Jan de Laffolie

Antibodies in the Diagnosis of Coeliac Disease: A Biopsy-Controlled, International, Multicentre Study of 376 Children with Coeliac Disease and 695 Controls

Diagnosis of coeliac disease (CD) relies on a combination of clinical, genetic, serological and duodenal morphological findings. The ESPGHAN suggested that biopsy may not be necessary in all cases. New guidelines include omission of biopsy if the concentration of CD-specific antibodies exceeds 10 times the upper limit of normal (10 ULN) and other criteria are met. We analysed the 10 ULN criterion and investigated multiple antibody-assays. Serum was collected from 1071 children with duodenal biopsy (376 CD patients, 695 disease-controls). IgA-antibodies to tissue transglutaminase (IgA-aTTG), IgG-antibodies to deamidated gliadin peptides (IgG-aDGL) and IgA-endomysium antibodies (IgA-EMA) were measured centrally. We considered 3 outcomes for antibody test procedures utilizing IgA-aTTG and/or IgG-aDGL: positive (≥10 ULN, recommend gluten-free diet), negative (<1 ULN, no gluten-free diet) or unclear (perform biopsy). Positive (PPV) and negative (NPV) predictive values were based on clear test results. We required that they and their lower confidence bounds (LCB) be simultaneously very high (LCB >90% and PPV/NPV >95%). These stringent conditions were met for appropriate antibody-procedures over a prevalence range of 9–57%. By combining IgG-aDGL with IgA-aTTG, one could do without assaying total IgA. The PPV of IgG-aDGL was estimated to be extremely high, although more studies are necessary to narrow down the LCB. The proportion of patients requiring a biopsy was <11%. The procedures were either equivalent or even better in children <2 years compared to older children. All 310 of the IgA-aTTG positive children were also IgA-EMA positive. Antibody-assays could render biopsies unnecessary in most children, if experienced paediatric gastroenterologists evaluate the case. This suggestion only applies to the kits used here and should be verified for other available assays. Confirming IgA-aTTG positivity (≥10 ULN) by EMA-testing is unnecessary if performed on the same blood sample. Prospective studies are needed.

Decline in Infantile Hypertrophic Pyloric Stenosis in Germany in 2000–2008

BACKGROUND AND OBJECTIVE: The incidence of infantile hypertrophic pyloric stenosis (IHPS) is highly variable over time and geographic regions. A decline in IHPS incidence was recently reported in Sweden, the United States, Denmark, and Scotland. In Sweden, the IHPS decline seemed to be concurrent with a declining incidence in sudden infant death syndrome (SIDS), which suggested a common cause; the latter was attributed to campaigns against the prone sleeping position. We investigated the time course of the IHPS incidence in all German federal states (N = 16) between 2000 and 2008. We examined correlations between the IHPS incidence and the SIDS incidence. METHODS: Data were extracted from the public report of health (Gesundheitsberichterstattung des Bundes). We collected the numbers of IHPS (International Classification of Diseases, 10th Revision [ICD-10], code 40.0), SIDS (ICD-10, R95), and live births (LB; male/female) in each federal state for 2000–2008. RESULTS: The IHPS incidence declined in Germany from 2000 (3.2086/1000 LB [range: 1.67–5.33]) to 2008 (2.0175/1000 LB [1.74–3.72]; P = .005). The recorded incidence was highly variable in different federal states and over time. The SIDS incidence also declined during the same time period (2000, median: 0.759/1000 LB [interquartile range: 0.54–1.029]; 2008, median: 0.416/1000 LB [interquartile range: 0.285–0.6485]; P = .0255). However, the SIDS regional distribution was different from that of IHPS. CONCLUSIONS: The IHPS incidence declined by ∼38% nationwide. A parallel decline in SIDS displayed a different pattern in regional distribution; thus, a common cause was unlikely. The regional differences indicated that etiologic factors remained unresolved.

Inflammatory bowel disease in pediatric patients: Characteristics of newly diagnosed patients from the CEDATA-GPGE Registry.

