PAEDIATRICIAN’S PAPER TRAIL – NINETIES

PAEDIATRICIAN’S PAPER TRAIL – NINETIES

Neutral fat on faecal microscopy

The method is applicable to spot faecal samples and can readily be carried out on an outpatient basis. In centres where faecal fat assays are not available (which is the majority) the simple and cheap microscopic examination will give some indication of the response to enzyme treatment and may also help to identify non-compliant individuals. (Full text for methods and tables on PubMed)

This is a very similar study to the one we published from Seacroft in 1977 which  I have described in some detail in the Seventies section (Ghosh S K et al 1977). 

These simple methods of estimating the severity of the fat losses in the stools in CF did not become popular in most centres in the UK where there was usually no measure of the fat absorption in CF patients other than the presence of symptoms and signs.

Fat absorption in patients on full care at Leeds CF Centre
Fat absorption in 380 patients at time of referral to the Leeds CF Centre

As many CF centres are “chest orientated” and directed by chest physicians, detailed management of malabsorption may take second place. For example, the measurement of malabsorption is dealt with very briefly in the latest edition of “Hodson and Geddes Cystic Fibrosis “ (2016) major textbook where it is stated “Objective monitoring of response to therapy still requires stool analysis for fat commonly by microscopy” but the two  references given  both refer to faecal elastase measurements!! Oh Dear! However, the excellent chapter in Nutritional Aspects of the same textbook by dietitians Sue Wolfe and Sarah Collins makes up for the adult gastroenterologists dubious referencing.                                                   
                                                                                                                                                                                                  

Smye SW. Shaw A. Norwood HM. Littlewood JM. Some factors influencing the efficiency of a jet nebuliser system. [ Journal Article] Clinical Physics & Physiological Measurement. 11(2):167-75, 1990 May. PMID:2364642
The operation of a commercially available nebuliser system (Medic-Aid Ltd) is reviewed and the efficiency with which it produces an aerosol assessed. Defining the efficiency of nebulisation E as the fraction of the original mass of solution released as an aerosol it is found that the internal surface area, mass of solution used, the surface tension of the solution and the angle of tilt are important factors in determining E. Reducing the internal surface area of the nebuliser by means of Perspex inserts significantly increases E for 3 g of water from 49% for the unmodified system to 67% for the modified nebuliser (P less than 0.01). E increases with the mass of solution used but only exceeds 60% when 4.5 g water are used. Decreasing the surface tension of the solution from 7.2 x 10(-3) N m-1 (water) to 3.7 x 10(-3) N m-1 and 3.1 x 10(-3) N m-1 (using two different concentrations of a detergent in water) significantly increases E for 3 g solution from 49% to 65% and 69% respectively (P less than 0.05). Operating the nebuliser at a tilt also increases E. 

The measurements emphasise the importance of reducing the internal surface area of this type of nebuliser, using an adequate volume of drug solution (at least 4 ml is suggested) and operating the nebuliser at an angle to the vertical (20 degrees suggested) in order to maximise E. The surface tension of the drug solution is a further important determinant of E. 

                           Steve Smye

Dr Steve Smye was the medical physicist at St James’s at the time and this was his first publication with our CF unit.  It represented a trend to increase the efficiency of nebulisers which CF patients spent much time using. Steve was always very interested and helpful and did further studies relating to CF which are mentioned below. Subsequently, Steve went on to have a very successful, indeed quite outstanding, career.  Steve eventually became Professor in the School of Medicine at the University of Leeds and a Specialty Cluster Lead (and Deputy Medical Director) for the National Institute for Health Research (NIHR) Clinical Research Network based at King’s College London. He was Research and Innovation Director at the Leeds Teaching Hospitals from 2004- 2017.

He was awarded an OBE in the 2014 New Years Honours as Theme Lead, National Institute of Health Research Clinical Research Network. For services to Healthcare Research. A very nice man who helped us a great deal in the CF Centre.

Smye SW. Jollie MI. Littlewood JM. A mathematical model of some aspects of jet nebuliser performance. Clinical Physics & Physiological Measurement. 12(3):289-300, 1991 Aug. PMID:1934916
A simple mathematical model describing the performance of an Acorn jet nebuliser system (Medic-Aid Ltd) has been developed in which nebuliser efficiency E, defined as the volume fraction of solution (water) released as an aerosol or lost by evaporation, and nebulisation time T, are given as functions of the initial volume of solution. The model identifies an initial phase during which the nebuliser output is at a constant, continuous rate of 0.007 ml s-1. This is followed by an intermittent phase of operation during which output is estimated to occur for 0.25 of the total duration of the phase and results from solution deposited on the walls being recycled. The model indicates that increasing the flow of solution to the nebulisation region in the nebuliser or decreasing the fraction of aerosol intercepted by the baffle, will decrease T whilst leaving E unaffected. Two residence times tau 1, tau 2 which are a measure of the time that solution droplets adhere to the inner walls of the nebuliser are also identified; tau 1 (= 1.6 s) is the residence time associated with the rapid recycling of the majority (a fraction eta 1 = 0.992) of the aerosol while tau 2 (= 200 s) the residence time associated with the remaining fraction 1 – eta 1. Increasing eta 1 will increase E for constant tau 1, tau 2 while increasing tau 1, tau 2 will decrease E, T remaining essentially unchanged. It is proposed that the model may be applicable to other jet nebulisers.

A practically useful study by Steve Smye. It was really outside my understanding and my name was among the authors only as the head of the unit and the person who first involved this excellent scientist and person involved in CF research!

Smye SW. Jollie MI. Cunliffe H. Littlewood JM. Measurement and prediction of drug solvent losses by evaporation from a jet nebuliser. [ Journal Article] Clinical Physics & Physiological Measurement. 13(2):129-34, 1992 May. PMID:1499255
The evaporative losses of solvent (water) from a commercial jet nebuliser  (Unineb, Unimed Ltd) were estimated and found to be approximately 14% of total nebuliser output. A simple analysis of the nebulisation process then enabled the amount of the drug colomycin released as potentially respirable aerosol to be predicted from measurements of the total nebulisation time. Good agreement was found between the predicted (P) and measured (M) values such that P = 1.07 M (r2 = 0.98).

The analysis also indicates that the proportion of the drug released as aerosol will increase as nebulisation proceeds provided nebuliser output is continuous and that for a given initial mass of drug a larger amount of drug is released as an aerosol if the volume of administration used in the nebuliser is as large as possible.

All these facts are interesting and provide practically useful information to improve the use of nebulisers for the CF patients – which steadily improve over the years. 

        Helen Cunliffe in 2019

Helen Cunliffe was a senior pharmacist at St James’s who became an indispensable member of our CF team at St James’s as the treatment and various drugs regimes became increasingly complicated. Over the years the role of the pharmacist has become an quite essential component of the CF team and they would always attend the weekly unit meeting

Littlewood JM. Smye SW. Cunliffe H. Aerosol antibiotic treatment in cystic fibrosis.  Archives of Disease in Childhood. 68(6):788-92, 1993 Jun.  PMID:8333776   FREE
This was one of the papers Steve Smye was involved in where I did make a substantial contribution – such as writing the paper!  The purpose of the article was to review the clinical indications, drugs used, and methods of administration of inhaled antibiotics in cystic fibrosis which I believe it did successfully.  Full details are in the free text on PubMed.

