Disease Activity Patterns in the First 5 Years After Diagnosis in Children With Ulcerative Colitis: A Population-Based Study.

BACKGROUND: The aim of this study was to define clusters of activity in a population-based cohort during the first 5 years after diagnosis in children with ulcerative colitis [UC] and to identify early prognostic risk factors. METHODS: All UC patients from the SIGENP IBD registry with a complete follow-up of at least 5 years were included. Active disease was defined every 6 months in the presence of at least one of the following: clinical activity [Paediatric Ulcerative Colitis Activity Index ≥ 35]; endoscopic activity [Mayo score ≥ 1]; faecal calprotectin > 250 µg/g; hospitalization; surgery; or treatment escalation. Formula-based clusters were generated based on four published questionnaire-based activity patterns in adults, plus one additional cluster. RESULTS: In total, 226 patients were identified. Forty-two [19%] had moderate-severe chronically active disease, 31 [14%] chronic-intermittent, 75 [33%] quiescent, 54 [24%] active disease in the first 2 years after the diagnosis, then sustained remission, and 24 [11%] a remission in the first 2 years then an active disease. Mild disease onset along with a lower clinical severity not requiring the use of corticosteroids at 6 months were related to a quiescent disease course at the next follow-up (logistic model area under the curve 0.86 [95% confidence interval 0.78-0.94]; positive predictive value 67%; negative predictive value 70%). Eight per cent of patients needed surgery, none in the quiescent group [p = 0.04]. CONCLUSIONS: More than one-third of children with UC present with a chronically active or intermittent course during the first 5 years of follow-up. A significant group of patients has active disease in the first 2 years and then sustained remission. Interestingly, after initial treatment, one-third of patients have well-controlled disease throughout.

Krill oil, vitamin D and Lactobacillus reuteri cooperate to reduce gut inflammation.

Current research into original therapies to treat intestinal inflammation is focusing on no-drug therapies. KLD is a mixture of krill oil (KO), probiotic Lactobacillus reuteri (LR), and vitamin D (VitD3). The aim of this study was to assess in vitro and in vivo the potential cooperative effects of KLD in reducing gut inflammation. Colorectal adenocarcinoma cell lines, CACO2 and HT29, and C57BL/6 mice were used for in vitro and in vivo analyses, respectively. Cells were exposed to cytomix (interferon gamma + tumour necrosis factor alpha (TNF-α)) to induce inflammation or co-exposed to cytomix and KO, LR and VitD3 alone or to cytomix and KLD. Animals were treated for 7 days with dextran sodium sulphate (DSS) to induce colitis or with DSS and KLD. In vitro assays: F-actin expression was analysed by immunofluorescence; scratch test and trans-epithelial electric resistance test were performed to measure wound healing; adhesion/invasion assays of adhesive and invasive Escherichia coli (AIEC) bacteria were made; mRNA expression of TNF-α, interleukin (IL)-8 and vitamin D receptor (VDR) was detected by quantitative PCR. In vivo assays: body weight, clinical score, histological score and large intestine weight and length were estimated; mRNA expression of TNF-α, IL-1ß, IL-6, IL-10 by quantitative PCR; VDR expression was detected by quantitative PCR and immunohistochemistry. In vitro: KLD restores epithelial cell-cell adhesion and mucosal healing during inflammation, while decreases the adhesiveness and invasiveness of AIEC bacteria and TNF-α and IL-8 mRNA expression and increases VDR expression. In vivo: KLD significantly improves body weight, clinical score, histological score and large intestine length of mice with DSS-induced colitis and reduces TNF-α, IL-1ß and IL-6 mRNA levels, while increases IL-10 mRNA and VDR levels. KLD has significant effects on the intestinal mucosa, strongly decreasing inflammation, increasing epithelial restitution and reducing pathogenicity of harmful commensal bacteria.

Paediatric ulcerative colitis surgery: Italian survey.

