Some previous publications on the history of cystic fibrosis
History of the Cystic Fibrosis (Research) Trust to 1984
History of the European Cystic Fibrosis Society
Index of authors’ images included in the text
Some previous publications on the history of cystic fibrosis
1972 Cystic Fibrosis. A Comprehensive Bibliography of the Medical Literature 1813-1972. US Department of Health Education and Welfare. National Institutes of Health. Complied and edited by Douglas S Holsclaw and Anne Lloyd Topham.
Details of over 5000 references on CF published between 1813 and 1972.
This must have been a massive undertaking in the pre-computer and pre-internet era. The entries are in alphabetical order of first author and there are also useful separate subject and author indices.
By 2013 there were over 37,000 references to cystic fibrosis on the medical reference databases; by the end of 2019 the number of references to cystic fibrosis on the PubMed database has risen to 51,991.
1981 1000 years of Cystic Fibrosis. Collected Papers. Presented at an International Conference on Cystic Fibrosis at the University of Minnesota, may 7-7-, 1981. Warren J Warwick Ed. Published by the University of Minnesota.
Warren Warwick (figure 2) organised this “one off” meeting where many of the leading international CF experts, past and present, presented a fascinating collection of papers on their work over the previous years. It is a wonderful collection of papers presented by virtually everyone with a significant involvement in CF treatment or research up to that time. Many had been involved with CF care or research since the first recognitioon of the condition in 1938 by Dorothy Andersen.
Presenters at the meeting included Warren Warwick, Guilo J Barbero, Paul di Sant’Agnese, Jack Lieberman, LeRoy Matthews, Lewis Gibson, Archie Norman, Lucas Kulczycki, Alexander Spock, Jean Feigelson, Jean Navarro, Niels Hoiby, Winge Flensborg, Peter Sciotz, Ettore Rossi, Richard Kraemer, Lynne Reid, KF Kerrebijn, Nancy Huang, Gianni Mastella, Ulrich Stephan, William Waring, George Polgar, Bettina Hillman, Carl Doershuk, Harry Shwachman.
1984 HISTORY OF THE CYSTIC FIBROSIS (RESEARCH) TRUST
A lecture by Sir Robert Johnson QC delivered at the CF Research Trust’s 20th Anniversary Weekend, Brighton, June 1984
Cystic fibrosis itself has, I suppose, a history as old as man. Until it’s eventual recognition by the medical world, fatalities from CF were attributed to other causes so that the number of people actually suffering from CF must be a matter of speculation. On the one hand, lack of diagnosis and therefore proper treatment must have meant that there were few living people with cystic fibrosis. On the other hand the number of carriers must have expanded unabated.
To put our Trust and the progress it has made into a historical perspective we must, I think, pause to remember that for many centuries cystic fibrosis existed but as a totally unrecognised condition. We all know of the Hungarian saying of many years ago – “soon will die the child whose brow is salty to the kiss” – I recollect seeing Ron’s (Ron Tucker) slide of that actually attributed to Rocholz, I think in 1857. The first report of cystic fibrosis in a scientific paper was in 1936 in the paper by Dr Guido Fanconi entitled, it may be noted Mr. Chairman, Cystic Fibrosis of the Pancreas. It is again a measure of that timescale in which I am recounting this history that is within my own, if not within your lifetime Mr Chairman. As that title implies the disorder was thought initially to relate only to the digestive system. The involvement of the lungs, to which our major problems seem now to relate, was not then recognised.
In 1938 there appeared the first comprehensive account of CF as a separate disorder based on work at the Babies Hospital at the Columbia Presbyterian Medical Center in New York City and written by Dr. Dorothy Andersen (figure 4), a name we all know, but significantly a pathologist. The following year there occurred the first diagnosis of a living CF patient. The diagnosis, obviously difficult for the doctor and uncomfortable for the patient, was achieved by the measurement of the pancreatic enzymes in the duodenal juice.
By 1944 however, it had become clear to the few doctors who had the knowledge, that CF was not confined only to the pancreas but was a widespread defect affecting other exocrine, that is to say secreting, glands. Cystic fibrosis of the pancreas was therefore a misnomer and a new name had to be invented. Dr Sydney Farber (figure 5), of Boston Massachusetts, named it Mucoviscidosis. All of us recognise in that word, the word mucus, but some of the more erudite will have recognised in it the Latin “viscidus” meaning sticky as well as the Greek “osis” meaning condition; condition of sticky mucus. To this day the International CF Association is called the ICFMA, the International Cystic Fibrosis (Mucoviscidosis) Association because that’s what cystic fibrosis is called in some other countries and you will find mucoviscidosis is defined still as Fibrocystic Disease of the Pancreas. It was then seen that the mucus of the respiratory tract was affected. The realisation roughly coincided fortunately with the development in the late 1940s of the early antibiotics which had evolved since the discovery of penicillin by Sir Alexander Fleming in 1929, working in that small second floor room in that gatehouse building at St Mary’s Hospital, Paddington where Professor Williamson is now carrying out important work for us. Fleming discovered penicillin but it wasn’t until 1941 that it became available for practical use.
In 1953, taking my chronology a stage further, an important step forward occurred in relation to CF in the detection of the CF defect in the sweat gland. This discovery occurred following a heat wave in the United States when it was observed that CF children were suffering heat prostration due to heavy salt loss. The discovery was made by Dr. Paul di Sant’Agnese (figure 6) – a doctor still alive (in 1984) who one hopes we will be seeing at this Congress next week. That was at the Babies Hospital in New York, again. That important discovery led eventually to the development of the sweat test.
In 1956, in the United States, they created their Cystic Fibrosis Foundation which in it’s early years made research grants to researchers whose names are household names in the world of cystic fibrosis – Dr Harry Shwachman (figure 7), Dr Paul di Sant’Agnese and Dr Dorothy Andersen. In 1959, ladies and gentlemen, only in 1959 there was introduced the ionisation technique (the Gibson and Cooke pilocarpine iontophoresis method of sweat stimulation and collection) which forms the basis of the sweat test as we know it and a major tool in the diagnosis of cystic fibrosis.
It is only now Mr Chairman, at this stage in my chronology, that I can usefully turn your attention to the evolution of CF work in the United Kingdom. The fact is that until then there had been little of a coordinated nature to merit inclusion in my history.True there were individual doctors, Dr Norman over there (figure 7) to name one as an example, who were all working in developing ways of managing the patients better, but the general picture here was of ignorance and distress unmitigated by hope or practical effective action.
Until 1964 there was no formal organisation in the United Kingdom of any kind for the support or coordination of CF research. Work was going on but it was sparse and those involved were isolated and facing the problems of any scientific pioneer. As to the organisation of parents there is only one of which I am aware. It was based in Somerset and consisted of a body of parents who had infrequent meetings and kept in touch by means of a duplicated newsletter. The meetings and the newsletter seemed to me to be largely devoted to the exchange of emotive and dismal family news, and in my view of it at the time, of little benefit to the members. Perhaps for this reason the group had little momentum and it suffered the additional handicap of being regarded by the medical profession as detrimental to the families involved. Certainly it gave families the feeling that they were not alone, but there was no hope and nothing practical.
At the time of the creation of our charity, I recall attempts to absorb the Somerset group in the Chest and Heart Association and to make that the main CF organisation in the United Kingdom, but fortunately that failed. I say fortunately because that charity would have been concerned with too wide a range of disabilities to give adequate emphasis to Cystic Fibrosis; I remember this was a great source of anxiety in the early years until the matter was resolved. What CF did not need was fragmentation amongst a number of competing groups.
The situation of young parents facing a diagnosis of CF and trying to adjust to its implications will never be easy. However, if one compares the position now with the position when our Trust was founded one has a useful measure of the value of the contribution which the Trust has made in this area. Diagnosis will probably always be occasionally missed or delayed. In those days, missed diagnosis and late diagnosis seemed to be the order of the day. Scarcely any general practitioners had knowledge of cystic fibrosis and such indeed, with respect to them, seemed to be the case even with some consultants. We cannot yet claim total elimination of professional ignorance but now it is very much the exception. The promotion that is necessary for fundraising has contributed to that in a way coupled with the present massive research effort which is often seen to be reflected in the medical press.
For the parents too, there is now available a range of information in understandable form which explains the meaning and significance of the diagnosis. None of that, I can tell you from my own experience, was available in former days. Further more, nowadays at our Groups and Branches there is available, in a thoroughly responsible way, advice and guidance from other parents. The Executive Committee is at the moment embarked on a scheme for some formal training in this voluntary counselling which is such an important part of the work of the Group and Branch Officers. But to revert to my history the picture I want to give you of the situation of a parent in the 1950s and the early 1960s is one of total hopelessness and despair. There was however one parent who was not content to wait passively for the inevitable. That parent as you know was John Panchaud (figure 8). His daughter Caroline had been diagnosed as having cystic fibrosis. John Panchaud’s father-in-law was a man called Percy Lovely (figure 9), a man highly respected in the City of London and a member of the Common Council.
At this time the Chairman of the National Dock Labour Board was Lord Crook who lived in Carshalton. In 1963 Lord Crook and the National Dock Labour Board gave a cocktail party at the Board’s Headquarters on the Albert Embankment in London to which Lord Crook invited a friend and neighbour from Carshalton, someone called David Lawson.
David Lawson (figure 11) was a paediatrician at Queen Mary’s Children’s Hospital in Carshalton and himself a CF parent. Among the other guests, at what was a City function for business dignitaries, were, by chance, Mr and Mrs Percy Lovely. In the course of the party Dr Lawson espied Mrs Lovely. She was apparently a lady of some elegance wearing on this occasion a particularly edible hat! Having attracted, so it seems, the attention of this young Dr Lawson, and finding that he was a doctor, she poured out her heart to him about the problem her grand-daughter Caroline. It was left that she would get her son-in-law John Panchaud to phone David Lawson to arrange a meeting. Mr. Chairman, it is in that cocktail party, in the unlikely setting of the National Dock Labour Board Headquarters in London, that one has the origin of the Cystic Fibrosis Research Trust.
The consequence was that John Panchaud went to see Dr Lawson and together they evolve a plan. David Lawson’s first suggestion was that they should set up a Medical or Scientific Committee. John Panchaud proposed this should include David Lawson and a physician who was looking after Caroline at Great Ormond Street – Dr Archie Norman. But who else?
Eventually Dr Lawson became Chairman of the Steering Committee. It included Dr. Norman and the late Dr. Cedric Carter (figure 12) the famous geneticist, the late Dr. Winifred Young (figure 13) of the Queen Elizabeth Children’s Hospital in Hackney – one of the early pioneers in the care of CF children and Dr. Lynn Reid (figure 14) of the Brompton Hospita, now a professor in the United States. A short time later they were joined by Dr. John Batten another physician from the Brompton who, as you know, is now the head of the Medical Household of Her Majesty the Queen.
In 1963 John Panchaud had his solicitor draw up the necessary legal documents for the formal creation of the charity. One of the first Trustees was Mr. Percy Lovely and as a result of his and John Panchaud’s contacts in the City they got together a Board of Trustees including as originals Mr. Joseph Levy (figure 16)and Lord Crook. Others were Lord Bossom and other prominent figures in the City of London. The inaugural meeting was held in February 1964. I have here the minutes. The date is the 20th February 1964 at 3.30pm in the Mansion House in the City of London under the auspices of the then Lord Mayor, Sir James Harman.
The Trust organisation in those days consisted of John Panchaud’s own secretary, Eileen Denham, who spent part of his and quite a bit of her own time in the affairs of the Trust. The premises were John Panchaud’s office in the Haymarket. The prime movers on the fund raising side were John Panchaud himself, Percy Lovely and Joseph Levy. They set about the seemingly impossible task of raising funds for researching into something of which scarcely anyone had heard. David Lawson and his committee set about the allocation of the funds and giving general advice. One of these early minutes that I’ve read records that because the Medical Steering Committee was putting forward such a wide ranging programme of research, it would be necessary for the Trustees to now raise £10,000 per year. One sees from that the measure of the progress we’ve made.
At first the organisation was limited to the raising of funds by the individual Trustees. However,it gradually became clear that parents had to be involved. John Panchaud had always been keen to enlist their help and I think perhaps the initial delay or inertia in
enlisting the help of parents came from the experience the doctors had had from parents groups. The doctors were reluctant to encourage the organisation of parents into what might prove, once again, to be little more than gatherings of the emotional, the bitter and frustrated. I think there was an increasing realisation that there would be parents groups and it was felt better to take the initiative and organise them in a proper way rather than leave them to developing in a random and negative fashion. I think too that it was realised that if research was to be effective the fundraising base of the organisation needed to be broadened and the hope was that this could be done in a way that was beneficial to the cause without detriment to the families.
Here the initiative was taken by Dr Norman. He selected one of the CF mothers (Linda Johnson – please see addendum) in his clinic at Great Ormond Street to organise the first group in London. I say in London but the existence of that first group acted as a magnet and parents wrote and telephoned and came to meetings from all over the United Kingdom. There was a small group at the time I recollect in Sheffield led by Mr Albert Clover and almost simultaneously there were groups starting at Aberystwyth – Mrs Jones I recollect and Dr Glencross in Glasgow.
