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 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 likely to be available within a few years.

• Improvements in outlook with conventional treatment are likely to continue
The effects of the improved treatment, which have occurred over the past two decades, are likely to be reflected in improved survival for the foreseeable future. In particular, the reduced proportion of people chronically infected with P. aeruginosa will reduce the number who will experience deterioration in their condition. Increased attention to 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 may also be more specific pharmacological treatments, which will improve the outlook of many patients, and in the intermediate future gene replacement therapy is like to further improve the condition and, in the long-term, the survival of people with cystic fibrosis.

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 in adults with CF, most of whom attend CF Centres primarily interested in respiratory problems. 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. 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 continue to exceed the doses recommend by the UK Committee on Safety of Medicines. Also more detailed evaluation of distressing abdominal symptoms, rather than considering all to be due to malabsorption requiring more enzymes, would 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/da y.

• 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 recognise and investigate the relevant problems. It is likely that further improvements in present treatment will continue to be made at CF Centres.

• 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, longer acting drugs reducing the doses needed for example once rather than three times daily as has occurred with intravenous tobramycin. Also increasing efforts to increase adherence from various psychosocial strategies are of increasing importance.
.
• Increasing the number of organ transplants for people with cystic fibrosis
This will remain a problem for the foreseeable future and it is reassuring that the problem is a high priority for the staff at the UK transplant centres and the situation is likely to improve. It is reassuring that the shortfall of transplants 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 into treating donor organs has already permitted the use of some lungs that would previously have been rejected

• 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, 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 increases.

• 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.

• 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, acted upon and appropriate treatment strategies agreed as they arise. Cooperation between Centres will be required. 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. The annual rate of acquisition of new P. aeruginosa does not appear to change (Lee et al 2004b), 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 - which does not appear 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 and other organisations will need to be enforced with increasing vigor and success by patients, families and professionals and indeed by everyone involved in CF care.

• 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 (Pseudomonas aeruginosa infection in people with cystic fibrosis, UK Cystic Fibrosis Trust, 2004; Saiman et al, 2003; Burkholderia cepacia complex, UK Cystic Fibrosis Trust, 2004; Methicillin resistant Staphylococcus aureus. UK CF Trust 2008).

• 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 general population screening has not been generally successful, the investigation of relatives for carrier status should be generally available and, for those who requested it in the UK, is available through the National Health Service.

• Pre-implantation diagnosis
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. This should be available to all couples that know they are carriers and is likely to be cost-effective in the long-term.

• Antenatal screening and diagnosis
For a time antenatal screening was offered to all pregnant women in Edinburgh and was available for over 10 years but has since been withdrawn; one reason 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. In Edinburgh, where antenatal CF screening has 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 a likely consequence of both antenatal and neonatal CF screening. Although not all prospective parents will wish to be screened for CF carrier status it should, and I’m sure will, be available as a choice for all who want it in due course. Antenatal screening has been accepted in principle by the UK National Screening Committee and is available in some parts of the United States.

• Neonatal screening will be introduced in most countries
The evidence and accumulated experience that screening is mandatory is now overwhelming and even in the UK, where there was considerable opposition from the National Screening Committee, 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 the 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 to say the least.

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 fall in the number of newborns with CF has already been noted in East Anglia, a region of the UK where there has been neonatal screening for over twenty years; perhaps due to an increased general awareness of cystic fibrosis. Also 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 most areas where neonatal screening has been introduced.

• 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 there 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 drug or gene therapy for the basic defect, attendance at a CF Centre will be necessary for it will be through selected Centres that trials will be 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 it being followed in Europe.

• Correction of persisting inequalities of care and funding problems
The persisting inequalities of care so clearly revealed in the past and yet still so obviously still present as revealed by the CF registries in North America, the UK and elsewhere, are quite unacceptable. Consensus meeting 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 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 review (as in the UK), ideally in partnership with the Government or appropriate funding body.

• Funding – a present and 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 may be even more expensive. However, perhaps it should become increasingly unacceptable for those in prosperous countries to deny adequate care to those with the misfortune to have a serious life-threatening disorder such as cystic fibrosis. To achieve adequate provision by funding agencies or government 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, an increasing feature of our 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 treatment for the basic defect whether it is gene replacement, drugs, or other means. It is very likely that within 5 to 10 years, or even considerably sooner, either gene replacement or pharmacological treatment or both (perhaps depending on the patient’s particular mutations) will effectively 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.

To the families and people with CF, progress seems to be painfully slow, even allowing for their understandably 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. We now know the basic defect – unbelievable progress if viewed from before 1980 – so why is progress so slow they ask. When no one had any idea as to the basic defect, “good science” for science sake, which may have a bearing on CF, was acceptable although there were numerous blind alleys, which lead nowhere – yet they just might have lead to the cause. However, now we know the cause – admittedly still lacking some details on regulation etc – there is enough known to focus our 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.

