PAEDIATRICIAN’S PAPER TRAIL – 2000 ONWARDS

Cade A. Walters MP. McGinley N. Firth J. Brownlee KG. Conway SP. Littlewood JM. Evaluation of fecal pancreatic elastase-1 as a measure of pancreatic exocrine function in children with cystic fibrosis. Pediatric Pulmonology. 29(3):172-6, 2000 Mar. PMID:10686036

ALAN CADE

One of the early paediatric studies on elastase-1 (EL-1) which proved to be a major advance in indicating pancreatic digestive function. We report our experience of EL-1 measurements in 142 patients from a large cystic fibrosis (CF) clinic and 85 controls. There were statically significant differences between non-CF controls (615 microg/g stool), the pancreatic sufficient CF patients (698 microg/g stool and the pancreatic insufficient  CF patients (10 microg/g stool) 

Following these findings we used fecal EL-1 as evidence of PI in screened CF infants (reliable over the age of 2 weeks); in older CF patients at diagnosis; for confirming the need for pancreatic enzymes in patients referred to the clinic already taking enzymes; for annual monitoring of PS patients to detect the onset of PI; and as supporting evidence when excluding the diagnosis of CF in patients attending the pediatric gastroenterology clinic. The low values in the first 2 weeks in some normal and premature infants, and the persisting normal values in PS infants, make the fecal EL-1 test unsuitable for neonatal CF screening. 

Undoubtedly this test was a major advance which came into widespread use 

Alan Cade at the time of the study was working at the Regional CF unit at St James’s in Leeds. Alan subsequently was appointed as consultant paediatrician in Plymouth where he continued his interest in cystic fibrosis.

Littlewood JM. Koch C. Lambert PA. Hoiby N. Elborn JS. Conway SP. Dinwiddie R. Duncan-Skingle F. A ten year review of colomycin. Respiratory Medicine. 94(7):632-40, 2000 Jul.   PMID: 10926333

As the person who had revived the use of colomycin in 1985 with our letter to the Lancet (discussed elsewhere) I was asked to coordinate this publication to which a number of distinguished contributors gave their time.    Essentially the new uses of colomycin were reviewed by experts in the area. I take the opportunity to say a few words about them!

Christian Koch was the director of the very successful CF Centre at the Rigshospitalet in Copenhagen. It was a privilege to be asked make a video there in 1998, during a 2-day visit, when I interviewed staff and patients. It was tragic that Christian died suddenly of cerebral haemorrhage in 2004 I sent condolences on behalf of myself as Chairman and all at the CF Trust

“We were shocked to hear the very sad news about Christian as my wife and I had so recently been with him at a congenial evening after the recent Irish CF Meeting in Killarney.  I had the great pleasure of visiting Christian, Niels and their team in Denmark for two days in 1997, which confirmed and enhanced my respect and admiration for their work.   The kindness and humanity, which was so obviously an integral part of the Danish approach, was undoubtedly in no small measure attributable to the dedication and character of Christian himself, their clinical leader.
It was a privilege to know Christian and he will be greatly missed by all factions of the worldwide CF community who will always be grateful for his major contribution to the care of people with cystic fibrosis.
All at the UK Cystic Fibrosis Trust extend their deepest sympathy to Christian’s family, friends and colleagues’.

Peter A Lambert was Professor of Microbial Chemistry at Aston University in Birmingham where he had held various increasingly senior academic appointments since 1980 He was involved in infectious diseases their diagnosis and treatment, molecular typing, pathogenicity, antibiotics, details of cell walls and membranes. I did not know him well. I do remember when going through the proofs of the article he was very liberal with his hyphens!

Niels Hoiby is the microbiologist at the University and the Rigshospitalet in Copenhagen and one of the early members of the team. In 1973 in the fourth of over 500 papers by Niels Hoiby listed on Medline, he published a classic study correlating clinical severity, presence of mucoid Pseudomonas aeruginosa and increased precipitins in the blood. He used a new more  sensitive technique of crossed immuno-electrophoresis with intermediate gel to identify precipitins against P. aeruginosa from 33 patients with CF. He suggested there was selection of mucoid strains in CF by means of the immune response; also that the persistent infection and multiple precipitins produced against the bacteria could cause a local immune reaction which could enhance the destructive lesions of the respiratory tract. Very much in line with the modern views on inflammatory damage and the use of anti-inflammatory therapy.

Niels Hoiby eventually worked with and became an absolutely key member of the Danish CF clinic for over 50 years during which time he became one the world’s leading authority on Pseudomonas aeruginosa and many other aspects of infection and immunity in CF (also Hoiby, 1977).   

Niels receives the ECFS Award from Stuart Elborn ,the President

The 2012 ECFS Award was presented to Professor Niels Hoiby in “recognition of his outstanding contribution to the understanding of Pseudomonas lung  infection and translating this knowledge into better outcomes for people with cystic fibrosis. He was also recognised for his contribution as the founding President of the European Cystic Fibrosis Society and his lifelong commitment to the CF centre in Copenhagen”.

In 2013 I was delighted to be invited to Copenhagen University, at Niels suggestion, to give a tribute lecture to Niels to celebrated his 25 years as a professor. In an address “Cystic fibrosis and Niels”  I outlined the highlights of his outstanding career since the early Seventies.

