A common IL-4 receptor variant promotes asthma severity via a Treg cell GRB2-IL-6-Notch4 circuit.

BACKGROUND: The mechanisms by which genetic and environmental factors interact to promote asthma remain unclear. Both the IL-4 receptor alpha chain R576 (IL-4RαR576) variant and Notch4 license asthmatic lung inflammation by allergens and ambient pollutant particles by subverting lung regulatory T (Treg ) cells in an IL-6-dependent manner. OBJECTIVE: We examined the interaction between IL-4RαR576 and Notch4 in promoting asthmatic inflammation. METHODS: Peripheral blood mononuclear cells (PBMCs) of asthmatics were analyzed for T helper type 2 cytokine production and Notch4 expression on Treg cells as a function of IL4RR576 allele. The capacity of IL-4RαR576 to upregulate Notch4 expression on Treg cells to promote severe allergic airway inflammation was further analyzed in genetic mouse models. RESULTS: Asthmatics carrying the IL4RR576 allele had increased Notch4 expression on their circulating Treg cells as a function of disease severity and serum IL-6. Mice harboring the Il4raR576 allele exhibited increased Notch4-dependent allergic airway inflammation that was inhibited upon Treg cell-specific Notch4 deletion or treatment with an anti-Notch4 antibody. Signaling via IL-4RαR576 upregulated the expression in lung Treg cells of Notch4 and its downstream mediators Yap1 and beta-catenin, leading to exacerbated lung inflammation. This upregulation was dependent on growth factor receptor-bound protein 2 (GRB2) and IL-6 receptor. CONCLUSION: These results identify an IL-4RαR576-regulated GRB2-IL-6-Notch4 circuit that promotes asthma severity by subverting lung Treg cell function.

Phenotypic Pattern of Early Versus Later-Onset Pediatric Inflammatory Bowel Disease in a Eurasian Country.

OBJECTIVES: It is not clear whether the characteristics of pediatric inflammatory bowel disease (IBD) differ between Eastern and Western countries. The aim of this study was to analyze the characteristics of PIBD in Turkey, according to the age at diagnosis. METHODS: The data of 176 children with IBD who were followed in our center were analyzed. Patients were divided into early (EO-IBD, onset at 2 to <10 years) and later-onset (LO-IBD, 10 to ≤17 years) IBD according to the age at diagnosis. Patients' data with ulcerative colitis (UC) and Crohn's disease (CD) were compared. RESULTS: Of 176 patients, 47 (26.7%) were diagnosed with EO-IBD. Patients with early-onset ulcerative colitis (EO-UC) had the highest rate of family history of IBD (17.6%). Pancolitis was the most common form of UC regardless of the age at onset. The rate of moderate-severe disease activity in later-onset UC (62.5%) was higher than in EO-UC (37.5%). A higher rate of extraintestinal manifestations was observed in EO-IBD patients, particularly in EO-UC (38.2%) than in LO-IBD patients. Patients with early-onset CD (EO-CD) had predominantly colonic involvement and nonstricturing, nonpenetrating disease behavior. The rate of perianal disease in patients with later-onset CD (LO-CD) (64.5%) was noticeably higher than those with EO-CD (23%). CONCLUSIONS: Our results suggest that patients with EO-UC represented a distinct phenotype with a mild disease activity, high rate of extraintestinal symptoms, and a high proportion of family history. The analysis of our IBD cohort also demonstrated remarkably high rate of perianal disease, particularly in patients with LO-CD.

Evaluation of mucosal status in the follow-up of pediatric patients with celiac disease: the role of serology.

