Efficient implementation of the 'non-biopsy approach' for the diagnosis of childhood celiac disease in the Netherlands: a national prospective evaluation 2010-2013.

The aim of this study was (1) to prospectively evaluate the nationwide implementation of the ESPGHAN-guidelines for the diagnosis of celiac disease (CD), (2) to investigate the incidence and clinical presentation of diagnosed childhood CD (0-14 years) in the Netherlands, and (3) to compare the findings with national survey data from 1975 to 1990 and 1993 to 2000 using the same approach. From 2010 to 2013, all practicing paediatricians were invited to report new celiac diagnoses to the Dutch Pediatric Surveillance Unit. Data were collected via questionnaires. A total of 1107 children with newly diagnosed CD were reported (mean age, 5.8 years; range, 10 months-14.9 years; 60.5% female). After the introduction of the non-biopsy approach in 2012, 75% of the diagnoses were made according to the guideline with a significant decrease of 46.3% in biopsies. The use of EMA and HLA-typing significantly increased with 25.8% and 62.1%, respectively. The overall incidence rate of childhood CD was 8.8-fold higher than in 1975-1990 and 2.0-fold higher than in 1993-2000. During the study period, the prevalence of diagnosed CD was 0.14%, far below 0.7% of CD identified via screening in the general Dutch paediatric population. Clinical presentation has shifted towards less severe and extra-intestinal symptoms.Conclusion: ESPGHAN guidelines for CD diagnosis in children were effectively and rapidly implemented in the Netherlands. Incidence of diagnosed CD among children is still significantly rising with a continuous changing clinical presentation. Despite the increasing incidence of diagnoses, significant underdiagnosis still remains. What is Known: • Since 2000 the incidence of diagnosed childhood CD in the Netherlands has shown a steady rise. • The rise in incidence has been accompanied by a changing clinical presentation at diagnosis. What is New: • The ESPGHAN guidelines 2012 for CD diagnosis were effectively and rapidly implemented in the Netherlands. • The incidence of diagnosed childhood CD in the Netherlands has continued to rise significantly during the reported period.

Is mid-upper arm circumference in Dutch children useful in identifying obesity?

BACKGROUND: Mid-upper arm circumference (MUAC) is suggested as being a valid measure in detecting overweight/obesity in children and adolescents, due to the strong relation with weight. We examined this relation and compared MUAC to body mass index (BMI) according to the International Obesity Task Force (IOTF) in children. METHODS: Anthropometric data including MUAC were collected in 2009 by trained healthcare professionals in the context of the fifth Dutch Nationwide Growth Study, in a sample of 6167 children (2891 boys and 3276 girls) aged 2-18 years of Dutch origin. We propose MUAC SDS cut-off values for overweight and obesity, and compared MUAC with BMI IOTF in sex-specific and age-specific categories (2-5, 6-11, 12-18 years). RESULTS: The area under the curve is used as a measure of diagnostic accuracy; the explained variance (R²) is good to excellent (0.88-0.94). Sensitivity ranges from 51.8% to 95.3% and specificity from 71.4% to 93.8%. Across age and gender groups, 65.1% to 89.0% participants are classified by both MUAC and BMI as normal weight, overweight or obese. We constructed three equations to predict weight using MUAC, with small differences between observed and predicted weight with an explained variance ranging from 0.88 to 0.94. CONCLUSIONS: Compared with BMI, MUAC is a valid measure for detecting overweight and obesity and thus a good alternative for BMI. When weight has to be estimated, it can be accurately predicted using MUAC. Based on our observations, we recommend developing diagrams with international (IOTF) cut-offs for MUAC SDS similar to BMI.

Iron Deficiency in Inflammatory Bowel Disease: The Use of Zincprotoporphyrin and Red Blood Cell Distribution Width.

