Looking back over 40 years (part I)

PROGRESS THROUGH THE DECADES
The improvement in the outlook for people with CF has been quite remarkable changing from death in infancy to survival into middle age and even beyond. However, this has only been achieved by ever more complex, demanding and expensive regimens of treatment. It is therefore appropriate to increase our efforts to improve or even correct the basic defect, in order to ease the almost intolerable burden of present day treatment.

THIRTIES, FORTIES & FIFTIES

“The major clinical advance during the fifties was the recognition of the increased salt content of the sweat in CF”

Dorothy Andersen, the pathologist at the New York Babies Hospital published the first clear description of cystic fibrosis in 1938, in particular, she described the characteristic pancreatic abnormalities - “Cystic fibrosis of the pancreas and its relation to celiac disease: a clinical and pathological study”. Initially the wasting and chest infection was considered to be secondary to the malabsorption, particularly of vitamin A, but it was soon recognised to be a generalised disorder, which was recessively inherited.
There were no antibiotics until the mid-forties when Paul di Sant’Agnese used both intramuscular and aerosolised penicillin to treat children with CF with “dramatic” results, the most common pathogen then being a penicillin-sensitive Staphylococcus aureus.

The major clinical advance during the fifties was the recognition of the increased salt content of the sweat in CF by Paul di Sant’Agnese following the occurrence of salt depletion in infants with CF during the New York heat waves of the early fifties. Sweat stimulation by the pilocarpine iontophoresis method (the sweat test) was a major advance and is still used.

“There was evidence of the beneficial effect of pancreatic enzyme therapy"

In 1958 Shwachman and Kulczycki published their classic review of experience with 105 patients.. Through the fifties, as more antibiotics became available, both their good and bad effects were recognised. There was evidence of the beneficial effect of pancreatic enzyme therapy but many patients were still unable to tolerate a normal fat intake. Physiotherapy using postural drainage had long been the traditional treatment for CF children with bronchiectasis in the UK, and was commended by Shwachman for his patients.

In 1957, LeRoy Matthews was appointed to plan and initiate a “comprehensive and prophylactic (preventive) treatment program” for the treatment of CF at the behest of CF parents in Cleveland.

THE SIXTIES & SEVENTIES

“…Cystic fibrosis – a not so fatal disease”

The impressive results of LeRoy Matthew’s comprehensive treatment program were published in 1964 and these methods of management and treatment eventually formed the basis of the CF Foundation’s network of CF Centres from 1961. In the UK encouraging results were reported from one UK clinic and David Lawson pioneered the early and continuous use of anti-staphylococcal antibiotics.
The first CF organisations started in the USA (1955), Canada (1959) and the UK (1964). The International Cystic Fibrosis (Mucoviscidosis) Association – now CF Worldwide was set up in 1965. Also established were professional organisations including the European Working Group for CF – now the European CF Society in 1960 and the North American CF Club (1959) followed by the North American CF Conferences in 1986.

An increasingly positive approach was exemplified in an article in 1974 by Douglas Crozier of Toronto - “Cystic fibrosis – a not so fatal disease”- in which he suggested, ”Success of treatment will depend on a complete assessment of the patient and then continuing attempts to obtain normal bodily function and maintain it”. Crozier was the first to abandon the low fat diet in 1972.

“... more aggressive antibiotic therapy for chronic Pseudomonas aeruginosa infection was started”

This lack of acceptance of the status quo approach was also evident in the Copenhagen CF clinic, where more aggressive antibiotic therapy for chronic Pseudomonas aeruginosa infection was started in 1976 and also cohort isolation which separated patients with Pseudomonas aeruginosa from those without the infection was practised.

“the new acid resistant pancreatic enzymes were soon to become available”

Various attempts to improve nutrition included a supplement consisting of beef serum protein hydrolysate, a glucose polymer and medium chain triglycerides – the so-called “Allan Diet”. Although some patients improved, the first of the new acid resistant pancreatic enzymes were soon to become available, permitting most patients a normal fat intake. Essential fatty acid (EFA) levels had been noted to be abnormal by many authors from the sixties to the present and improvements were experienced when these were supplemented. Interestingly, the precise role of essential fatty acids is yet to be determined.