Recent guidelines suggest non-biopsy serology-based approach for the diagnosis of celiac disease; however, there is no evidence-based data regarding noninvasive follow-up of mucosal healing. The aim of this study is to investigate the efficacy of serology in reflecting mucosal status in the follow-up of pediatric patients with celiac disease. This is a validation study conducted at a university hospital. Patients who had biopsy proven celiac disease (Marsh III) at diagnosis, and had been followed-up for at least 12 months, were prospectively evaluated with duodenal biopsies. tTG-IgA and EMA tests were performed on the day of endoscopy. One hundred four patients with a mean age of 7.4 ± 4.02 years were included in the study. The sensitivity and specificity of tTG-IgA were 85.2% and 61% respectively, with a high negative predictive value (NPV) of 92.2% but a very low positive predictive value (PPV) of 43.4%. We found that a cutoff value of 68.5 U/mL for tTG-IgA had a sensitivity, specificity of 85.2% and 85.7% respectively. The AUC was 0.891. The sensitivity and specificity of EMA was 77.8% and 87% respectively, with a high NPV of 91.8% but low PPV of 67.7%. CONCLUSION: This study suggests that negative tTG-IgA and/or EMA can be used as an indicator of mucosal improvement in the follow-up of pediatric patients with celiac disease. However, positive serology (i.e., < 10 × ULN) may be misleading in reflecting mucosal status in the follow-up of pediatric patients with celiac disease. WHAT IS KNOWN: • The tissue transglutaminase IgA (tTG-IgA) and endomysium IgA (EMA) tests are widely used, sensitive and reliable diagnostic tests, but their role in monitoring adherence to dietary treatment in celiac patients has not yet been demonstrated. • There is still no reliable and non-invasive marker of persistent villous atrophy or mucosal recovery. WHAT IS NEW: • Negative celiac serology detected in the follow-up of pediatric patients with celiac disease was successful in demonstrating histopathological mucosal healing. • Positive celiac serology, which is highly reliable in the diagnosis of celiac disease, has not been successful in reflecting mucosal status when used in the follow-up of pediatric patients with celiac disease.

Recommendations for Clinical Decision-making in Children with Type 1 Diabetes and Celiac Disease: Type 1 Diabetes and Celiac Disease Joint Working Group Report

It is well-known that in children with type 1 diabetes (T1D), the frequency of Celiac disease (CD) is increased due to mechanisms which are not fully elucidated but include autoimmune injury as well as shared genetic predisposition. Although histopathologic examination is the gold standard for diagnosis, avoiding unnecessary endoscopy is crucial. Therefore, for both clinicians and patients' families, the diagnosis of CD remains challenging. In light of this, a joint working group, the Type 1 Diabetes and Celiac Disease Joint Working Group, was convened, with the aim of reporting institutional data and reviewing current international guidelines, in order to provide a framework for clinicians. Several controversial issues were discussed: For CD screening in children with T1D, regardless of age, it is recommended to measure tissue transglutaminase-immunoglobulin A (tTG-IgA) and/or endomysial-IgA antibody due to their high sensitivity and specificity. However, the decision-making process based on tTG-IgA titer in children with T1D is still debated, since tTG-IgA titers may fluctuate in children with T1D. Moreover, seronegativity may occur spontaneously. The authors' own data showed that most of the cases who have biopsy-proven CD had tTG-IgA levels 7-10 times above the upper limit. The decision for endoscopy based solely on tTG-IgA levels should be avoided, except in cases where tTG-IgA levels are seven times and above the upper limit. A closer collaboration should be built between divisions of pediatric endocrinology and gastroenterology in terms of screening, diagnosis and follow-up of children with T1D and suspicious CD.

Outcomes of Pediatric Fistulising Perianal Crohn's Disease.

BACKGROUND: Perianal disease is reported more widely in pediatric Crohn patients than in the past, and has been stated as an independent modifier of the disease behavior. In this study, we aimed to analyze the clinical characteristics and outcomes of fistulising perianal Crohn's disease (fpCD) in the pediatric age group. METHODS: A total number of 149 children with an established diagnosis of inflammatory bowel disease who have been diagnosed before 18 years of age and followed in our tertiary center were revised. Clinical, endoscopic, laboratory, and radiologic data of 50 patients with CD, who had at least 18 months follow-up data, were compiled. RESULTS: Of 50 patients, 26 (52%) were diagnosed as fpCD (38% at onset). More than half of the patients without any notable external orifices around the perianal area were diagnosed as fpCD by an magnetic resonance imaging (MRI). Pediatric fpCD patients had a higher disease activity score and platelet count, lower serum albumin level, and a higher rate of granuloma in the biopsy samples, compared with non-fistulising patients. A considerably high rate of surgical interventions (i.e., seton placement 46% and abscess drainage 15%) was performed in combination with infliximab. CONCLUSION: Fistulising perianal Crohn's disease seems to be more common than previously reported in the pediatric age group. A severe course of the disease might serve as a warning for the development of fpCD. A careful physical examination and use of perianal MRI with a high index of suspicion may increase the likelihood of fistula detection, hence may change the treatment strategy.

