Patients

We analyzed data of patients that were included in CEDATA-GPGE between 01 January 2014 and 31 December 2018, during the first five years of the online platform by participating pediatric gastroenterological centers.

Patients that had no documentation within 90 days after the date of diagnosis were excluded. Additionally, patients recruited before the start of the registry’s online data entry tool 2.0 on 16 December 2016 and that had no documentation later than 14 days after diagnosis were excluded.

Participating centers

Information on the organizational and medical structures of the centers were taken from the homepage of the GPGE and the online available annual quality reports of the hospitals, which have been mandatory for publication in Germany since 2005. In Austria such a reporting system did not exist for our observation period. In the consequence, no structural data were available for Austrian centers.

Porto criteria

The international recommendations (Porto criteria) of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) are the evidence base for medical diagnostic examinations and therapeutic decisions in Germany and Austria. According to these criteria for diagnosis, the following diagnostic work up should be performed to confirm the diagnosis of PIBD (Table ​(Table11).

Children up to the age of six are subsumed under the term ‘very early onset-IBD’ (VEO-IBD). Patients at this age group should be screened for immunodeficiencies, because undetected immunodeficiencies can lead to severe complications in therapy [13]. According to the Porto criteria, immunological examinations and allergy tests are especially recommended for children under two years of age [17].

Analysis

Supplementary survey

The aim of this supplementary survey was to identify differences between the data documented in the registry and the screenings actually performed, i.e., whether there may be an underreporting. Based on the results on center structures using the quality reports, the five largest centers were contacted by email with a request to give information on the following questions: number of treated patients with PIBD; proportion of under 6-year-olds screened for immunodeficiencies and proportion of under 2-year-olds screened for immunodeficiencies and allergies; proportion of patients with PIBD reported in the CEDATA-GPGE registry; if not all patients are reported in the registry, reasons for that.

Identification of variables according to the guidelines in CEDTA-GPGE

We identified 41 diagnostic variables from the CEDATA-GPGE registry. These variables correspond to the Porto criteria in terms of content and fully reflect the recommendations for initial diagnostic work up. Only the disease activity indices PCDAI for CD and PUCAI for UC were not included as variables in the CEDATA-GPGE registry during the study period, but can be calculated from other parameters using validated algorithms. Instead of the Disease Activity Index, the registry included the regular variable Physician overall assessment, which is used to provide a subjective assessment of disease activity. All variables are listed in Table ​Table2.2. The right site of the table shows the 12 associated categories according to the Porto criteria.

Documented examinations

Parameters of the category ‘Case history’ were documented for the largest part of the patients: For more than 80% of patients 7 out of 9 variables in this category were documented. In the category ‘Physical examination’, the parameters ‘Extraintestinal manifestations’ (93.6%) and ‘Abdominal findings’ (92.0%) were the most documented diagnostic measures. The category ‘Puberty stage’ was documented by the variables ‘Breast development’ (48.8%, only female), ‘Pubic hair’ (49.5%, female and male) and ‘Testicular volume’ (36.3%, only male). The least documented category was ‘Imaging of the small bowel’ with 39.1%. In the category ‘Disease activity’, the parameter ‘Physician's overall Assessment’ was assessed for 68.9% of the patients with CD, for 72.2% of patients with UC and for 67.4% of patients with IBD-U. The disease activity index could be calculated for 43.3% of patients with CD and for 76.9% of patients with UC. All categories are listed in Table ​Table33.

Table 3

Measures documented in the diagnostic categories

Instrumental Diagnostic Category	Crohn ‘s Disease n=289	Ulcerative Colitis n=212	Unclassified IBD n=46
	%
Case history	79,9	76,4	73,9
Physical examination	74,1	76,6	69,6
Growth status	66,4	72,6	58,7
Nutrition status	48,4	47,6	47,8
Puberty stagea	74,9	59,7	53,2
Laboratory investigations	72,2	73,0	67,8
Stool samples	58,1	59,0	47,8
Ileocolonoscopy with multiple biopsies	41,1	43,4	42,0
Endoscopy of the upper abdomen	59,5	56,1	55,5
Imaging of the small bowelb	48,4	28,8	28,3
Overall medical assessment	68,9	72,2	67,4
Diagnosis by pediatric gastroenterologist	86,5	83,0	89,1
Disease activity indexc	43,3	76,9	-

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^aThere are 3 variables regarding puberty, but only 2 of 3 variables per patient and gender can be filled in

^bOnly 1 of 3 variables to be filled in per patient, because only one examination of these 3 is carried out—it depends on the type of imaging chosen

^cSelf-calculated from specific variables, which are basic for the determination of the disease activity index

For the categories ‘Case history’, ‘Physical examination’, ‘Nutrition status’, ‘Growth status’, ‘Laboratory investigations’, ‘Diagnosis by’, ‘Ileocolonoscopy with multiple biopsies’, ‘Endoscopy of the upper abdomen’, ‘Bone mineral status’ and ‘Stool tests’ there were no significant differences in frequencies between CD, UC, and IBD-U. Differences in frequencies existed in the category ‘Imaging of the small bowel’ (χ²=20.7, Cramer-V=0.2, p<0.001). In patients with CD, this category was documented more often than in patients with UC and IBD-U. The category ‘Puberty stage’ has significant differences in frequency as well (χ²=9.8, Cramer-V=0.1, p<0.05). It was documented in patients with CD more often than in patients with UC and IBD-U.

