WORKING PARTIES, ASSOCIATIONS, REPORTS

1982 British Paediatric Association (BPA) Working Party on Cystic Fibrosis was formed. Supported by the Royal College of Physicians of London (RCP) and the British Thoracic Society(BTS).
This was the start of a major change in the care of people with CF in the UK. The Phelan & Hey 1984 data was available in 1982 (Phelan & Hey, 1984 below) and prompted the formation of this British Paediatric Association Working Party on Cystic Fibrosis – funded by the CF Trust. Their brief was “To assess the advantages and disadvantages of regional centres for cystic fibrosis”. The members of the Working Party were John Dodge (Chairman, Paediatrician), Janet Goodall (Paediatrician), Duncan Geddes (Respiratory Physician), Jim Littlewood (Paediatrician), Margaret Mearns (Paediatrician) and George Russell (Paediatrician).
The working party initiated the UK Survey to determine the present state of the UK patients. The findings were summarised by Tony Jackson on behalf of the CF Trust (Working Party on Cystic Fibrosis. Arch Dis Child 1986; 61:724 below).
Also a fuller report eventually appeared (BMJ 1988; 297:1599-1602 below). John Dodge recalls that the report was accepted by the Royal College of Physicians and the British Thoracic Society but initially rejected by the British Paediatric Association council who were reluctant to have their patients' care taken over by CF centres; the paediatricians required it to be "watered down" before it was eventually published!

Prof. John Dodge CBE (Figure 21) was Director of the Cardiff CF Centre before moving to Belfast as Professor of Paediatrics. He has been involved in CF for many years and published widely on the subject. He set up regional CF clinics in Northern Ireland in 1965 when a lecturer there and in Cardiff in 1971. He was Chairman of the Scientific and Medical Advisory Committee of the International Cystic Fibrosis (Mucoviscidosis) Association and has chaired CF working parties for the WHO. A major contribution was the supervision and ongoing analysis of the data collection of which started with the UK Working Party in 1982, the final analysis of which was published in 2007 (Dodge et al, Eur Respir J 2007; 29:522-526).

1986 Jackson ADM. Working Party on Cystic Fibrosis. Arch Dis Child 1986; 61:724.
Dr Tony Jackson, (figure 31) who prepared this summary, was a paediatrician in London and involved with CF for many years working at the Queen Elizabeth Hospital Hackney and the London Hospital. He qualified at the Middlesex in 1943 and after war service in the RAMC trained in paediatrics, being appointed first to Epping Hospital and later to Queen Elizabeth Hospital Hackney, Great Ormond Street and the London Hospital. He was the longest serving officer of the British Paediatric Association and between 1967 and 1983 was secretary, assistant secretary or treasurer. He was involved with many national and international paediatric committees and latterly was Chairman of the UK Cystic Fibrosis Trust’s Research and Medical Advisory Committee.

1995 The Cystic Fibrosis and Genetic Disorders Group is a Collaborative Review Group (CRG) of The Cochrane Collaboration and was formed in 1995.
This Cochrane group for CF was formed in 1995 and was expanded to cover other genetic disorders in 1997. It consists of a team led by Prof. Ros Smyth of Liverpool (figure 35) who are interested in producing high quality Systematic Reviews of controlled clinical trials in CF and, since 1997, other genetic disorders. Initially supported by the UK CF Trust, the group is now supported by the NHS R&D (UK). Reviewers undertake the work on a voluntary basis and by 2008 there were over 70 Systematic Reviews on various aspects of treatment. Almost all the reviews highlight the lack of controlled trials on many aspects of treatment; however, the information from systematic reviews published on the website has proved an increasingly valuable source of information for those dealing with CF – even though the stringent standards of the Reviewers on occasion have proved irritating to some elderly clinicians! Undoubtedly Ros Smyth and the Group have had a major and favourable influence on the number and standards of clinical trials which have favourably influenced the management of people with CF.

Professor Archie Cochrane (1908-1988) (figure 36) was born in Kirklands, Galashiels, Scotland. He qualified in 1938 at University College Hospital, London, and joined the Medical Research Council's Pneumoconiosis Unit at Llandough Hospital, a part of Cardiff University School of Medicine in 1948. Here he began a series of studies on the health of the population of Rhondda Fach — studies which pioneered the use of randomised controlled trials. His 1971 Rock Carling monograph Effectiveness and Efficiency: Random Reflections of Health Services was very influential. These ideas and his advocacy of randomized controlled trials eventually led to the development of the Cochrane Library database of systematic reviews, the establishment of the UK Cochrane Centre in Oxford and the international Cochrane Collaboration (from Cochrane website).

