Henderson MJ. Littlewood JM. Miller M. Interpretation of sweat sodium and chloride concentrations. Annals of Clinical Biochemistry. 23 ( Pt 1):109, 1986 Jan. PMID: 3767251

                  Mick Henderson

Dr Mick Henderson was a keen chemical pathologist at St James’s and was always very helpful.   In this letter we substantiate the report of Ann Green, the Birmingham biochemist  (Green A et al. Ann Clin Biochem 1986;23:109), that chloride plays an important role in interpretation of the sweat electrolytes.  In our laboratory at St James’s during the past four years 756 sweat tests have been performed on patients shown NOT to have CF, 53 (7%) were borderline  50-70 mmol/l; in only 3 cases was chloride higher than sodium but in these the sum of the sodium and chloride was less than 140mmol/l. In four patients the sum of the sodium and chloride was greater than 140 but the Cl was lower than the sodium. So using the criteria suggested by Greene were used together ther would have been no false positives.

During the same period we performed sweat tests on  137 CF patients. Borderline results were found in only four, in all the chloride was higher than sodium, but in two the sum was less than 140mmol/l. More of our patients had lower chloride than sodium – possibly due to the method used to measure it. Therefore by the criteria suggested there were two false negatives by the suggested criteria – in both the diagnosis was certain from many other features

We stressed again the diagnosis does not rest entirely on the sweat test.

Littlewood JM. The sweat test. [Editorial] Archives of Disease in Childhood. 61(11):1041-3, 1986 Nov.  PMID: 3789783
I was invited to write an editorial on the sweat test for the Archives of Disease in Childhood. This was quite detailed dealing with history, sweat collection and interpretation of the electrolyte values mentioning the marginal values, various non-CF conditions where the electrolytes may be abnormal, before and after 5A-fludrocortisone tests and the importance of additional evidence of CF from malabsorption and evidence of pancreatic involvement. 

Misdiagnosis has usually followed one or more false positive sweat tests with subsequent uncritical acceptance of the results by the clinician. It is suggested if there is no evidence of a gastrointestinal lesion the patient should be referred to  CF centre.

Prof Anne Green in 1971 and more recently

Anne Green, a very experienced biochemist from Birmingham Chidren’s Hospital, commented on my editorial and suggests that many hospitals only measure one ion. Also she does not support the value of pancreaticfunction tests as diagnostic difficulty is commonly encountered in the 10% of CF patients who have normal pancreatic function. She quotes that of 441 sweat tests of the 9 that were abnormal only one had CF, the  other 8 had sodium values higher than chloride. She considers one should not relay on pancreatic function tests but rather the whole picture which is merely supportive.

I replied to Anne Green’s comments that I would not accept the sweat test and clinical picture were sufficient to excluded the diagnosis. Certainly parabenzoic acid test (PABA)  and faecal chymotrypsin will not exclude a minor degree of pancreatic insufficiency. Our Leeds experience of over 200 patients with CF suggests that individuals who have marginal sweat tests and CF usually have other supportive clinical evidence. Confirmation of the diagnosis must rely on criteria other than the sweat test.   

Most mistakes in diagnosis are usually due to an incorrect measurement of the sweat electrolytes and an uncritical acceptance of the result by the clinician who fails to demonstrate any gastrointestinal lesion or re-examine the doubtful diagnosis at a later date.

Gilbert J. Littlewood JM. Enteric-coated prednisolone in cystic fibrosis. [Letter] Lancet. 2(8516):1167-8, 1986 Nov 15. PMID: 2877319

       John Gilbert

We had a 12 year old child with CF in the ward for treatment of an exacerbation of her chest infection. Blood tests and chest X-ray were  suggestive of bronchopulmonary aspergillosis; they had been suggestive of ABPA a year previously but the parents were apprehensive  of steroids  and refused to have her treated with prednisolone and she improved slowly with antibiotic therapy.

One year later a routine X-ray showed signs of right upper lobe consolidation. After a 2 week course of enteric coated prednisolone prescribed by her GP there was  no improvement of the Xray nor did she show any signs of Cushingoid facial redness which should have appeared after 2 weeks of steroids. We changed her steroid therapy to ordinary non-enteric coated prednisolone and within two days her chest started improving, the X-ray changes started clearing

We concluded that the patient was unable to digest the enteric coated steroid and reported our experience to the Lancet to warn others that enteric coated tablets may not be adequately absorbed by people with cystic fibrosis.

Ehrhardt P. Miller MG. Littlewood JM. Iron deficiency in cystic fibrosis. [ Journal Article] Archives of Disease in Childhood. 62(2):185-7, 1987 Feb. PMID: 3827296   

     Peter Ehrhardt

Peter Ehrhardt was our paediatric senior registrar at the time. He was more senior than most as he had previously been a teacher before he took up medicine as a mature student qualifying in 1978. He was consultant in Dewsbury moving to Burnley in 1991. After a successful career he retired in 2011.

He was a very nice man and very precise; one could imagine his being a good school master. For his research project I put him onto the iron status of the CF patients.  The iron status was measured as part of the CF comprehensive assessment in 165 patients. Of 127 patients, 41 (32%) had low serum ferritin concentrations and at least this proportion were iron deficient. The iron state did not correlate with the clinical score, radiological score or the results of the sputum culture. There was evidence that patients with iron deficiency were neither in better or worse clinical condition than those with better or worse iron stores.

In 2020 there is still about the iron status of patients with cystic fibrosis and treatment.  One thing I remember clearly about Peter was that when the editor of the Arch Dis Child journal made some suggestion, I think, about the title of this article, Peter firmly refused to make any changes!  I was impressed by his confidence.  Finally, we were grateful to him for giving  one of our daughters some maths tuition!  

Heycock E. Heatley RV. Shires SE. Littlewood JM. An in vitro test for cows’  milk protein intolerance?. Scandinavian Journal of Gastroenterology. 21(10):1245-9, 1986 Dec.  PMID:3809998
The clinical features and results of standard laboratory investigations have been studied in children with cows’ milk protein intolerance and the results compared with an in vitro test, examining the degranulation of peripheral blood basophils to cows’ milk antigen. 

Of 67 children investigated, 26 had probable intolerance to cows’ milk, and maximal basophil degranulation responses in these children were significantly increased (p<0.01). The most striking differences were those observed between children with definite cows’ milk protein intolerance and control individuals (p<0.002). Of 14 children with definite cows’ milk intolerance clinically, only 4 had negative responses. 

We speculated the basophil degranulation test may be a valuable, simple and inexpensive investigation in the diagnosis of cows’ milk protein intolerance and perhaps also in other conditions in which food sensitivity plays a part.

This test never made any further progress and even in 2020 the only sure way to diagnose food allergy/intolerance is by withdrawal and challenge.

Dr Elizabeth Heycock was a research fellow in the Department of Medicine. She later appeared in a number of publications with Colin Robertson and the paediatric respiratory group in Melbourne. 

Dr Val Heatley was Senior Lecturer in Monty Losowsky’s Department of Medicine in St James’s. He was very much involved in publications and research and his output on a variety of gastrointestinal topics could be described as prolific. Many were with other members of Professor Losowsky’s University Department of Medicine at St James’s. Between 1977 and 2005 he has 150 publications listed on Pubmed in addition to a number of books.

I and other members of the Paediatric Department contributed chapters to a number of these books as follows- 

Littlewood JM, MacDonald A. Clinical aspects of food allergy and intolerance. In:Heatley R V, Losowsky MS, Kelleher J. editors.Clinical nutrition in gastroenterology. Churchill Livingstone 1986:202-234.

Mahony MJ, Littlewood JM. Campylobacter in paediatric populations. In: Campylobacter pylori and gastrointestinal disease. editors. Rathbone BJ, Heatley RV. Blackwell Scientific Publications. 1989:167-175.

Mahony MJ, Littlewood JM. Campylobacter in paediatric populations.  In: Campylobacter pylori and gastrointestinal disease. 2nd Edition. editors. Rathbone BJ, heatley RV. Blackwell Scientific Publications. 1992;177-186.

