[Paediatric gastroenterological and hepatological care in Germany: results of a nationwide survey]. / Kindergastroenterologische und hepatologische Versorgung in Deutschland: Ergebnisse einer deutschlandweiten Umfrage.

INTRODUCTION: Children and adolescents with chronic gastrointestinal, pancreatic and liver diseases need age-appropriate and qualified treatment. A representative survey is used to analyse the structural and personnel-related outpatient and inpatient care of children with chronic gastrointestinal, pancreatic and liver diseases in Germany. METHODOLOGY: 319 paediatric and adolescent medicine clinics and 50 paediatric gastroenterology practices in Germany were invited to participate in the anonymous online survey via EFS Survey. The structure of the facilities, further training authorisations, cooperations, treatment and care data and an assessment of the need for care were systematically recorded and descriptively evaluated. RESULTS: 81 clinics and 10 practices participated in the survey. Almost two thirds of the clinics (n=52) provide outpatient paediatric gastroenterology services. Mostly up to 10 (25.4%) or 20 hours/week (33.8%). A quarter of the clinics do not offer consultation hours. Outpatient care needs cannot be met by two-thirds of the institutions. Half of all clinics stated that inpatient paediatric gastroenterology care needs can be met. However, one third cannot cover this and only rarely are there unused capacities. 35 clinics (43.2%) have a further training authorisation according to the state medical association (n=33) and/or are a further training centre of the Society for Paediatric Gastroenterology and Nutrition (GPGE) (n=18). CONCLUSION: There is a deficit in both outpatient and inpatient care in paediatric and adolescent gastroenterology. This results, among other things, from the economic framework conditions and a lack of personnel. Well-trained specialists with specialisation in paediatric and adolescent gastroenterology are still needed to provide qualified care throughout the country. Future studies should also include the need for paediatric gastroenterological care from the perspective of other groups, such as affected patients, internal gastroenterologists and paediatricians in private practice.

Validation of Antibody-Based Strategies for Diagnosis of Pediatric Celiac Disease Without Biopsy.

BACKGROUND & AIMS: A diagnosis of celiac disease is made based on clinical, genetic, serologic, and duodenal morphology features. Recent pediatric guidelines, based largely on retrospective data, propose omitting biopsy analysis for patients with concentrations of IgA against tissue transglutaminase (IgA-TTG) >10-fold the upper limit of normal (ULN) and if further criteria are met. A retrospective study concluded that measurements of IgA-TTG and total IgA, or IgA-TTG and IgG against deamidated gliadin (IgG-DGL) could identify patients with and without celiac disease. Patients were assigned to categories of no celiac disease, celiac disease, or biopsy required, based entirely on antibody assays. We aimed to validate the positive and negative predictive values (PPV and NPV) of these diagnostic procedures. METHODS: We performed a prospective study of 898 children undergoing duodenal biopsy analysis to confirm or rule out celiac disease at 13 centers in Europe. We compared findings from serologic analysis with findings from biopsy analyses, follow-up data, and diagnoses made by the pediatric gastroenterologists (celiac disease, no celiac disease, or no final diagnosis). Assays to measure IgA-TTG, IgG-DGL, and endomysium antibodies were performed by blinded researchers, and tissue sections were analyzed by local and blinded reference pathologists. We validated 2 procedures for diagnosis: total-IgA and IgA-TTG (the TTG-IgA procedure), as well as IgG-DGL with IgA-TTG (TTG-DGL procedure). Patients were assigned to categories of no celiac disease if all assays found antibody concentrations <1-fold the ULN, or celiac disease if at least 1 assay measured antibody concentrations >10-fold the ULN. All other cases were considered to require biopsy analysis. ULN values were calculated using the cutoff levels suggested by the test kit manufacturers. HLA typing was performed for 449 participants. We used models that considered how specificity values change with prevalence to extrapolate the PPV and NPV to populations with lower prevalence of celiac disease. RESULTS: Of the participants, 592 were found to have celiac disease, 345 were found not to have celiac disease, and 24 had no final diagnosis. The TTG-IgA procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.934; the TTG-DGL procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.958. Based on our extrapolation model, we estimated that the PPV and NPV would remain >0.95 even at a disease prevalence as low as 4%. Tests for endomysium antibodies and HLA type did not increase the PPV of samples with levels of IgA-TTG ≥10-fold the ULN. Notably, 4.2% of pathologists disagreed in their analyses of duodenal morphology-a rate comparable to the error rate for serologic assays. CONCLUSIONS: In a prospective study, we validated the TTG-IgA procedure and the TTG-DGL procedure in identification of pediatric patients with or without celiac disease, without biopsy. German Clinical Trials Registry no.: DRKS00003854.