SIXTIES & SEVENTIES – Science

“Much effort went into attempting to isolate and further identify these various CF factors”

By the late seventies three abnormal “CF factors” had been recognised in the serum and their presence had been the subject of a great deal of research and speculation - these were the:
• Spock factor which affected the beating of fresh water mussels’ cilia the
• Mangos factor which inhibited resorption of sodium from rat saliva and the
• Lieberman factor - a lectin present in CF serum.

Spock reported ciliary dyskinesia (damaged ciliary movement) when the serum of people with CF was added to a preparation of fresh water mussels and observed under the microscope. Much effort went into attempting to isolate and further identify these various “CF factors” which unfortunately did not aid in identifying the location of the CF gene or in explaining its serious patho-physiological effects.

EIGHTIES

“our first CF Assessments appeared to be most effective in revealing areas where treatment could be improved”

The eighties was a decade of extraordinary progress in clinical care and science. The disappointing results of a small nutritional survey, which we reported in Toronto was a major factor in our starting regular so-called “Comprehensive CF Assessments” at St James’s in Leeds. This was done to determine any other areas where our treatment was sub-optimal and to identify potential for improvement – much on the lines suggested by Crozier. Since our first CF Assessments appeared to be most effective in revealing areas where treatment could be improved, we offered the service to other paediatricians for their patients in our region (population 3.5 million). More than 600 children and adults with CF from our region and beyond have subsequently had at least one Comprehensive Assessment at Leeds. We have described the development of the service in detail previously. The first 250 patients seen at our Regional Paediatric CF Centre in Leeds between May 1980 and September 1987 reflected the state of UK CF care at the time, with significant under-treatment both of the chest and the nutritional state reported. Following simple advice, significant improvements were noted in many areas at follow-up assessments of CF patients done some 15 months later.

“the fundamental difference (in the treatment) was a matter of degree rather than kind.”

In 1960, Terrence Gillespie, the Director of the CF Centre in Halifax, Nova Scotia questioned why the results were so much better in LeRoy Mathews’s CF centre in Cleveland than those in Halifax, as both clinics prescribed similar treatment. After he had worked in both places he concluded, “the fundamental difference (in the treatment) was a matter of degree rather than kind. Dr Matthews had developed the concept of starting full treatment on the day of diagnosis on every patient, regardless of the clinical condition”. This seems to be the most likely explanation for these persisting differences between Centres, which even now continue to be a major cause for concern.

“subsequent recommendation that all patients should have some contact with a Specialist CF Centre”

An important paper from Australia reporting better survival in Victoria, than in England and Wales prompted the formation of the British Paediatric Association UK Working Party on Cystic Fibrosis to report on the situation in the UK. Surprisingly, the Working Party’s subsequent recommendation that all patients should have some contact with a Specialist CF Centre, as occurred in Victoria, was initially rejected by the British Paediatric Association (UK CF Working Party Report, 1982) but fortunately accepted by the CF Research Trust who subsequently supported the appointment of key members of staff in the developing CF Centres.

There were major advances in clinical care during the Eighties. There was the introduction of nebulised antibiotics for chronic Pseudomonal infection by Margaret Hodson and the report from Leeds of successful early eradication of Pseudomonas by reviving the use of inhaled Colomycin. Successful eradication has resulted in a falling prevalence of chronic P. aeruginosa infection in clinics where inhaled Colomycin was introduced e.g. dropping below 4% in children in Leeds and Copenhagen.

There was earlier, more frequent and more “professional” use of an increasing variety of intravenous antibiotics at all stages of infection. Improved delivery systems and intravenous access such as totally implantable venous access devices were developed. EMLA local anaesthetic cream was introduced for use before venepuncture (which many children would rate as one of the more important advances of the decade!). Butterfly cannulas, long lines, and constant intravenous infusion pumps to maintain IV lines for many days at slow flow rates in small children are now routinely used. The increasing reliance on, and more frequent use of, intravenous antibiotics resulted in an increasing use of home intravenous antibiotics supervised by CF Nurse Specialists.

For those who had reached the more advanced stages of their disease there was now heart-lung transplantation in 1985, then double lung transplants and more recently, living donor lung transplants. Liver transplantation was used successfully in patients with CF and even heart-lung-liver transplantations and lung-liver transplantations.

Various new devices and techniques for physiotherapy of CF were described and evaluated during the eighties and an increasing proportion of people with CF received effective treatment from physiotherapists experienced in treating cystic fibrosis.

