Abstract: BACKGROUND: To date, a number of high-profile studies have yielded over 50 inflammatory bowel disease (IBD) disease genes/loci. The polymorphisms rs9858542 (BSN) and rs3197999 (MST1), on 3p21 locus, have been found associated with susceptibility to IBD. We aimed to replicate these associations in adult and early-onset cohorts of IBD Italian patients, by analyzing also potential gene-gene interactions with variants in NOD2/CARD15, IL23R, ATG16L1, and IRGM genes, and investigating genotype-phenotype correlation. METHODS: In all, 1808 patients with IBD, 855 with Crohn's disease (CD) and 953 with ulcerative colitis (UC), including 539 patients with their initial diagnosis <19 years of age, and 651 controls were analyzed for SNPs rs9858542 and rs3197999. RESULTS: BSN and MST1 were significantly associated with either CD (P(rs9858542) 2.5 x 10(-7); P(rs3197999) 3.9 x 10(-7)), and UC (P(rs9858542) = 3.1 x 10(-4); P(rs3197999) = 8 x 10(-4)). Prevalence of these variants was significantly increased in both adult and early-onset IBD patients. After stepwise logistic regression, the 2 variants were associated in adult UC with distal colitis (P(rs9858542) = 0.013, odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.16-3.59; P(rs3197999) = 0.018, OR 1.9, 95% CI 1.2-3.3), while the rs3197999 variant was inversely associated with occurrence of extraintestinal manifestations in adult CD(P = 0.017, OR 0.6, 95% CI 0.4-0.9). CONCLUSIONS: We confirmed the association of BSN and MST1 with IBD susceptibility, either in the adult or the early-onset cohorts. These variants appeared to influence either the distal location of the disease in the UC cohort and extraintestinal manifestations in CD patients.
Abstract: BACKGROUND: Small bowel endoscopy is critical in revealing an inflammatory bowel disease (IBD) previously undetected and in classifying the IBD patients, i.e. Crohn's disease or ulcerative colitis. METHODS: A prospective paediatric study on the usefulness of wireless capsule endoscopy (WCE) was performed in 117 children (age range: 4-17 years) with established or suspected IBD and compared with non endoscopic imaging tools. All patients underwent upper and lower gastrointestinal endoscopy. RESULTS: In Crohn's disease patients (CD, n=44), small bowel lesions were revealed by imaging tools in 8 and by WCE in 18 patients, respectively (p<0.01). No small bowel involvement was observed in 29 ulcerative colitis patients by both imaging tools and WCE. Of 26 unclassified IBD, small bowel lesions typical of Crohn's disease were detected by imaging in 7 and by WCE in 16 (p<0.05). Of 18 patients with suspected IBD, small bowel lesions typical of Crohn's disease were observed in 9 with WCE, vs. only in 4 with imaging (p<0.01). No cases of capsule retention occurred. CONCLUSIONS: WCE is valuable in revealing small bowel lesions in children with a previous diagnosis of CD and unexplained clinical and laboratory data. It is also helpful in unclassified IBD patients. This tool can influence the management and the course of IBD.
Abstract: AIM: Our aim was to compare the efficacy and tolerability of loperamide and racecadotril in elderly patients with acute diarrhea. RESEARCH DESIGN AND METHODS: We performed a randomized, prospective, double-blind, and parallel group design implemented in geriatric nursing homes in Catanzaro, Italy, from February 2008 to March 2009. Patients of both sexes were randomly allocated to receive either one tablet of racecadotril 100 mg every 8 h or two tablets of loperamide 2.0 mg followed by one tablet after each unformed stool, up to four tablets in any 24-h period. Patients were treated until recovery, defined as the production of two consecutive normal stools or no stool production for a period of 12 h. RESULTS: Normal stools were collected 36 +/- 4 h after the beginning of racecadotril and in 63 +/- 6 h from the beginning of loperamide administration (P < 0.01). The median time of abdominal pain in the intent-to-treat (ITT) population was 14 h for racecadotril and 28 h for loperamide. In the per-protocol (PP) population, the median time of abdominal pain was 14 h for racecadotril and 32 h for loperamide (P < 0.01). About the 50% of patients experienced at least one adverse event during the study: 12% in the racecadotril group and 60% in the loperamide group. The most frequently occurring adverse events were nausea and constipation. Genetic analysis did not report the presence of rapid or poor metabolizers. Pharmacoeconomic analysis performed at the end of our study documented an increase in costs in the loperamide group with respect to the racecadotril group (P < 0.01). CONCLUSIONS: Racecadotril is more effective than loperamide-probably due to drug interaction with loperamide-and it is not related to pharmacogenetic susceptibility. Racecadotril is also more cost effective than loperamide.
Abstract: 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.
Abstract: BACKGROUND: Celiac Disease (CD) is an autoimmune disorder of the small intestine in which dietary gluten ingestion leads to a chronic enteropathy. Recently, scientific evidence suggested a potential role of gut microbiota in CD. To have a snapshot of dominant duodenal microbiota we analyzed the mucosa-associated microbiota of 20 children with CD, before and after a gluten-free diet (GFD) regimen, and of 10 controls. Total DNA was extracted from duodenal biopsies and amplification products of 16S ribosomal DNA were compared by temporal temperature gradient gel electrophoresis (TTGE). TTGE profiles were analyzed by statistical multivariate analysis. RESULTS: The average number of bands in TTGE profiles was significantly higher (P < 0.0001) in active (n.b. 16.7 +/- 0.7) and inactive states (n.b. 13.2 +/- 0.8) than in controls (n.b. 3.7 +/- 1.3). Mean interindividual similarity index was 54.9% +/- 14.9% for active disease, 55.6% +/- 15.7% for remission state and 21.8% +/- 30.16% for controls. Similarity index between celiac children before and after GFD treatment was 63.9% +/- 15.8%. Differences in microbiota biodiversity were among active and remission state (P = 0.000224) and amid active CD and controls (P < 0.001). Bacteroides vulgatus and Escherichia coli were detected more often in CD patients than in controls (P < 0.0001). CONCLUSIONS: Overall, the results highlighted a peculiar microbial TTGE profile and a significant higher biodiversity in CD pediatric patients' duodenal mucosa. The possible pathophysiological role of these microbial differences needs further characterization.
Abstract: BACKGROUND: Innate immunity has been very rarely investigated in ulcerative colitis and never in paediatrics. The present study was aimed at describing expression of innate immunity genes (NOD2, RIP2, α-defensins HD5 and HD6) in inflamed colon and in ileum of children with ulcerative colitis. Expression of TNFα and IL-1β was also analyzed. METHODS: 15 children with ulcerative colitis (9 pancolitis, 6 left-sided colitis) and 10 control children were enrolled. mRNA and protein expressions were detected by real time PCR and western blot assays. RESULTS: NOD2, RIP2, IL-1β, TNFα expression levels were significantly increased in colonic mucosa of patients compared to controls (p<0.01). These genes were also upregulated (p<0.01) in the ileum of both pancolitis and left-sided colitis children. HD5 and HD6 were significantly upregulated (p<0.01) in the inflamed colon of patients as well as in the ileum of those with pancolitis. CONCLUSIONS: An increased mucosal expression of innate immunity genes was found in the inflamed colon of children with ulcerative colitis, outlining the role of the innate immune response in disease pathogenesis. Involvement of the ileum in ulcerative colitis suggests that an immune activation can also be established in intestinal sites classically uninvolved by the inflammation, carrying implications for the treatment and course of the disease.
Abstract: OBJECTIVES: Regulatory T cells (TR cells) play a crucial role in the regulation of intestinal inflammation. To examine the pathogenetic relevance of TR cells in inflammatory bowel disease (IBD), we evaluated their frequency in peripheral blood and inflamed and noninflamed mucosae of pediatric patients with IBD and age-matched controls without IBD; we also characterized the immune profile of the inflammatory infiltrate in the different phases of the disease. PATIENTS AND METHODS: Circulating TR cells were investigated on peripheral blood mononuclear cells by fluorescence-activated cell sorting analysis; mucosal TR cells and inflammatory cell populations were investigated by immunohistochemistry on bioptic specimens. FOXP3 messenger RNA expression levels were confirmed using real-time polymerase chain reaction. RESULTS: FOXP3+ TR cells were significantly increased in the intestinal lesions of patients with active IBD, and returned to normal levels in posttherapy remission phase. At variance, circulating TR cell frequency was elevated in patients with IBD independently of disease activity, as it persisted in the remission phase. A selective imbalance in the frequency of CD4+ T and natural killer cell subsets characterized the abundant inflammatory infiltrate of active intestinal lesions, and also persisted, at a lower level, in noninflamed mucosae of patients in the remission phase. CONCLUSIONS: TR cell frequency is differently regulated in mucosal tissues and at the systemic level during the distinct phases of pediatric IBD. The inactive stage of pediatric IBD is characterized by an incomplete normalization of the immune profile, independently of the clinical efficacy of the therapy. The pediatric, early-onset condition may represent a privileged observatory to dissect the immune-mediated pathogenetic mechanisms at the basis of the disease.
Abstract: OBJECTIVES:: This study was aimed at showing the safety, for young patients with celiac disease (CD), of sweet baked goods made of wheat flour, which was rendered gluten-free during sourdough fermentation. METHODS AND RESULTS:: As shown by R5 antibody-based sandwich and competitive enzyme-linked immunosorbent assay (ELISA), selected lactobacilli and fungal proteases, routinely used in bakeries, degraded gluten to <10 ppm during sourdough fermentation. The resulting flour was mainly a mixture of water-/salt-soluble low-size peptides and free amino acids. Gliadin and glutenin fractions extracted from the pepsin-trypsin (PT) digest of the fermented wheat flour induced the expression of interferon (IFN)-γ at the level comparable with the negative control. After fermentation, the wheat flour was spray dried and used for making sweet baked goods. Eight patients with CD in remission were enrolled for the clinical challenge, and they daily consumed 200 g of sweet baked goods equivalent to 10 g of native gluten. Hematology, serology (total serum IgA, IgG and IgA antigluten, endomysial and tissue transglutaminase IgA antibodies), and intestinal permeability analyses were carried out over time. One patient interrupted the trial after 15 days and another after 30 days only due to difficulties in the compliance of the daily consumption. All of the other patients showed normal values of hematology, serology, and intestinal permeability during 60 days of challenge. CONCLUSIONS:: This study showed that a wheat flour-fermented product, having gluten completely degraded, is not toxic for patients with CD. Nevertheless, these foods should not be recommended for patients with celiac disease until a formal trial has been done.
Abstract: 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.
Abstract: BACKGROUND:: Endoscopic balloon dilation (EBD) is an attractive conservative therapy for Crohn's disease (CD) with stricture; however, its long-term efficacy has been questioned because many patients require more dilations or postdilation surgery. Most reports are retrospective, and no pediatric data are available. OBJECTIVE:: To assess the effectiveness of corticosteroid intralesional injection after EBD in preventing stricture recurrence. DESIGN:: Single-center prospective, randomized, double-blind, controlled trial. SETTING:: Tertiary-referral university hospital. PATIENTS:: Between November 2005 and January 2009, 29 pediatric patients with stricturing CD were enrolled. INTERVENTIONS:: Enrolled patients were randomized to receive intrastricture injection of corticosteroid (CS) (n = 15) or placebo (n = 14) after EBD. Patients were followed clinically via small intestine contrast US and intestinal magnetic resonance imaging at 1, 3, 6, and 12 months; all underwent colonoscopy 12 months after dilation. MAIN OUTCOME MEASUREMENTS:: Time free of repeat dilation and time free of surgery in the 2 groups. RESULTS:: One of the 15 patients receiving CS required redilation, whereas the latter was needed in 5 of the 14 placebo patients; surgery was needed in 4 of the placebo patients, but in none of those receiving CS. The 2 groups statistically differed in the time free of redilation (P = .04) as well as for time free of surgery after EBD (P = .02), which were worse in the placebo group compared with the CS group. There were no significant differences in baseline demographics between the 2 groups. LIMITATIONS:: Sample size, participation bias, and short-term follow-up. CONCLUSION:: In pediatric CD with stricture, intralesional CS injection after EBD is an effective strategy for reducing the need both for redilation and surgery.
Abstract: OBJECTIVE: The aim of this prospective study was to compare the diagnostic yield of MR enterography (MRE) with small-bowel capsule endoscopy (SBCE) in paediatric patients with suspected Crohn's disease (CD). METHODS: Paediatric patients with suspected CD were considered eligible to be enrolled in the study. All patients underwent diagnostic work-up including 1.5-T MRE, ileo-colonoscopy and oesophagogastroduodenoscopy. SBCE was not performed if MRE showed SB stricture or extra-intestinal findings consistent with symptoms. RESULTS: Sixty consecutive paediatric patients (36 male; average age 14) were enrolled into the study. A positive diagnosis for CD was made in 19 patients, 29 had a negative result and 12 were affected by other gastro-intestinal conditions. SBCE was performed in 37 patients (61.7%); 23 patients were excluded (strictures in five, extra-intestinal findings in 11 and parents' refusal in seven cases). The accuracy, sensitivity, and specificity of MRE and SBCE were 98.3%, 100%, 97.6%, and 91.9%, 90.9%, 92.3%, respectively. CONCLUSION: Both MRE and SBCE are accurate methods for patients with suspected CD. MRE can be used as a primary imaging technique in suspected CD, in that it allows access to the ileal stricture, which forms a contra-indication for SBCE and provides extra-intestinal information.
Abstract: 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.
Abstract: 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.
Abstract: Inflammatory bowel diseases (IBDs) are lifelong inflammatory gastrointestinal diseases starting in about one third of patients during childhood. Treatment strategies aim to control this chronic inflammatory process. Owing to recent advances in the understanding of IBD, immunosuppressive agents (mainly against TNFalpha directed) as well as biological drugs are more and more often used. This therapeutic approach clearly improved the clinical condition of the majority of patients with IBD. However, with this more aggressive treatment strategy, safety concerns clearly arise. Recently, the description of a series of a particularly severe form of T cell lymphoma in pediatric and young adult patients with IBD under immunomodulator and biological combination therapy raised the question of the risks of treatment-induced side effects or complications. As reviewed in the present article, there is a slightly increased risk of not only lymphoma development in IBD patients, potentially related to the inflammatory process, but also to the use of immunosuppressive therapies. On the basis of the literature data, were analyzed current treatment strategies for children with moderate-to-severe IBD, who are candidates to receive immunomodulator and/or biological agents potentially accelerating the risk of lymphoma development. Comparative clinical studies in IBD are still missing; however, it is prudent to think about adapting immunosuppressive therapies to the inflammatory process of the underlying disorder and if possible to reduce them to monotherapy. Alternative treatment strategies for heavy immunosuppression exist (eg, enteral nutrition in Crohn disease or colectomy in patients with ulcerative colitis) and should be considered whenever appropriate. There is a major need for comparative studies before evidence-based guidelines can be established for safest and best treatment strategies of pediatric patients with IBD.
Abstract: OBJECTIVES: Food allergy is thought to trigger functional constipation in children but the underlying mechanisms are still unknown. Mast cells (MCs) and their relationship with nerve fibers (NFs) in the rectal mucosa, as well as anorectal motility, were studied in children with refractory chronic constipation before and after an elimination diet for cow's milk, egg, and soy proteins. METHODS: Thirty-three children (range: 1-10.8 years) underwent anorectal manometry and suction rectal biopsy before and after 8 weeks of oligoantigenic diet. MCs and NFs were identified immunohistochemically. Quantification of MCs (%MC/area) and MCs within 10 microm of NFs (%MC-NF/area) was performed by computer-assisted analysis. RESULTS: Eighteen children responded to the diet (R-group) and fifteen did not (the NR-group). At baseline there was a significant difference in anal resting pressure (ARP; mm Hg), percentage of relaxation (%R), and residual pressure (RP; mm Hg) of anal canal during rectal distension between the R-group (66+/-4.1, 84.3+/-2.8, 10.4+/-2.3, respectively) and the NR-group (49+/-5, 92.2+/-1.7, 4.8+/-1.7, respectively; P<0.05). After the diet, significant changes in ARP, RP, and %R were observed only in the R-group (44+/-3.7, 93.7+/-1.5, 3.8+/-1.2, respectively; P<0.05). At baseline, the R-group showed an increase in %MC/area (8.3+/-0.7) and %MC-NF/area (5.2+/-2.6) with respect to the NR-group (5.1+/-0.5 and 2.3+/-0.4, respectively; P<0.05). After the diet, only the R-group showed a significant reduction of %MC/area and %MC-NF/area (4.4+/-0.5 and 2.2+/-0.4, respectively; P<0.001). Both ARP and RP significantly correlated with %MC/area and %MC-NF/area; %R showed a significant inverse correlation with both %MC/area and %MC-NF/area. CONCLUSIONS: In children with food allergy-related chronic constipation, an increase in both rectal MC density and spatial interactions between MCs and NFs correlates with anal motor abnormalities. These variables are significantly affected by the diet.
Abstract: BACKGROUND: NOD2 is an intracellular protein involved in host recognition of specific bacterial molecules and is genetically associated with several inflammatory diseases, including Crohn's disease (CD). NOD2 stimulation activates the transcription factor, NF-kappaB, through RIP2, a caspase-recruitment domain-containing kinase. NOD2/RIP2 signaling also mediates the activation of antimicrobial peptides such as human alpha-defensin 5 (HD-5) and human alpha-defensin 6 (HD-6), both produced by Paneth cells. The present study is aimed at describing the downstream events triggered specifically by NOD2 induction in order to demonstrate that the protein, other than overexpressed, is also physiologically associated with RIP2 and Erbin in the bioptic intestinal inflamed specimens of children affected by CD. METHODS: Fifteen children with CD and 10 children used as controls were entered in the study. Mucosal biopsy specimens were taken during endoscopy and mRNA and protein expressions were detected by using real-time polymerase chain reaction and Western blot. RESULTS: NOD2 is able to form an immunocomplex with the kinase RIP2. As compared to controls, in the inflamed mucosa of patients both mRNA and protein expression levels of RIP2 are increased, and its active phosphorylated form is overexpressed. CONCLUSIONS: In this study we provide for the first time ex vivo evidence of physiologically relevant protein interactions with NOD2, which are able to trigger the innate immune response in intestinal mucosal specimens of children with CD.
Abstract: BACKGROUND: Studies performed in adults with inflammatory bowel disease (IBD) have suggested that mucosa-associated Escherichia coli strains may be involved in its pathogenesis. The aim of this study was to characterize E. coli strains from the intestinal mucosa of pediatric IBD patients to investigate whether a particular subset of strains could be associated with the disease. METHODS: We analyzed the genomic and phenotypic traits of 60 E. coli strains isolated from biopsies of pediatric patients with Crohn's disease (CD), ulcerative colitis (UC), and from age-matched controls. RESULTS: No noteworthy differences were found in the distribution of phylogroups. The percentage of adhesive E. coli strains was similar in biopsies from patients and controls. However, the adhesion ability of E. coli strains differed between ileal and colonic or rectal areas, only in the strains from CD and UC patients. The percentage of E. coli possessing more than 1 of the adhesive/virulence determinants was significantly higher in strains from UC than from CD and controls. Interestingly, the genetic profile examination revealed 2 large clusters of genetically linked E. coli strains from IBD patients. Ninety-two percent of the strains isolated from CD patients were in the first cluster (A) and were distributed between 2 genetic subclusters (A1 and A2), while a second cluster (B) contained most of the strains isolated from UC (78%; subcluster B1), and control strains (77%; subcluster B2). CONCLUSIONS: Genomic analysis of mucosa-associated E. coli strains found a close genetic association between strains isolated from CD and UC patients.
Abstract: 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).
Abstract: Diagnosis and follow-up of inflammatory bowel disease (IBD) in children represent a challenging issue for pediatricians. Nowadays MR studies of the bowel represent a valid diagnostic tool especially in the diagnosis and follow-up of ileal and perianal Crohn's disease in children as well as in adults. The lack of ionizing radiation of MRI enhances the interest of clinicians with respect to CT studies of the bowel in children. Thanks to recent technical development in terms of fast MR images acquisition a reasonable image quality can be easily achieved in scholar-age children. A majority of authors prefer MR-enterography approach in children with respect to the more invasive MR-enteroclysis in the assessment of ileal Crohn's disease. Using rigorous technique of MR-enterography represents a feasible and accurate test in the diagnosis of ileal Crohn's disease. Less experience is collected on MR-colonography in pediatric IBD while MRI of the pelvis represents the most accurate non-invasive diagnostic test in the assessment of perianal Crohn's disease in children as well as in adults.
