The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

There are excellent Patient Registries published annually by the CF Foundation, the Cystic Fibrosis Trust, the European CF Society and other national CF organisations

 

In this section there are a limited selection of publications relating to survival figures which have received attention over the years

 

With regard to interpretation of the survival data, Dr Sarah Walters has written a very clear article dealing with survival statistics which can be recommended to non-statisticians ("Survival in cystic fibrosis - what do the statistics mean?") the full text of which is on her website (www.cfstudy.com)  and also on the CF Trust website (www.cftrust.org.uk).

 

1966 Mantle DJ, Norman AP. Life tables for cystic fibrosis. BMJ 1966; 2:1238-1241. [PubMed]
First of a number of publications on survival in the UK from Dr. Archie Norman’s unit at Great Ormond Street, London. Life tables for 1943-1964 showed that 80% died by 5 years and 90% by 10 years. Infants with meconium ileus, 25% died by 1 week and 75% by 3 months.

Sydney Gellis, in an editorial comment in the corresponding Year Book of Pediatrics, observed that “Despite claims to the contrary, cystic fibrosis of the pancreas continues to carry a gloomy prognosis. Present day therapy is helpful but offers relatively little, and a realistic alteration of the course of the disease will require a major breakthrough in discovering the aetiology”. Gellis, although a distinguished pediatrician was not an expert on CF and in this prediction was obviously quite wrong for the outlook improved steadily over the years long before the aetiology was identified during the Eighties.

 

1967 Pugh RJ, Pickup JD. Cystic fibrosis in the Leeds region: incidence and life expectancy. Arch Dis Child 1967; 42:544-545. [PubMed]
This paper is included as it is one of the few reports from the UK of a survey between 1952 and 1962 from the North of England by Yorkshire paediatricians Richard Pugh of Hull and Douglas Pickup of Pontefract on behalf of the Leeds Regional Paediatric Club. During this decade 132 infants were confirmed as having CF among total of 546,764 births over 13 years – an incidence of 1/4142. Fifty six infants (42%) died in the first year.

The findings would be typical of the situation in the UK at the time where virtually all children with CF were treated at local hospitals and there were no specialised CF clinics in most towns and cities – or even in most provincial teaching hospitals. So few patients survived childhood. A significant number of affected infants must have gone unrecognised in this study for the incidence in this part of the UK is around 1/2400 births.

 

1967 Young WF, Jackson AD. The prognosis of cystic fibrosis. Bibliotheca Paediatrica 1967;86:350-352.
Winifred Young and Tony Jackson were paediatricians at the Queen Elizabeth Hospital Hackney where there was one of the few CF clinics in the UK which was started by Winifred Young in 1950. Margaret Mearns joined the staff there soon after.
Further data from these authors is described above in Cystic Fibrosis. A symposium. Report of a meeting on 28th May 1964 at the Wellcome Foundation London. Chest and Heart Association.

 

1967 Warwick WJ, Manson S. Life table studies of mortality. In Cystic Fibrosis Part I. Physiology and pathophysiology of serum secretion clinical investigation and therapy. Proc 4th Int Conf on CF. Geigy Symposium Berne/Grundewald 1966 (Modern Problems in Pediatrics Vol 10) PFI p353 Ed. Rossi E, Stoll E. Karger: Basle and New York. [Conference report]
In 2001 Warren Warwick commented “After 10 years of grants funding the US CF Patient Registry and indirectly supporting the Canadian CF Patient Registry and the beginning of the International Registry, the CF Foundation decided the Registry should become the property of the CF Foundation. When the CF Foundation took over the operation they discovered what a bargain the $10,000 annual grant was. So after spending over $100,000 and still not finishing the analysis, they decided to give up the analysis as too expensive. They were shamed into doing the analysis when the Canadian Foundation provided funds and manpower to complete the analysis. The fallout was that the Canadian Foundation went its own way and beginning the International Registry was abandoned. All the data from the first 10 years of the US Registry, including the magnetic tapes, were transferred to the CF Foundation

 

1968 Warwick W, Pogue RE. Computer studies in cystic fibrosis. In Lawson D (ed). Proceedings of 5th international Cystic Fibrosis Conference, Cambridge 1969; 320-330. London. Cystic Fibrosis Research Trust. [Conference]
Warren Warwick has pioneered databases in CF and was responsible for starting the CF Foundation Patient Registry. He maintains that US paediatricians initially agreed to cooperate with his first CF database as they did not believe Leroy Matthews excellent results and thought the data may confirm their suspicion! (also Warwick & Manson, 1967).

 

1971 George L, Norman AP. Life tables for cystic fibrosis. Arch Dis Child 1971; 46:139-143. [PubMed]
Archie Norman and colleagues produced a number of life tables for people with CF in the UK. Here 128 infants without meconium ileus (MI) and 43 with MI from 1964 for five years are compared with tables for previous 20 years showing obvious improvement in survival – suggested as being due to early diagnosis and treatment. The one year survival was 34% compared with 93%, and at five years 19% vs. 89% between the two periods.

