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.

Identification of lifestyle patterns, including sleep deprivation, associated with insulin resistance in children: the Healthy Growth Study.

BACKGROUND/OBJECTIVES: Although diet, physical activity (PA), sedentary behavior and sleep deprivation are factors that have been individually associated with insulin resistance (IR) in childhood, the combined effect of these lifestyle behaviors has not been examined yet. The current study aimed to examine the association of lifestyle patterns with IR, combining all these indices, in children. SUBJECTS/METHODS: Socio-economic, demographic, anthropometric (body weight, height and waist circumference), biochemical (plasma glucose and serum insulin), clinical (pubertal stage) and lifestyle (dietary intake, PA level and sleeping habits) data were collected from a representative sample of 2026 children (50.1% girls) aged 9-13 years in Greece. Homeostasis model assessment (HOMA-IR) was calculated, and principal component analysis was used to identify lifestyle patterns, combining all these lifestyle indices. RESULTS: In multivariable regression analyses, the lifestyle pattern characterized by more screen time, shorter sleep duration and higher consumption of sugared beverages was positively associated with HOMA-IR (ß=0.043; P=0.040), whereas the pattern characterized by more time spent on moderate-to-vigorous PA (MVPA) and more frequent eating occasions was inversely associated with HOMA-IR (ß=-0.061; P=0.003). In logistic regression analyses, children with 72.2 min/day of MVPA and 5.05 eating occasions/day and children with 141.8 min/day of MVPA and 5.22 eating occasions/day were less likely of being insulin resistant based on HOMA-IR, compared with children with 20.0 min/day of MVPA and 4.09 eating occasions/day. CONCLUSIONS: A lifestyle pattern of >72 min of MVPA and 5 eating occasions/day was associated with reduced likelihood of IR in children.

Neck circumference: a useful screening tool of cardiovascular risk in children.

OBJECTIVE: Early identification of cardiovascular risk factors consists an essential target for public health. The current study aims to examine the association between neck circumference and several cardiovascular risk factors and to compare it with well-established anthropometric indices. METHODS: Demographic, anthropometric (body weight and height, waist, hip and neck circumference [WC, HC and NC, respectively]), biochemical (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, triglycerides [TG], fasting plasma glucose and serum insulin), clinical (pubertal stage, systolic and diastolic blood pressure [SBP and DBP, respectively]) and lifestyle (dietary intake, physical activity level) data were collected from 324 children (51.5% boys; 48.5% girls) aged 9-13 in Greece. Body mass index z-score (BMI z-score), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI) and fasting glucose to insulin ratio (FGIR) were calculated. RESULTS: All indices (BMI z-score, NC, WC, HC, WHR and WHtR) were correlated with SBP, HDL and insulin-related indices (insulin, HOMA-IR, QUICKI and FGIR) and all indices except WHR with TG. LDL was correlated with BMI z-score, WC, WHR and WHtR, whereas DBP was correlated with BMI z-score, WC, HC and WHtR. In multivariate analysis, HDL, TG, SBP, insulin, HOMA-IR, QUICKI and FGIR were associated with all anthropometric indices; DBP with WC, HC, NC and WHtR; LDL with BMI z-score, WC, HC and WHtR. CONCLUSIONS: NC is associated with most cardiovascular disease risk factors. These associations are comparable with those observed for BMI z-score, WC, HC, WHR and WHtR. NC could be a simple, alternative screening tool of cardiovascular risk in children.

The presence of Helicobacter pylori in dental plaque of children and their parents: is it related to their periodontal status and oral hygiene?

