Determinant factors for first-line treatment choice and effectiveness in pediatric eosinophilic esophagitis: an analysis of the EUREOS EoE CONNECT registry.

This study compared short-term effectiveness of proton pump inhibitors (PPI), swallowed topical corticosteroids (STC), and dietary therapies in reversing clinical and histological features in pediatric patients with eosinophilic esophagitits (EoE). Determinants for treatment choice and PPI therapy effectiveness were also assessed.  A cross-sectional study analysis of patients under 18 years old recruited onto the multicenter EoE CONNECT registry was performed. Clinico-histological response was defined as symptomatic improvement plus a peak eosinophil count below 15 per high-power field after treatment. Effectiveness of first-line options used in monotherapy was compared. Overall, 393 patients (64% adolescents) receiving PPI, STC, or dietary monotherapy to induce EoE remission were identified. PPI was the preferred option (71.5%), despite STC providing the highest clinico-histological response rates (66%) compared to PPI (44%) and diet (42%). Logistic regression identified fibrotic features and recruitment at Italian sites independently associated to first-line STC treatment; age under 12 associated to dietary therapy over other options. Analysis of 262 patients in whom PPI effectiveness was evaluated after median (IQR) 96 (70-145) days showed that this effectiveness was significantly associated with management at pediatric facilities and use of high PPI doses. Among PPI responders, decrease in rings and structures in endoscopy from baseline was documented, with EREFS fibrotic subscore for rings also decreasing among responders (0.27 ± 0.63 vs. 0.05 ± 0.22, p < 0.001). Conclusion: Initial therapy choice for EoE depends on endoscopic phenotype, patient's age, and patients' origin. High PPI doses and treatment in pediatric facilities significantly determined effectiveness, and reversed fibrotic endoscopic features among responders. What is Known: • Proton pump inhibitors are widely used to induce and maintain remission in EoE in real practice, despite other first-line alternative therapies possibly providing higher effectiveness. What is New: • Proton pump inhibitors represent up to two-thirds of first-line monotherapies used to induce EoE remission in pediatric and adolescent patients with EoE. The choice of STC as first-line treatment for EoE was significantly associated with fibrotic features at baseline endoscopy and recruitment in Italian centers; age less than 12 years was associated with dietary therapy. • PPI effectiveness was found to be determined by use of high doses, attendance at pediatric facilities, presenting inflammatory instead of fibrotic or mixed phenotypes, and younger age. Among responders, PPI therapy reversed both inflammatory and fibrotic features of EoE after short-term treatment.

Presence of commensal house dust mite allergen in human gastrointestinal tract: a potential contributor to intestinal barrier dysfunction.

BACKGROUND: Abnormal gut barrier function is the basis of gut inflammatory disease. It is known that house dust mite (HDM) aero-allergens induce inflammation in respiratory mucosa. We have recently reported allergen from Dermatophagoides pteronyssinus (Der p1) to be present in rodent gut. OBJECTIVE: To examine whether Der p1 is present in human gut and to assess its effect on gut barrier function and inflammation. DESIGN: Colonic biopsies, gut fluid, serum and stool were collected from healthy adults during endoscopy. Der p1 was measured by ELISA. Effect of HDM was assessed on gut permeability, tight-junction and mucin expression, and cytokine production, in presence or absence of cysteine protease inhibitors or serine protease inhibitors. In vivo effect of HDM was examined in mice given oral HDM or protease-neutralised HDM. Role of HDM in low-grade inflammation was studied in patients with IBS. RESULTS: HDM Der p1 was detected in the human gut. In colonic biopsies from healthy patients, HDM increased epithelial permeability (p<0.001), reduced expression of tight-junction proteins and mucus barrier. These effects were associated with increased tumour necrosis factor (TNF)-α and interleukin (IL)-10 production and were abolished by cysteine-protease inhibitor (p<0.01). HDM effects did not require Th2 immunity. Results were confirmed in vivo in mice. In patients with IBS, HDM further deteriorated gut barrier function, induced TNF-α but failed to induce IL-10 secretion (p<0.001). CONCLUSIONS: HDM, a ubiquitous environmental factor, is present in the human gut where it directly affects gut function through its proteolytic activity. HDM may be an important trigger of gut dysfunction and warrants further investigation.

Swallowed topical corticosteroids for eosinophilic esophagitis: Utilization and real-world efficacy from the EoE CONNECT registry.