The nutritional state of many patients continued to improve largely due to the increasing involvement of dietitians. This allowed for individual advice in identification and then appropriate correction of the inadequate energy intake and resumption of a normal or high fat intake with the use of the new acid resistant enzymes Pancrease and Creon. Undoubtedly these new enzymes were one of the major advances in treatment during the eighties and markedly improved both the nutrition and also the lives of the many patients who had previously had uncontrolled and severely disabling bowel symptoms.

“ Towards the end of the eighties adult centres gradually appeared in order to cater for the increasing number of adults with CF”

Enteral (tube) feeding, first by the nasogastric route and then by gastrostomy (opening into the stomach through the skin of the abdomen) allowed intensive nutritional rehabilitation of those with more serious problems. Fat-soluble vitamin deficiencies were identified and corrected by appropriate doses of suitable supplements but these are still the subject of considerable debate. In 1989 Carla Colombo reported the beneficial effect of regular ursodeoxycholic acid treatment in improving CF related liver disease – the first specific treatment for those with liver involvement.

As the number and age of people with CF in the UK increased due to these improvements in treatment, paediatric CF Centres developed in most large cities. Towards the end of the eighties adult centres gradually appeared in order to cater for the increasing number of adults with CF.

EIGHTIES - Science
This was the first really productive decade in understanding the basic defect. First an abnormality of electrolyte (sodium chloride) transport across cell membranes was suggested. Michael Knowles provided direct evidence of this by demonstrating alterations in nasal potential difference in people with CF and finally Paul Quinton, showed that their sweat glands were impermeable to chloride. Impressive progress in 3 years!

“In 1989 the CF gene was eventually identified”

Also from the early eighties various groups, including Bob Williamson’s at St Mary’s hospital in London, attempted to identify the CF gene by using ‘reverse genetics’, as the protein was unknown. They studied families with more than one affected child. In 1985 Eiberg, in Copenhagen, demonstrated a linkage to the enzyme paraoxinase with this technique. Paraoxinase exists in two forms but was present in the same form in 90% of CF siblings. In the same year, Lap-Chee Tsui from Toronto, demonstrated a marker on chromosome 7 linked to both paraoxinase and cystic fibrosis in a series of mouse hybrid experiments. Two other markers, known to be on chromosome 7, were closely linked to CF. These are the Met oncogenes, Met H and Met D from Ray White in Salt Lake City and the DNA probe pJ3.11 from Bob Williamson’s laboratory in London. These findings were published in the same edition of Nature on 29th November 1985. In 1989 the CF gene was eventually identified by teams headed by Lap-Chee Tsui, Francis Collins and Jack Riordan and named the cystic fibrosis conductance regulator. To date practical benefits for the patients and their families include:

• confirmation of the diagnosis,
• accurate carrier detection,
• antenatal diagnosis, and
• improved neonatal screening.

THE NINETIES

A new major problem was the recognition of cross infection between people with cystic fibrosis.

In 1979 Pseudomonas (now Burkholderia) cepacia and its potential to spread between patients and cause the serious “cepacia syndrome” was first reported in North America and later the UK. The severity and at times, fatal nature of the associated illness in a proportion of infected patients with CF and its propensity to spread between patients has resulted in a radical change in both clinic practice and the social habits of people with cystic fibrosis. More recently cross-infection with so-called ‘highly transmissible’ strains of Pseudomonas aeruginosa has been increasingly reported and there are now many reports of cross-infection with P. aeruginosa in CF Centres. As a result of these developments it is currently recommended that people with CF should be segregated according to their microbiological status.

Support for the routine use of prophylactic anti-staphylococcal antibiotics (flucloxacillin) in young children came from a controlled trial in screened CF infants in East Anglia in the UK in 1994. The use of macrolides (azithromycin), due to their anti-inflammatory properties, has been a new widely introduced treatment for patients chronically infected with P. aeruginosa. This commenced as a result of confirmation of its beneficial effect in a number of excellent clinical trials.

Recombinant human DNase (Pulmozyme) is an important new drug for inhalation and is the first really effective mucolytic (expectorant) even for mildly affected patients. A special preparation of tobramycin for inhalation (TOBI) became available in the nineties. Although inhaled aminoglycosides (such as the IV preparations of gentamicin and tobramycin) have been widely used in the UK since Margaret Hodson’s 1981 paper, an important, well-conducted controlled trial to confirm the beneficial effect of the special preparation of tobramycin for inhalation (TOBI) was welcome.