Abstract: OBJECTIVES: The use of tumor necrosis factor-alpha (TNF-alpha) antagonists has changed the therapeutic strategy for Crohn's disease (CD). Adalimumab (ADA), a fully human anti-TNF-alpha monoclonal antibody, is an effective therapy for patients with CD, both naive patients and those intolerant or refractory to Infliximab (IFX), a chimeric anti-TNF-alpha agent. However, the use of ADA is rarely reported in pediatric CD. We performed an open prospective evaluation of short- and long-term efficacy and safety of ADA in children with moderate-to-severe CD. METHODS: A total of 23 pediatric CD patients (9 naive and 14 intolerant or unresponsive to IFX) received ADA subcutaneously as a loading schedule at weeks 0 and 2, and at every other week (eow) during a 48-week maintenance phase. Loading and maintenance doses were 160/80 and 80 mg eow in 13 cases, 120/80 and 80 mg eow in 2, and 80/40 and 40 mg eow in 8 cases. The primary efficacy outcomes were clinical remission and response at different scheduled visits along the maintenance phase. At baseline, 13 patients also received immunomodulators (IMs). RESULTS: At weeks 2, 4, 12, 24, and 48, remission rates were 36.3, 60.8, 30.5, 50, and 65.2%, respectively, whereas response rates were 87, 88, 70, 86, and 91%, respectively. Four patients at week 24 and 2 at week 48 received IMs; the mean daily corticosteroid dose, disease activity index, C-reactive protein level, and erythrocyte sedimentation rate decreased significantly throughout the trial. No serious adverse events were recorded. CONCLUSIONS: ADA can be an effective and safe biological agent for inducing and maintaining remission in children with moderate-to-severe CD, even in those with previous IFX therapy.
Abstract: Chronic intestinal pseudo-obstruction is a severe syndrome characterized by a profound derangement of the intestinal propulsive motility that resembles mechanical obstruction, in the absence of any mechanical obstruction. This syndrome represents one of the main causes of intestinal failure and is characterized by impairment of physical growth and development as well as by a high rate of morbidity and mortality. It may be idiopathic or secondary to a variety of diseases. Most cases are sporadic, even though familial forms with either dominant or recessive autosomal inheritance have been described. Based on histological features intestinal pseudo-obstruction is classified into 3 main groups: neuropathies, mesenchymopathies, and myopathies, according to the predominant involvement of enteric neurones, interstitial cells of Cajal, and smooth muscle cells, respectively. Treatment of intestinal pseudo-obstruction involves nutritional, pharmacological, and surgical therapies, but it is often frustrating and does not change the natural course in the majority of cases. The nutritional management has a crucial importance in pediatric age and involves the administration of special formulae, the enteral delivery of nutrients, by a nasogastric tube, percutaneous gastrostomy, or jejunostomy. In the most severe cases, parenteral nutrition becomes mandatory in order to satisfy nutritional requirements and manage appropriately obstructive episodes.
Abstract: The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.
Abstract: BACKGROUND: Many efforts were made in the past decades to assess the role of gut microbiota in inflammatory bowel diseases (IBD), leading to the hypothesis that an altered microbial composition, other than the presence of a specific pathogen, could be involved in the pathogenesis of the disease. On the other hand, existing differences in gut microbial community between distinct classes of age make sense of an increasing research in microbial shifts in IBD. METHODS: Cultural, molecular, metabolomic and metagenomic approaches are trying to define the human gut microbiota in different age groups. RESULTS AND CONCLUSION: An increase in anaerobic bacteria (Bacteroidesvulgatus, Streptococcus faecalis) was observed in adult IBD, whereas an increase in aerobic and facultative-anaerobic (Escherichia coli) was found in pediatric IBD. Overall higher bacterial cell counts were observed in IBD, jointly with a general loss of biodiversity and a preponderance of Bacteroidetes and a parallel decrease of Firmicutes phylum: a predominance of potential harmful members of Proteobacteria (E. coli) and low abundance of beneficial species (Faecalibacterium prausnitzii) was also reported in pediatric and adult age groups, respectively. Microbial community of elderly subjects contains a wider range of different species than those of children and adults, both in healthy and IBD status.
Abstract: 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).
Abstract: Inflammatory bowel disease in childhood has become the subject of intense scientific debate during the last two decades, when there has been a significant rise in its incidence. There is a commonly agreed view that the disorder in children has peculiarities both in terms of underlying mechanisms and clinical management. This review highlights the emerging pathophysiologic concepts and clinical issues in paediatric inflammatory bowel disease and their effects on the management of children with this disorder are discussed. Particular emphasis is given to the link between the improvement of the research in the pathogenetic mechanisms and the development of novel therapeutic strategies able to promote a change in the natural course of the disorder.
Abstract: BACKGROUND: Variants of myosin IXB (MYO9B) gene, encoding for a motor protein implicated in epithelial permeability, have been recently associated with inflammatory bowel disease. AIMS: To investigate the contribution of three polymorphisms of MYO9B gene for predisposition to Crohn's disease and ulcerative colitis, their association with clinical phenotypes, particularly intestinal permeability, and possible interaction with the CARD15 gene. METHODS: 549 Crohn's disease patients, 658 ulcerative colitis patients and 674 controls were genotyped for the rs962917, rs1545620 and rs2305764 single nucleotide polymorphisms. RESULTS: Highly significant genotypic association with Crohn's disease and ulcerative colitis was shown for all three single nucleotide polymorphisms, with odds ratio ranging from 1.5 to 1.7 (P-value: <0.01 to <0.002). A significant difference in allele frequencies was also observed in inflammatory bowel disease patients, with the single most significant association for rs1545620, detected in 47% of Crohn's disease, 47% of ulcerative colitis patients and 42% of controls (P < 0.005). No association with specific sub-phenotypes was found, with the exception of a trend towards an abnormal intestinal permeability (P = 0.043) in Crohn's disease carrying the rs1545620 risk allele. CONCLUSIONS: Our findings confirm the association between the MYO9B polymorphisms and susceptibility to both ulcerative colitis and Crohn's disease, with a weak influence on sub-phenotypic expression.
Abstract: BACKGROUND: Recent advances in the pathogenesis of Crohn's disease (CD) have suggested that an aberrant innate immune response initiates the cascade of events leading to T-cell activation and to disease development. NOD2 protein, which is mainly expressed by innate immunity cells, appears to play a key role against bacteria by triggering a host defense response through the activation of the transcriptor factor NF-kappaB and a consequent proinflammatory cytokine production. The present study was aimed at investigating the expression and activity of NOD2, NF-kappaB, and of 2 proinflammatory cytokines, TNFalpha and IL-1beta, in mucosal biopsies of CD affected children compared to healthy controls. METHODS: In all, 22 children with active CD and 10 matched controls were entered in the study. mRNA and protein expressions were detected using reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blot; NF-kappaB binding activity was assessed by electromobility gel shift assay (EMSA). RESULTS: NOD2 and IL-1beta mRNAs were upregulated in CD children. Protein levels of NOD2, TNFalpha, and nuclear NF-kappaB, as well as the binding activity of NF-kappaB to a consensus DNA sequence, were significantly increased in inflamed mucosa of patients as compared to controls. Moreover, NF-kappaB activity was strongly upregulated in patients also when bound to the NOD2 promoter site. No difference was seen between patients and controls when NF-kappaB binding activity was determined in the uninflamed tissue. CONCLUSIONS: This study suggests that altered mechanisms regulating NOD2 induction, NF-kappaB activation and cytokine production may contribute to dysregulate the innate immune response underlying pediatric CD.
Abstract: BACKGROUND: DLG5 p.R30Q has been reported to be associated with Crohn disease (CD), but this association has not been replicated in most studies. A recent analysis of gender-stratified data from two case-control studies and two population cohorts found an association of DLG5 30Q with increased risk of CD in men but not in women and found differences between 30Q population frequencies for males and females. Male-female differences in population allele frequencies and male-specific risk could explain the difficulty in replicating the association with CD. METHODS: DLG5 R30Q genotype data were collected for patients with CD and controls from 11 studies that did not include gender-stratified allele counts in their published reports and tested for male-female frequency differences in controls and for case-control frequency differences in men and in women. RESULTS: The data showed no male-female allele frequency differences in controls. An exact conditional test gave marginal evidence that 30Q is associated with decreased risk of CD in women (p = 0.049, OR = 0.87, 95% CI 0.77 to 1.00). There was also a trend towards reduced 30Q frequencies in male patients with CD compared with male controls, but this was not significant at the 0.05 level (p = 0.058, OR = 0.87, 95% CI 0.74 to 1.01). When data from this study were combined with previously published, gender-stratified data, the 30Q allele was found to be associated with decreased risk of CD in women (p = 0.010, OR = 0.86, 95% CI 0.76 to 0.97), but not in men. CONCLUSION: DLG5 30Q is associated with a small reduction in risk of CD in women.
Abstract: 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 </= 2 was consistent with remission. RESULTS: All 22 patients began the study with 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.
Abstract: BACKGROUND: The purpose was to assess in Italy the clinical features at diagnosis of inflammatory bowel disease (IBD) in children. METHODS: In 1996 an IBD register of disease onset was established on a national scale. RESULTS: Up to the end of 2003, 1576 cases of pediatric IBD were recorded: 810 (52%) ulcerative colitis (UC), 635 (40%) Crohn's disease (CD), and 131 (8%) indeterminate colitis (IC). In the period 1996-2003 an increase of IBD incidence from 0.89 to 1.39/10(5) inhabitants aged <18 years was observed. IBD was more frequent among children aged between 6 and 12 years (57%) but 20% of patients had onset of the disease under 6 years of age; 28 patients were <1 year of age. Overall, 11% had 1 or more family members with IBD. The mean interval between onset of symptoms and diagnosis was higher in CD (10.1 months) and IC (9 months) versus UC (5.8 months). Extended colitis was the most frequent form in UC and ileocolic involvement the most frequent in CD. Upper intestinal tract involvement was present in 11% of CD patients. IC locations were similar to those of UC. Bloody diarrhea and abdominal pain were the most frequent symptoms in UC and IC, and abdominal pain and diarrhea in CD. Extraintestinal symptoms were more frequent in CD than in UC. CONCLUSIONS: The IBD incidence in children and adolescents in Italy shows an increasing trend for all 3 pathologies. UC diagnoses exceeded CD.
Abstract: Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.
Abstract: AIM: To investigate gene variants in a large Italian inflammatory bowel disease (IBD) cohort, and to analyze the correlation of sub-phenotypes (including age at diagnosis) and epistatic interaction with other IBD genes. METHODS: Total of 763 patients with Crohn's disease (CD, 189 diagnosed at age < 19 years), 843 with ulcerative colitis (UC, 179 diagnosed < 19 years), 749 healthy controls, and 546 healthy parents (273 trios) were included in the study. The rs2241880 [autophagy-related 16-like 1 (ATG16L1)], rs11209026 and rs7517847 [interleukin 23 receptor (IL23R)], rs2066844, rs2066845, rs2066847 (CARD15), rs1050152 (OCTN1), and rs2631367 (OCTN2) gene variants were genotyped. RESULTS: The frequency of G allele of ATG16L1 SNP (Ala197Thr) was increased in patients with CD compared with controls (59% vs 54% respectively) (OR = 1.25, CI = 1.08-1.45, P = 0.003), but not in UC (55%). The frequency of A and G (minor) alleles of Arg381Gln, rs11209026 and rs7517847 variants of IL23R were reduced significantly in CD (4%, OR = 0.62, CI = 0.45-0.87, P = 0.005; 28%, OR = 0.64, CI = 0.55-0.75, P < 0.01), compared with controls (6% and 38%, respectively). The A allele (but not G) was also reduced significantly in UC (4%, OR = 0.69, CI = 0.5-0.94, P = 0.019). No association was demonstrated with sub-phenotypes and interaction with CARD15, and OCTN1/2 genes, although both gene variants were associated with pediatric-onset disease. CONCLUSION: The present study confirms the association of IL23R polymorphisms with IBD, and ATG16L1 with CD, in both adult- and pediatric-onset subsets in our study population.
Abstract: Headache and recurrent abdominal pain (RAP) are common disorders in children and adolescents, frequently referred to paediatricians. Both disorders show similarities in trigger and comorbid factors, their burden on family and individual life, and a paroxysmal trend with risks of chronicization over time. However, very few studies have compared directly headache and RAP. The main aim of this study was to compare the psychological profile of headache and RAP patients vs. healthy controls. A total of 210 children and adolescents [99 boys, 111 girls; age range 4-18 years; mean age (m.a.) = 11.04, SD 4.05] were assessed: 70 headache patients (m.a. 12.4 years; SD 2.9; F = 35, M = 35), 70 RAP patients (m.a. 9 years; SD 3.6; F = 30, M = 40) and 70 controls (m.a. 11.7 years; SD 4.6; F = 46, M = 24). The diagnoses had been made according to international systems of classification both for headache (ICHD-II criteria) and RAP (Rome II criteria). The psychological profile had been made according to the Child Behaviour Checklist 4-18 (CBCL). anova one-way analysis was used to compare CBCL scales and subscales between groups. Headache and RAP showed a very similar trend vs. control for the main scales of the CBCL, with a statistically significant tendency to show problems in the Internalizing scale (anxiety, mood and somatic complaints) and no problems in the Externalizing (behavioural) scale. Only for the Attention Problems subscale migraineurs showed a significant difference compared with RAP. In conclusion, headache and RAP show a very similar psychological profile that should be considered not only for diagnostic and therapeutic purposes, but also from the aetiological aspect.
Abstract: AIM: To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predisposition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). METHODS: Two hundred patients with Crohn's disease (CD), 186 ulcerative colitis (UC) patients, 434 parents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated. RESULTS: Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001). Homozygosis for both OCTN1/2 variants was more common in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an increased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was more frequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed. CONCLUSION: Polymorphisms of CARD15 and OCTN genes, but not DLG5 are associated with pediatric onset of CD. Polymorphisms of CARD15, OCTN, and DLG5 genes exert a weak influence on CD phenotype.
Abstract: AIM: We investigated the contribution of variants of tumour necrosis factor (TNF)-alpha and MDR1 genes in the predisposition and response to medical therapy in a large pediatric cohort of patients with Crohn disease (CD) and ulcerative colitis (UC). PATIENTS AND METHODS: In this study, 200 patients with CD, 186 patients with UC, 434 parents (217 trios), and 347 healthy unrelated controls were investigated. Single-nucleotide polymorphisms -G308A and -C857T of the TNF-alpha gene and C3435T of the MDR1 gene were investigated and correlated with clinical subphenotypes and efficacy of medical therapy. RESULTS: The frequency of the -308A allele of the TNF-alpha gene was significantly increased in both patients with CD (15%; odds ratio [OR] = 2.79; P < 0.01) and patients with UC (11%; OR = 1.96; P < 0.003) compared with controls (6%). Carriers of this allele were 27% in CD (OR = 2.94; P < 0.01) and 19% in UC (OR = 1.86; P = 0.015) compared with 11% in healthy controls. No significant difference was found for both the -C857T and C3435T single-nucleotide polymorphisms. With the genotype/phenotype analysis, no correlation in patients with UC with the MDR1 gene was found. CD carriers of the -308A allele had a higher frequency of surgical resection (35% vs 20%; OR = 2.1; P = 0.035) and more frequent resistance to steroids (22% vs 8%; OR = 0.29; P = 0.032) compared with noncarriers. These findings were confirmed by stepwise logistic regression. CONCLUSIONS: In our pediatric cohort, the promoter -308A polymorphism of TNF-alpha but not the MDR1 gene is significantly involved in the predisposition to both CD and UC. This polymorphism carries a significant reduction in response to steroid therapy, probably leading to a more frequent need for surgical resection.
Abstract: AIMS: To assess bone mineral density (BMD) in children with Crohn's disease (CD) and ulcerative colitis (UC) and to investigate the role of inflammation and steroids on BMD. METHODS: Lumbar spine areal BMD was measured by DXA, and volumetric BMD was then estimated (BMAD); inflammatory cytokines (TNF-alpha, IL-6, IL-10, and IL-12) were dosed in peripheral blood; and cumulative and daily doses of steroids were calculated. Therapy with infliximab (IFX) was considered for CD patients. RESULTS: Fifty-six patients with IBD (35 CD, 21 UC) were studied. An inverse correlation was found between BMAD and IL-6 in patients with UC (r = -0.65); no correlation was found between BMAD and serum levels of TNF-alpha, IL-10, and IL-12 in all patients. Disease activity indexes use inversely correlated with BMAD (r = -0.62 in patients with CD and r = -0.64 in patients with UC). Cumulative dose of corticosteroids and duration of therapy did not correlate with BMAD. The 10 patients with CD who were treated with IFX had higher BMAD (-1 +/- 0.8) than those never treated with IFX (-1.8 +/- 0.8). Mean Pediatric Crohn's Disease Activity Index and body mass index in patients with CD (R(2) = 0.48) and IL-6 level in patients with UC (R(2) = 0.43) were found to be independent and significant predictors of BMAD. CONCLUSIONS: In children with IBD, inflammation is an important determinant of bone loss, as shown by the correlation of BMAD with serum IL-6 and with disease activity indexes as well as by the beneficial effect of IFX on bone density. Corticosteroids seem to be a less important variable in pediatric IBD-related BMD reduction than previously believed.
Abstract: BACKGROUND: Pediatric onset Crohn's disease (CD) is associated with more colitis and less ileitis compared with adult onset CD. Differences in disease site by age may suggest a different genotype, or different host responses such as decreased ileal susceptibility or increased susceptibility of the colon. METHODS: We evaluated 721 pediatric onset CD patients from 3 cohorts with a high allele frequency of NOD2/CARD15 mutations. Children with isolated upper intestinal disease were excluded. The remaining 678 patients were evaluated for interactions between age of onset, NOD2/CARD15, and disease location. RESULTS: We found an age-related tendency for isolated colitis. Among pediatric onset patients without NOD2/CARD15 mutations, colitis without ileal involvement was significantly more common in first-decade onset patients (P = 4.57 x 10(-5), odds ratio [OR] 2.76, 95% confidence interval [CI] 1.72-4.43). This was not true for colonic disease with ileal involvement (P = 0.35), or for isolated colitis in patients with NOD2/CARD15 mutations (P = 0.61). Analysis of 229 patients with ileal or ileocolonic disease and a NOD2/CARD15 mutation disclosed that ileocolitis was more prevalent through age 10, while isolated ileitis was more prevalent above age 10 (P = 0.016). NOD2/CARD15 mutations were not associated with age of onset. CONCLUSIONS: In early-onset pediatric CD, children with NOD2/CARD15 mutations demonstrate more ileocolitis and less isolated ileitis. Young children without NOD2/CARD15 mutations have an isolated colonic disease distribution, suggesting that this phenotype is associated with genes that lead to a specific phenotype of early-onset disease.
Abstract: The advent of biological therapies has dramatically revolutionized the treatment options for refractory inflammatory bowel disease (IBD). Of all the biologics evaluated to date, infliximab, an anti-tumor necrosis factor-alpha monoclonal chimeric antibody, has been shown to be an extremely potent drug for acute and maintenance treatment of both adult and pediatric patients with severe IBD, especially in those with Crohn's disease, whereas other biological agents are undergoing evaluation in several clinical trials. Although infliximab has preferentially been used as rescue therapy for IBD patients refractory to traditional drugs, clinical and immunological arguments seem to indicate that the biological agents are an advantageous treatment for children with IBD when given early in the course of the disease. This, however, requires multicenter randomized controlled trials to prove.
Abstract: AIM: To evaluate the polymorphisms of several genes involved in the azathioprine and mercaptopurine metabolism, in an attempt to explain their toxicity and efficacy in Crohn's disease and ulcerative colitis. METHODS: In 422 consecutive patients (250 with Crohn's disease and 172 with ulcerative colitis) and 245 healthy controls, single nucleotide polymorphisms of thiopurine methyltransferase, inosine triphosphate pyrophosphatase and hypoxanthine phosphoribosyl transferase (HPRT1) genes were related to the occurrence of adverse drug reactions (ADRs) and efficacy of therapy. RESULTS: Seventy-three patients reported 81 episodes of ADRs; 45 patients did not respond to therapy. Frequency of thiopurine methyltransferase risk haplotypes was significantly increased in patients with leucopenia (26% vs. 5.7% in patients without ADRs, and 4% of controls) (P < 0.001); no correlation with other ADRs and efficacy of therapy was found. Conversely, the frequency of inosine triphosphate pyrophosphatase and HPRT1 risk genotypes was not significantly different in patients with ADRs (included leucopenia). Non-responders had an increased frequency of inosine triphosphate pyrophosphatase risk genotypes (P = 0.03). CONCLUSIONS: The majority of azathioprine/mercaptopurine-induced ADRs and efficacy of therapy are not explained by the investigated gene polymorphisms. The combined evaluation of all three genes enhanced the correlation with leucopenia (43.5% vs. 23% in controls) (P = 0.008), at the expense of a reduced accuracy (60%).