The present report of the Working Party on Cystic Fibrosis notes the difference in survival between centres the best being from Melbourne with an 80% survival to 20 years, compared with England and Wales where 80% survived to only 9 years. 99% of UK paediatricians responded to a national survey with details of 4557 patients. Only 16 centres treated more than 50 patients and only 1800 patients (46.5%) were on the records of these 16 centres. The working party supported the principle of specialised centres for CF which had been accepted both by the WHO and the International Cystic Fibrosis Association, but suggested that shared care would be appropriate for some children depending on local arrangements. Minimum staffing levels were suggested and close cooperation with adult physicians was recommended as was collaboration between centres in data collection, clinical trials and research.
The data on the better survival in Victoria, Australia than in England and Wales was a major factor in the formation of this UK Working party (Prof John Dodge commented on this data - "the original data 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!
Unfortunately the council of the British Paediatric Association initially rejected the report, the members of the council, we believe misguidedly, maintaining that children with CF could be quite adequately cared for by a general paediatrician at their local hospital. Nonetheless, this was a highly influential report which eventually had a major effect on the development of CF centres throughout the UK, thus steadily improving the care and survival of children with CF. The CF Survey, which the Working Party initiated, produced useful data on numbers and survival until replaced in 1995 by the UK CF Database in Dundee and then eventually by the UK CF Trust’s CF Registry in 2007- the latter using the North American Port CF system. (Also Dodge et al and BPA Working Party on Cystic Fibrosis. BMJ 1988; 297:1599-1602 for full report and details of a follow-up survey below).

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).

1998 Rosenstein BJ, Cutting GR for the Cystic Fibrosis Consensus Panel. The diagnosis of cystic 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 the characteristic phenotypic features OR a history of CF in a sibling OR a positive neonatal screening result AND an increase in sweat chloride concentration (> 60mmol/l) OR identification of two CF mutations OR demonstration of abnormal nasal epithelial transport.

2001 Standards for the Clinical Care of Children and Adults with Cystic Fibrosis in the UK. The CF Trust Clinical Standards and Accreditation Group. London. Cystic Fibrosis Trust, May 2001. Full text on the CF Trust website www.cftrust.org.uk
This document was influential in improving care both in the UK and Europe. The principles were similar to those subsequently incorporated in to the ECFS standards of care document in 2005 (Kerem et al. J Cyst Fibros 2005; 4:7-26. below). This UK document was still widely used in 2010 when it was due to be replaced by a care pathway document. However, the principles of good care remain much the same except the precautions against cross infection with P. aeruginosa have become more stringent during the decade as the problems associated with highly transmissible strain of P. aeruginosa were recognised (Jones et al. Lancet 2001; 358:557-558. ). [PubMed]

2002 van Koolwijk LM, Uiterwaal CS, van der Laag J, Hoekstra JH, Gulmans VA, van der Ent CK. Treatment of children with cystic fibrosis: central, local or both? Acta Paediatr 2002; 91:972-977. [PubMed]
The progress of 41 totally CF Centre treated patients, 23 who came to the CF centre annually for review and 41 treated in close cooperation between the CF Centre and local hospitals. After 3 years there were no significant differences in pulmonary function, nutritional status or microbiological status. The authors conclude the results - could signify that local paediatricians have a special role in the care of patients with CF in close cooperation with the specialist centre”.

So should every patient attend a CF Centre as recommended by virtually all experienced CF clinicians since the Sixties? There is still considerable discussion on this question. This study is reassuring as it provides some support for the concept of “shared-care” which, like it or not, is still widely practised in the UK and elsewhere. There is an appropriate standard, condoned in the CF Trust’s Standards of Care document but shared care is not recommended for adults. It is possible that as regimens of treatment become more established, the standard of care at smaller local clinics will approach that at CF centres.  However, there are still some children attending their local hospital with only sporadic visits to and advice from the staff at the Specialist CF Centre which is unsatisfactory. Also the numbers in this present study are small.

2003 Johnson C, Butler SM, Konstan MW, Morgan W, Wohl ME. Factors influencing outcomes in cystic fibrosis: a center based analysis. Chest 2003; 123:20-27. [PubMed]
The analysis was conducted using data from the Epidemiologic Study of Cystic Fibrosis from 1995 through 1996. Within-site rankings tended to be consistent across the three age groups. Patients who were treated at higher ranking sites had more frequent monitoring of their clinical status, measurements of lung function, and cultures for respiratory pathogens. These patients also received more interventions, particularly courses of IV antibiotics for pulmonary exacerbations. There were substantial differences in lung health across different CF care sites. Frequent monitoring and increased use of appropriate medications in the management of CF are associated with improved outcomes.

