Pediatric IBD patients show medication and disease activity dependent changes in NK cell and CD4 memory T cell populations.

Objectives: CD4+ memory T cells facilitate long-termed adaptive immune responses while NK cells are predominately rapid effector cells with significant functions for both intestinal homeostasis and inflammation. We wanted to study both populations in health and pediatric inflammatory bowel disease (IBD) and correlate them with disease activity and medication. Methods: We performed flow cytometric analyses of peripheral blood CD4 + CD45RO+ memory T cells and CD3-CD16 + CD56+ NK cells in 30 patients with IBD and 31 age-matched controls and correlated percentages of subsets with disease activity (PUCAI/PCDAI) and medication. Results: We found a significant reduction of peripheral NK cells in overall IBD patients with both clinical remission and disease activity, which was even more pronounced in patients treated with azathioprine. Otherwise, circulating CD4+ memory T cell populations were significantly enhanced in active IBD compared to controls. Enhancement of memory T cells was particularly found in new onset disease and correlated with disease activity scores. Discussion: Our single center cohort confirms previous results showing enhanced memory T cell populations in pediatric IBD patients, which correlate with disease activity scores. CD4+ memory T cells are a relevant pathogenic leukocyte population for disease development and perpetuation in IBD. In addition, we found a decrease of NK cells in IBD patients, which was pronounced by use of azathioprine. Surveillance of both cellular populations could possibly serve as biomarker for therapy control in pediatric IBD.

A Complex Intervention to Prevent Medication-Related Hospital Admissions.

BACKGROUND: Children are often treated off-label and are at a disadvantage in pharmacotherapy. The aim of this study was to implement and evaluate a quality assurance measure (PaedPharm) for pediatric pharmacotherapy whose purpose is to reduce medication-related hospitalizations among children and adolescents. METHODS: PaedPharm consisted of the digital pediatric drug information system PaedAMIS, pediatric pharmaceutical quality circles (PaedZirk), and an adverse drug event (ADE) reporting system (PaedReport). The intervention was implemented in a cluster-randomized trial (DRKS 00013924) in 12 regions, with a pediatric and adolescent medicine clinic in each and a total of 152 surrounding private practitioners, in 6 sequences over 8 quarters. In addition to the proportion of ADE-related hospital admissions (primary endpoint), comprehensive process evaluation included other endpoints such as coverage, user acceptance, and relevance to practice. RESULTS: 41 829 inpatient admissions were recorded, of which 5101 were patients of physicians who participated in our study. 4.1% of admissions were ADE-related under control conditions, and 3.1% under intervention conditions (95% CI: [2.3; 5.9] and [1.8; 4.5], respectively). A model-based comparison yielded an intervention effect of 0.73 (population-based odds ratio; [0.39; 1.37]; p = 0.33). PaedAMIS achieved moderate user acceptance and PaedZirk achieved high user acceptance. CONCLUSION: The introduction of PaedPharm was associated with a decrease in medication-related hospitalizations that did not reach statistical significance. The process evaluation revealed broad acceptance of the intervention in outpatient pediatrics and adolescent medicine.

Change of Sleep Stage during Gastroesophageal Reflux in Infants.

INTRODUCTION: This study intended to explore the existence of a temporal association of changes of sleep stage and gastroesophageal reflux (GER) in infants. MATERIALS AND METHODS: Documentation of sleep stage and GER was conducted via the use of synchronized polygraphic recording combined with impedance-pH-metry in 15 infants. The total recording-time (Rt) was divided into GER-"window-time" (five seconds before and after the onset of a GER episode), "remaining GER time", and "GER-free time", and analyzed for changes of sleep stage. RESULTS: a total of 462 GER episodes were identified during Rt (151.1 h) in all infants. During 1.3 h of window-time; 61 changes of sleep stage (47/h); during 5.9 h of Remaining GER-time, 139 changes of sleep stage (24/h); and during 143.9 h of GER-free time, 4087 changes of sleep stage (28/h) were documented. Change of sleep stage was strongly associated with the onset of GER (p < 0.02 and p < 0.05, respectively). CONCLUSIONS: There is a strong temporal association between sleep irregularities, i.e., changes of sleep and episodes of GER in infants. When dealing with disturbed sleep in infants, GER should be considered by caregivers.

