Based on the Joseph Levy Memorial Lecture
and Ettore Rossi Medal Lecture 2004
James Littlewood
OBE MD MB ChB FRCP FRCPE FRCPCH DCH
Chairman, UK Cystic Fibrosis Trust
|
|
| Mr Joseph Levy CBE BEM was Chairman of the Cystic Fibrosis Research
Trust for 20 years, from shortly after its formation in 1964 until 1984.
He and John Panchaud initiated the CF Research Trust and soon became leaders
on the fundraising side. |
Professor Ettore Rossi 1915-1999
Professor Ettore Rossi was Professor and Chairman of the Department of
Paediatrics of the University of Berne, Switzerland from 1956 until he
retired in 1985. He was one of the central figures involved in the development
of many areas of paediatrics in Europe, including cystic fibrosis. |
PROGRESS THROUGH THE DECADES
The improvement in the outlook for people with CF has been quite remarkable
changing from death in infancy to survival into middle age and even beyond.
However, this has only been achieved by ever more complex, demanding and
expensive regimens of treatment. It is therefore appropriate to increase
our efforts to improve or even correct the basic defect, in order to ease
the almost intolerable burden of present day treatment.
This second part of the Levy lecture looks at the present status of the
research effort and what lies on the horizon.
WHAT THE FUTURE HOLDS
Early diagnosis in the first weeks by neonatal CF screening, early expert
advice, support and monitoring by a specialist CF team, and early appropriate
treatment of respiratory infection and malabsorption are now well established
and should be (but unfortunately not always are) available for all people
with CF, both now and in the future.
It is likely that both current symptomatic treatment of the chest and
of nutritional problems will continue to improve and become available
to more people leading to better health and survival. Specialist CF Centre
staff will provide a greater proportion of care. Agreed protocols of treatment
will become the rule.
Expected improvements
Neonatal screening before lung damage or significant malnutrition should
continue to improve the outlook for many people. There are likely to be
more specific pharmacological treatments, perhaps depending on the mutations
present, which will improve the outlook for many patients. It is likely
that current demanding and time-consuming treatment will be simplified
by delaying the onset of chronic pulmonary infection and thus reducing
the items of therapy required. In addition, the methods of delivering
present day treatment are likely to be simplified by the development of:
• more efficient nebulisers and inhalers,
• powder rather than liquid delivery of inhaled drugs,
• assisted physiotherapy techniques,
• longer acting drugs reducing the doses needed, (once rather than
three times daily as has occurred with intravenous tobramycin).
Also, increasing efforts to improve adherence to various psychosocial
strategies are of increasing importance. The supply of donor organs will
remain a problem but is likely to improve as full use is made of all potential
donor organs.
The complexity of care and the new problems which have become more common
with the increase in the number of adults with CF are better dealt with
by the staff at a Specialist CF Centre. Diabetes, liver disease, osteoporosis,
pregnancy and fertility problems, as well as complex psychosocial issues
will become increasingly important as the number of adults continues to
increase.
“…with
good hygiene, segregation and optimal early antibiotic eradication
treatment, chronic infection can be, and will be increasingly avoided
or significantly delayed in the majority of children” |
CF Reference Laboratories, such as already exist in the UK, USA and some
other countries, will become increasingly important to identify, monitor
and advise on new infections. It is apparent that with early diagnosis
and treatment, good nutrition, good hygiene, segregation and optimal early
antibiotic eradication treatment, chronic infection can, and will be increasingly
avoided or significantly delayed in the majority of children. Certainly
hygiene and segregation policies with frequent expert microbiological
monitoring as recommended by the CF Foundation, UK CF Trust and other
organisations will need to be enforced with increasing vigour by patients,
families and professionals and everyone involved in CF care.
“….A
fall in the number of newborns with CF has already been noted in
East Anglia, a region of the UK where there has been neonatal screening
for over twenty years” |
The investigation of relatives for carrier status, pre-implantation diagnosis,
antenatal screening, and neonatal screening should and are likely to become
available on request. It is difficult to predict the effect of these procedures
on the eventual size of the CF population. A fall in the number of newborns
with CF has already been noted in East Anglia, a region of the UK where
there has been neonatal screening for over twenty years, perhaps due to
an increased general awareness of cystic fibrosis. In Leeds where neonatal
screening has been routine since 1975, the incidence of CF had fallen
from 1 in 2220 births between 1975 and 1985 to 1 in 4307 births between
1996 and 2002.
“ …The
role of the national CF organisations will be increasingly to identify
and campaign to correct these inequalities” |
The persisting inequalities of care so clearly revealed in the past and
yet so obviously still present, as revealed by the CF registries in North
America, the UK and elsewhere, are quite unacceptable. Consensus meetings
and publications outlining the best available treatments, making the information
available to all, and registries to monitor treatment received and the
results obtained will become routine. The role of the national CF organisations
will be increasingly to identify and campaign to correct these inequalities.
