Repeatability of transient elastography in children.

BACKGROUND: Poorly performing diagnostic tests can impact patient safety. Clinical investigations must have good precision and diagnostic accuracy before widespread use in clinical practice. Transient elastography (TE) measures liver stiffness, a surrogate marker of liver fibrosis in adults and children. Studies to evaluate its repeatability and reproducibility (precision) in children are limited. Our aim was to determine (i) the normal range of TE measurements and (ii) the repeatability and reproducibility of TE in healthy children. METHODS: TE was performed in 257 healthy children, of whom 235 (91%, mean age 11.7 years, standard deviation (SD) 2.51, 107 were males (45.5%)) had two valid TE measurements performed, at least 24 h apart, by two operators under similar circumstances. High-quality TE images were obtained for each examination. RESULTS: The normal range of TE was 2.88-6.52 kPa. The mean difference between paired measurements was 0.044 (SD 0.4). The 95% limits of agreement ranged from -0.8 to +0.76 kPa for repeat measurements. There was a difference of >1 kPa between measurements in 61/235 (25.9%) children. The lack of precision was similar across all age groups. CONCLUSIONS: This study demonstrates that TE does not have acceptable precision in healthy children, because random measurement variation results in the lack of agreement between paired measurements. IMPACT: The precision and diagnostic accuracy of a new technology must be determined before it is deployed in children in order to ensure that appropriate clinical decisions are made, and healthcare resources are not wasted. TE is widely used to diagnose liver disease in children without adequate evaluation of the precision (repeatability) of TE either in healthy children or children with liver disease. This study demonstrates that TE does not have adequate precision in children. This study was performed in accordance with methods previously published for children. Refinements to the test protocol, such as duration of fasting or probe size, will have to be evaluated for their impact on precision and accuracy before the test is deployed in research studies or clinical practice.

The use of stool specimens reveals Helicobacter pylori strain diversity in a cohort of adolescents and their family members in a developed country.

Helicobacter pylori infection occurs within families but the transmission route is unknown. The use of stool specimens to genotype strains facilitates inclusion of complete families in transmission studies. Therefore, we aimed to use DNA from stools to analyze strain diversity in H. pylori infected families. We genotyped H. pylori strains using specific biprobe qPCR analysis of glmM, recA and hspA. Concentration of H. pylori organisms before DNA isolation enhanced subsequent DNA amplification. We isolated H. pylori DNA from 50 individuals in 13 families. Tm data for at least 2 of the 3 genes and sequencing of the glmM amplicon were analyzed. Similar strains were commonly found in both mothers and children and in siblings. However, 20/50 (40%) individuals had multiple strains and several individuals harbored strains not found in other family members, suggesting that even in developed countries sources of infection outside of the immediate family may exist. Whether infection occurs multiple times or one transmission event with several strains occurs is not known but future studies should aim to analyze strains from children much closer to infection onset. The presence of multiple stains in infected persons has implications for antibiotic sensitivity testing and treatment strategies.

Helicobacter pylori lipopolysaccharide interacts with TFF1 in a pH-dependent manner.

BACKGROUND & AIMS: Little is known about how bacteria establish chronic infections of mucosal surfaces. Helicobacter pylori (H. pylori), a chronic pathogen that lives in the gastric mucosa of humans, interacts with the trefoil factor family (TFF) protein TFF1, which is found in gastric mucus. We aimed to characterize the interaction of H. pylori with TFF1 and to assess the role of this interaction in mediating colonization. METHODS: Subcellular fractions of H. pylori were immobilized and then probed with TFF1, TFF2, or TFF3. The effect of glycosidases and preincubation with monosaccharides on the interaction and binding of TFF1 to a H. pylori adhesin was assessed. The interaction between H. pylori adhesin and TFF1 was characterized using surface plasmon resonance, flow cytometry, nondenaturing polyacrylamide gel electrophoresis, coimmunofluoresence, and incubation with tissue sections. RESULTS: The H. pylori core oligosaccharide portion (rough form) of lipopolysaccharide (RF-LPS) bound to TFF1 and to a lesser extent TFF3; this interaction was inhibited by incubation of RF-LPS with mannosidase, glucosidase, or mixed monosaccharides. TFF1 also bound to human serum albumin-conjugated mannose and glucose. The optimum pH for binding was 5.0-6.0 for TFF1 and 7.0 for TFF3. H. pylori bound TFF1 in gastric mucus ex vivo; binding of LPS-coated latex beads to human antral gastric tissue was inhibited by TFF1. CONCLUSIONS: TFF1 interacts specifically with H. pylori RF-LPS. The pH dependence of this interaction indicates that binding of H. pylori to TFF1 in the stomach could promote colonization of the mucus layer adjacent to the gastric epithelial surface.

