Malignancy and mortality in paediatric-onset inflammatory bowel disease: a 3-year prospective, multinational study from the paediatric IBD Porto group of ESPGHAN.

BACKGROUND: Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and mortality in IBD have been associated with disease-related inflammation and immune suppression, but data are limited due to their rare occurrence. AIM: To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric-onset IBD. METHODS: Information on paediatric-onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42-month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years. RESULTS: In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD-therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T-cell lymphoma were identified, all were biologic-naïve but thiopurine-exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T-cell lymphoma). CONCLUSIONS: We report the largest number of paediatric-onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer-associated mortality. Disease-related adenocarcinomas were a commoner cause of death than lymphomas.

Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease.

Children and adolescents with Crohn's disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohn's and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

Rapid test for fecal calprotectin levels in children with Crohn disease.

Assessment of fecal calprotectin, a surrogate marker of mucosal inflammation, is a promising means to monitor therapeutic response in pediatric inflammatory bowel disease, especially if the result is readily available. We tested the performance of a novel calprotectin rapid test, Quantum Blue, versus the conventional enzyme-linked immunosorbent assay in 134 stool samples from 56 pediatric patients with Crohn disease. The intraclass correlation coefficient analysis reflected good agreement (intraclass correlation coefficient 0.97 [95% confidence interval 0.95-0.98]) but agreement was better in lower values, where dilutions were not required. Using a cutoff of 100 µg/g for normal values, the percentage agreement between the 2 tests was 87%. The optimal cutoff values to guide clinical decisions in the therapy of inflammatory bowel disease have yet to be determined.

Evidence-based recommendations for bowel cleansing before colonoscopy in children: a report from a national working group.

BACKGROUND: There are no current recommendations for bowel cleansing before colonoscopy in children. The Israeli Society of Pediatric Gastroenterology and Nutrition (ISPGAN) established an iterative working group to formulate evidence-based guidelines for bowel cleansing in children prior to colonoscopy. METHOD: Data were collected by systematic review of the literature and via a national-based survey of all endoscopy units in Israel. Based on the strength of evidence, the Committee reached consensus on six recommended protocols in children. Guidelines were finalized after an open audit of ISPGAN members. RESULTS: Data on 900 colonoscopies per year were accrued, which represents all annual pediatric colonoscopies performed in Israel. Based on the literature review, the national survey, and the open audit, several age-stratified pediatric cleansing protocols were proposed: two PEG-ELS protocols (polyethylene-glycol with electrolyte solution); Picolax-based protocol (sodium picosulphate with magnesium citrate); sodium phosphate protocol (only in children over the age of 12 years who are at low risk for renal damage); stimulant laxative-based protocol (e. g. bisacodyl); and a PEG 3350-based protocol. A population-based analysis estimated that the acute toxicity rate of oral sodium phosphate is at most 3/7320 colonoscopies (0.041 %). Recommendations on diet and enema use are provided in relation to each proposed protocol. CONCLUSION: There is no ideal bowel cleansing regimen and, thus, various protocols are in use. We propose several evidence-based protocols to optimize bowel cleansing in children prior to colonoscopy and minimize adverse events.

Response to medical treatment in patients with Crohn's disease: the role of NOD2/CRAD15, disease phenotype, and age of diagnosis.

PURPOSE: Factors influencing response to medications in Crohn's disease (CD) patients are not fully understood. We aimed to evaluate the relationships between NOD2/CARD15 mutations, disease phenotype and age of CD diagnosis and response to medical treatment with systemic steroids, azathioprine (AZA) or 6-mercaptopurine (6-MP), and infliximab. METHODS: A retrospective medical records analysis was made of patients previously tested for the CD-associated NOD2/CARD15 mutations. Harvey- Bradshaw score was used to assess remission or response to therapy. RESULTS: CD-associated NOD2/CARD15 mutations were not related to the rate of steroids dependency or clinical response to AZA/6-MP and infliximab. Steroid dependency was associated with colonic involvement. Thirty-three of 127 (26%) patients with colonic disease were steroid dependent, compared with 7/72 (9.7%) patients with isolated small bowel disease (ISBD), (p = 0.009). ISBD was mildly associated with a better remission/response to AZA/6-MP treatment. Disease behavior and age of diagnosis were not related to response to therapy. CONCLUSIONS: Response to treatment with systemic steroids, AZA/6-MP and infliximab are not related to NOD2/CARD15 mutations, age of diagnosis and disease behavior. Patients with colonic disease have higher rates of steroid dependency.

