GASTROENTEROLOGY

1907 Lockhart-Mummery P. Prolapse of the rectum in children, with fifty cases. Brit Med J 1907; 2:812.
A common disorder among children, writes Mr. Lockhart-Mummery a distinguished London surgeon, “especially that class which attends the surgical practice at a children’s hospital”. He had seen examples of the usually quoted causes of rectal prolapse (phimosis, stone in the bladder, colonic polyps, etc) to be rare but chronic diarrhoea, wasting and general weakness to be common – particularly the removal of fat from around the rectum in such cases.
Unfortunately there is no mention of long term outlook of these children that may have suggested some may have had CF; however, the fact that the average age was 2.56 years perhaps indicated that prior to 1907 most children that had a prolapse due to CF would have already died. Also in 1907 death in early childhood from gastroenteritis was relatively common as was malnutrition and wasting.
Subsequently rectal prolapse was described as a feature of CF (Kulczycki & Shwachman, 1958 below). The lack of fat around the rectum, as suggested by Lockhart-Mummery, is obviously relevant in CF for when this is restored with appropriate pancreatic enzyme treatment the tendency to rectal prolapse diminishes – usually completely. In over 600 people with CF I only recall one teenage girl who still complained of the rectal prolapse occasionally. However, one wonders if persistence of this embarrassing problem is under-reported as was later found to be the case with urinary incontinence in people with cystic fibrosis (Cornacchia et al, 2001 below). (Illustration of severe rectal prolapse in Kulczycki & Shwachman, 1958 below).

1951 Levy E. A case of fibrocystic disease of the pancreas with intestinal obstruction. Arch Dis Child 1951; 26:335-339. [PubMed]
The first of many reports of late intestinal obstruction which has proved to be an important and frequent complication as the age of survival has increased (also Fisher 1954 below). A seven month old infant underwent laparotomy for a presumed intussusception. The plum-coloured distended small bowel was obstructed by putty like material with haemorrhages at the root of the mesentery. The colon was empty and contracted. No surgery was done and the infant died the next day.

1951 Ayers WB, Stowens D, Ochsner A, Platou RV. Splanchnicectomy for pancreatic fibrosis: analysis of results in 24 patients. Pediatrics 1951; 8:657-663. [PubMed]
It was known that stimulation of various abdominal viscera could cause bronchospasm. So it was suggested that the changes of CF in the pancreas may cause a state of “autonomic dyskinesia” causing more or less persistent bronchospasm and bronchorrhoea. It was argued that interruption of the splanchnic nerves may break the afferent limb of such a reflex; so this rather alarming operation was performed to interrupt these nerves. The procedure in 15 patients with CF showed only temporary improvement in 3 and no change in the others.
Mercifully the operation was abandoned although the new and novel treatment caused considerable interest at the time as there was little else to offer many patients (also Am J Dis Child 1951; 82:238-239). Despite the negative results, the authors still believed the operation “may have a place” in controlling distressing respiratory symptoms. Dorothy Andersen said she had not advised the operation and welcomed this frank report from which “we may expect relief from the pressure on the part of referring physicians and referred patients to persuade us to do splanchnicectomies”. She queried the situations, if any, when the operation would be useful – the possibility of the relief of progressive respiratory distress when all else had failed was mentioned. Subsequently little was heard of this treatment.

1954 Fisher OD. Intestinal obstruction as a late complication of fibrocystic disease of pancreas (Mucosis). Arch Dis Child 1954; 29:262-264. [PubMed]
From the Royal Belfast Children’s Hospital, the second report of late obstruction (first was Levy, 1951 above), on this occasion in an infant aged 13 months with CF, which closely followed cessation of pancreatin therapy the supply of which had run out five days before admission. The whole bowel was intermittently obstructed by masses of putty-like material and material like liquid rubber was removed via an incision, pancreatin was restarted and the infant recovered. Fisher observed rather strangely “Suggesting use of pancreatin as a form of replacement therapy”.
Shwachman commented he had seen six such patients already, three were surgically treated. He mentions the presence of a palpable abdominal mass in lower right quadrant and material which was “rock-like” – the right iliac fossa hard mass was later recognised as a relatively common feature of children and adults with distal intestinal obstruction syndrome (DIOS) as more older children and adults attended CF clinics.

1958 Kulczycki LL, Shwachman H. Studies in cystic fibrosis of the pancreas: occurrence of rectal prolapse. N Eng J Med 1958; 259:409-412. [PubMed]

Figure 19: Severe rectal prolapse in a young child.

Rectal prolapse (figure 19) occurred in 22.6% of 386 patients with CF. It appeared to be related to combination of steatorrhoea, poor musculature and chronic coughing. Most frequently between three and six years and more common when the diagnosis is made later. In 16 (4%) patients prolapse was the presenting sign and the authors advised that CF should be excluded in any child with a rectal prolapse. In a later study Zempsky WT & Rosenstein (Am J Dis Child 1988;142:338-339) found of 54 children seen for rectal prolapse over 10 years the causes were constipation in 15, acute diarrhoea 11, neurological abnormalities 13 and cystic fibrosis in only six children (11%).
Rectal prolapse in patients with CF virtually always resolves after treatment with pancreatic enzymes. I only recall one adolescent girl, in over 600 patients, who reported occasional persisting problems with prolapse, although it is possible other older patients were reluctant to report that rectal prolapse was persisting.

1958 Blanc WA, Reid JD, Andersen DH. Avitaminosis E in cystic fibrosis of the pancreas: a morphologic study of gastrointestinal and striated muscle. Pediatrics 1958; 22: 494-506.
Ceroid pigment was present in the smooth muscle fibres of the gastrointestinal tract of patients with cystic fibrosis. It was first seen in those dying during the second year of life and present in all after 5 years of age, the amount increasing with age. The only other condition where this pigment is found is biliary atresia and cirrhosis. It was considered as probably due to prolonged and severe vitamin E deficiency. However, alterations in striated muscle are rare and minimal in CF but common in severe vitamin E deficiency (Martin AJP, Moore T. Some effects of prolonged vitamin E deficiency. J Hyg 1939; 39:643; Human occurrence in one case of CF by Pappenheimer AM, Victor J. Am J Path 1946; 22:395).

1958 Shwachman H, Fekete E, Kulczycki LL, Foley GE. Effect of long term antibiotic therapy in patients with cystic fibrosis of the pancreas. Antibiot Ann 1958-59; 692-699.

Figure 20: Teeth stained by tetracycline.

An early (possibly the first) report of severe yellow discolouration of the teeth due to tetracycline (figure 20) , an antibiotic which had become available between 1948-1950. Discolouration of the teeth was present in 80% of young children with CF receiving long term tetracycline prophylaxis; many subsequent reports have confirmed the problem (Zegarelli EV et al. Oral Surg Oral Med oral Pathol 1962; 15:929-933; Appelbaum E et al ibid 1964; 17: 366-367; Witkop CJ, Wolf RO. JAMA 1963; 185:1008-1011). Tetracycline is deposited in growing bone by forming complexes with the bone mineral.

