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SUMMARY Background: Recent studies have shown both interleukin 2 (IL-2) and interferon gamma (IFN) to be elevated in patients with active Crohn's disease compared to ulcerative colitis or non-inflammatory bowel disease controls. However the effect of treatment on these lymphokines has not been studied. Patients and methods: Using a reverse haemolytic plaque assay the percentage of lymphokine-secreting cells was determined in the intestinal mucosa of children with Crohn's disease before and after 8 weeks of treatment with either enteral nutrition, cyclosporin or steroids. Results: Before treatment, a high percentage of cells isolated from mucosal biopsies secreted IL-2 or interferon-gamma. Eight weeks’treatment with the immunosuppressive agents cyclosporin, or with corticosteroids, produced a significant reduction in the percentage of IL-2 secreting cells, although only for the former was there also a reduction in interferon-gamma secreting cells. Enteral nutrition however, produced a reduction in lymphokine-secreting cells equivalent to cyclosporin and produced the best histological and clinical improvement. Conclusion: Enteral nutrition and cyclosporin can down-regulate lymphokine secretion in the gut in Crohn's disease.

Objectives: Indeterminate intestinal inflammation may result from a variety of inflammatory conditions in addition to ulcerative colitis and Crohn disease. The primary systemic vasculitides may present with intestinal inflammation and an indeterminate colitis. We set out to describe a series of children with primary systemic vasculitis who initially presented with clinical features suggestive of inflammatory bowel disease (IBD) to establish criteria that might help discriminate between IBD and primary systemic vasculitis. Methods: Ten children (6 boys, median age at presentation 8.9 years, range 0.9-14.5 years) satisfied inclusion criteria. Results: All had abdominal pain, weight loss, diarrhea (6 of 10 bloody) and laboratory evidence of a severe acute phase response. Extraintestinal clinical features included vasculitic rash, renal impairment, myalgia, testicular pain and polyarthritis. Endoscopy showed vascular changes or other macroscopic findings suggestive of vasculitis in 5 of 10 patients. Gut histology revealed indeterminate chronic inflammatory mucosal changes and one patient with small artery fibrinoid necrosis in the submucosal vessels. Extraintestinal biopsy was performed in 6 patients and had a higher yield for the demonstration of vasculitis than intestinal biopsy. The results of selective visceral angiography was suggestive of vasculitis in all patients, but was normal in 7 cases of treatment-unresponsive classic IBD. Treatment comprised corticosteroid and azathioprine in all patients. Cyclophosphamide was given to 7 of 10 patients. Conclusions: Extraintestinal manifestations and inflammatory responses that may be disproportionate to the degree of intestinal inflammation provide clues to the presence of an underlying primary systemic vasculitis, and these data suggest that selective visceral angiography plays a key role in the diagnosis of vasculitis in this context. It is important to identify and treat any vasculitic component because failure to do so may result in consequential morbidity or mortality.

Food allergy may affect the gastrointestinal tract of children and adults too, albeit less commonly. The changing clinico-pathological expression of such food allergy in children over a 30 year period is related, from the eye witness perspective of a paediatric gastroenterologist in London. Tissue diagnosis by biopsy, related to dietary elimination and challenge has been the basis for the first clinico-pathological descriptions and accurate clinical diagnosis of these syndromes as they affect the gastrointestinal tract. In the 1970s cow's milk sensitive enteropathy presenting as chronic diarrhoea and failure to thrive in infancy often after infective gastroenteritis, especially with enteropathogenic Escherichia coli, was an important problem. By the late 1990s such presentations had become most uncommon in developed communities but they continue to occur in developing communities. By contrast in more recent times, multiple food allergy associated with minor small intestinal enteropathy and gastro-oesophageal reflux in older children has become an important clinical problem in children seen in developed communities. Accompanying these changes has been a dramatic fall in the number of children with clinically severe gastroenteritis with severe dehydration requiring hospital admission. Furthermore, the widespread diagnostic use of endoscopy of the upper and lower gastrointestinal tract in children with multiple biopsies has expanded gastroenterological diagnosis in children. This approach gives information about the oesophagus and ileo-colon not available in the earlier studies, which largely concentrated upon small intestinal biopsies, obtained by Crosby capsule biopsy. So, over this 30 year period clinico-pathological expression has altered but also the diagnostic approach has technically changed.