• The UK CF Gene Therapy Consortium
In the UK, in London, Oxford and Edinburgh, we are fortunate to have three of the leading CF gene therapy research teams in the world. We are aware that pharmacological approaches to treatment are the main focus of research in the USA. It was therefore decided to ask these three research groups to combine in their efforts with the promise of funding them for five years to permit continuity and cooperation to develop a compound to the stage of a Phase III trial within five years - which proved to be over optimistic. The concept of the UK CF Gene Therapy Consortium (UKGTC) was suggested by the Chief Executive of the UK CF Trust, Rosie Barnes, in 1999 after asking the scientists what they required to speed up the process, which seemed to many to be so painfully slow? They requested more senior scientists and technicians – experts, people to do the numerous experiments in the laboratories to move more projects forward at the same time. An important feature of the initiative was to guarantee regular funding and security to high quality scientists with proven track records in this field and also to avoid the delays caused by the search for piecemeal funding from the usual grant awarding bodies. As many scientists still work in relatively small isolated groups, the formation of a combined working approach of a number of major centres, such as the UKGTC, is a definite step forward with the aim of much greater sharing, to a previously unpredicted extent, of ideas, knowledge, resources and core facilities to speed progress and is already showing the advantages of such an arrangement. The members of the UK GTC are to be commended for their pioneering progress in putting progress in CF research before their career progress in
many cases to make the UKGTC work. Also thanks should go to our quite exceptional Chief Executive, Rosie Barnes, for her vision and drive in bringing everyone together to form the UKGTC and her subsequent relentless efforts and those of her team to secure adequate funding - still a major problem. There has been some opposition to the recent changes in policy but it surely must be the right way to go when one considers the current situation. The progress of the UK GTC up to present has been very encouraging. In 2010 the pilot trial of the GTC's product was underway and a multidose trial is due to start in 2011.

• The CF Foundation’s Therapeutics Development Programme
A major welcome 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
As part of the CF Foundation initiative, high throughput screening is likely 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 2011 a number of active compound had been developed - some already by 2010 have reached phase III trials. VX-770 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 Treatment leads to an impressive change in nasal potential difference and a significant fall in sweat electrolytes. Two Phase3 trials were in progress in 2010. VX-809 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 is planned. Ataluren (PTS 124) is an oral drug allowing a read through of premature stop mutations (so-called nonsense mutations with an X); a phase 3 trial is in progress aimed at determining if the drug can improve lung function.

• Other developments 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 other well advanced in clinical trials - for example denufosol acting on the transport defect and showing significant effects in the first Phase 3 trial.

CONCLUSION

I have endeavored to cover some of the many aspects of the CF story as seen by a general paediatrician initially involved in other areas, who gradually became very involved in CF care and since 1983 has been working closely with the UK CF Trust first as Member and then Chairman of the Research and Medical Advisory Committee and subsequently since 2003 as Chairman of the charity. I have tried to highlight lessons from the past, such as the absolutely central role of Specialist CF Centres and the advantages of collaboration, and speculate on how developments will continue.

I thank all those friends and colleagues, too numerous to mention, who over the years have contributed to and now continue with the development of the Leeds Regional CF service. In recent years, since my retirement from the Leeds CF Centre, it has been a great pleasure to work with Rosie Barnes and her staff at the UK CF Trust and more recently with our new Chief Executive Matthew Reed. 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 hopeless situation in the early years, the present state of knowledge, clinical care and scientific activity of highly regarded scientists would have been beyond belief even 20 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 gene replacement and pharmacological areas is gaining momentum.

Jim Littelwood 2011

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 internet era. The entries are in alphabetical order of first author and there are also useful separate subject and author indices. By 2009 there were over 30,000 references to cystic fibrosis on the medical data base “Medline”.

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 Lucas Kulczycki 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.

Figure 49: Lucas Kulczycki

1992 Super M. Milestones in cystic fibrosis. In; Warner JO, editor. Cystic Fibrosis. British Medical Bulletin 1992; 4:717-737.
Maurice Super’s account of the history of CF has a strong emphasis towards the genetic advances as he was both a paediatrician and also a geneticist in Manchester.

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 a UK paediatrician of great experience and one of the few UK paediatrician 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 Crit Care Med 1998; 157 Suppl: S148-S154.
A review of research in CF by Michael Welsh, 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. Physiological Reviews 1999; 79: S3-S22.
An interesting and 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 interesting multi-author account of the developments in CF with a strong emphasis on the North American scene edited by Dr Carl Doershuk. 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 leading figures 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.

Figure 50: Wellcome Witnesse Seminar held in 2002

Figure 51: Jim Littlewood receiving the Rossi Medal from Prof. Gerd Doring in 2004.

Figure 52: Ettori Rossi Medal of the European Cystic Fibrosis Society.

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 retired Paediatric Gastroenterologist and Dr Jim Littlewood.
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 Littlewood JM. “Looking back over 40 years and what the future holds”. The Joseph Levy Memorial Lecture of the Cystic Fibrosis Trust and the Ettore Rossi Medal Lecture of the European Cystic Fibrosis Society.
In 2004 Jim Littlewood (figure 51) was awarded the Joseph Levy Memorial Lectureship by CF Worldwide in 2004 and also the Ettore Rossi Medal (figure 52) by the European Cystic Fibrosis Society in 2004.

The Levy Lecture was given at the Opening Ceremony of the 27th European Cystic Fibrosis Conference 2004 in Birmingham. A full transcript of the Joseph Levy lecture with references can be downloaded from the UK CF Trust website www.cftrust.org.uk

2007 Littlewood JM. Chapter 1. “History”. In: Hodson ME, Geddes DM, Bush A. editors. Cystic Fibrosis. Third edition. London: Hodder Arnold Health Sciences, 2007:3-20.
An detailed account of the history of cystic fibrosis up to the discovery of the gene in 1989.

2008 Fanos JH. “We kept our promises”: An oral history of Harry Shwachman, MD. Am J Med Genet Part A 146A:284-293.
A fascinating account of an interview with Harry Shwachman and his wife in 1984 - some 2 years before his death.

Additional historical 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.

1971 Busch R. Zur Erfassung der Mukoviscidose beim Neugenboren. (Comprehension of mucoviscidosis in the newborn). Kinderarztliche Praxis 1971; 39:268-271. (German).
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 Morphologisches Jahrbuch 1983; 129:459-465.
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. Archiwum Historii I Filozofii Medycyny 1987; 50: 427- 434. (English with Polish summary)
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; 36:13-15.
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
“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 describings 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).

top