Many patients, when eating a normal fat require a large number of enzyme capsules and it was not surprising that patients, and their professional advisers, welcomed the introduction of the new "high lipase" preparations in 1992. However, in 1993 a new complication, fibrosing colonopathy (thickening of the lining of the large bowel) was observed first in Liverpool and subsequently elsewhere in the UK and the United States. It appeared to be related to the very high doses of enzymes some patients were taking. Studies in the UK and the US both confirmed a relationship with the very high doses of lipase achieved with the new enzymes in some people but differed as to the role of the copolymer coating of some preparations.

Other new problems have emerged as people with CF become older, including the development of diabetes, liver disease and osteoporosis. Pregnancy and fertility have become increasingly common with some associated major management problems.

THE NINETIES - Science
Following the identification of the CF gene in 1989, the defect was soon corrected in cultured CF cells in the laboratory. By 1992 three CF mouse models had been produced which was essential for further research into the function of CFTR and gene transfer.

The defect in the gene was shown to affect salt transport in and out of cells with the result that chloride transport out of the cells was reduced and also excessive sodium was retained. In normal cells, CFTR regulates this function, but in people with CF, the gene is not doing its job properly with the result that the water content of the airway secretion is depleted. This depletion, results in thickened mucus, which adversely affects mucus transport and expectoration and increased the tendency for infections and their tendency to become chronic

Early gene therapy

“…successful gene replacement therapy is still considered to be a reality within 5 to 10 years”

In 1993, the first successful adeno-viral mediated gene transfer was reported in a man with cystic fibrosis. Subsequently nasal studies have been reported using viral vectors (viruses used to carry the corrected gene into the cells of the CF patient), which have achieved no evidence of significant gene transfer except with high doses causing inflammation. Repeated applications lead to increasing inflammation and antibody formation. Three studies from the UK which involved application to the nose, used liposomes as the vector; another involved repeated nasal applications and the most recent from the Royal Brompton in London, involved transfer to both nose and lungs. Although progress has definitely been slower than originally expected, successful gene replacement therapy is still considered to be a reality within 5 to 10 years and gene therapy and the investigation of more suitable vectors is now a high priority area of research for both the UK CF Trust and many others.

An alternative strategy to gene therapy is to improve CFTR function by other means and a number of drugs are under investigation and showing promise as an alternative or complementary approach to treatment. Improved CFTR trafficking with some increase in CFTR function in the nasal epithelia of people with DF508 was achieved with oral sodium 4-phenylbutyrate (4-PBA); other possibilities include genistein, and CPX. Additional potential strategies include inhibition of sodium absorption by drugs such as amiloride or its more active analogues activators of chloride secretion such UTP and INS 365 mediated through P2Y(2) extra cellular receptors.

More recent possibilities are the corrective effect of gentamicin in people with stop mutations, of sildenafil on DF508 mutations and of the correction of fatty acid imbalance. Other possibilities have been reviewed recently. Unfortunately the favourable effect of curcumin on mice homozygous for DF 508 has not been confirmed in people with CF.

A recent survey of adults with CF by Dr. Sarah Walters gave some idea as to the present situation in the UK. The average age of the 1246 responders was 25.5 years, 30% had partners, self rating of disease severity was mild in 29%, moderate 64% and severe in 7%, 47% were in paid and 13% in voluntary work. Health problems accounted as the reason for 42% being unemployed and 40% were students. They reported the following medical problems - diabetes 28%, arthritis 23%, sinusitis 20%, infertility 19%, liver problems 14%, recurrent bowel problems and allergic broncho-pulmonary aspergillosis (both 10%), 58% had less than 2 weeks sick leave over the preceding year.

A recent survey by the UK CF Trust on the present concerns of patients and their families found that these were:

• the standard of care they receive,
• facilities and services available,
• person ultimately responsible for their care,
• “who does what” when care is shared between two hospitals,
• Lack of specialist staff in smaller clinics at the local hospital,
• poor communication between professionals,
• inadequate adult services and
• cross-infection issues.

Jim Littlewood June 2004

Editor’s Notes: Part II, What the future Holds, and the conclusion will be in the next volume of the CFW Newsletter, January 2005.

The complete Levy Lecture and the full list of references can be found on our website [ here ].