SUMMARY T cell hypersensitivity has been implicated in the tissue damage in Crohn’s disease (CD). All studies to date have examined mucosal T cells, although much of the tissue damage occurs in the submucosa and muscle layers. The aim of this work was to study T cell proliferation throughout the intestinal wall in children with IBD. Surgical resection material from 19 children with CD (10 ileal, 10 colonic), seven with ulcerative colitis (UC), and 12 normal controls was studied. The distribution of dividing T cells was investigated by double-immunohistochemistry using Ki67 to identify proliferating cells, and CD3 to identify T cells. In ileal and colonic lamina propria virtually no Ki67+, CD3+ cells were seen in control, UC or CD tissue. In contrast, there were significantly more Ki67+, CD3+ cells within the lymphoid follicles of ileal and colonic CD than in the follicles in UC and controls. Increased numbers of Ki67+, CD3+ cells were present in the submucosa, muscle layers (M) and serosa in Crohn’s ileitis and colitis compared with the lamina propria (LP), although only in the muscle of the colon was the difference statistically significant (LP, 0.4% (0–1%); M, 1.6% (0–5.2%); P = 0.03). Pooling data from ileal and colonic CD, however, did show significantly increased Ki67+, CD3+ cells in both serosa and muscle layers compared with the LP. Dividing T cells have been identified in the deeper layers of the gut wall in CD. These may contribute to the fibrosis and muscle hyperplasia characteristic of the condition.

Background Central to the management of cow's milk allergy in infancy is the complete elimination of cow's milk protein from the infant's diet for a variable period of time. The principal part of this approach is to provide nutrition for the child by means of hypoallergenic feeding formulas. Although a number of formulas are indeed marketed as hypoallergenic, it is not known with certainty how hypoallergenic they really are. A variety of ways of testing for hypoallergenicity have been developed, including the use of in vivo and in vitro animal model systems, chemical analyses, and patient studies, which are the ultimate test. Objective The purpose of the present report was to review the various ways of testing sensitizing capacity of infant feeding formulas for the treatment of children with cow's milk allergy. Data Sources English language articles were selected from PubMed, as were selected abstracts that would have immediate, practical clinical implications. The review focuses on themes related to animal models, chemical analysis, and clinical testing and clinical studies of intolerance to hydrolysates. Results Sensitizing capacity can be tested first in animal models either by in vivo or in vitro techniques. Although the information gained is valuable for preliminary evaluation, such techniques are intrinsically artificial. Second chemical analyses indicate that absence of larger peptides greater than 1,500 Da provides a critical industrial cutoff point. Third clinical effectiveness in child patients is of paramount importance. Conclusions The results of the present review demonstrate that extensively hydrolyzed formulas are usually effective, but recently intolerance to hydrolysates has been observed. However, use of amino acid-based formulas free of antigens is highly effective in such infants.

Colorectal polyps are an important albeit uncommon cause of rectal bleeding in children. Colonoscopy promotes both rapid and accurate diagnosis and the opportunity for immediate therapeutic polypectomy. A 10 year audit of polyps diagnosed and treated endoscopically has been undertaken in the children's endoscopy unit. Twenty nine polyps were diagnosed from 730 colonoscopies; 24 were juvenile, two inflammatory, two Peutz-Jeghers, and one an adenomatous polyp. All but one of the juvenile polyps were solitary. All children had bleeding per rectum as one of the major presenting features. About two thirds of the patients were under the age of 5 years; the mean age was 5.6 years. Most of the juvenile polyps were on the left side of the colon; 41% were distal to the sigmoid colon. However polyps were found throughout the colon, indicating that total colonoscopy is wise and rewarding in any child with persistent and intermittent rectal bleeding.