BACKGROUND AND AIMS: Recent epidemiological studies showed an increase in ulcerative colitis among children, especially in its aggressive form, requiring surgical treatment. Although medical therapeutic strategies are standardized, there is still no consensus regarding indications, timing and kind of surgery. This study aimed to define the surgical management of paediatric ulcerative colitis and describe attitudes to it among paediatric surgeons. METHODS: This was a retrospective cohort study. All national gastroenterology units were invited to participate. From January 2009 to December 2013, data on paediatric patients diagnosed with ulcerative colitis that required surgery were collected. RESULTS: Seven units participated in the study. Seventy-one colectomies were performed (77.3% laparoscopically). Main surgical indications were a severe ulcerative colitis attack (33.8%) and no response to medical therapies (56.3%). A three-stage strategy was chosen in 71% of cases. Straight anastomosis was performed in 14% and J-pouch anastomosis in 86% of cases. A reconstructive laparoscopic approach was used in 58% of patients. Ileo-anal anastomosis was performed by the Knight-Griffen technique in 85.4% and by the pull-through technique in 9.1% of patients. Complications after colectomy, after reconstruction and after stoma closure were reported in 12.7, 19.3 and 35% of cases, respectively. CONCLUSIONS: This study shows that there is general consensus regarding indications for surgery. The ideal surgical technique remains under debate. Laparoscopy is a procedure widely adopted for colectomy but its use in reconstructive surgery remains limited. Longer follow-up must be planned to define the quality of life of these patients.

Neuroimmune interactions at different intestinal sites are related to abdominal pain symptoms in children with IBS.

BACKGROUND: Neuroimmune interactions and inflammation have been proposed as factors involved in sensory-motor dysfunction and symptom generation in adult irritable bowel syndrome (IBS) patients. In children with IBS and healthy controls, we measured ileocolonic mast cell infiltration and fecal calprotectin and evaluated the relationships between these parameters and abdominal pain symptoms and stooling pattern. METHODS: Irritable bowel syndrome patients diagnosed according to Pediatric Rome III criteria and healthy controls kept a 2-week pain/stooling diary. Ileocolonic mucosal mast cells (MC) and MC in close proximity to nerve fibers (MC-NF) were identified immunohistochemically and quantified. Fecal calprotectin concentration was measured. KEY RESULTS: 21 IBS patients and 10 controls were enrolled. The MC-NF count was significantly higher in the ileum (p = 0.01), right colon (p = 0.04), and left colon (p < 0.001) of IBS patients compared with controls. No differences in fecal calprotectin concentration were noted. Abdominal pain intensity score correlated with ileal MC count (r(s) = 0.47, p = 0.030) and right colon MC-NF count (r(s) = 0.52, p = 0.015). In addition, children with IBS with >3 abdominal pain episodes/week had greater ileal (p = 0.002) and right colonic (p = 0.01) MC counts and greater ileal (p = 0.05) and right colonic (p = 0.016) MC-NF counts than children with less frequent pain. No relationship was found between MC and MC-NF and fecal calprotectin or stooling pattern. CONCLUSIONS & INFERENCES: Mast cells-nerve fibers counts are increased in the ileocolonic mucosa of children with IBS. Mast cells and MC-NF counts are related to the intensity and frequency of abdominal pain.

Size and dynamics of mucosal and peripheral IL-17A+ T-cell pools in pediatric age, and their disturbance in celiac disease.

Mucosal interleukin (IL)-17A-producing T cells contribute to protective antimicrobial responses and to epithelial barrier integrity; their role in celiac disease (CD) is debated. We analyzed the frequency and developmental dynamics of mucosal (intraepithelial lymphocytes (IEL)) and circulating (peripheral blood (PB)) IL-17A (T17) and/or interferon (IFN)-γ-producing (T1, T1/T17) T-cell populations in 86 pediatric controls and 116 age-matched CD patients upon phorbol myristate acetate/ionomycin or CD3/CD28 stimulation. T17 and T1/17 are physiologically present among IEL and PB populations, and their frequency is selectively and significantly reduced in CD IEL. The physiological age-dependent increase of Th17 IEL is also absent in CD, while IFN-γ-producing PB-T cells significantly accumulate with patient's age. Finally, the amplitude of IL-17A+ and IFN-γ+ T-cell pools are significantly correlated in different individuals; this relationship only applies to CD4+ T cells in controls, while it involves also the CD4- counterpart in CD patients. In conclusion, both size and dynamics of mucosa-associated and circulating IL-17A+ T-cell pools are finely regulated in human pediatric subjects, and severely disturbed in CD. The impaired IL-17A+ IEL-T pool may negatively impact on epithelial barrier efficiency, and contribute to CD mucosa damage; the disturbed dynamics of circulating IL-17A+ and IFN-γ+ T-cell pools may be involved in the extraintestinal autoimmune manifestations associated with CD.

Randomised clinical trial: the effectiveness of Lactobacillus reuteri ATCC 55730 rectal enema in children with active distal ulcerative colitis.