The incidence of cyclic vomiting syndrome in children: population-based study.

OBJECTIVE: Cyclic vomiting syndrome (CVS) is characterized by severe recurrent episodes of vomiting in an otherwise healthy child. Currently, there is no population data on the incidence of CVS. The aim of this study was to determine the incidence of CVS and to define the clinical characteristics of the condition at diagnosis. METHODS: Each pediatrician on the island of Ireland was surveyed on a monthly basis from January 1, 2005 to December 31, 2005 by the Irish Pediatric Surveillance Unit (IPSU) and was asked to report any incident cases of CVS according to the criteria outlined by the First International Symposium on CVS. Subsequently, data on demographics and clinical features were collected anonymously from the reporting pediatricians. RESULTS: Eighty-nine percent (1,647 of 1,848) of the surveillance cards were returned, reporting 41 valid cases of CVS. The incidence of CVS in Ireland was 3.15/100,000 children per annum for 2005 (95% confidence interval [CI] 2.19-4.11). The median age at diagnosis of CVS was 7.42 yr (range 1.8-15 yr). The median age at onset of CVS was 4 yr (range 0.5-14 yr) with 46% (19 of 41) of children having an onset at or before the age of 3 yr. The median number of episodes of CVS per child per year was eight (range 3-52); the median duration of an episode was 24 h (range 1 h to 5 days). Of school-age children, 85% (22 of 26) had missed school in the previous year due to CVS and 44% (18 of 41) were admitted to hospital for supportive treatment or investigation of CVS. CONCLUSION: CVS is a relatively common condition in pediatric patients, with an incidence comparable to other major gastrointestinal diseases of childhood, such as Crohn's disease. The onset of pediatric CVS is generally early in childhood and this disease causes significant morbidity in the majority of those affected.

An approach to functional abdominal pain in children and adolescents.

For children with chronic abdominal pain, the early introduction of stress as a potential cause is likely to improve outcome. Parents underestimate their child's awareness of and capacity to worry about everyday events. Parents, children, and teachers need to be convinced that functional symptoms are a normal feature of life. The need for empathy and quality discussion between doctor, parents, and child concerning potential causes of stress is critical. All reinforcement should be removed including insistence on continued school attendance. Cognitive behavioural therapy appears to be helpful in resistant cases. Medication such as antidepressants should be avoided unless prescribed by a child psychiatrist.

Results from the pediatric European register for treatment of Helicobacter pylori (PERTH).

