Introduction – A history of cystic fibrosis by Dr James Littlewood OBE
“To write an article of any sort is, to some extent, to reveal ourselves. Hence even a medical article is, in a sense, something of an autobiography” – John Chalmers Da Costa (1863-1933). Selected Papers and Speeches, 1931
The author and the Leeds Regional Cystic Fibrosis Service
There follows a miscellany on various aspects of cystic fibrosis (CF) as seen by one person, a general paediatrician from Leeds in the North of England who qualified in medicine in 1956. I was originally a general paediatrician in the true sense of the term involved in all aspects of paediatrics as was usual in the Fifties, but by the nature of the childrens’ problems referred to me following my appointment as a consultant general paediatrician in 1968, I became particularly involved with respiratory, gastrointestinal disorders and neonatal care. Over the next twenty years or so this eventually evolved into an increasing and ultimately a major involvement with the treatment of people with CF and the development of the Leeds Regional Cystic Fibrosis Centre. Since retirement from the National Health Service in 1997 and since the early Eighties I have had a continual close involvement with the UK Cystic Fibrosis Trust – first as a Member and then Chairman of their Research and Medical Committee, from 2003 I was Chairman of the CF Trust and eventually in 2011 elected its Honorary President.
The details of the development of the Leeds Regional Paediatric CF service, which started with a small monthly clinic at Seacroft Hospital, Leeds in 1975 and later at St James’s University Hospital, have been described elsewhere (Littlewood & Kelleher, Cystic Fibrosis News, Cystic Fibrosis Trust. Dec/Jan 1988/89), as has the later development of the service for adults with CF first under the leadership of Dr Steve Conway and now of Professor Daniel Peckham (Conway & Littlewood, Association of CF Adults Newsletter. Cystic Fibrosis Trust. December. 1990).
A detailed development of the Leeds Regional Paediatric CF Centre is recorded on my personal website (www.jimlittlewood.com).
The encouragement and support of the late Mr. Ron Tucker OBE, the then Director of the UK Cystic Fibrosis Trust from 1964, and his frequent advice to parents, patients and doctors in the UK to seek an opinion in Leeds, was another major factor encouraging the early development of our CF service.
Also there was invaluable financial support from the UK Cystic Fibrosis Trust and the Joseph Levy Foundation which allowed us to appoint a CF Research Fellow, Dr Mike Miller (a registrar grade doctor) and CF Nurse Specialist (Mrs. Teresa Robinson) from the early Eighties; both these colleagues, and those who followed them, were absolutely crucial in the development of the CF service and were among the first specialised CF appointments in the UK.
On this local note, for a service to flourish it must be perceived to be benefiting the patients. This must have been the case as many families and patients returned year after year, often from great distances, even from as far away as Hong Kong, for an Annual Comprehensive Assessment by the small but increasingly expert team at St. James’s University Hospital, Leeds (to where we had moved the 2 miles from Seacroft in 1980).
The Leeds CF Service is recognised by the Yorkshire Regional Health Authority in 1983
Paediatricians in the Yorkshire Region also found the Comprehensive Assessments of their patients helpful and in 1983 their Regional Paediatric Advisory Committee recommended that the Yorkshire Regional Health Authority officially recognise the service as a “tertiary referral service” for cystic fibrosis – the first to be so recognised and funded in the UK. The support of the hospital managers over the years was a major factor in establishing the regional status and funding through the Eighties – particularly Mr. Roger Canon, St James’s Finance Manager.
We are grateful to the numerous colleagues at Seacroft and St James’s Hospitals who, for over 30 years, have contributed their skill and expertise to the care of the patients allowing the development of a CF service which now provides full care for over 500 adults and children with cystic fibrosis (adults at St James University Hospital and children at Leeds General Infirmary); the involvement of these colleagues and their specialist skills was absolutely essential to the development and success of the service.
Access to information on Cystic Fibrosis via modern electronic communications
The major developments in electronic communications in recent years have been timely for an undertaking such as this History. The unprecedented advances in access to previous published work via the Internet, into Medline and PubMed in particular, and the availability and ease of transferring visual images, have presented an opportunity which I hope will add a slightly more human touch to some of the important contributions over the years. To actually see pictures of Harry Shwachman, Paul di Sant’Agnese, Archie Norman and many others, who have made such major contributions to our knowledge of the disorder will I hope add to the interest and value of this account of some aspects of the remarkable story of cystic fibrosis.
