The Nineties clinical Fibrosis and clinical... · The Nineties clinical Steady improvement in clinical care and important new treatments The improvement in outlook which characterised

The History of CysticFibrosis by Dr JamesLittlewood OBE

1990-1999

The Nineties clinical

Steady improvement in clinical care and important new treatments

The improvement in outlook which characterised the Eighties continued through the Ninetiesas a result of steady improvement in care and the increasing expertise of the staff at thenow well-established CF Centres. During the decade there were a number of notable additions tothe treatments available in addition to further validation of existing treatments. These includedrhDNase (Pulmozyme), a new preparation of tobramycin for inhalation (TOBI) and azithromycin.However, the provision of “optimal care”, which is complex and very expensive, for all people withCF, particularly in the UK, has proved increasingly difficult, not least due its very high cost(Littlewood JM, Cross E. Present day treatment of cystic fibrosis: its content and cost. In: ClinicalEconomics in Gastroenterology. Bodger K, et al. (Eds), Blackwell Science, Oxford 2000: 220-249).In the UK, inadequate funding remained one of the major factors preventing the provision ofoptimal care for all.

Cross-infection between people with CF - a new major problem

In 1979 Pseudomonas (now Burkholderia) cepacia in people with CF was first reported in NorthAmerica and thereafter reports of this new pathogen, with the potential to spread betweenpatients and cause serious illness, occurred with increasing frequency both from North America(Isles et al, 1984 above; Thomassen et al, 1985 above) and later from the UK (Simmonds et al,1990 below). At first some clinicians were slow to accept that cross infection with B. cepaciabetween patients occurred until the early Nineties when this was established beyond any doubt(LiPuma et al, 1990 below; Govan et al, 1993 below). The severity and fatal nature of theassociated illness (“cepacia syndrome”) in a proportion of infected patients with CF and itspropensity to spread between patients has lead to a radical change in both clinic practice and thesocial habits of people with cystic fibrosis. Holiday camps for people with CF – so popular in N.America and so appreciated by some patients from the UK - were a source of cross infection andeventually abandoned (Pegues et al, 1994 below). Eventually, in 1993, the Infection Control Groupof the UK CF Trust recommended strict the segregation of patients infected with Burkholderiacepacia. This was the start of the era of cross-infection control, which was to radically alter thewhole attitude to infection, cross-infection and social contact in CF Centres and in the community.

Also there was increasing evidence of cross-infection with Pseudomonas aeruginosa. The conceptof cross-infection between people with CF with organisms other than B. cepacia had not beenregarded as a major consideration by the staff in most CF centres; the exception was the DanishCF Centre in Copenhagen where Neils Hoiby and his colleagues realised segregation of patientsaccording to their microbiological status was important. Cross-infection with so-called ‘highlytransmissible’ strains of Pseudomonas aeruginosa has been increasingly reported (Cheng et al,1996 below; Jones et al, 2001 below) and there followed many reports of cross-infection with P.aeruginosa in cystic fibrosis.

As a result of these developments it is was recommended that people with CF should besegregated according to their microbiological status and those with B. cepacia should also besegregated even from each other as those with less virulent genomovars (strains) may be infectedby those with the more severe ones.

Other advances in treatment in the Nineties

Support for the routine use of prophylactic anti-staphylococcal antibiotics (flucloxacillin) in youngchildren came from a controlled trial in screened CF infants in East Anglia in 1994 (Weaver et al,1994 below), although some clinicians still considered the treatment predisposed to Pseudomonasaeruginosa infection. Intravenous antibiotics were increasingly used in less severely affectedpatients at a much earlier stage rather than as a last resort – a principle central to moderntreatment (“a matter of degree rather than kind”). Early eradication treatment for earlyPseudomonas infection became increasingly used in many European CF Centres.

Recombinant human DNase (Pulmozyme) was the first really effective mucolytic, which was veryeffective in reducing the viscosity of the sputum and improving respiratory function in a significantproportion of people with cystic fibrosis (Shak et al, 1990 below; Fuchs et al, 1994 below). Itbecame an important and effective part of the daily treatment for many patients with chronicinfection and there is also evidence that even mildly affected patients may benefit (Harms et al,1998).

A special preparation of tobramycin for inhalation (TOBI) became available in the Nineties.

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The History of Cystic Fibrosis by Dr James Littlewood OBE 1 Copyright © cfmedicine.com 2009-2011

Figure 15: Mrs RosieBarnes. ChiefExecutive Officer ofthe UK Cystic FibrosisTrust.

Although inhaled aminoglycosides (the IV preparations of gentamicin and tobramycin) have beenwidely used in the UK since Margaret Hodson’s 1981 paper (above), an important, well-conductedcontrolled trial to confirm the beneficial effect of this special preparation of tobramycin forinhalation (TOBI) was welcome (Ramsey et al, 1999 below). This preparation is now increasinglyused but unfortunately its use limited by cost in some parts of the UK.

From the early Nineties the new high strength pancreatic enzymes (Pancrease HL, Creon 25,000)were available and welcomed by people with CF many of whom, when taking a normal fat intake,did require a large number of standard enzyme capsules. So it was not surprising that patients,and their professional advisers, welcomed the introduction of the new "high lipase enzymes" in1992, However, in 1993 a new unexpected and serious complication, fibrosing colonopathy withcolonic strictures, was observed in Liverpool and eventually related to the very high doses ofenzymes some patients were taking (Smyth et al, 1994 below); subsequently further patients withcolonic strictures were reported from UK and the United States. Studies in the UK (Smyth et al,1995 below) and the US (FitzSimmons et al, 1997 below) showed a relationship with the very highdoses of lipase achieved with the new enzymes but the studies differed on showing an associationwith the copolymer covering of some preparations – the UK study suggested this was a factor. Theproblem has since receded in the UK following advice from the Committee on the Safety ofMedicines to restrict the daily dose to an equivalent of lipase to not more than 10,000 IU /kg/day(Littlewood, 1999 below).

With increasing survival, problems related to CF including diabetes mellitus, liver disease,osteoporosis, pregnancy and fertility became increasingly common and presented further majormanagement problems. New challenges, beyond imagination of the early CF clinicians, include themanagement of pregnancy in women with CF and successful treatment of infertility in men withcystic fibrosis. Also it is encouraging that even the problems of old age and CF are now beingaddressed (Warwick, 2003).

In 1996 Mrs Rosie Barnes (figure 15) was appointed as ChiefExecutive Officer of the UK Cystic Fibrosis Trust. Rosie, as she isaffectionately known, was a Member of Parliament (SDP) forGreenwich between 1987 and 1992. Prior to that she was involved inmarket research and marketing. Her interests in Parliament includedhealth, education and the problems of children in care. She joined theCystic Fibrosis Trust in 1996, after four years as Director ofWellBeing, formerly Birthright. She takes a keen interest in the NHS,particularly in relation to the clinical care of those with cystic fibrosis.Rosie has had a major impact on the work, development andinfluence of the CF Trust. In addition to the annual income increasingyear by year from £3 million to £11 million over the next decade, itwas under her initiative that the three leading gene therapy researchgroups in the UK came together to form the collaborative GeneTherapy Consortium to speed the translation of the gene discoveryinto the treatment of patients. This is now regarded as an importantmajor decision focusing the major part of the CF Trust’s researchfunds on treatment of the basic defect by gene therapy. Also the CFTrust, with the advice of a specially appointed Scientific Advisory

Committee, guaranteed ongoing financial support for the Gene Therapy Consortium.

1990 Pasque MK, Cooper JD, Kaiser LR, Haydock DA, Triantafillou A, Trulock EP.Improved technique for bilateral lung transplantation: rationale and initial clinicalexperience. Ann Thorac Surg 1990; 49:785-791. [PubMed]The first bilateral lung transplantation in CF was performed in Toronto in 1988 and 17 were carriedout between 1988 and 1991 (Ramirez JC et al. J Thorac Cardiovac Surg 1992; 103:287-293).[PubMed]. This improved operation was done through a transverse thoracosternotomy andinvolves sequential replacement of the two lungs. Positive features included separate bronchialanastomoses to reduce ischemic airway complications and elimination of the need for totalcardiopulmonary bypass. Three patients were reported, one had CF, all recovered withoutcomplications and post operative function was excellent. The double lung transplant operationgradually replaced heart-lung transplants for people with cystic fibrosis.

1990 Knowles MR, Church NL, Waltner WE, Yankaskas JR, Gilligan P, King M, Helms RW,Boucher RC. A pilot study of aerosolized amiloride for the treatment of lung disease incystic fibrosis. N Eng J Med 1990; 322:1189-1194. [PubMed] Michael Knowles first discovered the increased bioelectrical potential difference across respiratoryepithelium in CF (Knowles M et al. N Eng J Med 1981; 305:1489-1495 above). In this presentstudy Knowles and Boucher investigate whether the inhibition of excessive absorption of sodium byinhaled amiloride might favourably affect the course of CF lung disease. Fourteen of 18 patientscompleted a one year double-blind, crossover trial comparing aerosolized amiloride (5 mmol perlitre; 3.5 ml four times daily) with control solution. The mean (+/- SEM) loss of forced vitalcapacity (FVC) was reduced from 3.39 (+/- 1.13 ml) per day during treatment with vehicle aloneto 1.44 (+/- 0.67) ml per day with amiloride (P <0.04). Sputum viscosity and elasticity,mucociliary and cough clearance improved during treatment with amiloride suggesting somebeneficial effect. This trial created considerable interest but the effect of amiloride was modest and short-lived; alsothe loss of FVC in the control group seemed excessive. Apparently the action of inhaled amilorideis very transient and subsequently longer acting analogues were explored. However, this report did


Figure 16: Professor CarlaColombo.

encourage us in Leeds to look at the effect of giving nebulised amiloride during the intravenousantibiotic treatment of exacerbations of respiratory infection in CF. We observed a definite butinsignificant improvement in the early response to intravenous antibiotics in the amiloride group(Bowler et al, 1995 below). No benefit was seen from amiloride by Graham A et al (No addedbenefit from nebulised amiloride in patients with cystic fibrosis. Eur Respir J 1993; 6:1243-1248).[PubMed] nor in a French multi-centre randomized double blind placebo controlled trial in patientsmore than 5 years old (Pons G, et al, Pediatr Pulmonol 2000; 30:25-31). [PubMed] However,earlier Kohler et al showed inhaled amiloride improved mucociliary clearance in patients with CF(Kohler et al, Eur J Respir Dis 1986; 69 (Suppl 146:319-326); also the same group confirmed thiswith a larger study (App AM et al. Am Rev Respir Dis 1990; 141:605-612. [PubMed] AlsoLindemann et al from Giessen had reported 50.4% more sputum was produced by autogenicdrainage after inhalation of amiloride than after isotonic saline also visible liquefaction ofsecretions was noted by the physiotherapist and patients (Lindemann H et al. Elimination ofsecretions in CF patients under amiloride inhalation. Pneumologie 1990; 44:1148-1150 [PubMed][German]).Later more active and longer acting drugs (P- 680 & P- 522-O2-Parion Sciences/Gilead) thatInhibit excess Na absorption showed more promise and their development continues.

1990 Yacoub M, Banner NR, Khaghani A, Fitzgerald M, Madden B, Tsang V, Smyth R,Hodson ME. Heart lung transplantation for CF and subsequent domino cardiactransplantation. J Heart Transplantation 1990; 9:459-67. [PubMed] Between September 1984 and October 1988, 27 patients underwent combined heart-lungtransplantation for treatment of end-stage respiratory disease caused by CF: survival was 78% at1 year and 72% at 2 years. Lung function was greatly improved after transplantation, and long-term survivors achieved an excellent quality of life. Lymphoproliferative disorders developed in twopatients; these disorders regressed after a reduction in immunosuppression. Two patients requiredretransplantation: one because of obliterative bronchiolitis and the other because of recurrentrespiratory infections associated with a moderate tracheal stenosis and severe deterioration in lungfunction. A modification of the technique used for heart-lung transplantation allowed 20 heartsfrom cystic fibrosis patients to be used for subsequent heart transplantation. This report by Mr Yacoub and his team, who performed the first heart lung transplantations inpeople with CF at Harefields Hospital, London in 1984. There were also reports from Mr Wallwork’sunit at Papworth, Cambridge (Penketh et al, 1987 above; Jones et al, 1988 above and later fromProfessors Dark and Paul Corrie from Newcastle)>

1990 Devlin J, Beckett NS, David TJ. Elevated sweat potassium, aldosteronism andpseudo-Bartter's syndrome: a spectrum of disorders associated with cystic fibrosis. JRoy Soc Med 1989; 82 (Suppl 16): 38-43. The term “Pseudo-Bartter syndrome” is used to describe metabolic alkalosis in association with lowserum electrolyte concentrations (hyponatraemia, hypokalaemia and hypochloraemia). Thiscomplication is an Important cause of failure to thrive in CF and in this study was detected byestimation of the serum electrolytes in five non-thriving infants with cystic fibrosis (also Rendle-Short J Arch Dis Child 1956; 31:28-30; Beckerman RC, Taussig LM. Pediatrics 1979; 63:930-936;79:930-936; Kennedy JD et al. Arch Dis Child 1990; 65:786-787).

Pseudo-Bartter Syndrome in infants with CF is identified by estimation of the plasma electrolytes -a mandatory investigation in any infant, CF or non-CF, who is failing to thrive or chronicallyunwell. Rarely, in non-CF infants who are not thriving, genuine Bartter’s syndrome may bediscovered by estimating plasma electrolytes in a non-thriving infant (Littlewood et al, Arch DisChild 1978; 53:43-48).

1990 Colombo C, Battezzati PM, Crosignani A,Assaisso M, Ronchi M, Giunta A. Effects of taurineand ursodeoxycholic acid on liver function tests inpatients with cystic fibrosis. Acta UniversitatisCarolinae – Medica 1990; 36:148-151. [PubMed] The report of a memorable presentation by Prof. CarlaColombo (figure 16) of Milan at the European CF Societymeeting in Prague in 1989 which I was fortunate to hear.This was the first report of the beneficial effect of oralursodeoxycholic acid (URSO) in people with CF associatedliver disease – before this there was no treatment for theliver disease. In nine CF patients with clinical andbiochemical evidence of liver disease, taurine (30mg/kg/day) was administered one month before andduring the successive treatment with ursodeoxycholic acid(10-15 mg/kg/day). Standard liver function tests weredetermined before and after each period of treatment.

Taurine administration produced only inconsistent changes of liver function tests from baseline,whereas after the addition of ursodeoxycholic acid there was a substantial improvement in allabnormal liver function tests (details reported in J Pediatr 1990; 117:482-489 below).

1990 Colombo C, Setchell KD, Podda M, Crosignani A, Roda A, Curcio L, Ronchi M, GiuntaA. Effects of ursodeoxycholic acid therapy for liver disease associated with cysticfibrosis. J Pediatr 1990; 117:482- 489. [PubMed] The published report from Milan of data presented in 1989 at the European CF Society Meeting inPrague (1990 above) reporting the favourable effect of ursodeoxycholic acid (URSO) treatment 10-


15 mg /kg day in 9 patients with CF who had chronic liver disease (presumably the same patientsas reported in Prague in 1989). Liver function tests improved significantly (AST- by 34%, alanineaminotransferase – by 41%, gamma gutamyl transpeptidase – by 41% and alkaline phosphatase–by 19%).

Subsequently URSO was widely used in people with CF associated liver disease and representedone of the major advances in CF management. A further trail was published in 1996 (Colombo etal, 1996). Much information was published supporting URSO treatment at an early stage of liverinvolvement and eventually most people with evidence of liver involvement were treated withURSO.However, a Cochrane Review updated in 2008 concluded "There is insufficient evidence to justifyits (URSO) routine use in cystic fibrosis". In the writer's opinion this conclusion was unfortunate asit could influence clinicians to withhold treatment from people with liver involvement. The followingstatement would have been more appropriate - "There is a considerable amount of evidence thatURSO improves liver function in people with CF particularly if used at an early stage; but, as yet,there is no clinical trial that conforms to Cochrane standards to show this".

1990 Simmonds EJ, Conway SP, Ghoneim ATM, Ross H, Littlewood JM. Pseudomonascepacia: a new pathogen in patients with cystic fibrosis referred to a large centre in theUnited Kingdom. Arch Dis Child 1990; 65:874-877. [PubMed] Although the first reports from N. America of this organism appeared in the late Seventies(Lararya-Cuassay et al, 1977 above), this was the first to report Burkholderia cepacia in the UK –previously known as Pseudomonas cepacia. We were impressed by the very serious consequencesof this infection in some patients. Some clinicians in the UK still doubted the serious nature of thisinfection although three of our 11 patients died – two after an alarming and rapid deteriorationnow described as the “cepacia syndrome”. We could not identify any source of cross infection inthe Leeds CF centre at that stage nor was there an inappropriate use of antibiotics. However, inretrospect, we suspected that at least two of our patients had acquired the infection at CF holidaycamps in N. America some months before the organism appeared in their respiratory cultures.

A further report of 13 infected patients (three of whom died) from Manchester in the UK also failedto show evidence of cross infection and the authors suggested that further studies were requiredbefore segregation of patients should be recommended (Gladman G et al, Arch Dis Child 1992;67:192-195). It was not until 1993, following Professor Govan’s publication from Edinburgh(Govan et al, 1993 below), that the UK CF Trust’s advisory group recommended strict segregationof all B. cepacia infected patients.

1990 Strandvik B, Hollsing A, Mollby R, Granstrom M. Antistaphyloccocal antibiotics incystic fibrosis. Infection 1990; 18:48-50. [PubMed] Chronic Staphylococcus aureus infection was present in 40-50% of the Stockholm patients. Thepresence of IgG ELISA serum anti-Staphylococcal antibodies reflected the presence and severity ofthe infection. The authors suggested the raised antibodies may indicate significant tissue damageand more severe disease and would be an indication for treatment.

This paper supported the use of an aggressive anti-Staphylococcal policy originally advocated byDavid Lawson, both involving the long term use of an antistaphyloccocal antibiotics with additionalantibiotics when required. In our clinic this resulted in a low overall chronic S. aureus infection rate- in the whole clinic of only 14.5% with no children chronically infected below the age of 5 yearsand of only 8.3% of those less than 10 years old infected (Southern KW et al.1993 ECFS Madrid).Later the clinical trial of Weaver et al, (1994 below) supported the use of long term flucloxacillintherapy up to the age of two years of age. Brigitte Strandvik later noted that despite long termflucloxacillin treatment it was rare to isolate methicillin resistant strains (Strandvik B. Ann Nestlé(Engl) 2006; 64:131-140); this was our experience in Leeds - MRSA appeared to be acquired fromothers with the infection rather than developing when receiving longterm flucloxacillin. It wasinteresting that we noticed the few children who did grew S. aureus despite apparently takingflucloxacillin, also had low vitamin E levels and when their routine clinic urine specimen waschecked for antibiotic activity there was none!! Adherence, or lack of it, seemed to be a definitepossibility!!

