Origins and Development of the Leeds Regional Cystic Fibrosis service (Pt 2)

May 1980. We start “Comprehensive CF Assessments”  at St James’s

In view of the suboptimal treatment our first study had revealed, and on the basis of Crozier’s recommendation to “perform a complete assessment of the patient” and then “continuing attempts to obtain normal bodily function and maintain it”, in May 1980, as soon as I returned to Leeds from the Toronto meeting. With the help of a few colleagues at St James’s, we started regular Comprehensive CF Assessments (often referred to as “Assessments” in the following text).

During 1980 over the next year all our CF children had Assessments, both children from our own clinic and any referred from other consultants, to determine if there was any way we could improve their condition or treatment.  These Assessments involved all aspects of the child’s physical

condition and treatment (details below). I suspect in these days of Cochrane Systematic Reviews and evidence-based medicine, CF Assessments would not have been funded as, at that stage, we had absolutely no idea what such detailed and expensive Assessments would show or if acting on the knowledge so gained would result in long-term benefit for the patient – which at this stage of our knowledge meant survival. Fortunately, as I will describe, the frequent major changes in management introduced as a result of these Assessments did have a profound long term effect on the health and outlook for many children with CF. Over the years such annual Assessments eventually became an established and recommended part of management and were adopted by most CF centres – the “Annual MOT” using the analogy of the motorcar. Undoubtedly Leeds led the way in this practice.

The concept of dedicated specialist CF Teams at CF centres appeared to be well established in some parts of N. America by 1980. The concept had been encouraged and sponsored by the CF Foundation since the early Sixties following the excellent results from Leroy Matthews and Carl Doershuk (mentioned above). 

Many N. American “CF Teams” attended the 1980 Toronto conference 

In relation to CF centres, the other surprise for me at the 1980 Toronto conference was the presence of so many nurses, physiotherapists, dietitians and psychologists/social workers at the meeting. At that time there was only one specialist CF nurse in the UK at the Royal Brompton in London and there were few specialist nurses apart from Special Care Baby Unit Nurses attached to premature baby  units.  At that time it would have been unusual for UK nurses or allied health professionals to attend a major international medical conference. 

The care most of our CF children were receiving was quite obviously below the standard of that received by many children fortunate enough to be attending one of the major N. American centres. Although, as Ron Tucker told me many times in this context, the standards did vary widely between clinics in the USA.  In the UK very few CF children attended such clinics where care was of such a high standard as that provided by Drs. Winifred Young, Margaret Mearns, Archie Norman and David Lawson in their London clinics and Prof. Charlotte Anderson in Birmingham. Most UK children did not attend such clinics and most died in childhood, the dreadful prognosis being accepted as inevitable.

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Warren Warwick

As far back as the early Sixties Leroy Matthews and Carl Doershuk (Matthews & Doershuk, 1964; Doershuk et al, 1964; Doershuk et al, 1964) at the Cleveland Centre were already reporting improved results that some paediatricians in N. America found hard to believe. Veteran CF physician Dr. Warren Warwick of Minnesota (figure) wrote of Leroy Matthews – “Leroy Matthews, the greatest genius CF has seen, single handedly established the value of Comprehensive Treatment, laid the ground work for Pediatric Pulmonology, and led the CF Centres as well as planning and directing excellent research. He made only two mistakes. He allowed his “Comprehensive Treatment” plan to be equated with “mist tent therapy” so when the mist tent was discredited many also felt the Comprehensive Care Program was discredited”. The other was he tried too hard to control his own diabetes. 

In the context of the excellent Cleveland results, Warren Warwick (figure) considers “one of the factors that led to the establishment of a ten year annual grant (to Warwick for his database) from the CF Foundation was the desire of some of the early leaders in CF (connected to the CF Foundation) to prove that Leroy Matthews was a fraud in claiming to have reduced the annual mortality of CF by some tenfold”.  When Warwick’s Patient Registry data showed that the annual mortality was indeed less than 2% per year the same doubters engineered a conference in Philadelphia to show that the statistical studies done in Minnesota were incorrect. However, the opinion of a leading life insurance actuary was sought and he found the figures to be correct ! (Warwick, 2001). 

– Warren Warwick in Doershuk CF (ed). Cystic fibrosis in the 20th Century. AM Publishing, Cleveland 2001:319..    
– Matthews LW, Doershuk CF, Wise M, Eddy G, Nudelman H, Spector S. A therapeutic regimen for patients with cystic fibrosis. J Pediatr 1964; 65:558-575. 
– Doershuk CF, Matthews LW, Tucker AS, Nudelman H, Eddy G, Wise M, Spector S. A 5-year clinical evaluation of a therapeutic program for patients with cystic fibrosis. J Pediatr 1964; 65:677-93. 
– Doershuk CF, Matthews LW, Tucker A, Spector S. Evaluation of a prophylactic and therapeutic program for patients with cystic fibrosis. PlPediatrics 1965; 36:675-688. 

May 1981. We offer Comprehensive CF Assessments to paediatric consultant colleagues in the Yorkshire Region for their CF patients.

The first twelve month’s CF Assessments on our own CF patients from May 1980, started as soon as I returned from Canada. They revealed numerous areas where our management could be improved by more effective use of already available treatments.  

In 1981 the obvious importance of these disappointing results on our first 20 or so patients prompted me to write to all paediatric consultants in the Yorkshire Region (population 3.6 million), many of whom I had known for a number of years, describing the disturbing results on our own CF patients. I described how we had discovered many areas where treatment could be improved. So in the light of these findings, I offered for our small team to carry out Comprehensive CF Assessments on their children with cystic fibrosis. I made it clear from the outset we would not “take over” their patients – merely carry out a detailed assessment of every aspect of their treatment and condition, after which I would return them with a full report and suggestions for any changes in management considered appropriate.