1964 Freye HB, Kurtz SM, Spock A, Capp MP. Light and electron microscopic examination of the small bowel of children with cystic fibrosis. J Pediatr 1964; 64:575-579. [PubMed]
Twenty one duodenal/jejunal mucosal biopsies were obtained from children with CF and showed normal villi and cell structure but the surfaces were covered by “a coarse fibrillar substance probably mucus” in those children who had steatorrhoea but not from the one patient that had normal fat absorption. The findings were considered to support the concept of Dische that mucus may contribute to the absorptive defect (Dische Z et al. Pediatrics 1959; 24:74)
These were early days for per oral jejunal biopsy in children and this was the first large study in children with cystic fibrosis. Earlier di Sant’Agnese had observed that “the histological picture on peroral biopsy is apparently normal as might be expected” (di Sant’Agnese et al. Rev Nutr Res 1961; 22:29). However, the present findings did not carry matters forward a great deal. My impression was that the intestinal villi were unusually tall in the few children with CF whom we biopsied to exclude coeliac disease.

1959 Marie J, Salet J, Debris P, Hebert S, Corbin JL, Bezri A. Edematous form of cystic fibrosis of pancreas with hypoproteinaemia and anaemia (French). Sem Hop Paris 1959; 35:2140-6.
A report of the oedema and hypoproteinaemia in an infant with CF (also Lee PA et al, 1974; Gunn T et al, 1978 below). Also infants with CF presenting in this manner may have a false negative sweat test (MacClean WC, Tripp RW. J Pediatr 1973; 83:86-88).

1962 Jensen KG. Meconium ileus equivalent in a 15-year old patient with mucoviscidosis. Acta Paediatr Scand 1962; 51:344-345. [PubMed]
This report, often incorrectly quoted as first description of meconium ileus equivalent, describes the condition in a boy aged 15 years – however, it was the first time the term “meconium ileus equivalent” was used. Already Levy (1951 above) and Fischer (1954 above) and others had reported post neonatal intestinal obstruction. Also Fanconi (Helvet Paediat Acta 1960; 15:566-579) had used the term “post-neonatal meconium ileus”. This present patient of Jensen's had an ileostomy through which pancreatin was infused which relieved the obstruction.

1964 Freye HB, Kurtz SM, Spock A, Capp MP. Light and electron microscopic examination of the small bowel of children with cystic fibrosis. J Pediatr 1964; 64:575-579.
Twenty one duodenal/jejunal mucosal biopsies were obtained from children with CF and showed normal villi and cell structure but the surfaces were covered by “a coarse fibrillar substance probably mucus” in those children who had steatorrhoea but not from the one patient that had normal fat absorption. The findings were considered to support the concept of Dische that mucus may contribute to the absorptive defect (Dische Z et al. Pediatrics 1959; 24:74)
These were early days for per oral jejunal biopsy in children and this was the first large study in children with cystic fibrosis. Earlier di Sant’Agnese had observed that “the histological picture on peroral biopsy is apparently normal as might be expected” (di Sant’Agnese et al. Rev Nutr Res 1961; 22:29). However, the present findings did not carry matters forward a great deal. My impression was that the intestinal villi were unusually tall in the few children with CF whom we biopsied to exclude coeliac disease.

1962 Barbero GJ, Sibinga MS. Enlargement of the submaxillary glands in cystic fibrosis. Pediatrics NY 1962; 29:788-793. [PubMed]
This is the first record of enlarged submandibular glands in CF – a feature which is sometimes quite marked (figure 11). During their studies on secretory activity of the salivary glands the authors noted many patients had enlarged submandibular glands. The submandibular glands of 300 normal children, 106 with CF and 20 with chronic pulmonary disease were examined. Enlarged submandibular glands were palpated in 92% of children with CF and only 2% of healthy controls and those with chronic pulmonary disorders. The presence of enlargement can be helpful when considering a diagnosis of CF.

Figure 11: A boy with CF and markedly enlarged submandibular glands.

 

 

 

 

 

 

1963 Parkins RA, Eidelman S, Rubin CE, Dobbins WO III, Phelps PC. The diagnosis of cystic fibrosis by rectal suction biopsy. Lancet 1963; 38:851-6. [PubMed]
An interesting paper by workers with extensive experience in rectal biopsy. The histological picture was characteristic of CF in many patients. When the histological picture of rectal “mucosis” is present it is specific for CF as shown here (figure 12) and it cannot be confused with any other rectal condition. It was not clear as to the proportion of cases of CF could be diagnosed with certainty – six of 11 patients with CF examined in this study showed definite diagnostic changes. Understandably, rectal biopsy never became popular as an additional diagnostic aid for CF; although ion transport abnormalities in the rectal mucosa were described in number of later studies (Veeze et al, Gatroenterology 1981; 101:398-403; Hardcastle et al, 1991 below).

Figure 12: CF rectal specimen on left and normal on right. With permission of the Lancet.

1969 Gracey M, Burke V, Anderson CM. Treatment of abdominal pain in cystic fibrosis by oral administration of n-acetyl cysteine. Arch Dis Child 1969; 44:404-405. [PubMed]
For patients with troublesome abdominal pain, 5 ml of a 20% solution N-acetyl cysteine with 50% water was given four times daily. Five of the six patients ceased having pain within a week – the other patient refused to take the treatment. The authors were prompted to try the treatment by the first report of a 26 year old man with CF reported by Lillibridge CB et al,(J Pediatr 1967; 71:887) whose abdominal pain responded impressively with N-acetylcysteine 30 ml three times daily by mouth.
A particularly useful report as the results of surgery for meconium ileus equivalent were still poor.

1971 Holsclaw DS, Rocmans C, Shwachman H. Intussusception in patients with cystic fibrosis. Pediatrics 1971; 48:51-58. [PubMed]
Douglas Holsclaw estimated that intussusception occurred in 1% of children with CF with an average age of onset was between nine and 12 years - older than the age of presentation in non-CF children. (also Brown PM et al, NEJM 1960; 263:544; Flux M. South Med J 1976; 60:1184-1186). Compared with non-CF intussusception the onset was less acute and blood was passed rectally in less than a quarter of patients.
Even with present day treatment an appreciable number of people with CF have intermittent colicky abdominal pain and distal intestinal obstruction syndrome (DIOS). In attacks the concern is always that they have developed either appendicitis or intussusception. Although in later publications ultrasound was recommended as reliably identifying intussusception, I would disagree and suggest that a contrast enema should be an early investigation and will usually suggest the diagnosis (Littlewood JM. J R Soc Med 1992; 85 Suppl 18:13-19).