1990 Shak S, Capon DJ, Hellmiss R, Marsters SA, BakerCL. Recombinant human DNase 1 reduces the viscosityof cystic fibrosis sputum. Proc Natl Acad Sci 1990;87:9188-9192. [PubMed]An early report of the significant effect of recombinanthuman DNase1 (Pulmozyme) on sputum viscosity in peoplewith CF by Steve Shak (Figure 17). To evaluate the potentialclinical utility of recombinant human DNase I (rhDNase) inthe treatment of CF, the authors cloned, sequenced, andexpressed rhDNase. Catalytic amounts of rhDNase greatlyreduced the viscosity of purulent CF sputum, transforming itwithin minutes from a non-flowing viscous gel to a flowingliquid. The reduction in viscosity is associated with adecrease in size of the DNA in the sputum. The authorssuggested that inhalation of an rhDNase aerosol may be asimple direct approach that would help individuals with CF,and other patients with pneumonia or bronchitis, to cleartheir airways of purulent secretions.


Figure 17: Dr Steve Shak. FromNew Insights into Cysticfibrosis. September 1993.

In 1950 Armstrong JB & White JC (Lancet 1950;2:739-742. [PubMed]) had shown that bovine pancreaticDNase1, added to viscid purulent sputum, destroyed theextra cellular fibres of DNA and reduced the viscosity. LaterElmes PC & Armstrong JB (Thorax 1953; 8:295-300.

[PubMed]) reported its use in chronic bronchitis, but the side effects of the bovine preparationeventually precluded its use and further development at that time (Raskin P. Am Rev Respir Dis1968; 98:697-698). [PubMed] Subsequently the rhDNase (Pulmozyme) reported here proved tobe one of, if not the, major therapeutic advance of the Nineties. By 2005 Pulmozyme was taken byalmost 70% of people on the US CF Foundation patient registry; eventually it would be usedearlier and by milder affected and younger patients.

1990 Regelmann WE, Elliot GR, Warwick WI, Clawson CC. Reduction of sputumPseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosismore than do bronchodilators and physiotherapy alone. Am Rev Respir Dis 1990;141:914-921. [PubMed]This widely quoted paper provided definite objective evidence of the beneficial effect of antibioticsover and above the other measures used when patients with chronic Pseudomonas aeruginosainfection were treated for a pulmonary exacerbation. The study has a rather complex design but isgenerally accepted as providing evidence of the beneficial effect of intravenous antibiotics and so itis described here in some detail. For the first 4 days of study, all patients received bronchodilating aerosols and chest physiotherapybut no antibiotics. During this time, the patients showed significant improvement in mean FVC,FEV1, and maximal midexpiratory flow rate (FEF25-75). In 12 of 13 trials, the patients showed nosignificant increases in the density of Pseudomonas aeruginosa during these first four days. Inthese 12 trials, the patients were stratified by their initial FVC and randomized to receive eitherparenteral tobramycin and ticarcillin (n = 7) or placebo (n = 5), and in addition to continuingaerosol and chest physiotherapy. In the remaining trial, the patient had a significant rise in thedensity of P. aeruginosa during the run in and therefore was assigned to the antibiotic group. During the next 14 days of therapy, the antibiotic group showed significantly (p < 0.01) greaterreductions in log10 colony-forming units (cfu) of P. aeruginosa per gram of sputum and greaterincreases in FVC, FEV1, and FEF25-75 than did the placebo group. The degree of decrease in log10cfu P. aeruginosa/g sputum correlated significantly (p < 0.001) with the degree of improvement inFVC, FEV1, and FEF25-75.

The favourable effect of antibiotics had been questioned in a previous trial from Toronto where itwas stated “there was no difference in the course during the 6 to 24 months after the studyperiod. Intravenous antibiotics are not essential in the management of all acute respiratoryexacerbations of mild to moderate severity in patients with cystic fibrosis” (Gold R et al. J Pediatr1987; 111:907-913). [PubMed] This was a finding quite out of keeping with the experience ofmost experienced CF clinicians who, fortunately, did not heed the Toronto advice!

1990 Waters DL, Dorney SF, Gaskin KJ, Gruca MA, O'Halloran M, Wilcken B. Pancreaticfunction in infants identified as having cystic fibrosis in a neonatal screening program. NEng J Med 1990; 322:303-308. [PubMed] Assessment of pancreatic function in 78 children identified in the New South Wales neonatalscreening program as having cystic fibrosis. Measurements of faecal fat excretion, pancreatic-stimulation tests, and estimations of the serum level of pancreatic isoamylase indicated that 29 ofthe 78 children (37 percent) had substantial preservation of pancreatic function. These 29 children(median age, four years) had growth that was close to normal and comparable to growth inchildren with severe pancreatic insufficiency who received oral enzyme therapy. Pancreaticinsufficiency subsequently developed in 6 of the 29 patients, at 3 to 36 months of age. The authorsconcluded that the serum immunoreactive-trypsin assay used in neonatal screening programsidentifies patients with CF who have sufficient pancreatic function to achieve normal fat absorptionand that a substantial proportion of infants identified as having cystic fibrosis are in this category(also Gaskin et al, 1991 below)Thirty four of these 76 children had their pancreatic function assessed an average of 2.3 yearsafter diagnosis – so subsequently a further 20 infants were studied at the time of diagnosis(Gaskin et al, 1991 below). The number of children who were pancreatic sufficient in this series is higher than expected butwould depend on the proportion carrying a mild mutation.


Figure 18.2. DrRobert (Bob)Dinwiddie.

Figure 18: Faecal neutral fat -microscopy vs. chemicalanalysis. With permission of BMJPublishing Group.

Figure 18.1 Fat droplets in faecal sampleunder microscope

1990 Walters MP, Kelleher J, Gilbert J, Littlewood JM. Clinical monitoring of steatorrhoeain cystic fibrosis. Arch Dis Child 1990; 65:99-102. [PubMed] When compared with chemical faecal fat assays and steatocrit the simple microsopy method washighly sensitive (97%) and only three of 80 patients with steatorrhoea would have been missedusing this technique. All patient with severe steatorrhoea (> 60 mmol fat/day) were clearlyidentified (figure 18). This method is still used in the Leeds CF Centre and gives some indication asto the success of the enzyme replacement therapy as chemical estimations of faecal fat are rarelydone unless as part of a research project. This is unfortunate as severe fat malabsorption may bepresent without significant abdominal symptoms and conversely severe symptoms may be presentwithout there being steatorrhoea - a situation which would not respond to increasing the enzymedose as, unfortunately, does occur on occasion.

1990 Kennedy JD, Dinwiddie R, Daman-Willems C, Dillon MJ, Matthews DJ. Pseudo-Bartter's synrome in cystic fibrosis. Arch Dis Child `1990; 65:786-787. [PubMed] A further seven cases of Pseudo-bartter's syndrome are described from Great Ormond Street,London. Chronic salt depletion was associated with severe failure to thrive which was soonreversed when the salt deficit was corrected.

Dr Bob Dinwiddie (Figure 18.2), the senior author, was consultant RespiratoryPaediatrician at the Hospital for Sick Children, Great Ormond Street in Londonwhere he succeeded Dr Archie Norman as Director of the CF Unit. He washeavily involved in CF care and respiratory paediatrics both nationally andinternationally until his retirement in the 2000s.

1991 Gaskin K, Waters D, Dorney S, Gruca M, O'Halloran M, WilckenB. Assessment of pancreatic function in screened infants with cysticfibrosis. Pediatr Pulmonol 1991; Suppl 7:69-71. [PubMed]Previously these authors reported that 37% of infants with CF diagnosed byneonatal screening with the dried blood spot immunoreactive trypsin assaywere pancreatic sufficient (Waters et al, 1990 above). However, 34 of the 78infants had pancreatic function tests an average 2.3 years after diagnosis,thus it was possible that the percentage with neonatal pancreatic sufficiencywas even underestimated, due to the loss of pancreatic function with time in

some infants. To assess this hypothesis the authors assessed pancreatic function at the time ofdiagnosis in a further 20 infants since the completion of the previous study. Results of fecal fatdeterminations and/or pancreatic stimulation tests indicated that no less than 10 (50%) of theseinfants have pancreatic sufficiency. Combining these results with those of the previous study, 31 of64 patients (48%) have pancreatic sufficiency at this early age. The authors monitored theprogression of pancreatic disease in the 39 children with pancreatic sufficiency recognized to date.Eleven have developed pancreatic insufficiency and require enzyme replacement therapy. Fiveothers have shown further improvement of colipase secretion with age.

So the authors confirmed their previous conclusion that the dried blood immunoreactive trypsinscreening program for cystic fibrosis does recognize patients with pancreatic sufficiency and atdiagnosis nearly half their patients were in this category. To date, 28% of patients with pancreaticsufficiency have demonstrated a variable decline in pancreatic function with age.


Figure 18.2: Some of the Sydney CF doctors in 1998. PeterCooper (paediatrician), Kevin Gaskin (paediatrician), visitor(Jim Littlewood) and Peter Bye (respiratory physician).

Prof GerrardMcElvaney

In this study there were asurprisingly large numberof infants who werepancreatic sufficient (48%)and this is quite differentfrom our experience ofscreened infants with CFover the last 30 years inLeeds, although, of course,the frequency will dependon the mutations which theinfants have. For exampleof the last 15 screenedinfants with CF in Leedsonly 2 were pancreaticsufficient (Wolfe et al. JCyst Fibros 2005;4(S1):S94). The faecal pancreaticelastase is now aconvenient and reliable wayof determining pancreatic

function and following the progress of pancreatic function in these infants.The lesson here is thatnot all newborns with CF require enzyme replacement therapy so it is important to make surethere is evidence of pancreatic insufficiency before commencing enzymes - in practice easily donewith a faecal elastase measurement and a small specimen of stool for fat microscopy (Walters etal, 1990 above). The test is also reliable indicator of pancreatic function even when the infant istaking enzyme replacement therapy - in this respect it differs from faecal trypsin andchymotrypsin.

1991 McElvaney NG, Hubbard RC, Birrer P, Chernick MS, Caplan DB,Frank MM, Crystal RG. Aerosol alpha-1-antitrypsin treatment forcystic fibrosis. Lancet 1991; 337:392-394. [PubMed] A1-antitrypsin, the main inhibitor of neutrophil elastase, was given inaerosol form to 12 CF patients and found to suppress neutrophil elastase inrespiratory lining fluid and restore its anti-neutrophil elastase capacity.Also, the treatment reduced the reversed inhibitory effect of CF epitheliallining fluid on Pseudomonas killing. Apparently the material used in this trial (purified human plasma a1-antitrypsin - Prolastin, Cutter Biological) was very difficult to obtain insufficient quantities. A subsequent trial, with a genetically engineeredproduct which eventually became available, disappointingly failed to showsignificant benefit to patients and was not further developed as atreatment for cystic fibrosis (Martin SL, et al, 2006 below). However, someinterest continues in Germany and there may be further developments.

1991 Laroche D, Travert G. Abnormal frequency of delta F508 mutation in neonataltransitory hypertrypsinaemia Lancet 1991; 337:55. [PubMed] Neonatal CF screening programmes that involve DNA testing for CF mutations identify someinfants who are CF carriers. There was much discussion as to whether parents should be told theirinfant is a carrier of one CF mutation – most clinicians were quite firmly in favour of informing theparents. Most generally agreed that it was acceptable to detect CF carriers provided adequategenetic advice was provided to the parents and child bearing relatives for planning futurepregnancies now it was known that one of them may be a CF carrier.

1991 Malfroot A, Dab I. New insights on gastro-oesophageal reflux in cystic fibrosis bylongitudinal follow up. Arch Dis Child 1991; 66:1339-1345. [PubMed] Gastro oesophageal (GO) reflux was first described as a problem in CF by Jean Feigelson(Feigelson et al, 1975 above) and subsequently the problem was thought to be related toprogressive CF in older children. In this Belgian study 21 of 26 (81%) young children with CF agedless than 60 months were studied and 20 confirmed to have reflux by oesophageal pH tracings.Sixteen improved with anti-reflux treatment with improved weight gain, less cough and wheezebut half still had the reflux one year later. The authors concluded the reflux was not caused by theCF chest problems as it improved with time – at the same time as the CF gets worse – hence theirtitle “new insights into GO reflux”.

There was to be continuing interest in GO reflux both in respect to physiotherapy practices in CFinfants (Button et al, 1997 below) and in adults where GO reflux was shown to be frequent andimportant in exacerbating respiratory symptoms (Scott RB et al, 1985; Ledson MJ et al, 1998)particularly in relation to patients after lung transplantation (Button BM et al. J Heart LungTransplant 2005; 24:1522-1529). Newer techniques of oesophageal pH monitoring and alsofibreoptic endoscopy allowed more frequent recognition and more accurate diagnosis.

1991 Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas aeruginosainfection in cystic fibrosis by early treatment. Lancet 1991; 338:725-726. [PubMed] A randomised controlled trial from Copenhagen confirming that early P. aeruginosa infection couldbe eradicated in 80% of patients with CF by three weeks treatment with oral ciprofloxacin and


Figure 19: Dr. Christian Koch inthe clinic.

nebulised colistin. The infection became chronic in only 2 of 14 (14%) of treated patients but in 7of 12 (58%) of the controls. The authors comment - "Our results thus confirm and extend thepreliminary report by Littlewood et al, colleagues (1995 above) who used colistin inhalations Sincechronic colonisation with Ps aeruginosa is associated with increased morbidity and mortality werecommend the use of anti-Pseudomonas treatment whenever Ps aeruginosa is isolated from thesputum of cystic fibrosis patients"Even though the numbers were small and the patients not formally randomised, this was certainlyone of the most important papers of the decade and confirmed that early Pseudomonas infectioncould be eradicated with nebulised colomycin and oral ciprofloxacin. It is difficult to understandwhy this satisfactory trial from Copenhagen, which clearly contradicted the previous widely heldbelief that it was impossible to eradicate Pseudomonas once cultured, was not followed by thewidespread introduction of early eradication treatment for P. aeruginosa. Fortunately a few centresdid introduce early eradication treatment but they were a minority. The fact that early treatmentof Pseudomonas was so slow to be introduced in the UK and much of Europe (with notableexceptions) and was still not recommended in the USA over a decade after this report, wassurprising and still difficult to explain. It was predictable that these varied approaches to early treatment of Pseudomonas were reflectedgradually in the markedly different prevalence of chronic Pseudomonas infection in different CFcentres- this difference in the prevalence of chronic infection became increasingly obvious first inpaediatric patients as time progressed (Frederiksen et al, 1996; Lee et al, 2003; Lebecque et al,2006 all below).

In 1997 I had the good fortune to interview the late DrChristian Koch (figure 19), then the Medical Director ofthe Copenhagen CF centre, for a video. When I askedhim at the end of the day what aspect of CF treatment heregarded as the most important, he thought for sometime and then replied -

“When I look back on what we’ve done all through theyears that I’ve been involved with cystic fibrosis, I wouldsay that the early treatment of Pseudomonas is probablythe best thing that we have done for the patients. Itbecomes more and more clear that really whatdetermines the long term course is whether you getPseudomonas or not” .

It is of interest that even in 1998, reviewing the historyof Pseudomonas infection in people with CF, a highlyregarded US CF centre director wrote - “earlyadministration with aerosol colistin may delay colonisationwith P. aeruginosa. This intriguing observation has notbeen verified by prospective controlled studies” (RamseyBW. Pediatrics 1998; Supplement: 210-213) - even

though by this time early eradication of P. aeruginosa was widespread practice in Europe andalready supported by many publications in addition to that of Valerius et al, 1991 fromCopenhagen (Brett MM et al. Arch Dis Child 1992; 67:1066-1068; Frederiksen B et al, PediatrPulmonol 1997; 23:330-335; Weismann HG, et al. Pediatr Pulmonol 1998; 25:88-92; Ratjen F, etal. Lancet 2000; 358:983-984; Munck A et al. Pediatr Pulmonol 2001; 32:288-292).

1991 Hodson ME, Madden BP, Steven MH, Tsang VT, Yacoub MH. Non-invasivemechanical ventilation of CF patients – the bridge to transplantation. Eur Resp J 1991;4:524-7.[PubMed] This technique of non-invasive ventilation was developed as a direct result of attempting toprolong the survival of people with CF awaiting a heart-lung transplant at the Brompton Hospital –prior to the possibility of heart-lung transplantation assisted ventilation was usually regarded asinappropriate for people with CF in respiratory failure as their prognosis was uniformly bad. Thecase histories of six patients with CF using nasal ventilation while awaiting heart-lungtransplantation are reviewed; four patients did well.

This method of ventilation proved to be a useful bridge to transplantation when a patient suddenlydeteriorates. This is also a very cost effective method of ventilation and does not encroach onconventional Intensive Care Unit facilities.

1991 Morrison G, Morrison JM, Redmond AOR, Byers CA, McCormack KJ, Dodge JA,Guilford SA, Bowden MW. Comparison between a standard pancreatic supplement and ahigh enzyme preparation. Aliment Pharmacol Ther 1992; 6:549-555. [PubMed] First of a number of reports showing new “high strength” enzymes were effective. This studycompared the relative effectiveness of a standard pancreatic enzyme supplement ('Creon',Dumpcart) and a new high strength preparation ('Pancrease HL', Cilag) containing about 3 timesthe lipase and more than 5 times the protease activity. Capsule dosage was adjusted to a ratio ofapproximately 3 Creon to 1 Pancrease HL to provide similar intakes of lipase. Fat balances showedthat absorption of fat did not change significantly on conversion to the new high-lipase product,and the coefficient of absorption of total energy was similarly maintained. The coefficient of proteinabsorption was significantly enhanced with the high enzyme preparation (P < 0.01), which mayexplain the reported subjective improvement in stool odor. No adverse effects were recorded.Patient acceptability of the new compound was high; the great reduction in the number of capsules


Figure 20: Patient wearingthe vest.