BACKGROUND AND AIM: Data on the eradication treatment for childhood Helicobacter pylori are scanty. A register was established on the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) website to collect data on treatment performed by European pediatricians to ascertain what is practiced in the field. SUBJECTS: From January 2001 to December 2002, information on 597 children were entered by 23 European Centers, but only data of 518 treated children were completed and analyzed (86.7%, 262 male subjects, median age 9 years, range 1-14). According to their nationality, 226 children were from Southern Europe, 132 from Eastern Europe, 68 from Western Europe, and 4 from northern Europe, 68 from North Africa, and 20 from Asia. At endoscopy, 454 children had gastritis and 64 had ulcer (12.3%). Antibiotic sensitivity, tested in 361 cases, revealed 18% clarithromycin-resistant and 19% metronidazole-resistant H. pylori strains. RESULTS: Treatment was performed for 1 week in 388 and for 2 weeks in 130 children. Antibiotics were associated with proton pump inhibitors (PPI) in 345 and with bismuth in 121 children. Triple therapy was given to 485 children, dual therapy to 26, quadruple to 7. Follow-up data, by (13)C-Urea-Breath Test or histology or both, were available for 480 children. Overall eradication rate was 65.6%, significantly higher in children with ulcer (79.7%) than without (63.9%, p = .001). When given as first treatment, bismuth-containing triple therapies were more efficacious than PPI-containing ones (77% versus 64%, p = .02, OR 1.88, 95% CI 1.1-3.3). Twenty-seven different treatment regimens were used, but only six were administered to at least 18 children (range 18-157). There was no difference between treatments given for 1 or 2 weeks, or given as first or second therapies. CONCLUSION: European pediatricians entering data in the register used 27 different regimens. Bismuth-containing therapies resulted in higher eradication rate. Omeprazole-containing triple therapies were the most used although their efficacy was low. Therapies recommended for adults do not appear to be suitable for children.

Giant inflammatory polyposis coli as a manifestation of Crohn's disease in patients with coexistent cystic fibrosis.

Crohn's disease (CD) arising in children with cystic fibrosis (CF) is well recognized. Indeed, reports suggest that CD is significantly more common in patients with CF than in the general population. Giant inflammatory polyposis is a rare manifestation of idiopathic inflammatory bowel disease and may complicate both ulcerative colitis and CD. Giant inflammatory polyposis has not been specifically reported in patients with coexistent CF and CD. Herein, we report the occurrence of giant inflammatory polyposis in 2 boys attending a tertiary care hospital, with an established diagnosis of CF who subsequently developed CD. Both boys required surgical treatment for CD. In addition to classical features of CD, both colonic resection specimens showed giant inflammatory polyposis. The appearances were modified by the presence of a layer of thick mucus. It is suggested that the coexistence of CF in patients with CD may predispose to the development of giant inflammatory polyposis. In addition to contributing to their development, it also appears that there is a propensity for CF to alter the morphological appearance of giant inflammatory polyposis. This may lead to diagnostic confusion when examining endoscopic biopsies.

Age-specific incidence of Helicobacter pylori.

BACKGROUND & AIMS: Helicobacter pylori is most likely acquired in childhood, but the incidence of infection has not been determined prospectively by using an appropriate noninvasive test. The aim of this study was to determine the age-specific incidence of Helicobacter pylori infection in children and the risk factors for infection. METHODS: Three hundred twenty-seven healthy index children between 24 and 48 months of age were enrolled over 15 months. At baseline, the Helicobacter pylori infection status of each index child and his or her older siblings and parents was assessed by using the carbon 13-urea breath test. All noninfected index children were then followed up with an annual carbon 13-urea breath test for 4 years to determine whether they became infected with Helicobacter pylori and, if so, the age at first infection. Information on potential risk factors was collected at baseline and each subsequent visit. RESULTS: At baseline assessment, 28 of 327 (8.6%) index children were infected with Helicobacter pylori. The mean age of the 28 infected children was 32.78 months (SD, 5.14 months). Over the next 4 years, 279 index children not infected at baseline contributed 970 person-years of follow-up to the study. During this time, 20 children became infected with Helicobacter pylori. The rate of infection per 100 person-years of follow-up was highest in the 2-3-year age group (5.05 per 100 person-years of follow-up (95% confidence interval, 1.64-11.78) and declined progressively as children aged. Only 1 child became infected after 5 years of age. Having an infected mother, an infected older sibling, and delayed weaning from a feeding bottle (ie, after 24 months of age) were all risk factors for infection. CONCLUSIONS: Children who become infected with Helicobacter pylori are infected at a very young age, and the risk of infection declines rapidly after 5 years of age. These findings have important implications for studies on the mode of transmission of infection.

A prospective study of the oral manifestations of Crohn's disease.

