The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

1954 McIntosh R. Cystic fibrosis of the pancreas. Patients over 10 years of age. Acta Paediatr 1954; (Supp.100): 467. [PubMed]
From 1931 Rustin McIntosh (1894-1986) a distinguished general paediatrician, was Chairman of the Babies Hospital, New York where Dorothy Andersen and Paul di Sant’Agnese developed their CF service. Out of a large group of their patients McIntosh describes 27 who were over the age of 10 years (four of whom had died) from the Colombia Presbyterian Medical Center in New York. It is of note that all the patients already had severe respiratory involvement although all retained an optimistic outlook for the future. Fatty foods were avoided because of symptoms and only half took pancreatic enzymes and they did equally well without them.

The report was mentioned by Shwachman in 1958 as the largest series of older patients so far published.

 

1960 Marks BL, Anderson CM. Fibrocystic disease of the pancreas in a man aged 46. Lancet 1960; i: 365-367. [PubMed]
A very detailed report from Melbourne of a middle aged man with long standing bronchial infection, bronchial damage and chronic diarrhoea with pancreatic achylia determined by detailed pancreatic function tests. The sweat sodium and chloride were 85 and 71 meq/l respectively. Spermatozoa were absent from the seminal fluid. There was a family history of deaths in childhood.


This was the oldest well-documented patient reported up to this time – with very convincing evidence for the diagnosis.

 

1960 Leading article. Mucoviscidosis in adults. Lancet 1960; i: 963-964. [PubMed]
This article is confusing. The writer discusses the possibility of encountering CF in older patients and mentions the Marks & Anderson case (Marks & Anderson, 1960 above). Also there is discussion of a paper by Koch of Giessen (Koch E. Germ med Mon 1960; 5:40) who searched for CF in an adult hospital population and reviewed "84 such cases" - presumably considered to have cystic fibrosis. He searched through healthy students, gall bladder patients, peptic ulcer patients, 88 patients with unrelated complaints and 68 close relatives of CF patients. Diagnosis was based on sweat tests and pancreatic enzymes in duodenal aspirates - the activities of one or more were depressed.
However, the findings of this particular study of Koch’s are difficult to accept. For example “of the 68 relatives of 41 cases of mucoviscidosis only 9 were free from symptoms, signs or laboratory evidence of the disease”.

Also an article from the same author in 1959 entitled "Mucoviscidosis in adults, a very frequent dominant hereditary disease" (Bohn H Koch E. Die Mediz 1959; 4:1139-1149) does little to reassure one that the findings in the present paper are valid . Subsequent studies searching for undiagnosed CF in populations of patients with bronchiectasis and chronic bronchitis did not reveal patients with unrecognised cystic fibrosis (Muir et al, 1962 below).

Although the findings in this paper are questionable when viewed in the light of subsequent publications, the possibility of encountering this new disease – CF – was being suggested to clinicians dealing with adults and other gastrointestinal and respiratory conditions.

 

1961 Huhnstock K, Schwarz G. On mucoviscidosis in adults and diabetes mellitus. Klinische Wochenschrift 1961; 39:854-7. [PubMed]
These authors screened 250 adults with diabetes mellitus using Shwachman plates (Shwachman et al, 1956 above) and those who were positive had sweat tests performed by the bag method. Nine of the 250 diabetic adults had positive sweat tests but no other signs of cystic fibrosis.


These findings are difficult to explain as diabetes mellitus is usually a late feature in the progression of cystic fibrosis. Also the ages of the patients (between 49 and 66 years) were quite against their having cystic fibrosis. It is difficult to accept these findings particularly as there were no other signs of cystic fibrosis in these middle aged patients. Also a number of authors had found some apparently healthy adults with sweat tests with values of sodium and chloride over 60 meq/l. This paper was followed by a number of publications on the relationship between established diabetics and cystic fibrosis. The first description of diabetes mellitus in cystic fibrosis is usually attributed to Shwachman & Leubner, 1955.