This would not have been possible in 2017 in the NHS, due to funding problems, but in 1981 there was no restriction on referring patients from one hospital to another from any part of the country – no question of funding issues – that was to come later! In fact, cost did not figure high on our reckoning at that time although it gradually became a very significant factor. During the early years we had referrals from as distant as Glasgow, Bristol, Hong Kong and Poland.

This freedom to accept referrals from elsewhere was obviously a major factor facilitating the development of our regional CF service.

1981 There were soon referrals from around the Yorkshire Region 

Understandably the first children referred from elsewhere were those experiencing particular problems and whose condition was causing concern to their parents and the local paediatrician.  Also Ron Tucker, Director of the CF Trust, had advised other families to ask for a referral to my clinic at St James’s if they were  concerned about the treatment they were receiving at their local hospital, 

Thus, by 1982, we were providing a CF Assessment Service not only for our own Leeds patients but also for those referred by paediatric consultants from other hospitals in the region. Disappointedly, two senior Leeds consultant paediatricians did not refer their few patients.  Despite my best intentions not to “take over” the children, approximately 10% of those referred were in such poor condition that they were admitted at once to our ward at St James’s for intensive physiotherapy, intravenous antibiotics and nutritional rehabilitation; understandably some of these families opted to continue their follow-up at St James’s when they observed the often dramatic effect of more aggressive antibiotic and nutritional treatment.

Both the treatment and the physical state were frequently found to be suboptimal and, it must be said, reflected treatment in many general hospitals in the UK during the Eighties. For example, of our first 250 referred patients, the diagnosis was incorrect in 7 (3%), the chest was obviously under treated in 30%, physiotherapy was suboptimal or not preformed at all in 60%, the energy intake was inadequate and less than 120% of the recommended daily allowance in 75%, pancreatic supplements inadequate in 40% and vitamin supplements insufficient resulting in suboptimal plasma levels in 60%.

Peak flow rates during initial treatment
Weight, clinical score and laboratory findings during initial treatment

This was the type of patient referred to as “under-treated.” Unfortunately, although such patients improved quite dramatically initially and for a few years when treated aggressively, some then deteriorated despite treatment, as did this girl, who died aged 16 years. In her weight chart (figure) the initial dramatic improvement is evident with her first course of intravenous anti-pseudomonal antibiotics (lower vertical arrows); subsequent rapid deterioration followed until regular inhaled gentamicin and carbenicillin were introduced. However, although with frequent courses and IV antibiotics and the nebulised antibiotics there was a steady improvement in her weight, her condition gradually deteriorated until she died of respiratory failure.

As the numbers of referrals increased the medical, nursing and allied professionals – Sue Morton (physiotherapist) and Anita MacDonald  (dietitian) – gave more than their allotted time to the CF service and became increasingly knowledgeable, indeed experts, in the treatment of CF – but also they were increasingly over-worked. Indeed, it was not unusual to see Anita MacDonald on the children’s ward late into the evening.     

Anita MacDonald
Betty and Sue Morton

Anita MacDonald left Leeds to work at Birmingham  Children’s Hospital where she sought more involvement in metabolic disorders. She had a brilliant career making major contributions in the treatment of many paediatric disorders particularly phenylketonuria. She achieved a PhD, a Chair in Nutrition and in 2016 she was awarded an OBE.

We were continually impressed by the value of long term involvement of staff for the delivery of a good clinical service. This was greatly appreciated by the children and their families.

In the organisation and carrying out these assessments, Jeanette Firth was the Day Unit Nurse at the time and managed the complex day’s arrangements. There was outstanding secretarial support from Christine Silburn and her staff.Christine had been with me since Seacroft when she was a young secretary aged 17  years. She was a brilliant secretary and organiser. She is now (in 2019) a grandmother and recently retired as Senior Administrator of the present Regional Paediatric CF Unit now at the Leeds General Infirmary.

Paediatric/cystic fibrosis secretaries
Jane Axtell and Jeanette Firth
Christine Silburn and Jim Littlewood in 2019

Our Comprehensive CF Assessments were absolutely central for the development of the Leeds Regional CF Service

It was undoubtedly as a result of providing the Comprehensive CF Assessment service and our opportunity to gain experience from evaluating so many patients that our service developed so rapidly through the Eighties. It was a great learning experience both for myself and for key members of our team – the clinic nurses, physiotherapists, dietitians, social workers, various laboratory staff – and also the many medical colleagues involved. So I make no excuse for returning to discuss the details of a Comprehensive CF Assessment.

The CF Assessment facilitated referral from the local hospital as it provided an obvious reason for a consultant paediatrician to refer a child to our unit, providing extra information and a second opinion, without the need for a permanent transfer of the child’s care to our CF clinic (even in the early Eighties it would be misleading to refer to our small CF clinic a “centre”).

1982. The Leeds CF service is supported by the Yorkshire Regional Paediatric Advisory Committee

After the first two years these results on our own and referred patients, demonstrating suboptimal treatment and potential for significant improvement in many,   were reported to the regional paediatricians via the Regional Paediatric Advisory Committee – a committee on which there was a representative paediatrician from every town and city in the Yorkshire Regional health authority.  The majority accepted the need for improvement in management and acknowledged the value of the CF Assessment service in identifying areas where improvements could be made. The Regional Paediatric Advisory Committee recommended that the Yorkshire Regional Health Authority give official recognition to the Regional CF service provided at St James’s University Hospital, Leeds

Yorkshire pts
Eventual referrals to Leeds for CF Assessments around the Yorkshire region and beyond from 1981. markers from the edges of the map are patients from more distant parts of the UK or overseas.

