Publications by authors named "Bruno Hauser"

55 Publications

Significant variations across European centres in implementing recommended guidelines for the paediatric gastroenterology endoscopy suite during the COVID-19 pandemic.

JPGN Rep 2021 Aug 27;2(3):e061. Epub 2021 May 27.

University Children's Hospital, Basel, Switzerland.

The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) published recommendations regarding protection for the paediatric endoscopist during the coronavirus 2019 (COVID-19) pandemic.The aim of this survey was to investigate whether European paediatric gastroenterology centres applied the recommendations and how this extraordinary situation was handled by the different centres.

Results: Twelve paediatric European gastroenterology centres participated. Nine centres (75%) screened their patients for possible COVID-19 infection before the procedure, the same amount of hospitals changed their practice based on the ESPGHAN recommendations. Six-seven percentage of the centres reduced the staff in the endoscopy suite, 83% of the units used FFP2/3 masks and protective goggles during the procedure and 75% wore waterproof gowns.

Conclusion: Uniform guidelines could not be applied by all European hospitals at a certain time point of the viral spread, as different regions of Europe were not only affected differently by COVID-19, but also had different access to personal protective equipment.
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http://dx.doi.org/10.1097/PG9.0000000000000061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162040PMC
August 2021

Percutaneous Endoscopic Gastrostomy in Children: An Update to the ESPGHAN Position Paper.

J Pediatr Gastroenterol Nutr 2021 06 22. Epub 2021 Jun 22.

Centro Hospitalar S. João, Porto, Portugal

Background: The ESPGHAN position paper from 2015 on percutaneous endoscopic gastrostomy (PEG) required updating in the light of recent clinical knowledge and data published in medical journals since 2014.

Methods: A systematic review of medical literature from 2014 to 2020 was carried out. Consensus on the content of the manuscript, including recommendations, was achieved by the authors through electronic and virtual means. The expert opinion of the authors is also expressed in the manuscript when there was a lack of good scientific evidence regarding PEGs in children in the literature.

Results: The authors recommend that the indication for a PEG be individualized, and that the decision for PEG insertion is arrived at by a multidisciplinary team (MDT) having considered all appropriate circumstances. Well timed enteral nutrition is optimal to treat faltering growth to avoid complications of malnutrition and body composition. Timing, device choice and method of insertion is dependent on the local expertise and after due consideration with the MDT and family. Major complications such as inadvertent bowel perforation should be avoided by attention to good technique and by ensuring the appropriate experience of the operating team. Feeding can be initiated as early as 3 hours after tube placement in a stable child with iso-osmolar feeds of standard polymeric formula. Low- profile devices can be inserted initially using the single stage procedure or after 2-3 months by replacing a standard peg tube, in those requiring longer term feeding. Having had a period of non-use and reliance upon oral intake for growth and weight gain - typically 8-12 weeks - a PEG may then safely be removed after due consultation. In the event of non-closure of the fistula the most successful method for closing it, to date, has been a surgical procedure, but the Over-The-Scope-Clip (OTSC®) has recently been used with considerable success in this scenario.

Conclusions: A multidisciplinary approach is mandatory for the best possible treatment of children with PEGs. Morbidity and mortality are minimized through team decisions on indications for insertion, adequate planning and preparation before the procedure, subsequent monitoring of patients, timing of change to low-profile devices, management of any complications, and optimal timing of removal of the PEG.
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http://dx.doi.org/10.1097/MPG.0000000000003207DOI Listing
June 2021

European guideline on indications, performance and clinical impact of C-breath tests in adult and pediatric patients: An EAGEN, ESNM, and ESPGHAN consensus, supported by EPC.

United European Gastroenterol J 2021 Jun 14;9(5):598-625. Epub 2021 Jun 14.

Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.

Introduction: C-breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers.

Methods: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of C-breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and <10% disagreed.

Results: The guideline gives an overview over general methodology of C-breath testing and provides recommendations for the use of C-breath tests to diagnose Helicobacter pylori infection, measure gastric emptying time, and monitor pancreatic exocrine and liver function in adult and pediatric patients. Other potential applications of C-breath testing are summarized briefly. The recommendations specifically detail when and how individual C-breath tests should be performed including examples for well-established test protocols, patient preparation, and reporting of test results.

Conclusion: This clinical practice guideline should improve pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, this guideline identifies areas of future clinical research involving the use of C-breath tests.
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http://dx.doi.org/10.1002/ueg2.12099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259225PMC
June 2021

C-gastric emptying breath tests: Clinical use in adults and children.

Neurogastroenterol Motil 2021 Jun 17;33(6):e14172. Epub 2021 May 17.

Department of Paediatric Gastroenterology, Hepatology and Nutrition, KidZ Health Castle UZ Brussel, Brussels, Belgium.

C-gastric emptying breath tests ( C-GEBT) are validated, reliable, and non-invasive tools for measurement of gastric emptying (GE) velocity of solids and liquids without radiation exposure or risk of toxicity. They are recommended and routinely used for clinical purposes in adult as well as pediatric patients and can be readily performed onsite or even at the patient's home. However, the underlying methodology is rather complex and test results can be influenced by dietary factors, physical activity, concurrent diseases, and medication. Moreover, epidemiological factors can influence gastric emptying as well as production and exhalation of CO , which is the ultimate metabolic product measured for all C-breath tests. Accordingly, in this issue of Neurogastroenterology & Motility, Kovacic et al. report performance of the C-Spirulina breath test in a large group of healthy children and show significant effects of gender, pubertal status, and body size on test results. The purpose of this mini-review is to evaluate the clinical use of C-GEBT in adults and children, exploring available protocols, analytical methods, and essential prerequisites for test performance, as well as the role of GE measurements in the light of the current discussion on relevance of delayed GE for symptom generation.
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http://dx.doi.org/10.1111/nmo.14172DOI Listing
June 2021

Health Literacy and Quality of Life in Young Adults From The Belgian Crohn's Disease Registry Compared to Type 1 Diabetes Mellitus.

Front Pediatr 2021 5;9:624416. Epub 2021 Feb 5.

