The Care of Children and Adolescents with Chronic Inflammatory Bowel Disease

A Cluster-Randomized Trial on Improving the Guideline Conformity of Treatment by the Use of the CEDATA-GPGE Patient Registry

Background: For children and adolescents with chronic inflammatory bowel disease (IBD), treatment that is not in adequate conformity with the guidelines can adversely affect both the course of disease and the patients’ development. The targeted use of digital patient registries may improve real-life adherence to the recommendations of evidence-based guidelines.

Methods: In a cluster-randomized, controlled trial (DRKS00015505), treatment providers for the intervention group (IG) documented the treatment of children and adolescents with IBD in the CEDATA-GPGE patient registry; they received automated feedback on the data they entered and on potential deviations of the documented treatment from recommendations contained in the guidelines (care deficits). Treatments providers for the control group (CG) documented treatments as previously, i.e., only in the patients’ charts. At the end of a twelve-month observation period, the data from both groups at baseline and on follow-up were analyzed in an intergroup comparison. The primary endpoint was the number of care deficits at twelve months.

Results: 319 patients were recruited from 47 pediatric gastroenterological centers in Germany (IG: 21 centers and 160 subjects; CG: 26 centers and 159 subjects). Among the 146 subjects in the IG who were followed up at 12 months, there were an average (mean) of 0.17 care deficits per patient (95% confidence interval [0.10; 0.24]). Among the 134 subjects in the CG who were followed up at 12 months, there were an average (mean) of 0.55 [0.43; 0.66] identified care deficits per patient (p < 0.0001).

Conclusion: Registry-based feedback can help bring treatment and its documentation into better conformity with the relevant guidelines and thereby reduce or prevent care deficits in children and adolescents with IBD.

Chronic inflammatory bowel diseases (CIBD) include such disorders as Crohn’s disease (CD), ulcerative colitis (UC), and indeterminate colitis (IC) (1). An increase in incidence and prevalence of CIBD has been observed worldwide for many decades (2, 3). The patient group comprising children and adolescents is disproportionately affected by this rise (4).

In comparison with CIBD in adult patients, CIBD diagnosed in childhood or adolescence is often more extensive, adopts a more aggressive course, and therefore requires intensive monitoring with timely adjustments of treatment (5, 6, 7). In addition, the impact of the disease and its medication on growth, puberty, and psychosocial development must also be taken into account in young patients (4, 8). In the everyday care of children and adolescents with CIBD, the guidelines provided by the following institutions represent the standard of evidence-based diagnostics and therapy (1, 9, 10, 11):

• European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)
• European Crohn’s and Colitis Organization (ECCO)
• German Society for Pediatric Gastroenterology and Nutrition (GPGE)
• German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS).

Health services research studies show that therapy does not always conform with the guidelines (12, 13). Regular documentation of diagnostic investigations and therapy in patient registries can help improve conformity with guidelines. Since 2004, German and Austrian pediatric gastroenterologists have been able to document diagnostic and treatment data of their pediatric CIBD patients in the CEDATA-GPGE patient registry, the worldwide second largest registry for children and adolescents with CIBD. An analysis of registry data covering the period from 2013 to 2018 confirmed that internationally recognized diagnostic criteria for the treatment of pediatric patients with CIBD (Porto criteria) are fully reflected in the registry (14). An earlier study involving data taken from the registry shows that the incidence of diagnostic investigations has increased over a period of six years from 2004 to 2010 (15).

Automated plausibility and completeness checks now support manual data entry and keep data gaps to a minimum. They not only reflect a recommendation in the current registry report of the Federal Ministry of Health (BMG) (16) but have also been included in the CEDATA-GPGE registry since 2018. The improvement in guideline compliance is part of a continuous long-term quality improvement process (Learning Health System).

Aim

As part of the CLARA trial (CLARA, cluster-randomized trial to improve the care of children and adolescents with chronic inflammatory bowel diseases), registry-based algorithms and patient-specific feedbacks indicating deviations from the guidelines were developed to support clinical decision making and are implemented in the registry (17). The aim of this trial was to reduce the number of patient-specific care deficits in children and adolescents with CIBD by providing treating physicians with registry-based feedback.

Methods

The eMethods section and eTables 1 and 2 contain a detailed presentation of the study methods.

eTable 1

Feedbacks on the initial registration form (IRF) on completion of the form

eTable 2

Feedback at follow-up (DoF) on completion of the form (Supplement to eTable 1)

Study design

The CLARA trial (DRKS00015505) is a two-arm, controlled, cluster-randomized study. Randomization was performed at the level of the participating facilities (practices and clinics). Pediatric gastroenterology centers were recruited which had not yet reported data on the online tool of the CEDATA-GPGE registry at the start of the study.