AIM: To investigate the possible presence of H. pylori in subgingival dental plaque of children with upper gastrointestinal symptoms, as well as of their parents' and to detect any association between the presence of H. pylori and oral hygiene together with the periodontal status of children and their parents. MATERIALS AND METHODS: The study comprised of 35 children with upper gastrointestinal symptoms, aged 4 to 14 years and 45 family members (mothers and/or fathers). Gastric biopsies were collected from all children for CLO-test, histology and culture. Serology was used to assess the H. pylori infection status of their parents. Before endoscopy, subgingival dental plaque from children and their parents were collected from 4 healthy and 4 diseased sites, and the clinical indices (gingival index, plaque index, bleeding on probing, pocket depth, loss of clinical attachment) after plaque collection were recorded. STATISTICS: The Chi-square test was performed to investigate possible differences between children and their parents and logistic regression analysis was used to evaluate the association of parental infection status with that of children. RESULTS: 15 out of 35 children (42.86%) were found H. pylori-positive. In 6 out of the 15 infected children (40%) H. pylori was also identified in their subgingival plaque samples, as well as in one among the 20 non infected children. The presence of H. pylori in dental plaque was significantly associated with its presence in the gastric antrum (p=0.0274). H. pylori was identified in the dental plaque of 7 mothers corresponding to children with positive PCR in their dental plaque and of 4 fathers (one corresponding with his child found H. pylori positive in dental plaque). Children who had H. pylori identified in their dental plaque belonged to families with members also having H. pylori in dental plaque. No significant relationship between periodontal clinical parameters and detection of H. pylori in dental plaque in both children and their parents was found. However, the presence of H. pylori in the subgingival plaque samples was significantly correlated with the parental diseased sites (p=0.02). CONCLUSION: H. pylori was detected in subgingival dental plaque of children and their families, possibly acting as a "reservoir" contributing to the intra-familial spread. Efficient oral hygiene and healthy periodontal status could reduce this transmission.

New effective treatment regimen for children infected with a double-resistant Helicobacter pylori strain.

BACKGROUND: The increasing number of pediatric patients infected with multiresistant Helicobacter pylori strains calls for evaluation of treatment regimens. Second-line antibiotics such as tetracycline or quinolones are not licensed for children. Because in vivo resistance to metronidazole may be overcome in vivo by a high dose and prolonged intake, we evaluated the eradication rate and side effects of a high-dose triple therapy in pediatric patients with culture-proven double resistance. PATIENTS AND METHODS: In this open multicentre trial, 62 children (<18 years, body weight >15 kg) infected with an H pylori strain resistant to metronidazole and clarithromycin were treated according to body weight classes with amoxicillin (∼ 75 mg/kg/day), metronidazole (∼ 25 mg/kg/day) and esomeprazole (∼ 1.5 mg/kg/day) for 2 weeks. Adherence and adverse events were assessed by a 2-week diary and telephone interviews at days 7 and 14 of treatment. Primary outcome was a negative C-urea breath test after 6 weeks. RESULTS: Of 62 patients, 5 were lost to follow-up, 12 were nonadherent, and 45 treated per protocol. Eradication rates were 66% (41/62) [confidence interval 54-78] (intention to treat) and 73% (33/45) [confidence interval 60-86] (per protocol). Success of treatment was not related to dose per kilogram body weight. Mild to moderate adverse events were reported by 21 patients, including nausea (10.8%), diarrhoea (8.9%), vomiting (7.1%), abdominal pain (5.4%), and headache (3.6%), and led to discontinuation in 1 child. CONCLUSION: High-dose amoxicillin, metronidazole, and esomeprazole for 2 weeks is a good treatment option in children infected with a double resistant H pylori strain.

Biological agents in paediatric inflammatory bowel disease: a clinical observation study from Greece.

OBJECTIVES: Biological agents have contributed significantly in controlling inflammatory bowel disease during the last 15 years. This study aimed at recording and evaluating paediatric data regarding the efficacy and safety of infliximab and adalimumab during the last decade. PATIENTS AND METHODS: A total of 31 patients (43% males) with a mean age of 13.5 +/- 3.0 years were included and the majority (74%) had Crohn's disease (CD). Failure of previous treatment and steroid dependency were the main reasons for initiating anti-TNF-alpha therapy. Mean age at the first infusion was 11.0 +/- 2.8 years, while the mean disease duration at the introduction of infliximab was 2.6 +/- 2.7 years. The number of infusions per patient ranged from 1-25 (median 7, IQR: 4-13). RESULTS: Initial response was achieved in 82.8% of patients. After one year of treatment the estimated rate of remission was 53%. The rate of surgery-free disease at 12, 36 and 60 months, after the first dose of infliximab, was 89.6%, 89.6% and 74.7% respectively. The incidence of serious anaphylaxis was 4/268 infusions (1.5%) or 4/31 patients (12.3%). At three months after the first infusion only 2 children were on steroids. Adalimumab was administered to 5 patients for a mean duration of 7.4 months, as a second option after infliximab failure or infusion reaction. Two out of five patients failed to achieve remission with adalimumab and these two patients were also infliximab failures. CONCLUSION: Biological agents are valuable and safe options for children with refractory IBD. The results, so far, have been satisfactory, although, long-term outcomes remain yet to be determined.