[KARLOTTA (Kids + Adolescents Research Learning On Tablet Teaching Aachen) - randomized controlled pilot study for the implementation of a digital educational app with game of skill for pediatric patients with inflammatory bowel disease]. / KARLOTTA (Kids + Adolescents Research Learning On Tablet Teaching Aachen) ­ randomisierte kontrollierte Pilotstudie zur Anwendung eines digitalen Lernspiels für pädiatrische Patienten mit chronisch entzündlichen Darmerkrankungen.

OBJECTIVES: Improvement of disease-specific knowledge in pediatric patients with inflammatory bowel disease (IBD) using a digital app and individualized teaching from physician to patient. METHODS: We developed an app for Android Software called KARLOTTA (Kids + Adolescents Research Learning On Tablet Teaching Aachen) with a game of skill and IBD questionnaire with visual feedback and high scores. Randomized controlled study as a pilot project with 30 IBD patients, aged 10-18 years. The intervention group used the KARLOTTA app on a tablet before every consultation during a 12-month period. Outcome parameters were an increase in knowledge, changes in quality of life and analysis of the feedback questionnaires for patient and physician. The statistical analysis was carried out with the X2 -test, Mann-Whitney-U test and descriptive analysis. RESULTS: KARLOTTA was played 55 times by 14 patients. In all patients (100%) gaps in knowledge could be discovered and specific teaching took place. In the KARLOTTA group, 11 of 14 patients (79%) had an increase in knowledge, in the control group 7 of 15 patients (47%), p-value of 0.08 with the X2 -test. There were no differences in results for quality of life. The app could be used without any problems in 87% of the appointments. CONCLUSIONS: The KARLOTTA app reveals individual gaps in knowledge, provides tailor-made physician-patient teaching and can be easily implemented in the outpatient clinic.

European pediatricians' approach to children with GER symptoms: survey of the implementation of 2009 NASPGHAN-ESPGHAN guidelines.

OBJECTIVE: The aim of this study was to evaluate the current implementation of the 2009 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition-European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines, and to assess proton pump inhibitors' (PPIs) prescribing patterns among pediatricians from different European countries. METHODS: A randomly identified sample of general pediatricians distributed across 11 European countries. They were asked to complete a case report-structured questionnaire investigating their approaches to infants, children, and adolescents with symptoms suggestive of gastroesophageal reflux. RESULTS: A total of 567 European general pediatricians completed the study questionnaire. Only 1.8% of them showed complete adherence to the guidelines. Forty-six percent of them reported that they diagnose gastroesophageal reflux disease based on clinical symptoms irrespective of the age of the child; 39% prescribe PPIs in infants with unexplained crying and/or distressed behavior and 36% prescribe PPIs in infants with uncomplicated recurrent regurgitation and vomiting; 48% prescribed PPIs in children younger than 8 to 12 years with vomiting and heartburn, without specific testing; 45% discontinue PPI therapy abruptly rather than tapering the dose. The overall rate of pediatricians overprescribing PPIs was 82%. CONCLUSIONS: The overall results of our survey show that the majority of pediatricians are unaware of 2009 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition-European Society for Pediatric Gastroenterology, Hepatology, and Nutrition reflux guidelines and often prescribe PPIs despite a lack of efficacy for the symptoms being treated. The overdiagnosis of gastroesophageal reflux disease places undue burden on both families and national health systems, which has not been affected by the publication of international guidelines.

Efficacy and safety of once-daily esomeprazole for the treatment of gastroesophageal reflux disease in neonatal patients.