1975 Feigelson J, Sauvegrain J. Gastro-esophageal reflux in mucoviscidosis. Nouvelle Presse Medicale 1975; 4: 2729-2730. [PubMed]
This is the possibly first description of significant gastroesophageal reflux in people with CF detected on radiological examination in 56 patients aged four months to 27 years and showed that 26 (46%) had significant gastro-oesophageal reflux. Attention was drawn to this complication and its effects both on the oesophagus and the respiratory system.
Subsequently gastro oesophageal reflux was recognised as a frequent and important complication in people with CF of all ages. There was to be continuing interest in GO reflux both in infants (Malfroot & Dabb, 1991 below) and in relation to physiotherapy practices in CF infants (Button et al, 1997 below); also in adults where GO reflux was shown to be frequent and important in exacerbating respiratory symptoms (Scott RB et al, 1985 below; Ledson MJ et al, 1998 below) and particularly in relation to patients after lung transplantation (Button BM et al. J Heart Lung Transplant 2005; 24:1522-1529). Newer techniques of oesophageal pH monitoring and also fibreoptic endoscopy during the Eighties allowed more frequent recognition and more accurate diagnosis.

1976 Hodson ME, Mearns MB, Batten JC. Meconium ileus equivalent in adults with cystic fibrosis of pancreas: a report of six cases. BMJ 1976; 2:790-791. [PubMed]
Eleven episodes of meconium ileus equivalent (MIE) are described in six adult patients, four of whom were diabetic. Three were surgically treated with one fatality and there were two serious postoperative complications. Treatment with intravenous fluids, nasogastric suction, enemas and oral acetylcysteine was recommended followed by maintenance treatment with oral acetylcysteine.
A repeated complaint of CF physicians was of people with CF being admitted with acute gastrointestinal symptoms to a general surgical unit and undergoing unnecessary operations as the staff were unfamiliar with this condition. The use of gastrografin for the treatment of MIE had not yet been published from the Liverpool CF unit (O’Halloran SM et al. 1986 below). It is perhaps relevant that four of the six patients were diabetic and possibly could have been sub clinically slightly dehydrated. Later work suggested that a positive effort to increase hydration by drinking more water significantly reduced the incidence of meconium ileus equivalent in people with cystic fibrosis (Obideen et al, 2006 below)

1983 Bali A, Stableforth DE, Asquith P. Prolonged small-intestinal transit time in cystic fibrosis. BMJ 1983; 287: 1011-1013. [PubMed]
A lactulose hydrogen breath test was used to measure small intestinal transit time in patients with CF and controls. Seven of 10 CF individuals had high fasting breath hydrogen levels (25-170ppm; normals <20ppm) that fell to normal after prolonged fasting; this indicates bacterial colonisation of the small bowel and was the first report of this occurring in cystic fibrosis. Seven of the 10 patients had prolonged small intestinal transit times (160-390 minutes) compared with controls (50-150 minutes). Again, the first documentation of the prolonged small bowel transit time in CF which was confirmed in subsequent studies. Increased fasting breath hydrogen and after glucose (Bond JH, Levitt MD. J Clin Invest 1972; 51:1219-1225) or lactulose (Rhodes JM et al, Scand J Gastroenterol 1979; 14:333-336) indicates small bowel bacterial over growth. A later-than-normal rise after oral lactulose indicates prolonged small bowel transit time as the non-absorbable sugar is fermented by the bacteria in the large bowel at a later stage.
Although these were interesting first reports of small bowel bacterial colonisation and slow transit in CF, the results did not have a major impact on practical management as interest in most CF centres was focused on the chest infection. Fortunately, in 2009, there is increasing interest in these matters – both bacterial contamination and inflammation of the small bowel wall which appears to be a relatively frequent occurrence (Smyth et al, 2000 below; Werlin S et al, 2008 below).

Dr David Stableforth (figure 23) started the Birmingham Adult CF Centre initially to continue the treatment of young people with CF who had been attending Prof. Charlotte Anderson's clinic at the Birmingham Children's Hospital. As Director of the Birmingham Adult CF Centre he developed a major CF Centre at Heartlands Hospital Birmingham.

1986 O’Halloran SM, Gilbert J, McKendrick OM, Carty HML, Heaf DP. Gastrografin in acute meconium ileus equivalent. Arch Dis Child 1986; 61:128-130. [PubMed]
Gastrografin is a radiological contrast medium containing sodium diatrizoate, meglutamine diatrizoate and iodine plus flavoring and wetting agents. It is hypertonic with minimal absorption from the intestine. This is the first description from the Liverpool CF unit of the use of gastrografin as an effective and subsequently widely used treatment for distal intestinal obstruction syndrome, which, for some reason, was particularly common in the Liverpool CF clinic affecting 37% of the children. In one year 37 of 40 episodes were treated with a single oral dose of gastrografin with an 81% success rate.
It is interesting, and unexplained, that fibrosing colonopathy was later described in Liverpool children (Smyth et al, 1993 below) where it was more common than in any other UK CF centre.

1988 Stringer DA, Sprigg A, Joudis E, Corey M, Daneman A, Levison HJ, Durie PR. The association of cystic fibrosis, gastroesophageal reflux and reduced pulmonary function. Can Ass Radiol J 1988; 39:100-1002. [PubMed]
Between 1971 and 1984 fifty seven patients with CF had a barium meal for suspected gastroesophageal reflux which was found to be present in 18 (32%) of those examined – in six the reflux was associated with a hiatus hernia, oesophagitis or stricture. The 18 patients with reflux had significantly worse respiratory function than the other 412 people with CF in the clinic without known reflux.
In a number of subsequent publications gastroesophageal reflux was shown to be a frequent and significant problem in both children and adults with CF and other chest problems. The complication was first described by Jean Feigelson (Feigelson J, Sauvegrain J. Reflux gastroesophagien dans la mucoviscidose. N Press Med 1975; 4:2727-2730 above). Other notable contributions included Malfroot A, Dab I. New insights of gastro-oesophageal reflux in cystic fibrosis by longitudinal follow-up. Arch Dis Child 1991; 66:1339-1345 below; Ledson MJ et al. Prevalence and mechanism of gastro-oesophageal reflux in adult cystic fibrosis patients. J R Soc Med 1998; 91:7-9 below).
More recently the association of reflux with head down postural drainage manoeuvres in infants with CF has altered the practice of many physiotherapists by avoiding the head down position (Button BM et al. Postural drainage and gastro-oesophageal reflux in infants with cystic fibrosis. Arch Dis Child 1997; 76:148-150 below).

1988 Taylor CJ, Baxter PS, Hardcastle J, Hardcastle PT. Failure to induce secretion in jejunal biopsies from children with cystic fibrosis. Gut 1988; 29:957-962. [PubMed]
In this study by Prof. Chris Taylor (figure 5) and colleagues from Sheffield, the secretory activity of jejunal biopsies from children with CF was investigated using a modified Ussing chamber technique. The results showed that the defect in chloride transport observed in other epithelia in CF also exists in the jejunum and could contribute to the intestinal effects of the disease. Similar findings were obtained in a study from Chapel Hill (Berschneider HM, et al. Altered intestinal chloride transport in cystic fibrosis. FASEB Journal 1988; 2:2625-9) with the same suggestion that the existence of these abnormalities may contribute to the intestinal problems, such as meconium ileus, distal intestinal obstruction and chronic abdominal pain which are by no means all controlled even with the more effective acid resistant enzyme preparations such as Pancrease and Creon. Prof. Taylor is one of the UK's leading authorities on CF generally but particularly with regard to the gastroenterological and nutritional aspects. Also he and his colleagues in Sheffield have made major contributions to the scientific aspects of CF concerning membrane function.

