DÄ internationalArchive19/2017Inflammatory Bowel Disease in Childhood and Adolescence

Review article

Inflammatory Bowel Disease in Childhood and Adolescence

Diagnosis and treatment

Dtsch Arztebl Int 2017; 114(19): 331-8; DOI: 10.3238/arztebl.2017.0331

Däbritz, J; Gerner, P; Enninger, A; Claßen, M; Radke, M

Background: The incidence of inflammatory bowel disease (IBD) in childhood and adolescence is 5–11 cases per 100 000 persons per year, corresponding to a new diagnosis of IBD in 800–1470 patients in Germany each year.

Methods: This review is based on pertinent publications retrieved by a selective search in PubMed, including guidelines from Germany and abroad.

Results: Children and adolescents with IBD often have extensive involvement and an aggressive course of disease. Nonetheless, infliximab and adalimumab are the only biological agents that have been approved for this group of patients. In Crohn’s disease, exclusive enteral nutrition is the treatment of first choice for inducing a remission. Patients with (peri-)anal fistulae are treated primarily with infliximab. Corticosteroids and aminosalicylates should be used with caution. In contrast, children and adolescents with ulcerative colitis are treated with either aminosalicylates or prednisolone to induce a remission. As a rule, maintenance pharmacotherapy with thiopurines in Crohn’s disease and severe ulcerative colitis, or with aminosalicylates in mild to moderate ulcerative colitis, is indicated for several years, at least until the end of puberty. Patients with refractory disease courses are treated with methylprednisolone, anti-TNF-α-antibodies, and/or calcineurin inhibitors. The spectrum of surgical interventions is the same as for adults. Specific aspects of the treatment of children and adolescents with IBD include adverse drug effects, the areas of nutrition, growth, and development, and the structured transition to adult medicine.

Conclusion: Children and adolescents with IBD or suspected IBD should be cared for by pediatric gastroenterologists in a center where such care is provided. Individualized treatment with multidisciplinary, family-oriented long-term care is particularly important. Drug trials in children and adolescents are needed so that the off-label use of drugs to patients in this age group can be reduced.

LNSLNS

The incidence of Crohn’s disease in Germany is up to 6.6 per 100 000 population. Its prevalence is approximately 100 to 200 per 100 000 population (1). For ulcerative colitis, the incidence in Germany is 3.0 to 3.9 per 100 000 population, and its prevalence approximately 160 to 250 per 100 000 population (2). Inflammatory bowel disease (IBD) is diagnosed before the age of 18 years in approximately 25% of all patients; approximately one-quarter of all affected children and adolescents are under the age of 10 years at diagnosis (3). Children and adolescents with IBD are more likely to have more severe intestinal involvement at diagnosis and faster disease progression than adults (4). Treatment recommendations for children and adolescents are different than those for adults (513, e1). The treatment of children and adolescents with suspected or confirmed IBD should comply with these recommendations and be performed by pediatric gastroenterologists (1, 2). Multidisciplinary treatment of children and adolescents with IBD is complex, especially because it requires the availability of numerous subdisciplines (e2). Data on children and adolescents with IBD in Germany is recorded in the CEDATA-GPGE registry of the German-speaking Society for Pediatric Gastroenterology and Nutrition (GPGE, Gesellschaft für Pädiatrische Gastroenterologie und Ernährung) (14, 15). This paper addresses the increasingly important subject of medical care for children and adolescents with IBD in the context of aspects specific to ages at which development is ongoing.

Methods

This article is based on a selective search of the literature in PubMed. Both German (1, 2) and European (1113) guidelines for both the above-mentioned diseases are available and were consulted. For the diagnosis of IBD, the available data is mostly limited to case series, but treatment recommendations are usually based on controlled trials or meta-analyses of controlled trials.

Diagnosis

As with adults, IBD is suspected in children and adolescents when initial diagnostic examination reveals a combination of symptoms and abnormal laboratory findings (including fecal inflammatory markers). It is diagnosed if there are abnormal findings in clinical history and on physical examination using endoscopy and radiology, including histopathological evaluation of stepwise biopsies from the upper and lower gastrointestinal tract (16).