BACKGROUND: Swallowed topical corticosteroids (tC) are common therapy for patients with eosinophilic esophagitis (EoE). Widely heterogeneous results have occurred due to their active ingredients, formulations and doses. OBJECTIVE: To assess the effectiveness of topical corticosteroid therapy for EoE in real-world practice. METHODS: Cross-sectional study analysis of the multicentre EoE CONNECT registry. Clinical remission was defined as a decrease of ≥50% in dysphagia symptom scores; histological remission was defined as a peak eosinophil count below 15 per high-power field. The effectiveness in achieving clinico-histological remission (CHR) was compared for the main tC formulations. RESULTS: Overall, data on 1456 prescriptions of tC in monotherapy used in 866 individual patients were assessed. Of those, 904 prescriptions with data on formulation were employed for the induction of remission; 234 reduced a previously effective dose for maintenance. Fluticasone propionate formulations dominated the first-line treatment, while budesonide was more common in later therapies. A swallowed nasal drop suspension was the most common formulation of fluticasone propionate. Doses ≥0.8 mg/day provided a 65% CHR rate and were superior to lower doses. Oral viscous solution prepared by a pharmacist was the most common prescription of budesonide; 4 mg/day provided no benefit over 2 mg/day (CHR rated being 72% and 80%, respectively). A multivariate analysis revealed budesonide orodispersible tablets as the most effective therapy (OR 18.9, p < 0.001); use of higher doses (OR 4.3, p = 0.03) and lower symptom scores (OR 0.9, p = 0.01) were also determinants of effectiveness. CONCLUSION: Reduced symptom severity, use of high doses, and use of budesonide orodispersible tablets particularly were all independent predictors of tC effectiveness.

Differences between childhood- and adulthood-onset eosinophilic esophagitis: An analysis from the EoE connect registry.

BACKGROUND: Direct comparisons of childhood- and adulthood-onset eosinophilic esophagitis (EoE) are scarce. AIM: To compare disease characteristics, endoscopic and histological features, allergic concomitances and therapeutic choices across ages. METHODS: Cross-sectional analysis of the EoE CONNECT registry. RESULTS: The adulthood-onset cohort (those diagnosed at ≥18y) comprised 1044 patients and the childhood-onset cohort (patients diagnosed at <18 y), 254. Vomiting, nausea, chest and abdominal pain, weight loss, slow eating and food aversion were significantly more frequent in children; dysphagia, food bolus impaction and heartburn predominated in adults. A family history of EoE was present in 16% of pediatric and 8.2% of adult patients (p<0.001). Concomitant atopic diseases did not vary across ages. Median±IQR diagnostic delay (years) from symptom onset was higher in adults (2.7 ± 6.1) than in children (1 ± 2.1; p<0.001). Esophageal strictures and rings predominated in adults (p<0.001), who underwent esophageal dilation more commonly (p = 0.011). Inflammatory EoE phenotypes were more common in children (p = 0.001), who also presented higher eosinophil counts in biopsies (p = 0.015) and EREFS scores (p = 0.017). Despite PPI predominating as initial therapy in all cohorts, dietary therapy and swallowed topical corticosteroids were more frequently prescribed in children (p<0.001). CONCLUSIONS: Childhood-onset EoE has differential characteristics compared with adulthood-onset, but similar response to treatment.

Laparoscopic sleeve gastrectomy for morbid obesity.

The incidence of obesity is steadily rising, and it has been estimated that 40% of the US population will be obese by the year 2025 if the current trend continues. In recent years there has been renewed interest in the surgical treatment of morbid obesity in concomitance with the epidemic of obesity. Bariatric surgery proved effective in providing weight loss of large magnitude, correction of comorbidities and excellent short-term and long-term outcomes, decreasing overall mortality and providing a marked survival advantage. The Laparoscopic Sleeve Gastrectomy (LSG) has increased in popularity and is currently very "trendy" among laparoscopic surgeons involved in bariatric surgery. As LSG proved to be effective in achieving considerable weight loss in the short-term, it has been proposed by some as a sole bariatric procedure. This editorial focuses on the particular advantages of LSG in the treatment of morbid obesity.

Long-term results of subtotal colectomy with cecorectal anastomosis for isolated colonic inertia.

