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Sodium Cromoglycate in the Management of Chronic or Recurrent
Enterocolitis in Patients With Hirschsprung’s Disease
Background/Purpose: Chronic or recurring enterocolitis is a
Results: The follow-up of the patients ranges from 8 months
rare but perplexing complication of Hirschsprung’s disease to 26 months. Three of the 5 patients with chronic enteroco- affecting especially patients with altered immune defense litis responded favorably. In these 3 patients the median such as those with Down’s syndrome. Sodium cromoglycate number of daily bowel movements decreased from 6 to 3, (SCG) is a nonabsorbable mast cell stabilizing agent that has and none experienced bouts of abdominal distension. Diar- been documented to be effective in the treatment of inflam- rhea-related soiling decreased also significantly. Two of the 3 matory bowel disease. The authors studied the effect of SCG patients with recurrent enterocolitis have remained asymp- in Hirschsprung patients with refractory chronic or recurrent tomatic, and none has required antibiotics after the onset of SCG treatment; one patient had an episode of enterocolitisafter 12 months treatment. Two patients with chronic entero- Methods: Eight patients (4 with Down’s syndrome, 2 with
colitis did not respond to SCG. No side effects of SCG were other chromosomal aberrations, 2 otherwise healthy; age range from 4 to 22 years) with chronic (5 patients) or recur-rent (Ͼ6 episodes/year, 3 patients) enterocolitis received 100 Conclusions: This preliminary and nonrandomized study
to 200 mg of SCG 4 times a day depending on the age of the suggests that SCG is an effective treatment modality for patient. The chronic diarrhea or recurrent bouts of enteroco- chronic or recurrent enterocolitis in patients with Hirsch- litis in the patients were refractory to dietary management sprung’s disease. Because SCG is not absorbed from the and enteral antibiotics. Before the treatment all patients had intestinal tract there are no systemic side effects.
ileocolonoscopy, the results of which showed macroscopic J Pediatr Surg 36:1032-1035. Copyright 2001 by W.B.
and histological chronic inflammation in all cases. No neu- ronal abnormalities were detected in biopsy results. None ofthe patients had colonic dilatation or increased anorectal INDEX WORDS: Hirschsprung’s disease, enterocolitis, so- resting pressures suggesting outlet obstruction.
POSTOPERATIVE ENTEROCOLITIS is the main immune defence associated with abnormal T-lympho-
complication in patients who have undergone sur- gical repair for Hirschsprung’s disease. The reported Sodium cromoglycate (SCG) is a nonabsorbable mast incidences range from 10% to 33%.1-3 Many patients cell stabilizing agent that has been documented to be have more than one attack of enterocolitis.4 The fre- effective in the treatment of inflammatory bowel dis- quency of bouts of enterocolitis tends to decrease with ease.9 It also has been used in food allergies.10 We aimed time.5 A small proportion of patients continue to have to perform an open, nonrandomized study to explore the persisting symptoms, such as diarrhea and abdominal possible benefit of SCG in Hirschsprung patients with distension, or frequently recurring attacks of enterocoli- refractory chronic or recurrent enterocolitis.
tis. The exact nature of chronic or recurring enterocolitisis poorly understood; outlet obstruction or abnormal mucosal defence mechanism have been suggested to play During 1997 and 1998, 8 consecutive patients, with symptoms of a role in the pathogenesis.6,7 Chronic symptoms are chronic or frequently relapsing enterocolitis, were enrolled to the especially common in children with Down’s syndrome, sodium cromoglycate trial. The age range of the patients was from 4 to22 years. All patients had undergone repair of Hirschsprung’s disease who, in addition to other malformations, have altered during the first year of life. The original reconstruction was Duhameloperation in 2 patients and transanal endorectal coloanal anastomosis11in 6 patients.
Five of the patients had symptoms of chronic enterocolitis. Three of From Children’s Hospital, University of Helsinki, Finland. them had Down’s syndrome and 2 other chromosomal aberrations. All Address reprint requests to R.J. Rintala, MD, PhD, Professor of these patients had chronic diarrhea or loose stools (median 6 bowel Paediatric Surgery, Children’s Hospital, University, P.O. Box 281, movements per day; range from 4 to 12). Exacerbations of the condi- tion were common (several times per year) and were characterized by Copyright 2001 by W.B. Saunders Company abdominal distension, nausea and vomiting, and poor appetite. The continuous loose stools caused mild to moderate soiling in 3 of the 5 patients. The dietary management of the patients consisted of a low Journal of Pediatric Surgery, Vol 36, No 7 (July), 2001: pp 1032-1035 residue, lactose-free diet. Enteral antibiotics were used at the time of undergoing manometry were within the normal range of exacerbation of symptoms. During the preceding year, 2 of the patients healthy children and did not differ from the resting had required hospitalization for exacerbation of symptoms. Three pressures of patients with Hirschsprung’s disease but patients (1 with Down’s syndrome and 2 with normal chromosomes)had frequent attacks of enterocolitis (Ͼ6 episodes per year). During without postoperative enterocolitis.