However, the committee members were not initially unanimous. One senior paediatrician raised doubts about the need for such a service. However, by sheer coincidence, I reminded him of a child he had referred during the previous year for a CF Assessment whom we showed did not have cystic fibrosis; he unreservedly withdrew his objection. Some years later, after he had retired, he saw me on a television programme from Doncaster races being interviewed about the CF Trust by John Francome before a CF sponsored race. He wrote “while waiting with other OAPs for the afternoon film in black and white I saw your CF Trust advertisement and nearly wrote out a cheque”. He complimented me on my performance and commented “I suspect that when you retire in 1999 (?) we shall still be on the brink of a “cure”, but accept that much will have been achieved and much of it by you”. 

 For any referral service to thrive it must have the support of those who and will use the service for their patients.  So by obtaining the agreement of our regional paediatric consultant colleagues we had achieved the first major step.

1983. Recognition of the CF service by the Yorkshire Regional Health Authority (YRHA)

The YRHA Paediatric Advisory Committee comprised one or two consultant paediatricians from all towns and cities in the region where there was a paedaitric department. The committee who met every year to advise the Regional Board on paediatric matters and hear of new developments.    

In 1983 the YRHA officially recognised that a “tertiary referral service for cystic fibrosis” was provided by St James’s University Hospital but advised that referrals should be from regional consultant paediatricians  and not directly from general practitioners

Canon Roger
Roger Canon

Our senior financial manager, Roger Canon, (figure) at St James’s was delighted with this recognition for he forecast it would only be a matter of time before extra funding would be provided.         Roger was a major supporter of our CF Service. He was later involved with the provision of a purpose built Children’s Day Hospital at St James’s which contained accommodation for the Regional Cystic Fibrosis Unit, Paediatric Oncology unit and Regional Child Development Unit. Certainly Rogers longterm support was a major factor in our development.

1983 Our first Clinical CF Research Fellow, (Dr. Mike Miller) funded by the Cystic Fibrosis Trust, was appointed

Mike Miller (figure) made a major contribution to clinical care, co-ordination of the paediatric and  first adult service (more about this later) in St James’s.   Mike was closely involved with the early development of the computer storage of results of the Comprehensive CF Assessments which up to this time were stored on large sheets of paper and analysed using a hand held calculator. 

During the early Eighties more paediatricians were appointed at St James’s including a neonatologist, a second paediatric nephrologist, and a community paediatrician permitting me to devote more time to the CF service.  However I was still very busy and to have an experienced doctor of registrar status at St James’s, full time in CF, in post for at least two years was a major step forward.

A chest physician Dr. Richard Page agreed to set aside one clinic each month to see teenagers and the few older patients provided Mike Miller  or I would also attend. There was a close liaison with the paediatric staff and the CF Research Fellow usually attended this clinic. However, their were problems with the new adult service, particularly when inpatient care was required as I will describe later.

1983. The Regional Health Authority Recognise the “Tertiary referral service for CF” provided at St James’s.

The service was found useful by consultants outside Leeds and referrals were increasing. I presented the present situation to the Yorkshire paediatricians at their annual regional Paediatric Advisory Committee at their headquarters in Harrogate.  Most agreed that a tertiary service should be recognised i.e. referral from other consultants outside Leeds but not from general practitioners. However, one highly respected consultant paediatrician from another city in Yorkshire doubted if such a service was necessary. It was pure coincidence I had only recently seen a patient of his for CF Assessment, whom he had been treating for some years as having cystic fibrosis. However,  after full CF Assessment we found the child definitely did not have CF!  I mentioned this and he immediately withdrew his objection. It was a measure of the man that years later, after he had retired, he wrote to me acknowledging the major contribution made by the Leeds CF service. So the Yorkshire paediatricians supported recognition of our regional CF service and their support was accepted by the Leeds Regional Hospital Board – the first such service to be officially recognised in the UK.

 Pressure for funding from the St James’s hospital administration

From 1983 the increasing numbers of CF patients coming to St James’s not only for CF Assessments but for more prolonged courses of expensive intravenous antibiotic reatment received increasing attention from our administrators and managers.  These activities resulted in a substantial extra financial burden on their budget from patients who lived outside our own health district of East Leeds. So from 1983 our district manager and his staff submitted detailed costs of the CF service to the Yorkshire Regional Health Authority i.e. of the service the YRHA had officially recognised in 1983 but not funded.

Details of the Comprehensive CF Assessment – the basis of our service

 The Comprehensive CF Assessment is essentially a detailed review by the team of every aspect of the patient’s management and physical state with extensive laboratory and radiological investigations. 

Over the years we have included all investigations which may possibly be of some value and where action on an abnormal result may result in improvement in the patient’s condition. Fortunately in the Eighties we did not have justify every laboratory test or X-ray as evidenced based medicine had not yet taken over individual clinical judgment. Over the years interesting, but practically non-useful, time consuming tests were excluded, for example skeletal age and subcutaneous fat thickness didn’t provide any useful infirmation; new tests were included as they became available e.g. Pseudomonas antibodies, immunoreactive trypsin, fecal pancreatic elastase.

