The history of the development of cystic fibrosis care Perspective of a general paediatrician at a provincial teaching hospital

Foreword. This account is based presentations given at the Festschrift for the retirement of Professor Sir Roy Meadow at St James's University Hospital, Leeds on 30th September 1998 and a lecture at the 13th International Cystic Fibrosis Congress in Stockholm, June 2001. Also acknowledgements to Margaret Mearns (Mearns, 1993), Maurice Super (Super, 1992) and Lucas Kulczycki (1990) all of whom have written on CF history. The additional references after each decade (Also note from the Thirties etc) are not referred to in the main text but seem to be have some significance when considering the development of CF care.

THE THIRTIES AND BEFORE

Cystic fibrosis (CF) was recognised as specific entity during the Thirties. There is nothing resembling CF described in the 1032 pages of Sir Frederick Still's 1927 Edition of Common Disorders and Diseases of Childhood.

Although there are many early reports of infants from the middle of 17th century who almost certainly had cystic fibrosis (Busch, 1990), even before the well-known passage from German Children's Songs and Games from Switzerland forecasting that "The child will soon die whose forehead tastes salty when kissed".

In 1905, Landsteiner, of blood group fame, described meconium ileus, the neonatal intestinal obstruction that affects some 15% of infants with cystic fibrosis (Landsteiner et al, 1905). In 1912, Garrod described families some of whose children had steatorrhoea and who died of bronchopneumonia, suggesting a possible recessive mode of inheritance (Garrod & Hurley, 1912). During the Twenties and Thirties there were further reports of children who were likely to have had cystic fibrosis (Kulczycki, 1990).

In 1936 the legendary Swiss paediatrician Fanconi described children with 'coeliac syndrome' who also had pancreatic changes but he published in German! (Fanconi et al, 1936). In 1938 Blackfan and May described 35 infants with pancreatic changes (Blackfan & May, 1938), which had been reported in 1933 (Blackfan & Wolbach, 1933). Also Harper described a further 10 children with clinical features compatible with cystic fibrosis (Harper, 1938).

DOROTHY ANDERSEN'S 1938 PAPER

Although some consider Fanconi's paper to be the first clear description of cystic fibrosis (Fanconi et al, 1936), it was the 1938 report of Dorothy Andersen, the pathologist at the Babies' Hospital New York, which clearly defined CF a separate entity. Andersen described in great detail 49 patients, 20 from her hospital and others from colleagues and the literature. The paper, Cystic fibrosis of the pancreas and its relation to celiac disease: A clinical and pathologic study describes neonatal intestinal obstruction, intestinal and respiratory complications and many other features - particularly the characteristic pancreatic histology (Andersen, 1938). She likened much of the epithelial histology to that found in vitamin A deficiency but this causation was never substantiated although she continued to support this theory for many years (Andersen, 1949).

Thus, Cystic Fibrosis of the Pancreas was described as a definite clinical entity in 1938. But it is not surprising that CF infants could easily go unrecognised. We should recall that the state of health of children in this country was very different from today. Before the Second World War there was no National Health Service. Infant and child mortality was high, and throughout childhood respiratory disease, measles, non-respiratory tuberculosis, whooping cough, diphtheria and violence accounted for the majority of child deaths (Chief Medical Officer's Report, Lancet 1937; i: 299). Also communications were relatively primitive by modern standards - there were few medical meetings, no Medline, no e-mail, no fax, no photocopiers and no evidenced-based medicine.

Also note from the Thirties and earlier:

•Bramwell B. Pancreatic infantilism: remarkable improvement (growth of body and sexual development) as a result of the administration of pancreatic extract. Clinical Studies 1904; 2:348-352. Edinburgh. Rand R Clark.

•Herter CA. On infantilism from chronic intestinal infection. New York Macmillan. 1908.

•Passini F. Pankreaserkrangkung als urache des nichtgedeihens. Dtsch med Wschr 1919; 45:851-853.

•Clarke C, Hadfield G. Congenital pancreatic disease with infantilism. Quart J Med 1924; 17:358

THE FORTIES

In 1943, Sidney Farber, Chief of Pathology at the Children's Hospital in Boston, worked with Harry Shwachman studying children with cystic fibrosis. They recognised CF to be a generalised disease and coined the term 'mucoviscidosis' (Farber, 1943). Farber concluded "the respiratory tract damage therefore depends on primary obstruction by thick mucus, failure of proper lubrication of ciliated epithelium and secondary staphylococcal infection". However, there was no agreement as to the primary cause - a state of affairs, which would continue until the early Eighties.

In 1945, Dorothy Andersen and Hodges (not to be confused with later Charlotte Anderson of Australia and Birmingham, UK), investigating 47 of their own families and 56 more from the literature, concluded that the familial incidence indicated a recessive mode of transmission. Martin Bodian at the Hospital for Sick Children Great Ormond Street, London also considered there was a recessive mode of inheritance (Bodian 1952). However, Andersen and Hodges considered the disease also required another factor for its expression. Andersen suggested vitamin A as a possibility (Andersen, 1939; Andersen & Hodges, 1946). It is interesting that, even at that stage, an additional nutritional factor was implicated to modify phenotypic expression - in much the same way as essential fatty acids imbalance (increase in phospholipid bound arachidonic acid and reduction in docosahexanoic acid) has recently been implicated in the phenotypic expression of the condition in pancreatic tissue of CF mice (Freedman et al, 1999).

Treatment in these early years had a strong nutritional emphasis - remembering that sulphonamides had only recently become available and the first antibiotic (penicillin) did not appear until the mid-1940s. Recommended was a high protein diet, large doses of intramuscular vitamin A, crude pancreatin extract with meals and penicillin inhalations. The condition was considered to be primarily a nutritional problem with vitamin A deficiency being an important component. Pancreatic extracts had been available from the early Thirties and Andersen later reviewed their use in patients with congenital pancreatic deficiency (Andersen, 1945). She advised "a low fat, high protein diet with a liberal allowance of vegetables, fruits and sugar and moderate restriction of starch. Supplementary vitamin A is essential and pancreatic and vitamin B complex are given" (Andersen, 1945).

With regard to the malabsorption, in 1949 Andersen noted, "Patients excreted half the protein and half the fat fed and 15% of the carbohydrate. Good growth had been obtained with 6-8 g/kg/day protein of which casein hydrolysate forms 1-1.5 g. Because fat is poorly absorbed carbohydrate is used as the main source of calories. One or two eggs and fish liver oil is taken daily to provide fat-soluble essential substances. Skimmed milk is given and fried foods are forbidden. Supplements of vitamins A and B are given and 1-2 g of pancreatin with every meal" (Andersen, 1945; Andersen, 1949). In the same year, 1949, Andersen still considered that "persistent bronchitis complicating fibrocystic disease is the result of failure of absorption of vitamin A, and presumably other fat-soluble specific substances which, in turn, results from the inability of the diseased pancreas to secrete enzymes necessary for absorption of fat" (Andersen, 1949).

Another important message was Andersen's observation that dietary therapy should be started early - "the effectiveness of treatment depends on the degree and type of the respiratory tract infection present when dietary treatment is begun" and "when it is begun after the onset of suppurative bronchitis, it may prolong life somewhat but will not alter the prognosis".

But in the Forties the outlook remained very poor and 18 of 28 (64%) patients in one Mayo Clinic series failed to reach 7 years (Kennedy, 1946).

By the late Forties, the importance of vitamin A deficiency, regarded as so important by Andersen, was increasingly questioned and the possibility of an abnormal epithelial secretion (i.e. mucoviscidosis) was becoming a more popular theory of causation (Andersen, 1949). Discussing the suggestion that the disease may be a more generalised secretory defect, the lungs being affected with the same abnormality as the pancreas, she notes (as others have done subsequently) that "the lungs of children who die in the neonatal period appeared to be normal or show only evidence of aspiration; also no abnormality had been demonstrated in the secretions; also the mucus in the CF lungs more resembled that found in other lung disorders than the secretions in the pancreatic duct". In the same paper, Andersen presents evidence suggesting that the maintenance of adequate nutrition is protective to the bronchi if started early. She described 22 patients with no evidence of respiratory infection most of whom had been treated with good diets before cough had been present as long as 2 months.

Another leading clinician and researcher at this time was Paul di Sant'Agnese, who also considered nutrition to be a central component of the treatment package. He believed the improved prognosis, which had occurred during the decade, was due to "An appropriate diet began promptly and continued consistently, use of sulphadiazine during the stage of chronic cough and the use of (nebulised) penicillin" (Di Sant Agnese & Andersen, 1946).

Reviewing experience with 134 patients from Boston, Lowe noted "those who tended to survive longest had good gains in weight before the first symptoms and fair gains after" (Lowe et al, 1949).

Thus, in the decade following the description of CF, the nutritional aspects of the disease were regarded as of major importance, even to possibly pancreatic disease leading to secondary nutritional deficiencies being the main factor in the pathogenesis. It has subsequently been shown that early diagnosis and treatment after neonatal screening would protect against the known deficiencies of vitamins, essential fatty acids and other essential nutrients, which are known to occur within weeks of birth (Sokol et al, 1989). It is interesting that the early and long-term nutritional advantages of early diagnosis and treatment after neonatal screening are currently the strongest evidence in favour of neonatal screening and early treatment (Farrell et al, 2001).

Early antibiotic treatment

It was fortunate that in 1934 the first generally useful antibacterial drug, a sulphonamide (Prontosil), became available. The availability of sulphonamides and later penicillin by injection in 1944 (I remember how painful!) and later other antibiotics was to prove increasingly valuable in the treatment of patients with cystic fibrosis.

Antibiotics active against Staphylococcus aureus followed - sulphonamides (1936), chlorotetracycline (1948), oxytetracycline (1950), chloramphenicol (1951), erythromycin (1951), methicillin (1960), cloxacillin (1962), cotrimoxazole (1968), fusidic acid (1968), flucloxacillin (1970), Against Haemophilus influenzae ampicillin (1961) and amoxycillin (1972) and Pseudomonas aeruginosa streptomycin (1948), neomycin (1949), Colistin (1959), carbenicillin (1967), gentamicin (1968), tobramycin (1971), ticarcillin (1979), azlocillin (1980), piperacillin (1982), netilmicin (1982), ceftazidime (1983), aztreonam (1986), ciprofloxacin (1986) mereponem (in the Nineties) (Based on Table in Mearns, 1993).

Already, in the late Thirties, there were many early reports of the beneficial dramatic effects and (side effects!) of sulphanilamide appearing in the literature as diseases, which previously had carried a high mortality such as meningococcal meningitis and pneumococcal pneumonia, were cured. As with many other conditions, the understanding and improved treatment of cystic fibrosis has been dependent not only on antibiotics but also on many of the other quite astonishing scientific, medical and social advances which have occurred since the Thirties. But undoubtedly the development of Specialist CF Centres, where significant advances were applied effectively to patients by experienced staff, has been a central factor in improving treatment up to the present time.

In 1946, an early report of antibiotic treatment described the use of oral sulphonamides and nebulised penicillin (di Sant' Agnese & Andersen, 1946). The availability of penicillin from the mid-1940s was fortunate as the main pathogen at that time was S. aureus and many strains were still sensitive to the antibiotic. Patients were reported to respond favourably to penicillin aerosol 20,000 units 7 times daily alone or with intramuscular penicillin. No mention is made of adherence problems! The authors considered that the improved prognosis, which they were observing, was due to "an appropriate diet began promptly and continued consistently, use of sulphadiazine during the stage of chronic cough and the use of penicillin". Again the emphasis on nutrition was interesting and understandable in view of the gross malnutrition exhibited by affected infant and children.

Also note from the Forties: -
•Holter HV, Horwitz O. Spontaneous pneumothorax produced by ascent in an airplane. JAMA 1945; 127:519-520.
[First report of a now well-recognised complication in people who have advanced lung disease.]

•May CD, Lowe CU. Fibrosis of the pancreas in infants and children J Pediatr 1949; 34:663-687. [Questioned the effect of dietary or vitamin therapy on the eventual outcome.]

•Zuelzer WW, Newton WA. The pathogenesis of fibrocystic disease of the pancreas: a study of 36 cases with special reference to pulmonary lesions. Pediatrics N Y 1949; 4:53-69.
[Obstruction primary cause of emphysema as occurred in three infants without any infection.]

THE FIFTIES

The first Specialist CF Centres

During the Fifties the outlook for children with CF was still regarded as hopeless, but a few CF clinics developed on both sides of the Atlantic. At that time three of the principal groups working on CF in the United States were those of Harry Shwachman at the Boston Children's Hospital, Dorothy Andersen at the Babies' Hospital New York and Paul di Sant' Agnese at the National Institutes of Health, Bethesda.

In the UK, clinics were developing at the Queen Elizabeth Hospital, Hackney, London headed by Winifred Young, and later Margaret Mearns, and at the Royal Brompton Hospital, London by John Batten and Lynne Reid. Archie Norman at Great Ormond Street Hospital, London and David Lawson at Carshalton Hospital were also treating increasing numbers of children with CF and starting clinical research. However, it must be stated, that paediatric sub specialisation in the UK was not popular among most UK paediatricians. The hallmark of the sub specialist is the specialised technique or complex treatment at which he/she becomes skilled and many of these technical developments were to come later e.g. invasive biopsy procedures (in the 1960s); endoscopies (in the 1970s) and complex treatment regimens. Thus, for many years, certainly into the Eighties, the general paediatrician at the local hospital treated most children with CF in the UK and few survived to adulthood. It is surprising that, even to day, there are a few patients who are never seen by a specialist CF paediatrician or chest physician.

Diagnosis by sweat test

Diagnosis of CF in the early Fifties was not entirely clear-cut and still relied on a combination of clinical symptoms and signs supported by evidence of intestinal malabsorption and pancreatic insufficiency. A simple test to demonstrate trypsin activity in the stool, by digesting gelatine from X-ray film, had been described but problems occurred with effects of bacteria (Shwachman et al, 1949). However, in 1951, 7 of 12 infants admitted with heat prostration during a heat wave in New York were already known to have cystic fibrosis (Kessler & Andersen, 1951). Di Sant'Agnese and colleagues investigated these patients in 1952 and clearly showed sweat chloride, sodium and to a lesser extent potassium were considerably raised. They also showed slightly elevated sweat electrolyte levels in obligatory heterozygotes compared to controls (Darling et al, 1953; di Sant'Agnese et al, 1953).