1988 Goldstein JL, Nash NT, al-Bazzaz F, Layden TJ, Rao MC. Rectum has abnormal ion transport but normal cAMP-binding proteins in cystic fibrosis. Am J Physiol 1988; 254: C719-24. [PubMed]
In keeping with the small intestinal and colonic electrolyte transport abnormalities in CF, when the authors compared in vivo transrectal potential difference (PD) in CF, the base-line PD was different in normal and CF subjects and was eliminated by amiloride in both groups. However, in response to a Cl-free solution with amiloride, all six CF subjects exhibit less of a change in potential difference. They concluded that the rectum is also an involved epithelium in CF in which the aberration may lie at a point beyond the binding of cAMP to its protein kinase. This is not an unexpected findings as there are obvious histological abnormalities of the rectal epithelium (Parkins et al, 1963 above).

1989 Hill S, Phillips A, Mearns M, Walker-Smith JA. Cows’ milk sensitive enteropathy in cystic fibrosis. Arch Dis Child 1989; 64:1251-1255. [PubMed]
Over 12 years, proximal small intestinal mucosal biopsies were carried out in children with CF who had diarrhoea and failed to thrive in spite of adequate treatment, including pancreatic supplements. Histological examination of eight of the 17 biopsies taken over a period of 12 years from children with CF showed evidence of enteropathy, and accounted for one in 13 (8%) children with cystic fibrosis under 3 years of age attending Margaret Mearns's CF clinic. Seven children clearly responded to a cows' milk free diet; the diarrhoea stopped and weight gain increased. One of these responded only when gluten was also excluded from his diet. The eighth child remained on a normal diet and his symptoms did not improve. The enteropathy had resolved in all five patients who had further biopsies taken while receiving treatment, and from 15 months to 3 years of age all the children tolerated a normal diet and continued to thrive.

1989 Gray MA, Harris A, Coleman L, Greenwell JR, Argent BE. Two types of chloride channel on duct cells cultured from human fetal pancreas. Am J Physiol 1989; 257(2 Pt 1):C240-51. [PubMed]
This paper was from a number of the UK’s leading scientific CF researchers – including Michael Gray (right) and Barry Argent (left) from Newcastle. Using the patch-clamp technique, they identified two types of chloride channel on duct cells cultured from human fetal pancreas. While the physiological role of these channels was not entirely clear, they considered that one, the small-conductance channel, might function in parallel with a Cl- -HCO-3 exchanger to provide a mechanism for electrogenic bicarbonate secretion from the duct cell.

1989 Baxter PS, Wilson AJ, Read NW, Hardcastle J, Hardcastle PT, Taylor CJ. Abnormal jejunal potential difference in cystic fibrosis. Lancet 1989; i: 464-466. [PubMed]
Further work from Chris Taylor’s Sheffield team that had already described failure to induce secretion from CF jejunal biopsies (Taylor et al, 1988 above). Here the transmucosal potential difference (PD) and intraluminal pressure were recorded from the same jejunal site in 15 healthy adult controls and 4 adults with cystic fibrosis. In the controls, runs of contractions were associated with wave-like changes in PD that were absent in patients with cystic fibrosis. Intraluminal boluses of 4 mg pilocarpine, or 0.1 mg prostaglandin E2, caused changes of -4.6 mV and -4.5 mV, respectively, in controls; these responses were not seen in patients with cystic fibrosis. There were no significant differences in basal PD and PD changes caused by altered concentrations of infused saline or glucose between patients and controls.

1991 Hardcastle J, Hardcastle PT, Taylor CJ, Goldhill J. Failure of cholinergic stimulation to induce a secretory response from the rectal mucosa in cystic fibrosis. Gut 1991; 32:1035-1039. [PubMed]
One of many studies from Sheffield on the scientific and clinical aspects of the gut in cystic fibrosis. The secretory response to cholinergic stimulation failed in rectal biopsy specimens from 5 children with CF compared with controls.
Thus, the failure of chloride secretion in the small intestine observed by this group (Taylor CJ et al. 1987 above; Taylor CJ et al, 1988 above) was also present in the rectal mucosa of people with cystic fibrosis.

1991 Malfroot A, Dab I. New insights on gastro-oesophageal reflux in cystic fibrosis by longitudinal follow up. Arch Dis Child 1991; 66:1339-1345. [PubMed]
Gastro oesophageal (GO) reflux was first described as a problem in CF by Jean Feigelson (Feigelson et al, 1975 above) and subsequently the problem was thought to be related to progressive CF in older children. In this Belgian study 21 of 26 (81%) young children with CF aged less than 60 months were studied and 20 confirmed to have reflux by oesophageal pH tracings. Sixteen improved with anti-reflux treatment with improved weight gain, less cough and wheeze but half still had the reflux one year later. The authors concluded the reflux was not caused by the CF chest problems as it improved with time – at the same time as the CF gets worse – hence their title “new insights into GO reflux”.
There was to be continuing interest in GO reflux both in respect to physiotherapy practices in CF infants (Button et al, 1997 below) and in adults where GO reflux was shown to be frequent and important in exacerbating respiratory symptoms (Scott RB et al, 1985; Ledson MJ et al, 1998) particularly in relation to patients after lung transplantation (Button BM et al. J Heart Lung Transplant 2005; 24:1522-1529). Newer techniques of oesophageal pH monitoring and also fibreoptic endoscopy allowed more frequent recognition and more accurate diagnosis.

1994 Smyth RL, van Velzen D, Smyth AR, Lloyd DA, Heaf DP. Strictures of the ascending colon in cystic fibrosis and high strength pancreatic enzymes. Lancet 1994; 343:85-86. [PubMed]
T1he first report of fibrosing colonopathy – a new, unexpected and serious complication subsequently shown to be related to the use of the new high strength pancreatic enzyme preparations that had been introduced during the previous 2 years (Pancrease HL, Creon 25,000, Nutrizym 22). The authors observed five children with CF, who presented over a period of two months, with meconium ileus equivalent that failed to respond to medical management. At surgery, four had a stricture in the ascending colon (figure 31 similar), and all had histopathological changes of post-ischemic ulceration repair, with mucosal and submucosal fibrosis (figure 31). The only common change in the management of these children had been a switch from conventional enteric-coated pancreatic enzymes to a high-strength product between 12 and 15 months before presentation
.
A subsequent case controlled study from these authors (Smyth et al, 1995 below) showed a significant correlation with both a high enzyme dose and the make of preparation – only those enzymes containing a covering of the copolymer eudragit being implicated. A similar study from the USA confirmed the association with high enzyme dosage but not with the copolymer covering (Freiman JP, FitzSimmons SC. Colonic strictures in patients with cystic fibrosis: results of a survey of 114 cystic fibrosis care centers in the United States. J Pediatr Gastroenterol Nutr 1996; 22:153-156). [PubMed]. However, no further cases were reported or have been since reported, in patients taking the high strength Creon 25,000 preparation (which does not contain eudragit) even when given for 3 years in high doses to children (Connett et al, 1999 below).
In the UK the recommendations of the Committee on Safety of Medicines to avoid doses of enzymes in excess of 10,000 IU lipase per kg day and preparations containing the copolymer eudragit in children, abolished the condition in the UK although a few cases continued to occur in the USA. The enzyme content of the various preparations are described in detail elsewhere (Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of malabsorption in cystic fibrosis. Pediatr Pulmonol 2006; 41:35-49) [PubMed]

