Showing papers by "Simon Murch published in 2014"

Management guidelines of eosinophilic esophagitis in childhood.

Abstract: Objectives:Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. With few exceptions, 15 eosinophils per high-power fiel

Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial

Abstract: Environmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy. In this pilot double-blind randomized placebo-controlled trial, 44 children with severe acute malnutrition and evidence of EED were assigned to treatment with mesalazine or placebo for 28 days during nutritional rehabilitation. Primary outcomes were safety and acceptability of the intervention. Treatment with mesalazine was safe: there was no excess of adverse events, evidence of deterioration in intestinal barrier integrity or impact on nutritional recovery. There were modest reductions in several inflammatory markers with mesalazine compared to placebo. Depression of the growth hormone - insulin-like growth factor-1 axis was evident at enrollment and associated with inflammatory activation. Increases in the former and decreases in the latter correlated with linear growth. Intestinal inflammation in EED is non-essential for mucosal homeostasis and is at least partly maladaptive. Further trials of gut-specific immunomodulatory therapies targeting host inflammatory activation in order to optimize the growth benefits of nutritional rehabilitation and to address stunting are warranted. Funded by The Wellcome Trust. Registered at Clinicaltrials.gov NCT01841099 .

Intraepithelial lymphocyte eotaxin-2 expression and perineural mast cell degranulation differentiate allergic/eosinophilic colitis from classic IBD.

Abstract: Objectives: Allergic colitis shows overlap with classic inflammatory bowel disease (IBD). Clinically, allergic colitis is associated with dysmotility and abdominal pain, and mucosal eosinophilia is characteristic. We thus aimed to characterise mucosal changes in children with allergic colitis compared with normal tissue and classic IBD, focusing on potential interaction between eosinophils and mast cells with enteric neurones. Methods: A total of 15 children with allergic colitis, 10 with Crohn disease (CD), 10 with ulcerative colitis (UC), and 10 histologically normal controls were studied. Mucosal biopsies were stained for CD3 T cells, Ki-67, eotaxin-1, and eotaxin-2. Eotaxin-2, IgE, and tryptase were localised compared with mucosal nerves, using neuronal markers neurofilament protein, neuron-specific enolase, and nerve growth factor receptor. Results: Overall inflammation was greater in patients with CD and UC than in patients with allergic colitis. CD3 T-cell density was increased in patients with allergic colitis, similar to that in patients with CD but lower than in patients with UC, whereas eosinophil density was higher than in all other groups. Eotaxin-1 and -2 were localised to basolateral crypt epithelium in all specimens, with eotaxin-1+ lamina propria cells found in all of the colitis groups. Eotaxin-2+ intraepithelial lymphocyte (IEL) density was significantly higher in allergic colitis specimens than in all other groups. Mast cell degranulation was strikingly increased in patients with allergic colitis (12/15) compared with that in patients with UC (1/10) and CD (0/1). Tryptase and IgE colocalised on enteric neurons in patients with allergic colitis but rarely in patients with IBD. Conclusions: Eotaxin-2+ IELs may contribute to the periepithelial eosinophil accumulation characteristic of allergic colitis. The colocalisation of IgE and tryptase with mucosal enteric nerves is likely to promote the dysmotility and visceral hyperalgesia classically seen in allergic gastrointestinal inflammation.

Matrix expansion and syncytial aggregation of syndecan-1+ cells underpin villous atrophy in coeliac disease.

Abstract: Background: We studied the expression of sulphated glycosaminoglycans (GAGs) in coeliac disease (CD) mucosa, as they are critical determinants of tissue volume, which increases in active disease. We also examined mucosal expression of IL-6, which stimulates excess GAG synthesis in disorders such as Grave's ophthalmopathy. Methods: We stained archival jejunal biopsies from 5 children with CD at diagnosis, on gluten-free diet and challenge for sulphated GAGs. We then examined duodenal biopsies from 9 children with CD compared to 9 histological normal controls, staining for sulphated GAGs, heparan sulphate proteoglycans (HSPG), short-chain HSPG (Δ-HSPG) and the proteoglycan syndecan-1 (CD138), which is expressed on epithelium and plasma cells. We confirmed findings with a second monoclonal in another 12 coeliac children. We determined mucosal IL-6 expression by immunohistochemistry and PCR in 9 further cases and controls, and used quantitative real time PCR for other Th17 pathway cytokines in an additional 10 cases and controls. Results: In CD, HSPG expression was lost in the epithelial compartment but contrastingly maintained within an expanded lamina propria. Within the upper lamina propria, clusters of syndecan-1+ plasma cells formed extensive syncytial sheets, comprising adherent plasma cells, lysed cells with punctate cytoplasmic staining and shed syndecan ectodomains. A dense infiltrate of IL-6+ mononuclear cells was detected in active coeliac disease, also localised to the upper lamina propria, with significantly increased mRNA expression of IL-6 and IL-17A but not IL-23 p19. Conclusions: Matrix expansion, through syndecan-1+ cell recruitment and lamina propria GAG increase, underpins villous atrophy in coeliac disease. The syndecan-1+ cell syncytia and excess GAG production recapitulate elements of the invertebrate encapsulation reaction, itself dependent on insect transglutaminase and glutaminated early response proteins. As in other matrix expansion disorders, IL-6 is upregulated and represents a logical target for immunotherapy in patients with coeliac disease refractory to gluten-free diet.

Diagnosis of coeliac disease in children in primary care and clinical implications.

Abstract: Since the introduction of the Crosby capsule (a device used for obtaining biopsies of small bowel mucosa, necessary for the diagnosis of various small bowel diseases) in the 1970s, small intestinal biopsy has been the cornerstone of diagnosis of coeliac disease. In paediatric practice, successive position statements from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) have defined criteria for childhood diagnosis: initially based on three successive biopsies at presentation, on a gluten-free diet, and then challenge. Since 1990, the diagnosis has been dependent on a single biopsy with a clear clinical response to a gluten-free diet, supported by positive serology.1 This approach is similar to that recommended for adults2 and has been adopted by the National Institute for Health and Care Excellence (NICE).3 Great strides have been made in serological assessment and understanding coeliac disease pathogenesis since the 1990 guidelines were introduced. First, the non-specific gliadin antibodies used at that time were supplanted by the highly specific IgA endomyseal antibody (EMA) test. Subsequently tissue transglutaminase-2 (tTG) was identified as the true autoantigen causing EMA reactivity. EMA testing depends on immunofluorescence, giving a yes–no answer dependent on operator expertise. Importantly, assay of tTG autoantibody is performed by enzyme-linked immunosorbent assay (ELISA), allowing a quantitative assessment of immune response. The second major diagnostic advance was the determination of the relevant human leukocyte antigen (HLA) types that allow presentation of gliadin/tTG complexes to T cells, thus causing the autoimmune response to tTG. Persons of tissue types HLA-DQ2 and HLA-DQ8 (more than a quarter of the UK population) make up 99% of cases of coeliac disease, and true coeliac disease is very unusual in someone …