Simon Murch

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.

Congenital enterocyte heparan sulphate deficiency with massive albumin loss, secretory diarrhoea, and malnutrition.

BACKGROUND The molecular basis of protein-losing enteropathy is unknown. However it has been shown that sulphated glycosaminoglycans may be important in regulating vascular and renal albumin loss. METHODS We describe three baby boys who presented within the first weeks of life with massive enteric protein loss, secretory diarrhoea, and intolerance of enteral feeds. All required total parenteral nutrition and repeated albumin infusions. No cause could be found in any case despite extensive investigations, including small intestinal biopsy sampling, which were repeatedly normal. FINDINGS By specific histochemistry, we detected gross abnormality in the distribution of small intestinal glycosaminoglycans in all three infants, with complete absence of enterocyte heparan sulphate. The distribution of vascular and lamina propria glycosaminoglycans was, however, normal. INTERPRETATION The presentation of these infants suggests that enterocyte heparan sulphate is important in normal small intestinal function.

Colonic Crohn’s Disease in Children Does Not Respond Well to Treatment with Enteral Nutrition If the Ileum Is Not Involved

Data supporting a response to treatment with exclusive enteral nutrition in pediatric colonic Crohn’s disease are few. We examined clinical and biochemical responses of ileal, colonic, and ileocolonic Crohn’s disease and assessed the endoscopic and histological colonic mucosal response in the colonic and ileocolonic groups.We prospectively enrolled 65 children (age: 8–17 years) with acute intestinal Crohn’s disease (Pediatric Crohn’s Disease Activity Index [PCDAI] > 20). After ileocolonoscopy, gastroscopy, and a barium meal and follow-through, they were distributed into three groups (ileal, n = 12, ileocolonic, n = 39; and colonic, n = 14). All patients received exclusive polymeric feed as treatment, with a repeat endoscopy at completion of treatment. At enrollment the ileal group had significantly less severe disease (P = 0.05) compared to the colonic and ileocolonic groups. However, the colonic disease group showed the least fall in PCDAI scores at completion of treatment with enteral nutrition (P = 0.03), with the lowest remission rate (50%, vs 82.1% in the ileocolonic and 91.7% in the ileal group [χ2 test, P = 0.021]). Endoscopic and histologic colonic mucosal assessment showed a posttreatment improvement in the ileocolonic (P ≤ 0.01) but not in the colonic disease group (P = ns). Children with disease in the colon respond better to enteral nutrition if the ileum is also involved. This may be due to different underlying inflammatory mechanisms. Detailed pretreatment assessment in studies of Crohn’s disease according to disease distribution with appropriate individualized tailoring of treatment may be important in this regard.

Local and systemic effects of macrophage cytokines in intestinal inflammation

The activation of macrophages and newly recruited monocytes appears to be common to both Crohns disease and ulcerative colitis, despite different inductive stimuli. Similar activation occurs acutely during the course of invasive intestinal infections such as shigellosis, but is then usually downregulated. The macrophage cytokines tumor necrosis factor-alpha and interleukin-1 (IL-1) are centrally involved in the local inflammatory response, and blockade of either cytokine greatly attenuates the inflammatory lesion. Induction of focal vascular thrombosis and matrix degradation are thought to be an important component of this focal damage. Both cytokines and IL-6 are now recognized to contribute to the systemic effects of intestinal disease, including growth suppression, anorexia, and chronic anemia. Disturbance of sleep patterns, mood, and affect may also occur, and recent evidence points towards bidirectional interplay between macrophage cytokines and central nervous system function.

Infliximab delays but does not avoid the need for surgery in treatment-resistant pediatric Crohn' disease.

The aim of this study was to review the impact of infliximab therapy on children with treatment-resistant Crohn’s disease. Treatment resistance was defined as clinically active disease despite > 4 months of immunosuppressive therapy. The outcome variables were time to first remission, duration of remission and the need for surgery. 24 children received 90 infusions of infliximab (16 boys; median 10.3y, range 1.0–14.4y); all had three infusions as an induction course. 17 (70.8%) achieved clinical remission, with 14/17 (82.3%) relapsing within 4 months of the third infusion. 6/7 in the non-responding group and 8/17 of the responders required surgery with an insignificant difference in the median time to surgery (p = 0.49). Four remain dependent on regular infliximab. Infliximab is well-tolerated and highly effective in achieving clinical remission in children with refractory Crohn’s disease but may only delay and not avoid the need for surgery. Failure to achieve clinical remission by the 3rd infusion significantly increases the risk of surgery.

Human intestinal tissue tropism of intimin epsilon O103 Escherichia coli

Human intestinal in vitro organ culture was used to assess the tissue tropism of human isolates of Escherichia coli O103:H2 and O103:H- that express intimin epsilon. Both strains showed tropism for follicle associated epithelium and limited adhesion to other regions of the small and large intestine. This is similar to the tissue tropism shown by intimin gamma enterohaemorrhagic (EHEC) O157:H7, but distinct from that of intimin alpha enteropathogenic (EPEC) O127:H6.

Diarrhoea, diagnostic delay, and appendicitis

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