Stuart Elborn worked in Nottingham and Cardiff on CF before moving to Belfast in 1995 where he set up a thriving CF centre for adults at the City Hospital. When Di Bilton retired froth Brompton Stuart was appointed Director of the Adult CF Centre. 

Stuart was one of the longest-serving presidents of the  European Cystic Fibrosis Society, holding the role between 2007 and 2015. He has also spent time as a trustee and chair of the research and medical advisory committees  (RAMAC) of the Cystic Fibrosis Trust (2002 to 2014) and currently sits on the scientific advisory board. In 2012 he received a CBE for services to healthcare in Northern Ireland. In 2020 Stuart eventually returned to Belfast as Faculty Pro-Vice-Chancellor of the School of Medicine and Dentistry. He took over from me as chair of RAMAC at the CF Trust when I became Chairman; he was very good to work with.  My wife and I had known Stuart since he was a CF Trust Research Fellow in Nottingham and were delighted to be asked, along with Rosie Barnes,  to his 50th birthday party at Belfast University.

Steven Conway and his wife Ella have been our friends since Steve was my paediatric registrar at St James in the early Eighties. We have written many papers together. Steve had a degree in English before qualifying in Medicine  in 1978 (BA 1972; MA 1975; MBBS 1978) He graduated in 1978 from St George’s Hospital London. He specialised in general paediatrics, respiratory medicine and cystic fibrosis. He was consultant on a regional infectious disease unit from 1988-1998 and from 1998 to retirement from the NHS in 2013 Steve held the position of consultant Paediatrician & Lead Clinician in Cystic Fibrosis Services at St James’ & Seacroft Hospital, Leeds. He had dual accreditation in paediatrics and adult infectious disease medicine. He developed an interest and expertise in chronic fatigue syndrome over the whole age range and continued to see paediatric patients with fatigue syndrome in his private clinic and continued as a consultant paediatrician at the Spire Hospital Leeds in general paediatric medicine until August 2019.

Bob Dinwiddie was the senior paediatric respiratory  consultant at Great Ormond Street, London at the time and one of the UK’s leading paediatricians. He was a former chair of the European Respiratory Society’s Cystic Fibrosis group. Bob was greatly respected by his colleagues ,hard working and modest. With colleagues he published on a wide variety of paediatric respiratory  subjects.

In this publication he notes that in paedaitric practice colomycin has proved an effective agent for the treatment of early P. aeruginosa colonisation with oral ciprofloxacin significantly delaying or preventing chronic infection. It is a useful suppressive for those chronically infected with P. aeruginosa. Also useful and safe addition to a range of intravenous antibiotics when resistance becomes a problem. 

Fran Duncan-Skingle was the Senior Nurse Manager and Nurse Consultant in CF at the Royal Brompton Hospital in London. She was the first CF Clinical Nurse Specialist at the Royal Brompton Hospital in 1980 unit her retirement in 2002. She initiated the National CF Specialist Nurses’ Group in 1988 and CF Home Care Services in 1990.

She notes the importance of nebulised antibiotics including colomycin also the fact that patients find the administration reasonably easy and the drug well tolerated by most. Inhaled colomycin is used for some months after lung transplantation via face mask to clear the upper airways of Pseudomonas.  There is no doubt nebulised colomycin has played a part in reducing the number of admissions for IV antibiotics. It is easy to reconstitute and well tolerated by most patients. 

In the last paragraph of my summing up of this review I conclude that over the past decade colomycin has emerged as the first choice antibiotic for nebulised treatment, both for early and chronic P. aeruginosa infection, in people with cystic fibrosis. It is also a valuable addition to the IV antibiotics when the organism becomes resistant to the more frequently used drugs. Its particular characteristics as described in this review suggest that it will continue to have an important role in the treatment of people with CF during the next decade. (This proved to be the case)

 

Littlewood JM. Wolfe SP. Control of malabsorption in cystic fibrosis. [114 refs] Paediatric Drugs. 2(3):205-22, 2000 May-Jun. PMID: 10937471 [erratum in Paediatr Drugs 2000 Jul-Aug;2(4):252]
Malabsorption is severe and of early onset in virtually all people who have cystic fibrosis. The main cause is deficiency of pancreatic enzymes, but bicarbonate deficiency, abnormalities of bile salts, mucosal transport and motility, and anatomical structural changes are other contributory factors.  Appropriate pancreatic replacement therapy will achieve normal or near normal absorption in many patients.
It is important to identify both malabsorption and evidence of a pancreatic lesion in all patients who are to receive pancreatic enzymes. All who have evidence of fat malabsorption are deemed pancreatic insufficient and candidates for enzyme replacement therapy. Effective treatment should allow a normal diet to be taken, control symptoms, correct malabsorption and achieve a normal nutritional state and growth.

The occurrence of fibrosing colonopathy in some patients receiving very high doses of those enzymes that have the copolymer Eudragit L30 D55 in their covering has resulted in guidelines in the UK to avoid dosages greater than the equivalent of 10,000 IU lipase/kg/day for all patients and also to avoid preparations containing this copolymer in children and adolescents. 