BACKGROUND Inflammatory bowel disease (IBD) can arise at any age, with peak incidence in adolescence and young adulthood. A registry of pediatric cases of IBD offers the opportunity to document their diagnosis and treatment, with the ultimate aim of improving diagnosis and treatment in the future. METHODS In the German-language CEDATA-GPGE registry, 3991 cases of IBD in patients less than 18 years of age were documented from 2004 to 2014. The 1257 patients who were prospectively included in the registry upon diagnosis and whose further course was documented for at least three months were analyzed in two separate groups--under 10 years old, and 10 years and above--with respect to the type and duration of their symptoms until diagnosis, the completeness of the diagnostic evaluation, the disease phenotype, and the initial treatment. RESULTS Of the 958 patients for whom full documentation was available, 616 (64.3%) had Crohns disease (CD), 278 (29%) had ulcerative colitis (UC), 64 (6.7%) had an unclassified IBD, and 23.2% were under 10 years old. The latency to diagnosis was longer for CD than for UC (0.5 versus 0.3 years), regardless of age. 62.5% of the CD patients had ileocolonic involvement, and more than half had involvement of the upper gastrointestinal tract. 71% of the patients with UC had subtotal colitis or pancolitis. Continuous improvement was seen in diagnostic assessment according to published guidelines. For example, in 2004/2005, 69% of patients were evaluated endoscopically with ileocolonoscopy and esophagogastroduodenoscopy; this fraction had risen to nearly 100% by 2013/2014. Similarly, the percentage of patients who underwent a diagnostic evaluation of the small intestine, as recommended, rose from 41.2% to 60.9% over the same period. The most common initial treatments were 5- amino - salicylates (86.8% CD, 100% UC) and glucocorticoids (60.6% CD, 65.6% UC). 32% of the patients with CD received exclusive enteral nutrition therapy. CONCLUSION Most of these pediatric patients with IBD, whether in the younger or the older age group, had extensive bowel involvement at the time of diagnosis. The registry data imply that improvement in clinical course may be achieved by shortening the time to diagnosis and by closer adherence to the diagnostic and therapeutic guidelines.

Absent Adrenarche in Children with Hypopituitarism: A Study Based on Urinary Steroid Metabolomics

Background: Up to now, the regulation of adrenarche remains a myth although ACTH may possibly play an important role. Methods: Urinary steroid profiling by gas chromatography-mass spectrometry was used to study non-invasively the adrenarchal steroid metabolome in 13 children aged 6-16 years with partial or complete hypopituitarism (HP) whose ACTH/cortisol axis was affected and compared it with 24 healthy age-matched controls. The sum of DHEA, 16α-hydroxy-DHEA and 3β,16α,17β-androstenetriol served as markers for adrenarche parameters (AP). The excretion rates of major urinary cortisol metabolites were also determined. Results: The excretion rates for AP were significantly lower for the HP subjects than for the controls (p < 0.001). After dividing the HP group into a subgroup treated with hydrocortisone (HC) and an HC-untreated subgroup, a significant difference for AP remained for each subgroup when compared to the control group (p < 0.001 and p = 0.045, respectively). Treatment with HC had no influence on AP. Conclusion: The data imply indirectly a significant contribution of ACTH to the regulation of adrenarche. Our results also signify important diagnostic information: absent adrenarche can be indicative of ACTH deficiency.

Major cardiac surgery induces an increase in sex steroids in prepubertal children

While the neuroprotective benefits of estrogen and progesterone in critical illness are well established, the data regarding the effects of androgens are conflicting. Surgical repair of congenital heart disease is associated with significant morbidity and mortality, but there are scant data regarding the postoperative metabolism of sex steroids in this setting. The objective of this prospective observational study was to compare the postoperative sex steroid patterns in pediatric patients undergoing major cardiac surgery (MCS) versus those undergoing less intensive non-cardiac surgery. Urinary excretion rates of estrogen, progesterone, and androgen metabolites (μg/mmol creatinine/m(2) body surface area) were determined in 24-h urine samples before and after surgery using gas chromatography-mass spectrometry in 29 children undergoing scheduled MCS and in 17 control children undergoing conventional non-cardiac surgery. Eight of the MCS patients had Downs syndrome. There were no significant differences in age, weight, or sex between the groups. Seven patients from the MCS group showed multi-organ dysfunction after surgery. Before surgery, the median concentrations of 17β-estradiol, pregnanediol, 5α-dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA) were (control/MCS) 0.1/0.1 (NS), 12.4/11.3 (NS), 4.7/4.4 (NS), and 2.9/1.1 (p=0.02). Postoperatively, the median delta 17β-estradiol, delta pregnanediol, delta DHT, and delta DHEA were (control/MCS) 0.2/6.4 (p=0.0002), -3.2/23.4 (p=0.013), -0.6/3.7 (p=0.0004), and 0.5/4.2 (p=0.004). Postoperative changes did not differ according to sex. We conclude that MCS, but not less intensive non-cardiac surgery, induced a distinct postoperative increase in sex steroid levels. These findings suggest that sex steroids have a role in postoperative metabolism following MCS in prepubertal children.

