Multispectral optoacoustic tomography enables assessment of disease activity in paediatric inflammatory bowel disease.

Multispectral optoacoustic tomography (MSOT) allows non-invasive molecular disease activity assessment in adults with inflammatory bowel disease (IBD). In this prospective pilot-study, we investigated, whether increased levels of MSOT haemoglobin parameters corresponded to inflammatory activity in paediatric IBD patients, too. 23 children with suspected IBD underwent MSOT of the terminal ileum and sigmoid colon with standard validation (e.g. endoscopy). In Crohn`s disease (CD) and ulcerative colitis (UC) patients with endoscopically confirmed disease activity, MSOT total haemoglobin (HbT) signals were increased in the terminal ileum of CD (72.1 ± 13.0 a.u. vs. 32.9 ± 15.4 a.u., p = 0.0049) and in the sigmoid colon of UC patients (62.9 ± 13.8 a.u. vs. 35.1 ± 16.3 a.u., p = 0.0311) as compared to controls, respectively. Furthermore, MSOT haemoglobin parameters correlated well with standard disease activity assessment (e.g. SES-CD and MSOT HbT (rs =0.69, p = 0.0075). Summarizing, MSOT is a novel technology for non-invasive molecular disease activity assessment in paediatric patients with inflammatory bowel disease.

Further delineation of SLC9A3-related congenital sodium diarrhea.

BACKGROUND: Congenital sodium diarrhea (CSD) is a rare enteropathy displaying both broad variability in clinical severity and genetic locus and allelic heterogeneity. Eleven CSD patients were reported so far with SLC9A3 variants that impair the function of the encoded intestinal sodium-proton exchanger 3 (NHE3). METHODS: We report a 4-year-old patient, born prematurely in the 35th week of gestation, with antenatal polyhydramnios and dilated intestinal loops, and with diarrhea of congenital onset, 2-6 times a day, and with polydipsia. She thrived age-appropriately under a normal family diet. Serum sodium levels were repeatedly normal but urinary sodium excretion was low. Exome sequencing revealed compound heterozygous variants in SLC9A3 as the likely cause of the congenital diarrhea. RESULTS: While exome sequencing did not reveal pathogenic or likely pathogenic variants in other genes that cause syndromic or non-syndromic forms of congenital and intractable diarrheas, we identified novel compound heterozygous variants in SLC9A3, a complex allele with two missense changes, NP_004165.2:p.[Ser331Leu;Val449Ile] and in-trans the missense variant p.(Phe451Ser). CONCLUSION: The clinical phenotype here appears to localize to the milder end of the known CSD spectrum, and the identified variants suggest that this is the twelfth patient reported to date with CSD due to mutations in SLC9A3.

Mucosal Mast Cell Distribution in the Gastrointestinal Tract of Children: A Preliminary Study for Establishing Reference Values.

OBJECTIVES: The physiological number and distribution of mast cells (MCs) in the pediatric gastrointestinal (GI) tract is not well defined and reference values of normality are missing. To define a physiological and disease defining cut-off, a systematic histological exploration of MC distribution from the esophagus to the rectum in healthy as well as in patients with gastrointestinal food allergies (GFA) was performed. METHODS: Nine pediatric subjects that exhibited unremarkable histopathological evaluations or underwent endoscopy for surveillance reasons after a previous polypectomy of single colonic juvenile polyps served as reference cohort. In all of these subjects, a chronic inflammatory disease (eg, inflammatory bowel disease, celiac disease) or allergy was excluded. In addition, a group of 15 patients with gastrointestinal complaints suspected to be caused by a GFA were investigated. Immunohistochemistry was performed from all biopsies using CD117 (c-Kit) as a reliable marker to identify MCs in the lamina propria. RESULTS: There were distinct differences of MC counts in all parts of the pediatric GI tract. The highest counts of MCs in both symptomatic patients and control cohort, were found in the duodenum, terminal ileum, cecum and ascending colon. The lowest counts were found in the esophagus. Significant disparities between GFA and healthy subjects were found in the gastric corpus (22.1 ±â€Š4.0/ high power field [HPF] vs 32.0 ±â€Š10.1/HPF; P = 0.034) and ascending colon (44.8 ±â€Š10.4/HPF vs 60.4 ±â€Š24.3/HPF; P = 0.047). CONCLUSIONS: Mucosal MC counts in the pediatric GI tract are higher than previously reported, with a considerable overlap between healthy and GFA patients. These results provide detailed information on distribution and numbers of MCs in pediatric allergic patients while allowing estimates of physiological values in childhood for the first time. With regard to diagnostic procedures in GFA further laboratory parameters have to be integrated.

Distribution and Cytokine Profile of Peripheral B Cell Subsets Is Perturbed in Pediatric IBD and Partially Restored During a Successful IFX Therapy.