AIM: To evaluate the results of sub total colectomy with cecorectal anastomosis (STC-CRA) for isolated colonic inertia (CI). METHODS: Fourteen patients (mean age 57.5 +/- 16.5 year) underwent surgery for isolated CI between January 1986 and December 2002. The mean frequency of bowel motions with the aid of laxatives was 1.2 +/- 0.6 per week. All subjects underwent colonoscopy, anorectal manometry, cinedefaecography and colonic transit time (CTT). CI was defined as diffuse markers delay on CTT without evidence of pelvic floor dysfunction. All patients underwent STC-CRA. Long-term follow-up was obtained prospectively by clinical visits between October 2005 and February 2006 at a mean of 10.5 +/- 3.6 years (range 5-16 years) during which we considered the number of stool emissions, the presence of abdominal pain or digitations, the use of pain killers, laxatives and/or fibers. Patients were also asked if they were satisfied with the surgery. RESULTS: There was no postoperative mortality. Postoperative complications occurred in 21.4% (3/14). At the end of follow-up, bowel frequency was significantly (P < 0.05) increased to a mean of 4.8 +/- 7.5 per day (range 1-30). One patient reported disabling diarrhea. Two patients used laxatives less than three times per month without complaining of what they called constipation. Overall, 78.5% of patients would have chosen surgery again if necessary. CONCLUSION: STC-CRA is feasible and safe in patients with CI achieving 79% of success at a mean follow-up of 10.5 years. A prospective controlled evaluation is warranted to verify the advantages of this surgical approach in patients with CI.

Effects of physical activity on intestinal gas transit and evacuation in healthy subjects.

PURPOSE: To determine the effects of mild physical activity on intestinal gas transit and clearance. METHODS: In 8 healthy adults, a gas mixture was infused continuously into the jejunum (12 mL/min) for 120 minutes with simultaneous duodenal lipid perfusion (1 kcal/min). Gas evacuation, perception of abdominal sensations (on a scale of 0 [none] to 6 [pain]), and abdominal girth were measured at 15-minute intervals during rest and intermittent pedalling, with subjects in a supine position. RESULTS: Mean (+/- SD) intestinal gas retention was lower during exercise than at rest (-84 +/- 303 mL vs. 143 +/- 219 mL, P <0.05). Gas retention during rest was associated with significant abdominal distension (8 +/- 6 mm, P <0.01 vs. basal), which was decreased with exercise (3 +/- 7 mm, P <0.05 vs. rest). The gas challenge test was well tolerated both during exercise and rest (perception score: 0.6 +/- 0.5 vs. 0.9 +/- 0.4, P = 0.25). CONCLUSION: In healthy subjects, gut transit of intraluminal gas is enhanced by mild physical activity.

Osteopathy decreases the severity of IBS-like symptoms associated with Crohn's disease in patients in remission.

BACKGROUND: Osteopathy may decrease the severity of irritable bowel syndrome (IBS). About 35% of patients with quiescent Crohn's disease (CD) continue to suffer from IBS-like symptoms with impaired quality of life (Qol). We aimed to evaluate the effect of osteopathy on the severity of IBS-like symptoms in quiescent CD patients. METHODS: We prospectively included 38 patients with CD on remission over 12 months while receiving infliximab every 8 weeks. Patients were randomized 2/ 1 to receive three sessions of standardized osteopathy (n=25) at 15, 30, and 45 days after the last infusion of infliximab or simple follow-up. The severity of IBS-like symptoms, psychological factors, and its impact on Qol were assessed using questionnaires. MAIN RESULTS: Compared with baseline, the severity of IBS-like symptoms was significantly reduced in patients receiving osteopathy. The decrease was significantly more pronounced in patients receiving osteopathy at day 30 [-38.4 (-76.1 to 10.2) vs. 32.2 (-16.6 to 41.6), P=0.01], day 45 [-36.7 (-74.4 to 25.3) vs. 32.2 (-16.6 to 41.6), P=0.04], and day 60 [-39.5 (-60.9 to -9.2) vs. 6.1 (-38.7 to 28.5), P=0.05] with a concomitant increase in Qol (P=0.09 at day 30, P=0.02 at day 45, P=0.3 at day 60). Compared with baseline, the severity of fatigue was significantly reduced in patients receiving osteopathy, whereas depression and anxiety remained unchanged. CONCLUSION: Three sessions of osteopathy reduced the severity of IBS-like symptoms associated with CD in remission. Osteopathy should be viewed as a helpful therapeutic option to reduce the severity of abdominal pain and discomfort in patients with CD but in remission with IBS-like symptoms.