These developments resulted in the decision to publish this account on the web so as to provide easy access for all those interested in the story of cystic fibrosis. The excellent and widely used website developed by Professor Daniel Peckham and his colleagues in Leeds (www.cfmedicine.com and more recently www.cysticfibrosis.online) seemed to be the ideal place to publish this history. I am most grateful for Daniel’s suggestion that we publish it on his Leeds website and for his collaboration, guidance (and patience!) during implementation of the project. Daniel has kindly agreed to co-author the New Millennium sections to ensure a CF expert, currently involved in a busy CF centre, would ensure accuracy, relevance and credibility to the content and my personal comments relating to recent developments.
Main sources of information
Where abstracts were available for the more recent papers I have endeavoured to extract the relevant message and reduce the number of statistics as, with the modern electronic databases, the reader can obtain these from the abstracts or the originals if necessary. Also most of the articles mentioned have a [PubMed] link, which from around the mid-Seventies, allows access to the full abstract. In more recent years touching any of the authors’ names in the abstract will bring up a list of their PubMed references.
I have read and made photocopies of many of the early papers from before 1960 from the originals in the library of the Royal Society of Medicine (RSM) where I stayed regularly during my frequent visits from Leeds to London from 1995 until 2011. During this time I was first Chair of the Research and Medical Advisory Committee and then from 2003 to 2011 Chairman of the Cystic Fibrosis Trust. These trips to the RSM library involved many hours in the basement among the old bound journals dating back to the nineteenth century.
I am also particularly grateful to my friend and erstwhile St James’s surgical colleague Mr. Archie Crompton for the German translations of a significant number of these older articles I recovered from the basement of the Royal Society of Medicine .
During the Sixties I worked in the late Professor Stuart Craig’s Leeds University Department of Paediatrics and Child Health until moving to the NHS in 1968 as a NHS consultant paediatrician. When Professor Craig retired he kindly gave me most of the US Year Books of Pediatrics from 1934 to the late Fifties; these have been an invaluable source of information.
The content of the whole of this History is, of necessity, heavily biased towards publications in English, developments in the UK and my own slant on these developments. Progress was relatively non-existent during the Forties in the UK and Europe during the Second World War. It is almost certain that many important contributions in German, French and other languages have been overlooked. For this I apologize and do hope that those who recognise these omissions will contact me to rectify the situation as this present on line version of the History can be edited as soon as any omission or error is brought to our attention.
The various phases of research and understanding
Some research since the identification of CF in 1938, although of basic scientific interest, was of little or no immediate relevance to the treatment of people with cystic fibrosis. Unfortunately, and understandably, in the past a significant amount of CF research has fallen into this latter category, particularly when there was no clear idea as to the nature of the basic defect. Fortunately, since the early Eighties and particularly after the identification of the CF gene in 1989, much scientific research is clearly focused on the investigation and correction of the basic defect, by either gene therapy or pharmacological means. With the introduction of CFTR modulators over the past decade treatment has entered a new phase.
However, I am in total agreement with the late Maurice Super’s observation that “it is far easier to write on these milestones in retrospect, since discovery of the gene and agreement on the transport defect. For a long time CF was fertile only in the perfusion of false dawns and in controversy between workers who could not reproduce one another’s work. Now we have a fine distillate from what was once very muddy wine” (Super, 1992 below).
Maurice wrote these words in the heady days soon after the identification of the CF gene in 1989 and before the first papers on gene therapy were published from 1993 onwards i.e. before the many problems in correcting the basic defect were experienced. Nonetheless, the identification of the CF gene was the definite turning point in the investigation, understanding and treatment of CF after which there was steady, focused progress in correcting the basic defect by either gene replacement or pharmacological therapy. Undoubtedly with the introduction of CFTR modulars treatment has entered a quite different new and very encouraging phase.
