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Incidence, Paris Classification, and Follow-up in a Nationwide Incident Cohort of Pediatric Patients With Inflammatory Bowel Disease

Müller, Katalin E.*; Lakatos, Péter L.; Arató, András*; Kovács, Judit B.; Várkonyi, Ágnes§; Szűcs, Dániel§; Szakos, Erzsébet||; Sólyom, Enikő||; Kovács, Márta; Polgár, Marianne; Nemes, Éva#; Guthy, Ildikó**; Tokodi, István††; Tóth, Gergely‡‡; Horváth, Ágnes§§; Tárnok, András‡‡; Csoszánszki, Noémi¶¶; Balogh, Márta##; Vass, Noémi§; Bódi, Piroska***; Dezsőfi, Antal*; Gárdos, Lászl󆆆; Micskey, Éva‡‡‡; Papp, Mária§§§; Cseh, Áron*; Szabó, Dolóresz*; Vörös, Péter*; Veres, Gabor*Hungarian IBD Registry Group (HUPIR)

Journal of Pediatric Gastroenterology and Nutrition: November 2013 - Volume 57 - Issue 5 - p 576–582
doi: 10.1097/MPG.0b013e31829f7d8c
Original Articles: Gastroenterology

Objectives: The aim of the study was to evaluate the incidence, baseline disease characteristics, and disease location based on the Paris classification in pediatric inflammatory bowel disease (IBD) in the Hungarian nationwide inception cohort. In addition, 1-year follow-up with therapy was analyzed.

Methods: From January 1, 2007 to December 31, 2009, newly diagnosed pediatric patients with IBD were prospectively registered. Twenty-seven pediatric gastroenterology centers participated in the data collection ensuring the data from the whole country. Newly diagnosed patients with IBD younger than 18 years were reported. Disease location was classified according to the Paris classification.

Results: A total of 420 patients were identified. The incidence rate of pediatric IBD was 7.48/105 (95% confidence interval [CI] 6.34/105–8.83/105). The incidence for Crohn disease (CD) was 4.72/105 (95% CI 3.82–5.79), for ulcerative colitis (UC) 2.32/105 (95% CI 1.71–3.09), and for IBD-unclassified 0.45/105 (95% CI 0.22–0.84). Most common location in CD was L3 (58.7%); typical upper gastrointestinal abnormalities (ulcer, erosion and aphthous lesion) were observed in 29.9%. Extensive colitis in patients with UC (E4, proximal to hepatic flexure) was the most common disease phenotype (57%), whereas only 5% of children had proctitis. A total of 18.6% of patients had ever severe disease (S1). Frequency of azathioprine administration at diagnosis was 29.5% in patients with CD, and this rate increased to 54.6% (130/238) at 1-year follow-up. In UC, only 3.3% received azathioprine initially, and this rate elevated to 22.5% (25/111). Use of corticosteroid decreased from 50% to 15.3% in patients with UC. Rate of bowel resection in patients with CD during the first year of follow-up was 5%.

Conclusions: The incidence of pediatric IBD in Hungary was among the higher range reported. This is the first large, nationwide incident cohort analyzed according to the Paris classification, which is a useful tool to determine the characteristic pediatric CD phenotype.

*1st Department of Pediatrics

1st Department of Medicine, Semmelweis University

Heim-Madarász Hospital, Budapest

§Department of Pediatrics, Szent-Györgyi Albert University, Szeged

||BAZ County Hospital, Miskolc

Petz County Hospital, Győr

#Department of Pediatrics, Medical and Health Science Center, University of Debrecen, Debrecen

**Jósa Hospital, Nyíregyháza

††Szt. György Hospital, Székesfehérvár

‡‡Department of Pediatrics, University of Pécs, Pécs

§§Csolnoky Hospital, Veszprém, Hungary

¶¶2nd Department of Pediatrics, Semmelweis University, Budapest

##Markusovszky Hospital, Szombathely

***Pándy Hospital, Gyula

†††County Hospital, Zalaegerszeg

‡‡‡Budai Children's Hospital, Budapest

§§§2nd Department of Medicine, University of Debrecen, Debrecen, Hungary.

