Feature: Breathing easy

Cystic fibrosis (CF) is an extremely nasty disease. It is the most common inherited, life-shortening condition affecting Australian children. It is an autosomal recessive disorder caused by mutations in the cystic fibrosis trans-membrane conductance regulator (CFTR), a transport protein found in epithelial linings.

Defective CFTR function leads to the build-up of thick sticky mucus in a number of organs, the most problematic of which being the lungs. Bacteria is trapped in the mucus there causing progressive infective disease that eventually damages the lungs so much that normal gas exchange becomes more and more difficult until eventually a lung transplant is the only choice to prolong life.

The last 20 years has seen many new treatments introduced for CF that have improved survival, including Pharmaxis’ Bronchitol, but there is still no cure. Most CF sufferers survive into adulthood, with 37 years the current median survival age in Australia. However, patients live a very ‘medicalised’ life to stay well and push the disease boundaries, requiring ongoing treatment by a committed and multidisciplinary team comprising the patient, their medical team and their family.

According to Associate Professor John Massie, an invited speaker at this year’s Human Genetics Society of Australasia meeting, one of the most positive things to happen in CF care in the last 20-30 years is newborn screening. With first hand-experience of CF disease and its lifelong consequences, Massie has always been a passionate advocate for CF screening, which Australia introduced quite early in 1981, with genetic testing added in the 1990s.

With the CFTR gene identified in 1989, much has been learnt about the mutational genetics of CF, and testing for CFTR gene mutations is now reliable and relatively inexpensive.

Despite there being over 1500 known CFTR mutations, about 85 per cent of possible mutations, and all of the most commonly occurring ones, can be detected by a 12-mutation panel in the Australian population. Indeed, Australia was the first country to have a nationwide genetic test available for CF incorporated into newborn screening programs for the early identification of affected individuals.

Newborn screening ensures the early diagnosis of most affected individuals, and enables parents of affected individuals to be identified as carriers. Options with regard to further children can then be discussed, including pre-implantation genetic diagnosis and identification of carriers by genetic testing.

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“What I have noticed since I started in the field is that parents of babies with CF often ask what testing is available, and the obvious logic is if you could have done a test before – a pretty simple test really – why didn’t you?

“Our initial research in this area told us that of families who have a baby with CF and who know all about the testing available, about 80 per cent elect to have more children. And of those 80 per cent, the majority elects to use prenatal testing on the next pregnancy. So people who are informed about CF choose to do something about it and use that information.”

Carrier screening

Thus, several years ago Massie and his colleagues started to look at the issue of carrier screening in the community and why it wasn’t happening. “A big problem from my perspective is that all the relevant elements of the chain are disconnected, each with a different focus, especially in Australia.

“We have the obstetrician delivering pre-natal/pre-pregnancy health care and focused on the woman and the pregnancy. There is a genetic service who own the testing and do the counselling, but are not proactive in the CF area. Then the babies come to us and in lots of ways our focus is the care of the child and improving life. Finally, there are the support organisations, focused on the patient’s daily life and on finding a cure.

“We are very fortunate at the children’s hospital that there is a group of people, such as myself, who work closely with the geneticists and who have had a very good working relationship with CF Victoria so that we are able to pull some of those disconnected elements together.”

How and when carrier screening should be offered and/or recommended by doctors has been a subject of study by Massie and others including the HGSA in Australia for many years.

“In the US, carrier screening for CF was recommended by the regulatory and medical bodies in 2001, with a subsequent 50 per cent reduction in the incidence of affected infants,” says Massie.

Similar programs have been since introduced in other countries (including Scotland, Denmark and England) and uptake rates are generally up around the 80 per cent mark. Such results provided more fuel for Massie and his colleagues in advocating a national policy and funding scheme for CF carrier screening in Australia.