So cystic fibrosis is truly a disorder of our times
During the lifetime of many of us, including myself, the condition was first clearly described as a specific entity in 1938 by Dorothy Andersen, a New York pathologist (when I was 6 years old); she also first recognised the heredity aspects in 1946. The treatment has steadily improved, the gene and its product were identified in 1989 and by 2012 the first drug, ivacaftor (Kalydeco), to modify the effects of one of the genetic mutations (G551D), became available to treat patients first in the USA; also in 2012 the first multi-dose trial of gene therapy commenced by the UK Gene Therapy Consortium and was completed in 2015.
Advances in related fields relevant to cystic fibrosis are discussed
At times I will digress to discuss the impact of parallel developments in related fields of medicine where progress has been central to further understanding and treatment of cystic fibrosis, for such advances have been absolutely essential to the progress in CF research – for example the understanding of the role of gluten in coeliac disease, the many advances in genetics and molecular biology and the many technical advances in investigation and general laboratory medicine.
SOME SUGGESTIONS ON HOW TO USE THE “HISTORY’
The main format considers the developments by decades, starting each of the earlier decades with a short commentary followed by some of the important references of that decade with the author’s (JML) personal comments on many. One reader referred to the work as a “Paper Trail History” which seems appropriate.
To obtain a general overview of the History of Cystic Fibrosis
It would be appropriate to read the introduction at the start of each decade. Also refer to the section entitled “Some previous publications on the history of cystic fibrosis” in the “Future” section.
For readers requiring a more concise account there is also a recent article at the end of this Introduction – “A Short History of Cystic Fibrosis. from recognition (1938) to treatment of the gene (2012)”
Also I recommend you read my Joseph Levy Memorial Lecture – “Looking back over 40 years and what the future holds” delivered at the 2004 International Birmingham CF Conference; the full text of the lecture is on the CF Trust website (www.cysticfibrosis.org.uk) and also it can be accessed on the internet by entering ” Joseph Levy Lecture 2004″ which enters the CF Worldwide website where the full lecture is also available.
Also for those with access to a medical library or the appropriate textbook the following two chapters in the Fourth Edition of the textbook Hodson and Geddes’ Cystic Fibrosis Edited by Bush A, Bilton D, Hodson M. published in 2016 provide a concise account of the history of cystic fibrosis from early days to the present time –
Chapter 1. “Introduction: from the discovery of the CFTR gene in 1989 through to 2014”. by Kris de Boeck.
Appendix A. “History of cystic fibrosis (up to 1989)”. by James M Littlewood
To read about a particular subject consult the ‘Topics’ section or the Site Search Box on the headings of the website.
Although there is no index as such, the publications are presented in chronological order in the main text and the more frequently discussed subjects (for example antibiotics, sweat tests, neonatal screening, etc ) are also reproduced and grouped together in their individual Topics sections where the entries relating to particular subjects also appear in chronological order. The main entries in the sections of the new Millennium, where each year has an individual section, are in alphabetical order of the first author.
The words “above” and “below” after a particular reference indicate the particular reference is present either earlier or later in the main text and it can be identified there by its date. Some of the images that appear in the main text have not been transferred to the Topics section.
The Brief Biographical Details and Images section (part of the “Future” section)
Here are listed those authors where an image (I) and/or brief biographical details (B) are included. The date against the individual’s name indicates the date of their entry in the main text where their image and brief biographical details appear. The images do not always approximate to the appearance of the author at the time the reference first appeared!
Some publications on CF are designated as “Megapapers”
These are publications that have had a major influence on the understanding, diagnosis, treatment or outlook of people with cystic fibrosis. For example Dorothy Andersen’s 1938 paper clearly describing the condition (Andersen DH, 1938) following which CF was generally recognised as evidenced by the many reports that soon followed when pathologists reviewed their previous autopsies. Also Paul di Sant’Agnese’s recognition of the abnormal sweat electrolytes (di Sant’Agnese et al, 1953) clearly comes into this category.
Precisely which of many other important publications deserve a “megapaper” rating is a purely my own personal opinion – of a non-scientist clinician treating hundreds of people with CF and frequently learning from experience and from colleagues whilst doing the job. Some of these articles definitely influenced our treatment of people with CF and others advanced the general understanding of the condition.
Any suggestions of papers that deserve designation as megapapers would be most welcome.