OBJECTIVE: To evaluate the efficacy and safety of proton pump inhibitors in infants aged <1 year with gastroesophageal reflux disease (GERD). STUDY DESIGN: In this randomized, double-blind, placebo-controlled multicenter study, neonates (premature to 1 month corrected age; n = 52) with signs and symptoms of GERD received esomeprazole 0.5 mg/kg or placebo once daily for up to 14 days. Change from baseline in the total number of GERD symptoms (from video monitoring) and GERD-related signs (from cardiorespiratory monitoring) was assessed with simultaneous esophageal pH, impedance, cardiorespiratory, and 8-hour video monitoring. RESULTS: There were no significant differences between the esomeprazole and placebo groups in the percentage change from baseline in the total number of GERD-related signs and symptoms (-14.7% vs -14.1%, respectively). Mean change from baseline in total number of reflux episodes was not significantly different between esomeprazole and placebo (-7.43 vs -0.2, respectively); however, the percentage of time pH was <4.0 and the number of acidic reflux episodes >5 minutes in duration was significantly decreased with esomeprazole vs placebo (-10.7 vs 2.2 and -5.5 vs 1.0, respectively; P ≤ .0017). The number of patients with adverse events was similar between treatment groups. CONCLUSIONS: Signs and symptoms of GERD traditionally attributed to acidic reflux in neonates were not significantly altered by esomeprazole treatment. Esomeprazole was well tolerated and reduced esophageal acid exposure and the number of acidic reflux events in neonates.

Basic values for heart and respiratory rates during different sleep stages in healthy infants.

The aim of this study was to systematically register data for respiratory and heart rates (RR and HR, respectively) during different sleep stages [active (AS, i.e., rapid eye movement) and quiet (QS, i.e., non-rapid eye movement) sleep] and age in a large number of healthy infants (277) during the first year of life to simplify polysomnography. The reference values in this age group differ significantly between the number of patients and age at time of investigation. According to strict inclusion and exclusion criteria, the measurement of polysomnography included HR (beats per minute, or bpm), RR (breaths per minute, or breaths/min), brain waves, SO2, sound, and video. Data recording and evaluation occurred via Alice 3®/3.5®(Respironics®), classification into AS and QS sleep according to maturity. For RR, the 5th-95th percentiles during AS decreased from 25.8-47.7 breaths/min (1st month) to 17.8-27.7 breaths/min (>9 months). During QS, RR ranged from 27.4-51.5 breaths/min (1st month) to 17.8-29.2 breaths/min (>9 months). HR decreased during AS from 118.3-150.6 bpm (1st month) to 100.9-126.4 bpm (>9 months). During QS, HR decreased from 116.0-149.9 bpm (1st month) to 93.7-119.8 bpm (>9 months). The mean HR and RR significantly decreased with age in both sleep stages (p<0.05). The mean HR is significantly lower during QS compared with AS (p<0.05). Our data may serve as basic values for HR and RR in different sleep stages during the first year of life.

Indications, methodology, and interpretation of combined esophageal impedance-pH monitoring in children: ESPGHAN EURO-PIG standard protocol.

AIM: The aim of the study was to provide an updated position statement from the ESPGHAN European Pediatric Impedance Working Group on different technical aspects such as indications, methodology, and interpretation of multichannel intraluminal impedance-pH monitoring (MII-pH). METHODS: Evidence was used where available, but the article is based mainly on expert opinion and consensus. RESULTS: MII-pH provides more information than simple pH monitoring because reflux detection is not limited to acid reflux. Different companies provide commercialized MII-pH recording systems, making the method widely available and useable in daily clinical practice; however, the technique still has limitations: high cost, limited additional value regarding therapeutic implications, and lack of evidence-based parameters for the assessment of gastroesophageal reflux and symptom association in children. CONCLUSIONS: MII-pH recording is a promising procedure needing further validation and development to increase its additional benefit over conventional investigation techniques. The added value of the technique regards mainly clinical circumstances in which nonacid or weakly acid reflux may be relevant such as persisting symptoms during antireflux treatment with proton pump inhibitors and feeding-related reflux; and assessing specific discontinuous symptoms thought to be associated with gastroesophageal reflux; and research.

Interobserver and intraobserver variability in pH-impedance analysis between 10 experts and automated analysis.