BACKGROUND: Intestinal microbiota manipulation, one of the pathogenetic components of inflammatory bowel disease (IBD), has become an attractive therapy for ulcerative colitis (UC). AIM: To assess in children with active distal UC the effectiveness of Lactobacillus (L) reuteri ATCC 55730 enema on inflammation and cytokine expression of rectal mucosa. METHODS: A total of 40 patients (median age: 7.2 years range 6-18) with mild to moderate UC were enrolled in a prospective, randomised, placebo-controlled study. They received an enema solution containing 10(10) CFU of L. reuteri ATCC 55730 or placebo for 8 weeks, in addition to oral mesalazine. Clinical endoscopic and histological scores as well as rectal mucosal expression levels of IL-10, IL-1ß, TNFα and IL-8 were evaluated at the beginning and at the end of the trial. RESULTS: Thirty-one patients accomplished the trial (17 males, median age 13 year, range 7-18). Mayo score (including clinical and endoscopic features) decreased significantly in the L. reuteri group (3.2 ± 1.3 vs. 8.6 ± 0.8, P < 0.01) compared with placebo (7.1 ± 1.1 vs. 8.7 ± 0.7, NS); furthermore, histological score significantly decrease only in the L. reuteri group (0.6 ± 0.5 vs. 4.5 ± 0.6, P < 0.01) (placebo: 2.9 ± 0.8 vs. 4.6 ± 0.6, NS). At the post-trial evaluation of cytokine mucosal expression levels, IL-10 significantly increased (P < 0.01) whereas IL-1ß, TNFα and IL-8 significantly decreased (P < 0.01) only in the L. reuteri group. CONCLUSIONS: In children with active distal ulcerative colitis, rectal infusion of L. reuteri is effective in improving mucosal inflammation and changing mucosal expression levels of some cytokines involved in the mechanisms of inflammatory bowel disease.

Use of macrogol 4000 in chronic constipation.

BACKGROUND: Chronic constipation is a common functional disorder of the gastrointestinal tract, affecting up to 35% of the general population, and especially the elderly. However, its definition as perceived by the patient can vary, making it difficult to understand the problem and find appropriate therapeutic measures. The approach to chronic constipation, thus, needs a thorough understanding of the patient's complaint and the main pathophysiological mechanism requiring treatment. Lifestyle changes do not usually meet with complete patient satisfaction. Other treatments include different types of laxatives. Of these, osmotic laxatives appear one of the most effective and are, therefore, frequently prescribed. DESIGN: This review will cover the topic of osmotic laxatives, specifically focusing on polyethylene glycol (PEG/macrogol 4000) in chronic constipation and as a key agent for bowel cleansing prior to colonoscopy. PEG formulations, including macrogol 4000, are safe, effective treatments for constipation, even in children and elderly patients. Macrogol 4000 may well be more palatable than combined formulations (macrogol 3350 with electrolytes), which could help improve adherence to the long-term treatment required for chronic constipation. CONCLUSIONS: PEG/macrogol is also recommended as an effective option for bowel cleansing prior to colonoscopy. The improved cost-effectiveness of macrogol over other commonly prescribed laxatives, such as lactulose, should be taken into consideration.

Saccharomyces boulardii: a summary of the evidence for gastroenterology clinical practice in adults and children.

Probiotics are viable, nonpathogenic microorganisms (bacteria or yeast) which when administered in adequate amounts, confer a health benefit on the host. At this time, Saccharomyces boulardii is the only yeast commonly used in clinical practice. Literature on this probiotic is wide and even more data become available each year. Thus, it could be problematic for a physician summarize all the best information deriving from basic research and clinical studies. With the aim to help physicians in the use of Saccharomyces boulardii, this paper focuses on the available evidences for its efficacy and safety in different diseases in adult and pediatric patients in order to provide a practical guidance for gastroenterology clinical practice. Indications and dosage for several gastrointestinal diseases for a correct use of this probiotic are provided, and recent insights on its mechanisms of action and possible future clinical application are also discussed.

Autonomic imbalance in celiac children.

AIM: Involvement of many organs and apparatus such as heart, central and peripheral nervous systems have been reported in celiac disease. Autonomic neuropathy has frequently been reported both in untreated and in gluten free diet (GFD) adult patients and, to our knowledge, has never been investigated in celiac children. The aim of the study was to evaluate autonomic function in children with celiac disease. METHODS: Fifteen children with untreated celiac disease were enrolled. Fifteen healthy children served as controls. None of the patients was diabetic. Central or peripheral neurological diseases, were absent. In all participants, at recruitment and after 24 months of GFD, serum anti-tTG and AEA levels, inflammatory markers, IgG, IgM and IgA anti-ganglioside antibodies, were performed. Heart rate variability indexes were employed to evaluate autonomic system balance. RESULTS: Our results indicate that also children with celiac disease may exhibit an imbalance of the neurovegetative system with a prevailing sympathetic tone, persisting on a GFD. All presented symptoms such as abdominal pain, diarrhea or constipation, vomiting, meteorism, regurgitation in whom autonomic dysfunction could be involved, but these symptoms disappeared on gluten free diet. This tend to exclude the prevailing sympathetic tone as a main factor underlying symptoms of celiac disease. CONCLUSION: Children affected by celiac disease exhibit an enhanced sympathetic tone, persisting after 24 months of GFD whereas gastrointestinal and systemic symptoms disappear. The pathogenesis of this phenomenon still remains unclear.

