Breathing space

Consultant respiratory physician Dr Pallav Shah speaks to PEN about a promising clinical trial offering new hope to ex-smokers living with chronic bronchitis

For patients with chronic bronchitis – an often debilitating form of chronic obstructive pulmonary disease (COPD) in which the main airways of the lung, or bronchi, become irritated and inflamed – excess mucus production is a common and unpleasant problem which sees patients coughing up mucus on a daily basis for many months of the year.

Current medicines, e.g. mucolytics such as carbocisteine, help to facilitate mucus clearance by thinning it down, while inhalers help to open up the airways and deliver medicine right to where it’s needed, but up until now no treatment has been able to actually stop excess mucus production.

This looks set to change with the RejuvenAir™ System, a novel procedure developed by CSA Medical which uses liquid nitrogen to freeze and destroy the mucus-producing goblet cells in the upper layer of airway tissue without killing the stem cells underneath. It’s currently being trialled on ex-smokers at the UK’s Royal Brompton Hospital, in collaboration with Chelsea and Westminster Hospital NHS Foundation Trust, and at the University Medical Center Groningen, the Netherlands.

Leading the trial in the UK is consultant respiratory physician Dr Pallav Shah, who here speaks to PEN about the treatment, some of the safety concerns that need to be considered while performing the procedure, and how it might be used to treat conditions beyond chronic bronchitis.

On trial

“Smoking is the main cause of chronic bronchitis,” explains Shah. “What happens is the cigarette stimulates goblet cell hyperplasia, i.e. excess mucus production, which blocks off the airways, causes coughing and loss of breath, and also makes you more vulnerable to infection.

“Some colleagues in Boston had been using a liquid nitrogen treatment for cancers and noticed that in adjacent tissue the goblet cell hyperplasia on subsequent biopsies was reduced. They realised that if you ablate the mucosa with liquid nitrogen, the epithelial surface dies off and regenerates within 48 hours. That new, regenerated, healthy mucosa has fewer goblet cells in it, meaning you produce less mucus and in turn feel less breathless and, hopefully, have fewer infections – that’s what we’re trying to find out.

“We trialled the treatment on ten lung cancer patients in a previous study who were going to have their airways and lungs resected, and have so far treated 11 patients with chronic bronchitis – five here in the UK and six in the Netherlands.”

In March, the pioneering treatment was performed for the first time in the UK on Londoner Jayne Hewitt. “Days later my chest already didn’t feel as tight,” she said. “I was coughing less than before and breathing a bit better, even though only one part of my right lung had been treated. It used to feel like I had an elephant sitting on my chest and now it doesn’t. It has given me such a boost and I feel more hopeful about my future now.”

Despite Hewitt’s praise, Shah is cautious about labelling the treatment a success too soon: “At the moment we’re only treating part of the lung, so we’ll need to wait until we treat the whole lung before we can really claim any clinical improvement.”

It also remains to be seen whether or not the procedure will need to be repeated – Shah expects so, but it may also depend on the patient. “We’re currently only treating

ex-smokers, so the goblet cell hyperplasia hopefully shouldn’t come back, but say they take up smoking again, that could

re-stimulate the goblet cells. I would anticipate that it will need to be repeated, but we’re yet to find that out – and, of course, the good thing about this treatment is that it can be repeated if necessary.”

Safety considerations

During the procedure, liquid nitrogen, cooled to around -196˚C, is targeted at the lung via a bronchoscope and catheter and delivered at a carefully controlled dose corresponding to the patient and the part of the lung being treated. All in all, it takes as little as 30 minutes to perform under general anaesthetic, and the patient is free to leave the hospital just four hours later. Despite this relative simplicity, the procedure is not without its risks.

“The liquid nitrogen vaporises very quickly inside the body to form a gas and increases in volume quite significantly,” explains Shah. “Where you have an area of trapped gas you have a risk of lung puncture, so we always make sure that the patient is ventilated well and that we can remove the gas quickly to reduce that risk or the risk of pneumothorax (collapsed lung). Hypoxia is another potential problem: if you pump someone with nitrogen, you displace oxygen, which means your oxygen levels drop.

“But we monitor all of these, which is why a skilled team carries out the procedure very carefully under general anaesthetic and controls the dose each patient gets.”

Next steps

As for what comes next, the trial’s first step will be to establish the safety. “We haven’t had any

problems so far,” says Shah, “but we want to make sure that we don’t run into any of the problems we’ve thought about, i.e. pneumothorax or hypoxia, and that we don’t encounter any unexpected events.”

Following that, the second phase of the study will involve treating the whole of the lung in those patients who have already been partially treated. “We plan to recruit another 28-30 patients for whom we’ll treat both lungs, one in the first instance and the second a few weeks later. Depending on the results, we’ll do further studies to try and refine the treatment, with the final phase being some kind of randomised controlled study to evaluate whether it is making a big difference or not. It would be nice to have the RejuvenAir System ready quickly in order to get it to our patients, but realistically we’re looking at a three to

five-year plan for commercialisation.”

Looking ahead, it may also be possible to use the treatment for other conditions. “It’s already available in a slightly different format for treating lung cancer and tumours, etc., but the version we’re using for chronic bronchitis is a much more refined and sophisticated one,” says Shah. “It may be in the future that we’re treating asthmatics, who have similar problems of mucus hypersecretion and so on.”

It’s early days, of course, but Shah is optimistic: “What we want to do is evaluate the treatment very carefully and systematically and make sure that it’s working and effective and safe for our patients.

“It’s looking very promising.”

Dr Pallav Shah

Consultant Physician in

Respiratory Medicine

Royal Brompton Hospital

Chelsea and Westminster Hospital