F. Kiparissi

Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of 2 years

Objectives: Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity. Methods: Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing. Results: In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn’s disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities. Conclusions: IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn’s disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype.

The use of sirolimus (rapamycin) in the management of refractory inflammatory bowel disease in children

BACKGROUND Management of refractory inflammatory bowel disease (IBD) in children is challenging and once response to conventional medical therapy deviates from the expected, options are often limited. Sirolimus is commonly used in post-transplantation management and is used sparsely as rescue therapy in refractory Crohns disease. In the present study, we report the efficacy of sirolimus as an adjuvant immunosuppressive therapy in a retrospective case review of a selected group of IBD children who were refractory to the conventional treatments. METHODS Medical records of children with refractory IBD unresponsive to conventional therapy and started on sirolimus between 2006 and 2012 were retrospectively reviewed. Clinical response, through Pediatric Ulcerative Colitis Activity Index (PUCAI) and Pediatric Crohns Disease Activity Index (PCDAI), as well as intestinal inflammation, through specific histological scores, was evaluated. RESULTS The records of 14 patients were analyzed. Eleven of them had ulcerative colitis (UC) and 3 Crohns disease (CD); mean age at diagnosis was 9.1 years (standard deviation 3.8). Of UC patients, 5 (45%) achieved clinical remission and 2 (18%) showed clinical response. All CD patients went into clinical remission. Mucosal healing was achieved by 5 children (45%) with UC and 2 (67%) with CD patients. One child with ulcerative colitis was weaned off adalimumab, while 2 children with CD were weaned off prednisolone and methotrexate successfully. CONCLUSION Our data provide evidence that sirolimus seems to be effective as rescue therapy in a subgroup of children with severe IBD refractory to conventional therapies by inducing both clinical remission and mucosal healing.

Efficacy of the neurokinin-1 receptor antagonist aprepitant in children with cyclical vomiting syndrome

Aprepitant (Emend, Merck Sharp & Dohme Ltd, Haarlem, the Netherlands), a neurokinin‐1 receptor antagonist, prevents vomiting in a range of conditions. No data are available on its use in children with cyclical vomiting syndrome (CVS).

Lymphocytic leiomyositis and myenteric ganglionitis are intrinsic features of cystic fibrosis: studies in distal intestinal obstruction syndrome and meconium ileus.

Background: Cystic fibrosis (CF) is a multisystem disorder intrinsically associated with inflammation of mucosal surfaces. Because inflammation can result in enteric neuromuscular dysfunction we hypothesized that terminal ileitis in patients with CF may predispose to distal ileal obstruction syndrome (DIOS). Methods and Patients: Full-thickness terminal ileal tissues from 6 children with CF and severe DIOS, 6 infants with complicated meconium ileus (MI), and 6 children with non-CF intestinal atresia were studied. Results: Lymphocyte-predominant mucosal and transmural ileal inflammation was present in 6 of 6 patients with DIOS. Lymphocytic ganglionitis was present in 4 of 6 although numbers of myenteric neurons were not decreased (5/5). Myocyte proteins were preserved (6/6). Mild submucosal fibrosis was common in DIOS (5/6) and transformation of submucosal fibroblasts to a myofibroblastic phenotype was noted in 4 of 6. Inflammatory changes were distinct from those described in fibrosing colonopathy. Antroduodenal manometry in an individual who had experienced MI/DIOS was consistent with a neuropathic pseudo-obstructive process. Submucosal or transmural lymphocyte predominant inflammation was also present in 6 of 6 infants with complicated MI, which, when coupled with submucosal myofibroblast proliferation (5/6), appeared highly predictive of CF rather than non-CF atresia. Histological findings at birth were similar, although milder, than those seen in DIOS, suggesting that these changes are a primary abnormality in CF. Conclusions: Submucosal or transmural inflammation of the ileum is common in newborns with CF and MI and older children with DIOS. Severe recurrent DIOS should be investigated with seromuscular and mucosal biopsy of the ileum to seek a transmural ileitis potentially amenable to anti-inflammatory therapies.