Abstract: BACKGROUND AND AIM: Celiac disease (CD) is a multifactorial disease with involvement of both environmental and genetic susceptibility factors. The HLA-DQ loci account for <40% of CD heritability, but linkage studies have delineated other loci at the 5q31-33 (CELIAC2), and 19p13 regions (CELIAC4), similarly as in inflammatory bowel diseases. However, data in association studies are contradictory. To evaluate whether single nucleotide polymorphisms (SNPs) tagging the MYO9B susceptibility haplotype and the IBD5 locus (5q31-33) are involved in CD predisposition, we performed case-control and family-based analyses. Additionally, any possible correlation with the HLA-DQ status was investigated. Finally, our data were pooled with the results of other studies by a meta-analysis. PATIENTS AND METHODS: In all, 337 unrelated patients with CD, 424 parents (212 sets), and 452 healthy individuals were genotyped for the IGR2198a_1, rs12521868, rs1050152, and rs2631367 SNPs (IBD5 locus) and the rs962917, rs2305764, and rs1545620 SNPs of the MYO9B gene by the restriction enzyme method and the TaqMan system ABI PRISM 7700, respectively. RESULTS: In comparison with healthy control individuals, the allele, genotype, and haplotype frequencies of all investigated SNPs were not different in the CD patients, nor was any correlation observed with the HLA-DQ status or clinical presentation. The transmission disequilibrium test did not show a transmission distortion. Five other studies were available for meta-analysis on MYO9B variants; by pooling of data, no significant association was demonstrated by the random effect model. A significant heterogeneity (P < 0.002) among the studies was present, mainly explained by a single study in the Dutch population. CONCLUSIONS: Our results and those of the meta-analysis (>2000 CD patients and 4000 control individuals) question the role of MYO9B at the CELIAC4 locus as a disease-causing gene. Moreover, none of the investigated SNPs explain the linkage at the CELIAC2 locus.
Abstract: BACKGROUND: Clinical and experimental observations in animal models indicate that intestinal commensal bacteria are involved in the initiation and amplification of inflammatory bowel disease (IBD). No paediatric reports are available on intestinal endogenous microflora in IBD. AIMS: To investigate and characterise the predominant composition of the mucosa-associated intestinal microflora in colonoscopic biopsy specimens of paediatric patients with newly diagnosed IBD. METHODS: Mucosa-associated bacteria were quantified and isolated from biopsy specimens of the ileum, caecum and rectum obtained at colonoscopy in 12 patients with Crohn's disease, 7 with ulcerative colitis, 6 with indeterminate colitis, 10 with lymphonodular hyperplasia of the distal ileum and in 7 controls. Isolation and characterisation were carried out by conventional culture techniques for aerobic and facultative-anaerobic microorganisms, and molecular analysis (16S rRNA-based amplification and real-time polymerase chain reaction assays) for the detection of anaerobic bacterial groups or species. RESULTS: A higher number of mucosa-associated aerobic and facultative-anaerobic bacteria were found in biopsy specimens of children with IBD than in controls. An overall decrease in some bacterial species or groups belonging to the normal anaerobic intestinal flora was suggested by molecular approaches; in particular, occurrence of Bacteroides vulgatus was low in Crohn's disease, ulcerative colitis and indeterminate colitis specimens. CONCLUSION: This is the first paediatric report investigating the intestinal mucosa-associated microflora in patients of the IBD spectrum. These results, although limited by the sample size, allow a better understanding of changes in mucosa-associated bacterial flora in these patients, showing either a predominance of some potentially harmful bacterial groups or a decrease in beneficial bacterial species. These data underline the central role of mucosa-adherent bacteria in IBD.
Abstract: BACKGROUND: Comparative data on the therapeutic efficacy of different enteral nutrition formulas and corticosteroids to obtain clinical remission and to induce mucosal healing influencing long-term disease course in paediatric Crohn's disease are still scarce. AIMS: To investigate the efficacy of nutritional therapy using three different formulas versus corticosteroids to achieve clinical remission as well as to induce intestinal mucosal healing in active Crohn's disease children. Duration of remission and effect on growth recovery were also assessed. PATIENTS AND METHODS: Clinical, laboratory, endoscopic and histological data of all new diagnosed active Crohn's disease paediatric cases were retrospectively recorded and reviewed. Thirty-seven children (median age 12.1 years) received nutritional therapy (12 polymeric; 13 semi-elemental; 12 elemental diet) and 10 subjects (median age 12.4 years) received corticosteroids. RESULTS: Similar clinical remission rate were observed after 8 weeks of treatment: 86.5% children receiving nutritional therapy versus 90% treated with corticosteroids. Improvement in mucosal inflammation occurred in 26 out of 37 (64.8%) patients on nutritional therapy and in 4 out of 10 (40%) children on steroids (p < 0.05). Finally, seven subjects on nutritional therapy and none on corticosteroids achieved complete mucosal healing (p < 0.005) at the end of the treatment. Nutritional therapy was more effective than corticosteroids in improving nutritional status and linear growth recovery. Compared to corticosteroids, the duration of clinical remission was longer in the nutritional therapy groups without differences among the three different formulas. CONCLUSIONS: In children with active Crohn's disease, nutritional therapy is more effective than corticosteroids to improve intestinal inflammation and to maintain a more sustained clinical remission.
Abstract: BACKGROUND & AIMS: Nutritional therapy has been reported to have an almost equivalent efficacy of corticosteroids in achieving clinical remission in active Crohn's disease (CD). However, the effects of both treatments on intestinal mucosal inflammation rarely are reported. In a randomized controlled trial in children with active CD we compared the efficacy of nutritional therapy alone or corticosteroids on clinical variables and intestinal mucosal healing. METHODS: In a prospective, 10-week open-label trial, children with active, naive CD were randomized to orally polymeric formula alone or oral corticosteroids. The clinical activity index and nutritional and activity serum variables were evaluated at week 0 and then every 2 weeks; intestinal mucosal inflammation was assessed through endoscopy and histology at weeks 0 and 10. Primary efficacy outcomes were clinical remission and mucosal healing. RESULTS: Of the 37 children randomized, 19 received polymeric formula and 18 received corticosteroids. At week 10, on an intention-to-treat basis, the proportion of patients achieving clinical remission was comparable between the 2 groups (polymeric formula: 15/19 [79%; 95% confidence interval (CI), 56%-92%]; corticosteroid group: 12/18 [67%; 95% CI, 44%-84%]; P = .4; not significant). On the contrary, the proportion of children showing mucosa healing was significantly higher in the polymeric (14/19; 74%; 95% CI, 51%-89%) than the corticosteroid group (6/18 [33%; 95% CI, 16%-57%]; P < .05). At week 10 both endoscopic and histologic scores significantly decreased only in the polymeric group (P < .001). CONCLUSIONS: In children with active and recently diagnosed CD, a short course of polymeric diet is more effective than corticosteroids in inducing healing of gut inflammatory lesions.
Abstract: BACKGROUND & AIMS: Gastroesophageal reflux disease (GERD) is frequently experienced by infants, and disease-specific measures are needed to evaluate treatment benefits. We revised the Infant Gastroesophageal Reflux Questionnaire (I-GERQ) on the basis of information from parents of infants with GERD and physicians and subjected it to a psychometric evaluation. METHODS: A 3-week, multi-country observational study of 185 caregivers of infants younger than 18 months with GERD and 93 caregivers of control infants was conducted. Caregivers completed the I-GERQ-R weekly and recorded symptoms in a Daily Diary. Caregivers and physicians rated global disease severity and change in overall GERD symptoms. RESULTS: Slightly more than half of infants were male with a mean age of 6.7 months, and most infants had been diagnosed with GERD for a little more than 2 months (mean, 66.7 days). Internal consistency reliability for the I-GERQ-R ranged from 0.86 to 0.87, and test-retest reliability was 0.85. Construct validity was demonstrated by significant differences between cases and controls on all item scores (all P<.01) and the total score (P<.0001), correlations with relevant Daily Diary symptoms, and both physician-rated (P<.05) and caregiver-rated disease severity (P<.05). Mean baseline to 3-week I-GERQ-R change scores for those infants whose caregivers reported improvement was -5.7 compared with -0.3 for those whose caregivers reported worse/same (P<.001). Physician ratings of change resulted in similar findings, with mean changes of -5.7 for those rated improved and -0.1 for those rated as worse/same (P<.0001). CONCLUSION: This study demonstrated the I-GERQ-R is a reliable, valid, and clinically responsive measure of infant GERD symptoms.
Abstract: Experimental evidence indicates that chronic mechanical sub-occlusion of the intestine may damage the enteric nervous system (ENS), although data in humans are lacking. We here describe the first case of enteric degenerative neuropathy related to a congenital obstruction of the gut. A 3-year and 9-mo old girl began to complain of vomiting, abdominal distension, constipation with air-fluid levels at plane abdominal radiology. Her subsequent medical history was characterized by 3 operations: the first showed dilated duodeno-jejunal loops in the absence of occlusive lesions; the second (2 years later) was performed to obtain full-thickness biopsies of the dilated intestinal loops and revealed hyperganglionosis at histopathology; the third (9 years after the hyperganglionosis was identified) disclosed a Ladd's band which was removed and the associated gut malrotation was corrected. Repeated intraoperative full-thickness biopsies showed enteric degenerative neuropathy along with reduced interstitial cells of Cajal network in dilated loops above the obstruction and a normal neuromuscular layer below the Ladd's band. One year after the latest surgery the patient tolerated oral feeding and did well, suggesting that congenital (partial) mechanical obstruction of the small bowel in humans can evoke progressive adaptive changes of the ENS which are similar to those found in animal models of intestinal mechanical occlusion. Such ENS changes mimic neuronal abnormalities observed in intestinal pseudo-obstruction.
Abstract: OBJECTIVES: Although muscular dystrophy (MD) affects primarily striated muscles, smooth muscle cells of the gastrointestinal tract may also be involved. We recorded gastric electrical activity and gastric emptying time (GET) in children with MD at initial presentation and at 3-yr follow-up in order to detect gastric motor abnormalities and study their evolution along the clinical course. METHODS: Twenty children with MD (median age: 4.6 yr; range age: 3-7 yr) were investigated by means of ultrasonography, for measuring GET, and by electrogastrography (EGG); 70 children served as controls. RESULTS: Ten patients had Duchenne muscular dystrophy (DMD) and 10 Becker muscular dystrophy (BMD). GET was significantly more delayed in MD patients (DMD, median: 195 min; range 150-260 min; BMD, median: 197 min; range: 150-250 min) than in controls (median: 150 min; 110-180 min; p < 0.05); it markedly worsened at the follow-up in DMD (median: 270 min; range 170-310 min; p < 0.001 vs controls) but not in BMD patients (median: 205 min; 155-275 min; p < 0.05 vs DMD). Baseline EGG showed a significantly lower prevalence of normal rhythm and significantly higher prevalence of dysrhythmias in both groups of patients as compared to controls (% of normal rhythm: DMD 66.7 +/- 8.2, BMB 67.2 +/- 11.5, controls 85.3 +/- 7.2, p < 0.001; % of tachygastria: DMD 28.4 +/- 8.0, BMB 29.8 +/- 12.3, controls 10.6 +/- 5.1, p < 0.001; % of dominant frequency instability coefficient: DMD 36.1 +/- 6.0, BMB 33.2 +/- 2.9, controls 17.9 +/- 7.1, p < 0.001); furthermore, no difference in fed-to-fasting ratio of the dominant EGG power was found between the two groups and controls (DMD 2.84 +/- 1.27, BMB 2.82 +/- 0.98, controls 3.04 +/- 0.85, ns). However, at the follow-up no significant change in the prevalence of normal rhythm and dysrhythmias occurred in both groups (ns vs baseline values), whereas only DMD patients showed a marked reduction in fed-to-fasting power ratio (0.78 +/- 0.59; p < 0.001 vs controls and BMD; p < 0.05 vs baseline), which correlated with the progressive neuromuscular weakness occurring in DMD subjects (r, 0.75; p < 0.001). CONCLUSIONS: In children with MD, there is an early abnormality in gastric motility that is due to deranged regulatory mechanisms, whereas contractile activity of smooth muscle cells seems to be preserved. At the follow-up, DMD patients exhibited a progressive failure in neuromuscular function, which was accompanied by a gastric motility derangement with worsening in GET and in EGG features suggesting an altered function of gastric smooth muscle cells.
Abstract: BACKGROUND: Spondyloarthropathy in adults has been shown to be associated with either clinical or subclinical intestinal inflammation, however this association has rarely been described in children. AIM: To report paediatric patients primarily referred to a paediatric gastroenterology centre for suspected inflammatory bowel disease and found to be affected by a seronegative spondyloarthropathy. Intestinal inflammatory lesions and rheumatological features have been described in them. SUBJECTS: During a 18-month period, 129 children were referred because of symptoms and signs suggesting an inflammatory bowel disease; 31 of them (range age: 5-17 years) were selected because they also had signs of axial and/or peripheral arthropathy and form the basis of our study. METHODS: The investigated patients underwent ileo-colonoscopy with biopsy and rheumatological assessment that also included X-ray and magnetic resonance imaging of the sacroiliac joints. RESULTS: Only seven children had a classical inflammatory bowel disease (four had ulcerative colitis, three had Crohn's disease), 12 had an indeterminate colitis, 12 a lymphoid nodular hyperplasia of the distal ileum as main feature. In the latter two groups, endoscopy and histology revealed an intestinal inflammation of chronic type distinct from the classical pattern found in inflammatory bowel disease. All were HLA B27 negative and fulfilled the European Spondyloarthropathy Study Group criteria for spondyloarthropathy (except five children classified as undifferentiated spondyloarthropathy). CONCLUSIONS: In a group of children primarily investigated for suspected inflammatory bowel disease and also presenting a seronegative spondyloarthropathy we have described both intestinal and rheumatological features. The majority of them exhibited either an indeterminate colitis or a lymphoid nodular hyperplasia of the distal ileum as main feature. These patients may be a population at risk of developing a full inflammatory bowel disease phenotype.
Abstract: AIM: To assess the value of long-chain omega-3 fatty acids (FAs) supplementation in addition to amino-salicylic-acid (5-ASA) in pediatric patients with Crohn's disease (CD). METHODS: Thirty-eight patients (20 males and 18 females, mean age 10.13 years, range 5-16 years) with CD in remission were randomized into two groups and treated for 12 mo. Group I (18 patients) received 5-ASA (50 mg/kg/d)+ omega-3 FAs as triglycerides in gastro-resistant capsules, 3 g/d (eicosapentanoic acid, EPA, 400 mg/g, docosahexaenoic acid, DHA, 200 mg/g). Group II (20 patients) received 5-ASA (50 mg/kg/d)+olive oil placebo capsules. Patients were evaluated for fatty acid incorporation in red blood cell membranes by gas chromatography at baseline 6 and 12 mo after the treatment. RESULTS: The number of patients who relapsed at 1 year was significantly lower in group I than in group II (P<0.001). Patients in group I had a significant increase in the incorporation of EPA and DHA (P<0.001) and a decrease in the presence of arachidonic acids. CONCLUSION: Enteric-coated omega-3 FAs in addition to treatment with 5-ASA are effective in maintaining remission of pediatric CD.
Abstract: BACKGROUND: Infliximab has recently emerged as an efficacious agent for patients with severe Crohn's disease. There are only few studies on the use of infliximab in children with Crohn's disease: most of them are retrospective and deal only with the clinical response to the drug. AIM: We aimed at assessing the efficacy of infliximab in children and adolescents with severe Crohn's disease recruited consecutively and followed up prospectively at a single centre. Clinical response, intestinal inflammation and growth pattern were evaluated. PATIENTS: Eighteen patients entered into the trial (median age: 13 years, range: 6-18). They were referred because of severe symptoms with unsatisfactory response to conventional drugs. METHODS: All patients received a baseline schedule of three intravenous infusions of infliximab (0, 2 and 6 weeks), 5 mg/kg. Paediatric Crohn's Disease Activity Index, nutritional and activity serum variables, and ileocolonoscopy (with histology) were evaluated before and 8 weeks after beginning the therapy. All patients had long-term administration of azathioprine (2 mg/kg per day). After the baseline schedule, eight patients had a retreatment infusion of infliximab (5 mg/kg) every 8 weeks. Weight and height Z scores were measured before starting the baseline infusion programme and after 6 months. RESULTS: After 8 weeks of therapy, there was a dramatic improvement in Paediatric Crohn's Disease Activity Index, in nutritional and activity blood parameters, as well as in endoscopic and histological scores; 10 patients had a clinical remission (Paediatric Crohn's Disease Activity Index < or = 10), 12 patients had an inflammatory remission (decrease in both endoscopic and histological scores for > or = 50% as compared to baseline values). In all patients corticosteroids were stopped within 4 weeks after beginning infliximab therapy. After 6 months of therapy, Paediatric Crohn's Disease Activity Index was markedly lower than the pre-treatment value; however, it was significantly lower in patients on retreatment than in those who received only three infusions of infliximab. Furthermore, a significant increase in both weight and height Z scores was observed 6 months after beginning of the baseline infusion programme. Moreover, weight and height gain was significantly higher in patients on retreatment rather than in those treated only with three baseline infusions of infliximab. Mild infusion reactions controlled by slowing infusion rate were observed in four patients. No delayed hypersensitivity-like reactions were seen. CONCLUSIONS: In children with severe Crohn's disease, infliximab is a safe and valuable treatment in inducing remission, in healing inflammatory lesions of the gut, as documented by endoscopy and histology, and in promoting growth. Retreatment infusions of infliximab may be suggested in childhood-onset Crohn's disease to maintain remission and reverse growth failure.
Abstract: BACKGROUND: In coeliac disease (CD) mucosa, the histological lesion is associated with marked infiltration of T helper cell type 1 (Th1) cells. However, the molecular mechanisms which regulate Th1 cell differentiation in CD mucosa are unknown. AIMS: To analyse expression of transcription factors which control the Th1 cell commitment in CD. PATIENTS: Duodenal mucosal samples were taken from untreated CD patients and normal controls. METHODS: Interferon gamma (IFN-gamma) and interleukin (IL)-4 RNA expression was examined in T lamina propria lymphocytes by quantitative reverse transcription-polymerase chain reaction. T-bet and STAT-4, two Th1 promoting transcription factors, and STAT-6 and GATA-3, transcription factors which govern T helper cell type 2 (Th2) cell polarisation, were examined in duodenal biopsies by western blotting. The effect of gliadin and IFN-gamma on expression of T-bet was examined in an ex vivo culture of biopsies taken from normal and treated CD patients. RESULTS: As expected, IFN-gamma but not IL-4 RNA transcripts were increased in the mucosa of CD patients in comparison with controls. CD mucosal samples consistently exhibited higher levels of T-bet than controls. However, no difference in active STAT-4 expression was seen between CD patients and controls, suggesting that Th1 polarisation was not induced by local IL-12. GATA-3 and STAT-6 were also low in both CD and control mucosa. In normal duodenal biopsies, IFN-gamma stimulated T-bet through a STAT-1 dependent mechanism. Challenge of treated CD but not control biopsies with gliadin enhanced T-bet and this effect was also inhibited by STAT-1 inhibition. CONCLUSIONS: This study shows that activation of STAT-1 by IFN-gamma promotes T-bet in CD mucosa.
Abstract: BACKGROUND: To determine diagnostic accuracy of anti-Saccharomyces cerevisiae antibodies (ASCA) in identifying children with inflammatory bowel disease (IBD) and to differentiate Crohn's disease (CD) from other IBD forms; and to determine the effect of medical or surgical treatment and of disease location and activity on ASCA titers. METHODS: Serum samples were obtained from 196 IBD children and 142 controls. ASCA IgA and IgG titers were measured by ELISA. Measurements were repeated during the follow up of CD children. RESULTS: ASCA titers were significantly higher in CD than in other IBD and in control patients. Combination of IgA and IgG ASCA positivity was highly specific for CD. Medical treatment and disease location did not influence assay results. Significantly lower ASCA titers were obtained in CD children with intestinal resection compared to CD-affected children who did not undergo surgical resection. ASCA titers correlated significantly with disease activity, and children with severe active disease showed higher ASCA values compared to those in remission. A significant reduction of ASCA was observed during the follow-up of CD children when clinical remission was achieved. CONCLUSIONS: The diagnostic accuracy of ASCA is influenced by disease activity and this suggests an additional use for the follow-up of CD children of this assay.
Abstract: BACKGROUND: Data on the efficacy of eradication treatment for Helicobacter pylori gastritis in children are scarce. AIM: To evaluate the efficacy of triple therapy with lansoprazole plus amoxicillin and tinidazole vs. dual therapy with amoxicillin and tinidazole in a double-blind randomized multicentre trial, and the usefulness of eradication in terms of long-term symptom resolution. SUBJECTS: We enrolled 43 consecutive children undergoing endoscopy for upper gastrointestinal dyspepsia with H. pylori gastritis. They underwent a 13C-urea breath test, completed a 2-week symptom diary card, and were randomized. Treatment was given in a Redidose box (Redidose Company Ltd., Brighton, UK) containing either lansoprazole-amoxicillin-tinidazole (triple therapy) or placebo plus amoxicillin-tinidazole (dual therapy) for 1 week. The completion of a 2-week symptom diary card and the performance of a breath test were repeated 6 weeks and 6 months after the end of therapy. One to two years later, a structured telephone interview was conducted with 36 of the children. RESULTS: According to the breath test, 6 weeks after the end of therapy H. pylori was eradicated in 15 of 22 children on triple therapy [68.2%; 95% confidence interval (CI) = 45-88] and in 15 of 21 children on dual therapy (71%; 95% CI = 48-89; not significant), and 6 months after the end of therapy it was eradicated in 16 of 22 children on triple therapy (72.7%) and in 15 of 21 children on dual therapy. Six months after therapy, symptoms were analysed in 11 H. pylori-positive and 31 H. pylori-negative children, and it was found that dyspeptic symptoms had disappeared or improved in both groups, with no difference between them. One to two years later, 36 children were interviewed. Epigastric pain had recurred in three of 26 H. pylori-negative and in seven of 10 H. pylori-positive children (p = .001); in three of the latter, pain was severe and required additional treatment. CONCLUSION: One-week triple or dual therapy with two antibiotics achieved similar eradication rates. Soon after treatment, symptoms disappeared or improved in most children irrespective of eradication, but epigastric pain recurred in the majority of the still-infected children within 2 years.