OBJECTIVE: To determine interobserver and intraobserver variability in pH-impedance interpretation between experts and accuracy of automated analysis (AA). STUDY DESIGN: Ten pediatric 24-hour pH-impedance tracings were analyzed by 10 observers from 7 world groups and with AA. Detection of gastroesophageal reflux (GER) episodes was compared between observers and AA. Intraobserver agreement was assessed in 3 observers after 3 to 5 months. RESULTS: Overall, 1242 liquid and mixed GER events were detected, 490 (42%) were scored by the majority of observers, yielding moderate agreement (Cohen's kappa [κ] = 0.46). Intraclass co-efficient for numbers of GER per study was 0.84 (P < .001). AA has 94% sensitivity rate and 74% specificity rate compared with majority consensus (≥6 observers). Agreement for gas GER was poor (κ = 0.11). Intraobserver agreement was κ = 0.49, κ = 0.71, and κ = 0.85 in 3 observers. CONCLUSION: Interobserver agreement in combined pH-multichannel intraluminal impedance analysis in experts is moderate; only 42% of GER episodes were detected by the majority of observers. Detection of total GER numbers is more consistent. Considering these poor outcomes, AA seems favorable compared with manual analysis because of its reproducibility. However, the lower specificity rate suggests the need for refinement of AA before widespread use can be advocated.

Inter- and intraobserver agreement in 24-hour combined multiple intraluminal impedance and pH measurement in children.

OBJECTIVES: Assessment of intra- and interobserver agreement in multiple intraluminal impedance (MII) measurement between investigators from different institutions. METHODS: Twenty-four 18- to 24-hour MII tracings were randomly chosen from 4 different institutions (6 per center). Software-aided automatic analysis was performed. Each result was validated by 2 independent investigators from the 4 different centers (4 investigator combinations). For intraobserver agreement, 6 measurements were analyzed twice by the same investigator. Agreement between investigators was calculated using the Cohen kappa coefficient. RESULTS: Interobserver agreement: 13 measurements showed a perfect agreement (kappa > 0.8); 9 had a substantial (kappa 0.61-0.8), 1 a moderate (kappa coefficient 0.41 to 0.6), and 1 a fair agreement (kappa coefficient 0.11-0.4). Median kappa value was 0.83. Intraobserver agreement: 5 tracings showed perfect and 1 showed a substantial agreement. The median kappa value was 0.88. CONCLUSIONS: Most measurements showed substantial to perfect intra- and interobserver agreement. Still, we found a few outliers presumably caused by poorer signal quality in some tracings rather than being observer dependent. An improvement of analysis results may be achieved by using a standard analysis protocol, a standardized method for judging tracing quality, better training options for method users, and more interaction between investigators from different institutions.

Gastroesophageal Reflux and Body Movement in Infants: Investigations with Combined Impedance-pH and Synchronized Video Recording.

The aim of this paper was to investigate the temporal association of gastroesophageal reflux (GER) and body movement in infants. GER were registered by combined impedance-pH, documentation of body movement was done by video. Videorecording time (Vt) was divided into "resting time" and "movement time" and analyzed for occurrence of GER. Association was defined as movement 1 minute before/after the beginning of a GER. Statistical evaluation was by Fisher's exact test. In 15 infants, 341 GER were documented during Vt (86 hours). 336 GER (99%) were associated with movement, only 5 episodes (1%) occured during resting time. Movement was significantly associated with the occurrence of GER (P < .0001). There is a strong temporal association between GER and body movement in infants. However, a clear distinction between cause and effect could not be made with the chosen study design. Combined impedance-pH has proven to be the ideal technique for this approach.

Measurement of mucosal conductivity by MII is a potential marker of mucosal integrity restored in infants on acid-suppression therapy.

Esophageal multichannel intraluminal impedance (MII) allows measurement of the conductivity of adjacent contents. During esophageal rest, raw impedance levels may represent mucosal integrity. We assessed the influence of proton pump inhibitors (PPIs) on presumed mucosal integrity by reanalyzing raw MII levels of 21 pH-MII tracings from infants with gastroesophageal reflux (GER) disease before and after esomeprazole treatment. Median (interquartile range) esophageal MII increased during treatment, 938 (652-1304) versus 1885 (1360-2183) Ohm, P < 0.0001. Patients with lower MII levels demonstrated a larger increase on therapy: Spearman r2 = 0.28, P = 0.014. No correlation with standard GER parameters was observed. In conclusion, PPI therapy increases MII levels in infants with symptomatic GER disease.

Percutaneous endoscopic gastrostomy and gastro-oesophageal reflux in neurologically impaired children.