Bowler IM. Kelman B. Worthington D. Littlewood JM. Watson A. Conway SP. Smye SW. James SL. Sheldon TA. Nebulised amiloride in respiratory exacerbations of cystic fibrosis: a randomised controlled trial. Archives of Disease in Childhood. 73(5):427-30, 1995 Nov. PMID:8554360     FREE

     Richard Boucher
      Michael Knowles

The  prestigious CF group in North Carolina had published a study on the use of inhaled amiloride in CF. Previous studies had shown that inhaled amiloride could inhibit excessive absorption of sodium and water from the airways and thus improve mucociliary clearance. The main investigators in the N. Carolina study were Michael Knowles and Richard Boucher who showed amiloride long term could reduce the speed of deterioration (Knowles M R et al, A pilot study of aerolized amiloride for the treatment of lung disease in cystic fibrosis NEJM 1990;322:1189); however, this was not confirmed by others. 

              Ian Bowler

Our study was designed to assess the benefit of nebulised amiloride added to the standard inpatient treatment of a respiratory exacerbation in cystic fibrosis. It was a prospective, randomised, double blind, placebo controlled trial. 

Twenty-seven cystic fibrosis patients (mean age 12.8 years) at St James’s and Seacroft hospitals.  Both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) showed improvements over the course of treatment, although there was no difference in respiratory function between the two groups at any of three time periods during the study. However, the time to reach peak FVC was significantly reduced in the amiloride group (4.2 v 7.6 days; 95% CI 0.4 to 6.4 days), but not in the time to reach peak FEV1 (5.7 v 7.9 days; 95% CI -1.2 to 5.6 days).

Our conclusion was that amiloride did not result in a greater overall improvement in respiratory function. There was a suggestion that it may have an effect on the rate of improvement, and thus may possibly influence the duration of treatment.  However, we did not bring amiloride into routine use.

By the time this study was published Ian Bowler had moved to the Department of Child Health at Southampton. He eventually was appointed as consultant paediatrician in Newport, South Wales. He was a pleasure to have in the unit and not only very intelligent and very active but also he had a really great sense of humour!

More recently, in 2019, I was looking round a large M & S store on  the outskirts of Cardiff but who should I meet but Ian Bowler and his wife.  It was so good to see them; he did tell me he was retiring.

Physiotherapists – Betty Kelman, deborah Worthington and Anita Watson
     Trevor Sheldon

By the time of this trial the Leeds Adult CF Unit was now established at Seacroft with Steve Conway as consultant.  Anita Watson was physiotherapist for the CF Adults at Seacroft.  At St James’s Betty Kelman and Debbie Worthington were the two main paediatric physiotherapists dealing with CF childr

 Trevor Sheldon, who helped with the design of the trial, at the time was at NHS Centre for Reviews and Dissemination University of York. In 1996 he was appointed professor and Director of the centre. In 1999 he became Head of the University’s Department of Health Sciences and deputy Chair of the Commissioning Board for Service Delivery and Organisation of the NHS research programme. He was appointed Pro-Vice-Chancellor in 2004 with the portfolio of Teaching, Learning and Information.

Addendum.  I was asked to present the findings of this study at a respiratory meeting in Europe as the use of inhaled amiloride in people with CF was still a subject of general interest. I duly presented our findings and at the interval I was very surprised to see Mike Knowles, the lead author of the Carolina study, emerge from the audience. He made himself known to me and we had a very pleasant lunch together.

Dr Eddie Simmonds wrote his MD Thesis on Allergic Pulmonary Aspergillosis and his publications on ABPA are grouped together here.  Aspergillus fumigatus in a fungus widely distributed in nature which can cause invasive infection particularly in immunocompromised people and also allergic reactions in people with cystic fibrosis. 

Simmonds EJ. Littlewood JM. Evans EG. Allergic bronchopulmonary aspergillosis. Lancet. 335(8699):1229, 1990 May 19.  PMID:1971078 

typical ABPA shadow, (From Brueton et al, 1980)

Cases of allergic bronchopulmonary aspergillosis (ABPA) are reported in 12-yr-old female identical twins with cystic fibrosis (CF) who became unwell after spending several mornings cleaning out riding stables.
ABPA was confirmed in the first twin by isolation of Aspergillus fumigatus from sputum, by raised serum IgE levels, by Aspergillus-specific IgE, and by positive precipitins to Aspergillus antigens in the serum.
We subsequently advised children with CF who went horse riding to make sure someone else “mucked out” the stable!  The sad aspect was this was yet another problem for some children with cystic fibrosis

Martin Brueton

Dr Martin Brueton (whose X-ray I have borrowed) was working in Birmingham with Professor Charlotte Anderson at the time and his 1980 paper on ABPA in cystic fibrosis first raised general awareness of the complication in CF. He subsequently became consultant Paediatric Gastroenterologist at Chelsea and Westminster Hospital, London.

 

Simmonds EJ. Littlewood JM. Evans EG. Cystic fibrosis and allergic bronchopulmonary aspergillosis. Archives of Disease in Childhood. 65(5):507-11, 1990 May. PMID:  2357089
We prospectively screened 137 of our patients with cystic fibrosis for allergic bronchopulmonary aspergillosis. Over a three year period (Jan. 1986 – Dec. 1988) eight patients were identified, an incidence of 5.8%. Patients were  well at the time of diagnosis (Shwachman clinical scores 70-90, Chrispin-Norman chest x ray scores 2-15) and they responded rapidly to treatment with oral prednisolone. There has been little deterioration in their respiratory function and nutrition over the study period. 

We concluded that allergic bronchopulmonary aspergillosis is not uncommon in patients with cystic fibrosis. It is a potential cause of lung damage and prospective screening could lead to earlier detection and treatment. Martin Brueton has some impressive X-rays in his important early article in 1980 when he was working with Prof. Charlotte Anderson in Birmingham (Brueton M J et al, 1980. PMID:7002053. Free)

Simmonds EJ. Littlewood JM. Hopwood V. Evans EG. Aspergillus fumigatus colonisation and population density of place of residence in cystic fibrosis. [ Journal Article] Archives of Disease in Childhood. 70(2):139-40, 1994 Feb.PMID:8129438
The relation between antibody titres of aspergillus in patients with cystic fibrosis and the population density of their place of residence was investigated. Patients with high titres of antibodies to Aspergillus fumigatus were significantly more likely to live in an area of low population density. Living in a rural environment may predispose to A fumigatus colonisation.

     Glyn Evans

Dr E Glyn V Evans (1941-2003) was the Leeds mycologist and with Dr M D Richardson from Manchester edited “Medical Mycology: A Practical Approach”.   A former Secretary then President of the BSMM, Glyn Evans is someone who impressed all who knew him with the strength of his personality, his sense of humour and his obvious professionalism. He worked as a mycologist in Leeds for 31 years eventually becoming Professor and finally returning to Cardiff in 2001. There is a glowing appreciation of his life on the International Society for Human and Animal  Mycology website

 Littlewood JM. Conway SP. Page RL. Cystic fibrosis. 7. Management of cystic fibrosis in different countries. Cystic fibrosis in Leeds. Thorax. 46(5):387-9; discussion 389-90, 1991 May.   PMID: 2068699
I was invited by Dennis Shale to write one of a series of three articles for Thorax on CF care in three leading CF centres. Peter Phelan and G Bowes described care iMelbourne, Christian Koch and Niels Hoiby care in Denmark and myself, Steve Conway and Richard Page care in Leeds.   The articles are quite detailed and a useful record of the state of care in 1991 at three of the better CF centres. 