Very many thanks to the numerous colleagues in so many disciplines and many countries who have contributed to our knowledge of CF – not least the patients and their families. These people are too numerous to mention by name. Much of our experience in Leeds has been gained during treatment of hundreds of children and adults with CF – treatment which has been continually changing and improving; the experience gained forms the basis of the “The Leeds Method of Management” which by 2008 had reached the 7th edition; much of the information is now available on this www.cysticfibrosis.online website.
Finally, there will be many people and publications that should have been included but have been omitted. I would welcome comments if there are significant omissions; also if there are factual errors or misinterpretations. Comments from people with CF and their families would also be most welcome. Any anecdotes, images or personal recollections which would add interest to this History would be most welcome.
The text is revised frequently “on line” so there will be an opportunity for immediate alterations and additions rather than waiting for the next edition. The first ten years of the New Millennium were added in late 2010 and with this latest revision we have added 2010 to 2019.
Please do feel free to contact me, Jim Littlewood at email@example.com
For readers requiring a brief overview there follows –
A Short History of Cystic Fibrosis
From recognition (1938) to treatment of the gene (2012)
Cystic fibrosis (CF) is the most common life-shortening recessively inherited disorder of Caucasian people affecting as many as 1 in 2000 newborn infants in some countries. Both parents are healthy carriers as are up to 1 in 25 of the population. If untreated, signs of severe intestinal malabsorption, failure to thrive and lower respiratory infections, which are slow or fail to clear, are present from an early age. Mutations of the CFTR gene, of which there are now around 2000 described, result in salt and water transport abnormalities across the lining cells of a number of organs leading to viscid secretions which become infected and difficult to clear (lungs) or damage by obstruction (pancreas and liver).
Since 1938, CF has changed from a hopeless condition, fatal in infancy and early childhood, to a chronic condition affecting more adults than children
During the Thirties some infants with so-called “coeliac syndrome” had pancreatic abnormalities noted at autopsy. Dorothy Andersen1, (1) a New York pathologist, reviewed these and her own cases and described them as having “Fibrocystic Disease of the Pancreas”.
Review of experience at some of the larger children’s hospitals revealed some infants had fibrocystic disease of the pancreas. Sydney Farber recognised CF as a generalised disorder, rather than due entirely to the effects of the malabsorption, and he introduced the term “mucoviscidosis” (2). The recessive mode of inheritance was soon described (3). The major treatment advance in the Forties was the first use of penicillin in 19464 and later other antibiotics (aureomycin and terramycin) (5) without which most of these children did not survive.
Following the heat prostration suffered by some CF infants during the 1948 New York heat wave, Paul di Sant’Agnese later identified the increased salt content of the sweat (6) which became the main diagnostic test. Soon the more convenient pilocarpine iontophoresis was used to stimulate localised sweating (7). There were reports of an improving outlook from the few clinics in N. America gaining experience in treating the condition (8).
In 1957 a young Cleveland paediatrician, Leroy Matthews, funded by the CF parents, introduced a “comprehensive and prophylactic (preventive) treatment programme” which involved early accurate diagnosis, a programme to deal with all the aspects of the disease and data collection to validate the treatment (9, 10, 11).
Physiotherapy, in the form of postural drainage and percussion, the so-called “English” method of physiotherapy12 was introduced and commended by Harry Shwachman (12) – a leading expert for many years.
Various lay and professional organisations started. The first, the US National CF Research Foundation (later CF Foundation) had been was formed in 1955 and others followed usually on initiatives of the parents (13).
In 1960, di Sant’Agnese visited Europe and in 1965 the International Cystic Fibrosis (Mucoviscidosis) Association (ICFMA) (now CF Worldwide) was formed in Paris under his chairmanship – the aims to improve the care of people with CF, foster research and increase awareness. The European Working Group for Cystic Fibrosis (Later the European Cystic Fibrosis Society), chaired by Ettore Rossi, soon followed in 1969 (more information can be found here ).
However, although there was modest clinical progress during the Sixties, the nature of basic defect remained totally obscure and there were few scientists researching the problem.
During the Seventies there was a definite change to more comprehensive and intensive treatment in a few clinics for example Cleveland whose methods had formed the basis for the network of CF Centres in the USA from 1961 (9,10).