The early Comprehensive CF Assessments included – 

  • Detailed personal and family history
  •  Present clinical state and treatment
  •  Enquiry if siblings had been sweat tested
  • Immune state – particularly for measles and whooping cough
  • Awareness of and whether the family had any contact with the CF Trust
  • Physical examination: weight, height, subcutaneous fat folds, mid upper are circumference (the two latter later omitted)
  •  Physiotherapist’s full assessment and report for the patient’s local physiotherapist
  •  Dietitian’s assessment and report including a 5-day dietary history – combined with the fecal fat allows percentage fat absorption to be calculated. Report is provided for patient’s local dietitian
  •  Repeat sweat test by expert biochemist to confirm diagnosis
  •  Simple respiratory function tests using Vitalograph for FEV1 and FVC; Peak Expiratory Flow Rate using Wright’s Peak Flow Meter. Carried out by CF unit nurse or physiotherapist
  • Response of respiratory function tests to nebulised bronchodilator (salbutamol only)
  • Chest X-ray and Chrispin-Norman X-ray score
  • X-ray wrist for skeletal age (later omitted)
  • X-ray abdomen to estimate fecal overloading
  • Upper abdominal ultrasound for appearance of liver and spleen
  •  Sputum culture
  •  Routine urinalysis
  •  Fasting blood glucose and HbA1
  • Shwachman clinical score
  • 3 day fecal fat collection and fecal chymotrypsin

In the early years the Assessments were done in limited accommodation at the end of one of the paediatric wards (ward 8) in Chancellor Wing at St James’s University Hospital, adjacent to my office – eventually designated as the Paediatric Day Unit. Jeanette Firth, the nurse who’s sole responsibility was the children coming to the Day Unit, organized them. Eventually as the Day Unit developed she arranged other complex investigations such as endoscopies, colonoscopies, jejunal biopsies, liver biopsies, endocrine tests, allergy tests and challenges.  

I had overall clinical responsibility for the Day Unit and worked closely with Jeanette; my office and the secretaries’ office were next door. 

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Ann littlewood with Ian Bowler one of our excellent CF Research Fellows

From 1984 we also had a desk top computer in my office eventually managed by my wife, Ann Littlewood SRN, in collaboration with the hospital IT department and our various CF Research fellows.

A permanent dedicated Day Unit Nurse was essential

It was clear to me that to perform potentially dangerous complex investigations such as growth hormone tests on children admitted for the day to a bed on a busy paediatric ward, without a dedicated experienced nurse to give personal supervision, was fraught with problems and potentially very dangerous – as had proved elsewhere. So to have a permanent staff nurse designated to the Day Unit, close to the ward, but without ward responsibilities, was a major advance in efficiency and safety. Jeanette worked closely with the ward sisters and nurses but had no regular ward responsibilities. The permanent aspect is important, as many of the investigations are complex and requiring experience and learning. Also it is important for the children and parents to see a familiar friendly face when they come to the Day Unit.

The Assessment involved the Day Unit Nurse, and after she was appointed CF Nurse Specialist, paediatric clinical assistant (an experienced doctor), the CF Research fellow, paediatric physiotherapist and paediatric dietitian; later the social worker was involved also the pharmacist.    

]Photos; L to R. Greeted, weighed and measured by Jeanette Firth the Day Unit Nurse. Venepuncture on arrival after application of EMLA anaesthetic cream by the CF clinic practitioner; Jonathan Taylor who  performs a detailed history and physical examination.   Sweat test by Dr Shapiro. Respiratory function with simple Vitalograph; Sue Morton  and Betty physiotherapists. Dietitians Anita MacDonald and later Sue Wolfe dietary assessment. Hilary Hobbs social worker.  Interview with the consultant Jim Littlewood.  Christine Silburn for correspondence and organisation. Ann Littlewood data organiser with CF Fellows Ian Bowler.

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EMLA anaesthetic cream

The patient attends fasting in the morning and has a blood specimen on arrival (from 1984 after application of EMLA local anaesthetic cream – a blessing for children and staff!). There is a confirmatory sweat test by an experienced biochemist, Dr. Leonie Shapiro, then on to X-ray. A Polaroid photograph was taken in the Day Unit for the records. Other investigations are performed during the day.  On a second visit the 3-day fecal fat collection is returned and an abdominal ultrasound performed.

At the end of the first visit or during a second visit, or both, the consultant (Dr. Littlewood) interviews the parents and patient on the findings on examination,  and any initial tests which are already available such and sinuses those findings that are available such as the physical findings recorded by the Clinic Doctor (which he confirms), respiratory function tests and chest x-rays. He has by this time had a verbal or brief written report from both the physiotherapist and the dietitian. Any obvious abnormalities are discussed. 

At the second visit the bloods and bacteriology results are available. These interviews usually took about an hour or more. I tried to answer all their many questions; always there was plenty of time allocated and all the patients saw Dr. Littlewood at one or other visit usually both for a prolonged consultation. It was regarded as important that I personally wrote the final report rather than a more junior member of the medical staff – even the CF Research Fellow. The parents received a copy of the final report with recommendations for any change in treatment.

The continuity of involvement, often year after year, by myself and the key members of the team was an important major factor in the success of the service.  It is interesting that recent general research is reported to show that patient do better when seen by the same doctor and this has always been obvious – provided, of course, the doctor is informed and up to date on their conditioon!

By 1984 we were able to report the results of our first 103 assessments at the Brighton International CF Conference. The findings  supported the need for regular Assessments to avoid suboptimal treatment (below).

