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BRITISH BROADCASTING CORPORATION
RADIO SCIENCE UNIT
CASE NOTES Programme no. 6 - Cystic Fibrosis
RADIO 4
TUESDAY 12th February 2008 2100-2130
PRESENTER: MARK PORTER
REPORTER: LESLEY HILTON
CONTRIBUTORS: ANDREW BUSH
NICKY AND TONI CALLAGHAN
SOPHIE LONGTON
ERIC ALTON
PRODUCER: DEBORAH COHEN
NOT CHECKED AS BROADCAST
PORTER
Hello and welcome to today's programme which is all about cystic fibrosis - the most common genetically inherited life threatening disease in the UK. There are currently around 8,000 children and adults living with the condition, but at least two million of us carry the faulty gene.
All babies are now routinely screened for CF - which is how Fraser Brown, the Prime Minister's son was diagnosed 18 months ago. But in the past it has been an easy condition to miss. Nick and Toni Callaghan's son, Harry, wasn't diagnosed until he was three.
NICK CALLAGHAN
It was actually my father and Toni's mother that always called him Salty Boy and that was the single biggest worry was once I read the salty skin factor that was just alarm bells.
PORTER
More about why Harry tasted salty a bit later.
As well as a look at the latest advances in gene therapy which, so far, have failed to live up to early expectations.
And we'll be meeting 21-year-old student Sophie who has found that university life has had quite an impact on her CF.
SOPHIE
Growing up I had all my treatments at home, I was actually only in hospital about two or three times. But since being at university it's been quite a different story and I've been admitted to hospital four times in the last 18 months.
PORTER
My guest today is Andrew Bush, he's professor of paediatric respirology at the Royal Brompton Hospital, and Imperial College, London.
Andrew, what is the inherited abnormality in cystic fibrosis and what are the implications for those affected?
BUSH
Cystic fibrosis is an inherited condition and people with cystic fibrosis do not make a protein. This protein is concerned with transport of salt and water and as a result of this protein not being there or not functioning properly you get sticky secretions, particularly in the lungs and in the digestive system. This means that you're prone to chest infections and often have digestive problems as well.
PORTER
And explain the genetics involved because as I said there are two million people who carry the faulty gene, not all of them have got a problem, in fact none of them have got a problem, how does that work?
BUSH
You need two copies of the faulty gene if you're going to get cystic fibrosis. So if you're a carrier you have one copy of the gene and one normal gene and for practical purposes your health is just the same as anybody else. If, however, you have a child with somebody else who's a carrier one in four of your children will have cystic fibrosis.
PORTER
So you need to have both - both faulty genes to get the condition?
BUSH
Exactly.
PORTER
And are there any clues that someone may be a carrier?
BUSH
Not really, no, very often people will say I can't understand how my baby's got cystic fibrosis, we have no family history, we're both perfectly fit.
PORTER
And we'll talk about how the condition's managed a bit later on but presumably the earlier it's picked up the better. We now have a national screening programme, what does that involve?
BUSH
Absolutely. Before the screening programme you had to wait until somebody became ill or was born into a family where there were people who were ill already with cystic fibrosis before you made the diagnosis.
PORTER
I'll stop you there - I mean what would make you, as a consultant paediatrician, suspicious that someone might have had CF then before we were routinely testing?
BUSH
Typically infants and babies would present with chest infections, they would be very hungry babies, eating a lot, not gaining weight, a lot of diarrhoea, foul smelling stools, occasionally, as we heard, somebody would kiss the baby and taste salty.
PORTER
And that's because of the extra salt they've got in their sweat.
BUSH
That's the extra salt in the sweat, absolutely.
PORTER
So you needed a high index of suspicion basically but now presumably every baby's tested, is the screening test faultless?
BUSH
No test is perfectly faultless but it will pick up virtually every bad case of cystic fibrosis and the screening test is done on the routine heel prick that all babies have within a few days of life collected by the midwife.
PORTER
And the advantage to you, as a paediatrician looking after someone who's got cystic fibrosis, of that early diagnosis is what?