Following this classic report in 1953, I still remember, as a medical student in 1954-55, making unsuccessful attempts to collect sweat samples by enclosing children's' limbs in plastic Bunyan bags - originally intended for enclosing severely burned limbs. At least one fatality was reported when performing the Shwachman test for diagnosis when the "patient was placed in a plastic bag up to the neck and covered with a blanket" to promote sweating (Misch & Holden, 1958). Mercifully, in 1959, Gibson and Cooke described the pilocarpine iontophoresis method of sweat stimulation and collection, which has been the standard method of stimulating sweat production for over forty years (Gibson & Cooke, 1959). Values for normals and affected people were soon available (Anderson & Freeman, 1960; McKendrick, 1962). Also the test was helpful in deciding which newborns with intestinal obstruction had cystic fibrosis (Elian et al, 1961).

Over the years sweat tests have become widely available in most general hospitals - perhaps too widely available - for in some units they have been performed badly, having been delegated to inexperienced operators, even to inexperienced house officers, despite the awesome importance of a positive result. It was not surprising therefore that in 1978 a classic paper from Charlotte Anderson's unit in Birmingham described a number of children mistakenly diagnosed as having cystic fibrosis (Smalley et al, 1978). In 1987 Nick Shaw and I reported that 7 of the first 170 patients referred to Leeds from around the UK for a full CF Assessment, which included a sweat test to check the diagnosis, did not have the condition but had been misdiagnosed often years previously as having CF on erroneous false positive sweat tests (Shaw & Littlewood, 1987). There were other similar reports. Recently detailed Guidelines for the Performance of the Sweat Test for the Investigation of Cystic Fibrosis in the UK have been published by the Association of Clinical Biochemists and a multidisciplinary working group organised by Anne Green, Consultant Biochemist at the Birmingham Children's Hospital.

Detailed regimens of treatment are published

Postural drainage had been traditional treatment for bronchiectasis and Winifred Young started children with CF on similar therapy in 1950 from the time of diagnosis (Young, 1964 quoted by Mearns, 1993). Also the first report of the effect of bronchodilators was published at the end of the decade (Gandevia & Anderson, 1959). Physiotherapy has remained a central component of treatment in the UK and recently current practice has been reviewed in Clinical Guidelines for the Physiotherapy Management of Cystic Fibrosis by the Association of Chartered Physiotherapists in Cystic Fibrosis (published by Cystic Fibrosis Trust, 2002). However, over the years not all were convinced of the value of such therapy -"the ritual of carefully positioning the patient to drain every pulmonary segment separately is usually an exercise in futility" (Docter, 1981). "Physiotherapy will aid to expectorate sputum from only a limited, although essential, part of the airways. Clearance of sputum from peripheral airways can only be enhanced by reducing its amount and by modifying its viscosity and elasticity" (Kerrebijjn, 1981). The fact that in the USA, as one paediatrician remarked, "what a monstrosity it becomes financially on the hospital bill" may have had some relevance! (Gibbs, Question at Minnesota Meeting, 1981).

In 1955 Shwachman described a detailed method of management laying the foundations of modern treatment - early diagnosis, active early treatment of chest infection and attention to nutrition. Through the decade as described above, more antibiotics became available and both paediatricians, parents and patients, were becoming more familiar with both their good and bad effects. Antibiotics were obviously of benefit, but as early as 1951 when the usual organism isolated was Staphylococcus aureus, the increased frequency of Pseudomonas aeruginosa isolations was noted and, even then, attributed to prolonged use of antibiotics (Poncher, H Editor. Year Book of Pediatrics, 1951); also the organism was the most common to be isolated from the gastrointestinal tract of patients (Johnstone & Neter, 1951). However, the definite benefits of aggressive antibiotic therapy were becoming increasingly apparent (Stoppelman & Shwachman, 1954) and there appeared to be no point in dying from S. aureus (as most children did in those days) just to avoid acquiring P. aeruginosa infection. In a paper reporting the use of terramycin in 1952 Shwachman noted the most common pathogen was S. aureus and that many resistant forms appeared after treatment. Early diagnosis and prolonged therapy gave the best results and aerosol penicillin and streptomycin were useful (Shwachman et al, 1952).

In 1958 Shwachman and Kulczycki published their classic review of experience with 105 patients - the first such report from a large centre. This paper included a description of their clinical scoring system, which, although somewhat outdated, is still used today. They described an improving outlook for children with CF and noted that survival into adult life occurred with increasing frequency (Shwachman & Kulczycki, 1958).

In the Fifties, the mortality of newborns with CF who developed meconium ileus was still over 50%; but in 1957, Bishop and Koop described their ileostomy for the condition, which reduced the surgical interference required and greatly improved the survival (Bishop & Koop, 1957). Reduction of surgical "interference" was crucial for these were still early days for neonatal surgery with respect to antibiotics, neonatal venous access, acid-base balance, nutritional support and specialised neonatal anaesthetic and surgical skills. Neonatal resuscitation and ventilation by endotracheal intubation was not yet feasible. The few paediatric surgeons were only in some of the national centres of excellence. In Leeds one of the obstetricians insisted on operating on the infants born to his own patients!

Surgery was at times used in a rather surprising way. The suggestion that CF was a disorder of the autonomic dyskinesia (Farber, 1943) was quite popular and prompted surgeons to perform splanchnicectomies on 24 patients, interrupting the nerves to the pancreas. (Ayers et al, 1951). However, the 12 who remained alive long enough to evaluate the symptoms remained unchanged and interest in the procedure soon waned.

Pancreatin shown to improve the intestinal malabsorption

Although pancreatin had been available since the Thirties, Archie Norman and colleagues from London published some of the first objective evidence that pancreatic enzyme therapy was effective in children with CF by showing treatment resulted in considerable improvement in both fat and nitrogen absorption (Harris et al, 1955). Interesting comments came from Charles May who had been less convinced of the value of pancreatin and who warned against attributing the improvement due to treatment of infection to the action of pancreatin. He would give a clinical trial to each patient.

Also note in the Fifties:

•Nadas AS, Cogan G, Landing BH, Shwachman H. Studies in pancreatic fibrosis: cor pulmonale; clinical and pathologic observations. Pediatrics 1952; 10:319-327.
[One of the early reports of cor pulmonale in CF.]

•Studies on cystic fibrosis of pancreas: role of various diluents and dilution factor in interpretation of X-ray film test for fecal trypsin. AMA Am J Dis Child 1952; 84:191-198.
[Considerable interest in faecal trypsin and the problems encountered estimating it as measure of pancreatic function]

•O'Brien D, Powell BW. Tryptic activity of stools in newborn. Great Ormond Street J, 1952; 33-35.
[Two of a number of papers discussing the estimation of faecal tryptic activity.]

•Webster R, Williams H. Hepatic cirrhosis associated with fibrocystic disease of the pancreas: clinical and pathological reports of 5 patients. Arch Dis Child 1953; 28:343-350.

•Di Sant'Agnese PA. Bronchial obstruction with lobar atelectasis and emphysema in cystic fibrosis of pancreas. Pediatrics 1953; 2:178-190.
[Describes classical RU lobe collapse and notes bronchoscopy usually not effective in expanding. Still lingering thoughts of vitamin A deficiency "may contribute but not a major cause". Shwachman agrees - worsens the prognosis and notes "The hypothesis suggesting an imbalance of the autonomic nervous system which may affect many systems and organs is attractive".]

•West JR, Levin MS, di Sant'Agnese PA. Studies of pulmonary function in cystic fibrosis of the pancreas. Pediatrics 1954; 13:155-164.
[First report of pulmonary function testing in CF. Concluded difficulty moving air quickly in and
out of the lungs.]

•Olim CB, Ciuti A. Meconium ileus: new method of relieving obstruction. Ann Surg 1954; 140:736-740. Unusual success with hydrogen peroxide in removing the inspissated meconium in 2 patients.
[Robert Gross commenting was "so impressed with the authors' report that I shall certainly try the technique".]

•·Fisher OD. Intestinal obstruction as a late complication of fibrocystic disease of pancreas (Mucosis). Arch Dis Child 1954; 29:262-264.
[Second report of late obstruction in CF which closely followed cessation of pancreatin therapy - "suggesting use of pancreatin as a form of replacement therapy".]

•·Allen RA, Baggenstoss AH. Pathogenesis of fibrocystic disease of the pancreas: study of ducts by serial sections. Am J Path 1955; 31:337-351.
[Authors note current theories of pathogenesis are 1) vitamin A deficiency 2) imbalance of sympathetic nervous system 3) altered secretions of the glandular structures including the pancreas 4) Inflammation 5) congenital atresia or stenosis of the pancreatic duct. Their findings lend support to the theory the fundamental defect lies in maldevelopment of the pancreatic duct system.]

•Keats TE. Generalized pulmonary emphysema as an isolated manifestation of early cystic fibrosis of the pancreas. Radiology 1955; 65:223-226.
[Paul di Sant'Agnese commented he had seen this as the only early manifestation when infection had been held in check by antibiotics. Modern paediatricians will have seen this many times.]
·

•Di Sant'Agnese PA. Fibrocystic disease of the pancreas with normal or partial pancreatic function: current views on pathogenesis and diagnosis. Pediatrics 1955; 15:683-697.

•·Di Sant'Agnese PA, Blanc WA. A distinctive type of biliary cirrhosis associated with cystic fibrosis. Pediatrics 1956; 18:387-409.

•Shwachman H, Gahm N. Studies in cystic fibrosis. Simple test for detection of excessive chloride on the skin. NEJM 1956; 255:999-1001.
[People with CF produce white finger prints on plates containing silver nitrate and potassium chromate. Dr Kulczycki did 1443 controls at a mental institution. Suggested as a screening test for cystic fibrosis.]

•Shwachman H, Dooley RR, Guilmette F, Patterson PR, Weil C, Leubner H. Cystic fibrosis of the pancreas with varying degrees of pancreatic insufficiency. AMA J Dis Child 1956; 92:347-368.
[17 patients. They estimated the frequency as 10-15% of patients with CF. Chest disease may develop before malabsorption supporting the original hypothesis of Wolbach and Farber of a generalised disease if modified to include disturbance of sweat glands as an almost constant feature (in contrast to being secondary to pancreatic malabsorption/malnutrition.]

•Craig J, Haddad M, Shwachman H. The pathological changes in the liver in cystic fibrosis of the pancreas. Am J Dis Child 1957; 93:357-369.

•Gibson JB, Rodgers HW. Portal hypertension in fibrocystic disease of the pancreas. Arch Dis Child 1957; 32:355-358.
[Good result from splenectomy of massive spleen and liver showed marked fibrosis. "The main danger of liver disease in this condition is portal hypertension"]

•Di Sant'Agnese PA. A distinctive type of biliary cirrhosis of the liver in patients with cystic fibrosis of the pancreas. Pediatrics NY 1956; 3:387-409.
[First reports of liver disease - also noted by Andersen].

•Di Sant'Agnese PA, Andersen DH. Cystic fibrosis of the pancreas in young adults. Ann Intern Med 1959; 50:1321-1330.
[Appendiceal abscesses in cystic fibrosis.]
· Kulczycki LL, Shwachman H. Studies in cystic fibrosis of the pancreas: occurrence of rectal prolapse. NEJM 1958; 259:409-412.
[First report of rectal prolapse.]

•Lurie MH. Cystic fibrosis of the pancreas and the nasal mucosa. Ann Oto Rhinol Laryngol 1959; 68:478.
[First description of nasal polyps.]

THE SIXTIES

Start of the first CF organisations

Around this time a number of national CF organisations were formed engendering a collaborative approach between the medical community and the CF parents and more recently adults with CF (there were very few adults with CF in 1960). The US National CF Research Foundation (later the CF Foundation) was formed in 1955, and the Canadian CF Foundation in 1959. In 1964 the UK CF Research Foundation Trust was formed as a charitable organisation to raise funds for research (later renamed the CF Research Trust and finally CF Trust). Subsequently, national CF organisations formed in most countries where the disease occurred - most recently in Romania, Czechoslovakia and the USSR in 1990. Their programmes cover welfare, and support, advocacy, clinical care, professional education and research depending on the local stage of development (Morrison & Morrison, 1993). In 1965 the International Cystic Fibrosis (Mucoviscidosis) Association was formed in Paris under the medical chairmanship of Paul di Sant' Agnese. Its aims were to improve the care of children and adults who had cystic fibrosis, to foster research and to disseminate information. This was the start of the International CF (ICFMA) meetings, which still occur every 4 years but which have been somewhat eclipsed as international meeting events for CF workers by the large annual North American and European CF Conferences.

In 1960 there was the first meeting in European Working Group on Cystic Fibrosis in Vienna, apparently suggested by Professor Rossi of Berne; eventually this group became the European Cystic Fibrosis Society in the Nineties. From 1959 to 1986 there were annual meetings of the North American CF Club and from then the CF Foundation and Canadian CF Foundation have organised excellent annual North American CF Conferences.

As a general paediatrician with an increasing interest in CF, my first experience of such gatherings was at the 8th International CF Congress held at the Royal York Hotel, Toronto in 1980. I gave a paper on vitamins and I recall visiting Henry Levison at the Sick Children's Hospital with Archie Norman. The experience profoundly influenced my approach to the management of cystic fibrosis. I was particularly impressed by the North American team approach with many allied professionals attending and the general professionalism and dedication of their approach - "Rise and Shine" meetings and "Fireside Chats" were quite new to me!

Outlook for patients still poor in the Sixties

However in 1960 the outlook for affected children and their families remained terrible with most dying during infancy, childhood or adolescence after years of miserable chronic illness.