Figure 21: ProfessorWarren Warwick. Author'sphoto in 2005.

required at each meal was cited by all patients as the reason for their preference.

Later reports associated fibrosing colonopathy with the use of Pancrease HL but not with the newhigh strength Creon 25,000.(Smyth et al, 1994) which some considered due to the presence of thecopolymer, eudragit, in the covering of all the new high strength enzymes other than Creon25,000.

1991 Hammond KB, Abman SH, Sokol RJ, Accurso FJ. Efficacy of statewide neonatalscreening for cystic fibrosis by assay of trypsinogen concentrations. N Eng J Med 1991;325:769-774. [PubMed] Keith Hammond was one of the early enthusiasts for neonatal CF screening and was thebiochemist involved with these screening studies from Denver, Colorado on 278,399 infants from1982 to 1987, using immunoreactive trypsin. They confirmed that the method was feasible andcould be implemented with acceptable rates of repeat testing and false positives and falsenegatives. 95% of infants with CF who did not have meconium ileus could be identified by thescreening method.

Many subsequent valuable reports have resulted from this Denver screening programme includingthe early bacteriologic and clinical course (Abman SH et al. J Pediatr 1991; 119:211-217), earlyrespiratory course (Accurso FJ et al. Pediatr Pulmonol Suppl 1991; 7:42-45), fat soluble vitaminstatus (Sokol RJ et al. Pediatr Pulmonol Suppl 1991; 7:52-55) and pancreatic and nutritional state(Bronstein MN et al. J Pediatr 1992; 120:533-540).

1991 Scott-Jupp R, Lama M, Tanner MS. Prevalence of liver disease in cystic fibrosis.Arch Dis Child 1991; 66:698-701. [PubMed] A search for the presence of liver disease among 524 patients with CF in the UK by Dr RobertScott-Jupp working with Prof. Stuart Tanner in Leicester; details of a further 576 patients wereobtained from databases. The overall prevalence of overt liver disease as indicated by thepresence of an enlarged liver or spleen (or both) was 4.2%. The age related prevalence rose to apeak in adolescence, and then fell in patients over 20 years old. The implied increase in mortalityamong those with liver disease was not explained by deaths from liver disease, which were rare.Male patients were significantly more affected than female, the ratio being 3:1 among adolescents.Increasing prevalence of liver disease in patients with cystic fibrosis was not just a result oflongevity.

1991 Warwick WJ, Hansen LG. The long-term effect of highfrequency chest compression therapy on pulmonarycomplications of cystic fibrosis. Pediatr Pulmonol 1991;11:265-271.[PubMed] A high-frequency chest compression (HFCC) device for clearanceof mucous secretions from airways was tested in 16 patients withCF with significant improvement in pulmonary function for theHFCC period, which averaged 22 months per patient. The deviceconsists of a variable air pulse delivery system and a non-stretchinflatable vest worn by the patient to cover the entire torso.Ninety-four percent of patients' regression line slopes for percentpredicted forced vital capacity (FVC) and forced expiratory volumein 1 second (FEV1) became more positive during self-administered HFCC therapy as compared to slopes before HFCCtherapy, when manual chest physical therapy was used.

Although this device (figure 20) has never found favour amongstphysical therapist in the UK, over the next 15 years “the vest”became popular and widely used in North America by some 60%of people with CF and by many others with chronic respiratorydisorders. The device has been pioneered by veteran CF centredirector Warren Warwick (figure 21) from Minnesota and hasbeen the subject of many subsequent publications showingcomparative efficiency with other forms of physiotherapy andimprovements with alterations in the wave form created. The firstreports on high frequency chest wall compression were from KingM et al.(Am Rev Respir Dis 1983; 128:511-515.[PubMed]; AmRev Respir Dis 1984; 130:703-706. [PubMed]).

1991 Chatfield S, Owen G, Ryley HC, Williams J, AlfahamM, Goodchild MC, Weller P. Neonatal screening for cysticfibrosis in Wales and the West Midlands: clinicalassessment after five years of screening. Arch Dis Child1991; 66:29-33. [PubMed]

A UK neonatal CF screening study, funded by the Cystic Fibrosis Trust, using measurement ofimmunoreactive trypsin, was undertaken in Wales (Mary Goodchild) and the West Midlands (PeterWeller) on alternate weeks for five years from 1985. Fifty eight infants, not considered to be atrisk of CF (i.e. they did not present with meconium ileus and did not have a sibling with cysticfibrosis) were detected by screening and were compared with 44 children born on the non-screening weeks whose CF was diagnosed clinically. The false negative rate in the screened groupwas a disappointing 13.4%. Predictably, the screened group were diagnosed earlier and spent lesstime in hospital. In other respects the groups were similar to the age of 4 years.


Figure 22 Dr Peter Weller.

Figure 23: Dr Henry Riley

Treatment of CF in 1985 in the UK was often undertaken at the local hospitals (Littlewood et al,1984 above, 1988 above and 1993 below) and half these children were only seen at their localhospitals by general paediatricians who had no particular expertise in CF – this was the major flawof this Wales & West Midlands study. However, the study did show that if clinical care was not of ahigh standard there was no advantage in neonatal diagnosis.

Subsequently this study was not considered to provide support for the introduction of nationalneonatal CF screening by the UK National Screening Committee.

There was a final report of this data from Cardiff by Iolo Doull (Doull IJ et al. Pediatr Pulmonol2001; 31:363-366). Eligible children with CF who died in the first five years of life were identifiedfrom the local paediatricians and from the National UK CF Survey. In all, 230,076 infants had beenscreened and 234,510 unscreened. 176 children with CF were identified, of whom seven died inthe first five years of life, three having presented with meconium ileus. Median age of diagnosis inthe screened group was eight weeks (this would not be regarded as acceptable now but DNAtesting was not available in addition to IRT until after 1990). On an intention to treat analysis, allfour non-meconium ileus-related deaths occurred in the unscreened group; however, the clinicalpresentation of two of these infants led to their being diagnosed prior to eight weeks, i.e., earlierthan would have been likely by screening as practiced in the study. The authors concluded thatnewborn screening has the potential to decrease infant CF deaths, but if it is to be successful,identification and treatment must occur as soon as possible after birth.

Eventually neonatal CF screening was agreed by the UK government in 2001 after the CysticFibrosis Trust made personal representation to Ms Yvette Cooper the then Health Minister. As aresult of the overwhelming pressure from the CF Trust and the whole CF professional and laycommunity rather than on the advice of the National Screening Committee that, even then, stillconsidered the evidence for screening inadequate even after the Government recommendation!The 2001 Farrell paper, which showed a long term nutritional advantage in the screened infants(Farrell et al, 2001; 107:1-13 below), was important in finally convincing the government tointroduce national neonatal CF screening. The major lessons from all this being that, of course neonatal diagnosis is essential but must befollowed by good CF care from the start to prevent irreversible malnutrition and chronic respiratoryinfection.

Dr Peter Weller (figure 22) was Director of the CF Centre at the Birmingham Children’s Hospitalfrom 1980 to 2007 and closely involved with this screening study. Dr Henry Riley, (figure 23) wasthe microbiologist from Cardiff, who was closely involved with this and many other studies on CFand also with the European CF Society.

1991 Warner JO. Heart-lung transplantation: allthe facts. Arch Dis Child 1991; 66:1013-1017.[PubMed] John Warner, then paediatrician at the BromptonHospital, London, wrote this cautionary article on heartlung transplantation as it applied to children in the UKand called for open discussion on the subject. His articlewas published alongside two papers on heart-lungtransplantation in children from Great Ormond Street(Whitehead B et al. Arch Dis Child 1991;66;1018-1021[PubMed] & Whitehead B et al, Arch Dis Child 1991;66:1022-1026.[PubMed] Of 27 children referred to GOSfor assessment of suitability for heart-lung transplant,10 (37%) were actually transplanted. Six were still alivefrom three months to three years after the operationbut two thirds of the cohort had died at various stagesduring referral, assessment, and transplant. Warner maintained that while the transplant has offeredmiraculous new life to a few children, many more haveexperienced increased and unnecessary suffering.Planning of transplant programmes must take all factsinto account. Also he emphasised that the possibility ofheart-lung transplant must not deter further efforts tocontrol chronic lung diseases medically and must notinfluence appropriate terminal care.These were early days for transplantation (the firstadults had only received transplants in 1984), andalthough there were some similar views, the latest beingin 2008, the outlook for children having transplantscontinued to improve although as for older patientsshortage of donor organs remained a problem.Figure 24: Sonny Laing’s CF was not diagnosed until shewas 18 months old when she was referred to Leeds bywhich time her lungs were irreparably severelydamaged. She was the youngest child with CF to receivea heart-lung transplant at Great Ormond Street, Londonwhen she was 5 years old. In the figure she is 15 yearsold, very well, active and a keen gymnast.


Figure 24: Sonny Laing aged 15years. Photograph kindly providedby the family.

Figure 25: Ann Littlewood with thisposter in Denmark at 1991European Working Group for CysticFibrosis.

1991 Littlewood AE, Bowler IM, Littlewood JM. Amethod of data collection and computerisation inuse at a regional CF unit. 17th European CysticFibrosis Conference Denmark. June 1991. Poster94. Much of the clinical research data and the smoothrunning of the Leeds CF clinic were dependent on theAdministrator Mrs Christine Silburn, and the clerks andsecretaries. The computer data management had been in operationsince the early Eighties using first a computer funded bythe Variety Club of Great Britain. Ann Littlewood (figure25) a state registered nurse (and my wife!), wasresponsible for the running of our data service from theearly Eighties until we both retired from clinical work in1997. The introduction of a Comprehensive CF Assessmentservice in Leeds from 1981 generated such vastamounts of data on every patient that computerisationbecame essential and was introduced in 1982. Thesystem, initially using an Epson PC AX with 80Mb harddisk and 640K using Symantec Q&A software, provideda database and word processing facilities. By 1991 fourdatabases were in use – a patient register, clinic visitdatabase, an inpatient database and an assessmentdatabase for the results of Comprehensive Assessments.The system had been repeatedly modified and adaptedover the next eight years by interested colleagues andprofessional computer programmers. The Leeds CF unitsare now totally computerised for both clinical andresearch purposes - a system developed by Dr DanielPeckham, Respiratory Physician on the Adult CF Unit.

1992 Madden BP, Hodson ME, Tsang V, Radley-Smith R, Khaghani A, Yacoub MY. Intermediateterm results of heart-lung transplantation forcystic fibrosis. Lancet 1992; 339:1583-1587.[PubMed]

Between 1984 and 1991 79 patients with CF had heart-lung transplantations in London by MrYacoub’s team with a 69% survival to 1 year, 52% to 2 yrs and 49% to 3 years. Cumulativeprobability of development of obliterative bronchitis was 17%, 23% and 48% at 1, 2, and 3 years.These were encouraging results but the authors noted serious shortage of donor organs – which in2008 was still a major problem in the UK (Penketh et al, 1987 above; Yacoub et al, 1990 above;Scott et al, 1988 above for first reports from Brompton and Harefields and Cambridge)

1992 Handyside AH, Lesko JG, Tarin JJ, Winston RM, Hughes MR. Birth of a normal girlafter in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis. NEngl J Med 1992; 327:905-909. [PubMed] Preimplantation genetic diagnosis of cystic fibrosis was attempted in three couples, both membersof which carried the delta F508 deletion. In vitro fertilization techniques were used to recoveroocytes from each woman and fertilize them with her husband's sperm. Three days afterinsemination, embryos in the cleavage stage underwent biopsy and removal of one or two cells forDNA amplification and analysis. Only two oocytes from one woman were fertilized normally; DNAanalysis of one of the embryos failed and cystic fibrosis was diagnosed in the other (i.e. it washomozygous for delta F508), so neither was transferred. The oocytes of each of the other twowomen produced non-carrier, carrier, and affected embryos. Both couples chose to have one non-carrier embryo and one carrier embryo transferred. One woman became pregnant and gave birthto a girl free of the deletion in both chromosomes.

This is the first report of preimplantation genetic diagnosis to identify the delta F508 deletioncausing cystic fibrosis using in vitro fertilization, biopsy of a cleavage-stage embryo, andamplification of DNA from single embryonic cells (also Handyside et al, 1988 above). Subsequentreports indicated an approximately 30% chance of a successful pregnancy after such an embryohad been implanted.p

1992 Anguiano A, Oates RD, Amos JA, Dean M, Gerrard B, Stewart C, Maher TA, WhiteMB, Milunsky A. Congenital bilateral absence of the vas deferens. A primarily genitalform of cystic fibrosis. JAMA 1992; 267:1794-1797. [PubMed] It had been suggested that otherwise healthy men with congenital bilateral absence of the vasdeferens (CBAVD), previously considered a distinct genetic entity, have an increased frequency ofCF gene mutations (Dumur V et al. Abnormal distribution of CF delta F508 allele in azospermicmen with congenital aplasia of epididymis and vas deferens. Lancet 1990; 336:512; Rigot JJM etal. Cystic fibrosis and congenital absence of the vas deferens. N Eng J Med 1991; 325:64-65). The


association was first suggested by Douglas Holsclaw (Holsclaw DS, et al. Congenital abnormalitesin male patients with cystic fibrosis. J Urol 1871; 106:568-574). The present report of 25unselected men with CBAVD found 16 (64%) had at least one detectable CF mutation, 16 timesthe expected frequency; 3 men were compound heterozygotes.

Some, if not all, otherwise healthy men with CBAVD reflect a newly recognized, primarily genital,phenotype of CF. A very important practical suggestion was that prior to sperm aspiration toremedy infertility, CF mutation analysis should be recommended for them and their partners, aswell as for their relatives. In a later study (Chillon M et al. NEJM 1995; 332:1475-1480) 19 of 102(18.6%) CBAVD patients had 2 CF mutations and none had the 5T allele. 54 had one copy and 34had the 5T allele in the other CFTR gene. 29 had no CF mutations but 7 of them had the 5T allele.So most men with CBAVD have mutations in the CFTR gene. The combination of the 5T allele inone copy of the CFTR gene with a cystic fibrosis mutation in the other copy is the most commoncause of CBAVD. The 5T allele mutation has a wide range of clinical presentations, occurring inpatients with CBAVD or moderate forms of cystic fibrosis and also in fertile men.

1992 Mennie ME, Gilfillan A, Compton M, Curtis L, Liston WA, Pullen I, Whyte DA, BrockDJH. Prenatal screening for cystic fibrosis. Lancet 1992; 340:214-216. [PubMed] This is the first report of antenatal couple screening for CF in the Edinburgh maternity hospitals. Of4348 women, 14% declined prenatal screening and 13% were not sreened for other reasons.Amongst 3165 women there were 111 carriers detected of whom four had carrier partners and all4 couples opted for prenatal diagnosis. One pregnancy with an affected fetus was terminated. Theimportance of adequate counselling was stressed.

Antenatal screening for CF became routine in Edinburgh but was eventually discontinued in 2005for various reasons including the improving prognosis for CF and also the introduction of neonatalscreening in Scotland (also Brock 1985 above; Livingstone et al, 1994 below). National antenatalCF carrier screening had not been introduced in the UK by 2009 although accepted in principle bythe UK National Screening Committee.

1992 Lanng S, Thorsteisson B, Nerup J, Koch C. Influence of the development ofdiabetes mellitus on the clinical status in patients with cystic fibrosis. Eur J Paediatr1992; 151:684-687. [PubMed] The first of a series of papers about CF related diabetes (CFRD) from Copenhagen and othercentres. The new and important message from this paper being that diabetes mellitus adverselyaffects progress for some time before it becomes clinically obvious. When diabetes develops in CFpatients, an insidious decline in overall clinical status is observed for some years prior to itsclinical diagnosis. Whether clinical deterioration in CF leads to DM, or pre-diabetes results indeclining CF clinical status is unclear. Accumulating evidence suggests that the latter may be thecase since insulin therapy seems to improve lung function in cystic fibrosis. The subject is reviewed in detail in the CF Trust’s consensus document “Management of CysticFibrosis related Diabetes Mellitus. June 2004 - the full text of which is on the CF Trust websitewww.cftrust.org.uk. This Danish study encouraged the introduction of the policy of searching for glucose intolerancewhen patients of 12 years and older were seen for their Annual Review - a policy agreed by most,but not all, CF physicians.

1992 Conway SP, Simmonds EJ, Littlewood JM. Acute severe deterioration in cysticfibrosis associated with influenza A virus infection. Thorax 1992; 47:112-114. [PubMed]The role of non-bacterial infection in respiratory exacerbations of cystic fibrosis has been studiedless than that of bacterial infection. Some non-bacterial infections, such as influenza A, may beassociated with acute respiratory deterioration and may be preventable. Three patients reportedhere had severe deterioration in their lung function and general wellbeing during the influenza Avirus epidemic in the winter of 1989-90. Although a Cochrane Systematic Review found no evidence that annual influenza vaccination forpeople with CF was effective, with experience such as the present report patients with cysticfibrosis are offered immunisation at the beginning of each influenza season. Rapid diagnostic testsand the use of antiviral drugs may have a prophylactic role in minimising lung damage.

1992 Kristidis P, Bozon D, Corey M, Markiewicz D, Rommens J, Tsui LC. Geneticdetermination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet 1992;50:1178-1184. [PubMed] A review of the association of so-called "mild" mutations with pancreatic sufficiency. Although themajority of CF mutations - including the most common, delta F508 - are strongly correlated withpancreatic insufficiency (PI), approximately 10% of the mutant alleles may confer pancreaticsufficiency (PS). To extend this observation, genomic DNA of 538 CF patients with well-documented pancreatic function status were analyzed for a series of known mutations in theirCFTR genes. A total of 30 different, complete genotypes could be determined in 394 (73%) of thepatients. The data showed that each genotype was associated only with PI or only with PS, but notwith both. This result is thus consistent with the hypothesis that PI and PS in CF are predisposedby the genotype at the CFTR locus; the PS phenotype occurs in patients who have one or two so-called mild CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas the PIphenotype occurs in patients with two severe alleles, such as delta F508, delta I507, Q493X,G542X, R553X, W1282X, 621 + 1G---- T, 1717-1G----A, 556delA, 3659delC, I148T, G480C,V520F, G551D, and R560T. This large study from Toronto strengthens the view that pancreaticfunction status in CF is genetically determined by specific mutations at the CF locus. Subsequentstudies established this beyond any doubt.


Figure 26: Dr Sarah Walters.

Figure 27: Professor John Govan.