Pediatric Gastroenterology, UZ Brussels, Jette, Belgium.

The management of chronic inflammatory bowel diseases in youth is challenging. We aimed to determine health literacy (HL), quality of life (QoL) and clinical outcomes in young adults from the BELgian CROhn's disease registry (BELCRO) in comparison to type 1 diabetes mellitus (DM) as a control. In this prospective and observational study, young adults with Crohn's disease (CD) diagnosed < 18 years and with > 5 years disease duration and a comparable group of patients with DM completed validated HL, QoL and work productivity and activity impairment questionnaires (HLS-EU-Q16, EQ-5D-5L and WPAI). HL was scored as sufficient (13-16), problematic (9-12) or inadequate (0-8). QoL was dichotomized into "no problems" (EQ-5D level 1) or "problems" (EQ-5D levels 2 to 5). Non-parametric (Mann-Whitney ) analyses and Spearman correlations were performed. A total of 52 CD (median [IQR] age of 25.0 [23.8-27.0], 64% male) and 50 DM (age 20.0 [19.0-22.0], 50% male) patients were included. HL was 14.0 [11.0-16.0] for CD and 14.0 [11.3-14.8] for DM ( = 0.6) with similar proportions of sufficient (60 vs. 68%, = 0.4), problematic (34 vs. 26%, = 0.3) and inadequate HL (both 6%, = 1). Although QoL was comparable for CD and DM (77.0 [68.8-82.0] vs. 75.0 [65.0-80.0] %, =0.4), CD had a trend for higher pain/discomfort (50 vs. 32%, = 0.06). HL and QoL correlated in CD ( = 0.6, < 0.001) and DM patients ( = 0.6, < 0.001). Fewer CD patients with recent hospitalization/surgery had sufficient HL (31 vs. 69%, = 0.01) and had lower QoL (70.0 [60.0-77.0] vs. 80.0 [70.0-85.0], = 0.04) compared to those without. Selected young Belgian adults suffering from CD for >5 years have similar and sufficient HL compared to DM patients. However, CD patients requiring hospitalization/surgery have lower HL, which indicates the need for targeted educational programs.
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http://dx.doi.org/10.3389/fped.2021.624416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892785PMC
February 2021

Efficacy and Safety of the Local Application of Mitomycin C to Recurrent Esophageal Strictures in Children.

J Pediatr Gastroenterol Nutr 2019 11;69(5):528-532

National Reference Centre for Congenital Malformation of the Oesophagus University Lille, Inserm, CHU Lille, Lille.

Objectives: Research on long-term use of mitomycin C (MC) for recurrent esophageal stenoses is limited. We assessed the long-term efficacy and safety of local application of MC for recurrent esophageal stenoses in children.

Methods: This was a retrospective study of 39 patients (17 girls) with a median age of 19.5 months (range: 2.4-196.0) at the time of MC application. The etiologies of stenosis were esophageal atresia (n = 25), caustic ingestion (n = 9), congenital esophageal stenosis (n = 3), and other causes (n = 2). Stenosis was single in 35 (90%) patients and multiple in 4 (10%). Before MC, patients underwent multiple repeated dilations (median: 3 dilations per child [range: 2-26]) over a median period of 7 months (range: 2.6-49.3). Treatment success was defined a priori as a reduction in the number of dilations over the same period from before to after the application of MC.

Results: For 26 (67%) patients, the application of MC was considered a success: 102 versus 17 dilatations (P < 0.0001). Sixteen (41%) patients never required additional dilation during the follow-up after MC application (median: 3.1 years [range: 0.6-8.5]). No complication related to MC was observed. Biopsies at the site of MC application were performed at maximal follow-up in 16 patients and revealed no dysplasia. Three factors were associated with success of MC: single stenosis, short stenosis, and esophageal atresia type III.

Conclusions: This study is the largest series reported showing that topical application of MC is an efficient and safe treatment for recurrent esophageal stenosis in children.
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http://dx.doi.org/10.1097/MPG.0000000000002445DOI Listing
November 2019

Functional Gastrointestinal Disorders in Infancy: Impact on the Health of the Infant and Family.

Pediatr Gastroenterol Hepatol Nutr 2019 May 16;22(3):207-216. Epub 2019 Apr 16.

Department of Pediatrics, University of Insubria, Varese, Italy.

Functional gastrointestinal disorders (FGIDs) such as infantile colic, constipation and colic occur in almost half of the infants. The aim of this paper is to provide a critical and updated review on the management of FGIDs and their impact on the health of the infant and family to health care physicians. Guidelines and expert recommendations were reviewed. FGIDs are a frequent cause of parental concern, impairment in quality of life of infants and relatives, and impose a financial burden to families, health care, and insurance. Therefore, primary management of the FGIDs should be focused on improving the infants' symptoms and quality of life of the family. If more than parental reassurance is needed, available evidence recommends nutritional advice as it is an effective strategy and most of the time devoid of adverse effects. The role of healthcare providers in reassuring parents and proposing the correct behavior and nutritional intervention by avoiding inappropriate use of medication, is essential in the management of FGIDs.
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http://dx.doi.org/10.5223/pghn.2019.22.3.207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506429PMC
May 2019

Intestinal Spirochetosis: A Case Series and Review of the Literature.

Pediatr Gastroenterol Hepatol Nutr 2019 Mar 8;22(2):193-200. Epub 2019 Mar 8.

Kidz Health Castle, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

A clinical suspicion of intestinal spirochetosis is required when patients have long lasting complaints of abdominal pain, diarrhea, rectal bleeding, weight loss, and nausea. An endoscopy with biopsies needs to be performed to confirm the diagnosis of intestinal spirochetosis. The diagnosis of intestinal spirochetosis is based on histological appearance. Intestinal spirochetosis can also be associated with other intestinal infections and juvenile polyps (JPs). JPs seem to be more frequent in patients with intestinal spirochetosis than in patients without intestinal spirochetosis. Intestinal spirochetosis in children should be treated with antibiotics. Metronidazole is the preferred option. In this article, we describe 4 cases of intestinal spirochetosis in a pediatric population and provide a review of the literature over the last 20 years. Intestinal spirochetosis is a rare infection that can cause a variety of severe symptom. It is diagnosed based on histological appearance.
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http://dx.doi.org/10.5223/pghn.2019.22.2.193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416382PMC
March 2019

Diagnosis and Management of Gastroesophageal Reflux Disease in Infants and Children: from Guidelines to Clinical Practice.