 

1973 Taussig LM, Kattwinkel J, Friedewald WT, di Sant'Agnese PA. A new prognostic score and clinical evaluation system for cystic fibrosis. J Pediatr 1973; 82:380-390. [PubMed]
Often referred to as the NIH Score, this system by Lynn Taussig (figure 3.1) and colleagues stood up to evaluation well and apparently Shwachman and Kulczycki realised that a "more accurate method of assessment might become available" than their score. Respiratory function tests were included also complications that affected prognosis such as haemoptysis, cor pulmonale and pneumothorax. Some considered that the nutritional state was under represented. This and a number of subsequent scoring systems have been discussed by a number of authors (Cystic Fibrosis Clinical Scoring Systems. Conway SP, Littlewood JM. In Cystic Fibrosis - Current Topics. Volume 3. Dodge JA. Brock DJH, Widdicombe JH, editors Chichester: John Wiley & Sons Ltd, 1996:339-358.

Dr Lynn Taussig worked with Paul di Sant'Agnese at the NIH, then as Professor at the Arizona College of Medicine for 20 years and then at the National Jewish Research Center in Denver. He was particularly active in CF care and research during the Seventies and Eighties. In 1984 he edited one of the major textbooks on the CF (Cystic Fibrosis. Lynn Taussig. New York Theime-Stratton Inc. 1984). In the introduction to the book Charles Lobeck describes Lynn Taussig, Thomas Boat and Robert Schwartz as the professional descendants of Paul di Sant'Agnese who had in turn influenced their colleagues from Cleveland, Tuscon, Rochester and other academic locations. The book contains notable chapters on the gastrointestinal system, the pancreas and the hepatobiliary system by Paul di Sant'Agnese. There many other distinguished contributors who have made significant contributions to our knowledge of CF.

 

1976 Stern R, Boat TF, Doershuk CF, Tucker AS, Primiano FP Jr, Matthews LW. Course of cystic fibrosis in 95 patients. J Pediatr 1976; 89:406-411. [PubMed]
From the LeRoy Matthews and Carl Doershuk team at Cleveland reporting the long term results of their comprehensive system of management (Matthews et al. J Pediatr 1964; 65:558-575 above): these were the 95 patients they reported in 1964 after a mean follow up period of 14 years (minimum 13 years). Of the 45 diagnosed before extensive lung damage (Figure 18 Group1) only one had died and none were disabled. Of the other 50 diagnosed after substantial lung damage (Figure 18 Group 2) 26 had died – mortality being greater in females. Factors contributing to better prognosis were considered to be early diagnosis, aggressive management and comprehensive care, easy access to specialised care and improved antibiotic therapy.
The observations of this group on achieving successful treatment include - early inpatient treatment before significant lung damage in optimal facilities, as and when needed with flexible arrangements for daily absences, patient appointments throughout the week including Saturdays. Follow-up exclusively by a centre physician – usually the same physician each visit. All decisions are made by a CF centre physician.

 

1979 Phelan PD, Allan JL, Landau LI, Barnes GL. Improved survival of patients with cystic fibrosis. Med J Australia 1979; 1:261-263. [PubMed]
Three hundred and twenty patients with CF born after 1958 who were treated at Royal Children’s Hospital, Melbourne had an 80% survival to 11 yrs and a 64% survival to 18 yrs. Those managed between 1973-77, 91% survival to 12 yrs and 80% to 17 yrs. These were really excellent results for the time and were attributed, almost certainly correctly, to all patients having received Specialist CF Centre care as was later discussed in a very influential subsequent paper from Melbourne the contents of which prompted the formation of the UK Working Party on Cystic Fibrosis in 1982 (Phelan and Hey, 1984 below).

 

1984 Phelan P, Hey E. Cystic fibrosis mortality in England & Wales and in Victoria Australia. Arch Dis Child 1984; 59:71-83. [PubMed]
The contents of this paper had a major influence on CF treatment in the UK. In Victoria, Australia one death in 125 between the ages of 1 and 14 years was in a child with CF – in England and Wales the frequency was 1 in 44. A newborn child with CF had an 80% chance of surviving to 9 years in England and Wales and to 20 years in Victoria (figure 1 ). The better survival in Victoria during the Seventies was attributed to the Australian patients being treated at CF Centres rather than at by general paediatricians at their local hospitals. During the Seventies most UK children with CF were treated at their local hospital by general paediatricians all of whom saw only a few children with cystic fibrosis.
The authors note “It has been claimed in North America that management in a specialist centre, as in Victoria, is essential for optimal care and recent data from Denmark indicate a much better survival among patients attending a specialist clinic compared with those looked after by their local paediatrician, as happens for most children in England and Wales”.

The data in this report was available before publication through John Dodge who had visited Australia before its publication and the availability of the data was directly responsible for the formation of the British Paediatric Association’s Working Party on Cystic Fibrosis in 1982 whose terms of reference were “to assess the advantages and disadvantages of regional centres for cystic fibrosis”. For summary of the Working Party Report see Jackson 1986 (below).
John Dodge comments that he considers the original data in this report were seriously flawed because they compared mean age at death (UK) with standard survival calculations (Australia), but the point they erroneously made was of great value in setting up not only CF centres in the UK but also a CF registry, without which any data are totally unreliable!

Dr Edmund Hey, the co-author, is a UK consultant paediatrician with previous experience in neonatal physiology and paediatrics who, in 1973, became the first full time consultant respiratory paediatrician at Great Ormond Street Hospital, London; there he met Peter Phelan (figure 26) who spent a six month sabbatical there. In 1978, on the death of Gerald Neligan (the neonatal paediatrician in Newcastle, UK), Hey was invited to return to Newcastle, as neonatologist which he did. Later in 1982, Phelan invited Hey back to Melbourne to cover the sabbatical leave of a colleague; it was during this six months that Hey was involved in the present paper. When he returned to Newcastle, Hey concentrated on developing neonatal services there but later said to me (2008) “but I did watch the slow transformation of CF care across the UK with some knowledge that I had probably helped to nudge it into an important change of direction.” This is undoubtedly true!

