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Top 30 Papers, 1982–2012

Journal of Pediatric Gastroenterology & Nutrition: November 2012 - Volume 55 - Issue 5 - p 463–474
doi: 10.1097/MPG.0b013e31826f3916
Special Feature

“In the beginning….” Lebenthal E, Rossi E, Lee PC. Pediatric gastroenterology and nutrition--quo vadis? J Pediatr Gastroenterol Nutr 1982;1(1):1–2. On the occasion of the 30th anniversary of the Journal of Pediatric Gastroenterology and Nutrition (JPGN), the following papers were selected by colleagues around the world as the most important publications in our journal from the past 30 years. The selection process combined input from former JPGN Editors-in-Chief, the Publication Committees and leadership of NASPGHAN and ESPGHAN, the entire current JPGN Editorial Board, and many of our readers. We are proud of the significant impact and expanding influence of our journal in promoting the growth, scope and scientific advancements in pediatric gastroenterology, hepatology, and nutrition.

Melvin B. Heyman, MD, MPH, NASPGHAN Editor

David Branski, MD, ESPGHAN Editor

Haffen K, Kedinger M, Simon Assmann P. Mesenchyme-dependent differentiation of epithelial progenitor cells in the gut. J Pediatr Gastroenterol Nutr 1987;6(1):14–23.

State-of-the-art review of intestinal embryogenesis focused on mesoderm-derived stromal tissue, foreshadowing more recent work on the genetic control of embryogenesis.


The digestive tract and the gut as a paradigm represents an attractive system for the study of mechanisms involved in the differentiation of two types of progenitor cells: the endodermal cells during embryonic life and the undifferentiated crypt cells during epithelial renewal of the adult intestine. The morphological and functional events that accompany the differentiation processes of progenitor cells into the polarized epithelial cell types characteristic of the intestine appear comparable in both situations (1,2). During organogenesis of the gut, histological observations underlined a close relationship between epithelial cells and their underlying mesenchymal cells (3,4). Developmental biologists have emphasized experimentally the importance of interactions between the endoderm and mesenchyme during organogenesis of the digestive tract. In the adult intestine, gastroenterologists have focused their attention on a specialized mesenchymal cell type (the pericryptal fibroblasts) that displays, like epithelial cells, proliferative activities and migrating properties. The aim of this review is to provide current knowledge on epithelial-mesenchymal interactions during ontogenesis of the digestive tract and also to relate some experiments supporting the view of the perpetuation of epithelial-mesenchymal interactions beyond embryonic life.

Vargas JH, Ament ME, Berquist WE. Long-term home parenteral nutrition in pediatrics: ten years of experience in 102 patients. J Pediatr Gastroenterol Nutr 1987;6(1):24–32.

Representative publication from the UCLA experience, in which Dr Marvin Ament pioneered home parenteral nutrition. Documents the feasibility of a TPN program in a large pediatric patient population.


One hundred two pediatric patients received all or part of their nutritional needs parenterally at home during the past decade. All received total parenteral nutrition (TPN) at night during an 8- to 12-h infusion. Patients with short bowel syndrome (33%), inflammatory bowel disease (23%), chronic intractable diarrhea (15%), chronic idiopathic intestinal pseudo-obstruction syndrome (10%), and malignancy (10%) made up the largest groups. The mean duration of parenteral support was 735 days (range, 90–3650 days); the mean number of catheters per patient was 2.1 (range, 1–8). Twenty-one patients continue to receive full or partial home TPN: four for more than 10 years and seven for more than 5 years. Fifty-one no longer require it and have had healing of mucosa or bowel adaptation. Complications related to administration of fluid and electrolytes were quite rare. Biotin deficiency was recognized once. Thirty-one have died, but only 13 deaths were related to TPN. Sepsis in nine and liver failure in two were the most common causes of death in the TPN-related group. Three of 21 still on home TPN have graduated either from high school or college. All but one of the school age children attend regular school; one attends a school for the medically disabled, another attends a school for the mentally gifted.

Vandenplas Y, Sacr-Smits L. Continuous 24-hour esophageal pH monitoring in 285 asymptomatic infants 0–15 months old. J Pediatr Gastroenterol Nutr 1987;6(2):220–4.

Essential study documenting reference values for future pH probe studies and for physiologic gastroesophageal reflux in infants.


A continuous 24-h esophageal pH monitoring was performed in 283 asymptomatic infants between 5 days and 15 months old. Several parameters (reflux index, duration of the longest reflux episode, number of reflux episodes in 24 h, number of reflux episodes greater than 5 min in 24 h) were studied in different groups of infants according to their age: 5–15 days old, 24–37 days old, 3.5–4.5 months old, 5.5–6.5 months old, 7.5–8.5 months old, 14–16 months old. For all parameters we obtained statistically significant different results in infants younger and older than 4 months. The 24-h esophageal pH monitoring is an investigation technique in physiological circumstances in order to establish normal ranges for gastroesophageal reflux in asymptomatic infants.

Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, Griffiths AM, Katz AJ, Grand RJ, Boyle JT. Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr 1991;12(4):439–47.

Validation of the Pediatric Crohn's Disease Activity Index (PCDAI), establishing a quantitative parameter for drug and other treatment trials.


Clinical and laboratory observations of 133 children and adolescents with Crohn's disease were used to validate an index of severity of illness previously developed by a group of senior pediatric gastroenterologists at a research forum in April 1990. This pediatric Crohn's disease activity index (PCDAI) included (a) subjective reporting of the degree of abdominal pain, stool pattern, and general well-being; (b) presence of extraintestinal manifestations, such as fever, arthritis, rash, and uveitis; (c) physical examination findings; (d) weight and height; and (e) hematocrit, erythrocyte sedimentation rate, and serum albumin. Independent evaluation of each patient by two physician-observers was performed at the time of a visit, and each physician completed a PCDAI index and a modified Harvey-Bradshaw index and made a “global assessment” of disease activity as none, mild, moderate, or severe. Excellent interobserver agreement was noted for the PCDAI, modified Harvey-Bradshaw index, and global assessment. There was a strong correlation between global assessment and both the PCDAI or modified Harvey-Bradshaw. Increasing PCDAI scores were noted with increasing disease severity, and significant differences in scores were noted between the severity groups. We propose that the PCDAI could be used in multicenter projects to facilitate patient stratification by disease severity and that longitudinal PCDAI scores might provide a numerical measure of response to therapeutic regimens.