Pediatr Gastroenterol Hepatol Nutr 2019 Mar 8;22(2):107-121. Epub 2019 Mar 8.

KidZ Health Castle, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

The diagnosis and management of gastro-esophageal reflux (GER) and GER disease (GERD) in infants and children remains a challenge. Published guidelines and position papers, along with Embase, MEDLINE, and the Cochrane Database were reviewed and summarized with the intent to propose a practical approach and management of GER and GERD for healthcare providers and to standardize and improve the quality of care for infants and children. For this purpose, 2 algorithms were developed, 1 for infants <12 months of age and the other for older children. None of the signs and symptoms of GER and GERD are specific and there is no gold standard diagnostic test or tool. Nutritional management is recommended as a first-line approach in infants, while in children, a therapeutic trial with antacid medication is advised for early management. The practical recommendations from this review are intended to optimize the management of GER in infants and older children and reduce the number of investigations and inappropriate use of medication.
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http://dx.doi.org/10.5223/pghn.2019.22.2.107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416385PMC
March 2019

Recent advances in understanding and managing infantile colic.

F1000Res 2018 7;7. Epub 2018 Sep 7.

KidZ Health Castle, UZ Brussel, Vrije Universiteit Brussel, Brussel, Belgium.

A newborn brings joy to the family. Crying belongs to the spectrum of normal behaviour of young infants. However, although it occurs in about 20% of all infants, unsoothable and persistent crying in young infants distresses the family, although it is usually benign. The aetiology of infantile colic remains unknown, although an unbalanced gastro-intestinal microbiome, increased intestinal permeability, and chronic inflammation are involved, as well as behavioural factors, including over- and under-stimulation. It is a challenge for healthcare professionals to decide when organic disease needs to be excluded. Parental stress is a reason for babies to cry more, inducing a vicious cycle. Therefore, parental reassurance with explanatory guidance is the cornerstone of management. The placebo effect is estimated to be as high as 50%. If an intervention is felt to be necessary to offer further support to the baby and family, it is important to choose the options for which there is some efficacy without adverse effects. There is evidence that some specific probiotic strains such as DSM 19378, especially in breastfed infants, are effective. However, there are also promising data for some synbiotics and/or killed or tyndallized bacteria, as well as substances decreasing intestinal permeability. Formula management with extensive and/or partial hydrolysates may also bring relief. But, above all, offering parental support remains imperative.
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http://dx.doi.org/10.12688/f1000research.14940.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134333PMC
February 2019

Probiotics in cystic fibrosis patients: A double blind crossover placebo controlled study: Pilot study from the ESPGHAN Working Group on Pancreas/CF.

Clin Nutr ESPEN 2018 10 20;27:59-65. Epub 2018 Jul 20.

Hadassah University Hospitals, Pediatric Gastroenterology, CF Centre, Jerusalem, Israel.

Background: A potential positive effect of probiotics in cystic fibrosis (CF) on fecal calprotectin (FCP), pulmonary exacerbations and weight has been described in small controlled trials.

Methods: A double-blind multicenter cross-over study (2 × 4 m) was performed looking at abdominal pain, nutritional status, pulmonary function, pulmonary exacerbation, FCP and lactulose/mannitol gut permeability test. Patients kept a diary with daily scoring of abdominal pain, stool frequency and consistency as well as treatment changes.

Results: 31 CF patients entered the study of which 25 finished it. At start patients aged 9.3yrs (6.9-12.2), had a median BMI z-score of -0.5 (-1.5-0.08), height z-score of -0.4 (-1.1-0.05) and FEV1% of 100% (87.2-106.6). Median FCP at start was 61 μg/g (17-108) and gut permeability 0.079 (0.051-0.122). No significant changes were observed in the clinical parameters (BMI, FEV1%, abdominal pain, exacerbations). Despite being frequently abnormal (17/28 (61%) >50 mg/kg), FCP did not change significantly with probiotics. The proportion of patients with normal permeability was 8% during placebo and 32% during probiotic treatment (p = 0.031). FCP correlated to BMI z-score (p = 0.043) and gut permeability to abdominal pain (p = 0.015). The microbiome revealed a high predominance of Actinobacteria and Proteobacteriae. Probiotic supplementation did not result in a shift at the phylum nor at phylogenetic level.

Conclusion: Normalization of gut permeability was observed in 13% of patients during probiotic treatment. However, none of the previously described effects could be confirmed.
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http://dx.doi.org/10.1016/j.clnesp.2018.06.008DOI Listing
October 2018

Reflections on treatment of IBD in children and adolescents.

Immunopharmacol Immunotoxicol 2018 Dec 24;40(6):461-464. Epub 2018 Jul 24.

a Department Pediatric Gastroenterology and Nutrition , University Hospital Brussels, Kidz Health Castle, Free University Brussels , Brussels , Belgium.

Major pharmaceutical advancements in the field of inflammatory bowel diseases benefit to children and adolescents affected with this progressive chronic condition. Scientific organisations such as ESPGHAN and ECCO actively publish guidelines related to the many aspects of care from these patients. Clinical studies and long-term prospective registries in the appropriate age groups are crucial to support an evidence based strategy.
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http://dx.doi.org/10.1080/08923973.2018.1474922DOI Listing
December 2018

Long-term Outcomes with Anti-TNF Therapy and Accelerated Step-up in the Prospective Pediatric Belgian Crohn's Disease Registry (BELCRO).