Oral hygiene and periodontal treatment needs in children and adolescents with coeliac disease in Greece.

AIM: To evaluate the factors that influence the oral hygiene and the periodontal treatment needs of children and adolescents with coeliac disease (CD) in Greece. METHODS: The sample consisted of 35 children and adolescents, aged 4-18 years. The evaluation included consideration of the detailed medical history, the duration of CD and of gluten-free diet, the history of oral mucosal findings and a dental questionnaire that included information about oral hygiene habits, symptoms of periodontal disease and dental attendance. The clinical dental examination consisted of the simplified gingival index, the oral hygiene index and the periodontal screening and recording index. STATISTICS: The chi square and logistic regression analysis were performed in order to determine the factors or parameters that had a statistically significant (p ≤ 0.05) impact on oral hygiene and periodontal treatment needs of children and adolescents with CD. RESULTS: The periodontal treatment need of children and adolescents with CD were high and most of them needed treatment of gingivitis (60.01%) and only a few subjects had a healthy periodontium (34.29%). The periodontal treatment need index, the simplified gingival index and the hygiene index correlated statistically significantly with the presence of a coexisting disease, frequency of tooth brushing, bleeding upon brushing and oral malodor. CONCLUSION: The periodontal treatment need of children and adolescents with CD correlated with factors that related to the presence of a second medical condition and to the personal oral hygiene habits. Additionally, the oral hygiene level and periodontal status of children with CD do not have any specific characteristics but they have similarities to the oral hygiene level and periodontal status of the children of the general population.

Comparison of two methods for identifying dietary patterns associated with obesity in preschool children: the GENESIS study.

BACKGROUND/OBJECTIVES: The aim of this work was to identify dietary patterns based on reduced rank regression (RRR) and principal component analysis (PCA) and to evaluate the association of these patterns with the prevalence of childhood obesity. SUBJECTS/METHODS: A sample of 2317 toddlers and preschoolers from Greece (Growth, Exercise and Nutrition Epidemiological Study In preSchoolers) was used. In total, 12 food groups were used as predictors of RRR and PCA. Nutrients such as total fat, simple carbohydrate and fiber intake were used as response variables to apply RRR. RESULTS: One factor/pattern was retained from RRR and PCA in order to ensure the comparability of the methods. The pattern derived from PCA was mainly characterized by consumption of fruits, vegetables, legumes, fish and seafood, grains and oils. This pattern explained 12.5% of the total variation in food groups. On the other hand, the pattern extracted from RRR was mainly characterized by reduced consumption of fruits, vegetables and legumes, and by increased consumption of sweets and red meat. The pattern derived from RRR explained 8.2% of the total variation in food groups. Simple and multiple logistic regression revealed that the pattern extracted from RRR is significantly associated with the prevalence of childhood obesity (OR=1.11, 95% CI: 1.00-1.28 for each unit increase of dietary pattern) as opposed to the pattern derived from PCA. CONCLUSIONS: The preferable technique to derive dietary patterns related to childhood obesity seems to be RRR compared with PCA.

Thiopurine S-methyltransferase genotype and the use of thiopurines in paediatric inflammatory bowel disease Greek patients.

BACKGROUND AND OBJECTIVE: Azathioprine (AZA) and 6-mercaptopurine (6MP) are used in the treatment of paediatric inflammatory bowel disease (IBD). Genetic variations in thiopurine S-methyltranfarase (TPMT) gene have been correlated with enzyme activity and with the occurrence of adverse events to AZA and 6MP. The aim of the present study was to investigate the frequency of the functional TPMT polymorphisms and their association with the occurrence of adverse events during azathioprine therapy in a paediatric IBD cohort. METHODS: Ninety-seven thiopurine-treated paediatric IBD patients (41.24% boys and 58.76% girls) with a mean age 11.25 years (range 3-16), were assessed for TPMT polymorphisms and adverse events. RESULTS: Of the 97 patients enrolled in the study, 18 (18.56%) were heterozygous mutated; two (2.06%) were homozygous for a mutated TPMT gene. Ten patients (10.31%) developed adverse effects, and four of them (40%) had one of the variant alleles. CONCLUSIONS: In this small cohort of subjects, no association was found between TPMT polymorphisms and the occurrence of thiopurines-related adverse events.