Littlewood JM, Wolfe SP. Nutrition in cystic fibrosis. In:Heatley RV, Green Hilary J, Losowsky MS.Consensus in Clinical Nutrition.. Cambridge University Press. 1994:388-419

Littlewood JM, Cross Elaine. Present day treatment of cystic fibrosis: its content and cost. In: Clinical economics in gastroenterology. editors Bodger K, Daly MJ, Heatley RV.  Blackwell Science. 2000:220-249.

The co-authors in these chapters have been mentioned elsewhere in this Paper Trail with the exception of Mrs Elaine Cross who, at that time, worked in the Finance Department at St James’s. I discussed the

                   Roger Canon

possibility of this study with Mr Roger Canon our very supportive Finance Director.  He suggested Elaine would be a very suitable person to involve in the project – and he was certainly right!   Using the patient and treatment data collected on our excellent CF database system (conscientiously organised by my wife Ann Littlewood SRN since the early Eighties), Elaine meticulously costed every single aspect of a CF patient’s treatment and care – a major undertaking.

It was no surprise that Elaine became the Senior Finance Business Partner at Leeds Teaching Hospitals NHS Trust.

Gillies DR. Littlewood JM. Sarsfield JK. Controlled trial of house dust mite avoidance in children with mild to moderate asthma. Clinical Allergy. 17(2):105-11, 1987 Mar. PMID: 3581 459
At the time of this study there was considerable interest in the role of house dust mite in children with asthma.

Doug Ritchie Neil Gillies was my Senior Registrar at the time. I think he eventually became consultant paediatrician at Harrogate General Hospital. He has one other publication listed on PubMed with Steve Conway. Only additional information I could trace was  he was a Director of Harrogate Golf Club from 2012-2016.

Jim Sarsfield

Jim Sarsfield, the other co-author had carried out some very impressive research in the Seventies on the use of the radio allergosorbent test (RAST) in diagnosing allergies by detecting the specific IgE antibodies. For his research he was awarded the Medal of the British Paediatric Association.  He eventually succeeded Paddy Clarke as consultant paediatrician in Harrogate. Jim died prematurely of carcinoma of the pancreas.

[ The RAST – the suspected allergen is bound to an insoluble material and the patient’s serum is added. If the serum contains antibodies to the allergen, those antibodies will bind to the allergen. Radiolabeled anti-human IgE antibody is added where it binds to those IgE antibodies already bound to the insoluble material. The unbound anti-human IgE antibodies are washed away. The amount of radioactivity is proportional to the serum IgE for the allergen (Webb Medical Dictionary, 2006)][

In our present trial 26 asthmatic children participated in a controlled trial of house  dust mite avoidance including plastic mattress cover, vacuuming the mattress and avoidance of soft toys. Half had house dust mite avoidance for 12 weeks and half had 6 weeks observation followed by 6 weeks avoidance. Mite number s were extremely variable and often low. the only positive finding was that active avoidance produced a significant fall in the total IgE but this was not associated with any significant fall in the RAST, symptom score, peak expiratory flow ratter histamine induced reactivity.

So the results of this labour intensive trial were disappointing and the possible reasons are discussed including low numbers of  mites due to more than usual cleaning in ancipatoon of a medical visit! Published results were conflicting and we continued to recommend mattress covers for our asthmatic children.   Also Asthma UK, in 2020, recommend “use of allergy covers on your mattress and bedding. There’s evidence these can reduce the risk of needing to go to hospital with an asthma attack for children sensitised to dust mites”

Beverley DW. Kelleher J. MacDonald A. Littlewood JM. Robinson T. Walters MP. Comparison of four pancreatic extracts in cystic fibrosis. Archives of Disease in Childhood. 62(6):564-8, 1987 Jun PMID:3304172  FREE

David Beverley with CF Research Fellows Edwardo Moya (L) and Ian Bowler (R)

This was one of the first trials confirming the marked superiority of the new acid resistant microsphere pancreatic enzyme preparations.

Four different pancreatin products Pancrease, Creon, Pancrex V Forte and Pancreatin Merck were compared in a random crossover trial in children with cystic fibrosis.

Creon and Pancrease microspheres

The results of the study showed that patients who received Creon and Pancrease had fewer gastrointestinal symptoms than patients who received Pancreas V Forte and Pancreatin Merck. Also the fat absorption with Creon was superior to that with Pancrex V Forte. There was no significant difference in fat absorption between Pancrease and Creon, Pancrex V Forte and Pancreatin Merck, or Pancreatin Merck and Creon. Faecal nitrogen content was less with both Creon and Pancrease compared to Pancreatin Merck. Creon and Pancrease allow the patient with Cystic Fibrosis to take a high energy diet without any dietary restrictions.

Intact Pancrease microspheres recovered from  duodenum having past through the stomach undamaged by the gastric acid

The acid resistant microspheres of Pancrease and Creon are released from the capsule in the stomach but pass through the stomach into the duodenum intact protected by their acid resistant coating which dissolves releasing their enzymes when they reach the alkaline duodenum.


The graph shows the marked improvement in absorption with Pancrease and Creon.

These new enzymes represented one of the major advances of the decade for people with cystic fibrosis many of whom had terrible problems with their bowels. One 15-year old girl wept as she told me how Pancrease had revolutionised her life by controlling her severe gastrointestinal symptoms and signs . 

David Beverley was a Senior registrar with us at St James’s at the time of  this study. He subsequently moved to York as consultant paediatrician where de developed a good  cystic fibrosis clinic. I went over to York and saw the patients with him every 3-6 months. He had a successful career in York.

Please see the following paper for further work on the enzymes used in this trial.

Littlewood JM. Kelleher J. Walters MP. Johnson AW. In vivo and in vitro studies of microsphere pancreatic supplements. Journal of Pediatric Gastroenterology & Nutrition. 7 Suppl 1:S22-9, 1988. PMID: 2457072

Dr Jerry Kelleher with Mr Mike Walters

The efficacy of the microsphere enzyme preparations used in the above trial (Beverley et al, 1987) is dependant on the microsphere coating ability to resist dissolution until the pH exceeds approximately 5.5 and thus prevent inactivation of lipase in the acid environment of the stomach. Because of the different physical characteristics of the enzyme preparations used in the trial the dissolution rates of Pancrease, Creon and pancreatin Merck were compared in vitro.

In aqueous buffers striking differences were seen at pH 5.5: whereas only 25% of available lipase was released from Creon both Pancrease and and pancreatin Merck showed almost complete dissolution. Only at pH 6.5 do all preparations show completed dissolution. In duodenal juice, as in aqueous buffers, lipase release from Creon takes place at a slower rate than with the other two preparations until pH 6 or higher is attained. Bile salts at pH 5.75 accelerated lipase release from Creon but not the other two preparations; albumin had no effect.

We suggested that these differences may account for the better response some patients have to one particular preparation or even the general poor control some patients have with all preparations.

 Littlewood JM. MacDonald A. Rationale of modern dietary recommendations in cystic fibrosis. [Review] [120 refs] Journal of the Royal Society of Medicine. 80 Suppl 15:16-24, 1987. PMID:3116241 Free
This is the expanded text of a lecture I gave at the annual RSM cystic fibrosis meeting.   Anita McDonald and I combined to write a comprehensive review of the present state of knowledge on the dietary recommendations – 120 references. The full text can be accessed via the PubMed PMID.

Anita Macdonald

As I have described elsewhere, Anita was by now an established authority on the nutritional aspects of cystic fibrosis and involved in many of our publications from Leeds both on CF and food intolerance.
It was no surprise she eventually ended up as Dr Anita MacDonald OBE, Consultant Dietitian in Inherited Metabolic Disorders at Birmingham Children’s Hospital, and an Honorary Professor in Dietetics at Plymouth University, UK! A quite exceptional lovely person who made a very significant contribution to building up our Regional Cystic Fibrosis Service.