Suddenly there was hope. Suddenly, there was something one could do to fight back. A chance even to win. I look back on those days with great emotion. For those of us who were involved those days still mark a turning pointing in our lives, when hope arose and work began. After a depressing history of chaos and despair one man had been instrumental in bringing together a group of people from totally diverse backgrounds and uniting them into what was truly a crusade. A crusade to do something about it. Of course each of those I have mentioned was a person of talent and dedication in their own field, but without the catalyst of John Panchaud, it is I think doubtful that we would be here today celebrating the 20th Anniversary of a lively and successful charity. There would have been an organisation but not one of this calibre.
Of our founders some are still with us, others have passed on. Lord Crook as you know is our President, 83, and because of ill health not able to be with us this week. Joseph Levy (figure 16) is the much respected, and I wish to say much loved, Chairman of our Council. Dr Norman is just coming to the end of his term as Chairman of the Scientific and Medical Advisory Committee. Mr Lovely has died and so has John Panchaud. He died in 1974 when he was 58. His memory lives on. We have inaugurated, as you know a John Panchaud Medal (figure) which is to be awarded on rare occasions to those who have given outstanding service to the Trust. John’s widow is I hope to be at this Congress. Caroline is married and living in Switzerland.
Dr Lawson continued for many years his enormous endeavour on the research side. He was, as you know, Chairman of our Medical Committee and again of the Medical and Scientific Committee of the international organisation and has been, in many ways, on the medical side one of the major figures in the International CF Organisation but most importantly, has come out of his supposed retirement to play a major part in the organisation of the Scientific Programme of this Conference. I myself was a minor figure on the Organising Committee and I bear witness to the enormous effort that David Lawson and every member of the Committee put into the congress that we hope is going to be a great success this week.
To return to my history, after the formation of the Trust and that first parents group, the enthusiasm and the pace was colossal. Judged by today’s figures the funds seem small but they were hard earned and they were well spent, and they primed the pump. As early as Christmas 1964, the Trust was selling its own Christmas cards. I remember a meeting at the house of Dr Smith near Hangar Lane in West London, to choose a range of cards. The meeting I recall was much too large for the purpose and there was no consensus but somehow cards were chosen and the name of Cystic Fibrosis began to appear on other peoples’ mantelpieces. Dr Smith himself is worth a mention. He worked I think for the Wellcome Foundation doing research into asthma. His CF daughter was a source of wonder to the rest of us. She was, believe it or not, taking O levels. At that time when the expectation of life of our children was 3 or 4 years, here was a sign of hope if ever there was one. When she went to university I remember thinking to myself that surely she couldn’t have Cystic Fibrosis at all. There must have been a misdiagnosis, but such, ladies and gentlemen, was the situation in which we parents were in those early days.
No history of this Trust, however brief, could be written without mention of the services of Ron Tucker (figure 17). He was born on the 29th June so his birthday, his 65th in fact, is in 3 weeks time, when he will retire. Ron had a proud war service, he was wounded at Dunkirk, he went with the Commandos on the Dieppe raid and he was mentioned in dispatches. Before the war and during the war he became interested in youth work and when he left the army became full time organiser of boys’ clubs in Lancashire and Cheshire. By 1964 he was in London as Organising Secretary of the Keystone Cops, an organisation made up of famous and influential people who raised money for boys clubs. In 1965 the time had already come when the Cystic Fibrosis Trust needed, although it could scarcely afford, a full time executive. Advertisements were placed and interviews arranged. An interviewing panel was selected of those whose judgement in these matters could, so it was hoped, be relied on to select an appropriate candidate. I suspect, although I am not sure, that it was because of Joe Levy’s support of the boys clubs movement, that Ron Tucker was asked to be one of the pa
The interviews were concluded, the panel was unanimous. There had been no suitable candidate. The whole operation it seemed had been in vain. As the meeting broke up in an atmosphere of some gloom and disappointment, a panel member, addressing himself to Ron Tucker, said “Why don’t you do it?” Whether the remark was a flippant attempt at a joke to dispel the gloom or was a serious enquiry, I cannot relate. However, it was in that casual remark that there came to the service of Cystic Fibrosis, the life of Ron Tucker, to whose dedication and enthusiasm this Congress and our presence here today is modest tribute. This is not the occasion for a definitive account of the contribution made by Ron Tucker. We all of us know the enormous expansion in our organisation, the number of branches formed, the money raised, the families helped, almost single-handedly by Ron Tucker.
I want too, in my history, to mention the contribution made by Her Royal Highness Princess Alexandra (figure 18) . She takes a genuine and helpful interest in our endeavours but, particularly for the purpose of my history, I want to remind you that she became our Patron very early in the life of this charity, in 1968 at a time when this charity was struggling for recognition. Her granting of her patronage to us gave us a status which helped us very considerably. (Prince Charles (figure 18) succeeded Princess Alexandra as Patron in 2014).
I have already mentioned the international body. There had been some initial earlier contact between doctors on an international basis initiated I think by Dr. Paul di Sant’Agnese, involving in the UK significantly Dr Norman and Dr Lawson who were recognised as leaders of the UK medical effort. The first Congress of the ICF(M)A was held in Paris in March 1965. The practice has since become to hold such Congresses every 4 years but there were four earlier ones in the USA which were closer together in time and the Paris meeting was called the fifth; the last one in 1980 was in Toronto and the one in Brighton this week is the Ninth.
This is not the first International Congress to be held in England. Again, it is a measure of the progress that was made and one must add the esteem in which our UK researchers were held by the international medical and scientific community. As early as 1969 the International Congress was held in England. The funds available to the executive committee, the resources available to it were limited. We were asked to underwrite a pretty substantial project in terms both of organisation and finance, but everyone recognised the enormous benefit that can flow from bringing together in one place CF researchers from all over the world. We took over one of the Cambridge colleges, Churchill College, so that the visiting scientists and doctors were all accommodated under one roof. The format of the conference has become the pattern for subsequent international medical and scientific gatherings. That conference proved, I think, to be one of the most successful of the international conferences. Let us hope that this Congress is another such success and that the information and ideas that are exchanged and talked about here will speed the ambition of us all to find improved techniques of clinical management and to identify the basic defect.
In this account of the history of the Trust, I have passed over the intervening years and the expansion, the successes, and the failures too, that we have experienced in these past 20 years. My endeavour has been to record for you, who do not know the starkness of the contrast that exists between the state of things now and when we started. Progress can never be fast enough for us who have become involved but the record of this organisation is, in my judgement of it, truly worthy of praise.
I leave you then with two cautionary observations. The first is that maybe seeing the massive attendance at this Congress of researchers from all over the world, we may be tempted to the belief that efforts can be relaxed and the research left safely to those in perhaps more affluent countries. One thinks for example of the United States. If so you would be badly wrong. The research contribution made by the United Kingdom Trust is of the very greatest possible importance in the context of international research. As I see it, from my involvement in the Trust, the work done by our researchers, and I include those in England and also Wales, Scotland and Northern Ireland, is regarded as of the very highest quality. Thanks no doubt to those involved but largely I think to painstaking and I would add time consuming care that is given on a voluntary basis by the Members of our Scientific and Medical Advisory Committee to ensure that those projects that are supported by our funds are of sufficient scientific and clinical merit.
If however I may put the matter in terms of not only technical excellence but of hard cash, the following figures may interest you. In the United States, obviously by far the largest member of the international CF community, the total annual sum raised is about 17 million dollars, about 12 million pounds sterling, of which only about one pound out of 12 is spent on research. The reason is that, in the absence of a universal health service such as is available in this country, our US sister body has to devote much of it’s resources to the support of the CF patients and families. You will recognise the importance of the UK research contribution which is the product of our efforts, when you compare that figure of 1 million pounds spent on research in the United States with the figure, not much less, of £700,000 odd spent in the United Kingdom. No doubt some allowance must be made in comparing those figures for the fact that because of higher costs a million pounds buys much less research in the United states than it would in the United Kingdom. So we cannot leave it to others.
My other cautionary observation related to matters nearer home. Under the guidance and, as we all know, exhortation of Ron Tucker the income of the UK Cystic Fibrosis Research Trust has risen progressively over the years. Only once in our 20 years has there been no increase. Usually the sum raised by our groups and branches, which is as you know the major source of income, has increased by 10 to 20% each year. Now Ron Tucker has gone. His successor Charles Spottiswoode has our total confidence and I know he will have our strong support. However, he cannot have instantaneously the same intimate knowledge of our families and of local as well as general CF circumstances. We all know that in the 18 years that he was our Executive Director Ron Tucker developed a close attachment with us all, individual and collectively and with our supporters. It is I believe unavoidable that some of the value of that special relationship will be lost to us with the changeover to a new Executive Director. So I say this. We must all rally to our new Director and give him the extra support that is necessary to sustain our research efforts in this period of transition.
In concluding this history of the Cystic Fibrosis Research Trust therefore, I record my belief that we are potentially in a period where our support could slacken and our income drop. Equally I record my strong conviction that when someone comes to recount the history of the next 20 years it will be found that our membership recognised the possibility a slackening of effort and responded with added vigour. I believe that under the leadership of Charles Spottiswoode we will go on progressing in the way and at the rate we have done in the past and I for one, and I know the members of the Executive Committee have every confidence, that that will be so.
It is my belief too that in our research into improved clinical management and the search for the basic defect spectacular development is imminent After our special history we must not falter now. This Trust, Mr Chairman, has most certainly won its laurels. We who work for it must not rest upon them!
Addendum (Jim Littlewood 2018)
As parents of two children with Cystic Fibrosis, Robert and Linda Johnson were the parents involved in forming the first CF Parents Support Group in London and South East England in 1963, even before the CF Research Trust was officially formed in 1964. In this they were encouraged by Dr Archie Norman whose paediatric clinic their children attended at the Hospital for Sick Children Great Ormond Street in London. Linda and Robert have been continuously involved in one role or another both in the UK and internationally making a major and unrivalled contribution to the care and outlook of people with CF for 50 years. For their contribution to advancing the cause of Cystic Fibrosis both Robert and Linda were awarded Panchaud Medals of the CF Trust – Linda in 1983 and Robert in 2005.
1989 Dodge JA. Cystic fibrosis in Wales. Welsh Paed J 1989; 1:4-6. (www.welshpaediatrics.org.uk/cystic) Full text on the web.
A brief account of paediatric developments in Wales by Professor John Dodge both in terms of clinical care and also mentioning the research carried out there.
1990 Kulczycki LL. Five decades of cystic fibrosis (1938-1988). Acta Universitas Carolinae Medica 1990; 36:7-12.
A brief outline of recent history as seen by Dr Lucas Kulczycki (figure 19) who worked closely with Harry Shwachman in Boston from 1955 to 1970 until he moved to Georgetown. For many years Lucas Kulczycki was a leading figure in the CF world and published widely on the subject.
“Dr. K,” as he is affectionately known by his colleagues and patients, escaped Poland as the Nazi’s marched through in September 1939 and literally walked over the Carpathian Mountains into Hungary, then to France and eventually across the English Channel to Liverpool and then to Scotland where he received his medical degree from the University of Edinburgh. Dr. Kulczycki then emigrated to Canada to continue his medical studies and then went to Boston where he started to specialize in treating children with a severe respiratory disease known as cystic fibrosis. While in Boston, in 1958, he worked with Dr. Harry Shwachman to devise the Shwachman-Kulczycki Score for determining the severity of a patient’s cystic fibrosis. The Shwachman-Kulczycki Score is a tool still used by medical professionals today. In 1962, Dr. Kulczycki came to Washington, DC where he served as the director of the Cystic Fibrosis Center and a Professor of Pediatrics at Georgetown University School of Medicine. (information and image from the MedStar Georgetown University Hospital website with permission)
1992 Super M. Milestones in cystic fibrosis. In; Warner JO, editor. Cystic Fibrosis. British Medical Bulletin 1992; 4:717-737.
Maurice Super (figure 20) wrote a short account of the history of CF which has a strong emphasis towards the genetic advances as he was both a paediatrician and also a geneticist in Manchester, UK.
1993 Mearns MB. Cystic Fibrosis: the First 50 Years. A review of the clinical problems and their management. In: Dodge JA, Brock DJH, Widdicombe JH, editors. Cystic Fibrosis – Current topics. Vol I. Chichester: John Wiley and Sons, 1993: 217-250.
An account of the treatment of cystic fibrosis by Margaret Mearns,(figure 21) a UK paediatrician of great experience and one of the few UK paediatricians who was closely involved with CF for many years from the Fifties, first working with Winifred Young and then as Consultant Paediatrician in charge of the Cystic Fibrosis Clinic at the Queen Elizabeth Hospital for Children, Hackney, London.
1998 Welsh MJ, Ramsey BW. Research on cystic fibrosis: a journey from the Heart House. Am J Respir CritCare Med 1998; 157 Suppl: S148-S154.[PubMed]
A review of research in CF by Michael Welsh (figure 22) , one of the leading US researchers in the field, tracing the “pathway of discovery leading to understanding and cure of a genetic disease”. The stages can be summarised as follows – first the clinical identification of the condition, then description of the physiological/biochemical defect, identification of the gene and mutations, elucidation of the function of the gene product, understanding how mutations cause dysfunction of the gene product, explanation how mutations cause disease and the development of therapies.