OBJECTIVES: Iron deficiency (ID) in children with inflammatory bowel disease (IBD) is either an absolute (depleted iron stores) or a functional deficiency (caused by chronic inflammation). Differentiating between these 2 types of ID is important because they require a different therapeutic approach. Zinc protoporphyrin (ZPP) and red blood cell distribution width (RDW) are parameters of functional ID. Studies using these parameters to differentiate are nonexistent. We aimed to evaluate the prevalence of and risk factors for absolute and functional ID in paediatric IBD patients while using ZPP and RDW. METHODS: We evaluated the iron status and medical charts of 59 paediatric IBD patients in a secondary hospital in the Netherlands. Absolute ID was defined as serum ferritin <15 µg/L in the absence of infection and/or acute inflammation (C-reactive protein <10 mg/L). Iron deficiency anaemia (IDA) was defined as absolute ID in combination with anaemia. Functional ID, in patients without absolute ID, was defined as ZPP >70 µmol/mol haem and/or an RDW >14%. Anaemia of chronic disease (ACD) was defined as functional ID in combination with anaemia. RESULTS: Absolute and functional ID were found in 19/59 (32.2%) and 32/40 (80%) patients, respectively. The prevalence of IDA and ACD was 27.1% (16/59) and 20% (8/40), respectively. Multivariate analyses showed that absolute ID and IDA were both associated with a more recent IBD-diagnosis (both P < 0.05). CONCLUSIONS: Absolute and functional ID are common in paediatric IBD patients, and this differentiation is important because of therapeutic consequences. Furthermore, absolute ID and IDA are associated with a more recent IBD-diagnosis.

Comparison of Patients' and Doctors' Reports on Health-related Quality of Life in Celiac Disease.

OBJECTIVE: To investigate whether implementation of a celiac disease (CD)-specific health-related quality of life (HRQOL) questionnaire would add value to CD follow-up visits; we compared patients' self-reported CD-specific HRQOL with the physician's report provided during a regular CD follow-up visit in children and young adults. METHODS: A cross-sectional study in the control group of a study on self-management in CD (CoelKids). Eligible patients had CD for ≥1 year and were 25 years or younger. They completed a CD-specific HRQOL questionnaire (CDDUX) after their regular follow-up visit. Their physicians were unaware of the present study's objectives or self-reported HRQOL. PRIMARY OUTCOME: agreement between physician-reported and self-reported HRQOL. SECONDARY OUTCOMES: patient variables predicting a discrepancy between reports, or a lower HRQOL. RESULTS: Physician-reported HRQOL was available in 70 of 78 enrolled patients. The self-reported and physician-reported HRQOL were concordant in 30 of 70 (K = 0.093), 6 of them had a poor self-reported HRQOL. Reports were discrepant in 40 of 70; all 40 self-reported a poor HRQOL. Discrepancies occurred more frequently in patients with a disease duration <9 years (32/40 with discrepant reports were diagnosed <9 years ago vs 17/30 with no discrepancy, P<0.001) and in females (35/40 with discrepant reports were girls versus 16 of 30 with no discrepancy, P = 0.001). Both factors were predictors of a poorer HRQOL. CONCLUSIONS: During regular CD follow-up visits, physicians did not report a poor HRQOL in 40 of 46 children and young adults with a poor self-reported HRQOL. This is consistent with previous studies examining other chronic diseases and supports the implementation of self-reported CD-specific HRQOL measurements in CD follow-up visits.

Coeliac disease and gluten-related disorders in childhood.