For patients not  responding to 10,000 IU lipase/kg/day, review of adherence to treatment, change of enzyme preparation, variation of the time of administration and reduction in gastric acid may improve absorption. The importance of excluding other gastrointestinal disorders as a cause of the patient’s symptoms and the need for early investigations, rather than merely increasing the dosage of enzymes, is stressed. 

Leeds chief CF dietitians, Alison Morton (adults) and Sue Wolfe (children)

With modern enzymes, adequate control of gastrointestinal symptoms and absorption can be achieved at dosages of 10,000 IU lipase/kg/day or only slightly more, and a normal nutritional state and growth rate maintained in most patients with cystic fibrosis (figure).

 

 

Littlewood JM.  Good care for people with cystic fibrosis. Paediatr Respir Rev. 2000 Jun;1(2):179-89. PMID: 12531112
Many of the talks and lectures I have given over the previous 20 years, both in the UK and overseas, had been on standards of care and the fine practical details of providing good care. So, in this article, I have described, in minute detail, the components of good care – in my opinion. As space is not a problem in this Paper Trail, I have expanded the original table that appeared in this article.  I also asked a few respected senior CF consultants if they approved of the fine details of the table – which they did.

I realise it’s very long and involved but I don’t apologise – good CF care is long and involved and these were details I learned over 20 years treating over 600 children with cystic fibrosis. 

Some features of best care for people with cystic fibrosis  – some of which may not appear in Standards and Guidelines

(CFF) next to an entry indicates these were the CF Foundation’s ‘Fatal Flaws’ when accrediting their CF clinics in the USA.

                                  

BEST CARE

SUBOPTIMAL CARE

Diagnosis

Antenatal screening & Diagnosis No antenatal screening or diagnosis
Routine neonatal screening No neonatal screening
Single person receives positive screening result and deals with family and coordinates the subsequent investigation. One person responsible. Ideally at a CF centre Confusion and multiple people, such as the family doctor and inexperienced junior doctors involved who have little recent knowledge of CF
Early diagnosis – before symptoms. The weight falls off within weeks Late, after prolonged symptoms, chronic lung damage and malnutrition
Rapid, confident & correct diagnosis and early treatment and advice by experts Slow, unsure, sometimes incorrect by inexperienced people
Good, effective communication by staff experienced in CF Poor, ineffective communication by staff inexperienced in CF care
Reliable sweat tests even on infants Unreliable sweat tests (CFF)
Genotype always determined Genotype unknown
Siblings all checked for CF Siblings not checked for CF
Genetic advice for parents & relatives particularly those of child bearing age No genetic advice to family or relatives

CF Centre Clinic

Segregation of all patients according to their microbiological status No segregation of patients according to microbiology
High standards of general hygiene Poor hygienic standards – common in UK
More than 50 patients on full care Fewer than 50 patients on full care (CFF)
Adequate clinic session time identified for CF patients only Seen in an overcrowded general clinic (CFF)
Regular follow-up (every 1 to 2 months) Infrequent, often missed, follow-up
A few permanent CF doctors familiar with each patients’ details Changing doctors, unfamiliar with CF and the patients they are seeing
One named senior CF doctor (consultant) ultimately responsible for long term care Unclear who in the “team” is ultimately responsible
Experienced permanent clinic nurses who know patients, cross infection problems, weighing and measuring, spirometry and taking throat swabs and various treatment protocols Inexperienced temporary nurses who are unfamiliar with the clinic routines
CF Nurse Specialist available if required No CF Nurse Specialist available or one who is heavily overworked
Usually sees CF Physiotherapist or can have an early appointment as needed Rarely or never sees Physiotherapist
Usually sees CF Dietitian or early appointment as needed Rarely or never sees Dietitian
Clear detailed clinic records & data sheets Brief illegible medical notes
Accurate weight and height, charted at every attendance Inaccurate, irregular or not charted weights and heights
Computer print out of or access to previous important basic respiratory and nutritional data readily visible in notes – print out or computer Doctor searches through disorganized notes for information of previous data every time patient attends
Accurate, bacteriologically clean, spirometer used at every attendance Infrequent, inaccurate, unclean or no spirometry
Sputum/throat swab cultures every attendance and also when unwell. Arrangements to send to lab’ by post Infrequent sputum/throat swab cultures
Patient asked to ring if doesn’t hear culture result – rapid treatment of positive cultures No action on positive culture for weeks until next clinic
Patients/parents  should be aware of their microbiology and its significance Patients/parents unaware of their microbiology
Annual chest X-ray & whenever needed Chest X-rays rarely done – “chest clear – doesn’t need an X-ray”
Antibiotic treatment at first sign of even a viral respiratory tract infection (RTI). Treatment only when RTI well established and obviously progressing – has to prise antibiotic out of doctor.
Patient/parents have prescription for an antibiotic or an antibiotic course at home to use when required Difficulty obtaining an extra antibiotic with colds etc.
Vigorous eradication policy for early Pseudomonas aeruginosa positive cultures. Known to all staff. No clear policy of early Pseudomonas eradication
Early resort to IV antibiotics with option of home IV antibiotics IV antibiotics used only as a last resort
Annual Review completed each year No or incomplete Annual Review
Centre Director personally discusses Annual Review results with parents/patient Junior doctor discusses results with parents/patient
Centre Director or CF Consultant writes Annual review letter to family doctor with recommendations Junior doctor does letter with recommendations
Copy of letter goes to patient/parents Patient/parents not informed of results
24-hour access to a member of the CF team for advice No 24-hr direct access to CF team (CFF)
Regular review of eligibility for TOBI, Pulmozyme and ventilatory support Patients missing out on effective treatments which may help them
Direct access to Director / Consultant with phone number Senior staff unavailable out of hours
Agreed but flexible transition arrangements to adult CF unit known to parents and patients Unclear transition policy or no adult CF unit with care continuing n the paediatric unit (CFF)