Figure 28: Dr Ian Bowler (then theLeeds CF Research Fellow)undergoing indirect calorimetrymeasurements.

1992 Heeley AF, Bangert SK. The neonatal detection of cystic fibrosis by measurementof immunoreactive trypsin in blood. Ann Clin Biochem 1992; 29:361-376. [PubMed] Anthony Heeley has been a pioneer of neonatal CF screening in the UK. This is a detailed review ofthe situation at this time (also Green et al, 1993 below for Heeley’s East Anglian results; alsoCrossley et al, 1979 above).(Also comments after Crossley & Elliott 1979 above; Heeley et al,1982 above).

1993 Green MR, Weaver LT, Heeley AF, Nicholson K, Kuzemko JA, Barton DE, McMahonR, Payne SJ, Austin S, Yates JR, et al. Cystic fibrosis identified by neonatal screening:incidence, genotype, and early natural history. Arch Dis Child 1993; 68:464-467.[PubMed] This is the main report of the East Anglian neonatal CF screening programme. The incidence ofcystic fibrosis over the 10 years in East Anglia (a region of the United Kingdom with a populationof 2.1 million) had halved. Neonatal screening allowed early diagnosis, genetic counselling ofparents and relatives, and more recently the option of prenatal diagnosis in subsequentpregnancies. One hundred and seven children were born with cystic fibrosis between 1981 and1990, eight of whom were siblings. The Guthrie blood spots of the 82 infants detected by neonatalimmunoreactive trypsin screening between 1981 and 1990 were examined for the presence of themost common cystic fibrosis gene mutation (delta F508). It was present in 135 (82%) of the 164cystic fibrosis genes analysed with 54 (66%) cases being homozygous and 27 (33%)heterozygous. Sixty nine per cent of infants were symptomatic at the time of diagnosis regardlessof genotype. No association was found between the early clinical or biochemical features of thedisease and homozygosity or heterozygosity for this mutation.

Screening for CF using the blood immunoreactive trypsin assay alone remains an effective methodof identifying infants with the CF within the first weeks, thereby allowing early therapeuticintervention. Genetic counselling and prenatal diagnosis have contributed to a reduction in thenumber of children born with CF, but may not entirely explain the decreasing incidence of thedisease (also Heeley AF et al, 1982 above).

1993 Walters S, Britton J, Hodson ME.Demographic and social characteristics of adultswith cystic fibrosis in the United Kingdom. BMJ1993; 306:549-552. [PubMed] A survey of adults with CF in the UK by Dr SarahWalters, (figure 26) a Birmingham doctor who herselfhas CF, which gave a picture of the relatively new andexpanding population of adults with cystic fibrosis in theUK. 1052 adults were members of the Association ofCystic Fibrosis Adults UK, accounting for the majority ofadults. Most were living fulfilling lives. 26% of men and44% of women were married or cohabiting. 55% wereworking, fewer than 56% had less than two weeks' sickleave a year. Half of those not employed gave ill healthas the reason. Unfortunately, revealing that they had CFat job interviews reduced the likelihood of beingemployed for those with mild to moderate disease.People with CF had been less successful than thegeneral population in achieving O level or equivalentqualifications, but more successful in achieving A levelor higher qualifications. So contrary to an image of chronic ill health anddisability, a high proportion of adults with CF were livingfull and productive lives - marked contrast to some ofthe earlier reports of adults with CF.A further survey by Sarah Walters in 2000 showedconsiderable further improvement in many aspects ofthe condition and also the hospital care of the adultswith CF in the UK.

1993 Govan JR, Brown PH, Maddison J, Doherty CJ,Nelson JW, Dodd M, et al. Evidence fortransmission of Pseudomonas cepacia by socialcontact in cystic fibrosis Lancet 1993; 342:15-19.[PubMed] Prof. John Govan of Edinburgh (Figure 27) has for manyyears been a leading UK and international authority onCF microbiology. In this important paper he reported thedefinite transfer of B. cepacia infection between peoplewith CF which finally convinced most CF clinicians. Ananalysis of isolates from 210 patients attending regionalCF clinics in Edinburgh and Manchester between 1986and 1992 showed that the main cause of increasedisolations of P. cepacia from 1989 was the emergence ofan epidemic strain that had spread between patients inboth clinics. Epidemiological evidence indicated thatsocial contact was important in spread of the epidemic


Figure 27.1 Dr Ty Pitt

strain within and between clinics. Guidelines to limit theacquisition of B. cepacia should not be restricted topatients in hospital, and that intimate or frequent socialcontact is associated with a high risk of cross-infection. Following this important paper the UK CF Trust advisorygroup of clinicians and microbiologists advised that strictsegregation of B. cepacia-infected patients was essentialas some clinics, even in 1993, were not yet segregatingB. cepacia infected patients from others in the clinic.The widespread introduction of segregation from thistime led to a steady reduction in the incidence of new B.cepacia infections and a reduction in the prevalence ofchronic B. cepacia infections.

1993 Phillips RJ, Crock CM, Dillon MJ, Clayton PT, Curran A, Harper JI. Cystic fibrosispresenting as kwashiorkor with florid skin rash. Arch Dis Child 1993; 69:446-448.[PubMed] Two infants with a florid erythematous rash and generalised oedema, hypoalbuminaemia, andanaemia were found to have cystic fibrosis. This rare presentation is associated with false negativesweat tests, delays in diagnosis, and a considerable mortality. The authors suggested that thispresentation represents a manifestation of kwashiorkor secondary to intestinal malabsorption.

1993 Ranasinha C, Assoufi B, Shak S, Christiansen D, Fuchs H, Empey D, Geddes D,Hodson M. Efficacy and safety of short-term administration of aerosolised recombinanthuman DNase I in adults with stable stage cystic fibrosis. Lancet 1993; 342:199-202.[PubMed] A phase II trial of DNase (Pulmozyme) from the Brompton Hospital, London, in which the meanpercentage change in FEV1 from baseline was a 13.3% rise on rhDNase and only a 0.2% fall onplacebo (p < 0.001). There was an insignificant rise of FVC of 7.2% in the rhDNase group and2.3% in the placebo group. This study provided further confirmation that short-termadministration of rhDNase in stable patients with cystic fibrosis was safe and resulted in animpressive improvement in lung function (also Shak et al, 1990 above; Fuchs et al. 1994 below).

1993 Smith DL, Gumery LB, Smith EG, Stableforth DE, Kaufmann ME, Pitt TL. Epidemic ofPseudomonas cepacia in an adult cystic fibrosis Unit: Evidence of person-to-persontransmission. J Clin Microbiol 1993; 31:3017-3022. [PubMed]Report of transmission between patients in the Birmingham Adult CF Centre investigated incollaboration with Dr Ty Pitt of the Central Public Health Laboratory, London. Prevalence rose from1.4% in 1988 to 8.3% in 1992. At the time of writing five (30%) of the 17 affected patients haddied. In only two of the six patients referred to the CF centre had P. cepacia been identified beforereferral.

Dr Ty Pitt (fig 27.1) has been a central figure in understanding the microbiological aspects of cysticfibrosis collaborating closely with clinicians both at the Brompton Hospital in London and also withnational studies. Of particular importance was the national survey of CF centres revealingwidespread evidence of cross infection both within and between CF Centres in the UK (Scott andPitt, 2003. below).

1993 Bowler IM, Green JH, Wolfe SP, Littlewood JM. Resting energy expenditure andsubstrate oxidation rates in cystic fibrosis. Arch Dis Child 1993; 68:754-759. [PubMed] Ian Bowler (figure 28) coordinated this study on the resting energy expenditure (REE) andsubstrate oxidation rates in 16 patients with CF who had mild chest disease and 11 healthycontrols were measured using indirect calorimetry. The mean REE (% predicted) in the patientswith CF was 11% greater than in the controls. Five patients with CF were hypermetabolic but onlyone of these had a clinically significant reduction of respiratory function. A greater proportion ofREE was derived from carbohydrate oxidation in the CF patients (43.5% v 29.9%). However, the24 hour dietary intake of carbohydrate was greater in the cystic fibrosis group (49.6 v 45.8% ofenergy intake). These data suggest that a high dietary intake of carbohydrate may contribute tothe increased oxidation of carbohydrate in these CF patients. <1>1993 Littlewood JM. The value ofcomprehensive assessment and investigation in the management of cystic fibrosis. In ClinicalEcology of Cystic Fibrosis. H Escobar, CF Baquero Suarez (Eds). Elsevier Science Publishers.1993:181-187.[Conference publication]

This was a report of the 427 new patients seen at the Leeds CF centre for a Comprehensive CFAssessment between 1980 and 1992, 364 of whom had at least one follow-up assessment. Theywere referred from 10 hospitals in Yorkshire and a further 26 hospitals in the UK. The details oftheir management and condition are recorded and a comparison made between a previous 100referral between 1985 and 1987 and 100 new referral between 1988 and 1992 showingimprovement in their condition in a number of areas reflecting the general improvement in CF carein the UK (figure 29). The details give an idea of the condition of the patients at the time.See alsoLittlewood et al, 1984 above; Littlewood et al, 1988 above)


Figure 29.1 Dr Henry JFuchs. Fromwww.bmm.com

Figure 29: One hundred new referrals 1988 -1992. Previous 100 newreferrals 1985-1987 bracketed.

1994 Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW,Rosenstein BJ, Smith AL, Wohl ME. Effect of aerosolized recombinant human DNase onexacerbations of respiratory symptoms and on pulmonary function in patients withcystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994; 331:637-642. [PubMed]

Dr Henry J Fuchs, while working at Genentech from 1987 to 1996,led the clinical programme that resulted in the approval ofPulmozyme - one of the major clinical advances introduced duringthe Nineties. Dr Fuchs is now Senior Vice President and ChiefMedical Officer of Biomarin.This report, the main publication onrhDNase (Pulmozyme) describes a randomized, double-blind,placebo- controlled study to determine the effects of once-dailyand twice- daily administration of rhDNase on frequency ofexacerbations of respiratory symptoms requiring parenteralantibiotics and on pulmonary function. A total of 968 adults andchildren with cystic fibrosis were treated for 24 weeks asoutpatients. As compared with placebo, the administration ofrhDNase once daily and twice daily reduced the age-adjusted riskof respiratory exacerbations by 28 percent (P = 0.04) and 37percent (P < 0.01), respectively. The administration of rhDNase

once daily and twice daily improved forced expiratory volume in one second during the study by amean (+/- SD) of 5.8 +/- 0.7 and 5.6 +/- 0.7 percent, respectively. Transient voice alteration andlaryngitis were more frequent in the rhDNase-treated patients.

This was the definitive Phase III trial showing the significant effect of inhaled rhDNase – one of themost important large multicentre studies of the 1990s. Pulmozyme was undoubtedly one of themajor clinical advances of the decade and was licensed by the FDA in 1994 following this study.Regular treatment with DNase would become widely used (by almost 70% of people with CF onthe CFF registry by 2005) first amongst those with significant chest involvement and then later forthose with milder chest problems (Quann et al, 2001 below) and eventually, in some CF units forinfants. The cost (approximately £7000 per year) proved a problem in certain parts of the UK.(Also Shak et al, 1990 above; Ranasinha et al, 1993 above)

1994 Sawyer S, Bowes G, Phelan PD. Vulvovaginal candidiasis in young women withcystic fibrosis. BMJ 1994; 308:1609. [PubMed] Vulvovaginal candidiasis was more common in 55 women with CF than in controls (13 vs.4) andmore difficult to treat. Many women with CF had recognized the association of the Candidainfection with their use of antibiotics. The authors suggested women with CF should be givenroutine advice about the possibility of candidiasis.

This was an important paper as it is unlikely that women would be asked about such problems ina busy CF clinic for adults which are often “chest orientated” – yet adequate treatment of thecandidiasis would significantly improve the patient’s quality of life. Somewhat analogous to thisproblem was the later recognition of the increased incidence of urinary incontinence in women withCF (see Cornacchia et al, 2001).

1994 Super M, Schwarz MJ, Malone G, Roberts T, Haworth A, Dermody G. Active cascadescreening for carriers of cystic fibrosis gene. BMJ 1994; 308:1462-1467. [PubMed]Dr Maurice Super (1936-2006) (figure 30) first encountered CF in Windhoek in South West Africa(Namibia) in 1967 where he started a CF clinic. He subsequently became a leading geneticist andpaediatrician in the UK working in Manchester. He was a major protagonist of carrier screening inthe extended families of people with cystic fibrosis – so-called “cascade screening”. The presentpaper describes 15 carrier couples detected out of 1563 relatives of people with CF who weretested; eight had prenatal tests and three pregnancies were terminated. An average of 16 peopleper family had been tested. Cascade screening was acceptable to relatives, particularly on themother’s side of the family and 10 times more successful in detecting carrier couples thanunfocused screening. <


Figure 30: Dr Maurice Super.

The genetic testing of all child-bearing relatives of a person with CF is now provided by the UKNHS if the individuals wish to be tested.

1994 Arens R, Gozal D, Omlin KJ, Vega J, Boyd KP,Keens TG, Woo MS. Comparison of high frequency chestcompression and conventional physiotherapy inhospitalized patients with cystic fibrosis. Am J Res CritCare 1994; 150:1154-1157. [PubMed] A study of 50 people with CF admitted for acute pulmonaryexacerbations that were randomly allocated to receive eitherhigh frequency chest compression (HFCC) or conventionalphysiotherapy (CPT) three times a day. After seven and 14days of treatment, improvements were similar in the two studygroups, leading to patient discharge after similar periods ofhospitalization. The authors concluded that HFCC and CPT areequally safe and effective when used during acute pulmonaryexacerbations in CF patients. They suggested that HFCC mayprovide an adequate alternative in management of CF patientsin a hospital setting. (Also Warwick WJ, Hansen LG, 1991above)

1994 Livingstone J, Axton RA, Gilfillan A, Mennie M,Compton M, Liston WA, Liston WA, Calder AA, Gordon

AJ, Brock DJ. Antenatal screening for cystic fibrosis: a trial of the couple model. BMJ1994; 308:1459-1462. [PubMed] The second report of antenatal screening of 8536 couples in Edinburgh. 8.4% were “ineligible”,1900 declined screening for various reasons and 5922 (69.4%) were screened. There were fourpositives (i.e. both partners were CF carrier heterozygotes) and all four couples opted for prenataldiagnosis. There were three terminations where the fetus was affected and one couple elected tohave the CF infant. There was 99% satisfaction by those screened.

Antenatal CF screening was pioneered in Edinburgh by David Brock and his colleagues and this isone of the first reports (also Mennie et al, 1992 first report above). Screening was introduced intothe two Edinburgh trial hospitals following this report. However, the service was eventuallydiscontinued in 2005 soon after neonatal CF screening was introduced into Scotland. As theoutlook for CF improved parental attitudes changed to antenatal diagnosis and termination, alsothe mutations tested differed from the neonatal ones, and finally funding for both antenatal andneonatal screening was inadequate. It has been estimated from various studies that for every CFfetus detected by antenatal screening the cost is between £50K and £100K.

1994 Walters S, Britton J, Hodson ME. Hospital care for adults with cystic fibrosis: anoverview and comparison between special cystic fibrosis clinics and general clinics usinga patient questionnaire. Thorax 1994; 49:300-306. [PubMed] Another study from Sarah Walters on this occasion to assess the current pattern of medical servicereceived by adults with CF in the UK and to compare the type of care between special CF centresand general clinics. Two thirds of the patients were attending special CF centres for either adults oradults and children. Significant differences between cystic fibrosis and general clinics were noted.Patients attending special cystic fibrosis clinics were more likely to have had simple clinicalinvestigations (blood tests, sputum culture, oxygen saturation, chest radiography, weight and lungfunction measurement) in the previous year. They were also more likely to have receivedintravenous antibiotics at home, and to have access to paramedical personnel. Patients attendingcystic fibrosis clinics were taking higher doses of pancreatic enzyme supplements with respect toquantity and potency of preparation. Such patients also had less severe symptoms irrespective ofsocial class, and were more likely to be satisfied with professional aspects of their care. Regardlessof type of clinic, potential deficiencies were identified in overall medical care with omission ofclinical investigations in severely affected patients and evidence of under treated respiratory anddigestive symptoms in patients with moderate and severe disease. This survey provides evidence that adults with cystic fibrosis attending special cystic fibrosis clinicsat that time received more intensive care, had better symptom control, and are more satisfiedwith the service provided than those attending general chest clinics. The introduction of CF centrecare was slow in the UK and was opposed by some consultants working in general hospitals with afew CF patients. Even in 2008 there was still considerable discussion about the best carearrangements for people with CF. It is recommended by all CF organisations including the UK CFTrust that all adults with CF should receive all their medical care at a specialist CF Centre foradults.

1994 Weaver LT, Green MG, Nicholson K, Mills J, Heeley ME, Kuzemko JA, et al.Prognosis in cystic fibrosis treated with continuous flucloxacillin for the neonatal period.Arch Dis Child 1994; 70:84-89. [PubMed] This study from East Anglia provided satisfactory evidence for most people that regularprophylactic flucloxacillin during the first two years in 38 screened CF infants was associated withless cough, fewer Staphylococcus aureus isolates, a lower hospital admission rates (19 versus 5)and for shorter periods (6.4 versus 2.2 days) and the need for only half the number of additionalantibiotics. The study was possible as neonatal screening had been introduced into East Anglia byAnthony Heeley and his colleagues in 1981 – the first IRT screening in the UK ( Heeley et al, 1982above).


Figure 30.1: ProfessorLawrence Weaver.

Prophylactic anti-Staphylococcal therapy had been recommended many years ago by DavidLawson, paediatrician at Carshalton, London and was routine practice in some large CF centres inthe UK, from the mid-Seventies. Evidence from this trial provided a basis for the CF TrustAntibiotic Group's recommendations in 2002 (and later in 2009) for all infants with CF to receivecontinuous flucloxacillin for the first 2 years; in fact the first 3 years was recommended in 2009. Arguments continued for the next decade as to whether this treatment increased the likelihood ofPseudomonas infection – this was not the case in centres where early eradication of Pseudomonashad been practiced since the early Eighties but probably was the case in the USA where earlyeradication of Pseudomonas was not routine practice. As an alternative to long term flucloxacillin,the levels of chronic S. aureus infection can also be reduced by early active treatment wheneverthe organism was cultured as shown in Copenhagen by Szaff and Hoiby (Szaff & Hoiby, 1981above). It is important to note that in Copenhagen respiratory cultures are performed every monthso S. aureus is detected at an early stage when it can be eradicated; as with P. aeruginosa, onceallowed to become chronic eradication is difficult if not impossible.The very high prevalence of chronic S. aureus infection reported in recent CF Registry figures (inup to 50% of patients) and from a number of countries, including the UK, is surprising consideringthat S. aureus was the main cause of death in the early years and is still associated with a definiteinflammatory response as shown in bronchoscopic studies of young CF infants (Armstrong et al,1995 below).