Poor endoscopic findings in children with non variceal upper gastrointestinal bleeding: is biopsy necessary?

BACKGROUND: Gastrointestinal bleeding in infants and children is a potentially serious condition in the practice of general pediatrics that requires investigation. The objective of this study is to describe the endoscopic and histopathological findings in children with upper gastrointestinal (UGI) bleeding of non variceal origin. PATIENTS AND METHODS: We performed a retrospective study of the medical records of 181 children, aged 1 month to 15.2 years, with non variceal UGI bleeding, who were admitted in our department over the period 1988-2008 and underwent upper GI endoscopy accompanied by histology. Patients were divided in 4 groups according to their age (=0-1 years, = 1-6 years, C=6-12 years, D= 12-16 years). RESULTS: An endoscopically evident bleeding source was detected in only 5% of all patients. Histological examination revealed increased incidence of eosinophilic infiltration in infants, in contrast to all other age groups, where non-specific or H. pylori related inflammation predominated. Peptic ulcer was found in 4.4% of all patients. CONCLUSION: Although an evident bleeding source was detected in only a small percentage of patients, the accompanying histological examination provided additional information regarding possible underlying diseases and contributed to the subsequent therapeutic management.

Diet quality of preschool children and maternal perceptions/misperceptions: the GENESIS study.

OBJECTIVES: To quantify maternal perceptions regarding the quality of their child's diet, and to identify factors associated with misperceptions. STUDY DESIGN: A representative sample of 2287 children aged 2-5 years from a cross-sectional study (GENESIS study) was used. METHODS: Maternal perceptions of the quality of their child's diet, child's and mother's anthropometric characteristics, and other characteristics (i.e. socio-demographic and lifestyle) were recorded. The actual quality of each child's diet was estimated using the Healthy Eating Index (HEI) score. RESULTS: Based on the HEI score, 18.3% of participants had a 'poor' diet, 81.5% had a diet which 'needs improvement' and only 0.2% had a 'good' diet. Almost 83% of mothers overestimated the quality of their child's diet. The overestimation rate was 86% among mothers who declared that they choose their child's food based on what they consider to be healthy, and 72% among those who reported that other factors play the predominant role in food choices for their child (P<0.001). Moreover, total energy intake as well as the intake of fruits, grains, vegetables, meat and milk was significantly higher among children whose mothers overestimated the quality of their diet. CONCLUSION: The vast majority of mothers overestimate the quality of their child's diet. Given that maternal perceptions regarding the quality of their child's diet are likely to be one of the predominant factors determining the child's food intake, health professionals should make mothers aware of the existence of particular dietary recommendations that their children should meet in order to eat a healthy diet.

Prospective multicentre study on antibiotic resistance of Helicobacter pylori strains obtained from children living in Europe.

AIM: To prospectively assess the antibacterial resistance rate in Helicobacter pylori strains obtained from symptomatic children in Europe. METHODS: During a 4-year period, 17 paediatric centres from 14 European countries reported prospectively on patients infected with H pylori, for whom antibiotic susceptibility was tested. RESULTS: A total of 1233 patients were reported from Northern (3%), Western (70%), Eastern (9%) and Southern Europe (18%); 41% originated from outside Europe as indicated by mother's birth-country; 13% were <6 years of age, 43% 6-11 years of age and 44% >11 years of age. Testing was carried out before the first treatment (group A, n = 1037), and after treatment failure (group B, n = 196). Overall resistance to clarithromycin was detected in 24% (mean, A: 20%, B: 42%). The primary clarithromycin resistance rate was higher in boys (odds ratio (OR) 1.58; 1.12 to 2.24, p = 0.01), in children <6 years compared with >12 years (OR 1.82, 1.10 to 3.03, p = 0.020) and in patients living in Southern Europe compared with those living in Northern Europe (OR 2.25; 1.52 to 3.30, p<0.001). Overall resistance rate to metronidazole was 25% (A: 23%, B: 35%) and higher in children born outside Europe (A: adjusted. OR 2.42, 95% CI: 1.61 to 3.66, p<0.001). Resistance to both antibiotics occurred in 6.9% (A: 5.3%, B: 15.3%). Resistance to amoxicillin was exceptional (0.6%). Children with peptic ulcer disease (80/1180, 6.8%) were older than patients without ulcer (p = 0.001). CONCLUSION: The primary resistance rate of H pylori strains obtained from unselected children in Europe is high. The use of antibiotics for other indications seems to be the major risk factor for development of primary resistance.

