Anca M. Safta

Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: an immunomodulating antibiotic.

Background: Primary sclerosing cholangitis is a rare chronic cholestatic condition of unknown etiology, frequently associated with inflammatory bowel disease and characterized by diffuse fibrosing and inflammatory destruction of the intra- and/or extrahepatic biliary duct system. Patients and Methods: The study involved 14 children with primary sclerosing cholangitis confirmed by either liver biopsy, endoscopic retrograde cholangiopancreatography, and/or magnetic resonance cholangiogram. In each of the 14 cases, liver histology showed characteristic features consistent with primary sclerosing cholangitis. Eleven children had intrahepatic biliary beading and strictures (6 by endoscopic retrograde cholangiopancreatography; 5 by magnetic resonance cholangiogram). Biochemical tests of liver function including alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase and the erythrocyte sedimentation rate were elevated for a mean 17 ± 22 months before vancomycin treatment was initiated. All of the patients were shown to have inflammatory bowel disease histologically; 13 of those patients had clinical evidence of colitis. Oral vancomycin was given to all 14 patients. Results: All 14 patients showed improvement in their alanine aminotransferase (P = 0.007), γ-glutamyl transpeptidase (P = 0.005), erythrocyte sedimentation rate (P = 0.008), and clinical symptoms with oral vancomycin treatment. There was less improvement noted in the patients with cirrhosis when compared with the patients without cirrhosis. Conclusions: Before this study, there has not been an effective long-term treatment for sclerosing cholangitis to prevent the usual progression of this disease to cirrhosis. This study showed that oral vancomycin could be an effective long-term treatment of sclerosing cholangitis in children, especially those without cirrhosis.

Pediatric celiac disease

Purpose of review Celiac disease is an extremely common, although underdiagnosed, disorder. Knowledge about the varied clinical manifestations and the proper approach to screening and diagnosing celiac disease will lead to appropriate early intervention in affected children Recent findings New age-dependent algorithms are emerging to properly screen for celiac disease. There is new evidence on the patchy nature of celiac disease supporting the practice of multiple duodenal biopsies including the bulb of the duodenum. Therapeutic dietary compliance, particularly in asymptomatic children, can be poor, and therefore, the involvement of a dietician trained in celiac disease is instrumental in keeping patients up to date with dietary guidelines and to improve their compliance to the diet. Expanding knowledge about the pathogenesis of celiac disease has led to the development of investigational therapeutic alternatives to the gluten-free diet. Ongoing clinical trials are evaluating methods of celiac disease prevention in at-risk infants. Summary This review aims at outlining the different manifestations of celiac disease in children as well as a step-wise approach to screen and diagnose the disease. A better understanding of the pathogenic mechanisms of celiac disease is paving the way to innovative diagnostic tools, preventive strategies, and therapeutic interventions alternative to a gluten-free diet.

Mucosal-Associated Invariant T Cells in the Human Gastric Mucosa and Blood: Role in Helicobacter pylori Infection

Mucosal-associated invariant T (MAIT) cells represent a class of antimicrobial innate-like T cells that have been characterized in human blood, liver, lungs, and intestine. Here, we investigated, for the first time, the presence of MAIT cells in the stomach of children, adults, and the elderly undergoing routine endoscopy and assessed their reactivity to Helicobacter pylori (H. pylori – Hp), a major gastric pathogen. We observed that MAIT cells are present in the lamina propria compartment of the stomach and display a similar memory phenotype to blood MAIT cells. We then demonstrated that gastric and blood MAIT cells are able to recognize H. pylori. We found that CD8+ and CD4−CD8− (double negative) MAIT cell subsets respond to H. pylori-infected macrophages stimulation in a MR-1 restrictive manner by producing cytokines (IFN-γ, TNF-α, IL-17A) and exhibiting cytotoxic activity. Interestingly, we observed that blood MAIT cell frequency in Hp+ve individuals was significantly lower than in Hp−ve individuals. However, gastric MAIT cell frequency was not significantly different between Hp+ve and Hp−ve individuals, demonstrating a dichotomy between blood and gastric tissues. Further, we observed that the majority of gastric MAIT cells (>80%) expressed tissue-resident markers (CD69+ CD103+), which were only marginally present on PBMC MAIT cells (<3%), suggesting that gastric MAIT cells are readily available to respond quickly to pathogens. These results contribute important new information to the understanding of MAIT cells function on peripheral and mucosal tissues and its possible implications in the host response to H. pylori.

Characterization and Functional Properties of Gastric Tissue-Resident Memory T Cells from Children, Adults, and the Elderly

T cells are the main orchestrators of protective immunity in the stomach; however, limited information on the presence and function of the gastric T subsets is available mainly due to the difficulty in recovering high numbers of viable cells from human gastric biopsies. To overcome this shortcoming we optimized a cell isolation method that yielded high numbers of viable lamina propria mononuclear cells (LPMC) from gastric biopsies. Classic memory T subsets were identified in gastric LPMC and compared to peripheral blood mononuclear cells (PBMC) obtained from children, adults, and the elderly using an optimized 14 color flow cytometry panel. A dominant effector memory T (TEM) phenotype was observed in gastric LPMC CD4+ and CD8+ T cells in all age groups. We then evaluated whether these cells represented a population of gastric tissue-resident memory T (TRM) cells by assessing expression of CD103 and CD69. The vast majority of gastric LPMC CD8+ T cells either co-expressed CD103/CD69 (>70%) or expressed CD103 alone (~20%). Gastric LPMC CD4+ T cells also either co-expressed CD103/CD69 (>35%) or expressed at least one of these markers. Thus, gastric LPMC CD8+ and CD4+ T cells had the characteristics of TRM cells. Gastric CD8+ and CD4+ TRM cells produced multiple cytokines (IFN-γ, IL-2, TNF-α, IL-17A, MIP-1β) and up-regulated CD107a upon stimulation. However, marked differences were observed in their cytokine and multi-cytokine profiles when compared to their PBMC TEM counterparts. Furthermore, gastric CD8+ TRM and CD4+ TRM cells demonstrated differences in the frequency, susceptibility to activation, and cytokine/multi-cytokine production profiles among the age groups. Most notably, children’s gastric TRM cells responded differently to stimuli than gastric TRM cells from adults or the elderly. In conclusion, we demonstrate the presence of gastric TRM, which exhibit diverse functional characteristics in children, adults, and the elderly.

Remission of Refractory Celiac Disease With Infliximab in a Pediatric Patient

Refractory celiac disease (RCD) is a rare but life-threatening complication of celiac disease (CD), and only 1 pediatric case has been reported. We report a case of a 14-year-old girl with CD presenting with persistent symptoms and positive tissue celiac-specific antibodies despite a gluten-free diet. Push enteroscopy showed jejunal scalloping and partial villous atrophy on histology. She was diagnosed with RCD and treated with infliximab with subsequent complete serological and histological remission.