Toilet reading habits in Israeli adults.

Although toilet reading (TR) is a common habit, the effect of TR on bowel movements is neglected in the medical literature. Our hypothesis was that TR provides a distraction and acts as an unconscious relaxation technique and allows an easier defecation process. The aim of this study was to assess how common is TR and to map the reading/playing toilet habits in the Israeli adult population. In addition, we aimed to explore a possible connection between TR and the nature of bowel habits in general and constipation and haemorrhoids in particular. Five hundred adults who represent the diverse demographic backgrounds have been asked to fill an anonymous short questionnaire. The subjects were questioned regarding their demographic details, their TR and playing habits, their bowel habits, whether they suffer from haemorrhoids and whether they use some sort of faecal softener. We found that TR is common and involves 52.7% of the population. Males, younger age, secular population, higher education level and white collar workers compose the TR profile. Although toilet readers spent significantly more time in the toilets, no differences were noted for the type or frequency of stools. Nevertheless, the TR group considered themselves to be less constipated (8.0%vs 13.7%) and had more haemorrhoids (23.6%vs 18.2%). These differences, however, were not significant. Toilet reading is a common and benign habit. It is involved with a longer time spent in the toilet. It seems to be more for fun and not necessarily to solve or due to medical problems.

Effect of elevated intra-abdominal pressure and hyperoxia on portal vein blood flow, hepatocyte proliferation and apoptosis in a rat model.

BACKGROUND/PURPOSE: Indications for a laparoscopic approach for the management of biliary atresia in children are not clearly defined. We have recently shown that persistent intra-abdominal pressure (IAP) significantly decreased portal vein (PV) flow. Ventilation with a high concentration of oxygen after abdomen deflation raises concerns of increased oxidative stress but has also been shown to exert beneficial effects on splanchnic ischemia/reperfusion. The purpose of the present study was to evaluate the effects of IAP and hyperoxia on liver histology, hepatocyte proliferation and apoptosis in a rat model of abdominal compartment syndrome (ACS). METHODS: Male Sprague-Dawley rats were anesthetized with intraperitoneal ketamine and xylasine. After a midline laparotomy, the PV was isolated. Ultrasonic blood flow probes were placed on the vessel for continuous measurement of regional blood flow. Mean arterial blood pressure (MABP) was continuously measured. Two large-caliber percutaneous peripheral intravenous catheters were introduced into the peritoneal cavity for inflation of air and measurement of IAP. Rats were divided into three experimental groups: 1) Sham rats were subjected to IAP of 0 mmHg; 2) ACS rats were subjected to IAP of 6 mmHg for 2 hours and were ventilated with air; and 3) ACS-O (2) rats were subjected to IAP of 6 mmHg for 2 hours and were ventilated with 100 % O (2) during the operation and ventilation was continued for 6 hours after operation. Liver structural changes, hepatocyte proliferation (using BrdU assay) and apoptosis (using Tunel assay) were determined 24 hours following operation. RESULTS: IAP at 6 mmHg caused a twofold decrease in PV flow compared to sham animals. Hyperoxia resulted in a less significant decrease in PV flow compared to air-ventilated animals. Despite a significant decrease in PV blood flow, 24 hours after abdominal deflation only a few animals demonstrated histological signs of liver damage. The small histological changes were accompanied by increased hepatocyte apoptosis and enhanced hepatocyte proliferation in 25 % of animals, suggesting a liver repair response. CONCLUSIONS: Despite a significant decrease in PV blood flow, persistent IAP for 2 hours results in few changes in liver histology, and stimulates hepatocyte proliferation and apoptosis in only a few animals, supporting the presence of a recovering mechanism. Treatment with hyperoxia did not significantly change hepatocyte proliferation and apoptosis.

Evaluation of topical pharyngeal anaesthesia by benzocaine lozenge for upper endoscopy.