Dalzell AM, Shepherd RW, Dean B, Cleghorn GJ, Holt TL, Francis PJ. Nutritional rehabilitation in cystic fibrosis: a 5 year follow-up study. J Pediatr Gastroenterol Nutr 1992;15(2):141–5.

Documentation of the effectiveness of nutrition support via gastrostomy tube in children with cystic fibrosis.


Previously, we reported catch-up weight gain, growth, and improved lung function in a group of malnourished cystic fibrosis (CF) children receiving aggressive nutritional supplementation for 1 year compared with a forced expiratory volume in 1 s (FEV1)-, height-, and sex-matched comparison group receiving standard therapy. To evaluate long-term effects, the clinical progress of both groups has been studied over a 5 year period. The supplemented group (n = 10) received supplements for a median of 1.35 years to achieve nutritional rehabilitation. Compared with the nonsupplemented group (n = 14), the previously supplemented group had lower mortality (2 vs. 4, N.S.) and significantly greater weight and height z scores at 4 and 5 years. The progression of pulmonary function abnormalities as measured by FEV1 and forced vital capacity (FVC) slopes was greater at 3 years in the nonsupplemented group (FEV1, p less than 0.05) but no significant differences in rates of deterioration of pulmonary function were seen after 5 years in the two groups of survivors. We conclude that intensive nutritional support for 1 year has both short- and long-term effects on nutrition and growth, still evident some years after the cessation of this therapeutic modality. Supplementation for periods of longer than 1 year may produce greater gains and possibly prolong the improvement in pulmonary function observed in the earlier study.

Silveira TR, Salzano FM, Donaldson PT, Mieli Vergani G, Howard ER, Mowat AP. Association between HLA and extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 1993;16(2):114–7.

The first paper to propose a link between HLA and biliary atresia,


The etiopathogenesis of extrahepatic biliary atresia (EHBA) remains undefined. There are clinical and pathological suggestions supporting the idea that EHBA could consist of at least two forms: the congenital (embryonic or fetal) and the acquired (perinatal) types. To test the hypothesis that susceptibility to this disease would be influenced by host genetic factors, we studied the human leukocyte antigen (HLA) system in 55 patients with and without major extrahepatic congenital anomalies. We found, especially in those without associated malformations, a significantly higher frequency of HLA-B12, of haplotypes A9-B5 and A28-B35, and of their disequilibrium values, as compared with the 8th International Histocompatibility Workshop controls. This study suggests that immunogenetic factors may play a role in determining susceptibility to EHBA, and the different HLA frequencies in those with and without anomalies lend support to the hypothesis that biliary atresia may be an etiologically heterogeneous disorder

Bhutta ZA, Hendricks KM. Nutritional management of persistent diarrhea in childhood: a perspective from the developing world. J Pediatr Gastroenterol Nutr 1996;22(1):17–37.

An encyclopedic review of diarrheal disease as one of the most common causes of infant mortality worldwide.


Nearly a decade ago the World Health Organization (WHO) estimated that there were approximately 700 million episodes of diarrhea annually among children under 5 years old in developing countries, resulting in 4.6 million deaths. Despite vast improvement in the management of acute diarrheal disorders and oral rehydration therapy, it is estimated that diarrheal diseases still account for up to 30% of all hospital admissions in developing countries. A recent review of the global status of diarrhea indicates that although there has been a general reduction in mortality rates due to acute dehydration, there has been little decrease in the incidence of diarrheal disorders. Of the various aspects of childhood diarrheal disorders, in recent years persistent diarrhea (PD) has assumed special importance for health workers and program planners.

Louis Jacques O, Olson AD. Cost-benefit analysis of interferon therapy in children with chronic active hepatitis B. J Pediatr Gastroenterol Nutr 1997;24(1):25–32.

Cost–benefit investigation of conventional therapy in children with chronic hepatitis B, a model for subsequent studies.


Background: alpha-Interferon is widely accepted for treatment of adults with chronic hepatitis B, but its use remains limited in children, partly because of questions regarding its cost effectiveness. The aim of this study was to evaluate the cost effectiveness of alpha-interferon for children with chronic active hepatitis B.

Methods: We estimated the cost per year of life saved by alpha-interferon therapy for three cohorts of patients with chronic active hepatitis B treated at 2, 12, or 25 years of age. We assumed that only patients with active viral replication would be treated and that alpha-interferon would prevent cirrhosis and hepatocellular carcinoma in a portion of the population treated. We calculated costs per year of life saved. Medical costs and years of life saved were discounted at 5% per year.

Results: With a 30% response rate to alpha-interferon, there was a net savings in both money and lives in the children's group with a minimal cost per year of life saved for adolescents ($510) and adults ($934). Years of life saved per person were greater for children (1.0) than adults (0.5). With a 6% response rate, estimated costs per year of life saved for children ($5,700) were one-fourth of those of adults ($22,100).

Conclusions: alpha-interferon therapy for patients with chronic active hepatitis B is cost effective. Alpha-Interferon is more cost effective in toddlers than adults because of the smaller dose required and the greater increase in life expectancy of children.

Dellert SF, Nowicki MJ, Farrell MK, Delente J, Heubi JE. The 13C-xylose breath test for the diagnosis of small bowel bacterial overgrowth in children. J Pediatr Gastroenterol Nutr 1997;25(2):153–8.

This report demonstrated the reliability of the 13C-xylose breath test in children with small intestinal bacterial overgrowth.


Background: We evaluated the clinical utility of the 13C-xylose breath test for the diagnosis of small bowel bacterial overgrowth in children.

Methods: To determine the optimal dose of 13C-xylose, 29 healthy children, 3 to 12 years old, were randomly assigned to receive one of three doses of 13C-xylose (10, 25, or 50 mg). After an overnight fast, the oral dose of 13C-xylose was administered, and breath samples were collected every 30 minutes for 4 hours. Samples were analyzed for 13CO2 by gas chromatography with mass spectrometry. Using the 50 mg dose, we then performed nine breath tests with concurrent duodenal bacterial cultures in 6 children, 3 to 12 years old, with short-bowel syndrome (n = 2), immunodeficiency states (n = 1), and motility disorders (n = 3).

Results: Excretion of 13CO2 in breath peaked at 2.5 hours in all three control groups. The 50-mg dose produced the highest median peak and the smallest range of 13CO2 excretion in breath within each time period. The time of peak 13CO2 excretion in breath varied among the diseased children; however, the six patients with small-bowel bacterial overgrowth (2 × 10(5)-3.5 × 10(5) gram negative rods) all had peak 13CO2 that exceeded the maximum breath 13CO2 level in breath of the control subjects at the corresponding time period (100% sensitivity). Of the three patients with negative cultures, two had negative breath test results and one had positive results (67% specificity). One subject had normalization of both duodenal culture and breath test results after antibiotic treatment of small-bowel bacterial overgrowth.

Conclusions: Our preliminary results suggest that with a dose of 50 mg 13C-xylose, breath test results reliably predict small-bowel bacterial overgrowth in susceptible children.

Aggett PJ, Bresson J, Haschke F, Hernell O, Koletzko B, Lafeber HN, Micheli J, Rey J, Salazar dS, Weaver LT. Recommended dietary allowances (RDAs), recommended dietary intakes (RDIs), recommended nutrient intakes (RNIs) and population reference intakes (PRIs) are not “recommended intakes.” J Pediatr Gastroenterol Nutr 1997;25(2):236–41.

Established the basis for nutrient recommendations for infant formulae followed by subsequent European regulations and reports.


Recommended intakes of nutrients are hypothetical, perhaps even mythical, concepts used as yardsticks for the assessment of dietary surveys and food statistics; to provide guidance on appropriate dietary composition and meal provision; or for food labelling. The United States, Canada, and European countries, including The Netherlands, Germany, United Kingdom, France, and the Nordic countries, publish their own standards, and recently the European Union's Scientific Committee for Food has produced its own report, Nutrient and Energy Intakes for the European Community. Each committee has created its own terminology; and the many terms and their meanings have caused considerable confusion, which is exacerbated by the use of recommendations for purposes for which they were not intended. Many paediatricians and other health professionals think that the recommendations provide a reliable basis for the specific advice that they give families on the feeding of neonates, infants, children, and adolescents. Unfortunately, many users of these statistical terms do not appear to appreciate their real meanings and uses as expressed in the full reports: Instead they base their interpretation on the summary tables alone. They have therefore misunderstood the meaning of reference values, the underpinning assumptions, or the individual groups at which they are aimed. In addition, government agencies and industry are equally culpable in misusing reference values with their own objectives in mind, which are most often to increase the values rather than to reduce them. Finally, additional confusion arises from a failure to understand that, in contrast to labelling reference values, recommended intakes are not policy recommendations per se, but a set of reference standards developed by nutritional scientists that may be used to inform and to implement a sound public health policy. These are the points that we would like to clarify in this commentary.

Goulet OJ, Brousse N, Canioni D, Walker Smith JA, Schmitz J, Phillips AD. Syndrome of intractable diarrhoea with persistent villous atrophy in early childhood: a clinicopathological survey of 47 cases. J Pediatr Gastroenterol Nutr 1998;26(2):151–61.

Redefined “intractable diarrhea of infancy” according to histological criteria applied in future studies.


Background: The syndrome of intractable diarrhoea of infancy is heterogeneous and includes several diseases with diverse aetiologies. This study determines whether diagnostic categories can be defined on the basis of clinicopathological analysis.

Methods: European Society of Paediatric Gastroenterology, Hepatology and Nutrition members were surveyed to identify cases of intractable diarrhoea with persisting small intestinal enteropathy. A retrospective clinicopathological analysis was performed on cases showing life-threatening diarrhoea within the first 24 mo of life and requiring total parenteral nutrition, which were characterized by persistent villous atrophy, and resistance to therapy.

Results: Forty-seven infants were identified with intractable diarrhoea. Villous atrophy was of varying degrees with (group I, n = 24) or without (group II, n = 18) lamina propria mononuclear cell infiltration. Group I presented later, had gut autoantibodies, and a higher prevalence of protein-losing enteropathy; a subset (group Ia, n = 12) also had extraintestinal symptoms of autoimmunity associated with a later onset of larger volume diarrhoea. Group II presented early; 8 cases (group IIa) had phenotypic abnormalities and a low birth weight; the remaining 10 (group IIb) showed mild-to-moderate villous atrophy, epithelial tufting, and abnormal crypts. Group III included five patients in whom no specific features were recognised. Twenty-one (45%) died at a median age of 24 months, 20 (43%) remained dependent on parenteral (n = 16) or enteral tube (n = 4) feeding, 4 (9%) received elimination diets plus other therapies, and 2 (4%) were lost to follow-up.

Conclusions: Clinicopathological analysis allowed distinct disease groups to be identified, allowing a provisional classification to be made. This straightforward approach forms a basis for future research in this exceptionally difficult paediatric condition.

Liacouras CA, Wenner WJ, Brown K, Ruchelli E. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr 1998;26(4):380–5.

As noted in the accompanying editorial by Dr Glenn Furuta, this was the first report to document the efficacy of oral corticosteroid therapy for eosinophilic esophagitis.


Background: The histologic appearance of esophageal eosinophils has been correlated with esophagitis and gastroesophageal reflux disease in children. Esophageal eosinophilia that persists despite traditional antireflux therapy may not represent treatment failure, but instead may portray early eosinophilic gastroenteritis or allergic esophagitis. In this study, a series of pediatric patients with severe esophageal eosinophilia who were unresponsive to aggressive antireflux therapy were examined and their clinical and histologic response to oral corticosteroid therapy assessed.

Methods: Of 1809 patients evaluated prospectively over 2.5 years for symptoms of gastroesophageal reflux, 20 had persistent symptoms and esophageal eosinophilia, despite aggressive therapy with omeprazole and cisapride. These patients were treated with 1.5 mg/kg oral methylprednisolone per day, divided into twice-daily doses for 4 weeks. All patients underwent clinical, laboratory, and histologic evaluation before and after treatment.

Results: Histologic findings in examination of specimens obtained in pretreatment esophageal biopsies in children with primary eosinophilic esophagitis indicated significantly greater eosinophilia (34.2+/−9.6 eosinophils/high-power field [HPF]) compared with that in children with gastroesophageal reflux disease who responded to medical therapy (2.26+/−1.16 eosinophils/HPF; p < 0.001). After corticosteroid therapy, all but one patient with primary eosinophilic esophagitis had dramatic clinical improvement, supported by histologic examination (1.5 +/−0.9 eosinophils/HPF, p < 0.0001).

Conclusions: Pediatric patients in a series with marked esophageal eosinophilia and chronic symptoms of gastroesophageal reflux disease unresponsive to aggressive medical antireflux therapy had both clinical and histologic improvement after oral corticosteroid therapy.

Gronlund MM, Lehtonen OP, Eerola E, Kero P. Fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery. J Pediatr Gastroenterol Nutr 1999;28(1):19–25.

First demonstration that infants born by vaginal versus C-section develop distinctively different microbiota.


Background: Newborn infants in modern maternity hospitals are subject to numerous factors that affect normal intestinal colonization--for example, cesarean delivery and antimicrobial agents. To study the duration of the effect of external factors on intestinal colonization, two groups of infants with different delivery methods were investigated.

Methods: The fecal flora of 64 healthy infants was studied prospectively. Thirty-four infants were delivered vaginally, and 30 by cesarean birth with antibiotic prophylaxis administered to their mothers before the delivery. The fecal flora was cultured on nonselective and selective media in infants 3 to 5, 10, 30, 60, and 180 days of age. Gastrointestinal signs were recorded daily by the mothers for 2 months.

Results: The fecal colonization of infants born by cesarean delivery was delayed. Bifidobacterium-like bacteria and Lactobacillus-like bacteria colonization rates reached the rates of vaginally delivered infants at 1 month and 10 days, respectively. Infants born by cesarean delivery were significantly less often colonized with bacteria of the Bacteroides fragilis group than were vaginally delivered infants: At 6 months the rates were 36% and 76%, respectively (p = 0.009). The occurrence of gastrointestinal signs did not differ between the study groups.

Conclusions: This study shows for the first time that the primary gut flora in infants born by cesarean delivery may be disturbed for up to 6 months after the birth. The clinical relevance of these changes is unknown, and even longer follow-up is needed to establish how long-lasting these alterations of the primary gut flora can be.

Thomson M, Kitching P, Jones A, Walker Smith JA, Phillips A. Are endoscopic biopsies of small bowel as good as suction biopsies for diagnosis of enteropathy? J Pediatr Gastroenterol Nutr 1999;29(4):438–41.

Justification of endoscopic compared with capsule biopsies.


Background: Endoscopy is increasingly used in paediatric practice for diagnosis of enteropathy, although the quality of grasp forceps-obtained biopsy specimens required for reliable diagnosis has been questioned in comparison with suction capsule biopsy specimens. This study prospectively compared the diagnostic suitability of grasp forceps biopsy versus suction biopsy in the same patient during the same procedure.

Methods: A double-port paediatric suction biopsy capsule was front-loaded onto an endoscope and directed to the fourth part duodenum-proximal jejunum for biopsy sampling. Subsequently, three grasp biopsy specimens were taken from the same region. All biopsies were coded, photographed, and measured for area, using computed morphometry. A single blinded histopathologist assessed sample adequacy for diagnosis. Twenty-nine patients were enrolled (age range, 8–185 months).

Results: On three occasions the suction capsule failed to fire, and on four occasions only one sample was obtained. Three grasp biopsy specimens were obtained on each occasion by endoscopy, and the first two were used for comparison with suction biopsy samples. Median total area of individual biopsy samples obtained by the two procedures was not different (21.3 vs. 22.5 mm2; P = 0.027). Muscularis mucosae was obtained more commonly with grasp biopsies (P < 0.001), and no difference was observed for the presence of three or more villus-crypt units, degree of haemorrhage, or optimal orientation. Two suction biopsy procedures and one grasp biopsy procedure were inadequate for diagnosis.

Conclusions: Endoscopic grasp biopsies are perfectly adequate for the assessment of small intestinal histology. In addition, endoscopy affords advantage in diagnosis of other upper gastrointestinal disease with avoidance of radiologic screening involved with the suction capsule technique.

Baker SS, Liptak GS, Colletti RB, Croffie JM, Di Lorenzo C, Ector W, Nurko S. Constipation in infants and children: evaluation and treatment. A medical position statement of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 1999;29(5):612–26.

NASPGHAN evidence-based clinical practice guideline, the first to use a systematic review of the literature, standardized grading of the evidence and a structured format for developing consensus. First of a series of authoritative guidelines in pediatric gastroenterology issued by NASPGHAN.


Background: Constipation, defined as a delay or difficulty in defecation, present for 2 or more weeks, is a common pediatric problem encountered by both primary and specialty medical providers.

Methods: The Constipation Subcommittee of the Clinical Guidelines Committee of the North American Society for Pediatric Gastroenterology and Nutrition has formulated clinical practice guidelines for the management of pediatric constipation. The Constipation Subcommittee, consisting of two primary care pediatricians, a clinical epidemiologist, and pediatric gastroenterologists, based its recommendations on an integration of a comprehensive and systematic review of the medical literature combined with expert opinion. Consensus was achieved through Nominal Group Technique, a structured quantitative method.

Results: The Subcommittee developed two algorithms to assist with medical management, one for older infants and children and the second for infants less than 1 year of age. The guidelines provide recommendations for management by the primary care provider, including evaluation, initial treatment, follow-up management, and indications for consultation by a specialist. The Constipation Subcommittee also provided recommendations for management by the pediatric gastroenterologist.

Conclusions: This report, which has been endorsed by the Executive Council of the North American Society for Pediatric Gastroenterology and Nutrition, has been prepared as a general guideline to assist providers of medical care in the evaluation and treatment of constipation in children. It is not intended as a substitute for clinical judgment or as a protocol for the management of all patients with this problem.

Guandalini S, Pensabene L, Zikri MA, Dias JA, Casali LG, Hoekstra H, Kolacek S, Massar K, Micetic Turk D, Papadopoulou A, de Sousa JS, Sandhu B, Szajewska H, Weizman Z. Lactobacillus GG administered in oral rehydration solution to children with acute diarrhea: a multicenter European trial. J Pediatr Gastroenterol Nutr 2000;30(1):54–60.

This multicenter European trial showed efficacy and safety of oral rehydration formula with added Lactobacillus GG in children with acute diarrhea. This study led to investigations of different patient subpopulations, types and content of probiotic strains, and delivery systems.


Background: The probiotic Lactobacillus GG is effective in promoting a more rapid recovery of acute, watery diarrhea in children with rotavirus enteritis. Very limited information is available, however, on the potential role of such agents in non-rotaviral diarrheal episodes. Furthermore, no evidence is available concerning the efficacy of Lactobacillus GG administered in the oral rehydration solution during oral rehydration therapy. A multicenter trial was conducted to evaluate the efficacy of Lactobacillus GG administered in the oral rehydration solution to patients with acute-onset diarrhea of all causes.

Methods: Children 1 month to 3 years of age with acute-onset diarrhea were enrolled in a double-blind, placebo-controlled investigation. Patients were randomly allocated to group A, receiving oral rehydration solution plus placebo, or group B, receiving the same preparation but with a live preparation of Lactobacillus GG (at least 10(10) CFU/250 ml). After rehydration in the first 4 to 6 hours, patients were offered their usual feedings plus free access to the same solution until diarrhea stopped.

Results: One hundred forty children were enrolled in group A, and 147 in group B. There were no differences at admission between the groups in age, sex, previous types of feeding, previous duration of diarrhea, use of antibiotics, weight, height, weight-height percentile, prevalence of fever, overall status, degree of dehydration, and percentage of in- versus outpatients. Duration of diarrhea after enrollment was 71.9 +/−35.8 hours in group A versus 58.3 +/−27.6 hours in group B (mean +/−SD; P = 0.03). In rotavirus-positive children, diarrhea lasted 76.6 +/− 41.6 hours in group A versus 56.2 +/− 16.9 hours in groups B (P < 0.008). Diarrhea lasted longer than 7 days in 10.7% of group A versus 2.7% of group B patients (P < 0.01). Hospital stays were significantly shorter in group B than in group A.

Conclusions: Administering oral rehydration solution containing Lactobacillus GG to children with acute diarrhea is safe and results in shorter duration of diarrhea, less chance of a protracted course, and faster discharge from the hospital.

Wizla Derambure N, Michaud L, Ategbo S, Vincent P, Ganga Zandzou S, Turck D, Gottrand F. Familial and community environmental risk factors for Helicobacter pylori infection in children and adolescents. J Pediatr Gastroenterol Nutr 2001;33(1):58–63.

Original documentation of intrafamilial infection with Helicobacter pylori.


Background: The aim of the study was to identify familial and community environmental risk factors associated with Helicobacter pylori infection in a pediatric population.

Methods: Children requiring diagnostic upper endoscopy were included in the study during a 2-year period. During endoscopy, five gastric biopsies were performed for the histologic or bacteriologic diagnosis, or both, of H. pylori infection. Epidemiologic data collected by a questionnaire were analyzed using the chi-square test or Fisher test and stepwise logistic regression.

Results: The authors included 436 patients (242 boys), aged 2 days to 17.9 years (median, 2.7 years). H. pylori prevalence was 7.3%. Univariate analysis found H. pylori was more common in older patients (P < 0.00001), in children who had at least one parent born in a developing country (P < 0.02) or with a low socioeconomic status (P < 0.02), and in those living in crowded conditions (P < 0.02). Children whose mother worked at home were more frequently infected than children whose mother worked outside the home (P < 0.02). Attendance at nursery or school before the age of 6 years was not associated with infection. Logistic regression showed a strong association with H. pylori only for age and number of persons at home.

Conclusions: The source of H. pylori is intrafamilial rather than from a community, such as nursery and school attended at a young age. The number of persons in the home influences the infection status of children but not by the presence of the mother in home. These data suggest that H. pylori infection transmission occurs from siblings or the father rather than from mother.

Loening Baucke V. Polyethylene glycol without electrolytes for children with constipation and encopresis. J Pediatr Gastroenterol Nutr 2002;34(4):372–7.

Early documentation of polyethylene glycol in the treatment of constipation and encopresis in children.


Background: Children with functional constipation and encopresis benefit from behavior modification and from long-term laxative medication. Polyethylene glycol without electrolytes has become the first option for many pediatric gastroenterologists.

Methods: Twenty-eight children treated with polyethylene glycol without electrolytes were compared with 21 children treated with milk of magnesia to evaluate the efficiency, acceptability, side effects, and treatment dosage of polyethylene glycol in long-term treatment of functional constipation and encopresis. Children were rated as “doing well,” “improved,” or “not doing well,” depending on resolution of constipation and encopresis.

Results: At the 1-, 3-, 6-, and 12-month follow-ups, bowel movement frequency increased and soiling frequency decreased significantly in both groups. At the 1-month follow-up, children on polyethylene glycol were soiling more frequently (P < 0.01) and fewer were improved (P < 0.01). At the 3- and 6-month follow-ups, both groups had similarly improved. At the 12-month visit, 61% of children on polyethylene glycol and 67% of children on milk of magnesia were doing well. Children on polyethylene glycol soiled more frequently (P < 0.01). None refused polyethylene glycol, but 33% refused to take milk of magnesia. The mean initial treatment dosage of polyethylene glycol was 0.6 +/−0.2 g/kg daily. Polyethylene glycol had no taste, and no loss of efficacy occurred. Polyethylene glycol did not cause clinically significant side effects.

Conclusions: Polyethylene glycol without electrolytes is an alternative for long-term management of children with constipation and encopresis.

Turck D, Bernet J, Marx J, Kempf H, Giard P, Walbaum O, Lacombe A, Rembert F, Toursel F, Bernasconi P, Gottrand F, McFarland LV, Bloch K. Incidence and risk factors of oral antibiotic-associated diarrhea in an outpatient pediatric population. J Pediatr Gastroenterol Nutr 2003;37(1):22–6.

Prospective study that documented a relatively low incidence of antibiotic-associated diarrhea in an ambulatory pediatric population. An accompanying editorial by Dr Christina Surawicz discussed the need for cost–benefit studies of probiotics in targeted subpopulations.


Background: Little information is available on the epidemiologic characteristics of antibiotic-associated diarrhea (AAD) in children. The authors’ aim was to evaluate the incidence of AAD in an outpatient pediatric population and to identify risk factors.