Methotrexate in paediatric ulcerative colitis: a retrospective survey at a single tertiary referral centre.

BACKGROUND: Patients with ulcerative colitis often receive thiopurines as immunomodulators (IMs) to maintain remission and avoid corticosteroids. If unresponsive or intolerant to these agents, patients are treated with methotrexate, an antimetabolite never assessed in paediatric ulcerative colitis. AIM: To describe the experience with methotrexate in children with ulcerative colitis. METHODS: Thirty-two patients (median age 13.9 years) received methotrexate. Pediatric Ulcerative Colitis Activity Index (PUCAI) and use of corticosteroids were the main outcomes evaluated at baseline and at 3, 6 and 12 months. RESULTS: Indications to methotrexate were azathioprine unresponsiveness in 18 patients, azathioprine intolerance/toxicity in 10 and spondyloarthropathy in four. Response or remission was achieved in 72%, 63% and 50% of patients at 3, 6 and 12 months respectively. Mean PUCAI were 49.5 ± 23.3 at baseline and 32.9 ± 21.9, 29.5 ± 21.8 and 29.4 ± 19.9 at 3, 6 and 12 months respectively (P: 0.03). At the beginning of methotrexate, 16 patients (50%) received corticosteroids that were discontinued in 13 of them (81%) by 6 months. At the end of the study, 11 patients (33%) needed short courses of corticosteroids for disease relapse. CONCLUSIONS: Methotrexate may be useful in treating children with ulcerative colitis, although large, controlled trials are warranted to define better its effectiveness.

JC Viral reactivation in a pediatric patient with Crohn's disease.

This is a report concerning human polyomavirus JC (JCV) reactivation in a pediatric patient with Crohn's disease (CD) during the treatment with 5-aminosalicylic acid (5-ASA), a non-steroidal anti-inflammatory drug (NSAID). We examined 9 bioptic samples from three different bowel districts (ileum, cecum, rectum) of this child. These samples were analyzed by Quantitative PCR (Q-PCR) to investigate the presence of JCV DNA. JCV DNA was detected in one rectum biopsy taken two months after 5-ASA treatment. Although our result must be validated in a larger group of subjects and with a longer follow-up period, it underlines the importance of JVC monitoring in CD patients.

Non-acid gastro-oesophageal reflux in children with suspected pulmonary aspiration.

BACKGROUND & AIMS: In a group of children with suspected pulmonary aspiration, we aimed to describe the type and physical characteristics of gastro-oesophageal reflux (GOR) episodes, and to determine their correlation with the lipid-laden macrophage (LLM) content in bronchoalveolar lavage (BAL). PATIENTS AND METHODS: Twenty-one children with a diagnosis of bronchial asthma, recurrent lung consolidations and recurrent laryngotracheitis underwent 24-h multichannel intraluminal impedance and pH (MII-pH) monitoring, fibreoptic bronchoscopy and BAL. The following parameters were evaluated: total number of reflux episodes, number of acid reflux [AR; pH<4] and non-acid reflux [NAR] episodes [pH>4], height of reflux episodes, LLM content and percentage of neutrophils in the BAL. RESULTS: The number of NAR episodes and the number of those reaching the proximal oesophagus were significantly higher in patients with recurrent lung consolidations than in those with bronchial asthma and laryngotracheitis (p<0.01 and p<0.01). BAL studies showed a significantly higher LLM content in children with recurrent lung consolidations than in those with bronchial asthma and laryngotracheitis (p<0.01). The LLM content correlated significantly with the total number of reflux episodes (r=0.73; p<0.001) and with those reaching the proximal oesophagus (r=0.67; p<0.001). Finally, the LLM content correlated with the number of NAR episodes (r=0.61; p<0.01), with those reaching the proximal oesophagus (r=0.64; p<0.01) and with the percentage of BAL neutrophils (r=0.7; p<0.01). CONCLUSION: NAR episodes reaching the proximal oesophagus correlate with diagnostic marker for pulmonary micro-aspiration. MII-pH monitoring increases the yield in identifying types and proximal extension of reflux episodes, that discriminate between patients with and without pulmonary aspiration.