BACKGROUND: Among the randomized controlled trials evaluating the effect of pharyngeal anaesthesia only some suggest benefit. Spray is irritating for some people and leaves bitter taste in the throat. We hypothesized that delivering the local anaesthetic as a sucking lozenge would benefit the patients in terms of decreasing anxiety and will improve procedure performance and patient tolerance. AIM: To determine whether benzocaine/tyrothricin sucking lozenges with conscious sedation is superior to conscious sedation alone, with respect to procedure performance and tolerance in patients undergoing upper endoscopy. METHODS: One hundred and seventy-four adult patients undergoing upper endoscopy with conscious sedation completed the study. They were randomized to receive sucking lozenge containing benzocaine or placebo before the procedure. Patients were asked to rate prestudy anxiety, tolerance for topical pharyngeal anaesthesia, comfort during endoscopy, degree of difficulty of intubation, postprocedure throat discomfort and willingness to undergo subsequent examinations using a 10-cm visual analogue scale. Endoscopists were asked to estimate the ease of oesophageal intubation and procedure performance. RESULTS: No significant statistical differences regarding all the points studied were found between the groups. CONCLUSIONS: Topical pharyngeal anaesthesia with benzocaine/tyrothricin lozenges with conscious sedation has no advantages over conscious sedation alone in patients undergoing upper endoscopy.

Changes in creatine phosphokinase (CK) concentrations after minor and major surgeries in children.

BACKGROUND: During surgery, damage occurs to muscles in the area of the operation. The few studies that have examined creatine phosphokinase (CK) values after surgery have been in adults. The only study in children was after cardiac surgery. Understanding the normal enzyme pattern of change may help to differentiate malignant hyperthermia, anaesthesia-induced rhabdomyolysis and elevated CK values resulting from inherited muscle disease in cases in which these are suspected. The aim of this study was to delineate the normal rise of CK after minor and major surgery in children. METHODS: A total of 71 patients aged 1 month-17 yr were studied. From the cohort of 71 patients, 46 underwent elective surgery (14 major, 32 minor) and in 25 the surgery was designated as an emergency surgery (21 major, 4 minor). The anaesthesia protocol was similar for both groups with halothane induction and isoflurane maintenance. Owing to its possible effect on CK, succinylcholine was avoided during the study. RESULTS: The mean values of CK concentration before and after surgery were 63.1 iu litre(-1) and 151.5 iu litre(-1), respectively. The median CK elevation (range) for the major and minor surgery groups was 43 iu litre(-1) (4-647) and 10 iu litre(-1) (-28 to 122), respectively (P<0.0001). CONCLUSIONS: CK concentrations in the major surgery group were significantly higher than the minor surgery group. This profile can contribute to the evaluation of patients who present with the possibility of malignant hyperthermia, anaesthesia-induced rhabdomyolysis and underlying muscle disease. Any rise of CK concentration above what is expected should prompt further investigation.

Silent acetaminophen-induced hepatotoxicity in febrile children: does this entity exist?

UNLABELLED: Several descriptions of acetaminophen-associated liver injury caused by therapeutic or a dosage slightly above the recommended dosage have been described. Our hypothesis is that in sick febrile infants and children, who may also be calorie depleted, there might be an increased hepatic vulnerability to acetaminophen. AIM: (1) To correlate serum acetaminophen levels in febrile infants and children with the following parameters: aspartate aminotransferase (AST) levels, fever, vomiting and/or decreased caloric intake; and (2) to assess parental knowledge regarding the medication dosage and hazards of acetaminophen. METHODS: Healthy children with an acute febrile illness, who had received acetaminophen, were eligible to participate in the study. AST and acetaminophen levels were drawn, and a detailed questionnaire was completed for every child. RESULTS: 107 children participated in the study; 50 girls and 57 boys with ages ranging from 1 mo to 16 y (mean 33 mo). All serum acetaminophen levels were within the safety range. Although 32% of parents administered a single acetaminophen dose above 15 mg/kg and 46% gave a daily dose above 60 mg/kg/d, no significant differences were observed in the serum acetaminophen and AST levels compared to those who received the appropriate dose. In about 60% of cases, the high doses were recommended by a physician. Young age and high fever were associated with significantly higher acetaminophen levels. We could not find an association between acetaminophen levels and vomiting, decreased caloric intake and AST levels. Only 24 parents (22%) were aware of the possible toxicity of acetaminophen. CONCLUSIONS: No evidence of increased hepatic vulnerability to acetaminophen was noted in a cohort of febrile infants and children. Furthermore, significant numbers of parents and physicians were unaware of acetaminophen dangers.