CF Ward

Segregation according to microbiological status as in clinic No segregation according to microbiological status
Highest standards of hygiene for all including all ancillary staff and visitors, cleaners, etc Poor hygiene standards, inadequate routines & hand washing faculties
Sufficient, knowledgeable ward nurses Temporary overworked nursing staff
Seen regularly by senior CF doctors Inexperienced CF naive doctors
Protocols for all routine procedures No protocols – variable procedures
Single rooms with en suite facilities Open ward with shared facilities
Good ward cleaning service Inadequate ward cleaning
Daily visits from CF physiotherapist No regular physiotherapy
Supervision by CF dietitian No regular supervision by dietitian
Appropriate palatable food Unattractive unpalatable hospital food
Regular ward rounds and information to patient/parents Irregular ward rounds / inadequate information regarding progress
Education / occupation / interests while in the ward No education occupation or interests
Communication with other patients via internal phone, internet, etc Isolation and boredom in cubicle

Prevention, Immunization

Fully immunized against common infectious disease Incompletely immunized
Annual influenza injections No influenza injections
Avoidance of people with viral ‘colds’ when possible Unnecessary exposure to ‘colds’
Avoidance of tobacco smoke Smoking in the environment
Avoidance of fungal spores Indoor work at horse stables
Adequate dry housing Overcrowded damp house
Avoids others with CF e.g. camps/holidays and social  gatherings etc Attends CF camps/holidays etc
Always avoids others with CF Mixes freely with others with CF
Adequate personal/family finances Financial difficulties

General

Patients should be aware of their respiratory function (FEV1 or even PEFR for young patients) and have some idea of where they lie in terms of severity May be quite unaware of how they are compared to others with CF
All patients severe enough to be in the “transplant window” are reviewed every 6 months Some patients who reach need for transplant referral are overlooked as need not reviewed regularly
Advice on and aware of state benefits to which they are entitled. Reviewed by the CF social worker Not receiving full entitlements as not had adequate advice
Aware of and contact with the  national CF patients’/parents’ organization (CF Trust) Unaware of and unknown to national CF organization.
Aware of reliable and useful CF websites (www.cftrust.org.uk and www.cysticfibrosismedcine.com) Unaware of or no access to reliable CF websites
Well informed and “adjusting” to having CF Ill-informed and not adjusting to having CF
Regular contact with Specialist CF center staff (if a child on ‘shared care’ who is attending the local hospital) All care at local clinic; irregular or no contact with staff at Specialist CF centre
Registered with UK national CF Database or their national database and regular data entry to local and national database Not registered with national database and no local database

Other

Close collaboration with Microbiologist and laboratory staff experienced in culturing CF sputum specimens Routine laboratory with only occasional CF specimens and little contact with clinicians
Efficient centre secretary/coordinator who knows staff and families/patients Temporary secretarial help to only deal with letters, telephone, appointments, etc
Other laboratories and X-ray departments in the hospital regularly perform specialist CF investigations and procedures Other departments rarely do investigations on CF patients and so unfamiliar with techniques and likely findings
Help of other colleagues familiar with CF –surgeons, ENT, diabetologist, gastroenterologist, radiologists obstetrician, fertility expert, geneticist, medical physics, pharmacist Referral to specialists who rarely see people with CF and unfamiliar with particular problems
Suitable funding arrangements agreed with referring health authorities Constant difficulties prescribing CF drugs and care
Attention to user requirements/ satisfaction/ suggestions No regular discussion with patients / parents on their views on the adequacy of the CF service
Appropriate management of terminal care and ongoing family support – letters from senior nurse and Centre Director. Possible bereavement counselling No contact with relatives after patient dies
Attention to the physical and mental well being of all members of the CF team Overwork, stress, conflict and poor relationships between members leading to inefficient service and illness. Inadequate leadership.
Mandatory weekly meetings of all members of the CF team + microbiologist and pharmacist (when possible) No regular team meetings to discuss patients, policies and problems (CFF)
Clear, informed, decisive leadership from the Centre Director – coordinating the individual views into agreed decisions and communal policies. A basis for written protocols. Independent policies and practises by different team members leading to conflict and confusion for other team members and patients
Consultants and CF team undertake clinical research and present the results at CF meetings and in publications No research, publications or attendance at CF meetings
Efficient CF Clinic and Data Clerk to ‘guard’ the notes and organise clinics Reliance on central appointments system & secretarial pool
Clinical notes and recent X-rays held in the Cystic Fibrosis Unit Notes and X-rays in hospital main records office and frequently unavailable

(CFF) = CF Foundation’s ‘Fatal Flaws’ when they are accrediting CF clinics. I was invited to attend a CF Centres committee at the CF Foundation when I took over as chairman of  the CF Trust Research and Medical Advisory Committee where I learned of these fatal flaws.