Kelleher J. Miller MG. Littlewood JM. McDonald AM. Losowsky MS. The clinical effect of correction of vitamin E depletion in cystic fibrosis. International Journal for Vitamin & Nutrition Research. 57(3):253-9, 1987.  PMID:  3679696
Thirty patients with cystic fibrosis, 24 of whom had longstanding low serum vitamin E, were treated with 50 mg of a water miscible preparation of alpha-tocopherol acetate per day for periods of 18-24 months. None of the patients received haematinics during the study period. Throughout the period of study the overall clinical state of the patients did not alter significantly.

The serum vitamin E level increased in all patients (361+-167 to 830+- 304) but to a variable degree which was not related to the severity of steatorrhoea. A range of nutritional parameters, including anthropometry, vitamin levels, essential elements, haemoglobin and albumin, as well as dietary intake and faecal fat excretion, were assessed at the beginning and end of the study. 

Haemoglobin was the only parameter to change significantly from 13.14 to 13.47 g/100 ml. Twenty-one of the 30 patients showed some increase in haemoglobin values and this increase could not be related to clinical state, fat absorption or dietary intake but was related to the improved vitamin E status. Vitamin E deficiency may cause a host of conditions such as  haemolytic anaemia, cerebellar ataxia and cognitive difficulties. 

Addendum: The authors of a recent Cochrane Database Syst Rev 2020. (P O Okebukola, Kansara S, Barrett Joanne) make the usual complaints regarding the low quality of the evidence and a need for larger studies. This writer’s opinion this would be a waste of resources and patients’ time. Most experienced clinicians responsible for treating people with CF will supply a vitamin supplement containing vitamin E and periodically check the plasma levels, increasing the supplement as required to achieve normal levels. The repeated need of Cochrane reviewers for larger trials is not helpful when there are too many trials for the number of patients available anyway and more important trials.

Shaw NJ. Littlewood JM. Misdiagnosis of cystic fibrosis. Archives of Disease in Childhood. 62(12):1271-3, 1987 Dec. PMID:3435163  FREE
Of 179 children referred to the Regional CF Centre at St James’s for Comprehensive Assessment of their cystic fibrosis seven (4%) were found not to have the disease. Smalley et al from Birmingham had published 14 children referred there where the diagnosis of CF was reversed.
Our seven patients all had normal sweat tests, normal faecal chymotrypsin, normal faecal fat excretion less than 5g/day, normal fat soluble vitamin A and E levels, 5 had normal pancreatic ultrasound where visualised.(full details in free version).





(Apologies for the quality of these tables. Clear in full free version on PubMed)

In each case the referring paediatrician and the parents were told that the child did not have cystic fibrosis. The two cases in which there was a family history of the disease the parents refused to accept the reversed diagnosis The parents of one child who had received considerable welfare benefits and a trip to Disneyland in Florida had attempted to sue their  paediatrician. When they finally accepted the reverse of the diagnosis the child featured in a daily newspaper article which proclaimed that she had been cured of Cystic Fibrosis. The mother of another child transferred his care to another paediatrician.

In the hundreds of children referred to Leeds for assessment over the  next 10 years there were others who were shown not to have CF – the usual mistake was an inaccurate sweat test and a failure to seek further objective evidence of CF and failure to review the diagnosis some time after the initial diagnosis.

Most were not from teaching hospitals except for  one 11-year old boy was attending a teaching hospital CF clinic. He had had some bowel problems in the newborn period presumed to be mild meconium ileus that settled with conservative treatment and he had been surprisingly well since. On this occasion he was seen in the clinic by the CF consultant who was teaching medical students. One student asked the consultant the result of the  patient’s sweat test. The consultant searched the notes but could not find the result. In fact, the boy had never had a sweat test.

           Nick Shaw

When transferred by the neonatal surgeons to the paediatric clinic it was presumed a sweat test had been done confirming CF. A sweat test was now performed and this was normal.

Nick Shaw was a lecturer in paediatrics at the time from 1985-1989. He later specialised in paediatric endocrinology and eventually became Professor of Paediatric Endocrinology at Birmingham Children’s Hospital with over 250 publications to his name.

Littlewood JM. MacDonald A. Food intolerance: our practice. [Review] [52 refs] [ Journal Article. Review. Review, Tutorial] Nutrition & Health. 5(3-4):119-35, 1987. PMID:3328115
A long heavily referenced article putting down virtually all we knew about the subject.  The paper describes the clinical presentation of food allergy and/or intolerance. The role of a diagnostic dietary trial is reviewed. Finally dietary management is discussed.

Lipkin G W, Vickers D W. Allergy in cystic fibrosis nurses to pancreatic extract. Lancet, Feb 14th 1987.
This is a report of allergic symptoms in 6 of 11 permanent nurses on our paediatric ward at St James’s in Leeds where the children with CF were admitted. Symptoms developed when Cotazym pancreatic enzymes powders were removed from the capsules before administering to CF infants. 

Some infants could  manage the new microspheres but powdered preparations were recommended for infants.

Both the authors of the letter were Senior House Officers on our paediatric ward at St James’s where all my CF patients were treated.  It was surprising that this letter was never discussed with me and was a total surprise when I read it in the Lancet!! It is usual practice to ask permission of the consultant responsible for the patients to publish even a case report.  However, these two doctors seem to have done well career wise and obviously had plenty of initiative!  

Graham Lipkin

Graham Lipkin is a distinguished Consultant Kidney Specialist, Honorary Senior Lecturer,. Lead for Rare Diseases & Centre for Rare Diseases at the Queen Elizabeth Hospital Birmingham. He was president of the Renal Association 2018-2021

David Vickers

David Vickers is Medical Director of Cambridgeshire Community Services NHS Trust. He has held a number of senior roles at the Royal College of Paediatrics and Child Health, is a Trustee and currently (202O) standing (unsuccessfully as it turned out) for the Presidency of the College. He has served on numerous other committees and advisory groups.

Littlewood JM. Johnson AW. Edwards PA. Littlewood AE. Growth retardation in asthmatic children treated with inhaled beclomethasone dipropionate. [ Letter] Lancet. 1(8577):115-6, 1988 Jan 16.  PMID:2891952                                                                                  

The author learning in the clinic

There are advantages for a senior clinician personally seeing and treating many patients over a prolonged period. A prolonged period is necessary to observe the effects of many interventions. There is great value in continuity of care – sometimes sadly lacking in modern times.

As a general paediatric consultant appointed in the late Sixties it was to be expected there would be many children with asthma of varying degrees of severity referred to my outpatient clinic. As my experience increased and the numbers of children with asthma attending my outpatients mounted, on moving to St James’s in 1980 I devoted a regular outpatient session to children with asthma. We published a number of papers on various aspects of asthma during the Eighties; also I was invited to give postgraduate lectures on the subject around the country. 

There was a very efficient paediatric outpatient clinic at St James’s with one of my regular session devoted to children with asthma. The clinic was run by an efficient Sister and experienced Nurses who appreciated the importance of careful weighing and measuring each child in minimal clothing on every attendance. The height was measured very accurately with an expensive Harpenden Stadiometer which I arranged to be purchased when we moved our clinics to St James’s.

The Harpenden Stadiometer is a counter recording instrument with an effortless counter-balanced movement.   It will give an accurate and direct reading through the high speed counter to the nearest millimetre, over a range of 600 to 2100mm. 

The results were recorded on a standard outpatient asthma follow-up form. Simple respiratory function tests using a peak flow meter were carried out each attendance. When the child came in to see the doctor (always myself or my Registrar) the recorded height and weight were charted by the doctor on the child’s Tanner growth chart.This routine became a permanent method of accurately documenting and recording the child’s progress. 

It was following the child heights measured with this accurate equipment, recorded on these charts over a number of years that first drew my attention to the fall off in growth of some children who were receiving inhaled corticosteroids. We had been assured in publications by a number of acknowledged paediatric respiratory experts that inhaled steroids did not affect growth. Nonetheless, in some of our children, despite a marked improvement of their asthma, there was a definite slowing of height gain but normal or even accelerated weight gain – and many of these were children in mid-childhood and nowhere near puberty.