Value of laboratory studies in assessment of dehydration in children.

BACKGROUND: Due to the lack of a reliable way of clinically measuring dehydration, laboratory tests are usually used to improve the accuracy of clinical assessment of dehydration in children. The purpose of this study was to compare the relationship between clinical and laboratory parameters in the assessment of dehydration and to evaluate the improvement of those parameters over time. METHODS: We conducted a retrospective study to assess the relationship between clinical assessment of dehydration and laboratory findings. RESULTS: Three hundred children were eligible for the study. Twenty-six per cent of those with mild dehydration had serum urea concentrations greater than 14.3 mmol/L, compared with 38% and 5% of those with moderate or no dehydration, respectively. Urea concentration showed a good specificity, 95%. Creatinine concentrations and mean pH were similar whether or not dehydration was present. Bicarbonate and base excess concentrations decreased with the increasing severity of dehydration and were significantly greater in subjects with moderate dehydration than in those without. The sensitivity (71%) and specificity (74%) of both tests were rather poor. All groups had an abnormal anion gap, which was significantly greater in those with mild or moderate dehydration. CONCLUSION: This study confirms that there is a discrepancy between clinical assessment and laboratory parameters of dehydration. Urea showed good specificity, and anion gap was the most sensitive laboratory parameter for assessment of dehydration. These findings need further validation.

[Ménétriér's disease in children].

Ménétriér's disease in children is a rare disorder that is characterized by the presence of marked protein losing gastropathy associated with enlarged and thickened gastric folds. Abnormal regulation of gastric epithelial growth, probably triggered by an infectious agent, has been suggested as an etiology for this disorder. We describe a case of Ménétriér's disease in a young child and review the current literature encompassing the different aspects of the disease.

Gastric metaplasia: a frequently overlooked feature of duodenal biopsy specimens in untreated celiac disease.

BACKGROUND: Duodenal gastric metaplasia is rarely reported in untreated celiac disease, although it is seen in 60% to 100% of duodenal biopsy specimens in nonceliac patients with histologic duodenitis. The low incidence could represent underreporting, a decreased incidence in pediatric patients generally, or the more distal sampling site that is customary for most biopsy specimens that are obtained to diagnose celiac disease. It could also be a unique feature of the inflammatory reaction that characterizes this disease. The purpose of this study was to examine the incidence of gastric metaplasia in duodenal specimens from children with untreated celiac disease with special reference to patient age and biopsy site. METHOD: Formalin-fixed paraffin-embedded specimens of duodenal mucosa were selected from the pathology department's archival material. Sections were either stained histochemically or by immunochemical methods, according to an antigen-retrieval protocol. Forty-four duodenal specimens from untreated patients with celiac disease (n = 22) and control subjects of similar age with normal histology (n = 22) were examined. Ten of each were obtained during upper endoscopy from the proximal duodenum (proximal site) and 12 of each by Crosby capsule near the ligament of Treitz (distal site). RESULTS: All specimens from patients with celiac disease exhibited marked villous atrophy. None had been noted to have gastric metaplasia during routine examination of sections stained by hematoxylin and eosin. Fifteen (68%) of 22 of the celiac specimens and 2 of 22 (9%) control specimens contained gastric metaplasia, identified as patches of gastric-type cells containing MUC5AC (gastric mucin), pS2 (gastric trefoil factor) and neutral (periodic acid-Schiff-positive) mucin. Five of the seven celiac specimens that had no metaplasia showed increased numbers of goblet cells expressing gastric markers. The incidence of gastric metaplasia was not different for endoscopic (70%) or capsule (67%) specimens. Sixty-eight percent (7/11) of patients aged less than 3 years had gastric metaplasia. CONCLUSION: The presence of gastric metaplasia has been previously underreported in celiac disease specimens. Detection would be improved by the routine use of period acid-Schiff/ alcian blue staining. The incidence of gastric metaplasia in celiac disease is not significantly influenced by biopsy site or age at time of the biopsy.