Growth impairment of undefined aetiology occurs in approximately 30% of children with chronic inflammatory bowel disease. We measured urinary growth hormone concentrations in 36 children with chronic inflammatory bowel disease and 51 normal controls. The median urinary concentration of growth hormone in the stunted children with chronic inflammatory bowel disease was 15.8 ng/g creatinine (range 4.3-32.6), compared with 11.7 ng/g creatinine (range 4.1-35.9) in those with normal growth. The difference was statistically not significant (p = 0.15). Moreover, there was no significant difference between the patients and the control group. One stunted patient had a urinary growth hormone (UGH) concentration below the normal range, whereas four patients with normal height were also below the normal range. Four of these five patients (80%) were on corticosteroid treatment at the time of urinary collection, whereas only 26% of the patients with normal UGH were also on corticosteroid treatment. We conclude that growth retardation in children with chronic inflammatory bowel disease is probably not related to growth hormone deficiency but must involve other mechanisms.

SUMMARY Gamma/delta T cells are increased in the gut epithelium of patients with coeliac disease compared with normal controls. The aim of this study was to determine whether the increase in yd intraepithelial lymphocytes (IEL) is specific for coeliac disease, in which case it could be of diagnostic importance. Biopsies were obtained from children with no intestinal disease, coeliac disease, cow-milk-sensitive enteropathy/post-enteritis syndrome (CMSE/PES) and miscellaneous other enteropathies (n = 67). Intraepithelial CD3+ and γδ T cells were identified in frozen sections using peroxidase immunohisto-chemistry. In normal biopsies there were 0-7 γδ IEL/100 cells in the epithelium. In untreated coeliac patients this increased to 9-22 γδ IEL/100 cells in the epithelium (P=0.000004). Of 27 patients with morphologic intestinal damage which was not due to coeliac disease, four with CMSE/PES had γδ IEL/100 cells in the epithelium in the same range as the patients with coeliac disease. Of these, two had high densities of CD3+ IEL in the epithelium and were indistinguishable from patients with untreated coeliac disease. The other two could be excluded as possible coeliacs because their CD3f IEL/100 epithelial cells were in the normal range. Thus an increase in γδ IEL is not specific for coeliac disease. However, enumeration of both of γδ IEL and CD3+ IEL densities will be useful in the exclusion of coeliac disease as a diagnosis in some children.

Between 1966 and 2000 the pattern of gastroenterological disease in children in developed communities changed. Clinically severe infective gastroenteritis has declined in incidence. Infection of children with the conventional serotypes of Escherichia coli dramatically declined. During this period many new infective agents notably rota virus were recognised. By contrast, more children with chronic inflammatory bowel disease (IBD), especially Crohn's disease, have been diagnosed than ever before. Gastrointestinal allergy is increasingly recognised but the pattern of disease has changed. Technological advance in accurate diagnosis occurred with an emphasis upon tissue diagnosis. Introduction to clinical practice of ileocolonoscopy in the late 1970s immensely increased the ability to make the diagnosis of chronic IBD in children. Therapeutic advance has seen development of parenteral nutrition and enteral feeding as major therapies for children. In the UK there has been a rise and fall in university departments of paediatric gastroenterology.

The findings on barium follow through, ileoscopy and biopsy of the terminal ileum in 46 children with suspected chronic inflammatory bowel disease have been compared to the final clinical diagnosis. Ileoscopy and barium follow through agreed in 91%, barium follow through and biopsy in 80% and barium follow through, ileoscopy and biopsy in 76% of cases. A pronounced lymphoid hyperplasia pattern was present radiologically in 24%, and was a source of error in two cases. Barium follow through compared favourably to ileoscopy or biopsy individually, detecting 18 of 20 and 17 of 20 cases respectively; however, ileoscopy combined with biopsy diagnosed every case. The sensitivity of the barium follow through was 0.90 with a specificity 0.96 for the diagnosis of Crohn's disease in the terminal ileum.