1999 Quinton PM. Physiological basis of cystic fibrosis: a historical perspective. Physiol Rev 1999; 79:S3-S22 [PubMed] A very clear review by one of the pioneers of CF research particularly putting into perspective the various phases of understanding of the basic defect; in particular. discussing the two apparently distinct faces of CF – that of a mucus abnormality and one with defects in electrolyte transport. Quinton notes that CF “has advanced from innumerable speculations about its cause to a precise definition of causative mutations accompanied by accurate quantitative descriptions of their physiological effects”.
2001 Cystic Fibrosis in the 20th Century. People Events and Progress. Doershuk CF (Ed). A M Publishing Ltd, Cleveland, Ohio. 2001
A very substantial and interesting multi-author account of the developments in CF with a strong emphasis on the North American scene edited by Dr Carl Doershuk (figure 24). Carl Doershuk joined Leroy Matthews at the CF clinic in Cleveland in 1960, initially as a Senior Resident, within 3 years of Matthews starting his “comprehensive and prophylactic (preventive) treatment programme” in 1957. There are chapters by many of the those involved in CF in North America, such as Paul di Sant’Agnese, Paul Quinton and many others, looking back with their personal views on the developments in many areas
Dr Doershuk kindly gave me permission to use illustrations and material from his book for which I am very grateful.
2004 Wellcome Witnesses to Twentieth Century Medicine. Volume 20. Cystic Fibrosis. Christie DA, Tansey EM. (Eds). Wellcome Trust Centre for the History of Medicine at University College. London.
The transcript of a Witness Seminar held by the Wellcome Trust Centre for the History of Medicine at UCL, London, on 11 June 2002. Introduced and co-chaired by Professor John Walker-Smith, a retired Paediatric Gastroenterologist and Dr Jim Littlewood – the then Chairman of the CF Trust’s Research and Medical Advisory Committee. Some 40 people who had been involved with either the science or clinical aspects of CF spent the afternoon reminiscing on their experiences. In particular Dr Archie Norman and Sir John Batten both contributed as did Dr Phillip Farrell, who was visiting from the USA at the time.
2004 The Joseph Levy Memorial Lecture. “Looking back over 40 years and what the future holds”. Littlewood JM.
In 2004 Jim Littlewood was awarded the Joseph Levy Memorial Lectureship by CF Worldwide. Every fourth year the North American and European CF organisations combined and joined with CF Worldwide to put on an international meeting which replaced the annual European meeting. The Joseph Levy Memorial Lecture was delivered at the Opening Ceremony of the 27th European Cystic Fibrosis Conference 2004 in Birmingham, UK. The lecturer usually based his/her lecture on a subject which had been a major interest of their’s over the years. I had by that time had quite a long experience since qualifying in 1956, almost amounting to history! So I choose to review the history of cystic fibrosis much of which I had been involved in and speculate on the future.
A full transcript of the 2004 lecture with references can be downloaded from the UK CF Trust website (www.cysticfibrosis.org.uk) or directly from the Internet (enter Joseph Levy Memorial Lecture 2004)
In 2004, at the same meeting, Jim Littlewood was awarded the Rossi Medal of the European Cystic Fibrosis Society.(figure 25a).
2008 Fanos JH. “We kept our promises”: An oral history of Harry Shwachman, MD. Am J Med Genet Part A 146A:284-293.[PubMed]
A really fascinating account of an interview with Harry Shwachman and his wife in 1984 – some 2 years before his deathHarry Shwachman, M.D., was Chief of the Division of Clinical Nutrition at Children’s Hospital, Boston, which eventually became the largest Cystic Fibrosis (CF) center in the world. For over four decades he pioneered understanding of the disease and developed a program of diagnosis and treatment that dramatically extended the lives of children affected with CF. During his own childhood, he developed bilateral pneumonia and nearly died. He received a BS from M.I.T in 1932, and an MD from Johns Hopkins in 1936. He completed his internship and residency at Johns Hopkins and Children’s Hospital, Boston (1937–1941). In 1947 he returned from Army service to Boston where he resumed his medical practice and research. Dr. Shwachman discovered a less invasive screening procedure for CF than the intubation technique used previously. In the late 1940s he and his colleagues identified pulmonary involvement to be the primary manifestation of CF. He was instrumental in establishing the autosomal recessive genetic pattern of CF [Allen et al., 1956]. He introduced new treatment methods that changed the management of CF, including the use of antibiotics in 1948, a new pancreatic enzyme replacement, and chest physical therapy. In 1954 Shwachman developed the first reproducible sweat test at Children’s Hospital, Boston, and in 1955 he helped establish the Cystic Fibrosis Foundation. He authored over 250 publications, trained generations of researchers, and was a dedicated clinician, legendary for his devotion to his patients and their families. In addition, he was an accomplished violinist and founding member of the Newton Symphony Orchestra. He and Irene, his wife of 42 years, had three children: Elizabeth, Joan, and Alan, and at the time of interview, three grandchildren. This autobiographical vignette is based on excerpts from an interview I conducted of Dr. Shwachman and his wife in their home in Boston in 1984, 2 years prior to his death. © 2008 Wiley‐Liss, Inc.
2016 Wilmott Robert W. An invited article. “A Historical Perspective of Cystic Fibrosis”. Hong Kong Journal Paediatrics 2016;21:280-285.
A concise very readable chronological history of cystic fibrosis by Professor Robert Wilmott (fig25b) Robert, who qualified in England, is a paediatric pulmonologist in St Louis. After a successful career there he has recently been appointed Vice President for Medical Affairs and Dean of the University School of Medicine, effective from August 2019 until 2021.
Robert Wilmott has served in leadership positions at St Louis University since 2001, including 17 years as Chair of the Department of Pediatrics. He has received numerous awards and has been named a St. Louis “Best Doc” by St. Louis Magazine every year since 2002.
2016 Hodson and Geddes’ Cystic Fibrosis. Fourth Edition Eds. Andrew Bush, Diana Bilton & Margaret Hodson. CRC Press. Taylor and Francis Group.
The following two chapters in this recent textbook (figure 26) relate to the history of cystic fibrosis
– Kris De Boeck. Introduction: From the discovery of the gene in 1989 through to 2014 pp 3-17
VARIOUS ARTICLES BY DR RONALD BUSCH
Dr Med. Roland Busch (Medizinisches Zentrum Mitte Rostock, E.-Hilzheimer-Straffe 22-29, Rostock 1, DDR-2500, GDR) has written extensively on the history of cystic fibrosis and reviewed many reports from the Middle Ages onwards of children many of whom may have had the condition. Unfortunately I have not been successful in contacting him.
1971 Busch R. Zur m der Mukoviscidose beim Neugenboren. (Comprehension of mucoviscidosis in the newborn). Kinderarztl Prax 1971; 39:268-271. (German)[PubMed]
A short article dealing mainly with newborn screening which in 1971 was by examination of the meconium for excess albumin. There is mention of the suggestion of Schutt & Isles (1968, above) to use the Albustix test for detecting the excessive albumin in a solution of meconium.
1978 Busch R. The history of cystic fibrosis. NIH Lib. Trans.53; 316-381.
1978 Busch R: On the history of cystic mucoviscidosis. Deutche Gesundhs.1978; 33:316-320.
This article is in German and contains many references. The English summary: Up to now the casuistry on a newborn that had died of a meconium ileus, its pancreas showing histological typical alterations, published by Karl Landsteiner in 1905 was considered to be the oldest scientific publication. From the literature published before Landsteiner preponderantly cases of gastrointestinal or mixed form of mucoviscidosis may be traced back to the first half of the 19th century. A postmortem record from Vienna in 1838 signed by Rokitansky contains the oldest scientific exactly described presentation in the form of a perforation of the small intestine accompanied by a meconium peritonitis. Besides that by means of an ancient superstition the mucoviscidosis in the folklore area may be traced back till the 17th century.
1979 Busch R. Zur Fruhgeschichte der zystischen Pankreasfibromatose. NTM-Schriftenr Gesch Naturwuiss 1979; 16:95-109. (German).
Only 11 of the 104 references are in English. An extensive review of the previous reports suggesting cystic fibrosis with pictures of Landsteiner, Heubner and Fanconi but interestingly no mention of Dorothy Andersen!
1983 Busch R. Mucoviscidosis (cystic fibrosis), a disease of unclear structure until recently. (German). Gegenbaurs Morphol Jahrb 1983; 129:459-465.[PubMed]
The summary is as follows – “Cystic fibrosis (mucoviscidosis) is described in a review article. The cause of this common lethal hereditary disease of white people is hitherto unknown. The early death of patients with cystic fibrosis, a genetic paradoxon, a lot of hypotheses and very high demands in treatment should challenge more scientists for research. There are added some short notes about the authors work in the history of cystic fibrosis.
1986 Busch R. Historical aspects of cystic fibrosis. Wissenshaftlike zeitsschrift der Willempieck Universistat Rostock. 1986; 35:84-87. 1987 Busch R. Cystic Fibrosis in the XIX century. Arch Hist Filoz Med 1987; 50: 427- 434. (English with Polish summary)[PubMed]
The author investigated the medical literature of the 19th century to detect case records suggestive of the patients having had cystic fibrosis. During the century, not withstanding microscopic techniques, there was little progress in research about the pancreas and meconium. There are useful references to and comments on the German literature dealing with this subject. A number of these reports suggested that the children may have had cystic fibrosis.
1990 Busch R. The history of cystic fibrosis. Acta Univ Carol Med 1990; [PubMed]
Cystic fibrosis is said to have arisen due to a gene mutation 4000 to 5000 years ago (but also see Busch 2005 below). Migration of peoples, gene mutations and new conditions in nourishment could have been the causes. Resulting from old cleaning ceremonies and preventing or treating uncanny effects in children, it was usual to lick the forehead of newborns and children crosswise. If one perceived a salty taste, the child was called bewitched or fascinated and was feared to die soon. The author identified such descriptions in 12 states of modern Europe. Medical documents are reviewed from the first case report until Carl von Rokitansky in 1838 (see below).
1991 Busch R. On the history of cystic fibrosis. Nord Medicinhist Arsb 1991; 95-98.[PubMed]
It is supposed that CF appeared about 3000 BC. Migration of peoples, gene mutations and new conditions in nourishment could have been the cause. Resulting from old cleaning ceremonies and preventing or treating uncanny effects in children, it was been usual to lick the forehead of newborn and children crosswise. If one perceived a salty taste, the child was called bewitched or fascinated and was feared to die soon. The author found describing in 12 states of modern Europe. Medical documents from first case reports are reviewed”.
It is noted that there are no suggestive reports from the United Kingdom and Northern Ireland, nor does the Encyclopedia of Superstitions by Radford and Radford, 1948, contain any key word on cystic fibrosis. The case of Pauw (1595 above) is mentioned also a girl of 3 years treated in 1673 by Georg Seger, a German doctor. Fever, vomiting, diarrhea and wasting for a considerable time before death; the only pathological finding at autopsy was an indurated and scirrhous pancreas
2005 Busch R. What do we know about the history of cystic fibrosis? Quebec Adult CF Newsletter. 2005; 28-30.
An excellent brief account of many of the earlier references to children who may possibly have had cystic fibrosis. “Around the time when Palaeolithic man left Africa and entered eastern Mediterranean, that is about 52,000 years ago, a gene mutation, the gene mutation responsible for cystic fibrosis first appeared, likely in the Near East” (note also Busch 1990 above re. the dates of the suggested mutation).
2007 Westwood T, Ramsay M. Medical/Scientific topic. Something New Out of Africa: Cystic Fibrosis Affects All Peoples. http://www.cfww.org. CF Worldwide Newsletter Jan 15th 2007.
An interesting account of CF in South Africa. The article can be downloaded from the website.
Dr. Tony Westwood is a general paediatrician at the Red Cross War Memorial Children’s Hospital in Cape Town. He is the head of the Outpatient and Emergency Departments of the hospital. He is also a senior lecturer in the School of Child and Adolescent Health of the University of Cape Town. He has worked in the hospital’s CF Clinic since 1992 and recently completed a doctoral thesis based on his research on CF in Cape Town and its environs.
Professor Michele Ramsay (figure 27) is head of the Molecular Genetics Laboratory in the Division of Human Genetics at the
National Health Laboratory Service and the University of the Witwatersrand. Her PhD was followed by a two-year Postdoctoral Fellowship in London, working on the molecular basis of CF. Currently, her laboratory provides a diagnostic service for the molecular investigation of multiple single gene disorders. Her research interests include CF in the black African population, pigmentation in health and disease, hermaphroditism and genetic predisposition to fetal alcohol syndrome.
2009 Robert Steven Kaplan, Sophie Hood. “Bob Beall at the Cystic Fibrosis Foundation”. Published by The Harvard Business School. 9-409-107. April 17th 2009. Copies and permissions from www.hbsp.harvard.edu/education.
This is a fascinating account, originally developed for class discussion, of the history and workings of the CF Foundation and its President and Chief Executive Officer Bob Beall (figure 28) .
2013 Watt P. For the Roses. Cystic Fibrosis Ireland. Published by Cystic Fibrosis Ireland (www.cfireland.ie)
A very interesting and liberally illustrated account of the history of the Cystic Fibrosis Association of Ireland (now Cystic Fibrosis Ireland) and CF developments there over the 50 years since the organisation was formed in 1963.