The diagnosis was confirmed by a pediatric gastroenterologist in more than 80% of patients in all three diseases (IBD-U: 89.1%, UC: 83.0%, CD: 86.8%).

The proportion of documented instrumental diagnostics showed an overall positive trend over the study period in all three categories ‘Endoscopy of the upper abdomen’, ‘Ileocolonoscopy with multiple biopsies’ and ‘Imaging of the small bowel’ (see Additional file 2). Especially the number of the reported ‘Esophagogastroduodenoscopy’ increased over all three diagnoses during the observation period.

Practical application of the guideline recommendations documented in the registry

The observed symptoms in our study sample corresponds to the typical triad of symptoms of PIBD reported in the literature [15, 24]. The proportion of documented diagnostic examinations varied within the 12 diagnostic categories and also between the three diagnoses. Some categories have a high level of documentation across the three diagnoses, e.g. ‘Case history’ and ‘Physical examination’. Some of the frequencies of the instrumental diagnosis categories, such as the ‘Imaging of the small bowel’, differ between documented diseases. ‘Imaging of the small bowel’ and ‘Ileocolonoscopy with multiple biopsies’ are categories in which examinations are documented poorly for all three diseases. Furthermore, the very low documentation of ‘screening for immunodeficiencies’ in children and adolescents under 6 years of age is conspicuous. The supplementary survey indicated that while the majority of screening is performed, documentation in the registry is often missing. This suggests an underreporting, e.g., due to lack of capacity. Another possible reason is the effort involved in documentation. The documentation needs to be minimal and performed by dedicated personnel. This is further underlined by three phenomena: First, categories that are less relevant in the disease context tend to be less complete, e.g., growth retardation and pubertal delay are far more common in CD than in UC. This is also applicable for upper GI endoscopy and small bowel imaging, although the later may be delayed or at another institution depending on access to MRI or video capsule endoscopy. The second category involves high detail data input, e.g. laboratory values. This needs to be simplified by offering various entry methods (SI units or common other units) or automated transfer of data from hospital information systems (HIS), like evaluated in current and future projects. The last category is data with search effort in the registry, e.g. less common lab investigations like trough levels, vaccination status, or screening for immunodeficiencies. Our survey revealed, that far more of these investigations are performed than reported. This underreporting can only be addressed by improving data entry mechanisms and active query management for missing data and plausibility checks, as also addressed in current projects in CEDATA-GPGE. The registry has been intensely improved from 2016 on to address these issues, including live plausibility checks and improvement in data entry mechanisms. The increase in data documentation from 2016 on may be due to the Online-Tool 2.0. Automated or semiautomated data transfer from HIS is still not possible, but will be implemented in future projects in concurrence with rollout of the German Telematic infrastructure initiative.

The increase in instrumental diagnostics in all three diagnoses between 2014 and 2018 is in line with the observed increase in ileocolonoscopy and esophagogastroduodenoscopy by Buderus et al. for the period 2004 to 2014 [24]. Since 2011, the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) recommend esophagogastroduodenoscopy not only in CD but also in UC [33]. The Porto criteria recommend esophagogastroduodenoscopy in all suspected cases of IBD, too [17]. During our observation period, a lower rate of ileocolonoscopy and esophagogastroduodenoscopy was performed compared to Buderus et al. [24]. The low rates of some instrumental diagnostic measures, such as endoscopy, must be viewed with caution, considering input errors or incorrect reporting procedures or a diagnosis including endoscopy that took place outside the reporting center. The documentation characteristics in the registry have changed in 2016, as described above, which may lead to better documentation. This will be evaluated in future studies.

Which examination technique was used may depend on advances in medical technology and availability at a clinic or practice [34]. For example, X-ray was a common examination for imaging of the small bowel for a long time. However, because radiography has undesirable side effects (radiation exposure) for young patients, gentler examinations such as MRI or video capsule endoscopy should be preferred [17]. The data of Buderus et al. [24] as well as our study show that this recommendation finds acceptance among documenting centers.