Professor Lawrence Weaver (figure 30.1) is Professor of Child Healthin Glasgow and paediatrician at the Royal Hospital for Sick ChildrenGlasgow. The present research, on the neonatal screened infantsfrom East Anglia, was carried out when he was working at the MRCDunn Nutrition Unit

1994 Green MR, Weaver LT. Early and late outcome of cysticfibrosis screening. J R Soc Med 1994; 87 (Suppl 21): 5-10.[PubMed] More data from the East Anglian screened CF infants. During thedecade although the birth rate in the region had increased, theincidence of CF had halved. Early detection of CF by neonatalscreening allows genotyping of infant and family. It also offersparents of an affected child the opportunity of counselling beforefurther pregnancies and if desired subsequent antenatal testing. Soboth neonatal and antenatal CF screening (Cunningham et al, 1998

below) appear to reduce the incidence of CF. This has been the experience in a number of regionsbut not all – for example Colorado.

1994 Smyth RL, van Velzen D, Smyth AR, Lloyd DA, Heaf DP. Strictures of the ascendingcolon in cystic fibrosis and high strength pancreatic enzymes. Lancet 1994; 343:85-86.[PubMed] The first report of fibrosing colonopathy – a new, unexpected and serious complicationsubsequently shown to be related to the use of the new high strength pancreatic enzymepreparations that had been introduced during the previous 2 years (Pancrease HL, Creon 25,000,Nutrizym 22). The authors observed five children with CF, who presented over a period of twomonths, with meconium ileus equivalent that failed to respond to medical management. Atsurgery, four had a stricture in the ascending colon (figure 31 similar), and all hadhistopathological changes of post-ischemic ulceration repair, with mucosal and submucosal fibrosis(figure 31). The only common change in the management of these children had been a switchfrom conventional enteric-coated pancreatic enzymes to a high-strength product between 12 and15 months before presentation

A subsequent case controlled study from these authors (Smyth et al, 1995 below) showed asignificant correlation with both a high enzyme dose and the make of preparation – only thoseenzymes containing a covering of the copolymer eudragit being implicated. A similar study fromthe USA confirmed the association with high enzyme dosage but not with the copolymer covering(Freiman JP, FitzSimmons SC. Colonic strictures in patients with cystic fibrosis: results of a surveyof 114 cystic fibrosis care centers in the United States. J Pediatr Gastroenterol Nutr 1996; 22:153-156). [PubMed] However, no further cases were reported or have been since reported, in patientstaking the high strength Creon 25,000 preparation (which does not contain eudragit) even whengiven for 3 years in high doses to children (Connett et al, 1999 below). In the UK the recommendations of the Committee on Safety of Medicines to avoid doses ofenzymes in excess of 10,000 IU lipase per kg day and preparations containing the copolymereudragit in children, abolished the condition in the UK although a few cases continued to occur inthe USA. The enzyme content of the various preparations are described in detail elsewhere(Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of malabsorption in cystic fibrosis.[PubMed]


Figure 32: Partial fibrosing colonopathyshowing narrowing of the ascending colonwhich did not progress after the highstrength enzyme preparation (PancreaseHL), containing the copolymer eudragit,was stopped

Figure 31: Fibrosing colonopathy.Barium enema and histology of thecolon.

1994 Wilfond BS, Farrell PM, Laxova A, Mischler E. Severe hemolytic anemia associatedwith vitamin E deficiency in infants with cystic fibrosis. Implications for neonatalscreening. Clin Pediatr 1994; 33:2-7. [PubMed] Three infants with CF and malnutrition leading to severe anemia beginning as early as six weeks ofage. They had high reticulocyte counts, negative Coombs' tests, abnormal peroxide haemolysistest results, and biochemical evidence of vitamin E deficiency. Oral administration of alpha-tocopherol resulted in rapid correction of the laboratory abnormalities. Phillip Farrell has published extensively on vitamin E deficiency both in premature infants andthose with CF (see Farrell et al, J Clin Invest 1977; 60:233-241 above). This report emphasisesthe early onset of fat soluble vitamin deficiencies in infants with CF as also found in the Coloradoscreened infants (Sokol et al, 1991 above)

1994 Conway SP, Pond MN, Bowler I, Smith DL, Simmonds EJ, Joannes DN, HambletonG, Hiller EJ, Stableforth DE, Weller P, Littlewood JM. The chest radiograph in cysticfibrosis: a new scoring system compared with the Chrispin-Norman and Brasfield scores.Thorax 1994; 49:860-862.[PubMed]A chest X-ray score devised and evaluated by members of the Northern CF Club (NCFC) (figure33) – an informal group of senior paediatricians and respiratory physicians treating increasingnumbers of children with CF in the North of England. The group was formed in the mid-Eighties byJim Littlewood to discuss difficult clinical problems encountered with increasing frequency by thoseof us responsible for treating people with cystic fibrosis. The initial format of the meeting was tomeet at the Cottons Hotel in Cheshire to discuss specific patients during the late afternoon andevening. It was essentially a mutual support group fro clinicians to help each other to decide thebest treatment for some of these problems which many of us were encountering

Figure 33: Some of the original members of the NCFC in 1985outside the Cottons Hotel in Knutsford, Cheshire. Left to right;Pharmaceutical firm representative (PFR), PFR, Tim David(Manchester), PFR, Kevin Webb (Manchester), John Gilbert(Leeds), David Heaf (Liverpool), Richard Page (Leeds), JerryKelleher (Leeds), Bob Nelson (Newcastle), Gary Hambleton(Manchester), Jim Littlewood (Leeds).

“Northern X-ray Score” is now used routinely in many CF centres in the UK and the authorssuggested it - “fulfils the requirements of a chest radiograph score more successfully than theChrispin-Norman or Brasfield systems and does not require a lateral film” – hence reducing


Figure:34: Dr CarolynBeardsmore.www.academicmedicne.ac.uk

considerably the irradiation to the patient. So the published research output of our Northern CFClub was quality not quantity; but countless patients benefited from the advice their

1994 Beardsmore CS, Thompson JR, Williams A,McCardle EK, Gregory GA, Weaver LT, Simpson H.Pulmonary function in infants with cystic fibrosis: effectof antibiotic treatment. Arch Dis Child 1994; 71:133-137. [PubMed] Children from the East Anglian neonatal screening programme(1985-1992) who were included in the flucloxacillin trial(Weaver et al, 1994 above) underwent infant respiratoryfunction tests at three to four months and one year of age(measurements of thoracic gas volume and airway conductanceusing an infant whole body plethysmograph and maximumexpiratory flow by the “squeeze” technique). There was nodifference in lung function between the flucloxacillin treatedinfants and the control CF infants at any age. Dr Carolyn Beardsmore (figure 34) was one of the few expertsin infant lung testing at the time in the UK and since haspublished

Periodically studies are published on infant respiratory function testing but the techniques are socomplicated and time-consuming that they are usually only performed by the authors of thepapers. Although valuable for research they have never been of great practical value in the clinicfor most patients. In the present study it is not surprising that there was no difference betweenthe treated and control infants as some hyperinflation is present in all CF infants from early infancywhether they are infected or not. Hyperinflation in most CF infants was confirmed in subsequentstudies (Ranganathan et al, 2001 below).

1994 Konstan MW, Hilliard KA, Norvell TM, Berger M. Bronchoalveolar lavage findings incystic fibrosis patients with stable clinically mild lung disease suggest ongoing infectionand inflammation. Am J Respir Crit Care med 1994; 150:448-454. [PubMed] A rather surprising study on 18 patients which appears to demonstrate the obvious i.e. thatbronchiolar alveolar lavage in adolescents, who were all chronically infected with P. aeruginosa, S.aureus and/or H. influenzae reveals evidence of ongoing inflammation. It would have beensurprising if it had not revealed evidence of inflammation. The authors conclude “there issignificant ongoing infection and inflammation in the airways of CF patients with clinically mild lungdisease (FEV1 79%+/- 4%) and suggest a more aggressive intervention might preserve their lungfunction for few of these patient had received recent IV antibiotics (nine never and five not in thepast three years) and there is no mention of their taking

The unfortunate use of the term “colonised” is evident from this study – repeated positive culturesindicates that there is certainly “chronic infection” of tissue, which also would have been evidentfrom serum antibody studies and by the presence of inflammatory markers in the airways. Theauthors’ conclusions that “intervention aimed at reducing ongoing infection and destructiveinflammatory response might be beneficial even when patients do not have signs and symptoms ofacute exacerbations” – is a policy already adopted by the Danish CF centre since the early Eightiesand by many CF centres in the UK and Europe for many years. This does highlight the markeddifferences in approach between different CF centres and countries.

1995 Gan K-H, Geus WP, Bakker W, Lamers CBHW, Heijerman HGM. Genetic and clinicalfeatures of patients with cystic fibrosis diagnosis after the age of 16 years. Thorax1995; 50:1301-1304. [PubMed] Predictably, adult patients with late diagnosis have a better prognosis. The differences between theearly diagnosis of 4.6 years (ED) and late diagnosis 27.7 years (LD) were FEV1 52% vs 72.5%;Pseudomonas infection in 70% vs 24%; pancreatic insufficiency 81% vs 12%; homozygous forDF508 58% vs none.

In other series of adults with CF many have been diagnosed late and had other featuressuggesting many had milder mutations – supported by the high frequency of pancreaticsufficiency. However, it has been emphasised that these patients require just as careful follow upand treatment as those with the more usual clinical picture - rather than waiting until they developmore obvious chest symptoms (Lording A, et al. Pulmonary infection in mild variant cystic fibrosis:implications [PubMed]

1995 Gan, K H. Veeze, H J. van den Ouweland, A M. Halley, D J. Scheffer, H. van derHout, A. Overbeek, S E. de Jongste, J C. Bakker, W. Heijerman, H G. A cystic fibrosismutation associated with mild lung disease. New Eng J Med 1995; 333:95-99. [PubMed] Among Dutch patients A455E the second most common mutation and associated with preservedpancreatic function and some residual secretion of chloride across membranes. Thirty threepatients with compound heterozygosity for the A455E mutation were compared with matchedcontrols homozygous for the delta F508 mutation. In those with the A455E mutation diagnosis waslater (mean age at diagnosis, 15.0 vs. 3.1 years; P < 0.001); fewer had pancreatic insufficiency(21.2 percent vs. 93.9 percent, P < 0.001), and none had diabetes mellitus (0 percent vs. 27.3percent, P = 0.004). FEV1 and FVC were significantly higher (FEV1, 73.9 vs. 54.3 % predicted P =0.002) and FVC, 88.7 vs. 76.3 % predicted P = 0.04). Fewer had chronic pseudomonas infection(33.3 vs. 60.6 % P = 0.02). Although several mutations were known to be associated with less


Fig: 34.1 Dr Harry Heijerman

Figure 35: Professor.Ros Smyth. FromUniversity of Liverpoolwebsite.

Figure 36: ProfessorArchie Cochrane. Fromthe Cochrane website.

severe pancreatic disease, these findings showed a correlation between the A455E mutation andmild pulmonary disease resulting in a better

Dr Harry Heijerman (figure 34.1) was the Founding Editor ofthe Journal of Cystic Fibrosis. Under his guidance the journalwas increasingly successful; the editorship was taken over byProf. Gerd Döring in 2006 (see 2002 Journal of Cystic Fibrosisbelow). Harry Heijerman is Physician at Haga Teaching Hospital, DebHaag in the Netherlands and a leading figure in CF care andresearch in Europe.

1995 The Cystic Fibrosis and Genetic Disorders Group isa Collaborative Review Group (CRG) of The CochraneCollaboration and was formed in 1995.

This Cochrane group for CF was formed in 1995 and was expanded to cover other geneticdisorders in 1997. It consists of a team led by Prof. Ros Smyth of Liverpool (figure 35) who areinterested in producing high quality Systematic Reviews of controlled clinical trials in CF and, since1997, other genetic disorders. Initially supported by the UK CF Trust, the group is now supportedby the NHS R&D (UK). Reviewers undertake the work on a voluntary basis and by 2008 therewere over 70 Systematic Reviews on various aspects of treatment. Almost all the reviews highlightthe lack of controlled trials on many aspects of treatment; however, the information fromsystematic reviews published on the website has proved an increasingly valuable source ofinformation for those dealing with CF – even though the stringent standards of the Reviewers onoccasion have proved irritating to some elderly clinicians! Undoubtedly Ros Smyth and the Grouphave had a major and favourable influence on the number and standards of clinical trials whichhave favourably influenced the management of people with CF.

Professor Archie Cochrane (1908-1988) (figure 36) was born inKirklands, Galashiels, Scotland. He qualified in 1938 at UniversityCollege Hospital, London, and joined the Medical Research Council'sPneumoconiosis Unit at Llandough Hospital, a part of CardiffUniversity School of Medicine in 1948. Here he began a series ofstudies on the health of the population of Rhondda Fach — studieswhich pioneered the use of randomised controlled trials. His 1971Rock Carling monograph Effectiveness and Efficiency: RandomReflections of Health Services was very influential. These ideas andhis advocacy of randomized controlled trials eventually led to thedevelopment of the Cochrane Library database of systematicreviews, the establishment of the UK Cochrane Centre in Oxford andthe international Cochrane Collaboration (from Cochrane website).

1995 Armstrong DS, Grimwood K, Carzino R, Carlin JB,Olinsky, Phelan PD. Lower respiratory infection andinflammation in infants with newly diagnosed cystic fibrosis.BMJ 1995; 310:1571-1572.[PubMed] An important study from Melbourne documenting the early onset ofinfection in screened infants with CF who, incidentally, were nottreated with long term anti-Staphylococcal antibiotics. Forty fiveinfants (32 screened and 12 with meconium ileus) hadbronchoalveolar lavage at a mean age of 2.6 months. Sixteen(36%) already had respiratory symptoms and seven were receivingantibiotics at the time, although long term flucloxacillin was notroutine policy. Already lower respiratory infection, usually with S.aureus, was present in almost 40% (17/45) of these young CFinfants of whom a third were symptom free. Follow up showed P.aeruginosa to be present in some infants as early as 4 months.

I believe this study lends strong support to the use of long termanti-Staphylococcal flucloxacillin, at least for the first 2 or 3 yearsas recommend by the UK CF Trust’s Antibiotic Group in both 2002and 2009 (full text on CF Trust website); also this policy issupported by the trial of Weaver et al.1994 (above).

1995 Bowler IM, Kelman B, Worthington D, Littlewood JM,Watson A, Conway SP, Smye SW, James SL, Sheldon TA.Nebulised amiloride in respiratory exacerbations of cysticfibrosis: a randomised controlled trial. Arch Dis Child 1995;73:427-430. [PubMed] As a result of Michael Knowles’s amiloride trial (Knowles et al, 1990

above), we assessed the benefit of nebulised amiloride added to the standard treatment of arespiratory exacerbation in people with cystic fibrosis. We performed a prospective, randomised,double blind, placebo controlled trial with 27 patients (mean age 12.8 years) in two hospitals inLeeds, UK. Both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)showed improvements over the course of treatment as would be expected but there was nodifference in respiratory function between the two groups at any of three time periods during thestudy. However, the time to reach peak FVC was significantly reduced in the amiloride group (4.2


v 7.6 days; 95% CI 0.4 to 6.4 days), but not in the time to reach peak FEV1 (5.7 v 7.9 days;95% CI -1.2 to 5.6 days). Amiloride did not result in a greater overall improvement in respiratoryfunction.

On the modest results of this trial we did not introduce amiloride into the treatment regimen forexacerbations. Apparently the duration of action of amiloride is so very short to the extent that itwould be unlikely to have a significant beneficial effect. (Also negative trials by Graham et al EurRespir J 1993; 6:1243-1248; Pons G et al, Pediatr Pulmonol 2000; 30:25-31). Eventually morepotent and more durable ENaC blockers were synthesised e.g. compound 552-02 which was up to100 fold more potent and had a 170 fold slower fall off of effect (Hirsch AJ, et al. J Pharmacol ExpTher 2008; 325:77-88).

1995 Smyth RL, Ashby D, O'Hea U, Burrows E. Lewis P. van Velzen D. Dodge JA.Fibrosing colonopathy in cystic fibrosis. Results of a case controlled study. Lancet 1995;346:1247-1251. [PubMed] Fibrosing colonopathy was first described in children with CF in 1994 (Smyth et al, 1994 above).This study confirmed the relationship between fibrosing colonopathy and high doses of lipase andthe relation of fibrosing colonopathy with certain brands of high strength enzymes, whichcontained a copolymer – Eudragit. This is a report of a nested case-control study to identifypossible associations with this condition. A case ascertainment within the UK CF population toidentify any cases that had occurred between January, 1984, and April, 1994, revealed 14 cases,all less than 14 years and all confirmed by independent histopathological review. All had presentedsince April, 1993; 12 were boys and six had received some or all of their care in Liverpool. Eachchild was matched, by date of birth, with four controls from the UK CF Registry. Information wasobtained about the cases and the controls from their case records and by a structured interviewwith the families. In the 12 months before surgery, there was a dose related association betweenthe occurrence of fibrosing colonopathy and use of high-strength pancreatic enzyme preparations.Odds ratio per extra 1000 high-strength capsules was 1.45 (95% CI 1.14-1.84). For use ofprotease, the odds ratio per million extra units per kg was 1.55 (1.19-2.03). For usage ofindividual high-strength products at any time during the 12 months before surgery somedifferences were observed; for Creon 25000 the odds ratio was 0.38 (0.10-1.42), for Nutrizym 22it was 43.4 (2.51-751), and for Pancrease HL 8.4 (1.95-36.1). These last two confidence intervalsare extremely wide and compatible with these two products having the same odds ratios. Laxativeuse was independently predictive (odds ratio 2.42 [1.20-4.94]). The authors concluded that therewas a definite dose-related association between high-strength pancreatic enzyme preparations andfibrosing colonopathy. (Also Fibrosing colonopathy in children with cystic fibrosis. Proceedings of aconference in Manchester organised by the Cystic Fibrosis Trust, 5th Nov. 1995. Littlewood JM,Hind CRK (eds). Postgrad Med J 1996; 72 (Suppl 2):S1-S64).