– Littlewood JM, Kelleher J, Losowsky MS, Page R, Crollick AJ, Miller MG, Conway SP, Firth J, MacDonald A, Henry F. Comprehensive clinical and laboratory assessment in cystic fibrosis. In Cystic Fibrosis: Horizons Ed. David Lawson. John Wiley & Sons, 1984 Poster 3.34

One hundred and three CF patients from the Yorkshire Region had a clinical, laboratory, radiological, dietetic and physiotherapy assessment. In a further five patients, previously considered to have cystic fibrosis, the diagnosis was not confirmed and an alternative diagnosis established.    There were 55 males and 48 females; the average age was 8.2 years, the mean Shwachman clinical score 74 (range 100-34) and the mean Chrispin Norman Xray score 9. At the time of the initial assessment 57 patients were attending our CF clinic and 46 referred from clinics of 20 other paediatricians and chest physicians.  Delays in diagnosis were common (20%> 1 year, 27% > 6 months and 40% >3 months). Ten families had never heard of the CF Trust and 22 siblings had not had a sweat test.

Detailed clinical, laboratory and X-ray evaluation revealed evidence of active chest infection in 34 patients. 34 had inflammatory infiltrates on chest X-ray, 24 had an absolute neutrophil count of more the 7,500 per cu.mm, 9 patients were growing Staph. aureus or H. influenzae or both but not on an appropriate antibiotic. 23 has an ESR of more than 25 and 27 a WBC of more than 12,000. These findings usually resulted in more aggressive treatment of the chest infection.

Significant intestinal malabsorption persisted in 78 treated patients and evidence of gastrointestinal involvement was invariable. Subnormal fat-soluble vitamin levels were present; Vitamin A 68%, Vitamin E 88%. Mineral levels were normal except for iron, which was low in 43%. Despite the usually recommended daily energy intake of 120% RDI, only 21 patients out of 86 achieved this in practice. In many patients total energy intake was compromised by the traditional “low fat diet”.    In the majority of patients there were multiple areas where changes in therapy were indicated. Expectations of doctors and parents was often low by modern standards. We concluded “regular comprehensive assessment by a team experienced in CF would significantly improve the management and quality of life of CF patients in the UK. A “tertiary referral service” appears to be accepted and used by the majority of the paediatricians in our region”

Those involved in this first report from St James’s were –

  • Jim Littlewood – Consultant paediatrician responsible for the service
  • Jerry Kelleher – Senior Lecturer Biochemistry, Univ. Dept. of Medicine St James’s 
  • Monty Losowsky – Professor of Medicine, St James’s University Hospital
  • Richard Page – Consultant Chest Physician, St James’s
  • Avril Crollick – Clinical Assistant with Dr. Littlewood St James’s
  • Mike Miller – CF Research Fellow with Dr. Littlewood
  • Steve Conway – Paediatric Registrar St James’s
  • Jeanette Firth – Paediatric Day Unit Nurse, St James’s
  • Anita MacDonald – Paediatric Dietitian St James’s
  • Fiona Henry – Paediatric Physiotherapist St James’s

A number of our staff attended this Brighton meeting and presented other posters-

– Miller MG, Littlewood JM. Storage retrieval and comparison of data. Use of a microcomputer at St James’s Tertiary Referral centre. Poster 3.21       The Variety Club had funded a Sirius computer and Barons Systems developed a software package. 120 items of information from each assessment were stored and also a system for patient management developed.

– Miller MG, Whitaker l, Brocklebank JT, Littlewood JM. The nephrotoxicity of of aminoglycosides in cystic fibrosis. Poster 4.05                                                                         A combined study with Trevor Brocklebank our paediatric nephrologist  suggesting aminoglycosides did cause some renal damage and this appeared to be reversible and not cumulative.

– MacDonald A. High, moderate or low fat diets for cystic fibrosis. Poster 8.12    Anita MacDonald had a poster on the effect of the commonly recommended low fat diet on compromising energy intake and advised, “more emphasis should be placed on encouraging generous fat intakes and an appropriate dose of pancreatic enzymes. The traditional low fat diet is unnecessary for the majority of CF patients”

As a team we were definitely still on a steep learning curve in 1984 and for subsequent years. There were always new problems some relating to the more intensive and repeated treatments; for example overcoming the difficulties of maintaining venous access for 2-3 weeks in small children, preventing P. aeruginosa infection becoming chronic. Also we were taking on responsibility for an increasing population of children with a very serious eventually fatal condition and we wanted to ensure that we were doing all we could for them.

1985. The Leeds CF Service was attracting national attention

By 1985, our Leeds CF clinic was attracting some attention nationally and in 1986 I was invited by Prof. Tim David of Manchester to give a detailed review of the current management of CF at the first Royal Society of Medicine Annual CF meeting that he was organising

–  Littlewood JM. An overview of the management of cystic fibrosis. J R Soc Med 1986; 79 (Suppl. 12): 55-63.

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I gave a detailed review of treatment in 1985 at the first annual CF meeting at Royal Society of Medicine (RSM) in London. Prof. Tim David organised these annual meetings which were still held in 2019. Although by now I was an experienced general paediatrician, I was a relative newcomer to CF compared with some of the audience – for example Dr Margaret Mearns. Margaret,  who sat on the front row and obviously did not altogether approve of my giving the final talk at the meeting! (she used to call me “the young healer”!).  However, over the previous five years I had seen many new patients, often referred to me as they were not doing well, for full Assessments from many different hospitals – well over a 100 new patients by 1984. I always spent at least an hour with them towards the end of the day of their assessments often saw them on their second visit. I also did all the reports to the referring consultant and the GP and also the letters recommending any changes in treatment. Copies of these letters always went to the parents. Drawing from this experience and the literature in my lecture and the subsequent publication I tried to describe the areas where treatment appeared to make a significant difference to the long-term outlook.