Expert groups need to define standards of care and ensure the application
of these standards by regular accreditation (as already occurs in the
USA), ideally in partnership with the Government or appropriate funding
body.
The provision of the best available treatment for CF is very expensive
and is likely to remain so and funding problems are a major obstacle to
the delivery of optimal care in a number of countries. It is difficult
to predict if this situation will improve in the future.
“ …Expert
psychological advice can do much to assist patients and families
to come to terms with their many and varied problems as they occur” |
Even with the improved outlook for people with CF, having a family member
with the condition remains a major life-changing situation for parents,
siblings and other members of the family. Most professionals involved
with CF care appreciate this and will continue to provide a sympathetic,
high standard service for patients. It is important that the tendency
to production line treatment, an increasing feature of our NHS in the
UK, does not become common in CF care and that Centre staff, in particular
Directors, continue to be always accessible whenever advice is required.
Expert psychological advice can do much to assist patients and families
to come to terms with their many and varied problems as they occur.
Opportunity to treat the basic defect rather than the secondary
effects
It is good that there are increasing efforts to develop any treatment
(“cure”), which shows promise as a repair for the basic defect
whether it is gene replacement, drugs, or other means. It is very likely
that within 5 to 10 years or even considerably sooner, either gene replacement
or pharmacological treatment or both (perhaps depending on the patient’s
particular mutations) will effectively normalise, or significantly improve
the disturbed physio-chemical condition within the CF airways, so that
much less treatment or even no other treatment will be required for the
respiratory tract.
“ …It
was therefore decided to ask these three research groups to combine
in their efforts with the promise of funding for five years to permit
continuity and cooperation” |
In the UK, in London, Oxford and Edinburgh, we are fortunate to have
three of the leading CF gene therapy research teams in the world. We are
aware that pharmacological approaches to treatment are the main focus
of research in the USA. It was therefore decided to ask these three research
groups to combine in their efforts with the promise of funding for five
years to permit continuity and cooperation to develop a compound to the
stage of a Phase III clinical trial in humans within five years. The Chief
Executive of the UK CF Trust, Rosie Barnes, suggested the concept of the
UK CF Gene Therapy Consortium (UKGTC) in 1999. An important feature was
to guarantee regular funding and security to keep high quality scientists.
“ …
All the complex machinery for conducting a large clinical trial
in people with CF is in place” |
A welcome and major initiative came from the USA CF Foundation in 1998
with their Therapeutics Development Program designed to halve the time
and reduce the cost of bringing new drugs to the patient. Drugs to be
tested would be those which their drug-screening program had identified,
or those identified by other means – some of which are already licensed
and used for other conditions. So all the complex machinery for conducting
a large clinical trial in people with CF is in place. There is a specially
trained network of CF Care Centres coordinated by the Children’s
Hospital and the Regional Medical Centre in Seattle. This initiative has
come from the CFF in order to foster collaboration between clinics, laboratories
and industry and this is a major advance designed to speed introduction
of new treatments.
As part of the CFF initiative, high throughput screening is likely to
identify active compounds, which can be brought as quickly as possible
to trials in CF patients. An automated method of analysing potential activity
is already identifying a small number of potentially active compounds
from many thousands tested.
CONCLUSION
“…There
has not been a time when there was more hope of major progress in
CF care than the present” |
I have endeavoured to cover some of the many aspects of the CF story
as seen by a general paediatrician initially involved in other areas,
who gradually became very involved in CF care and more recently has been
working closely with the UK CF Trust. I have tried to highlight lessons
from the past, such as the absolutely central role of Specialist CF Centres
and the advantages of scientific collaboration, and speculate on how developments
will continue.
I thank all those friends and colleagues, too numerous to mention, who
over the years have contributed to and now continue with the development
of the Leeds Regional CF service. In recent years, since my retirement
from the Leeds Centre, it has been a great pleasure to work with Rosie
Barnes and her staff at the UK CF Trust. Last, but by no means least,
our thanks go to the hundreds of patients and parents who have proved
such an inspiration and example over the years, and who have uncomplainingly
taken part in numerous clinical trials and research studies.
There has not been a time when there was more hope of major progress
in CF care than the present. While research and improvement in diagnosis,
treatment and provision for people in all stages of the condition will
remain of the highest priority and will, of course, continue, it is abundantly
clear that with the knowledge and progress that has been made up to the
present, there must be an even greater concerted effort to modify, influence,
treat or even cure the basic defect now this has been clearly identified.
Progress both in the gene replacement and pharmacological areas is gaining
momentum and I have no doubt that there should be a message of great encouragement
and optimism from this meeting.
It has been a great privilege to receive these two honours and I thank
the Levy family, CF Worldwide and the European CF Society most sincerely.
Editor’s Notes:
See this address for more information about drugs that are being studied
in clinical trials: www.cfww.org/pub/ (Edition 3)
Part I of the Levy Lecture, Looking back over 40 years, was in the previous
volume of the CFW Newsletter.