There were no adult CF clinics in the UK in the Sixties for there were no adults except for a few exceptional patients at the Royal Brompton Hospital in London where, in the mid 1960s, John Batten had started the UK's first adult CF service (Batten, 1980). In 1976, 45 patients over 12 years were reported from three London Hospitals (Mitchell-Heggs et al, 1976). The tendency in North America was for paediatricians to continue the care of those children who survived to adulthood. In 1966, Mantle and Norman published life tables of 499 patients seen with CF between 1943 and 1964 (Mantle & Norman, 1966). Two thirds had died by one year and 80% by 5 years. Three quarters of those with meconium ileus died by 3 months. Sydney Gellis, a distinguished USA paediatrician and editor of the Year Book of Pediatrics commenting on this paper, observed, "Despite claims to the contrary, cystic fibrosis of the pancreas continues to carry a gloomy prognosis. Present day therapy is helpful but offers relatively little, and a realistic alteration of the course of this disease will require a major breakthrough in discovering the aetiology." This summed up the general situation at the time but Gellis's second prophecy proved to be quite incorrect - the prognosis did improve significantly with better conventional treatment before there were any major breakthroughs in understanding the aetiology. Reading Gellis's comments in this and other Pediatric Year Books suggest that he was not an admirer of those treating children with cystic fibrosis! After one of the earlier papers on psychological implications of CF (Lawler et al, 1966), after criticising the CF Foundation for alarming the parents by making them "more aware of the prognosis" he states "We suspect that a minister or priest would prove more helpful than a psychiatrist in assisting the parents"!

Diagnosis more accurate with Gibson-Cooke sweat tests and jejunal biopsy

Through the 1960s sweat tests became more generally available and the accuracy of diagnosis was considerably improved. At Seacroft Hospital in Leeds from the early Sixties, the biochemist, Alan Steele, provided an expert sweat testing service for many years, using the Gibson-Cooke iontophoresis method, for paediatricians in Leeds and neighbouring towns and cities. However, he did all the tests himself. As sweat tests became more generally available standards fell in some hospitals and mistakes occurred with both over diagnosis and under diagnosis being observed (Smalley al, 1978; Shaw & Littlewood, 1987).

Also during the Sixties the increasing availability of jejunal biopsy for infants and children (Anderson, 1960) to identify the characteristic duodenal villous atrophy of coeliac disease further improved the accuracy of diagnosis. The general introduction of paediatric jejunal biopsy was somewhat slowed in the UK by a report from Great Ormond Street Hospital suggesting that the dangers outweighed the advantages and we did not start paediatric intestinal biopsies until 1968 (Littlewood, 1995). The use of jejunal biopsy later permitted the diagnosis of cow's milk intolerance in infants with CF (Hill et al, 1989).

Thus, from the Sixties, with the availability of sweat tests and jejunal biopsies there were now specific tests for the two most important conditions causing significant chronic intestinal malabsorption in early childhood - cystic fibrosis and coeliac disease. Now the paediatrician could identify fat malabsorption by arranging estimation of the faecal fat. If there was fat malabsorption the sweat test could be checked and if this was normal a jejunal biopsy was arranged.

Further characteristics of the lungs defined

Day to day variability in respiratory function was described and recognised as factor limiting the value of routine respiratory function tests. Further studies on reversibility in response to a bronchodilator were published (Mearns 1968). It was observed that after exercise the bronchodilatation was greater and subsequent bronchoconstriction less severe than in asthmatic children (Day & Mearns, 1973).

The rise and fall of mist tent therapy

Mist tent therapy was a popular form of treatment in the USA in the Sixties (Matthews & Spector, 1961). Arranging for the child with CF to sleep in a fine mist seemed a reasonable way of attempting to relieve mucoid impaction of the airways and reducing the viscosity of the sputum. In 1967 objective evidence of the positive value of mist tent therapy was published by respected paediatricians in the USA (Matthews et al, 1967). The results were accepted by such as Paul di Sant'Agnese "results reported here confirm the clinical observation of the value of mist tent therapy…it is generally accepted by almost all clinicians, who have had adequate experience with this disease, that most patients have considerable benefit from such a treatment program". Unfortunately subsequent studies failed to demonstrate significant fluid deposition below the larynx (Wolsdorf et al, 1969). The treatment was finally discredited by further studies from Toronto and elsewhere showing little or no lung deposition (Bau et al, 1971; Chang et al, 1973; Alderson et al, 1974).

Mist tents were never popular in the UK perhaps because too many general paediatricians each had too few patients to become involved. One paediatrician, Archie Norman, in day-to-day contact with affected children and their families in London, attempted a clinical trial and although there were no significant differences between the treated children and controls, the parents nevertheless observed that expectoration was easier after a night in the tent (Norman & Hall, 1972). Perhaps there was some benefit after all - I was quite impressed by our single mist tent.

Signs of hope from London

Yet, amid the disappointing reports in the Seventies, there were some, which were more encouraging from clinics specialising in treating children with CF suggesting that with meticulous monitoring and treatment the prognosis would improve. An example was Margaret Means's report in 1972 from the Queen Elizabeth Hospital in London, where she and Winifred Young had reduced the mortality for children under 5 years old from 14% to 6.5% for patients treated from the first year after 1957, when effective anti-staphylococcal antibiotics first became available. "Most patients admitted in early infancy and treated since 1957 remain free of detectable lung damage up to the age of 5 years. Vigorous treatment and attempts to control or eradicate infection in infancy can prevent most of these patients from becoming chronic respiratory invalids in early childhood". Thus, they showed that early vigorous, meticulous treatment seemed to pay dividends (Mearns, 1972).

David Lawson, at Carshalton in London, was also thinking along the same lines. In 1969 he was the first to suggest the use of continuous anti-staphylococcal prophylaxis. In 1972, reviewing the current treatment of the disease, he suggested that "earlier diagnosis, by improved neonatal screening was essential for improvement of results as by the time diagnosis was presently made lung damage was already present" (Lawson, 1972). It is salutary and really requires a research study in its own right, to reflect that it took another 30 years for national neonatal CF screening to be recommended in the UK! Fortunately, some individual health authorities in the UK introduced neonatal screening from the mid 1970s so that 20% of infants were already being screened by the time national neonatal CF screening was eventually recommended by the National Screening Committee in 2001 (Murray et al, 1999).

More accurate description of exocrine pancreatic function in CF

The name of Beat Hadorn is closely associated with accurate pancreatic function tests in CF describing the pancreozymin-secretin stimulation test. He showed that in CF there was a reduced volume of stimulated pancreatic juice and abnormally low bicarbonate levels even in those few people with CF who had sufficient residual pancreatic function to achieve normal fat absorption. He describes his work in detail in Charlotte Anderson's book (Hadorn et al, 1968; Hadorn, 1975).

First description of meconium ileus equivalent
In 1960 and later a number of reports described episodes of intestinal obstruction in older children with CF and termed 'meconium ileus equivalent' (Fanconi, 1960; Jensen, 1962). Such episodes, which are now termed 'distal intestinal obstruction syndrome', are still a significant problem particularly in minority of older people with cystic fibrosis (Littlewood, 1992; Littlewood, 1995).

Also note in the Sixties:

•Shwachman H, Kulczycki LL, Mueller HL. Nasal polyposis in patients with cystic fibrosis. Am J Dis Child 1961; 102:768-769.
[Early description of nasal polyps.]

•Kunstadter RH, Mendelsohn RS. Norethandrolone in children with and without cystic fibrosis of the pancreas. Illinois M J 1961; 120:156-161.
[14 children with CF showed "remarkable gains in weight". Shwachman commented he had used Nilevar on 30 patients "very useful but not to be used routinely".]

•Barbero GJ, Sibinga MS. Enlargement of the sub maxillary glands in cystic fibrosis. Pediatrics NY 1962; 29:788-793
[First record of enlarged submandibular glands.]

•Meeker IA Jr, Kincannon WN. Acetyl cysteine used to liquefy inspissated meconium causing intestinal obstruction in the newborn. Surgery, St Louis 1964; 56:419-425.

•Grossman H, Denning CR, Baker DH. Hypertrophic osteoarthropathy in cystic fibrosis. Am J Dis Child 1964; 107:1-6.
[Early report of PHO. Shwachman mentions condition in Post Grad Med 1963; 34:251.]

•Danks DM, Allan J, Anderson CM. A genetic study of fibrocystic disease of the pancreas. Ann Hum Genet 1965; 28:323-356.

•Mearns MB, Young W, Batten JC. Transient pulmonary infiltrations in cystic fibrosis due to allergic aspergillosis. Thorax 1965; 20:385-392.
[First description of allergic bronchopulmonary aspergillosis in cystic fibrosis.]

•Kopito L, Mahmodian A, Townley RRW, Khaw KT, Shwachman H. Studies in cystic fibrosis: analysis of nail clippings for sodium and potassium. NEJM 1965; 272:504-509.

•Wilroy RS Jr, Crawford SE, Johnson WW. Cystic fibrosis with extensive fatty replacement of the liver. J Pediatr 1966; 68:67-73.
[First description of fatty infiltration of the liver, which is in part reversible.]

•Esterley J, Oppenheimer E. Observations in cystic fibrosis of the pancreas I: Thee Gallbladder. Bull Johns Hopkins Hosp 1968:110:247-254.
[Blockage of the cystic duct by white mucous material.]

•Denning CR, Sommers SC, Quigley HJ. Infertility in male patients with cystic fibrosis. Pediatrics NY 1968; 41:7-17.

•Kissane JM, Smith MG. Pathology of infancy and childhood. St Louis C V Mosby. 1967.
[Cholecystitis and cholelithiasis more common in cystic fibrosis]

•Andersen DH. Pathology of cystic fibrosis. Ann NY Acad Sci 1962; 93:500-517.
[Lungs normal at birth]

•Mearns M, Young W, Batten J. Transient pulmonary infiltrations in cystic fibrosis due to allergic aspergillosis. Thorax 1965:20:385-392.

•Schuster SR, Shwachman H, Harris GBC, Khan K-T. Pulmonary surgery for cystic fibrosis. J Thorac Cardiovasc Surg 1964; 48:750760.

•Rickham DP, Boeckman CR. Neonatal meconium obstruction in the absence of mucoviscidosis. Am J Surg 1965; 109:173-177.
[Report 7 infants over 7 years who did not have cystic fibrosis.]

•Doggett RG, Harrison GM, Stillwell RN, Wallis ES. An atypical Pseudomonas aeruginosa associated with cystic fibrosis of the pancreas. J Pediatr 1966; 68:215-221.
[First description of mucoid form of Pseudomonas aeruginosa.]

•Huang NN, Harley RD, Promadhattavedi V, Sproul A. Visual disturbances in cystic fibrosis following chloramphenicol administration. J Pediatr 1966; 68:32-44.
[9/33 patients had doses of 81-283 gm. Mention another treated 135 gm over 4.5 months.]

•Keith CG, de Haller J, Young W. Side effects to antibiotics in cystic fibrosis: 1. Ocular changes in relation to antibiotic administration and severity of pulmonary involvement. Arch Dis Child 1966; 41:262-266.
[Only one of 42 had changes from chloramphenicol 425 gm over 15 months.]

•Doershuk CF, Matthews LW, Gillespie CT, Lough MD, Spector S. Evaluation of jet-type and ultrasonic nebulizers in mist tent therapy for cystic fibrosis. Pediatrics NY 1968; 41:723-732.
[Ultrasonic nebulisers said to be better then jet for mist tent therapy.]

•Lifschitz MI, Bowman FO, Denning CR, Wylie RH. Pneumothorax as a complication of cystic fibrosis. Am J Dis Child 1968; 116:633-640.

•Kaplan E, Shwachman H, Perlmutter AD, Rule A, Khaw KT, Holsclaw DS. Reproductive failure in males with cystic fibrosis. NEJM 1968; 279:65-69.
[Histological abnormalities of the testis and structural abnormalities of the vas deferens described.]

•Valman HB, France NE. The vas deferens in cystic fibrosis. Lancet 1969; ii: 566-567.
[Early description of vas deferens abnormalities.]

•Milner AD. Blood glucose and serum insulin levels in children with cystic fibrosis. Arch Dis Child 1969; 44:351-355.

•Phelan PD, Gracey M, Williams HE, Anderson CM. Ventilatory function in infants with cystic fibrosis. Physiological assessment of inhalation therapy. Arch Dis Child 1969; 44:393-400.

THE SEVENTIES

There were a number of further significant advances during this decade.

In 1970 Noblett and colleagues described a successful non-operative treatment for meconium ileus using gastrografin enemas (Noblett, 1969) and the success of the technique was confirmed by others (Wagget et al, 1970). The improved survival reported for these infants was attributed mainly to the earlier introduction of the Bishop-Koop enterostomy (Bishop & Koop, 1957). However, steady improvements were occurring in many areas of neonatal medical and surgical care - not least, the ventilation of neonates was gradually becoming more feasible.

Additional manifestations of the disease were described including CF in people of Afro-Caribbean origin (Kulczycki & Schauf, 1974), recurrent pancreatitis in patients with CF who had near normal pancreatic function (Shwachman et al, 1975). Pulmonary resection was reported as an option for patients with localised severe lung damage (Mearns et al, 1972).

The Chrispin-Norman X-ray scoring system was published in 1974 (Chrispin & Norman, 1974) and subsequent clinical papers concerning CF usually required both the Chrispin Norman X-ray scores and Shwachman clinical scores (Shwachman & Kulczycki, 1958) of the included patients.

Early work on neonatal CF screening
Some progress on neonatal CF screening occurred in the Seventies but with the treatment available then the outlook was poor whenever the diagnosis was made. The reported increased in protein content of the meconium of infants with CF (Buchanan & Rapoport, 1952) was confirmed and proposed as a screening test (Green & Shwachman, 1968). I recall clearly a meeting of the Paediatric Research Society when Verna Schutt suggested that the urine Albustix test strip would be suitable for this purpose. He showed a quite memorable slide of an Albustix turned deep blue (strong positive for albumin) at the edge of a small spot of CF meconium mixed with a drop of water (Schutt & Isles, 1968). This led to the BM meconium screening test (Stephan et al, 1975; Ryley et al, 1979). However, false negatives proved a problem with the BM test in Wales and elsewhere (Prosser et al, 1974) and the test was gradually abandoned. In East Leeds we started screening newborns for CF in 1975 with the BM tests and eventually included the whole city from 1995; by then we were using the IRT/DNA/IRT technique (Littlewood et al, 1995). By arranging for the BM test to be carried out in the biochemistry laboratory, rather than on the wards where the busy midwives found it difficult to find time to do, our laboratory managed to achieve an acceptable false negative rate of around 12% (Evans et al, 1981). However, the test was eventually replaced by the far more satisfactory immunoreactive trypsin (IRT) test (Crossley & Elliott, 1979). Anthony Heeley of Peterborough was the first to introduce IRT screening to East Anglia back in 1981 (Heeley et al, 1982; Green et al, 1993). Gradually a number of receptive regions/health authorities introduced neonatal CF screening at the request of some paediatricians (East Anglia, Trent, N. Ireland, Northampton, Wales and Leeds.). Unfortunately, a large study funded by the Cystic Fibrosis Trust comparing screened and unscreened infants in Wales and the West Midlands failed to show an advantage of screening, almost certainly because the infants detected did not receive Specialist CF Centre care (Chatfield et al, 1991). However, in 2002 after considerable discussion and public pressure from the CF Trust, at the same time as the publication of a convincing trial from Wisconsin (Farrell et al, 2001), the National Screening Committee eventually recommended that all infants in the UK should be screened for cystic fibrosis.