Address correspondence and reprint requests to Gábor Veres, MD, PhD, 1st Department of Pediatrics, Semmelweis University, 53 Bókay Street, 1083 Budapest, Hungary (e-mail:

Received 1 April, 2013

Accepted 27 May, 2013

Hungarian IBD Registry Group (HUPIR): Ildikó Kis, Szt. Borbála Hospital, Tatabánya, 2800, Hungary; Éva Pollák, Magyar Hospital, Ajka, 8401, Hungary; Ildikó Rosta, Schweitzer Hospital, Hatvan, 3301, Hungary; Károly Schultz and Ferenc Harangi, Balassa Hospital, Szekszárd 7101, Hungary; Katalin Szabados, Hetényi Hospital, Szolnok, 5000, Hungary; Erzsébet Szathmári, Kenézy Hospital, Debrecen, 4043, Hungary; Judit Czelecz and Katalin Szigeti, Bethesda Children's Hospital, Budapest 1146, Hungary; Katalin Tamás, Budapest, Hungary; András Tóth, Szt. László Hospital, Budapest 1097, Hungary; Éva Vajdovich, Bugyi Hospital, Szentes, 6600, Hungary; Gabriella Tomcsa, Jósa Hospital, Nyíregyháza, 4400, Hungary; Erika Tomsits, MD, PhD, 2nd Department of Pediatrics, Semmelweis University, Budapest, 1094, Hungary, Kriszta Molnár, 1st Department of Pediatrics, Semmelweis University, Budapest, 1083, Hungary, Petra A. Golovics, MD, 1st Department of Medicine, Semmelweis University, Budapest, 1083, Hungary, Barbara D. Lovász, MD, 1st Department of Medicine, Semmelweis University, Budapest, 1083, Hungary

G.V. is holder of the János Bolyai Research grant.

This article was supported by the János Bolyai Research and Scholarship of the Hungarian Academy of Sciences (OTKA-K 105530).

The authors report no conflicts of interest.

Increasing numbers of pediatric and adolescent patients with Crohn disease (CD) and ulcerative colitis (UC) have been reported. It is estimated that 15% to 25% of patients experience the onset of their symptoms at younger than 20 years of age (1). In addition, reports have shown an increasing incidence of pediatric CD in the last decades (from 1.3–2.3 to 3.1–4.2/105), whereas the incidence of UC has remained stable (range 0.1–0.7/105) (2,3); however, a recent study has shown that this phenomenon is not caused by a trend toward disease onset at a younger age, but this may rather be a consequence of the overall increasing incidence of chronic inflammatory bowel disease (IBD) (4).

Data from epidemiological pediatric IBD studies have shown special features unique to pediatric IBD, including disease location. With a specific focus on facilitating research, an international group of IBD experts developed a new classification, the Paris classification (5), which reflects presently available evidence and clinical practice of pediatric IBD. Important modifications include classifying age at diagnosis as A1a (0–<10 years), A1b (10–<17 years), A2 (17–40 years), and A3 (>40 years). Furthermore, upper gastrointestinal (GI) involvement proximal to ligament of Treitz (L4a) has been distinguished from upper GI involvement distal to ligament of Treitz (L4b). The new criteria system allows for classifying both stenosing and penetrating disease in the same patient (B2B3), and denoting the presence of growth failure in the patient at any time as G1 versus G0. In UC, E4 indicates extent of the disease proximal to the hepatic flexure, and S1 designates ever severe UC during disease course.

Data on clinical course of pediatric IBD are scarce. There are only a few population-based, short-term follow-up studies that involved medical and surgical management (6–9). Eleven percent to 44% of patients with CD had undergone intestinal resection, and the total colectomy rate was 17.6% to 24% of children with UC (7,9). Of note, the prevalence of azathioprine use was as high as 25% at the end of the 1-year follow-up. Moreover, an increasing use of immunomodulators and decreasing 1-year surgery rates in pediatric patients with IBD were observed in a 12-year-prospective population-based cohort study from eastern Denmark 2007 to 2009 (10).