 

1988 Wood RE, Piazza F. Survival in cystic fibrosis: correlation with treatment in three cystic fibrosis centres. 10th International Cystic Fibrosis Congress, Sydney 1988 Excerpta Medica Asia Pacific Services 74:79.
An impressive and important, if disturbing, study presented as a poster at the 1988 Sydney CF meeting. The medical records of three US CF Centres for the years 1971-1980 were reviewed including 24,000 outpatient visits and 2000 hospitalisations. Median survival ages at the three centres were 9.5, 18.1 and 22.8 years for centres A, B and C respectively. No differences in the content of treatment between centres correlated with group survival. But for each patient year in A, B and C the mean number of outpatient visits was 4.4, 8.0 and 12.1 and the number of hospital days was 4.7, 5.0 and 9.5. – usually hospitalisations would be for IV antibiotics. Hospitalisation was considered necessary in 19.3, 20.9 and 31.2% of patients at least once a year. There was strong correlation between group survival and the use of oral and aerosolized antibiotics, vitamins E and K, and aerosols of epinephrine. When the data was separated into 1971-1975 and 1976-1980, changes in antibiotic use correlated well with improved survival. The authors concluded “more frequent outpatient visits, more aggressive use of antibiotics and more frequent hospitalisation correlate well with increasing survival”.

It is disappointing that this excellent study was never published. I suspect the marked differences between the CF centres were unacceptable and too sensitive data for publication at that time. Interestingly similar studies, some very recent, repeatedly show patients are better when seen more frequently and receive more antibiotics – which is exactly what one would expect!

 

1988 Dodge JA, Goodall J, Geddes D, Littlewood JM, Mearns MB, Owen JR, Russell G. Cystic fibrosis in the United Kingdom 1977-85: an improving picture. British Paediatric Association Working Party on Cystic Fibrosis. BMJ 1988; 297:1599-1602. [PubMed]
A further publication from the Working Party on Cystic Fibrosis chaired by Prof. John Dodge. The national survey included all patients with CF known to paediatricians, chest physicians and others between 1977 and 1985 or whose deaths were reported through death certification authorities in the United Kingdom. The number indicated an incidence of 1 in 2500 live births. Mortality was 7.6% in the first year and greater for females than males under 20 years of age. Survival improved through the study particularly in the first five years with 100 more births than deaths each year. In particular, death from meconium ileus was increasingly less frequent. It was estimated that there were some 5000 people with CF in 1985. (1982 Formation of UK CF Working Party above; Jackson 1986 for summary of the initial Working Party report, above; Dodge et al, 2007 final data, below)

Figure 1: Survival curve from the paper by Phelan and Hey 1984. With permission from the BMJ Publishing Group.

 

1991 Littlewood AE, Bowler IM, Littlewood JM. A method of data collection and computerisation in use at a regional CF unit. 17th European Cystic Fibrosis Conference Denmark. June 1991. Poster 94.
Much of the clinical research data and the smooth running of the Leeds CF clinic were dependent on the Administrator Mrs Christine Silburn, and the clerks and secretaries.
The computer data management had been in operation since the early Eighties using first a computer funded by the Variety Club of Great Britain. Ann Littlewood (figure 25) a state registered nurse (and my wife!), was responsible for the running of our data service from the early Eighties until we both retired from clinical work in 1997.
The introduction of a Comprehensive CF Assessment service in Leeds from 1981 generated such vast amounts of data on every patient that computerisation became essential and was introduced in 1982. The system, initially using an Epson PC AX with 80Mb hard disk and 640K using Symantec Q&A software, provided a database and word processing facilities. By 1991 four databases were in use – a patient register, clinic visit database, an inpatient database and an assessment database for the results of Comprehensive Assessments. The system had been repeatedly modified and adapted over the next eight years by interested colleagues and professional computer programmers. The Leeds CF units are now totally computerised for both clinical and research purposes - a system developed by Dr Daniel Peckham, Respiratory Physician on the Adult CF Unit.

 

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 annual mortality rate for 1989-1993 was 0-1.2%. Using the age-specific mortality rate for 1989-1993, it was impossible to calculate the median survival probability because the curve did not fall below 50% (age up to 45 years); however, it was possible to show that the survival probability for a newborn CF child to reach his 45th birthday was 80.4% (confidence interval 76.5-84.6%). The median age at diagnosis was 0.63 years with no sex difference (surprisingly there was and is no neonatal CF screening in Denmark). The probability of surviving 40 years after the diagnosis of CF was made was 83.3% (confidence interval 80.1-86.6%).

These survival figures are considerably better than any other published survival probability at the time. The only item that I would not agree with the Danish CF centre is their policy of not screening neonates for CF.

 

2000 Fogarty A, Hubbard R, Britton J. International comparison of median age at death from cystic fibrosis. Chest 2000; 117:1656-1660. [PubMed]
Data from ten countries in North America, Europe, and Australasia of all persons registered as having died of CF from 1980 to 1994 were analysed by Prof. John Britton and his colleagues from Nottingham, England. The overall median age at death increased from 8 years in 1974 to 21 years in 1994. Median age at death also increased within all countries and was consistently highest in the United States. Women were significantly more likely to die at a younger age than men.