Gluten-related disorders such as coeliac disease, wheat allergy and noncoeliac gluten sensitivity are increasingly being diagnosed in children. Coeliac disease occurs frequently, affecting 1-3% of the Western population. The condition manifests at a very young age, more so in girls, and is related to the HLA genotype. Coeliac disease might be considered a public health problem and, as primary prevention is not possible, the debate on mass screening should be reopened. Wheat proteins, including gluten, are responsible for one of the most common food allergies in children: wheat allergy. Unlike coeliac disease and wheat allergy, noncoeliac gluten sensitivity is an unclear and controversial entity. These three gluten-related disorders are treated with a gluten-free diet. In coeliac disease, the diet should be strictly followed, whereas wheat allergy only requires wheat elimination and in noncoeliac gluten sensitivity occasional trials of gluten reintroduction can be done. A good diagnostic work-up is important for gluten-related disorders in childhood to avoid unnecessary restrictive diets in children. In this Review, we provide an overview of the pathogenesis, diagnosis and management of the most common gluten-related disorders in children.

Validation of the Rome III criteria and alarm symptoms for recurrent abdominal pain in children.

OBJECTIVES: Rome criteria were formulated to define functional gastrointestinal disorders (Rome III criteria, 2006) excluding organic diagnoses when alarm symptoms were absent. The aims of the study were to validate the Rome III criteria as to their capacity to differentiate between organic and functional abdominal pain and to assess the role of alarm symptoms in this differentiation. METHODS: During 2 years all of the patients (ages 4-16 years) presenting with recurrent abdominal pain (Apley criteria) and referred to secondary care were included. Clinical diagnoses were based on protocolized evaluation and intervention with 6-month follow-up. Alarm symptoms were registered. Rome III criteria for functional pain syndromes were assigned independently. Descriptive statistical analyses were performed. RESULTS: In 200 patients (87 boys, mean age 8.8 years), organic (17%), functional (40%), combined organic and functional (9%), spontaneous recovery (27%), and other (8%) clinical diagnoses were established. Alarm symptoms were found in 57.5% (organic causes 56%, functional causes 61%). The evaluation for Rome symptom clusters revealed symptoms of irritable bowel syndrome in 27%, functional dyspepsia in 15%, functional abdominal pain in 28%, functional abdominal pain syndrome in 14.5%, and no pain syndrome in 15.5%. Rome diagnoses, based on symptoms and absence of alarm symptoms, predicted functional clinical diagnosis with sensitivity 0.35 (95% confidence interval 0.27-0.43), specificity 0.60 (0.46-0.73), positive predictive value 0.71 (0.61-0.82), and negative predictive value of 0.24 (0.17-0.32). CONCLUSIONS: The Rome III criteria for abdominal pain are not specific enough to rule out organic causes. Alarm symptoms do not differentiate between organic and functional abdominal pain.

Gastrointestinal acute graft-versus-host disease in children: histology for diagnosis, mesenchymal stromal cells for treatment, and biomarkers for prediction of response.

Steroid-nonresponsive acute graft-versus-host disease (aGVHD) after hematopoietic stem cell transplantation carries a poor prognosis. Various groups have reported beneficial effects of mesenchymal stromal cell (MSC) infusion as salvage treatment. Response to treatment is typically evaluated using the diagnostic clinical criteria for aGVHD. In this study, we evaluated the usefulness of additional gastrointestinal biopsy specimens paired with serum biomarkers. In a cohort of 22 pediatric patients, persistent or recurrent diarrhea was seen in 18 children treated with MSC infusion for steroid-refractory aGVHD. To exclude other causes of gastrointestinal pathology, patients were biopsied for histological analysis. Eight of 12 patients exhibited residual tissue damage and villous atrophy, but no active aGVHD. Serum biomarkers have been identified as an alternative tool for monitoring the response to aGVHD treatment. The value of biomarkers for inflammation, tissue, and endothelial cell damage was evaluated in our cohort. Although predictive of response to treatment and survival, these markers lack the necessary specificity and sensitivity to predict response to MSC therapy. Objective endpoints for clinical trials on the treatment of steroid-refractory aGVHD remain to be defined. Thus, we recommend including biopsies and biomarkers to discriminate between ongoing aGVHD and postinflammatory malabsorption.

Protozoa as a cause of recurrent abdominal pain in children.