The book was written by Philip Watt (figure 29) the present Chief Executive Officer, who kindly provided with me with a copy. In a letter with the copy Philip writes – “In researching the book and in particular talking to some of those involved in the early days, it quickly struck us that in CF Ireland that we had not done nearly enough to document, acknowledge and thank people who have made such a difference to the CF narrative in Ireland. We were very fortunate that the two women who founded the association were (and remain) alive and well”. Philip refers to Anne O’Dwyer and Bridie Maguire who are widely acknowledged as the two most important people in the establishment and development of the CF Association of Ireland.
2007 “History of the European Working Group for Cystic Fibrosis & European Cystic Fibrosis Society Conferences” A lecture by Professor Niels Hoiby adapted by Dr Jim Littlewood
This lecture on the history of the European Working Group for Cystic Fibrosis (EWGCF) and the European Cystic Fibrosis Society (ECFS) conferences was given by Professor Niels Hoiby in 2007 at the 30th Annual Conference of the European Cystic Fibrosis Society in Belec, Turkey. We are grateful to Niels for permission to publish the presentation and allow the addition of some comments.
Professor Ettore Rossi (figure 1) was 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 very many areas of paediatrics in Europe, including cystic fibrosis. I (Jim Littlewood) met Professor Rossi only briefly on a few occasions – one incident left me with a lasting impression of his kindness and humanity. At an International CF Conference, when he was chairing a plenary session, he had no hesitation in informing one very senior presenter, who had just described a study involving children with CF in numerous annual needle biopsies of the liver, in no uncertain terms, precisely what he thought of the ethics of the study!
He was obviously held in high regard by those who knew him and described as an enthusiastic teacher, a serious hard working paediatrician and a superb medical friend – “the beloved father of hundreds of paediatricians in the whole world”.
In 1969 the first informal meeting of the European Working Group for Cystic Fibrosis (EWGCF) was held at Interlaken, Switzerland and chaired by Professor Rossi. The European Working Party for Cystic Fibrosis was an informal group the founding meeting being held in Cambridge in the UK 1969 with Professor Rossi of Bern, Switzerland (figure 1) as the founding father and first president. The EWGCF only task was to organise annual
European CF Conferences in different countries and in that way develop CF care and research throughout Europe. There were no bye-laws. The Secretary, Dr Beat Hadorn is remembered for his early work on pancreatic function tests (Hadorn et al, 1968).
The treasurer, Ron Tucker OBE (figure 2) was the first Director of the UK Cystic Fibrosis Research Trust (now the CF Trust). The second secretary representing Eastern Europe, Vera Vavrova of Prague, was involved in CF care for many years and was awarded the medal of the ECFS in 2008 (figure). Her very interesting presentation “The Story of Cystic Fibrosis in Prague” is available on the ECFS website
Annual meetings of the EWGCF from 1970 to 1977. The President of the conference was usually the senior clinician involved in CF care in that city. (Details from the ECFS website)
1969 Cambridge, UK – Founding Meeting of the European Working Group for Cystic Fibrosis (EWGCF) – E Rossi elected President
1970 1st ECFC – Stockholm, Sweden – Local President/Secretary: Lindquist/Kollberg – Society President/Secretary: E. Rossi/Hadorn
1971 2nd ECFC – London, UK – Local President: Lawson – Society President/Secretary: E. Rossi/Hadorn
1972 3rd ECFC – Reinhardshausen, Germany – Local President: Stephan – Society President/Secretary: E. Rossi/Hadorn
1973 4th ECFC – Warsaw, Poland – Local President: Bozkowa – Society President/Secretary: E. Rossi/Hadorn
1974 5th ECFC – Verona, Italy – Local President/Secretary: Mengoli/Mastella – Society President/Secretary: Mengoli/Hadorn
1975 6th ECFC – Dublin, Ireland – Local President/Secretary: Lyons/Harris – Society President/Secretary: Tempany/Hadorn 1976 No Meeting – 7th International CF Conference – Paris, France
1977 7th ECFC – Dresden, Germany (figure 7) – Local President/Secretary: Dietzsch/Gottschalk – Society President/Secretary: E. Rossi/Hadorn
By 1977 the EWGCF conferences were becoming larger and there were 170 participants from 19 European countries, USA and Canada, at the Dresden conference of that year.
Professor Hans-Joachim Dietzsch and Dr Bodo Gottschalk worked in Dresden in the German Democratic Republic. In the Eighties Dr Gottschalk visited a number of CF centres in the UK, including our own in Leeds and did not return to Eastern Germany.
EWGCF Conferences 1978 – 1984 During most of this period Manfred Gotz of Vienna (figure 4) and Richard Kraemer of Berne (figure 5) were involved as EWGCF Present and Secretary respectively.
1984 No Meeting – 9th International CF Conference – Brighton, UK 1983 12th ECFC – Athens, Greece – Local President/Secretary: Adam/Manolaki – Society President/Secretary: M. Götz/Kraemer 1982 11th ECFC – Brussels, Belgium – Local President/Secretary: D. Baran/Van Geffel 1981 10th ECFC – Bern, Switzerland – Local President/Secretary: E. Rossi/Kraemer – Society President/Secretary: M. Götz/Kraemer 1980 8th International CF Conference – Toronto, Canada 1979 9th ECFC – Noordwijkerhout, the Netherlands – Local President: Kerrebijn – Society President/Secretary: M. Götz/Kraemer 1978 8th ECFC – Badgastein, Austria – Local President/Secretary: Stur/Götz – Society President/Secretary: Stur/Hadorn
At the 1979 Leuwen meeting in the Netherlands, Warren Warwick is seen talking with Niels Hoiby. (figure 6) Warren Warwick of Minnesota is one of the pioneers of CF care in N. America – in particular, he started the first CF patient registry in the USA in the early Sixties. Warren was still attending CF meetings in 2011. He was also closely involved in the development of the physiotherapy vest eventually used by over half the people with CF in North America.
Warren Warwick was an admirer of the Copenhagen CF centre and wrote in 1982 – “Beginning early in the nineteen-sixties the excellence of the work in pulmonary and cystic fibrosis research done at the Paediatrics Department TG attracted interest from around the world and cystic fibrosis researchers from everywhere began to visit Denmark to learn from Doctor Erhard Winge Flensborg. I joined that group of visitors in 1966 when I wrote to Doctor Flensborg for permission to visit his department. Like all the others, I was welcomed. The intellectual stimulation there surrounded by the sparkling hospitality of Erhard and Inga Flensborg and the doctors studying at Paediatric Department TG was so helpful that I have eagerly returned on many occasions over these past 16 years, as have others who have made a first visit to Paediatric Department TG”.
Niels Hoiby (figure 7) had entered the CF field in the early Seventies in Copenhagen, where a CF centre had been started in the mid-Sixties by Erhard Winge Flensborg. By 2011 Niels was the author or co-author of over 500 publications, most on the microbiological and immunological aspects of cystic fibrosis.
EWGCF Conferences 1985 – 1990 From 1987 Niels Hoiby (figure 7) was the President and Martin Schoni (figure 8) the secretary of the EWGCF.
1985 13th ECFC – Jerusalem, Israel – Local President/Secretary: Katznelson/Godfrey – Society President/Secretary: M. Götz/Kraemer 1986 14th ECFC – Budapest, Hungary – Local President/Secretary: Boda/Gyurkovits – Society President/Secretary: M. Götz/Kraemer 1987 15th ECFC – Oslo, Norway Local President: Michalsen – Society President/Secretary: N. Høiby/M. Schöni 1988 Meeting – 10th International CF Conference – Sydney, Australia 1989 16th ECFC – Prague, Czech Republic – Local President/Secretary: Houstek/Vávrová – Society President/Secretary: N. Høiby/M. Schöni
1990 Joint meeting with the North American CF Conference – Washington, USA
1986 the 1st Latin American CF Congress in Buenos Aires, Argentina. (figure 9)
Omar Pivetta is a local paediatrician. Robert (“Bob”) McCreery was President of the International Cystic Fibrosis (Mucoviscidosis) Association (ICF(M)A). (figure 9). He had been elected in 1976 and for many years was a major international figure on the CF scen
John Mangos (figure 9) from the USA was a leading CF researcher and paediatrician – he was also a priest. It is reported that he was once asked to see a patient while still in his priest’s robes. The startled patient awoke and declared “Surely I’m not that bad!!”
Robert and Linda (figure 10) (later Sir Robert and Lady Linda) Johnson had two children with CF and were involved with the UK CF Research Trust from the early Sixties and later with the ICF(M)A. Sir Robert only retired as Vice Chairman of the UK CF Trust in 2009. Both were awarded the John Panchaud medal of the CF Trust for their work.
George Adam (sitting in the figure 10) was a leading paediatrician in Athens and health issues among children called involved in CF care in Greece. He was President of the 1983 EWGCF conference in Athens. He had followed Dr Maria Nicolaidou who had been a pioneer of CF care in Greece, after she returned to Athens in the Sixties having visited Dr Harry Shwachman in Boston.
Paul Quinton (standing at the desk in figure 10) is a leading US scientific researcher, who described the impermeability of the sweat gland duct to chloride, regarded as one of the key scientific discoveries of the Eighties. Paul Quinton has cystic fibrosis.
THE CYSTIC FIBROSIS GENE WAS IDENTIFIED IN 1989
There was a memorable NACFC Conference held in the autumn of 1989 soon after the publication of the three historic papers in Science reporting the identification of the CF gene (for more details see “1989 Science”). There was a general air of euphoria that it would only be a short time before gene therapy would be available for patients – unfortunately within a few years the difficulties soon became apparent and even by 2011 gene therapy was still not available for the patients. However, the UK Gene Therapy Consortium of clinicians and scientists in London, Oxford and Edinburgh embarked on a multi dose year-long trial of gene therapy in 2012.This showed some effect but not sufficient to recommend as a treatment. However, by 2018 the UKGTC were preparing to embark of a further gene therapy trial this time using a more efficient viral derived vector
In 1965 the International Cystic Fibrosis (Mucoviscidosis) Association (ICFMA), the predecessor of CF Worldwide, was formed in Paris under the medical chairmanship of Paul di Sant’ Agnese.
At this time the EWGCF was contributing to the work on ICF(M)A grants. In 1960, prior to his moving from New York to The National Institutes of Health, di Sant’Agnese visited Europe to meet other clinicians interested in cystic fibrosis. These included Prof. Guido Fanconi and Prof. Ettore Rossi (Switzerland), Prof. Andre Hennequet and Dr Jean Feigelson (France), Drs Archie Norman and David Lawson (England), Prof. G de Toni (Italy) and Profs. Wejiers, Dicke and Van de Kamer (Holland).
The aims of the ICF(M)A were to improve the care of children and adults who had CF, to foster research and to disseminate information. Also di Sant’Agnese notes that prior to this meeting those working in CF did not know each other except through the literature and so the ICFMA brought together physicians, paramedical personnel and lay people giving them a sense of common purpose. This was the start of the International CF (ICFMA) now CF Worldwide meetings, which occur every 4 years. It is difficult to appreciate the problems with communication and travel in the Sixties – before the days of easy air travel, photocopiers, fax machines, e-mail, internet and medical databases such as Medline and Pubmed. So the formation of the ICF(M)A was undoubtedly a major milestone.
On the left of this group in St Petersburg (figure 12) are Christian Koch (paediatrician) and Niels Hoiby (microbiologist), respectively the clinical and scientific leaders of the very successful Danish CF Centre in Copenhagen.
In the previous year a seminal publication from their centre (1991 Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas aeruginosa infection in cystic fibrosis by early treatment. Lancet 1991; 338:725-726) had reported that early Pseudomonas aeruginosa infection could be eradicated by a 3 week course of inhaled colomycin and oral ciprofloxacin. Undoubtedly one of the more important papers in the CF literature up to that ti
1988 10th International CF Conference Sydney Australia EWGCF Conferences 1991-1997
EWGCF Conferences 1991-1997
1991 Copenhagen, Denmark Hoiby/Schoni (Hoiby/Pedersen) 1992 International Meeting Dublin Eire 1993 Madrid, Spain Hoiby/Schoni (Escobar/Baquero/Suarez)
1994 Paris, France Hoiby/Schoni(Navarro)
1995 Brussels, Belgium Hoiby/Schoni (Baran/Dab)
1996 International Meeting – Jerusalem
1997 Davos, Switzerland EWGCF Hoiby/Schoni (Schoni/Kraemer/Rossi) ECFS Hoiby/Ryley
Jean Feigelson of Paris (figure 13 upper) is one of the pioneers of CF care and still, in 2010 attending CF conferences in Europe and North America. He trained in paediatrics at the Sick Children’s Clinic in Oslo in 1952. In a career spanning over 45 years he has treated over 250 people with cystic fibrosis. Jean Feigelson’s first recorded paper on cystic fibrosis was in 1960 (Feigelson J. The treatment of mucoviscidosis or cystic fibrosis of the pancreas. Bull Mem Soc Med Paris 1960; 9:4-17); his most recent is as a co-author of a paper on partial splenectomy, which was published in 2007 (Louis D et al, Pediatr Pulmonol 2007; 42:1173-1180). He has 48 references noted in Medline produced steadily over 40 years
Dr Kapranov (figure 13) presented an account of CF developments in Russia at a meeting of the Royal Society of Medicine in 1995. (Cystic Fibrosis in Russia: background and a model for future collaboration with the West. Kapranov N, Ginter E, Kashirskaja N, Hill CM, Ilangovan P, Rolles CJ. J R Soc Med. 1996;89 Suppl 27:44-7. Review. No abstract available). The first case of CF was diagnosed in Russia in 1967 and it was not until 1989 that the first two CF centres opened, the first in Moscow and the second in St Petersburg.