Background Because of the high prevalence of cow's milk allergy as one of the most frequent clinical presentations of food allergy in infancy and early childhood, it is important to define the condition accurately. Allergy must be distinguished from the broader term food intolerance , which may be defined as a reproducible adverse reaction to the ingestion of a food or to any of its components, ie, proteins, carbohydrates, fats, and additives, and which includes toxic, metabolic, and allergic reactions. By contrast, food allergy may be defined as an adverse clinical reaction to a specific food component and that is immunologically mediated. The rapid increase in knowledge resulting from research in immunology in recent years has not only led to a better understanding of the basis for cow's milk allergy in infancy, but has also yielded considerable promise for improved diagnosis and management of the condition. Objective To review recent developments in immunology which demonstrate how they may lead to a better understanding of the clinical spectrum of cow's milk allergy in infants and children. Data Sources English language articles were selected from PubMed and selected abstracts that would have immediate, practical clinical implications. The review focuses on themes related to gastro-enterology, focusing upon the esophagus and small intestine. Results In cow's milk-sensitive esophagitis, there is dense infiltrate of eosinophils and increased T cell activation with upregulation of the chemokine eotaxin. In cow's milk-sensitive enteropathy, there is T cell activation, and it often results as a sequela of gastro-enteritis. Changing patterns in recent years suggests that sensitization occurs via mother's breastmilk to cow's milk and multiple food antigens. There is evidence of reduced Th 1 response in these children. This is related to associated IgA deficiency and low levels of cytokine transforming growth factor β. Conclusions The results of the present review demonstrate that the clinical manifestations of cow's milk allergy are very diverse, with differences between developing and developed countries. Understanding the immunologic mechanisms is of key importance in understanding this diversity.

The cytokine profiles of mononuclear cells freshly isolated from Peyer's patch (PPMC), adjacent ileal lamina propria lymphocytes (LPMC) and peripheral blood (PBMC) in children without histological evidence of gastrointestinal disease has been investigated by single-cell enzyme-linked immunoabsorbent spot forming assay (ELISPOT) and reverse transcriptase (RT)-PCR. In the blood, interferon gamma and IL-4 ELISPOTs were regularly detected albeit at low frequency (< 50/10(5) cells). IL-5 and IL-10 ELISPOTs were not seen in most patients. In Peyer's patches and lamina propria there was a dramatic increase in cytokine secreting cells of all types compared to blood, reaching a very high frequency for interferon gamma in the lamina propria (1000-3000/10(5) cells). IL-4 and IL-5 ELISPOTs were 20-100-fold less common in both PP and LPL. At all sites, cytokine secretion depended on protein synthesis and enrichment for CD4+ cells in PP increased the frequency of all cytokine-secreting cells. Quantification of messenger RNA for cytokines using RT-PCR demonstrated that IL-4 and IL-10 transcripts were significantly greater than interferon gamma transcripts in PP and in lamina propria, IL-4, IL-10 and interferon gamma transcripts were equivalent. IL-5 transcripts were not detected in most samples of PP and lamina propria. These results clearly show that cells secreting interferon gamma predominate in human PP and LPL. However the high mRNA concentrations for IL-4 and IL-10 shows that although these cells are quantitatively few, they are highly transcriptionally active.

In children with complicated inflammatory bowel disease, conventional ultrasound imaging may not define the extent of extraluminal disease and the involvement of other viscera. Three children with chronic inflammatory bowel disease are presented, where computed tomography was well tolerated and provided valuable information on extraluminal disease, involvement of other organs, and the state of the bowel wall and mesentery. In children in whom ultrasound examination is inconclusive or limited by gas or tenderness, computed tomography can provide important information that may determine clinical management.