1995 Pamucku A, Bush A, Buchdahl R. Effects of Pseudomonas aeruginosa colonisationon lung function and anthropomorphic variables in children with cystic fibrosis. PediatrPulmonol 1995; 19:10-15. [PubMed] Sixty two children with CF had three or more Annual Assessments of their lung function at theBrompton Hospital, London. Despite optimal pulmonary management children who were chronicallyinfected with P. aeruginosa deteriorated significantly faster than those not so infected. The term “chronically infected” would have been preferable to the term “colonised” used in thispaper.

This is one of a number of valuable studies confirming an increasing rate of pulmonarydeterioration following the onset of chronic Pseudomonas infection – an event which has beenaptly described as “The point of no return” (Drittanti et al,1997 below). There are other studiesconfirming the importance of avoiding chronic Pseudomonas infection (Kerem E et al, J Pediatr1990; 116::714-719; Henry RL et al. Pediatr Pulmonol 1992;12:158-161; Hudson VL et al. JPediatr 1993; 122:854-860; CF Foundation Registry, 1996; Frederiksen B et al. Pediatr Pulmonol1997;21:153-158; Kosorok MR et al, Pediatr Pulmonol 2001; 32:277-287).

1995 Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high dose ibuprofen inpatients with cystic fibrosis. N Engl J Med 1995; 332:848-854. [PubMed] This was a major study funded by the CF Foundation to determine the benefits of treatinginflammation in the CF airways with long term oral ibuprofen. A double-blind trial involving 85patients, five to 39 years of age, with mild lung disease who received oral ibuprofen or placebotwice daily for four years in doses to achieve peak plasma concentrations of 50 to 100 microgramsper ml. The patients on ibuprofen had a slower annual rate of change in FEV1 than the patientsassigned to placebo (mean [+/- SE] slope, -2.17 +/- 0.57 percent vs. -3.60 +/- 0.55 percent inthe placebo group; P = 0.02), and weight (as a percentage of ideal body weight) was bettermaintained in the former group (P = 0.02). Among the patients who took ibuprofen for four yearsand had at least a 70 percent rate of compliance, the annual rate of change in FEV1 was evenslower (-1.48 +/- 0.69 percent vs. -3.57 +/- 0.65 percent in the placebo group, P = 0.03), andthis group of patients also had a significantly slower rate of decline in forced vital capacity, thepercentage of ideal body weight, and the chest-radiograph score. There was no significantdifference between the ibuprofen and placebo groups in the frequency of hospitalization. Onepatient was withdrawn from the study because of conjunctivitis, and one because of epistaxisrelated to ibuprofen. The authors concluded that in patients with CF and “mild” lung disease, high-dose ibuprofen, taken consistently for four years, significantly slows the progression of the lungdisease without serious adverse effects.

Despite these results, the benefits of ibuprofen in this trial were not convincing to most clinicians.


Figure 37: ProfessorMichael Konstan

Figure 38: Dr JeffWagener.

Subsequently the modest effect and frequent side effects prevented the widespread use ofibuprofen and the treatment never became popular even in the United States – only some 5% ofpatients on the CF Foundation’s registry reported taking the drug. For example Fennell PB et al (JCyst Fibros 2007; 6:153-158) reported half their patients stopped ibuprofen because of sideeffects (mainly gastrointestinal pain and bleeding) and the treatment had no effect on either therate of pulmonary decline or hospitalisation rates in those who tolerated the drug. Yet subsequent reports from Michael Konstan remained supportive (Konstan MW et al, Am J RespCrit Care Med 2007; 176:1084-1089) and Larry Land’s separate Canadian study showed slowerFVC but not FEV1 decline (Lands LC et al. J Pediatr 2007; 151:249-254). An interesting and unrelated observational report suggested the recurrence of nasal polyps wasreduced while patients were receiving ibuprofen (Lindstrom DR et al J Otolaryngol 2007; 36:309-314). So few clinicians in the UK now advise using ibuprofen.

Professor Michael Konstan (figure 37) is Director of the Leroy Matthews Cystic fibrosis Centre,Cleveland and particularly identified as being associated with this study. He is a leading figureinvolved in CF in the USA and heavily involved in both research and patient

1995 Khan TZ, Wagener JS, Boast T, Martinez J, Accurso FJ,Riches DWH. Early pulmonary inflammation in infants withcystic fibrosis. Am J Respir Crit Care Med 1995; 151:1075-1082. [PubMed] This paper from Denver is frequently quoted as providing evidenceof the presence of inflammation in the airways in the absence ofinfection. Bronchoalveolar lavage fluid (BALF) from 16 infants withCF and 11 disease control infants was examined for a variety ofinflammatory parameters. Each index of airway inflammation wasincreased in the BALF of infants with CF as compared with controlinfants – including those with negative microbiological cultures forcommon CF-related pathogens, common respiratory viruses andfungi at the time of bronchoalveolar lavage (BAL). The authorsconcluded that these findings suggested that airway inflammationwas already present in infants with CF as young as four weeks. However the authors did not know if the seven infants withevidence of inflammation but negative cultures had receivedtreatment previously for infections from their own paediatriciansprior to being referred for bronchoscopy i.e. was there residualinflammation from a previous bacterial infection? The number withpositive lower respiratory tract cultures was high (9/17) althoughthe care of some infants was with the local referring paediatriciannot the authors.

Although, from other publications, it seems very likely that there isa tendency to an excessive inflammatory response in the CFairways, it is doubtful if this study established that non-bacterialinflammation is common in young screened CF infants. For examplethe study of Armstrong et al 1996 (below) shows cells andinflammatory markers only where there was also bacterial infection.It is therefore likely that inflammation does not occur withoutinfection but when it does occur the degree of inflammation may beexcessive.

Dr Jeff Wagner (figure 38) of the University of Colorado Children's Hospital is heavily involved inboth CF care and research in the USA

1995 Littlewood JM. Abdominal pain in cystic fibrosis. J R Soc Med 1995; 88 (Suppl): 9-17.[PubMed]A detailed review of the causes, investigation and treatment of abdominal pain in CF summarisingexperience with over 600 patients with CF seen at the Leeds Regional Paediatric CF Centre. Assub-specialisation increased in paediatrics in the UK, the majority of paediatricians working in CFcentres were primarily interested in the treatment of the chest – understandably as most peoplewith CF died from this cause. So the gastrointestinal aspects were relatively under-investigatedalthough a significant number of patients had, and still do have, abdominal symptoms. In this study recurrent abdominal pain occurred in 11% of children receiving their care at theLeeds centre (where there was considerable interest in and investigation of gastrointestinalproblems) and in 31% of those referred for Comprehensive CF Assessment from other hospitals -admittedly a selected group. It was interesting that the prevalence of recurrent abdominal pain differed greatly with the modeof presentation e.g. meconium ileus 38%, respiratory 39%, malabsorption 47%, presence of a CFsibling 30% but only in 4% in those diagnosed by neonatal screening and treated from the age ofa few weeks (Littlewood JM J R Soc Med 1992; 85 (Suppl 18):13-19).

1995 Ghosal S, Taylor CJ, Pickering M, McGraw J, Beckles-Wilson, Wales JKH.Disproportionate head growth retardation in cystic fibrosis. Arch Dis Child 1995; 72:150-152. [PubMed] Fifty children with CF (18 diagnosed with meconium ileus, four by post natal screening, 30 byclinical diagnosis) were followed over four years. The length SD scores improved from -1.24 atbirth to -0.15 at four years and the weight SD scores from -1.37 at 6 months to -0.53 at four


Figure 39: Dr Jeanette Dankert-Roelse.

years. In contrast the head circumference SD score reached a plateau of -1.0 from the age of 1.5to four years and remained significantly low throughout the four years of measurement being -1.05 at four years. (also Lloyd-Still JD et al, Pediatrics 1974; 54:306-311 - "malnutrition in infancycan affect intellectual development in the first five years").

This was the first report that the head circumference of children with CF may be slightly smallerthan expected. The high proportion of infants with meconium ileus (34%) in the series probablywas due to Sheffield Children’s Hospital being a regional centre for neonatal surgery. The authorssuggested that the data may support the expression of CFTR in the choroid plexus and ependyma.There is very little in the literature on head circumference in CF although in the Wisconsinscreening data on cognitive score index (CSI) – “the highest proportion of CSI scores >84occurred in the control <300E group (41%). Patients in this group also had the lowest mean headcircumference z-scores at diagnosis” (Koscik RL et al. J Pediatr 2005; 147(3 Suppl):S51-6). Afurther study of screened CF infants from Sheffield confirmed that head growth appeared to lagbehind somatic growth supporting the functional expression of CFTR in the brain (Ghosal S et al.Arch Dis Child 1996; 75:191-193. [PubMed]

1995 Morkeberg JC, Edmund C, Prause JU, Lanng S, Koch C, Michaelsen KF. Ocularfindings in cystic fibrosis patients receiving vitamin A supplementation. Graefe’s ArchClin Exp Ophthalmol 1995; 233:709-713. [PubMed] Only 26% of 35 patients examined in the Copenhagen clinic had normal vitamin A status asmeasured by serum retinol and light sensitivity but reduced contrast sensitivity. Conjunctivalimprints showed dry eye in 42%; decreased tear stability in 49% and other abnormalities of lowtear production (31%) and increased numbers of dying cells (23%). In fact 26% were consideredto have the criteria for “keratoconjunctivitis sica”. The authors even suggested that the highincidence of dry eye could be a primary manifestation of CF.These findings are more likely the result of suboptimal vitamin A status particularly as only 26%had normal vitamin A levels. In studies where vitamin A status is regularly monitored to maintainnormal serum levels, only reduced contrast sensitivity is found (Ansari et al. 1999 below) and thecause of this is unexplained.

1995 Dankert-Roelse JE, Meerman GJ. Long termprognosis of patients with cystic fibrosis inrelation to early detection by neonatal screeningand treatment in a cystic fibrosis centre. Thorax1995; 50:712-718. [PubMed] Comparative clinical follow up in three birth cohorts ofpatients with CF was performed at the Cystic FibrosisCentre in Groningen. The first birth cohort (n = 19)was detected by screening and the two other cohortswere detected clinically, one (n = 30) consisting ofpatients born during the screening programme and theother (n = 32) of patients born during the six yearsimmediately after the screening programme ended.Patients born during the screening programme butdetected clinically appeared to have a reduced lifeexpectancy compared with patients detected byscreening. The patients detected by screening showedless deterioration in lung function, a smaller increase inimmunoglobulin levels, and minimal catch-up growth

compared with the non-screened birth cohort of the same age. Expert management when started immediately after an early diagnosis of CF by neonatalscreening results in important beneficial effects on the outcome and clinical course of thecondition. The institution of very early treatment may be critical for the outcome and long termprognosis for most patients with cystic fibrosis. The authors believe that neonatal screeningprogrammes for cystic fibrosis should be introduced more widely.

Jeanette Dankert-Roelse (figure 39) from the Netherlands has been a tireless advocate of CFneonatal screening since the early Eighties and is still, in 2010, involved in the European CFSociety neonatal CF screening programme. It is a relief that the obvious benefits of neonatalscreening are now accepted and supported by studies that are acceptable to virtually all.

1996 Armstrong, DS. Grimwood K, Carlin JB, Carzino R, Olinsky A, PhelanPD.Bronchoalveolar lavage or oropharyngeal cultures to identify lower respiratorypathogens in infants with cystic fibrosis. Pediatr Pulmonol 1996; 21:267-275. [PubMed] A study designed to determine whether oropharyngeal cultures predicted the presence ofpathogens in the lower airways. In children with CF during 1992-1994, 75 of 90 (83%) infants withCF diagnosed by neonatal screening had 150 simultaneous bronchoalveolar lavage (BAL) andoropharyngeal specimens collected for quantitative bacterial culture at a mean age of 17 months(range, 1-52 months). Ten children undergoing bronchoscopy for stridor served as controls. Some,in fact many, of the infants with CF were currently receiving antibiotics – either anti-Staphylococcal antibiotics (44) or inhaled tobramycin (11). Total and differential white cell countsand interleukin-8 concentrations were measured in BAL fluid. A subset of bacterial pathogens wastyped by pulsed field gel electrophoresis. A non-linear relationship with inflammatory markerssupported a diagnosis of lower airway infection when > or = 10(5) colony-forming units/ml weredetected. This criterion was met in 47 (31%) BAL cultures from 37 (49%) children. Staphylococcusaureus (19%), Pseudomonas aeruginosa (11%), and Hemophilus influenzae (8%) were the major


lower airway pathogens. In oropharyngeal cultures, S. aureus (47%), Escherichia coli (23%), H.influenzae (15%), and P. aeruginosa (13%) predominated. The sensitivity, specificity, and positiveand negative predictive values of oropharyngeal cultures for pathogens causing lower respiratoryinfections were 82%, 83%, 41%, and 97%, respectively. When there was agreement betweenpaired oropharyngeal and BAL cultures, genetic fingerprinting showed some strains of the sameorganism were unrelated. The authors concluded that oropharyngeal cultures do not reliablypredict the presence of bacterial pathogens in the lower airways of young CF children.

This is an important study if only for showing that an alarming number of infants with CF hadinfected lower airways even at an average age of only 17 months. In many clinics, such asCopenhagen, children with CF have frequent cultures, every month or more often - for examplewhen ever they are unwell. The multiple cultures then available allow a more accurate assessmentof the likelihood of lower respiratory tract infection over time – rather than the “one off”correlation as occurred in this and a number of similar studies. Also this practice of evaluatingfrequent throat cultures as an indicator of lower respiratory infection is supported by Pseudomonasantibody levels which correlate with the culture results. So if the upper respiratory cultures arerepeatedly negative it is likely that the lower airways are also uninfected - such an infant willvirtually always have negative Pseudomonas antibody levels.

1996 Doull IJ, Freezer NJ, Holgate ST. Growth of prepubertal children with mild asthmatreated with inhaled beclomethasone dipropionate. Am J Resp Crit Care Med 1996;151:1715-1719. [PubMed] The effect of 7 months inhaled beclomethasone propionate 400 micrograms/day on linear growthand adrenal function in 94 children aged seven to nine years. Mean regressed daily growth wassignificantly decreased during the treatment period 0.79 mm versus 1.14 mm per week. At theend of the seven months study the BDP treated children had grown significantly less than thechildren on placebo (mean 2.66 versus 3.64 mm). There was no catch up over 4 months.

So inhaled BDP at these relatively modest doses in children with mild asthma significantlydecreased statural growth - a side effect so vigorously denied for so long by many respiratorypaediatricians since the first reports (Littlewood et al, 1988 above). This is important in thecontext of CF as many children are treated, at times unnecessarily, with inhaled steroids (Balfour-Lynn I M et al. Am J Resp Crit Care Med 2006; 173:1356-1362), and the doses used may be largeand growth impairment is not a rare finding.

Dr Iolo Doull is the Director of the Cardiff Paediatric CF Centre. He is heavily involved in both CFcare and research. He has developed a shared care network for most of Wales which involves heand his team traveling periodically to the various general hospitals.

1996 Carles S. Desgeorges M. Goldman A. Thiart R. Guittard C. Kitazos CA. de Ravel TJ.Westwood AT. Claustres M. Ramsay M. First report of CFTR mutations in black cysticfibrosis patients of southern African origin. J Med Genet 1996; 33:802-804. [PubMed] Cystic fibrosis was thought to be rare in the black populations of Africa and only a few patientshave been reported but they had not been studied at the molecular level. This report, fromMichelle Ramsay’s laboratory, concerns the detection of CFTR mutations in three black SouthAfrican patients. One was homozygous for the 3120 + 1G-->A mutation, while the other two werecompound heterozygotes each with this mutation on one chromosome. The other mutations wereG1249E and a previously unreported in frame 54 bp deletions within exon 17a involvingnucleotides 3196-3249 (3196del54).

The 3120 + 1G-->A mutation was first described in black American patients and has been shownto be a relatively common mutation in this population (9-14% of CF chromosomes). It was alsofound in a black CF patient whose father, the 3120 + 1G-->A carrier, is from Cameroon. Thesedata suggest that it is an old mutation which accounts for many of the CFTR mutations in blackAfricans (Also Pileggi A. 1962; Kulczycki LL et al, 1964 above and other reports find a lowincidence in black patients).

1996 Brock DJH. Prenatal screening for cystic fibrosis: 5 years’ experience reviewed.Lancet 1996; 347:148-150. [PubMed] Antenatal screening had been available at two maternity clinics in Edinburgh, UK, since January,1992, first on a research basis and then routinely. 25,000 couples had been screened. The take-uprates for the two-step and couple models of delivery were very similar at about 70%. Of 22 high-risk couples identified entirely through screening, 20 (91%) opted for prenatal diagnosis. Fourcouples returned for second and two for third monitored pregnancies. In all eight cases whereaffected fetuses were identified, pregnancy was terminated.

David Brock concluded that “these data remove one of the few remaining obstacles to a generalimplementation of prenatal screening for CF”. However, although prenatal screening wasrecommended in the UK by a Health Technology Assessment (Murray et al, 1999) and after thiswas accepted in principle by the National Screening Committee, prenatal screening had not beenintroduced in the UK by 2009. Furthermore, antenatal CF screening was discontinued in theEdinburgh hospitals in 2005 on grounds of both cost and also the introduction of neonatalscreening and the evidence of improving prognosis for infants with CF diagnosed soon after birth(also Mennie et al, 1992 above; Livingstone et al, 1994 above).

1996 Bikangaga P, Canny GJ. Benign intracranial hypertension in infants with cysticfibrosis. Arch Pediatr Adolesc Med 1996; 150:551-552. [PubMed] Four of 53 (7.7%) newly diagnosed infants with CF in Toronto developed transient benign raised


Figure 40: Dr DavidHeaf,

intracranial pressure during their initial treatment. This is an apparently benign occurrenceaccording to previous reports (Roach ES, Sinai SH. Clin Pediatr 1989; 27:371). Vitamin Adeficiency has been described as a cause (Abernathy RS. AJDC 1976; 130:1360-1362 above) alsosystemic steroid withdrawal. Catch up growth after severe malnutrition has also been implicatedbut many cases are unexplained. The complication has also been described with tetracyclineantibiotics since the Sixties.