A major problem at that time was to communicate the established facts to the hundreds of paediatricians  who were responsible for the long-term management of only a few CF children.  Most of these general paediatric consultants had numerous conflicting demands on their time ranging from neonatal care to child abuse. They rarely had the opportunity to attend major CF meetings in Europe or North America, which were by now occurring on a regular basis, as they had so few affected patients. So I made my presentation at the RSM and the resulting article a very detailed account of modern CF care. I made a particular plea for some form of CF centre specialist care for all – either full care or shared with the local hospital as already recently recommended by the British Paediatric Association Working Party (v. infra).   Sadly there was still considerable opposition to the concept of CF centre care by some of the more senior UK consultant paediatricians. So I concluded at the close of this meeting as follows –

“if the outlook for CF patients in the UK was similar to that expected in large CF centres both here and overseas, these suggestions (of some CF centre care for all) would be superfluous. However, it is not and until such time as it is, we must give such an arrangement a trial for the sake of CF patients and their families”.

I felt very strongly about this issue having, by this time, seen so many children with CF referred to Leeds for Comprehensive CF Assessment during the preceding 5 years who had been severely under-treated by modern standards to the extent that it had a devastating effect on their health, quality of life and ultimate survival and also a major effect on the lives of their families. Sadly many had already past “the point of no return” by the time they were referred. This is concept not all doctors appreciated.

–    Drittanti L, Masciovecchio MV, Gabbarini J, Vega M. Cystic fibrosis: gene therapy or preventive gene transfer? Gene Therapy 1997; 4:1001-1003.

I was very impressed by this paper of Drittanti et al, which few clinicians have read, for although published in 1997, it accurately described the situation that was becoming apparent to those of us who followed many patients year after year. Patients’ respiratory function tests are usually stable before they develop the chronic infection (usually Pseudomonas or Staph. aureus) but when infection becomes established there begins a slow but relentless deterioration i.e. they pass the “point of no return” 

Stages of pulmonary infection
Point of no return

These authors suggested that before the onset of chronic infection people with CF can be considered to be in the phase of “CF Disease” i.e. they have various physicochemical alterations in the electrolyte and liquid composition of the airway fluid but no permanent tissue damage. Although they get respiratory infections these can be eradicated if treated early with antibiotics and their respiratory function remains stable. However, eventually a new respiratory infection is not eradicated and chronic infection of the bronchial and pulmonary tissues becomes established. At this stage the patient then enters the phase of “Lung disease” where infection and chronic inflammation become established, self perpetuating and progress independently of the basic CFTR abnormality – this change is referred to as the  “Point of no return”; there follows a slow deterioration in the patient’s condition, the speed of which 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 delay for as long as possible the onset of chronic infection of the airways. So it can be appreciated that if the airway cultures are repeatedly positive for Pseudomonas, even if the patient has few or even no symptoms he already has passed the “Point of No Return”. In a later paper Drittanti is one of the authors who state that “The interactivity between the CFTR gene and cystic fibrosis would be limited to the initial phase of the disease” (Genetics in Medicine 2000;2:124-130.)  While the initial phase was related to the CFTR genotype, the kinetics of the second phase seems to be common to all groups considered. The hypothesis that the interactivity 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 from the CFTR gene itself.

1985 The Northern CF Club – two (or more) heads are better than one

As we were frequently facing new and difficult problems in the early Eighties, I thought it would be helpful to discuss our problems with the relatively few consultants in the North of England who were also seeing more children with CF. They were also building CF clinics as we were in Leeds; they must be facing similar problems.  So with financial support from Cilag (makers of the enzyme Pancrease) and later Pharmax and Forest Laboratories (makers of Colomycin), I formed the Northern CF Club. This turned out to be a great success. It was essentially a relatively small group of consultant paediatricians, and later some chest physicians, who were treating increasing numbers of children with CF at various hospitals in the North of England. 

The initial format, was to meet at the Cottons Hotel, Knutsford in Cheshire at 4.30pm on a Friday once a month – this was all arranged by our sponsors. I would chair the meeting and we would discuss specific clinical problems during the late afternoon and early evening. Members would bring along specific clinical problems to the group to hear the opinions and advice of their colleagues, rather than hearing formal presentations.  The NCFC remained very popular for many years – it filled a real need, the feedback from colleagues in the group on difficult clinical problems was very helpful to those of us ultimately responsible for the care of these children. 

After the meeting we had an excellent meal, the drink and talk was very plentiful. Overnight accommodation was provided at the Cottons Hotel. It was essentially a mutual support group that I restricted to consultants, full time CF Research Fellows and an occasional involved scientists (but certainly no juniors – it was not a teaching group). It certainly filled a real need at the time during the Eighties. The fact that busy senior doctors were prepared to travel from as far away as Newcastle, Birmingham, Nottingham and other northern cities on a Friday evening was a measure of how valuable everyone found the meetings.

The concept of a CF Club for those involved in treatment of substantial numbers of patients proved to be so popular that other regions demanded similar clubs and the two pharmaceutical companies eventually funded other clubs around the country.  The NCFC involved doctors from all over the North and a far south as Nottingham and also from N. Ireland.  I stressed that we only had consultants with responsibility for patients, full time CF Research Fellows and an occasional scientist working on CF – for example Dr. Jerry Kelleher. This was very important.