Antibody Concentrations Decrease 14-Fold in Children With Celiac Disease on a Gluten-Free Diet but Remain High at 3 Months.

BACKGROUND & AIMS: Celiac disease can be identified by a serologic test for IgA against tissue transglutaminase (IgA-TTG) in a large proportion of children. However, the increased concentrations of antibody rarely normalize within the months after children are placed on a gluten-free diet (GFD). Early serologic predictors of sufficient adherence to GFD are required for optimal treatment. METHODS: In a prospective study, we observed the response to a GFD in 345 pediatric patients (67% girls; mean age, 8.4 y) who underwent duodenal biopsy to confirm or refute celiac disease from October 2012 through December 2015. Baseline serum samples were tested centrally for IgA-TTG and IgG against deamidated gliadin. Follow-up serologic analyses of children on a GFD were performed about 3 months later. RESULTS: The geometric mean concentration of IgA-TTG decreased from 72.4-fold to 5.2-fold the upper limit of normal (ULN), or by a factor of 14.0 (95% CI, 12.0-16.4). A substantial response (defined as a larger change than the typical variation in patients not on a GFD) was observed in 80.6% of the children. Only 28.1% of patients had a substantial response in the concentration of IgG against deamidated gliadin. Concentration of IgA-TTG remained above 1-fold the ULN in 83.8% of patients, and above 10-fold the ULN in 26.6% of patients with a substantial response. CONCLUSIONS: Serum concentration of IgA-TTG decreases substantially in most children with celiac disease within 3 months after they are placed on a GFD, but does not normalize in most. This information on changes in antibody concentrations can be used to assess patient response to the diet at short-term follow-up evaluations. Patients with a substantial response to a GFD often still have high antibody levels after 3 months. German Clinical Trials Registry no. DRKS00003854.

Varicella-zoster-virus vaccination of immunosuppressed children with inflammatory bowel disease or autoimmune hepatitis: A prospective observational study.

BACKGROUND AND AIMS: Children with inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH) receiving immunosuppressive treatment are at risk for severe varicella zoster virus (VZV)-induced disease. This study evaluated vaccination of susceptible patients with stable disease and documented immunoreactivity without interruption of their current immunosuppression (IS). METHODS: This prospective multicentre observational study used a prevaccination checklist to select patients with low-intensity and high-intensity IS for VZV vaccination. Tolerability and safety after immunization were assessed by questionnaire. The immune response was measured by the VZV-IgG concentration, relative avidity index (RAI), and specific lymphocyte proliferative response. RESULTS: A total of 29 VZV vaccinations were performed in 17 seronegative patients aged 3-16 years (IBD n = 15, AIH n = 2). Eight patients received high-intensity immunosuppression, another six low-intensity immunosuppression, and three patients interrupted IS before VZV vaccination. All 29 vaccinations were well tolerated; only minor side effects such as fever and abdominal pain, were reported in two patients. One patient experienced a flare of Crohn's disease the day after vaccination. The VZV-IgG-concentration increased significantly (p = 0.018) after vaccination, and a specific lymphocyte response towards VZV in vitro was detected in all tested patients which correlated with the RAI (r = 0.489; p = 0.078). CONCLUSIONS: VZV vaccination was well tolerated, safe and immunogenic in children receiving ongoing IS due to IBD and AIH. Ensuring immunoreactivity by clinical and laboratory parameters, rather than the type and dosage of IS, is a reasonable approach to decide on live-attenuated virus vaccinations in immunosuppressed children (German clinical trials DRKS00016357).