1996 Cheng K, Smyth RL, Govan JRW, Doherty C, WinstanleyC, Denning N, Heaf DP, Saene H van, Haret CA. Spread of ß-lactam resistant Pseudomonas aeruginosa in a cystic fibrosisclinic. Lancet 1996; 348:639-642. [PubMed] A high proportion of children attending the Liverpool paediatric CFcentre were found to be chronically infected with a P. aeruginosathat was resistant to ceftazidime and other beta-lactam antibiotics.Two genomic fingerprinting techniques were used to see if this hadarisen from epidemic spread of a single strain. 92 (76.7%) of the120 children attending the clinic were infected with P aeruginosa,and 65 (71%) of these 92 infected infants harboured isolates thatwere resistant to ceftazidime; 55 of the 65 children harboured thesame epidemic strain - resistant to ceftazidime, azlocillin, andimipenem, and sensitive to tobramycin and ciprofloxacin.

This study provides the first molecular evidence of a long-term“outbreak” of P. aeruginosa in a CF centre. The authors suggested

that careful surveillance of the prevalence of antibiotic resistance in CF centres should beinstituted with measures to prevent cross-infection. They suggested that anti-Pseudomonalmonotherapy “should be considered with caution”. This lesson had already been learned inCopenhagen in the early Eighties (Pedersen et al, 1986 above) and in the past a number of writershad already cautioned against the use of monotherapy. Most CF centres at the time alreadyfollowed the recommendation to use two antibiotics when treating exacerbations of Pseudomonasinfection. However, prior to this outbreak, intravenous ceftazidime monotherapy had been routinein the Liverpool CF clinic.

This was a very important paper which highlighted the risk of cross infection with Pseudomonasaeruginosa in CF clinics now clearly identified by genomic finger printing techniques. Later thishighly transmissible “Liverpool epidemic strain” of Pseudomonas aeruginosa was reportedelsewhere and subsequently spread to many other CF centres in the UK.. It is cause for concern that, even after experience such as reported here, there is still discussionas to the use of one or two antibiotics for the treatment of exacerbations – even to the extent of aCochrane review which failed to give firm advice to use two antibiotics!! (Ephick HE, Tan A. Singleversus combination intravenous antibiotic therapy for people with cystic fibrosis. CochraneDatabase of Systematic Reviews. 2005).

Dr David Heaf (figure 40) is the Director and senior paediatrican at the Alder Hey Children'sHospital CF Unit in Liverpool. He has developed an extensive shared care service for children withCF in the North West of England and North Wales.

1996 Frederiksen B, Lanng S, Koch C, Hoiby N. Improved survival in the Danish center-treated cystic fibrosis patients: results of aggressive treatment. Pediatr Pulmonol 1996;21:153-158. [PubMed] Survival data for Danish center-treated CF patients, covering the period 1974-1993. The annualmortality rate for 1989-1993 was 0-1.2%. Using the age-specific mortality rate for 1989-1993, itwas impossible to calculate the median survival probability because the curve did not fall below50% (age up to 45 years); however, it was possible to show that the survival probability for anewborn CF child to reach his 45th birthday was 80.4% (confidence interval 76.5-84.6%). Themedian age at diagnosis was 0.63 years with no sex difference (surprisingly there was and still isno neonatal CF screening in Denmark). The probability of surviving 40 years after the diagnosis ofCF was made was 83.3% (confidence interval 80.1-86.6%). These survival figures are considerably better than any other published survival probability at thetime. The only item that I would not agree with the Danish CF centre is their policy of notscreening neonates for CF.

1996 Robinson M, Regnis JA, Bailey DL, King M, Bautovich GJ, Bye PTP. Effect ofhypertonic saline, amiloride, and cough on mucociliary clearance in patients with cysticfibrosis. Am J Respir Crit Care Med 1996; 153:1503-1509. [PubMed] After inhalation of hypertonic (7%) saline alone, and with amiloride, the amount of radio aerosolcleared from the right lung at 60 and 90 minutes was significantly increased. The authorssuggested that inhaled hypertonic saline was a potentially useful treatment for CF.

Peter Bye’s group at St Vincent’s Hospital in Sydney continued their work on hypertonic saline andeventually carried out a successful clinical trial of hypertonic saline in adults with CF and eventuallyconfirmed the value of hypertonic saline treatment (Elkins et al, 2006 below). Hypertonic 7%saline inhalations were originally reported to double the rate of removal of bronchial secretions inchronic bronchitis in an interesting study using radio aerosols (Pavia et al, Am Rev Respir Dis1978; 117:199-203). I recall consulting Margaret Hodson in the early Eighties asking her for anysuggestions for treating a girl with CF who had excessively viscid secretions. She advised a trial ofnebulised hypertonic saline which, from her personal experience, had proved helpful!


1997 Katznelson D, Szeinberg A, Augarten A, Yahav Y. The critical first six months incystic fibrosis: a syndrome of severe bronchiolitis. Pediatr Pulmonol 1997; 24:134-136.[PubMed]The syndrome of infantile bronchiolitis in cystic fibrosis (CF) carries a high mortality. Fifteen casesof CF encountered over the past 19 years with severe bronchiolitis with onset during the first 6months of life are described. Treatment includes steroids in high doses. All patients recovered.Further progress resembled the usual natural course of CF and showed no evidence of persistinglung damage. The mechanism of this syndrome is not clear and is probably dependent on manyfactors involved in early lung disease in CF. The frequency of severe bronchiolitis in cystic fibrosismay not be high, but it continues to be seen in clinical practice today.

This paper is one of many on CF and a wide range of paediatric subjects by Professor DanielKatznelson of the National CF Center, Sheba Medical Center, Israel.

1996 Colombo C, Battezzi PM, Podda M, Bettinadi N, Giunta A. Ursodeoxycholic acid forliver disease associated with cystic fibrosis:a double blind multicenter trial. Hepatology1996; 23:1484-1490. [PubMed] A trial of ursodeoxycholic acid by Carla Colombo and colleagues from MIlan who first reported theuse of URSO in people with CF (Colombo et al, 1990 above). Fifty five patients from 12 CF centresover one year had either UDCA + taurine, UDCA + placebo, placebo + taurine or double placebo.The UDCA treated patients showed better clinical condition and improved biochemistry; also thosetreated with taurine had improved prealbumin levels. Despite this trial, a Cochrane review, revised in 2009, considered "There is insufficient evidence tojustify its (URSO) routine use in cystic fibrosis". However, it is reassuring that most cliniciansconsider there is clinical evidence and would disagree with the Cochrane Review and ignore theiradvice and use URSO at an early stage if there is any evidence of liver involvement.

1997 Conway SP, Pond MN, Watson A, Etherington C, Robey HL, Goldman MH.Intravenous colistin sulphomethate in acute respiratory exacerbations in adult patientswith cystic fibrosis. Thorax 1997; 52:987-993. [PubMed] Intravenous colistin was shown to be an effective safe treatment for P. aeruginosa associatedpulmonary exacerbations in patients with cystic fibrosis. Assessment of the individual effect ofeach treatment regimen suggests a greater efficacy when colistin is combined with a secondantibiotic to which the Pseudomonas shows in vitro sensitivity. It was advised that renal functionshould be monitored.

Intravenous colomycin was first used by Robert Stern who gives an interesting account of hisdecision to use of the intravenous route, instead of the painful intramuscular route, in a wastedgirl who already had an intravenous drip running for hydration purposes. Colomycin was the onlyparenteral antibiotic in the early Sixties. Later an intravenous preparation became available andbut was soon replaced by intravenous gentamicin and then carbenicillin and piperacillin becameavailable. Stern describes the early developments including the heparin lock in the early Seventies,the gradual involvement of the patients with CF in managing their own IV therapy first in hospitaland eventually at home (Stern RC. Intravenous treatment: where we are and how we got there.In: Doershuk CF, editor. Cystic Fibrosis in the Twentieth Century. Cleveland: AM Publishing, Ltd,2001:93-111).

1997 Everard ML, Sly P, Brenan S, Ryan G. Macrolides antibiotics in diffusepanbronchiolitis and in cystic fibrosis. Eur Respir J 1997; 10:2926. [PubMed] Mark Everard (figure 41) confirmed with me that this was the first report from Sheffield UK andPerth Western Australia showing the anti-inflammatory effect of macrolides in people with cysticfibrosis. Four of six patients with CF had significant reduction in IL-8 sputum levels after onemonth treatment with low dose (200 mg tds) oral erythromycin. He believes the first report of theuse of macrolides in CF was in a Japanese publication by Nakanishi et al in 1995 – "A 16-year-oldboy was admitted to our hospital because of coughing, sputum, and exertional dyspnoea. Sevenmonths after birth cystic fibrosis had been diagnosed. The chest roentgenogram on admissionshowed diffuse reticulonodular shadows and overinflation. Pulmonary function tests revealedobstructive and restrictive impairment. Erythromycin and Lomefloxacin were administered bymouth, and aminoglycosides were administered by inhalation. His symptoms were alleviated, andhe is now an outpatient. In Japan, cystic fibrosis is rare, and this patient is extremely rare becausehe has grown up to be a 16-year-old. In this case, low-dose and long-term erythromycinadministration was very effective". (Nakanishi N, Ueda N, Kitade M, Moritaka T. A case of cysticfibrosis in a Japanese student. Jpn J Thoracic Dis 1995; 33:771-774.) [PubMed]

The beneficial effect of 600 mg/day of erythromycin for 1 to 12 months in chronic panbronchiolitisin Japanese patients had been reported previously (Nagai H et al. Respiration 1991; 58:145-9).[PubMed] The effect appeared to be independent of the presence of chronic Pseudomonas infectionand an anti-inflammatory action was suggested (Fujii T et al. Thorax 1995; 50:1246-52; Hoiby N.Thorax 1994; 49:531-532; Kudoh S et al. Jpn J Thorac Dis 1987; 25:632-42; Kudoh S. et al. Am JRespir Crit Care Med 1998; 157:1829-32 below; Kudoh et al, 1998 below).

These were important developments eventually leading to a number of large clinical trials and thewidespread use of azithromycin in people with CF – undoubtedly one of the major clinicaltreatment advances of the Nineties and new Millennium (Equi et al, 2002 below; Saiman et al,2003 both below). By 2005 nearly 54% of all the patients on the CF Foundation Registry weretaking azithromycin.


Figure 41: Dr Mark Everard.

Figure 42: Dr Colin Wallis.

Figure 43: Brenda Button.

1997 Wallis C, Leung T, Cubbitt D, Reynolds A. Stoolelastase as a diagnostic test for pancreatic functionin children with cystic fibrosis. Lancet 1997;350:1001.[PubMed] The first published report of faecal pancreatic elastase 1 inchildren with CF from Colin Wallis, (figure 42)paediatrician at Great Ormond Street, London. All non-CFchildren had normal faecal elastase levels but 26 of 30children with CF had undetectable levels. Three of theothers were pancreatic sufficient. Normal levels werereached by normal infants within 2 weeks. The test was further evaluated in a larger series ofchildren with CF in Leeds (Cade et al, 2000 below) andbecame the accepted method of determining pancreaticfunction. The test had a major advantage over faecalchymotrypsin as it still remained low (negative) inpancreatic insufficient patients whilst the patient wastaking pancreatic enzyme supplements. This test was a major advance - a really usefulstandardised non-invasive test for accurately confirmingthe presence of pancreatic insufficiency without having tostop the pancreatic enzyme treatment of patients referredto a CF Centre for full investigation - a far cry fromduodenal intubation for tryptic activity which was essentialbefore the sweat test was introduced during the Fifties;also it was a major advance on faecal chymotrypsin.However, faecal chymotrypsin did provide a usefulindication as to whether the patient was taking theirpancreatic enzyme supplements – a low chymotrypsinwhen thought to be taking pancreatic enzymes suggestednon-adherence.

1997 Button BM, Heine RG, Catto-Smith AG, PhelanPD, Olinsky A. Postural drainage and gastro-oesophageal reflux in infants with cystic fibrosis.Arch Dis Child 1997; 76:148-150. [PubMed] First of series of papers from Brenda Button (figure 43), aphysiotherapist from Melbourne, Australia, noting thepossible dangers of inhalation when infants with CF werein the head down position during postural drainage;infants with CF were known to have an increasedincidence of gastro-oesophageal (GO) reflux.Physiotherapy with and without head down tilt werecompared using 24 hour pH oesophageal monitoring.Standard physiotherapy with head down tilt wasassociated with a significant increase in GO reflux in theinfants with CF.

This was an important study and, with Brenda Button’ssubsequent publications, certainly had a major influence

on the techniques of physiotherapy recommended for CF infants (see also Malfroot & Dab, 1991above for earlier studies on reflux in CF infants; Button et al, 2004 also confirmed GO reflux ascommon and important in adults with CF).

1997 Drittanti L, Masciovecchio MV, Gabbarini J, Vega M. Cystic fibrosis: gene therapy orpreventive gene transfer? Gene Therapy 1997; 4:1001-1003.[PubMed] I was very impressed by this, not widely known, paper for it accurately described the situationclinicians, who followed many patients year after year, had been observing in the clinic. Patients’respiratory function tests are usually stable before chronic infection (usually Pseudomonas)becomes established but begin a slow deterioration after chronic Pseudomonas infection becomesestablished i.e. they pass the "point of no return" (figure 44 - my figure).. These authors suggested that before the onset of chronic infection people with CF can beconsidered to be in the phase of “CF Disease” i.e. they have various physicochemical alterations inthe electrolyte and liquid composition of the airway fluid but no tissue damage. Although they getrespiratory infections these can be eradicated, if treated early with antibiotics and their respiratoryfunction remains stable. However, eventually a new respiratory infection is not eradicated andchronic infection of the tissues becomes established. At this stage the patient then enters thephase of “Lung disease” where infection and chronic inflammation become established, selfperpetuating and progress independently of the basic CFTR abnormality – this change is referredto as the “Point of no return” and there follows a slow deterioration in their condition, the speed ofwhich is determined by the type and intensity of treatment they receive. So the aim of modern treatment is to avoid passing the “Point of no return” i.e. prevent or delayfor as long as possible the onset of chronic infection of the airways. So it can be appreciated that ifthe airway cultures are repeatedly positive for Pseudomonas, even if the patient has few or evenno symptoms (as in the paper by Konstan et al, above), he already has passed the "Point of NoReturn".


In a later paper Drittanti is one of the authors who state that "The interactivity between the CFTRgene and cystic fibrosis would be limited to the initial phase of the disease" (Genetics in Medicine2000;2:124-130. [PubMed])While the initial phase was related to the CFTR genotype, the kineticsof the second phase seems to be common to all groups considered. The hypothesis that theinteractivity between the CFTR gene and CF disease would be limited in time is presented,suggesting that mutant CFTR would trigger a disease that evolves to become independent fromthe CFTR gene itself

Figure 44: The Point of No Return.

1997 Frederiksen B, Koch C, Hoiby N. Antibiotic treatment at time of initial colonisationwith Pseudomonas aeruginosa postpones chronic infection and prevents deterioration ofpulmonary function in patients with cystic fibrosis. Pediatr Pulmonol 1997; 23:330-335.[PubMed] Follow up of the important Valerius et al, 1991 study (above) showing successful eradication ofearly infection with P. aeruginosa with nebulised colistin and oral ciprofloxacin. Three monthscolistin and ciprofloxacin gave longer freedom from recurrence of infection than did three weekstreatment. This study was criticised as historic controls were used. However, it was already quite obvious thatthe early eradication treatment prevented chronic P. aeruginosa infection (Littlewood et al, 1985;Valerius et al, 1991 above) and most clinicians in Europe would have regarded it as unethical toinvolve a placebo group at this stage; vigorous early eradication treatment was already routinepractice in many European CF clinics. But it is difficult to understand how three months treatmentincreases the time to further Pseudomonas infection as the next episode of infection is usually, butnot always, with a different genotype presumably acquired from the environment (Munck A et al.Pediatr Pulmonol 2001; 32:288-292). However, also using genotyping, it was later shown that aminority of Pseudomonas strains were suppressed but not completely eradicated – so presumablythree months treatment would make this less likely to happen.

The great delay in the general introduction of early eradication therapy for Pseudomonas to reducethe prevalence of chronic infection, particularly in North America, was difficult to understand whenthe results of the earlier Copenhagen study were so impressive (Valerius et al, 1991 above). Surprisingly, a later Cochrane Systematic review on early eradication of Pseudomonas aeruginosa,almost a decade later in 2006, could only conclude that “there is some evidence that antibiotictreatment of early P. aeruginosa results in short term eradication but it remains uncertain whetherthere is clinical benefit to people with cystic fibrosis” – a conclusion most experienced clinicians,including Neils Hoiby would fiercely question (as he and I did in critical letters to the Cochranereviewers!). The views of the late Christian Koch summarise the Danish experience and of mostexpereinced CF clinicians as to the importance of avoiding chronic Pseudomonas infection (theseare quoted in the comments on Valerius et al, 1991 above). I'm afraid there are definitedownsides to Evidenced Based Medicine !!!!

1998 Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastro-oesophageal reflux in adult cystic fibrosis patients. J R Soc Med 1998; 91:7-9. [PubMed] Fifty adults with CF were surveyed by questionnaire and ten with reflux symptoms hadoesophageal manometry and 24 hour pH recording. Forty seven patients (94%) had uppergastrointestinal symptoms: 40 (80%) heartburn (27 worse when supine); 26 (52%) regurgitation;and 28 (56%) dyspepsia. At oesophageal manometry, lower oesophageal sphincter barrierpressure (LOSBP) was subnormal in 6 of the 10 patients and 3 had uncoordinated peristalsis in themid-oesophagus. Eight patients had significant gastroesophageal reflux. Adult CF patients havehigh rates of GOR symptoms, diminished LOSBP, and acid reflux.

This study re-emphasised the fact that GOR was a frequent and important problem and asignificant cause of symptoms in adults with cystic fibrosis. The complication had been recognisedsince first described by Jan Feigelson (Feigelson & Sauvegrain, 1975 above) and later by Scott RB


et al, 1985 (above); the frequency and importance was again highlighted in this present paper.Brenda Button in Australia had already pointed out the problem of the occurrence of reflux in CFinfants in the head down position during physiotherapy (Button et al, 1997 above) – later she alsofound reflux to be common in adults with CF (Button et al, 2004).

Dr Martin Walshaw (figure 45) was the first Director of the Liverpool CF Centre for adults and waslater joined by Dr Malcolm Ledson (figure 45.1). The Liverpool CF Centre for adults is now one ofthe major units in the UK.

Figure 45: Dr Martin Walshaw Figure 45.1: Dr Malcolm Ledson.