The median age of death is one of the basic indicators of survival. It is encouraging that the median age of death steadily increases each year as the effect of better treatment is reflected in better survival. The relatively recent figures for median age of death for patients registered with the UK CF Patient Registry are encouraging - in 2002 the median age of death was 23 yrs, in 2003 24.2 yrs and in 2004 25.6 years and in 2008 it had risen to 27 years.

Dr Sarah Walters has written a very clear article dealing with survival statistics which can be recommended to non-statisticians (Survival in cystic fibrosis - what do the statistics mean?) the full text of which is on her website (www.cfstudy.com)  and also on the CF Trust website (www.cftrust.org.uk).

 

2000 Cheng K. Smyth RL. Motley J. O'Hea U. Ashby D. Randomized controlled trials in cystic fibrosis (1966-1997) categorized by time, design, and intervention. Pediatr Pulmonol 2000; 29:1-7. [PubMed]
Ros Smyth, Deborah Ashby and colleagues developed a register of RCTs in CF and have studied when they were performed, their design, and what interventions were investigated. They identified 506 RCTs; 37.5% were identified solely as abstract reports in conference proceedings. There has been about a 30-fold increase in the number of RCTs in CF since 1966. A high proportion of the RCTs (72.7%) had a sample size of 30 or less, and only 8.7% were multicenter trials. Reporting of study design was poor: in 51.4% the report did not state whether there was any blinding in the trial design; 53.6% of studies were of crossover design. The most common interventions studied were antibiotic treatments and physiotherapy, but a number of commonly used therapies had been evaluated only in a small number of patients. Although the number of RCTs of interventions in CF patients has increased over the last 25 years, the sample sizes of these trials are generally too small to indicate whether the intervention was effective, and very few were multicenter. Future RCTs in CF are more likely to provide clinically useful answers if higher numbers of patients are recruited into large, well-designed multicenter trials. This should be a priority of the organization of future research in CF.

 

2007 Dodge JA, Lewis PA, Stanton M, Wilsher J. Cystic fibrosis mortality and survival in the UK: 1947-2003. Eur Respir J 2007; 29:522-526. [PubMed]
Data up to 1995 on the survival of 3-yr cohorts of patients with CF born in the UK in the period 1968-1992 had previously been published (Dodge et al. Arch Dis Child 1997; 77:493-496. 9496181). The present study, coordinated by John Dodge and the last from the original Survey of the UK CF Working party, reports survival data up to the end of 2003 together with a 2003 population estimate. All subjects with CF born in the UK in the period 1968-1992 were identified up to 1997 and information from the death certification authorities up to the end of 2003 was added.
The observed survival up to 2003 of CF patients born in 1978 was 55% for males and 49% for females. For 1988 and 1992 the data were 91 and 88%, and 97 and 96%, respectively. The estimated 2003 mid-year CF population was 8,284. The continuing improvement in survival of cystic fibrosis patients in successive cohorts means that the previous prediction of median survival of >50 yrs of age for individuals born in 2000 continues to look realistic, even in the absence of proven effective therapy aimed at correcting the basic cystic fibrosis defect.

2010 Hult G, Li Z, Scotet V, Dugueperoux I, Ferec C, Roussey M, Laxova A, Farrell PM. Participating CF centres of Brittany, France. Pulmonary outcome differences in U. S. and French cystic fibrosis cohorts diagnosed through newborn screening. J Cyst Fibros 2010; 9:44-50. [PubMed]

A comparison of the longitudinal progression of lung disease in cystic fibrosis patients identified through newborn screening (NBS) in cohorts located in two different countries is a "first".

The study included 56 patients in Brittany diagnosed through NBS between 1989 and 1994 and 69 similar patients in Wisconsin between 1985 and 1994. The onset and progression of lung disease was radiographically quantified using the Wisconsin Chest X-ray (WCXR) scoring system. A single pediatric pulmonologist blinded to all identifiers scored the films. RESULTS: Generalized estimating equation analyses adjusted for age, genotype, sex, pancreatic insufficiency, and meconium ileus showed worse WCXR scores in Brittany patients compared to Wisconsin patients (average score difference=4. 48; p<0. 001). Percent predicted FEV1 was also worse among Brittany patients (p<0. 001). The finding of milder radiographically-quantified lung disease using the WCXR scoring system, as well as better FEV1 values, may be explained by variations in nutrition, environmental exposures, or health care delivery.

 

This is the first long term comparison of children diagnosed by neonatal screening in two different countries. The clearly worse condition of the Brittany children compared to those born in Wisconsin is not explained. Although the suggestion was made that the French children had less rigorous infection avoidance and more hospitalizations, the bacteriological data was said to be not suitable for comparison which is unfortunate for it is likely to be relevant.