Inflamm Bowel Dis 2017 09;23(9):1584-1591

1Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium; 2Pediatric Gastroenterology, UCL St Luc, Brussels, Belgium; 3Pediatric Gastroenterology, UZ Brussel, Brussels, Belgium; 4Pediatric Gastroenterology, HUDERF, Brussels, Belgium; 5Pediatric Gastroenterology, UZ Leuven, Leuven, Belgium; 6Pediatric Gastroenterology, Jessa Ziekenhuis, Hasselt, Belgium; 7Pediatric Gastroenterology, ZOL Genk, Genk, Belgium; 8Gastroenterology, ST Lucas, Ghent, Belgium; 9Pediatric Gastroenterology, UZ Gent, Ghent, Belgium; 10Pediatric Gastroenterology, CHC Liège, Liège, Belgium; 11Pediatric Gastroenterology, UZ Antwerpen, Antwerp, Belgium; 12Gastroenterology, UZ Gent, Ghent, Belgium; 13Gastroenterology, Imelda Ziekenhuis, Bonheiden, Belgium; 14Gastroenterology, UCL Mont Godinne, Mont Godinne, Belgium; 15Gastroenterology, UCL St Luc, Brussels, Belgium; 16Gastroenterology, ULB Erasme, Brussels, Belgium; 17Gastroenterology, CHU Liège, Liège, Belgium; 18Gastroenterology, St Pierre, Ottignies, Belgium; 19Gastroenterology, Heilig Hart Ziekenhuis, Roeselaere, Belgium; and 20DNA Lytics, Louvain-la-Neuve, Belgium.

Background: Accelerated step-up or anti-tumor necrosis factor (TNF) before first remission is currently not recommended in pediatric Crohn's disease.

Methods: Five-year follow-up data from a prospective observational cohort of children diagnosed with Crohn's disease in Belgium were analyzed. Disease severity was scored as inactive, mild, or moderate to severe. Remission or inactive disease was defined as sustained if lasting ≥2 years. Univariate analyses were performed between anti-TNF-exposed versus naive patients and anti-TNF before versus after first remission and correlations assessed with primary outcomes average disease severity and sustained remission.

Results: A total of 91 patients (median [IQR] age 12.7 [10.9-14.8] yrs, 53% male) were included. Disease location was 12% L1, 23% L2, and 64% L3 with 76% upper gastrointestinal and 30% perianal involvement. Disease severity was 25% mild and 75% moderate to severe. Of 66 (73%) anti-TNF-exposed patients, 34 (52%) had accelerated step-up. Anti-TNF use was associated with age (13.1 [11.5-15.2] versus 11.8 [8.7-13.8] yrs; P < 0.05), L2 (29% versus 8%; P = 0.04), and average disease severity (1.7 [1.4-1.9] versus 1.4 [1.3-1.6]; P < 0.001). Duration of anti-TNF correlated with average disease severity (r = 0.32, P = 0.002). Accelerated step-up was also associated with age (13.3 [12.1-15.9] versus 12.5 [10.2-14.1]; P = 0.02) and average disease severity (1.8 [1.6-1.9] versus 1.6 [1.3-1.8]; P = 0.002). Duration of sustained remission was similar in all patients, and no serious infections, cancer, or deaths were reported.

Conclusions: Anti-TNF therapy and accelerated step-up in older patients with more severe disease leads to beneficial long-term outcomes.
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http://dx.doi.org/10.1097/MIB.0000000000001193DOI Listing
September 2017

Proposal for An Algorithm for Screening for Undernutrition in Hospitalized Children.

J Pediatr Gastroenterol Nutr 2016 11;63(5):e86-e91

*Department of Pediatric Gastroenterology, Universitair Ziekenhuis Brussel †Vakgroep Pediatrie, Faculteit Geneeskunde en Farmacie, Vrije Universiteit Brussel (VUB), Brussels ‡Department of Pediatrics, Centre Hospitalier Universitaire Tivoli, La Louviere §Academic Hospital Erasme, Université Libre de Bruxelles, Brussels ||Department of Pediatrics, Jessa hospital, Hasselt ¶Department of Pediatrics, ZNA Paloa Kinderziekenhuis, Antwerpen #Environment and Health, Department of Public Health and Primary Care, KU Leuven-University of Leuven, Leuven **Department of Pediatric Gastroenterology, Ghent University Hospital, Ghent University, Ghent, Belgium.

The prevalence of disease-related undernutrition in hospitalized children has not decreased significantly in the last decades in Europe. A recent large multicentric European study reported a percentage of underweight children ranging across countries from 4.0% to 9.3%. Nutritional screening has been put forward as a strategy to detect and prevent undernutrition in hospitalized children. It allows timely implementation of adequate nutritional support and prevents further nutritional deterioration of hospitalized children. In this article, a hands-on practical guideline for the implementation of a nutritional care program in hospitalized children is provided. The difference between nutritional status (anthropometry with or without additional technical investigations) at admission and nutritional risk (the risk of the need for a nutritional intervention or the risk for nutritional deterioration during hospital stay) is the focus of this article. Based on the quality control circle principle of Deming, a nutritional care algorithm, with detailed instructions specific for the pediatric population was developed and implementation in daily practice is proposed. Further research is required to prove the applicability and the merit of this algorithm. It can, however, serve as a basis to provide European or even wider guidelines.
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http://dx.doi.org/10.1097/MPG.0000000000001288DOI Listing
November 2016

Paediatric Crohn Disease: Disease Activity and Growth in the BELCRO Cohort After 3 Years Follow-up.

J Pediatr Gastroenterol Nutr 2016 08;63(2):253-8

*Paediatric Gastroenterology, UZ Brussel †Free university Brussels (VUB), Brussel ‡Paediatric Gastroenterology, UZ Gasthuisberg, Leuven §Paediatric Gastroenterology, UCL St Luc, Brussel ||Paediatric Gastroenterology, UZ Gent, Gent ¶Pediatric Gastroenterology, HUDERF, Brussel #Pediatric Gastroenterology, CHC Espérance, Liège **Paediatric Gastroenterology, Jessa Hospital, Hasselt ††Paediatric Gastroenterology, ZOL, Genk ‡‡Gastroenterology, UCL St Luc, Brussel §§Gastroenterology, UZ Gent, Gent ||||Gastroenterology,H Hart Hospital, Roeselare ¶¶Gastroenterology, Imelda Hospital, Bonheiden ##Gastroenterology, UCL Mont Godinne, Mont Godinne ***Gastroenterology, ULB Erasme, Brussel †††Gastroenterology, UZ Gasthuisberg, Leuven ‡‡‡Gastroenterology, CHU St Joseph §§§Gastroenterology, CHU and University of Liège, Liège ||||||Gastroenterology, Clinique St Pierre, Ottignies, Belgium.