 

1965 Batten J. Cystic Fibrosis: A Review. Brit J Dis Chest 1965; 59:1-9. [PubMed]
In the mid Sixties Sir John Batten started the first clinic in UK for adults with CF at the Royal Brompton Hospital, London. This clinic eventually became the world’s largest centre for adults with cystic fibrosis. In the UK it was the only large clinic for adults with CF until the Eighties as there were so few adults surviving.

Sir John remained closely involved in the developments of CF care in the UK and with the work of the UK CF Trust eventually becoming its President from 1986 to 2003. He was physician to Her Majesty the Queen from 1974 to 1989.

 

1965 Shwachman H, Kulczycki LL, Khaw Kon-Taik. Studies in cystic fibrosis. A report of sixty-five patients over 17 years of age. Pediatrics 1965; 36:689-699. [PubMed]
Harry Shwachman had treated 1700 patients over a period of 25 years. Ten years previously he had only three patients aged over 17 years. Here he is reporting 65 patients over 17 yrs - not including the 15 who died aged over 17 yrs. As in all other series of older patients the diagnosis was made later than average. For example in this series only 8 were diagnosed in the first year and only 34 of 65 were diagnosed less than 10 years. It is almost certain, as eventually shown by mutation analysis, that many of these late diagnosed patients had milder mutations. Shwachman considered the most important single advance in treatment (as did others) was the introduction of broad spectrum antibiotics in 1948. The authors mention many aspects of management now regarded as features of optimal care that warrant quoting verbatim as follows -
“A few minor changes evolved over the years that may play a greater role than we are able to quantitate. Factors that have to deal with the economic, emotional and psychological problems of parents and of growing children having a disease expensive to treat and with an unpredictable future. Our constant availability for their guidance, the close and harmonious relationship to the family physician or paediatrician and of highly skilled experts in our medical centre, our attempt to secure financial assistance and to provide continuous long-term care by the same group of individuals regardless of the age of the patient, coupled with efforts to instruct our parents and above all our positive approach undoubtedly contributes to the relative success of our programme and survival of some of these patients beyond adolescence.”


These main components of good CF care have remained much the same over the years. One particular feature stressed by a number of the successful CF paediatricians over the years has been availability of the doctor for advice and continuity of care by the same group of individuals – two features which are less readily available in the modern UK National Health Service. However, one point must be made - many paediatricians in the USA - including Shwachman - were initially slow to refer their patients to chest physicians treating adults most of whom lacked the knowledge and experience to continue providing the expert treatment the patients had received to achieve their adult status. One factor may have been the problems with medical insurance arrangements.

 

1976 Mitchell-Heggs P, Mearns M, Batten JC. Cystic fibrosis in adolescents and adults. Q J Med 1976; 45:479-504. [PubMed]
The first report from Europe of 45 patients over 12 years from John Batten’s adult CF unit at the Brompton Hospital, London. The mean age at first visit to the adult clinic was 17 years and the patients were followed for an average of 4 years. Most had been cared for previously at paediatric units in London by Drs Winifred Young, Margaret Mearns, Richard Dobbs, Archie Norman and David Lawson. Thirty two (71%) already had severe lung disease. All had cough and sputum, 23 had haemoptysis and 8 pneumothorax. Forty three (96%) were considered to be pancreatic insufficient although 5 had stopped enzyme supplements apparently without problems. Only three had diabetes mellitus.


This is a detailed paper of experience at the Brompton Hospital of the management and physical state of CF adults in the mid-Seventies and a review of previous reports of adults with CF from the first of McIntosh (1954 above) from New York. The survival of some of these patients suggest that they may have had “mild” mutations – hence the ability to stop pancreatic extracts without problems may indicate some of these patients were pancreatic sufficient. In some of the earlier reports of adults with CF, the late age of presentation and diagnosis certainly suggests that some may have had milder mutations.