          Richard Page

Richard Page (194? – 2007).  Richard had been a consultant chest physician at St James’s University Hospital, Killingbeck Hospital and the Leeds Chest Clinic since 1979.  He was active in the British Thoracic Society and for a time chair of their professional standards committee.  In the mid-Eighties Richard kindly agreed to be involved in the  care of some of our St James’s CF patients as they became young adults. This became an increasing commitment but the adult respiratory ward, where the patients were mostly very elderly patients with bad chests, was not acceptable to many of the young teenage patients accustomed to the CF oriented paediatric ward many of them had known for many years. In fact one young woman told me she would rather die than be treated in the Respiratory ward.    Many patients gradually opted to change to Seacroft Hospital under the nominal care of my friend Dr John Stevenson and his CF trained Lecturer in Infectious Diseases Dr Steve Conway who had worked with me at St James’s.  Eventually the care of the CF adults moved to Seacroft. Steve Conway was appointed as consultant and subsequently developed a major adult CF service there. 

            Dennis Shale

Dr Dennis Shale (1948-2017) — then Senior lecturer in Nottingham – notes that the role of specialist centres is emphasised in all three articles. He also noted that median survival is 30 years in Melbourne, over 25 years in Denmark and 20 years in the United Kingdom. It is some comfort that as CF centre care became more the rule in the UK survival steadily improved. Dennis became Professor of Respiratory Medicine in Cardiff and Director of the Adult CF Centre at Llandough.

 

Simmonds EJ. Conway SP. Ghoneim AT. Ross H. Littlewood JM. Pseudomonas cepacia: a new pathogen in patients with cystic fibrosis referred to a large centre in the United Kingdom.  Archives of Disease in Childhood. 65(8):874-7, 1990 Aug.        PMID: 2400225 

This was one of the first reports of Pseudomonas cepacia infection (later known as Burkholderia cepacia) in the UK.

Pseudomonas cepacia infection had become increasingly common among patients with cystic fibrosis in North America. In our large Leeds cystic fibrosis centre in the United Kingdom 11 cases have been identified during the last six years, with a maximum prevalence of 7% in 1988. Three patients had died, two of whom deteriorated rapidly shortly after acquisition of the organism despite intensive treatment with appropriate antibiotics. Analysis of possible causes of the increase in P. cepacia infection suggested that neither patient to patient transmission nor the use of nebulised antibiotics was associated with an increased risk of infection cross infection was eventually recognised.

            John Govan

In the late 1970s and early 1980s an increasing incidence and prevalence of Burkholderia cepacia was reported in N. American CF Centres (Isles et al 1984; Thomassen et al, 1985) and to have an increased morbidity and  mortality (Tablen et al, 1985; and 1987; Muhdi et al, 1996). Subsequently studies using molecular finger printing techniques established compelling evidence of cross-infection including direct patient-to-patient spread via contacts within specialist CF Centres and outside of clinics through social contacts (LiPuma et al1990; Govan et al, 1993; Smith et al, 1993). However, a review of published studies by John Govan (1996) showed cross infection was not inevitable even in the case of siblings suggesting that spread may be strain dependent

In the UK John Govan’s 1993 paper “Evidence for transmission of pseudomonas cepacia by social contact in cystic fibrosis. PMID 7686239) was central to the introduction of prevention policies in the UK. The introduction of strict segregation policies led to a dramatic fall in the incidence of cross infection in Specialist CF Centres where in 2019 only 1.3% of patients had B. cepacia isolated. In 1997 a taxonomic study revealed that isolates previously identified as B. cepacia comprised a complex of closely related species or genomovars.  As mentioned above, once precautions to avoid cross infection were implemented the incidence fell dramatically.

In 2004 the CF Trust Infection Control Group, produced the second edition of “The Burkholderia cepacia complex – suggestions for prevention and control”.

Mrs Sandra Kennedy

I chaired the group and wrote the document along with Mrs Sandra Kennedy, the excellent CF Trust Publications Manager, on behalf of the distinguished committee which contained virtually all the UK authorities on the subject. Although I say it myself, it was an excellent document distilling the present UK expertise with over 100 references. In 2020 the more than 3000 references on Pubmed attest to the continuing interest in the subject of B.cepacia

                  UMC Groningen

So our 2004 CF Trust document was well-received and I was asked to present the findings at a medical meeting at the University Medical Centre, Groningen in the Northern Netherlands. This new centre opened in 1997 and is affiliated with the University of Groningen and offers supra-regional tertiary care to the northern part of the Netherlands. It employs almost 17,000 people and numbers almost 1400 beds. It is very light and airy and each ward has a balcony that opens to one of the main ‘streets’ of the hospital – some patents were sitting out on the balconies. The meeting went well.

Littlewood AE, Bowler IM, Littlewood JM. A method of data collection and use at a Regional CF Unit. Poster 94. 17th European Cystic Fibrosis Conference. Copenhagen, Denmark. 17th-21st June 1991
The introduction of a comprehensive assessment service for patients referred to our Regional CF Unit 1981 generated such a large amount of data that computerisation became essential and was introduced in 1982 when we had our first CF Research Fellow Dr Mike Miller. 

          an Bowler and Ann Littlewood
CF Research Fellows John Gilbert and Mike   Miller with Ann Littlewood

A system based on an Epson PC AX 80 Mb hard disk and 640K using Symantec Q&A software provides database and word processing facilities. Four databases were now in use: a patient register; a clinic database for  regular outpatient visits; an inpatient database and also an assessment database for the periodic assessments.

The system had been recently modified and adapted over the past eight years by interested colleagues and professional computer programmers. The system has been recently networked to allow a maximum of four computers run simultaneously from a dedicated server, this was found to be essential for efficient secretarial backup. The information collected is used regularly to generate reports and graphs the state of our clinic attenders and also for administrative and was essential for research purposes.  We have found that computerisation of data is essential for the adequate organisation and utilisation the the mass of data accumulated in a complex multi system disease such as cystic fibrosis.

Ann littlewood with poster

Ann Littlewood SRN was closely involved on a voluntary basis with the data management from the early years until we both retired in 1997. She was responsible for data input and combined with the various CF Research Fellows in organising data for their publications.

In 1993 I was invited to a meeting of German Respiratory Physicians to give a lecture on “The importance of a CF database in management and Genotype Phenotype analysis”. 

During the lecture I stressed the importance of having only one or two people responsible for the database. I mentioned the difficulty in the early years of changing the person responsible for the computer data as staff joined and left the unit. I told the audience that I searched for someone who would be permanent, had some medical knowledge, was thorough, would be able to deal with the wide range of people who would be involved in providing and requesting data, and someone whom I would be able to work with.   After a pause I exclaimed “My wife!”   There was a moments silence round the auditorium then a ripple of laughter as the German doctors realised what I had said then hearty laughter. “Ja, Ja His wife very good, very good!

Littlewood JM. Gastrointestinal complications in cystic fibrosis.  Journal of the Royal Society of Medicine. 85 Suppl 19:13-9, 1992.PMID:1597835    FREE
Abdominal symptoms and signs are less frequent in those patients whose intestinal absorption is well controlled.Although even in 2020 a significant number of CF patients have some persisting abdominal symptoms such as pain, bloating, constipation or temporary obstruction (meconium ileus equivalent). The CF patient may, of course, suffer from any of the abdominal conditions which occur in the non CF individual. and also as an additional complication of an existing CF-related disorder, eg appendicitis or intussusception in a patient who already has ileal obstruction.  The increased longevity of people with CF have increased the likelihood of gastrointestinal complications and additional disorders.