Reduced height velocity (left hand charts) after starting inhaled beclomethasone (arrowed) in two children

So I decided we should look at our whole clinic to see how many children had changes in growth rate. The co-authors were Dr Andrew Johnson, a scientist from the University Department of Medicine at St James’s, Dr Phoebe Edwards a general practitioner who worked with me for two days a week and Ann Littlewood SRN, a nurse who was responsible for the unit’s clinical computerised database.

Ann Littlewood at the database 
    Phoebe Edwards

We reviewed 346 children with asthma attending my outpatients, 81 of whom were receiving inhaled beclomethasone in doses ranging from 200 to 800 ug daily. Those receiving the inhaled corticosteroids had significantly lower height standard deviation scores than those not on steroids. The slowing of growth in some was quite obvious on the growth charts (examples above).

For example although Balfour-Lynn at the Hammersmith had noted a high prevalence of delayed puberty in asthmatic children he had not noted adverse growth effects with inhaled corticosteroids with doses up to 600 ug daily (Balfour-Lynn L. Growth and childhood asthma. Arch Dis Child 1986;61:1049-55). It was noted that there was a difference in age between the two groups and it was suggested the difference could be related to the natural pattern of prepubertal growth deceleration seen in older corticosteroid treated patients.

George Russell
 Stephen Holgate






There were quite vigorous objections to our findings from a number of  colleagues   There was a comment from Professor (now Sir) Stephen Holgate who is the MRC Clinical Professor of Immunopharmacology and Hon. Consultant Physician within Medicine at the University of Southampton. However, although at the time of writing (2020) he had published over 1000 reviewed papers, he is not a paediatrician; nevertheless in 1988 he said he was surprised at our findings as he “uses inhaled beclomethasone in young children and has not come across the problem”. I was surprised he was treating children at all!

Dr George Russell of Aberdeen, a leading academic respiratory paediatrician, was particularly and repeatedly critical of our findings (Russell G. Asthma and growth. Arch Dis Child 1993;69:695-98). Previously he had published, with Dr Titus Ninan (now a paediatrician in Birmingham), a much smaller study of 58 prepubertal children receiving budesonide or beclomethasone in doses ranging from 200-1600 ug daily.  They had failed to detect a relation between height standard deviation score and corticosteroid use although there was a relation with asthma severity (Ninan T, Russell G. Asthma, inhaled corticosteroid treatment and growth. Arch Dis Child 1992; 67:703-705). Commenting on our publication they noted “many of their (Leeds) patients were of an age where pubertal changes would be expected to be influencing growth”. Russell and Ninan therefore concluded they had been “unable to demonstrate any adverse effect of inhaled ICT on growth” 

In 1994 George Russell was yet again reviewing the side effects of inhaled corticosteroids in children in a Editorial for Thorax and wrote – “Despite anxieties raised by the series of Littlewood et al, which included older children in whom the effects of delayed puberty could not be excluded, studies on the effect of inhaled corticosteroid therapy on growth have generally continued to give reassuring results”.    However, Russell continues “However the introduction of knemometry, a technique for measuring the length of the ulna or lower leg with great accuracy, has re-opened the debate. Using knemometry Wolthers and Pedersen demonstrated a convincing dose-related suppression of short term lower leg growth in children receiving inhaled corticosteroid therapy. (Wolthers OD, Pedersen S. BMJ1991;303:163-5 and also Pediatrics 1992; 89:839-42); similar results had been reported by MacKenzie CA, Wales JCH.(BMJ1991; 303:416)”.

So the tide was turning and the truth was becoming apparent! Two further studies confirmed the adverse effect of inhaled corticosteroids on childrens’ growth (Doull IJM et al, Am Rev Respir Dis 1993; 147:A265; Doull IJM et al Thorax 1994; 49:398-9P)

So George Russell, despite all the early criticism of our findings by him and many other UK respiratory paediatricians and chest physicians, in 1994 was forced to conclude “Inhaled corticosteroid therapy therefore affects growth”.

Harrison’s sulcus from pre-inhaled steroid days

The subsequent literature on the subject is vast and beyond the scope of this piece – suffice it to say the effect of inhaled steroids on some children’s growth is now an established fact but the emphasis must be on their value as one of the really important treatments for asthma – now well established. I remember the days before inhaled steroids became available when asthma was terrible condition for some children. In the experience of this writer they are also a valuable treatment for a minority of children with cystic fibrosis.

This story does emphasise there still remains a place for careful clinical observation. The wise observation of that great physician Sir William Osler is relevant to the following section – “Medicine is to be learned by experience; and is not an inheritance; it cannot be revealed. Learn to see, learn to hear, learn to feel, learn to smell, and know that by practice alone can you become expert”. 

One could also add the value of continuity of care, sometimes increasingly sadly lacking in modern times, is also of crucial importance. One doctor treating many patients in a    well run clinic with careful dedicated nurses over a prolonged period may reveal more important information than a Cochrane Systematic Review.

Morton S. Gilbert J. Littlewood JM. The current physical therapy regimens of 108 consecutive patients attending a regional cystic fibrosis unit. Scandinavian Journal of Gastroenterology – Supplement. 143:110-3, 1988.  PMID: 3164494 

                 Sue Morton

Comprehensive assessment of patients attending the Regional Cystic Fibrosis Unit includes a detailed evaluation of their physical therapy habits and management. The following were analysed during the assessment by the physiotherapist: the frequency of patient contact with a physiotherapist, the techniques used for chest clearance, the exercise habits, the postural drainage equipment used, if any, and the frequency of respiratory cultures. 

The results were divided into three groups: group 1, 72 patients (66%), were first-referral patients (FR) to our cystic fibrosis unit; group 2, 26 (24%), received all their care at our unit (CFU); group 3, 10 (9%), were  attending a local hospital but had had a previous assessment at our unit (PA). For all factors examined the CFU and PA patients had a more effective management than the FR patients cared for by local hospitals, with the conclusion drawn that regular contact with a physiotherapist at a cystic fibrosis unit improves the understanding, compliance, and effectiveness of the patient’s treatment programme.

Mrs Sue Morton was one of the first physiotherapists to be closely involved with our cystic fibrosis patients in the Eighties both when they were inpatients for intravenous antibiotic treatment and when they first came to the CF unit for Comprehensive Assessment or for their Annual Review. A very important member of our team.  This presentation was given at the European CF Society meeting in Oslo. Sue is a very attractive person. Her beauty obviously impressed the Norwegians as it is rumoured that within 24 hours she had 3 proposals of marriage and an offer of a trip round the bay in a luxurious yacht!

Gilbert J. Kelleher J. Littlewood JM. Evans DF. Ileal pH in cystic fibrosis. [ Journal Article] Scandinavian Journal of Gastroenterology – Supplement. 143:132-4, 1988. PMID: 3164499   

John Gilbert in Oslo

This was one of John Gilbert’s main research projects using pH-sensitive swallowed radio-telemetry capsule. In cystic fibrosis jejunal hyperacidity has an adverse effect on fat digestion. It is not known whether increased acidity  extends as far as the ileum. In this study the pH through the whole length of the small bowel in 42 normal and 6 cystic fibrosis subjects was recorded by means of the pH-sensitive radio-telemetry capsules measuring 24 mm by 7.3 mm.

In cystic fibrosis subjects the time  spent below pH 6.0 was significantly greater during the 1st hour in the small bowel than in normal subjects. (This is to be expected as the bicarbonate secretion from the pancreas is deficient in CF).  In the rest of the small bowel the pH remained above 6.0 in both groups. The recordings in the cystic fibrosis group did not show the clear distinction between ileum and colon which is seen in normal subjects. 

So in cystic fibrosis low pH conditions are confined to the proximal small intestine. There is adequate time at optimal pH in the small bowel for dissolution of enzyme supplements and assimilation of nutrients.



Dr David F Evans, of the Department of Surgery Nottingham, published on the method (Gut 1988; 28:1035-1041) and also on a wide variety of similar subjects such as oesophageal Ph monitoring.