Perception of lactose intolerance in irritable bowel syndrome patients.

INTRODUCTION: The importance of lactose malabsorption in irritable bowel syndrome (IBS) is not well defined and these patients often complain of lactose intolerance. To objectively measure lactose malabsorption, a hydrogen breath test (HBT) can be performed, but a discrepancy emerges between the results of the HBT and the symptomatic response during the HBT. AIMS: To determine in a group of IBS patients whether self-perceived lactose intolerance and the symptomatic response to lactose HBT were conditioned by other factors besides the presence of lactose malabsorption. MATERIALS AND METHODS: Oral challenge to lactose (50 g) was tested in 51 IBS patients to assess HBT malabsorption and the symptomatic response to lactose intolerance was scored on a validated questionnaire. Allergological screening for common inhalants and food allergens (including cow's milk) was performed. The presence of psychological factors (e.g. anxiety, depression, fatigue) was evaluated using validated questionnaires. RESULTS: A total of 21 out of 51 patients (41.1%) were self-perceived to be lactose intolerant, 24/51 (47%) had a positive HBT, and 14/51 (27.4%) presented with symptoms of lactose intolerance during HBT. The serological screening for inhalant and food allergens was positive in 6/21 (28.6%) and 4/21 (19%) of patients who self-perceived lactose intolerance and in 5/14 (37.5%) and 3/14 (21.4%) in intolerant patients symptomatic during HBT. Only 1/51 (1.9%) presented evidence of IgE-mediated hypersensitivity to cow's milk. Patients who experienced symptoms of lactose intolerance during HBT presented more severe IBS symptoms [326 (296-398) vs. 215 (126-295) P=0.05] and a higher score of anxiety, depression, and fatigue. Factors influencing the symptoms of lactose intolerance during HBT resulted in an increase in hydrogen produced and in the severity of IBS. CONCLUSION: In a cohort of 51 IBS patients, the symptoms of lactose intolerance during HBT were influenced by the capacity to absorb lactose and the severity of IBS. Other factors, such as the psychological status or an adverse reaction to milk, merit consideration as potential cofactors involved in lactose perception and tolerance.

Multispecies probiotic protects gut barrier function in experimental models.

AIM: To investigate the effect of the probiotic combination Lactibiane Tolerance(®) (LT) on epithelial barrier function in vitro and in vivo. METHODS: The effect of the multispecies probiotic LT was assessed on several models of epithelial barrier function both in vitro (in basal and inflammatory conditions) and in vivo [visceral hypersensitivity induced by chronic stress or by colonic perfusion of a fecal supernatant (FSN) from patients with irritable bowel syndrome (IBS)]. In vitro, we measured the permeability of confluent T84 cell monolayers incubated with or without LT by evaluating the paracellular flux of macromolecules, in basal conditions and after stimulation with lipopolysaccharide (LPS) or with conditioned medium of colonic biopsies from IBS patients (IBS-CM). In vivo, male C57/Bl6 mice received orally NaCl or LT for 15 d and were submitted to water avoidance stress (WAS) before evaluating visceral sensitivity by measuring the myoelectrical activity of the abdominal muscle and the paracellular permeability with (51)Cr-EDTA. Permeability and sensitivity were also measured after colonic instillation of FSN. Tight-junctions were assessed by immunoblotting and TLR-4 expression was evaluated by immunohistochemistry RESULTS: Incubation of T84 cell monolayers with LT in basal conditions had no significant effect on permeability (P > 0.05 vs culture medium). By contrast, addition of LT bacterial bodies (LT) completely prevented the LPS-induced increase in paracellular permeability (P < 0.01 vs LPS 10 ng/mL (LPS 10); P < 0.01 vs LPS 100 ng/mL (LPS 100), P > 0.05 vs culture medium). The effect was dose dependent as addition of 10(9) LT bacterial bodies induced a stronger decrease in absorbance than 10(6) LT (10(9) LT + LPS 10: -20.1% ± 13.4, P < 0.01 vs LPS 10; 10(6) LT + LPS 10: -11.6% ± 6.2, P < 0.01 vs LPS 10; 10(9) LT + LPS 100: -14.4% ± 5.5, P < 0.01 vs LPS 100; 10(6) LT + LPS 100: -11.6% ± 7.3, P < 0.05 vs LPS 100). Moreover, the increase in paracellular permeability induced by culturing T84 cells with conditioned medium of colonic biopsies from IBS patients (IBS-CM) was completely inhibited in the presence of 10(9) LT (P < 0.01 vs IBS-CM). LT also significantly prevented the epithelial disruption induced by intracolonic infusion of fecal supernatant from IBS patients (P < 0.01 vs IBS FSN) or water avoidance stress P < 0.01 vs WAS) in C57/Bl6 mice and increased the expression of occludin in vitro and in vivo, as assessed by immnunoblotting. The WAS-induced effect on visceral sensitivity was prevented by LT treatment since values obtained for all steps of colorectal distension were significantly (P < 0.01) different from the WAS group. Finally, LT down-regulated the response mediated through TLR-4 in vitro (decrease in tumor necrosis factor α secretion in response to LPS: -65.8% for 10(9) LT and -52.5% for 10(6) LT, P < 0.01 vs LPS) and in vivo (inhibition of WAS induced an increase in TLR-4 expression in the LT treated mice colon, P < 0.01 vs WAS). CONCLUSION: The probiotic LT mix prevented the disruption to the epithelial barrier induced by LPS, stress or colonic soluble factors from IBS patients and prevented visceral hypersensitivity.