From the early Seventies, Douglas Crozier, who founded the Toronto CF clinic in 1958, abandoned the traditional low fat diet and changed his patients to a high saturated fat diet requiring the patients to take 60-100 pancreatic enzyme capsules daily (15) improving their nutrition, growth and eventually their long term survival (16). In Copenhagen, Niels Hoiby showed by immunological studies that chronic Pseudomonas infection carried a bad prognosis (17) so a policy of regular 3-monthly courses of intravenous antibiotics was introduced for infected patients with an improvement in survival (17, 18, 19).
There was increasing interest in nutrition as survival lengthened. When energy intake was measured accurately, many CF children had a very poor nutritional intake (20). Various regimens and supplements were tried some with modest success, for example an unappetising elemental diet of beef serum protein hydrolysate, glucose polymer and medium chain triglycerides (21, 22). However, the new, acid resistant pancreatic microsphere enzymes (Pancrease and later Creon) became available in the early Eighties and revolutionised the control of the intestinal malabsorption 23.
The few scientists working on CF in the Seventies explored a wide variety of possible abnormalities and serum “CF factors” which may be related to the pathophysiology but by the end of the decade they were no nearer identifying the basic defect.
This was a decade of remarkable scientific and clinical progress. Michael Knowles’s demonstration of an abnormally high potential difference across the nasal mucosa providing direct evidence of epithelial dysfunction (24) was followed by Paul Quinton showing by microperfusion experiments that the sweat gland abnormality was chloride impermeability rather than defective exchange (25). Hans Eiberg and co-workers, in Copenhagen, demonstrated a linkage between a liver enzyme marker paraoxinase, which exists in two forms but was present in the same form in 90% of CF siblings (26). In the same year, Lap Chi Tsui demonstrated a marker on chromosome 7 linked to both paraoxinase and cystic fibrosis (27) and in 1989 the CF gene was eventually identified and termed the cystic fibrosis transmembrane conductance regulator (28, 29, 30).
There were many important clinical advances during the Eighties. The CF Foundation’s patient registry and others confirmed a rise in median survival of those patients on the registry from 14 years in 1968 to 20 years in 1977 (31), matched by one centre in the UK (32). The use of the blood immunoreactive trypsin test for neonatal CF screening was a major advance (33) and became the basis of most neonatal CF screening programmes (34,35,36,37). CF Centre care was already well established in some parts of N. America, Europe and Australia where survival improved almost certainly due to CF Centre care (38). Subsequently the UK CF Research Trust gradually financed the appointment of an increasing number of doctors (CF Research Fellows), CF nurses, physiotherapists, dietitians and social workers in the UK hospitals where CF clinics were developing.
During the Eighties, in Europe in contrast to N. America, there was a gradual increase in the use of nebulised anti-Pseudomonal antibiotics to stabilise patients chronically infected with Pseudomonas aeruginosa (39) also to eradicate early P. aeruginosa infection (40, 41) thus delaying or preventing chronic P. aeruginosa infection (42, 43). Intensive courses of intravenous antibiotics became routine treatment for exacerbations of the chest infection and new anti-Pseudomonal antibiotics became available. The repeated courses of intravenous antibiotics required improved venous access and delivery systems e.g. totally implantable venous access devices (44, 45). Also home intravenous antibiotics became available at most CF centres (46, 47, 48).
A major advance, for those who had reached the end stages of their disease, was heart-lung transplantation in 1985 by Magdi Yacoub in London andJohn Wallwork in Cambridge (49, 50). Bruce Reitz had performed the first successful heart–lung transplant in 1981 on non-CF patient in Stanford; later double lung transplants became more popular (51) and a few surgeons had success with living donor lung transplants (52). The results of liver transplantation in the few patients with severe CF-related liver disease were surprisingly good (53). Various new devices and techniques for physiotherapy of CF were described and evaluated during the Eighties e.g. the forced expiratory technique (54, 55), positive expiratory pressure (56) and high frequency chest compression 57.