Treatment of Intractable Ulcerating Enterocolitis of Infancy by Allogeneic Bone Marrow Transplantation

BACKGROUND & AIMS Intractable ulcerating enterocolitis of infancy (IE) is an uncommon, autosomal-recessive, and devastating inflammatory bowel disorder that arises as a consequence of a poorly defined underlying immunologic disorder. Infants with IE suffer from recurrent severe oro-anal disease and an enterocolitis that is unresponsive to conventional immunosuppressive therapy and requires early pancolectomy to control the severity of the disease. Despite such aggressive treatment these individuals remain at high risk of Epstein-Barr virus-driven lymphomatous proliferations, including non-Hodgkins lymphoma. The underlying genetic basis for this disease remains undefined. This report aims to describe the use of bone marrow transplantation as a treatment for this condition. METHODS This was a case series report. RESULTS We describe the successful treatment of IE by allogeneic bone marrow transplantation in 2 brothers, now aged 7 and 11 years, one of whom had developed an Epstein-Barr virus-related monomorphous B-lymphocyte lymphoproliferative disorder. This treatment has resulted in prolonged clinical remission in both boys and abrogated the need for aggressive immunosuppression. CONCLUSIONS Bone marrow transplantation can be used for the treatment of intractable ulcerating enterocolitis of infancy, which may support a role in other intractable inflammatory bowel conditions in the pediatric population.

Eosinophilic gastrointestinal disease and inflammatory bowel disease in children: is it a disease continuum?

Eosinophilic gastrointestinal disease (EGID) and inflammatory bowel disease (IBD) are two distinct disorders that share some clinical manifestations but have different diagnostic criteria. In this article, we reviewed the clinical data of three children with EGID who later developed IBD. This study is a retrospective case note review that was conducted between 2007 and 2012. EGID seems to precede IBD in some subsets of children in whom the diagnosis of IBD may take a few years to fully develop.

Adalimumab as a second-line biological therapy in children with refractory ulcerative colitis.

Aim The role of adalimumab in medically refractory ulcerative colitis (UC) in children remains to be defined. The aim of this study was to describe 11 cases of paediatric patients who received adalimumab as a second-line anti-TNF-&agr; treatment for paediatric UC. Methods A retrospective review of all patients with UC who received adalimumab between April 2008 and October 2013 at our hospital was conducted. Clinical efficacy and safety were assessed. Results Eleven patients (three boys, eight girls) with a median age of 13.8 years (5.7–16.6 years) were included. All patients had been previously treated with infliximab. Six patients achieved and maintained clinical remission, with a median duration of treatment of 25 months. One patient was successfully weaned off adalimumab after 26 months of therapy. Treatment was unsuccessful in four out of 11 patients (36%) who underwent colectomy 4–13 months (median 7 months) from the first adalimumab dose. The remaining patient developed extensive rash and was switched to alternative therapy. Conclusion In this case series, our experience shows that there is a role for adalimumab as a combination therapy in a subgroup of children with refractory UC.

P-007: Effect of Th-1 and Th-17 prototype cytokines on endothelial microparticle formation in vitro: implication for vascular dysfunction in inflammatory bowel disease

2.75±0.14, P = 0.11). Dysbiosis was observed in all CD patients prior to therapy. EEN therapy had a positive effect in all patients, with 80% going into remission. In some patients, the positive effect diminished following the conclusion of EEN therapy. Significantly, the number of operational taxonomic units (OTU) decreased dramatically upon starting EEN and this corresponded with CD remission. Recurrence of CD corresponded with an increase in OTUs. Six families within Firmicutes were found to behave consistently during and following EEN therapy, frequently correlating with disease activity, a finding confirmed by whole genome HTS. Our results demonstrate that EEN leads to common and patientspecific alterations in the microbiota of CD patients, a number of which correlate with disease activity.

The role of exclusive enteral nutrition in the management of orofacial granulomatosis in children.