A more recent account (2007) on the “Management of Cystic Fibrosis in Russia” by Kashirskaya N.Y and Kapranov N.I. from the Russian CF Centre, Research Centre for Medical Genetics, RAMS, Moscow, Russia, is published on the internet under that title.
Professor Isi Dab (figure 14) made many important contributions to CF (Malfroot A, Dab I. New insights on gastro-oesophageal reflux in cystic fibrosis by longitudinal follow up. Arch Dis Child 1991; 66:1339-1345). Gastro oesophageal (GO) reflux was first described as a problem in CF by Jean Feigelson (Feigelson et al, 1975) and subsequently the problem was thought to be related to progressive CF in older children. However, in the Belgian study from Anne Malfroot and Isi Dab, 21 of 26 (81%) young children with CF aged less than 60 months were studied and 20 confirmed to have reflux by oesophageal pH tracings. Sixteen improved with anti-reflux treatment with improved weight gain, less cough and wheeze but half still had the reflux one year later. The authors concluded the reflux was not caused by the CF chest problems as it improved with time – at the same time as the CF gets worse – hence their title “new insights into GO reflux”.
Professor David Baran (figure 14) from Brussels has published on a wide variety of topics related to CF since 1970 most recently on the use of N-acetylcysteine (App EM, et al. Eur Respir J. 2002;19:294-302).
Dr Henry Riley,(figure 15) the microbiologist from Cardiff, has been involved in CF care and research for many years. He has also been involved in various senior roles with the EWGCF and then the ECFS. He still is active in the production of the ECFS newsletter.
1997 THE EUROPEAN CYSTIC FIBROSIS SOCIETY WAS FOUNDED IN DAVOS
European CF Society Conferences 1998 – 2005
1998 Berlin, Germany Hoiby – Gerd Döring (WahDöring) elected new President
(Van der Laag/Heijerman)
1999 Latin American CF Congress Buenos Aires
2000 International Stockholm, Sweden
2001 Vienna, Austria Döring(Gotz)
2002 Genoa, Italy Döring (Romano)
2003 Belfast, N Ireland Döring (Elborn)
2004 Birmingham UK Döring (Littlewood/Geddes)
2005 Crete, Greece Döring (Nousia-Arvanitakis)
Marie Johannessonn was elected President starting after the 2006 congress
1999 First Consensus Conference, Artimino, Florence
Gerd Döring arranged a number of consensus conferences in Artimino, Italy (figure 18) A subject was chosen and preliminary documents prepared by leading workers in the particular area. A meeting was then convened of about 30 participants who had a strong interest and expertise in the topic under discussion and a consensus statement was developed at the meeting over 2 days. A report was then prepared and submitted for publication. Most of these consensus documents are available on the ECFS website as free downloads.
These conference that Gerd arranged proved to be a great success both from the consensus documents that resulted but also they were a very pleasant social occasion where delegates and the relatives could get together in a very pleasant informal environment.
European Cystic Fibrosis Society Conferences 2006-2012
2006 Copenhagen, Denmark Döring (Hoiby)
2007 Belek, Turkey Johannesson(Gocmen)
Marie Johannesson retired on the grounds of ill health and was succeeded by Stuart Elborn as President
2008 Prague, Czech Republic Elborn (Pohunek/Macek)
2009 Brest, France Elborn (Ferec/Lehn)
2010 Valencia, Spain Elborn (Sole/Vasquez)
2011 Hamburg, Germany Elborn (Ballman/Mall)
2012 Dublin Elborn (McElaveny/McKone/Plant
2013 Lisbon, Portugal Elborn (Amaral/Barreto)
2004 “New Frontiers in Basic Science of Cystic Fibrosis”
In 2004, the ECFS began another annual conference which is entirely dedicated to basic science. The “New Frontiers in Basic Science of Cystic Fibrosis” Conferences are characterised by active discussion of data and ideas at the forefront of research on CF and CFTR, in an informal, co-operative environment. The ECFS acknowledge the enormous contribution of Prof. Margarida Amaral made in establishing these (figure 25).Two stalwarts of the European Working Group for Cystic Fibrosis and later the European Cystic Fibrosis Society receiving their well – deserved ECFS Awards from the President, Stuart Elborn (figures 26 and 27)The 2013 ECFS Award was presented to Professor Kevin Webb (United Kingdom) to acknowledge his substantial and remarkable contribution to cystic fibrosis care over 30 years. Also to recognise and honour the huge contribution his scientific research has had on our understanding of clinical care, genetics, and therapy – and the importance of cross infection of Burkholderia cepacia complex organisms and Psaeruginosa
Two stalwarts of the European Working Group for Cystic Fibrosis and later the European Cystic Fibrosis Society receiving the week-deserved ECFS Awards from the President, Stuart Elborn.
The 2011 ECFS Award was presented to Prof. Gerd Döring (Germany) (figure 21) in recognition of his outstanding contribution to unravelling of the complexities of infection and innate immunity in the CF lung and translating this knowledge into better treatment for people with CF. The ECFS also wished to recognise and honour the huge contribution he has made to the development of scientific research and clinical care in Europe through his leadership of the European Cystic Fibrosis Society.
The 2012 ECFS Award was presented to Professor Niels Høiby (Denmark) (figure 20) in recognition of his outstanding contribution to the understanding of Pseudomonas lung infection and translating this knowledge into better outcomes for people with cystic fibrosis. He was also recognised for his contribution as the Founding President of the European Cystic Fibrosis Society and his lifelong commitment to the CF center in Copenhagen.
The 2013 Award was presented to Professor Kevin Webb to acknowledge his substantial and remarkable contribution cystic fibrosis care over 30 years. Also to recognise and honour the huge contribution his scientific research has had on our understanding of the clinical care genetics and therapy and the importance of cross infection of Burkholderia cepacia complex organisms and Pseudomonas aeruginosa.
The 2014 ECFS Award was presented to Professor Eitan Kerem (Israel)
To acknowledge his substantial and remarkable contribution to cystic fibrosis research. His interest in cystic fibrosis spans all aspects i.e. the association between phenotype and genotype, the molecular mechanisms for disease variability and the development of new mutation specific pharmacological therapies to correct the basic defects of cystic fibrosis. The promotions of the medical, ethical and rights aspects of children with chronic diseases is at the forefront of his interest. He has published many papers in this field and is known for his advocacy of children in need. He also has a record of building bridges between Israelis and Palestinians furthering peace through medicine wherever possible.
The 2015 ECFS Award was presented to Dr Carlo Castellani (Italy)
To acknowledge his substantial and remarkable contribution to cystic fibrosis research and care. His main clinical and research interests lie in CF epidemiology, genotype/phenotype correlation, CF diagnosis, CFTR-related disorders, neonatal screening and CF adult car
Fig 24. Carlo Castellani receiving the award
Fig 25. Professor Diana Bilton received the ECFS Award in 2016 for her outstanding contribution to the treatment and care of patients with cystic fibrosis.
Dr Jeffrey Beekman received the award in 2017
Dr Beekman received the award for his extensive research work, in particular stratifying infants with cystic fibrosis disease severity using intestinal organoid swelling as a biomarker of CFTR function.
Dr. J.M. Beekman obtained a PhD in molecular immunology in 2004, and performed multiple post docs in molecular and cell biology within various immunological settings. In October 2010, he became principle investigator at the UMC Utrecht, and started a novel translational research line focusing on cystic fibrosis, a genetic disease characterized by chronic inflammation and infection, in the largest clinical CF center of the Netherlands
Dr Sue Madge received the award in 2018
Susan Madge is a consultant nurse at the Royal Brompton Hospital and has been working with children and adults with CF for over 25 years. Her areas of interest and research included adolescence, burden of care, fertility and pregnancy, quality if life and end of life issues. Susan runs a multidisciplinary course on CF twice a year. She is also involved nationally and internationally on various aspects of CF. She is also involved with standards of care for CF and is currently a board member of the ECFS,
IMAGES INCLUDED IN THE TEXT OF THIS “HISTORY OF CYSTIC FIBROSIS”
If an image (“I”) of an author is included anywhere in the History, the name and date of inclusion will recorded here. For example. SURNAME/FIRST NAME/BIOGRAPHICAL DETAILS(B) + IMAGE(I)/ DATE OR SECTION where the image is included.
Abbott Jan BI 2000 (in Gee 2000) Accurso Frank BI 2008, Adam George I Future Fig 14, Aitken M BI 2012, Arawaal Abhinav BI 2017, Alani Mikkel 2016, Al-Aloul Mohamed BI Antibiotic Topics 2005 BI, 1999, Albert B 2018, Amaral Margarida 1969 I, Andersen Dorothy BI 1938, Anderson Charlotte BI 1960 Ansell Barbara BI 1979 (In Newman), Archibald Alison 2017, Argent Barry I 1989, Argent Penney BI in Physiotherapy Topic 2011, Aris Robert BI 1998, Artimino Nutrition Conference I 2000, Arooj Parniya BI 2018, Ashby Deborah 1995 IB, (Smyth RL) Avery Mary Ellen I 1967, Axon Tony BI 1979, Fares Walid Ayoub BI 2018.
Bachelor Hannah 2017 BI, Balfour-Lynn BI 2006, Ballman Manfred BI 2000 & 2018, Banting Frederick BI 1922, Baran D BI 1975, Barbero Giulio BI 1963, Barker David 2016, Barnes Rosie BI 1990, Batten John BI 1965, Baxter Peter BI 1989, Beauchamp Norma BI Fifties, Beall Robert BI 1955, Bear Christine I Beardsmore Carolyn BI 1994, Bedwell David BI 1997, Becq Fred BI 2001 (in Dormer 2001), Belessis Yvonne BI 2012, Bell Scott BI 2011, Bellin Melena BI 2013, Bellon Gabriel BI 2007, Benden Christian BI 2018, Bessonova Leona BI, 2018Beverley David BI 1987, Bilton Di BI 2008 (in Nash 2008), BethiamaYves BI 2018. Blackfan Kenneth BI 1932, Blackman Scott M 2016, Blanchard Ana BI 2017, Boat Thomas BI 1976, Bodian Martin BI 1952, Bombard Yvonne 2016, Borowitz Drucy BI 2004, Boucher Richard BI 2007, Bourke Stephen BI 2009, Bowler Ian BI 1993, Boyle Michael BI 2001, Bradley Judy BI 2013, Bramwell Byron BI 1904, Brandt Claudia BI 2018, Bratcher Preston 2016, Bray Peter BI 1978, Brennan Amanda I 2010, Brett Moira BI 1986, Bridges Nicola BI 2013,2018, Bright-Thomas Rowland I 2010, Britton John BI 2000 (In Fogarty), Brock David BI 1979, Brownlee Keith BI 2007 (in Etherington 2007), Bryon Mandy BI 2008, Buchdahl R BI 1988, Burns Jane BI 2001, Bush Andy BI 2002 (in Equi 2002), Button Brenda BI 1997, Bye Peter BI 2006 (in Elkins 2006), Bye Peter BI 2007 (in picture with Coultard) Bye Peter I 1991, Byrnes Laura J BI 2018..
Cade Alan BI 2000, Calvo-Lerma Joaquim BI 2017, Carrion Andres BI 2017, Carroll Mary BI 2006, Carter Cedric BI (in Bodian 1952), Carter Dee 2016, Castellani Carlo BI 2009, Ceulemans Laurent 2016, Chain Ernst BI 1929, 2018, , Cirilli Natalie BI 2018, Charles HRH Prince (Future), Chazalette Jean-Pierre BI 2007, Clancy John BI 2001, 2007, Campbell III Preston BI 1955 (also in Ramsay 1999), Charlier Phillipe 2018, Chazalette Jean-Pierre B 2007, Clancy John BI 2018, Cho Do-Yeoh BI 2018, Chokoshvili Davit BI 2018, Clifton Ian BI 2010, Coates Allan BI 2011, Cochrane Archie BI 1995 (in Cochrane entry) Cochrane William BI Fifties, Coffey Michael BI 2017, Cogen Jonahan BI 2017, Cohen-Cymberknoh Malena 2016, Collaco Michael 2016, Colledge Bill BI 1995, Collins Francis I 1989, Collins sarah BI 2018, Colombo Carla BI 1990, Connett Garry BI 1999, Conway Steve BI 1985, Cooke Robert E BI 1959, Cooper Peter I 1990, Cooper Yvette BI 2001, Corey Mary BI 1988, Corris Paul BI 2008, Coultard Kingsley BI 2007, Coultard Kingsley I 2006 (in Elkins 2006), Cortes-Santiago Nadia, BI 2018, Crook Lord (Future), Crossley Jeannette BI 1979, Crozier Douglas BI 1974, Crystal Ron BI 1994, Cuppens Harry BI 2008, Cuthbert Alan BI 2001 (in Duszyk 2001), Cutting Garry BI 2000 (in Mickle 2000).