Objective: The Belgian registry for paediatric Crohn disease (BELCRO) cohort is a prospective, multicentre registry for newly diagnosed paediatric patients with Crohn disease (CD) (<18 years) recruited from 2008 to 2010 to identify predictive factors for disease activity and growth.

Methods: Data from the BELCRO database were evaluated at diagnosis, 24 and 36 months follow-up.

Results: At month 36 (M36), data were available on 84 of the 98 patients included at diagnosis. Disease activity evolved as follows: inactive 5% to 70%, mild 19% to 24%, and moderate to severe 76% to 6%. None of the variables such as age, sex, diagnostic delay, type of treatment, disease location, disease activity at diagnosis, and growth were associated with disease activity at M36. Paediatricians studied significantly less patients with active disease at M36 compared with adult physicians. Sixty percent of the patients had biologicals as part of their treatment at M36. Adult gastroenterologists initiated biologicals significantly earlier. They were the only factor determining biologicals' initiation, not disease location or disease severity at diagnosis. Median body mass index (BMI) z score evolved from -0.97 (range -5.5-2.1) to 0.11 (range -3.4-2) and median height z score from -0.15 (range -3.4-1.6) to 0.12 (range -2.3-2.3) at M36. None of the variables mentioned above influenced growth over time.

Conclusions: Present treatment strategies lead to good disease control in the BELCRO cohort after 3 years. Logistic regression analysis did not show any influence of disease location or present treatment strategy on disease activity and growth, but patients under paediatric care had significantly less severe disease at M36.
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http://dx.doi.org/10.1097/MPG.0000000000001132DOI Listing
August 2016

Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis.

J Cyst Fibros 2016 07 8;15(4):540-7. Epub 2016 Jan 8.

Department of Paediatrics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

Background: Gastro-oesophageal reflux (GOR) is common in patients with cystic fibrosis (CF). The aim of this study was to investigate the relationship between gastric emptying (GE) and GOR in children with CF.

Methods: Multichannel intraluminal impedance-pH monitoring (MII-pH) to measure GOR and GE breath test (GEBT) to measure GE were performed in 28 children with symptoms suggestive for GOR disease (GORD) (group 1). GEBT was performed in another 28 children with/without GOR symptoms who agreed to undergo GEBT but not MII-pH (group 2).

Results: In group 1, we found increased acid GOR (AGOR) in 46.4% and delayed GE (DGE) in 21.4% but no relationship between increased AGOR and DGE. There was no DGE in group 2. We found DGE in 10.7% and rapid GE in 12.5% of the whole group.

Conclusions: Almost half of the children with CF and symptoms suggestive for GORD have increased AGOR and almost a quarter has DGE. However, there was no relation between GOR and GE.
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http://dx.doi.org/10.1016/j.jcf.2015.12.015DOI Listing
July 2016

An updated review on gastro-esophageal reflux in pediatrics.

Expert Rev Gastroenterol Hepatol 2015 28;9(12):1511-21. Epub 2015 Sep 28.

a Department of Pediatrics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.

Comprehensive guidelines for the diagnosis and management of gastro-esophageal reflux (GER) and GER disease (GERD) were developed by the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition. GERD is reflux associated with troublesome symptoms or complications. The recognition of GER and GERD is relevant to implement best management practices. A conservative management is indicated in infants with uncomplicated physiologic reflux. Children with GERD may benefit from further evaluation and treatment. Since the publications of the European and North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition guidelines in 2009, no important novelties in drug treatment have been reported. Innovations are mainly restricted to the management of regurgitation in infants. During the last 5 years, pros and cons of multichannel intraluminal impedance have been highlighted. However, overall 'not much has changed' in the diagnosis and management of GER and GERD in infants and children.
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http://dx.doi.org/10.1586/17474124.2015.1093932DOI Listing
September 2016

Gastric Emptying of Liquids in Children.

J Pediatr Gastroenterol Nutr 2016 Mar;62(3):403-8

*Department of Paediatrics, Universitair Kinderziekenhuis Brussel, Vrije Universiteit Brussel, Brussels †Department of Public Health and Primary Care, Katholieke Universiteit Leuven, Leuven ‡Department of Nuclear Medicine, Universitair Ziekenhuis Brussel, Brussels, Belgium.

Objectives: The present study was performed to determine normal values for gastric half-emptying time (t1/2GE) of liquids in healthy children.

Methods: Gastric emptying (GE) of a standardized test milk-drink measured with technetium scintigraphy and the C-acetate breath test (C-ABT) was compared in 19 children ages between 4 and 15 years with upper gastrointestinal symptoms. The C-ABT was subsequently used to determine normal values for GE of the same liquid test meal in 133 healthy children ages between 1 and 17 years.

Results: In the group of children with upper gastrointestinal symptoms, the results showed a significant correlation (r = 0.604, P = 0.0006) between t1/2GE measured with both techniques. In the group of healthy children, the results of t1/2GE showed that there was no influence of age, sex, weight, height, and body mass index on GE.

Conclusions: Normal values for GE of a standardized test milk-drink in healthy children were determined with the C-ABT. This technique is considered reliable and is well accepted by the patients.
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http://dx.doi.org/10.1097/MPG.0000000000000954DOI Listing
March 2016

The course of anaemia in children and adolescents with Crohn's disease included in a prospective registry.

Int J Colorectal Dis 2015 Jan 30;30(1):51-6. Epub 2014 Oct 30.

Paediatric Gastroenterology and Hepatology, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium,

Aim: The aim of this study is to determine the prevalence and evolution of anaemia in prospectively followed children and adolescents diagnosed with Crohn's disease (CD).