Symptoms

Although the clinical presentation of IBD in children and adolescents can be similar to that found in adults, some of the disease phenotype is substantially different. This can be caused by, for example, specific complications, sometimes age-specific, such as growth retardation or delayed puberty (Table). For Crohn’s disease in particular, variability between individuals is particularly great in childhood and adolescence. It is not uncommon for symptom onset to be very hard to notice. Because symptoms differ in degree of severity and intensity, in individual cases they can be confused with nonspecific or functional complaints (17, 18). The most common extraintestinal manifestation of IBD in children and adolescents is impaired growth/growth retardation; this is particularly true of Crohn’s disease, in which impaired growth/growth retardation occurs in 10 to 30% of cases. Approximately 10% of children and adolescents have other extraintestinal manifestations of IBD at diagnosis; these can also occur in adults (19) (Table).

Clinical history and physical examination

Children and adolescents with IBD are more likely than adults to have a positive family history of IBD. This indicates that genetic factors play a greater role in IBD when initial manifestation occurs during childhood or adolescence (20, e3). Intestinal inflammation in infants and young children can be caused by a number of genetic defects that can lead to involvement of the immune system and the intestinal epithelium (this is known as monogenic IBD). Approximately 1% of children and adolescents with IBD are less than 1 year old; around 15% are younger than 6 years (21). Full physical examination must include oral and perianal inspection (rectal examination if necessary) and evaluation of height and weight using age- and sex-specific percentile curves and pubertal development (Tanner stages). A height z-score of less than –2.5 indicates significant impaired growth/growth retardation. Body mass index (BMI) and rate of growth (in centimeters per year) are also calculated, on the basis of anthropometric data. BMI below the 10th percentile and/or rate of growth less than 5 cm per year (in children older than 2 years) indicates significant impaired growth/growth retardation.

Laboratory diagnostics

As in adults, diagnosis of IBD requires blood and stool tests (1, 2, 16) (eTable 1). Diagnostic procedures for celiac disease must be performed in children and adolescents with growth retardation and/or nonbloody diarrhea (22). In children with suspected IBD before the age of 2 years, primary immunodeficiency must also be ruled out (21). Disease onset before the age of 6 years is probably caused by a genetic, possibly monogenic, immunodeficiency with intestinal inflammation typical of IBD. The incidence of very early disease onset is approximately 4.37 per 100 000; its prevalence is 14 per 100 000 (21). The possibility of an underlying food allergy must also be considered (23, e4).

eTable 1

Endoscopy and histopathology

If suspected IBD is confirmed on the basis of clinical history, physical examination, and laboratory findings, the patient requires treatment by an experienced pediatric gastroenterologist. Upper gastrointestinal endoscopy and ileocolonoscopy are usually performed under sedation (or general anesthesia). During endoscopy stepwise biopsies are taken from all sections of the gastrointestinal tract, including those which are endoscopically normal. These then undergo histopathological evaluation (e5e7).

Imaging diagnostics

Involvement of the small intestine is assessed using either magnetic resonance (MR) enterography with oral contrast only (administered per os or via nasogastric tube) or video capsule endoscopy (16). MR enterography can be performed from the age of 3 or 4 years. In addition, high-resolution transabdominal Doppler ultrasound is highly suitable as a screening or monitoring examination in children. Conventional X-ray is used if ileus, subileus, or toxic megacolon is suspected, and to determine bone age (left hand). Computed tomography is used only in emergencies or where other diagnostic procedures have failed, due to the radiation burden it entails. MR cholangiopancreatography (MRCP) is used in children and adolescents for certain specific issues (e.g. suspected liver/bile duct involvement).

Differential diagnoses

The main differential diagnoses for IBD in children and adolescents are summarized in the Table (17, 18, 22, 24, 25).

Classification

The Paris classification for inflammatory bowel disease in children and adolescents is closely based on the Montreal classification for IBD in adults. Among other issues, it stratifies risk before the beginning of treatment (16, 28, e8). Clinical indices are of proven value in assessing disease activity, particularly within studies. They were developed specifically for children and adolescents with Crohn’s disease (eTable 2) and ulcerative colitis (eTable 3) (8, 9, e1). However, because of the increasing importance of specific biomarkers (particularly fecal calprotectin), these indices require revision (e9, e10).