In this article in 1992 I suggested a person with CF who has persisting abdominal symptoms despite adequate doses of pancreatic enzymes deserves full gastrointestinal investigation (Table) to exclude the other disorders which are unrelated to the CF. This list was based on considerable experience over more than 25 years, with over 15 years a CF centre with considerable professional gastroenterological input from colleagues at St James’s.

Review diet, faecal fat and percentage absorption
Check enzyme therapy and faecal chymotrypsin
Consider whether medication is causing symptoms
Urinalysis(renal ultrasound if urine abnormal)
Full blood count, erythrocyte sedimentation rate or plasma viscosity
Urea, electrolytes, amylase, liver function tests Helicobacter pylori antibodies
Abdominal radiograph for faecal loading
Check for gut infection and giardiasis
Hydrogen breath test for small bowel infection
Ultrasound gallbladder, bile ducts and pancreas
Radiograph contrast studies to check gut anatomy
Exclude coeliac disease and food intolerance
Gastroscopy, colonoscopy with biopsies
Consider emotional factors
Surgical opinion?laparotomy

  Certainly  abdominal problems remain relatively frequent in CF adults.

            Bu Hayee
      Caroline Elston

In 2019 a survey of adults at Kings College Hospital in London 69/107 (65%) had abdominal symptoms independent of their pancreatic enzyme replacement therapy (PMID:31428412). These were bloating/distension (26%), flatulence (20%), abdominal pain (19%) and gurgling (12.5%) a minority had burping (12.5%), nausea (12.5%), incomplete evacuation (11,5%), heartburn (8.3%), acid regurgitation (7.3%), and urgency of defaecation (6.3%).  The senior authors were Caroline Elson the director of the Adult CF centre and Bu”Hussain Hayee, the chief of the gastroenterology service  at King’s in London.

A recent survey and review (Sherie Smith et al, 2020. PMID:32900780) is informative and the full version is available on line – top 3 symptoms reported were – stomach cramps /pain, bloating and a combination of symptoms. Top three symptoms reported to health care professionals were reduced appetite, bloating and constipation. (Sherie Smith is a researcher and Cochrane Systematic Reviewer in  Nottingham)

Obviously abdominal symptoms are still a major problem in 2020 for many people with CF, particularly adults.  There is hope of more professional hands on gastroenterological investigational involvement in addition to mere surveys. Also it seems likely that CFTR modulators are going to help some patients.

Littlewood JM. Cystic fibrosis: gastrointestinal complications.  British Medical Bulletin. 48(4):847-59, 1992 Oct. PMID:1458304                                                              
Very similar content to the previous article above – a detailed review..

Conway SP. Simmonds EJ. Littlewood JM. Acute severe deterioration in cystic fibrosis associated with influenza A virus infection. Thorax. 47(2):112-4, 1992 Feb.  PMID:1549818     FREE                                                         
Three patients with cystic fibrosis showed severe deterioration in lung function and general wellbeing during the influenza A virus epidemic in the winter of 1989-90. Serological confirmation of influenza A virus infection was obtained in each case.
As immunisation against influenza A virus is safe and 70-80% effective and provokes an adequate antibody response in patients with cystic fibrosis, it is concluded that patients with cystic fibrosis should be offered immunisation at the beginning of each influenza season. Rapid diagnostic tests and the use of antiviral drugs, amantadine and ribavirin, may have a prophylactic role in minimising lung damage.

With regard to CF and virus infections in the 2020 Covid pandemic, a study using international Registry data suggests encouraging health outcomes for those people with cystic fibrosis who have developed COVID-19 but nevertheless highlights the need to stay safe. 

Bowler IM. Littlewood JM. Episodic arthritis in cystic fibrosis. [ Case Reports. Letter] Lancet. 340(8813):244, 1992 Jul 25.
Although episodic arthritis was not usually considered to be associated with exacerbations of the chest infection, we observed a close relationship in three children. There was an impressive improvement in the arthritis observed soon after starting intravenous antibiotic treatment.

 

Bowler IM. Green JH. Wolfe SP. Littlewood JM. Resting energy expenditure and substrate oxidation rates in cystic fibrosis. [ Journal Article] Archives of Disease in Childhood. 68(6):754-9, 1993 Jun. PMID:8333766                                                               
The resting energy expenditure (REE) and substrate oxidation rates in 16 patients with cystic fibrosis who had mild chest disease and 11 healthy controls were measured using indirect calorimetry with a commercially available system – the Datex Deltatrac Metabolic Monitor, Data Instrument Corporation to measure respiratory gas exchange.  

Carbon-based nutrients (i.e. fuels) are converted into CO2, H2O and heat in the presence of oxygen (O2). Indirect calorimetry (IC) assesses the amount of heat generated indirectly according to the amount and pattern of substrate used and byproducts generated. Specifically, EE can be calculated by measuring the amount of oxygen used (VO2), and carbon dioxide released (VCO2) by the body.   

Ian Bowler in the Datex Deltatrac Metabolic Monitor

The mean REE (% predicted) in the patients with cystic fibrosis was 11% greater than in the controls. Five patients with cystic fibrosis were hyper-metabolic but only one of these had a clinically significant reduction of respiratory function. A greater proportion of REE was derived from carbohydrate oxidation in the cystic fibrosis patients (43.5% v 29.9%). However, the 24 hour dietary intake of carbohydrate was greater in the cystic fibrosis group (49.6 v 45.8% of energy intake). 

These data suggest that a high dietary intake of carbohydrate may contribute to the increased oxidation of carbohydrate in these cystic fibrosis patients. All patients with cystic fibrosis, including those with apparently mild lung disease, should continue to receive a high energy diet.

This study essentially confirmed pervious work regarding the raised energy expenditure and also for mildly affected CF patients. Pulmonary infection and inflammation maybe a contributory factor to the raised energy expenditure. 

Not sure how the findings of this very impressive study changed our management except to confirm that carbohydrates seemed important and a high energy diet was important. 

       Dr J Hilary Green

Dr J Hilary Green was a physiologist working in the University Department of Medicine in St James’s. Hilary Green subsequently  published four papers between 2002-2003 from the Milk and Health Research Centre, Institute of Food, Nutrition and Human Health, Massey University, Palmerston North, New Zealand. All the

      Sue Wolfe

publications related to calcium metabolism. 

Subsequently she worked at Nestles Research Centre, Lausanne Switzerland in various senior scientific and educational roles until her retirement in 2020 when she became an independent consultant. Hilary has an extensive entry on Linkedin.      

Sue Wolfe, the dietitian involved, was now the Senior Paediatric Dietitian at St James’s and on her way to eventually becoming an international expert on cystic fibrosis nutrition.                                                                     

Bowler IM. Estlin EJ. Littlewood JM. Cystic fibrosis in Asians. Archives of Disease in Childhood. 68(1):120-2, 1993 Jan.  PMID:8434995
The clinical course of cystic fibrosis in nine Pakistani Asians was compared with 18 non-Asian age and sex matched controls. The Asian patients grew Pseudomonas aeruginosa at an earlier age (4.0 v 7.5 years), tended to have lower respiratory function test results (forced vital capacity 58.5 v 76.8% predicted; forced expiratory volume in one second 79.8 v 100.3% predicted), and had significantly greater concentrations of immunoglobulin IgG (13.4 v 10.1 g/l). They had a lower weight for age (78.4 v 95.7%) and weight for height (90 v 98.5%) despite similar intakes of dietary energy. Four of the nine Asians carried the delta F508 mutation compared with 17 of 18 controls. All the Asian patients were born in the UK; seven of their mothers were born in Pakistan and had moderate or severe difficulties with the English language. It is concluded that Asian patients may have a more severe clinical course than matched controls and that genetic and environmental factors may be contributory. 