Methods: The BELCRO registry (inclusion May 2008-April 2010), describing current clinical treatment practice of children diagnosed with CD, provided data on age, height, body mass index (BMI), paediatric Crohn's disease activity index (PCDAI), therapy and haemoglobin (Hb) at diagnosis 12 and 24 months follow-up. Anaemia was defined as Hb < -2 sd, while severe anaemia was defined as Hb < -4 sd. Patients were classified as child ≤13 and adolescent >13 years of age.

Result: Ninety-six were included, 13 dropped out due to insufficient Hb data (37 females/46 males; median age 13.3 years, range 2.2-17.8 years). At diagnosis, the median Hb sd was -2.66 (-8.4; 1.07) and was correlated with the PCDAI (p = 0.013). At diagnosis, 51/83 (61%) were anaemic and all had active disease. Hb z-score significantly improved (p < 0.0001) but 26/68 (38%) remained anaemic at 12 months and 29/76 (38%) at 24 months of follow-up. The correlation to the PCDAI disappeared. At 24 months, children were more likely to be anaemic. There was no difference in iron dose nor duration of iron supplements between children and adolescents. Iron treatment was more readily given to patients presenting with anaemia. Hb did not differ between patients with (n = 28) or without iron supplements. Half of the patients with persisting anaemia were given iron supplements, of which, only three were given intravenously.

Conclusion: Anaemia remains an important extra-intestinal manifestation of CD in children. Physicians, lacking optimal treatment strategies, undertreat their patients.
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http://dx.doi.org/10.1007/s00384-014-2042-4DOI Listing
January 2015

An extensively hydrolysed rice protein-based formula in the management of infants with cow's milk protein allergy: preliminary results after 1 month.

Arch Dis Child 2014 Oct 9;99(10):933-6. Epub 2014 Jun 9.

Universitair KinderZiekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

Background: Guidelines recommend extensively hydrolysed cow's milk protein formulas (eHF) in the treatment of infants diagnosed with cow's milk protein allergy (CMPA). Extensively hydrolysed rice protein infant formulas (eRHFs) have recently become available, and could offer a valid alternative.

Methods: A prospective trial was performed to evaluate the clinical tolerance of a new eRHF in infants with a confirmed CMPA. Patients were followed for 1 month. Clinical tolerance of the eRHF was evaluated with a symptom-based score (SBS) and growth (weight and length) was monitored.

Results: Thirty-nine infants (mean age 3.4 months, range 0.5-6 months) diagnosed with CMPA were enrolled. All infants tolerated the eRHF and experienced a normal growth.

Conclusions: In accordance with current guidelines, this eRHF is tolerated by more than 90% of children with proven CMPA with a 95% CI, and is an adequate alternative to cow's milk-based eHF.

Trial Registration Number: ClinicalTrials.gov NCT01998074.
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http://dx.doi.org/10.1136/archdischild-2013-304727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173818PMC
October 2014

Safety and tolerance of a new extensively hydrolyzed rice protein-based formula in the management of infants with cow's milk protein allergy.

Eur J Pediatr 2014 Sep 12;173(9):1209-16. Epub 2014 Apr 12.

Department of Pediatrics, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium,

Unlabelled: Guidelines recommend the use of extensively hydrolyzed cow's milk protein-based formulas (eHF) in the treatment of infants with cow's milk protein allergy (CMPA). Extensively hydrolyzed rice protein infant formula (eRHF) has recently become available and could offer a valid alternative. A prospective trial was performed to evaluate the hypo-allergenicity and safety of a new eRHF in infants with a confirmed CMPA. Patients were fed the study formula for 6 months. Clinical tolerance of the eRHF was evaluated with a symptom-based score (SBS) and growth (weight and length) was monitored. Forty infants (mean age, 3.4 months; range, 1-6 months) with CMPA confirmed by a food challenge were enrolled. All infants tolerated the eRHF and the SBS significantly decreased as of the first month of intervention. Moreover, the eRHF allowed a catch-up to normal weight gain as of the first month as well as a normalization of the weight-for-age, weight-for length, and BMI z-scores within the 6-month study period.

Conclusion: In accordance with current guidelines, this eRHF was tolerated by more than 90 % of children with proven CMPA with a 95 % confidence interval. This eRHF is an adequate and safe alternative to cow milk-based eHF.
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http://dx.doi.org/10.1007/s00431-014-2308-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134482PMC
September 2014

Esophageal impedance baseline is age dependent.

J Pediatr Gastroenterol Nutr 2013 Oct;57(4):506-13

*Department of Pediatrics, University of Insubria, Varese, Italy †UZ Brussel, Vrije Universiteit Brussel, Brussels ‡Systems and Modeling Unit, Montefiore Institute, University of Liege, Belgium §University of Naples "Federico II," Naples, Italy ||King Hussein Medical Center, Amman, Jordan.

Objective: Esophageal impedance (multichannel intraluminal impedance [MII]) baseline (impedance baseline [IB]) has been recently considered to be related to esophageal integrity. The aim of this study was to analyze the age effect on IB in a large population of pediatric patients.

Design: A total of 816 children with symptoms of gastroesophageal reflux and submitted to MII were included. Mean IB was automatically calculated in the different MII channels (Chs) throughout 24-hour tracings by the specific software without removing any episode of increased/decreased IB. Acid and nonacid reflux parameters and age subgroups analysis were performed. Unpaired t test, Spearman rank correlation, polynomial and regression plot, multiple regression analysis, factorial analysis of variance, and the least mean squares method were used for statistical analysis and age-related percentile curves. P < 0.05 was considered as statistically significant.

Results: Mean IB was significantly (P < 0.001) lower in younger compared with older children up to 48 months. The mean increase of IB per month was 2.9 Ω in Ch 1 and 2.3 Ω in Ch 6, but much higher in the first 36 months of life (47.5 Ω in Ch 1 and 29.9 Ω in Ch 6, respectively). From 48 months onward, there was no significant increase of the mean IB (P = 0.73). In the multiple regression analysis, only age and reflux index (but no other reflux parameters) significantly correlated with IB. Distal IB was significantly (P < 0.05) lower in patients with esophagitis and in subjects taking proton pump inhibitors compared with subjects off (any) treatment. Percentiles of IB in proximal and distal Chs were provided according to different age groups.