BUSH
First of all they are basically well, you haven't got lost ground to make up. The second thing is for the parents - before the screening test very often mothers would take their babies to doctors, to nurses, to health visitors saying there's something wrong, there's something wrong, I don't know what it is. And sometimes sadly they were told they were just neurotic mothers, there was nothing the matter with the baby and of course if you're told that and found out that your baby really is seriously ill this is not a great start to your relations with the medical profession.
PORTER
Well both Nicky and Toni Callaghan's sons have cystic fibrosis. Harry was diagnosed when he was three, raising the possibility, of course, that his younger brother Jack, who was just eight weeks old at the time, could have the condition too. He did. Two years on and family life at the Callaghan's revolves around keeping the boys healthy. As I discovered when I visited them at home, east of London.
NICKY CALLAGHAN
We've got quite a large kitchen, one of the reasons we moved here in the first place was following the diagnosis we found we were overburdened with medication.
PORTER
So let's just open the cupboard here and - well it looks like the back shelf of a pharmacy.
NICKY CALLAGHAN
Exactly right. The Creon 10,000 you see there, the lots of it, they're the dietary enzymes that they have to take because their pancreas doesn't produce the necessary enzymes mainly to digest fat, so the children would each take around 30 capsules per day. We have to help them a bit with apple puree on a spoon but ...
PORTER
Is that 30 each?
NICKY CALLAGHAN
Yeah.
PORTER
So it's 60 capsules a day, well that's why the cupboard's half full of Creon.
NICKY CALLAGHAN
Yes, yeah, there's probably just over a week's supply there.
PORTER
But that's just part of it isn't it because you've got some more over here?
NICKY CALLAGHAN
Oh yeah, yeah,
PORTER
Let's have a look in - ah right, so the utility room which has yet more cupboards with even bigger boxes.
NICKY CALLAGHAN
So there we've got mostly nebulised antibiotics.
PORTER
So by nebulised these are the machines that produce a mist that Jack and Harry's breathing in?
NICKY CALLAGHAN
That's correct, yeah. It basically delivers the antibiotic in a fine mist straight into the lungs.
PORTER
And how often do they need to have that?
NICKY CALLAGHAN
That would be twice daily because they were both tested positive for a bacteria called pseudomonas aeruginosa for at least three months.
PORTER
And how long does each nebulising take?
NICKY CALLAGHAN
It can take up to 20 minutes in a conventional nebuliser . Thankfully we have an electronic one called an eflow which cuts it down to less than five minutes, so that's a real godsend.
PORTER
Got a very reluctant Jack sitting on your lap here Toni. Tell us when you first realised something was wrong.
TONI CALLAGHAN
Jack was already born and we were trying to potty train Harry at the time and on one Saturday, due to Harry's lack of cooperation with doing the potty training, he obviously sort of held himself and then eventually when he did go he had a rectal prolapse in the time of actually getting him to the hospital it rectified itself. When we'd gone home Nick, my husband, actually looked up on the internet ...
PORTER
Googled it.
TONI CALLAGHAN
... rectal prolapse and saw links with cystic fibrosis. And looking at the symptoms of it he then noticed that Harry did actually have a couple of CF symptoms which one of them was the salty tasting skin.
NICKY CALLAGHAN
As soon as I read that you know the alarm bells really did start ringing because ...
PORTER
Did you notice when you'd been kissing him and things that he actually tasted?
NICKY CALLAGHAN
It was actually my father and Toni's mother that always called him Salty Boy.
PORTER
So you then asked for him to be formally tested.
NICKY CALLAGHAN
The GP was very good, obviously contacted the paediatric team at the Royal London Hospital, Whitechapel and we had basically the next available sweat test which was just over a week away. They always repeat a positive sweat test with another one, just to make sure, so yeah within - by the following day we had the diagnosis.
PORTER
That must have been quite a shock.
NICKY CALLAGHAN
From the first symptom to the actual diagnosis probably the worst period of my life, you know, you're just so ill with worry. So having said that it didn't really - the diagnosis didn't come as a relief really but yeah, yeah terrible, terrible time.