The figures are from Dr Evans’s  paper. The arial array is worn around the abdomen inside a cloth band (figure)


J Gilbert, T Robinson, JM Littlewood.  Home intravenous antibiotic treatment in cystic fibrosis. Archives of Disease in Childhood. 63(5):512-7, 1988 May.  PMID:  3389866    FREE                                                         

 Mrs Teresa Robinson                                    CF Nurse Specialist

The prognosis for patients with cystic fibrosis who are chronically infected with Pseudomonas aeruginosa has improved as a result of the regular use of intravenous antibiotics; however, this necessitates long periods of hospitalisation. Home intravenous antibiotic treatment has potential advantages over hospital treatment.
We describe our experience during the first 20 months of using a system of home intravenous antibiotic treatment in which a cystic fibrosis liaison sister has an essential role.
Thirteen patients have received 40 courses of treatment. There were highly significant improvements in weight, respiratory function, and white cell count during home treatment. There was no significant difference in weight and forced expiratory volume in one second between the end of home treatment and the end of hospital treatment while forced vital capacity was better after home treatment. All patients preferred home treatment. The advantages of home visits by the cystic fibrosis liaison sister, Teresa Robinson,  during treatment   are emphasised.

This work was carried out by Dr John Gilbert, the CF Research Fellow and Teresa Robinson the CF Liaison Sister. It was the first report of home intravenous antibiotic therapy in the UK in children there having been one brief report in adults from London in 1984 (Winter RJ et al. Lancet 1984;i:1338-9).  However, after our paper was published I discovered a publication from Texas (Rucker RW, Harrison GM, Pediatrics 1974;54:358-360).  They report using a scalp vein needle and tube as a heparin lock; it usually required replacing once during the 10 to 12 day course. They used mainly gentamicin but also colistin in 127 courses in 62 patients with a 68% success rate and no major complications. Seven of the  failures subsequently died – a definite sign of the times.

   Dr Robert Stern

Dr Robert Stern, who had already described the use of the “Heparin lock” (Stern RC et al. Clin Pediatr 1972; 11:521-523.) recalls starting home IV antibiotics in the early Seventies in Cleveland when a 15 year old asked if her heparin lock could be covered with a bandage so she “could leave hospital for a few hours to work at the Pronto Room as a waitress that afternoon”! (Stern R. In Cystic Fibrosis in the 20th Century. Doershuk CF (ed.) 2001).

Home IV antibiotic therapy was definitely a major advance and much appreciated by the children and their families. The various medico-legal aspects were considered carefully. The success of the method was highly dependent on the specialist medical and nursing support.   Subsequently numerous studies were published attesting to the feasibility, effectiveness and patient acceptability of home intravenous antibiotic therapy for people with CF – an obvious major advance in treatment.  However, surprisingly (or perhaps not so surprisingly!!) a Cochrane Review in 2000, most recently updated in 2012 (PMID:22419283) considered only one small study as suitable for inclusion which showed home therapy did not harm the patients, entails fewer investigations, reduces social disruptions and can be cost effective!  However, Dr Albert Balaguer, of Barcelona the main Cochrane Reviewer still considered “more research is urgently needed’  In my opinion this is quite frankly ridiculous! Despite this view, home IV therapy is one of the major advances and remains a central component of modern CF treatment. Failure of a CF Centre to provide this option for patients would be regarded as a major deficiency. It may be relevant that the only three publications on cystic fibrosis of the first reviewer have been the  three Cochrane reviews! The second reviewer, J Gonzales de Dios, similarly had only three publications on CF among his 153 papers – and these were the three Cochrane reviews! 

MacDonald A. Kelleher J. Littlewood JM. A normal fat diet for cystic fibrosis: is a dietitian still needed?. Scand J Gastroenterol – Suppl. 143:157-9, 1988.  PMID: 3164503                                                                                         The dietary intakes of 90 patients receiving various degrees of dietetic support were assessed by a 7-day dietary history. Patients who had contact with a dietitian at least twice a year achieved higher energy and protein intakes than patients with little or no dietetic help. Patients who had one intensive interview with a specialist CF dietitian but had little local dietetic support attained better nutrient intakes than patients with no dietetic support.
At this time, in the Eighties, dietary misconceptions, which led to restriction of fat and even sugar, still were common when patients or parents of CF children received little dietary advice.
Anita McDonald, our Leeds senior paediatric dietitian, with a typical forceful introduction to this article, states that “some paediatricians consider the role of the dietitian to be passive, and some even think the dietitian is an unnecessary member of the CF team”. She sets about proving them wrong!
A dietitian experienced in cystic fibrosis was certainly still needed at that time and is still needed at the present (2020).

Mahony MJ. Littlewood JM. Losowsky MS. Robinson PJ. Giles GR. Budd-Chiari syndrome treated by Senning operation. Archives of Disease in Childhood. 63(6):669-71, 1988 Jun. PMID:  3389903  FREE 

The Budd-Chiari syndrome, characterised by hepatic venous outflow obstruction, was diagnosed in a 13 year-old boy who presented with gross ascites (fluid in the peritoneal cavity of the abdomen). He had been well apart from a traffic accident 6 years previously.

The diagnostic possibilities included tuberculous peritonitis, malignancy or chronic liver disease. After extensive investigations angiographic studies by an expert interventional radiologist occlusion at the ostia (outlets) of the hepatic veins into the slightly narrowed inferior cava were demonstrated, The hepatic veins could not be entered suggesting occlusion which was confirmed by percutaneous transhepatic venography. 

Figure: Contrast injected into the right lobe of the liver (black arrow on left) showing patency of the veins within the liver and occlusion of the outlets of the hepatic veins.

After medical treatment for his ascites he underwent a Senning operation of transcaval dorsocranial resection of the liver and hepatocaval anastomosis opposing the liver to the cardiac end of the inferior vena cava. The patient’s ascites cleared and he remained well 10 months after surgery.

This management of this really complex patient showed Jimmy’s at its best. Paediatricians taking overall care of a child with a difficult complex problem enlisting the help of the Professor of Medicine Monty Losowsky, an expert on liver disease, Dr Phil Robinson an expert interventional radiologist and the Professor of Surgery  Geoffrey Giles. 

Geoffrey R Giles (1936-1992) was Professor of Surgery at St James’s from 1973 to 1992. Mr Ralph Kester was his first senior lecturer and recalls Geoff’s first remarks to him were – “Jimmy’s had to be liberated of its ‘workhouse’ attitude to become an effective competent general hospital despite its size. Next it should be moved up a gear into becoming a respected teaching hospital of clinical and academic excellence”.  He said he would prefer his portrait to eventually be in the hospital board room rather than the Royal College of Surgeons. He became head of the organ transplant team and the excellent results for kidney and liver transplants placed Leeds firmly on the transplant map – the hospital became the third UK national liver transplant centre in1987.

Geoffrey Giles was a brilliant hard working surgeon with whom it was always a pleasure to meet – often greeted by a touch of humour. I frequently used to ware a Cystic Fibrosis Trust tie – “Does that mean you treat it or you’ve got it Jim?” Apparently he would set a shattering pace of stamina and endurance for his younger assistants by operating all day or all night. It was a great loss when he died suddenly in 1992 with a massive stroke after giving a lecture in Jersey.

The premature death of Geoff Giles in mid-career on 2 April 1992 at the age of 55 years deprived British surgery of one of its leaders, Leeds University of an outstanding Professor and St James’ Hospital of a pioneering surgeon who had contributed so much to its reputation.

Mahony MJ. Wyatt JI. Littlewood JM. Campylobacter pylori gastritis. Arch Dis Child 1988; 63(6):654-5. PMID: 3389897
A paediatrician from a nearby city referred a 12-year-old girl to me at St James for an upper GI endoscopy. He wanted to be sure there was no organic reason for her recurrent abdominal pain which had caused her to miss a great deal of school. The school was regarded as the main cause of her problem – in fact she already had an appointment to see a child psychiatrist after she had been to our unit at St James in Leeds for the endoscopy.
At endoscopy the gastric mucosa was obviously abnormal and typical of Helicobacter gastritis; this was confirmed on the histology of the mucosal biopsies. Within 48 hours of starting treatment for the H. pylori her symptoms of nausea and abdominal pain disappeared and she was able to return to school with no further problems! 