Extradigestive manifestations of IBD in pediatrics.

Inflammatory bowel diseases (IBD) are often associated with extraintestinal manifestations (EIMs), which occur in approximately one third of patients. There is only few published data on the occurrence of these manifestations in children and adolescents, so most of the data are taken by studies in adult patients. The organs most commonly affected are joints, skin, eyes and biliary tract, although nearly every organ may be involved. Some of the EIMs are clearly related to intestinal disease activity (i.e., erythema nodosum, peripheral arthritis, orofacial lesions), whereas others occur independently (i.e., pyoderma gangrenosum, anterior uveitis/iritis, ankylosing spondylitis, primary sclerosing cholangitis). Many extraintestinal disorders may be direct inflammatory and metabolic complications of the intestinal inflammation (i.e., osteoporosis, growth retardation, nephrolithiasis, ureteral obstruction, thromboembolic disease). In this review we provide an overview on the prevalence and clinical aspects of the more commonly reported EIMs of Crohn's disease and ulcerative colitis in pediatric patients, focusing on specific issues of children affected by IBD (growth failure and metabolic osteopathy).

Polymorphism of the IRGM gene might predispose to fistulizing behavior in Crohn's disease.

OBJECTIVES: Recently, genome-wide association analyses have identified single nucleotide polymorphisms in the IRGM gene (rs1000113 and rs4958847) as strong candidate susceptibility factors for Crohn's disease (CD). The aim of our study was to test whether these variants are associated with inflammatory bowel disease (IBD) in adult- and childhood-onset Italian patients. METHODS: Allele and genotype frequencies of rs1000113 and rs4958847 were determined in 823 CD (265 younger than 19 years at diagnosis), 353 ulcerative colitis (UC) (130 younger than 19 years at diagnosis), and 578 controls. Genotype distributions were examined both within IBD clinical sub-phenotypes and CARD15 genotypes. RESULTS: rs1000113 and rs4958847 were both associated with adult-onset (P=2 x 10(-4); P=2.5 x 10(-3), respectively) and childhood-onset (P=4 x 10(-4); P=8 x 10(-3), respectively) CD cohorts. Similarly, the genotype frequencies remained significantly different for both variants (adult rs1000113, P=1 x 10(-4); rs4958847, P=1 x 10(-3); pediatric rs1000113, P=2.3 x 10(-4); rs4958847, P=9.6 x 10(-3)). At logistic regression, the rs4958847 polymorphism was associated with fistulizing behavior (P=0.037, OR=1.54, CI=1.02-2.31) and perianal fistulas (P=0.045, OR=1.55, CI=1.01-2.38). Conversely, no association with UC and sub-phenotypes was shown. CONCLUSIONS: We replicated the previously reported associations between CD and rs1000113 and rs4958847, confirming that IRGM is a susceptibility locus only for CD, either adult- or early-onset in the Italian population; furthermore, we have also shown its influence on specific clinical features (fistulizing disease).

Infliximab for pediatric ulcerative colitis: a retrospective Italian multicenter study.

BACKGROUND: Infliximab (IFX), the chimeric anti TNFalpha antibody, an established treatment for Crohn's disease in adults and in children, is used less frequently in ulcerative colitis (UC). AIM OF THE STUDY: To report the clinical course of pediatric patients with active UC receiving IFX. PATIENTS AND METHODS: Charts of 22 patients were reviewed (13 male, 9 female): 4 with a severe UC attack refractory to systemic corticosteroids (CS); 18 with a protracted course, of which 16 CS-dependent and 2 CS-resistant. The baseline therapeutic program consisted of 3 consecutive intravenous infusions (0, 2, 6 weeks) of IFX (5 mg/kg), followed by a retreatment schedule (infusion every 8 weeks); azathioprine (AZA) was administered chronically in all. Clinical evaluation was done with the Lichtiger Colitis Activity Index (LCAI). Follow-up was performed until week 54. LCAI >/= 9 was considered treatment failure; a LCAI 9: 12 had a full response and were on remission at week 54 and did not receive CS (8 on IFX re-treatment and AZA, 4 on AZA alone); 6 had a partial response; 4 were non responders. Colectomy was performed in 7 patients, beyond the period of the acute attack in all but one. CONCLUSIONS: In children with severe ulcerative colitis IFX is a valuable treatment for inducing remission, avoiding emergency colectomy; retreatment may be offered to maintain remission.