 

1979 di Sant’Agnese PA, Davies PA. Cystic fibrosis in adults. 75 cases and a review of 232 cases in the literature. Am J Med 1979; 66:121-132. [PubMed]
This is a detailed review of CF as seen in adults at the time. The 75 patients were aged 18 to 47 years. Chronic obstructive pulmonary disease was present in 97% and the major cause of mortality and morbidity and all were infected with Pseudomonas aeruginosa and Staphylococcus aureus. 60% had minor and 7% major haemoptysis, pneumothorax occurred in 16%. Sinusitis in all and 48% had nasal polyposis, pancreatic insufficiency in 95%, and meconium ileus equivalent in 21%. Some had glycosuria, biliary cirrhosis, cholelithiasis or aspermia. Height and weight were usually in the lower limits of normal but some older patients with CF may look quite well.


An interesting paper describing adults in the Seventies by one of the leading US experts of the time and one of the future experts. As with other series of people with CF who had reached adulthood, many (22% in this series and 17% in a series of Shwachman, 1977) had been diagnosed after the age of 15 years. A significant number of such patients would almost certainly have at least one so-called mild mutation. The presence of these late-diagnosed but longer surviving patients has always confounded studies designed to show the importance of early diagnosis; but they are, of course, a minority of patients.

 

1987 Penketh ARL, Wise A, Mearns MB, Hodson ME, Batten JC. Cystic Fibrosis in adolescents and adults. Thorax 1987; 42:526-532. [PubMed]
This is a report of the extensive experience of adults with CF at the Brompton Hospital in London, one of the first and still the largest adult CF centre in the world. Three hundred and sixteen patients with CF had attended the Brompton Hospital during 1965-83; 178 (56.3%) of them were male and 136 female, and their ages ranged from 12 to 51 years. Most patients presented in infancy with respiratory symptoms and malabsorption, but 19 (6%) were diagnosed in adult life, three in their thirties. Pulmonary disease was almost universal (99.7%), being responsible for 97% of all deaths and three quarters of hospital admissions. All patients had developed a productive cough by the age of 21 and over half before the age of 5 years. Many complained of wheezing and reversible airflow obstruction was present in 40% of those tested. Minor haemoptysis was very common (62%), but major episodes less so (10%). Pneumothorax was seen in 61 cases (19%), and was often recurrent. Some irreversible airflow obstruction was present in all patients with pulmonary disease. Two patients had been followed for over 20 years without showing appreciable decline in lung function. Thirty five patients (11%) had no symptoms of malabsorption. Acute meconium ileus equivalent was seen in 16% and a chronic partial obstruction with episodic symptoms in a further 19%. Diabetes mellitus developed in 36 patients, 13 of whom were insulin dependent. Hepatomegaly was common (29%), often occurring without abnormal results in biochemical tests of liver function; only 1% of patients developed portal hypertension with varices and as cites. Skin reactions to at least one common allergen, including Aspergillus fumigatus, were positive in 70%, but very few patients suffered from hay fever or eczema. One hundred and twenty one patients have died, 97% from infection or other pulmonary complications, and 195 were alive in December 1983 (mean age 23 years). Seventy eight per cent of patients were in full time education or full or part time employment, or were housewives, and only 41 were unemployed for reasons for health. Many patients were married and 10 women had borne children. Most patients were admitted to hospital only three or four times during the period of follow up and 50 individuals (16%) had never been in hospital at all. The authors suggested that the improvement in prognosis and quality of life for adults with cystic fibrosis should encourage a positive attitude in those who care for them.


A detailed account of experience from 1965 at the Brompton Hospital, London which was and still is the largest centre in the world for adults with CF - hence summarised here in some detail. The clinic was started by Sir John Batten in 1965 and attracted patients from near and far – many coming from Archie Norman’s clinic at Great Ormond Street, London or from Margaret Mearns and Winifred Young at the Queen Elizabeth Hospital Hackney, London - at both these paedaitric clinics the treatment was of a higher than average standard.