Conclusions: IB is significantly lower in infants (especially in the first months of life) compared with older children. Low IB in both proximal and distal esophagus in young infants may be related to anatomical and functional difference other than the presence of esophagitis.
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http://dx.doi.org/10.1097/MPG.0b013e31829b68cdDOI Listing
October 2013

Probiotics and IBD.

Acta Gastroenterol Belg 2013 Mar;76(1):15-9

Pediatric Gastroenterology, Hepatology and Nutrition, UZ Brussel, Belgium.

The pathophysiology of inflammatory bowel disease is still incompletely understood. While the development of the immune system and the establishment of the microflora take place during infancy young patients often have a more severe and extensive disease. The differences in composition and concentration of intestinal microbiota and aberrant immune responses towards the luminal bacteria prompted the concept of an 'ecological' approach to control the disease course. Probiotics, living, non pathogenic micro organisms with a beneficial effect on the host, and prebiotics, oligosaccharides promoting the growth of the beneficial microflora, have been studied to this effect. Results have so far been disappointing for Crohn's disease but encouraging for ulcerative colitis. An overview of studies using probiotics in adults or children and a perspective on specific pediatric issues is provided in this review.
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March 2013

Probiotics and prebiotics in pediatric diarrheal disorders.

Expert Opin Pharmacother 2013 Mar 13;14(4):397-409. Epub 2013 Feb 13.

Vrije Universiteit Brussel, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium.

Introduction: In pediatrics, prebiotics and/or probiotics are added to infant formula, mainly to prevent diseases such as diarrheal disorders. Probiotic food supplements and medication are frequently used in the treatment of diarrheal disorders. This paper reviews the recent published evidence on these topics.

Areas Covered: Relevant literature published using PubMed and CINAHL was collected and reviewed. Recent review papers were give special attention.

Expert Opinion: The addition of pre- and/or probiotics to infant formula seems not harmful, but the evidence for benefit is limited. Most probiotics are commercialized as food supplements, and therefore do not qualify for medication legislation. Worldwide, Saccharomyces boulardii is the only strain which is registered as "medication" in the majority of countries. Efficacy data can only be considered if performed with the commercialized product. Some products reduce the risk for antibiotic-associated diarrhea and reduced the duration of acute infectious diarrhea with about 24 h. Overall, data in the other indications (inflammatory bowel disease, irritable bowel syndrome) are disappointing, although there are some recent promising results. The use of food supplements as medication opens the discussion to create a category of "medical food."
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http://dx.doi.org/10.1517/14656566.2013.771632DOI Listing
March 2013

Effect of proton pump inhibition on acid, weakly acid and weakly alkaline gastro-esophageal reflux in children.

World J Pediatr 2013 Feb 7;9(1):36-41. Epub 2013 Feb 7.

University Children's Hospital, University Medical Centre, Ljubljana, Slovenia.

Background: The effect of proton pump inhibitors on the characteristics of gastroesophageal reflux (GER) in children and adolescents was evaluated.

Methods: Twenty-one children and adolescents with symptoms suggesting GER disease (GERD) underwent upper endoscopy and a 24-hour multichannel intraluminal impedance/pH (MII-pH) monitoring before and at the end of 2 months of therapy with proton pump inhibitors (PPIs).

Results: Fourteen (67%) patients reported clinically relevant symptom improvement after 2 months of PPIs intake. At the first endoscopy, 8 (38%) patients had macroscopic signs of reflux esophagitis; after two months of therapy, 6/8 (75%) patients had a complete mucosal recovery. There was a significant reduction in the total percentage of mean acid reflux time (from 13.1% to 3.8%), and the De Meester score dropped to normal (from 46.4 to 13.1). The mean number of acid refluxes decreased significantly from 48 to 15 per 24 hours, while inversely, the mean number of weakly acid refluxes increased significantly from 26 to 64 per 24 hours. PPI therapy did not affect the total number of reflux episodes, the number of liquid and mixed refluxes, the duration of esophageal bolus exposure and proximal extent of the reflux.

Conclusions: In children and adolescents with GERD, PPIs do not affect the total number of reflux episodes. PPIs only decrease the acidity of refluxate. Nevertheless, the majority of patients with typical reflux symptoms may report symptom improvement. Esophagitis can be healed after PPI treatment. The treatment of weakly acid and weakly alkaline reflux remains a challenge for physicians in the future.
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http://dx.doi.org/10.1007/s12519-013-0405-5DOI Listing
February 2013

Outcomes of endoscopy and novel pH-impedance parameters in children: is there a correlation?

J Pediatr Gastroenterol Nutr 2013 Feb;56(2):196-200

Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital AMC, Amsterdam, The Netherlands.

Objectives: Discordance exists between outcomes of endoscopy, multichannel intraluminal impedance monitoring (pH-MII), MII baselines, and gastroesophageal reflux symptoms. The aim of the present study was to determine the association between endoscopy, pH-MII and MII baselines, in children with gastroesophageal reflux symptoms.

Methods: Endoscopies were graded for reflux esophagitis (RE). Biopsies of the distal esophagus were assessed for signs suggestive of esophagitis. Reflux index (RI), symptom association probability (SAP), number of reflux episodes, and mean baseline values were calculated. pH-MII was considered positive in children when RI was ≥ 3% and/or SAP was ≥ 95% and for infants when RI was ≥ 10% and/or SAP was ≥ 95%. Baselines were manually calculated and compared with an automated analysis. For MII baselines, patients were divided in 3 groups: normal endoscopy and negative overall pH-MII; normal endoscopy and an overall positive pH-MII; and RE.

Results: A total of 26 children and 14 infants were included, median age: 26.5 months (2 months-16.2 years). Thirteen (32.5%) had RE. A significant negative association was found for RI and MII baselines (P = 0.009) and between SAP and RE (P = 0.039, odds ratio 1.018). MII baseline values were predictive for neither conventional pH-MII parameters nor RE. Manual analysis and automated calculation of MII baselines showed a perfect correlation. Distal MII baselines were significantly lower in children with a positive overall pH-MII outcome compared with the proximal esophagus (P = 0.049). No significant changes were found in baselines among the different groups 1 to 3.