1998 Kudoh S. Azuma A. Yamamoto M. Izumi T. Ando M. Improvement of survival inpatients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J RespirCrit Care Med 1998; 157:1829-32. [PubMed] Diffuse panbronchiolitis (DPB) is a chronic inflammatory disease of the airways with a highmortality despite treatment with a combination of antibiotics and the use of supportive therapy.Low-dose erythromycin therapy (EM) (400 to 600 mg/d) improved the survival and most patientsin Japan have been treated with this regimen since 1984. The authors compared the survival ratesof 498 patients with DPB after dividing them into three groups (Group a: 1970-1979, Group b:1980-1984, Group c: 1985-1990). The survival rate of Group c was significantly higher than thatof Groups a (p < 0.0001) and b (p < 0. 0001). In Group c (1985-1990), eight of 87 patients died;five (21%) died in the EM non-treated subgroup (n = 24), and three (5%) died in the EM-treatedsubgroup (n = 63). So treatment with erythromycin was associated with a significant improvementin the survival of patients with DPB which was more significant in the older than in the youngerpatients.

These findings were the basis for the gradual evaluation of macrolide therapy in people with cysticfibrosis. The first report of the favourable effect of erythromycin in DPD was Kudoh S, et al.Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis. Jpn JThorac Dis 1987; 25:632-642. Mark Everard et al, (1997 above) was the first in the UK to reportan effect on sputum inflammatory markers in cystic fibrosis.

1998 Aris RM, Renner JB, Winders AD, Buell HE, Riggs DB, Lester GE, Ontjes DA.Increased rate of fractures and severe kyphosis: sequelae of living into adulthood withcystic fibrosis. Ann Int Med 1998; 128:186-193. [PubMed] Bone mineral density was measured with dual-energy x-ray absorptiometry, patient-reportedfracture events were confirmed by radiography, and kyphosis angles were measured by using theCobb method. Mean bone mineral densities for the spine, femur, and total body were severelydepressed in patients with cystic fibrosis, averaging 2 SDs below those of age-matched normalcontrols (P<0.001). Patient interviews showed that 54 fractures had occurred over 1410 patient-years, and chest radiographs showed evidence of 14 additional rib and 62 additional vertebralcompression fractures. The database (which covered 1410 patient-years) showed that fracturerates were approximately twofold greater in women with cystic fibrosis aged 16 to 34 years (P =0.015) and men with cystic fibrosis aged 25 to 45 years (P = 0.04) than in the general population.Vertebral compression and rib fractures were 100- and 10-fold more common than expected,respectively (P<0.001 for both comparisons). The mean kyphosis angle (+/- SD) for this groupwas markedly abnormal (44 +/- 14 degrees; 62% > or = 40 degrees) and probably contributed todiminished stature (mean height loss, 5.8 cm in men with CF and 5.9 cm in women with cysticfibrosis). Cumulative prednisone dose, body mass index, and age at puberty were the strongestpredictors of bone mineral density.

Although osteoporosis had been mentioned in a number of previous reports, this was the firstmajor study on osteoporosis in adults with cystic fibrosis. The study drew attention to the fact thatosteoporosis is almost universal in adults with late-stage CF and its complications includeincreased fracture rates and severe kyphosis. The findings stimulated a great deal of research intoosteoporosis in adults with cystic fibrosis. Later the subject was reviewed in many publications andin a consensus document from the UK Cystic Fibrosis Trust (Bone Mineralisation in Cystic Fibrosis.UK Cystic Fibrosis Trust Bone Mineralisation Working Group. February 2007. Full text available onthe UK CF Trust website (www.cftrust.org,uk) .

1998 Lowden J, Goodchild MC, Ryley HC, Doull I. Maintenance of growth in cystic fibrosis


Fig. 45.2 Dr Iolo Doull.

despite reduction in pancreatic enzyme supplementation. Arch Dis Child 1998; 78:377-378. [PubMed] study from Cardiff, in the post-fibrosing colonopathy era, further supported the view that childrenwith CF in the UK were taking unnecessarily large doses of pancreatic enzyme. Fifteen childrenwith CF on a mean enzyme intake equivalent to 18,300 U lipase/kg/day were able to reduce theirenzyme supplements to a mean of 8,647 U lipase/kg/day. There were no changes in energy or fatintake but significant increases in weight, height and weight for height.

Many UK patients were taking considerably more enzymes supplements than the equivalent of10,000 U lipase/kg/day advised as a result of the occurrence of fibrosing colonopathy (Mehta A.Lancet 2001;358:1547-1548). This study from Cardiff supported this and confirmed that in somepatients the doses were not required.

Dr Iolo Doull (Fig. 45.2) followed Mary Goodchildas the Director of the Cardiff Paediatric CF centre.He became heavily involved with CF care andresearch in the UK and Europe, also in thedevelopment and running of a shared care networkfor children with CF in most of Wales.

1998 Jaffe A, Francis J, Rosenthal M, Bush A.Long-term azithromycin may improve lungfunction in children with cystic fibrosis.Lancet 1998; 351:420. [PubMed] The second very convincing observational study onmacrolides and CF from the UK (first report byEverard et al, 1997 above) showing impressiveimprovement in the respiratory function of severelyaffected children given regular azithromycin inaddition to their usual treatment. These impressiveobservations were followed by a controlled trialfrom the Brompton Hospital, London whichconfirmed the beneficial effect (Equi et al, 2002below) and also by a major trial from the US CFFoundation (Saiman et al, 2003 below).

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

1998 Cunningham S, Marshall T. Influence of five years of antenatal screening on thepaediatric cystic fibrosis population in one region. Arch Dis Child 1998; 78:345-348.[PubMed] The incidence of CF in the five years before and after antenatal screening was introduced inEdinburgh decreased from 4.6 to 1.6 infants per year – a reduction greater than could beaccounted for by prenatal diagnosis and termination.

Much of the early work on antenatal screening during the Eighties was done in Edinburgh by DavidBrock and his colleagues (Brock 1992; Livingstone et al. 1994; Brock, 1996 all above). It isdisappointing that the antenatal screening which Brock pioneered was eventually abandoned inEdinburgh and has not been introduced elsewhere in the UK. The introduction of neonatal CFscreening in Scotland and the steady improvement in prognosis, being two reasons given forwithdrawal of the antenatal screening in Edinburgh. Financial reasons prevented introduction inEngland.

1998 Mahadeva R, Webb K, Westerbeek RC, Carroll NR, Dodd ME, Bilton D. Clinicaloutcome in relation to care in centres specialising on cystic fibrosis: cross sectionalstudy. BMJ 1998; 316:1771-1775. [PubMed] This is one of the few papers which is accepted as supporting the superiority of CF Centre care tothe care received at a general paediatric clinic in the local hospital. Patients at the adult cysticfibrosis centre were subdivided into three groups. Those who had received continuous care frompaediatric and adult cystic fibrosis centres (group A), those who had received paediatric care attheir local hospital then at an adult CF centre (group B) and those who had received neitherpaediatric nor adult specialist care (Group C). Body mass index was 21.3, 20.2 and 18.3 forGroups A B and C respectively (P<0.001) and the improved nutritional status was correlated with


a higher FEV1 and better chest X-rays (P<0.001 for both). These findings are widely quoted asproviding the first direct evidence that management in cystic fibrosis centres resulted in a betterclinical outcome. This had been appreciated for years by doctors dealing with people with CF, andindeed by patients and parents, but is still contested by a minority of general paediatricians andphysicians.

Professor Kevin Webb (figure 45.4) started the first CF centre for adults at Monsall HospitalManchester in 1982; the unit later moved to the purpose-built Bradbury Unit at WythenshaweHospital in 1994. The CF Centre is one of the largest in the UK and the staff have made majorcontributions to improving CF care in the UK.

1997 McIlwaine PM, Wong LT, Peacock D, Davidson AG. Long-term comparative trial ofconventional postural drainage and percussion versus positive expiratory pressurephysiotherapy in the treatment of cystic fibrosis. J Pediatr 1997; 131:506-508. [PubMed] Forty patients were randomised to receive either postural drainage and percussion or PEP maskphysiotherapy over one year. Those using the PEP mask had significantly better respiratoryfunction after 1 year and the authors concluded that this was the more effective method ofphysiotherapy.This study from Professor George Davidson’s CF centre in Vancouver, Canada had a significantinfluence on physiotherapy practice in North America. A subsequent study from this unit,comparing PEP and Flutter methods, showed PEP to be superior in maintaining pulmonary functionand reducing the need for hospital admissions (McIlwaine et al. J Pediatr 2001; 138:845-850). The study was influential in changing the routine physical therapy practice in North America.

Maggie Mcllwaine is the Senior Physiotherapist at the British Columbia Children's Hospital,Vancouver CF Centre.

Figure 45.5: ProfessorKevin Webb.

Figure 45.3: ProfessorGeorge Davidson

Figure 46: Dr Beryl Rosenstein (right) Professor ofPediatrics at Johns Hopkins Hospital, Baltimore and DrRichard Grand (left), Head of Pediatric Gastroenterology,The Children's Hospital, Boston with the author at NACFCongress 2008.

1998 Rosenstein BJ, Cutting GR for the Cystic Fibrosis Consensus Panel. The diagnosis ofcystic fibrosis: a consensus statement. J Pediatr 1998; 132:589-595. [PubMed] A helpful publication summarising the criteria for diagnosis as follows - One or more of thecharacteristic phenotypic features OR a history of CF in a sibling OR a positive neonatal screeningresult AND an increase in sweat chloride concentration (> 60mmol/l) OR identification of two CFmutations OR demonstration of abnormal nasal epithelial transport.

1999 Waters DL, Wilcken B, Irwing L, Van Asperen P, Mellis C, Simpson JM, Brown J,Gaskin KJ. Clinical outcomes of newborn screening for cystic fibrosis. Arch Dis Child1999; 80: F1-F7. [PubMed] An important long term observational study from Sydney of 10 year follow-up of screened infants


Figure 47: Dr Bruce Montgomery. 2008.

with CF, showing significant nutritional and respiratory benefits from neonatal CF screening firstintroduced in 1981 in New South Wales. Fifty seven unscreened CF children (born 1978-1981) arecompared with 60 screened infants (born 1981-1984). Height and weight of screened areconsistently better (SDs of 0.3 and 0.4 better respectively) and respiratory function is higher –FEV1 difference of 9.4% and FVC 8.4% in favour of the screened infants.

In New South Wales a more progressive attitude to neonatal CF screening has prevailed over theyears than in the UK. Although Cochrane reviewers considered this paper unsatisfactory as thecontrols were historical, most people accepted that the results were predictable and and providedfurther supportive evidence for neonatal CF screening.

1999 Ansari EA, Sahni K, Etherington C, Morton A, Conway SP, Moya E, Littlewood JM.Ocular signs and symptoms and vitamin A status in patients with cystic fibrosis treatedwith daily vitamin A supplements. Br J Ophthalmol 1999; 83:688-691. [PubMed] Since the first Leeds studies on vitamin levels in 1978 (Congden et al, 1981 above), oralsupplementation has been guided by annual monitoring of vitamin levels; also all patients areseen regularly by a CF specialist dietitian and most have a comprehensive annual dietaryassessment. None of the 28 patients in this study had vitamin A deficiency, the median value ofserum retinol being 48 microg/dl, range 31-80 microg/dl (normal range 30-80 microg/dl). Darkadaptation was normal in all patients compared with the control group where the mean value was3.4 log units of threshold luminance (95% confidence interval 2.4-4.0). None of the test group hada value of threshold luminance 2 SD above the mean value for the control group. Eight patientshad reduced contrast sensitivity. The median value for serum zinc was 14.2 micromol/ l, range 13-81 micromol/l (normal range 8-23 micromol/l) and the median value for retinol binding proteinwas 36 mg/l, range 13-81 mg/l (normal range 35-58 mg/l). There was no correlation betweendark adaptation and serum retinol, zinc, or retinol binding protein. Two patients had clinicalevidence of dry eye.

So regular estimates of plasma vitamin A, together with appropriate supplementation and expertdietetic review, can maintain normal dark adaptation in patients with cystic fibrosis. Theoccurrence of reduced contrast sensitivity function is well documented in CF and confirmed in thisstudy but remains an unexplained phenomenon (also Morkeberg et al, 1995 above).

1999 Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J,Vasiljev-K M, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL.. Intermittentadministration of inhaled tobramycin in patients with cystic fibrosis. Cystic FibrosisInhaled Tobramycin Study Group. N Engl J Med 1999; 340:23-30. [PubMed] One of the most important clinical trials of the decade showing a significant benefit of inhaledpreservative free tobramycin (TOBI) given during alternate four week cycles for 24 weeks topatients chronically infected with Pseudomonas aeruginosa. Treated patients had an averageincrease of FEV1 of 10% predicted at 20 weeks where as those on placebo had a 2% decline; alsothe treated patients had 23% fewer hospital admissions.>

The introduction of TOBI, supported by this excellent clinical trial, was one of the major clinicaladvances of the decade and the culmination of work started in the late Eighties by Arnold Smithand others (Smith AL et al. 1989 above). By 2005 nearly 60% of people with CF in the US CFFRegistry were receiving nebulised TOBI. Although the cost (£10K per annum in the UK) has restricted the use of the TOBI preparation inthe UK, inhaled anti-Pseudomonal antibiotics (colistin, tobramycin for injection and gentamicin)have been widely used in the UK for CF patients with chronic Pseudomonas infection sinceMargaret Hodson’s important 1981 paper (Hodson et al, 1981 above).

Dr Bruce Montgomery (Figure 47) nowSenior Vice President and head ofRespiratory Therapeutics at Gilead Sciences,,was closely involved with the developmentand trials of this preparation and has beeninvolved subsequently with other newtreatments including, more recently,nebulised aztreonam lysine for inhalation.

1999 Howarth CS, Selby PL, Webb AK,Dodd AK, Musson H, McL Niven R,Economu G, Horrocks AW, Freemont AJ,Mawer EB, Adams EJ. Low bone densityin adults with cystic fibrosis. Thorax1999; 54:961-967. [PubMed] An early detailed study of a population of151 adults aged 15-52 ears with CF fromManchester using DEXA and quantitativecomputed tomography and biochemicalmarkers of bone turnover. 34% of adultswith CF had BMD Z scores of -2 or less atone or more skeletal sites. The respiratoryfunction and physical activity were related tothe BMD Z scores. Markers of bone turnoverwere negatively related and vitamin D


Figure 48: Dr Charlie Howarth.

Figure 49: CF Trust Consensus

Figure 50: Professor Vera Vavrovareceiving the European CysticFibrosis Society Award from thePresident, Professor Stuart Elborn in2008.

positively related to the BMD Z scoresdespite supplementation with vitamin D.

Dr Charlie Haworth (figure 48) has majorcontributions to the increasingly importantbone problems in CF both when working nManchester and after moving to Papworth CFAdult centre where he is now Director.Subsequent reviews and consensusstatements on bone problems in CF followedfrom North America and the UK.

2005 Aris RM, Merkel PA, Bachrach LK,Borowitz DS, Boyle MP, Elkin S, Guise

TA, Hardin DS, Haworth CS, Hollick MF, JosephM, O'Brien K, Tullis E, Watts NB, WhiteTB.Consensus statement: Guide to bone health and disease in cystic fibrosis. J ClinEndocrinol Metab 2005; 90:1888-1896. [PubMed]

2007 Bone mineralisation in cystic fibrosis. Report of the UK Cystic Fibrosis Trust BoneMineralisation Working Group. London. Cystic Fibrosis Trust, february 2007. Conway S(Chairman), Compston J, Cunliffe H, Dodd M, Elkin S, Haworth C, Jaffe A, Morton A,Redfern J, Truscott J.

1999 Vavrova V, Zemkova D, Bartsova J,Zapletal A, Smolikova L. Krebsova A, Macek M jr.Cystic fibrosis - a disease of adolescents andadults. [Czech]. Casopis Lekaru Ceskych 1999;138:654-659. [PubMed] The summary of this article gives an account of thesituation regarding CF in the CF centre of the FacultyHospital in Prague Motol in 1999. 349 patients arefollowed; also included are the 95 who died since1985. 126 (36.1%) survived to the age of 18 years.The median age of death increased from 12.2. yearsin 1985-1990 to 18.8 years in 1991-1998. Adultstatus was satisfactory 40.4%, poor in 33.3% andmarginal in 26.3%. Pulmonary function was normal in17.5%, and severely affected in 22.8% - the restbetween 40-80% predicted. Modern intensivetreatment has improved the prognosis and quality oflife of people with CF.

Professor Vavrova (figure 50) of Prague published herfirst paper on CF in 1962 and her most recent in2009. She has been involved in CF care and researchfor nearly 50 years and involved in over 80 papersdealing with many aspects of the condition. Shereceived the ECFS Award in 2008.

1999 Sokol RJ, Durie PR. recommendations forthe management of liver and biliary tractdisease in cystic fibrosis. Cystic FibrosisFoundation hepatobiliary Disease ConsensusGroup. J Pediatr Gastroenterol Nutr 1999; 28Suppl 1:S1-13. [PubMed] Recommendations of an expert group onmanagement of CF related liver disease.

1999 Connett GJ, Lucas JS, Atchley JT, FairhurstJJ, Rolles CJ. Colonic wall thickeninbg is relatedto age and not dose of high strength pancreaticmicrospheres in child ren with cystic fibrosis.Eur J Gastro Hepatol 1999; 11:181-183.[PubMed] Thirty three children with CF, including 25 who hadbeen receiving high strength pancreatin in the form ofCreon 25,000 continuously for 3 years. Median lipaseintake was 19,330 u/kg/day (range 0-59,000). Therewas no relationship between enzyme dosage andcolonic wall thickness. The most importantrelationship of colonic wall thickness appeared to bewith age.This was a useful report and reassuring that highdoses of pancreatic enzymes, when given in the formof Creon 25,000, did not appear to cause colonicdamage. It had already been evident from the UK CFDatabase that many UK patients were taking more


Figure 51. Dr Garry Connett.

than the recommended equivalent of 10,000 Ulipase/kg/day (Mehta A.Lancet 2001; 358:1547-1548). Obviously it would be unwise to translatethese findings to other brands of high strengthenzymes.

Dr Garry Connett (figure 51) is a PaediatricRespiratory Consultant who succeeded Dr Chris Rollesas Director of the Southampton Paediatric CF Centre.He is heavily involved in CF care and clinical researchand over the next ten years published on a widevariety of aspects of cystic fibrosis.

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