Role of serological markers of activated eosinophils in inflammatory bowel diseases.

BACKGROUND: Activated eosinophils can infiltrate the intestinal mucosa in patients with inflammatory bowel disease (IBD), and eosinophils are also implicated in the histological damage seen in allergic diseases. AIM: To assess, in a group of patients with IBD in remission or with a mild disease activity, whether serological markers of eosinophil activation, eosinophil cationic protein (ECP) and eosinophil protein X (EPX), are related to evidence of IgE hypersensitivity and to the eosinophilia in gut mucosa. METHODS: Sixty-one patients with IBD (21 Crohn's disease and 40 ulcerative colitis) in remission or with a mild disease activity were screened for IgE hypersensitivity and serological levels of ECP and EPX. Colonic biopsies were taken to assess mucosal eosinophilic infiltration. RESULTS: Skin prick test were positive in 31.1% of the patients with IBD, showing skin reactions to food allergens in 17.7%. Skin prick test findings were unrelated to ECP or EPX levels, or to clinical activity or eosinophil counts in the gut mucosa. A significant correlation was found between ECP and EPX levels (r=0.77; P<0.0001). CONCLUSION: Serological ECP and EPX findings did not correlate with IgE hypersensitivity findings or eosinophilic colonic infiltration in patients with IBD in remission or with mild disease activity. The role of eosinophils in IBD needs to be better characterized in the colonic mucosa, instead of relying on serological tests.

Osteopathy improves the severity of irritable bowel syndrome: a pilot randomized sham-controlled study.

BACKGROUND: Effective therapies for irritable bowel syndrome (IBS) are disappointing. Therefore, IBS patients have a growing interest for alternative medicines including osteopathy. AIM: We aimed to evaluate the effect of osteopathy on the severity of IBS in a randomized sham-controlled trial. METHODS: We prospectively assigned 30 patients with IBS (23F, 7M, mean age 45.8±16.4 years) fulfilling the Rome III criteria in a 2/1 ratio to receive either osteopathy or sham osteopathy. Two separate sessions were performed at a 7-day interval (days 0 and 7) with a further 3 weeks of follow-up (day 28). The primary outcome included at least a 25% improvement in the IBS severity score at day 7. The secondary outcomes included the impact of IBS on quality of life, psychological factors, and bowel habits. RESULTS: The severity of IBS decreased in both groups at days 7 and 28. At day 7, this decrease was significantly more marked in patients receiving osteopathy compared with those receiving the sham procedure (-32.2±29.1 vs. -9.0±16.0, mean difference normalized to the baseline P=0.01). This difference did not persist at day 28 (P=0.4). Both anxiety and depression scores decreased without difference between groups. Stool frequency and consistency were not significantly modified. CONCLUSION: Osteopathy improves the severity of IBS symptoms and its impact on quality of life. Osteopathy should therefore be considered for future research as an effective complementary alternative medicine in the management of IBS symptoms.