Systematic review of the evidence base for the medical treatment of paediatric inflammatory bowel disease.

OBJECTIVE: To systematically review the evidence base for the medical (pharmaceutical and nutritional) treatment of paediatric inflammatory bowel disease. METHODS: Key clinical questions were formulated regarding different treatment modalities used in the treatment of paediatric (not adult-onset) IBD, in particular the induction and maintenance of remission in Crohn disease and ulcerative colitis. Electronic searches were performed from January 1966 to December 2006, using the electronic search strategy of the Cochrane IBD group. Details of papers were entered on a dedicated database, reviewed in abstract form, and disseminated in full for appraisal. Clinical guidelines were appraised using the AGREE instrument and all other relevant papers were appraised using Scottish Intercollegiate Guidelines Network methodology, with evidence levels given to all papers. RESULTS: A total of 6285 papers were identified, of which 1255 involved children; these were entered on the database. After critical appraisal, only 103 publications met our criteria as evidence on medical treatment of paediatric IBD. We identified 3 clinical guidelines, 1 systematic review, and 16 randomised controlled trials; all were of variable quality, with none getting the highest methodological scores. CONCLUSIONS: This is the first comprehensive review of the evidence base for the treatment of paediatric IBD, highlighting the paucity of trials of high methodological quality. As a result, the development of clinical guidelines for managing children and young people with IBD must be consensus based, informed by the best-available evidence from the paediatric literature and high-quality data from the adult IBD literature, together with the clinical expertise and multidisciplinary experience of paediatric IBD experts.

Use of ACE inhibitors and ARBs in hypertensive women of childbearing age.

BACKGROUND AND OBJECTIVE: Treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) during pregnancy can cause severe foetal abnormalities. This study aimed to identify the proportion of women of childbearing age taking ACE inhibitors or ARBs on referral to a tertiary Hypertension Clinic. DESIGN: Retrospective cohort study. METHODS: A cohort of female patients aged 16-45 years was identified from approximately 1500 new referrals from January 2004 to October 2006, excluding those not taking antihypertensive medication. ACE inhibitors and ARBs were grouped together for the purposes of the study. Contraceptive status was established where possible. RESULTS: Forty seven of 101 (47%) women aged 16-45 years were taking an ACE inhibitor (35) an ARB (11) or both (1) of whom 26 (55%) were aged 16-40 years. In this younger group, eight were using no contraception and three were using barrier methods only. CONCLUSIONS: Many GPs continue to prescribe ACE inhibitors and ARBs to women of childbearing age. A quarter of women in the study were taking these agents and were 40 years or less; of these many were not using reliable contraception. These women are at risk of foetal malformation and poor perinatal outcomes if they become pregnant. The British Hypertension Guidelines may put younger women at risk if general practitioners are unaware of potential foetotoxic and teratogenic consequences of prescribing ACE inhibitors and ARBs to women of child bearing age.

Low-dose intravenous azathioprine may be effective in the management of acute fulminant colitis complicating inflammatory bowel disease.

BACKGROUND: The management of acute fulminant colitis unresponsive to intravenous steroids is usually surgical. However, recent evidence suggests that intravenous administration of azathioprine at very high doses may allow more rapid onset of clinical efficacy, although its use has not previously been reported in the emergency situation. AIM: To report the successful use of intravenous azathioprine in the management of acute fulminant colitis complicating both Crohn's disease and ulcerative colitis. METHOD: We initially used intravenous azathioprine because of the refusal of the family of the first patient to accept surgery following failure of conventional medical management. Importantly the azathioprine was successful at the low dose of 3 mg/kg.day, equivalent to standard oral doses. Two subsequent patients demonstrated a similar resolution. All were weaned successfully to oral azathioprine and have remained in long-term endoscopic and histological remission. CONCLUSION: These preliminary data suggest that low-dose intravenous azathioprine may be helpful adjunct therapy in selected cases of severe fulminant colitis. However, the need for close monitoring and daily surgical assessment remains paramount, and a formal trial of low-dose intravenous azathioprine is required before it may be more widely recommended.

Cholelithiasis in early infancy

This report describes three children, age range 7 weeks to 5 months, who presented with obstructive jaundice secondary to gallstones. Previous Escherichia coli septicaemia and frusemide therapy were predisposing risk factors in two of the patients. All three were successfully treated with cholecystectomy and exploration of the common bile duct.

Surgical management of inflammatory bowel disease.

AIM: To evaluate the outcome and morbidity after major surgical interventions for inflammatory bowel disease (IBD). METHODS: Retrospective case note analysis of 227 children referred to a tertiary referral centre between 1994 and 2002 for treatment of IBD. RESULTS: 26 of 125 children with Crohn's disease (21%) required surgical management. 13 with disease proximal to the left colon underwent limited segmental resections and primary anastomosis, without significant morbidity. Primary surgery for 13 children with disease distal to the transverse colon included 6 subtotal-colectomies or panprocto-colectomies. All seven children undergoing conservative segmental resections (three with primary anastomosis, four with stoma formation), required further colonic resection or defunctioning stoma formation. All three children undergoing primary anastomosis developed a leak or fistula formation. 22 of 102 children with ulcerative colitis (22%) required surgery. Definitive procedures (n = 17) included J-pouch ileoanal anastomosis (n = 11), ileorectal anastomosis (n = 2), straight ileoanal anastomosis (n = 3), and proctectomy/ileostomy (n = 1). Five children await restorative surgery after subtotal colectomy. Median daily stool frequency after J-pouch surgery was 5 (range 3-15), and 10 of 11 children reported full daytime continence. All three children with straight ileoanal anastomosis had unacceptable stool frequency and remain diverted. CONCLUSION: The complication rate after resectional surgery for IBD was 57% for Crohn's disease, and 31% for ulcerative colitis. In children with Crohn's disease, limited resection with primary anastomosis is safe proximal to the left colon. Where surgery is indicated for disease distal to the transverse colon, subtotal or panproctocolectomy is indicated, and an anastomosis should be avoided. Children with ulcerative colitis had a good functional outcome after J-pouch reconstruction. However, the overall failure rate of attempted reconstructive surgery was 24%, largely owing to the poor results of straight ileoanal anastomosis.

