Zrinjka Mišak

Lactobacillus GG in the prevention of gastrointestinal and respiratory tract infections in children who attend day care centers: A randomized, double-blind, placebo-controlled trial

BACKGROUND & AIMS The aim of our study was to investigate the role of Lactobacillus GG (LGG) in the prevention of gastrointestinal and respiratory tract infections in children who attend day care centers. METHODS We conducted a randomized, double-blind, placebo-controlled trial in 281 children who attend day care centers. They were randomly allocated to receive LGG at a dose of 10(9) colony-forming units in 100ml of a fermented milk product (LGG group, n=139) or placebo that was the same post-pasteurized fermented milk product without LGG (placebo group, n=142) during the 3-month intervention period. RESULTS Compared to the placebo group, children in the LGG group had a significantly reduced risk of upper respiratory tract infections (RR 0.66, 95% CI 0.52 to 0.82, NNT 5, 95% CI 4 to 10), a reduced risk of respiratory tract infections lasting longer than 3 days (RR 0.57, 95% CI 0.41 to 0.78, NNT 5, 95% CI 4 to 11), and a significantly lower number of days with respiratory symptoms (p<0.001). There was no risk reduction in regard to lower respiratory tract infections (RR 0.82, 95% CI 0.24 to 2.76). Compared with the placebo group, children in the LGG group had no significant reduction in the risk of gastrointestinal infections (RR 0.63, 95% CI 0.38 to 1.06), vomiting episodes (RR 0.60, 95% CI 0.29 to 1.24), and diarrheal episodes (RR 0.63, 95% CI 0.35 to 1.11) as well as no reduction in the number of days with gastrointestinal symptoms (p=0.063). CONCLUSION LGG administration can be recommended as a valid measure for decreasing the risk of upper respiratory tract infections in children attending day care centers.

Compliance With Gluten-free Diet in Children With Coeliac Disease

Objectives: Coeliac disease (CD) is a lifelong disorder with gluten-induced manifestations in different organs. Gluten-free diet (GFD) is required to achieve remission and prevent complications; however, study reports on GFD growth effect are not consistent. Methods: Compliance with GFD was estimated according to current body mass and height; presence of anaemia and other signs and symptoms; and attitude toward GFD. Results: Seventy-one patients with CD (mean age = 12 years; mean age after CD diagnosis = 9 years) were examined and their blood sampled for determination of endomysial antibodies (EMA), haemoglobin, and red blood cell count. Questionnaire analysis revealed 42 (59.1%; 4 EMA positive) patients to be on strict GFD, 19 (26.8%; 5 EMA positive) were taking small amounts of gluten, and 10 (14.1%; all EMA positive) were not on a diet at all. The patients on strict GFD had greatest body height, yet the difference was not significant. These patients also had a higher mean body mass (P = 0.05) and significantly higher mean haemoglobin and mean cell haemoglobin levels (P = 0.05 and P < 0.05, respectively). Apart from chronic fatigue in patients on partial diet (P = 0.05), patient groups did not differ significantly in the frequency of symptoms. Anaemia and delayed puberty were recorded only in noncompliers (P < 0.01 and P < 0.05, respectively). Noncompliers often found the specific diet to pose a major life burden (P < 0.01) and did not visit a gastroenterologist on a regular basis (P < 0.01). Conclusions: Almost half of the coeliac patients were likely to abandon GFD without experiencing major symptoms, thus increasing the risk for developing complications later in life. An active attitude is required in the follow-up of patients with CD.

Burden of celiac disease in the Mediterranean area

AIM To estimate the burden of undiagnosed celiac disease (CD) in the Mediterranean area in terms of morbidity, mortality and health cost. METHODS For statistics regarding the population of each country in the Mediterranean area, we accessed authoritative international sources (World Bank, World Health Organization and United Nations). The prevalence of CD was obtained for most countries from published reports. An overall prevalence rate of 1% cases/total population was finally estimated to represent the frequency of the disease in the area, since none of the available confidence intervals of the reported rates significantly excluded this rate. The distribution of symptoms and complications was obtained from reliable reports in the same cohort. A standardized mortality rate of 1.8 was obtained from recent reports. Crude health cost was estimated for the years between symptoms and diagnosis for adults and children, and was standardized for purchasing power parity to account for the different economic profiles amongst Mediterranean countries. RESULTS In the next 10 years, the Mediterranean area will have about half a billion inhabitants, of which 120 million will be children. The projected number of CD diagnoses in 2020 is 5 million cases (1 million celiac children), with a relative increase of 11% compared to 2010. Based on the 2010 rate, there will be about 550,000 symptomatic adults and about 240,000 sick children: 85% of the symptomatic patients will suffer from gastrointestinal complaints, 40% are likely to have anemia, 30% will likely have osteopenia, 20% of children will have short stature, and 10% will have abnormal liver enzymes. The estimated standardized medical costs for symptomatic celiac patients during the delay between symptom onset and diagnosis (mean 6 years for adults, 2 years for children) will be about €4 billion (€387 million for children) over the next 10 years. A delay in diagnosis is expected to increase mortality: about 600,000 celiac patients will die in the next 10 years, with an excess of 44.4% vs age- and sex-matched controls. CONCLUSION In the near future, the burden of CD will increase tremendously. Few Mediterranean countries are able to face this expanding epidemic alone.