Burkholderia cepacia - a new pathogen with the potential to spread

In 1979 Pseudomonas (now Burkholderia) cepacia was first reported in North America and thereafter reports of this new potentially dangerous pathogen occurred with increasing frequency both North America (Isles et al, 1984) and later from the UK (Simmonds et al, 1990). The severity and fatal nature of the associated illness in a proportion of infected CF patients and its propensity to spread within a CF Centre has lead to a radical change in both clinic practice and in the social habits of patients (Govan et al, 1993).

Cystic Fibrosis Holiday Camps - so popular in N. America - were eventually abandoned. IN 1993 the Infection Control Group of the CF Trust recommended strict segregation of patients infected with B. cepacia.

"Cystic fibrosis - a not so fatal disease" (Crozier, 1974)

Dr. Crozier who started the Toronto CF clinic did not publish a great deal by modern standards but I suspect was the main influence in the development of that excellent service - particularly regarding the abandonment of dietary fat restriction. I was much influenced by an article of his published in 1974 entitled - "Cystic fibrosis- a not so fatal disease", and particularly by his advice that "success of treatment will depend on a complete assessment of the patient and then continuing attempts to obtain normal bodily function and maintain it". According to Ros Shepherd of Brisbane, who worked with him in Toronto, Crozier would not accept that it was inevitable CF patients should deteriorate and strove constantly to prevent this occurring (Crozier, 1974).

Changing attitudes
Thus, towards the end of the Seventies the attitudes of some paediatricians and physicians changed as the results of improved conventional therapy became apparent and the possibility of controlling the condition became a reality. Norman suggested that a new phase of CF was beginning and "it was time we stopped talking in terms of the most lethal genetically determined disease" and discussing "problems of individuals expected to die in early childhood" (Norman, 1981).

This lack of acceptance of the status quo approach was exemplified by the Danish CF Clinic in Copenhagen (Szaff et al, 1983) who treated 80% of the 225 living patients in Denmark. In 1976 they realised that chronic Pseudomonas aeruginosa infection and its severity, as judged by the number of precipitins in the patient's serum, was closely associated with the prognosis (Hoiby, 1977). This resulted in the introduction of the Danish policy of regular 3-monthly courses of intravenous antibiotics (Schiotz et al, 1981; Szaff et al, 1983; Jensen et al, 1989). Their improving results, even in 1981, were used to support the value of specialised CF clinics (BPA Working Party on Cystic Fibrosis, London, 1982).

Certainly the Seventies was characterised by increasing interest in the extent and severity of the chronic nutritional problems as survival steadily improved. The weight and height of children with CF at the time showed an initial 'catch up' phase following diagnosis and treatment, although usually not reaching normal levels. Thereafter the weights were around 1.0 SD below normal for age throughout childhood but then fell off severely during adolescence and the respiratory disease became more severe and many died (Sproul & Huang, 1964; Berry et al, 1975).

Typical nutritional advice at the time for infants and children with CF was that "the general attitude should be liberal rather than restrictive and rigid. The aim should be for an acceptable compromise between troublesome steatorrhoea and severe restriction of dietary fat". Older children with CF were said to "tolerate 30-40 g of fat daily, should be well supplied with calories, some 200 Kcal/kg/day and 4-5 g of protein/kg/day" (Gracey, 1975).

The "Allan Diet" to improve intestinal absorption and nutrition
As the pancreatic enzyme supplements in the Seventies were still relatively inefficient, attempts were made to improve absorption and nutrition by modifying the type of food taken. It had been shown previously that children with CF achieved better nitrogen absorption with casein hydrolysate than with whole protein (West et al, 1946). Also substitution of medium chain triglycerides (MCT) for long chain fats had been shown to be beneficial in improving abdominal symptoms and absorption in patients with CF even if there was no significant effect on growth (Gracey et al, 1969; Gracey et al, 1970).

Thus, in an attempt to improve absorption by dietary manipulation, Dr. Allan, a general paediatrician from Macclesfield in England, used a nutritional supplement consisting of beef serum protein hydrolysate, a glucose polymer and medium chain triglycerides - the so called "Allan diet" (Allan et al, 1970; Allan et al, 1973). Seventeen patients with CF were treated for 3-31 months. In 7 of 11 patients, where the supplement provided 100% of the protein and calorie needs and in those with a poor initial nutritional state, there were increased rates of weight gain. The effect was less pronounced when the supplement was taken with ordinary food and provided only 50% of the dietary needs. A subsequent study from Cincinnati, treating 15 of the most nutritionally compromised patients with the diet, showed significant gains in weight (>0.5SD) and improvement in biochemical parameters over a year, lending further support to the beneficial effect of the "Allan Diet" (Berry et al, 1975).

Another controlled trial of the Allan diet confirmed the improvement in 28 treated patients receiving the diet for 12 months (Yassa et al, 1978). Although the group as a whole had some improvement in growth and nutrition, only 10 (36%) had significant improvement in weight, height or both (>0.5 SD) the greatest improvements being in young, mildly affected patients. The authors' conclusions were that "such an unpleasant and expensive diet should be restricted to a few selected cases, rather than given as routine treatment" (Yassa et al, 1978). Subsequently most clinicians found that patient acceptance of a monotonous and relatively unpalatable formula presented the greatest challenge; also the new acid resistant enzymes were soon to become available; they were a major advance in nutritional management permitting a normal fat intake, and therefore increased energy intake, in most patients.

Essential fatty acids and cystic fibrosis

Abnormal fatty acid (EFA) composition of serum chylomicrons and adipose tissue of children with CF was described first in 1962 and in subsequent publications (Kuo et al, 1962; Rosenlund et al, 1977; Rivers & Hassam, 1975; Chase & Dupont, 1978). There has been considerable discussion as the whether the EFA abnormalities are a primary metabolic abnormality or merely secondary to the intestinal malabsorption. Even if not a primary defect it has been suggested that the abnormal EFA status may affect the severity of organ disease. This was first suggested by the unusual course of child with CF treated by Bob Elliott in New Zealand with IV infusions of soya oil emulsion, which contains mainly linoleic acid (Elliott & Robinson, 1975). Following the initial case report, a further 7 children with CF were treated for at least a year with infusions of Intralipid. The authors suggested that the course of the treated children was "remarkably better" than that of unsupplemented children with CF in Auckland at the time. A partial correction of an error of prostaglandin metabolism was postulated (Elliott, 1976). Rosenlund also reported some fall of sweat sodium levels with this treatment (Rosenlund et al, 1977). Chase & Dupont (1978) reported low levels of linoleic acid in 12 children with CF and a higher production of prostaglandin F2 than controls. Oral supplementation with 10-g linoleic acid in 6 children increased the linoleic acid levels and reduced prostaglandin F2 production. They postulated that over-production of prostaglandins might be causally related to the chronic pulmonary disease (Chase & Dupont, 1978).

The first double blind nutritional intervention study in cystic fibrosis

The possible role of essential fatty acids caused considerable interest and In a subsequent controlled trial, 10 children were given either infusions of 20 ml/kg of 10% Intralipid or the calorific equivalent infusions of 10% glucose on alternate weeks for a year (Chase et al, 1979). The children given either Intralipid or glucose gained similar amount of weight - more than either had gained in the previous year. Height gain was just significantly better in the test children (4.8+-1.3 cm and 6.4+-1.3 cm (P>. 05)) during the trial year but they did not gain significantly more weight and height than during the previous year. "Cumulative analysis" showed a greater improvement in the test group although numbers seemed hardly adequate. This is said to be the first double blind study of nutritional intervention in cystic fibrosis. A subsequent trial of Intralipid failed to produce a fall in sweat electrolytes (Kussavsky et al, 1983). Subsequently paradoxical effects of essential fatty acid supplementation with primrose oil on lipid profiles and sweat electrolytes were reported in 16 patients (Dodge et al, 1990). There was a significant fall in sweat sodium concentrations after 6 weeks, but sweat chloride was unchanged - effects on membrane function or Na+ pump activity were suggested.

Crozier in Toronto abandoned the traditional low fat diet

Undoubtedly, restriction of dietary fat was a major reason for the poor energy intake of many patients but was necessary in many to control unpleasant gastrointestinal symptoms. Dr Crozier, in Toronto, would appear to have laid the foundations of the nutritional philosophy of that clinic, later considered to be a major factor in the exceptionally good survival of their patients (Corey et al, 1988). From the early Seventies Crozier abandoned the traditional low fat diet believing that "to deprive the child with cystic fibrosis, who usually has very little subcutaneous fat, of this important nutrient seems ridiculous". Thus, as early as 1972, he changed his patients to a high saturated fat diet of whole milk, butter, eggs, and animal fats. This new regimen resulted in improved body weight and an increase in cholesterol (by 11%) and triglycerides (by 12%). However, the increased fat intake did require the patients to take 60-100 Cotazym enzyme capsules each day (Crozier, 1974). There was considerable discussion on the influence of nutrition on the state of the chest and the prognosis and comparison made between the series of Lapey where more modest doses of enzymes were used - 3 capsules per meal (Lapey et al, 1974). Later the superior nutritional state and longer survival of Toronto patients than Boston patients was attributed to their better nutrition (Corey et al, 1988).

Many patients had inadequate energy intakes when they were measured

A number of important studies in the late Seventies and early Eighties measured the actual energy intake people with cystic fibrosis. Contrary to the traditional impression, that people with CF had voracious appetites, when intakes were actually measured professionally by nutritionists or dietitians, these studies confirmed that many children consumed less energy even than that recommended for unaffected children of their age (Chase et al, 1979; Hubbard & Mangum, 1982; Parsons et al, 1983). It is disappointing that more recent studies continued to show many people with CF continued to have suboptimal energy intakes (Morrison et al, 1994).

Towards the end of the Seventies, an important paper supported the suggestion that a good nutritional state was associated with a better prognosis (Kraemer et al, 1978). Also pancreatic sufficient patients had a significantly better nutritional state and better lung function than those who were pancreatic insufficient (Gaskin et al, 1982). It was later shown that pancreatic sufficient patients more often had so called mild mutations and indeed even had lower sweat chloride values. This may have been an additional factor contributing to their better clinical state.

In the late Seventies a nutritional study of 36 Leeds children with CF revealed unexpectedly low fat-soluble vitamin levels in many despite supplements (Congden et al, 1981). Also despite enzyme treatment many still had a severe degree of fat malabsorption (10 children excreted more than 100 mmol (24.8 g)/day and 17 more than 50 mmol (14.2 g)/day). These results prompted us to start regular Comprehensive Assessments, which have continued to the present day as Annual Reviews (Littlewood et al, 1984; Littlewood et al, 1988; Littlewood, 1993; Carr & Dinwiddie, 1996). Sydney Gellis, commenting on our first nutritional study in the 1983 Year Book of Pediatrics observed "The lesson to be learned from this study seems to be that despite treatment patients with cystic fibrosis can be expected to have serious problems with malnutrition." This certainly described the situation in the UK in the Seventies and early Eighties.

Data collection and patient registries

Data collection was becoming increasingly important both on a national and local CF centre basis. Also the availability of computers for this purpose in the early 1980s revolutionised this area of management. The CF Foundation's patient registry developed by Warren Warwick and Pogue had demonstrated a rise in median survival from 14 years in 1968 to 20 years in 1977. Archie Norman published a number of papers between 1967 to 1975 recording the improving prognosis in the UK (Norman, 1967; George & Norman, 1969; George & Norman 1971; Robinson & Norman, 1975). In 1977 Mary Corey started data collection at the Toronto CF clinic and has been making major contributions in this field consistently since then. At the 1980 Toronto International CF Congress she reported a median survival of Toronto patients of over 30 years, far better than in any other North American centre or indeed European CF clinics (Corey, 1980). Later she reported that the clinical state and survival of the patients were significantly better in Toronto than in Boston (Corey et al, 1988).

The UK Survey, instigated by the BPA Working Party in 1982, and supervised by John Dodge, recorded the situation in the UK at that time (Jackson, 1986). There were some 3870 patients in the UK, of whom some 46.5% attended one of the 16 Centres treating more than 50 patients. The recommendations regarding CF Centre care were very similar to those of the CF Trust's recent Standards of Care for Children and Adults with Cystic Fibrosis, 2002.

Also note from the Seventies:

•Holsclaw DS, Grand RJ, Shwachman H. Massive haemoptysis in cystic fibrosis. Pediatr 1970; 75:829-838.

•Valman HB, France NE, Wallis PG. Prolonged jaundice in cystic fibrosis. Arch Dis Child 1971; 46: 805-809.
[Review of previous reports of early hepatic changes and report of 4 children showing good prognosis for early obstructive jaundice in CF - resolving in 2 survivors and one that died.]

•Mearns MB. Natural history of pulmonary infection in cystic fibrosis. In: Perspectives in Cystic Fibrosis. Ed: Sturgess JM. Toronto 1980; 325-334.
[Patients are living longer; the predominant organism to be cultured from the respiratory tract is as likely to be P. aeruginosa as S. aureus; both have a unique association with cystic fibrosis.]

•Danes BS, Bearn AG. Oyster ciliary inhibition by cystic fibrosis culture medium. J Exp Med 1972; 136:1313-1317.
[Great interest in the 'cilia test'. The CF Factor present in the serum of people with CF would inhibit the beating of cilia]

•Danes BS, Litwin SD, Hutteroth TH, Cleve H, Bearn AG. Characterisation of cystic fibrosis factor and its interaction with human immunoglobulin. J Exp Med 1973; 137:1538-1543.

•McCrae WM, Cull AM, Dodge J. Cystic fibrosis. Parent's response to the genetic basis of the disease. Lancet 1973; I: 141-143.