Issues and experience around the Paediatric Register of Inflammatory Bowel Disease.

Accurate epidemiological data is one of the most important tools to elucidate disease aetiology and natural history. Disease registers are the cornerstone of this process. The importance of registers in facilitating an efficient health service is clear. We have been engaged in the development of a register of paediatric inflammatory bowel diseases, and in this article we present a general overview of registers and of lessons we have learnt along the way.

Aspergillus endocarditis in chronic granulomatous disease.

We report the first case, to our knowledge, of Aspergillus endocarditis in chronic granulomatous disease in a patient who also had an atrial septal defect. A diagnosis was made on culture of the organism from the mass despite extensive prior investigation. The presence of distinctive skin lesions as a diagnostic clue of fungaemia is highlighted. Possible advances in diagnosis by detection of fungal cell wall components and in prophylaxis by use of itraconazole are referred to. We conclude that fungal endocarditis should be considered in this condition, especially in the presence of a structural heart defect.

The biotransformation of t-butylacetonitrile and its boron-containing analogue trimethylamine-cyanoborane by Brevibacterium R312.

The ability of the nitrile hydratase/amidase system from Brevibacterium R312 to biotransform tert-butylacetonitrile was studied with a view to their utilisation in the production of novel amino acids from isostructural compounds. Brevibacterium R312 was able to transform nitriles with this structure; however, the wide spectrum amidase from this organism was unable to biotransform the corresponding amide to the carboxylic acid.

Cholelithiasis in early infancy.

This report describes three children, age range 7 weeks to 5 months, who presented with obstructive jaundice secondary to gallstones. Previous Escherichia coli septicaemia and frusemide therapy were predisposing risk factors in two of the patients. All three were successfully treated with cholecystectomy and exploration of the common bile duct.

Topical tacrolimus may be effective in the treatment of oral and perineal Crohn's disease.

BACKGROUND: Crohn's disease of the mouth or perineum is more common in young people, and notably resistant to treatment. However, there is increasing evidence that topical therapy with tacrolimus (FK506) may be effective in skin diseases resistant to cyclosporin because of its high uptake in inflamed skin and subsequent reduction in keratinocyte chemokine production. PATIENTS AND METHODS: Tacrolimus ointment was made up inhouse from the intravenous or oral formulation and suspended in appropriate vehicles for perioral or perianal administration at an initial concentration of 0.5 mg/g. This was administered open label to eight children (aged 5-18 years) with treatment resistant oral (three patients) and/or ulcerating perineal (six patients) Crohn's disease. RESULTS: Marked improvement was seen in 7/8 patients within six weeks and healing within 1-6 months. One child with gross perineal and colonic disease showed little response. Two of the responders showed rebound worsening when tacrolimus was stopped or the dosage reduced rapidly, and one of these eventually required proctectomy. Slower weaning of drug concentration has been successful in 6/8 patients, with four receiving intermittent treatment and two on regular reduced dosage (0.1-0.3 mg/g) with follow up times of six months to 3.5 years. Serum concentrations of tacrolimus were undetectable in all patients. CONCLUSIONS: Topical tacrolimus at low concentrations (0.5 mg/g) shows promise in the management of childhood perineal and oral Crohn's disease, with no evidence of significant systemic absorption. However, rapid weaning or abrupt cessation of therapy may cause rebound worsening of disease. Further controlled studies are required to assess the efficacy and safety of this treatment.

Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children.

BACKGROUND: We investigated a consecutive series of children with chronic enterocolitis and regressive developmental disorder. METHODS: 12 children (mean age 6 years [range 3-10], 11 boys) were referred to a paediatric gastroenterology unit with a history of normal development followed by loss of acquired skills, including language, together with diarrhoea and abdominal pain. Children underwent gastroenterological, neurological, and developmental assessment and review of developmental records. Ileocolonoscopy and biopsy sampling, magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar puncture were done under sedation. Barium follow-through radiography was done where possible. Biochemical, haematological, and immunological profiles were examined. FINDINGS: Onset of behavioural symptoms was associated, by the parents, with measles, mumps, and rubella vaccination in eight of the 12 children, with measles infection in one child, and otitis media in another. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. Histology showed patchy chronic inflammation in the colon in 11 children and reactive ileal lymphoid hyperplasia in seven, but no granulomas. Behavioural disorders included autism (nine), disintegrative psychosis (one), and possible postviral or vaccinal encephalitis (two). There were no focal neurological abnormalities and MRI and EEG tests were normal. Abnormal laboratory results were significantly raised urinary methylmalonic acid compared with age-matched controls (p=0.003), low haemoglobin in four children, and a low serum IgA in four children. INTERPRETATION: We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers.