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Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555. © 2017 AGA Institute

PN is used to treat children that cannot be fully fed by oral or enteral route, for example due to severe intestinal failure (1). Intestinal failure occurs when the gastrointestinal tract is unable to ingest, digest and absorb sufficient macronutrients and/or water and electrolytes to maintain health and growth. Children differ from adults in that their food intake must provide sufficient nutrients not only for the maintenance of body tissues but also for growth. This is particularly true in infancy and during adolescence when children grow extremely rapidly. At these times children are particularly sensitive to energy restriction because of high basal and anabolic requirements. The ability to provide sufficient nutrients parenterally to sustain growth in infants and children suffering from intestinal failure or severe functional intestinal immaturity represents one of the most important therapeutic advances in paediatrics over the last three decades. Improvements in techniques for artificial nutritional support now ensure that children in whom digestion and absorption are inadequate or who are unable to eat normally no longer need to suffer from the serious consequences of malnutrition including death. Since the 1960s, the wider availability of intravenous amino acid solutions and lipid emulsions resulted in successful prescription of PN in small infants, which was followed by the development of more appropriate solutions and delivery systems. PN can now be used not only for patients who require short-term parenteral feeding but also on a long-term basis for patients with chronic intestinal failure. With PN children with prolonged intestinal failure have the potential to grow and develop normally and to enjoy a good quality of life within the constraints of their underlying disease, and selected patients with irreversible intestinal failure may thus become candidates for intestinal transplantation (2). Whilst advances in knowledge of nutrient requirements, improved methods of nutrient delivery and understanding of the prevention and management of complications ensure that paediatric PN can generally be delivered safely and effectively, areas of uncertainty and controversy remain. PN is usually indicated when a sufficient nutrient supply cannot be provided orally or enterally to prevent or correct malnutrition or to sustain appropriate growth. Every effort should be made to avoid PN with the use of adequate care, specialised enteral feeds and artificial feeding devices as appropriate. PN is not indicated in patients with adequate small intestinal function in whom nutrition may be maintained by oral tube or gastrostomy feeding. Malnutrition in children, in addition to the general effects of impaired tissue function, immuno-suppression, defective muscle function and reduced respiratory and cardiac reserve also results in impaired growth and nutrition. Whilst somatic growth exhibits a bi-model pattern being fastest in infancy, then dropping off and receiving a further spurt around puberty, other organs of the body may grow and differentiate only at one particular time. This is particularly true with respect to the brain for which the majority of growth occurs in the last trimester of pregnancy and in the first two years of life. Poor nutrition at critical periods of growth results in slowing and stunting of growth which may later exhibit catch-up when a period of more liberal feeding occurs. In adolescence the risk is of not achieving growth potential if severe and continuous disease occurs and adequate provision is not made for their nutritional needs. The sick child is at the greatest risk of growth failure and nutritional disorder. Infants and children are particularly susceptible to the effects of starvation. The small preterm infant of 1 kg body weight contains only 1% fat and 8% protein and has a non-protein caloric reserve of only 110 kcal/kg body weight (460 kJ/kg). As fat and protein content rise with increase in size, the non-protein caloric reserve increases steadily to 220 kcal/kg body weight (920 kJ/kg) in a one year old child weighing 10.5 kg. If it is assumed that all non-protein and one third of the protein content of the body is available for caloric needs at a rate of 50 kcal/kg body weight (210 kJ/kg) per day in infants and children, estimates of the duration of survival during starvation and semi-starvation may be made. A small preterm baby, therefore, has sufficient reserve to survive only four days of starvation and a large preterm baby has enough for twelve days (3). With increased caloric requirements associated with disease this may be cut dramatically to less than two days for small preterm infants and perhaps a week for a large preterm baby. Recently it has become clear that small infants have special nutrition needs in early life and there is now a considerable body of evidence to suggest that nutrition at this age may determine various outcomes later in life, including both physical growth and intellectual development (4, 5). Clearly infants are at a considerable disadvantage compared with adults and early recourse to PN is essential when impaired gastrointestinal function precludes enteral nutrition.

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.