Abstract: PURPOSE: To report our experience using MR of the small bowel with polyethylene glycol (PEG) solution as an oral contrast agent in a population of adults and children with known Crohn's disease. MATERIALS AND METHODS: 40 patients (29 males; 11 females), 15 adults (age range 24-52 years) and 25 children (age range 5-17 years), with known Crohn's disease, underwent MR of the small bowel using a supeconductive 1.5 T magnet, and polyethylene glycol solution as an oral contrast agent. The fixed amount of contrast agent was 750-1000 ml for adults and 10 ml/kg of body weight for children. The Crohn's Disease Activity Index (CDAI) was available in all patients. Our study protocol included the acquisition of T2-weighted half-Fourier single-shot turbo spin-echo (HASTE) sequences and true fast imaging in the steady-state precession (true-FISP) sequences, followed by the acquisition of "spoiled" 2D gradient echo T1-weighted sequences with fat suppression (FLASH, fast low-angle shot) or alternatively "spoiled" 3D (VIBE, volume interpolated breath-hold examination), acquired 70 seconds after intravenous administration of gadopentetate dimeglumine (Gd-DTPA) (0,1 mmol/kg). A specific MR score was created and calculated for each patient and was compared by means of the Spearman rank with CDAI. RESULTS: In all patients no significant side effects were observed and the MR examination was well tolerated even by paediatric patients. In all cases MR showed a small bowel wall thickening (> 4 mm) in the terminal ileum, with lumen stenosis in 26 patients. In 3 cases pathological segments proximal to the terminal ileum were observed and in another 3 cases caecal involvement was visible. The MR examination was able to show abnormalities of perivisceral fat tissue in 15 patients, mesenteric lymphadenopathy in 1 patient and abdominal abscess in 1 case. The Spearman rank showed a statistically significant correlation between CDAI and the MR score (r = 0.91, P = 0,0001). DISCUSSION: MR using PEG as an oral contrast agent could be considered a test of great interest in the evaluation of the small bowel in patients suspected of having Crohn's disease in that it is easily reproducible, well tolerated even by paediatric patients and it provides useful information about the localisation, extension and activity of inflammatory disease without the use of ionising radiation.
Abstract: BACKGROUND: Esophageal achalasia is not a frequent disorder in children and different treatments have been proposed during past decades. This study reviews the results of the laparoscopic Heller-Dor procedure performed in pediatric patients in two different surgical units. METHODS: We included the patients aged <14 years with a minimum follow-up of 6 months operated on in the period 1994-2001. A single longitudinal anterior esophageal myotomy (Heller) and a 180 degrees anterior gastropexy (Dor) were laparoscopically performed. The patients were checked to detect intra- or postoperative complications and recurrence. RESULTS: Twenty children were operated on. Mean follow-up was 45 months (range 6-102). Postoperative clinical score was Visick 1 in 15 cases and Visick 2 in five. CONCLUSIONS: As complication and recurrence rates are very low we consider modified Heller myotomy and Dor gastropexy through a laparoscopic approach our first choice to treat esophageal achalasia in the pediatric population.
Abstract: BACKGROUND AND AIMS: Recently, magnetic resonance imaging (MRI) has been introduced in the diagnosis of patients with inflammatory bowel disease (IBD). However, it is still rarely reported in paediatric IBD. We studied the diagnostic value of gadolinium enhanced MRI in revealing inflammation of the distal ileum in children with Crohn's disease (CD) and in differentiating them from patients with other inflammatory diseases of the gut. MRI was performed using a polyethylene glycol (PEG) solution as oral contrast agent to distend the small bowel (CE-PEG-MRI). SUBJECTS AND METHODS: Seventy five consecutive patients (median age 13.6 years, range 8-17) with suspected CD underwent ileocolonoscopy with biopsy and CE-PEG-MRI. CD activity was measured by the paediatric Crohn's disease activity index (PCDAI). CE-PEG-MRI was evaluated with an overall score calculated, taking into account both wall thickness and contrast enhancement. RESULTS: Active CD with distal ileitis was diagnosed in 26 cases, active ulcerative colitis (UC) in 18, and spondyloarthropathy and indeterminate ileocolitis in 11; 20 children served as controls. In all CD patients, CE-PEG-MRI revealed a marked ileal involvement with increased wall thickness and parietal contrast enhancement and showed a high concordance with endoscopy and histology, whereas the test was negative in all controls. Of the 18 UC patients, CE-PEG-MRI was negative in 15 and showed a mild parietal contrast enhancement of the terminal ileum in only three of seven patients with backwash ileitis. Among the group of spondyloarthropathy patients, six had mucosal erosions and five mild superficial ileitis: CE-PEG-MRI was negative in four and revealed only mild parietal contrast enhancement of the ileal wall in seven. CE-PEG-MRI did not show an increase in wall thickness of the distal ileum in any of the UC or spondyloarthropathy patients. The sensitivity and specificity of CE-PEG-MRI related to the presence of erosive ileitis, as documented by endoscopy, were 84% and 100%, respectively. In addition, the test correlated markedly with endoscopy and histology in the entire population (r=0.94; r=0.95, respectively) as well as with the PCDAI in CD patients (r=0.91). CONCLUSIONS: In children with active CD, CE-PEG-MRI is a very sensitive and specific test for the detection of distal ileitis and for differentiation from other inflammatory diseases of the gut. The test could also be useful for the firstline diagnostic approach in children with suspected CD. The high correlation of CE-PEG-MRI with ileal endoscopy and histology as well as with PCDAI makes this test of great interest for future studies as a tool for monitoring the clinical course and the effect of therapy in CD patients.
Abstract: OBJECTIVES: To assess the severity and causes of inflammation of the gastric cardia in children undergoing endoscopy for symptoms of acid peptic disease. STUDY DESIGN: Patients undergoing upper gastrointestinal endoscopy for symptoms of acid peptic disease had biopsies from gastric cardia, gastric, and esophageal sites, and 24-hour intraesophageal pH monitoring. Gastric cardia was defined at endoscopy as the anatomic zone from the squamocolumnar junction to 0.5 cm below it. Severity of gastric cardia inflammation was scored 0 to 9 according to densities of inflammatory cells and epithelial abnormalities in surface and pit epithelium. A score > or =2 was considered positive. RESULTS: Forty-seven children (median age, 6.5 years; range, 3-15) had Helicobacter pylori infection, gastroesophageal reflux disease (GERD), or both. In 22 patients, H pylori was detected in cardiac biopsies by rapid urease test and histology; it was detected also in the corpus and antrum in only seven of the 22. No patient had H pylori in gastric corpus/antrum without having the organism at the cardia as well. In 12 H pylori-positive patients, GERD was also diagnosed. Twenty-five patients had GERD and no H. pylori infection. Severity score was 3.8+/-0.8 in the H pylori group and 2.08+/-0.9 in the GERD alone group (P<.001); however, there was no difference in reflux index (24-hour % of gastroesophageal reflux) between the two groups. In neither group was correlation found between reflux index and severity score (H pylori, r=0.22; GERD alone, r=0.31; NS) nor between cardia inflammation and esophagitis grade (H pylori, r=0.37; GERD alone, r=0.22; NS). CONCLUSIONS: In children with symptoms of acid peptic disease, inflammation of the gastric cardia does occur. It is more severe when the cardiac zone is infected with H pylori than in its absence. Of major practical significance is the finding that the gastric cardia is a highly sensitive site for the detection of H pylori infection.
Abstract: AIM: To investigate the presence of inflammatory bowel disease (IBD) and to evaluate the progression of bowel involvement after two years' follow-up in seven patients affected by glycogen storage disease type Ib (GSDIb). METHODS: Seven patients (5F, 2M, aged 4.5-20.6 y) entered the study. Bowel involvement was evaluated by ileocolonoscopy and specific IBD serologic markers. To evaluate disease activity, Paediatric Crohn's Disease Activity Index (PCDAI), terminal ileum wall thickness detected at ultrasonography (US), 99mTechnetium labelled autologous White Cell Scan (Tc-WCS) and barium meal with follow-through were investigated. RESULTS: Ileocolonoscopy and histology examination revealed variable degrees of bowel involvement in all patients. The results of serologic markers were indicative of a Crohn's-like ileocolitis. US and Tc-WCS, could clearly define patients with severe inflammatory involvement, but failed to identify all patients with mild to moderate disease. For the most severely affected patients, anti-inflammatory agents and steroids were prescribed, whereas nutritional therapy with polymeric formula and antibiotics were assumed by two other patients and antibiotics only by one patient. Granulocyte colony-stimulating factor (G-CSF) was prescribed to all patients. Ileocolonoscopy and histology data improved in all patients. The assumption of G-CSF and/or gastric drip feeding (g.d.f.) was inversely associated with the PCDAI results (p < 0.05). CONCLUSION: IBD is common in patients affected by GSDIb independently of the severity of gastrointestinal signs and symptoms. Different therapeutic approaches can be used according to the severity of IBD. G-CSF treatment and g.d.f. can be protective factors for IBD.
Abstract: AIM: To assess the efficacy and safety of azathioprine in a paediatric population with inflammatory bowel disease. PATIENTS AND METHODS: One hundred and twenty-three Italian children treated with azathioprine were studied retrospectively. The treatment duration and causes of its discontinuation, side-effects and variation in corticosteroid dose were assessed. RESULTS: The mean age at inflammatory bowel disease diagnosis was 9.8 +/- 3.6 years, and at the start of azathioprine therapy 11.8 +/- 4.3 years. The mean duration of treatment was 19 +/- 16 months. Fifty patients (41%) stopped treatment due to surgery (12%), prolonged remission (11%), non-response (7%), severe side-effects (7%) and poor compliance (3%). Of the 73 patients (59%) remaining on azathioprine, 11 had never been treated with corticosteroids, 27 were able to stop them and 35 were still on a very low daily dose (91% < 0.3 mg/kg). The difference in the daily corticosteroid dose between the beginning of azathioprine treatment (1 +/- 0.6 mg/kg) and the conclusion of the study (0.18 +/- 0.16 mg/kg) was statistically significant. Side-effects were recorded in 48 of the 123 patients (39%), but only eight required discontinuation of azathioprine. CONCLUSIONS: Azathioprine was efficacious in 70% of patients, but ineffective in 20% and induced severe toxicity in 7%. Corticosteroids were stopped or markedly reduced in 62% of patients, but they were never given in 9%.
Abstract: BACKGROUND: Disorders of gastrointestinal motility are commonly detected in patients with insulin-dependent diabetes mellitus and are associated with significant morbidity. They contribute to poor metabolic control of diabetes. AIM: To assess the effect of an 8-week course of domperidone or cisapride on gastric electrical activity, gastric emptying time and dyspeptic symptoms in children with insulin-dependent diabetes mellitus and gastroparesis. METHODS: Dyspeptic symptoms were assessed by a score system, gastric emptying time was measured by ultrasonography and gastric electrical activity was obtained by electrogastrography. Fourteen children received domperidone and 14 received cisapride. The median (range) ages were 11.6 years (5-15 years) and 12 years (6-16.9 years), respectively. Symptom assessment, ultrasonography and electrogastrography were repeated at the end of the trial. Fasting and fed (180 min after feeding) glycaemia and haemoglobin A, C (HbA1c) levels were also measured. RESULTS: At the end of the trial both groups showed a significant decrease in symptomatic score; however, the score was markedly lower in the domperidone group than in the cisapride group (P < 0.01). Domperidone was significantly more effective than cisapride in reducing the gastric emptying time (P < 0.05), normalizing gastric electrical activity (P < 0.05) and decreasing the prevalence of episodes of gastric dysrhythmia (P < 0.01). Domperidone was also more effective than cisapride in improving diabetic metabolic control. No potentially drug-related adverse effects occurred. CONCLUSIONS: In children with insulin-dependent diabetes mellitus complicated by dyspeptic symptoms and gastroparesis, domperidone is superior to cisapride in reversing gastric emptying delay and gastric electrical abnormalities, as well as in improving dyspeptic symptoms and diabetic metabolic control.
Abstract: An increased incidence of coeliac disease has recently been reported in patients with idiopathic dilated cardiomyopathy. This report deals with three patients with idiopathic dilated cardiomyopathy and coeliac disease who underwent clinical and laboratory evaluation to establish the effect of a gluten-free diet on cardiac performance. Two patients observed the gluten-free diet regimen very strictly, and, after a 28-month follow-up period, showed an improvement in echocardiographic parameters as well as in cardiological features and quality of life, as evaluated by the Minnesota Living with Heart Failure questionnaire and the Gastrointestinal Symptom Rating Scale questionnaire. The third patient did not observe the gluten-free diet and presented a worsening in the echocardiographic parameters and cardiological symptoms which required supplementary drug therapy. These preliminary data appear to suggest that the gluten-free diet may have a beneficial effect on cardiac performance in patients with idiopathic dilated cardiomyopathy.
Abstract: AIM: To asses the efficacy and safety of ciclosporin in a paediatric population with inflammatory bowel disease. PATIENTS AND METHODS: Twenty-three Italian children treated with ciclosporin were studied retrospectively. The indications for treatment were severe unresponsive colitis, chronic active colitis or severe fistulizing Crohn's disease. The treatment duration, follow-up and causes of drug discontinuation were assessed. RESULTS: Sixteen patients were treated intravenously for a mean time of 10 +/- 7 days (1-24 days) and 19 orally for a mean time of 133 days (17-660 days). The mean follow-up of all patients was 13.2 months. Ciclosporin was totally ineffective, being discontinued for surgery, in nine of 23 patients (39%); it was discontinued for partial response in three patients (13%). During treatment, clinical remission was achieved in eight children (35%) and maintained after drug withdrawal in four (17%). In severe unresponsive colitis, urgent colectomy was avoided in 12 (85%) of 14 patients who tolerated the drug. Side-effects appeared in six of 23 patients (26%), and three (13%) required ciclosporin to be discontinued due to neurotoxicity. CONCLUSIONS: Ciclosporin shows disappointing long-term results in the treatment of refractory inflammatory bowel disease, but can play an important role in preventing urgent surgery in unresponsive severe colitis. Severe side-effects can occur.
Abstract: Current evidence supports the view that oral administration of probiotics may be of therapeutic usefulness in several clinical disorders by reestablishing normal flora in the gastrointestinal tract. These entities include inflammatory and infectious diseases of the gut as well as extraintestinal disorders (such as atopic eczema) in which a defective intestinal permeability plays a role. The probiotic effects are attributed to restoration to normal of increased intestinal permeability, unbalanced gut microecology, improved immunological gut barrier function, downregulation of the intestinal inflammatory responses with reduced generation of proinflammatory cytokines. Entities for which the impact of probiotic administration can be considered as proven are Rotavirus diarrhoea, Clostridium difficile diarrhoea, post-antibiotic diarrhoea, allergic diseases. On the other hand, entities for which administration of probiotics is considered under investigation are inflammatory bowel disease, necrotizing enterocolitis, cystic fibrosis, small bowel bacterial contamination, functional gastrointestinal disorders. The value of probiotics as therapy for a variety of gastrointestinal disorders in childhood still needs to be investigated in detail, through well controlled and rigorous studies, including a placebo group and strict criteria of randomisation. Much work needs to be done in this area by clearly defining indications, delivery system, costs, safety long-term effects.
Abstract: Intestinal lymphangiectasia is characterized by obstruction of lymph drainage from the small intestine and lacteal dilation that distorts the villus architecture. Lymphatic vessel obstruction and elevated intestinal lymphatic pressure in turn cause lymphatic leakage into the intestinal lumen, thus resulting in malabsorption and protein-losing enteropathy. Intestinal lymphangiectasia can be congenital or secondary to a disease that blocks intestinal lymph drainage. We describe the first case of intestinal lymphangiectasia in a premature infant. The infant presented with peripheral edema and low serum albumin; high fecal concentration of alpha(1)-antitrypsin documented intestinal protein loss. Endoscopy showed white opaque spots on the duodenal mucosa, which indicates dilated lacteal vessels. Histology confirmed dilated lacteals and also showed villus blunting. A formula containing a high concentration of medium chain triglycerides resulted in a rapid clinical improvement and normalization of biochemical variables. These features should alert neonatologists to the possibility of intestinal lymphangiectasia in newborns with hypoalbuminemia and peripheral edema. The intestinal tract should be examined for enteric protein losses if other causes (ie, malnutrition and protein loss from other sites) are excluded. The diagnosis rests on jejunal biopsy demonstrating dilated lymphatic lacteal vessels.
Abstract: OBJECTIVE: Previous studies have reported genetic anticipation, genomic imprinting, and phenotypic concordance of some clinical features in familial cases of Crohn's disease (CD) and ulcerative colitis (UC). The aim of our study was to investigate the phenotypic features of affected members in a large sample of CD and UC Italian families. METHODS: In a multicenter study, CD and UC families were recruited. Affected members were questioned about date of birth, gender, age at onset of symptoms and at diagnosis, location and extension of disease, occurrence of extraintestinal manifestations, use of steroids and/or of immunosuppressive drugs, need for resective surgery, and number of relapses per year (< 1 yr or > or = 1 yr). Statistical analysis was performed with chi2, Fisher's, Mann-Whitney U, and binomial probability tests, when appropriate. RESULTS: A total of 128 families with 270 affected members were studied: 35 were CD, 64 UC, and 29 mixed families (when UC and CD affected different members). In 99 of 128 families (77%), the diagnosis was concordant. In CD families, a high concordance for localization (46%), extraintestinal manifestations (67%), need for steroids (77%), need for immunosuppressive drugs (100%), need for surgery (29%), and relapse rate (36%) was found. In UC families, a high concordance for disease extension (33%), need for steroids (47%), and relapse rate (34%) was disclosed. A higher than expected concordance for ileal localization (p < 0.4) in CD families and extensive colitis (p < 0.05) in UC families was demonstrated. A generation difference of 15-20 yr in mean ages at onset of symptoms and at diagnosis was recorded. No features of more aggressive disease in subsequent generations and no differences in gender of transmitting parents and relatives were found. CONCLUSIONS: Our study shows a high rate of concordance for diagnosis and clinical features in UC and, especially, CD families. The disease occurred 15-20 yr earlier than in previous generations without features of increased severity.
Abstract: OBJECTIVE: Both transient lower esophageal sphincter (LES) relaxations (TLESRs) and periods of low/absent LES pressure (LESP) are the main mechanisms of gastroesophageal reflux. These events are believed to be triggered by stimuli from different areas of the upper GI tract. We aimed at investigating the relationship between LESP profile and gastric emptying and distension after meals of different composition in 30 children with gastroesophageal reflux disease (median age 7.0 yr, range 12 months-12 yr). METHODS: Recordings of LESP and intraesophageal pH for 1 h fasting and for 2 postprandial h were performed with a perfused sleeve catheter and flexible electrode, respectively; gastric emptying and distension of antral area were simultaneously recorded with real-time ultrasonography. Ten patients had a standard meal (group A), 10 had a high-volume meal (group B), and 10 had a high-volume and osmolality meal (group C). RESULTS: Postprandial esophageal acid exposure was significantly higher in patients of groups B and C than in patients of group A (p < 0.01); it was also more prolonged in patients of group C than in subjects of group B (p < 0.05). A higher postfeeding rate of reflux episodes caused by TLESRs was detected in patients of groups B and C as compared with patients of group A (p < 0.01). This increase did not statistically differ in patients of groups B and C. Patients of group C exhibited a higher postprandial rate of reflux episodes associated with low/absent tone of the LES as well as a more prolonged gastric emptying time and a higher postfeeding gastric distension as compared with patients of groups A and B (p < 0.01). Finally, a significant correlation was only found between the postprandial rate of reflux events resulting from low/absent LESP and the degree of antral distension in patients of group C (p < 0.01). CONCLUSION: Gastroesophageal reflux is worsened by increasing the volume and osmolality of meals through significant changes of LESP. Meals of high volume and meals with high volume and osmolality cause a comparable increase of reflux episodes as a result of TLESRs. However, meals with high volume and osmolality cause the higher degrees of esophageal acid exposure than meals with high volume resulting from a higher rate of reflux episodes associated with low/absent LESP. This finding correlates with a high postfeeding antral distension.