 

1993 Walters S, Britton J, Hodson ME. Demographic and social characteristics of adults with cystic fibrosis in the United Kingdom. BMJ 1993; 306:549-552. [PubMed]
A survey of adults with CF in the UK by Dr Sarah Walters, a Birmingham doctor who herself has CF, which gave a picture of the relatively new and expanding population of adults with cystic fibrosis in the UK. 1052 adults were members of the Association of Cystic Fibrosis Adults UK, accounting for the majority of adults. Most were living fulfilling lives. 26% of men and 44% of women were married or cohabiting. 55% were working, fewer than 56% had less than two weeks' sick leave a year. Half of those not employed gave ill health as the reason. Unfortunately, revealing that they had CF at job interviews reduced the likelihood of being employed for those with mild to moderate disease. People with CF had been less successful than the general population in achieving O level or equivalent qualifications, but more successful in achieving A level or higher qualifications.
So contrary to an image of chronic ill health and disability, a high proportion of adults with CF were living full and productive lives - marked contrast to some of the earlier reports of adults with CF.
A further survey by Sarah Walters in 2000 showed considerable further improvement in many aspects of the condition and also the hospital care of the adults with CF in the UK.

 

1994 Walters S, Britton J, Hodson ME. Hospital care for adults with cystic fibrosis: an overview and comparison between special cystic fibrosis clinics and general clinics using a patient questionnaire. Thorax 1994; 49:300-306. [PubMed]
Another study from Sarah Walters on this occasion to assess the current pattern of medical service received by adults with CF in the UK and to compare the type of care between special CF centres and general clinics. Two thirds of the patients were attending special CF centres for either adults or adults and children. Significant differences between cystic fibrosis and general clinics were noted. Patients attending special cystic fibrosis clinics were more likely to have had simple clinical investigations (blood tests, sputum culture, oxygen saturation, chest radiography, weight and lung function measurement) in the previous year. They were also more likely to have received intravenous antibiotics at home, and to have access to paramedical personnel. Patients attending cystic fibrosis clinics were taking higher doses of pancreatic enzyme supplements with respect to quantity and potency of preparation. Such patients also had less severe symptoms irrespective of social class, and were more likely to be satisfied with professional aspects of their care. Regardless of type of clinic, potential deficiencies were identified in overall medical care with omission of clinical investigations in severely affected patients and evidence of under treated respiratory and digestive symptoms in patients with moderate and severe disease.


This survey provides evidence that adults with cystic fibrosis attending special cystic fibrosis clinics at that time received more detailed care, had better symptom control, and are more satisfied with the service provided than those attending general chest clinics. The introduction of CF centre care was slow in the UK and was opposed by some consultants working in general hospitals with a few CF patients. Even in 2012 there is still considerable discussion about the best care arrangements for people with CF. It is recommended by all CF organisations including the UK CF Trust that all adults with CF should receive all their medical care at a specialist CF Centre for adults unless there are special circumstances such as geographical problems of distance or access.

 

1995 Gan K-H, Geus WP, Bakker W, Lamers CBHW, Heijerman HGM. Genetic and clinical features of patients with cystic fibrosis diagnosis after the age of 16 years. Thorax 1995; 50:1301-1304. [PubMed]
Predictably, adult patients with late diagnosis have a better prognosis. The differences between the early diagnosis of 4.6 years (ED) and late diagnosis 27.7 years (LD) were FEV1 52% vs 72.5%; Pseudomonas infection in 70% vs 24%; pancreatic insufficiency 81% vs 12%; homozygous for DF508 58% vs none.
In other series of adults with CF many have been diagnosed late and had other features suggesting many had milder mutations – supported by the high frequency of pancreatic sufficiency. However, it has been emphasised that these patients require just as careful follow up and treatment as those with the more usual clinical picture - rather than waiting until they develop more obvious chest symptoms (Lording A, et al. Pulmonary infection in mild variant cystic fibrosis: implications for care. J Cyst Fibros 2006; 5:101-104. [PubMed]).

Dr Harry Heijerman was the Founding Editor of the Journal of Cystic Fibrosis. Under his guidance the journal was increasingly successful; the editorship was taken over by Prof. Gerd Döring in 2006 (see 2002 Journal of Cystic Fibrosis below)
Harry Heijerman is Physician at Haga Teaching Hospital, Deb Haag in the Netherlands and a leading figure in CF care and research in Europe.