PORTER
Of course the key thing about this story is that by then your next worry must have been well is Jack affected too?
TONI CALLAGHAN
That's right, yeah, because when this rectal prolapse happened Jack was eight weeks old and obviously his result came back positive.
PORTER
I'm intrigued by the physio because that's quite demanding. The aim of the physio, on the chest, is to do what?
TONI CALLAGHAN
If there's any secretions lurking about in the lungs it's obviously to help them to release from the lungs and come out.
PORTER
How long do you spend doing physio on a typical day?
TONI CALLAGHAN
In the morning generally sort of only about sort of 15-20 minutes on each of them because you just don't have the time to do a really long session. But in the evenings sort of 45 minutes to an hour. We generally do one each, so that it's not both of us.
PORTER
Show me - show me what you do if Jack agrees and doesn't mind. It's not looking promising I must say.
TONI CALLAGHAN
Let's just show how we do pat back. He just lies down and it's a percussion on his back. It involves both sides of his back, the front of his chest each side and also the sides as well. He's not very cooperative, I generally do have to wait for him to fall asleep before I can actually do his physio.
PORTER
Two children, what have you thought about extending the family further, have you considered that or have you worried about the implications?
TONI CALLAGHAN
There is obviously big implications because depending on you as a couple you would have to decide on what route to go down. There is an IVF procedure now called PGD which once the embryo is fertilised you can have a cell removed.
PORTER
Because if you were to conceive naturally the odds of having ...
TONI CALLAGHAN
There's still a one in four chance of having another CF baby.
PORTER
...one in four chance each pregnancy.
TONI CALLAGHAN
Yeah. There are two chances of the baby being a carrier, one that he could be all clear and one chance that it would also have CF again. So personally my view is I would never risk with another pregnancy for the outcome of another CF baby.
PORTER
Toni Callaghan. You are listening to Case Notes. I am Dr Mark Porter and I am discussing cystic fibrosis with my guest Professor Andrew Bush.
Andrew, we talked about the heel prick test there as a screening test but we heard in the package there mention of the sweat test, that's still the definitive test for making the diagnosis, how does that work?
BUSH
More than 99% of patients with cystic fibrosis will be diagnosed by a properly performed sweat test. It's a simple outpatient procedure and you collect sweat into a tiny little tube, you need less than 50 micro litres of sweat. It's very important it's done in a centre that is doing lots of them because it's quite a skilled test to do to collect the sweat properly. But it's usually diagnostic.
PORTER
And that's because their sweat is uncharacteristically salty?
BUSH
Exactly as we heard that they have much more salt in their sweat than normal as the family noticed.
PORTER
We heard there Jack and Harry's regimes I mean they seem to centre around keeping the lungs as healthy as possible and trying to normalise their digestive function with enzyme supplements, is that a typical regime for most children with CF?
BUSH
Yes pretty typical indeed. Some children don't have the digestive problems but most do and keeping the lungs clear is one of the most important things there is for cystic fibrosis.
PORTER
Let's just start with the digestive problems, that's presumably because the secretions in the pancreas as thicker and stickier than they should be, is that right?
BUSH
Yes, the pancreas produces digestive enzymes - proteins that break down the food that we eat - in cystic fibrosis, often before the baby is born, the pancreas has been destroyed and cannot produce these digestive enzymes. So these capsules replace them and you have to swallow capsules with virtually every bit of food you take.
PORTER
Now your special interest is the chest and that's where most people with CF have problems, what actually happens to their lungs?
BUSH
The risks for the patient with cystic fibrosis are recurrent and chronic infections, they get infected with particular germs, bugs - things like staphylococcus, pseudomonas - so a lot of energy is devoted firstly to trying to prevent infection by careful hygiene precautions and prevention of cross infection, secondly with physiotherapy - as we heard described there ...
PORTER
And that's literally just helping them do what you and I do normally and bring things up.
BUSH
Exactly, it's helping them to clear secretions from their chest, physiotherapy - as they get older we encourage lots of physical exercise, which is also very important to help clear the chest.