eTable 2
eTable 3

Treatment

Specific features of IBD in children and adolescents

Treatment for IBD in patients under the age of 18 years differs from treatment recommendations for adults, sometimes substantially (1, 2, 27, 28). Two examples of this are intensiveness of treatment and drug authorization. eTable 4 details randomized clinical trials in children and adolescents with IBD (e11e22). The main differences between treatment algorithms for children and adolescents and those for adults are shown in the eBox (11, 12, 27, e17, e23). Detailed written information on all aspects of IBD written specifically for children, adolescents, parents, schoolteachers, and kindergarten teachers is available, as are apps for smartphones and tablets and an IBD booklet specifically for children and adolescents. The treatment concept also includes seminars for physicians, patients, and parents and IBD training programs for children and adolescents. Children from the age of approximately 4 years must be either supervised when they take tablets or trained in doing so; alternatively, medication can be provided in alternative pharmaceutical forms. Treatment algorithms for children and adolescents with IBD are summarized in Figures 1 and 2.

Figure 1
Figure 2
eTable 4

Preparation for immunosuppressant therapy

Patients’ vaccination status and infectious disease history should be ascertained before beginning treatment. If a patient is not sufficiently protected by prior vaccinations, the necessary vaccinations—in line with the patient’s age and with current vaccination recommendations—should be administered before immunosuppressant treatment is begun. This is particularly important for live vaccines, as these are usually contraindicated later, i.e. during immunosuppressant treatment (e24, e25). Inactivated vaccines can and should be used even in immunosuppressed children and adolescents (ideally, for optimal efficacy, at least 2 weeks before the beginning of immunosuppressant treatment or during stable disease phases). In addition, latent tuberculosis must be ruled out using clinical history, chest X-ray, and a tuberculosis blood test (γ-interferon assay) before immunosuppressant treatment is begun (particularly before anti-TNF-α antibody therapy). The genotype (or activity) of thiopurine methyltransferase (TPMT) should be determined before thiopurine therapy is administered; this is because hereditary low or absent TPMT activity entails an increased risk of severe thiopurine-induced bone marrow toxicity (11, 29, e26).

Inducing remission

First-line treatment to induce remission in children and adolescents with Crohn’s disease, regardless of severity, is exclusive enteral nutrition (EEN) via liquid or tube feeding (11, 3032). Exceptions to this are children and adolescents who present risk factors (particularly anal fistulae): for this group, primary treatment is infliximab therapy (11). Formula feeding can be administered orally, via a nasogastric tube, or via a percutaneous endoscopic gastrostomy (PEG) tube as part of EEN. Regarding PEGs, caution is required in cases of isolated involvement of the upper gastrointestinal tract proximal to the Treitz ligament (e27). If therapy has had no effect after 1 to 2 weeks or if treatment is refused by the patient or the patient’s family, glucocorticoid treatment is administered instead. TNF-α blockers (adalimumab, infliximab) are authorized for the treatment of Crohn’s disease in patients over the age of 6 years. If any risk factors are present, TNF-α blockers should be used as initial remission induction therapy (11). Prognostic risk factors for severe disease progression in children and adolescents with Crohn’s disease are listed in Figure 1b (11). In children and adolescents with mild to moderate ulcerative colitis, remission is induced using 5-aminosalicylates; corticosteroids are used if disease activity is high or the disease is severe (12). Long-term and/or frequent use of corticosteroids in children and adolescents is no longer current practice, among other reasons because of their severe side effects for growth and physical development (11). eTable 5 states the recommendations for tapering prednisone or prednisolone dosing (11, 13).

eTable 5

Maintaining remission

Immunosuppressants (thiopurines, methotrexate) and/or biologics (adalimumab, infliximab) are generally used to maintain remission in children and adolescents with Crohn’s disease (11). Because of the high relapse rate after cessation of EEN, in moderate to severe Crohn’s disease immunomodulators (i.e. thiopurines, or methotrexate if thiopurines are not tolerated) should be used to maintain remission at the same time as EEN is begun to induce it. Partial enteral nutrition (PEN), if appropriate in combination with 5-aminosalicylates (if there is only colonic involvement), can be used as maintenance therapy if the patient responds well to EEN and Crohn’s disease activity is initially mild (11). Even when Crohn’s disease activity is initially moderate or severe, PEN can be used as supportive therapy in addition to pharmacological maintenance therapy. Budesonide is used rarely and only for selected Crohn’s disease patients under the age of 18 years with mild to moderate ileocecal involvement (11). In children and adolescents with ulcerative colitis, 5-aminosalicylates are used to maintain remission, in combination with thiopurines or biologics (infliximab) if involvement is extensive or severe (12). Surgery is an established part of therapy for serious or complicated progression in the long term. Indications for surgery in children and adolescents with IBD are de facto the same as for adults; as it is known to have the potential for complications, it should be performed only by surgeons experienced in IBD surgery (e28). Finally, due to the trials conducted to date and drug authorizations for children and adolescents with IBD, off-label drug use or individualized treatment approaches such as other biologics (e.g. vedolizumab, ustekinumab, or golimumab in children under the age of 6 years) are often required (27).

Acute severe ulcerative colitis

Acute severe ulcerative colitis in children and adolescents is treated with methylprednisolone (1 to 1.5 mg/kg/day intravenously in 2 divided doses, maximum 60 mg/day) (13, 33). Until thiopurines take effect, second-line treatment involves calcineurin inhibitors (cyclosporine, tacrolimus) or infliximab. TNF-α blockers (infliximab) are an option for maintenance therapy if there is no response to thiopurines, steroids are not tolerated, or if there is increased cyclosporine toxicity (13). Subtotal colectomy with ileostomy should be considered early in cases of acute severe ulcerative colitis or toxic megacolon if there is no response to conservative treatment (13).

Optimizing treatment

Treatment adherence problems are not uncommon, particularly during puberty and among adolescents (e29). Adherence has been found to decrease between the ages of 7 and 17 years (e30). Optimization of existing treatment should be the first step if treatment failure is suspected and before every escalation of therapy. This includes checking medication adherence, dosing, and efficacy. In addition, therapeutic drug monitoring with testing for thiopurine metabolites (6-TGN and 6-MMP) or for trough levels and antibodies against infliximab and adalimumab (29, 34) and biomarker dynamics (particularly fecal calprotectin) plays an important role in the treatment of children and adolescents with IBD. This is particularly true when thiopurines and/or TNF-α blockers lose clinical efficacy (e9, e10). Testing for thiopurine metabolites is part of checking for adherence.

Long-term treatment

Follow-up

Subsequent checkups performed by a pediatric gastroenterologist are usually required at least every 3 months (more frequently in complicated or treatment-refractory cases). These are particularly important to enable impaired growth, delayed puberty, nutritional deficiencies, drug side effects, opportunistic and other infections, and extraintestinal manifestations to be treated promptly (35, e31). Endoscopic or histological re-evaluation is indicated before major changes to treatment and when response to treatment is uncertain (12). Colitis-associated cancers can occur in IBD patients even before the age of 18 years and necessitate appropriate screening (35, 36).

Growth and nutrition

Impaired growth can be prevented or mitigated through swift diagnosis (calculation of genetic target height, growth prognosis based on bone age), appropriate/intensive treatment with sparing corticosteroid use, and sufficient energy/nutrient intake (36). Children and adolescents with IBD require concomitant treatment by nutritional therapists, as their nutritional status is usually critical (37, e32, e33). Intravenous ferric carboxymaltose is the preferred treatment for iron deficiency, which is common. Vitamin D should be administered at a dose of 600 IU/day in children and adolescents with IBD, as for healthy children and adolescents; the recommended calcium intake is 1000 mg/day for children aged between 4 and 8 years and 1300 mg/day for those aged 9 to 18 years. Children and adolescents with IBD require regular vitamin D and calcium supplementation, as regular family food often fails to comply with these recommendations (35, 36, e34, e35). Alternatively, single oral administration of vitamin D3 may be sufficient (e36). The target serum concentration of 25 hydroxyvitamin D (25-OHD) is above 30 ng/mL (e37).

Psychosocial treatment

Children and adolescents with IBD are at increased risk of psychosocial problems and psychiatric illness (particularly depression). These can have adverse effects on school attendance, education, leisure activities, medication adherence, and quality of life (38, e38e41). Case studies suggest that 25 to 40% of IBD patients, usually adolescents, show signs of clinical depression (e42, e43). Concomitant treatment in the form of initial psychological counselling/evaluation and, if necessary, psychotherapy is therefore recommended for children and adolescents with IBD (e44, e45).

Transition

A structured transition program (e.g. the Berlin Transition Program) should provide a comprehensive, accompanied transition from adolescent to adult care, with costs covered. This is because deficiencies in care during this particularly critical phase result in treatment interruptions, insufficient treatment compliance, and increased frequency of complications that are probably avoidable (10, 39, e28, e46, e47).

