Original article

485

Authors

Salvatore Oliva1, *, Giovanni Di Nardo1, *, Cesare Hassan2, Cristiano Spada2, Marina Aloi1, Federica Ferrari1, Adriano Redler3, Guido Costamagna2, Salvatore Cucchiara1

Institutions

1

Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy Gastrointestinal Endoscopy Unit, Catholic University of Rome, Rome, Italy 3 Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy 2

submitted 30. September 2013 accepted after revision 12. February 2014

Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1365413 Published online: 28.4.2014 Endoscopy 2014; 46: 485–492 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Salvatore Oliva, MD Department of Pediatrics and Childhood Neuropsychiatry Pediatric Gastroenterology and Liver Unit Sapienza University of Rome Viale Regina Elena 324 00161 Roma Italy Fax: +39-06-49979325 [email protected]

Background and study aims: Second-generation colon capsule endoscopy (CCE-2) may overcome the invasiveness of colonoscopy in the evaluation of mucosal inflammation, especially in pediatric ulcerative colitis. The aim of this pilot study was to determine the diagnostic accuracy of CCE-2 in evaluating disease activity, using colonoscopy as a gold standard. Disease extent, tolerability, interobserver agreement, and safety were also evaluated. Methods: A total of 30 consecutive pediatric patients with ulcerative colitis were prospectively enrolled (mean age 14.1 ± 3.2 years). Patients underwent CCE-2 followed by colonoscopy in the late afternoon or the following day. The blinded procedures were performed, and the diagnostic accuracy of CCE-2 to assess disease activity was determined using a modified Matts score, which classified patients as either normal (Matts score ≤ 6) or with active inflammation

(Matts score > 6). Interobserver agreement was assessed using the kappa statistic. Results: One patient was excluded from the analysis because they were unable to swallow the capsule, leaving 29 patients available for analysis. The sensitivity of CCE-2 for disease activity was 96 % (95 % confidence interval [CI] 79 – 99) and specificity was 100 % (95 %CI 61 – 100). The positive and negative predictive values of CCE-2 were 100 % (95 %CI 85 – 100) and 85 % (95 %CI 49 – 97), respectively. No serious adverse events were reported. CCE-2 had a higher overall tolerability than colonoscopy (P < 0.05). Interobserver agreement was excellent in all cases (κ > 0.86). Conclusions: Using a modified Matts score, CCE2 was accurate in evaluating significant mucosal inflammation in children with ulcerative colitis. Trial registration: ClinicalTrials.gov – NCT01740349

Introduction

ly for pediatric patients who have a longer illness history and a greater need for anesthesia. Colon capsule endoscopy (CCE) is a novel minimally invasive and painless endoscopic technique allowing exploration of the colon without the need for sedation, rectal intubation, or gas insufflation [8, 9]. A second-generation CCE device (CCE-2), which has been released recently, provides a higher number of images per second and a larger viewing angle [10, 11]. Consensus guidelines issued by the European Society of Gastrointestinal Endoscopy (ESGE) on CCE have established that CCE-2 may be useful to monitor inflammation in ulcerative colitis, which may help to guide therapy [12]. To date, there have been only a few studies on this topic, with results showing that CCE is a safe procedure to monitor mucosal status and healing in ulcerative colitis, but that it cannot replace conventional colonoscopy. These studies have all been conducted in adults, and only one of the studies used CCE-2

!

Ulcerative colitis is an inflammatory bowel disease (IBD), characterized by remitting and relapsing inflammation of the colon [1, 2] with variable disease extension. An accurate and objective assessment of disease activity and the extent of lesions are crucial because this information has prognostic implications [3 – 5]. The advent of biological therapy has generated an interest in mucosal healing [6], which is becoming a key end point in clinical trials on IBD therapy, and is currently widely agreed as a standard goal in daily clinical practice [7]. Monitoring mucosal status (i. e. the presence or absence of colonic inflammation) may require colonoscopy to be repeated at different stages of the disease, adding inconvenience, discomfort, and risk to the patient, especial-

* These authors contributed equally to the study

Oliva Salvatore et al. Colon capsule endoscopy in pediatric ulcerative colitis … Endoscopy 2014; 46: 485–492

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Second-generation colon capsule endoscopy vs. colonoscopy in pediatric ulcerative colitis: a pilot study

Original article

[13 – 16]. Based on this background, the current prospective pilot study was performed to investigate the diagnostic accuracy of CCE-2 in pediatric patients with ulcerative colitis. The interobserver agreement between physicians was also determined in order to assess reproducibility of the technique. The study was supported by Given Imaging who provided 30 CCE-2 capsules. No other financial support was received for the study.

Patients and methods !