PORTER
And what about the drugs that you're using - is it just a matter of giving antibiotics or are there any special drugs that we can use? We heard there about an enzyme to break up the secretions in the lungs, is that standard practice?
BUSH
Yes in terms of the nebulisers antibiotics, if you have a chronic infection of pseudomonas aeruginosa it's very clear that using nebulised antibiotics is highly beneficial. And with modern nebulisers, like the eflow that we heard about, nebulisation time has come down from 20 minutes to two or three. As well as that sometimes you would have oral antibiotics, there is an enzyme that you can give again with nebuliser that breaks down the secretions and helps you to clear them more easily, the enzyme tends to be reserved for those who are chronically producing mucus but some people are using it early on in their course.
PORTER
We talked about lungs and the digestive system but obviously this is something that affects the whole body, do they run into trouble elsewhere?
BUSH
Yes, as people are growing older with cystic fibrosis we're learning about new complications. One of those is diabetes and about a third of adults with cystic fibrosis will eventually go on to require insulin. Another issue, fortunately less common, is liver disease. We're also learning about bone disease, that about a third of adults with cystic fibrosis have bone disease, may get a pathological fracture or have reduced bone mineral density. Another issue is stress incontinence, in women in particular with cystic fibrosis who are coughing a lot this can be a big issue and is often not diagnosed because people don't like talking about it and it's something that people perhaps find not easy to ask about.
PORTER
You're a paediatrician so presumably your responsibility ends when your patient stops being a child, who do you hand them over to and what speciality?
BUSH
Well at the Brompton Hospital we have the largest adult cystic fibrosis clinic in the country, if not the world, with around 600 adult patients attending it. So we have specialist chest physicians who understand cystic fibrosis and have a unit - a multidisciplinary unit - that is able to deal with the complications.
PORTER
Is that available across the country?
BUSH
Increasingly it is, until relatively recently cystic fibrosis was a disease of children and not many survived into adult life, pretty soon now there will be more adults with cystic fibrosis than there are children, as people are surviving longer. So really excellent adult units have sprung up through the country and it's really important, in my view, that an adult with cystic fibrosis gets care linked to a cystic fibrosis centre.
PORTER
Well Sophie Longton was diagnosed with CF when she was eight. Up until then her recurrent chest problems had been put down to nothing more than a combination of bad luck and childhood illnesses. She's now 21 and leading life to the full at Manchester University. We sent our reporter Lesley Hilton along to see if she could keep up.
LONGTON
These are my huffs, this is part of my physio routine which I do every morning. [Breathing and coughing]
My parents were devastated when they found out that I had cystic fibrosis because before - before they'd been told that I had it they'd never even heard of it and they went to the local library and got books out and read up on cystic fibrosis which were out of date and it was a very morbid and very devastating diagnosis - life expectancy very short. Being so young I didn't realise how serious it was and at first I sort of enjoyed the attention and being told that I had to start taking tablets - all different colours and shapes and quite exciting. And it did start to sink in eventually and I think the first time that I realised how serious cystic fibrosis was was when I had to stay overnight in hospital and have my first ever IV therapy.
HILTON
Okay, and now you're 21 you're at university how does your condition affect your life now?
LONGTON
It was a huge change for me to start university and to have to order all my own prescriptions, have to do all my own physio, prepare my nebulisers myself and wash them myself, make sure that I take all my tablets. For me my new university lifestyle - partying, going out every night, doing sports, not eating a high calorie diet, not getting enough sleep, this crazy sort of lifestyle - after six weeks really impacted on me and I actually ended up being admitted to the adult CF centre in Manchester.
HILTON
Why do you think that is, do you think it is down to the lifestyle?
LONGTON
I think that partly it is due to the lifestyle and also due to the fact that I'm getting a bit older and CF, as you grow up, it does progress and I've had quite a few problems with hemoptysis, which is coughing up blood, and potentially this could be related to the lifestyle and it does tend to happen when I get stressed or when I've had a particularly busy time.
This is one of my nebulisers, this is what I do every morning and it's got like a sea salt solution in which helps to loosen the mucus, it makes my lungs moist and it helps me to cough. [Breathing] So overall throughout the course of the day I'd say CF takes up at least two hours and that's when I'm well. When I'm not well it's a very different story and sometimes the whole day can be taken up with treatments.
