The spectrum of autoimmune cholangitis in childhood

Abstracts / Digestive and Liver Disease 39 (2007) A49–A87 Results. Forty-six single-nucleotide polymorphisms (SNPs) were identified. The SNPs indicated below were significantly (p < 0.05) more frequently identified in IBD affected children than in healthy controls: hBD1-113T/C, hBD1-361A/G, hBD2-319+26A/G, hBD2-319+53G/A, hBD3-87A/G, hBD4-73+29G/T, hBD4-73+192T/C, hBD4-73+158A/G, hBD473+114C/A, hBD4-73+77C/T, hBD4-285+26C/T, hBD4-285+99C/T, hBD4-285+13C/T and hBD-285+26A/G. No associations between genotype and type of disease were identified. Conclusions. This is the first investigation on hBD genotyping in children with IBD. Some hBDs genetic variants are significantly associated with IBD. Our preliminary data support the hypothesis of a role of hBDs in the development of paediatric onset IBD. doi:10.1016/j.dld.2007.07.055 CO 5 CHARACTERIZATION OF MUCOSA-ASSOCIATED ESCHERICHIA COLI STRAINS FROM PAEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE M.P. Conte, S. Schippa, O. Borrelli, V. Lebba, M. Aleandri, L. Seganti, C. Longhi, F. Chiarini, J. Osbornand, T. Federici, S. Cucchiara Department of Public Health Sciences and Department of Pediatrics, La Sapienza University of Rome, Italy Background and aims. Most studies performed on adult patients with inflammatory bowel disease have been addressed to mucosa-associated Escherichia coli strains, which more than others seem to be involved in the pathogenesis of this illness. This study aimed to investigate whether, among E. coli isolated from biopsies of children affected by Crohn’s disease and ulcerative colitis, a specific bacterial subset could be delineated. Methods. Biological and molecular techniques were used to explore some common virulence-associated biological properties and determinants in 60 E. coli strains isolated from biopsy samples (Crohn’s disease, n = 10; ulcerative colitis, n = 6; healthy controls, n = 10). Results. The analysis of biochemical and enzymatic activities did not indicate any characteristic biochemical profile associated with a specific disease. A significant higher percentage of adhesive strains to Caco-2 cells were found in ulcerative colitis and controls than in Crohn’s disease, as well as a general increase of the adhesion level to neuraminidase-treated cells in all studied groups. Phylogenetic analysis did not show significant differences in the distribution among the IBD patients and controls. The genomic and plasmidic analysis of the E. coli strains highlighted the absence of a dominant genotype associated with a specific pathology and the presence of indistinguishable or correlated genotypes only within the same patient. Conclusions. The overall results obtained from this investigation fail to identify a specific pathogenic bacterial subset among mucosa-associated E. coli strains isolated from paediatric IBD, and strengthen the hypothesis that these strains are part of the normal transient flora. doi:10.1016/j.dld.2007.07.056 CO 6 SHORT-TERM RESPONSE TO ADALIMUMAB IN CHILDREN WITH INFLAMMATORY BOWEL DISEASE F. Civitelli, F. Nuti, F. Viola, M. Paganelli, E. Romeo, M. Aloi, M. Neaga, M. Barbato, S. Lucarelli, T. Federici, S. Cucchiara Pediatric Gastroenterology and Liver Unit – University of Rome “La Sapienza”, Italy Adalimumab (HUMIRA, Abbott® ), a fully human anti-TNF␣ monoclonal antibody, is approved for treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and Crohn’s disease (CD) in adults; it is indicated in the induction and maintenance of remission in patients (pts) with Crohn’s disease, regardless of their previous experience with anti-TNF␣ therapy. There are no reports on its use and efficacy in paediatric IBD.

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Aim. To evaluate efficacy and tolerability of Adalimumab (ADA) in paediatric pts with CD and enteropathic spondyloarthropathy (SpA), na¨ıve to or with prior infliximab (IFX) therapy. Patients and methods. Eleven (nine CD and two SpA) paediatric pts, na¨ıve (three pts: one CD and two SpA) or who had failed prior anti-TNF therapy (eight pts), were treated with ADA. For induction of remission we used 160 mg (in four pts) or 80 mg (in six pts) sc at week 0 followed, respectively, by 80 mg or 40 mg at week 2. The maintenance dose was, respectively, 80 mg or 40 mg every 2 weeks (weeks). One patient received an induction dose of 120 mg sc followed by 80 mg after 2 weeks. Results. The mean age at time of first treatment with HUMIRA was 15.9 ± 4 years. The mean disease duration was 44.7 ± 28.1 months. Eight pts had previously received infliximab therapy (6.5 ± 3.2 doses), which was discontinued for loss of efficacy (five pts) or intolerance (three pts; acute infusion reactions); the mean time from the last IFX dose and the beginning of ADA therapy was 21 ± 23.1 months. Concomitant immunosuppressors were maintained in five pts (AZA at 2 mg/kg/day); seven pts were receiving corticosteroids at the entry into the study. The mean PCDAI and ESR values at weeks 0, 2, 4 and 12 are shown in Table 1. Mean PCDAI decreased from 42.9 ± 8.1 at week 0 to 16.4 ± 6.1 (p < 0.01) at week 2. Six pts reached at least 3 months follow-up; five maintained clinical response; at week 12 there was a trend towards a slight increase in PCDAI. No patient had serious adverse effects; three pts complained of local pain and erythema. Conclusion. Our preliminary data suggest that ADA can rapidly induce clinical response in children with IBD, regardless of their prior treatment with infliximab. These encouraging findings need to be investigated with a longer follow-up in a larger paediatric population. Further investigation is also needed to find the best dose for maintenance therapy in children. Table 1 Week 0 PCDAI 42.9 ± 8.1 ESR 50.3 ± 36