Homozygous IL37 mutation associated with infantile inflammatory bowel disease.

Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function IL37 mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell-derived macrophages from the patient revealed an activated macrophage phenotype, which is more prone to lipopolysaccharide and IL-1ß stimulation, resulting in hyperinflammatory tumor necrosis factor production. Insights from this patient will not only shed light on monogenic contributions of I-IBD but may also reveal the significance of the IL-18 and IL-37 axis in colonic homeostasis.

Gastrointestinal sarcoidosis presenting with malabsorption at an early age.

Sarcoidosis is a chronic multisystemic granulomatous disease that predominantly involves the thoracic lymph nodes and lungs and primarily occurs in young adults. Isolated extrapulmonary localization is uncommon in adults, and exceptionally rare in the pediatric age group. A 4-year-old male patient with chronic diarrhea and abdominal distention for the last 8 months is presented. Endoscopic biopsies, obtained during gastroscopy and colonoscopy, revealed noncaseating granulomas in all segments of the gastrointestinal tract. A noncaseating granuloma was also demonstrated in the liver biopsy. Granulomatous inflammation of both the gastrointestinal system and liver along with elevated serum angiotensin-converting enzyme were consistent with sarcoidosis. The peculiarity of our pediatric sarcoidosis was the involvement of whole gastrointestinal system, which is exceptionally rare in all age groups. Furthermore, this is the youngest case in the literature with gastrointestinal and hepatic sarcoidosis in the absence of pulmonary involvement at onset.

Bowel Preparation for Colonoscopy in Children: 1 Day PEG-3350 with Bisacodyl versus 3 Day Sennosides.

BACKGROUND AND OBJECTIVES: Bowel preparation (BP) for colonoscopy is a challenging procedure in children and different regimens have been used for this purpose. Polyethylene glycol (PEG) is the most preferred agent in recent years. The primary aim of this study was to evaluate the efficacy of 1-day PEG-3350 with bisacodyl (PEG-B) and comparing it with 3-day sennosides A+B. METHOD: In this prospective, randomized, and single-blinded study, children aged 2-18 years were included in the PEG-B group for 1 day or in Senna group for 3 days. The effectiveness of BP was assessed according to the Ottawa and Boston BP scales, compliance and adverse effects were also recorded. Pre- and post-preparation biochemistry were obtained for investigation of safety of both regimens. RESULTS: Successful BP was observed in 88.3% (n = 53/60) of PEG-B and 86% (n = 55/64) of Senna groups according to Boston scale, and it was 85% (n = 51/60) and 84.4% (n = 54/64), respectively, according to Ottawa scale. The cecal intubation rate was 96.7% (n = 58/60) in the PEG-B group and 93.8% (n = 60/64) in the Senna group. Ease of administration and disturbance in regular daily activities was better in the PEG-B group (p < 0.05). There was no major adverse event and biochemical abnormality in both groups. The correlation between Ottawa and Boston scales was found to be excellent (r2 = -0.954, p < 0.01). CONCLUSIONS: The efficacy, safety, and adverse effect profile of 1-day BP with PEG-B regimen was found to be similar to 3-day sennosides regimen, however, the PEG-B regimen had advantages such as short duration, ease of administration, and better patient comfort. Also, high correlation rate between the Boston and Ottawa scales in pediatric patients was remarkable.

Sequential therapy versus standard triple therapy for Helicobacter pylori eradication in children: any advantage in clarithromycin-resistant strains?