    Eddie Estlin

As the Asian population of Leeds and nearby Bradford increased we gradually saw more Asian children with CF referred to St James’s. One of our SHOs Eddie Estlin joined Ian Bowler in reviewing them. The details were available in our excellent CF database.  At the time there were only two previous reports of CF in people of Asian origin.

Dr Eddie Estlin was a general paediatric registrar with us at the time.  He eventually became Professor of Paedaitric Oncology at Manchester Children’s Hospital.  In 2014 he was dismissed after clashing with management at the Central Manchester NHS Foundation Trust.  He raised a number of concerns with senior colleagues regarding consultants non-attendance at clinics, consultant cover at night and patient safety. He is mentioned on the internet both regarding various medical matters, politics  and also as editor of a textbook “Central Nervous System Tumours of Childhood”.                                                        
 

Bowler IM. Wolfe SP. Owens HM. Sheldon TA. Littlewood JM. Walters MP. A double blind lipase for lipase comparison of a high lipase and standard pancreatic enzyme preparation in cystic fibrosis. [ Clinical Trial. Journal Article. Randomized Controlled Trial] Archives of Disease in Childhood 68(2):227-30, 1993 Feb. PMID:7683190
A standard acid resistant microsphere pancreatic enzyme preparation was compared with identical capsules half filled with mini-tablets of a new high  lipase preparation in a randomised double blind crossover study in children with cystic fibrosis.
Each patient received his/her usual number of capsules and the same dose of lipase during each period of the study. Eighteen patients completed the study.
There were fewer gastrointestinal symptoms when pancreatic enzyme was supplied as the high lipase preparation. There was also a significant improvement in fat absorption (17%, 95% confidence interval (CI) 6 to 27), reduction in faecal fat output (15.8 g/day, 95% CI 6.4 to 22.5), and faecal energy loss (789 kJ/day, 95% CI 211 to 1384). It is concluded that half filled capsules of the new high lipase preparation are more effective than the standard preparation and it is likely that filled capsules would allow patients to use fewer than half the number of pancreatic enzyme capsules.

 There was much enthusiasm for the new high lipase enzyme preparations in the early Nineties and they were certainly a major advance.  Our present study showed how they were also more efficient lipase for lipase equivalent when presented as mini-tablets.  Fully filled NUtrizym 22, the new high lipase preparation, contains 22,000 lipase units per capsule compared with 10,000 per capsule in standard Nutrizym GR. Our trial showed that even on a lipase for lipase comparison the mini tablets in the half filled standard capsule were more efficient.

      Trevor Sheldon

Professor Trevor A Sheldon was the statistician for the study and is now Professor at Queens’ Mary University of London – Health Services Research and Policy. Described in 2020 on Wikipedia as “a British academic and University administrator who is a former Dean of Hull York Medical School. He has held academic posts at Kingston University, the University of Leicester and the University of Leeds“. I suspect he was employed by the pharmaceutical firm that sponsored our study.

It was disappointing that within a year Dr Ros Smyth and colleagues in Liverpool reported a new and serious complication – fibrosing colonopathy.  They observed five children with cystic fibrosis, who presented over 2 months, with meconium ileus equivalent that failed to respond to medical management. At surgery, four had a stricture in the ascending colon, and all had histopathological changes of post-ischaemic ulceration repair, with mucosal and submucosal fibrosis. The only common change in the management of these children was a switch from conventional enteric-coated pancreatic enzymes to high-strength products 12-15 months before presentation (Smyth RL et al. Lancet 1994;343(8889):85-6). The whole matter of fibrosing colonopathy and high strength enzymes will be discussed suffice it to say that all high lipase preparations were advised against for children. 

Some of our publications relating to fibrosis colonopathy from Leeds are reviewed together below  for continuity.

Green MR. Southern KW. Wolfe SP. Littlewood JM. Najmaldin AS. Wyatt JI. Colonic strictures in cystic fibrosis. Archives of Disease in Childhood. 72(2):191, 1995 Feb.  PMID:7702393
We reported two colonic abnormalities in children with CF that’s seemed to represent similar colonic strictures to those described for the first time in  the previous year by Dr Ros Smyth from Liverpool. I recall both these children very clearly.

Severe narrowing of the colon; severe deep submucosal fibrosis

The first was very serious and tragic. A 5-year old with persisting bowel symptoms since removal of some ileum and ileocaecal valve for meconium ileus, was changed from standard Pancrease to high strength Pancrease HL. not response to increasing doses.At 4.7 years  persisting diarrhoea and blood in the stools prompted a barium enema which revealed extensive stricture from the remaining ascending colon to the descending colon. An ileostomy was formed. Biopsies from the colon showed a 4-5mm thick wall which there was mild subserosal fibrosis and very prominent deep submucosal fibrosis. He had received up to 66,000 BP units lipase/kg/day.  He continued to have serious handicapping bowel problems.

Early fibrosing colonopathy with narrowing of ascending colon

A girl of 7 years had been on two brands of high strength pancreatic enzymes – Pancrease HL for 14 months and Nutrizym 22 for one month had a barium enema for abdominal pain. The ascending colon was featureless and slightly narrowed. Biopsies were normal but inadequate to see the submucosa. She had received up to 33,500 BP units/kg/day of lipase.

She was changed onto a standard strength enzyme and her symptoms  settled. As I recall the narrowing of the ascending colon did not progress and her symptoms settled.

Michael Green

These were undoubtedly similar cases to those reported fromLiverpool. It seems likely to us then that the high lipase enzymes were exerting some toxic effect but it was not known at that stage how this was mediated. Subsequent work from Liverpool identified the copolymer covering of certain brands of high strength enzymes to be responsible although the precise role of the copolymer remained controversial.

Dr Michael Green was in the Academic Unit of Paediatrics at St James’s at this time and then via the MRC Dunn Nutrition Unit in Cambridge, he eventually became, clinical lead consultant paediatrician in Children’s Hospital  University Hospitals, Leicester.

Littlewood JM. Fibrosing colonopathy in children with cystic fibrosis. [ Editorial] Postgraduate Medical Journal. 72(845):129-30, 1996 Mar. PMID: 8731700
I was asked to chair this meeting on the subject of fibrosing colonopathy held in November 1995. Most  people with experience of the condition were invited and this is my editorial and introduction to the meeting. It was a very worrying situation at the time so I will summarise my editorial which covers the background in some detail.

Although intestinal structures have been described in association with potassium chloride and non-steroidal anti-inflammatory drugs fibrosing colonopathy appears to be a new entity in cystic fibrosis children. In the absence of effective pancreatic enzyme supplements, the intestinal malabsorption associated with cystic fibrosis is severe when compared to that associated with other conditions such as coeliac disease. 

Prior to the introduction of acid resistant enzyme preparations in the UK in the early 1980s (Pancrease in 1983, Creon in 1985) there were many cystic fibrosis patients who had persisting distressing gastrointestinal symptoms and signs associated with severe intestinal malabsorption. It was impossible to control the intestinal absorption of these patients even with large doses of the older unprotected enzyme preparations even with additional strategies including gastric acid suppression with alkalis and H2-blockers. The quality of life for many of those patients was severely impaired; some had to restrict their fat intake in an attempt to reduce their unpleasant bowel symptoms In doing so they reduce their energy intake and compromise their nutritional state.