BACKGROUND & AIMS: Recent studies suggest that the mouth may be involved frequently in patients with Crohn's disease (CD). The aim of this study was to document prospectively the proportion of children with oral lesions at diagnosis of CD, to describe the type of lesions found, and to examine the ability of gastroenterologists to identify correctly oral Crohn's manifestations. METHODS: In a prospective 3-year study, systematic dental examinations were performed on all children with suspected inflammatory bowel disease. Each child underwent upper endoscopy, colonoscopy, and barium follow-through radiography. RESULTS: Forty-eight of 49 children with CD were examined by the dentist. Oral CD was found in 20 patients (41.7%). Oral findings included mucogingivitis (12 patients), mucosal tags (4 patients), deep ulceration (4 patients), cobblestoning (3 patients), lip swelling (3 patients), and pyostomatitis vegetans (1 patient). Noncaseating granulomas were found in all 8 oral biopsy specimens from oral CD lesions (100%). Two patients with granulomas in oral biopsy specimens had no granulomas found in any other biopsy specimens. The presence of oral manifestations was associated with perianal disease. In only 9 patients (45%) with oral CD was the mouth found to be abnormal by the consultant gastroenterologists. Only nonspecific oral changes were seen in children with ulcerative colitis and indeterminate colitis. CONCLUSIONS: More than one third of all children presenting with CD had involvement of the mouth. The ability of physicians to recognize oral lesions was poor. Expert dental evaluation may be useful during the investigation of patients with suspected inflammatory bowel disease.

Helicobacter pylori infection of human and murine primary gastric cells.

The effect of Helicobacter pylori infection on human and murine primary gastric cells was determined. CagA was phosphorylated following adherence of H. pylori to primary human gastric cells. However, it did not adhere to human primary duodenal cells or murine gastric cells, and CagA could not be detected in cell lysates. Identification of an easily available animal model of infection in which the organism adheres to gastric mucosal cells would enhance studies of the virulence of H. pylori.

Importance of parental conceptual model of illness in severe recurrent abdominal pain.

OBJECTIVES: Recurrent abdominal pain (RAP) affects up to 15% of children. A biopsychosocial approach to the treatment of children with RAP has been proposed as an alternative to the traditional medical model. The aim of this study was to examine whether the parental conceptual model of illness is a factor in the long-term outcome of children with severe RAP. METHODS: The study was undertaken in 2 parts: 1) a review of the medical and psychiatric records (including Child Behavior Checklist [CBCL]) of all children with RAP of sufficient severity to necessitate hospitalization during a 5-year period and 2) a structured telephone interview to collect information on ongoing abdominal pain, other somatic symptoms, school attendance, and the parents' opinion as to the cause of the child's pain. RESULTS: Twenty-eight of 30 children who were identified were available for follow-up. Twenty-three (82%) were tertiary referrals from other pediatric services, and 20 had pain for >6 months. On admission 7 (25%) of 28 had a depressive disorder, and 8 (29%) had an anxiety/depressive disorder. Twenty-one of 28 parents completed the CBCL, and on analysis of the CBCL, 11 (52%) children had scores in the clinical range (>65). At follow-up (mean: 3.56 years; standard deviation: 1.59), 14 (50%) of 28 continued to complain of pain. These children also complained of multiple other somatic complaints and had repeated school absences. Only 1 (7%) of 14 parents of children with ongoing pain believed that there was a psychological cause for their child's pain, whereas 11 (78%) of 14 parents of the children who had recovered believed that the cause was attributable to psychological factors (odds ratio: 47.67; 95% confidence interval: 3.56-1511.6). CONCLUSIONS: The acceptance by parents of a biopsychosocial model of illness is important for the resolution of recurrent abdominal pain in children.

Helicobacter pylori interacts with the human single-domain trefoil protein TFF1.