Involvement of dietitians and the use of the new acid resistant enzymes improved nutrition (58, 59) – undoubtedly the availability from the early Eighties of the new acid resistant enzymes (23) was one of the major advances in treatment during the Eighties. For the severely malnourished there was nasogastric (60), gastrostomy (61) or parenteral feeding (62). In 1989 the beneficial effect of regular ursodeoxycholic acid treatment in improving CF related liver disease was reported (63). Towards the end of the Eighties more CF Centres for adults were started for the increasing number of people with CF who were now reaching adulthood and the transition of these adolescents to the adult clinics received increasing attention.
The steady improvement in clinical progress continued and although the hoped-for gene therapy treatment did not materialise during the decade there was steady scientific progress in this direction. Welsh and his colleagues were the first to achieve correction of the defective chloride channel in CF epithelial cells (64). It was soon shown that the most frequent gene mutation, DF508, was incompletely processed (65) and did not reach the cell membrane (66) but when it did, it functioned reasonably well. Also growing CF cells at a reduced temperature improved expression of CFTR chloride channels (67). Eventually CFTR was confirmed to be an actual chloride channel (68).
It was important to develop an animal model for CF for research to progress and in the early Nineties this was achieved by three groups – in North Carolina (69), Edinburgh (70) and Cambridge (71). Within a year the first report of successful gene transfer into the airways of a CF mouse was reported (72); eventually in 2008 a pig model with CF was produced (73).
In 1993 the first attempt at gene therapy into the nasal passages of a person with CF was reported (74). There followed further reports of gene transfer into animals and humans using either viral or liposome vectors but none resulted in clinically adequate gene expression. However, there were some practical benefits for people with CF resulting from identification of the CF gene including reliable carrier detection, accurate antenatal diagnosis, pre-implantation genetic diagnosis and the incorporation of DNA testing into most neonatal screening programmes.
Attempts to correlate phenotype and genotype indicated that some “mild” mutations were associated with some residual pancreatic function 75. CF carriers were over represented among non-CF infertile men 76, and those with recurrent pancreatitis (77, 78).
The improvement in outlook which characterised the Eighties continued through the Nineties as a result of steady improvement in care and the increasing expertise of the staff at the now well-established CF Centres in many countries. Notable additions to the treatments available included recombinant human DNase (Pulmozyme), the first really effective mucolytic (79,80), a new preparation of tobramycin for inhalation (TOBI) (81) permitting a more widespread use of inhaled antibiotics in N. America, and long term Azithromycin (82) also for patients with chronic Pseudomonas infection. However, the provision of “optimal care”, which is complex and very expensive, for all people with CF proved to be increasingly difficult.
Cross-infection between people with CF, with B. cepacia complex and transmissible P. aeruginosa, resulted in a radical change in the organisation of CF care. In 1977 Pseudomonas (now Burkholderia) cepacia in people with CF was first reported in North America 83 and later in the UK 84; later the organism was shown to spread between patients causing serious even fatal illness (85,86,87,88).
Also there was increasing evidence of cross-infection with particular “highly transmissible” strains of Pseudomonas aeruginosa (89, 90). So the need for cross-infection control radically altered the whole attitude to cross-infection and social contact in both CF Centres and in the community. From the early Nineties all people with CF were strictly segregated according to their microbiological status.
Another significant advance in treatment during the Nineties was the widespread adoption of eradication treatment for early Pseudomonas infection in Europe but not in the USA (41) which subsequently resulted in a significant reduction in the incidence of chronic infection in the UK and Europe (42).
From the early Nineties the new high strength pancreatic enzymes (e.g. Pancrease HL, Creon 25,000) were available and welcomed by people with CF and used by many today although care was needed to avoid very high doses which rarely could cause damage to the lower bowel. With increasing survival into adulthood major problems related to CF including diabetes mellitus, liver disease, osteoporosis, pregnancy and infertility became increasingly common and presented further chronic management problems.
The New Mellennium
The main scientific research efforts were directed towards better understanding the function and control of CFTR and continuing efforts to treat the basic genetic defect with either gene replacement therapy or pharmacological correctors or potentiators of the mutant gene.
In 1999 three research teams in London, Oxford and Edinburgh were encouraged to form the UK Gene Therapy Consortium (GTC) and eventually a multidose gene therapy trial started in 2013 and succsessfully completed in 2015 although unfortunately the modest effect was not sufficient to take the product forward (www.cfgenetherapy.org.uk) The use of CF animal models remained an essential part of research, particularly CF mice, which had been available since the early Nineties (69, 70, 71). Eventually towards the end of the decade a CF pig was produced (73) and also a CF ferret (91).