 

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

To evaluate the survival of patients with cystic fibrosis whose lung function has deteriorated to a forced expiratory volume in one second (FEV(1)) below 30% predicted in the recent treatment era and to explore factors associated with any change in survival. 276 patients (147 (53%) male) attending the Brompton whose FEV(1) was first observed to be less than 30% predicted between 1 January 1990 and 31 December 2003. The median survival improved from 1.2 years in the 1990-1 group to 5.3 years in the 2002-3 group, with a marked improvement in survival from 1994. The use of nebulised recombinant human DNase was significantly associated with a reduced risk of death (hazard ratio 0.59, 95% confidence interval 0.44 to 0.79). Significantly increased risks were associated with a body mass index under 19 (hazard ratio 1.52, 1.10 to 2.10), long term oxygen therapy (3.52, 2.49 to 4.99), and nebulised antibiotics (1.84, 1.05 to 3.22). The authors concluded that a marked improvement has occurred in the survival of patients with cystic fibrosis with an FEV(1) less than 30% predicted. Secondary analyses suggest that some of this improvement may be due to use of recombinant human DNase.

This is interesting and encouraging data from the UKs major adult CF centre showing a much improved survival for these severely affected patients, presumably related to improved treatment. For some years a survival;- in this study the authors suggest that the use of DNase may be a significant factor.

2011 Reid DW, Blizzard CL, Shugg DM, Flowers C, Cash C, Greville HM. Changes in cystic fibrosis mortality in Australia, 1979-2005. Med J Australia 2011; 195:392-395. [PubMed]Between 1979 and 2005, the mean age at death increased from 12.2 years to 27.9 years for males and from 14.8 years to 25.3 years for females. Overall, female deaths in childhood (0-14 years) occurred at an age-standardised rate of 0.40 per 100,000 (95% CI, 0.34-0.45) during 1979-2005, which exceeded the corresponding rate for males of 0.24 (95% CI, 0.20-0.28) per 100,000. Among 0-14-year-old boys, event rates declined markedly after 1989, but they declined later and more gradually for girls, with the result that the age-standardised rate for girls was 2.38 times that of boys during 1989-2005 (95% CI, 1.69-3.36). The authors concluded that the pattern of CF mortality in Australia has changed substantially. Mortality rates continue to be higher for girls than for boys, but death in childhood has become uncommon. Survival has increased since 1979, but females continue to have reduced length of life.

 

2011 Barr HL, Britton J, Smyth AR, Fogarty AW. Association between socioeconomic status, sex, and age at death from cystic fibrosis in England and Wales (1959 to 2008): cross sectional study. BMJ 2011; 343:d4662.[PubMed] Free full version available

Series of annual cross sectional studies of all registered deaths with a diagnosis of cystic fibrosis in England and Wales, from 1959 to 2008. From 2001 onwards, the National Statistics Socioeconomic Classification was implemented and socioeconomic status was split into three groups: professional and managerial, intermediate, and routine and manual. The authors calculated median age at death for every study year and the effects of sex and socioeconomic status on the odds of death above the median age at death for every study decade using logistic regression.                                                From 1959 to 2008, 6750 deaths were attributed to cystic fibrosis in England and Wales. Males were more likely to die above the annual median age at death than females (from 1959 to 1999, adjusted odds ratio for socioeconomic status 1.28, 95% confidence intervals 1.13 to 1.45; from 2000 to 2008, 1.57, 1.18 to 2.08). Individuals in the highest socioeconomic class were also more likely to die above the median age of death than those in the lowest socioeconomic class (from 1959 to 2000, adjusted odds ratio for sex 2.50, 2.16 to 2.90; from 2001 to 2008, 1.89, 1.20 to 2.97).                     

The authors comment that socioeconomic status and sex remain strong determinants of survival from cystic fibrosis in England and Wales, and the magnitude of these effects does not appear to have substantially reduced over time.

 

2011 Stern M, Niemann N, Wieddemann B, Wenzlaff P, on behalf of the German CFQA Group. Benchmarking improves quality in cystic fibrosis care: a pilot project involving 12 centres. Int J Qual health Care 2011; 23:349-56.[PubMed] (Full text is available to download via PubMed entry)

A group of 12 CF centres in Germany, treating a total of 1200 patients of all ages, enrolled in a nationwide pilot benchmarking project from 2004 to 2007. Key nutritional and respiratory parameters were used as quality indicators. Numerical benchmarks were set and used for ranking. Applying the plan-do-check-act cycle, quality improvement interventions were introduced, such as harmonization of definitions and references, improvement of measurement standards, data quality, completion of missing data, enforcement of early aggressive antibiotic treatment and individual adaptation of dietary counselling. Ranking alone was not sufficient for identification of the best performing centres unless it was accompanied by longitudinal follow-up. Improvement was possible in the 3 years' period as shown by benchmarking for single centres that introduced new interventions in nutritional and antibiotic treatment most consequently.

 

CF provides a model of the link between processes of health care delivery and health outcomes of patients. Quality improvement is a continuous goal in CF care with realistic potential as exemplified by our data. Accountability was introduced and transparency was improved by our pilot benchmarking project. Using the benchmarking procedure, our long-term project will reinforce standards, programmes, and individual attitudes and principles to ensure continuous quality improvement in CF health care.

 

Professor Martin Stern (figure 5) is Head of the Paediatric Department at the University Children's Hospital, University of Tubingen, Germany. He is involved in many aspects of CF care and research both nationally and internationally.