Despite the increasing number of epidemiological studies conducted in pediatric IBD, there are only few reports available from eastern Europe, and to our knowledge, no nationwide study investigated the early disease course. Therefore, our aim was to determine the incidence of pediatric IBD in Hungary in a prospective nationwide epidemiological study and to evaluate disease location according to the Paris classification.

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On behalf of the Hungarian Pediatric Gastroenterology Society, a prospective registry of pediatric IBD was launched on January 1, 2007. The cooperation of 27 institutes ensured the coverage of the whole country (Hungarian Pediatric IBD Registry). The participating institutes include all 4 academic (university) centers in Hungary; 17 tertiary hospitals, where pediatric gastroenterology is present; 4 secondary hospitals with pediatric gastroenterologists; and 2 pediatric gastroenterology outpatient offices. Private pediatric gastroenterology offices with endoscopy are not available in Hungary. Furthermore, coordinators are in contact with the main adult IBD centers to find adolescents diagnosed in adult centers. We contacted regularly the centers via e-mail or telephone calls (every month). The coordinators contacted the gastroenterologist if there had been any discrepancies in the survey (eg, confirm the proper diagnosis of IBD, discuss the discrepancies between macroscopic and microscopic endoscopic findings).

Questionnaires were filled out by gastroenterologists who made the IBD diagnosis. Newly diagnosed patients with IBD younger than 18 years were reported. Exclusion criteria were age at diagnosis older than18 years, missing information on ileocolonoscopy and ileocolonic histology, and a diagnostic workup without endoscopic, histologic, and radiologic abnormalities. The questionnaires were collected via e-mail and original data were validated. If data had been lacking (no time to complete the questionnaire), we visited the centers and personally collected data from medical records. We also organized personal meetings to discuss difficult cases, mostly patients with IBD type unclassified (IBD-U).

We analyzed the data of patients recorded from January 1, 2007 to December 31, 2009 (36 months). Age, sex, weight, height, presenting symptoms, concomitant diseases, extraintestinal manifestations (EIM), familiarity (first-degree), and complications were recorded. Furthermore, characteristics of diagnostic procedures including endoscopy, radiology, histology, and surgical interventions were documented. The survey collected the data of the patients anonymously.

The diagnosis of IBD was based on the Porto criteria, although esophagogastroduodenoscopy and small-bowel follow-through (SBFT) were not always performed despite the recommendation (11). Every child was reevaluated 12 months following the diagnosis. Physicians had to confirm the diagnosis and report the applied therapy, as well as surgical interventions at 1-year follow-up.

Location and phenotype of disease were based on the Paris classification criteria (5). The site of the disease was evaluated only for those patients who underwent a complete bowel investigation (colonoscopy and esophagogastroduodenoscopy and/or small and large bowel were visualized for CD; large bowel was visualized up to the cecum for UC).

The therapeutic strategy in pediatric IBD in Hungary was based on international guidelines. Available therapies at diagnosis for induction of remission include corticosteroids, exclusive enteral nutrition, sulfasalazine or mesalazine, and antibiotics and for maintenance include azathioprine. Calcineurin inhibitors or methotrexate are used as second-line immunosuppressive therapies. Infliximab has been available for children with CD in Hungary since 2007. It is used for both induction and maintenance (Pediatric Crohn Disease Activity Index >30, despite immunosuppression therapy for a minimum of 3 months). Indications for surgery included intractable disease, perianal disease, and complications of intestinal disease, such as abscess, stricture, intestinal obstruction, and intraabdominal fistulas.

The age- and sex-specific demographical data for calculating incidence were obtained from the Hungarian Central Statistical Office. The population, a total of 10.04 million, is predominantly white in Hungary. In 2007, 1.8 million of the inhabitants were younger than 18 years. Height, weight, and body mass index results were converted into standard deviation z scores using the nomogram of the Hungarian Longitudinal Survey of Children's Growth. Impaired growth was defined as z score <−2. The study was approved by the national ethical committee.