Dab Isi BI Future Fig 21, Dankert-Roelse Jeanette BI 1995, Darrah Rebecca BI 2016, Dark John BI, 2008 Darling Robert BI 1952, David Tim BI 1986, 1994 (In Conway, 1994) Davidson George BI 1971, Davidson George BI 1997 (in McIlwaine 1997), Davis Stephanie 2016, Davies Jane BI 2005, 2008, Davis Pamela BI 1980, De Boeck Kris BI 2006 (in Sanders 2006), De Jonge Hugo BI 2010, Denning Carolyn (in Bruce) BI 1960, Denton Miles BI 2004 (in Lee 2004), Denton R only B 1955, Destouni Apasia BI 2017, di Sant’Agnese BI 1946, Deterding Robin BI 2005, Dicke Willem BI 1953, Dietzsch Hans-Joachim I Future Fig 7, Di Magno Eugen BI 1973, Dinwiddie Bob BI 1990, Dodd Katherine BI 1936, Dodd Mary BI 2005, Dodge John BI 1982, Doershuk Carl BI 1964 also 200, Donaldson Scott BI 2017,2018, Döring Gerd 1969 BI, Dorin Julia BI 1992, 2018, Dormer Bob BI 2001, Doull Iolo BI 1998 (in Lowden 1998), Downes Kevin BI 2017, Doyle Barbara BI 1959, Drumm Mitch BI 1990, Duclos Vallee Jean Charles 2018, Dubois Christine BI 1969, Duchesne Ernest BI 1929, Durie Peter I 1988, Dryden Carol BI 2018.
Edenborough Frank BI 2000, Edmondson Claire 2018, Edwards Sir Robert BI 2000 (in Rodgers 2000) Eiberg Hans BI 1985 Elborn Stuart BI 2000, 2005 (in Coraux 2000), 1999 (in Vavrova 1999)Elkins Mark B I 2006 Ellemunter Helmut 2015 Elliott Robert (Bob) BI 1974Ellis James BI 2012 Englehardt John F BI 2011 Essex-Cater Alison I 1989, Esterly John B 1960 Etherington Christine BI 2007 Equi Amanda C BI 2001 Evans Martin BI 1993 (in Ratcliff 1993) Everard Mark BI 1997
Fanconi Guido BI 1936 Farber Sidney BI 1943 I Farrell Philip BI 2001 Feigelson Jean BI 1960 Ferec Claude BI (in Scotet 2010), Ferrera Loretta 2018, Fisher Andrew BI 2008 Fink Aliza BI 2017 Fitzgerald Muiris BI (in Mulherin 1991) 2012, Flemming Alexander BI 1929, Flensborg Erhard 95th Birthday I 1968, BI 1968 Floto Andres 2016, Frasaniak Jason 2016, Florey Howard BI 1929, Flume Patrick BI 2007, Foong Rachel E BI 2018, Forstner Gordon BI 1982, Frederiksen Birgitte 2016, Freeman Rowland I 1922, Frizzell Raymond BI 2006 (in Myerburg 2006), Fuchs Henry BI 1994
Gallagher Charles BI 2008 Garaci Enrico BI 2017, Garrod Sir Archibald BI 1912, Gascgoine A BI 2009 (in Bourke 2009), Gaskin Kevin only I 1991, Gawande Atul BI 2004, Geddes Duncan BI 1984 (in Winter 1984), Gee Samuel BI 1888, Gelfond Daniel BI 2017, Geller D BI 2011, Gellis Sydney BI 1966, Ghosal Shomik BI 1995, Gibson Lewis E B 1959, Gibson Ron BI 2003, Gilbert John BI 1988, 1994 (in Conway, 1994), Gill Deborah BI 1993 (in Steve Hyde 1993), Gillespie Terence BI Fifties, Giraerdet Anne 2005, Mehta Gita BI 2007 (in Sims 2007), Göçmen Ayhan 1993 BI (in Ozçelik U et al, 1994), Godfrey Simon BI 1971, Goodchild Mary BI 1973, Goldenberg Rachel BI 2018, Goldman Martin BI Antibiotic Topic 1997, Goldstein Allan BI 2017, Gonska Tanya 2015, Goss Christopher 2015, Gotz Manfred BI 1989, Govan John BI 1993, Graeber Simon BI 2018, Gracey Micheal BI 1969, Grand Richard BI 1998 (in Rosenstein 1998), Grasemann Hartmut 2015, Graub Milton BI 1989, Gray Michael BI 1989, Green Anne BI 2007, Gregg Anthony BI 2018, Greening Andrew BI 2018, Griesenbach Uta BI 2012, Grubb Barbara BI 2017, Gyi Kim BI 2016.
Hadjiliadis Denis BI 2018, Hadorn Beat I Future Fig 7, 2006 Hambleton Gary I 1994 (in Conway 1994), Hammond Keith BI 1984 (in Reardon 1984,), Handelsman Jayne BI 2017, Hansen A BI 1991 (in Valerius 1991), Hansen Christine BI 2008, Hansson Gunnar BI 2012, Hardin Dana BI 2009, Harun Sabariah Noor BI 2018, Handyside Allan BI 2010, Hardcastle Jacqueline BI 1988, Hardcastle P BI 1988, Harper Joyce BI 2017,2018, Harper Margaret BI 1938 [1930, 1949], Harris Ann BI 1987, 2018, Harris Ryan 2016, Harris William BI 2017, Hayes Don Jr BI 201, Heaf David BI 1996 (in Cheng 1996),, 1994 (in Conway 1994), Heeley Anthony BI 1982, Heeley Mary BI 1982, Heijerman Harry BI 1995 (in Gan 1995), Heijerman Harry BI 2002, Heltshe Soya 2015, Herter Christian BI 1908, Hess Julius H BI 1935, Heubner Otto BI 1909, Hey Edmund BI 1984, Higgins Chris BI 1986, Hiller Joan BI 1986, Hilman Bettina BI 1967, Hisert Katherine BI 2016, Hodson Margaret BI 1981, Hoiby Niels BI 1973, Holtkamp Kim BI 2018, 1969 Holsclaw Douglas BI 1965, Holt Richard BI 2018, Holzel Aaron BI 1962, Home Sir Everard BI 1813, Honeybourne David BI 2012, Hoo Zhe Hui BI 2018, Horsley Alex BI 2009, Haworth Charles BI 1999, 2011 Huang Nancy BI 1963, Hubert Dominique BI 2017,2018, Hurley Matthew BI 2018, Hussain Noreen BI 2018, Hyde Steve BI 1993.
Innes Alistaire BI 2010 (in MacDuff 2010) Ivy Andrew BI 1941 (in Beazell JM 1941)Jackson TB only I 1986
Jablonski Christine Rousset BI 2018, Jaffe Adam BI 1998, Jenkins Rowena 2015, Jelin Angela BI 2017, Jensen Tim BI 1987, Johansen H, Krogh I Future Fig 22, Johnson Charlie BI 2003, Johnson Sir Robert BI Sixties, Jones Andy BI 2001.
Kalnins Daina BI 2006, Katznelson Daniel BI 2006, Kelleher Jerry BI 1986, 1981, 1994 (in Conway 1994), Kapranov N I BI Future Fig 19, Kashirskaya Nataliya BI 2015, Kariyawasam Harsha BI Antibiotic Topic 2000, Keating Dominic BI 2018, Kelly Andrea BI 2018, Kelly Deidre BI 2006, Kerem Batseva only I 1989, Kerem Eitan BI 2008 Kerem Eitan only I 2005, Kessler Laurence BI 2018, Kirman Laura BI 2018, Kissner BI 2018, Kleijnen Jos BI 2014, Knight Ron BI 1983, Knowles Michael BI 1981, Koch Christian BI 1991 (in Valerius 1991), Kollberg Hans BI 2003, Konigbruggen Silke von 2018, Konstan Michael BI 1995,2018, Keogh Ruth BI 2018, Kopp Benjamin BI 2017, Kraemer Richard BI 1978, Kulczycki Lucas BI 1990 (in other publications section).
Larhiri Thomas 2016, Lobeck Charles C BI 1963, Laing Sony BI 1991, Lands Larry BI 2007, Landsteiner Karl BI 1905, Langton-Hewer Simon BI 2017, Lannefors Louise BI (in Doyle 1959), Lawson David BI 1971, Latzin Phillipe BI 2018, Le Grys Vicky A BI 2018, Lebecque Patrick BI 2006, Ledson Malcolm BI 1998, Lee Ann Marie BI 2017, Lee Sun Y BI 2018, Lee Tim BI 2004, Lehn Pierre BI 2012, Lehoux Bubois Catherine BI 2018, Lenney Warren BI 2011, Lavelle Gillian BI 2017, Leung Daniel BI 2017, Levine Hagit 2016, Levison Henry BI 1987, Levy Joe BI 1962, Lieberman jack BI 1962, Lindblad Anders BI 1998, Linnane Barry 2016, Littlewood Ann BI 1991, Littlewood Jim & Doring Gerd BI 2004 (in “Other Publications”), Littlewood Jim I 1985, 1998 (in Rosenstein 1998), LiPuma JJ BI 1990, Lloyd-Still John BI 2006, Laraya-Cuasay Lourdes I (in Huang 1963), Lovely Percy (Future), Lowe Charles U BI (in May 1954).
Macek Milan BI 2002,2008, Malfroot Anne BI 1991, MacDonald Anita BI 1988, Madge Sue BI 2006, Mahadeva Ravi BI 1998, Mahenthiralingam E BI 2001, Mahony Michael BI 2010, Mangos John BI 1967, Marshall Bruce C BI 1955, Marshal Susan BI 2006, Massie John BI 2000, Mastella Gianni BI 1981, Matthews Leroy BI 1964, May Charles B only 1954 no image, Mayer-Hamblett BI 2001, 2018, McCormick Jonathan (I), McCabe Helen BI 2001 2002, McCormick Jonny BI 2002, McCrae Morris BI 1976, McElvaney Gerry BI 1991, McIntosh Rustin BI 1954, McKendrick Tom BI 1962, Mckenzie Cameron BI 2017, McKenzie Shiela BI 2007, McGarry Megan BI 2017, McIlwaine Maggie BI 1997, McColley Susanna BI 2015,2018, McKone Ed BI 2006, McPherson Maggie BI 2001, McVinish Lesley BI 1993 (megapapers), Mearns Margaret BI 1965, Mehta Anil BI 2007 (in Sims 2007), Middleton Peter BI 2010, Milla Carlos BI 2017, Millar Bronagh BI 2018, Milliken Eliza BI 2018, Miller Michael BI 1985, Mogayzel Peter BI 2013, Montgomery Bruce BI 1999 (in Ramsay 1999,)Montgomery Mark BI 2010, Moore John BI 2001, Moran Antoinette BI 2000, Morrison Cathleen BI 1959, Morrison Lisa BI Physiotherapy Topic 2011 1959, Morton Alison BI 2000 (in Conway 2000), Moser C I Future Fig 55, Moss Richard BI 2010, Mukhopadhyay Somanth BI 2006, Muhlbach Marianne BI 2017, Munck Anne BI 2001, Murphy Desmond BI 2013.
Nadas Alexander BI 1952, Navarro Jean BI (Fiegelson 1975), Nelson Bob BI 1973, 1994 (in Conway 1994), Newsome Simon BI 2018, Nicholas David BI 2017, Norman Archie BI (in Bodian 1952, Northern CF Club BI 1994, Norris Andrew BI 2018,
Olivier K BI 2015, Oh Youngman BI 2018, Olivier Kenneth BI 2015, O’Neill Katherine BI 2017, Oppenheimer Ella BI 1968, Onofrio Laselva BI 2018.
Pagaduan Jason BI 2018, Page Richard I 1994 (in Conway 1994), Panchaud John BI 1962, Pantin Charles only I 1986, Parmelee AH BI 1935, Panchaud Alice BI 2017, Parsons Leonard BI 1932, Pasque Michael BI 1990, Patterson Donald BI 1943, Puna Henrique BI 2017, Pauw Pieter BI 1595, Peckham Daniel BI 2007 (in Etherington 2007), Pedemonte Nicoletta 2018, Pelg Anton BI 2017, Pencharz Paul BI 1984, Penketh Andrea BI 1987, Percicante Antonio 2018, Pezzulo Alejandro BI 2012, Phelan Peter BI 1969, 1984, Pitt Ty BI 1993 (in Smith DL 1993), Pivetta Omar I Future Fig 13, Plant Barry BI 2013, Pollitt Rodney BI 1997, Porteous David BI 1997,2018, Poynton Frederick J BI 1914, Prader Andrea BI 1970, Prasad Armmani BI 2006, Prevaes Sabine BI 2017, Pressler Tacjana BI 2005, 1987, Price John BI 1979, Proesmans Marijke BI 2006.
Quinton Paul BI 1983 Quittner Alexandra BI 2005 Quon Bradley S BI 2015, 2018.
