for non-invasive cardiac output measurements. It contains a highly sensitive gas analyser, which allows us to perform washout tests using very low concentrations of the inert tracer gas sulphur hexafluoride (SF6). In order to use Innocor in this way, we have rebuilt the patient interface, and use custom-built software to analyse the raw data from the machine.

In the first part of the test, the subject breathes in air enriched with 0.2% SF6, this is 1/20th of the SF6 concentration normally used for such tests. It normally takes 5-10minutes for this to be evenly distributed throughout the lungs. Only normal tidal breathing is required, and the subject is distracted by watching TV. When the inspiratory and expiratory concentrations of this gas are equal, we remove the source of tracer gas and the subject breathes room air. With successive breaths the concentration of SF6 falls as it is then washed out of the lungs. From this we can calculate a number of indices of how efficiently gases are mixing in the lungs. This in turn tells us about the state of the lungs, and in early lung disease reflects changes in the small airways.

This test forms an important part of the assessment of CF lungs in the CF Gene Therapy Run-In Study at the Western General Hospital in Edinburgh, the Royal Hospital for Sick Children in Edinburgh and the Royal Bromptom Hospital in London.

Key Publications

Horsley, AR, Gustafsson PM, Macleod KA, Saunders C, Greening AP, Porteous DJ, Davies JC, Cunningham S, Alton EWFW, Innes JA. Lung Clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis. Thorax 2008;63:135-140