BackgroundOrofacial granulomatosis (OFG) is a term used to describe a persistent, painless swelling of lips and orofacial region. It can be associated with ulceration, gingival hypertrophy and cobble stone appearance of the buccal mucosa. OFG is commonly associated with Crohn’s disease and can precede the intestinal manifestation of the disease. Exclusive enteral nutrition (EEN) is a recognized treatment for induction of remission for Crohn’s disease. The aim of this study was to review the use of EEN in the management of OFG in children.MethodsRetrospective review of medical records of all children diagnosed with OFG between 2007 and 2012 was conducted. Presence of comorbidities, progression to inflammatory bowel disease (IBD) and response to EEN was evaluated.ResultsTwenty-nine children were included, mean age at diagnosis was 9 years (standard deviation 3.9) years. Ten children had isolated OFG and 19 had OFG and IBD, of which 12 presented with OFG and IBD and 7 developed IBD later. Median time to progression to IBD was 33 months (inter quartile range: 9.8-85.5). Twenty-two children completed 6 weeks of EEN, and 19 showed clinical improvement in the OFG appearance.ConclusionEEN appears to be an effective treatment option for children with isolated OFG or OFG and IBD.

OP-16 DIETARY INTERVENTION USING THE LOW FODMAP DIET VERSUS THE "MILK, EGG, WHEAT AND SOYA FREE" DIET FOR TREATMENT OF FUNCTIONAL GUT DISORDERS A SINGLE CENTRE EXPERIENCE.

Introduction: The adolescent clinic is a tertiary referral clinic including patients with a wide variety of complex gastroenterology conditions predominantly tertiary referrals fromGreat Ormond Street Hospital transition clinic. Purpose: To assess the benefit of the low FODMAP diet versus the “Milk, egg, wheat and soya” (MEWS) free diet for symptom control in patients with functional gut disorders and/or food allergy from June 2013 to June 2015. Methods: A total of 436 patients were seen during this time period for dietetic advice and the age range varied from 13–21 years old with 43terms of diagnosis used. These included the broad categories of inflammatory bowel disease, food allergy, functional gut conditions, congenital gut disorders, autoimmune disorders and oncology conditions. For functional gut disorders/food allergy there were 14 terms used which varied from “Functional gut disorder” to “Irritable bowel syndrome” and also included patients with delayed gastric emptying. For patients with food allergy the terms “multiple food allergy” or EosinophilicOesophagitis or Colitis were used. A total of 40 patients with functional gut disorders were referred for the MEWS or low FODMAP diet. The efficacy of the diet was measured using a symptom scale pre and post dietary intervention assessing if patients symptoms changed from nil/mild/moderate tosignificant. The results indicate whether the presenting predominant symptom e.g., bloating, constipation or abdominal pain improved following the dietary intervention. Results: A total of 29 patients were seen for the “MEWS” free diet.These were 17 functional, 3 food allergy, 6 IBS, 2 EosinophilicOesophagitis, 1 oncology patient. The age ranged from 14 to 21 and average ageat treatment was 16.6 years old with 11 males and 18 females. 13 patients were referred for the low FODMAP diet. The patients referred for the low FODMAP diet were 7 with a functional gut disorder, 5Irritable Bowel Syndrome and1 EosinophilicColitis.The age range was 14 to 19 years old with average age at treatment 16.3 years old. There were 6 males and 7 females. The success rate of the MEWS diet measured by reported significant improvement in predominant presenting symptom was 14/29 (48.2%),moderate 4/29 (13.7%) mild 2/29(6.9%) and 9/29 (31%) nil improvement. For the low fodmap diet 6/13 (46.1%) of patientsreported a significant improvement in symptoms,0/13 (0%) moderate,mild 2/13 (15.4%)and 5/13 (38.5%) had nil improvement. Conclusions: This review suggests that although there were larger referral rates for the MEWS diet both the MEWS and low FODMAP diet appear to beequally effective dietary approaches for treating patients with functional gut disorders and/or food allergy.