Rabassa-Lhoret Remi 2016, Rabin Harvey R BI 1980, Raeburn Sandy BI 1976, Ramsay Michelle BI 1996, Ramsay Bonnie BI 1989, Ramsey Kathryn BI 2016 2007, Ranganathan Sarath BI 2001, Ratjen Felix BI 2001, Rayner Rosie BI 2006 (in Williams 2006), Redmond Aileen BI (in Maxwell 1979), Regelmann Warren BI 1990, Refolo Pietro BI 2018, Reitz Bruce 1985 BI (mega), Reid Lynne BI 1961, Ren Clement BI 2017, Retsch-Bogart George Z BI Antibiotic Topic 2009, Reznikov Leah 2016, Rickham Peter BI 1965, Riethmuller Joachim BI 2009, 2016, Riordan Jack only I 1989, Robberecht Eddie BI 2006 (also in Sinaasappel 2002), Roberts James 2017, Robertson James BI 2017, Robertson CF BI 2012, Robinson Phil BI 2003, Robinson Teresa I 1988, Rodriquez-Miguelez Paula 2016,2018, Rokitansky Karl BI 1838, Rolles Chris BI 1999, Romani Luigina BI 2017, Ronan Nicola BI 2017, Rossant Janet BI 2012, Rosenfield Margaret BI 2001, Rosenstein Beryl BI 1998, Ross Alan BI Fifties, Rossi Etorre BI 1969, Rowe Steven BI 2017, Rowe Rachel I 2010, 2018, Rowbottam Nicola BI 2017, Rowland Marion BI 2015,, Rubin Bruce BI 2017, Ryley Henry BI 1991 (in Chatfield 1991).
Saiman Lisa BI 2000, Sanders Don B BI 2081, Stanojevic Sania BI 2017, Sander-Struckmeier Suntje BI 2013, Sarsfield Jim BI 1975, Savant Adrienne BI 2015, Sawacki Gregory BI 2018, Schidlow Daniel V BI 2000, Schneider Elena 2018, Schnyder Marie-Angela 2016, Schoni Martin BI 1984, Scott-Jupp Robert 1990, Saavendra Miline 2018, Sermet-Gaudelus Isabelle BI 2010, Shoseyov David 2016, Shwachman Harry BI 1943, Schultz Andre BI 2015, 2018, Schwarz Martin BI 1998, Schechter Michael BI 2010, Shak Steve BI 1993, Sheldon Christopher BI 1993, Sheppard David BI 1999, Shiner Margot BI 1888, Shute Janis BI 2007, Shumway Norman BI 1985 (mega), Shwachman Harry BI (in Farber 1943), Simoneau Tregony BI 2015, Simmonds Eddie BI 2000, Simmonds Nicholas BI 2009, Simon Andre BI 2013, Sims Erika BI 2005, Sinaasappel Marrten BI 2002, Siracusa Christopher 2018, Sly Peter BI 2009, Smith Arnold BI 1989, Smyth Alan BI 2009 (in Antibiotic Treatment etc), Smyth Ros BI 1995 (in Cochrane entry 1995), Sokol Ronald BI 1989, Soulez Sommerwerck Urte BI 2017, Gilles BI 2006, Southern Kevin BI 1997 (in Gill 1997),2018, Spock Alexander BI 1967, Spoletini Giulia 2018, Stableforth David BI 1983, Stafler Patrick BI 2016, Stallings Virginia BI 2010,2018, Stahl Miriam BI 2017, Stanojevic Sunja 2017, Stalvey Michael BI 201,7 Starnes Vaughn BI 2004, Starzl Thomas BI 1989, Steinkamp Gratian 2016, Stern Martin BI 2011, Stern Robert BI 1972, Stern Robert + Cleveland team I 197,6 Stephen Stick BI 2012 (in Mott 2012), Stephenson Anne BI 2017, Still George Frederick BI 1918, Stocks Janet BI 2012, Stoltz David 2018. Strandvik Birgitta BI 2001, Strang Abigail BI 2017, Sturgess Jennifer BI 1984, Subbarao Padmaja BI 2013, Summerhayes Donna & Doug BI 1959, Super Maurice BI 1994.
Takemoto Clifford BI 2012, Taussig Lynn BI 1973, Taylor Chris BI 1988, Taylor-Cousar Jennifer BI 2015, 2017, Tomati Valeria 2018, Taylor-Robinson 2015, Tempany Eddie BI 1982, Tepper Leoni 2016, Thaker Vidhu BI 2015, Thomson John BI 1904, Tiddens Harm BI 2012, Tramper-Strander Gerdien BI Antibiotic Topic 2010, Trapnell Bruce BI 2012, Traverts G BI 1981, Treggiari Miriam BI Antibiotic Topic 2009, Trimble Aaron 2018, Tsui Lap Chi BI 1985, 1989, Tucker Ron BI 1962, Tullis Elizabeth BI 2000 (in Mitchell 2000), Tummler Burkhard BI 2000, Tyrrell Jenny BI 1986.
Ulph Fiona BI 2015
Valerius NH BI 1991, Valman Bernard I 1969, van der Ent CK BI 2006 (in van Ewijk et al), van de Peppel 2018, van Heynigen Veronica only I 1987, van Konigsbruggen-Rietschel Silke 2016, Vanstone Michelle BI 2005, Vavrova Vera BI 1999, Verkman A 2016, Vermeulen Francois BI 2017, Villella Valeria 2018.
Wagener Jeff BI 1995, Wainwright Brandon BI 1985, Wainwright Claire BI 2008, Walker-Smith John BI 1989, Walkowiak Jaroslaw BI 2005, Wallis Colin BI 1997, Wallwork John BI 1987, Walshaw Martin BI 1998 (in Ledson 1998), Walters Mike I 1981, Walters Sarah BI 1993, Waring William BI 1967, Warner J BI 1991, Warwick Warren BI 1991, Waters Valerie BI 2015,2017, Weaver Lawrence BI 1994, Webb Kevin BI 1998 (in Mahadeva 1998), Weber Heinrich BI 2017, Weibel Martin Future Fig 19, Weller Peter 1991 BI (in Chatfield 1991), Welsh L BI 2014, Welsh Michael BI (in Rich 1990), Westwood Tony B 2007 (in Topics), White Ray BI 1885, Widger John 2016, Wigglesworth FW I 1946, Wilcken Bridget BI 1983, Wilder-Smith BI 2015, Williamson Robert (Bob) BI 1991, Wilmott Robert W 2016 BI (in Future), Wilschanski Michael BI 2000, Wilson John BI 2017, Wine Jeffrey I 2010, Witt Micheal 2018, Woestenenk J W BI 2015, Wohl Mary BI 2000, Wolbach Simeon BI 1932, Wolman Irving BI 1942, Wood Robert BI 1976, 1988, Woodruff Samantha BI 2017, Wong Amy BI 2012, Wright Martin BI 1959, Wu Hao 2018.
Yacoub Magdi BI 1985 Yadav Hemang 2016 Yankaskas James BI 2001 Yassa Jeanette BI 1979 Yen Elizabeth BI 2013 Young Winifred BI 1960 Young Winifred BI 1965 Young Sarah BI 1969 Yen Elizabeth BI 2013
Zabner Joe BI 1993 Zach Maximillian BI (in Heinzl 2002) Zamboli Marco 2016 Zar Heather 2016 Zeitlin Pamela BI 2004 Zenanick Edith BI 2015 Zlotogora Joel BI 2015 Zuelzer Wolf B 1949
SOME REFLECTIONS ON THE FUTURE
BY JIM LITTLEWOOD
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 the right of all people with CF both now and in the future. In particular the improvements in the increasingly successful “conventional” treatment will continue so as many people as possible will remain in good a condition to benefit from more specific treatments of the basic defect which are already becoming available.The effects of the improved treatment, which have occurred over the past three decades, are likely to be reflected in an increasingly improved survival for the foreseeable future. In particular, the reduced proportion of young people chronically infected with P. aeruginosa will reduce the number who will experience deterioration in their condition. Increased attention to early nutrition after the introduction of neonatal screening and subsequent optimal nutritional management will also improve the nutritional state, growth and ultimate stature of people with cystic fibrosis.
There will also be more specific pharmacological treatments the first of which, ivacaftor (Kalydeco) for people with the G551D mutation, became available in 2012 and more recently lumacaftor used in combination with ivacaftor for those with Df508 mutations; in the same year the first multidose trial of gene replacement therapy started in 2012 in the UK the results of which were reported in 2015. Unfortunately the results of this trial were modest compared with the dramatic effects of ivacaftor and lumacaftor although it is likely that further developments in this area will result in more effective products.
Despite involvement of expert dietitians and the availability of more effective pancreatic enzymes since the early Eighties, chronic gastrointestinal problems of pain and distal intestinal obstruction syndrome are still relatively common particularly in adults with CF, most of whom attend CF Centres. It is likely that more attention will be given to the gastrointestinal tract with consideration of perhaps methods of preserving the remaining endocrine pancreatic function which could delay the onset of diabetes mellitus; for although most children with CF already have pancreatic insufficiency, few have yet developed clinical diabetes. There is some early encouraging evidence that ivacaftor may have a favourable effect on the CF pancreas. With regard to the malabsorption, it is likely that more detailed monitoring of both the malabsorption and gastrointestinal problems by established methods will occur with a more precise use of pancreatic enzymes in the many patients who still continue to greatly exceed the doses recommended by the UK Committee on Safety of Medicines or indeed necessary. Also more detailed evaluation of distressing abdominal symptoms, rather than considering all to be due to malabsorption requiring more enzymes, would undoubtedly lessen the frequency of abdominal symptoms. A reduction in the enzyme dose to recommended levels does not seem to be associated with an increase in symptoms or nutritional problems. Satisfactory fat absorption is reported in clinics where the majority of patients do not exceed the recommended daily enzyme intake of less than 10,000 IU lipase/kg/day. There is increasing evidence of an CF intestinal component to the malabsorption which is likely to receive more attention.
A greater proportion of care from Specialist CF Centre staff.
Virtually all advances in clinical care to the present time have occurred at Specialist CF Centres where there are sufficient patients and experienced staff to encounter, recognise and investigate the relevant problems. It is likely that further improvements in present treatment will continue to be made at CF Centres. Increasingly people with CF will attend specialist centres for all their care.
More user-friendly “conventional” treatment to control symptoms.
It is increasingly obvious that the detailed and demanding lifelong treatment required to maintain people with CF in the best possible condition, represents an almost unattainable regimen for many to continue year after year, particularly as adolescence approaches. It is likely that current treatment will be simplified, first by delaying the onset of chronic pulmonary infection by neonatal screening, early identification of infection and early eradication treatment, thus reducing the items of therapy required. Alternatively, the methods of delivering the present day treatment are likely to be simplified e.g. more efficient nebulisers and inhalers, powder rather than liquid delivery of inhaled drugs, assisted physiotherapy techniques such as the vest, regimens of reducing the doses of drugs needed for example once rather than three times daily as has occurred with intravenous tobramycin. Also increasing efforts to improve adherence by various psychosocial strategies are of increasing importance.
Increase in the number of organ transplants for people with cystic fibrosis
At the time of writing this remains one of the major problems for people with advanced lung involvement. As the number of people requiring transplants increases iit is likely to remain a problem for the foreseeable future. It is reassuring that the problem is a high priority for the staff at the UK transplant centres. The shortfall of transplants in the UK is not due to lack of funding but of donor organs the supply of which could possibly be improved by changes in donation arrangements and help at the donor’s hospital and transplant centre. Recent research in Newcastle and elsewhere into treating donor organs has already permitted the use of some lungs that would previously have been rejected. It is likely that the early use of the mutation specific drugs will reduce the need for some of the present day numerous treatments. This shortage of donor organs is an understable major concern of older people with CF and their relatives.
New problems with increasing age – even growing old!
The complexity of care and the new problems which have gradually immerged and become more common with the increase in the number of adults with CF who now outnumber the children e.g. diabetes, liver disease, osteoporosis, pregnancy and fertility, renal problems, organ transplantation and the management ond complications, as well as complex psychosocial issues are better dealt with by the staff at a Specialist CF Centre. Already these disorders are receiving considerable attention at many CF centres and will become increasingly important as the adult population ages and increases in number.
Agreed protocols of treatment
Most countries, including the UK, now have agreed consensus documents for standards of care and routine managements and treatments derived from the views of expert committees, published data, Cochrane Reviews and other sources. The availability of such documents, many of which are available on the internet, has proved a valuable means of communicating new information to those responsible for treating patients and also to the patients themselves. These and subsequent revisions will continue to be an important source of information.
National and International Microbiological Reference Laboratories
Management of infection will undoubtedly continue to be central to effective treatment and is likely to become even more important. It is almost certain that new unfamiliar pathogens will become an increasing problem – either those we already know in a more resistant form or new ones. These trends will need to be identified at an early stage, acted upon and appropriate treatment strategies agreed as they arise.
Cooperation between centres and microbiological laboratories will be require. There has been a tendency, on the part of some clinicians, to be slow to accept the pathogenicity of new organisms, if they have not personally observed their ill effects. It is likely that clinical care will continue to improve but the established CF pattern, of new problems appearing when older ones recede, is bound to continue. Just as P. aeruginosa replaced S. aureus, so, as the prevalence of chronic P. aeruginosa falls with successful early eradication, it is already apparent that Aspergillus fumigatus and Stenotrophomonas maltophilia are cultured more often. It is interesting that the annual rate of acquisition of new P. aeruginosa does not appear to change, even with strict segregation and good hygiene, as many new infections are acquired from the environment outside the hospital; but with early and more complete eradication, the prevalence of chronic Pseudomonas infection should continue to fall even further until either drugs or gene replacement therapy reduces the susceptibility of the patient’s airways to infection or an effective vaccine is introduced. A vaccine does not seem likely in the near future. It is apparent that with early diagnosis and treatment, good nutrition, good hygiene, segregation and optimal early eradication antibiotic treatment, chronic infection can be and will be increasingly avoided or significantly delayed in the majority of children. Certainly the hygienic and segregation policies with frequent expert microbiological monitoring, as recommended by the CF Foundation, UK CF Trust, ECFS and other organisations will need to be enforced with increasing vigour and success by patients, families and professionals and indeed by everyone involved in CF care. It is possible control of infection will be more effective when the mutation specific therapies are used particulalrly from an early age.