•Landau LI, Phelan PD. The variable effect of a bronchodilating agent on pulmonary function in cystic fibrosis. J Pediatr 1973; 82:863-868.

•Feigelson J, Pecau Y, Cathelineau L, Navarro J. Additional data on hepatic function tests in cystic fibrosis. Acta Paediatr Scand 1975; 64:337-344.
[Early contribution from Jan Feigelson who must have attended every CF meeting since they started and still does!]

•Lawson D, Porter J. Serum precipitins against respiratory pathogens in 522 "normal children" and 48 cases of cystic fibrosis treated with cloxacillin. Arch Dis Child 1976; 51:890-891.
[David Lawson treated children with CF on continuous cloxacillin form 1964 which prevented the development of staphylococcal precipitins]

•Pryor JA, Webber BA, Hodson ME, Batten JC. Evaluation of the use of forced expiration technique as an adjunct to postural drainage in treatment of cystic fibrosis. BMJ 1979; 2:417-418.
[Classical paper on the forced expiration technique]

THE EIGHTIES

Science - from suggested function to identification of the gene

Things began to happen in the Eighties on the scientific side both in understanding the basic problem and also in the clinic in the delivery of care - this was particularly true for the many patients in the UK not fortunate enough to be attending one of the few already established Specialist CF Centres.

The research up to this time had involved properties of mucus, a nebulous CF factor in the serum, which slowed the beat frequency of fresh water mussels, lectins, and glycoproteins. Scientist were no nearer an explanation for the pathophysiology of the condition. However, at the 1980 Toronto International CF Congress there was one prophetic poster suggesting that abnormal epithelial electrolyte transport may reflect the primary defect (Hopfer et al, 1980).

Following this in 1981 Michael Knowles and colleagues, from the University of North Carolina, demonstrated abnormal nasal potential (PD) in patients with CF thus providing more direct evidence of epithelial dysfunction (Knowles et al, 1981). These electrophysiological abnormalities were present even in CF neonates prior to any infection. The abnormal nasal PD was almost corrected by application of amiloride, which affects sodium transport indicating that it also contributes to the raised potential difference. In the UK a clinical method for measuring nasal potential difference was developed by Eric Alton in London (Alton et al, 1987).

In 1983 Paul Quinton, who himself has CF, showed that the chloride impermeability he had demonstrated in sweat glands was the basis for the raised sweat electrolytes in patients with cystic fibrosis (Quinton, 1983). This was regarded as a major step forward in understanding the basic defect.

From the early Eighties various groups attempted to identify the CF gene by using reverse genetics, the protein being unknown. They studied families with more than one affected child. With this technique Eiberg in Copenhagen demonstrated a linkage to the enzyme paraoxinase, which exists in two forms but was present in the same form in 90% of CF siblings (Eiberg et al, 1985). In the same year Lap Chi Tsui from Toronto, in a series of mouse hybrid experiments, demonstrated a marker on chromosome 7 linked to both paraoxinase and cystic fibrosis (Tsui et al, 1985). Two other markers, known to be on chromosome 7, were closely linked to CF, the Met oncogenes, Met H and met D from Ray White in Salt Lake City (White et al, 1985) and the DNA probe pJ3.11 from Bob Williamson's laboratory in London (Wainwright et al, 1985). All these findings were published in the same edition of Nature on 29th November 1985.

These advances had a considerable practical benefit for CF families as the close proximity to the CF gene allowed carrier testing of siblings and reliable antenatal diagnosis for the first time (Farrall et al, 1986; Super et al, 1987). A further marker probe Cs7 was so close to the gene that it was, at first, incorrectly considered to be the gene itself (Estivill et al, 1987).

The CF gene was eventually identified by teams headed by Lap-Chi Tsui, Collins and Riordan in 1989 and termed cystic fibrosis conductance regulator (CFTR) (Kerem et al, 1989; Riordan et al, 1989; Rommens et al, 1989). The most common mutation was DF508 indicating a missing phenylalanine molecule in position 508 of the 1480 amino acid protein. These workers were awarded the Paul di Sant'Agnese Prize at a memorable ceremony at the 1989 North American CF meeting. Since then over 1000 different mutations have been described.

Clinical Care in the Eighties

Increasingly reliable antenatal diagnosis

Since 1983 antenatal diagnosis became available for families who had a previously affected child using assay of the microvillous enzymes of the amniotic fluid at the 17th -18th week of pregnancy (Brock, 1986) and later by using DNA markers closely linked to the CF gene earlier at 7-8 weeks on tissue obtained by chorionic villous biopsy (Farrall et al, 1986)

A lesson from 'down under'

The impressive scientific advances of this decade had relatively little influence on the everyday treatment of people with CF other than to improve antenatal diagnosis. The major influence on the clinical management of CF in the UK was undoubtedly a key paper from Peter Phelan in Australia who reported significantly better survival of people with CF in New South Wales than in England and Wales during the 1970s (Phelan & Hey, 1984). When all the various reasons for the difference were considered, care of Australian patients at Specialist CF Centres was thought to be the most important factor accounting for their better survival; during the Seventies and Eighties many patients in the UK received all their care at their local hospitals in the general paediatric clinic.

British Paediatric Association's Working Party on Cystic Fibrosis

This disturbing data from Australia was directly responsible for the formation of the British Paediatric Association's Working Party on Cystic Fibrosis in 1982 whose brief was "To assess the advantages and disadvantages of regional centres for cystic fibrosis" (Jackson, 1986; Dodge et al, 1993). The Working Party and the subsequent UK CF Survey were fully supported by the Cystic Fibrosis (Research) Trust.

More Specialist CF Centres develop

Through the Eighties there was a gradual and very impressive improvement in the treatment and condition of people with cystic fibrosis in the UK reflected in their improving survival (Dodge et al, 1997). However, it must be noted that the Council of the British Paediatric Association (BPA), initially rejected their Working Party's 1983 recommendation for the provision of Specialist CF Centres in every region. Despite this lack of support from the BPA, CF Centres gradually developed in most large cities. The Centres were developed by enthusiastic paediatricians, nurses, physiotherapists, dietitians and social workers who realised that many patients were being treated sub-optimally particularly when they observed the obvious benefits of more aggressive antibiotic and nutritional treatment following detailed assessment at a Centre (Littlewood et al, 1984; Littlewood, 1986; Littlewood et al, 1988; Littlewood, 1993). Around this time the improvement in some children following only the basic treatment of a 2-week course of intravenous antibiotics, effective physiotherapy, appropriate nutritional support and adequate doses of pancreatic enzymes, was so blatantly obvious to all concerned that parents increasingly voted with their feet and sought treatment at one of the developing CF Centres. There are moving accounts of parents' bad experiences from that time (Standing, 1987;Grant, 1987; Wilkinson, 1987). Increasingly staff at the developing CF Centres devoted more time to CF care and became increasingly expert in management.

The quite widespread opposition of many general paediatricians to the development of Specialist CF Centres during the Eighties will not be discussed in detail - let's just say they were misguided and ultimately proved wrong. Surprisingly there are still consultants who do not see the need to refer their patients to Specialist CF Centres even for shared care. It is worth reflecting that all the significant advances in management, which have been responsible for the impressive improvement in health and survival, have occurred at Specialist CF Centres.

CF Trust support clinical staff at developing CF Centres

In the early Eighties the CF Research Trust started to provide financial support for clinic staff - in particular medical CF Research Fellows and Specialist CF Nurses. This was a new role for the CF Research Trust - to such an extent that the scientists on its Research & Medical Advisory Committee eventually suggested, in the early Nineties, that the name be changed to the Cystic Fibrosis Trust as research was not its only function.

Intravenous antibiotics increasingly became the cornerstone of treatment for the chronic Pseudomonas aeruginosa infection, which eventually affected virtually all the patients. There were steady advances in detailed patient monitoring (Conway et al, 1985), microbiology, new and more effective intravenous anti-pseudomonal antibiotics and the more professional use of these in terms of administration and dosage. Also the first oral anti-pseudomonal quinolone antibiotics became available in the mid-Eighties and were increasingly used for mild exacerbations of the chronic P. aeruginosa infection (Bosso, 1989), but they did not replace intravenous antibiotics for most exacerbations.

Although patients chronically infected with P. aeruginosa had significant improvement in their symptoms, signs, respiratory function, chest X-ray during a course of intravenous antibiotics, many experienced a gradual deterioration in their condition as soon the treatment was stopped. In view of this, and anticipating this decline, the Danish CF Centre in Copenhagen had introduced their regimen of 3-monthly courses of 2 weeks of intravenous antibiotics in 1976, which coincided with an impressive improvement in survival of their patients (Szaff et al, 1983). In the early Eighties there were still children in the UK with advanced respiratory infection due to P. aeruginosa who had never had a course of IV antibiotics!

Through the Eighties in UK Specialist CF Centres, doctors (CF Fellows of registrar grade usually funded by the CF Trust) and nurses (CF Nurse Specialists), and other staff treating many patients, gained increasing experience with progressively better drugs and equipment. This resulted in greater skill at venous access and hence a more frequent resort to the intravenous route rather than this route being used as a last resort. This early resort to antibiotics via the IV route at an early stage, for even mild persisting symptoms short of an "exacerbation", was one of the major advances of the decade and often characterised treatment at paediatric Specialist CF Centres. At CF Centres staff had followed patients and observed the insidious start of chronic infection, which would eventually prove fatal and thus tended to be more aggressive with treatment in the early stages and with so-called "mild" cases.

Nevertheless, the difficulties of IV access in some patients, even for experienced CF Centre staff, prompted the use of 'totally implantable venous access devices' in both adults (Stead et al, 1987) and children (McDowell et al, 1986; Martin et al, 1986; Essex-Cater et al, 1989) and these are now widely used in patients with CF of all ages. They were a godsend in young patients where repeated venous access was becoming a major problem. Another very important advance from the patient's point of view was the introduction of an effective local anaesthetic, EMLA cream, to apply to the skin before venepuncture. To clinicians required to perform repeated venepuncture on small children, and for the children, EMLA was another godsend introduced in 1986 (Maunuksela & Korpela, 1986). I recall Professor John Davies's prophetic comments at a BPA meeting in York in the mid-Eighties, where EMLA cream was on show at the trade exhibition, that it was probably the most important advance he had seen at that year's meeting - I'm sure thousands of children, parents, doctors and nurses would agree with him!

During the Eighties intravenous antibiotic treatment became increasingly a major component of treatment, particularly for patients with chronic P. aeruginosa infection (Rabin et al, 1980; Conway et al, 1985). However, repeated hospital admissions were traumatic for the child and caused disruption of the family's routine. This prompted the gradual introduction of home intravenous antibiotic treatment for both adults (Winter et al, 1984) and children (David, 1986; Kuzemko, 1988; Gilbert et al, 1988). The practice of home intravenous antibiotic treatment was already gaining favour in the USA where, at that time, hospital costs were more of a major and immediate consideration than they were in the UK at that time (Swenson, 1981; Bosso et al, 1985; Donati et al, 1987)

Renewed interest in nebulised antibiotics

Some patients with chronic P. aeruginosa infection, although responding well to the course of intravenous antibiotics, started to relapse as soon as the IV treatment was stopped. To deal with this problem, Margaret Hodson in a classic paper in 1981, reported that long-term twice-daily nebulised gentamicin and carbenicillin was effective in stabilising the condition of such patients who had relapsing chronic P. aeruginosa infection (Hodson et al, 1981). Following this publication and despite considerable discussion that there would be an increase in antibiotic resistance, there was a gradual increase in the use of nebulised these anti-pseudomonal antibiotics for chronically infected patients. Also much basic work was published subsequently on the most efficient nebulisers and compressors to use (Newman, 1988).

Chronic P. aeruginosa infection not inevitable

In the early Eighties, once P. aeruginosa was cultured form the airways, it was considered inevitable that chronic infection would supervene. However, in 1985 a short report suggested when a child first started growing P. aeruginosa treatment with nebulised colomycin would eradicate the organism and chronic infection was not inevitable (Littlewood et al, 1985). We chose colomycin for it was an effective anti-pseudomonal antibiotic, which was no longer used. This short report prompted a later controlled trial from Copenhagen, which confirmed the feasibility of eradicating the initial P. aeruginosa infection with nebulised colomycin and oral ciprofloxacin in 80% of patients (Valerius et al, 1991). Such early eradication treatment is now accepted practice in the UK - but, surprisingly, not yet in North America. (Details in Antibiotic treatment for cystic fibrosis. 2nd Edition. Cystic Fibrosis Trust. 2002).

First heart-lung transplantations in 1985

A really major advance, for those who had reached the end stages of their disease, was the successful introduction of heart-lung transplantation in 1985 (Yacoub et al, 1990; Scott et al, 1988). The possibility of successful treatment in what were previously the terminal stages of the condition had a major influence on both prognosis and the treatment of severely affected individuals. The first results of heart-lung transplantations were quite remarkable and were related both to surgical skills, concentrated medical expertise in assessment and after care and also to more successful immunosuppressive therapy.

Later double lung transplants became more popular (Pasque et al, 1990) and are now the most common performed operation. Living donor lung transplants have been used and successful particularly in the USA in part used due to the shortage of donor organs (Starnes et al, 1996); a 72% survival at 1 year was reported recently for 101 operations by Starnes who pioneered the operation (Cohen & Starnes, 2001).

Liver transplantation and heart-lung-liver transplantation

Liver transplantation has been used successfully in patients with CF whose condition is seriously compromised by hepatocellular failure or the complications of portal hypertension. The results are surprisingly good and the lung function, far from deteriorating as a result of the operation and immunosuppressive therapy has improved in some patients (Mieles et al, 1989; Noble-Jamieson et al, 1994). In patients with CF who have liver failure and seriously affected lungs there have been a number of successful heart-lung-liver transplantations Noble-Jamieson et al, 1996) and lung-liver transplantations (Couetil et al, 1995; Couetil et al, 1997).