AIM: To investigate the effects of percutaneous endoscopic gastrostomy (PEG) feeding on gastro-oesophageal reflux (GOR) in a group of these children using combined intraluminal pH and multiple intraluminal impedance (pH/MII). METHODS: Ten neurologically impaired children underwent 12 h combined pH/MII procedures at least 1 d before and at least 12 d after PEG placement. METHODS: Prior to PEG placement (pre-PEG) a total of 183 GOR episodes were detected, 156 (85.2%) were non-acidic. After PEG placement (post-PEG) a total of 355 episodes were detected, 182 (51.3%) were non-acidic. The total number of distal acid reflux events statistically significantly increased post-PEG placement (pre-PEG total 27, post-PEG total 173, P = 0.028) and the mean distal pH decreased by 1.1 units. The distal reflux index therefore also significantly increased post-PEG [pre-PEG 0.25 (0-2), post-PEG 2.95 (0-40)]. Average proximal pH was lower post-PEG but the within subject difference was not statistically significant (P = 0.058). Median number of non-acid GOR, average reflux height, total acid clearance time and total bolus clearance time were all lower pre-PEG, but not statistically significant. CONCLUSION: PEG placement increases GOR episodes in neurologically impaired children.

Detection of gastroesophageal reflux in children using combined multichannel intraluminal impedance and pH measurement: data from the German Pediatric Impedance Group.

OBJECTIVE: To validate the use of combined multichannel intraluminal impedance (MII)-pH (MII-pH) monitoring for detecting gastroesophageal reflux (GER) in children in daily clinical practice. STUDY DESIGN: The patients were divided into 3 symptom groups based on the main indication for the procedure. MII-pH monitoring was performed in 700 children presenting with symptoms suggestive of GER, including 329 children with pulmonary symptoms, 325 with gastrointestinal symptoms, and 46 with neurologic symptoms. The MII-pH results were compared with pH monitoring alone, and retrograde bolus movements, symptom index, and symptom association probability were compared. RESULTS: Overall, 270 measurements were abnormal: 101 (37%) showed abnormal MII-pH study, 49 (18%) showed only pathological pH measurements and 120 measurements (45%) had an abnormal MII recording only. Extraintestinal symptoms of GER were seen more often in younger children and were more often related to a normal pH study but an abnormal MII study. Infants had a significantly higher number of retrograde bolus movements than older children. Symptom index and symptom association probability showed moderate agreement (Cohen kappa, 0.54). CONCLUSIONS: From this large systematically standardized data collection of MII-pH measurements in children, we conclude that 45% of the patients with abnormal GER would not have been recognized by 24-hour pH measurement alone. Our findings confirm that MII-pH is superior to pH monitoring alone in detecting GER.

Re-treatment of children with chronic hepatitis C who did not respond to interferon-alpha treatment.

BACKGROUND: Many patients with chronic hepatitis C do not respond to antiviral treatment. In adult patients the re-treatment of these patients has been extensively investigated. Because the response to re-treatment in children is not well defined we evaluated the efficacy and safety of interferon (IFN)-alpha plus ribavirin in patients who have failed to respond to previous treatment. PATIENTS AND METHODS: In an open-label, uncontrolled study, 18 chronically infected children were investigated. Fifteen children had been treated with IFN-alpha plus ribavirin and 3 patients with IFN-alpha alone. Fourteen patients were nonresponders; 4 experienced viral breakthrough during treatment and/or relapse after treatment. Patients received IFN-alpha 3 times per week subcutaneously plus ribavirin for 48 weeks. Sixteen patients were infected with hepatitis C virus (HCV) genotype 1, 2 with genotype 4, and 1 with genotype 3 and co-infection with hepatitis B. RESULTS: Four patients showed early viral response to therapy and became HCV-RNA negative after 12 weeks. Sustained viral response (HCV-RNA negative 6 months after end of treatment) was documented in 2 of them. These 2 patients belonged to the group of 4 children who relapsed or experienced a viral breakthrough during previous treatment. None of the 14 patients with prior nonresponse had sustained viral response. CONCLUSIONS: Re-treatment with IFN-alpha plus ribavirin may be useful in children who relapsed in a previous antiviral treatment but seems not to be useful in nonresponders. These results are in line with studies from adult patients and should be therefore encouraged to provide a second chance for healing in a subgroup of patients.