Abstract: Pulmonary manifestations have been described in Crohn's disease (CD). Bronchial responsiveness to methacholine (MCh) was evaluated in 14 children with CD with no evidence of airway disease, 10 asthmatics, and 10 healthy subjects. In patients with CD total blood eosinophils and serum IgE were 0.20 x 10(9) x L(-1) (95% CI -1.68 to 2.08) and 138.4 kU x L(-)(1) (95% CI 18.84 to 257.96), respectively. Three patients with CD had positive prick tests. Bronchial hyperresponsiveness (BHR) was demonstrated in 10 patients with CD (71%) and in the asthmatics, but not in control subjects. In patients with CD PD(20) appeared significantly greater than in asthmatics (699 microg [95% CI 238 to 1,115] versus 104 microg [95% CI 37.35 to 293]; p < 0.05), and was not related either to baseline FEV(1) or IgE or eosinophils (r = 0.32; r = -0.5; r = -0.15, p = NS, respectively). Neither activity nor treatment or duration of CD affected BHR. Five nonatopic CD patients underwent a second MCh challenge over a 25-mo period: the PD(20) appeared significantly greater than basal PD(20) (1,941 microg versus 575 microg, p < 0.05, respectively), in the absence of significant changes of disease activity. BHR might be the expression of subclinical airway inflammation, a phenomenon which can be responsible for the development of various pulmonary manifestations in CD.
Abstract: BACKGROUND: Albeit rare in children, achalasia is a disorder with severe symptoms that causes growth impairment. The treatment of choice in children is the esophagomyotomy, although there are variations in the surgical approaches available and differences of opinion regarding the inclusion of an adjunctive antireflux procedure. The recent advent of the laparoscopic approach has had a profound impact on the treatment of achalasia in both adults and children. METHODS: In this report, we describe eight patients with severe achalasia who were treated by laparoscopic Heller's operation associated with a fundoplication according to either Dor's or Toupet's technique. The patients' ages ranged between 2 and 13 years. A five-port technique was used: a 10-mm port placed infraumbilically for the optics and four 5-mm ports. One was placed in the right abdominal quadrant for retraction of the left hepatic lobe, one in the left abdominal quadrant for the first operative instrument, one below the xyphoid appendix for the second operative instrument, and the last one to introduce a 5-mm cannula laterally to the umbilicus to retract the stomach below. A 7-8-cm laparoscopic Heller esophagomyotomy was completed, followed by an anterior Dor fundoplication in six cases and a Toupet in two. The longitudinal division of the anterior esophageal musculature was performed with a scalpel or scissors. The myotomy was made along the stomach, extending for >/=2-3 cm. RESULTS: Mean operating time was 120 mins. Three complications were recorded. There were two perforations of the gastroesophageal mucosa; the first was sutured in laparoscopy and the second required a second operation. The third complication was a case of dysphagia resolved by dismounting a fundoplication that was too tight. At follow-up, which lasted from 6 months to 5 years, the children were all free of symptoms. CONCLUSIONS: Laparoscopic Heller esophagomyotomy appears to be a complex and difficult operation, but it is as safe and effective as laparotomy in children with achalasia. However, complications can be numerous and severe at the beginning of a surgeon's experience.
Abstract: Gastro-oesophageal reflux (GOR) is the effortless passage of gastric contents into the distal oesophagus. It can be classified as functional (or symptomatic), in which the infant remains free from disease, or a pathological (GOR disease, GORD), in which gastrointestinal, respiratory or neurobehavioural signs occur with intraoesophageal acidification and the development of oesophagitis. Functional or symptomatic GOR is successfully treated by conservative measures and does not require investigative diagnostic tools; however, both drug administration and an investigative approach are mandatory in patients with GORD. There is currently a great range of proven therapeutic options for GORD that are directed at counteracting the pathogenetic components of the disorder. In this report we discuss the role of different drug classes for treating GORD in children. The choice of therapy for GORD depends upon the severity of signs and the degree of oesophagitis. The presence of oesophagitis, as documented by endoscopy, suggests the use of antisecretory drugs; H2 receptor antagonists are the first-line agents. Nevertheless, individuals with refractory disease or those patients requiring potent inhibition of acid secretion (for example, GORD with respiratory involvement) can be given proton pump inhibitors. Other groups of patients who need potent inhibition of acid secretion are children with neurological dysfunction and those with Barrett's oesophagus. It is still unclear whether patients with frequent relapses are candidates for long term administration of antisecretory drugs or for surgical fundoplication.
Abstract: Gastrointestinal manometry has gained wide acceptance in the approach to patients with suspected enteric neuromuscular disorders. However, performing gastrointestinal manometry in these subjects without a previous exhaustive diagnostic evaluation is unjustified. Twelve children (median age: 7.0 years; range: 8 months-13 years), with clinical and x-ray features suggesting chronic intestinal pseudoobstruction, were referred to our unit for gastrointestinal manometry. The latter was performed with a perfused catheter for 5 hr in the fasting state and for 90 min after feeding. Data were compared with those recorded in eight age-matched controls. In all patients and controls, interdigestive motor complexes with propagated phases III were detected; a regular postprandial antroduodenal motor activity was also recorded. Patients and controls did not differ for fed antral and duodenal motility indexes, fed antroduodenal coordination, and length of duodenal phase III. Most of the patients showed short or prolonged bursts of nonpropagated activity in the fasting and/or fed states; in four cases fasting and/or fed sustained phasic activity was recorded. Manometric evidence of migrating motor complexes and postfeeding activity did not support the diagnosis of intestinal pseudoobstruction and suggested redirecting the diagnostic evaluation. Final diagnoses were: Munchausen syndrome-by-proxy (four cases), celiac disease (two cases), intestinal malrotation (two cases), Crohn's disease (two cases), multiple food intolerance (one case), and congenital chloride-losing diarrhea (one case). It is concluded that in children with suspected chronic intestinal pseudoobstruction manometric evidence of migrating motor complexes and fed motor activity excludes an enteric neuromuscular disorder and suggests a reassessment of the diagnostic work-up. Furthermore, if gastrointestinal manometry shows migrating motor complexes and postfeeding motor activity, qualitative abnormalities of the manometric tracings do not indicate an underlying enteric neuromuscular disorder and must not be overemphasized. Patients referred for gastrointestinal manometry should previously undergo an extensive diagnostic investigation to exclude disorders mimicking chronic intestinal pseudoobstruction.
Abstract: To assess and compare gastric electrical activity and gastric emptying recorded from dyspeptic and healthy children, cutaneous electrogastrography and ultrasound examination of the gastric emptying were simultaneously performed in 52 children with nonulcer dyspepsia and 114 healthy children. Symptoms were scored from 0 (none) to 6 (severe). A higher percentage of tachygastria, a higher instability of gastric power, and a lower post/preprandial ratio were present in dyspeptic children than healthy children. As regards the ultrasound parameters, the fasting antral area and T1/2 were similar in dyspeptic children and controls. Only 32% of dyspeptic children had a normal gastric emptying time vs 66% of healthy children. Marked postprandial antral dilatation was found in the dyspeptic children, which correlated with the total symptom score. Electrogastrographic and gastric emptying parameters show specific differences in dyspeptic children with respect to controls, both fasting and after a meal. The postprandial antral distension correlates with the severity of the symptoms.
Abstract: BACKGROUND: Acid suppressive therapy is the mainstay of pharmacologic treatment of gastro-oesophageal reflux disease. Use of proton pump inhibitors in children is still limited and has only included omeprazole in a few controlled studies. AIM: To determine efficacy of lansoprazole, a relatively new proton pump inhibitor, on symptoms and oesophagitis in a group of children with gastro-oesophageal reflux disease refractory to H2 receptor antagonists. The required dose of the drug for inhibiting gastric acidity was also determined. PATIENTS AND METHODS: A series of 35 children (median age: 7.6 years, range: 3-15) with oesophagitis refractory to H2 receptor antagonists received a 12-week therapeutic course with lansoprazole. Prior to the study children underwent symptomatic and endoscopic assessment, oesophageal manometry and 24-hour intragastric and intra-oesophageal pH test. The latter was repeated after one week of therapy while patients were on treatment in order to monitor the degree of acid suppression and adjust the dose of the drug. Symptomatic assessment and endoscopy were repeated at the end of the trial RESULTS AND CONCLUSIONS: In 12 patients (group A), the initial dose of the drug was efficacious (1.3 to 1.5 mg/kg/day), whereas in 23 [group B) the initial dose (0.8 to 1.0 mg/kg/day) was increased by half because of insufficient inhibition of intragastric acidity (i.e., when the intra-gastric pH remained below 4.0 for more than 50% of the recording time). Nine patients in group A (75%) and 8 in group B (53.5%) healed (chi2: 3.6, p<0.05); 1 patient in group A [8.3%) and 7 in group B (30.5%) remained unchanged (chi2: 6.9, p<0.01); 2 patients in group A and 8 in group B improved and underwent a further month of therapy. The two groups did not differ as far as concerns baseline pH, endoscopic and clinical variables. In both groups, those patients failing to respond at the end of the trial showed a more impaired oesophageal motility than improved or healed patients. The drug was well tolerated and no significant laboratory abnormalities occurred. In children with gastro-oesophageal reflux disease refractory to H2 receptor antagonists, a 12-week course of lansoprazole is effective both in healing oesophagitis and improving symptoms. An initial dose of 1.5 mg/kg/day of the drug is suggested. However, if during treatment, patients remain symptomatic the dose should be increased and a prolonged intra-gastric and intra-oesophageal pH test performed to evaluate the acid suppression efficacy of the adjusted dose. A short course of lansoprazole appears to be safe and well tolerated in paediatric age.
Abstract: Crohn' s disease (CD) is a chronic intestinal inflammatory disorder characterized by aberrant mucosal Th1 cell activation and production of IL-12, the major Th1-driving factor. The T cell response to IL-12 is dependent on the expression of a specific receptor composed of two subunits, termed IL-12Rbeta1 and IL-12Rbeta2. The content of IL-12Rbeta2, as measured at the mRNA level, is crucial in regulating Th1 differentiation. In this study we therefore investigated IL-12Rbeta2 RNA transcripts in CD. IL-12Rbeta2 expression was increased in active CD as well as Helicobacter pylori (HP)-associated gastritis and Salmonella colitis compared with that in inactive CD, ulcerative colitis, noninflammatory controls, and celiac disease. In contrast, IL-12Rbeta1 transcripts were expressed at comparable levels in all samples. In CD, IL-12Rbeta2 expression strictly correlated with tyrosine phosphorylation of STAT4, a key component of the IL-12-dependent Th1 polarization. This was associated with a pronounced expression of IFN-gamma. Transcripts for IL-12/p40 were detected in CD, HP-positive, and Salmonella colitis patients, but not in celiac disease, indicating that IL-12Rbeta2 up-regulation occurs only in IL-12-associated Th1 gastrointestinal diseases. Finally, we showed that stimulation of lamina propria mononuclear cells with IL-12 enhanced IL-12Rbeta2, suggesting that IL-12 regulates IL-12Rbeta2 expression in human gastrointestinal mucosa. The data show that the signaling pathway used by IL-12 to induce Th1 differentiation is increased at the site of disease in CD, further supporting the view that IL-12/IL-12R signals contribute to the inflammatory response in this condition.
Abstract: BACKGROUND: Eosinophils may be involved in the pathogenesis of inflammation in inflammatory bowel disease. The purpose of this study was to verify whether concentrations of eosinophilic cationic protein in gut lavage fluid from children with inflammatory bowel disease correlate with clinical and laboratory indexes of disease activity. METHODS: Twenty-three children with Crohn's disease, 14 with ulcerative colitis, and 22 age-matched control subjects entered the study. Radioimmunoassay and sandwich enzyme-linked immunosorbent assay techniques were used to measure eosinophilic cationic protein, total immunoglobulin G and interleukin-1beta, respectively. RESULTS: Gut lavage eosinophilic cationic protein levels were significantly (p < 0.005) higher in patients with Crohn's disease and ulcerative colitis than in control subjects. Intestinal eosinophilic cationic protein levels decreased in three of four children with Crohn's disease who were fed an elemental diet. There was a significant (p < 0.001) correlation between eosinophilic cationic protein concentrations and immunoglobulin G and interleukin-1beta levels in gut lavage fluid. CONCLUSIONS: Elevated intestinal eosinophilic cationic protein levels in inflammatory bowel disease suggest that eosinophils are involved in the gastrointestinal inflammation in this disease. Intestinal eosinophilic cationic protein concentration is another marker with which to discriminate between active and inactive inflammatory bowel disease.
Abstract: BACKGROUND: Cisapride is a gastrointestinal prokinetic agent that is used worldwide in the treatment of gastrointestinal motility-related disorders in premature infants, full-term infants, and children. Efficacy data suggest that it is the most effective commercially available prokinetic drug. METHODS: Because of recent concerns about safety, a critical and in-depth analysis of all reported adverse events was performed and resulted in the conclusions and recommendations that follow. RESULTS: Cisapride should only be administered to patients in whom the use of prokinetics is justified according to current medical knowledge. If cisapride is given to pediatric patients who can be considered healthy except for their gastrointestinal motility disorder, and the maximum dose does not exceed 0.8 mg/kg per day in 3 to 4 administrations of 0.2 mg/kg (not exceeding 40 mg/d), no special safety procedures regarding potential cardiac adverse events are recommended. However, if cisapride is prescribed for patients who are known to be or are suspected of being at increased risk for drug-associated increases in QTc interval, certain precautions are advisable. Such patients include those:(1) with a previous history of cardiac dysrhythmias, (2) receiving drugs known to inhibit the metabolism of cisapride and/or adversely affect ventricular repolarisation, (3) with immaturity and/or disease causing reduced cytochrome P450 3A4 activity, or (4) with electrolyte disturbances. In such patients, ECG monitoring to quantitate the QTc interval should be used before initiation of therapy and after 3 days of treatment to ascertain whether a cisapride-induced cardiac adverse effect is present. CONCLUSIONS: With rare exceptions, the total daily dose of cisapride should not exceed 0.8 mg/kg divided into 3 or 4 approximately equally spaced doses. If higher doses than this are given, the precautions above are advisable. In any patient in whom a prolonged QTc interval is found, the dose of cisapride should be reduced or the drug discontinued until the ECG normalizes. If the QTc interval returns to normal after withdrawal of cisapride, and the administration of cisapride is considered to be justified because of its efficacy and absence of alternative treatment options, cisapride can be restarted at half dose with control of the QTc interval. Unfortunately, at present, normal ranges of QTc interval in children are unknown. However, a critical analysis of the literature suggests that a duration of less than 450 milliseconds can be considered to be within the normal range and greater than 470 milliseconds as outside it.
Abstract: OBJECTIVES: To determine the utility of the technetium-labeled autologous white cell scintigraphy (Tc-WCS) for detecting intestinal inflammation in children with suspected inflammatory bowel disease (IBD). Tc-WCS was compared with colonoscopy and histologic examination. STUDY DESIGN: Forty-eight children (26 boys; median age, 10 years; range, 2-17 years) with symptoms and signs suggesting IBD had colonoscopy with exploration of terminal ileum and mucosal biopsies. The scans were judged to be abnormal if activity was seen in the gut within the first hour. RESULTS: Twenty-one patients had a diagnosis of IBD (Crohn's disease, 13; ulcerative colitis, 5; indeterminate colitis, 3); results of scintigraphy were positive in 16 and negative in 5 (sensitivity, 76.2%); the latter had a moderate degree of intestinal inflammation. In 27 patients, IBD was ruled out. Results of scintigraphy were negative in children with non-specific colitis and in those with lymphoid hyperplasia of the terminal ileum, whereas results were positive in 6 of 12 patients with spondyloarthropathy. In children with IBD, there was a significant correlation between results of scintigraphy and endoscopy for the intensity of inflammation (r = 0.70); however, there was a poor correlation regarding the number of involved segments (r = 0.30) because in 16 patients, endoscopy revealed additional diseased segments as compared with scintigraphy. CONCLUSIONS: A positive Tc-WCS result indicates the presence of an inflammatory process of the gut, whereas a negative test result does not rule out intestinal inflammation, especially when the latter is of moderate degree. Colonoscopy and biopsy are the investigations of choice to establish the diagnosis of IBD and are superior to Tc-WCS in assessing topographic extension of IBD.
Abstract: This is the first attempt at defining criteria for functional gastrointestinal disorders (FGIDs) in infancy, childhood, and adolescence. The decision-making process was as for adults and consisted of arriving at consensus, based on clinical experience. This paper is intended to be a quick reference. The classification system selected differs from the one used in the adult population in that it is organized according to main complaints instead of being organ-targeted. Because the child is still developing, some disorders such as toddler's diarrhea (or functional diarrhea) are linked to certain physiologic stages; others may result from behavioral responses to sphincter function acquisition such as fecal retention; others will only be recognizable after the child is cognitively mature enough to report the symptoms (e.g., dyspepsia). Infant regurgitation, rumination, and cyclic vomiting constitute the vomiting disorders. Abdominal pain disorders are classified as: functional dyspepsia, irritable bowel syndrome (IBS), functional abdominal pain, abdominal migraine, and aerophagia. Disorders of defecation include: infant dyschezia, functional constipation, functional fecal retention, and functional non-retentive fecal soiling. Some disorders, such as IBS and dyspepsia and functional abdominal pain, are exact replications of the adult criteria because there are enough data to confirm that they represent specific and similar disorders in pediatrics. Other disorders not included in the pediatric classification, such as functional biliary disorders, do occur in children; however, existing data are insufficient to warrant including them at the present time. For these disorders, it is suggested that, for the time being, clinicians refer to the criteria established for the adult population.
Abstract: Gestational maturation of gastrointestinal motility is a key factor in readiness of the preterm neonates for enteral nutrition. Since gastric motility mainly depends on the electrical activity of the smooth muscle cells, it was of interest to investigate the developmental aspects of electrical activity of the stomach. The latter was recorded weekly through cutaneous electrogastrography in 27 preterm infants (aged 29-34 weeks of gestation). Recordings were done for 1 hr before and 1 hr after meal. The electrogastrographic variables measured were: percentage of normal gastric rhythm, ie, 2-4 cpm; percentage of tachygastria (>4 cpm); the fed-to-fasting ratio of the dominant electrogastrographic power; and the instability coefficient of the dominant frequency. Data were compared with those measured in 10 full-term infants. Peaks of normal electrical activity (2-4 cpm) were present in most of the recordings at all the gestational ages; however, percentages of both normal electrical rhythm and tachygastria in preterm infants were similar to those measured in full-term infants (mean +/- SD) (normal rhythm; fasting: 70.2 +/- 3.8, fed: 72.2 +/- 5.0; tachygastria: fasting: 24.6 +/- 4.0, fed: 19.1 +/- 3.5) by 35 weeks of gestation (normal rhythm; fasting: 67.5 +/- 2.0, fed: 69.6 +/- 4.4; tachygastria: fasting: 27.1 +/- 4.0, fed: 25.6 +/- 4.1). The coefficient of instability of the dominant frequency in preterm infants was also similar to the value measured in full-term infants by 35 weeks of gestation, whereas the EGG power showed a significant increase in the postprandial state at all the gestational ages. We conclude that a maturation pattern of the electrical activity of the stomach can be detected by means of a noninvasive tool such as cutaneous electrogastrography: a normal electrical rhythm can be detected at very early gestational ages; however, this activity becomes dominant at around the 35 weeks of gestational age. In preterm infants developmental changes of gastric electrical activity are a function of advancing postnatal age.
Abstract: BACKGROUND: Prostaglandin E2 (PGE2) is said to be both protective and detrimental for esophageal mucosal integrity. Nitric oxide (NO) controls several esophageal neuromuscular functions, including relaxation of the lower esophageal sphincter. The purpose of this study was to verify PGE2 and NO levels in esophageal mucosa of children with reflux esophagitis. METHODS: The patients were 10 children, age range 7 to 12 years, affected by reflux esophagitis. The control subjects were 10 children, age range 6 to 11 years, with recurrent abdominal pain. Tissue fragments obtained by esophageal biopsies were placed in a culture medium and processed to obtain a cell suspension. Cells were incubated for 24 hours at 37 degrees C. Thereafter, supernatants were collected and divided into aliquots to determine the amounts of PGE2 and NO metabolites. RESULTS: Esophageal cells obtained from reflux esophagitis patients synthesize and release a significantly higher (p < 0.01) amount of PGE2 and NO (PGE2 1.9 +/- 0.56 ng/10(6) cells per 24 hours; NO 124.94 +/- 18.36 microM/10(6) cells per 24 hours) than did the control group (PGE2 0.66 +/- 0.14 ng/10(6) cells per 24 hours; NO 68.03 +/- 12.3 microM/10(6) cells per 24 hours). CONCLUSIONS: These results suggest that in esophageal mucosa, PGE2 and NO, in low concentrations, are protective, whereas, at high doses, they can be harmful. Higher amounts of PGE2 and NO in the esophageal mucosa of reflux esophagitis patients suggest that similar noxious stimuli trigger the inducible forms of the respective enzyme.