 

Lee TW, Brownlee KG, Conway SP, Denton M, Littlewood JM.  Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. PMID: 15463843 Free article.
This article of Tim Lee’s is one of the Leeds publications most quoted in the literature in recent years.  By 2020 it had been cited by 516 authors; next most frequent was that of Tacjana Pressler from Copenhagen and the EuroCare CF Working group with 141 citations!

Patients attending the Leeds Paediatric CF Centre were defined each successive month as either – ‘chronic’ when more than 50% of the preceding 12 months were PA culture positive,
‘intermittent’ when < or =50% of the preceding 12 months were PA culture positive,
free of PA’,
with no growth of PA for the previous 12 months, having previously been PA culture positive, or
‘never infected’, when PA had never been cultured.

Cross-sectional analysis of the 146 children attending the Leeds Regional Cystic Fibrosis Centre was performed to assess the relationship between the new definitions and clinical scores and investigations. The response variable was regressed on age and sex and the residuals analysed using the Kruskal-Wallis test.
Results: The ‘chronic’ group (18% of patients) had significantly worse Shwachman-Kulczycki (SK) and Northern chest X-ray scores, and FEV(1)% predicted  values than the ‘free’ (28%) or ‘never’ (20%) categories (P<0.004). The ‘intermittent’ group (34%) had a significantly higher SK score than the ‘chronic’ group (P<0.0001), and a significantly lower % predicted FEV(1) value than the ‘free’ or ‘never’ groups (P<0.0003). ‘Chronic’ patients were significantly associated with a positive, and ‘never’ patients with a negative, PA antibody result (P<0.001).
Conclusions: The validity and importance of identifying these four subgroups is demonstrated. Previous definitions may over-estimate the prevalence of chronic infection.

Most clinicians agree with the Leeds definitions but some question the criteria suggested. Certainly numerous subsequent publications dealt with the subject, most recently there was a detailed publication from the ECFS-CTN Microbiology Group (Taccetti G  et al. J Cyst Fibros 2020 Jan; 19(1):52-67.PMID:31526710) who pronounced- Microbiological monitoring, regular sampling from the airways and standardisation of culture methods remain essential requisites for microbiological definitions. Despite limitations, serology should be incorporated in the definitions of initial infection and eradication used in clinical trials to better classify patients at enrolment, mainly in non-expectorating children. This requires standardisation of serological testing. 

Incidentally we had been using P. aeruginosa serology in Leeds from the mid-Eighties; it had been the subject of a number of publications by Dr Moira Brett when she was working with our unit in Leeds (all reviewed in the Eighties (2) section of this  Paper Trail).

                  Tim Lee

Dr Tim Lee is now Head of Studies for the Postgraduate Programmes in Child Health, one of the largest Postgraduate Programmes within the Leeds School of Medicine. He is also Lead Clinician and Consultant at the Leeds Regional Paediatric Cystic Fibrosis Centre. He has been involved in the clinical care of children and young people with cystic fibrosis since 1995. He has a PhD focussed on improving the effectiveness of gene therapy, and is Principal Investigator on a number of current clinical trials. Leeds is part of the European Cystic Fibrosis Society Clinical Trial Network, which comprises 43 large and experienced CF Centres across 15 European countries, caring for a total of 17,500 people with CF. Tim also represents ECFS-CTN on the coordinating group of Enpr-EMA, the network of paediatric research networks at the European Medicines Agency. He also is NIHR Children’s Theme Specialty Lead for Yorkshire and Humber, working to support children and young people throughout Yorkshire and Humber having appropriate opportunities to access clinical trials, wherever they live. 

Tim works closely with children’s research nurses and children’s research clinical leads across all hospital Trusts in Yorkshire and Humber. He has been a great asset to the Leeds Paediatric Service which he now directs.

Lee TW, Brownlee KG, Denton M, Littlewood JM, Conway SP. Reduction in prevalence of chronic Pseudomonas aeruginosa infection at a regional pediatric cystic fibrosis center. Pediatr Pulmonol 2004 Feb;37(2):104-10. PMID:14730654
This Birmingham Conference poster and this subsequent publication in Pediatric Pulmonology were written by Tim Lee (now Hon. Clinical Associate Professor and senior consultant paediatrician in the Leeds Paediatric CF Centre).

The data represented the culmination of our early CF aggressive approach to P. aeruginosa infection from the early Eighties.  Miles Denton was, and still is, a microbiologist closely involved with the CF centre who subsequently made major contributions to the microbiological aspects of CF.   Tim Lee describes how over the years we introduced various management strategies at the Leeds CF centre in an attempt to reduce the prevalence of chronic Pseudomonas aeruginosa respiratory infection, previously thought to be inevitable in most children with CF. These included neonatal screening (1975), regular microbiological monitoring (1975), early nebulised antibiotic treatment of first isolations of P. aeruginosa (1984), intensive intravenous antibiotic treatment where nebuliser antibiotics failed to eradicate P. aeruginosa (1988), and separate clinics for patients chronically infected with P. aeruginosa and uninfected patients (1991).