OBJECTIVES: The aim of this study was to investigate whether protozoa can be identified as a cause of recurrent abdominal pain (RAP), and whether protozoan infections can be recognized by a specific clinical presentation. METHODS: For 2 years, all patients (ages 4-16 years) fulfilling the Apley criteria of RAP referred to secondary care were prospectively evaluated for protozoa (Giardia lamblia, Dientamoeba fragilis, Blastocystis hominis) and treated if positive. Re-examination followed at least 10 days after treatment. Disappearance of pain with eradication and a pain-free follow-up of at least 6 months were considered to be indicative of a causal relation with RAP. The predictive value of the characteristics of the pain for protozoan infections was calculated. RESULTS: Of 220 included patients (92 boys, mean age 8.8 years), 215 brought a stool sample; 73 (34%) carried parasites, 10 of whom had 2 parasites, 2 had 3 parasites. Sixty-five patients were treated. Twenty-five (11%) were pain-free after eradication (21 had D fragilis, 8 B hominis, 4 G lamblia), of whom 11 had another infection (2) or constipation (9) as second diagnosis for the pain. Five had recurrence of infection with D fragilis and were again pain-free with eradication. Patients with protozoa as cause of their pain did not show differences with respect to their presentation when compared with patients with an asymptomatic infection and patients without protozoa. CONCLUSIONS: Protozoa were found as the cause of pain in 6% to 11% of children with RAP. These patients did not show a characteristic presentation when compared with patients with other causes of abdominal pain.

Screening for unrecognized coeliac disease in subfertile couples.

OBJECTIVE: Subfertility has been reported as a long-term complication of unrecognized and/or untreated coeliac disease (CD); however, the results from studies on this topic are ambiguous. We aimed to determine the prevalence of unrecognized CD in subfertile male-female couples visiting a fertility clinic compared with the general population. METHODS: Subjects included 1038 male-female couples (n = 2076) who visited the fertility clinic of the Leiden University Medical Center in the Netherlands between 2003 and 2009. All consecutive patients were routinely, serologically screened, and those with positive test results for antibodies against IgA anti-tissue transglutaminase type 2 and IgA endomysial antibodies were considered to have unrecognized CD. Clinical data on gender, age, height, weight, diagnosis of subfertility, and previously diagnosed CD were collected from the clinical files. Subsequently, after serological screening, all patients were anonymized. The prevalence of unrecognized CD was compared with the one in the general adult population in the Netherlands (0.35%). RESULTS: The prevalence of unrecognized CD in subfertile male-female couples was 0.48% (10/2076; 6 females and 4 males) and was not significantly more frequent compared with the general population. Compared with the control group, similar CD prevalences were found within the different subfertility categories separately: unexplained subfertility, anovulation, tubal pathology, and male factor (p = NS). CONCLUSION: In our large study cohort of subfertile male-female couples, the prevalence of unrecognized CD is comparable to the general population in the Netherlands. No association was observed between CD and subfertility in the different subfertility categories and genders.

[A progressive vomiting pre-schooler]. / Een progressief brakende kleuter.

A 4-year-old boy with persistent vomiting had a peptic stenosis of the oesophagus.

Multiple common variants for celiac disease influencing immune gene expression.

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.

Long-term health and quality-of-life consequences of mass screening for childhood celiac disease: a 10-year follow-up study.