Methods: Children aged 1 month to 15.4 years treated with oral antibiotics for a proven or suspected infection were enrolled from an ambulatory pediatric practice during an 11-month period. Parents recorded the daily frequency and characteristics of stools using a diary during the antibiotic treatment and for 1 week after it was stopped. An episode of diarrhea was defined by at least 3 soft or liquid stools/d for at least 2 consecutive days. Risk factors for AAD-age, type of antibiotic treatment, type of combined treatment, and site of infection-were analyzed.

Results: Of 650 children included, 11% had an episode of AAD, lasting a mean of 4.0 +/−3.0 days, beginning a mean of 5.3+/−3.5 days after the start of antibiotic treatment. No child was hospitalized because of AAD. The incidence of AAD was higher in children less than 2 years (18%) than in those more than 2 years (3%; P < 0.0001). The incidence of AAD was particularly high after administration of certain antibiotics (amoxicillin/clavulanate, 23%; P = 0.003 compared with other antibiotics). The type of combined treatment and site of infection did not influence the onset of AAD.

Conclusions: Antibiotic-associated diarrhea was common in these outpatient children, especially for those aged less than 2 years and after the prescription of certain antibiotics, particularly, the combination of amoxicillin/clavulanate.

Agostoni C, Axelsson I, Braegger C, Goulet O, Koletzko B, Michaelsen KF, Rigo J, Shamir R, Szajewska H, Turck D, Weaver LT. Probiotic bacteria in dietetic products for infants: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2004;38(4):365–74.

The first official document from ESPGHAN on the use of probiotics in infant formula. A subsequent publication on prebiotics was published later the same year (J Pediatr Gastroenterol Nutr 2004;39(5):465–73).


The consumption of nondigestible carbohydrates is perceived as beneficial by health professionals and the general public, but the translation of this information into dietary practice, public health recommendations, and regulatory policy has proved difficult.

Nondigestible carbohydrates are a heterogeneous entity, and their definition is problematic. Without a means to characterize the dietary components associated with particular health benefits, specific attributions of these cannot be made. Food labeling for “fiber” constituents can be given only in a general context, and the development of health policy, dietary advice, and education, and informed public understanding of nondigestible carbohydrates are limited.

There have, however, been several important developments in our thinking about nondigestible carbohydrates during the past few years. The concept of fiber has expanded to include a range of nondigestible carbohydrates. Their fermentation, fate, and effects in the colon have become a defining characteristic; human milk, hitherto regarded as devoid of nondigestible carbohydrates, is now recognized as a source for infants, and the inclusion of nondigestible carbohydrates in the diet has been promoted for their “prebiotic” effects.

Therefore, a review of the importance of nondigestible carbohydrates in the diets of infants and young children is timely. The aims of this commentary are to clarify the current definitions of nondigestible carbohydrates, to review published evidence for their biochemical, physiologic, nutritional, and clinical effects, and to discuss issues involved in defining dietary guidelines for infants and young children.

Moyer V, Freese DK, Whitington PF, Olson AD, Brewer F, Colletti RB, Heyman MB. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2004;39(2):115–28.

Recommendations for evaluation of cholestatic infants.


For the primary care provider, cholestatic jaundice in infancy, defined as jaundice caused by an elevated conjugated bilirubin, is an uncommon but potentially serious problem that indicates hepatobiliary dysfunction. Early detection of cholestatic jaundice by the primary care physician and timely, accurate diagnosis by the pediatric gastroenterologist are important for successful treatment and a favorable prognosis. The Cholestasis Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has formulated a clinical practice guideline for the diagnostic evaluation of cholestatic jaundice in the infant. The Cholestasis Guideline Committee, consisting of a primary care pediatrician, a clinical epidemiologist (who also practices primary care pediatrics), and five pediatric gastroenterologists, based its recommendations on a comprehensive and systematic review of the medical literature integrated with expert opinion. Consensus was achieved through the Nominal Group Technique, a structured quantitative method. The Committee examined the value of diagnostic tests commonly used for the evaluation of cholestatic jaundice and how those interventions can be applied to clinical situations in the infant. The guideline provides recommendations for management by the primary care provider, indications for consultation by a pediatric gastroenterologist, and recommendations for management by the pediatric gastroenterologist. The Cholestasis Guideline Committee recommends that any infant noted to be jaundiced at 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin. However, breast-fed infants who can be reliably monitored and who have an otherwise normal history (no dark urine or light stools) and physical examination may be asked to return at 3 weeks of age and, if jaundice persists, have measurement of total and direct serum bilirubin at that time. This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition on the evaluation of cholestatic jaundice in infants. The American Academy of Pediatrics has also endorsed these recommendations. These recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the care of all patients with this problem.

Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, Hoffenberg EJ, Horvath K, Murray JA, Pivor M, Seidman EG. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005;40(1):1–19.

Recommendations for current diagnosis and treatment of celiac disease, also forming the basis of a NASPGHAN CME lecture program for general practitioners.


Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in children and adolescents with gastrointestinal symptoms, dermatitis herpetiformis, dental enamel defects, osteoporosis, short stature, delayed puberty and persistent iron deficiency anemia and in asymptomatic individuals with type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective immunoglobulin (Ig)A deficiency and first degree relatives of individuals with celiac disease. The Celiac Disease Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has formulated a clinical practice guideline for the diagnosis and treatment of pediatric celiac disease based on an integration of a systematic review of the medical literature combined with expert opinion. The Committee examined the indications for testing, the value of serological tests, human leukocyte antigen (HLA) typing and histopathology and the treatment and monitoring of children with celiac disease. It is recommended that children and adolescents with symptoms of celiac disease or an increased risk for celiac disease have a blood test for antibody to tissue transglutaminase (TTG), that those with an elevated TTG be referred to a pediatric gastroenterologist for an intestinal biopsy and that those with the characteristics of celiac disease on intestinal histopathology be treated with a strict gluten-free diet. This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition on the diagnosis and treatment of celiac disease in children and adolescents.

Koletzko B, Baker S, Cleghorn G, Neto UF, Gopalan S, Hernell O, Hock QS, Jirapinyo P, Lonnerdal B, Pencharz P, Pzyrembel H, Ramirez Mayans J, Shamir R, Turck D, Yamashiro Y, Zong YD. Global standard for the composition of infant formula: recommendations of an ESPGHAN coordinated international expert group. J Pediatr Gastroenterol Nutr 2005;41(5):584–99

This paper provided the standard for the latest revision of the Codex Alimentarius, the world reference for lower and upper limit content of infant formula. The values adapted by the Codex largely derived from this publication.