The introduction of acid resistant enzyme preparations in the early 1980s (Pancrease and later Creon) improved the control of intestinal malabsorption and permitted adequate control of the gastrointestinal symptoms in 90% of patients. Both the quality of life and nutrition of the patients were improved. However some patients required large doses of the acid resistant enzymes to achieve control of their symptoms and a reasonable degree of fat absorption over 85%.

In 1992 the high strength enzyme preparations (Creon 25.000, Pancrease HL and Nutrizym 22) became available in the UK. The first clinical trials indicated that all the preparations are effective at permitted most patients to reduce significantly the number of capsules required to achieve a compatible degree of fat absorption. An occasional patient did not tolerate a particular preparation but seem to respond to one of the others. So effective were the new preparations that many cystic fibrosis clinics had changed the majority of their patients to the high-strength enzymes by the end of 1993. However some patients did not achieve a direct conversion in terms of lipase. Although the lipase content of the new preparations was three (Creon to Creon 25,000) to five (Pancrease to Pancrease HL) times that of a standard capsules, some patients required up to 2/3 as many high strength capsules  i.e. rather more than expected.  Analysis of the enzyme intake of cystic fibrosis children showed that most patients had a higher lipase intake after transfer to the new preparations than they had before. There was only a 30% reduction in number of capsule/day while the number of lipase units/kg/day almost doubled. At the time this absolute increase in enzyme dose was not considered of other than financial importance and the majority of patients and their doctors were well pleased with the new high strength enzymes. We did not consider the possibility of serious side effects.

It was at this stage, between July and September 1993, that Ros Smith and her colleagues in Liverpool observed the first children with colonic strictures which they reported in the Lancet in early 1994. Earlier in December 1993 the Committee on Safety of Medicines (CSM) had reported the occurrence of these colonic strictures to clinicians and advised against the use of high strength preparations in children until the cause of the new complication was determined. Also cystic fibrosis patients and their families were warned of the complications by the CF Trust. In November 1994 the CSM recommended that “unless special reasons exist patients with cystic fibrosis should not use high potency pancreatin”. Following the report of colonopathy in two children taking high doses of a standard preparation (Nutrizym GR) the CSM recommended that “it would be prudent to avoid doses of pancreatic enzyme supplement in excess of of 10,000 units lipase/kg/day irrespective of the preparation”

Since the original description of fibrosing colonopathy a great deal of information has been made available and there has been considerable progress in the understanding of the course of the condition both in the UK and North America.   More patients have been described and  the association with high strength enzymes seems to be in established both in the UK and North America by epidemiological studies.

Littlewood JM. Update on the United States epidemiology study.  Postgraduate Medical Journal. 72 Suppl 2:S6; discussion S7-10, 1996 Mar. PMID: 8869178   

Littlewood JM. Management of malabsorption in cystic fibrosis: influence of recent developments on clinical practice. Postgraduate Medical Journal. 72 Suppl 2:S56-62; discussion S59-62, 1996 Mar. PMID:8869184  

Ramsden WH. Moya EF. Littlewood JM. Colonic wall thickness, pancreatic enzyme dose and type of preparation in cystic fibrosis. Arch Dis  Child 1998; 79(4):339-43. PMID:9875045    

     William Ramsden

At the time of this paper William Ramsden was a young radiologist at Jimmy’ s (see below). He combined with our CF Research Fellow, at the time Eduardo Moya, to correlate the colonic wall thickness with the type and dose of enzyme treatment in our CF children. Fibrosing colonopathy and which enzymes were involved was still a very topical subject.
The relation between sonographically measured colonic wall thickness and pancreatic enzyme preparation and dose was studied in 86 children with cystic fibrosis. Colonic wall thickness of a control group of children was also measured. The average thickness in all colonic regions was higher in the CF group (overall average range 0.7-2.5 mm v 0.6-1.4 mm in the control group). There was no significant relation between colonic wall thickness and age, sex, total dose of lipase, or the presence of copolymer in the enzyme used.  Apart from one patient with an early colonic stricture, none of those exposed to high doses of lipase, or the methacrylic acid copolymer Eudragit L30 D55, showed evidence of subclinical damage to the colon. Although the reproducibility of the sonographic measurements was poor, nonetheless, the results were reassuring.

                        Eduardo Moya

Dr William H Ramsden subsequently became a consultant paediatric radiologist at the Leeds Children’s Hospital also, at one period, the Medical Director Education and Training at the Royal College of Radiologists. In 2020 William was elected as Vice president (clinical radiology) of the RoyalCollege of Radiologists for a three year term

Dr Eduardo Moya was one of our CF Research Fellows and this was one of a number of combined studies he organised. Subsequently, he moved to Bradford as a consultant paediatrician.

Eduardo  in 2020

In 2020 Eduardo  made a video advising everyone to have the COVID vaccine.

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            Littlewood JM. Update on intestinal strictures. [Review] [65 refs] Journal of the Royal Society of Medicine. 92 Suppl 37:41-9, 1999. PMID:10472252
This article is the text of the last lecture I gave at the Royal Society of Medicine Annual CF meeting. It is a useful detailed review of fibrosing colonopathy, (a serious narrowing and fibrosis of the colon in children with cystic fibrosis).

Fibrosing colonopathy

The complication first appeared in CF children in Liverpool in 1993 and eventually involved 17 UK children and over 30 children in the USA.  All the published evidence suggested that fibrosing colonopathy is in some way related to the use of large doses of the pancreatic enzymes which contain methacrylic acid copolymer (EudragitL30D55) as a covering.  It is very probable that there are other factors that determine which patients exposed to these products will develop fibrosing colonopathy.  However, it seemed advisable to use only enzymes which did not contain the copolymer covering. 

Many of us were confident that avoidance of enzymes containing the copolymer covering was responsible for the disappearance of the condition. It is only fair to note that not every paediatrician agreed including my friends Prof.  John Dodge and Prof. Chris Taylor.  In fact, I had some heated letters from them on the subject when we at the CF Trust advised UK paediatricians that those prescribing pancreatic enzymes for children avoid those which contain the copolymer and use only Creon 10,000, standard Pancrease or Creon 25,000.  

The full text of this detailed review article is available on PubMed and it is an interesting story – but about a  terrible complication for the few affected children. 

John Dodge & Chris Taylor. A brace of gastroenterological professors

Sadly the subject was not dead yet!  In correspondence to the Lancet in November 2001 John Dodge questions the findings of the previous research  by Ros Smyth et al,. in which the discredited pathologist Dick van Velzen was involved, which was the basis of the CSM working party report chaired by John Dodge himself and he calls for a review.  In a letter to me on 24.11.01 my friend regards me as ”being intemperate in my discussion of the matter” “bewildering serious  gastroenterologists in this country and abroad by refusing to acknowledge that the copolymer hypothesis remains unproven”. He states that himself and Chris Taylor are “the only two paediatric gastroenterologists in the frame”.

As the advice to avoid high strength preparations and Nurizym GR (which all contained copolymer) it had abolished fibrosing colonopathy in the UK. The CF Trust Research and Medical Advisory Committee, of which I was Chairman, agreed with me that no further time or CF Trust money should be wasted on the matter.

It was interesting that as recently as December 2013 Chris Taylor criticised  a review on drug induced complications in CF by Daniel Peckham and Paul Whitaker as they mentioned the possible role of the copolymer eudragit in the aetiology of fibrosing colonopathy. Chris Taylor insists the relationship  has not been established. The good news is that the condition has disappeared from the UK. 