 

1999 Vavrova V, Zemkova D, Bartsova J, Zapletal A, Smolikova L. Krebsova A, Macek M jr. Cystic fibrosis - a disease of adolescents and adults. [Czech]. Casopis Lekaru Ceskych 1999; 138:654-659. [PubMed]

The summary of this article gives an account of the situation regarding CF in the CF centre of the Faculty Hospital in Prague Motol in 1999. 349 patients are followed; also included are the 95 who died since 1985. 126 (36.1%) survived to the age of 18 years. The median age of death increased from 12.2. years in 1985-1990 to 18.8 years in 1991-1998. Adult status was satisfactory 40.4%, poor in 33.3% and marginal in 26.3%. Pulmonary function was normal in 17.5%, and severely affected in 22.8% - the rest between 40-80% predicted. Modern intensive treatment has improved the prognosis and quality of life of people with CF.

Fig. 1: Professor Vera Vavrova receiving the European Cystic Fibrosis Society Award from the President, Professor Stuart Elborn in 2008.

Professor Vavrova (figure 1) of Prague published her first paper on CF in 1962 and her most recent in 2009. She has been involved in CF care and research for nearly 50 years and involved in over 80 papers dealing with many aspects of the condition. She received the ECFS Award in 2008.

 

 

1998 Conway SP. Transition from paediatric to adult-orientated care for adolescents with cystic fibrosis. Disability & Rehabilitation 1998; 20:209-216.
The Leeds CF Centre had been running a monthly transition clinic for the previous 10 years since the adult CF unit was started, first at Seacroft Hospital in 1988; Dr Conway had been involved since its inception. All patients should have the opportunity to transfer to a properly equipped and properly staffed adult cystic fibrosis centre where they can continue to receive the highest standards of care from an experienced multidisciplinary team.
In some cities the paediatric and adult CF units are closely related both geographically and administratively. For example, in Leeds Dr Conway is the “Lead Clinician” in both the paediatric and adult CF units. Also in Copenhagen the same team care for both children and adults. Certainly this arrangement does reduce the stress experienced by many patients (and their parents) in transferring to a new hospital and different CF staff. On the other hand some of the problems of small children and adults with CF are very different. An ideal is to have a lead clinician involved with both units sharing the responsibility of the adults with an adult physician and of the children with a paediatrician.

 

2000 Mitchell I, Nakielna E, Tullis E, Adair C. Cystic fibrosis. End-stage care in Canada. Chest 2000; 118:80-84. [PubMed]
The mean age at death of the 45 Canadian individuals included in this study was 25.8 years (in UK in 2002 median age of death was 23 yrs, in 2003 24.2 yrs, in 2004 25.6 years and in 2008 27 years). The major cause of death was respiratory failure and lung transplantation was considered in 42 patients (93.2%), with 7 patients (17.1%) being entered on a list, but it was carried out in only 2 patients (4.4%). Autopsies were performed on only 10 patients (22.2%). Most patients died in hospital (37 patients; 82.2%), and 7 patients (15.6%) died in intensive care units while receiving intermittent positive-pressure ventilation. Palliative care was never discussed in 10 patients (25%); in a further 16 patients (40%), it was not discussed until the last month before death.

Although lung transplantation is frequently considered and requested, many patients still die without having the opportunity of a transplant – in the UK this is solely due to the shortage of donor organs. These authors considered that discussions on end-of-life care could be considered sooner. In comparison with the earlier reports there were few autopsies performed. Our own view on this was that there was ample information on the likely findings in the past literature and the procedure would only cause further distress for both the relatives and professional carers - so in Leeds we rarely suggested an autopsy to the families. The need to discuss these end-of-life issues is rightly emphasised as some adults with CF do not realise the serious stage their condition has reached, showing genuine surprise when the subject of transplantation is raised.