The aim of Tim’s present analysis was to assess the impact of these interventions. All 232 patients receiving full-time care at the Leeds Paediatric CF Centre during the period January 1990-December 2000 were categorised into four groups as follows : never grown P. aeruginosa; free of P. aeruginosa for at least 1 year; intermittent grower of P. aeruginosa with < 50% of months with samples positive for P. aeruginosa over the previous 12 months; and chronic P. aeruginosa infection with >50% of months with samples positive for P. aeruginosa over the previous 12 months.

The yearly prevalence of patients having chronic P. aeruginosa infection fell significantly during the study, from 24.5% in 1990 to 18.1% in 2000 (P < 0.05), despite an increase in mean age of patients from 7.73 to 9.42 years. The number of patients aged less than 11 years who had chronic P. aeruginosa infection fell from 23.8% in January 1990 to only 4.3% by December 2000. The annual incidence and mean age of first acquisition of P. aeruginosa did not alter significantly. In conclusion, antipseudomonal management strategies were associated with both reduced prevalence, and an increase in the mean age of onset of chronic P. aeruginosa infection.

 

Lee TWR, Ho SA, Littlewood JM, Brownlee KG, Conway SP. Eradication of first growth of Pseudomonas aeruginosa in 95 cystic fibrosis patients. Factors associated with success. POSTER
This was a poster relating experience from Leeds and related to Tim Lee’s following paper below. This present study is a retrospective analysis of patients receiving their care at the Leeds Regional Paediatric CF Centre from January 1990 to March 2003. There were 97 patients with first growth of Pseudomonas aeruginosa (PA); 95 patients with full documentation were included in the study. Eradication was considered successful if the patient had at least three negative airway cultures over a period three months after cessation of treatment.

Eradication was achieved in 74.7% (71/95) of patients. 4.2% of first isolations were mucoid PA and those of those 50% (2/4) had successful eradication.  16.8% (16/95) were resistant to at least one antibiotic, of these 68% (11/16) had successful eradication. In patients who had antibody  levels checked in the 12 months prior to the first growth 22.2% (14/63) were positive prior to the first positive airway culture. Patients who had a positive PA antibody level 0 to 4 months after first growth of PA had a significantly greater chance of successful eradication 92.9% (13/14) than those with a negative antibody level 69.1% (38/55). 

Conclusion. In CF most first isolations of PA are fairly sensitive and non-mucoid. Measurement of PA antibody levels at least annually may often allow early detection prior to positive airway culture. For four months following first positive airway culture, positive antibodies to PA identify patients that are significantly more likely to undergo successfully eradication suggesting the early stages of infection antibodies may be protective.

“Looking back over 40 years and what the future holds”  The Joseph Levy Memorial Lecture. James Littlewood     27th European Cystic Fibrosis Conference 2004   Full text on internet. Published by CF Worldwide.
Every fourth year the North American and European CF organisations combined and joined with CF Worldwide to put on an international meeting which replaced the annual European meeting.

                Joe Levy
The Joseph Levy Lecture

The Joseph Levy Memorial Lecture was delivered at the Opening Ceremony of the 27th European Cystic Fibrosis Conference 2004 in Birmingham, UK and supported by the Levy family.
Joseph Levy was one of the key founders of the CF Trust in 1964 and subsequently chairman and benefactor. Sir Robert Johnson described the events at that time in his interesting 1984 lecture “History of the Cystic Fibrosis (Research) Trust” (which, with Sir Robert’s approval, I have reproduced verbatim in the “History – Future” section of Daniel Peckham’s Leeds CF website (www.cysticfibrosis.online). The following is from Sir Robert’s 1984 lecture at the Brighton meeting.

“In 1963 John Panchaud had his solicitor draw up the necessary legal documents for the formal creation of the charity. One of the first Trustees was Mr. Percy Lovely and as a result of his and John Panchaud’s contacts in the City they got together a Board of Trustees including as originals Mr. Joseph Levy and Lord Crook. Others were Lord Bossom and other prominent figures in the City of London. The inaugural meeting was held on the 20th February 1964 at 3.30pm in the Mansion House in the City of London under the auspices of the then Lord Mayor, Sir James Harman”

The Levy lecturer usually based his/her lecture on a subject which  had been a major interest of their’s over the years. I was awarded the Levy Lecture in 2004 by CF Worldwide and had by that time had quite a long experience since qualifying in 1956, almost amounting to history!  So I choose to review the history of cystic fibrosis much of which I had been involved in and speculated on the future.

A full transcript of my 2004 lecture with references can be downloaded from the UK CF Trust website (www.cysticfibrosis.org.uk) or directly from the CF  Worldwide Internet (enter “Joseph Levy Memorial Lecture 2004”).

Rossi Medal of the European Cystic Fibrosis Society.

The medal was originated in the memory of Professor Ettore Rossi a distinguished European paediatrician and awarded annually by the ECFS.
Professor Ettore Rossi was Chairman of the  Department of Paediatrics of the University of Berne, Switzerland from 1956 until he retired in 1985. He was one of the central figures involved in the development of very many areas of paediatrics in Europe, including cystic fibrosis.