these bouts the patients had diarrhea, abdominal distension, nausea or Three of the 5 patients with chronic enterocolitis vomiting, and poor appetite. Between the episodes of enterocolitis the responded favorably. The median follow-up period of patients were continent and had 1 to 3 bowel movements a day. The these patients is 14 months (range from 8 to 26 months).
enterocolitis episodes were managed with enteral antibiotics and bowel In these 3 patients the median number of daily bowel decompression by saline enemas if necessary. All patients requiredhospitalization with intravenous fluid therapy at least once a year movements decreased from 6 to 3 (range from 1 to 5).
before the onset of SCG treatment. The dietary management of these The consistency of the stools became more solid, and patients was similar to those with chronic enterocolitis.
soiling related to loose or diarrheic stools diminished.
All patients had repeated stool cultures, the results of which did not The effect of SCG became apparent in a few weeks after show specific infective agents in any case; particularly, Clostridium the onset of the therapy. During the follow-up, none of difficile— growth was not isolated in any case. The most commonlyused antibiotics were metronidazole and norfloxacine. Long-term these 3 patients have required antibiotics for exacerba- symptom control with this treatment modality was poor in 5 cases and tion of symptoms. These 3 patients have continued the SCG therapy throughout the follow-up period. In one of All patients underwent ileocolonoscopy before the onset of SCG them the daily dose of SCG was tapered to 200 mg from therapy. Standard biopsies for H&E staining were taken from the the original dose of 400 mg per day and in one to 400 mg terminal ileum, cecum or ascending colon, hepatic flexure, splenicflexure, descending colon, and neorectum. Before SCG treatment, 5 patients had anorectal manometry; the manometric techniques have Two of the patients with chronic enterocolitis did not respond to the therapy after a trial of 4 months, and SCG The SCG treatment was initiated with 100 mg of the drug 4 times a treatment was discontinued. One of these 2 patients day enterally. The regimen was continued for 6 weeks, when the gained benefit from a predominantly intraluminally act- patients were reassessed. In 2 older patients (ages 10 years and 22years) who did not respond initially, the dose was increased to 200 mg ing glucocorticoid, budesonide. All the 3 patients with 4 times a day. The following clinical reassessment was performed 4 recurrent enterocolitis responded favorably to SCG treat- months after the onset of the therapy. In patients who did not benefit ment. Two patients (follow-up period 8 months and 14 from the therapy, the medication was discontinued. In the responders, months) have remained completely asymptomatic and a trial to taper the dose to the minimal effective level was made.
have had no attacks of abdominal distension or diarrheaafter the onset of the therapy. One patient had an episode of enterocolitis requiring antibiotics after a rotavirus At endoscopy the macroscopic findings were consis- gastroenteritis 1 year after the onset of SCG therapy. All tent with mild to moderate colitis predominantly in the these patients have continued the SCG therapy through- left colon. None of the patients had megacolon. The out the follow-up period. The daily dose of SCG has histology results findings showed chronic inflammation remained in 400 mg in 1 and was tapered to 300 mg in in all cases, especially in the distal biopsies. In histology 2. The clinical features of the patients are summarized in there were no specific findings suggesting other forms of chronic colonic inflammatory disease such as ulcerativecolitis or Crohn’s disease. Biopsy results from distal ileum were normal in all patients. Biopsy specimens for The prevalence of chronic or frequently recurring acetylcholinesterase staining were taken from the distal enterocolitis among patients with surgically repaired colon in 5 patients. No neuronal abnormalities were Hirschsprung’s disease is unknown. It is clear that this detected either in standard histology or in the acetylcho- problem affects more commonly patients with defective immune systems such as those with Down’s syndrome.
On rectal examination, all patients had normal sphinc- In the current series 4 of the 8 patients had Down’s ter tone. The anorectal resting pressures in the 5 patients syndrome and 2 more had other chromosomal aberra- Table 1. Clinical Features of Patients With Chronic Enterocolitis
Patient No., Age, Associated Abnormalities 4, 7 yr, syndromic chromosomal aberration 5, 6 yr, syndromic chromosomal aberration Table 2. Clinical Features of Patients With Recurrent Enterocolitis
tions. Postoperative enterocolitis also has been attributed colitis. As therapeutic modalities for ulcerative colitis are to bowel outlet obstruction.6 In the current series none of relatively nonspecific and mainly aim at suppression of the patients had a stricture or stenosis of the bowel outlet.
the inflammatory activity in the large bowel mucosa, it Moreover, the anal resting pressures of the patients did may be speculated that similar therapy may be effective not differ from those of Hirschsprung’s patients with no also for chronic enterocolitis after repair of Hirsch- enterocolitis or from those of healthy children.