BACKGROUND: The role of B cells in inflammatory bowel disease (IBD) is ambiguous, as B cells may have both pathogenic and protective functions in IBD. We studied B cell subsets before and after initiation of an anti-tumor necrosis factor alpha (anti-TNFα) therapy in pediatric IBD. The aim of the study was to examine the behavior of B cells in pediatric IBD patients undergoing an anti-TNFα therapy and, more specifically, to clarify their association with a successful or an unsuccessful infliximab (IFX) treatment. METHODS: A total of N = 42 pediatric IBD patients (Crohn disease, n = 30; ulcerative colitis, n = 12) for whom an anti-TNFα therapy with and without a concomitant azathioprine (AZA) medication was administered were recruited. Fourteen healthy age-matched children served as control patients. Blood samples were collected before initiation of the anti-TNFα therapy, before the fourth infusion at the end of the induction phase, and after 6 and 12 months under therapy maintenance. Flow cytometry (CD20, CD27, CD38, CD138) and intracellular staining (interleukin 10 [IL10], TNFα, granzyme B) were performed. Responders to successful IFX therapy were classified exhibiting a fecal calprotectin level of below 100 µg/g or achieving levels of <10% of the baseline value at initiation than at the end of the 12-month follow-up period. RESULTS: Before initiation of anti-TNFα therapy, flow cytometry revealed increased percentages of naïve B cells whereas transitional B cells were reduced compared with those in the healthy control patients. The IL10-producing B cells of both ulcerative colitis and Crohn disease patients were reduced at the initiation of IFX therapy, whereas TNFα-producing transitional CD24hiCD38hi B cells in ulcerative colitis patients were increased compared with those in healthy control patients. After 12 months of therapy, we detected a significant increase of IL10-producing transitional B cells in responding patients.The IFX trough levels in the responding patients showed a significant increase until 6 months after IFX initiation, attaining mean values of 9.9 µg/mL, whereas the IFX dosage was significantly lower than that in the nonresponding patients. The IFX trough levels in AZA-treated patients reached earlier therapeutic levels than in patients without AZA comedication, whereas during the course of the IFX therapy, comedication with AZA had no significant effect on the outcome. CONCLUSIONS: Attaining a normalization of IL10 production among CD24hiCD38hi B cells after 12 months of therapy may represent additional information about the reconstitution of a patient's immune system in responding patients. The achievement of an IFX trough level of ~10 µg/mL at 6 months of treatment is associated with a successful anti-TNFα therapy. In addition, AZA comedication supports an earlier achievement of therapeutic IFX trough levels.

Case report: Tension pneumoperitoneum after diagnostic colonoscopy in an 11 y/o boy with Crohns disease.

INTRODUCTION: Endoscopy is an established diagnostic and therapeutic tool in paediatric gastroenterology and a save method with rare complications. PRESENTATION OF CASE: We present the case of an 11-year-old Caucasian boy with a long history of inflammatory bowel disease. Three years prior an ileostomy was created and is still in position. After diagnostic panendoscopy (colonoscopy, gastroscopy, endoscopy of small intestine via ileostomy) the patient showed progressive abdominal distension and pain. After diagnosis of tension pneumoperitoneum by radiological proof of massive intraabdominal air and altered vital signs, we initiated emergency laparotomy. Surgical intervention ruled out a free gastrointestinal perforation as well as peritonitis. There was a gaseous insufflation of the mesenteric tissue of the sigmoid and upper rectum most likely according to microperforations to the mesentery. Due to the pre-existing ileostomy, we took no further surgical action. The abdomen was lavaged and drains inserted. Upon further conservative treatment with intravenous antibiotics, the patient showed quick recovery and was discharged on postoperative day 6. DISCUSSION: With an incidence of 0.01%, perforation after diagnostic colonoscopy in children is very uncommon. The zone most frequently affected is the sigmoid colon due to direct penetration or indirect force due to flexure, or insufflation. Even without macroscopic perforation, the development of a tension pneumoperitoneum seems to be possible. CONCLUSION: Even though Colonoscopy in children is a safe tool, the treating physician must never underestimate the risks of such an intervention. Especially chronically altered intestine as in long-time persisting chronic inflammatory bowel disease demand special care and intensive observation of the patient after intervention.

Idiopathic Mast Cell Activation Syndrome With Associated Salicylate Intolerance.

Idiopathic mast cell activation syndrome can be a rare cause for chronic abdominal pain in children. It remains a diagnosis by exclusion that can be particularly challenging due to the vast variety of possible clinical manifestations. We present a 13-year-old boy who suffered from a multitude of unspecific complaints over a long period of time. In this case, an assessment of mast cell-derived metabolites and immunohistochemical analysis of bioptic specimen was worthwhile. After ruling out, primary (oncologic) and secondary causes for mast cell activation, pharmacologic treatment adapted to the patient's salicylate intolerance resulted in a major relief of symptoms.

Anakinra (IL-1R antagonist) lowers pulmonary artery pressure in a neonatal surfactant depleted piglet model.

In acute respiratory distress syndrome (ARDS) with pulmonary hypertension, interleukin-1 beta (IL-1 beta) and interleukin-8 (IL-8) are involved in the pulmonary inflammatory reaction. The purpose of this study was to determine whether systemic and aerosolized administered IL-1 receptor antagonist (IL-1Ra) Anakinra (Kineret) improves lung mechanics and pulmonary artery pressure in surfactant depleted newborn piglets. After induction of acute lung injury by lung lavage, neonatal piglets received repetitive treatment of either aerosolized IL-1Ra (IL-1Ra-Aerosol) or intravenous IL-1Ra (IL-1Ra-i.v.), or saline solution as control. IL-1Ra given as aerosol or intravenously significantly reduced mean pulmonary artery pressure (MPAP) but did not influence mean systemic arterial pressure (MAP) compared with the control group. IL-1 beta and IL-8 mRNA expressions normalized to beta-actin and hypoxanthine-guanine-phosphoribosyl transferase were significantly reduced in the IL-1Ra-Aerosol group but not in IL-1Ra-i.v. group compared to the control group. The lung injury score was not significantly different between IL-1Ra groups and the control group. Application of aerosolized IL-1Ra reduced MPAP without affecting MAP in a piglet model of surfactant depletion with pulmonary hypertension. Furthermore, there is evidence for reduction of early pro-inflammatory pulmonary reaction.