Steffen Husby

European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac 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.

A prospective study of cow's milk allergy in exclusively breast-fed infants. Incidence, pathogenetic role of early inadvertent exposure to cow's milk formula, and characterization of bovine milk protein in human milk.

ABSTRACT. A cohort of 1749 newborns in the municipality of Odense were followed prospectively for the development of cows milk allergy (CMA) during their first year of life. Altogether 39 fulfilled the criteria for CMA (2.2%). Out of the 39 infants, 17 developed symptoms of CMA during breast‐feeding, in all cases before the age of 3 months. Nine of these were solely breast‐fed at the time of diagnosis, giving a one year incidence of CMA in exclusively breastfed infants of 0.5% (9/1 749) in a study population with a frequency of exclusive breast‐feeding of 52% at 3 months of age. None of the infants had signs of CMA in the neonatal period. Review of records from the newborn nursery revealed that all 9 infants had been exposed to cows milk formula in amounts corresponding to approximately 0.4‐3.0 g of Beta‐lactoglobulin (BLG) during the first three days of life. Human milk samples were analyzed by enzyme‐linked immunosorbent assay (ELISA) for the content of bovine BLG. Detectable amounts (0.5–45 ng/ml) were found in 3/9 samples of human milk against which the infants reacted clinically. Analysis of the size distribution by high pressure liquid gel permeation chromatography in combination with ELISA indicated a molecular weight of BLG corresponding to that of monomeric BLG (18 kD). Possibly early inadvertent and occasional exposure to cows milk proteins may initiate sensitization in predisposed neonates. Subsequent exposure to minute amounts of bovine milk proteins in human milk may act as booster doses eliciting allergic reactions.

Diagnostic Approach and Management of Cow's-Milk Protein Allergy in Infants and Children: ESPGHAN GI Committee Practical Guidelines

OBJECTIVES This guideline provides recommendations for the diagnosis and management of suspected cows-milk protein allergy (CMPA) in Europe. It presents a practical approach with a diagnostic algorithm and is based on recently published evidence-based guidelines on CMPA. DIAGNOSIS If CMPA is suspected by history and examination, then strict allergen avoidance is initiated. In certain circumstances (eg, a clear history of immediate symptoms, a life-threatening reaction with a positive test for CMP-specific IgE), the diagnosis can be made without a milk challenge. In all other circumstances, a controlled oral food challenge (open or blind) under medical supervision is required to confirm or exclude the diagnosis of CMPA. TREATMENT In breast-fed infants, the mother should start a strict CMP-free diet. Non-breast-fed infants with confirmed CMPA should receive an extensively hydrolyzed protein-based formula with proven efficacy in appropriate clinical trials; amino acids-based formulae are reserved for certain situations. Soy protein formula, if tolerated, is an option beyond 6 months of age. Nutritional counseling and regular monitoring of growth are mandatory in all age groups requiring CMP exclusion. REEVALUATION: Patients should be reevaluated every 6 to 12 months to assess whether they have developed tolerance to CMP. This is achieved in >75% by 3 years of age and >90% by 6 years of age. Inappropriate or overly long dietary eliminations should be avoided. Such restrictions may impair the quality of life of both child and family, induce improper growth, and incur unnecessary health care costs.

Passage of undegraded dietary antigen into the blood of healthy adults. Quantification, estimation of size distribution, and relation of uptake to levels of specific antibodies.

The absorption into the blood of ovalbumin (OA) and beta‐lactoglobulin (BLG) was investigated in eight healthy adults. Enzyme immunoassays showed up to 10.5 ng OA/ml serum in seven out of eight individuals 2‐3 h after a test meal, whereas no BLG was demonstrated. The apparent size distribution of the absorbed OA was investigated by high‐pressure liquid gel permeation chromatography fractionalion, followed by enzyme‐linked immunosorbemt assay, which in the fractionated sera showed OA in all eight individuals. OA was found at the elution volume of intact OA and, in addition, was present in high molecular weight fractions, as part of the immune complexes. The serum concentrations of OA could not be clearly correlated to levels of serum and secretory anti‐OA antibodies. No significant alterations of the levels of circulating immune complexes could be demonstrated by two antigen‐nonspecific assays. The presented data indicate that, for certain dietary proteins, low‐grade absorption of apparently undegraded protein into the blood occurs regularly in healthy adults.

Accuracy of diagnostic antibody tests for coeliac disease in children: summary of an evidence report.