 

2011 Bell SC, Bye PT, Cooper PJ, Martin AJ, McKay KO, Robinson PJ, Ryan GF, Simms GC. Cystic fibrosis in Australia, 2009: results from a data registry. Med J Aust 2011; 195:396-400. [PubMed]

In 2009, data were submitted on 2986 people (48% female). Median age was 17.6 years and 49% of people were aged 18 years or over. Seventy-eight people were newly diagnosed. Fourteen people died and 14 people underwent lung transplantation in the year. Lung function and nutrition were relatively normal among children but deteriorated (more rapidly) among adolescents. With increasing age, progressive respiratory disease was apparent, and the frequency of CF-related complications and use of health care resources increased. In all age groups, there was a wide range in severity of lung disease and nutritional status. CF remains a progressive respiratory disease and is associated with multisystem complications. The acceleration in disease severity in adolescence and early adulthood suggests that better treatment at these stages is required to further improve survival.

 

Dr Scott Bell (figure 4) is head of the Adult Cystic Fibrosis Unit at the Prince Charles Hospital in Queensland and has published on a wide variety of aspects of CF care and research.

 

2012 Salvatore D, Buzetti R, Baldo E, Furnari ML, Lucidi V, Manunza D, Marinelli, Messore B, Neri AS, Raia V, Mastella G. An overview of international literature from cystic fibrosis registries. Part 4: Update 2011.J Cyst Fibros 2012; 11:480-493. [PubMed]

A total of 53 national cystic fibrosis (CF) patient registry studies published between July 2008 and November 2011 have been reviewed, focusing on the following topics: CF epidemiology, nutrition, microbiology, clinical complications, factors influencing diagnosis and lung disease, effects of socioeconomic status, therapeutic strategy evaluation, clinical trial methodology. The studies describe the clinical characteristics of CF patients, the incidence and prevalence of disease and role of gender gap, as well as the influence of socioeconomic status and environmental factors on clinical outcomes, covering a variety of countries and ethnic groups. Original observations describe patients as they get older, with special reference to the adult presentation of CF and long-term survival. Methodological aspects are discussed, covering the design of clinical trials, survival analysis, auxometry, measures of quality of life, follow up of lung disease, predictability of disease progression and life expectancy. Microbiology studies have investigated the role of selected pathogens, such as Burkholderia species and MRSA. Pulmonary exacerbations are discussed both as a factor influencing morbidity and an endpoint in clinical trials. Finally, some studies give insights on complications, such as CF-related diabetes and hemoptysis, and emerging problems, such as chronic nephropathy.

A comprehensive review supporting the value of patient registries which yield so much important information.

 

2012 Rowe SM, Borowitz DS, Burns JL, Clancy JP, Donaldson SH, Retsch-Bogart G, Sagel SD, Ramsey BW. Progress in cystic fibrosis and the CF Therapeutics Development Network. Thorax 2012; 67:882-890.[PubMed] Full text available

Cystic fibrosis (CF), the most common life-shortening genetic disorder in Caucasians, affects approximately 70 000 individuals worldwide. In 1998, the Cystic Fibrosis Foundation (CFF) launched the CF Therapeutics Development Network (CF-TDN) as a central element of its Therapeutics Development Programme. Designed to accelerate the clinical evaluation of new therapies needed to fulfil the CFF mission to control and cure CF, the CF-TDN has conducted 75 clinical trials since its inception, and has contributed to studies as varied as initial safety and proof of concept trials to pivotal programmes required for regulatory approval. This review highlights recent and significant research efforts of the CF-TDN, including a summary of contributions to studies involving CF transmembrane conductance regulator (CFTR) modulators, airway surface liquid hydrators and mucus modifiers, anti-infectives, anti-inflammatories, and nutritional therapies. Efforts to advance CF biomarkers, necessary to accelerate the therapeutic goals of the network, are also summarised.

This is an excellent update of the growing points in CF clinical research; full text is available online.

 

2012 Doull I, Evans H. South and Mid Wales Paediatric Cystic Fibrosis Network. Full, shared and hybrid paediatric care for cystic fibrosis in South and Mid Wales. Arch Dis Child 2012; 97:17-20. [PubMed]
Although care for children with cystic fibrosis (CF) is increasingly shared between CF centres and local CF clinics, the optimal model is unclear. The authors compared three models of care within a well established CF network in Wales: full centre care; local clinic based care with annual review by the CF centre; and hybrid care, where the child is usually reviewed at least three times a year by the specialist CF centre.

Of 199 children and young people with CF in South and Mid-Wales, 77 were receiving full care, 102 shared care and 20 hybrid care. There were no significant differences in baseline characteristics, nutritional outcomes or use of chronic therapies. There was however a statistically significant difference between full, shared and hybrid care in mean forced expiratory volume in 1 s (FEV(1)) per cent predicted (89.2% vs 74.5% vs 88.9%; p=0.001).

These differences in pulmonary function are likely to reflect the model of care received, and may affect long term outcomes.

This important study shows an advantage for children who received all their care at the Wales CF Centre in Cardiff however the results were not accepted by all Iolo Doull's colleagues in Wales and drew a vigorous response from paediatricians working in two of the local CF clinics involved - in Newport (Bowler I, Pierrepoint M, Evans R. Arch Dis Child 2012; 97:88) and Lanarkshire (Dryden C et al. Arch Dis Child 2012; 97: 88-89). So the discussion continues in the UK as to whether CF centre care is superior to care shared between a CF Centre and a local hospital clinic.

 

2012 Martin B, Schechter MS, Jaffe A, Cooper P, Bell SC, Ranganathan S. Comparison of the US and Australian cystic fibrosis registries: the impact of newborn screening.
Pediatrics 2012; 129:e348-55. [PubMed]

The authors compared the 2003 US and Australian registries.