Fig. 32: Dr Charlie Johnson
Fig. 37: Professor Eitan Kerem, Professor Batsheva Kerem and Sandra Sufian

This study by Dr Charlie Johnson (figure 32) and colleagues confirmed the value of collecting data in a registry and analysis to yield valuable information. Their findings reinforce the value of more frequent monitoring and interventions in achieving better clinical outcomes.

2005 Kerem E, Conway S, Elborn S, Heijerman H for the Consensus Committee. Standards of care for patients with cystic fibrosis: a European consensus. J Cystic Fibrosis 2005; 4:7-26. [PubMed]
An important document developed at an ECFS Artimino conference. The document is now generally accepted throughout Europe and provides a basis for developing optimal CF care and a standard against which care in individual centres can be judged. Most European countries have accepted the standards. Full text available on the European CF Society website (www.ecfsoc.org). There is a commentary on this report by Littlewood JM. 2005 (below).

Eitan Kerem, is Professor of Paediatrics at Hadassah Hospital Israel, his wife Batsheva Kerem, is Professor of Genetics Jerusalem and Sandra Sufian.

2007 Flume PA., O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB, Bujan J, Finder J, Lester M, Quittell L, Rosenblatt R, Vender RL, Hazle L, Sabadosa K, Marshall B. Cystic Fibrosis Foundation, Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Amer J Respir Crit Care Med 2007; 176: 957-969. [PubMed]
In 2005 the Cystic Fibrosis Foundation established a committee to examine the clinical evidence for each therapy used for CF and to provide guidance for the prescription of these therapies. The committee members developed and refined a series of questions related to drug therapies used in the maintenance of pulmonary function. Questions were addressed in one of three ways, based on available evidence: (1) commissioned systematic review, (2) modified systematic review, or (3) summary of existing Cochrane reviews. The strength of the evidence and the estimate of benefit were recorded and the recommendations graded. Grade A-good evidence and substantial benefit. Grade B- fair evidence, benefit outweighs harm. Grade C - no recommendation, benefits and harm balance too close. Grade D - fair evidence not effective or harm outweighs benefit. Grade I - insufficient evidence”.
The current treatments received the following grades-
Nebulised tobramycin - grade A for severe, grade B for mild persistent Pseudomonas infection; evidence for other inhaled antibiotics insufficient; (surprisingly even in 2005 the important area of early Pseudomonas treatment was not dealt with); rhDNase grade A recommendation; hypertonic saline grade B; inhaled and oral steroids both grade D;
non-steroidal anti-inflammatory drugs grade B; leukotriene modifiers insufficient evidence ; macrolides grade B;
prophylactic anti-staphylococcal antibiotics grade D; ß-agonist bronchodilators grade B; anti-cholinergic bronchodilators Grade I; n-acetylcysteine grade I.
The treatments that have been the subject of a CF Foundation Phase III trial are awarded either A or B recommendation. It is quite surprising that even in 2007 the early eradication treatment of Pseudomonas is not considered in a document on inhaled therapy. Not all would agree with the grading of prophylactic anti-Staphylococcal antibiotics for which there is a good European trial (Weaver et al, 1995 above) and a wealth of European experience.

Dr Patrick Flume works at the Medical University of South Carolina where he is Professor of Medicine and Pediatrics. He is also Director of the CF Centre there. He is co-chair of the Pulmonary Practice Guidelines Committee.

2008 Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr 2008; 153:S4-S14. [PubMed]
The diagnosis of infants detected by neonatal CF screening is not always straightforward and this report gives advice to employ a combination of clinical presentation, laboratory testing and genetics to confirm a diagnosis of CF.
A European CF Society consensus report also dealt with problem of equivocal diagnosis after neonatal CF screening and dealt with sweat testing, further assessment and investigations, review arrangements and the database (Mayell SJ et al. J Cyst Fibros 2009; 8:71-78. [PubMed]

2009 Flume PA, Robinson KA, O'Sullivan B, Finder JD, Vender RL, Willey-Courand DB, White TB, Marshall BC. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Clinical Practice Guidelines for Pulmonary Therapies Committee. Respiratory Care 2009; 54:522-537. [PubMed]
A CF Foundation committee found no evidence that one method of airway clearance was superior to the others and although the evidence for benefit was not strong, recommended daily airway clearance be performed and regular exercise taken by all patients.

A number of studies have failed to show one method of airway clearance better than the others although physiotherapy is better than no physiotherapy.  