Additional information on IBD is provided by the German-speaking Society for Pediatric Gastroenterology and Nutrition (GPGE, Gesellschaft für Pädiatrische Gastroenterologie und Ernährung) at www.gpge.de and the German Association for Crohn’s Disease and Ulcerative Colitis (DCCV, Deutsche Morbus Crohn/Colitis ulcerosa Vereinigung) at www.dccv.de.

Conflict of interest statement

Prof. Däbritz has received consultancy and lecture fees and reimbursement of travel expenses from Abbvie, Nestlé, Shire, Humana, and Takeda.

Prof. Gerner has received consultancy fees from Abbvie and lecture fees and reimbursement of travel expenses from Abbvie and MSD.

Dr. Enninger has received consultancy fees from the Nestlé Nutrition Institute and lecture fees and reimbursement of travel expenses from Abbvie, Nutricia, and the Nestlé Nutrition Institute.

Dr. Claßen has received lecture fees from Abbvie, Falk, Nestlé, Nutricia, and MSD; reimbursement of travel expenses from Abbvie and MSD; and funding for a commissioned clinical study from Janssen Biologics B.V.

Prof. Radke has received consultancy fees from MSD and Abbvie; reimbursement of travel expenses from MSD, Abbvie, Falk, and Nestlé; lecture fees from MSD, Abbvie, and Falk; authors’ fees from MSD and Abbvie; and research funding from MSD.

Manuscript received on 17 November 2016, revised version accepted on 2 March 2017.

Translated from the original German by Caroline Shimakawa-Devitt, M.A.

Corresponding author:
Prof. Dr. med. Jan Däbritz
Kinder- und Jugendklinik, Universitätsmedizin Rostock
Ernst-Heydemann-Str. 8, 18057 Rostock, Germany
Jan.Daebritz@med.uni-rostock.de

Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref1917

eTables, eBox:
www.aerzteblatt-international.de/17m0331

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e18.
Escher JC, European Collaborative Research Group on Budesonide in Paediatric IBD: Budesonide versus prednisolone for the treatment of active Crohn‘s disease in children: a randomized, double-blind, controlled, multicentre trial. Eur J Gastroenterol Hepatol 2004; 16: 47–54 MEDLINE
e19.
Romano C, Famiani A, Comito D, Rossi P, Raffa V, Fries W: Oral beclomethasone dipropionate in pediatric active ulcerative colitis: a comparison trial with mesalazine. J Pediatr Gastroenterol Nutr 2010; 50: 385–9 MEDLINE
e20.
Ferry GD, Kirschner BS, Grand RJ, et al.: Olsalazine versus sulfasalazine in mild to moderate childhood ulcerative colitis: results of the Pediatric Gastroenterology Collaborative Research Group Clinical Trial. J Pediatr Gastroenterol Nutr 1993; 17: 32–8 CrossRef MEDLINE
e21.
Cezard JP, Munck A, Mouterde O, et al.: Prevention of relapse by mesalazine (Pentasa) in pediatric Crohn‘s disease: a multicenter, double-blind, randomized, placebo-controlled trial. Gastroenterol Clin Biol 2009; 33: 31–40 CrossRef MEDLINE
e22.
Levine A, Weizman Z, Broide E, et al.: A comparison of budesonide and prednisone for the treatment of active pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2003; 36: 248–52 CrossRef MEDLINE
e23.
Boyle BM, Kappelman MD, Colletti RB, Baldassano RN, Milov DE, Crandall WV: Routine use of thiopurines in maintaining remission in pediatric Crohn‘s disease. World J Gastroenterol 2014; 20: 9185–90 MEDLINE PubMed Central
e24.
Schleker T, Speth F, Posovszky C: Impfen beim immunsupprimierten Kind. Pädiatrische Praxis 2016; 85: 363–84.
e25.
Wasan SK, Baker SE, Skolnik PR, Farraye FA: A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol 2010; 105: 1231–8 CrossRef MEDLINE
e26.
Coenen MJ, de Jong DJ, van Marrewijk CJ, et al.: Identification of patients with variants in TPMT and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease. Gastroenterology 2015; 149: 907–17 e7.
e27.
Heuschkel RB, Gottrand F, Devarajan K, et al.: ESPGHAN position paper on management of percutaneous endoscopic gastrostomy in children and adolescents. J Pediatr Gastroenterol Nutr 2015; 60: 131–41 CrossRef MEDLINE
e28.
Radke M: [Chronic inflammatory bowel disease: transition from pediatric to adult care]. Dtsch Med Wochenschr 2015; 140: 673–8 MEDLINE
e29.
Spekhorst LM, Hummel TZ, Benninga MA, van Rheenen PF, Kindermann A: Adherence to oral maintenance treatment in adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2016; 62: 264–70 CrossRef MEDLINE
e30.
LeLeiko NS, Lobato D, Hagin S, et al.: Rates and predictors of oral medication adherence in pediatric patients with IBD. Inflamm Bowel Dis 2013; 19: 832–9 CrossRef MEDLINE
e31.
Veereman-Wauters G, de Ridder L, Veres G, et al.: Risk of infection and prevention in pediatric patients with IBD: ESPGHAN IBD Porto Group commentary. J Pediatr Gastroenterol Nutr 2012; 54: 830–7 CrossRef MEDLINE
e32.
Bischoff SC, Koletzko B, Lochs H, Meier R: [Clinical nutrition in gastroenterology (part 4)—inflammatory bowel diseases]. Aktuel Ernahrungsmed 2014; 39: e72–e98.
e33.
Valentini L, Volkert D, Schütz T, et al.: [DGEM terminology for clinical nutrition]. Aktuel Ernahrungsmed 2013; 38: 97–111.
e34.
Levin AD, Wadhera V, Leach ST, et al.: Vitamin D deficiency in children with inflammatory bowel disease. Dig Dis Sci 2011; 56: 830–6 CrossRef MEDLINE
e35.
Pappa HM, Mitchell PD, Jiang H, et al.: Maintenance of optimal vitamin D status in children and adolescents with inflammatory bowel disease: a randomized clinical trial comparing two regimens. J Clin Endocrinol Metab 2014; 99: 3408–17 CrossRef MEDLINE PubMed Central
e36.
Shepherd D, Day AS, Leach ST, et al.: Single high-dose oral vitamin D3 therapy (Stoss): a solution to vitamin D deficiency in children with inflammatory bowel disease? J Pediatr Gastroenterol Nutr 2015; 61: 411–4.
e37.
Pappa H, Thayu M, Sylvester F, Leonard M, Zemel B, Gordon C: Skeletal health of children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2011; 53: 11–25 CrossRef MEDLINE PubMed Central
e38.
Engelmann G, Erhard D, Petersen M, et al.: Health-related quality of life in adolescents with inflammatory bowel disease depends on disease activity and psychiatric comorbidity. Child Psychiatry Hum Dev 2015; 46: 300–7 CrossRef MEDLINE