Objective: The aim of this study was to summarise the evidence from 2004 to September 2009 on the performance of laboratory-based serological and point of care (POC) tests for diagnosing coeliac disease (CD) in children using histology as reference standard. Patients and Methods: We searched MEDLINE and EMBASE for studies reporting on children for tests based on IgA and IgG anti-gliadin (AGA), endomysial (EmA), anti-transglutaminase-2 (TG2), and anti-deamidated gliadin peptides (DGP) antibodies or POC tests. For inclusion, histological analysis of duodenal biopsies and sensitivity and specificity for index tests had to be reported. Data were pooled and summary measures calculated for sensitivity, specificity, positive and negative likelihood ratios (“LR+”, “LR−”), and diagnostic odds ratios (DOR). In case of elevated statistical heterogeneity, studies reaching 90% sensitivity or specificity were reported. Results: A total of 2510 articles were reviewed; 16 entered meta-analysis, reporting on 3110 patients (1876 with CD, 1234 without CD). For IgA-EmA, sensitivity was ≥90% in 7/11 studies and pooled specificity 98.2%. For IgA-anti-TG2, 11/15 studies yielded sensitivities ≥90% and 13/15 specificities ≥90%. For IgA-DGP, sensitivity ranged between 80.7% and 95.1% (specificity 86.3%–93.1%); for IgG-DGP between 80.1% and 98.6% (specificity 86.0–96.9%). IgA-EmA had the highest pooled DOR (554) and LR+ (31.8) for a laboratory test, followed by IgA-anti-TG2, IgG-DGP, IgA-DGP and IgA-AGA. POC tests showed a pooled sensitivity of 96.4% for IgA-TG2 (specificity 97.7%). Conclusions: IgA-EmA and IgA-anti-TG2 tests appear highly accurate to diagnose CD. IgG-anti-DGP tests may help in excluding CD. IgA-AGA and IgA-DGP tests show inferior accuracy. POC tests may achieve high accuracy in the hands of experienced readers, but IgA-anti-TG2/EmA were superior.

Clinical Benefit of a Gluten-Free Diet in Type 1 Diabetic Children With Screening-Detected Celiac Disease: A population-based screening study with 2 years’ follow-up

OBJECTIVE—This study was performed to 1) determine the prevalence of celiac disease in Danish children with type 1 diabetes and 2) estimate the clinical effects of a gluten-free diet (GFD) in patients with diabetes and celiac disease. RESEARCH DESIGN AND METHODS—In a region comprising 24% of the Danish population, all patients <16 years old with type 1 diabetes were identified and 269 (89%) were included in the study. The diagnosis of celiac disease was suspected in patients with endomysium and tissue transglutaminase antibodies in serum and confirmed by intestinal biopsy. Patients with celiac disease were followed for 2 years while consuming a GFD. RESULTS—In 28 of 33 patients with celiac antibodies, an intestinal biopsy showed villous atrophy. In 5 patients, celiac disease had been diagnosed previously, giving an overall prevalence of 12.3% (95% CI 8.6–16.9). Patients with celiac disease had a lower SD score (SDS) for height (P < 0.001) and weight (P = 0.002) than patients without celiac disease and were significantly younger at diabetes onset (P = 0.041). A GFD was obtained in 31 of 33 patients. After 2 years of follow-up, there was an increase in weight SDS (P = 0.006) and in children <14 years old an increase in height SDS (P = 0.036). An increase in hemoglobin (P = 0.002) and serum ferritin (P = 0.020) was found, whereas HbA1c remained unchanged (P = 0.311) during follow-up. CONCLUSIONS—This population-based study showed the highest reported prevalence of celiac disease in type 1 diabetes in Europe. Patients with celiac disease showed clinical improvements with a GFD. We recommend screening for celiac disease in all children with type 1 diabetes.

Management guidelines of eosinophilic esophagitis in childhood

Objectives: Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. With few exceptions, 15 eosinophils per high-power field (peak value) in ≥1 biopsy specimens are considered a minimum threshold for a diagnosis of EoE. The disease is restricted to the esophagus, and other causes of esophageal eosinophilia should be excluded, specifically proton pump inhibitor–responsive esophageal eosinophilia. This position paper aims at providing practical guidelines for the management of children and adolescents with EoE. Methods: Relevant literature from searches of PubMed, CINAHL, and recent guidelines was reviewed. In the absence of an evidence base, recommendations reflect the expert opinion of the authors. Final consensus was obtained during 3 face-to-face meetings of the Gastroenterology Committee and 1 teleconference. Results: The cornerstone of treatment is an elimination diet (targeted or empiric elimination diet, amino acid–based formula) and/or swallowed, topical corticosteroids. Systemic corticosteroids are reserved for severe symptoms requiring rapid relief or where other treatments have failed. Esophageal dilatation is an option in children with EoE who have esophageal stenosis unresponsive to drug therapy. Maintenance treatment may be required in case of frequent relapse, although an optimal regimen still needs to be determined. Conclusions: EoE is a chronic, relapsing inflammatory disease with largely unquantified long-term consequences. Investigations and treatment are tailored to the individual and must not create more morbidity for the patient and family than the disease itself. Better maintenance treatment as well as biomarkers for assessing treatment response and predicting long-term complications is urgently needed.