NOD2/CARD15 mutations in Croatian patients with Crohn's disease : prevalence and genotype-phenotype relationship

Background Crohns disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract with variations in localization and behaviour. Mutations in the NOD2/CARD15 gene on chromosome 16q have been implicated in the pathogenesis of the disease and three main sequence variants, all single nucleotide polymorphisms (SNPs), have been identified in North American and European populations. Aims and methods As no data exist in the Croatian population, we consecutively collected a cohort of 136 CD patients and 91 healthy controls to determine the prevalence of NOD2/CARD15 mutations and their association with phenotypic expression of the disease. All patients and controls were genotyped for Arg702Trp (Hugot SNP8), Gly908Arg (Hugot SNP12), and Leu1007fsinsC (Hugot SNP13) and allele frequencies were compared between the Crohns patients and controls. The correlation of NOD2/CARD15 genotypes with the phenotypic expression of Crohns disease was further assessed by logistic regression analysis. Results NOD2/CARD15 variants were found in 38/136 CD patients (27.9%) compared to 10/91 (10.9%) healthy controls (P=0.0022). Allele frequencies in patients with CD were 13.97%, 4.4% and 11.76%, respectively, for SNP8, 12 and 13, compared to 5.49%, 1.12% and 4.40% in controls (P=0.041, P=0.162, P=0.055). Six CD patients carried double mutations and, remarkably, we identified two homozygous mutants amongst the healthy control group. Surgery over the course of the disease and a younger age at onset of the disease were significantly more frequent in patients who were carriers of NOD2/CARD15 mutations. Conclusions This report on NOD2/CARD15 mutations in Croatian patients with CD demonstrates that this gene is also implicated in susceptibility to CD in the Croatian population. Phenotypic association showed a younger age at diagnosis and a higher need for surgery in patients carrying NOD2/CARD15 mutations. However, the prevalence is somewhat lower compared to other reports, likely due to a more prominent colonic inflammation.

Infant nutrition and allergy

Over the past several decades, the incidence of atopic diseases such as asthma, atopic dermatitis and food allergies has increased dramatically. Although atopic diseases have a clear genetic basis, environmental factors, including early infant nutrition, may have an important influence on their development. Therefore, attempts have been made to reduce the risk of the development of allergy using dietary modifications, mainly focused on longer breast-feeding and delayed introduction or elimination of foods identified as potentially most allergenic. Recently, there is also an increasing interest in the active prevention of atopy using specific dietary components. Many studies have shown that breast-feeding may have the protective effect against future atopic dermatitis and early childhood wheezing. Concerning complementary feeding, there is evidence that the introduction of complementary foods before 4 months of age may increase the risk for atopic dermatitis. However, there is no current convincing evidence that delaying introduction of solids after 6 months of age has a significant protective effect on the development of atopic disease regardless of whether infants are fed cows milk protein formula or human subjects milk, and this includes delaying the introduction of foods that are considered to be highly allergic, such as fish, eggs and foods containing peanut protein. In conclusion, as early nutrition may have profound implications for long-term health and atopy later in life, it presents an opportunity to prevent or delay the onset of atopic diseases.

Gluten-Free Diet Has a Beneficial Effect on Chromosome Instability in Lymphocytes of Children With Coeliac Disease

Objectives. Children with coeliac disease (CD) have an increased number of chromosome aberrations in peripheral blood lymphocytes. Whether genetically determined or a secondary phenomenon in CD, chromosome abnormalities may be involved in the predisposition to cancer in CD patients. The aim of the study was to follow a group of children with CD in whom the initial frequency of chromosome aberrations at diagnosis was known and to measure the same variable after a minimum of 2 years on a gluten-free diet. Methods. Chromosome aberrations in peripheral blood lymphocytes were determined in 17 patients with CD, before and after at least 24 months of a gluten free diet (mean, 33 months), and in 15 healthy children. The differences in the frequency of aberrations were analyzed by Mann-Whitney U test and Wilcoxon matched-pairs signed-ranks test. Results. Twelve patients adhered to the diet and had a significantly lower frequency of chromosome aberrations than did 5 patients not following the diet (0.16%v 1.2%; P = 0.03), whereas at presentation there had been no difference (1.54%v 1.2%; P = 0.09). The frequency of aberrations at follow-up in patients who were diet adherent was significantly lower than at presentation (1.54% v 0.16%; P = 0.02) and remained unchanged in patients who were not diet adherent (1.2%v 1.2%; P = 1). After at least 24 months of a gluten-free diet, children with CD did not differ from healthy control subjects (0.16%v 0.27%; P = 0.54), whereas children not following the diet had an increased frequency of aberrations (1.2%v 0.27%; P = 0.05). Conclusions. The frequency of chromosome aberrations in peripheral blood lymphocytes of patients with CD decreased significantly on a gluten-free diet. We conclude that genomic instability is a secondary phenomenon, possibly caused by chronic intestinal inflammation.