OBJECTIVE: There has been a marked decrease in the eradication rates of Helicobacter pylori infection with standard triple therapy worldwide. Hence, sequential therapy has gained attention as a promising treatment during the last few years. This study was carried out to compare the efficacy of sequential versus standard triple therapy in the context of clarithromycin (CLA) resistance. MATERIALS AND METHODS: In this study, children between 3 and 18 years of age, who had documented H. pylori infection, were randomized to receive either standard triple or sequential therapy. H. pylori eradication was ascertained using the C-urea breath test 4-6 weeks after the completion of the treatment. Real-time PCR was performed on gastric biopsy samples for assessment of CLA resistance. RESULTS: In all, 148 children (median age: 12.18±3.51 years) were recruited randomly into the study. The intention-to-treat eradication rates were 50% (37/74) for the sequential treatment group and 52.7% (39/74) for the standard triple treatment group (P=0.87). A total of 136 children completed the study. The per-protocol eradication rates were 56% (37/66) and 55.7% (39/70) for sequential and standard triple therapy groups, respectively. CLA resistance was assessed and 113 children were included in the final analysis. Of 113 participants, 53 were in the sequential treatment group and 60 were in the standard triple treatment group. The success rates of the respective therapies (29/53=54.7% in sequential, 33/60=55% in standard therapy) were similar (P=0.98). CLA resistance was detected in 29 (25.7%) of the patients. Eradication rates with sequential therapy in CLA susceptible and resistant cases were 60.5% (23/38) and 40% (6/15), respectively (P=0.23). The corresponding figures for the standard triple treatment group were 63% (29/46) and 28.6% (4/14) (P=0.033). Although a higher eradication rate was observed in CLA-resistant cases with sequential therapy, the difference did not reach statistical significance (P=0.69). CONCLUSION: In this study, standard triple treatment failed to eradicate H. pylori infection in the majority of the children, and sequential therapy offered only a small advantage over standard triple therapy in the eradication of CLA-resistant strains.

What is the diagnostic utility of endoscopic scoring systems in children?

BACKGROUND/AIMS: The aim of this study was to evaluate the consistency of the Savary-Miller, the Hetzel-Dent and the Los Angeles endoscopic classification systems and to compare them with the esophageal histopathology in children. MATERIAL AND METHODS: Children between the ages of 5-17 years who underwent esophagogastroduodenoscopy were included in the study. The endoscopic reports and the still images of the esophagus were reclassified by the same gastroenterologist according to the Savary-Miller, Hetzel- Dent and Los Angeles scoring systems. The esophageal biopsies were also reevaluated by the same pathologist and the consistency between endoscopic and histopathologic esophagitis was evaluated. RESULTS: A total of 113 out of 192 pediatric patients were included in the study. Seventy-three patients (64.6%) had esophagitis according to the Hetzel-Dent classification, whereas only 20 (17.7%) patients were defined as having esophagitis according to the other two classification systems. The consistency between the Savary-Miller and Los Angeles classifications was excellent (κ: 0.92) but the agreement between the Hetzel-Dent and Savary-Miller and between the Hetzel-Dent and Los Angeles classifications were poor. A total of 82 patients (72.6%) had histopathological esophagitis, and there was a weak consistency between all 3 endoscopic scoring systems and the histopathology. CONCLUSIONS: Since pediatric patients have milder esophagitis than in adults, the use of endoscopic scoring systems developed for adults seems to be inapplicable for children. The inclusion of minimal endoscopic changes in endoscopic scoring systems by using more sensitive and novel endoscopic techniques would increase the sensitivity of these scoring systems in children.

Anti-inflammatory effect of obestatin and ghrelin in dextran sulfate sodium-induced colitis in rats.