Participants

The study included pediatric patients with a confirmed diagnosis of CIBD who had been diagnosed no more than three months prior to the date of the initial registration and who were under 18 years of age at the time of diagnosis.

Intervention

Centers in the intervention group (IG) documented diagnostic investigations and treatment of their pediatric patients in the CEDATA-GPGE patient registry using the online platform. The centers’ own in-house documentation remained unaffected by participation in the registry. The treatment providers received structured automated feedback on the data submitted for their patients relating to potential deviations of the diagnostic investigations and treatment from the recommendations in the guidelines (potential care deficits). The respective IG treatment provider had the opportunity to correct, and/or provide comments on, the entries in the documentation form before signing off the documentation.

Treatment providers for the control group (CG) did not document any data in the registry during the observation period and did not receive feedback on their patients. Treatment of the pediatric patients and documentation of data were conducted as usual (usual care).

On completion of the observation period, diagnostic and treatment data in the CG centers were collected retrospectively from the patient records and transferred to the registry by the study team in order to generate data-related feedback similar to that for the IG.

Endpoints

The study’s primary endpoint was the number of identified care deficits at 12 months. Data on inflammatory activity and steroid-free remission as well as the number of complications and side effects at 12 months constituted secondary endpoints.

Data analysis

Pediatric patients with available data at 12-month follow-up were included in the analysis. Registry feedback at the respective survey dates (baseline, 12-month follow-up) were assessed separately from one another during the analysis as different parameters were recorded each time. The evaluation was conducted using t-tests and chi-square tests (alpha = 0.05). A multilevel analysis and a t-test with an imputed data set for dropouts were performed as sensitivity analyses. The results were evaluated and visualized using the statistics programs SPPS, STATA, and SAS (JMP). Data analysis was performed according to the guidelines of “Good Epidemiological Practice” (18).

Results

Participants

Forty-seven centers in Germany were included in the study, and a total of 323 patients were recruited. Of these, 21 centers and 160 patients had been assigned to the IG, with 26 centers and 164 patients in the CG. A total of 160 initial IG registration forms and 159 initial CG registration forms were available for evaluation (Figure 1). The documentation forms of 146 IG patients and 134 CG patients (total n = 280) were included in the analysis at 12-month follow-up.

Figure 1

Analysis flow diagram

Baseline data

Table 1 shows that the majority of patients of both the IG and the CG suffered from CD, followed by UC and IC. There was a balanced distribution of boys and girls with CIBD. The median age in both study groups was 14 years at initial registration.

Table 1

Characteristics of the study group at initial registration

The two study groups were first assessed for structural equality before further analysis was conducted. There were no differences between the IG and the CG on comparing the parameters age and sex distribution, center size (as measured by the number of CIBD cases treated during the year 2019 per center), and GPGE certification.

Endpoints

Table 2 shows the primary endpoint (number of care deficits at 12 months) and the secondary endpoints (data on inflammatory activity, steroid-free remission, complications, and side effects at 12 months).

Table 2

Feedback on completion of the documentation form per study group

Primary endpoint

A total of 99 feedbacks were triggered in the IG from 78 initial registration forms. Of these, 16 care deficits were identified (0.1 care deficits/patient (95% CI: [0.05; 0.15]). No registry feedbacks were triggered in 82 of 160 initial registration forms (51.3%). There were 125 feedbacks at 12-month follow-up, also distributed over 78 documentation forms. Of these, 25 feedbacks turned out to be care deficits (0.17 care deficits/patient [0.10; 0.24]). No registry feedbacks were triggered in 68 of the 146 documentation forms (46.6%).

There were 111 feedbacks from the registry regarding the 84 initial registration forms in the CG. Of these, 20 were care deficits (0.13 care deficits/patient [0.07; 0.19]). No registry feedbacks were triggered in 75 of 159 initial registration forms (47.2%). There were 148 feedbacks in 93 documentation forms at 12-month follow-up. Of these feedbacks, 73 were care deficits (0.54 care deficits/patient [0.43; 0.66]). No registry feedbacks were triggered in 41 of the 134 documentation forms (30.6%).

In the intergroup comparison for the primary endpoint, the number of identified care deficits was lower in the IG (n = 25; 0.17 deficits/patient) as compared with the CG (n = 78; 0.54 deficits/patient) (t[219.03] = 2.58, p <0.0001).