Abstract: Regurgitation is a common manifestation in infants below the age of 1 y, and is a frequent reason for counselling of general practitioners and paediatricians. Current recommended therapeutic management starts with parental reassurance and dietary measures, followed by prokinetics. In this paper, the efficacy, safety and nutritional implications of the dietary treatment of regurgitation are evaluated. Industrially prepared thickened feeds may contain cereals of fibres; some have a low lipid content and are casein-predominant. Milk-thickened agents can also be added to regular infant feeding. Formulae claimed as "anti-regurgitation formulae", or positioned as such, should be considered as medical foods or therapeutic diets, and only be available on medical prescription. It is proposed to limit the "anti-regurgitation" (AR) label to those diets which have been proven clinically effective on regurgitation and which are nutritionally safe.
Abstract: OBJECTIVE: Patients with diabetes can develop gastrointestinal motor complications; however, prevalence of gut dysmotility in children with diabetes is poorly understood. We measured gastric emptying time and gastric electrical activity in children with IDDM; presence of dyspeptic symptoms was also assessed. RESEARCH DESIGN AND METHODS: Gastric emptying time and gastric electrical activity were measured by ultrasonography and electrogastrography (EGG), respectively, in 40 consecutive IDDM children (median age: 9 years [6-14]) without autonomic neuropathy; 15 healthy children (median age: 7 years [4-15]) served as control subjects. The EGG variables studied were percent of electrical dysrhythmias (bradygastria or 0.5-2.0 cpm, tachygastria or 4.0-9.0 cpm; normal rhythm is 2.0-4.0 cpm) and fed-to-fasting ratio of the dominant EGG power. Blood glucose level in the fasting state and 180 min after feeding and HbA1C concentration were also measured. Data are given as median (ranges) and means +/- SD. Statistical analysis was performed using the parametric t test and the nonparametric signed-rank tests, with P < 0.05 considered significant. RESULTS: Gastric emptying time was delayed in 26 patients (group A), whereas in 14 patients (group B), it was in the same range as control values; group A patients significantly differed from group B for increased prevalence of gastric electrical dysrhythmias (P < 0.01) and for a lower fed-to-fasting ratio of the dominant EGG power (P < 0.01). Group B patients did not differ from control subjects for the EGG variables measured. Diabetic children with gastroparesis had significantly higher levels of both HbA1C and blood glucose measured 180 min after feeding than those with normal gastric emptying time (P < 0.05); there was a significant correlation between levels of HbA1C and degree of gastric emptying delay, whereas a significant inverse correlation between gastric emptying time and fed-to-fasting ratio of the dominant EGG power was found both in patients and control subjects. CONCLUSIONS: Delay of gastric emptying time and gastric electrical abnormalities are found in a high proportion of children with diabetes and can contribute to poor glycemic control, most likely by causing a mismatch between the onset of insulin action and the delivery of nutrients into the small intestine. Diabetic children with unexplained poor glycemic control should be investigated for abnormalities in gastric motility.
Abstract: Prolonged recordings of esophageal motility have shown that dynamic changes of lower esophageal sphincter (LES) pressure such as transient LES relaxation and LES pressure drifts are the most common mechanisms underlying gastroesophageal reflux (GER). The coexistence of a delayed gastric emptying has also been reported in a high proportion of patients with reflux disease. However, not much information is available on the effects of antireflux therapy on the pathogenetic mechanisms of GER. The purpose of this study was to determine in a group of children with severe reflux disease the effect of omeprazole therapy on motor changes of LES underlying GER as well as on gastric emptying time. Twenty-two children (median age: 6.6 years) with GER disease, refractory to combined ranitidine and cisapride administration, entered into an eight-week omeprazole course. Ten subjects with moderate GER disease served as controls (median age: 6.0 years). Before and after omeprazole administration, the following variables were assessed: esophagitis grading, fasting and fed simultaneous prolonged recording of distal esophageal sphincter pressure (with a sleeve catheter) and intraesophageal pH, LES and esophageal peristalsis amplitude, and gastric emptying time of a mixed solid-liquid meal (measured with gastric ultrasound). As compared to controls, patients showed a higher rate of transient LES relaxation and LES pressure drift (P < 0.01), a reduced amplitude of basal sphincter pressure (P < 0.01) and peristalsis (P < 0.05), and a more prolonged gastric emptying time (P < 0.05). After ending omeprazole, there was no significant change in any of the motor abnormalities of the esophagus and in gastric emptying time despite a marked improvement of symptoms and esophagitis in all patients. Sixteen patients were symptomatic when reevaluated on a clinical basis two months after ending therapy. We conclude that in children with severe GER disease, an abnormally high rate of both transient LES relaxation and LES pressure drift and slow gastric emptying are not affected by omperazole treatment, even though esophageal mucosal damage is markedly improved or cured. These abnormalities represent a primary motor disorder and can be implicated in the refractoriness of reflux disease.
Abstract: BACKGROUND: The macrolide antibiotic erythromycin (EM) affects gastrointestinal motor activity by acting as agonist of motilin receptors located on the smooth muscle cells of the gastroduodenal tract. We studied the effect of intravenous EM on fasting antroduodenal motility in controls and children with gastrointestinal dysmotility. METHODS: EM lactobionate (rate, 3.0 mg/kg/h) was infused intravenously while antroduodenal manometry was recorded in 10 controls, in 7 patients with functional dyspepsia and in 6 patients with gut pseudo-obstruction. The mean (SD) age (years) was 5.7 (1.4), 6.5 (2.4), and 6.7 (3.2), respectively. Manometry was performed by means of a four- or six-lumen catheter introduced through the nose and perfused with a low compliance pneumohydraulic system. Five controls received EM and five received saline. RESULTS: EM, infused 5 minutes after passage of an activity front (AF), induced in controls a premature antroduodenal AF occurring 15.4 +/- 3.2 minutes after starting infusion; no motor changes were seen after saline; duration and propagation velocity of EM-induced AFs did not differ from spontaneous AFs. In patients with functional dyspepsia EM induced various patterns such as premature antroduodenal AFs, antral phase III-like pattern with short duodenal bursts or prolonged phasic antral waves and no duodenal activity. In patients with neurogenic pseudo-obstruction rare or absent antral activity with incoordinated or absent duodenal activity was induced; no contractions were elicited in two patients with myogenic pseudo-obstruction. CONCLUSIONS: It is confirmed that EM, given at subtherapeutic doses, is a powerful prokinetic agent that can have clinical applications in patients with gastrointestinal dysmotility; however, the effect of the drug seems to be influenced by the nature of the underlying disorder.
Abstract: Regurgitation is a common manifestation in infants below the age of 1 year and a frequent reason of counselling of general practitioners and paediatricians. Current management starts with postural and dietary measures, followed by antacids and prokinetics. Recent issues such as an increased risk of sudden infant death in the prone sleeping position and persistent occult gastro-oesophageal reflux in a subset of infants receiving milk thickeners or thickened "anti-regurgitation formula" challenge the established approach. Therefore, the clinical practices for management of infant regurgitation have been critically evaluated with respect to their efficacy, safety and practical implications. The updated recommendations reached by the working party on the management of infant regurgitation contain five phases: (1 A) parental reassurance; (1 B) milk-thickening agents; (2) prokinetics; (3) positional therapy as an adjuvant therapy; (4 A) H2-blockers; (4 B) proton pump inhibitors; (5) surgery.
Abstract: BACKGROUND/AIMS: A retrospective study has been carried out on the last 20 consecutive patients operated for gastro-oesophageal reflux to compare the results of the traditional operation with those using the laparoscopic approach. METHODS: In ten cases, the operation was performed with an open traditional approach and in the other 10 cases using laparoscopy. The mean age of the patients was 7 years and their mean weight was 20 kg. There were 11 girls and 9 boys. We used a 360 degrees Nissen fundoplication in the patients operated on via laparotomy and a Nissen-Rossetti fundoplication in patients operated on via laparoscopy. RESULTS: Mean operating time was 65 minutes for traditional surgery and 100 minutes for laparoscopy. There were two complications: 1 case of oesophageal perforation in a child affected by endo-brachyoesophagus with peri-oesophagitis, operated using the laparoscopic technique, and one case of wound infection in a child operated with the open technique. The hospital stay was remarkably shorter and less painful for the children operated on laparoscopically. At 13-month mean follow-up, all 20 patients are alive and present no reflux symptoms. CONCLUSIONS: Our results demonstrate that laparoscopic surgery is a valid alternative to the traditional surgical approach for the treatment of gastro-oesophageal reflux.
Abstract: OBJECTIVE: Deranged gastric motility and delayed gastric emptying are commonly implicated in the pathophysiology of gastroesophageal reflux disease. We measured gastric electrical activity and gastric emptying time of a solid-liquid meal by electrogastrography and antral ultrasound, respectively, in 42 patients with gastroesophageal reflux disease (age 7.4 +/- 1.6 yr). METHODS: Based on endoscopy and histology of the esophageal mucosa, reflux disease was moderate in 20 patients and severe in 22. Electrogastrography was measured by placing two Ag-AgCl electrodes on the epigastric skin, signals were digitized and fed into a personal computer, and data were obtained by running spectrum analysis. The electrogastrographic variables calculated were: 1) percent of electrical dysrhythmias and normal electrical rhythm (bradygastria or 0.5-2.0 cycles/min, tachygastria or 4.0-9.0 cycles/min; normal rhythm is 2.0-4.0 cycles/min); 2) fed:fasting ratio of dominant electrogastrographic power; 3) fed:fasting ratio of the dominant frequency instability coefficient. Gastric emptying time and electrical activity results were compared with those measured in 15 controls (7.1 +/- 1.7 yr). RESULTS: Dysrhythmic episodes were more common in both groups of patients than in controls (p < 0.01); furthermore, gastric emptying time was significantly more delayed in patients than in controls (p < 0.01). Children with severe gastroesophageal reflux were distinguished from those with moderate disease for post-feeding gastric electrical abnormalities consisting of reduced electrogastrographic dominant power and increased frequency variability (p < 0.01), as well as for a more prolonged gastric emptying time (p < 0.05). Prevalence of both normal electrical rhythm and dysrhythmias did not discriminate the two groups of patients. In patients and in controls, a significant inverse correlation between fed electrogastrographic power and gastric emptying time was found (r -0.88, p < 0.01). CONCLUSIONS: Fed gastric electrical abnormalities consisting of reduced dominant power and increased variability of the electrical dominant frequency are detected in patients with severe gastroesophageal reflux disease and are associated with delayed gastric emptying. Gastric electrical dysrhythmias may be included among the pathogenetic components of gastroesophageal reflux disease.
Abstract: BACKGROUND: Whole gut lavage is currently used as preparation before radiological or endoscopic examination of the large bowel. AIM: To validate the gut lavage technique for the assessment of mucosal inflammation, by measuring intestinal IgG and interleukin 1 beta (IL-1 beta) in the fluid obtained. PATIENTS: Sixteen children with Crohn's disease (CD), 14 with ulcerative colitis (UC), and 22 age matched controls. METHODS: Isotonic, non-absorbable polyethylene glycol based lavage solution was given orally or by nasogastric tube. Clear fluid was collected, filtered, and treated with protease inhibitors. IgG, IL-1 beta and IL-1-receptor antagonist (IL-1-ra) were measured by sandwich enzyme linked immunosorbent assay (ELISA). RESULTS: In patients with UC and CD, IgG and IL-1 beta levels were significantly (p < 0.001) higher than in controls. A positive correlation (p < 0.05) was found with disease activity scores. IL-1-ra levels were not significantly different in UC and CD, when compared with controls, but the IL-1-ra:IL-1 beta ratio was significantly (p < 0.01) lower in patients with UC and CD, and negatively (p < 0.001) correlated with IgG levels in lavage fluid. CONCLUSIONS: Gut lavage fluid IgG and IL-1 beta levels and IL-1-ra:IL-1 beta ratio may provide objective discrimination between active and inactive disease in children with inflammatory bowel disease.
Abstract: BACKGROUND: Paediatricians are familiar with infants complaining of regurgitation and emesis from gastrooesophageal reflux. These subjects, usually growing satisfactorily and healthy, are affected by "functional" or "symptomatic" gastrooesophagel reflux and are treated with posture changes and thickened feedings. AIM: To evaluate in infants with symptomatic gastrooesophageal reflux the effect of a new formula (Nutrilon AR), containing carob flour/locus bean gum as a thickening agent; both clinical features and oesophageal acid exposure were evaluated. PATIENTS: Twenty-four infants (age range: 5-11 months; median age: 8 months; 8 females) presented at our Unit with a history of chronic postprandial regurgitation. METHODS: During a 24-hour intraoesophageal pH test a traditional formula thickened with rice flour at a concentration of 5% was alternated with the formula Nutrilon AR; thereafter infants were randomly allocated to receive, for two weeks, either a traditional thickened formula or the new formula, in addition to posture changes. RESULTS: Intraoesophageal acid exposure was significantly lower in the periods following the new formula than after traditional formula; at the end of the treatment period patients receiving the new formula had a more significant decrease of both symptomatic score and number of episodes of emesis than patients on traditional formula. CONCLUSIONS: The new available formula, with the characteristics of a thickened meal, is better than a formula, traditionally thickened with added rice flour, in the conservative treatment of infants with symptomatic gastrooesophageal reflux.
Abstract: Intestinal dysmotility is commonly reported in patients with cystic fibrosis (CF); however, gastric motor activity has rarely been investigated. We measured with real-time ultrasonography the antral distention and gastric emptying time of a solid-liquid meal in 29 patients with CF (age range, 5 to 17 years). A significantly prolonged gastric emptying time was present in 26 patients compared with 13 healthy control subjects (age range, 5 to 16 years); an exaggerated antral distention in the fed period was also detected. The patients with CF and delayed gastric emptying were randomly allocated to receive cisapride or ranitidine for 4 weeks. Twelve patients treated with ranitidine and 11 with cisapride completed the trial. There was a marked decrease in gastric emptying time, antral distention, and dyspeptic symptomatic score in patients receiving ranitidine but not in patients treated with cisapride. We conclude that gastric dysmotility is commonly detected in patients with CF and that H2 receptor blockers are more effective than prokinetics in improving dyspeptic symptoms and gastric emptying and distention.
Abstract: OBJECTIVES: The aim of the study was to evaluate, in 42 children with gastroesophageal reflux disease, the predictive value of both esophageal manometry and gastroesophageal intraluminal pH on the responsiveness of the disease to medical therapy. METHODS: Motility of lower esophageal sphincter and esophageal body was carried out through a perfused pediatric sleeve-probe; prolonged recording of the sphincteric profile was evaluated at the occurrence of reflux episodes as detected by an esophageal electrode; intraluminal pH of the esophagus and stomach was also measured for 24-h through portable equipment. Children were treated for 8 wk with cisapride and ranitidine and were classified as healed or refractory after endoscopy and clinical evaluation. RESULTS: Twenty one children healed, and 21 were refractory. Compared with healed patients, refractory patients showed, at basal evaluation, an increased esophageal acid exposure (p < 0.05), a reduced basal sphincteric pressure and peristalsis amplitude (p < 0.01), an increased rate of sphincteric pressure drifts (p < 0.01), and a higher rate of transient lower esophageal sphincter relaxations (p < 0.01). The following parameters contributed significantly (p < 0.01) to a multivariate discriminant analysis: peristalsis amplitude, basal sphincter pressure, rate of transient relaxations of the sphincter, and rate of sphincteric pressure drifts. A correct classification of virtually all cases (97.62%) was reached. CONCLUSIONS: Motor dysfunctions of both lower esophageal sphincter and esophageal body are the major factors predicting refractoriness of reflux disease in children to a standard medical treatment. Of the two main mechanisms of reflux, i.e., transient lower esophageal sphincter relaxation and lower esophageal sphincter pressure drift, the latter had the highest predictive value for the refractoriness of reflux disease.
Abstract: Efficacy of one-week triple antimicrobial therapy (bismuth, tinidazole, amoxicillin) as compared to the same drug combination given for 4 weeks was assessed in children with Helicobacter pylori (H. pylori) gastritis and non-ulcer dyspepsia. Twenty-six patients (group A) and 30 (group B) had one-week and four-week schedule, respectively. Eradication (absence of organism at endoscopy at least 1 month after ending treatment) was achieved in 84.6% of group A (22) and 83.3% of group B (25), with marked reduction of histological gastritis score in both groups. Among patients with eradicated H. pylori, symptoms improved significantly in 14 and 16 patients of group A and B, respectively, but were still present in 17 (8 group A, 9 group B). The latter showed gastroparesis and abnormal gastro-oesophageal reflux at a subsequent diagnostic work-up and improved with prokinetic therapy. In 3 patients of group A and 3 of group B, symptoms improved despite persistence of bacterium into the stomach. Finally, in 3 cases (1 group A, 2 group B) both symptoms and H. pylori infection were unchanged. At 6 month follow-up, symptoms were present in 7 patients (3 group A, 4 group B): 6 of them (3 group A, 3 group B) showed H. pylori gastritis at endoscopy. We conclude that in children with dyspepsia and H. pylori gastritis one-week triple antimicrobial schedule is effective in eradicating bacterium; however, detection of H. pylori gastritis in dyspeptic children does not invariably indicate a pathogenic role of the organism in these patients.
Abstract: The great majority of children referred to Pediatric Gastroenterologic Units for chronic constipation have a functional disorder and do not require investigative techniques, since functional constipation is easily recognized an anamnestic and clinical basis. Severe chronic constipation indicates a chronic condition believed to be of functional type but unresponsive to the traditional pharmacologic treatment. However, several clinical features might suggest an organic type of constipation during the initial diagnostic approach: growth failure, distension, episodes of diarrhea intermingled with constipation, subocclusive events, dilatation of areas of the gut (megaduodenum, megajejunum) at x-ray examination of the entire gastrointestinal tract. Hirschsprung's disease is the best known organic type of constipation; however, there are other neurogenic and myogenic abnormalities of the colonic (and/or ileal) tract that mimick Hirschsprung's disease and represent development abnormalities of the enteric nervous plexus. Other organic types of constipation are due to systemic diseases, endocrine and metabolic disorders, central nervous system disorders. Organic constipation usually requires extensive investigative approach, including pathologic examination of enteric nervous plexus on full thickness biopsies.
Abstract: Regurgitation in infants is a common problem. Recent issues, such as the increased risk of sudden infant death in the prone sleeping position, the finding of persisting occult gastro-oesophageal reflux with feed thickeners, and the increasing awareness of the cost-benefit ratio of medications may challenge the currently recommended management approach. A round table was organized to elaborate on the impact of (i) the pro supine sleeping campaigns in relation to sudden infant death and (ii) advancement in medical treatment on therapeutic strategies in regurgitating infants. The participants were opinion leaders from Europe and North America (Belgium, Canada, France, UK, Italy, Switzerland and The Netherlands). The importance of parental reassurance is stressed. As a consequence of the supine sleeping campaigns aiming to decrease the incidence of sudden infant death syndrome, the "prone elevated sleeping position" is no longer advised as a first-line therapeutic approach, although it is still recommended in "complicated reflux". It is emphasized that milk thickeners are an adequate therapeutic tool for regurgitation, but not in reflux disease. According to the literature, the efficacy of (alginate )antacids, although very popular in some countries, is questionable. These recommendations will be of interest to first-line paediatricians, since about 40% of their patients, according to the literature, present because of regurgitation.
Abstract: We examined the effect of oral cisapride on gastric emptying time and myoelectrical activity using real-time ultrasonography and cutaneous electrogastrography in 10 children with nonulcer dyspepsia. A clear dominant frequency close to 3 cpm was present both at baseline and after eight weeks of cisapride. After cisapride, nine children had an increase in the normal slow wave percentage and the mean percentage of normal slow wave was significantly different (71.90 +/- 5.19% vs 79.16 +/- 5.54%; P < 0.01). Moreover, an increased stability of the dominant frequency, determined by computing the coefficient of variation before and after cisapride, was found (28.12 +/- 1.72% vs 23.61 +/- 3.47%; P < 0.01). At baseline the gastric emptying time, expressed as T1/2, was 139.76 +/- 40.04 min and at eight weeks 119.76 +/- 30.04 min (P = 0.06). As regards the relationship between EGG and gastric emptying, the proportion of children with improved normal slow wave percentage was similar to that with improved T1/2 emptying (Z = 0.57, P = 0.57). Thus, gastric electrical activity seems to be an important factor in the pathophysiology of nonulcer dyspepsia in children.
Abstract: We describe a case of semi-lethal chondrodysplasia with skeletal manifestations, detectable at birth, typical of the round femoral inferior epiphysis dysplasia (RFIED) or 'Glasgow' variant. Immunological abnormalities and Hirschsprung disease, so far described only in cartilage hair hypoplasia (CHH), were documented during the first months of life in our patient. These findings confirm the hypothesis that RFIED is a form of CHH with early infantile onset.