A decade of major gastrointestinal advances

Increasing involvement of dietitians experienced in CF

A major factor in improving nutrition of people with CF in the UK was the increasing involvement of professional dietitians/nutritionists in the multidisciplinary teams at the few Specialist CF Centres. With the involvement of dietitians, there was more accurate measurement of both the quantitative and qualitative aspects of the dietary intake. When the qualitative aspects of the intake were analysed, it was apparent that patients who had a normal fat intake clearly had a higher energy intake, and better growth and nutritional state than those with a restricted fat intake (MacDonald, 1984). The dietitian was also able to recommend the most appropriate method of increasing the energy intake for a particular patient, having assessed the general family situation and the patient's likes and dislikes. This was beyond the practical abilities of most CF clinicians. Even a single review by a dietitian experienced in CF, at the time of an Annual Review, resulted in an improved energy intake when this was measured a year later (MacDonald et al, 1988).

Increasing attention to improving the dietary energy Intake

As the repeated reports of inadequate energy intake became generally appreciated, more attention was given to ways this could be improved. The relaxation of fat restriction, a major advance made possible by the availability of the new acid resistant enzymes, was only slowly implemented in the UK. In the early Eighties, the usual diet recommended for a person with CF was still high in calories, protein and carbohydrate, with moderate fat restriction. In 1985 Goodchild recommended an increased energy intake and a normal fat intake for patients with cystic fibrosis (Goodchild, 1986) but progress was very gradual and some experienced CF clinicians considered that "steatorrhoea is seldom controlled by pancreatin alone and reduction of fat in the diet is necessary" (Mearns, 1985).

However, after gaining experience with the new acid-resistant enzymes (Pancrease since 1983 and Creon from 1985), it was clear to many clinicians and dietitians that "many patients were having their energy intake severely compromised by the traditional prescription of a low fat diet. Fat restriction is seldom required now if adequate doses of pancreatic extracts are given" (Littlewood, 1986; Littlewood & MacDonald, 1987).

Enteral and parenteral nutrition

In some patients increasing the intake of food and fat, even with the help of an experienced dietitian, failed to achieve an energy intake, which would achieve adequate weight gain and growth. Intravenous nutrition could circumvent both the problems of intake and absorption and provide a satisfactory short-term solution. Twelve such patients with CF were given intravenous nutrition for 3 weeks with Intralipid, amino acids and glucose. There was significant weight gain, which persisted for over 6 months, fewer pulmonary infections, improved clinical scores and pulmonary function tests (Shepherd et al, 1980).

But the intravenous route was obviously inconvenient (particularly so in the early Eighties) and therefore various methods of enteral feeding were tried. At the 1984 International CF Congress in Brighton, supplementary enteral feeding of various types was a major topic. However, it was a Tony Axon, a general gastroenterolgist from Leeds, who first reported nocturnal elemental enteral feeding in a 13-year-old girl with CF (Bradley et al, 1979). Enteral feeding, both nasogastric and by gastrostomy, became more widely used and it was obvious that such methods could rehabilitate patients with severe nutritional problems where oral methods had failed (Levy et al, 1985; Shepherd et al, 1986; Boland et al, 1986; O'Loughlin et al, 1986; Dalzell et al, 1992; Steinkamp & von der Hardt, 1994). Enteral feeding is now established practice for some patients in most Specialist CF Centres. Fine bore nasogastric feeds are an alternative to gastrostomy (Holden et al, 1991; Smith et al, 1994). The CF Trust has recently published a consensus view of their Nutrition Working Group - Nutritional Management of Cystic Fibrosis. 2002.

As the more mechanical aspects of nutritional management were improved, the behavioural aspects of nutrition received increasing attention.

Increased energy expenditure

As the condition of the chest deteriorated, the increasing energy requirement, adversely affected efforts to improve the net energy balance. Undernourished older patients with CF were shown to have increased energy requirements 25-80% higher than in healthy individuals (Pencharz et al, 1984). Indirect calorimetry in 71 stable patients with CF aged 8.9 to 35.5 years showed the resting energy expenditure (REE) to be raised in most to 95 to 153% of the predicted value even in patients with mild chest disease (Vaisman et al, 1987). The REE was also raised in infants (Girardet et al, 1994). Subsequent studies confirmed these findings but all showed a considerable variation in REE between individual patients (Buchdahl et al, 1988; Bowler et al, 1993; Thomson et al, 1996) and also before and after antibiotic treatment in the same patient (Naon et al, 1993; Steinkamp et al, 1993). Some authors suggested that the increased REE was related to the presence of the CF mutation itself (O'Rawe et al, 1992), a factor that was independent of inflammatory activity (Thomson et al, 1996); although not all studies have confirmed this relationship (Bronstein et al, 1995). More recent studies in adults with CF emphasise the important contribution of the oxygen cost of breathing in CF but, in contrast to chronic obstructive pulmonary disease, this does not appear to be the main reason for the increased energy expenditure (Bell et al, 1996).

While these studies explain the increased energy requirements necessary to maintain energy balance in some patients, particularly those with severe chest involvement, each patient still requires individual assessment of intake, output and the state of the chest. The adequacy of their energy intake will be ultimately be measured by evaluation of their nutritional state and, in children, their rate of growth (Littlewood & Wolfe, 2000a).

Measures to improve function of older enzyme preparations

In the early Eighties, before the obvious superiority of the new acid resistant enzymes was widely appreciated, there was considerable interest in, and some success with, measures to preserve the activity of the exogenous enzymes by reduction of gastric acid with agents such as bicarbonate, cimetidine and ranitidine (Cox et al, 1979; Gow et al, 1981; Chalmers et al, 1985). However, in the early Eighties, the new acid resistant enzymes, Pancrease (1983) and later Creon (1985), were increasingly used and, as they were quite obviously so much better than the older preparations, most clinicians lost interest in measures designed to augment the activity of the older preparations. However, more recently, with the advent of fibrosing colonopathy in 1993 (Smyth et al, 1994), and the Committee on the Safety of Medicine's recommendation to avoid high doses of pancreatic enzymes, there has been renewed interest in gastric acid reduction using more effective agents such as omeprazole and lansoprazole as a means of reducing the dose of enzymes (Littlewood & Wolfe, 2000b).

Acid resistant pancreatic enzymes - a major advance

Until the end of the Seventies pancreatic enzymes were crude, impure and inefficient and were regarded more as a food supplement than a drug. The modest effect of these early preparations in improving intestinal absorption was, in part, explained by the fact that 90% of their enzyme activity was destroyed by the gastric acid (Di Magno et al, 1977). The increasingly large doses of the older pancreatic enzymes recommended by some clinics, although improving absorption, raised concerns about hyperuricaemia and hyperuricosuria (Davidson et al, 1978). Fortunately the reduction in enzyme dose achieved with the new acid resistant enzymes solved the problem.

Another reason for suboptimal response to exogenous pancreatic enzymes was the bile salt abnormalities described in cystic fibrosis (Leyland, 1970). Subsequent duodenal intubation studies in 13 children with CF and controls confirmed low total bile salt concentrations, abnormal glycine/taurine ratios and percentage of dihydroxy bile salts in patients with pancreatic insufficiency. The findings were considered consistent with a broken enterohepatic circulation, which could contribute to lipid malabsorption (Harries et al, 1979). Although these studies were done prior to the use of more efficient acid resistant enzymes, even with more effective enzymes, the excretion of bile acids in people with CF is still twice normal (Walters & Littlewood, 1998).

When the first acid resistant microspheres (Pancrease) became available in North America the first encouraging reports of their use were presented at the North American CF Club (Khaw et al, 1977; Suskind et al, 1979; Weber et al, 1979; Holschlaw & Keith, 1980) and published (Graham, 1979). I remember a poster on these new enzymes at the 1980 Toronto meeting (Holschlaw & Keith, 1980) and the results seemed too good to be true - but they turned out to be just as good as reported! These new enzymes were undoubtedly a major advance in nutritional management of cystic fibrosis. After changing from the older unprotected preparations, the improvement in severe and previously intractable bowel symptoms and improved quality of life in some patients was quite dramatic. One 16-year-old girl wept and told me the new enzymes had had totally revolutionised her life, which had previously been dominated by her severe bowel problems. Later studies confirmed the marked superiority of the new acid-resistant preparations (Mischler et al, 1982; Beverley et al, 1987).

Certainly, through the Eighties, there was a noticeable and statistically significant improvement in the state of the respiratory tract and the nutritional state the patients as judged by their condition at the time of first referral to our Leeds unit for Comprehensive Assessment (Littlewood, 1993). Towards the end of the decade the need for and start of adult CF units also reflected the improved survival.

Also note in the Eighties: -

•Warwick WJ. 1000 Years of Cystic Fibrosis. Collected Papers. Minnesota. 1981.
[A wonderful collection of state of the art papers by leading CF experts of the day]

•Efthimiou J, Smith MJ, Hodson ME, Batten JC. Fatal pulmonary infection Mycobacterium fortuitum in cystic fibrosis. Br J Dis Chest 1984; 78:299-302
[An early report of atypical mycobacterial infection in cystic fibrosis] .

•Abman SH, Ogle JW, Butler-Simon N, Rumack CM, Accurso FJ. Role of respiratory syncytial virus in early hospitalisation for respiratory distress in young infants with cystic fibrosis. J Pediatr 1988; 113:826-830.

•O'Halloran SM, Gilbert J, McKendrick OM, Carty HML, Heaf DP. Gastrografin in acute meconium ileus equivalent. Arch Dis Child 1986; 61:128-130.
[An important paper describing an effective treatment for meconium ileus equivalent - the method was used eventually by most CF Centres]

•Brueton MJ, Ormerod LP, Shah DJ, Anderson CM. Allergic bronchopulmonary aspergillosis complicating cystic fibrosis. Arch Dis Child 1980; 55:348-353.
[Helpful account of ABPA with X-rays in children with cystic fibrosis]

•O'Halloran SM, Gilbert J, McKendrick OM, Carty HML, Heaf DP. Gastrografin in acute meconium ileus equivalent. Arch Dis Child 1986; 61:128-130.
[Description of an effective and now widely used treatment for distal intestinal obstruction syndrome]

•O'Loughlin E, Forbes D, Parsons H, et al. Nutritional rehabilitation of malnourished patients with cystic fibrosis. Am J Clin Nutr 1986; 43:732-737.

THE NINETIES

Scientific progress

This decade began on a wave of enthusiasm, near euphoria, following the successful identification of the CF gene in 1989 (Rommens et al, 1989; Riordan et al, 1989; Kerem et al, 1989). Some patients and families considered that a cure had been found - perhaps not entirely unrelated to the enthusiasm and rash predictions of some of some of the scientists involved! Also it is true that initial progress was encouraging. Two papers in 1990 reported correction of the CF defect in cultured CF cells by transfer of CFTR cDNA using viral vectors (Drumm et al, 1990; Rich et al, 1990). Thus, it appeared it was possible to correct the CF defect in cultured cells. Many experiments appeared to confirm that CFTR functioned as a chloride channel.

In 1992 three CF mouse models were produced. The Cambridge mouse (Ratcliff et al, 1993) and the North Carolina Mouse (Snowuart et al, 1992) had null mutations and were unable to produce any CFTR. The Edinburgh mouse (Dorin et al, 1992) did produce a little CFTR. These mouse models were essential for further in vivo investigations of CFTR function and transfer.

Further research work concerned gene transfer into various cell lines and animal tissues using viral vectors. Immunological problems were less likely with non-viral vectors and the first in vivo successful gene transfer into the airways of CF mice was achieved using cationic liposomes (Hyde et al, 1993), which have subsequently been the preferred vector of the three UK gene therapy groups working at London, Oxford and Cambridge and Edinburgh.

Studies of gene transfer in people with cystic fibrosis

In 1993, the first successful adenoviral mediated gene transfer was reported in man with cystic fibrosis (Zabner et al, 1993). Subsequently a number of nasal studies have been reported including three from the UK. The first involved application to the nose and was similar to the Zabner study except that liposomes were used as the vector (Caplen et al, 1995; Gill et al, 1997); one involving repeated nasal applications (Hyde et al, 2000). The most recent, from the Royal Brompton in London, involved transfer to both nose and lungs (Alton et al, 1999). Although progress has definitely been slower than originally expected, gene replacement therapy is still considered to be a reality within 5 to 10 years (Davies et al, 2001).

Pharmacological treatments

An alternative strategy is to improve CFTR function by other means and a number of drugs are in phase I and II trials and showing promise as an alternative or complementary approach to treatment. The mechanisms of these agents can be divided into drugs which affect the most common mutation which increase trafficking of the mutant CFTR protein to the apical membrane; those which increase chloride secretion and those which reduce sodium reabsorption across the apical membrane. The possibilities have been reviewed recently (Rodgers & Knox, 2001)

Essential fatty acids revisited - imbalance in CF mice

The advent of CF mice has renewed interest in essential fatty acids following the suggestion that a membrane lipid imbalance plays a role in the phenotypic expression of CF in cftr-/-mice. In cftr-/- mice there is a marked imbalance with increase in phospholipid-bound arachidonic acid (AA) and reduction in docosahexanoic acid (DHA) in organs affected by cystic fibrosis and which was not secondary to intestinal malabsorption or reduced hepatic synthesis. Oral administration of DHA to the mice corrected the lipid imbalance and prevented the early pathological changes observed in the pancreas (Freedman et al, 1999). It was suggested that certain phenotypic manifestations might result from remediable alterations in phospholipid-bound arachidonic acid and DHA levels. The results of clinical trials are awaited with interest but progress has been slow.
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Phenotype/genotype correlations

Attempts to correlate phenotype and genotype have proved less successful than at first expected but the major influence of environmental factors has been a major confounding factor. However, the definite correlation of so-called mild mutations with preservation of pancreatic function and better clinical condition is now well established (Corey et al, 1989; Kristidis et al, 1992). The vast majority of people homozygous for DF508 are pancreatic insufficient and many of those with an R117H mutation pancreatic sufficient (Cystic Fibrosis Genotype/Phenotype Consortium, 1993). Also, certain mild mutations are associated with late presenting disease often with normal pancreatic function and normal or near normal sweat electrolytes (Cutting GR, 2000). Also an association of congenital bilateral absence of the vas deferens (CBAVD) in infertile males has been associated with a high incidence of CF mutations (Chillon et al, 1995), some with two mutations the most common being DF508/R117H - somewhat blurring the edges of the traditional CF diagnosis. More recently and increase in CF carriers has been described in patients with chronic pancreatitis (Cohn et al, 1998; Choudari et al, 1999; Cohn et al, 2000).