OBJECTIVE: Mass screening for celiac disease is controversial. The objective of this study was to determine whether detection of childhood celiac disease by mass screening improves long-term health status and health-related quality of life. METHODS: We conducted a prospective 10-year follow-up study of 32 children who were aged 2 to 4 years, had celiac disease identified by mass screening, and had a gluten-free diet (19) or a normal gluten-containing diet (13). The follow-up included assessments of general health status, celiac disease-associated symptoms, celiac disease-associated serum antibodies, and health-related quality of life. RESULTS: Ten years after mass screening, 81% of the children were adhering to a gluten-free diet. The health status improved in 66% of the treated children: in 41% by early treatment and in 25% by prevention of the gluten-dependent symptoms that they developed after diagnosis. For 19% of the children, treatment after screening would not have improved their health status, because they had no symptoms at screening and have remained symptom-free while consuming gluten. The health-related quality of life of the children with symptoms improved significantly after 1 year of gluten-free diet. Ten years after screening, the health-related quality of life of the children with celiac disease was similar to that of the reference population. CONCLUSION: Identification by mass screening led 10 years later to health improvement in 66% of children without deterioration of generic health-related quality of life. There is a good compliance after mass screening. In a research setting, delaying treatment for children without symptoms seems to be an option after a positive screening test. Long-term follow-up studies are needed to assess possible long-term complications in untreated, nonsymptomatic celiac disease.

Is gluten challenge really necessary for the diagnosis of coeliac disease in children younger than age 2 years?

OBJECTIVE: In the diagnosis of coeliac disease (CD), gluten challenge is recommended for children under the age of 2 years at initial biopsy. The aim of the study was to investigate the diagnostic yield of gluten challenge in this group of children. PATIENTS AND METHODS: We included children aged 2 years or younger who were analysed for possible CD and who had villous atrophy at initial small bowel biopsy in the period 1993-2004. We subsequently identified all patients who underwent a complete gluten challenge. RESULTS: We identified 333 children with possible CD. In 100 children (30%), a gluten challenge was performed, with the diagnosis being confirmed in 97. Retrospectively, in 2 of the 3 children without mucosal relapse, data available before gluten challenge did not justify the initial diagnosis of CD. In the third patient, transient gluten intolerance could not be excluded. At first biopsy, the 2 children without mucosal relapse had negative serological parameters, whereas the third patient had IgA antigliadin antibodies, but no IgA anti-endomysium antibodies (EMA). Indeed, all of the patients with EMA at diagnosis had a relapse at gluten challenge. CONCLUSIONS: Routine gluten challenge in children younger than 2 years at initial diagnosis of CD has an extremely low diagnostic yield. We suggest that routine gluten challenge in this group of patients is not necessary when patients have villous atrophy in combination with EMA. Therefore, a revision of the current diagnostic criteria has to be considered.

Infliximab dependency in pediatric Crohn's disease: long-term follow-up of an unselected cohort.

BACKGROUND: Infliximab is effective for induction and maintenance of remission in Crohn's disease. It is unknown how long patients should be kept on infliximab therapy. The primary aim of this study was to assess duration of effective maintenance therapy and infliximab dependency in pediatric CD patients initially responding to infliximab therapy. METHODS: All pediatric patients treated with infliximab by pediatric gastroenterologists in the Netherlands because of severe luminal or fistulizing CD with initial response to infliximab therapy were reviewed. Duration of therapy, clinical response and adverse events were recorded. RESULTS: Sixty-six CD patients (37 boys) in 10 hospitals were initially responding to infliximab therapy. Mean age at the start of infliximab therapy was 14.5 years (range, 8.1-18.5 years). Mean follow-up since infliximab was started was 41.3 months (range 12-165). In total, 991 infusions were administered. Analysis demonstrates that 15.2% of patients had prolonged response, while 56.1% were infliximab dependent and 28.8% lost response. In total, 10 patients (15.2%) developed an infection during infliximab therapy and 8 (12.1%) had an immediate allergic reaction. CONCLUSIONS: Good clinical response to maintenance infliximab therapy was seen in 70% of patients. Infliximab maintenance therapy seems very effective and safe in pediatric CD. However, more than half of the patients in this cohort is dependent on repeated infliximab infusions. The number of infliximab infusions received when patients lost response to infliximab was diverse. There was no statistical difference regarding response to infliximab therapy when started early as compared to later in the course of Crohn's disease.