Figure 32: Partial fibrosing colonopathy showing narrowing of the ascending colon which did not progress after the high strength enzyme preparation (Pancrease HL), containing the copolymer eudragit, was stopped	Figure 31: Fibrosing colonopathy. Barium enema and histology of the colon.

1995 Smyth RL, Ashby D, O'Hea U, Burrows E. Lewis P. van Velzen D. Dodge JA. Fibrosing colonopathy in cystic fibrosis. Results of a case controlled study. Lancet 1995; 346:1247-1251. [PubMed]
Fibrosing colonopathy was first described in children with CF in 1994 (Smyth et al, 1994 above). This study confirmed the relationship between fibrosing colonopathy and high doses of lipase and the relation of fibrosing colonopathy with certain brands of high strength enzymes, which contained a copolymer – Eudragit. This is a report of a nested case-control study to identify possible associations with this condition. A case ascertainment within the UK CF population to identify any cases that had occurred between January, 1984, and April, 1994, revealed 14 cases, all less than 14 years and all confirmed by independent histopathological review. All had presented since April, 1993; 12 were boys and six had received some or all of their care in Liverpool. Each child was matched, by date of birth, with four controls from the UK CF Registry. Information was obtained about the cases and the controls from their case records and by a structured interview with the families. In the 12 months before surgery, there was a dose related association between the occurrence of fibrosing colonopathy and use of high-strength pancreatic enzyme preparations. Odds ratio per extra 1000 high-strength capsules was 1.45 (95% CI 1.14-1.84). For use of protease, the odds ratio per million extra units per kg was 1.55 (1.19-2.03). For usage of individual high-strength products at any time during the 12 months before surgery some differences were observed; for Creon 25000 the odds ratio was 0.38 (0.10-1.42), for Nutrizym 22 it was 43.4 (2.51-751), and for Pancrease HL 8.4 (1.95-36.1). These last two confidence intervals are extremely wide and compatible with these two products having the same odds ratios. Laxative use was independently predictive (odds ratio 2.42 [1.20-4.94]). The authors concluded that there was a definite dose-related association between high-strength pancreatic enzyme preparations and fibrosing colonopathy. (Also Fibrosing colonopathy in children with cystic fibrosis. Proceedings of a conference in Manchester organised by the Cystic Fibrosis Trust, 5th Nov. 1995. Littlewood JM, Hind CRK (eds). Postgrad Med J 1996; 72 (Suppl 2):S1-S64).

1995 Littlewood JM. Abdominal pain in cystic fibrosis. J R Soc Med 1995; 88 (Suppl): 9-17. [PubMed]
A detailed review of the causes, investigation and treatment of abdominal pain in CF summarising experience with over 600 patients with CF seen at the Leeds Regional Paediatric CF Centre. As sub-specialisation.. increased in paediatrics in the UK, the majority of paediatricians working in CF centres were primarily interested in the treatment of the chest – understandably as most people with CF died from this cause. So the gastrointestinal aspects were relatively under-investigated although a significant number of patients had, and still do have, abdominal symptoms.
In this study recurrent abdominal pain occurred in 11% of children receiving their care at the Leeds centre (where there was considerable interest in and investigation of gastrointestinal problems) and in 31% of those referred for Comprehensive CF Assessment from other hospitals - admittedly a selected group.
It was interesting that the prevalence of recurrent abdominal pain differed greatly with the mode of presentation e.g. meconium ileus 38%, respiratory 39%, malabsorption 47%, presence of a CF sibling 30% but only in 4% in those diagnosed by neonatal screening and treated from the age of a few weeks (Littlewood JM J R Soc Med 1992; 85 (Suppl 18):13-19).

1997 Button BM, Heine RG, Catto-Smith AG, Phelan PD, Olinsky A. Postural drainage and gastro-oesophageal reflux in infants with cystic fibrosis. Arch Dis Child 1997; 76:148-150. [PubMed]
First of series of papers from Brenda Button (figure 43), a physiotherapist from Melbourne, Australia, noting the possible dangers of inhalation when infants with CF were in the head down position during postural drainage; infants with CF were known to have an increased incidence of gastro-oesophageal (GO) reflux. Physiotherapy with and without head down tilt were compared using 24 hour pH oesophageal monitoring. Standard physiotherapy with head down tilt was associated with a significant increase in GO reflux in the infants with CF.
This was an important study and, with Brenda Button’s subsequent publications, certainly had a major influence on the techniques of physiotherapy recommended for CF infants (see also Malfroot & Dab, 1991 above for earlier studies on reflux in CF infants; Button et al, 2004 also confirmed GO reflux as common and important in adults with CF)

1998 Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastro-oesophageal reflux in adult cystic fibrosis patients. J R Soc Med 1998; 91:7-9. [PubMed]
Fifty adults with CF were surveyed by questionnaire and ten with reflux symptoms had oesophageal manometry and 24 hour pH recording. Forty seven patients (94%) had upper gastrointestinal symptoms: 40 (80%) heartburn (27 worse when supine); 26 (52%) regurgitation; and 28 (56%) dyspepsia. At oesophageal manometry, lower oesophageal sphincter barrier pressure (LOSBP) was subnormal in 6 of the 10 patients and 3 had uncoordinated peristalsis in the mid-oesophagus. Eight patients had significant gastroesophageal reflux. Adult CF patients have high rates of GOR symptoms, diminished LOSBP, and acid reflux.
This study re-emphasised the fact that GOR was a frequent and important problem and a significant cause of symptoms in adults with cystic fibrosis. The complication had been recognised since first described by Jan Feigelson (Feigelson & Sauvegrain, 1975 above) and later by Scott RB et al, 1985 (above); the frequency and importance was again highlighted in this present paper. Brenda Button in Australia had already pointed out the problem of the occurrence of reflux in CF infants in the head down position during physiotherapy (Button et al, 1997 above) – later she also found reflux to be common in adults with CF (Button et al, 2004).

Dr Martin Walshaw (figure 45) was the first Director of the Liverpool CF Centre for adults and was later joined by Dr Malcolm Ledson (figure 45.1). The Liverpool CF Centre for adults is now one of the major units in the UK.