The recommendation ‘Diagnosis by gastroenterologists with pediatric expertise’ is not in itself a diagnostic measure in the strict sense, but it is the most frequently documented variable from the recommended measures for diagnosis. This is due to the fact that mainly pediatric gastroenterologists document in the registry. Patients with IBD-U were diagnosed by a pediatric gastroenterologist more frequently than patients with CD or UC. It is conceivable that patients present to a specialist more often when findings are unclear, that is typical for IBD-U. IBD-U patients are younger and thus more prone to be treated by pediatric gastroenterological specialists.

The accurate documentation in the registry according to current guidelines is an important challenge for the participating centers but also for the administration of the CEDATA-GPGE registry. Missing documentation may influence the determination of important parameters, such as disease activity indices. An accurate documentation leads to improved process and outcome measures in children and adolescents with IBD, as Crandall et al. showed [23].

It should be considered that in some cases deviations from guidelines are justifiable [35]. Reasons may be disease type, age group, previous diseases, comorbidities, but also acceptance and reliability of parents. In practice, local availability is also likely to play a role. For example, by far not all outpatient clinics have access to video capsule endoscopy or easy access to MRI. The documentation of structural data of the reporting centers should be implemented in CEDATA-GPGE in the future in order to expand the possibilities of the registry for scientific questions of health services research. This kind of data allows comparisons between hospitals (benchmarking) [36] but also between the levels of care, staff and their qualification. Furthermore, they can provide insights into the use of certain equipment in the clinics [16, 34].

There may be reasons why some measures were not applied or documented in the registry, but these reasons were not documented in the registry during the observation period. Automated plausibility checks offer the opportunity to facilitate manual data input and to minimize missing data [26]. Since 2016, a new feature in the registry is that practitioners can use comments to inform about their decision on a specific issue. To increase data quality, regular data monitoring will be conducted so that individualized feedback can be provided to the recruiting centers [37]. Financing of dedicated personnel capacity for external quality assurance, as is mandatory by German law (§135a SGB V German Social Law), should be strictly implemented to ensure adequate participation and representative data extraction.

Limitations

Generalizations or transfer of the results to the entire patient population with PIBD in German-speaking countries are not possible, because the documenting centers are selective compared to the overall treatment of PIBD. Only patients who were diagnosed in specialized centers and gave written consent were included in the registry. Other reasons why patients are not included in the registry may be time restrictions during data collection or in the centers; presentation in the emergency department or other clinics; change of clinic with loss to patient’s first reports; changes in the nursing, medical and scientific staff of an outpatient clinic. Four of the five centers of the additional survey stated, that they report between 50 and 70% of patients in the registry. Lack of staff and time were frequently mentioned as reasons for not reporting all patients. Therefore, the number of patients documented in the registry is smaller than the number who actually were diagnosed at the participating centers. Consequently, the registry is at risk of inclusion and exclusion bias, respectively, and there is a risk of overinterpretation of the results (selection bias). By choosing to survey the five largest centers rather than a random sample, it is likely that there is a selection bias here as well. A funnel plot was performed to check the relative contribution of each participating center to the results. This revealed heterogeneity, meaning larger centers included more patients, that may dominate the results.

We thank all members of the CEDATA-GPGE study group for their support in recruitment as well as our patients and their families. We would like to thank H. Gurmai (Giessen) and T. Weidenhausen (Giessen) for their cooperation in database evaluation.

CEDATA GPGE Study Group

Buderus, S⁵, Bufler, P⁶, Däbritz, J⁴, Dammann, S⁷, de Laffolie, J³, Hauer, A⁸, Keller, K-M⁹, Krahl, A¹⁰, Laaß, M¹¹, Lang, T¹², Posovszky, C¹³, Rodeck, B¹⁴, Trenkel, S¹⁵

³General Pediatrics & Neonatology, Justus-Liebig-University, Giessen, Germany

⁴Department of Pediatrics, Greifswald University Medical Center, Greifswald, Germany

⁵Department of Pediatrics, St. Marien-Hospital-Bonn, Bonn, Germany

⁶Department of Pediatrics, Charité – Berlin University Medical Center, Berlin, Germany

⁷Department of Pediatrics, Stuttgart Medical Center, Stuttgart, Germany

⁸Department of General Pediatrics, Graz University Medical Center, Graz, Austria

⁹Department of Pediatrics, Wiesbaden DKD Helios Hospital, Wiesbaden, Germany

¹⁰Department of Pediatrics, Offenbach Sana Medical Center, Offenbach, Germany

¹¹Department of Pediatrics, Dresden University Medical Center Carl Gustav Carus, Dresden, Germany

¹²Medical Center St. Hedwig, KUNO University Children’s Clinic, Regensburg, Germany

¹³Gastroenterology & Nutrition, University Children's Hospital Zurich, Zurich, Switzerland

¹⁴Department of Pediatrics, Osnabrück Christian Children's Hospital, Osnabrück, Germany

¹⁵Department of Pediatrics, Western Brandenburg Medical Center, Potsdam, Germany