sprung’s disease. SCG was selected for the current open The clinical diagnosis of chronic or recurring entero- trial because it is well tolerated and lacks systemic side colitis is not always straightforward. Many patients with effects. To our knowledge, the use of SCG or any other Hirschsprung’s disease have abnormal colonic motili- anti-inflammatory therapy for IBD has not been reported ty,13 which may cause bacterial overgrowth and paradox- before in conjunction of postoperative enterocolitis after ical diarrhea. In the current series the diagnosis of chronic enterocolitis was confirmed in all patients by Significant clinical improvement was detected in 6 of ileocolonoscopy and segmental biopsies.
our 8 patients. In the 3 responders with diarrhea or fre- The treatment of acute enterocolitis traditionally has quent loose stools related to chronic enterocolitis the qual- been comprised of decompression of the colon, bowel ity of life improved significantly as the solidification of rest, and antibiotics. However, there are no generally the stools and decreased stool frequency diminished soil- accepted treatment guidelines for chronic or recurring ing. All these patients were mentally retarded and did not enterocolitis. In our institution the standard treatment has cope well with the frequent soiling episodes before SCG been low residue, lactose-free diet to diminish substrates therapy. One of the 2 nonresponders received more potent for bacterial overgrowth, and enteral antibiotics at times antiinflammatory agent, local glucocorticoid therapy with of symptom exacerbation. In the current series the symp-toms of the patients were poorly controlled by this budesonide, which resulted in significant improvement.
The patients with recurrent bouts of enterocolitis have re- The likely mode of action of SCG is stabilization of mained free of symptoms except for one patient who had mast cells by decreasing the release of histamine from a single attack following viral gastroenteritis.
these inflammatory cells.14 SCG has been used widely The current study suggests that chronic and recurring for allergic conditions of the respiratory tract. More enterocolitis is associated with chronic inflammatory recently, SCG has proven to be effective in the treatment changes in the large bowel mucosa. The study also gives of food allergies and inflammatory bowel disease.9,10 strong preliminary evidence that anti-inflammatory med- SCG is not absorbed significantly from the alimentary ication that has been shown to be effective in patients tract and, therefore, has no systemic side effects. Clini- with IBD appears to alleviate the symptoms in the cally, chronic and recurring enterocolitis resembles in- majority of patients suffering from chronic or recurrent flammatory bowel disease (IBD), especially ulcerative 1. Carneiro PMR, Brereton RJ, Drake DP, et al: Enterocolitis in 6. Carcassonne M, Guys JM, Morrison-Lacombe G, et al: Manage- Hirschsprung’s disease. Pediatr Surg Int 7:356-360, 1992 ment of Hirschsprung’s disease: Curative surgery before 3 months of 2. Ikeda K, Goto S: Diagnosis and treatment of Hirschsprung’s disease in Japan. An analysis of 1628 patients. Ann Surg 199:400-405, 7. Teitelbaum DH, Caniano DA, Qualman SJ: The pathophysiology of Hirschsprung’s-associated enterocolitis: Importance of histologic 3. Rescorla FJ, Morrison AM, Engles D, et al: Hirschsprung’s correlates. J Pediatr Surg 24:1271-1277, 1989 disease. Evaluation of mortality and long-term function in 260 cases.
8. Nair MPN, Schwatrz SA: Association of decreased T-cell-medi- ated natural cytotoxicity and interferon production in Down’s syn- 4. Elhalaby EA, Coran AG, Blane CE, et al: Enterocolitis associated drome. Clin Immunol Immunopathol 33:412-424, 1984 with Hirschsprung’s disease: A clinical-radiological characterization 9. Grace RH, Gent AE, Hellier MD: Comparative trial of sodium based on 168 patients. J Pediatr Surg 30:76-83, 1995 cromoglycate enemas with prednisolone enemas in the treatment of 5. Fortuna RS, Weber TR, Tracy TF Jr, et al: Critical analysis of the operative treatment of Hirschsprung’s disease. Arch Surg 131:520-524, 10. Lunardi C, Bambara LM, Biasi D, et al: Double-blind cross-over trial of oral sodium cromoglycate in patients with irritable bowel syndrome due to food intolerance. Clin Exp Allergy 21:569-572, 13. Baillie CT, Kenny SE, Rintala RJ, et al: Long-term outcome and colonic motility after the Duhamel procedure for Hirschsprung’s dis- 11. Rintala R, Lindahl H: Transanal endorectal coloanal anastomo- sis for Hirschsprung’s disease. Pediatr Surg Int 8:128-131, 1993 14. Selbekk BH: Neurotensin-induced mast cell degranulation in 12. Rintala R: Postoperative internal sphincter function anorectal human jejunal mucosa. Additive effects of IgE or compound 48/80 and malformations—A manometric study. Pediatr Surg Int 5:127-130, inhibition by sodium cromoglycate. Scand J Gastroenterol 19:595-602,

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