Figure 45: Dr Martin Walshaw	Figure 45.1: Dr Malcolm Ledson.

1999 Connett GJ, Lucas JS, Atchley JT, Fairhurst JJ, Rolles CJ. Colonic wall thickening is related to age and not dose of high strength pancreatic microspheres in child ren with cystic fibrosis. Eur J Gastro Hepatol 1999; 11:181-183. [PubMed]
Thirty three children with CF, including 25 who had been receiving high strength pancreatin in the form of Creon 25,000 continuously for 3 years. Median lipase intake was 19,330 u/kg/day (range 0-59,000). There was no relationship between enzyme dosage and colonic wall thickness. The most important relationship of colonic wall thickness appeared to be with age.
This was a useful report and reassuring that high doses of pancreatic enzymes, when given in the form of Creon 25,000, did not appear to cause colonic damage. It had already been evident from the UK CF Database that many UK patients were taking more than the recommended equivalent of 10,000 U lipase/kg/day (Mehta A.Lancet 2001; 358:1547-1548). Obviously it would be unwise to translate these findings to other brands of high strength enzymes.

Dr Garry Connett (figure 51) is a Paediatric Respiratory Consultant who succeeded Dr Chris Rolles as Director of the Southampton Paediatric CF Centre. He is heavily involved in CF care and clinical research and over the next ten years published on a wide variety of aspects of cystic fibrosis.

2000 Israel NR, Khanna B, Cutler A, Perry M, Caplan D, Weatherly M, Gold BD. Seroprevalence of Helicobacter pylori infection in cystic fibrosis and its cross-reactivity with anti-Pseudomonas antibodies. J Pediatr Gastroenterol Nutr 2000; 30:426-431. [PubMed]
The seroprevalence of H. pylori in a cohort of patients with CF and its cross-reactivity with Pseudomonas antibodies were investigated using competitive inhibition assay. The research ELISA and 3 commercial tests initially showed H. pylori seropositivity of 47%, 28%, 24%, and 37%, respectively but post adsorption seropositivity declined to 8%, 0%, 0%, and 15%, respectively – and all these positives were confirmed endoscopically to have H. pylori infection. So cross-reactivity between solid-phase H. pylori antigens and anti-Pseudomonas antibodies occurs in patients with CF. The authors advise that preadsorption of CF sera with Pseudomonas proteins should be used in serologic testing if testing for H. pylori.

This was a useful study as there had been confusion about the prevalence of H. pylori in people with CF since the existence of cross reactivity with Pseudomonas antibodies had been reported from Neils Hoiby’s laboratory in Denmark (Johansen HK et al. Clin Diag Lab Immunol 1995; 2:149-155. 7697522 ). One might perhaps have predicted the expected the prevalence of H pylori in people with CF to be low (8-15%) in view of the numerous courses of antibiotics they receive!
This and subsequent studies (Yahav J et al. Dig Dis Sci 2006; 51:2274-2279). [PubMed] confirm that H. pylori is not a significant problem for people with CF.

2000 Smyth RL, Croft NM, O'Hea U, Marshall TG, Ferguson A. Intestinal inflammation in cystic fibrosis. Arch Dis Child 2000; 82:394-399. [PubMed]
To determine whether there is increased inflammation in the gastrointestinal tract of CF children who had developed fibrosing colonopathy, whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF who had had fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, alpha1-antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin1beta) were measured. Compared to controls, all the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1beta, and interleukin 8. Similar values were obtained for the CF patients who had had fibrosing colonopathy.

Whole gut lavage is essentially washing out the gut and counting the inflammatory cells in the washings as an indication of the degree of intestinal inflammation. These data suggest that there is immune activation in the gastrointestinal mucosa of all children with cystic fibrosis, which may result from the basic cellular defect perhaps with secondary bacterial infection of the gut. Certainly the children who had previously had fibrosing colonopathy did not appear to have more signs of inflammation than in those who had not had the complication.
The finding of evidence of intestinal inflammation is not unexpected as it has been reported, and confirmed, that small bowel bacterial overgrowth affects some 70% of people with CF which is likely to be related to these findings (Bali et al, 1983 above). Also more recent work using capsule endoscopy showed that many patients had diffuse areas of inflammation in the small bowel associated with very high caloprotectin levels confirming the inflammatory response (253+/- 97 ug/g Normal <50) (Werlin S et al. Pediatr Pulmonol 2008; Suppl 31:Poster 610:422). Interest in this area increased progressively throughout the decade.

2003 Gilljam M. Chaparro C. Tullis E. Chan C. Keshavjee S. Hutcheon M. GI complications after lung transplantation in patients with cystic fibrosis. Chest. 2003; 123:37-41. [PubMed]
Lung transplantation is now available for patients with cystic fibrosis (CF) and end-stage lung disease. While pulmonary graft function is often considered the major priority following transplantation, the non pulmonary complications of this systemic disease also continue. GI complications after lung transplantation were common in patients with CF, and the authors advised that attention should be paid to the risk for DIOS in the early postoperative period. Prevention and early medical treatment are important in order to avoid acute surgery. Close collaboration with the CF clinic, in order to diagnose and treat CF-related complications, is recommended.

The gastrointestinal aspects of treatment may receive insufficient attention if there are serious respiratory problems. This report of extensive experience from Toronto of patient after lung transplantations documents this advice and records experience of 27 of 75 patients. The present writer is aware of an instance where failure to give enzymes in the post operative period resulted in intestinal obstruction then complications with resulting fluid and parenteral nutrition eventually leading to fatal systemic candida infection.

2003 Dialer I. Hundt C. Bertele-Harms RM. Harms HK. Sonographic evaluation of bowel wall thickness in patients with cystic fibrosis. J Clin Gastroenterol 2003; 37:55-60. [PubMed]
Fibrosing colonopathy causing severe thickening of the colon wall was recently described in cystic fibrosis (CF). Since it has been suspected that subclinical colon-wall thickening is a common feature in CF patients, bowel-wall thickness was measured in a series of patients and compared with controls. Additionally, possible clinical factors influencing wall thickness were investigated. STUDY: In 83 CF patients and 31 controls transabdominal ultrasound was performed in the terminal ileum, cecum, ascending and descending colon. The relation of the measured wall thickness to age, sex, pancreatic enzyme intake, and intestinal diseases was analyzed. RESULTS: In controls, mean wall thickness depending on gut region was 1.1 to 1.3 mm (SD 0.19-0.23). In CF patients, no evidence of severe thickening or stricture was found, but wall thickness was significantly higher than in controls in all measured regions (1.5-1.6 mm; SD 0.31-0.41). Patients with meconium ileus and distal intestinal obstruction syndrome had significantly increased thickness of the terminal ileum compared with patients without these complications. Neither the intake of high-strength enzymes nor enzyme dosage, age or sex were associated with wall thickness. CONCLUSIONS: We found no evidence that a subclinical stage of fibrosing colonopathy is prevalent among the CF patients. Slightly thickened gut walls in CF can be interpreted as an expression of glandular dysfunction in the CF intestine.