Twenty children with active ulcerative colitis were assessed before and after 8 weeks of medical therapy with 5-aminosalicylic acid (5-ASA) derivatives and corticosteroids. Local therapy was given for distal disease (seven cases) ; other disease was treated with oral prednisolone (1-2 mg/kg/day, maximum 40 mg). Eighteen of the children showed a clinical improvement on therapy, and complete remission of clinical disease activity by 8 weeks was seen in 17 (85%). C-reactive protein was elevated initially in 10 of 20 children and returned to normal posttreatment in all but one. Reassessment of the colon after treatment showed an improved endoscopic appearance in 15 and complete remission in eight (40%). Histological improvement was seen in 13, with full remission in only three (15%). In conclusion, remission of clinical disease activity by corticosteroid therapy in ulcerative colitis may not be accompanied by endoscopic remission and uncommonly by mucosal healing. This finding may be important prognostically because of the risk of dysplasia in long-standing persistent mucosal inflammation.

SUMMARY Background: Corticosteroids are widely used to treat children with inflammatory bowel disease although the response is variable, side-effects are common, and many patients develop a partial or complete steroid resistance. The mechanism underlying these phenomena are unclear. Corticosteroids mediate some of their actions through lipocortin-l, and the inductic of autoantibodies to lipocortin has been proposed as a possible mechanism by which steroid efficacy is suboptimal in vivo. Patients and methods: We have measured serum lipocortin-1 antibody concentration by ELISA in 38 children with Crohn's disease, 12 with ulcerative colitis and in 15 controls. Results: IgG and IgA anti-lipocortin-1 antibody levels were higher in the Crohn's group than in the ulcerative colitis or control groups. Elevated concentrations did not relate to disease activity, history of steroid therapy or steroid-responsiveness. Lipocortin IgM antibody status was similar in all three groups. Conclusion: It is therefore unlikely that serum antibodies to lipocortin-1 have a role in the development of steroid-resistance in children with inflammatory bowel disease.

Eighteen children and adolescents, of a total of 90 treated in our unit between 1982 and 1992, underwent colectomy for ulceractive colitis. Six (6.7%) of the 90 patients had short stature, i.e., a height below the 3rd centile, and 8 of the 18 who had surgery had a subnormal height velocity, i.e., below the 25th centile for age at the time of surgery. Surgery was performed for resistance to medical therapy (n = 13) or toxic megacolon (n = 5). Surgery was followed by catch-up growth, i.e., increasing height velocity, in eight subjects and cessation of the trend of diminishing height velocity, but without catch-up growth, in five. In 11 of the subjects who were prepubertal, the median height velocity increased from 3.85 cm/year preoperatively to 7.35 cm/year postoperatively (p < 0.01). One year after surgery, 14 of the 18 patients were either asymptomatic or substantially improved. Surgery therefore led to improved linear growth and a prolonged symptom-free period in most of the children and adolescents with ulcerative colitis undergoing this treatment.

Soluble interleukin-2 receptor (IL-2R) concentrations were measured in 110 serum samples from 102 children undergoing routine small bowel biopsy for a wide range of gastrointestinal symptoms. Young children in the control group who had no gastrointestinal disease and a normal intestinal mucosa were found to have high concentrations of IL-2R. There was a significant inverse relationship between IL-2R concentration and age in the control group. Children with a gastrointestinal diagnosis appeared to have increased IL-2R concentrations, although some of the diagnostic groups were too small in size for statistical analysis. Children with cow's milk sensitive enteropathy had IL-2R concentrations equivalent to those of age-matched controls. High concentrations of IL-2R in young healthy children implies that serum IL-2R is of no clinical use as an index of inflammation in this age group.

There are two types of food sensitive enteropathy; permanent and temporary. Celiac disease belongs to the former, the temporary food sensitive enteropathies of early childhood to the latter. A food sensitive enteropathy is characterized by an abnormal small intestinal mucosa while having the offending food in the diet; the abnormality is reversed by an elimination diet, only to recur once more on challenge with the relevant food. These disorders are temporary and may follow gastroenteritis. Cow's milk sensitive enteropathy is the most frequent and best known example but soy protein, egg, fish, chicken meat, ground rice and probably gluten may also temporarily damage the small intestinal mucosa in infancy. Treatment is with an elimination diet and protein hydrolysates as a cow's milk substitute. The reason why these enteropathies are temporary has not yet been established.