HILTON
So what would you think about having a lung transplant, is that an option that you would want to consider?
LONGTON
At the moment I'm very lucky in the sense that my lung function is very high, it's actually in the 90s, which is for a person with cystic fibrosis is exceptional and I do believe that's because I'm compliant on the medication and I really work hard at my physio and doing my exercise. However, I am aware that because there's no cure for CF, as I get older and my condition progresses this is going to decrease and there may be a point when I do need to decide on a lung transplant. But at the moment because I'm so well that's not really in my mind, I'm not really thinking about that.
Every day I usually go running in the park and I leave a trail of mucus behind me because of all the mucus that I cough up and my friends don't like to run behind me.
HILTON
How do you see your future with CF, I mean does it influence your choice of career and things like that?
LONGTON
Well I try and not let it influence anything, however, practicalities such as when I finish university I want to go to travelling round the world, I went for three weeks last summer and half my rucksack was taken up by medication. But career wise I mean at one point I was considering being a physiotherapist but when I did work experience and looked into it I realised I would be working in a hospital everyday and decided that potentially that wasn't going to be the best thing for me because I was exposing myself to infection. So I changed my career path and decided to do a different degree. But I think it will be important that I find a career that is flexible; if I need some time off to do my medication or if I'm having a bad day on my CF, you know, is quite bad at that time, I will need a career that will provide for that. So unfortunately it does affect different choices and decisions in life.
PORTER
Sophie Longton talking to Lesley Hilton.
Professor Andrew Bush, one thing Sophie didn't mention there was whether or not she might start a family, which I suppose is becoming more of an issue now that people with CF are living much longer, what are the implications for her?
BUSH
Yes indeed and for the Sophie if she had children with somebody who was not a carrier her own children would not have cystic fibrosis but they would themselves be carriers. If, however, she had children with somebody who was a carrier himself then 50% of her children would have cystic fibrosis.
PORTER
So genetic counselling would be a sensible thing to do and that's what genetic counselling exists for.
BUSH
Absolutely and I think anybody with cystic fibrosis or the relative of somebody who has cystic fibrosis ...
PORTER
It's not just Sophie, it might be her brothers and sisters as well.
BUSH
Indeed and our routine advice to say to parents who have a baby with cystic fibrosis is their own brothers and sisters who may be a risk of being carriers should seek genetic counselling.
PORTER
And what about the implications for fertility because it does affect male fertility but not necessarily female fertility?
BUSH
Indeed. Males with cystic fibrosis, 98% of them, are infertile. Now they can have babies with test tube fertilisation techniques and these are already up and running and working but they are infertile like a man who's had a vasectomy. Women with cystic fibrosis are fertile and can have babies and many of them do have babies.
PORTER
Of course another possible benefit of having identified the faulty gene responsible for CF is that we could use gene therapy to replace it with the correct one. And the lungs are a good place to start - not only do they pose the biggest threat to the welfare of patients with CF, but the cells lining the airways are easy to get to. Inserting the correct gene into cells in the lungs should mean they switch to producing normal secretions, instead of the thick sticky phlegm seen in CF. But how do you get the replacement gene into the cells? Professor Eric Alton heads up the work of UK Cystic Fibrosis Gene Therapy Consortium at the Royal Brompton.
ALTON
If you've got a disease that is due to a single gene going wrong the first thing you need to do is to identify the gene and that happened in 1989 with groups in America and Canada. And once you've got that you're through a bottleneck where you can say I now want to replace the faulty gene - that doesn't mean to say the old gene goes away, you just simply put the new gene there on top of it. The key issue is that we are working against evolution. We're trying to get it into lung cells and lung cells are made to keep things out, so when you go out into the road, into the high street, and you breath in all the pollutants you mustn't take those into your lung cells. What we're trying to do is to go against evolution and that's why gene therapy's so difficult because you're trying to put in a new gene into a cell that says no thanks.
PORTER
What you need is some form of Trojan horse..