Also the mutations have been classified depending on the functional fault in the cell. This may have a bearing on future treatment already evident in the response to gentamicin application, which will improve the CFTR trafficking defect in patients with stop mutations (Wilschanski et al, 2000).

Clinical care

The steady improvement in clinical care, which characterised the Eighties, has continued through the Nineties. However, the provision of "optimal care", which is complex and very expensive, for all people with CF has proved increasingly difficult, not least due to the financial restraints in an increasingly under-funded National Health Service.

Further development of Specialist CF Centres for children and adults

Throughout the decade more Specialist CF Centres have been established; in particular, new Adult Specialist CF Centres have been established in most major population centres in the UK. There are more respiratory physicians specialising in the care of adults with CF. Two surveys of adults with CF confirmed that more adults with CF are attending Specialist CF Centres and more are satisfied with their medical care (Walters et al, 1993; Walters et al, 1994). Further evidence of the advantages of Specialist CF Centre is published (Mahadeva et al, 1998).

The arrangements for transition from the paediatric to adult Specialist CF Centre have been discussed, evaluated and improved during the decade (Conway et al, 1998; David, 2001) and are now routine in most large centres.

The documentation of patient numbers, which had started after the UK Survey in the early Eighties following the report of the CF Working Group, was gradually taken over by the Dundee based UK CF Database a major project of the Cystic Fibrosis Trust.

CF Cochrane Group established

There was an increasingly more professional use of antibiotics and other drugs, lead by the new Specialist CF Centres, during the decade. Established treatments came under scrutiny from the new CF Cochrane Group lead by Professor Ros Smyth of Liverpool (Smyth, 1998).
As part of an increasing interest in evidenced based medicine, many treatments were reviewed and scrutinised in Systematic Reviews by the CF Cochrane Group. Intravenous antibiotics did actually work except for a puzzling paper from Toronto (Gold et al, 1987). Intravenous antibiotics also reduced the number of organisms and inflammatory markers. Bronchodilators were proven to be effective and inhaled steroids were effective in some people but needed further trials. Long-term oral steroids were discredited as too toxic. Nebulised antibiotics worked to control chronic Pseudomonas infection. Pulmozyme was effective in improving respiratory function even in mildly affected patients. Pseudomonas aeruginosa could be eradicated if treated early and chronic infection benefited from long-term nebulised antibiotics and 3-monthy courses of IV antibiotics.

Steady evaluation of physiotherapy techniques

Physiotherapists further evaluated the newer techniques including positive end expiratory pressure, PEP, mask (Falk et al, 1984) and the Flutter device (Gondor et al, 1999). Even the wisdom of starting all infants on the traditional percussion and postural drainage was questioned, suspecting that the frequent reflux which had been demonstrated as a feature in many CF infants, may be result in oesophageal reflux and inhalation leading to a worse respiratory condition in the treated infants (Button et al, 1997; Button et al, 1998). The tendency to evaluate both traditional and new physical treatments was a feature of the decade. In 2002 the Association of Physiotherapist in Cystic Fibrosis reviewed the current consensus on physiotherapy treatment in "Clinical Guidelines for the Physiotherapy Treatment of Cystic Fibrosis" (published by the UK CF Trust).

Increasing evidence of cross infection between patients

The concept of cross-infection by increasingly virulent organisms between people with CF attending CF Centres gradually gained acceptance through the decade although clinicians still differ in their opinion as to its importance. In the USA, Burkholderia cepacia had been shown to be extremely virulent and capable of transmission between people with CF (Isles et al, 1984). The organism was also making its appearance in the UK in the late Eighties (Simmonds et al, 1990) and soon evidence of transmission between patients with CF was reported (Govan et al, 1993). In the UK segregation of patients infected with B. cepacia was recommended from 1993 and the advice reinforced in a revised statement in 1999 from the Cystic Fibrosis Trust's, Infection Control Group, July 1999 - "A Statement on Burkholderia cepacia". Through the decade all communal CF holidays were stopped.

Highly transmissible strains of Pseudomonas aeruginosa

More recently highly transmissible strains of P. aeruginosa were reported from a large paediatric CF Centre (Cheng et al, 1996) and highly transmissible strains were found in two adult CF centres (Jones et al, 2001; McCallum et al, 2001). Segregation of patients according to bacteriological status became more usual in CF Centres and Clinics and was considered to be advisable (CF Trust Infection Control Group, 2001. Pseudomonas aeruginosa infection in people with cystic fibrosis. Suggestions for prevention and infection control. In Denmark patient segregation according to P. aeruginosa status had been practised since the early 1980s and reported to be responsible for a reduction in new isolations of P. aeruginosa.

The impact of these developments has resulted in a fundamental alteration in advice regarding infection control. Meetings and social gatherings for people with CF have virtually ceased in view of the risk of cross infection, which has a major impact on the social activities of many people with cystic fibrosis. Some clinicians consider that the measures have been too Draconian (Geddes, 2001); however, most patients and parents are accepting that they are taken in their best interests.

Support for long-term prophylactic anti-staphylococcal treatment

Support for the routine use of prophylactic anti-staphylococcal antibiotics in young children up to 2 years with CF, as suggested and practised by David Lawson 25 years earlier, came from a controlled trial in screened infants in East Anglia (Weaver et al, 1994). The availability of these infants for study had been made possible by the introduction of neonatal CF screening to East Anglia by Anthony Heeley as early as 1981 (Heeley et al, 1982).

Feasibility of early eradication of P. aeruginosa confirmed

Also the feasibility and success of eradication of early P. aeruginosa infection suggested in 1985 (Littlewood et al, 1985) was confirmed in a controlled trial from Denmark (Valerius et al, 1991) and further confirmed by later publications from Copenhagen (Frederiksen et al, 1997) and other centres (Ratjen et al, 2001). By the end of the decade most clinicians treated early P. aeruginosa with oral ciprofloxacin and nebulised colistin. Although there had been some doubts about the exact significance of P. aeruginosa infection (Mearns, 1980) there were now many studies showing that the onset of chronic infection with P. aeruginosa was an important event and almost invariably followed by a worse clinical course and to be avoided if at all possible (reviewed in Pseudomonas aeruginosa infection in people with cystic fibrosis. Suggestions for prevention and infection control. Cystic Fibrosis Trust, 2001).

Benefits 3-monthly intravenous antibiotics still non-proven

Although the Danish CF Centre had recommended 3-monthly courses of IV antibiotics for patients chronically infected with P. aeruginosa to minimise the pulmonary damage and slow the decline of respiratory function since the late Seventies, this routine was not generally practised in the UK but was almost routine in a minority of Specialist CF Centres. In fact a multicentre UK study failed to show any advantage to those patients receiving 3-monthly treatments. However, even the control patients had 3 courses of IV antibiotics each year and the study was regarded as underpowered (Elborn et al, 2000). Nonetheless, intravenous antibiotics were increasingly used in less severely affected patients at earlier stages rather than as a last resort. There were further improvements in IV access with increased experience with totally implantable venous access devices and IV infusion pumps - the latter being a major advance in maintaining venous access in infants and small children.

Pulmozyme - the first highly effective mucolytic

One drug introduced in the Nineties was an effective mucolytic, a recombinant human DNase (Pulmozyme) that is capable of depolymerising endogenous DNA and dramatically reducing the viscosity of the sputum (Shak et al, 1990). Previously UK clinicians had considered traditional mucolytics to be ineffective in people with cystic fibrosis. However, Pulmozyme was shown to be highly effective in reducing the viscosity of CF sputum and improving respiratory function of people with cystic fibrosis (Fuchs et al, 1994). Subsequent experience has shown it to be very effective in about 30% of patients, less effective in 30% and of no apparent benefit in 30%. In the UK some 30-40% of adults and 15-20% of children take the nebulised Pulmozyme twice daily.

Renewed interest in hypertonic saline

Another significant advance was the confirmation that inhalation hypertonic saline improved sputum clearance and improved pulmonary function (Robinson et al, 1996). Interestingly this had already been shown in the Seventies (Pavia et al, 1978) and was also known to some experienced CF clinicians (Hodson, personal communication).

High strength pancreatic enzymes - a welcome advance

Many patients, when taking a normal fat intake, did require a large number of enzyme capsules (average 30 per day in the Leeds paediatric clinic) to control their intestinal malabsorption; some children referred to our unit for Assessment were taking over 100 capsules per day. It was not surprising that patients, and their professional advisers, welcomed the introduction of the new "high lipase enzymes" in 1992, which contained 3 to 5 times as much lipase as the standard preparations (Creon 25,000, Pancrease HL and Nutrizym 22). Studies showed these preparations to be as effective as the standard strength enzymes on a lipase for lipase basis thus permitting a reduction in the number of capsules taken to achieve the same lipase intake and degree of control (Morrison et al, 1991; Bowler et al, 1993; Taylor et al, 1996; Robinson et al, 1998).

However, others and we noticed that, in practice, although a considerable and welcome reduction in capsule numbers was possible, to achieve adequate absorption in some patients the actual intake of lipase increased considerably when using the new high strength enzymes (unpublished data). As a result, the enzyme intake and lipase intake of many patients increased considerably although the number of capsules required was reduced significantly.

Fibrosing colonopathy - a new and serious complication

In 1993 a new complication, fibrosing colonopathy (FC), was observed in Liverpool. Five children with CF who had unusual strictures of the ascending colon, four of whom had FC, were reported from Liverpool (Smyth et al, 1994). Studies in the UK (Smyth et al, 1995) and the US (FitzSimmons et al, 1997) showed a relationship with the very high dose of lipase achieved with the new enzymes. An epidemiological study of 14 cases detected in the UK showed they had been taking 46,200 IU lipase/kg/day (range 15,250-84,560) compared with the controls' 21,500 (range 0-85,870). In the UK study, there was also an association with enzyme preparations that contained the copolymer Eudragit L30 D55 in their covering (Smyth et al, 1995). A case controlled study of 29 confirmed cases in the USA confirmed the association with the high lipase intake (mean 50,046 IU lipase/kg/day compared to controls' 18,985 IU). Subsequent studies have added further support to the role of copolymer as one important factor in the pathogenesis (Bakowski & Prescott, 1997; Prescott & Bakowski, 1999; Littlewood, 1999). However, its role in the pathogenesis of FC not generally accepted (Dodge, 2001). Although only 17 patients in the UK have developed FC since its first recognition in 1993, the condition has had a major influence on attitudes to pancreatic enzyme treatment.

Pancreatic enzymes since 1994

Although there is lack of agreement on the role of copolymer, all agree that high doses of lipase are relevant in the aetiology of fibrosing colonopathy. In the UK, the Committee on the Safety of Medicines has advised "avoidance of the high strength enzymes Pancrease HL and Nutrizym 22 in children aged 15 and under. Restriction of dose to less than 10,000 IU lipase/kg/day regardless of the preparation used". Most clinicians in the UK now avoid copolymer containing enzymes and use standard Pancrease, Creon 10,000 or Creon 25,000, which do not contain copolymer and have not been associated with fibrosing colonopathy. It is interesting that the only 3 cases of fibrosing colonopathy in the UK since the CSM's advice have all been taking high doses of Nutrizym GR - the only standard strength enzyme which still contains copolymer in the covering (Jones et al, 1995). The increased caution with which enzymes are used has led to a considerable reduction in dose in many clinics without adverse effects on absorption or nutrition (Lowdon et al, 1998). Most people with CF can be well controlled (fat absorption over 85%) with doses of less than or only slightly in excess of 10,000 IU lipase/kg/day. Also, the need to avoid high enzyme doses has renewed interest in methods of reducing enzyme dose e.g. acid reduction or even adding bicarbonate to the microsphere preparation.

CF related diabetes mellitus

With increasing survival CF related diabetes mellitus (CFRDM) affects over 30% of adults with CF and during the Nineties there has been greater attention given to CFRDM. An important observation was that the gradual onset of glucose intolerance (in contrast to clinical diabetes mellitus) as judged by glucose tolerance tests, was associated with a worse clinical course (Lanng et al, 1992; Lanng et al, 1995). As survival improves, as it certainly will, an increasing proportion of the CF population, perhaps the majority will be affected by CFRDM or at least glucose intolerance. The increasing use of dietary energy supplements, particularly enteral feeds, and the use of oral corticosteroids are both recognised as important precipitating factors.

CF related liver disease - the first effective treatment
The recognition and treatment of CF related liver disease (CFRLD) is an increasingly relevant clinical issue (Sokol & Durie, 1999). Focal biliary cirrhosis was present in 70% of older patients at autopsy (Vawter & Shwachman, 1979) and 2-5% of patients have serious multilobular cirrhosis. When severe uncontrolled malabsorption was more common, fatty infiltration was seen and was reversible by more appropriate treatment. Thus, it is not surprising that the definition and prevalence of CFRLD varies with time and between CF clinics. Undoubtedly, the introduction of ursodeoxycholic acid treatment (URSO) for CF liver disease by Colombo in 1989 was a major advance in nutritional management (Colombo et al, 1990; Nakagawa et al, 1990). Other than reversing the changes of fatty infiltration by improving absorption and nutrition, there was no treatment for CFRLD up to this time.

Osteoporosis

Although osteoporosis was described as a complication of CF in the Seventies (Mischler et al, 1979), there has been a great increase in interest during the last decade. . Although some patients with advanced disease had obvious X-ray changes of osteoporosis with kyphosis, vertebral collapse and an increased frequency of fractures (Aris et al, 1998), the availability of Dual Energy X-ray Absorptiometry (DEXA) scanning has allowed more accurate recognition in a greater proportion of CF patients. Severity of disease and nutritional factors has been identified as important in a number of studies (Gibbens et al, 1988). Some 75% of patients who receive a transplant have severe osteoporosis worsened by their postoperative inactivity and steroid therapy (Aris et al, 1998; Donovan et al, 1998).

Better nutrition in childhood, more effective enzymes to improve intestinal absorption and attention to energy, calcium and vitamin D intake and regular monitoring of intestinal absorption and plasma vitamin D levels should reduce the incidence and severity of osteoporosis in adolescents and adults (Salamoni et al, 1996; Conway, 1999). Drug therapy with the biphosphonate family of drugs is under investigation in a number of centres for those with established osteoporosis.

Pregnancy.