Allen MB. Mellon AF. Simmonds EJ. Page RL. Littlewood JM. Changes in nocturnal oximetry after treatment of exacerbations in cystic fibrosis.  Archives of Disease in Childhood. 69(2):197-201, 1993 Aug. PMID: 8215520  FREE
Sleep related arterial oxygen desaturation has been described in clinically stable young adults with cystic fibrosis. The incidence and severity of nocturnal oxygen desaturation in children during infective exacerbations and the changes that occur with treatment were examined in this study. 

Forty five children with proved cystic fibrosis, median age 8.9 years, admitted to the Regional Cystic Fibrosis Unit underwent clinical evaluation, spirometry, and measurement of peak flow and nocturnal oxygen saturation on admission and after 10 days’ treatment using a Biox 3740 pulse oximeter. There was a significant improvement in all the above measurements, with the averaged overnight saturation changing from a mean (SD) 92.7 (2.7)% to 94.3 (2.0)%, mean (SE) difference 1.58 (0.37). The time spent with a saturation 4% or more below their clinic value showed a marked improvement from 122 (152) minutes on the  first night to 21 (30.7) on the second, mean (SE) difference 101 (22.4). 

Eight young children could not perform pulmonary function tests, all desaturated on the admission night. Nocturnal hypoxaemia is a common finding in young cystic fibrosis patients during infective exacerbations but improves with treatment. Overnight oximetry is simple to perform, well tolerated, and identifies patients with marked nocturnal desaturation.

This was the first study of nocturnal oxygen desaturation in children with CF and the effect of IV antibiotic treatment. Dr M B  Allen was from the respiratory unit and working with Dr Richard Page consultant chest physician who had some involvement with a few adult CF patients. There is no discussion as to treatment of those patients with desaturation after IV antibiotic treatment

Andy Mellon – now
Andy Mellon – then

Dr Andy Mellon was our paediatric registrar working on our ward at the time.  He eventually became consultant paediatrician at Sunderland Royal Hospital and Hon. Clinical Senior Lecturer in Newcastle medical school.
Andy retired in 2020 after a successful career. Chief Executive Ken Bremner said: “Over the course of almost a quarter of a century, Andy has worked to support the needs of countless local children and their families. Alongside this extremely important, high-pressure role, he has worked tirelessly in the field of medical education – training and inspiring the doctors of the future. On behalf of the Trust, I’d like to thank him for his fantastic contribution. I wish him all the best in retirement, although it’s good to know that we will not be losing his vast knowledge and skills entirely as he will still be involved in some clinical wo

Littlewood JM. Coeliac disease in childhood. [Book chapter] [125 refs] Baillieres Clinical Gastroenterology. 9(2):295-327, 1995 Jun. PMID: 7549029                                                             

With Peter Howdle at a Coeliac meeting

Dr Peter Howdle, then a Senior Lecturer in Monty Losowsky’s University Department of Medicine at St James’s, asked me to write a chapter on Coeliac disease in Childhood in his book on Clinical Gastroenterology.  I had investigated and treated many children who had coeliac disease over the past 25 years, had introduced paediatric jejunal biopsies in Leeds in 1968, provided this service for the surrounding areas and published a number of papers on the condition. 

Much of this chapter involved a considerable amount of my own and colleagues’ experience of 108 children with coeliac disease. Various aspects of our previous published work are discussed elsewhere in this Paper Trail.  There are detailed clinical descriptions of presenting features, genetic features, laboratory aspects and diagnostic criteria.  Jejunal biopsy techniques are discussed in detail both with the standard capsule and using a paedaitric endoscope. Our radiology colleague Dr Sidney Smith was invaluable in screening the capsule.  Many of the biopsies in recent years were performed by Dr Avril Crollick who worked with me for a number of years.

Dr Avril Crollick

Not all children with coeliac disease present with the textbook description of an unhappy blonde child with slender limbs, wasted buttocks and prominent abdomen.

For example Mary, aged 10 years, was well grown and looked healthy but had troublesome recurrent abdominal pain for 2 years diagnosed as abdominal migraine by an experienced paediatrician. She was eventually referred to me for upper gastrointestinal endoscopy the pain was so troublesome. The endoscopy procedure included small duodenal grab biopsies which suggested subtotal villous atrophy; this was confirmed on a standard jejunal biopsy specimen. Her pain settled completely and permanently on a gluten free diet.

John, aged 10 years, was referred by the school doctor as his height reached only the 10th centile although his growth rate was normal and he had no symptoms. His skeletal age on wrist x-ray was only 5 years which prompted a jejunal biopsy; this revealed subtotal villous atrophy of active coeliac disease. His growth accelerated markedly after he started a gluten free diet.

The chapter is liberally referenced (125 references) yet full of personal and colleagues’ experience from the first time I fired a jejunal biopsy capsule in 1968. I must be honest – I’m proud of it!

Bush A. Hodson ME. Geddes DM. Rosenthal M. Dinwiddie R. Wallis C. Stableforth DE. Conway SP. Littlewood JM. Dornase alfa for cystic fibrosis. Patients should not be denied a safe, effective treatment. [ Letter] BMJ. 310(6993):1533, 1995 Jun 10.  PMID: 7787614
In this letter consultants with considerable experience in CF from the Royal Brompton (Andy Bush, Margaret Hodson, Duncan Geddes, Mark Rosenthal), Great Ormond Street (Bob Dinwiddie, Colin Wallis), Birmingham (David Stableforth) and Leeds (Steve Conway, Jim Littlewood) write to complain about a ridiculous article in the Drug and Therapeutics Bulletin (1995;33(2):15-16) which stated that “on the evidence available dornase alpha should not be added to the formulary”. 

         Andy Bush

The trouble with this and any undersigned recommendations is that readers do not know how many clinicians with experience of cystic fibrosis treatment were responsible for the final draft similarly they cannot judge whether considerations of cost were paramount. All the authors The authors of this letter had seen many patients improve their respiratory function by more than 10% following the use of the drug The paper has missed several points which they lis

– The licensing authorities reviewed all the evidence before recommending the drug be licensed.

– Many patients’ respiratory function has been stabilised with the drug for prolonged periods

– A double blind trial showed patient with severe respiratory involvement after three months treatment.

– Many patients die on the transplant waiting list Cyclosporin costs more the dornase alpha – it seems reasonable to prevent transplant by its use.

– Both CF Foundation and UK CF Trust concluded the drug had a role in treatment.

In the opinion of the writers, patients with a life-threatening condition should not be denied treatment with a drug that has been shown to be safe and in a number of studies, not only stabilise lung function, but also to improve it, reduce exacerbations, and improve various measures of quality of life. All patients who may benefit should have the opportunity to use this drug. In each case the clinician dealing with the case must decide whether there is enough benefit for treatment to be continued.

Joe Collier. the unrepentant editor of the Drug and Therapeutics Bulletin replied to our letter that studies from New Zealand and Australia failed to recommend the drug! He wrote  “It would be reasonable to consider the drug as essentially experimental”. However it was a concern that Joe Collier was an undoubted “heavyweight” in the pharmacology field.  

        Joe Collier

Joseph Gavin Collier FRCP (born 1942) was a British retired clinical pharmacologist and emeritus professor of medicines policy at St George’s Hospital and Medical School in London, whose early research included establishing the effect of aspirin on human prostaglandins and looking at the role of nitric oxide and angiotensin converting enzyme in controlling blood vessel tone and blood pressure. Later, in his national policy work, he helped change the way drugs are priced and bought by the NHS, and ensured that members of governmental advisory committees published their conflicts of interest.