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Statistical Analysis

Normality of the data was tested by Kolmogorov-Smirnov tests. Data are expressed as mean (±standard deviation) and for statistical analyses, parametric tests were used. Univariate comparisons were made among different subgroups (type of diagnosis, sex, extraintestinal manifestation, familiarity, initial therapy) with regard to disease phenotype and anthropometrical data. We used Fisher exact tests or χ 2 tests to compare binominal variables, whereas t test with separate variance estimates was used to compare continuous variables. To assess the correlation of 2 parameters in case of dichotomous and continuous outcomes, logistic and linear regression models were used, respectively. Kaplan-Meier survival curves were plotted to analyze the need for surgery. A P < 0.05 was considered significant. Statistical analyses were performed using the SPSS statistical package, version 15.0 (SPSS Inc, Chicago, IL) for Windows. Kaplan-Meier analysis was calculated by StatsDirect, versions 2, 7, and 8 (StatsDirect Ltd, Cheshire, UK).

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Incidence of Newly Diagnosed Pediatric IBD in Hungary

A total of 420 children with IBD were diagnosed between January 1, 2007 and December 31, 2009 in Hungary. Twice as many CD cases were registered as UC cases; CD, 265 patients (63%); UC, 130 patients (31%); and 25 patients (6%) IBD-U. The clinical characteristics of patients are presented in Table 1.



The overall incidence of IBD was 7.48/105 per year (95% confidence interval [CI] 6.34–8.83) in children younger than 18 years. The incidence of CD was 4.72/105 per year (95% CI 3.82–5.79), of UC 2.32/105 (95% CI 1.71–3.09), and of IBD-U, 0.45/105 per year (95% CI 0.22–0.84). There was no significant difference in incidence rate in the 3 following years (data not shown).

A male predominance was observed in all patients with CD (male:female ratio 1.43:1); in contrast we found a slight female predominance in UC (1:1.15) (Table 1). Mean age was 12.9 ± 3.47 years for all patients with IBD, 12.7 ± 3.51 years for patients with UC, 13.2 ± 3.54 years for patients with CD, and 12.7 ± 4.28 years for patients with IBD-U (Table 1). Figure 1 shows the age-specific incidence of IBD.



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Clinical Presentation at Diagnosis


Height z score <−2 SD was reported in 6.5% of patients with CD, whereas in only 0.8% of children with UC. Mean z score of BMI was significantly lower in CD than in UC (−0.64 vs −0.26, P = 0.005). Growth retardation in UC was less severe by increasing age (r = −0.296, P = 0.013). Sex distribution and normal growth were comparable in CD and UC. There was no association among family history, sex, location, and growth failure.

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Paris Classification

Most patients with CD belonged to the age group A1b (n = 197, 74.3%). Thirteen percent of the patients (33/247) showed L1 (involvement of terminal ileum and/or cecum) location (Table 2). Isolated colonic disease (L2) was seen in 27.5% (n = 68) of children with CD, and ileocolonic disease (L3) occurred in 58.7% (n = 145) of patients with CD.



Esophagogastroduodenoscopy was performed in 184 (68%) pediatric patients with CD. Upper GI abnormality was based on macroscopic lesions (erosion, ulcer, aphthous lesion) or on radiological findings (magnetic resonance imaging/computed tomography/SBFT). Upper GI abnormality was found in 74 (29.9%) of all children with CD, and there was only 1 patient in 247 (0.4%) with isolated upper GI disease. Esophagogastroduodenal involvement (L4a) was present in 30.4% (n = 56) of pediatric patients with CD, whereas L4b (jejunal/proximal ileal) disease occurred in 13.6% (n = 25) of children.

Most patients with CD had inflammatory disease at diagnosis (B1 + B1p 84.4%), whereas 12.1% patients with CD had stricturing disease (B2), 2.3% had fistulizing disease (B3), and 1.2% belonged to B2/B3 phenotype. Frequency of perianal disease (abscess, fistula) was 14.5% (37/247). There was no significant correlation among sex, phenotype, familiarity, and location.