Primate liver tissue as an alternative substrate for endomysium antibody immunofluorescence testing in diagnostics of paediatric coeliac disease.

BACKGROUND Immunofluorescence assays of antibodies against endomysium (EmA) on primate oesophagus sections represent the gold standard in serological testing for coeliac disease (CD). As alternative immunofluorescence technique, staining of primate liver tissue is in use. We compared performance and predictive power of IgA- and IgG-EmA on primate oesophagus and primate liver sections. METHODS Sera of 298 paediatric biopsy-proven CD patients under gluten-containing diet and 574 disease controls were investigated. Samples were collected between 2004 and 2013 in six childrens hospitals. The antibodies were assayed blinded to diagnoses and histological data. Sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) were calculated for different assays. RESULTS (Oesophagus vs liver): For IgA-EmA, sensitivity (0.953 vs 0.956) and specificity (0.981 vs 0.972) as well as PPV (0.963 vs 0.947) and NPV (0.976 vs 0.979) were comparable on both tissues. IgG-EmA on liver showed significantly higher sensitivity (0.520 vs 0.631; p=0.006) but significantly lower specificity (0.995 vs 0.963; p=0.002) and PPV (0.981 vs 0.899; p=0.0002) than on oesophagus. NPV on liver was higher than NPV on oesophagus, however, the difference was not statistically significant (0.799 vs 0.834; p=0.099). CONCLUSION Primate liver can be used as alternative, equally well functioning substrate for IgA-EmA testing.

Correlation of maternal age and migration on IHPS epidemiology in Germany 2000-2008.

A decline in the incidence of infantile hypertrophic pyloric stenosis (IHPS) was recently reported in Sweden, the US, Denmark, Scotland, and Germany. Data to explain this phenomenon, however, are scarce. Given our previous epidemiologic data showing a decline in the incidence of IHPS, we collected data on maternal age and history of migration from regional administrative centers to obtain data that might support an explanation for our previous findings. We examined the correlation between these factors and the incidence of IHPS. Data were extracted from the public report of health (Gesundheitsberichterstattung des Bundes) and population data from federal state governments. We obtained the numbers of IHPS (ICD-10 code 40.0) and live births in each federal state for the period 2000-2008. Further data were collected from federal state administrative agencies on age of the mother at the birth of their first child and history of migration for all mothers at first birth. There were significant differences in the regional distribution of both variables and the variability of these factors over time. Average maternal age and the percentage of mothers with a history of migration showed a negative correlation with the regional incidence of infantile hypertrophic pyloric stenosis. Conclusion: The wide variation in the incidence of infantile hypertrophic pyloric stenosis over time and for different regions is significantly inversely correlated with rising maternal age and the percentage of mothers with a history of migration.

Lung volume reduction surgery in preterm infants with bronchopulmonary dysplasia. A case report

A preterm infant at the age of 9 months with severe bronchopulmonary dysplasia (BPD) and large lobar emphysema, compromising ventilation into adjacent lobes with respiratory failure under maximal conservative treatment and pulmonary arterial hypertension recovered initially well after bilateral lung volume reduction surgery, but progressed 2 years later into respiratory failure. The initial imaging with Magnetic‐Resonance‐Imaging (MRI)‐Angiography and decision‐making was difficult and interdisciplinary treatment was essential.