However, despite these early doubts dornase alpha (Pulmozyme) became one of the most valuable additions to the treatment of people with cystic fibrosis as I will discuss in the next abstract.  In the UK by 2019  63.1% of children and 70.8% of adults with CF were taking Pulmozyme regularly; its use is supported by numerous clinical trials which now total 279 on PubMed.   Nebulised in-line endotracheal dornase alpha and albuterol are now (2020) being used in mechanically ventilated COVID-19 patients with encouraging results. One of the major advances of the Nineties. 

Conway SP. Littlewood JM. rhDNase in cystic fibrosis. [Review] [14 refs] British Journal of Hospital Medicine. 57(8):371-2, 1997 Apr 16-May 6. PMID:9274660
I was asked to write a review of Pulmozyme (rhDNase) two years after our letter to the Lancet. My colleague Steve Conway was a very good writer (he already had a degree in English before studying medicine!) kindly agreed to do the main writing of the article as I was about to retire that year 1997.        

With Steve Shak and Steve Conway

In 1990 there was an early report of the significant effect of recombinant human DNase1 (Pulmozyme) on sputum viscosity in people with CF by Steve Shak (PMID: 2251263). To evaluate the potential clinical utility of recombinant human DNase I (rhDNase) in the treatment of CF, the authors cloned, sequenced, and expressed rhDNase. Catalytic amounts of rhDNase greatly reduced the viscosity of purulent CF sputum, transforming it within minutes from a non-flowing viscous gel to a flowing liquid (figure). The reduction in viscosity is associated with a decrease in size of the DNA in the sputum.

      Henry J Fuchs

Dr Henry J Fuchs, while working at Genentech from 1987 to 1996, led the clinical programme that resulted in the approval of Pulmozyme – one of the 

major clinical advances introduced during the Nineties and licensed for people with CF by the FDA in 1994 (Fuchs HJ et al. N Engl J Med 1994; 331:637-642. PMID: 7503821).

Regular treatment with DNase would become widely used (by 78.4% of people with CF over 6 years old on the CFF registry in 2010) first amongst those with significant chest involvement and then later for those with milder chest problems and eventually, in some CF units, for infants. The cost (approximately £7000 per year) proved a problem in certain parts of the UK as described above.

          Viscid CF sputum
Viscid CF sputum (R tube) liquified by Pulmozyme (L tube)

The history is interesting.  As far back as 1950 Armstrong JB & White JC (Lancet 1950; 2:739-742. PMID: 14795699) had shown that bovine pancreatic DNase1, added to viscid purulent sputum, destroyed the extra cellular fibres of DNA and reduced the viscosity.  Later Elmes PC & White JC (Thorax 1953; 8:295-300. PMID: 13122659) reported its use in chronic bronchitis, but the side effects of the bovine preparation eventually precluded its use and further development at that time (Raskin P. Am Rev Respir Dis 1968; 98:697-698. PMID: 4877872)

Subsequently the rhDNase (Pulmozyme) reported here proved to be one of, if not the, major therapeutic advance of the Nineties. Numerous subsequent reports confirmed both short and long term benefits. 

Littlewood JM. Abdominal pain in cystic fibrosis. [Review] [75 refs] Journal of the Royal Society of Medicine. 88 Suppl 25:9-17, 1995.PMID:7776329 FREE
Another very detailed article based on a lecture I gave at the Royal Society of Medicine CF Meeting – a “panoramic” review of abdominal pain both as seen in children with CF and in childhood.
In our paediatric CF clinic at St James’s 11% of children have occasional abdominal pain whereas regular abdominal pain is a problem in 31% of children referred from general paediatric clinics for assessment.
The prevalence of abdominal pain is related to the mode of presentation – meconium ileus 38%, respiratory 39% malabsorption 47%, diagnosed as having a CF sibling 30%, but those diagnosed by neonatal screening only 4%. The reasons for this difference are not understood but certainly significant.

The main message was thorough investigation of all CF patients with persisting or recurrent abdominal pain and the bowel symptoms at an early stage rather than assuming they have uncontrolled malabsorption and progressively increasing their enzyme dose, particularly important in view the recent reports of colonic strictures

O’Connor PJ. Southern KW. Bowler IM. Irving HC. Robinson PJ. Littlewood JM. The role of hepatobiliary scintigraphy in cystic fibrosis. Hepatology. 23(2):281-7, 1996 Feb.  PMID: 8591853                                                            
Recent promising results with ursodeoxycholic acid (UDCA) have led to an increased interest in early and thorough assessment of the hepatobiliary system.  This was a prospective open study that examined the quantitative and qualitative analysis of hepatobiliary scintigraphy (DISIDA) in detecting liver involvement in cystic fibrosis (CF).
Forty-four adult and paediatric patients (median age, 12.1 years; range, 1.1-36.3 years) were divided into three groups: group 1, no evidence of liver involvement (n = 8); group 2, biochemical evidence of liver involvement on two or more occasions (n = 26); and group 3, clinical evidence of liver disease (n = 10). 

 

 

 

Normal appearances. (A) Fifteen minutes postinjection, there is homogenous hepatic activity. The gallbladder can already beseen clearly (arrow). (B) Forty minutes postinjection, there is good clearance of the hepatic activity with no focal intrahepatic retention.Tracer can be seen within the gallbladder (arrowhead) and small bowel (long arrow).
(A) Homogenous hepatic activity with an area of focal intrahepatic retention (arrow) 45 minutes postinjection. No gallbladderfilling was observed in this patient. (B) Focal intrahepatic retention (arrow) in a patient with heterogenous hepatic activity 45 minutespostinjection.
A) Irregularity (beading) of the left main intrahepatic bile duct at 15 minutes. (B) Irregularity (beading) of the main intrahepaticbile ducts 15 minutes postinjection
Secondary and tertiary ducts at 25 minutes

In groups 1 and 2, the most common qualitative scintigraphic finding was focal intrahepatic retention of tracer (26/34 patients, 12 of whom had normal findings on ultrasonography). This finding corresponds to focal cholestasis and may warrant treatment with the choleretic agent ursodeoxycholic acid (UDCA). In the group 3 patients, the abnormal qualitative scintigraphic appearances (heterogeneous uptake of tracer and nodular liver outline) added little to the findings on ultrasonography; however, these patients had a prolonged mean hepatic clearance time compared with those in groups 1 and 2 (one-way ANOVA; P < .015). 

It is proposed that scintigraphy with DISIDA has a role in the detection of early liver involvement in cystic fibrosis.

At the time it was our practice to perform ultrasonography and hepatobiliary scintigraphy on all patients with abnormal liver function tests on more than two occasions.  Treatment with UDCA is started on all patients with evidence of hepatic abnormality on imaging. Twelve patients investigated after UDCA showed improved clearance and serum ALT levels 

Phil O’Connor

Dr Phil O’Connor after radiology training in Leeds,  North Carolina and Leiden and was appointed consultant Musculoskeletal Imaging Radiologist at Leeds in 1996. He helped develop the team of 8 MSK radiologists currently in Leeds

Philip Robinson

Dr Philip Robinson initially trained in  Medicine. He obtained MRCP in 1994 and entered radiology training at the University of Manchester in 1995 obtaining the FRCR in 1998. He completed a fellowship in musculoskeletal radiology at the University of Toronto in 2000. He was appointed a Consultant Musculoskeletal Radiologist, Leeds Teaching Hospitals NHS Trust in 2001.

Henry Irving

Dr Henry Irving is a senior consultant radiologist with the Teaching Hospitals in Leeds. He has published widely on a variety of aspects of imaging and invasive radiology up to 2014.