The Codex Alimentarius Commission of the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) develops food standards, guidelines and related texts for protecting consumer health and ensuring fair trade practices globally. The major part of the world's population lives in more than 160 countries that are members of the Codex Alimentarius. The Codex Standard on Infant Formula was adopted in 1981 based on scientific knowledge available in the 1970 s and is currently being revised. As part of this process, the Codex Committee on Nutrition and Foods for Special Dietary Uses asked the ESPGHAN Committee on Nutrition to initiate a consultation process with the international scientific community to provide a proposal on nutrient levels in infant formulae, based on scientific analysis and taking into account existing scientific reports on the subject. ESPGHAN accepted the request and, in collaboration with its sister societies in the Federation of International Societies on Pediatric Gastroenterology, Hepatology and Nutrition, invited highly qualified experts in the area of infant nutrition to form an International Expert Group (IEG) to review the issues raised. The group arrived at recommendations on the compositional requirements for a global infant formula standard which are reported here.

Gupta SK, Fitzgerald JF, Kondratyuk T, HogenEsch H. Cytokine expression in normal and inflamed esophageal mucosa: a study into the pathogenesis of allergic eosinophilic esophagitis. J Pediatr Gastroenterol Nutr 2006;42(1):22–6.

An early study showing that IL-5 is involved in the pathogenesis of eosinophilic esophagitis.


Objectives: We studied the expression of cytokines and inflammatory cells in normal and inflamed esophageal mucosa of children with the aim of furthering our understanding of the pathophysiology of allergic eosinophilic esophagitis (AEE).

Methods: Controls and AEE patients (>or=15 eosinophils/high-power field on esophageal mucosal biopsies) between the ages of 1 and 18 years were recruited. Esophageal biopsies were obtained for histologic examination, immunohistochemical studies, and cytokine analysis.

Results: Eight controls (4 males; mean age 9.99 years) and 11 AEE patients (8 males; mean age 7.15 years) were studied. mRNA expression of interferon (IFN)-gamma, interleukin (IL)-4, IL-5, IL-13, eotaxin-1, eotaxin-2, eotaxin-3, and RANTES was studied. IFN-gamma and IL-5 expressions were significantly up-regulated in AEE patients compared with controls. Expressions of IL-4 and IL-13 were similar between AEE patients and controls. Eotaxin-1 expression was significantly up-regulated in AEE patients, whereas eotaxin-2 was up-regulated in controls. Expression of RANTES and eotaxin-3 was similar between the two groups. There was increased staining for mast cells in AEE patients compared with controls.

Conclusions: Our data suggests that AEE is primarily an IL-5 selective TH2 response, with a possible TH1 component, and a differential role of eosinophilic chemoattractants. The role of mast cells in the pathogenesis of AEE needs additional study.

Mackey AC, Green L, Liang L, Dinndorf P, Avigan M. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007;44(2):265–7.

This and subsequent updates (eg, Cucchiara S, et al. J Pediatr Gastroenterol Nutr 2009;48:257–67) informing all of us about the potential deadly risks associated with the use of infliximab in adolescent males with IBD.


Hepatosplenic T cell lymphoma (HSTCL) are rare cancers (approximately 100 published cases worldwide) and comprise 5% of peripheral T cell lymphomas. As of October 5, 2006, the FDA's Adverse Event Reporting System has received 8 cases of HSTCL in young patients using infliximab, a tumor necrosis factor-alpha blocking agent, to treat inflammatory bowel disease (6 of the 8 cases had a fatal outcome). All 8 patients were receiving concomitant immunosuppressant therapy (e.g., azathioprine, prednisone). It has not been established that infliximab had an exclusive or primary role in the pathogenesis of these HSTCL cases; however, it appears that patients using this product may be at greater risk for developing this rare lymphoma.

Pfefferkorn M, Burke G, Griffiths A, Markowitz J, Rosh J, Mack D, Otley A, Kugathasan S, Evans J, Bousvaros A, Moyer MS, Wyllie R, Oliva Hemker M, Carvalho R, Crandall W, Keljo D, Walters TD, LeLeiko N, Hyams J. Growth abnormalities persist in newly diagnosed children with Crohn disease despite current treatment paradigms. J Pediatr Gastroenterol Nutr 2009;48(2):168–74.

Effects of current treatment regimens on growth in children with Crohn disease.


Objectives: We analyzed growth outcomes in children newly diagnosed with Crohn disease and determined whether growth abnormalities persist despite current therapies.

Methods: Clinical and growth data were prospectively obtained on an inception cohort younger than 16 years old at diagnosis and Tanner I to III during the study.

Results: In all, 176 children (mean age 10.1 years; 65% male) with mild (33%) or moderate/severe (67%) disease at diagnosis were studied. Disease activity at 1 year was inactive/mild (89%) or moderate/severe (11%). First-year treatments included immunomodulators (60%), corticosteroids (77%), 5-aminosalicylates (61%), infliximab (15%), and enteral nutrition (10%). By 2 years, 86% had received immunomodulators and 36% infliximab. Mean height z scores at diagnosis, 1 year, and 2 years were −0.49 ± 1.2 standard deviations (SDs), −0.50 ± 1.2, and −0.46 ± 1.1, respectively. Of the subjects, 10%, 8%, and 6.5% had height z scores less than −2 SD at diagnosis, 1 year, and 2 years. A height velocity z score less than −1 SD was seen in 45% of subjects at 1 year and 38% at 2 years. The mean height velocity z score, however, increased between 1 and 2 years from −0.71 to 0.26 (P < 0.03). Corticosteroid use greater than 6 months in the first year was associated with abnormal height velocity at 1 year (adjusted odds ratio 4.5; 95% confidence interval [CI] 2.2–9.6). No statistically significant effect on height velocity z scores was noted when comparing those receiving or not receiving infliximab.

Conclusions: Growth delay persists in many children with CD following diagnosis, despite improved disease activity and the frequent use of immunomodulators and biologics. Additional strategies to improve growth outcomes require development.