Between January 1981 and February 1987 I had performed 111 upper GU endoscopies in children.  In this retrospective study of 38 of the gastric biopsy specimens taken during upper gastrointestinal endoscopy, we found C. pylori in nine (24%). 

Judy Wyatt, our pathologist, found ten biopsy specimens showed histological evidence of gastritis and C. pylori was found in eight. We published our findings in this first 1988 paper.  We knew that Campylobacter pylori colonisation of the stomach is strongly associated with type B non-autoimmune gastritis in adults.

In collaboration with Professor Monty Losowsky (who taught me upper GI endoscopy in the late Seventies) and other colleagues at St James’s and Dr Mike Mahony our excellent senior paediatric registrar at the time, we did much further work on H. pylori in children (then known as Campylobacter pylori). 

    Mike Mahony and the author

Dr Mike Mahony. We were fortunate that Mike was with us at St James’s as Senior Registrar for 4 years.  He eventually performed many of the upper GI endoscopies and became an expert in the subject of H. pylori in children.

How I first became involved with H. pylori in children

During the mid-Eighties I was travelling to London on the early morning train from Leeds. Sitting opposite to me was a pleasant young lady. We started talking and it appeared she was a doctor and had recently been appointed as a consultant pathologist at St James’s University Hospital in Leeds. 

Judy Wyatt

Dr Judy Wyatt was the lady in question. I discovered that she was particularly interested in a new bacteria Campylobacter (soon to be called Helicobacter) pylori that had recently been shown to be associated with gastritis and peptic ulcers. I mentioned that I also worked at Jimmy’s and furthermore since the early Eighties regularly performed gastric endoscopies and biopsies on children referred to me with abdominal pain by other consultants in the region. Judy offered to seek out and review these biopsies to check for H. pylori infection. So by the time we reached Kings Cross the plans for this first study of H. pylori had been agreed!   This was a very fortunate meeting as Judy Wyatt proved to be a very pleasant, knowledgeable and excellent colleague with whom we were fortunate to have a productive collaboration over the next decade.

Further publications from St James’s on Helicobacter pylori in children are reviewed together here for the sake of continuity-

J E Crabtree, M J Mahony, J D Taylor, R V Heatley, J M Littlewood, D S Tompkins.Immune response to helicobacter pylori in children with recurrent abdominal pain. Clin Pathol. 1991 Sep; 44(9): 768–771.  PMID: 1918408 FREE

         Jean Crabtree

Dr Jean Crabtree, (later Professor) was an immunologist in Professor Losowsky’s Department. She examined the systemic immune response to Helicobacter pylori in 69 children with recurrent abdominal pain and upper gastrointestinal symptoms. Twenty-one (30%) children  were histologically positive for H. pylori. Eighteen of the 21 positive subjects and two H. pylori negative subjects (one with normal mucosa, one with lymphocytic gastritis) were positive for H. pylori IgG antibodies by enzyme linked immunosorbent assay (ELISA) (86% sensitivity, 98% specificity).
This was a very detailed study of the immunological aspects of H. pylori infection in children by an expert. Jean Crabtree’s conclusions were that H. pylori ELISA and immunoblotting techniques are sensitive and specific tests for determining gastric infection with H. pylori. Serological testing of children with recurrent abdominal pain for H. pylori antibodies will identify those subjects who warrant further investigations and avoid unnecessary invasive investigation in seronegative children.

Subsequent publications on H.pylori in children from a number of countries are of very variable quality – some terrible. Sensible practical advice would be to exclude H. pylori when investigating any child with troublesome and recurrent abdominal pain. A number of our child patients have been ‘saved‘ from the child psychiatrist by diagnosing, treating and curing their “H. pylori induced” school phobia abdominal pains! We’ve had moved on from John Apley’s days.

Professor Jean Crabtree is in the Leeds Institute of Molecular Medicine and has published extensively on a wide variety of aspects of H. pylori including a number on iron deficiency in relation to the infection in children. It was fortunate that she was working in the department of medicine at St James’s when we were identifying children with H. pylori infections.  

M J Mahony, J I Wyatt, J M Littlewood. Management and response to treatment of Helicobacter pylori gastritis. Arch Dis Child. 1992 Jul; 67(7): 940–943. PMID:1519961 FREE  

Helicobacter pylori seen on gastric biopsy (the tiny dark rods in the space above/between the gastric mucosa).

Gastritis associated with Helicobacter pylori was present in gastric biopsies from 24/95 (25%) children and adolescents undergoing endoscopy for recurrent abdominal pain and upper gastrointestinal symptoms. H. pylori associated gastritis occurred mainly in older children (8-16 years) and was significantly associated with low socioeconomic class and a family history of peptic ulcer disease. Antral nodularity was a common endoscopic finding in H. pylori positive children. Eighteen children, all over 5 years of age, were treated with tripotassium dicitratobismuthate (De-Nol) for two months and ampicillin for two weeks. In 12 children follow up gastric biopsies were obtained six weeks after completion of treatment. In 9/12 (75%) children H pylori was eradicated, and gastritis improved.

Mahony MJ, Littlewood  JM. Campylobacter pylori in paediatric populations. In: Rathbone BJ, Heatley RV. editors. Campylobacter pylori and gasproduodenal disease. Blackwell Scientific Publications 1989:167-175. 

Mahony MJ, Littlewood JM. Helicobacter pylori in paediatric populations. In: Rathbone BJ, Heatley RV. editors. Helicobacter pylori and gasproduodenal disease. 2nd Edition Blackwell Scientific Publications 1992;177-186.

Our experience up to this time is reviewed in detail in these chapters.


New developments and techniques such as described here have reduced the “Non-Specific” element of recurrent  abdominal pain.  Some 10% of school children have attacks of recurrent abdominal pain. 

              DR JOHN APLEY

Dr John Apley, a distinguished Bristol paediatrician, virtually made the subject his own, attributing the majority of cases (19/20) to emotional/functional causes. His articles on the subject  are regarded as a paediatric classics.

Certainly stress is an important factor in some children with recurrent abdominal pain but in my experience, as a busy general paediatrician from a different era in a northern city, stress is certainly not the prime cause in many children. 

Dr John Apley did most of his writing on non-specific abdominal pain during the 1950s and 1960s before many of the present day gastrointestinal investigations were available e.g. jejunal biopsy, fibreoptic endoscopy, colonoscopy, hydrogen breath tests, Helicobacter pylori serology, reliable serological tests for coeliac disease and an awareness that of food allergy/intolerance as an important cause of gastrointestinal and other disordersEven the realisation that chronic constipation may cause chronic central abdominal pain without the patient complaining of hard, infrequent stools – the traditional definition of constipation.  So many factors have certainly reduced the number of children thought to have a psychosomatic cause for their frequent abdominal discomfort. As a hospital paediatrician I always made a habit of thinking “organic” first!

It is only fair to observe the widespread prevalence of H. pylori in adults and children particularly in developing countries. A number of publications mention the asymptomatic nature of many infections and the low risk of subsequent gastric cancer in children. The literature is now vast.
So recent recommendations of the Joint ESPGHAN/NASPGHAN Guidelines for the Management of Helicobacter pylori in Children and Adolescents (Update 2016) PMID:28541262 are as follows –

The consensus group recommended that invasive diagnostic testing for H pylori be performed only when treatment will be offered if tests are positive. To reach the aim of a 90% eradication rate with initial therapy, antibiotics should be tailored according to susceptibility testing. Therapy should be administered for 14 days, emphasising strict adherence. Clarithromycin-containing regimens should be restricted to children infected with susceptible strains. When antibiotic susceptibility profiles are not known, high-dose triple therapy with proton pump inhibitor, amoxicillin, and metronidazole for 14 days or bismuth-based quadruple therapy is recommended. Success of therapy should be monitored after 4 to 8 weeks by reliable noninvasive tests.
The primary goal of clinical investigation is to identify the cause of upper gastrointestinal symptoms rather than H pylori infection. Therefore, we recommend against a test and treat strategy. Decreasing eradication rates with previously recommended treatments call for changes to first-line therapies and broader availability of culture or molecular-based testing to tailor treatment to the individual child”.