2009 Goubau C, Wilschanski M, Skalicka V, Lebecque P, Southern KW, Sermet I, Munck A, Derichs N, Middleton PG, Hjelte L, Padoan R, Vasar M, De Boeck K. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax 2009; 64:683-691. [PubMed]
Patients with intermediate sweat chloride values in whom either additional CF diagnostic test was abnormal were compared with subjects in whom this was not the case and patients with classic CF. The phenotypic features of four groups were compared: 59 patients with CFTR dysfunction, 46 with an intermediate sweat chloride concentration but no evidence of CFTR dysfunction (CF unlikely), 103 patients with CF and pancreatic sufficiency (CF-PS) and 62 with CF and pancreatic insufficiency (CF-PI). The CFTR dysfunction group had more lower respiratory tract infections (p = 0.01), more isolation of CF pathogens (p<0.001) and clubbing (p = 0.001) than the CF unlikely group, but less frequent respiratory tract infections with CF pathogens than the CF-PS group (p = 0.05). Patients in the CF-PS group had a milder phenotype than those with PI. Many features showed stepwise changes through the patient groups. The authors concluded that patients with intermediate sweat chloride values and two CFTR mutations or an abnormal NPD measurement have a CF-like phenotype compatible with CFTR dysfunction and, as a group, differ phenotypically from patients with intermediate sweat chloride values in whom further CF diagnostic tests are normal as well as from CF-PS and CF-PI patients.

Although these conclusions seem obvious there are helpful when considering patients with a dubious diagnosis.<

2009 Dequeker E, Stuhrmann M, Morris MA, Casals T, Castellani C, Claustres M, et al. Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders – updated European recommendations. Eur J Hun Genet 2009; 17:51-65. [PubMed]
An increasing number of laboratories offering molecular genetic analysis of the CFTR gene and the growing use of commercial kits strengthen the need for an update of previous best practice guidelines (published in 2000). The importance of organizing regional or national laboratory networks, to provide both primary and comprehensive CFTR mutation screening, is stressed. Current guidelines focus on strategies for dealing with increasingly complex situations of CFTR testing. Diagnostic flow charts now include testing in CFTR-related disorders and in fetal bowel anomalies. Emphasis is also placed on the need to consider ethnic or geographic origins of patients and individuals, on basic principles of risk calculation and on the importance of providing accurate laboratory reports. Finally, classification of CFTR mutations is reviewed, with regard to their relevance to pathogenicity and to genetic counselling.

2009 Castellani C, Southern KW, Brownlee K, Dankert Roelse J, Duff A, Farrell M, Mehta A, Munck A, Pollitt R, Sermet-Gaudelus I, Wilcken B, Ballmann M, Corbetta C, de Monestrol I, Farrell P, Feilcke M, Férec C, Gartner S, Gaskin K, Hammermann J, Kashirskaya N, Loeber G, Macek M Jr, Mehta G, Reiman A, Rizzotti P, Sammon A, Sands D, Smyth A, Sommerburg O, Torresani T, Travert G, Vernooij A, Elborn S. European best practice guidelines for cystic fibrosis neonatal screening. J Cyst Fibros 2009; 8:153-173.
A European document full of good advice. When starting a newborn screening programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes.

2007 Padman R. McColley SA. Miller DP. Konstan MW. Morgan WJ. Schechter MS. Ren CL. Wagener JS. Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Infant care patterns at epidemiologic study of cystic fibrosis sites that achieve superior childhood lung function. Pediatrics 2007; 119:e531-537. [PubMed]
The aim of this study was to assess whether patterns of care for infants at cystic fibrosis sites with superior average lung function in 6- to 12-year-old children showed any differences from those at the lowest outcome sites. Upper quartile sites had more infants whose disease was diagnosed by family history or newborn screening, fewer infants with symptoms at diagnosis, higher weight for age at enrollment, more white patients, and more deltaF508 homozygotes. Medical conditions and respiratory tract microbiology differed between sites. Infants at upper quartile sites had more office and sick visits; more respiratory tract cultures; and more frequent use of intravenous antibiotics, oral corticosteroids, mast cell stabilizers, and mucolytics; but they received less chest physiotherapy, inhaled bronchodilators, oral nutritional supplements, and pancreatic enzymes.

As would be expected, both enrollment characteristics and infant care patterns are associated with lung function outcomes in later childhood. Our analysis suggests that pulmonary function of older children may be improved through specific interventions during the first 3 years of life. This very useful study confirms that progress of children with CF is commonly determined by their early treatment - particularly before significant chest damage has occured.