Agostoni C, Braegger C, Decsi T, Kolacek S, Koletzko B, Michaelsen KF, Mihatsch W, Moreno LA, Puntis J, Shamir R, Szajewska H, Turck D, van Goudoever J. Breast-feeding: a commentary by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2009;49(1):112–25.

The current worldwide reference for feeding premature infants.


This medical position article by the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition summarises the current status of breast-feeding practice, the present knowledge on the composition of human milk, advisable duration of exclusive and partial breast-feeding, growth of the breast-fed infant, health benefits associated with breast-feeding, nutritional supplementation for breast-fed infants, and contraindications to breast-feeding. This article emphasises the important role of paediatricians in the implementation of health policies devised to promote breast-feeding. The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition Committee on Nutrition recognises breast-feeding as the natural and advisable way of supporting the healthy growth and development of young children. This article delineates the health benefits of breast-feeding, reduced risk of infectious diarrhoea and acute otitis media being the best documented. Exclusive breast-feeding for around 6 months is a desirable goal, but partial breast-feeding as well as breast-feeding for shorter periods of time are also valuable. Continuation of breast-feeding after the introduction of complementary feeding is encouraged as long as mutually desired by mother and child. The role of health care workers, including paediatricians, is to protect, promote, and support breast-feeding. Health care workers should be trained in breast-feeding issues and counselling, and they should encourage practices that do not undermine breast-feeding. Societal standards and legal regulations that facilitate breast-feeding should be promoted, such as providing maternity leave for at least 6 months and protecting working mothers.

Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, Sondheimer J, Staiano A, Thomson M, Veereman Wauters G, Wenzl TG, North American Society for Pediatric Gastroenterology Hepatology and Nutrition, European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 2009;49(4):498–547.

One of the most highly cited papers in JPGN, this revision of the original guideline published in 2001 provides state-of-the-art recommendations for diagnosis and treatment of GER and GERD in pediatric patients.


Objective: To develop a North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) international consensus on the diagnosis and management of gastroesophageal reflux and gastroesophageal reflux disease in the pediatric population.

Methods: An international panel of 9 pediatric gastroenterologists and 2 epidemiologists were selected by both societies, which developed these guidelines based on the Delphi principle. Statements were based on systematic literature searches using the best-available evidence from PubMed, Cumulative Index to Nursing and Allied Health Literature, and bibliographies. The committee convened in face-to-face meetings 3 times. Consensus was achieved for all recommendations through nominal group technique, a structured, quantitative method. Articles were evaluated using the Oxford Centre for Evidence-based Medicine Levels of Evidence. Using the Oxford Grades of Recommendation, the quality of evidence of each of the recommendations made by the committee was determined and is summarized in appendices.

Results: More than 600 articles were reviewed for this work. The document provides evidence-based guidelines for the diagnosis and management of gastroesophageal reflux and gastroesophageal reflux disease in the pediatric population.

Conclusions: This document is intended to be used in daily practice for the development of future clinical practice guidelines and as a basis for clinical trials.

Wirth S, Kelly D, Sokal E, Socha P, Mieli-Vergani G, Dhawan A, Lacaille F, Raymond AS, Olivier S, Taminau J. Guidance for clinical trials for children and adolescents with chronic hepatitis C. J Pediatr Gastroenterol Nutr 2011;52(2):233–7

ESPGHAN guideline in collaboration with the European Medicines Agency on treatment of hepatitis C in children; results of clinical trials.


Most children with chronic hepatitis C are infected vertically, have a low natural seroconversion rate, and carry a lifetime risk of cirrhosis and cancer. Affected children are usually asymptomatic, and histological findings are mild with a low risk of progression, although 5% develop significant liver disease in childhood. The use of combination treatment with pegylated interferon-α and ribavirin has changed the outcome and prognosis for this disease, with approximately 60% of children achieving sustained viral clearance. Combination therapy is not ideal for children because pegylated interferon is administered subcutaneously, impairs growth velocity, and both interferon and ribavirin have significant adverse effects that affect compliance. In addition, approximately 50% of children infected with genotype 1 do not respond to therapy. Thus, additional treatment options are required, including improvement in dosing, reduction in the length of treatment, and evaluation of new drugs, such as protease inhibitors, which could be more effective for patients infected with genotype 1. The primary goal of treatment is to eradicate the infection. The future clinical trial design should ensure that any new drugs demonstrate noninferiority to the present standard regimen in both children and adults. The measure for documenting substantial improvement above present therapy should be increased viral clearance rate or the same clearance rate, with a shorter duration of treatment and/or fewer adverse effects. We do not believe there is any need for a placebo arm because approved therapy is available and new treatments can be compared with present therapy. Safety measures should include the standard recommended laboratory investigations, growth parameters, quality-of-life or psychological measures, and a requirement for long-term follow-up for up to 5 years.

Mack CL, Gonzalez Peralta RP, Gupta N, Leung D, Narkewicz MR, Roberts EA, Rosenthal P, Schwarz KB. NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants, children, and adolescents. J Pediatr Gastroenterol Nutr 2012;54(6):838–55.

NASPGHAN guideline on treatment of hepatitis C in children; results of multicenter collaborative studies.


Hepatitis C virus (HCV) is an RNA virus that affects >180 million individuals worldwide with a high propensity for chronic infection. Children with HCV infection differ from adults in several ways, including some modes of transmission, rates of clearance, progression of fibrosis, and the duration of potential chronic infection when acquired at birth. Since the discovery of HCV in 1989, there have been significant advances in the understanding of the virology and natural history of chronic HCV infection in children. In addition, there are now several treatment options for children with chronic hepatitis C infection and many new therapies on the horizon. As a consequence, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition brought together experts in pediatric hepatology to review the available data in children and provide clinicians with approaches to the diagnosis, management, and prevention of HCV infection in children and adolescents. The guideline details the epidemiology and natural history of HCV infection in children, the diagnostic workup, monitoring, and treatment of disease, and provides an update on future treatment options and areas of research.

Husby S, Koletzko S, Korponay-Szabó IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Mäki M, Ribes Koninckx C, Ventura A, Zimmer KP. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012;54(1):136–60.

ESPGHAN guidelines for diagnosis of celiac disease.


Objective: Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved.

Methods: A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing.

Results: In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative.

Conclusions: The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.

Copyright 2012 by ESPGHAN and NASPGHAN