Week 2

p

Week 4

p

Week 12

p

16.4 ± 6.1 <0.01 17.8 ± 9.7 <0.05 29 ± 13.2 ns 24.7 ± 10.9 <0.05 25 ± 16.2 <0.05 39.3 ± 19 ns

doi:10.1016/j.dld.2007.07.057 CO 7 THE SPECTRUM OF AUTOIMMUNE CHOLANGITIS IN CHILDHOOD M. Sciveres a , O. Bernard b , N. Giurici c , A. Ventura c , G. Maggiore a a

Dip. di Medicina della Procreazione e dell’Et`a Evolutiva, Universit`a di Pisa, Italy b Service d’H´ epatologie P´ediatrique, Hˆopital Le Kremlin-Bicˆetre, France c IRCSS “Burlo Garofalo”, Trieste, Italy

Aims. Autoimmune cholangitis (AC) is debated as a distinct clinical entity. In childhood autoimmune liver disease (ALD), biliary damage occurs frequently, independently to the evidence of large bile ducts changes; however, a systematic description of a large series of children with AC has never been attempted to date. Patients and methods. We followed 70 paediatric patients with ALD and histological and/or imaging evidence of bile duct damage by transhepatic and/or RM cholangiography, referred to one of the three institutions participating to the study in the last two decades. Results. There were 39 males (M:F 1.3:1), median age at onset was 9.6 years. In 48 (70%), an inflammatory bowel disease (IBD) was associated and was symptomatic in all but eight. Mean ALT activity was 7.06 × N, mean gGT 5.65 × N and all but nine patients presented hypergammaglobulinaemia. AutoAb was present in 87% of patients (SMA 57%, ANA 51%, p/c-ANCA 39%, LC1 5%, LKM1 none). Histological examination showed autoimmune hepatitis (AIH) with minimal biliary damage in 9, an overlap of cholangitis/hepatitis in 22 and an autoimmune sclerosing cholangitis (ASC) in 27. Signs of acute and chronic cholangitis were equally present; 40% showed ductular fibrosis and 11% biliary granulomas. Cirrhosis was histologically evident in 15% at onset. Imaging of biliary tree at onset showed a normal

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Abstracts / Digestive and Liver Disease 39 (2007) A49–A87

picture in 36%, dilatation of intra-/extra-hepatic ducts without obstacles in 26% and a typical picture of ASC in 38%. Median follow-up was 7.5 years. At histological re-evaluation evidence of disease progression to F3/4 fibrosis was present in 50% and radiological evidence of sclerosing lesions in 64 %. In nine patients imaging follow-up documented evolution from normal or dilated bile duct to ASC. However, fully recovery on immunosuppressive treatment of dilated bile ducts was documented in three out of seven patients. Two patients underwent orthotopic liver transplantation. Conclusion. AC in childhood is a slowly progressive disease, strictly associated to IBD and distinct from AIH. Progression toward ASC is frequent but not mandatory. doi:10.1016/j.dld.2007.07.058 CO 8 FOOD ALLERGY IN LIVER TRANSPLANTED CHILDREN N. Di Cosmo, M. D’Ambrosi, M. Caropreso, G. Capuano, S. Lenta, R. Iorio, P. Vajro Department of Pediatrics - University of Naples “Federico II”, Naples, Italy Background and aims. Calcineurin inhibitors – mainly tacrolimus – are involved in paediatric organ transplant-acquired food allergy (TAFA) as a result of imbalance between Th1/Th2 cells. Incidence varies among series. We evaluated the incidence of TAFA in 91 Italian liver transplanted children and looked at whether peripheral eosinophilia and/or elevated total IgE are common findings in this condition. Material and methods. A retrospective charts review of 91 children who underwent liver transplantation was performed. Biliary atresia was the most common indication (76%). Sixty-six patients were taking tacrolimus, 25 cyclosporine. Intestinal, respiratory and cutaneous allergic signs and symptoms, total (normal values according to age) and specific IgE (normal values <0.35 KU/l) for most common food allergens and eosinophils count (normal values <450 mm3 and/or <6% WBC) were recorded. Results. More than half of liver transplanted patients taking tacrolimus had eosinophilia (55%) and increased total IgE (52.6%) versus 12% (p < 0.001) and 32% (p = NS) of those taking cyclosporine, respectively. 13/91 (14%) patients developed clinical symptoms suggestive of single (N = 5) or multiple (N = 8) food allergy at the age of 3.1 ± 3.0 years (range 0.8–11). All of them (100%) were taking tacrolimus. Age at transplantation of TAFA patients was significantly lower than that of patients without TAFA (0.9 ± 0.3 years; range 0.4–1.4 vs. 4.2 ± 4.5 years; range 0.4–18; p = 0.0088). None had relevant abnormalities of liver tests. Eosinophils count was elevated in 7/13 (54%); total IgE were elevated in 13/13. The most common food allergens were legumes (8/13) and egg (6/13). Angiooedema was the most common clinical sign (N = 9; associated with urticaria in 2 of them), followed by isolated urticaria (N = 2) and GI symptoms (N = 2). 12/13 patients responded to exclusion of the most probable clinical triggering food allergen(s), although 3 of them presented minor relapses. One patient with multiple food allergy dependent giant urticaria needed switching to cyclosporine to control TAFA symptoms followed by successful reintroduction of food allergens. Conclusions. Our results confirm that tacrolimus plays a relevant role in triggering TAFA and show that early age at liver transplantation may be an additional risk factor. Eosinophilia (especially in patients taking tacrolimus) and increased serum total IgE are a frequent finding in liver transplanted children with and without TAFA. Food allergy should be included in the list of not uncommon complications in early liver transplanted pediatric patients taking tacrolimus. Switch to cyclosporine should be proposed if TAFA symptoms persist after exclusion diet. doi:10.1016/j.dld.2007.07.059