Vaccination rate and immunity of children and adolescents with inflammatory bowel disease or autoimmune hepatitis in Germany.

BACKGROUND AND AIMS: Immunosuppressed patients are at risk of severe infections with vaccination preventable diseases. We evaluated vaccination rate and immunity of children and adolescents with inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). METHODS: Immunization rate of 329 children with IBD (n = 300) and AIH (n = 29) was assessed in seven German centres using vaccination certificates, history of chicken pox and by determining anti-varicella zoster virus (VZV) and anti-measles IgG antibodies. RESULTS: Of the total cohort 86% received long-term immunosuppression. Four doses of a hexavalent vaccine were documented in 89%, at least one dose of measles, mumps, and rubella (MMR) vaccination was documented in 325 (99%), with 300 (92%) receiving two doses. Anti-measles IgG concentrations were insufficient in 11% of the immunized patients. VZV vaccination was officially recommended in Germany since 2004, and implemented in 88% born from 2005 onwards. In patients born earlier VZV catch up vaccination only reached 25% (n = 67). Of 118 patients with documented VZV vaccination 25 (21%) did not display sufficient anti-VZV IgG. Of 198 patients with a history of chicken pox, six had undetectable anti-VZV IgG. Of 29 patients having neither had chicken pox nor VZV vaccination, 20 were found to have sufficient anti-VZV IgG. CONCLUSIONS: In our cohort vaccination coverage for hexavalent and MMR vaccinations was good, but insufficient for VZV vaccination in patients born before 2005. Neither the vaccination certificate nor the history of chicken pox is reliable to predict VZV immunity indicating a need for serologic investigations and if needed vaccination before initiating immunosuppressive therapy.

Vitamin E treatment for children with chronic hepatitis B: a randomized placebo controlled trial.

AIM: To evaluate the safety and efficacy of Vitamin E in children with chronic hepatitis B. METHODS: We randomly assigned patients with chronic hepatitis B, positive for hepatitis B e antigen (HBeAg), to receive either Vitamin E or placebo once daily for 6 mo in a 3:1 ratio and double-blind manner. The primary end point was HBeAg seroconversion, defined as the loss of HBeAg, undetectable levels of serum hepatitis B virus DNA, and the appearance of antibodies against HBeAg 12 mo after therapy. RESULTS: At baseline visit, 49 patients had normal and 43 had increased serum aminotransferase levels. Twenty-nine patients did not respond to previous treatment with interferon-alpha or lamivudine. Seventy-six children completed the study; 16 were non-compliant (n = 7), lost to follow-up (n = 7), or started another antiviral treatment (n = 3). Intention-to-treat analysis showed HBeAg seroconversion in 16 children (23.2%) treated with Vitamin E and two (8.7%) in the placebo group (P = 0.13). Vitamin E was well tolerated. CONCLUSION: There is only a tendency that Vitamin E may promote HBeAg seroconversion. Therefore larger studies are needed to clarify the role of antioxidants in the therapy of chronic hepatitis B.

Prevalence and clinical significance of Staphylococcus aureus small-colony variants in cystic fibrosis lung disease.