NCFclubGroup
Some of the original members of the NCFC in 1985 were photographed out side the Cottons Hotel Knutsford Cheshire.  They are ((L to R)–
Two pharmaceutical representatives, Tim David (Both Hall, Manchester), a Pharma representative, Kevin Webb (Adults Manchester), John Gilbert (CF Research Fellow Leeds), David Heaf (Alder Hey, Liverpool), Richard Page (Adults Leeds), Jerry Kelleher (Biochemistry University Department of Medicine Leeds), Bob Nelson (Newcastle), Gary Hambleton (Manchester Children’

On the evening in 1997 that I retired as Chairman of the NCFC and Kevin Webb took over, there was a good turnout and I was presented with a nice decanter!  By this time the NCFC had become considerably larger; there were new consultants and more CF Research Fellows.  Eventually some years after I retired, the NCFC was opened up to all who were interested and lost its original purpose. It became just one of many medical meetings but it certainly served its purpose as a mutual support society in the early years.

Northern CF Club
Among those present were – Alan Smyth (Nottingham), Warren Lenny (Stoke), Garry Hambleton (Manchester), Chris Taylor (Sheffield), Maurice Super (Manchester), Kevin Webb (Manchester), Christine Etherington (Leeds), Charles Pantin (Stoke), Steve Conway (Leeds)

The NCFC eventually decided to produce one combined publication – although I stress this was certainly not the main purpose of the club. It was intended and 

pasted-image-small-156
Steven Conway

succeeded as a mutual support group for doctors responsible for the care of people with CF. However, we did manage one publication on the “Northern CF X-ray Score” which was essentially a chest X-ray scoring system which did not require a lateral view as was needed for the widely used Chrispin-Norman X-ray score. This was important as the lateral was yet more radiation and patients who had numerous x-rays over the years. Steve Conway deserves credit for the scoring and writing of the article. The “Northern score” was widely used in the UK  in preference to the Chrispin-Norman Score which required a lateral X-ray. The article was eventually completed and published mainly due to Steve Conway’s organisational and literary skills (figure)

Conway SP, Pond MN, Bowler I, Smith DL, Simmonds EJ, Joanes DN, Hambleton G, Hiller EJ Stableforth DE, Weller P, Littlewood JM.  The chest radiograph in cystic fibrosis: a new scoring system compared with the Chrispin-Norman and Brasfield scores. Thorax 1994; 49:860-62.

More about Comprehensive CF Assessments/Annual Reviews

The CF Assessments are described in detail as they were not only started at our unit in Leeds but were a major, perhaps the main, reason for our quite impressive and rapid development during the Eighties as a CF referral centre.  Now the initial basis of the Annual Assessments/Reviews are now recommended in all modern CF standards documents in the UK and Europe (CF Trust Standards; ECFS Standards).  Below are some of the supportive publications from other units – it is true controlled trials are lacking but some times common sense must be used!

  Comprehensive clinical and laboratory assessment in cystic fibrosis. Littlewood JM, Kelleher J, Losowsky MS, Page R, Crollick AJ, Miller MG, Conway SP, Firth J, MacDonald A, Henry F. In Cystic Fibrosis: Horizons Ed. David Lawson. John Wiley & Sons, 1984 Poster 3.3
  Littlewood JM, Kelleher J, Rawson J, Gilbert J, Firth J, Morton S Wall C. Comprehensive assessment of patients at a CF centre identifies suboptimal treatment and improves management, symptoms and conditions.  10th International Cystic Fibrosis Congress, Sydney. Excerpta Medica Asia Pacific Congress Series 74 1988;89. Improved respiratory and nutritional state after assessment
  Littlewood JM. Value of comprehensive assessment and investigation in the management of cystic fibrosis. In: Escobar H, Basquero L, Suarez L, editors. Clinical ecology of cystic fibrosis. Elsevier; 1993. p. 181 – 7.  Our results on 427 patients between 1980-1992. 

Reports from other CF centres – majority supporting Annual Reviews

– Carr SB, Dinwiddie R. Annual review or continuous assessment? J R Soc Med 1996;89 (Suppl. 27):3–7 [Epub 1996/01/01].                                                                          Siobhan Carr and Bob Dinwiddie at the Hospital for Sick Children, Great Ormond Street in London recommend annual reviews.

  Long JM, Fauset-Jones J, Dixon MJ, Worthington-Riley D, Sharma V, Patel L, et al. Annual review hospital visits for patients with cystic fibrosis. J R Soc Med 2001;94(Suppl. 40):12–6 [Epub 2001/10/17].                                                                              “Like shared care, annual major centres introduced reviews in part in an effort to improve the quality of care given to patients in outlying districts……There is little basis on which any of these measures should be imposed either on a regional centre or on a district service, particularly given that there is no objective evidence of benefit of these strategies”. The authors also complain that “without any controlled  studies of benefit or cost, it has become the received wisdom and part of standard guidelines in the UK.      This is the only non-supportive publication – surprisingly from Prof. Tim David’s CF unit at Booth Hall Children’s Hospital Manchester!!!

  Jaffe A, Buchdahl R, Bush A, Balfour-Lynn IM. Are annual blood tests in preschool cystic fibrosis patients worthwhile? Arch Dis Child 2002;87(6): 518–20 [Epub 2002/11/29].                                                                                                                                       These results from the Royal Brompton support the recommendations for routine blood tests at annual review in preschool CF children. Authors suggest the results may help to rationalise which tests are performed and thus reduce laboratory costs.

  Kerem E, ConwayS, Elborn S, Heijerman H. Standards of care for patients with cystic fibrosis: a European consensus. J Cyst Fibros 2005; 4(1):7–26 [Epub 2005/03/09].                                                                                                                             Recommend an annual review quoting Crozier 1975 and Littlewood 1993 (below).

  Fitzgerald DE. Cystic fibrosis standards of care, Australia 2008 1st December 2011. Available from: http://www.cysticfibrosis.org.au/pdf/.                                      Annual review is recommended.