The role of combined 24-h multichannel intraluminal impedance-pH monitoring in the evaluation of children with gastrointestinal symptoms suggesting gastro-esophageal reflux disease.

The aim of this study was to determine the role of multichannel intraluminal impedance‐pH (pH‐MII) monitoring in the diagnosis of gastro‐esophageal reflux disease (GERD) in children who presented with gastrointestinal (GI) symptoms in comparison with the results of pH‐metry alone and endoscopy.

Central venous catheter related sepsis in children on parenteral nutrition: A 21-year single-center experience

BACKGROUND & AIMS The aim was to assess the rate of central venous catheter (CVC) related sepsis in patients on parenteral nutrition (PN) at our hospital center during a period of 21 years. METHODS Data on all children hospitalized at our tertiary hospital center during the 1989-2010 period, who received PN for more than 4 weeks (n = 62) were retrospectively analyzed. RESULTS The mean age at the time of introducing PN was 2.9 years (range 6 days-17.4 years), male/female ratio 26/36. Out of these 62 patients, nine (14.5%) patients continued home PN (HPN) after discharge from the hospital. Altogether 86 CVCs were used (mean 1.39 per patient) and total CVC time was 21,459 days, which makes 243.9 days per CVC. During the study period, there were 36 CVC related sepsis episodes (1.7/1000 days of PN). Total number of septic episodes was significantly lower in HPN compared to hospital PN (0.94/1000 vs. 2.75/1000 days of PN; P < 0.001). Septic episodes led to removal of 11 (12.8%) catheters. Two patients died due to CVC related septic shock (0.93 deaths/10,000 days of PN), one in HPN patient (0.79 per 10,000 days of HPN). CONCLUSION The rate of CVC related sepsis in our PN cohort was exceptionally low in both hospital and home setting.

Incidence of Clostridium difficile Infection in Children with Inflammatory Bowel Disease Compared to Oncology and Immunocompetent Patients

Aims: The aim of this study was to determine the incidence of Clostridium difficile infection in hospitalized children with inflammatory bowel disease (IBD) and to compare it to other immunosuppressed patients at risk (oncology patients) as well as to immunocompetent patients. Methods: We analyzed data from all hospitalized children who underwent stool detection of C. difficile toxins A and B (n = 757) in a 5.5-year study period. Results: The number of positive tests was significantly increased in the oncology group compared to the IBD group (12.45 vs. 6.02%, p = 0.03) and immunocompetent group (12.45 vs. 5.7%, p = 0.01). Patients who had C. difficile infection used antibiotics prior to the test more often than patients who did not (12.69 vs. 1.73%, p = 0.03). Pearson’s correlation was positive for C. difficile infection and both antibiotics and immunosuppressants, while no correlation was found regarding age and gender. There were no significant differences regarding either IBD diagnosis (Crohn’s disease vs. ulcerative colitis, p = 0.71) or treatment used for IBD (p = 0.53) and C. difficile infection. Conclusion: In our setting, the incidence of C. difficile infection among hospitalized children with active IBD was found to be low. Children at increased risk for C. difficile infection were oncology patients receiving immunosuppressants and antibiotics.

Diagnosis of coeliac disease in children younger than 2 years.

Background and Aim: To diagnose coeliac disease (CD) in children younger than 2 years, the old ESPGHAN criteria based on 3 small bowel biopsies were recommended until recently. The aim of the present study was to investigate the applicability of only 1 small intestinal biopsy plus positive serology for the diagnosis of CD in children younger than 2 years. Methods: A prospective cohort study included 81 patients younger than 2 years with symptoms suggestive of CD, who all completed the diagnostic procedure based on 3 small bowel biopsies. According to the finding of the third biopsy, patients were divided into group A—CD confirmed (N = 44), and group B—CD not confirmed, after the gluten challenge (N = 37). Results: At the time of the first biopsy, total villous atrophy (Marsh IIIc) was found more often in group A than in group B (77% vs 27%, P < 0.01). Also, all of the studied antibodies were more frequently positive in group A than in group B (P < 0.01 for all of the tested antibodies). Positive anti-endomysial antibodies and Marsh IIIc finding were the best discriminators between the group A and the group B and considerably contributed to the prediction of CD. Conclusions: The second and the third biopsies (before and after the gluten challenge) may also be avoided when diagnosing CD in children younger than 2 years provided that the child, at the time of presentation, has positive anti-endomysial antibodies and Marsh IIIc on the small bowel biopsy. A gluten challenge should be still considered in all other children younger than 2 years.