e39.
Kilroy S, Nolan E, Sarma KM: Quality of life and level of anxiety in youths with inflammatory bowel disease in Ireland. J Pediatr Gastroenterol Nutr 2011; 53: 275–9 CrossRef MEDLINE
e40.
Reigada LC, Hoogendoorn CJ, Walsh LC, et al.: Anxiety symptoms and disease severity in children and adolescents with Crohn disease. J Pediatr Gastroenterol Nutr 2015; 60: 30–5 CrossRef MEDLINE
e41.
Giannakopoulos G, Chouliaras G, Margoni D, et al.:
Stressful life events and psychosocial correlates of pediatric inflammatory bowel disease activity. World J Psychiatry 2016; 6: 322–8 CrossRef MEDLINE PubMed Central
e42.
Szigethy E, Levy-Warren A, Whitton S, et al.: Depressive symptoms and inflammatory bowel disease in children and adolescents: a cross-sectional study. J Pediatr Gastroenterol Nutr 2004; 39: 395–403 CrossRef MEDLINE
e43.
Clark JG, Srinath AI, Youk AO, et al.: Predictors of depression in youth with Crohn disease. J Pediatr Gastroenterol Nutr 2014; 58: 569–73 CrossRef MEDLINE PubMed Central
e44.
Thompson RD, Craig A, Crawford EA, et al.: Longitudinal results of cognitive behavioral treatment for youths with inflammatory bowel disease and depressive symptoms. J Clin Psychol Med Settings 2012; 19: 329–37 CrossRef MEDLINE
e45.
Keethy D, Mrakotsky C, Szigethy E: Pediatric inflammatory bowel disease and depression: treatment implications. Curr Opin Pediatr 2014; 26: 561–7 CrossRef MEDLINE PubMed Central
e46.
Paine CW, Stollon NB, Lucas MS, et al.: Barriers and facilitators to successful transition from pediatric to adult inflammatory bowel disease care from the perspectives of providers. Inflamm Bowel Dis 2014; 20: 2083–91 CrossRef MEDLINE PubMed Central
e47.
Müther S, Rodeck B, Wurst C, Nolting HD: [Transition to adult care for adolescents with chronic disease. Current developments]. Monatsschr Kinderheilkd 2014; 162: 711–8 CrossRef
Department of Pediatrics, University Hospital Rostock: Prof. Dr. Däbritz, M.D., Prof. Dr. Radke, M.D.
Centre for Immunobiology, Blizard Institute, Barts Cancer Institute the Barts & The London School of Medicine & Dentistry, Queen Mary University of London, Großbritannien: Prof. Dr. med. Däbritz
Department of Pediatrics, University Hospital Freiburg: Prof. Dr. Gerner, M.D.
Department of Pediatrics, Olgahospital Stuttgart: Dr. Enninger, M.D.
Department of Pediatrics, Klinikum links der Weser, Bremen: Dr. Claßen, M.D.
Department of Pediatrics, Klinikum Westbrandenburg, Potsdam: Prof. Dr. Radke, M.D.
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e18.Escher JC, European Collaborative Research Group on Budesonide in Paediatric IBD: Budesonide versus prednisolone for the treatment of active Crohn‘s disease in children: a randomized, double-blind, controlled, multicentre trial. Eur J Gastroenterol Hepatol 2004; 16: 47–54 MEDLINE
e19.Romano C, Famiani A, Comito D, Rossi P, Raffa V, Fries W: Oral beclomethasone dipropionate in pediatric active ulcerative colitis: a comparison trial with mesalazine. J Pediatr Gastroenterol Nutr 2010; 50: 385–9 MEDLINE
e20.Ferry GD, Kirschner BS, Grand RJ, et al.: Olsalazine versus sulfasalazine in mild to moderate childhood ulcerative colitis: results of the Pediatric Gastroenterology Collaborative Research Group Clinical Trial. J Pediatr Gastroenterol Nutr 1993; 17: 32–8 CrossRef MEDLINE
e21.Cezard JP, Munck A, Mouterde O, et al.: Prevention of relapse by mesalazine (Pentasa) in pediatric Crohn‘s disease: a multicenter, double-blind, randomized, placebo-controlled trial. Gastroenterol Clin Biol 2009; 33: 31–40 CrossRef MEDLINE
e22.Levine A, Weizman Z, Broide E, et al.: A comparison of budesonide and prednisone for the treatment of active pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2003; 36: 248–52 CrossRef MEDLINE
e23.Boyle BM, Kappelman MD, Colletti RB, Baldassano RN, Milov DE, Crandall WV: Routine use of thiopurines in maintaining remission in pediatric Crohn‘s disease. World J Gastroenterol 2014; 20: 9185–90 MEDLINE PubMed Central
e24.Schleker T, Speth F, Posovszky C: Impfen beim immunsupprimierten Kind. Pädiatrische Praxis 2016; 85: 363–84.
e25. Wasan SK, Baker SE, Skolnik PR, Farraye FA: A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol 2010; 105: 1231–8 CrossRef MEDLINE