Childhood Crohn's disease may cause significant morbidity. T cell activation is considered to be central to Crohn's disease pathology, and as cyclosporin is a powerful inhibitor of T cell activation, and has been used in adult Crohn's disease with encouraging results, it may offer the prospect of remission if given early in the course of disease. Children with newly diagnosed Crohn's disease or those relapsing off treatment were therefore given cyclosporin or conventional treatment (enteral nutrition or corticosteroids) by random allocation. Evaluation was performed initially and at two months. Twenty four children were studied (10 on cyclosporin and 14 on conventional treatment; one child on cyclosporin withdrew). Significant clinical improvement occurred in the group on conventional treatment, but not in the cyclosporin group. Colonoscopic improvement was noted in 5/9 on cyclosporin and 8/14 on conventional treatment, but neither group produced a significant fall in median colonoscopic index. Histological improvement was seen in 7/8 on cyclosporin and 8/13 on conventional treatment, but cyclosporin was not significantly better. Cyclosporin produced improved clinical and histological appearance without matched improvement in blood disease indices. It was not better than conventional treatment, and simple oral administration is probably not suitable for newly diagnosed patients with Crohn's disease.

Factors influencing outcome after surgery have been studied in 67 children requiring bowel resection or diversion of the faecal stream for Crohn's disease. Patients were divided into four groups on the basis of disease location at time of surgery, and mean follow-up was 4–5 years. All three children with panenteric disease (group 1) have relapsed. Best results were observed in cases with disease confined to the small bowel (group 2) and ileocaecal region (group 3), in whom surgery was followed by sustained remission in six out of seven and 24 out of 30 patients respectively. In the 27 children with colitis (group 4), results were mixed. Six of the seven patients who had staged colonic resections with a primary anastomosis relapsed, as did three out of four patients given a loop ileostomy to divert the faecal flow; in contrast, 15 out of 16 children who had a subtotal colectomy with ileostomy as the primary procedure have remained well, with only minor problems involving the rectal stump. An acceleration in growth velocity was observed during the first year after operation in 89 per cent of 40 children studied. Outcome after surgery for Crohn's disease in childhood depends mainly on disease location, but is influenced by the type of primary operation performed. In addition to symptomatic relief the principal early benefit of surgery is improved growth.

A retrospective analysis of pubertal parameters of 30 children with Crohn's disease (N = 26) or ulcerative colitis (N = 4) was compared with standards. Four parameters were analyzed

42 children requiring surgery for Crohn's disease before 17 yrs of age were studied to determine the effect of bowel resection on their growth and pubertal development. Height, weight, pubertal status and bone age were recorded by an auxologist for at least 1 yr post-operatively (mean 3.12 yrs). 20 (48%) were below the 3rd centile for height at surgery, and 13 (31%) had pubertal delay of 2 yrs or more. 6 cases had a small bowel resection, 22 right hemicolectomy, and 14 sub-total colectomy (8 with ileostomy). The children were divided into 3 groups according to pubertal status at surgery - group A (prepubertal), group B (breast/genitalia stages 2+3), and group C (stages 4+5). Mean annual growth velocities (GV, cm/yr) for the 12 months before and after surgery were: Groups A+B showed a highly significant increment in GV after surgery, and pubertal acceleration was seen in 8 of the 13 with delay. GV correlated well with weight gain, and inversely with disease activity index and serum C-reactive protein. Poor growth in the first year post-operatively was a predictor of early disease relapse. GV varied little with site of disease or the type of operation performed. These findings suggest that surgery has an important role in the management of growth failure in CD, but should be performed before puberty becomes too advanced.