Multiple imputations (Poisson) were performed to analyze the dropouts (n = 39). The subsequent t-test did not reveal any deviations from the main analysis (t[317] = 6.18, p <0.0001). Furthermore, multilevel analyses were conducted as sensitivity analyses with centers as a random effect specifically for the hospitals (n = 302). Adjustments were made for age at diagnosis, sex, GPGE certification, the number of CED cases treated each year, and for centers which recruited more or less than ten patients. The results of the sensitivity analyses did not differ from the main results; only group membership had a significant effect on the endpoint (p <0.001).

Figure 2 illustrates the distribution of the care deficits across the total number of patients at 12-month follow-up per study group. There was no care deficit for 124 of the 146 patients in the IG (85%), with 19 patients (13%) having such a deficit. In the CG, no care deficit was categorized for 75 of the 134 patients (56%), while the forms of 46 patients (34%) did contain such a deficit.

Figure 2

Proportions of patients (pats.) with care deficits during the 12-month follow-up

Table 3 presents the three most common registry feedbacks per data entry date (initial registration or 12-month follow-up) and study group. Low hemoglobin levels on the initial registration form (54 times) and on the follow-up form (65 times) for which no subsequent therapeutic measures were taken were the most commonly documented deficits in the IG. The registry feedback “Disease involvement is incorrect”– which means that the pattern of involvement could not be explained by the stated disease or could not be adequately explained by the diagnostic tests – was categorized as important information in all cases. This happened either because further diagnostics (magnetic resonance enterography) had been documented or the presence of atypical UC was alluded to by the comments of the treatment providers at the intervention centers.

Table 3

The three most frequent registry feedbacks per study group and survey date

Hemoglobin levels which were too low and elevated gamma-GT levels in patients who had not undergone further liver function tests were the most frequent deficits on the initial registration forms of the CG. At 12-month follow-up, the corresponding deficits were insufficient dosage at the start of mesalazine therapy and undocumented thiopurine methyltransferase (TPMT) activity in conjunction with the administration of azathioprine.

Secondary endpoints

Table 2 shows that percentage-wise slightly more patients in the CG were in remission at 12 months (IG: 71.2%; CG: 80.3%). The proportion of patients in whom remission was achieved without the administration of steroids, on the other hand, was larger in the IG (IG: 93.6%; KG: 85.7%). The number of complications at 12-month follow-up was higher in the CG than in the IG (IG: 2.9%; CG: 5.6.%). The opposite picture was evident for the side effects (IG: 19.0%, CG: 13.1%).

Discussion

A total of 134 care deficits were identified (IG: n = 41, CG: n = 93). The number of care deficits at 12 months (primary endpoint) was significantly lower in the IG (n = 25) than in the CG (n = 78). The differences between the two data survey dates per group regarding the number of care deficits do not indicate an increase in the number of deficits but are based more on the different parameters which were recorded in the registry at baseline and at follow-up. Nevertheless, the intervention resulted in a noticeable reduction of registry feedbacks in the IG. Also, the number of documentation forms which did not result in feedbacks from the registry – i.e., which contained guideline-compliant documentation – was distinctly higher in the IG than in the CG.

There was no significant difference between the groups with regard to the secondary endpoints inflammatory activity, steroid-free remission, complications, and side effects. The results of the secondary endpoints should be considered within the context that follow-up was too short for a hard clinical endpoint and that distinctly fewer data were available from the CG for a between-group comparison. Overall, however, it was shown that registry-based algorithms and patient-specific feedback can be useful tools in supporting clinical decision making for treatment providers to reduce patient-specific care deficits during the further course of therapy.

In terms of the type of feedback, it was found that many patients in both study groups had hemoglobin (Hb) levels which were too low. This pattern is known to occur more often in patients with CIBD. Chronic intestinal blood loss is a possible cause of chronic anemia, potentially resulting in growth retardation, learning difficulties, and intellectual disability in childhood and adolescence (19). Chronic anemia should be recognized early and treated with oral or intravenous iron replacement. Failure to administer iron for low Hb blood levels resulted in a categorized care deficit more often in the IG (n = 4) than in the CG (n = 2) despite important information being flagged to the treatment providers by the registry (“The result is too low”). This may be due to the fact that the Hb result was less often documented in the CG (omissions: CG: n = 19, 14.2%; IG: n = 4, 2.7 %), thus potentially triggering fewer feedbacks.