BACKGROUND AND OBJECTIVES: Obestatin and ghrelin are hormones derived from the same gene but have opposing effects. Ghrelin has anti-inflammatory activities; however, the role of obestatin in the inflammatory processes has not been clearly demonstrated yet. The aim of the study was to analyse and compare the anti-inflammatory effect of exogenous ghrelin and obestatin in a rat model of colitis. METHODS: Acute and chronic colitis was induced in 96 rats by adding 3% dextran sulfate sodium to the drinking water for 5 and 10 days, respectively. Intraperitoneal pretreatment with ghrelin or obestatin was started before the induction of colitis, and continued for 5 and 10 days. Clinical signs of the disease and histopathological changes were evaluated. By-products of neutrophil activation, lipid peroxidation, and inflammatory and anti-inflammatory cytokines were measured in colonic tissues. RESULTS: Obestatin and ghrelin significantly ameliorated clinical and histopathological severity of chronic colitis, whereas they were less effective in the acute form. Therapeutic effect of ghrelin and obestatin in acute colitis was associated with reduced lipid peroxidation and TH1-induced inflammatory response, whereas obestatin in chronic colitis was protective via the suppression of polymorphonuclear leukocyte infiltration and enhancement of glutathione synthesis. Moreover, therapeutic effects of ghrelin and obestatin in chronic colitis appear to be associated with inhibition of inflammatory and activation of anti-inflammatory cytokines. CONCLUSIONS: This study demonstrated the novel anti-inflammatory effect of obestatin and ghrelin in an experimental model of colitis. Although both obestatin and ghrelin exerted anti-inflammatory effects in chronic colitis, they were less effective in acute colitis.

Clinical practice: Helicobacter pylori infection in childhood.

Helicobacter pylori infection is recognised as a cause of gastritis and peptic ulcer disease (PUD) and usually acquired during the first years of life. While there is a decline in the prevalence of H. pylori infection in northern and western European countries, the infection is still common in southern and eastern parts of Europe and Asia. Symptoms of H. pylori-related PUD are nonspecific in children and may include epigastric pain, nausea and/or vomiting, anorexia, iron deficiency anaemia and hematemesis. Besides, only a small proportion of children develop symptoms and clinically relevant gastrointestinal disease. H. pylori infection can be diagnosed either by invasive tests requiring endoscopy and biopsy or non-invasive tests including the (13)C-urea breath test, detection of H. pylori antigen in stool and detection of antibodies in serum, urine and saliva. The aim of treatment is at least 90 % eradication rate of the bacteria, and a combination of two antibiotics plus a proton pump inhibitor has been recommended as first-line treatment. However, frequent use of antibiotics during childhood is associated with a decline in eradication rates and the search for new treatment strategies as well. This is an overview of the latest knowledge and evidence-based guidelines regarding clinical presentation, diagnosis and treatment of H. pylori infection in childhood.

Endoscopic and histopathologic findings associated with H. pylori infection in very young children.

Most of the individuals infected with H. pylori acquire the infection early in life. However, there is limited data regarding endoscopic and histopathologic findings of H. pylori infection when it is acquired during infancy. The aim of this study was to investigate the H. pylori-related endoscopic and histopathological findings in children younger than 2 years of age. One hundred and fifty-two infants who underwent upper gastrointestinal endoscopy were included in the study. The diagnosis of H. pylori infection was based on histopathology and a positive rapid urease test. Forty of 152 (26.3%) infants were infected with H. pylori, and 65% of the infected infants had histopathologic gastritis. There were no clinical or endoscopic findings suggestive of H. pylori infection. No correlation could be found between the density of H. pylori and the severity of gastritis. H. pylori infection is associated with various degrees of gastritis in more than half of the infected infants. Since the likelihood of normal histopathology is rare in H. pylori-infected infants, its long-term complications should be cautiously followed up in endemic areas.

Reactive oxygen species and chemokines: are they elevated in the esophageal mucosa of children with gastroesophageal reflux disease?