In N. America, and to a lesser extent in Europe, the emphasis of research has been on pharmacological correctors and potentiators of the abnormal gene (www. cff.org/treatments/pipeline) including gentamicin for “stop mutations” (92) and subsequently of PTC 124 (Ataluren) (93).
Drugs to treat specific genetic mutations represent a major advance.
In 2012 the first, Ivacaftor (VX-771), became available for treating people with one or two G551D mutations; the results were quite dramatic (94). However, this mutation affected only some 4% of people with cystic fibrosis. By 2015 Orkambi, a combination of lumacaftor (VX-809) and ivacaftor was approved for treating patients with two F508del mutations (95). in 2018 a combination of tezacaftor (VX-661) and ivacaftor (known as Symdeko) was approved for treating people with homozygous for F508del or with at least one such mutation (96). In 2019 a more effective triple combination, Trikafta, (elexacaftor (VX-445), ivacaftor (VX-771) and tezacaftor (VX-661) ) was introduced for patients with a single F508del mutation (97,98,99). The results of this last triple therapy are quite dramatic and are considered will have a major impact on the care and lives of of those treated.
Trials with inhaled hypertonic sodium chloride solution showed positive results in reducing exacerbations and this was introduced into the treatment regimens of some patients (100).
What of the Future?
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 as essential and should be the right of all people with CF both now and in the future. Chronic gastrointestinal problems of pain and distal intestinal obstruction syndrome are still relatively common and it is encouraging that they are receiving more attention. A greater proportion of care will be provided from Specialist CF Centres – virtually all advances in clinical care have occurred at such centres. The persisting inequalities of care so clearly revealed in the past and yet still present as revealed by the CF registries in North America, the UK and elsewhere, hopefully will lessen.
More user-friendly “conventional” treatment to control symptoms will be available e.g. more efficient nebulisers, powder rather than liquid delivery of inhaled drugs. Also increasing efforts to improve adherence from various psychosocial strategies are of increasing importance.
More lung transplants will be required and measures are being taken to increase the supply of donor organs where this is a problem. Other major and complex problems will increase as the population ages e.g. diabetes, liver disease, osteoporosis, pregnancy, infertility, chronic renal problems, drug allergies as well as complex psychosocial issues. There will be increasing use of home care and CF Nurse Specialists as part of the CF centre team will be increasingly important. Protocols for prevention of cross-infection will be even more important as new organisms emerge and resistance and allergies to current antibiotics increase.
Carrier testing of relatives, the option of antenatal screening and, if positive diagnosis, and pre-implantation diagnosis (PIGD) for high risk couples should be encouraged and available. Unfortunately this opportunity to ensure an infant of two carriers does not have CF by the use of PIGD does not receive the attention it deserves at present.
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 even more important. Provision of the best available treatment for CF is very expensive and is likely to remain so. Unfortunately funding will continue to be a major problem.
Most professionals involved with CF care appreciate the major problems of people with CF and their families and will continue to provide a sympathetic, high standard service. The addition of 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 will continue and increase and CF is a template for other genetic diseases. 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. There are many other encouraging developments relating to restoring the airway surface liquid some are already of proven value e.g. hypertonic saline, dry powder mannitol.
There has not been a time when there was more hope of major progress in CF care than the present. In contrast with the really hopeless outlook in the early years, the present state of knowledge, clinical care and the involvement of so many 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, prevention, improvement in diagnosis, treatment and provision of optimal care for people at all stages of the condition will remain of the highest priority, progress both in the pharmacological treatment and gene replacement therapy to correct the basic defect is definitely gaining momentum and success in this area is likely to benefit even patients whose condition is more advanced. It is no exaggeration to say that the availability of the new modulators, singly or in combinations has significantly altered the lives and outlook for an increasing number of people with cystic fibrosis
Jim Littlewood 2019
Based on -“The History of Cystic Fibrosis” by Dr James Littlewood OBE Edited and produced by Prof. Daniel Peckham.
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