In the initial registration form, most of the children in the CG with elevated gamma-glutamyl transferase (GT) levels as an indication of liver impairment did not undergo further diagnostic assessment, such as magnetic resonance cholangiopancreatography (MRCP) or liver biopsy. This can result in potential disorders, such as primary sclerosing cholangitis (PSC) or autoimmune hepatitis (AIH) going undetected, thus risking further complications. In the CG, the dose of mesalazine was too low for their weight in 24 children who were not in remission at the time of follow-up. This 5-aminosalicylic acid (5-ASA) preparation is regarded as best practice for mild to moderate UC (PUCAI 10–65) (20) and, according to the guideline recommendation, should be administered at a dose of 60 to 80 mg/kg body weight, divided into two doses per day (21).

It is important to determine thiopurine methyltransferase (TPMT) activity before starting azathioprine therapy in order to identify a disproportionately high risk of complications in good time (22). An earlier study from North America showed that TPMT levels were measured in only 61% of patients prior to initiating thiopurine therapy (23). For an assessment of the extent to which measuring TPMT activity is recommended as a preliminary test for treatment with thiopurines, we refer to the ESPGHAN guideline and the heated discussion amongst pediatric gastroenterologists. Despite the difference in the recommendation level as compared with the other deficits described, most pediatric gastroenterologists consider it justified and endorse it in the guideline, particularly with respect to rapid dosing. It is not possible to conclusively assess whether the levels were indeed not determined in every case or whether the result was just not documented (loss of information outside the registry). A literature review showed that data relevant to therapy is often lost during information transfer between hospitals and general practitioners’ offices, such as diagnostic test results (33 to 63%) or details regarding discharge medications (2 to 40%) (24).

Applicability of the study results

More centers should join the CEDATA-GPGE patient registry in future and so improve quality of data documentation as well as quality of care of pediatric patients with CIBD across the board, especially against the background of increasing incidences. The results of the CLARA study show that registry-based feedbacks should be placed on a permanent footing. Furthermore, the results could be applied to other registries or other rare disorders in the future to effectively reduce possible care deficits.

Limitations

The documentation forms were not always recorded in the registry immediately after treatment. As a result, it was not possible to react promptly to, potentially relevant, important information flagged by the registry for the IG. A reason for this could be the additional time needed for documentation. This took between four and 12 minutes for a full registry entry, depending on the complexity of the individual case.

Some registry feedbacks in the IG were categorized as input errors yet may have also resulted in an underestimation of potential care deficits. Furthermore, four centers in the IG did not recruit any patients. The main reason for this was staff adjustments at these centers.

The CLARA project was conducted during the coronavirus pandemic, so the study team was unable to collect CG data on site. The CG centers were requested to send all patient documentation data to the study head office where data was evaluated from the documentation and transferred to the registry. It is not possible to conclusively assess whether the patient documentation data sent was transferred in full in every case.

Conclusions

The inclusion of diagnostic and treatment data in the CEDTA-GPGE patient registry makes a significant contribution to standardized documentation and guideline-based, patient-centered care. Patient-specific feedback can reduce care deficits in diagnostics and therapy. In future, this approach should be made available for all children and adolescents with CIBD.

Data sharing

We agree to make anonymized patient data available to those researchers who submit a methodologically meaningful analysis proposal three months to five years after publication in the Deutsche Ärzteblatt.

Funding

The CED-KQN project associated with this study was funded by the German Federal Joint Committee (G-BA) (funding code: 01VSF17054).

Acknowledgments

We would like to thank the CEDATA-GPGE study group and all participating centers and their patients for their willingness to cooperate in the study (eTable 3). We would particularly like to mention the cooperation in the CLARA study of the following individuals: Kalina Kaul, Melanie Knorr, Maren Leiz, Prof. Wolfgang Hoffmann, Hanna Gurmai, Tanja Weidenhausen, Nicolas Schneider, Philip Krieb, Prof. Henning Schneider, Prof. Volker Groß, Prof. Keywan Sohrabi and Prof. Klaus-Peter Zimmer.

eTable 3

Acknowledgements

Conflict of interest statement
JdL received research funding from Abbvie and Takeda. He is a member of the advisory boards of Sanofi, Danone, and Mirum.

The other authors confirm that there are no conflicts of interest.

Manuscript received on 24 October 2023, revised version accepted on 31 July 2024.

Translated from the original German by Dr. Grahame Larkin

Corresponding author
Luisa Tischler
Medical University of Greifswald

Institute for Community Medicine

Ellernholzstraße 1/2, 17489 Greifswald

Cite this as:
Tischler L, Boerkoel A, Krause H, van den Berg N, de Laffolie J: The care of children and adolescents with chronic inflammatory bowel disease: A cluster-randomized trial on improving the guideline conformity of treatment by the use of the CEDATA-GPGE patient registry. Dtsch Arztebl Int 2024; 121: 627–33. DOI: 10.3238/arztebl.m2024.0168

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