Design
The primary goal was to assess the rate and time interval of CD-related hospitalizations and operations after the follow-up (2nd ) colonoscopy. The first colonoscopy was performed during the initial diagnostic workup at the time of diagnosis. Furthermore, the Pediatric CD Activity Index (PCDAI) was recorded. The second colonoscopy was indicated after the introduction of therapy within week 16 up to week 38 of new treatment according to clinical symptomatology. At the time of the 2nd colonoscopy, MH was assessed (with histology), and laboratory parameters of inflammation (C-reactive protein and erythrocyte sedimentation rate (ESR)) were recorded. According to MH achievement, the patients were divided into two groups: “MH” and “No MH.”
Patients
Pediatric patients with CD from a single tertiary care center of the University Hospital in Hradec Králové were evaluated retrospectively (2000–2015) and followed till January 2019. CD diagnosis was made according to the Porto criteria (9). The phenotype of the CD was estimated by the pediatric modification of the Montreal classification (10). The upper gastrointestinal tract was examined by esophagogastroduodenoscopy, while magnetic resonance enterography was used to examine the small bowel. Inflammatory bowel disease in a first-degree relative was marked (Table 1). Perianal disease included anal fissure. PCDAI was used for the evaluation of the clinical and laboratory activity of the disease (11). The study follows the principles outlined in the Declaration of Helsinki. Informed consent was not obtained from the patients or parents because of the retrospective character of the study.
Table 1
Study group characteristics.
| MH n = 17 | No MH n = 59 | P value |
Ethnicity | 17 Caucasian | 59 Caucasian | |
Gender (M/F), % | 11/6 65%/35% | 31/28 53%/47% | 0.42 |
Age of diagnosis (years), [median, IQR] | 11.5 [10.9–15.9] | 14.0 [12.1–15.4] | 0.33 |
Weight at diagnosis (kg), [median, IQR] | 37.0 [30.3–53.0] | 40.0 [31.0-51.5] | 0.89 |
Weight at 2nd colonoscopy (kg) [median, IQR] | 60.0 [46.0–70.0] | 53.0 [44.0–60.0] | 0.09 |
Family history (positive/negative) | 3/14 | 7/52 | 0.68 |
Paris classification, n (%) | | | |
Location | | | |
L1 | 2 (12%) | 21 (36%) | 0.08 |
L2 | 2 (12%) | 5 (8%) | 0.65 |
L3 | 13 (76%) | 33 (56%) | 0.16 |
L4a (positive/examined) | 3/7 (41%) | 6/15 (25%) | 1.0 |
L4b (positive/examined) | 5/17 (29%) | 11/55 (20%) | 0.51 |
Behavior | | | |
B1 | 15 (88%) | 54 (92%) | 0.65 |
B2 | 2 (12%) | 3 (5%) | 0.31 |
B3 | 0 (0%) | 2 (3%) | 1.0 |
p (perianal disease - including anal fissure) | 5 (29%) | 9 (15%) | 0.28 |
Period (1st -2nd colonoscopy) (months), [median, IQR] | 28 [17–36] | 21 [13–38] | 0.31 |
Period of observation (months), [median, IQR] | 91 [51–113] | 80 [48–105] | 0.74 |
PCDAI (1st colonoscopy), [median, IQR] | 27.5 [21.3–38.8] | 25.0 [17.5–32.5] | 0.01 |
ASCA IgA at diagnosis (U/ml) [median, IQR], examined, n (%) | 280.0 [11.5–300.0] 9 (53%) | 225.5 [36.3–300.0] 32 (54%) | 0.69 |
ASCA IgG at diagnosis (U/ml) [median, IQR], examined, n (%) | 39.0 [5.0-102.0] 7 (41%) | 74.0 [43.7-157.5] 29 (49%) | 0.06 |
ESR (1st /2nd hour) (2nd colonoscopy) [median, IQR], examined, n (%) | 7 / 19 [4.0-14.3] [10.8–32.5] 14 (82%) | 24 / 48 [12.0–35.0] [28.0–70.0] 51 (86%) | 0.0003 0.0001 |
CRP, mg/l (2nd colonoscopy), [median, IQR] | 0.3 [0.05-2.0] | 8.4 [4.0-17.4] | < 0.0001 |
Bold font indicates P value < 0.05. |
L1 – distal 1/3 ileum ± limited cecal disease; L2 – colonic disease; L3 – ileocolonic, L4a – upper disease proximal to ligament of Treitz; L4b - upper disease distal to ligament of Treitz and proximal to distal 1/3 ileum. B1 – non-stricturing and non-penetrating, B2 – stricturing, B3 – penetrating |
Abbreviations: ASCA, anti-Saccharomyces cerevisiae antibodies, CRP, C-reactive protein, ESR, erythrocyte sedimentation rate; IQR, interquartile range; MH, mucosal healing, PCDAI, Pediatric Crohn´s Disease Activity Index. |
MH definition
We defined MH as a combination of total endoscopic and histological healing. MH was determined as complete endoscopic disappearance of all mucosal ulcerations (including aphthous ulcers) and the absence of any signs of mucosal inflammation (erythema, edema) in the terminal ileum and large bowel. A complete colonoscopy with terminal ileum intubation was performed on all MH patients. In 6 of the No MH patients, the terminal ileum was not intubated, and in 11 patients, a histology sample was not obtained. In all of these patients, endoscopic findings showed apparent signs of inflammation. In most patients (and all MH patients), at least one histologic sample from the terminal ileum and one from the colon were taken. In the normal-appearing bowel segments, the biopsies were taken randomly. Biopsy specimens were stained with hematoxylin and eosin and read by experienced pathologists. Histologically, we distinguished low, medium, and high inflammatory activity based on the description by the pathologists. In the case of a normal endoscopic assessment but with histological signs of high inflammatory activity, the patient was classified as “No MH.”
Operations and hospitalizations
CD-related surgical interventions were represented mainly by major abdominal surgery, then anal fistula surgery, and anal divulsion. In some patients, a combined surgical procedure was performed. CD-related hospitalizations included only admissions for deterioration in disease activity. Hospitalizations for operation were assessed separately. Repetitive surgical procedures and hospitalizations were recorded during the whole follow-up period.
Therapy
Any therapy between the 1st and 2nd colonoscopy and immediately after the 2nd colonoscopy was registered. EEN given for at least four weeks was recorded. Treatment with 5-aminosalicylic acid (5-ASA), adalimumab (ADA), azathioprine (AZA), CS, infliximab (IFX), methotrexate (MTX), or mycophenolate mofetil was documented.
Statistical methods
For the patients’ characteristics, descriptive analysis (median and interquartile ranges [IQR]) was used. Normality was tested with the D’Agostino-Pearson omnibus normality test. t-test and, for dichotomous data, Fisher’s exact test were performed for the comparison of variables between the two groups. For variables without normal distribution, we used Mann-Whitney U-test. Differences were considered statistically significant at a value of p < 0.05. The calculations (except for the statistical power) were carried out using GraphPad Prism 6 (GraphPad Software, Inc.). For the time-to-event survival analysis, Kaplan Meier curves were constructed. There were no missing data during the follow-up.