Antibody Concentrations Decrease 14-Fold in Children With Celiac Disease on a Gluten-Free Diet but Remain High at 3 Months

Background & Aims Celiac disease can be identified by a serologic test for IgA against tissue transglutaminase (IgA‐TTG) in a large proportion of children. However, the increased concentrations of antibody rarely normalize within the months after children are placed on a gluten‐free diet (GFD). Early serologic predictors of sufficient adherence to GFD are required for optimal treatment. Methods In a prospective study, we observed the response to a GFD in 345 pediatric patients (67% girls; mean age, 8.4 y) who underwent duodenal biopsy to confirm or refute celiac disease from October 2012 through December 2015. Baseline serum samples were tested centrally for IgA‐TTG and IgG against deamidated gliadin. Follow‐up serologic analyses of children on a GFD were performed about 3 months later. Results The geometric mean concentration of IgA‐TTG decreased from 72.4‐fold to 5.2‐fold the upper limit of normal (ULN), or by a factor of 14.0 (95% CI, 12.0–16.4). A substantial response (defined as a larger change than the typical variation in patients not on a GFD) was observed in 80.6% of the children. Only 28.1% of patients had a substantial response in the concentration of IgG against deamidated gliadin. Concentration of IgA‐TTG remained above 1‐fold the ULN in 83.8% of patients, and above 10‐fold the ULN in 26.6% of patients with a substantial response. Conclusions Serum concentration of IgA‐TTG decreases substantially in most children with celiac disease within 3 months after they are placed on a GFD, but does not normalize in most. This information on changes in antibody concentrations can be used to assess patient response to the diet at short‐term follow‐up evaluations. Patients with a substantial response to a GFD often still have high antibody levels after 3 months. German Clinical Trials Registry no. DRKS00003854.

Laser Doppler spectroscopy of testes after unilateral orchiopexy

OBJECTIVE Undescended testes are the most common urogenital malformation in boys. Impaired microcirculation is among other factors addressed as a potential complication of surgery and scar formation, leading to long-term suboptimal results. OBJECTIVE Our aim was to compare the postoperative microcirculation in operated versus non-operated contralateral testis groups after unilateral orchiopexies versus a healthy control cohort. METHODS Ninety-nine consecutive patients were included after unilateral orchiopexy procedures at the age of 3.5 years (±2.9 years) at a single center for pediatric surgery. Eight-five patients were examined with a combination of laser Doppler (blood flow determination) and white-light spectroscopy (oxygen saturation and hemoglobin amount determinations) to determine the microcirculation at two different depth levels non-invasively. All relevant surgery data were obtained retrospectively. RESULTS The right side was operated in 53.5% of cases. Previous hormone treatment had been prescribed in 46.5%. There were no significant differences in perfusion measurements between patients with previous hormone therapy and patients without. There was no significant difference in age and clinical pubertal stage between groups; however, 65% of patients underwent surgery after their second birthday. When comparing oxygen saturation (So2), relative hemoglobin (rHb), flow, and velocity in the operated testis with the contralateral testis of the same patients, we found significantly higher flows and velocities for the contralateral testes (p = 0.041, p = 0.022). Similar higher flows and velocities were found in the healthy controls (p < 0.001). The differences between healthy controls and contralateral testis that were not operated on did not reach statistical significance. There was no difference in measurements at 2 mm depth (skin and subcutaneous tissue) between groups to rule out systemic or capillary differences. DISCUSSION Important limitations include the limited and relatively heterogeneous samples that were obtained for follow-up and retrospective surgery data collection. An additional limitation is missing presurgical data, which we hope to obtain in future studies. Hormonal data or bone age could not be obtained for study reasons. The age in our study was on average above the recommended age for orchiopexy in Germany (6-12 months), which could also restrict generalizability. In terms of complications, we observed reascending testes within the range but a rather high incidence of wound infections. The combination of Doppler and white-light spectroscopy was easily applicable and produced reliable data at 2 and 8 mm depth simultaneously in a standardized setting. CONCLUSIONS After orchiopexy, differences were found in the microcirculation between the operated and contralateral testes or healthy controls. It remains unclear if this is an effect of primary disease or surgery. The microcirculation of contralateral testes was also seemingly different from controls. This is most likely not a consequence of surgery alone, but a common problem for both testes in the affected patients.