Small-colony variants (SCVs) of Staphylococcus aureus can be isolated from the chronically infected airways of patients suffering from cystic fibrosis (CF). These slow-growing morphological variants have been associated with persistent and antibiotic-resistant infections, such as osteomyelitis and device-related infections, but no information is available to date regarding the clinical significance of this special phenotype in CF lung disease. We therefore investigated the prevalence of S. aureus SCVs in CF lung disease in a 12-month prospective study and correlated the microbiological culture results with the patients' clinical data. A total of 252 patients were screened for the presence of SCVs. The prevalence rate was determined to be 17% (95% confidence interval, 10 to 25%) among S. aureus carriers. S. aureus isolates with the SCV phenotype showed significantly higher antibiotic resistance rates than those with the normal phenotype. Patients positive for SCVs were significantly older (P = 0.0099), more commonly cocolonized with Pseudomonas aeruginosa (P = 0.0454), and showed signs of more advanced disease, such as lower forced expiratory volume in 1 s (P = 0.0148) than patients harboring S. aureus with a solely normal phenotype. The logistic regression model determined lower weight (P = 0.016), advanced age (P = 0.000), and prior use of trimethoprim-sulfamethoxazole (P = 0.002) as independent risk factors for S. aureus SCV positivity. The clinical status of CF patients is known to be affected by multiple parameters. Nonetheless, the independent risk factors determined here point to the impact of S. aureus SCVs on chronic and persistent infections in advanced CF lung disease.

Serum leptin and cytokines in whole blood in relation to clinical and nutritional status in cystic fibrosis.

OBJECTIVES: Leptin plays an important role in the energy balance and may be affected by hormonal and metabolic derangement associated with chronic disease. The aim of this study was to assess the correlation between leptin, proinflammatory cytokines and nutritional status with regard to clinical status in homozygous delta F 508 cystic fibrosis patients. METHODS: Patients with mild (Shwachman score 71-100 points, group A) disease were compared with those with moderate disease (Shwachman score 41-55 points, group B) and age-matched controls (group C, n = 22). Leptin was assessed by enzyme-linked immunosorbent assay and cytokines (interleukin-8, tumor necrosis factor alpha) before and after stimulation with 5 ng lipopolysaccharide by a chemiluminescent immunometric assay. RESULTS: Twenty-two patients were recruited for each group (median A/B/C forced expiratory volume in 1 second 80%/59%/-; median age 12/13.5/12.5 years). Leptin (median 3.25/2.65/3.3 pg/mL; P = 0.083) and body mass index were lower (group A/B/C 18.55/16.75/20.5 kg/m(2); P = 0.023), but dietary intake was significantly higher (group A/B/C 50.5/68/43 kcal/kg body weight; P = 0.026) in moderate disease. Cytokines before stimulation with lipopolysaccharide were highest in moderate disease, but there was no significant difference after stimulation (interleukin-8 median A/B/C before--15/25.1/8.0 pg/mL, P < 0.005; after--570.5/573.5/415.5 pg/mL, not significant; tumor necrosis factor alpha median A/B/C 43/56/30 pg/mL, P < 0.0001; 580/427/720.5 pg/mL, not significant.). CONCLUSIONS: There is a physiological regulation of leptin even in more advanced states of disease with significantly lower body mass index than controls. However, our data do not support the idea of elevated cytokine levels inducing anorexia in homozygous delta F 508 cystic fibrosis patients.

Lipopolysaccharide binding protein, cytokine production in whole blood, and lipoproteins in cystic fibrosis.

According to the endotoxin lipoprotein hypothesis, lipoproteins may down-regulate cytokine production by neutralizing lipopolysaccharide (LPS) binding protein (LBP) complexes. We investigated the correlation between lipoproteins, LBP, cytokine production, and clinical status in Delta F 508 (homozygous) individuals. Cystic fibrosis patients with mild disease were compared with those with more severe disease and age-matched controls. LBP, IL-8, and tumor necrosis factor-alpha, using a chemiluminescent immunometric assay, and fat intake, as well as serum triglycerides, cholesterol, very low density lipoprotein, LDL, and HDL were measured. In more severe disease there was a correlation between maximum expiratory flow at 25% of vital capacity and HDL. To adjust for the influence of colonization with Pseudomonas aeruginosa, those who were colonized with P. aeruginosa were analyzed separately. There was a significant correlation between LBP and forced expiratory volume in 1 s. Lipoproteins may have a modulating effect in more advanced disease and are not influenced by fat intake. LBP correlates those who were colonized with P. aeruginosa (Psa+) with clinical status as well as lung function and may be a critical molecule regulating LPS-induced inflammation.