CO 9 GASTRO-OESOPHAGEAL REFLUX AND CHRONIC UNEXPLAINED COUGH IN CHILDREN: USE OF COMBINED MULTICHANNEL INTRALUMINAL IMPEDANCE AND PH-METRY (MII-PH) O. Borrelli a , C. Marabotto a , M. Aloi a , F. Galos a , T. Federici a , F. Macr`ı b , F. Midulla b , V. Mancini a , S. Cucchiara a a

Department of Pediatrics, Gastroenterology Service, University of Rome, Rome, Italy b Department of Pediatrics, University of Rome, Rome, Italy

The prevalence of relationship between gastro-oesophageal reflux disease (GERD) and chronic cough in children is estimated to be 15%. Although oesophageal acid reflux has traditionally been considered the most important cause, it has recently been suggested that non-acid reflux may have a role in the genesis of chronic cough. Aim. We aimed at assessing the temporal relationship between cough and different types of reflux (acid, weakly acidic, weakly alkaline), as measured by multichannel intraluminal impedance and pH monitoring (MII-pH), and at comparing the reflux patterns between children with refluxrelated cough and those with typical symptoms of erosive reflux disease (ERD). Methods. Thirty-two children (median age 5.8 years; range 1–12 years) with unexplained chronic cough underwent 24-h MII-pH. The MII-pH parameters evaluated were: total numbers of reflux episodes (TN), numbers of acid reflux episodes (pH < 4; AR), weakly acidic reflux episodes (pH 4–7; MAR), weakly alkaline reflux episodes (pH > 7; NAR) and height of refluxate (proximal, intermediate, distal extension). Symptom index (SI) was also evaluated. The 24-h MII-pH was considered abnormal on basis of quantitative (oesophageal acid exposure was >5%) or qualitative analysis (symptom index >50%). Controls consisted of 17 children (median age 5.3 years; range 1–14 years) with typical gastrointestinal symptoms and ERD. Results. Twenty children (62%) were classified as chronic cough-related GERD (CRG), whereas in the remaining 12 (37%) no relationship between cough and GER was found. A total of 1487 and 1260 reflux episodes were detected in children with CRG and in controls, respectively. No differences in the proportion of AR, MAR and NAR were found between the two groups [CRG group: AR 1049 (70%), MAR 260 (17%), NAR 178 (13%); Controls: AR 857 (68%), MAR 251 (20%), NAR 152 (12%); p > 0.05]. Although in both groups the majority of reflux episodes had proximal extent, the proportion was significantly higher in controls [CRG: 936/1487 (63%); controls: 857/1260 (68%; p < 0.05)]. In CRG group, a total of 209 cough were recorded, and 102 (49%) were temporally related to reflux episodes: 74 (73%) with AR, 28 (27%) with MAR and NAR (p < 0.01). Cough bursts during the study were recorded in 16 of CRG children, and among them 11 (69%) patients had a positive SI [6 (37.5%) with AR, 3 (19%) with AR and NAR, and 2 (12.5%) with NAR], whereas 5 (31%) had a negative SI. Conclusions. In children with chronic chough-related GERD, non-acid reflux plays an important role in the genesis of symptom. MII-pH, providing a temporal relationship between cough and the different reflux types (acid, weakly acid, weakly alkaline), increases the yield of standard pH testing in identifying positive symptom indices. Finally, the type and the proximal extent of reflux episodes seem to be not involved in the genesis of cough, suggesting that different factors may underlie clinical expression of the disease. doi:10.1016/j.dld.2007.07.060