Paediatric gastroenterology 1966-2000.

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.

Correspondence of George Newman (1870-1948) during his years as school boy, medical student and recent graduate (1880-1907).

The correspondence is reported of Sir George Newman, the first Chief Medical Officer of the United Kingdom, during his school and university education. Extracts are included of this hitherto unpublished correspondence with his family members. His conception of idealistic service to the community, first enunciated in his school days, was expanded by practical action as a medical student among the urban poor of the Cowgate, Edinburgh. The correspondence reveals his unmarried maternal aunt as the person who influenced him most.

An eye witness perspective of the changing patterns of food allergy.

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.

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 [chi2 test, P = 0.021]). Endoscopic and histologic colonic mucosal assessment showed a post-treatment improvement in the ileocolonic (P < or = 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.

Improved nutritional recovery on an elemental diet in Zambian children with persistent diarrhoea and malnutrition.

The persistent diarrhoea-malnutrition syndrome (PDM) remains a leading cause of morbidity and mortality in hospitals in resource-poor countries. In view of the benefits of elemental or oligomeric feeds in inflammatory bowel diseases, we performed a randomized controlled trial of an exclusive diet of amino acid-based elemental feed (AAF) compared with standard nutritional rehabilitation (based on skimmed milk and then soya) for PDM. Treatment was given for 4 weeks in the malnutrition ward of the University Teaching Hospital, Lusaka, in a single-blind study. Intestinal and systemic infections were treated with routine therapies. The main outcome measures were weight gain, recovery from diarrhoea, and mortality. Two hundred children (106 HIV seropositive, 90 HIV seronegative) were randomized; 155 children completed therapy, 39 died, and six were lost to follow-up. At randomization, they were severely malnourished: median baseline weight-for-age z-score was -4.0 (interquartile range, IQR -4.4, -3.5); 9 per cent were underweight, 23 per cent had marasmus, 47 per cent had kwashiorkor, and 21 per cent had marasmic-kwashiorkor. Weight gain was greater in the AAF group (median gain in weight-for-age z-score was 1.23, IQR 0.89-1.57) compared with the control group (0.87, IQR 0.47-1.25; p=0.002), although calorie intakes were higher in the control group. The increase in haemoglobin concentration was also greater in the AAF group (0.8 g/dl, IQR 0-1.8) than in the control group (0.3, IQR -0.6, -1.6; p=0.04). Diarrhoea frequency and global recovery scores improved equally in both treatment groups and mortality did not differ. A diet of reduced molecular complexity was associated with significantly improved weight gain.

A consistent pattern of minor immunodeficiency and subtle enteropathy in children with multiple food allergy.

OBJECTIVE: Although immunoglobulin (Ig)E-mediated allergies are readily identifiable, non-IgE-mediated allergies present more diagnostic difficulty. We performed a formal retrospective analysis to determine whether there is a recognizable clinical pattern in children. METHODS: We studied 121 children (mean age, 17.3 months) with multiple food allergies who were recruited on the basis of adequate immunological assessment by using case notes and parental questionnaire. RESULTS: Group 1 (n=44) had rapid reactions to dietary antigens, of whom 41 also showed delayed reactions. Group 2 (n=77) had delayed reactions only. Mean IgE was increased in group 1 but both groups otherwise shared a pattern of increased IgG1, decreased IgG2/4, and low-normal IgA. Lymphocyte subsets were skewed, with an increased percentage of CD4 and CD19 and decreased CD8 and natural killer cells. Gastroesophageal reflux, esophagitis, subtle enteropathy, and constipation were frequent in both groups. Of 55 exclusively breast-fed infants, 44 sensitized before weaning. Twenty-one of the mothers suffered from autoimmunity. CONCLUSIONS: There appears to be a recognizable pattern of immune deviation and minor enteropathy in children with multiple food allergy, irrespective of the speed of reactions. Disturbed gut motility is particularly common, as is a maternal history of autoimmunity.

Cow's milk allergy: a new understanding from immunology.

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 Th1 response in these children. This is related to associated IgA deficiency and low levels of cytokine transforming growth factor beta. 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.

Hypoallergenic formulas: are they really hypoallergenic?

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.

Reduced transforming growth factor-beta1-producing T cells in the duodenal mucosa of children with food allergy.

Infant food allergies are increasing, and many breast-fed infants now sensitize to maternally-ingested antigens. As low-dose oral tolerance requires generation of suppressor lymphocytes producing TGF-beta1 (Th3 cells), we studied these cells in duodenal biopsies after diagnostic endoscopy. Spontaneous production of Th1, Th2 and Th3 cytokines by duodenal lymphocytes was studied using flow cytometry in 20 children with no eventual clinico-pathological diagnosis (controls), 30 children with multiple food allergy, nine with celiac disease and six with inflammatory enteropathies. Immunohistochemistry and in situ hybridization were used to localize TGF-beta1 protein and mRNA in matched biopsies. We found no significant Th1/Th2 skewing amongst mucosal lymphocytes in allergic children compared to controls, although celiac and inflammatory enteropathy patients showed increased Th1 responses. By contrast, the allergic children showed reduction of TGF-beta1(+) lymphocytes in both epithelial and lamina propria compartments. Reduction of TGF-beta1 expression was also seen in mononuclear cells and epithelium in food allergy by immunohistochemistry and in situ hybridization. The dominant mucosal abnormality in food allergic children was, thus, not Th2 deviation but impaired generation of Th3 cells. As generation of these cells requires innate immune response to enteric bacteria, we suggest that changing infectious exposures may inhibit primary establishment of basic oral tolerance mechanisms.

Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology.

Inflammatory intestinal pathology has been reported in children with regressive autism (affected children). Detailed analysis of intestinal biopsies in these children indicates a novel lymphocytic enterocolitis with autoimmune features; however, links with cognitive function remain unclear. To characterize further, the nature and extent of this disease we examined the mucosal infiltrate using flow cytometry. Duodenal, ileal, and colonic biopsies were obtained from 52 affected children, 25 histologically normal, and 54 histologically inflamed, developmentally normal controls. Epithelial and lamina propria lymphocyte populations were isolated and examined by multicolor flow cytometry. Adjacent biopsies were assessed by semiquantitative histopathology. At all sites, CD3(+) and CD3(+)CD8(+) IEL as well as CD3(+) LPL were significantly increased in affected children compared with developmentally normal noninflamed control groups (p<0.01) reaching levels similar to inflamed controls. In addition, two populations--CD3(+)CD4(+) IEL and LP CD19(+) B cells--were significantly increased in affected children compared with both noninflamed and inflamed control groups including IBD, at all sites examined (p<0.01). Histologically there was a prominent mucosal eosinophil infiltrate in affected children that was significantly lower in those on a gluten- and casein-free diet, although lymphocyte populations were not influenced by diet. The data provide further evidence of a pan-enteric mucosal immunopathology in children with regressive autism that is apparently distinct from other inflammatory bowel diseases.