Abstract: The antroduodenal motor effects of ranitidine, and H2-receptor antagonist with cholinergic activity, and neostigmine, a cholinomimetic drug, were compared in 16 patients with idiopathic gastroparesis characterized by dysmotility-like dyspepsia, delayed gastric emptying at scintigraphy and absence of gastroduodenal phase 3 of the migrating motor complex during a manometric recording of at least 300 min. After overnight fasting in 8 of these patients, neostigmine was administered intravenously at a dose of 0.5 mg, and in the remaining 8 patients ranitidine was given intravenously at a dose of 100 mg. Ranitidine induced a gastroduodenal phase 3 activity in a significantly (p < 0.02) higher percentage of patients (87.5%) in comparison with neostigmine (25%). In the majority of patients, neostigmine induced only an irregular increase in gastroduodenal motor activity sometimes characterized by propagated and nonpropagated clustered contractions. This property of ranitidine of inducing a phase 3 activity in these patients cannot be ascribed to its weak cholinergic activity, as neostigmine, which has a more intense cholinergic activity than ranitidine, is unable to produce the effect demonstrated by ranitidine. Another unknown mechanism able to trigger the neurohormonal program of migrating motor complex phase 3 or to abolish inhibitory influences should be taken into account to explain this effect of ranitidine.
Abstract: OBJECTIVES: To characterize both proximal and distal esophageal acid exposure in children with gastroesophageal reflux-related respiratory disease and to investigate the usefulness of dual-channel intraesophageal pH monitoring in these patients. METHODS: Continuous simultaneous recording of distal and proximal esophageal pH was performed in 40 patients with gastroesophageal reflux disease and respiratory symptoms (wheezing, nocturnal cough, obstructive bronchitis) (age range 3-168 months) (group A), in 20 patients with reflux disease alone (age range 7-156 months) (group B), and in 14 controls (age range 5-108 months) (group C). RESULTS: (expressed as median +/- SD) 1) The two groups of patients did not differ with regard to distal and proximal esophageal acid exposure (percentage of reflux) during both the total recording period [distal, A: 9.2 +/- 4, B: 10.7 +/- 7 (NS), C: 1.9 +/- 1.0; and proximal, A: 4.8 +/- 3.3, B: 4.0 +/- 3.3 (NS), C: 1.0 +/- 0.7] and during nighttime [distal, A: 8.0 +/- 6.2, B: 10.4 +/- 6.1 (NS), C: 0.9 +/- 0.65; and proximal, A: 3.72 +/- 3, B: 3.6 +/- 3.0 (NS), C: 0.75 +/- 0.45]. 2) The two groups did not differ with regard to the ratio between proximal and distal esophageal acid exposure during both total and nocturnal periods of analysis. 3) No significant correlation was found between distal and proximal esophageal acid exposure during total and nocturnal recording periods. 4) In patients with reflux-related respiratory disease, the respiratory symptomatic index was significantly higher during distal esophageal acid exposure alone (47.0 +/- 28.6%) than during simultaneous reflux at the two esophageal levels (26.9 +/- 27%) (p < 0.05). Furthermore, reflux episodes associated with respiratory symptoms reached lower pH values than those in patients without symptoms at the two recording sites. CONCLUSIONS: Gastroesophageal reflux into the proximal esophagus does not discriminate between patients with reflux disease alone and those with reflux disease complicated by respiratory symptoms. Symptoms of asthma in reflux patients appear to be elicited more by a reflex mechanism than by aspiration of gastric refluxate into the airways. Intraesophageal acidification seems to be involved in eliciting respiratory symptoms related to reflux disease, and prolonged intraesophageal two-level pH measurement does not seem to be useful in the approach to patients with reflux disease associated with respiratory symptoms.
Abstract: Severe and protracted diarrhea (SPD) is the most severe form of diarrhea in infancy and has also been defined as intractable diarrhea. Its etiology is poorly defined. We have retrospectively evaluated the etiology, the outcome, and the risk factors of 38 children, admitted with protracted diarrhea and need for total parenteral nutrition (TPN) from 1977 to 1993. Children with anatomic abnormalities and/or primary immunodeficiency were excluded. There was an inverse relationship between the number of patients and the age of diarrheal onset (mean age, 2.9 +/- 3.5 months). Etiology of SPD was an enteric infection in 18 cases (eight Salmonella, three Staphylococcus, five rotavirus, one adenovirus, one Cryptosporidium), multiple alimentary intolerance (eight cases), familial microvillous atrophy (two), autoimmune enteropathy (two), celiac disease, lymphangectasia, eosinophilic enteropathy, intestinal pseudoobstruction, and intestinal neurodysplasia (1 case each). Etiology was not detected in three cases. Overall, 12 children died, five are presently being treated, and 21 had full remission. Comparative evaluation of risk factors between children with SPD and a control population of children with diarrhea but without the need for TPN showed that low birth weight, no breast feeding, history of fatal diarrhea in a relative, and early onset of diarrhea had a significantly higher incidence in the former. Social background was similar in the two populations. We conclude that a specific etiology can be identified in the majority of cases of SPD. The etiologic spectrum of SPD is broad, but an enteric infection is the most common cause of SPD. The severity of this condition is related, at least in part, to established risk factors.
Abstract: Colonization of the gut by intestinal bacteria begins at birth and progresses rapidly in the immediate postnatal period. Host defense mechanisms that mediate enteric colonization include gastric acidity and intestinal motility. The small bowell overgrowth syndrome is a condition characterized by large numbers of bacteria, often anaerobes, in the upper intestine. Steatorrea, carbohydrate malabsorption and abdominal pain are frequently present. Predisposing conditions are localized anatomic disorders (surgical blind loops, small bowel strictures caused by surgery or Crohn's disease, short-gut syndrome without ileocaecal valve), motility derangements or reduction of gastric acidity. Diagnosis of the overgrowth syndrome is often difficult and quantitative cultures of jejunal-aspirated fluid is the best diagnostic test. Antimicrobial therapy directed against anaerobes is often successful, but the best therapeutic approach is the correction of predisposing conditions, if present.
Abstract: Real-time ultrasonography (US) of the gastric antrum after ingestion of a mixed solid-liquid meal was performed in 60 patients (median age, 8.2 years; range, 3-17) being investigated for symptoms suggesting upper intestinal dysfunction (vomiting, regurgitation, abdominal pain, early satiety, and anorexia) and in 13 controls (median age, 5 years; range, 3-15). The diagnostic work-up allowed identification of 14 patients with esophagitis (group A) and 26 with Helicobacter pylori (HP) gastritis (group B); median age in group A was 9 years (range, 3-15) and in group B was 9.5 years (range, 3-17). Group A patients had significantly more prolonged gastric-emptying times (median, 180 min; range, 110-270) than did controls (median, 150 min; range, 110-180; p < 0.01); however, group A times were not significantly longer than those of group B patients (median, 160 min; range, 90-265). In the remaining 20 patients (group C; median age, 7.1 years; range, 3-15) without a specific diagnosis, markedly delayed gastric emptying was detected (median, 237 min; range, 165-270; p < 0.01 vs. group B patients and vs. controls; p < 0.05 vs. group A patients); in this group, GI manometry revealed findings of deranged motility of the gut. Distension of the antral area (percentage of increase vs. baseline values) 60 and 90 min after feeding was higher in group C (60 min: median, 185%; range, 70-614%; 90 min: median, 175%; range, 60-400%) than in both controls (60 min: median, 80%; range 26-148%; 90 min: median 90%; range 20-253%; p < 0.01) and HP patients (60 min: median, 120%; range, 35-311%; 90 min: median, 98%; range, 23-400%; p < 0.05); there was no significant difference versus esophagitis patients. The latter differed from controls only for the 60-min postfeeding antral distension (p < 0.01), whereas HP patients did not differ from controls. In group C patients, symptomatic dyspeptic score correlated with both 60- and 90-min fed antral distension (r = 0.61 and r = 0.64, respectively; p < 0.05), but no correlation was found with gastric-emptying time. In group A patients, histologic score of esophagitis correlated with 60-min postfeeding antral distension (r = 0.56; p < 0.05), whereas poor correlation was found with 90-min postfeeding antral distension and with gastric-emptying time. However, the latter significantly correlated with 90-min fed antral distension in esophagitis patients (r = 0.70; p < 0.01). We conclude that US imaging of the antral area of the stomach reveals abnormalities of gastric motility in most children referred for dyspeptic symptoms; this technique should be included among the investigative tools in the diagnostic approach to these patients.
Abstract: Although from the clinical point of view a GI motor disorder can be suspected in celiac disease, objective evidence for this is still lacking. We therefore conducted a study on children with active celiac disease to detect possible GI motor abnormalities in this disease. Fourteen children (age range, 1-13 years) were studied; they underwent fasting and fed manometric recordings in the gastroduodenojejunal area. Four patients were restudied after a 6-month gluten-free diet. Data were compared with those obtained in eight control children. As compared with controls, celiac disease patients showed a shorter duration of activity fronts (p < 0.01) and a significant (p < 0.01) reduction of the postprandial antral motility index; furthermore, > 90% of the patients displayed marked fasting and/or fed motor abnormalities, suggesting a neuropathic disorder. Interestingly, gut dysmotilities disappeared in the four subjects reassessed after the gluten-free diet. It is concluded that celiac disease frequently affects the motor behavior of the gut and that its effects may be reversed by appropriate diet.
Abstract: The diagnostic usefulness of intraepithelial cells with irregular nuclear contours (CINC) (squiggle cells) in esophageal biopsies was investigated in 76 children (range age: 6 months-12 years) with gastroesophageal reflux disease. A further 20 subjects (range age: 10 months-11 years) served as controls. Based on the microscopic changes of the esophagus, according to traditional histological criteria, four groups of patients were identified; esophagitis was severe in 27, moderate in 20, mild in 21, and 8 patients had no clear-cut evidence of microscopic esophagitis. Data are given as mean +/- SD. Intraepithelial CINC had an immunohistochemical profile consistent with T lymphocytes. Patients with severe esophagitis had a CINC density (number per high-power filed) (9.0 +/- 3.5) significantly higher than patients with mild esophagitis (7.0 +/- 3.0) and those without evidence of microscopic esophagitis (6.5 +/- 1.9) (P < 0.05), but not different from those with moderate esophagitis (8.0 +/- 3.6); in all patients groups the CINC density was higher than in controls (2.2 +/- 0.3) (P < 0.01). The percentage of reflux at 24-hr intraesophageal pH monitoring was higher in severe esophagitis patients (11.4 +/- 6.0) as compared to the other groups (moderate: 7.8 +/- 6.3; mild: 6.5 +/- 3.6; no microscopic esophagitis: 6.3 +/- 2.0; P < 0.05). There was no correlation between CINC density and the amount of intraesophageal acid exposure in all patients. Furthermore, 27 of our patients had a normal intraesophageal acid exposure at the prolonged pH test (24-hr % of reflux < or = 4.5): the CINC density was significantly higher in them than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: We analyzed the antroduodenojejunal (ADJ) manometric patterns in a group of 19 consecutive children (mean age, 53 months; range, 5 months to 14 years) referred for suspected chronic idiopathic intestinal pseudoobstruction. Diagnosis was based on typical symptoms, absence of extraintestinal diseases, and structural lesions of the gut at endoscopy and radiology. Surgical full-thickness intestinal biopsies were evaluated in nine patients. Manometry of the stomach and small bowel was performed in the fasting and fed state with a multilumen perfused probe. All patients showed severe abnormalities of ADJ motor activity that were not seen in the eight controls (mean age, 38.2 months; range, 1-9 years). In 12 patients, manometric patterns suggesting neuropathic disease were detected with fasting and/or fed sustained and incoordinated duodenojejunal phasic waves, aberrant propagation and/or configuration of phase III of the inter-digestive motility complex, inability of a meal to convert a fasting into a fed pattern, and prolonged groups of fasting and fed nonpropagated phasic waves. In seven of these patients, histology revealed marked changes of the intrinsic neurons. In four cases, manometry disclosed features suggestive of a myogenic disease, including severe fasting and fed infrequent low-amplitude contractions, sometimes with some degree of propagation; in two of these cases, histology showed morphological abnormalities of smooth muscle cells of the gut wall. In three patients, manometry revealed signs suggestive of mechanical obstruction of the gut, such as repetitive post-feeding clusters and simultaneous repeated broad-based waves; in these patients, more detailed x-ray studies showed organic obstructive causes (ileal lymphoma, Hirschsprung's disease, and intestinal malrotation).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: In order to define the mechanisms of gastroesophageal reflux (GER) in children, we performed simultaneous intraluminal esophageal motility and pH studies in 24 children with symptomatic reflux and abnormal prolonged pH probe study, ten (group A) without endoscopic and histologic esophagitis, 14 (group B) with endoscopic and histologic esophagitis. Median (ranges) age (years) was 5.0 (6 months-10 years) and 3.0 (6 months-12 years), respectively. Recordings were done for 1 hr before and 1 hr after feeding apple juice (15 ml/kg; pH 4.0). All episodes of GER in group A patients and 77.1% in group B patients were accounted for by abrupt transient lower esophageal sphincter (LES) relaxation (TLESR); 22.9% of reflux events in group B patients occurred during gradual drifts of LES pressure (LESP) to undetectable levels. Esophageal refluxate exposure (mean percentage time with esophageal pH < 4.0), the rate of TLESR (number of episodes/hr), and the percentage of TLESRs associated with reflux significantly increased in the fed period both in group A (18.5 +/- 5.4%, 6.2 +/- 2.65, 87.1%) and in group B (29.7 +/- 6.5, 7.8 +/- 3.05, 84.9%) as compared to the fasting state (group A: 10.8 +/- 3.9, 3.9 +/- 3.17, 46.1%; group B: 16.1 +/- 2.6, 4.14 +/- 3.06, 55.17%) (p < 0.01). The rate of LESP drifts (number of episodes/hr) was also significantly higher postprandially (4.85 +/- 1.24 vs 1.8 +/- 0.9, p < 0.01); furthermore there was a postfeeding increase of the LESP drift percentage associated with reflux (79.41% vs 46.15%, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: In this paper, a Working Group on Gastro-Oesophageal Reflux discusses recommendations for the first line diagnostic and therapeutic approach of gastro-oesophageal reflux disease in infants and children. All members of the Working Group agreed that infants with uncomplicated gastro-oesophageal reflux can be safely treated before performing (expensive and often unnecessary) complementary investigations. However, the latter are mandatory if symptoms persist despite appropriate treatment. Oesophageal pH monitoring of long duration (18-24 h) is recommended as the investigation technique of choice in infants and children with atypical presentations of gastro-oesophageal reflux. Upper gastro-intestinal endoscopy in a specialised centre is the technique of choice in infants and children presenting with symptoms suggestive of peptic oesophagitis. Prokinetics, still a relatively new drug family, have already obtained a definitive place in the treatment of gastro-oesophageal reflux disease in infants and children, especially if "non-drug" treatment (positional therapy, dietary recommendations, etc.) was unsuccessful. It was the aim of the Working Group to help the paediatrician with this consensus statement and guide-lines to establish a standardised management of gastro-oesophageal reflux disease in infants and children.
Abstract: Thirty two consecutive patients (age range 6 months-13.4 years) with severe reflux oesophagitis were randomised to a therapeutic trial for eight weeks during which they received either standard doses of omeprazole (40 mg/day/1.73 m2 surface area) or high doses of ranitidine (20 mg/kg/day). Twenty five patients completed the trial (12 on omeprazole, 13 on ranitidine). At entry and at the end of the trial patients underwent symptomatic score assessment, endoscopic and histological evaluation of the oesophagus, and simultaneous oesophageal and gastric pH measurement; results are given as median (range). Both therapeutic regimens were effective in decreasing clinical score (omeprazole before 24.0 (15-33), after 9.0 (0-18); ranitidine before 19.5 (12-33), after 9.0 (6-12)), in improving the histological degree of oesophagitis (omeprazole before 8.0 (6-10), after 2.0 (0-60); ranitidine before 8.0 (8-10), after 2.0 (2-6), and in reducing oesophageal acid exposure, measured as minutes of reflux at 24 hour pH monitoring (omeprazole before 129.4 (84-217), after 44.6 (0.16-128); ranitidine before 207.3 (66-306), after 58.4 (32-128)) as well as intragastric acidity, measured as median intragastric pH (omeprazole before 2.1 (1.0-3.0), after 5.1 (2.2-7.4); ranitidine before 1.9 (1.6-4), after 3.4 (2.3-5.3)). Serum gastrin concentration was > 150 ng/l in four patients on omeprazole and in three patients on ranitidine. It is concluded that in children with refractory reflux oesophagitis high doses of ranitidine are comparable with omeprazole for the healing of oesophagitis and relief of symptoms; both drugs resulted in efficacious reduction of intragastric acidity and intra-oesophageal acid exposure.
Abstract: Interdigestive gastroduodenal motility was studied manometrically in 16 patients with ulcer-like dyspepsia due to hypersecretory gastroduodenitis (group A) and in a control group of 6 healthy subjects (group B). After a basal recording period sufficient to record at least two activity fronts (AF) of the migrating motor complex (MMC) of the gastroduodenal tract, we administered 100 mg of ranitidine intravenously to 8 patients of group A (group A1), and the same dose of ranitidine to the remaining 8 patients of group A (group A2) after pretreatment with cimetidine 200 mg i.v. to block the acid secretion. The interdigestive motility of patients with hypersecretory gastroduodenitis is characterized by a decrease in frequency and duration of the activity fronts of MMC, which may play a role in the pathogenesis of mucosal lesions. Ranitidine induced premature and prolonged activity fronts in all patients without antisecretory pretreatment, and in the majority of patients in whom the acid secretion was previously blocked.
Abstract: Three children (ages 5, 7.6, and 8 years), with recurrent unexplained upper abdominal symptoms such as vomiting, epigastric pain, anorexia, early satiety and without structural or mucosal abnormalities of gastrointestinal tract, underwent electrogastrography (EGG)--recording of gastric electrical activity using cutaneous electrodes positioned on the epigastric region and connected to a recording polygraph. Frequency of EGG signals was analyzed by fast Fourier transform. Significant changes of fasting and fed gastric myoelectrical activity (tachygastria, bradygastria, flatline pattern) were recorded in the three patients; furthermore, gastric emptying (GE) of a solid-liquid mixed meal, measured by ultrasonography, was significantly prolonged in them. A follow-up study was carried out after an eight-week course with oral cisapride: in all patients symptoms improved, GE time normalized, and EGG analysis showed normal electrical rhythm. It is suggested that gastric dysrhythmias can play a pathogenetic role in patients with functional gastrointestinal symptoms and that symptomatic improvement is accompanied by normalization of gastric electrical rhythm.
Abstract: Fasting and fed gastric electrical activity was recorded by cutaneous electrodes (electrogastrography) in 14 children with unexplained recurrent symptoms of upper intestinal dysfunction, and in 10 controls. The unexplained symptoms included vomiting, epigastric pain, fullness, and early satiety. Mean (SD) age was 7.0 (3) and 7.5 (2) years, respectively. Gastric emptying time of a solid-liquid meal was also measured by real time ultrasonography in all subjects (patients and controls). In all patients radiography and endoscopy excluded structural and focal abnormalities of the gastrointestinal tract. Gastric emptying time was significantly more prolonged in patients than in controls. It was also found that there were appreciable irregularities of gastric electrical rhythm (tachygastria, bradygastria, flat line pattern, and mixed arrhythmia) in 12 fasting and 10 fed patients, whereas controls showed short and rare episodes of arrhythmia during both fasting and fed recording periods. The percentage distribution of the total electrogastrographic energy power across three frequency bands of electrical activity (low, normal, and high) showed that patients were different from controls both for reduced activity of normal frequency and for increased incidence of high and low abnormal frequencies. It is concluded that gastric electrical abnormalities are found in a high proportion of children with recurrent unexplained upper gastrointestinal symptoms. Electrogastrography can be a valuable tool in the assessment of these patients.
Abstract: During the recent years, intraluminal esophageal manometry has developed into an important method for detecting motor function of the esophagus and pharynx. High fidelity instrumentation is now available to perform adequate recording of pressure phenomena of the esophagus. It consists of water-filled catheters systems, perfused by minimally compliant hydraulic system and of intraluminal strain gauge probes. A sleeve catheter assembly is suitable for recording lower sphincteric pressure for long period, despite the respiratory and deglutitive axial movements of the sphincter along the catheter. The pressure events of interest are phasic pressure wave along the esophageal body (usually peristaltic) as well as resting tone and relaxation of upper and lower esophageal sphincters. Recording instrumentation available allows accurate detection of esophageal motor activity both in healthy subjects and in patients.
Abstract: The efficacy of cisapride, a new prokinetic drug, as a treatment for chronic functional constipation of childhood was studied in 20 constipated children. Each subject had a stool frequency less than 4/week and/or total gastrointestinal transit time greater than 33 hr and was randomly assigned to double-blind treatment with either cisapride (N = 10) or placebo (N = 10) for 12 weeks. Stool habits, total gastrointestinal transit time, and anorectal motility were evaluated in all children before and at the end of the treatment period. Cisapride significantly increased stool frequency from 1.2 +/- 0.6 to 5.1 +/- 1.9 stools/week (mean +/- SD; P less than 0.05), whereas the lesser effect of placebo was not significant (1.2 +/- 0.8 to 2.8 +/- 0.8 stools/week; P = 0.4). Both treatments significantly (P less than 0.05) decreased laxative or suppository use. Total gastrointestinal transit time was decreased by cisapride (90.8 +/- 9.2 hr to 57.2 +/- 20.2 hr; P less than 0.05) but was not affected by placebo. Anorectal manometry showed that cisapride, but not placebo, significantly decreased the rectoanal inhibitory reflex threshold and the conscious rectal sensitivity threshold. It is concluded that cisapride improves gastrointestinal motility and bowel habits in children with chronic idiopathic constipation and may be useful in the management of some children with this disorder.