Why Helicobacter pylori colonizes only gastric tissue is unknown. It is found on gastric mucus-secreting cells and in the overlying gastric mucus but not deep in gastric glands. This localization mirrors the expression of trefoil factor 1, TFF1. We hypothesized that H. pylori interacting with TFF1 could explain the tropism of this bacteria for gastric tissue. Recombinant human TFF1 expressed in Escherichia coli was purified by affinity chromatography, ion-exchange chromatography, and gel filtration. Binding of H. pylori was assessed by using flow cytometry and the BIAcore system, which allows real-time monitoring of molecular interactions. In flow cytometry, H. pylori bound to the TFF1 dimer, but Campylobacter jejuni strains and the laboratory strain of E. coli, HB101, did not bind. When the BIAcore system was used, H. pylori bound strongly to TFF1-coated dextran chips compared with uncoated chips. Binding was inhibited by a TFF1 monoclonal antibody and by soluble TFF1. H. pylori bound to porcine gastric mucin only if it was pretreated with TFF1. In conclusion, H. pylori interacts avidly with the dimeric form of TFF1, and this interaction enables binding to gastric mucin, suggesting that TFF1 may act as a receptor for the organism in vivo. This interaction may underline the previously unexplained tropism of this organism for gastric tissue and its colocalization with the gastric mucin MUC5AC.

Cystic fibrosis-associated liver disease: a population-based study.

OBJECTIVES: The aim of this study was to explore the clinical factors associated with the development of cystic fibrosis-associated liver disease (CFALD). STUDY DESIGN: This was a case-control study of all children (age 5-18 years) with established CFALD in the Republic of Ireland between January 1999 and June 2000. Each child was pair matched for age and sex with a patient with cystic fibrosis (CF) without evidence of liver disease. Only children with clinically overt liver disease were enrolled in the disease group. RESULTS: Patients with established CFALD (n = 42; 26 boys) were enrolled. Children with CFALD had worse forced expiratory volume in 1 second values than those without CFALD. However, chest radiography and clinical scores did not differ between groups. Height (mean difference, -4.2 cm [95% confidence interval [CI], -7.41 to -0.90], P =.014), weight (mean difference, -3.21 kg [95% CI, -6.03 to -0.40], P =.026), and mid-upper arm circumference (mean difference, -1.23 cm [95% CI, -2.35 to -0.12], P =.031) were significantly lower among children with CFALD. Children with CFALD were given diagnoses of CF later than children without liver disease. There were more children with meconium ileus in the control group (14 vs 4) than among those with CFALD. CONCLUSIONS: Children with established CFALD have impaired growth and nutrition, altered body composition, and worse forced expiratory volume in 1 second values. CFALD is associated with later age of diagnosis of CF.

Clinical and genetic characteristics of hereditary pancreatitis in Europe.

BACKGROUND & AIMS: Hereditary pancreatitis is an autosomal dominant disease that is mostly caused by cationic trypsinogen (PRSS1) gene mutations. The aim was to determine phenotype-genotype correlations of families in Europe. METHODS: Analysis of data obtained by the European Registry of Hereditary Pancreatitis and Pancreatic Cancer was undertaken using multilevel proportional hazards modelling. RESULTS: There were 112 families in 14 countries (418 affected individuals): 58 (52%) families carried the R122H, 24 (21%) the N29I, and 5 (4%) the A16V mutation, 2 had rare mutations, and 21 (19%) had no PRSS1 mutation. The median (95% confidence interval [CI]) time to first symptoms for R122H was 10 (8, 12) years of age, 14 (11, 18) years for N29I, and 14.5 (10, 21) years for mutation negative patients (P = 0.032). The cumulative risk (95% CI) at 50 years of age for exocrine failure was 37.2% (28.5%, 45.8%), 47.6% (37.1%, 58.1%) for endocrine failure, and 17.5% (12.2%, 22.7%) for pancreatic resection for pain. Time to resection was significantly reduced for females (P < 0.001) and those with the N29I mutation (P = 0.014). The cumulative risk (95% CI) of pancreatic cancer was 44.0% (8.0%, 80.0%) at 70 years from symptom onset with a standardized incidence ratio of 67% (50%, 82%). CONCLUSIONS: Symptoms in hereditary pancreatitis start in younger patients and endpoints take longer to be reached compared with other forms of chronic pancreatitis but the cumulative levels of exocrine and endocrine failure are much higher. There is an increasingly high risk of pancreatic cancer after the age of 50 years unrelated to the genotype.