Data on 12994 US and 1220 Australian patients aged <=18 years were analyzed. A significant difference was noted in the proportion who had been diagnosed after newborn screening (Australian 65.8% vs United States 7.2%; P < .001). Australian children had significantly greater mean height percentile (41.0 vs 32.6; P < .001) and weight percentile (43.5 vs 36.1; P = .028) than US children. Mean forced expiratory volume in 1 second (FEV(1)) percent predicted adjusted for age, gender, and genotype was similar in the 2 countries (P = .80). Patients diagnosed after newborn screening had higher mean FEV(1) (5.3 [95% confidence interval (CI): 3.6-7.0]) percent predicted and BMI (0.26 [95% CI: 0.09-0.43]). Mean FEV(1) of Australian patients diagnosed after newborn screening was lower by 5.2 (95% CI: 2.8-7.6) percent predicted compared with US children.

CONCLUSIONS: Children diagnosed with CF after newborn screening benefited from better lung function and BMI than those diagnosed clinically. The benefit of newborn screening on lung function was significantly less in Australian children compared with US children. Statistical comparisons between CF registries are feasible and can contribute to benchmarking and improvements in care

 

2012 Scotet V, Dugueperoux I, Saliou P, Rault G, Roussey M, Audrezet MP, Ferec C. Evidence for decline in the incidence of cystic fibrosis: a 35-year observational study in Brittany, France. Orphanet J Rare Dis 2012; 7:14. [PubMed]
This study assessed time trends in the birth incidence of CF over a long period (35 years: 1975-2009) in an area where CF is frequent (Brittany, France) and where NBS has been implemented for more than 20 years. The average number of patients born each year declined from 18.6 in the late 1970's (period 1975-79) to 11.6 nowadays (period 2005-09). The corresponding incidence rates dropped significantly from 1/1983 to 1/3268, which represented a decline close to 40% between these two periods A clear breakpoint in incidence rate was observed at the end of the 1980's (p < 0.0001). However, the incidence rate has remained quite stable since that time. The authors observed a 40% drop in incidence which seems consecutive to the availability of prenatal diagnosis.

In other areas where neonatal screening (UK, Australia, Italy) and indeed antenatal screening (Edinburgh) have been introduced there has been a significant reduction in the incidence of infants born with CF. Theoretically the means are now available to prevent all CF births (carrier detection, antenatal diagnosis, preimplantation genetic diagnosis) however neither the finances nor the will to do this appear to be in place at present.

 

2015 Goss CH; MacNeill SJ; Quinton HB; Marshall BC; Elbert A; Knapp EA; Petren K; Gunn E; Osmond J; Bilton D. Children and young adults with CF in the USA have better lung function compared with the UK. Thorax 2015; 70(3):229-36.    [PubMed]
A cross-sectional study using 2010 data from patients in the US Cystic Fibrosis Foundation and the UK Cystic Fibrosis patient registries. The a priori outcome measures of interest were lung function and nutritional status. Descriptive statistics and two sample comparisons were performed. Stratification and multivariable linear regression were used to adjust for confounding.
The study cohort included 13,777 children and 11,058 adults from the USA and 3968 children and 3965 adults from the UK. In children, mean body mass index centiles were similar. Lung function (FEV1 and FVC% predicted) was significantly higher in US patients ages 6-25 years of age. In a regression model adjusted for only age, FEV1% predicted was on average 3.31% of predicted (95% CI 2.65 to 3.96) higher in the USA compared with the UK. When adjusted for age, age at diagnosis, gender, pancreatic insufficiency and genotype, FEV1% predicted was on average 3.03% of predicted (95% CI 2.37 to 3.69)
higher in the USA compared with the UK. These differences persisted despite adjustment for possible confounders. Hypertonic saline and dornase alfa were much more commonly prescribed in US children.
The authors concluded children and young adults with CF have better lung function in the USA compared with the UK despite similar nutritional status.
 
- This is an important study involving international collaboration made possible using the national CF databases. The observation made by the authors, that certain preparations such a dornase alpha and hypertonic saline were much more frequently prescribed in the USA, is likely to be a major factor in the difference in respiratory function (see abstract of the editorial by Taylor-Robinson et al. below).

 

2015 Taylor-Robinson D C, Schechter M, Smyth RL. Comparing cystic fibrosis outcomes across the pond. Thorax 2015; 70:203-204 Editorial. [PubMed]
This is a very interesting commentary on the study of Goss et al. (Thorax 2015; 70(3):229-36.  [PubMed]). The authors raise some questions concerning the conclusion that lung function of USA children is significantly better than that of UK children – a difference most marked around 6 years. 
They ask if the samples are fully representative of the entire CF populations of the respective countries? The UK captures almost the entire CF population whereas the US data is for patients attending US accredited centres (an estimated 75%) containing fewer socially disadvantaged patients. However, even removing such patients from the UK data did not account for most of the difference.  Also genetic and ethnic differences were not responsible.  The data is cross sectional and may not represent true longitudinal differences and the older patients may represent only those healthier individuals who have survived. But even so, the differences in early lung function seem to be genuine albeit less than stated.
Possible reasons for the great discrepancies are the use of rhDNase and possibly nebulised hypertonic saline between young patients (<18yrs) in the UK and USA are possible reasons. For example at the time of the study use of treatments in USA vs. UK were - hypertonic saline 40.9% vs. 8.4%, any nebulised antibiotic 44 .7% vs. 42.9%, rhDNase 77.2% vs. 35.4% and macrolides 33.6% vs. 24.1%
Also all the US patients included attended recognised specialist CF Centres, which is not always the case in the UK, even though health and survival have been shown to be better with the more expert experienced care at specialist centres. Such centre care includes more frequent clinic visits, more frequent respiratory cultures and antibiotic treatments particularly at an earlier stage in milder affected patients - all factors known for generations to improve health and survival of people with CF.
 