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In the absence of a federally supported program and to gather better data on such efforts in Australia, the Victorian Clinical Genetics Service initiated a pilot carrier-screening program for CF in 2006. It was offered to couples planning a pregnancy or in early pregnancy on a fee-for-service basis.

Massie has been actively involved in this program since its inception. His 2009 analysis of the first three years of screening, published in the Australian & New Zealand Journal of Obstetrics and Gynecology, concluded that such screening was practical and feasible for obstetricians and general practitioners to undertake as part of their normal care.

Attitudes towards the program from those offered the test were generally positive, particularly if accompanied by their doctor’s recommendation and the understanding of CF as a severe condition.

“We also described getting those disconnected elements together and starting a program that then represented genetics, CF and the CF organisation and a sympathetic ear from the obstetricians. But we couldn’t convince the state government to fund it, and we didn’t have health economic data at the time, hence the fee.

“We then put it out there to obstetricians and then GPs. We have had various seminars, mail outs and talk fests and things and the literature to try and spread the word. So far, the program has had fairly stable numbers of 1500 women per year. Now we want to really step it up and make it broader.”

Massie also wants to standardise how the information is distributed, which now differs widely amongst those offering it. “GPs would be an ideal source, but if we want to target the pre-pregnancy stage, not many people in Australia really turn up for pre-pregnancy advice.

“Thus, we need better access to information from a range of sources, but I think actually the bottom line is that a lot of people take direction from their doctor. And I think that governments coming on board would sort of give it that extra stamp of approval in peoples’ minds.”

Massie has also noted that the HGSA has put out a position paper on the CF carrier screening program, available to view on the HGSA website. “It’s very carefully worded to focus on the provision of appropriate knowledge and information. Basically, we want to get everyone informed, and not advocate that everyone get screened. Then what people do with the information is their business.”

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Attitudes under the spotlight

“The other study we’ve just completed is based on asking clients at The Alfred Clinic about their attitudes to carrier screening for CF. We wanted to see what people with CF thought about the whole issue of screening prospective partners and genetic counselling. Would they test your partner and/or consider pre-natal or pre-implantation diagnosis?

“The majority of people with a partner and who are planning a family have done that. They’ve tested their kids, tested their partner and done pre-natal testing. The response was about 90-95 per cent said this should be offered to the community. Even if they haven’t necessarily followed it through themselves, they’ve said and recognised that pre-conception is the best time.”

A heartening aspect of this study for Massie was that most of these young CF-affected adults visiting the clinic thought that people should be offered information, especially for pre-pregnancy planning, and that doing so was not de-valuing their lives.

“Most of the group plan to find out if their partner is a carrier. It also underlined one of the things we found out way back in the beginning from CF Victoria: that when you screen people you actually increase the awareness in the community of CF, and that it is certainly not counterproductive for a CF support group to support carrier screening.

“I’ve always advocated that it’s about choice. You tick the box, you want one of these tests, but not another. Of course, that raises a whole lot of issues around pre-test information. How many tests do you have to tell everyone about and how much detail do you provide on each of the tests? At the end of the day people who agree to screen don’t care so much about the detail, I suspect, they just want a healthy baby.

“In my opinion, we as clinicians all have an obligation to inform our patients about the available options, especially when it comes to pregnancy. It doesn’t take very long. If you provide 100 per cent information and get 70 per cent uptake, you might find 50 per cent reduction in incidence. This not about eugenics – it’s not trying to save the health care system – this is a personal choice by individuals. So, that’s what we are trying to do: simply offer people choice.”

Associate Professor John Massie is the Head of Education and Training in Respiratory Medicine at the Royal Children’s Hospital in Melbourne. He is also a clinical faculty member at the University of Melbourne and a Research Fellow at the Murdoch Children’s Research Institute. Massie has published extensively in the area of CF diagnosis and population screening, and helped to establish the population-based carrier-screening program for CF in Victoria. Massie was also on the subcommittee that developed the HGSA policy on CF carrier screening.