I (Jim Littlewood) met Professor Rossi only briefly on a few occasions – one incident left me with a lasting impression of his kindness and humanity. At an International CF Conference, when he was chairing a plenary session, he had no hesitation in informing one very senior presenter, who had just described a study involving children with CF in numerous annual needle biopsies of the liver, in no uncertain terms, precisely what he thought of the ethics of the study!

Professor Rossi was obviously held in high regard by those who knew him and described as an enthusiastic teacher, a serious hard working paediatrician and a superb medical friend.

In recent years the Rossi Medal has been replaced by the ECFS Annual Award.

 

J M Littlewood.  European cystic fibrosis society consensus on standards–a roadmap to “best care”. J Cyst Fibros. 2005 Mar;4(1):1-5. Editorial
I was invited to write this editorial commenting on the new ECFS “Standards for CF care for patients with cystic fibrosis: A European Consensus”.
When I was Chair of the UK CF Trust’s Research and Medical Advisory Committee, along with Sandra Kennedy (the charity’s excellent publications manager), I had written, on behalf of the committee, much of the 2001 UK Standards of Care which had been published by the CF Trust and very well received in the UK.
The new 2005 ECFS publication, on which I was asked to comment, followed much of what was written in the CF Trust’s 2001 UK document. There was a large advisory group but the main authors of this European document were “CF heavy weights” Eitan Kerem (Israel) Steve Conway (Leeds), Stuart Elborn (Belfast) and Harry Heijerman (Netherlands).

I made quite a meal of the subject in this invited editorial, describing the remarkable improvement in prognosis, the  medical advances and more effective treatment, the new positive attitude and higher expectations. I described my concept of the “point of no return”, if infection was allowed to establish, early diagnosis and effective treatment, the importance of good communications so new treatments could be implemented with our delay, the still difference in outlook at different centres, treatment differences that are often a matter of degree rather than kind and the complexity of delivering the best care. I stressed the importance of developing a Patient Registry.

         Medici Villa “La Ferdinanda

As background to this European document, in 2004 there was an “epidemic” of local guidelines. So in March 2004 Prof. Gerd Döring, the President of the ECFS, arranged a 2-day ECFS Consensus meeting on Standards of Care for People with Cystic Fibrosis in   the picturesque Italian village of Artimino. The working meetings were held in the Medici Villa (figure).  The 34 members of the consensus group were from most European Countries with two from N. America; all were experienced in various aspects of cystic fibrosis  The eventual publication resulting from this meeting was a success and sets out the standards to which all centres should be aiming and it was hoped all centres would follow.

These Artimino meetings which Gerd Doring arranged were really excellent and dealt with various aspects of CF care such as nutrition and treatment of infection. The wives, husbands and partners of the participants were also invited so the weekends were also excellent social occasions and trips into Florence were arranged. 

Littlewood JM, Wolfe SP, Conway SP.  Diagnosis and treatment of intestinal malabsorption in cystic fibrosis. Pulmonol. 2006 Jan;41(1):35-49. doi: 10.1002/ppul.20286.PMID: 16288483
I thought it was important to document our experience in this area and this article  was the summary of our experience in Leeds over 25 years with two of my Leeds colleagues who had been closely involved for many years, Sue Wolfe, the senior paediatric dietitian and Steve Conway the Leeds CF Centre Director. Both these colleagues are good friends of Ann and myself and had worked with me for many years before I retired in 1997.

By the time of this   paper both were recognised international experts. I thought it would be good to record the experience of people, such as ourselves, who had “done the job” in the clinic for many years in contrast to some,(such as certain Cochrane reviewers!!) who only reviewed other people’s work and then demanded more controlled trials! The result was a substantial paper full of practical advice and results of experiential learning.  I was very proud of this paper and very grateful to the two co-authors who were still in active practice at the time it was written. It was accepted by Pediatric Pulmonology at once without revisions; apparently it was one of their most downloaded papers at the time.

Three long serving members of the paediatric Cystic Fibrosis (CF) team have retired in recent years and between them they have a combined 67 years of fantastic care for children and young people with CF.

         Sue Wolfe

Sue Wolfe, Consultant CF dietitian has retired after 30 years in dietetics. She spent 28 years in the paediatric CF Unit, and joined the CF team in 1989 at St James’s. Ann and I regard Sue as one of our oldest friends and we were pleased to attend her retirement party in Leeds in 2017.

Rosemary Ball

Helen Blyth, CF nurse specialist began working as a sister in the 1980’s on a surgical  ward at LGI and then moved to children’s ward 12 in Gledhow wing after an 8 year career break. She then moved to the CF Unit in 1999 as a nurse specialist. 

Rosemary Ball, Clinical Specialist Physiotherapist qualified in 1978 in Leeds, and then spent time working in Burnley before returning to the Trust in 1986. She joined the CF Team in 1996, 21 years ago and retired in 2013.

 

Colombo C, Littlewood JM. The implementation of standards of care in Europe: State of the art. J Cyst Fibros 2011 Vol 10 Suppl 2 S7-S15. PMID: 21658645
We reported the care and condition of people with cystic fibrosis (CF) in 34 European countries using data obtained from publications, registries and professionals providing CF patient care. Care and outcomes differ markedly between countries. Although the 2005 European standards of patient care publication was widely known (reviewed above), in many countries there were no specialised CF centres. In only a minority of countries was funding considered adequate and in some countries costs covered by patients compromised care. Only 15/34 countries had a national CF patient registry. Neonatal screening was routine in only 10/34 countries, but this included 59% of European infants. The initiatives of EuroCareCF Workpackage 1 to form networks for professionals working with CF patients are described. 