Conclusions: Acid-related parameters are significantly related to MII baselines. A perfect correlation between manual- and automated analysis of MII baselines was found. Large prospective studies are needed to confirm the exact role of endoscopy and MII baselines.
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http://dx.doi.org/10.1097/MPG.0b013e31827167e2DOI Listing
February 2013

Gastroesophageal reflux evaluation in patients affected by chronic cough: Restech versus multichannel intraluminal impedance/pH metry.

Laryngoscope 2013 Apr 28;123(4):980-4. Epub 2012 Sep 28.

Department of Pediatrics, UZ Brussel, Brussels, Belgium.

Objectives/hypothesis: Oropharyngeal (OP) pH monitoring has been developed to detect supra-esophageal gastric reflux (SEGR). The results obtained with OP pH-metry and multichannel intraluminal impedance/pH monitoring (MII/pH) were compared.

Study Design: Diagnostic study.

Methods: Ten patients (age 46.33 ± 9.86 years) presenting with chronic coughing underwent simultaneous OP and MII/pH recording. A 2-minute interval was allowed between events detected with both techniques to be considered simultaneous.

Results: A total of 515 reflux episodes were recorded with MII/pH (acid: 181; weakly acid: 310; weakly alkaline: 24); 180 (35%) reached the highest impedance channel (hypo-pharynx); 74/180 (41%) were not related to a change in pH, according to the antimony electrode of the MII/pH catheter located at the upper esophageal sphincter. The OP monitoring measured 39 acid events; 17 (43.6%) were swallows according to MII, and 15 (38.5%) were not associated with MII or pH change. Only seven episodes were detected simultaneously with both techniques (1.3% for MII vs. 18% for OP; P = 0.0002). We found 49 pH-only refluxes at the pH sensor in the hypo-pharynx with MII/pH; only three (6.1%) correlated with OP reflux. Correlation in time between cough and reflux events was positive in 5/10 patients for MII (symptom index 5/10, symptom association probability 4/10), but in 0/10 patients according to OP pH metry.

Conclusion: OP pH metry detected less reflux episodes than MII/pH; 35% of the OP events were swallows according to impedance. Time correlation between cough and reflux could not be demonstrated with OP pH metry.
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http://dx.doi.org/10.1002/lary.23738DOI Listing
April 2013

Gastrointestinal manifestations of cow's milk protein allergy and gastrointestinal motility.

Acta Paediatr 2012 Nov 29;101(11):1105-9. Epub 2012 Aug 29.

UZ Brussel, Vrije Universiteit Brussel, Belgium.

Unlabelled: Cow's milk protein allergy (CMPA) may cause gastrointestinal motility disorders. Symptoms of both conditions overlap and diagnostic tests do not reliably differentiate between both. A decrease of symptoms with an extensive hydrolysate and relapse during challenge is not a proof of allergy, because hydrolysates enhance gastric emptying, a pathophysiologic mechanism of gastro-oesophageal reflux (GER). Thickened formula reduces regurgitation, and failure to do so suggests CMPA. A thickened extensive hydrolysate may induce more rapid improvement, but does not always differentiate between CMPA and GER. Different hypotheses are discussed: is the overlap between CMPA and functional disorders coincidence, or do both entities present with identical symptoms, or does the fact that symptoms are identical indicates that there is only one entity involved? Studies on the prevention of CMPA focused on 'at-risk families', and resulted in a decrease of CMPA and atopic dermatitis, but did not provide data on the incidence of GER.

Conclusion:   As long as there are no objective diagnostic tools to separate GER from CMPA, the physician has two options: first treat the most likely diagnosis, and switch if after 2-4 weeks there is no improvement, or treat both conditions with one intervention, what will not result in a diagnosis.
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http://dx.doi.org/10.1111/j.1651-2227.2012.02808.xDOI Listing
November 2012

Esophageal impedance baseline according to different time intervals.

Eur J Med Res 2012 Jun 19;17:18. Epub 2012 Jun 19.

Department of Pediatrics, Universitair KinderZiekenhuis Brussel, Vrije Unversiteit Brussel, Belgium.

Background: The impedance baseline has been shown to reflect esophageal integrity, and to be decreased in patients with esophagitis. However, different methods for the determination of the impedance baseline have not been compared.

Methods: The median impedance baseline was calculated in 10 consecutive multichannel intraluminal impedance recordings in children with non-erosive reflux disease. All children underwent an endoscopy with a biopsy as part of the clinical work-up to exclude esophagitis. The impedance baseline was obtained both by including and excluding all impedance episodes (IE; reflux, swallows and gas episodes) during the full recording, and during the first 1-minute period without an IE every hour (method 1), every 2 hours (method 2) or every 4 hours (method 3). The impedance baseline obtained during the full recording was set at 100%, and the variation (difference in impedance baseline for the different methods) and variability (difference in impedance baseline during one analysis period) were assessed.

Results: None of the participants had esophagitis. The mean difference over the six channels between the impedance baseline over the total recording with and without IE was approximately 2.5%, and comparable for each channel (range 0.47% to 5.55%). A mean of 1,028 IEs were excluded in each tracing, and it took between 4 and 24 hours to delete all events in one tracing. The difference in the impedance baseline obtained with and without IEs was mainly caused by the gas episodes in the upper channels and swallows in the lower channels. The median impedance baseline according to the three one-minute analysis methods was comparable to the median impedance baseline according to the 24 hour analysis.

Conclusions: The automatic determination of the median impedance baseline over the total tracing including IEs is an adequate method. In isolated tracings with numerous IEs, the calculation of the median impedance baseline over one minute every 4 hours is an alternative option. Companies should develop software to calculate the median impedance baseline during the whole registration deleting all IEs for the analysis.
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http://dx.doi.org/10.1186/2047-783X-17-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489845PMC
June 2012
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