New challenges beyond imagination of the early CF clinicians include the management of pregnancy in women with CF, although the first pregnancy was reported in 1960, when the median age of survival was only 10 years (Siegel & Siegel, 1960), The patient died 6 weeks after birth and the authors concluded "cystic fibrosis is seriously complicated by pregnancy". Whilst this is to some extent still true subsequent reports have documented a gradual improvement (Cohen et al, 1980; Edenborough, 2001). The close collaboration of the CF Team and Diabetic Team are stressed as of major importance.

Vitamin deficiencies - conveniently discussed here

The relevant fat-soluble vitamins A, D and E had been discovered in the earlier part of the century. Deficiencies of fat-soluble vitamins in CF patients were described in the Sixties and Seventies. Biochemical deficiencies were common even in patients receiving regular vitamin supplements of A, D and E in doses considered reasonable at the time (Congden et al, 1981). However, there have only been occasional reports of clinical deficiency syndromes.

Vitamin A.

Shortly after the original description, Andersen reported evidence of vitamin A deficiency in 10 of 49 patients. Vitamin A deficiency keratinises the bronchial epithelium, changes she considered predisposed to the pulmonary disease (Andersen, 1939). The plasma level usually correlates with the retinol binding protein (Ramussen, 1986). Clinical deficiency syndromes previously described included xerophthalmia and night blindness (Petersen et al, 1968; Rayner et al, 1989) and intracranial hypertension (Abernathy, 1976). Adherence with treatment, excessive faecal losses over and above the degree of fat malabsorption (Ahmed et al, 1990) and metabolic abnormalities has been suggested as reasons for persisting deficiencies despite supplements. However, in practice, with appropriate supplements in doses to maintain a normal plasma level, and close monitoring, most patients are vitamin A replete and have normal visual function (Ansari et al, 1999).
In our experience in Leeds the correction of vitamin A deficiency is associated with an improved clinical course (Rayner & Littlewood, 1992), which is interesting considering the previous suggestions as to its importance in the pathogenesis (Andersen, 1939). Nowadays the antioxidant role is considered to be of importance.

Vitamin D

Although rickets (Scott et al, 1977) and osteomalacia (Friedman et al, 1985) are rarely reported even in older people with CF, osteoporosis, osteopenia and low levels of vitamin D metabolites are being increasingly recognised both in children and adults with CF (Stead et al, 1987; Stamp & Geddes, 1993; Conway et al, 2000). Although normal levels were reported by some in patients supplemented with 800 IU daily (Hubbard et al 1979) our early studies, even in supplemented people with CF, suggested that subclinical vitamin D deficiency was not uncommon (Congden et al, 1981); others had similar experience (Hahn et al, 1979). In older unsupplemented patients, 75% had levels below the normal range (Hanly et al, 1985) and not all recovered with 800 IU vitamin D daily, emphasising the need for regular monitoring and dose adjustment. The increasing interest in osteoporosis has revived an interest in both calcium and vitamin D.

Vitamin E

The first report of vitamin E deficiency in CF involved an infant with necrotic muscle changes (Oppenheimer, 1956). Farrell reviewed the subject. Vitamin E levels vary with the severity of the steatorrhoea and are also related to the plasma lipid levels; unsupplemented patients with CF have very low plasma levels (Farrell et al, 1977). Deficiency may be associated with neurological problems (Willison et al, 1985; Sitrin et al, 1987), increasing haemolysis and at times frank haemolytic anaemia (Dolan, 1976). Correction of the deficiency reduces red cell fragility and improves haemoglobin levels (Kelleher et al, 1987).
All studies show levels can be normalised with 100-200mg (5-10 times usual daily requirement) of either a water or fat-soluble preparation of alpha-tocopherol (Winklhofer-Roob, 1996).

Vitamin K

Vitamin K deficiency, causing hypoproteinaemia and bleeding, was described in a number of CF infants during the Seventies, initially presumed to be due to vitamin K deficiency (Tortenson et al, 1970); at times there has been confusion with child abuse (Carpenteri et al, 1978). A later study showed no association of increase in prothrombin time with vitamin K1 and similar levels in CF and controls although no infants were included (Choonara et al, 1989). More recently subclinical vitamin K levels, (as shown by elevated PIVKA II levels) are almost universal in pancreatic insufficient patients (Rashid et al, 1999; Alexander et al, 1998).

As vitamin K is required for the formation of osteocalcin, the role of subclinical deficiency in osteopenia and osteoporosis is of increasing importance although, as yet, there is no convincing evidence correlating vitamin K deficiency and bone disease (Vermeer et al, 1995; Shearer, 1995). Intestinal malabsorption and the use of antibiotics affecting gut flora could both aggravate the tendency to vitamin K deficiency in CF patients (Lipsky, 1995).
Present studies are investigating the need and dose for long-term supplementation (Beker et al, 1997). There is no doubt that patients with CF who have liver disease and those having surgery should receive vitamin K supplements.

Water-soluble vitamins

No deficiencies were found in one study of 36 patients - normal levels of B1, B2, B6, C, and folic acid (Congden et al, 1981). Recent work, while confirming normal levels of vitamin C, does show some association of vitamin C levels and indices of inflammation (Winklhofer-Roob et al, 1997).

Essential element nutritional status

Minerals and trace elements have tended to be normal (Kelleher et al, 1986) although there are isolated reports of deficiencies even when taking pancreatic enzymes (Aggett et al, 1979). Our results suggested that in the vast majority of patients with CF, essential element status, apart from iron, is adequate (copper, zinc, calcium, magnesium) and it is unlikely that supplementation of these elements is required (Kelleher et al, 1986).

Although recent suggestions that zinc deficiency may be more common than generally appreciated, particularly in patients with liver disease, but absorption seems to be adequate with enzymes (Easley et al, 1998) and a supplemental study failed to show any advantage in one series of treated patients (Safai-Kutti et al, 1991).

Iron has received attention ever since Andersen noted hemosiderosis in 13 of 49 patients reported in her original paper (Andersen, 1938). In 127 patients 41 (32%) had low serum ferritin levels but the iron state did not correlate with the clinical score, radiological score or sputum cultures and there was no evidence the patients with low iron levels differed from the rest (Ehrhardt et al, 1987). More recently 44/71 (62%) adult patients who had a lower haemoglobin concentration and 10 were anaemic. The cause was not dietary but their condition was worse and chronic inflammation was considered to be the main cause in these adults. Fifteen patients completed a 3-month course of iron with no clinical effect or change in haemoglobin (Pond et al, 11996).
Most recently of 40 adult CF patients the mean transferrin was reduced in 16% and 63% were iron deficient (transferrin saturation < 16%), 36% had low serum ferritin but the study did not add to understanding the cause (Hansen et al, 1999). The situation regarding iron is still not clear.

Sodium chloride

Chronic salt depletion is now recognised as an important reason for failing to thrive. The initial salt depletion in the original children admitted in the New York heat wave of 1951 was the result of excessive salt loss. Occasionally fully breast-fed infants with CF developed chronic salt depletion and failed to thrive. The characteristically low plasma electrolytes with raised renin and aldosterone are appropriately termed the pseudo-Bartter's syndrome (Devlin et al, 1990). The occurrence of 7 cases in five years during the summer months in London may have been related to a reduction in the electrolyte content of proprietary baby milks (Kennedy et al, 1990).

Also note from the Nineties:

•Chatfield S, Owen G, Ryley HC, Williams J, Alfaham M, Goodchild MC, et al. Neonatal screening for cystic fibrosis in Wales and the West Midlands: clinical assessment after five years screening. Arch Dis Child 1991; 66:29-33.
[No benefit from screening when children received care at local hospital general paediatric clinic]

•Doull IJM, Weller P, Desai M, Goodchild MC, Ryley HC. Five and ten year follow up of the effect of newborn screening for cystic fibrosis: the Wales and West Midlands study. Arch Dis Child 2002; 86(Suppl 1): A38 (G103)
[No differences at 5 or 10 years - conclude reason is lack of centralised management]

•Laroche D, Travert G. Abnormal frequency of dF508 mutation in neonatal transitory hyoertrypsinaemia. Lancet 1991; 337:55.
[First description of a phenomenon which resulted in considerable discuss in the context of neonatal screening and disclosure of the infant's carrier status to the parents]

•Rayner RJ, Hiller EJ, Ispaphani P, Baker M. Haemophilus influenzae infection in cystic fibrosis. Arch Dis Child 1990; 65:255-258.
[Evidence for the role of H. influenzae as an important pathogen, which should be treated]

Conclusions

Changed attitudes

The changes, which have occurred in the treatment and outlook for people with CF, have been quite remarkable. But having CF is still a massive permanent problem, which permanently alters the lives of both the affected individual and their family. Nevertheless, during the course of the professional lifetime the older clinicians attitudes have changed from one of questioning the attempts to treat a condition, which was almost always fatal in early childhood, to a striving to maintain the affected person in the best possible condition to reach adulthood with minimal respiratory and nutritional damage. Even to the extent that failure to recognise the condition and deliver the best treatment is increasingly a regarded as a medico-legal problem - the condition should have been recognised earlier and the damage prevented.

Advances occur at Specialist CF Centres

It is clear that the detailed demanding treatment, which is likely to be recommended at a Specialist CF Centre, now provides most people with CF the best means of maintaining good health - provided they and their family follow the treatment regimen advised - and this is not always easy or the case. Although some children now grow normally and pass through a normal adolescence without chronically infected lungs, it is disappointing that there is still a tendency for the median values for both height and weight to fall below normal particularly during adolescence. National data from many countries still show that the majority still develop chronic infection of the respiratory tract with P. aeruginosa during childhood and adolescence, which inevitably is followed by a slow but progressive deterioration in their respiratory function and nutritional state. The patients reach what has been described as "the point of no return" - the patient passing from "CF disease" (where there is an alteration in the physicochemical characteristics fluid within the airways) to chronic "lung disease" (where infection and inflammation lead to progressive destruction of the lungs) (Drittanti et al, 1997).

The fact that there is still a steady continuing improvement in the respiratory state, the nutritional state and survival of people with CF and that there are significant differences between the condition of patients in different Specialist CF Centres between those in the upper quartile from those in the lower quartile for many parameters (Morgan et al, 1999). This suggests that there is room for improvement, particularly in Centres whose patients lie in the lower quartiles, until such time as more specific therapies become available.

The complexity of care and the new problems which are appearing with increasing age (e.g. diabetes, liver disease, osteoporosis, pregnancy and fertility problems, as well as complex psychosocial issues) are better dealt with by the staff at a Specialist CF Centre. Most significant advances, indeed virtually all advances, have been made at Specialist CF Centres where staff have sufficient patients to recognise important clinical problems and then respond by developing treatments to deal with them; eventually these treatments are tested in formal trials.

The need to ensure that significant advances conventional treatment are available for all people with CF

A major problem to day is ensuring that all people with CF benefit from the latest advances in treatment. The introduction of likely important advances in treatment must be balanced between the views of the modern zealots of evidenced-based medicine and the common sense and long experience of those clinicians involved with the condition for many years. The CF Trust's Clinical Standards and Accreditation Group recognise the central role of the Specialist CF Centre in this area by their firm recommendation that all adults with CF should attend a Specialist CF Centre, even if shared care between the local CF Clinic and the Specialist CF Centre is acceptable for many affected children. Considerably more development of Specialist CF Centres and improvements in their shared care with CF Clinics for children are needed. Unfortunately such developments are often prevented due to inadequate National Health Service funding to provide the extra staff and facilities and - it must be said - occasionally by the attitudes of a minority of professionals working in general hospitals who are reluctant to share the care of their patients with the staff of the Specialist CF Centre.

Cystic Fibrosis Trust's expert consensus groups to advise on care

Increasingly standards of care, incorporating published evidence and the experience of consensus groups, are available to clinicians, parents and patients. Increasing efforts are being made to get significant advances to those responsible for prescribing treatment particularly the non-specialist paediatricians running CF Clinics in general hospitals. Even so the undue delay in introduction of the impressive advances of the past 20 years has been disappointing. In my view, there is still considerable room for improvement in all these areas and many people with CF in the UK are still not receiving the care recommended by the expert advisory committee of the CF Trust in their Standards for the Clinical Care of Children and Adults with Cystic Fibrosis in the UK. 2001. Other recent publications from the Cystic Fibrosis Trust's expert Groups include A Statement on Burkholderia cepacia. July, 1999; Antibiotic Treatment for Cystic Fibrosis. April, 2000; Pseudomonas aeruginosa Infection in People with Cystic Fibrosis - Suggestions for Prevention and Control. May, 2001; Clinical Guidelines for the Physiotherapy Management of Cystic Fibrosis (Association of Physiotherapists in Cystic Fibrosis). January, 2002; National Consensus Standards for the Nursing Management of Cystic Fibrosis (UK Cystic Fibrosis Nurse Specialist Group). May, 2001; Nutritional Management of Cystic Fibrosis. April, 2002.

New opportunities with national neonatal CF screening

The impending introduction of national neonatal CF screening will identify infants with CF before there are lung changes or nutritional and growth problems. The modern management available now should allow early identification and eradication of respiratory infection and thus preserve respiratory function. Also presently available nutritional treatment with regular dietetic advice, appropriate enzymes and vitamin supplements should maintain good nutrition and sustain normal growth in the majority.

The future

So it is clear that clinical and scientific progress, particularly over the past 20 years, has been very impressive (albeit somewhat slowly implemented in some areas). Of course, there have been major advances in many fields of medicine and science that have made this progress possible. However, there is certainly no place for complacency when one considers the long term prognosis and there are still considerable improvements to be made in so-called conventional treatment not least the provision of adequate staff and facilities and a more even application of established knowledge.

Undoubtedly in the next 5 to 10 years, either gene replacement, gene repair and/or some pharmacological approach will radically improve the outlook for many of those affected - provided they receive early and effective treatment to avoid significant pulmonary damage. It is important that people with CF remain in the phase of CF Disease when they are likely to benefit from preventive gene transfer therapy (or pharmacological treatment) rather than attempting the more uncertain gene therapy for a chest already in the phase of chronic Lung Disease and already irreparably damaged by infection and inflammation.

For the present follow-up must be frequent and meticulous by experts and treatment early and aggressive; we could do worse than follow the advice of the late Dr.Crozier who observed that that: - "Success of treatment will depend on a complete assessment of the patient and then continuing attempts to obtain normal bodily function and maintain it"

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