Suggestions for the future include at least one adequately staffed CF Centre in each country, improved funding, neonatal screening, national patient registries and the formation of national CF parent and patient organisations. 

Carla Colombo is Professor and Director of the CF Reference Center, Dept of Pathophysiology and Transplantation, Universita  degli Studi di Milano enlisted my help with this study and I did a considerable amount of the data collection and writing. This necessitated a very pleasant trip to Milan for Ann and myself to collaborate with Carla and her staff. I did much of the writing there. The paper is full of a vast amount of data and does confirm the very variable progress made by 2011 towards implementing the 2005 European Standards of Care.

Carla Colombo

Carla Colombo is a very active person (382 publications listed – one of which I wrote!). She has a particular interest in in gastroenterology and livers. In 1989 she introduced the use of ursodeoxycholic acid (URSO) for the treatment of CF liver disease in a memorable presentation at the European Working Group in Prague. Subsequently URSO was widely used in people with CF associated liver disease and represented one of the major advances in CF management;  prior to URSO there was simply no treatment for CF liver disease. I told her the URSO paper is in my “ Megapaper” section on www.cysticfibrosis.online/hist

 

Littlewood JM, Connett GJ, Sander-Struckmeier S, Henniges F; Creon 40,000 Study Group. 2-year post-authorization safety study of high-strength pancreatic enzyme replacement therapy (pancreatin 40,000) in cystic fibrosis. Opin Drug Saf. 2011 Mar;10(2):197-203. doi: 10.1517/14740338.2011.552499. PMID: 21342076
I was asked by the manufacturers (Abbott GmbH, Hanover, Germany) to be involved in this publication as there was still some lingering concern that the high lipase pancreatic preparations may rarely be associated with fibrosing colonopathy, a very serious complication and a subject with which I had been involved and published on.

At the request of the Medicines and Healthcare Regulatory Agency and in agreement with the appropriate authorities, an observational, multi-centre, non-interventional, post-authorisation safety study of high-strength pancreatic enzymes had been conducted. Sixty-four patients were enrolled at nine UK centers. Two deaths occurred during the study, which were considered unrelated to therapy by investigators. No safety concerns were identified with pancreatin 40,000 therapy for up to 2 years. Daily lipase doses were not increased when switching to pancreatin 40,000.

Our conclusions were –

1. There were no safety concerns identified with pancreatin 40,000 therapy: symptoms were improved
2. Lipase does s were not increased when switching to pancreatic 40,000
3. All evidence suggests that even high doses of non-methacrylic acid coated enzymes do not cause fibrosing colonopathy
4. Occurrence of fibrosing with mesalazine in  non-CF patients supports the importance of the copolymer
5. Also other factors are present in some patients
6. Avoidance of MAC-coated enzymes abolishes FC in people with CF

As you will read in the previous abstracts on fibrosing colonopathy in this Paper Trail (1995-1999) there is still some disagreement on the precise role of methacrylic acid in the aetiology. The good news is the complication has disappeared.

Suntje_Sander-Struckmeier
      Gary Connett

Prof. Garry Connett is consultant paediatrician in Southampton with extensive  experience in enzyme use. He had published evidence that high doses of lipase as Creon 25,000 did not give rise to complications – particularly fibrosing colonopathy. This was because (in  his and my opinion) FC was caused by the copolymer eudragit covering of some of the other enzyme preparations.

Dr Suntje Sander-Struckmeier is the Global Director Clinical Development/Global Medical Affairs GI-Hepatology Abbott Laboratories GmbH. She organised the project. Subsequently I presented the results at the ECFS meeting in Hamburg.

Jim littlewood, Daniel Peckham. The role of medicines in changing the clinical history of cystic fibrosis. Optimizing pharmaceutical care in cystic fibrosis. Eds: Sián Bentley, Carlo Castellani, Daniel Peckham, Nicola Shaw. European Cystic Fibrosis Society. 2020:13-25. 

       Daniel Peckham

Daniel Peckham asked me to write the first chapter in this substantial book published by the ECFS, drawing on the extensive history on our website (www.cysticfibrosis.online). Essentially it is a review of the important treatments that have had a major favourable effect on the course of the condition over the years up to the introduction of modulators – most of these previous treatments I personally remember.

And so this Paper Trail comes to an end. My lasting impression of these years is how many really good people I have the privilege to meet and work with.  

Also the totally different situation in the CF clinics when in the Seventies, we had no idea how many of the children we treated would reach adulthood to the present time where there are more adults than children and the new modulators have revolutionised treatment and almost certainly out look.

Even though I am Honorary President of the CF Trust, Daniel is now my main link with cystic fibrosis as he manages the Leeds website. I enjoy updating my History section of (www.cystisfibrosiis.online) and observing the increasing use that other authors make of it; the numerous images are very popular.  It has been a pleasure working with Daniel and I was very fortunate when he suggested incorporating my History into his Leeds website some twenty years ago.