ALTON
You could simply put the gene into a nebuliser that CF patients are familiar with and spray it into the lungs and that doesn't do any good at all, the lung immediately says no I recognise that, no thank you. So it is, as you say, a Trojan horse and you have to carry it into the cell somehow. The most obvious thing to do is to use a virus, so you can put the CF gene into a virus, the life ambition of any self respecting virus is to give you a cold, what it does, of course, is it infects your epithelium, your lining cells, and it puts its own genes in there, which is why you feel awful. Well why don't you just simply put the CF gene along with the virus's genes into the same virus, it'll do the dirty work for you. And that works spectacularly well but unfortunately you can only do it once because the body recognises the virus and says aha I've seen you before and when you do it the second time, because you do have to do it more than once because it only lasts a couple of weeks, the expression of the gene, the body says no I've seen you before and the immune system rejects it. So you can do gene therapy for a couple of weeks but that's not going to make anything better. So viruses are very interesting and very efficient and they've spent two million years getting over evolution, but they're not going to be the answer, at least for the moment.
And so the other way is to wrap the gene in fat globules, called Liposomes, and the reason you do that is because the cell membrane - the outside of the cell - is also made of fat. So the fat and the fat mix with each other, it's a bit like cooking, and they mix with each other and therefore the gene can slip into the cell because of that. It's less efficient than viruses but you can do it repeatedly. So all our efforts in the consortium are all based on using these called non-viral approaches, in other words lipsomes.
PORTER
So what stage are we at now?
ALTON
With the patients at the moment we have selected within the consortium what we think is the very best way of transferring the gene into cells. There are all sorts of different fat globules, so we've selected the one we think is the best and we are now undertaking the world's biggest trial of gene therapy for any disease which we started a couple of months ago. And we're starting with 200 CF patients and we're following them over a year to see how they behave in terms of various markers and at the end of that time period a hundred of them will go on to get either the gene or a placebo because of course we need to know whether there was a real effect or it was simply our enthusiasm at delivering things into the patients. And by the end of 2010 beginning of 2011 we will now for the first time ever whether gene therapy can make a difference to the patient, rather than an interesting paper that we write because we've done something to the cells.
When we tried to recruit these 200 patients - and we were assuming this was going to be a long hard struggle - we were knocked over in the rush for patients coming to see us both here and in Edinburgh, which is the other site recruiting the patients and undertaking the clinical trial with us. I think when it comes down to the choosing placebo and active that is so well ingrained in our patients, who are very much research orientated, that they understand, almost as well as we do, and probably sometimes better, how to run these clinical trials. The other thing to say is if of course this is very successful then we will immediately begin to think about offering patients who had the placebo the active compound. So we're very, very much thinking along these ethical lines.
PORTER
Professor Eric Alton.
Andrew, we touched upon the outlook for people with CF, it's got a lot better but what do you tell your patients or indeed their parents when you make the diagnosis in clinic?
BUSH
What I would say is that if no new treatments are ever discovered ever again, which is a scenario that is highly unlikely, that the average survival is 40 years, which means of course sadly some die before 40 years but more than half go on to live longer than 40 years, and indeed talking to colleagues in Europe the oldest person I've heard of with cystic fibrosis lived to the age of 86. Now of course I have to say I don't know whether I'm going to live to 86 or you or your baby or anybody but the outlook is much, much better and it's been one of medicine's success stories. Cystic fibrosis was first discovered as a separate disease as recently as 1938 and in the early days all the babies were dead by a year of age, now, as I say, half of them are living beyond the age of 40.
PORTER
Well that seems a good enough note as any to end it on. Andrew, thank you very much.
Don't forget you can listen to any part of the programme again - either on your computer or via a podcast on your MP3 player - by visiting the website at bbc.co.uk/radio4.
Next week's programme is all about the liver. We all know the importance of looking after our hearts, brains and even our bones, but few of us give our livers a second thought. Until that is things start to go wrong, by which time it's often too late. I'll be finding out just how much damage you can do to yours by eating and drinking too much - and looking at the new technology that can spot problems before they become irreversible.
ENDS
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