Stricter protocols for prevention of cross-infection, staff and facilities
The consensus documents from both the CF Foundation and the UK CF Trust give clear guidance on the most effective way experts in the field consider are the best ways of reducing the risks of cross-infection and although these are difficult to accept by some families and even more difficult for some professionals, they are the best advice available at the present taking all factors into consideration.
Increasing use of home care and CF Nurse Specialists
With the increasing problem of cross-infection and fear of hospital acquired infection, home care by members of the multidisciplinary CF Team is likely to become more the rule with a considerable expansion in the role of the CF Nurse Specialist – again dependent on adequate funding. Expansion in this area would certainly be one of the most effective and cost-effective means of improving the standard of care of a significant number of people with CF as well as improving their quality of life and reducing the chances of cross-infection.
Carrier testing of relatives
Although the introduction of general population screening has not been introduced in the UK, the investigation of all blood relatives of a person with CF for carrier status should be generally available. This is available through the National Health Service in the UK for those who requested it. The decision to inform parents of babies identified as carriers by neonatal screening is welcome and now accepted by most as the sensible policy. It is likely that the take up of this carrier identfication will gradually improve.
CF is now a virtually preventable disorder with the use of population carrier screening, antenatal diagnosis or preimplantaion genetic diagnosis.
Certainly in many countries where medical care is relatively advanced population carrier screening of those intending to have children is available and preimplantation genetic diagnosis should be available for all couples when both are carriers. There is a disappointing lack of enthusiasm in the UK for both carrier screening and antenatal screening although in other countries the incidence of CF is being reduced not only by neonatal screening (leading to the recognition of carrier parents and their blood relatives),but also population carrier screening of those of child bearing age for example in Italy, N. America, France and Australia. The majority of people in the CF community, both parents and people with CF, appear to be in favour of population carrier screening with the subsequent use of preimplantation genetic diagnosis if required to choose an unaffected or carrier infant.
In vitro fertilisation using the eggs and sperms of parents who are known CF carriers, and subsequent selection of unaffected embryos, is more acceptable to many couples than antenatal diagnosis and if necessary subsequent termination of an early pregnancy. Pre-implantation genetic diagnosis should be available to all couples who know they are carriers and will undoubtedly prove to be cost-effective in the long-term.
Antenatal screening and diagnosis
For a time antenatal screening was offered to all pregnant women and their partners in Edinburgh and was available for over 10 years but has since been withdrawn; one reason given being the improved prognosis and the introduction of neonatal screening. Undoubtedly the cost of identifying an affected fetus of £50K to £100K is also a deterrent (although small by comparision with the cost of modern CF treatment). In Edinburgh, where antenatal CF screening had been routine since 1992, a significant reduction in the number of infants born with CF has occurred; some reduction in the number of infants born with CF is now established as a definite consequence of both population, antenatal and neonatal CF screening. Although not all prospective parents will wish to be screened for CF carrier status it should be available as a choice for all who want it in due course. Routine antenatal screening has been accepted in principle by the UK National Screening Committee but not introduced on grounds of cost. It is increasingly available in the United States.
Failure to introduce population screening and antenatal screening into the UK represents a major missed opportunity to reduce the number of infants born with CF.
Neonatal screening will be introduced in most countries
The evidence and accumulated experience that neonatal screening is mandatory is now overwhelming and even in the UK, where there was considerable and quite remarkable opposition from the National Screening Committee, newborn screening was agreed by the Government in 2001 and has been countrywide since late 2007. Fortunately, neonatal screening is gradually being introduced worldwide wherever CF occurs and economics allow. Unfortunately if there is not a good clinical service available to look after the CF infants identified there is little merit in neonatal screening. Failure to identify a serious condition at birth, whose outlook is so entirely dependent on early and appropriate treatment received, should now be regarded as suboptimal care. It is difficult to predict the effect of these procedures on the eventual size of the CF population. Increase in survival would tend to increase and prevention of the birth of infants with CF would reduce the number of people with cystic fibrosis. It is understandable that termination of pregnancy has become less acceptable to couples as the prognosis for people with CF continues to improve and the prospect of more specific treatment becomes a more realistic possibility. However, a significant 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 also in other regions; perhaps due to an increased general awareness of cystic fibrosis and also as family memebers who are carriers can be identifed by cascade screening. In Leeds where neonatal screening has been routine since 1975, the incidence of CF between 1975 and 1985 was 1/2220 births and between 1996 and 2002 had fallen to 1/4307. This is the general experience in other areas where neonatal screening has been introduced; it is likely this trend will continue.
Infertility treatment for men with cystic fibrosis
The success of the various techniques of assisted conception, which have already resulted in successful pregnancies where the father has CF, are likely to become more successful and more readily available. Obviously for many men with CF and their partners this will be of major importance.
More clinical trials organised through CF Centres and CF Registry
With the inevitable future trials both of new conventional treatments and of more specific pharmacological or gene replacement therapy for the basic defect, attendance at a CF Centre will be necessary for it will be through selected Centres that trials are organised. Also registration on the national CF Registry will be essential so that patients of appropriate age, sex and genotype can be identified. The CF Foundation Therapeutics Development Programme is an example that is now being followed in Europe. This is particularly important as the Cochrane reviewers seem to regard the majority of published trials as of unacceptable design and low quality.
Correction of persisting inequalities of care
The persisting inequalities of care so clearly revealed in the past and yet still so obviously 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 will become routine. The value of national CF registries (which some busy clinicians find so irksome!) is now clearly established and all patients (with their permission) will be registered. The role of the national CF organisations will be increasingly to identify and campaign to correct these inequalities after their expert advisory groups have defined standards of care. Subsequently, they will ensure the application of their standards by regular accreditation (as already occurs in the USA) and peer reviews (as in the UK), ideally in partnership with the Government or appropriate funding body.It is this writer’s firm and considered opinion that, unless distances or other factors make regular travel to a CF Centre quite impracticable (as does rarely occur), CF centre care should be available to all who wish to have it and will always be the ideal.
Funding – a present, major and will be an increasing future problem
Provision of the best available treatment for CF is very expensive and is likely to remain so. Funding problems are a major obstacle to the delivery of optimal care in many countries and it is difficult to predict if this will be eased in the future. New treatments are likely to be increasingly more expensive as already has been seen with ivacaftor (Kalydeco), the new drug for people with one or two G551D mutations – said to cost a staggering $294,000 per year. However, in the USA the firm (Vertex) will supply the drug free for patients without medical insurance and have an annual income of less than $150,000. To achieve adequate provision by funding agencies or government in discussions with the pharmaceutical inductry must be a high priority for the next few years for all concerned.
Appreciation of the major problems of families with a person with CF
Even with the improved outlook for people with CF, having a family member with the condition remains a major and life-changing situation for the 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 and particularly the lack of continuity, an increasing feature of our UK NHS, 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.
Major efforts to treat the basic defect – “ to treat the cause rather than effects”
The identification of the CF gene in 1989 presented a new opportunity – that of treating the cause rather than the secondary effects and we must now increase our efforts to take full advantage of this opportunity – indeed, major efforts are already in progress. A top priority is now treatment for the basic defect whether it is gene replacement, drugs, or other means. It is very likely that either gene replacement or pharmacological treatment (perhaps depending on the patient’s particular mutations) or both will effectively normalize, or significantly improve, the disturbed physicochemical condition within the CF airways, so that much less treatment or even no other treatment will be required for the respiratory tract. As already mentioned ivacaftor (Kalydeco) which became available for people with one or two G551D mutations in February 2012 in the USA and soon after in Europe, has a dramatic effect on the clinical state and even normalises the sweat electrolytes; in terms of medical progress it has been compared man’s landing on the moon by a leading US paediatrician! However, to the families and people with CF, progress seems to be painfully slow, even allowing for their understandable over-optimistic hopes and expectations following the discovery of the CF gene in 1989. No one was clear in which direction to go before 1989. However, now the basic defect is known – admittedly still lacking some details on regulation etc – there is enough known to focus research effort on its correction. As occurred on the clinical side following the development of CF Centres, advances only really started to happen for the majority of patients when these CF Centres acquired many patients presenting the staff with the opportunity to identify, study and solve some of the many clinical problems. It cannot be over emphasised that virtually all significant clinical advances have been made at the Specialist CF Centres. The same joining of forces surely must happen with science and research, which must also be increasingly linked with clinical research. It is reassuring that this is already happening on a national and international level. In the UK we are fortunate to have three of the leading CF gene therapy research teams in London, Oxford and Edinburgh who, with the encouragement and substantial financial support of the Cystic Fibrosis Trust, formed the Gene Therapy Consortium (GTC). The Consortium has received £30 million funding from the supporters of the UK CF Trust over the past 10 years during the development of their gene product. To carry their research forward in 2012 they received full funding from the EME programme funded by the MRC for their multidose gene therapy clinical trial the results of which were published in 2015 showing only a modest beneficial effect. It intended to improve results the GTC intend using a more efficient viral based vector in the near future (2018).
The CF Foundation’s Therapeutics Development Programme
A major initiative came from the USA CF Foundation in 1998 with their Therapeutics Development Programme designed to halve the time and reduce the cost of bringing new drugs to the patient. Either drugs which their drug-screening programme had identified or those identified by other means – some of which are already licensed. 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 Seattle. Initiative has come from the CFF in the establishment of their clinical network to foster collaboration between the clinic, laboratories and industry and this is a major advance designed to speed introduction of new treatments.
High throughput screening for new CF therapies which are already revolutionising treatment
As part of the CF Foundation initiative, high throughput screening is intended to identify active compounds, which can be brought as quickly as possible to trials in the CF patients. An automated method of analysing potential activity already identifying a small number of potentially active compounds from many thousands tested. By 2012 a number of active compound had been developed – the notable being VX-770 ivacaftor (Kalydeco) is a “potentiator” that acts on the defective CFTR protein and helps to open the chloride channel in people with CF who have at least one G551D mutation; the drug became available for patients in 2012. VX-809 lumacaftor is a new “corrector” that helps defective CFTR in those with the DF508 mutation to reach the cell surface and a combined trial with VX-770 (orkambi) shows sufficient benefit to warrant its approval in the USA and other countries, but not the UK until 2019, for treatment of people with DF5008 mutation. Undoubtedly this programme has been a major success and will continue to be so as new compounds are identified. Ataluren (PTS 124) is an oral drug allowing a read through of premature stop mutations (so-called nonsense mutations with an X). However, clinical improvements in early trials were not observed in a phase 3 trial if the patients were also receiving inhaled tobramycin.
Other new modulators, particular the recently available triple therapy (elexacaftor, tezacaftor and ivacaftor), show increasing improvement in CFTR function both in respiratory function but also in many other areas where CFTR is involved. It is no exageration that these drugs have revolutions the treatment and almost certainly the outlook for the majority of people with CF. However, there are many problems not least the enormous cost when added to the already expensive conventional treatments. Also the addition of the modulators in relation to the established treatments will perhaps prove a new problem for clinicians.
There are many other encouraging developments relating to restoring the airway surface liquid some are already of proven value such as hypertonic saline and dry powder mannitol and others are well advanced in clinical trials.
I have endeavored to cover some of the many aspects of the CF story as seen by a general paediatrician initially involved in many other areas. Since 1975 I gradually became very involved in CF care and since 1983 have been working closely with the UK CF Trust first as Member (1983), then Chairman of the Research and Medical Advisory Committee (1995 -2003), subsequently from 2003 to 2011 as Chairman and finally from December 2012 as Honorary President.I have tried to highlight lessons from the past, such as the absolutely central role of Specialist CF Centres and the advantages of collaboration with colleagues in other disciplines, and speculate on how developments will continue.
In recent years, since my retirement from the Leeds CF Centre in 1997, it was a great pleasure to continue to work with Rosie Barnes and her staff at the UK CF Trust. Last, but by no means least, 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, both in terms of clinical care, or drug and gene therapy, for even in 1989 after the identification of the CF gene, we realised that it would be some time before this major discovery would be translated into a treatment for patients. However, now, in contrast with the really hopeless outlook in the early years, the present state of knowledge, clinical care and scientific activity of highly regarded scientists would have been beyond belief even 25 years ago. In fairness to the early workers, there have also been massive advances in medicine, science and technology generally, many of which have facilitated the advances in CF research.
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 pharmacological treatment and gene replacement therapy is definitely gaining momentum and will have a major impact on the clinical management of people with CF. It is hoped that with the very welcome and awesome progress which is occuring in relation to treatment of those with CF, the opportunity to avoid the condition which is now feasible, into which so much research has been carried out over the years, will not be overlooked.
Jim Littlewood 2018