 

2009 Simmonds NJ. Cullinan P. Hodson ME. Growing old with cystic fibrosis - the characteristics of long-term survivors of cystic fibrosis. Respir Med 2009; 103:629-635. [PubMed]
The proportion of patients with cystic fibrosis (CF) who are middle-aged is increasing - and is likely to continue to do so. We surveyed a population of long-term CF survivors to assess their burden of illness and profile their disease characteristics. The full spectrum of disease is represented in this population and, importantly, 30% are DeltaF508 homozygous. Provision needs to be made for the health care needs of this increasing population of older patients.

This is invaluable experience from the largest adult CF centre in the world.

 

2010 Simmonds NJ, Macneill SJ, Cullinan P, Hodson ME. Cystic fibrosis and survival to 40 years: a case-control study. Eur Respir J 2010; 36:1277-1283. [PubMed]
People with CF (112) who were long-term survivors (aged 40 years and more) were compared with those who died before reaching the age of 30 years. Factors associated with increased probabilities of survival included a high BMI, FEV1 and FVC at transfer to the adult clinic and the exclusive use of oral antibiotics. Factors resulting in decreased probabilities of survival included P. aeruginosa acquisition or pneumothorax before transfer to the adult clinic and referral from a paediatric clinic in a deprived area. Long-term survival is associated with the clinical features present by the time of referral to an adult clinic; even "early-diagnosis" disease appears to have different phenotypes, possibly independent of CF gene function, that have different survival patterns.

The findings of this study from the Royal Brompton Adult CF centre in London are not unexpected with fewer of the “survivors being deltaF508/deltaF508, more being pancreatic sufficient, fewer infected with P. aeruginosa or Aspergillus fumigatus, requiring fewer hospital admissions, better nourished with better lung function". 

This type of data helps in the planning of future facilities for the care of the increasingly older CF populations.

 

2009 Hull JH. Garrod R. Ho TB. Knight RK. Cockcroft JR. Shale DJ. Bolton CE. Increased augmentation index in patients with cystic fibrosis. Eur Resp J 2009; 34:1322-1328. [PubMed]
Increased large artery stiffness occurs in a range of inflammatory conditions indicating an ageing of the vasculature and additionally being an independent risk factor for cardiovascular events. Augmentation index (AIx) is increased in adults with CF, in the presence of a normal blood pressure and independent of diabetic status. AIx was related to the systemic inflammatory status. These findings have implications for management and require further exploration so that cardiovascular health can be maintained.

As more adults are studied new findings arise. This contrasts with a previous report that there was a reduction in atheroma in patients with CF.

 

 

*2011 George PM, Banya W, pareek N, Bilton D, Cullinan P, Hodson ME, Simmonds NJ.  Improved survival at low lung function in cystic fibrosis: cohort study from 1990 to 2007.BMJ 2011;342:d1008. [PubMed]

A study to evaluate the survival of patients with cystic fibrosis whose lung function has deteriorated to a forced expiratory volume in one second (FEV(1)) below 30% predicted in the recent treatment era and to explore factors associated with any change in survival.

276 patients (147 (53%) male) whose FEV(1) was first observed to be less than 30% predicted between 1 January 1990 and 31 December 2003. Survival during follow-up to 31 December 2007 in two year sub-cohorts was determined.

Median survival improved from 1.2 years in the 1990-1 group to 5.3 years in the 2002-3 group, with a marked improvement in survival from 1994. The use of nebulised recombinant human DNase was significantly associated with a reduced risk of death (hazard ratio 0.59, 95% confidence interval 0.44 to 0.79). Significantly increased risks were associated with a body mass index under 19 (hazard ratio 1.52, 1.10 to 2.10), long term oxygen therapy (3.52, 2.49 to 4.99), and nebulised antibiotics (1.84, 1.05 to 3.22).

A marked improvement has occurred in the survival of patients with cystic fibrosis with an FEV(1) less than 30% predicted (usually considered to be associated with 2 year survival). Secondary analyses suggest that some of this improvement may be due to use of recombinant human DNase