AIM: To determine the role of inflammatory cytokines and reactive oxygen species (ROS) in childhood reflux esophagitis. METHODS: A total of 59 subjects who had complaints suggesting GERD underwent esophagogastroduodenoscopy. Endoscopic and histopathologic diagnosis of reflux esophagitis was established by Savary-Miller and Vandenplas grading systems, respectively. Esophageal biopsy specimens were taken from the esophagus 20% proximal above the esophagogastric junction for conventional histopathological examination and the measurements of ROS and cytokine levels. ROS were measured by chemiluminescence, whereas IL-8 and MCP-1 levels were determined with quantitative immunometric ELISA on esophageal tissue. Esophageal tissue ROS, IL-8 and MCP-1 levels were compared among groups with and without endoscopic/histo-pathologic esophagitis. RESULTS: Of 59 patients 28 (47.5%) had normal esophagus whereas 31 (52.5%) had endoscopic esophagitis. In histopathological evaluation, almost 73% of the cases had mild and 6.8% had moderate degree of esophagitis. When ROS and chemokine levels were compared among groups with and without endoscopic esophagitis, statistical difference could not be found between patients with and without esophagitis. Although the levels of ROS, IL-8 and MCP-1 were found to be higher in the group with histopathological reflux esophagitis, this difference was not statistically significant. CONCLUSION: These results suggest that the grade of esophagitis is usually mild or moderate during childhood and factors apart from ROS, IL-8 and MCP-1 may be involved in the pathogenesis of reflux esophagitis in children.

Gastric histopathology, iron status and iron deficiency anemia in children with Helicobacter pylori infection.

OBJECTIVES: Helicobacter pylori has been established as a major cause of gastritis and peptic ulcer disease in adults and children. H. pylori infection may also have a role in the development of some extra-gastrointestinal diseases, including iron deficiency anemia. The aim of this study is to investigate H. pylori-related changes in gastric physiology and histology and the relationship of these changes to iron deficiency anemia in children. METHODS: Fifty-two patients with gastrointestinal complaints were studied. Hematologic parameters, 3-day vitamin C and iron consumption, serum gastrin levels, and gastric juice ascorbic acid levels were compared in patients with and without H. pylori infection. Dietary intake of vitamin C and iron, serum gastrin, gastric juice ascorbic acid content, and gastric histology were compared in patients with H. pylori infection and anemia and in patients with H pylori infection and no anemia. The CagA status of the H. pylori organisms was evaluated. RESULTS: Twenty-eight of 52 patients had H. pylori. Thirty-one patients had iron deficiency anemia. H. pylori infection was associated with low serum iron levels. H. pylori gastritis was associated with a decrease in the gastric juice ascorbic acid level. Infection with CagA-positive strains was associated with a greater decrease in gastric juice ascorbic acid than infection with CagA-negative strains. However, the gastric juice ascorbic acid levels of patients with H. pylori and anemia were not different from those of non-anemic patients with H. pylori. Among patients with H. pylori infection, pangastritis was twice as common in those with anemia than in those without anemia. CONCLUSIONS: H. pylori infection was associated with a decrease in gastric juice ascorbic acid concentration, and this effect was more pronounced in patients with the CagA-positive strain. Pangastritis was more common in patients whose H. pylori.infection was accompanied by anemia.

High-dose interferon results in high HBsAg seroclearance in children with chronic hepatitis B infection.

Clinical trials for chronic hepatitis B (HBV) infection in children have shown usefulness of interferon alpha 2b (IFN-alpha) in eliminating HBV replication and in improving liver histology. Although it is not the ultimate goal of the interferon treatment for chronic HBV infection, it has been suggested in adults that HBsAg clearance decreases the likelihood of development of hepatocellular carcinoma, and prolongs the survival. HBV DNA clearance has been shown to be higher with higher doses of interferon in children, but it was rarely associated with HbsAg clearance. Ten MU/m2 was tried in 46 children who had biopsy-proven chronic HBV infection. They received IFN-alpha subcutaneously three times/week for six months. The treatment regimen was completed in 41 children and the second liver hiopsy was carried out one year after the end of the treatment in 30 of 41 patients. With this schedule, 15 (36.6%) children showed persistent loss of HBV DNA 12 months after the cessation of the treatment, 20 (48.7%) lost HBeAg, and eight (19.5%) developed anti-HBs antibody with loss of HBsAg. A significant improvement in liver histology was obtained in children with HBV DNA clearance. Serum ALT levels normalized in all HBeAg seroconverters. These findings suggested that the 10 MU/m2 IFN-alpha treatment was well tolerated and resulted in a high rate of HbsAg clearance in addition to HBV DNA clearance in a group of chidren with chronic HBV infection.