Influence of gestational age, cesarean section, and type of feeding on fecal human beta-defensin 2 and tumor necrosis factor-alpha.

OBJECTIVE: : Development of the mucosal immune system is essential for controlling antigenic response. External factors are known to influence the immune system, such as breast-feeding or the mode of delivery. The aim of the present study was to investigate maturation of the enteric immune system. PATIENTS AND METHODS: : In stool samples of 59 preterm and term-born infants we measured the concentration of human beta-defensin 2 (HBD 2), an endogenous antimicrobial peptide, and tumor necrosis factor-alpha (TNF-alpha), a cytokine playing a central role in mucosal inflammation, by enzyme-linked immunosorbent assay. RESULTS: : Mode of delivery as well as nutrition (breast-feeding or formula) had no influence on the fecal concentration of HBD-2 or TNF-alpha, but there was a significant increase in the concentration of HBD-2 in correlation with gestational age. TNF-alpha showed no change in concentration. CONCLUSIONS: : Low fecal HBD-2 may be a risk factor in preterm infants to develop neonatal enteric disease, such as necrotizing enterocolitis.

[Non-contact monitoring of heart and lung activity using magnetic induction measurement in a neonatal animal model]. / Kontaktlose Uberwachung von Atemtätigkeit und Herzaktion mittels magnetischer Bioimpedanzmessung in einem neonatalen Tiermodell.

BACKGROUND: Magnetic induction measurement (MIM) allows the identification of resistance in biologic tissues by alternating magnetic fields. These occur when well-conducting (blood) and poor-conducting matter (air) is moved through the thorax during heart and lung activity. As a result, allocation of the resistance changes and the total resistance of the thorax is shifted. By using coils, these changes can be registered in a non-contact manner and recorded. To date, this measuring principle was employed only in adult volunteers or in full-grown pigs. A neonatal animal model has not yet been described. The aim of this study was to test the hypothesis that non-contact monitoring of heart and lung activity using MIM in a porcine newborn piglet model can be applied in order to evaluate neonatal disorders of heart and lung activity in the future. MATERIALS AND METHODS: By using five coils (three measurement and two excitation coils), placed at the bottom of an experimental incubator, magnetic induction changes, depending on the heart and lung activity in 16 analgosedated piglets, were simultaneously measured and compared with pulse oximetry and airflow detection (flow resistance and pressure differential sensor) as reference signals. In addition, spontaneous breathing, including apnea, CPAP (continuous positive airway pressure to prevent end-expiratory alveolar collapse, flow 8 l/min; pressure 5 cm H(2)O), mechanical ventilation (inspiratory pressure 14 cm H(2)O; frequency 40/min) and high frequency oxygenation ventilation (HFOV, ventilation method in lung failure) (frequency 10 Hz, mean pressure 10 cm H(2)O, amplitude 1.5) were performed. Lung activity with MIM compared with the reference signal was estimated with a detection rate (%) of "correct registered lung activity". To quantify the analogy between MIM and reference signal for heart activity, the concordance correlation coefficient after Lin (95% confidence interval) and the Bland-Altman plot were calculated. RESULTS AND DISCUSSION: The detection rate for breathing [%] of MIM compared with the reference signal under CPAP was 88% [95% CI: (87.1%; 88.5%)], mechanical ventilation 91% [95% CI: (90.3%; 91.2%)] and under HFOV 95% [95% CI: (94.7%; 94.9%)]. For heart activity, during apnea the difference between MIM and reference signal was 1.1 bpm (+/-11.3 SD) in apnea and during HFOV 5.3 bpm (+/-26.4 SD). Under spontaneous breathing it was not possible to achieve a correlation. Owing to interference problems, registration of heart activity with MIM during simultaneous breathing activity (CPAP, conventional mechanical ventilation, HFOV) was insufficient. CONCLUSION: Non-contact monitoring of lung activity using MIM in a neonatal piglet model is possible under specific conditions. These results might be a basis for the development of non-invasive parameters in neonatology. It also provides the possibility of obtaining more information about the characteristics of lung activity of the newborn.