– Nazareth D, Phitidis M, Tan H, Ledson M, Walshaw M, Greenwood J. The cystic fibrosis annual review — a need to update the guidance? J Cyst Fibros 2011;10:S83. Survey of 43 UK centres 18 Adult 25 Paediatric.                                                            Approved of annual reviews but need some standardisation. No measure of value of assessment in abstract

  Evans C, Davies R, Nash E, Whitehouse J, Honeybourne D. Patient satisfaction survey of the annual review service at a regional adult cystic fibrosis (CF) centre. J Cyst Fibros 2011;10:S99.                                                                                                                      No detailed information available but Birmingham doing reviews.

  Chuang S, Doumit M, McDonald R, Hennessy E, Katz T, Jaffe A. Annual Review Clinic improves care in children with cystic fibrosis. J Cyst Fibros. 2014 Mar; 13(2):186-9. doi: 10.1016/j.jcf.2013.09.001. Epub 2013 Sep 30.                                         Annual Review clinic significantly improves the number of annual investigations and multidisciplinary reviews performed. Families were satisfied with this new process. The majority of the families surveyed (85%) were satisfied or very satisfied with the Annual Review clinic.

National developments influenced the CF service 

An Australian publication by Phelan & Hey in 1984, had a major influence on CF care in the UK  Up to that time sub-specialisation in paediatrics was unusual in the UK in contrast to many countries in Europe, N. America and Australia. In fact, it was a publication from Professor Peter Phelan, (figure) a respiratory paediatrician in Melbourne, in collaboration with a UK paediatrician Edmund Hey, on a sabbatical there, that had a major influence on CF care in the UK in the Eighties (Phelan & Hey, 1984).    

26Phelan2
Peter Phelan

 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). The authors attributed the better survival in Victoria during the Seventies to the Australian children being treated at CF Centres rather than at their local hospitals.         The authors noted “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”.   

Phelan P, Hey E. Cystic fibrosis mortality in England and Wales and in Victoria Australia 1976-80. Arch Dis Child 1984; 59(1):71-3.

The data in this 1984 publication were available before publication to us in the UK through Professor John Dodge who had visited Phelan in Australia before its publication.  This Australian data was directly responsible for the Cystic Fibrosis Research Trust initiating and funding the formation of the British Paediatric Association’s Working Party on Cystic Fibrosis (WPCF) in 1982. The terms of reference of the WPCF established by the council of the BPA were “to assess the advantages and disadvantages of regional centres for cystic fibrosis”. (For summary of the Working Party Report see Jackson 1986 below).

Professor John Dodge many years later commented that he considers the original data in this report were seriously flawed because the authors 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!                  

Hey Edmund
Edmund hey

Dr. Edmund Hey (1934-2009) the co-author of this paper, was 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 the Australian Peter Phelan 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. 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 he concentrated on developing neonatal services and had an outstanding career in neonatology. However, he later commented 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 was undoubtedly true!

1982. The British Paedaitric Association (BPA) Working Party on Cystic Fibrosis (WPCF) is formed

Professor John Dodge a paediatrician from Belfast was the convener and author of the report.  Members of the working party  were Dr Tony Jackson (CF Trust), Duncan Geddes (respiratory physician from the Brompton),  paediatricians Janet Goodall (Stoke), Jim Littlewood (Leeds), Margaret Mearns (London) and George Russell (Aberdeen). All the members were practicing consultants with considerable experience in treating children or adults with cystic fibrosis. Dr. E C Coles and Dr. P A Lewis were statistical advisers and Mrs. C D Turner the Research Assistant.

 From L to R. George Russell, Tony jackson, Jim Littlewood, Duncan Geddes, Janette Goodall, Margaret Mearns, John Dodge

The Working Party met regularly at the British Paediatric Association offices in Queen’s Square London and produced their report.  Dr. Tony Jackson, Chair of the CF Trust Research and Medcial Advisory Committee wrote a short summary of our report.  

– Jackson A. Working party on cystic fibrosis. Arch Dis Child 1986;61:724.

The report emphasised 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, requested by the Working Party, with details of 4557 patients. However, only 16 centres were treating 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 CF Centres in data collection, clinical trials and research

The BPA council initially rejected the CF Working Party’s report!

The members of the BPA council (mostly composed of general paediatricians representing various regions of the UK), misguidedly in the opinion of all the WPCF members, maintained that children with CF could be quite adequately cared for by a general paediatrician at their own local hospital (despite the fact that at the time most died in childhood). Many paediatricians (including some on the council of the British Paediatric Association and my two senior consultant colleagues in Leeds!) saw no need for specialised units for children with CF – “Any paediatrician worth his salt can look after a cystic” one well-known professor of paediatrics was heard to remark; other consultants wished to retain care of one or two CF children “for teaching purposes”.

However, despite these objections this was a highly influential report, which eventually had a major effect on the development of CF centres throughout the UK, and thus steadily improved the care and survival of children with CF. 

The CF Survey, which the Working Party had 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.  A second survey 1985-6, in which data from death certification was incorporated, checked and extended the findings of the first 1983 survey.

British Paediatric Association Working Party on Cystic Fibrosis. Dodge JA, Goodall J,  Geddes D, Littlewood J M, Mearns M, Owen JR, Russell G. BMJ 1988; 297:1599-1602. 

A national survey of  patients known to paediatricians, chest physicians and other or whose deaths reported through death certification in the UK between 1977 o 1985. A revised incidence of one affected baby in 2500 live births was produced. mortality was very high in the first year (7.6%). meconium ileus, previously the primary cause of early mortality was decreasing in frequency. The total prevalence in the UK in 1985 was estimated as about 5000.