Pyruvate kinase deficiency associated with severe liver dysfunction in the newborn.

Significant hyperbilirubinaemia, anemia, and splenomegaly are common features in patients with severe haemolysis due to pyruvate kinase (PK) deficiency. Until now, severe neonatal PK deficiency has not been associated with fatal liver disease at this age. We present two neonatal cases of severe PK deficiency complicated with progressive fatal liver disease. The patients presented with severe haemolysis, progressive cholestasis, and hepatosplenomegaly, and both patients ultimately developed liver failure at a very young age. Despite extensive investigations, no specific explanation for liver disease and failure was found. We suggest that the PK deficiency itself directly led to liver dysfunction.

A toddler with recurrent oral and genital ulcers.

In western countries, when a child presents with recurrent oral ulcers and colitis, the diagnosis of Crohn's disease is mostly made. In our patient, the diagnosis was Behçet's disease with gastrointestinal manifestations. Behçet's disease with gastrointestinal manifestations has a similar clinical presentation to Crohn's disease, but there is more organ involvement and the prognosis is more severe in the former. Because there is limited experience in the treatment of Behçet's disease in the paediatric population, successful and unsuccessful treatment modalities in both paediatric and adult populations should be reported.

European multi-centre study on coeliac disease and non-Hodgkin lymphoma.

INTRODUCTION: Coeliac disease (CD) is associated with an increased risk of non-Hodgkin lymphoma (NHL), but there is little information about whether this is true for clinically silent CD. OBJECTIVE: To investigate the frequency of CD in two European populations; one with NHL and another derived from the general population. METHODS: A prospective, multi-centre, case-control study in 10 European countries was conducted between May 1998 and April 2001. A total of 1446 consecutive patients with newly diagnosed NHL aged over 18 years was collected. The control group consisted of a population of 9676 individuals who were screened for CD. The number of patients with a previous diagnosis of CD and those with silent CD detected by screening were determined in the two groups. RESULTS: The patients with CD had a significantly increased risk of developing NHL [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.9]. This risk was only present in patients with CD diagnosed clinically before the study (OR 3.3, 95% CI 1.4-7.9), but not in those with silent CD detected by screening (OR 1.3, 95% CI 0.6-2.7). CONCLUSION: Patients with CD have an increased risk of developing NHL, although this is lower than previously thought. Clinically silent CD is rare in patients with NHL.

Infliximab therapy in 30 patients with refractory pediatric crohn disease with and without fistulas in The Netherlands.

OBJECTIVE: The purpose of this study was to describe the clinical experience with the anti-tumor necrosis factor chimeric monoclonal antibody, infliximab, in pediatric patients with Crohn disease in The Netherlands. DESIGN: Descriptive. METHODS: Clinical response and adverse effects of infliximab were recorded for pediatric patients with Crohn disease treated from October 1992 to January 2003. RESULTS: Thirty patients (aged 7-18 years) with refractory Crohn disease (with or without severe fistulas) were treated with infliximab. Patients were treated with up to 30 infusions. Mean follow-up was 25.3 months. A total of 212 infusions were administered. Thirteen patients had refractory Crohn disease without fistulas. Six patients showed good long-term response to infliximab treatment (defined as clinical index < or =10 points). Sixteen patients had refractory Crohn disease with draining fistulas. Nine showed good long-term response (closure or nonproductiveness of fistulas). One patient with metastatic Crohn disease in the skin had a good long-term response. Six patients developed an allergic reaction during infusion. In one patient, the allergic reaction occurred after an infliximab-free interval of 9 years. One patient died of sepsis. CONCLUSIONS: Infliximab was an effective therapy in 53% of patients with refractory pediatric Crohn disease, with or without fistulas. Approximately half of the patients become unresponsive to infliximab therapy. Randomized controlled studies are mandatory to assess long-term efficacy and safety to define the optimal therapeutic strategy of infliximab therapy in children with Crohn disease.