Fiber intake and childhood appendicitis.

In order to investigate the possible role of fiber in the etiology of acute appendicitis, 203 consecutive appendectomized children with histologically proved appendicitis and 1922 controls were studied by the diet history method. Statistics were performed by multivariate analysis of variance, discriminant analysis and chi 2. Appendectomized children had statistically significant lower mean daily intake of fiber (17.4 g versus 20.4 g, P < 0.001) including all fiber fractions: cellulose, uronic acid, pentose, exose and lignin. No statistical difference was found for energy, protein, carbohydrate and fat intake. Discriminant analysis proved that only cellulose and exose are independently correlated to appendicitis and lower fiber intake is thought to be the cause in 70% of the cases. Recurrent abdominal pain, chronic constipation and positive family history of appendectomy were more frequent in appendectomized children (P < 0.001). This study gives evidence that low fiber intake could play an important role in the pathogenesis of appendicitis.

In vivo effect of sodium valproate on mouse liver.

The in vivo effect of sodium valproate (SV) on the activity of uridine diphosphate glucuronosyltransferase (UDP-GT) and hepatotoxicity in the mouse liver was studied. Mice were injected intraperitoneally (IP) with SV at doses varying from 50 to 800 mg/kg per day, for six consecutive days (dose-response group) or at a standard dose of 300 mg/g per day for 2-10 days (time-response group), whereas the controls were injected with normal saline. Valproic acid levels had a positive correlation to the dose (P < 0.001) and duration of drug administration (P = 0.006). A gradual increase in UDP-GT activity was observed in doses of up to approximately 400 mg/kg per day, whereas in higher doses the enzyme activity gradually decreased. The time course of UDP-GT activity at the standard dose of 300 mg/kg per day increased progressively, with a maximum up to the sixth day and then had a gradual reduction. Hepatic necrosis (which was unrelated to the dose or the duration of drug administration) was found in 13% of the SV-treated animals and in none of the controls. We conclude that at an optimal dose (300-400 mg/kg per day) and at a time course of 6 days, SV causes liver UDP-GT induction, whereas in higher doses and longer duration of administration, UDP-GT activity is gradually reduced. SV also causes hepatotoxicity unrelated to dose and time course.

Nutritional survey in Greek children: nutrient intake.

The aim of the survey was to record the food habits and nutrient intake of Greek children. Data was obtained by a 3 d household measured diet record from a random stratified sample (1936 children aged 2-14 y). Mean daily protein intake was much higher than PRI and none of the children had lower intake than AR. Mean energy intake from protein was 15%, carbohydrate 44% and fat 41%. Eighty-four percent of children had energy intake from fat higher than the AR. Saturated fatty acids (SFA) provided approximately 15%, monounsaturated (MUFA) 17% and polyunsaturated (PUFA) 6% of energy. Eighty-seven percent of children had higher intake of SFA than the AR. Six percent of children had SFA intake lower than the AR and 50% higher than the AR. None of the children had PUFA intake lower than PRI and 0.3% higher than the maximum limit. 4.2% of children had calcium intake lower than LTI and 88% higher or equal to PRI. All children had phosphorus intake higher than PRI and less than the lower safe ratio of Ca/P; 50% of them had P intake higher than 1.5 g/d. The majority of children had sufficient iron intake with the exception of menstruated girls. Mean vitamin A intake was higher than PRI and lower than the toxic levels. All children had vitamin C intake higher than LTI. Median vitamin D intake varied from 1.7-2.1 micrograms. Median energy intake was higher than the AR in preschool children, but lower in the older children. We conclude that Greek children do not underintake energy and protein, overintake SFA, have safe intake of PUFA, vitamin A and C and high intake of MUFA, underintake carbohydrates, have adequate Ca, but a considerably high P intake. Vitamin D is low in small children, but the biological available vitamin D is obviously higher due to sunlight.