Fifty-seven percent of patients with UC had disease location E4, and 13 of 121 children have ever had severe disease (S1) at diagnosis (Table 3). Disease location did not differ either by age at diagnosis or by sex. Familiarity and anthropometrical parameters did not show any association with location either in CD or in UC.



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EIMs were present in 10.9% of patients with IBD at the time of the diagnosis (Table 1). It was more common in patients with CD than in children with UC (12.9% vs 7%), although the difference was not statistically significant. The most common EIM was joint involvement (42.5%), followed by cutaneous manifestations (31.9%). Multiple EIMs were observed in 10.6% of patients with EIM. There were no associations among sex, age, family history, and EIM.

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Therapy at Diagnosis and After 1-Year Follow-up

Medical Therapy

One hundred 77 patients with CD (177/259, 68.3%) were treated with systemic corticosteroid as initial therapy (Table 4). 19.3% (46/238) of patients received corticosteroid at 1-year follow-up. Azathioprine was started directly after diagnosis in 32.8% (85/259) of children with CD (42.5% within 3 months after diagnosis), and in 54.6% (130/238) at 1-year follow-up. Infliximab was administered in 14% (33/238) of patients with CD 1 year after diagnosis. Exclusive enteral nutrition was applied in 6 patients with CD.



In UC, the rate of corticosteroid use was 50% (62/124) at diagnosis, and it decreased to 15.3% (17/111) at 1-year follow-up. Immunomodulator as an initial therapy was reported in only 4 patients (3.2%, 4/124) and 22.5% (25/111) received azathioprine after 1 year. Infliximab was not available in pediatric UC during this period.

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In CD, the need for surgery for any indication was 11.3% (27/238) within 1 year from diagnosis. Surgical intervention was performed because of perianal abscess in 10 cases, fistulectomy in 3 cases, and appendectomy related to diagnosis in 2 cases.

Cumulative incidence of intestinal resection (small bowel resection or/with partial colectomy) was 5.04% (12/238) at 1 year. Intestinal resection within the first 3 months after diagnosis was performed in 7 cases. One patient with IBD-U (1/19) had an operation because of perianal abscess. There was no need for surgical intervention in 111 patients with UC during the first year of the disease course.

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The present study is the first prospective nationwide cohort—based on the Paris classification—reporting on the incidence and management in the first year after the diagnosis in pediatric IBD. The incidence rate (7.5/105 per year) of pediatric IBD in Hungary is comparable with that reported from high incidence areas (Wisconsin (12), Ontario (13)) within the same age group (younger than 18 years) (Fig. 2). Increasing incidence rates were reported in IBD in the last decades in western Europe in both children and adults (12,14,15). The same trend was reported from eastern European adult studies; however, data on pediatric incidence are limited. According to a population-based inception cohort from Veszprem Province in Hungary, the incidence in adult patients has been rising steadily in the last 25 years (incidence 1977–2001: in UC from 1.66 to 11.01/105per year, in CD from 0.41 to 4.68/105 per year) (16). Even higher incidence rates were reported between 2002 and 2006 (17), similar to those observed with high incidence in western European and Nordic countries.



Previous studies have suggested a difference in location between pediatric and adult-onset patients with IBD because pediatric patients have more frequently extensive small- and large-bowel disease, whereas the prevalence of limited ileal disease is lower (2.65% vs 31.5%) (18,19), and panenteric disease is more common in children (20). Disease extension in CD (L1, L2, L3) in the present study was comparable with disease location in other studies (21,22). Another important feature of pediatric CD is the frequent upper GI involvement (30%–70%) (21,23). The wide range of upper GI abnormality may be explained by the different definition of upper GI disease (any abnormalities or specific abnormalities: erosions, aphthous lesions, ulcers at endoscopy) in some reports. The diagnostic yield of upper endoscopy was 9% as described in details in our recent article (24).

The Paris classification was applied in the report of the Eurokids Registry (22). Location in CD and UC were comparable with the results of the present study; however, isolated upper GI disease was less frequent in our cohort. This discrepancy is probably the result of the different population of the 2 studies. The Eurokids Registry is not a population-based cohort, but a selection of centers with special interest in IBD; meanwhile, the Hungarian Pediatric IBD Registry is a population-based incident cohort involving less severe cases. This phenomenon emphasizes the importance of nationwide registeries that enroll all pediatric patients with IBD including less severe cases.