This is a reassuring study failing to reveal significant bowel wall thickening in CF although slightly thicker bowel wall than in controls.

2004 Mack EH. Brett AS. Brown D. Fibrosing colonopathy in an adult cystic fibrosis patient after discontinuing pancreatic enzyme therapy. Southern Med J 2004; 97:901-904. [PubMed]
Fibrosing colonopathy, a complication of cystic fibrosis, has generally been reported in young children with exposure to high doses of pancreatic enzymes. The authors report the case of a 25-year-old male with cystic fibrosis who presented with gradually progressive symptoms of bowel obstruction. Pathologic examination of the right colon revealed findings consistent with fibrosing colonopathy. This case is distinctive because of the adult presentation, and because the patient's symptoms developed long after he had discontinued taking a high-strength enzyme preparation. The authors suggest this case suggests that multiple etiologic factors, and not simply exposure to pancreatic enzymes, may result in fibrosing colonopathy in adults with cystic fibrosis.

There is no need to postulate other factors as the obstruction may have developed on an existing partial obstruction from previous high strength enzymes as we have seen in one patient.

2004 Bruzzese E. Raia V. Gaudiello G. Polito G. Buccigrossi V. Formicola V. Guarino A. Intestinal inflammation is a frequent feature of cystic fibrosis and is reduced by probiotic administration. Aliment Pharmacol Therapeut 2004; 20:813-819. [PubMed]
To assess the incidence of intestinal inflammation in children with cystic fibrosis and to investigate whether probiotics decrease it.Mean faecal calprotectin was significantly higher in the two groups of patients than in controls. Abnormal values were detected in 27 of 30 cystic fibrosis and in 15 of 15 inflammatory bowel disease children. Also mean nitric oxide production was increased in both group of patients, and abnormal values were detected in 19 of 20 cystic fibrosis and in 15 of 15 inflammatory bowel disease children. Calprotectin and nitric oxide concentrations were reduced after probiotics administration. Intestinal inflammation is a major feature of cystic fibrosis and is reduced by probiotics. The latter finding suggests that intestinal microflora play a major role in intestinal inflammation in cystic fibrosis children.

Fortunately the gastrointestinal aspects of CF are receiving more attention. There is increasing evidence that the bowel is inflamed in CF as shown by inflammatory markers in the faeces as in the present paper, by breath tests and endoscopic camera studies. Although, as the authors suggest, the intestinal microflora play a part in the inflammation, although contributory, it is probably not the whole story.

2006 Yahav J. Samra Z. Blau H. Dinari G. Chodick G. Shmuely H. Helicobacter pylori and Clostridium difficile in cystic fibrosis patients. Digest Dis Sci 2006; 51:2274-9. [PubMed]
Stool specimens from 30 consecutive patients with CF, aged 1-44, and from 30 healthy similarly aged subjects were tested for the H. pylori antigen by specific monoclonal antibodies and for CD toxins by Tox A/B assay and Tox A assay. CF patients were assessed clinically and tested for specific H. pylori serum antibodies and for mutations. In CF patients, the prevalence of H. pylori antigen was 16.6% (5/30), compared to 30% (9/30) in controls. Of the 26 CF patients with PI, only 2 (7.6%) were infected by H. pylori, compared with 3 of the 4 (75%) patients with PS (P=0.001). H. pylori infection was diagnosed in 3 of 5 (60%) CF patients carrying mild mutations, compared to 1 of 25 (4%) CF patients carrying severe mutations (P=0.01). Fourteen of 30 (46.6%) stool specimens from CF patients tested positive in the ToxA/B assay, and 3 of 14 tested positive for ToxA. No significant differences in antibiotic use, severity of lung disease, PI, chronic abdominal pain, or genotype were found between the two groups. None of the controls was positive for CD toxins. Prevalence of H. pylori infection in CF patients was lower than in similarly aged non-CF controls. CF patients with PI or a history of distal intestinal obstruction syndrome and those carrying mutations associated with a severe phenotype were protected against H. pylori infection. Almost half of the CF patients were asymptomatic carriers of CD producing mostly toxin B. More studies are needed to confirm our results in a larger group of CF patients.

This paper confirms the previously reported low incidence of H. pylori in people with CF.

2006 Dellon ES. Morgan DR. Mohanty SP. Davis K. Aris RM. High incidence of gastric bezoars in cystic fibrosis patients after lung transplantation. Transplantation 2006; 81:1141-6. [PubMed]
We performed a retrospective analysis of patients who underwent lung transplantation from December, 1992 through July, 2005 at our tertiary care medical center. Of the 215 patients who received lung transplantation, 17 (7.9%) developed gastric bezoars confirmed by upper endoscopy. Cystic fibrosis was the leading indication for lung transplantation (n=145), and 11% of cystic fibrosis patients (16 of 145) formed gastric bezoars after transplant. Additionally, 94% of patients with bezoars (16 of 17) had cystic fibrosis (P=0.02), with the exception being a subject with primary ciliary dyskinesia. No patient who underwent lung transplant for another indication was found to have a bezoar. The mean time to diagnosis was 34 days, with two-thirds of bezoars diagnosed within one month after transplant. The annual incidence was unchanged during the study period. Gastric bezoars are common in cystic fibrosis patients after lung transplantation. The etiology is likely multifactorial, related to gastric motility, respiratory secretions, and medications. Further investigation is needed to understand the pathogenesis of bezoar formation in this selected population, and strategies for primary prevention may be beneficial.

Thsi complication seems to be relatively common after transplants in people with CF.

2006 Obideen K, Wehbi M, Hoteit M, Cai Q. Nocturnal hydration an effective modality to reduce recurrent abdominal pain and recurrent pancreatitis in patients with adult-onset cystic fibrosis. Dig Dis & Sci 2006; 51:1744-1748. [PubMed]
The proportion of older people with CF who have recurrent troublesome abdominal symptoms is as high as 20-30% in some clinics. In this study patients were encouraged to “drink plenty of water through the night” and assessed with regard to abdominal symptoms for 3 months before and after starting this regimen. The frequency and severity of pain was reduced as was the medication required, emergency room visits and hospitalisations and even episodes of acute pancreatitis.

This is a simple measure which would be likely to reduce the pain which, in our experience, is commonly due to constipation and faecal accumulation in the lower ileum and colon even though the patient does not complain of constipation i.e. defined as the passage of infrequent hard stools.

Figure: 43: The grossly overloaded colon (outlined) in a 6 year old child with CF who complained of troublesome recurrent central abdominal pain; but neither she nor her parents complained of any disturbance in her bowel habit. Her symptoms resolved completely when constipation was treated with laxatives (Littlewood et al, Pediatr Pulmonol 2006; 41:35-49). [PubMed]

So this suggestion of increasing fluid intake is simple, cheap and potentially very useful measure to reduce the incidence of abdominal pain in adults with CF. An extremely economical, and apparently effective, way of improving quality of life.
An additional reason for persisting abdominal symptoms could be the presence of inflammation of the bowel which has been shown in a number of recent studies by breath tests, inflammatory markers in the stools, endoscopic means and most recently by capsule visualisation).