Finally, the interesting early Helicobacter pylori story from Robin Warren’s first 1979 observations of small curved bacteria in gastric biopsies

Barry Marshall, Robin Warren and Helicobacter pylori  (Information from Gastroenterology 2005; 129(6):1813-14) 

The story of Campylobacter/helicobacter pylori is really fascinating.  The 2005 winners of the Nobel Prize for Physiology or Medicine were the Australian researchers Dr. Barry J. Marshall and Dr. J. Robin Warren . They won for their “remarkable and unexpected” discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease. Robin Warren, Professor of Pathology at Royal Perth Hospital, in 1979 had observed small curved bacteria colonising the lower part of the stomach  (antrum) in about half of the patients from which biopsies had been taken. He then made the crucial observation that signs of inflammation were always present in the gastric mucosa close to where H pylori was observed.

    Robin Warren and Barry Marshall

Barry Marshall, Senior Principal Research Fellow at the University of Western Australia, first teamed up with Warren in August 1981 to help prove the theory that bacteria, and not stress and lifestyle, cause most peptic ulcers. At the time, while at Royal Perth Hospital, Marshall was a gastroenterology research fellow in search of a project.   For the young research fellow, Warren’s work appealed partly because it went against conventional wisdom. In medical texts, the acidic gastric environment was considered inhospitable to bacteria and therefore was viewed as sterile. Thus, Warren’s bacterium, one that had not been described in texts, should not have been in the stomach.

Initially in their collaboration, Marshall reviewed the clinical records of 25 patients in whom Warren had found the bacteria in gastric biopsies, describing the diseases the patients did or did not have. Not all had ulcers and not all had cancer, “so it was hard to see a pattern in those 25,” he has said. A subsequent blinded study of 100 patients, during which an independent gastroenterologist performed the endoscopies, was conducted from January to May 1982. The results established a link between the bacterium and peptic ulcer disease. During the study period, Marshall cultured and gave the microbe its name, one that included a new genus because it was similar to both Campylobacter and Vibrio-like cholera.

An abstract was submitted 1 year later to the Australian Gastroenterology Association and was flatly rejected. Still, the findings were published for the first time in The Lancet, June 1983, in 2 separate letters under the same title Unidentified curved bacilli on gastric epithelium in chronic active gastritis, one signed by Warren, the other Marshall. The letters preserved the separate contributions of each author: Warren’s observation of the bacteria and preliminary information on the link with gastritis; Marshall’s original culture and the observation that the bacteria were linked to peptic ulcer disease.

Also in 1983, Marshall discovered the in vitro sensitivity of H pylori to bismuth and, later, to metronidazole. Early in 1984, 11 patients with “difficult duodenal ulcer problems” were referred to him by a general practitioner friend. Marshall treated them with bismuth and metronidazole eradicating H pylori in 9 patients without further relapse and without further cimetidine therapy.

Marshall, who has been described as “unconventional” may have lived up to that adjective in July 1984 when he became his own guinea pig by swallowing a pure live culture of H pylori. The researcher, who was married with 4 children, became violently ill but had thus made his point to the world. “I did it out of frustration,” he has said. “Part of it was that when I presented at scientific meetings, the audience was always skeptical and was convinced that these bacteria infected the patient after the gastritis developed. So I did it prove that that did not have to be the case. That was the main reason.”

Another reason, he asserted, was the failure of his pig experiment. Despite Marshall’s attempts to do so, he was unable to infect the animals with Helicobacter. In addition, there were his clinical observations that many patients were asymptomatic or had minimal symptoms. Marshall also knew that in most of his cases he had eradicated the infection with antibiotic therapy; thus, it was a calculated risk. As it turned out, his own infection cured spontaneously, “so that by the time I had taken the antibiotics, the infection was already gone.” Biopsy after endoscopy at day 8 showed the infection. After a second endoscopy at day 14, biopsy showed the mucosa beginning to heal and no bacteria present. These findings confirmed his in vitro discovery that bismuth could kill H pylori, which meant that bismuth, long thought an antacid or coating agent, might actually be an antibiotic.

“One of the difficulties with the infection was that it was so difficult to treat, and we did not have successful therapies until 1992,” Marshall told an interviewer in October 2005. “That’s when the general opinion of the medical community changed, when they could actually test our hypothesis on their own with treatment that was available.”   “In treatment studies, Marshall and Warren as well as others showed that patients could be cured from their peptic ulcer disease only when the bacteria were eradicated from the stomach. 

Thanks to the pioneering discovery by Marshall and Warren, peptic ulcer disease is no longer a chronic, frequently disabling condition, but a disease that can be cured by a short regimen of antibiotics and acid secretion inhibitors.


A Essex-Cater, J Gilbert T Robinson J M Littlewood.  Totally implantable venous access systems in paediatric practice.  Archives of Disease in Childhood. 64(1):119-23, 1989 Jan. PMID: 2923461    FREE                                                         
One of the first reports of successful use of totally implantable venous access devices (TIVAD) in UK children; this followed a report of the successful use of these devices in children from the Liverpool paediatric oncology unit (McDowell et al, 1986)

Port-A-Cath & PASport
Dr Alison Essex-Cater

This present study was a combined effort with the paediatric oncologists

at St James University Hospital in Leeds. They were already using the devices but had been somewhat discouraged by various serious complications including  massive bleeding around the site in one case.        Our  study was coordinated by our excellent CF Research Fellow (John Gilbert) and Dr Alison Essex-Cater who was the paediatric oncology registrar at the time. She later was appointed consultant paediatrician at Northallerton where I would do a combined CF clinic with her there every few months until I retired from the NHS in 1997.

The paper describes our early experience at St James’s with TIVADs and discusses the problems we

                      Devices in place

encountered over the first three years. Forty-seven TIVADs were inserted in 45 children for the management of malignant disease (n = 29), haematological disorders (n = 5), and cystic fibrosis (n = 11). Subsequently the devices became widely used in CF centres as intravenous antibiotic treatment increasingly became a major and essential component of treatment and, with repeated courses of treatment, venous access became increasingly difficult in many patients.

Mr John Beck
Paediatric Surgeon

Although the insertion of TIVADs would appear to be a minor procedure to  an experienced surgeon, it became apparent that a surgeon with experience in inserting TAVIDS was absolutely essential to minimise subsequent complications. All but one of the devices we reported were inserted by one of three paediatric surgeons under general anaesthesia John Beck (figure) being the first. Also meticulous management to avoid infection of the device was important and the province of the CF or Oncologist nurse specialist – often better given by conscientious well-trained parents than by inexperienced overworked temporary medical and nursing staff unfamiliar with the devices! The teaching about TIVADs and their management became the responsibility of the CF Nurse Specialist who was also closely involved in organising and developing home intravenous antibiotic therapy. The details of the use of the devices are described in the full paper which is freely available on PubMed.

Undoubtedly these totally implantable venous access devices were one of the major advances of the Eighties with regard to CF care and the more frequent use of prolonged courses of intravenous antibiotics.

Gilbert J. Kelleher J. Walters MP. Littlewood JM. Markers for faecal fat estimation in monitoring steatorrhoea in cystic fibrosis. Gut. 29(9):1286-8, 1988 Sep.   PMID: 3198006  FREE
Polyethylene glycol (PEG) 4000 is one of numerous substances used as non-absorbable markers to correct for variable faecal output when assessing daily faecal losses of nutrients.         Unfortunately, these enzyme preparations themselves contain significant quantities of PEG 4000 or polyvinyl pyrrolidine (PVP) as components of the enteric coating and thus PEG 4000 cannot be used either as a faecal marker, or in intubation studies, if these enzyme preparations are being used.  So radiopaque pellets have now been used in many thousands of balance studies and the harmful side-effects have not been described.