In addition, isolated colonic disease was noted significantly more often in the A1a age group than in A1b in the Eurokids Registry (22). A similar trend was found in the Hungarian cohort, although the difference was not significant. In this population, we could not describe any significant difference in the subgroups of the Paris classification. The reason for that is probably the small sample size of the subgroups; however, tendencies were similar to other studies (22).

Disease behavior has been shown to progress during the disease course. Penetrating/stricturing phenotype and perianal disease are associated with a more aggressive disease course and an increased risk of surgery. Approximately one-third of newly diagnosed adults presented with complicated CD (17). In contrast, the majority of pediatric patients with IBD had inflammatory behavior in a previous study (91.25%) (20,22), in concordance with figures in the present study (85.3%). The rate of perianal disease was comparable with earlier studies (16.9% vs 14.9%) (22,25).

Need for surgery is often regarded as the marker of disease severity. Only a few pediatric studies report the incidence of surgery after 1 year of diagnosis. The surgical rate (5.04%) in our cohort is comparable with the finding of the Pediatric Consortium (6%) (26). It should be noted that this is the first nationwide pediatric IBD study in which incidence of surgery after 1 year is shown.

Colectomy among patients with UC was not detected. Similarly, Jakobsen et al (27) described no need for surgical intervention in children with UC within the first 2 years after diagnosis. In contrast, the probability of colectomy in UC was 8% at 1 year, 11% at 2 years, and 20% at 2 years in an earlier study (9).

The cumulative probability of surgery after 1 year in adult patients with CD was 10% to 19% in recent reports (17,28). Reduction in surgery rates was reported in population-based adult studies in the last 20 years, which is probably the result of increasing use of immunomodulation (10). The cumulative incidence of surgery during the first year was 15% to 35% in studies before the era of immunomodulators (29,30). The role of immunomodulators in the reduced need for surgery during the first year is questionable. In a population-based pediatric cohort (1962–1987), reported by Langholz et al, the mean yearly operation rate was 13%. In a population-based cohort of children with IBD enrolled between 1984 and 1995 in Sweden, 38 of 639 patients (5.9%) were operated on within 1 year (31). Interestingly, surgical rates during the first year after diagnosis in the pediatric population are lower than in adults both in recent and earlier studies. The slight decrease (from 13% to 4.4%–7%) in operation rate in the pediatric population in the last decades may be explained as a consequence of increased use of azathioprine (20,21).

Administration of 5-aminosalicylic acid (5-ASA) is high in this CD cohort; however, this phenomenon is not restricted to our registry. Initial use of 5-ASA was 95% in a pediatric CD cohort collected between 1998 and 2009 (32). In addition, in a Finnish study, 96% of 97 pediatric patients with CD still used 5-ASA during the first year after diagnosis of CD (33).

Although we applied a nationwide approach, the study has some limitations. A relatively large proportion of the patients with CD (62/265) did not have small bowel investigations (computed tomography, magnetic resonance imaging, SBFT) or esophagogastroduodenoscopy; thus, upper GI location may be underestimated. The decrease in the incidence in the 16- to 18-year-olds is virtual and associated with the fact that adolescents more frequently tend to receive medical care from adult gastroenterologists (40). As a result, the incidence in older age groups is probably underestimated.

In summary, the data of our study are remarkable because this is a nationwide incident cohort; participants are not only from a few tertiary centers. Important observations of pediatric IBD based on the Hungarian Pediatric IBD Registry include incidence of pediatric IBD is comparable in eastern European countries to Western countries; after 1 year of follow-up, the surgical rate in pediatric patients with CD is 5%; a large population-based cohort has been analyzed according to the Paris classification, which is a useful tool to determine the characteristic pediatric CD phenotype.

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    Crohn disease; epidemiology; pediatric inflammatory bowel disease; therapy; ulcerative colitis

    © 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,