Oesophageal atresia: prevalence, prenatal diagnosis and associated anomalies in 23 European regions

Objective To describe prevalence, prenatal diagnosis and epidemiological data on oesophageal atresia from 23 well-defined European regions and compare the prevalence between these regions. Design Population-based study using data from a large European database for surveillance of congenital anomalies (EUROCAT) for two decades (1987–2006). Settings Twenty-three participating registries based on multiple sources of information including information about live births, fetal deaths with gestational age ≥20 weeks and terminations of pregnancy. Patients 1222 cases of oesophageal atresia in a population of 5 019 804 births. Results The overall prevalence was 2.43 cases per 10 000 births (95% CI 2.30 to 2.57). There were regional differences in prevalence ranging from 1.27 to 4.55. Prenatal detection rates varied by registry from >50% of cases to <10% of cases. A total of 546 cases (44.7%) had an isolated oesophageal anomaly, 386 (31.6%) were multiple malformed and 290 (23.7%) had an association or a syndrome. There were 1084 live born cases (88.7%), 43 cases were fetal deaths and 95 cases were terminations of pregnancy. One-week survival for live births was 86.9% and 99.2% if the gestational age was ≥38 weeks and isolated oesophageal atresia was present. Males accounted for 57.3% of all cases and 38.5% of live born cases were born with gestational age <37 weeks. Conclusion There were regional differences in prevalence of oesophageal atresia in Europe. Half of all cases had associated anomalies. Prenatal detection rate increased from 26% to 36.5% over the two decades. Survival in infants with isolated oesophageal atresia born at term is high.

Prospective estimation of IgG, IgG subclass and IgE antibodies to dietary proteins in infants with cow milk allergy. Levels of antibodies to whole milk protein, BLG and ovalbumin in relation to repeated milk challenge and clinical course of cow milk allergy.

Prospectively, serum levels of IgE, specific IgE antibodies (AB) to whole cow milk protein (CMP), bovine se‐albumin, bovine immunoglobulin, bovine lactoferrin, bovine lactalbumin and beta‐lactoglobulin (BLG), IgG and IgG subclass antibodies to ovalbumin (OA) and BLG, and IgG4 RAST to CMP (bovine whey) were measured in 39 infants with cow milk protein allergy (CMPA) at birth (cord blood), at time of diagnosis and before and after milk challenge at the age of 12 months. Immunological measurements were also undertaken in 33 control infants without CMPA at birth, at 6 months and at 18 months. At no time, were differences found between the levels of IgG and IgG subclass AB to OA and BLG in control versus infants with CMPA. In the 39 infants with CMPA no correlation was found between the levels of IgE, IgG and IgG subclass AB in cord blood and subsequent levels of these values, irrespective of the type of CMPA (IgE‐mediated (CMA) or non‐IgE‐mediated (CMI)), and irrespective of whether remission had occurred. In cord blood 25/33 (76%) of the infants with CMPA had specific IgE‐AB to one or more of the bovine milk proteins indicating a prenatal intrauterine sensitization to cow milk protein. At 6 months the frequency of specific IgE‐AB to bovine milk proteins was significantly (p<0.05) higher in infants with CMA versus CMI, and at 12 months total serum‐IgE and the increase of these specific IGE‐AB and RAST to CMP were significantly higher (p<0.05) in infants with persistent CMA. From 6 to 12 months withholding milk resulted in a significant fall in specific IgE‐AB to CMP, and IgG, IgG, and IgG4 anti‐BLG followed by an increase after milk challenge. Decreasing levels of IgG anti‐OA from birth to 6 months reflect passive maternal transfer of IgG through the placenta, and increasing levels of IgG anti‐BLG, already from birth to 6 months, may represent an early exposure to CMP in all infants. Significantly higher levels (p<0.05) of IgG anti‐OA AB, IgG, and IgG4 anti‐BLG AB were found in infants with persistent CMA, indicating a close relation between the synthesis of IgE and IgG and between IgE and IgG subclasses (IgG, and IgG4) in symptomatic cow milk‐allergic individuals. Determination of IgG AB and IgG subclass AB (IgG, and IgG4) to BLG and bovine whey in cord blood appears unable to discern infants at high risk of development of CMPA. However, infants with persistent CMPA have an increased antibody response of specific IgE and IgG subclasses (IgG, and IgG4) to CMP exposure.

High prevalence of coeliac disease in Danish children with type I diabetes mellitus

The purpose of this population‐based study was to determine the prevalence of coeliac disease (CD) in 106 Danish children (age 2‐18 y) with type I diabetes mellitus compared with 106 age‐and sex‐matched healthy controls. Serum samples were analysed for immunoglobulin A (IgA) and IgG gliadin antibodies by enzyme‐linked immunosorbent assay (ELISA), for IgA endomysium antibodies (EMA) by immunofluorescence and for IgA tissue transglutaminase antibodies (tTGA) by ELISA. None of the controls had EMA or tTGA. Two diabetics previously diagnosed with CD were antibody negative on a gluten‐free diet. Ten diabetics had both EMA and tTGA. Intestinal biopsy was performed in nine of them. All biopsies showed a histological picture of partial or total villous atrophy confirming the diagnosis of CD. Diabetics with CD were significantly younger (p= 0.026), had an earlier onset of diabetes (p= 0.005), had a lower height standard deviation score (p= 0.019) and more often had thyroid antibodies (p= 0.040) compared with diabetics without CD.