We were nearly caught out by this in a previous study when using PEG as a faecal marker where the results were totally unexpected until it was realised the enzymes themselves contained PEG. The principle of the use of radio opaque markers and detailed comparison are described in the text of this article of which a free copy is available on PubMed.    Our subsequent policy in Leeds was to use radiopaque pellets in all patients capable of swallowing a small capsule containing the pellets and in younger children to use a three day collection without any markers.

Simmonds E J, Mahony M J, Littlewood J M.  Convulsion and coma after intranasal desmopressin  in cystic fibrosis. BMJ 1988;297:1614. PMID; 3147111
This is a rather alarming report of a 13-year old girl with CF admitted to our ward for routine intravenous antibiotic treatment of her chest infection.. She also had nocturnal enuresis and so in the hope of improving this she was started on desmopressin nasal spray – four doses on consecutive nights 10, 20, 20 and 10 ug. After the fourth dose she developed a headache, nausea and vomiting – but had remained dry overnight for the first time for some time. However, her weight showed a sharp increase from 41.35kg to 43.15 kg. By the fourth day her sodium had fallen to 114 mmol/l and she had a grand mal convulsion lasting 5 minutes. Her desmopressin was discontinued and she was managed with fluid restriction. 24 hours after, a normal fluid intake was started and within 5 days, her sodium had returned to normal. She slowly regained consciousness over the next two weeks with no neurological sequelae.

It is not clear why our patient responded how she did with hyponatraemic convulsions.  Certainly her nasal mucosa had abnormal properties associated with her CF as well as her nasal polyps. This may have affected the action of the drug. It is tempting to speculated that the patient’s abnormal reaction was related to the abnormal electrolyte transport in the CF mucosa.

We recommended desmopressin should be used with caution, if at all, in children with cystic fibrosis or nasal polyps. At the very least frequent weighing and electrolyte measurement should be done (hardly practical).This was a really alarming case and, to put it mildly, we were greatly relieved that the patient returned to her normal state before discharged from hospital.

In a subsequent letter to the BMJ (BMJ 1989;299:391) we expressed our concern that this serious reaction to desmopressin in a child with CF was not mentioned in a later editorial on desmopressin by Roy Meadow and J H C Evans (BMJ 1989;298; 1596-7). We again suggested it would be wise to avoid the use of desmopressin in children with CF.

Choonara IA. Winn MJ. Park BK. Littlewood JM. Plasma vitamin K1 concentrations in cystic fibrosis. [ Journal Article] Archives of Disease in Childhood. 64(5):732-4, 1989 May.  PMID: 2730129  FREE                                                           
Plasma concentrations of vitamin K1 were similar in 37 patients with cystic fibrosis (median 46 ng/l) and 16 controls (49 ng/l). The plasma concentrations were lower than those previously described in adults, but higher than in neonates. There was no association between an increase in prothrombin time and vitamin K1 plasma concentration.
These results suggest that children with cystic fibrosis do not have vitamin K deficiency and do not required supplements, However, subsequent studies using more recent methods (prothrombin inducted by vitamin K absence (PIVKA-II) and undercarboxylated osteocalcin (u-OC)) suggest some deficiency of vitamin K and supplements are now recommended. 

However, it is interesting that the latest 2020 Cochrane Database Syst. Rev (PMID: 325497260) states –“There is very low-quality evidence of any effect of vitamin K in people with cystic fibrosis. While there is no evidence of harm, until better evidence is available the ongoing recommendations by national CF guidelines should be followed”. 

        Imti Choonara

Dr Imti Choonara is now (2020) one of the leading paediatric clinical pharmacologists in the world.  He has been involved in ensuring that paediatric clinical pharmacology is an accredited subspecialty of paediatrics in the UK.   He is Editor in Chief of the journal BMJ Paediatrics Open.  His research interests include drug toxicity, clinical trials, epidemiology of the use of medicines, inequalities in child health  and access to medicines in children. He is interested in international child health and organises an annual workshop in Child health in Cuba.    Despite recently retiring, he is still active in research and supervising postgraduate students, as an Emeritus Professor in Child Health at the University of Nottingham.

Brocklebank JT. Simmonds EJ. Littlewood JM. Cystic fibrosis and renal tubular acidosis. Archives of Disease in Childhood. 64(7):1054-5, 1989 Jul. PMID: 2629629  FREE
Cystic fibrosis is relatively common but renal tubular acidosis is rare. Most cases are sporadic but it has been reported to occur in families. The primary defect in distal renal tubular acidosis is defect in the acidification of urine caused by an inability to generate an adequate hydrogen iron gradient between the blood and the tubular fluid. The nature of the cellular defect is unknown.

A baby girl of Pakistani first cousins had talipes equinovarus. She was diagnose as having cystic fibrosis after neonatal BM meconium screening. However, she seemed well and was discharged home aged 10 days. At 13 days she was admitted to the infectious disease unit wasted, dehydrated and acidotic with a pronounced disturbance of electrolytes : sodium 128, potassium 2.0, bicarbonate 7.4  urea 13.6 mmol/l and creatinine 65 umol/l. She was rehydrated but failed to gain weight despite various dietary changes.
So she was transferred to my unit at 31 days where the diagnosis of cystic fibrosis was confirmed. Alkaline urine (pH7.5) despite a persisting severe acidosis (pH 7.15) suggested a diagnosis of renal tubular acidosis.  Further investigations showed persisting plasma electrolyte abnormalities sodium 138, potassium 3.1, bicarbonate 10.3 mmol/l creatinine 45umol/l. at this time the urine electrolytes were sodium 28, potassium 33, bicarbonate 12 mmol/l creatinine 1.6mmol/l.
She received standard CF treatment and oral electrolyte supplements according to the plasma electrolytes. Her feet responded to splinting.

At 7 years she was well but both height and weight lie below the 3rd centile. Her electrolytes were usually normal with daily oral supplements. Her chest Xray is normal.

Electrolyte disturbances in CF are reported in  number of circumstances such a chronic loss of sweat. In addition both low solute milks and breast feeding may result in inadequate electrolyte intake

Dr Trevor Brockelbank. Trevor is on the left of group  with myself, Monty Losowsky and Peter Howdle. He was, at the time, Senior Lecturer  Consultant in Roy Meadow’s University Paediatric Department at St James’s and an expert paediatric nephrologist. He was always a very pleasant and helpful colleague. This patient was fortunate to be in St James’s, a hospital with both Regional Paediatric Nephrology and Regional Cystic Fibrosis units and also to have been born in the East Leeds where neonatal CF screening was routine – in contrast to the General Infirmary in West Leeds where CF screening did not start, and then only reluctantly, until 1995!!

Littlewood JM. Kelleher J. Effect of misoprostol on fat malabsorption in cystic fibrosis.[comment]. Archives of Disease in Childhood. 64(7):1096-7, 1989 Jul.  PMID:2637701                                                             
Our comments on an article by PJ Robinson PD Sly and AL Smith who suggested misoprostol, a synthetic prostaglandin, that reduced gastric acid  production and stimulated duodenal bicarbonate, significantly reduced the fat absorption if this was greater than 10% of intake.

Melbourne evening meeting in 1998 chair by Phil Robinson
Phil Robinson

We suggested that their cases were under-dosed with enzymes and they wouldhave been better to give larger doses of pancreatic enzymes. They did not agree! That’s Aussies for you!!

Subsequently, I met Phil Robinson on a number of occasions. When I visited Melbourne on a lecture tour of Australia in 1998 he was chairing the meeting for my lecture and made a crack about it! We had a good chat.


Abstract not obtained  –

Hey F. Buchan PC. Littlewood JM. Hall RI. Differential diagnosis in child sexual abuse. [ Case Reports. Letter] Lancet. 1(8527):283, 1987 Jan 31. PMID: 2880109