In this reviewer’s (JML) opinion, the expert care delivered at specialist centres and the great difference in the use of rhDNase are likely to be the main reasons for the discrepancy in respiratory function of the children. Also the overall coverage in the UK will include more patients not attending specialist centres. It is sad that, even today, some UK paediatricians are not convinced of the benefit of referring their patients to a specialist CF centre and complain of the lack of “controlled studies”. As Sir William Osler observed “ Medicine is to be learned by experience and is not an inheritance; it cannot be revealed. Learn to see, learn to hear, learn to smell, and know that by practice alone can you become expert”
With regard to the use of rhDNase, almost every study since the treatment became available in the early Nineties has shown significant improvement in some aspect of the condition of the treated patients even amounting to improving survival. Please see Topics -> Mucolytics -> Pulmozyme (rhDNase) where I have reviewed many of the earlier publications, particularly relevant being those showing improvement even in young and mildly affected patients. These findings encouraged the earlier use of rhDNase in infants and preschool children as soon as they were able to inhale the drug at both the Leeds and Copenhagen CF Centres.
This study highlights the great value of such comparative studies which are possible using reliable national databases such as are now established at the CF Foundation, the UK CF Trust and elsewhere.  They certainly justify the many problems we experienced in collecting and processing data the early years when the databases were started by these two national organisations.
 

2015 Merlo CA; Clark SC; Arnaoutakis GJ; Yonan N; Thomas D; Simon A; Thompson R; Thomas H; Orens J; Shah AS.  National Healthcare Delivery Systems Influence Lung Transplant Outcomes for Cystic Fibrosis. Am J Transplant 2015; 15(7):1948-57.  [PubMed]
Successful lung transplantation (LTx) depends on multiple components of healthcare delivery and performance. The authors conducted an international registry analysis to compare post-LTx outcomes for cystic fibrosis (CF) patients using the UNOS registry in the United States and the National Health Service (NHS) Transplant Registry in the United Kingdom.
 
- Both the United States and United Kingdom have similar early survival outcomes, suggesting important dissemination of best practices internationally. However, patients using US Medicare/Medicaid insurance had significantly worse survival after lung transplant.
 

Burgel PR1, Bellis G2, Olesen HV3, Viviani L4, Zolin A4, Blasi F5, Elborn JS; ERS/ECFS Task Force on The Provision of Care for Adults with Cystic Fibrosis in Europe.Future trends in cystic fibrosis demography in 34 European countries.Eur Respir J. 2015 Mar 18. pii: ERJ-01963-2014. [Epub ahead of print][PubMed]
The aim of this study was to estimate the number of children and adults with CF in 34 European countries by 2025. Western European countries' forecasts indicate that an increase in the overall number of CF patients by 2025, by approximately 50%, corresponds to an increase by 20% and by 75% in children and adults, respectively. In Eastern European countries the projections suggest a predominant increase in the CF child population, although the CF adult population would also increase.
It was concluded that a large increase in the adult CF population is expected in the next decade. A significant increase in adult CF services throughout Europe is urgently required.

 

 

2015 Peckham D, Williams K, Wynne S, Denton M, Pollard K, Barton R.  Fungal contamination of nebuliser devices used by people with cystic fibrosis.  J Cyst Fibros. 2015 Jun 20. pii: S1569-1993(15)00153-8. doi: 10.1016/j.jcf.2015.06.004. [Epub ahead of print] [PubMed]
A total of 170 nebulisers from 149 subjects were screened by wetting a sterile cotton swab with sterile water and swabbing each drug chamber. The swab was then plated out on Sabouraud and on Scel+agar and incubated at 27°C for up to 2weeks.
Fungal cultures were positive in 86 (57.7%) patient's devices. In 28/149 (18.8%), 39/149 (26.2%), 47/149 (31.5%) and 20/149 (13.4%) of subjects Aspergillus species, yeasts, moulds and both yeasts and moulds were isolated respectively. There was no difference in contamination rates between different devices.
Nebuliser devices are frequently contaminated by moulds and yeasts and emphasis should be placed on ensuring adequate nebuliser hygiene.

 
 
2015 Peckham D, Whitaker P, White H.  Research in progress-electronic patient records: a new era. Thorax 2015 May; 70(5):473-5. doi: 10.1136/thoraxjnl-2014-206573. Epub 2014 Dec 10.     [PubMed]
 
Clinical information systems and electronic records are starting to appear in secondary care and herald new potentials for improving health provision and capturing high quality data. In 2006, the authors set up a program to develop electronic patient records (EPR) for chronic disease using Cystic Fibrosis (CF) as their initial model. Seven years on they are now exploring the real time clinical data to identify risks, trends and outcomes in chronic disease management. The authors are also working to establish new models of integration and to connect information between the client and all areas of health care.
 

-  The author’s Regional CF Centre for adults at St James’s University Hospital in Leeds has pioneered the use of electronic records and the unit now is mostly without paper records.