e26.Coenen MJ, de Jong DJ, van Marrewijk CJ, et al.: Identification of patients with variants in TPMT and dose reduction reduces hematologic events during thiopurine treatment of inflammatory bowel disease. Gastroenterology 2015; 149: 907–17 e7.
e27.Heuschkel RB, Gottrand F, Devarajan K, et al.: ESPGHAN position paper on management of percutaneous endoscopic gastrostomy in children and adolescents. J Pediatr Gastroenterol Nutr 2015; 60: 131–41 CrossRef MEDLINE
e28. Radke M: [Chronic inflammatory bowel disease: transition from pediatric to adult care]. Dtsch Med Wochenschr 2015; 140: 673–8 MEDLINE
e29.Spekhorst LM, Hummel TZ, Benninga MA, van Rheenen PF, Kindermann A: Adherence to oral maintenance treatment in adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2016; 62: 264–70 CrossRef MEDLINE
e30. LeLeiko NS, Lobato D, Hagin S, et al.: Rates and predictors of oral medication adherence in pediatric patients with IBD. Inflamm Bowel Dis 2013; 19: 832–9 CrossRef MEDLINE
e31.Veereman-Wauters G, de Ridder L, Veres G, et al.: Risk of infection and prevention in pediatric patients with IBD: ESPGHAN IBD Porto Group commentary. J Pediatr Gastroenterol Nutr 2012; 54: 830–7 CrossRef MEDLINE
e32. Bischoff SC, Koletzko B, Lochs H, Meier R: [Clinical nutrition in gastroenterology (part 4)—inflammatory bowel diseases]. Aktuel Ernahrungsmed 2014; 39: e72–e98.
e33. Valentini L, Volkert D, Schütz T, et al.: [DGEM terminology for clinical nutrition]. Aktuel Ernahrungsmed 2013; 38: 97–111.
e34. Levin AD, Wadhera V, Leach ST, et al.: Vitamin D deficiency in children with inflammatory bowel disease. Dig Dis Sci 2011; 56: 830–6 CrossRef MEDLINE
e35.Pappa HM, Mitchell PD, Jiang H, et al.: Maintenance of optimal vitamin D status in children and adolescents with inflammatory bowel disease: a randomized clinical trial comparing two regimens. J Clin Endocrinol Metab 2014; 99: 3408–17 CrossRef MEDLINE PubMed Central
e36.Shepherd D, Day AS, Leach ST, et al.: Single high-dose oral vitamin D3 therapy (Stoss): a solution to vitamin D deficiency in children with inflammatory bowel disease? J Pediatr Gastroenterol Nutr 2015; 61: 411–4.
e37.Pappa H, Thayu M, Sylvester F, Leonard M, Zemel B, Gordon C: Skeletal health of children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2011; 53: 11–25 CrossRef MEDLINE PubMed Central
e38.Engelmann G, Erhard D, Petersen M, et al.: Health-related quality of life in adolescents with inflammatory bowel disease depends on disease activity and psychiatric comorbidity. Child Psychiatry Hum Dev 2015; 46: 300–7 CrossRef MEDLINE
e39.Kilroy S, Nolan E, Sarma KM: Quality of life and level of anxiety in youths with inflammatory bowel disease in Ireland. J Pediatr Gastroenterol Nutr 2011; 53: 275–9 CrossRef MEDLINE
e40.Reigada LC, Hoogendoorn CJ, Walsh LC, et al.: Anxiety symptoms and disease severity in children and adolescents with Crohn disease. J Pediatr Gastroenterol Nutr 2015; 60: 30–5 CrossRef MEDLINE
e41.Giannakopoulos G, Chouliaras G, Margoni D, et al.:
Stressful life events and psychosocial correlates of pediatric inflammatory bowel disease activity. World J Psychiatry 2016; 6: 322–8 CrossRef MEDLINE PubMed Central
e42.Szigethy E, Levy-Warren A, Whitton S, et al.: Depressive symptoms and inflammatory bowel disease in children and adolescents: a cross-sectional study. J Pediatr Gastroenterol Nutr 2004; 39: 395–403 CrossRef MEDLINE
e43.Clark JG, Srinath AI, Youk AO, et al.: Predictors of depression in youth with Crohn disease. J Pediatr Gastroenterol Nutr 2014; 58: 569–73 CrossRef MEDLINE PubMed Central
e44.Thompson RD, Craig A, Crawford EA, et al.: Longitudinal results of cognitive behavioral treatment for youths with inflammatory bowel disease and depressive symptoms. J Clin Psychol Med Settings 2012; 19: 329–37 CrossRef MEDLINE
e45.Keethy D, Mrakotsky C, Szigethy E: Pediatric inflammatory bowel disease and depression: treatment implications. Curr Opin Pediatr 2014; 26: 561–7 CrossRef MEDLINE PubMed Central
e46.Paine CW, Stollon NB, Lucas MS, et al.: Barriers and facilitators to successful transition from pediatric to adult inflammatory bowel disease care from the perspectives of providers. Inflamm Bowel Dis 2014; 20: 2083–91 CrossRef MEDLINE PubMed Central
e47.Müther S, Rodeck B, Wurst C, Nolting HD: [Transition to adult care for adolescents with chronic disease. Current developments]. Monatsschr Kinderheilkd 2014; 162: 711–8 CrossRef