Abstract: Abnormal degrees of gastro-oesophageal reflux (GOR) were detected by 24 hour intraoesophageal pH measurement in 12 of 14 children (mean age 7.9 years; range 5 months-16 years) affected by cystic fibrosis and complaining of symptoms suggesting GOR. These patients underwent combined recording of distal oesophageal motility and intraluminal pH in order to investigate mechanisms of GOR. Inappropriate lower oesophageal sphincter relaxation was the most common mechanism of reflux in all patients. Other mechanisms (appropriate relaxation or lowered pressure of the lower oesophageal sphincter, increased intragastric pressure) were detected less frequently. Frequency of inappropriate lower oesophageal sphincter relaxations was significantly higher in patients with cystic fibrosis than in other study groups (symptomatic GOR, GOR disease complicated by respiratory complaints). Inappropriate lower oesophageal sphincter relaxations occurred with the same frequency in patients with cystic fibrosis and in a group of children with GOR disease complicated by oesophagitis. Abnormalities of distal oesophageal contractions such as decreased amplitude or uncoordinated waves were also recorded in cystic fibrosis patients. Seven patients with cystic fibrosis completed a therapeutic trial for eight weeks consisting of postural treatment and oral cisapride, a new prokinetic drug. The oesophageal acid exposure improved in only three patients. We conclude that pathologic GOR is commonly associated with cystic fibrosis. The predominant reflux mechanism in these patients is a transient inappropriate lower oesophageal sphincter relaxation rather than a low steady state basal lower oesophageal sphincter pressure.
Abstract: A group of 25 children affected by different degrees of psychomotor retardation (severe (n = 13); mild-moderate (n = 12)) and symptoms suggesting gastro-oesophageal reflux (GOR) underwent oesophageal manometry and oesophageal pH monitoring. Of these patients, 21 (84%) were affected by GOR. In all children with severe brain damage and GOR (12/13), oesophageal manometry showed marked motility abnormalities that persisted after cure of GOR. In patients with minor retardation and GOR (9/12), oesophageal manometry showed normal motility or a less severe degree of oesophageal motor dysfunction which improved after curing the GOR. These results suggest that oesophageal motor dysfunction is a frequent occurrence in children affected by severe psychomotor retardation and GOR.
Abstract: In 11 children (mean age 44.2 months) with symptoms suggesting upper intestinal dysfunction (nonulcer dyspepsia), in nine children (mean age 27.3 months) with gastroesophageal reflux (GER) disease, and in seven controls (mean age 20.4 months) we investigated fasting [for 3 hr or until two migrating motor complexes (MMC) were observed] and fed (90 min) antroduodenal motility by means of perfused catheter system; furthermore, we measured both gastric emptying of a radiolabeled milk formula and fasting duodenogastric reflux during manometry by assessing bile salt concentration in gastric aspirates. No structural abnormalities of gastrointestinal tract and organic disorders were detected in the patients. In a high proportion of both groups of patients we found manometric abnormalities of interdigestive and fed motor patterns that were not seen in the controls: absence of antral phase III of MMC; significant decrease of antral and/or duodenal motor activity during fasting and/or fed periods; abnormal propagation or configuration of MMC phase III that was significantly shorter than in controls; bursts of sustained fasting and/or fed phasic duodenal activity, frequently uncoordinated with adjacent gut segments. When compared to controls, the mean intragastric concentration of bile salts during all MMC phases and the mean 1-hr percent gastric activity of the radiolabeled milk were significantly higher in the two groups of patients. We conclude that in a high proportion of children with nonulcer dyspepsia and of children with GER disease, gastrointestinal manometry may reveal significant irregularities of antral and duodenal motility, which are associated with increased duodenogastric reflux and delayed gastric emptying.
Abstract: The effect of cisapride, a new gastrointestinal prokinetic drug, on oesophageal motility and acid reflux was studied in 14 children with gastro-oesophageal reflux disease, receiving either placebo or cisapride 0.15 mg/kg intravenously. Cisapride significantly (p less than 0.01) increased the lower oesophageal sphincter pressure (+124%), the amplitude (+84%) and duration (+24%) of oesophageal peristaltic waves, whereas the placebo treatment did not produce any changes. Subsequently, all 14 children underwent 24 hour oesophageal pH-monitoring before and after four weeks of treatment with oral cisapride 0.2 mg/kg tid given in addition to postural therapy and thickened feedings. The 24 hour intraoesophageal pH recordings and symptomatic scores were compared with those of 10 control patients treated only by postural therapy and thickened feedings. When compared with baseline pH data, cisapride significantly reduced the oesophageal acid exposure time, the mean duration of each reflux episode, the duration of the longest reflux episode and the number of long lasting reflux episodes; the number of reflux episodes was not influenced. The effect of cisapride was marked and consistent during fasting and sleep periods. Oesophageal acid exposure was reduced more significantly in patients given cisapride (-61%) than in controls (-24%; p less than 0.001). Symptom improvement was greater after four weeks of cisapride treatment (score reduction: 61%) than after postural and dietary therapy alone (score reduction: 42%; p less than 0.01). No adverse effects occurred. These findings suggest that cisapride is a valuable drug in the management of gastro-oesophageal reflux disease in children.
Abstract: Twenty four hour oesophageal intraluminal pH probe studies were performed in 114 children (range age: one month-12 years) referred for symptoms or signs compatible with gastroesophageal reflux. Forty five patients had reflux disease alone, 69 had evidence of oesophagitis which was assessed endoscopically and histologically. Recordings were also performed in 63 control patients. The occurrence of reflux was analysed for the total study period and particularly while awake, asleep, fasting, and during postcibal periods. Oesophageal acid exposure time and the number of reflux episodes lasting greater than five minutes during the total study period provided the best discrimination between patients and controls; however, 20% and 30% of all reflux patients had both normal (with 2 SD of control) acid exposure time and number of long lasting reflux episodes, respectively. Patients with oesophagitis had significantly more acid reflux than those with simple uncomplicated disease during postcibal, fasting, awake periods, but not during sleep; however, increasing severity of oesophagitis was not associated with increasing acid exposure. The ability of the intraluminal oesophageal pH test to discriminate patients with various degrees of reflux disease decreased if only postprandial pH variables were taken into account. We conclude that: (1) the 24 hour intraoesophageal pH monitoring may present false negative results that limit overall sensitivity of the test; (2) the presence of oesophagitis does not seem to be associated with increased oesophageal acid exposure during sleep; (3) limiting the pH recording to postprandial periods reduces the discriminatory power of the test.
Abstract: The effectiveness of cimetidine (30-40 mg/kg/day) was evaluated in 32 children with gastroesophageal reflux disease complicated by esophagitis who entered a random double-blind trial for 12 weeks. Esophagitis was diagnosed in all patients by endoscopy with biopsy. Seventeen patients (age, mean +/- SD: 21.7 +/- 37.65 months) received cimetidine (c-pts), and 15 (age, mean +/- SD: 29.03 +/- 39.73 months) received a placebo (p-pts). All patients received intensive postural therapy. Based on clinical and endoscopic (and histologic) data, 12 c-pts and three p-pts were healed (p less than 0.01), the condition of four c-pts and three p-pts had improved (not statistically significant), and the condition of one c-pt and nine p-pts had worsened (p less than 0.01). Both clinical and esophagitis scores significantly decreased only in the c-pt group, as compared with p-pts. Improvement of esophagitis was seen in all (100%) of c-pts with mild or moderate esophagitis versus 57.14% of p-pts (p less than 0.01) and in 87.5% of c-pts with severe esophagitis as compared with 25% of the p-pt group (p less than 0.01). We conclude that cimetidine is an effective agent for treatment of reflux esophagitis in children. Although gastroesophageal reflux disease in infancy has a naturally self-limited course with conservative care (thickened feedings and posture adjustment), extensive pharmacologic therapy is needed in the presence of esophagitis.
Abstract: Chronic functional constipation is a common clinical disorder in pediatric age. Thirteen children with functional constipation were treated by administration of vegetable fibres together with a toilet training program, for two months. In each patient anorectal manometry showed presence of inhibitory anal reflex and diagnosis of constipation was confirmed by a prolonged gastrointestinal transit time measured by radio-opaque markers. In all patients there was a significant improvement in both stool frequency and intestinal transit time; furthermore, a normalization of anorectal motility variables was observed at rectal manometry. No changes in the blood levels of nutritional parameters were seen in any patient. It is concluded that vegetable fibres represent an effective treatment of functional chronic constipation in children.
Abstract: Bowel frequency was recorded, on a diary sheet basis, in 662 children from six Italian cities. There is a wide interindividual variability, showing a sharp decrease with age; we report the distribution of the percentiles in the different age groups. Among infants, the breast-fed ones pass significantly more stools than the formula-fed.
Abstract: Two small infants with gastroesophageal reflux disease and esophagitis are reported. Esophageal manometry revealed in both patients severe abnormalities consisting of aperistalsis and simultaneous low-amplitude motor waves. In one of the patients, defective relaxation of lower esophageal sphincter was also noted. Short-term intensive treatment with H2 antagonists resulted in symptomatic and endoscopic improvement as well as in manometric normalization. It is suggested that severe esophagitis may affect control mechanisms of esophageal motility, resulting in loss of coordination and decreased amplitude of contractions.
Abstract: The effect of the new prokinetic drug cisapride on the resting lower oesophageal sphincter pressure and on the strength of peristaltic contractions was studied in 10 healthy controls and in 10 reflux patients with abnormally low (less than 10 mm Hg) basal lower oesophageal sphincter pressure. A slow intravenous injection of cisapride 10 mg significantly increased the sphincter pressure in the controls but even more in the patients in whom it almost doubled the resting lower oesophageal sphincter pressure of 8.7 (0.5) mm Hg to between 15 and 20 mm Hg for at least 90 min. Results are expressed as mean (SE). Cisapride also significantly increased the amplitude of peristaltic contractions in controls and reflux patients. Therefore, cisapride might be useful in the treatment of reflux.
Abstract: We investigated the mechanisms of gastroesophageal reflux (GER) and esophageal motility during endogenous esophageal acid exposure in 17 patients with reflux disease alone (age range 3-20 months) (group A) and in 10 patients with reflux disease complicated by esophagitis (age range 4-19 months) (group B), by simultaneous recording distal esophageal sphincter relaxation was the predominant mechanism of reflux in both groups of subjects; however, it was more frequent in group B patients (Bpts), whereas reflux episodes due to appropriate sphincter relaxation were detected more frequently in group A patients (Apts). During endogenous acid exposure, primary peristalsis was the most frequent esophageal motor event in all patients; furthermore, its amplitude was significantly higher in Apts as compared with Bpts. Primary peristalsis was more efficacious (rise of intraluminal pH by at least 0.5 unit) in patients with reflux disease alone, whereas nonspecific motor irregularities were more common in children with reflux esophagitis. It is concluded that the major mechanism of GER in patients with reflux esophagitis is an inappropriate sphincter relaxation; reflux due to appropriate sphincter relaxation is associated with less severe reflux disease; and patients with esophagitis exhibit a deranged esophageal motility during spontaneous acid exposure.
Abstract: Twenty children (age range 75 days-47 months) with reflux oesophagitis entered a random double blind trial in which they received either Cisapride (Janssen Pharmaceutical Ltd), a new prokinetic agent, or an identical placebo syrup. Diagnosis of gastro-oesophageal reflux was made by measurement of intraluminal oesophageal pH combined with manometry. Oesophagitis was assessed in all patients by histological examination of mucosal specimens taken during oesophagogastroduodenoscopy. Manometry, pH test, and endoscopy with biopsy examination were repeated at the end of the treatment period. Seventeen patients completed the trial, eight of whom were taking the drug and nine the placebo. Mean total clinical score and post-prandial reflux time (% of reflux) significantly improved in patients in the group given Cisapride but not in the group given placebo. Furthermore, there was a significant improvement of the histological oesophagitis score only in the children in the group given Cisapride, whereas placebo was ineffective. It is concluded that Cisapride is a useful agent both for the relief of symptoms of gastro-oesophageal reflux and for the healing of peptic oesophagitis in infancy.
Abstract: Dysfunction of the upper esophageal sphincter was found in five out of 44 children with gastroesophageal reflux. Three of the five children had mental retardation associated with Silver Russell syndrome, 5p syndrome, or minimal change myopathy. The five patients had swallowing disorders, vomiting, and failure to thrive; four also had pulmonary aspiration. Esophageal manometry showed incomplete upper esophageal sphincter relaxation in two patients, upper esophageal sphincter relaxation incoordinated with pharyngeal contractions in two other patients, and both incomplete and incoordinated upper esophageal sphincter relaxation in the last patient. Intensive and successful treatment of gastroesophageal reflux did not improve swallowing or symptoms of pulmonary aspiration in four children. The fifth patient underwent cricopharyngeal myotomy, with complete resolution of respiratory and swallowing symptoms. It is suggested that a dysfunction of the upper esophageal sphincter, either primary or secondary to neuromuscular disorders, may play a role in the swallowing disorders and respiratory symptoms of pediatric patients.
Abstract: The clinical case of a 14-month-old girl with esophageal achalasia is described. Manometry revealed aperistalsis throughout the esophageal body and impaired relaxation of the lower esophageal sphincter. Six months after Heller's myotomy, manometric examination of the esophagus showed the return of peristalsis.
Abstract: Esophageal motility was studied in 26 children with gastroesophageal reflux. In 11 patients (group A), esophagitis was severe; in the remaining 15 (group B), either mild or no microscopic changes were found. Lower esophageal sphincter pressure and amplitude, as well as velocity and duration of esophageal pressure waves, were manometrically measured. All patients underwent a 12-week intensive antacid course. Manometric tracings, blindly read, were compared with those of 16 age-matched children with emesis without proven reflux (group C). Among the variables analyzed, amplitude of the motor waves was significantly lower in patients with severe esophagitis than in group B and C patients (P less than 0.01). Nonspecific motor defects (simultaneous, broad-based, double-peaked waves) were more commonly present in group A. At the end of therapy, symptoms had either disappeared or significantly improved. Endoscopic and histologic studies showed disappearance of the severe inflammatory changes. Manometry, repeated in patients with cured severe esophagitis, showed normalization of the amplitude and significant decrease of the nonspecific motility abnormalities. We conclude that severe gastroesophageal reflux disease in children causes esophageal motor dysfunction, resulting from esophageal inflammation. The occurrence of esophageal motility disorders only in patients with severe esophagitis and its disappearance after therapy may account for the favorable course of reflux disease in infancy.
Abstract: Total gastrointestinal transit time (TGITT), frequency of defecation, and anorectal manometry were evaluated in 63 pediatric patients referred for chronic nonorganic constipation; in 39, segmental transit times of the right and left colon and rectum were also measured. TGITT was significantly longer in chronically constipated children than in matched normal controls. Although bowel frequency was highly significantly correlated with TGITT in patients with prolonged transit time, not all children with prolonged TGITT had reduced bowel frequency. Moreover, not all children with constipation had prolonged TGITT. In children with idiopathic chronic constipation, slowing of intestinal transit occurred most frequently at the level of the distal colon and rectum. Anorectal motility variables were not significantly different in children with functional chronic constipation and in normal children. Maximal resting and pressure and mean intrarectal distending volume causing threshold inhibition in constipated patients did not significantly differ from the control values. Therefore, anorectal manometry did not detect relevant motor abnormalities in constipated children.
Abstract: Among 10 children with giardiasis, eight had iron deficiency; iron deficiency anemia was the main complaint in three. Evaluation of iron absorption by the oral iron load test demonstrated a subnormal response (i.e., increase in serum iron levels of less than 100 micrograms/dl) in all eight patients with iron deficiency. In contrast, in two iron-sufficient patients with giardiasis the response to an oral iron load was normal. Xylose absorption was abnormal in five of the 10 patients. After metronidazole dosing, iron absorption became normal in seven patients but remained abnormal in one patient, who also had IgA deficiency. Xylose absorption became normal in all five patients who underwent a second test, but remained abnormal in the patient with IgA deficiency. Concomitant morphologic-studies of jejunal biopsy material from these patients revealed moderate changes in the intestinal mucosa of two patients. We conclude that malabsorption of iron is a complication of giardiasis.
Abstract: One hundred thirteen children referred for chronic constipation were examined by means of diagnostic work-up including anal inspection, rectal exploration, weekly bowel frequency evaluation, measurement of total and segmental intestinal transit times (TITT, SITT), contrast enema, anorectal manometry (ARM), suction rectal biopsy for histochemistry. Final diagnosis were: chronic functional "simple" constipation in 53 children; chronic functional constipation and soiling in 32; Hirschsprung's disease in 18. In 10 children, initially referred for constipation, TITT was in the normal range so they underwent no further examination. Conclusions are that bowel frequency identifies a real gastrointestinal problem, but definite diagnosis of constipation is relied on TITT. In the assessment of chronic constipation nature, ARM is more sensitive than radiology. Suction rectal biopsy is reliable in detection of aganglionosis: its accuracy can be improved by histochemical or biochemical determination of Acetylcholinoesterase.
Abstract: Thirty three children aged 2 to 42 months (mean 9 months) with gastro-oesophageal reflux and peptic oesophagitis took part in a treatment trial comparing cimetidine (20 mg/kg/day) with an intensive regimen of antacids (Maalox, 700 mmol (mEq)/1 X 73 m2/day). All children were evaluated clinically and by radiology, acid reflux test, and endoscopy. After 12 weeks of treatment all were again evaluated clinically, by pH measurement, and endoscopy. Twenty nine children, 15 on antacid and 14 on cimetidine, completed the trial. Eight patients on antacid and seven on cimetidine were cured; five on antacid and six on cimetidine improved; and two patients on antacid and one on cimetidine underwent surgery. Both groups of children showed a statistically significant reduction in the score of clinical, pH, and endoscopic variables after treatment. Lower oesophageal sphincter pressure before treatment did not correlate significantly with the final total score. Antacids in large quantities are as effective as cimetidine in medical treatment of gastro-oesophageal reflux and peptic oesophagitis.
Abstract: Fifty-three children with chronic idiopathic constipation, 32 with fecal soiling and 21 without soiling, were investigated by total gastrointestinal transit time (TGITT) and anorectal manometry (ARM). TGITT and ARM were also performed, respectively, in 46 and 32 healthy subjects. Twenty-two of the 32 children with soiling were successfully managed by medical treatment and toilet training. TGITT was significantly longer in all constipated children than in normal children. Furthermore, some parameters of anorectal motility (threshold volume, amplitude of threshold inhibitory anal reflex) of the patients differed markedly from those measured in controls. Rectal compliance was significantly higher in children with fecal soiling than in children with constipation without soiling and healthy controls. In the successfully treated children, soiling disappeared, TGITT normalized, and anorectal variables changed significantly. It is concluded that TGITT is useful in assessing the degree of constipation. Electromanometry of the anorectum is of great help in the diagnosis of functional constipation by excluding aganglionosis; furthermore, it provides additional information allowing better understanding of the mechanisms involved in functional constipation in children.
Abstract: The authors of this paper report the first case of epicardial oesophageal duplication causing hiatal hernia in a patient afflicted with Turner's syndrome, and they discuss its possible etiology.
Abstract: The authors evaluated the diagnostic role of sigmoidoscopy, colonoscopy, and double contrast radiology in 103 children with rectal bleeding, with or without other gastrointestinal symptoms. The children's mean age was 44 months, with a range from 1 month to 12 years. In 74.5% of the subjects investigated, visual inspection of the anus and sigmoidoscopy with rectal biopsy disclosed a positive diagnosis. Of the remaining patients, a conclusive diagnosis was reached by either colonoscopy or double contrast radiology in all but six patients. These six, with mild painless hematochezia, remained without a diagnosis. The diagnostic procedure in pediatric patients with rectal bleeding should include an initial visual inspection of the anus, and sigmoidoscopy; air contrast enema and colonoscopy should be performed only in children whose sigmoidoscopy is negative, in diagnostic assessment of inflammatory bowel disease, and in cases of recurrent bleeding after removal of rectal polyps. Colonoscopy is important also in the follow-up examination of children with inflammatory bowel disease and allows the removal of polyps located in the proximal colon.
Abstract: The authors studied 52 patients aged from 1 month to 8 years with symptoms consistent with gastro-esophageal reflux and esophagitis. The employed methods were radiological examination, esophageal manometry, acid reflux test, endoscopy. The gastro-esophageal reflux was diagnosed in 38 children. The authors compare the results of radiological examination to those of the other methods. The analysis of the results led the authors to believe that the association of every methods is necessary to define the diagnostic picture. However, the authors emphasize that the conventional X-rays examination is the first stage that cannot be substituted in the management of children with non acute gastro-esophageal disease.