2007 Boesch RP, Acton JD. Outcomes of fundoplication in children with cystic fibrosis. J Pediatr Surg 2007; 42:1341-1344. [PubMed]
Twenty five children with CF underwent fundoplication to treat gastro-oesophageal reflux. 12% had complications that required a subsequent surgical procedure. Although 28% were able to discontinue their anti-reflux medications, no less than 48% developed symptoms of recurrent gastro-oesophageal reflux. Only children who had an FEV1 of less than 60% predicted at the time of fundoplication exhibited an improvement in FEV1 slope.
The complication rate of fundoplication is similar to that reported in large series in children without CF. There is a high rate of recurrent reflux and little apparent benefit for either nutritional or pulmonary outcomes.

Fig. 52: An individual child may benefit from the procedure e.g. this child had severe reflux causing uncontrollable vomiting, severe oesophagitis and progressive weight loss. He required fundoplication after which his symptoms and general progress improved

2007 Fridge JL. Conrad C. Gerson L. Castillo RO. Cox K. Risk factors for small bowel bacterial overgrowth in cystic fibrosis. J Pediatr Gastroenterol Nutr 2007; 44:212-218. [PubMed]
Fifty patients, 25 pancreatic-insufficient CF study patients (mean age, 17 y) and 25 gastrointestinal clinic control patients (mean age, 15 y), completed a glucose-hydrogen breath test after an overnight fast. A positive breath test was defined as a fasting hydrogen > or =15 ppm or a rise of > or =10 ppm hydrogen over baseline during the test. The prevalence of positive breath tests was higher in the CF study group (56%) than in the control group (20%) (P = 0.02). The mean fasting hydrogen levels of patients in the study and control groups were 22 and 5 ppm (P = 0.0001). The mean QOL questionnaire scores were not significantly different between breath test-positive and -negative study patients. The use of azithromycin was associated with an increased risk of a positive breath test. Use of laxatives and inhaled ipratropium was associated with a decreased risk of a positive breath test.

This study confirmed that patients with CF were more likely to have elevated fasting hydrogen levels compared with controls. This suggests a high prevalence of small bowel bacterial overgrowth in CF patients. Also medications commonly used by CF patients may influence intestinal health.

2007 Bruzzese E, Raia V, Spagnuolo MI, Volpicelli M, De Marco G. Maiuri L, Guarino A. Effect of Lactobacillus GG supplementation on pulmonary exacerbations in patients with cystic fibrosis. Clinical Nutrition 2007; 26:322-328. [PubMed]
Nineteen children with CF received a probiotic Lactobacillus GG (LGG) for 6 months and then changed to a placebo of oral rehydraton solution (ORS) for 6 months; in parallel nineteen received ORS and then changed to LGG. Patients treated with LGG showed a reduction of pulmonary exacerbations (Median 1 vs. 2)  and of hospital admissions (Median 0 vs. 1, range 3 vs. 2,).   LGG resulted in a greater increase in FEV1 (3.6% +/- 5.2 vs. 0.9% +/- 5; p=0.02) and body weight (1.5 kg +/- 1.8 vs. 0.7 kg +/- 1.8; p=0.02). The authors concluded that Lactobacillus GG reduces pulmonary exacerbations and hospital admissions in patients with CF, that probiotics may delay respiratory impairment and that a relationship exists between intestinal and pulmonary inflammation.

There is an increasing interest on the part of patients, parents and doctors in the role probiotics in treating people with CF (Borowitz D et al, J Pediatr Gastroenterol Nutr 2005; 41:273-285. [PubMed]); however, as yet, few CF clinics advise their routine use – perhaps because the evidence of their value is still sparse but also there are so many other components to treatment that there is reluctance to add yet another medicine to gain a marginal benefit.

2008 Infante Pina D. Redecillas Ferreiro S. Torrent Vernetta A. Segarra Cantón O. Maldonado Smith M. Gartner Tizziano L. Hidalgo Albert E. [Improvement of intestinal function in cystic fibrosis patients using probiotics]. [Spanish] Anales de Pediatria 2008; 69:501-505. [PubMed]
In some cases, cystic fibrosis may include intestinal inflammation and bacterial overgrowth. Probiotics are considered as immunomodulatory, anti-inflammatory and microbiotic regulator substances. The aim of our study is to determine the prevalence of bacterial overgrowth in cystic fibrosis patients and try to improve the intestinal function with the administration of probiotics. We examined 20 patients with cystic fibrosis (mean age 10.33, range 5 to 17 years). The expired hydrogen test with a 2 g/kg of 20% dextrose overload was performed on 10 patients. After the test, Lactobacillus rhamnosus LGG 10(11) CFU was administered twice daily for four weeks. Faecal near infrared spectroscopy (FENIR) of water, fat, nitrogen and sugar content in faeces was performed before and after probiotics administration. Five patients (50%) showed bacterial overgrowth. We obtained a positive correlation between the hydrogen test and steatorrhea (R = 0.57) and sugar in faeces (R = 0.52). The FENIR results pre-treatment vs post-treatment were: fat 6.2 g +/- 3.3 g vs. 4.9 g +/- 2.1 g (p < 0.05), sugar 6.7 +/- g 3.6 g vs. 5 g +/- 2.6 g (p < 0.05) and nitrogen 0.87 g +/- 0.27 g vs. 0.91 g +/- 0.14 g (NS) respectively. Thirteen patients (81.25%) had improved stool appearance and intestinal comfort and nine (56.25%) decreased the number of daily stools. Probiotics improved not only clinical but also biochemical intestinal function in cystic fibrosis patients. These could be given as a regular treatment in this type of patients and in those with bacterial overgrowth.

One of the few papers on the use of probiotics in people with CF. With the increasing evidence of bacterial overgrowth and tissue inflammation in the gut it is likely that probiotics may have a role in treatment of gastrointestinal problems as shown in this study from Spain..

2008 Barker HC. Haworth CS. Williams D. Roberts P. Bilton D. Clostridium difficile pancolitis in adults with cystic fibrosis. J Cyst Fibros 2008; 7:444-447. [PubMed]
Three cases of Clostridium difficile pancolitis in adults with cystic fibrosis (CF) in whom the presenting symptoms were atypical. All three required treatment with systemic steroids, in addition to oral vancomycin and metronidazole to achieve resolution of the colitis. This experience suggests that C. difficile colitis should be considered in individuals with CF presenting with non-specific abdominal symptoms.

There have been sporadic reports of C difficile infection in people with CF. Some have been in patients who have had lung transplants. Also asymptomatic carriage seems to be relatively common in CF. In a minority the infection leads to serious clinical illness as in the cases reported here.

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