Patients Eligible patients were recruited at the Pediatric Gastroenterology and Liver Unit of the Sapienza University of Rome between November 2011 and October 2012. The Unit is a tertiary referral pediatric center for IBD. A total of 30 consecutive pediatric patients with known ulcerative colitis were prospectively enrolled. Inclusion criteria were: age between 6 and 18 years, a diagnosis of ulcerative colitis made at least 3 months prior to enrollment, and the need for standard colonoscopy and endoscopic follow-up. Exclusion criteria were: dysphagia, renal insufficiency, suspected Crohn’s disease, and prior abdominal surgery of the gastrointestinal tract other than uncomplicated procedures that would be unlikely to lead to bowel obstruction, based on the clinical judgment of the investigator. Disease activity was evaluated at baseline using a clinical score – the Pediatric Ulcerative Colitis Activity Index (PUCAI). An episode of severe colitis was defined as a PUCAI score > 65 [17]. The study protocol was defined in accordance with the Declaration of Helsinki and approved by the ethical committee of the University Hospital Umberto I in Rome. Written informed consent was obtained from parents of all children; children over 12 years of age signed a statement of assent.

Bowel preparation A bowel preparation regimen was selected according to adult data, with dose adjustments for the polyethylene glycol (PEG), as for pediatric colonoscopy [12, 18]. On the day before the examination day (Day – 1), a clear-liquid diet was given together with " Ta50 mL/kg (up to a maximum of 2 L) of PEG solution to drink (● ble 1). On the day of endoscopy (Day 0), 50 mL/kg (maximum 2 L) of PEG was given at 06:00 – 07:00. The patient swallowed the CCE-2 (PillCam COLON-2; Given Imaging Ltd., Yoqneam, Israel) at 08:00 am, and if the capsule remained in the stomach for more than 1 hour, 0.25 mg/kg of domperidone was administered in order to stimulate gastric empting. Once the CCE-2 had exited the stomach and the small bowel had been detected and confirmed by the real-time viewer, a booster of oral sodium phosphate solution (30 mL) was given. A second booster of sodium phosphate (15 mL) was given 3 hours later. These doses were designed to promote distal movement of the capsule through the bowel and to improve capsule excretion. One bisacodyl suppository (10 mg) was given to facilitate bowel emptying and excretion of the CCE-2, if necessary 3.5 hours after " Table 1). If the capsule was not excreted the second booster (● before 20:00, patients were admitted as inpatients. Fasting was maintained and 25 mL/kg of PEG plus intravenous hydration were initiated.

Table 1

Bowel preparation schedule.

Day

Hours

–1

All day

Liquid diet

–1

18:00 – 21:00

50 mL/kg up to 2 L of PEG

0

06:00 – 07:00

50 mL/kg up to 2 L of PEG

0

08:00

0

Action

Ingestion of CCE-2 Domperidone 0.25 mg/kg if capsule remained in the stomach > 1 hour

0

On detection of small bowel

30 mL NaP + 1 L water

0

3 hours later

15 ml NaP + 0.5 L water

0

3.5 hours later (if necessary)

10 mg bisacodyl suppository

Battery expired or excretion of capsule

Continue liquid diet

0

Late afternoon

Colonoscopy

0

20:00 if capsule not excreted

Admit as inpatient 25 mL/kg PEG + intravenous hydration

08:00

Colonoscopy

or 1

CCE, colon capsule endoscopy; PEG, polyethylene glycol; NaP, sodium phosphate.

Endoscopy The CCE-2 examination was performed before colonoscopy. Both procedures were recorded. After capsule excretion, patients were offered optical colonoscopy under general anesthesia in the late afternoon or the day after (depending on the availability of the anesthesiologist and an endoscopy room), but no more than 24 " Table 1). Two endoscopists (S.O. hours after CCE-2 ingestion (● and G.D.N.) performed CCE-2 and colonoscopy, respectively. Both endoscopists had vast experience in pediatric endoscopy and were blinded to the results of the other procedure. Routine colonic biopsies were taken from lesions during conventional optical colonoscopy, in order to provide a histological evaluation of the mucosa.

End points The primary end point was the assessment of disease activity, which was classified as normal or with active inflammation. The diagnostic accuracy of CCE-2 was calculated using colonoscopy as the gold standard. Disease activity was assessed according to the Matts score, and was calculated for each colon segment [19]; the overall score for each patient was obtained by totalling the scores from each segment. For the primary end point, a modified version of Matts score was used, consisting of a dichotomous assessment of disease activity (normal or active): a value ≤ 6 was considered as “normal,” and a value > 6 as “active.” Several secondary end points were considered as follows.

Disease activity In order to calculate the sensitivity and specificity of CCE-2 in discriminating between “mild” and “severe” disease activity, an additional analysis was performed using the standard classification of Matts score. Patients were classified into three categories: < 6 = normal or not related to ulcerative colitis; > 6 – ≤ 12 mildly active; > 12 active.

Oliva Salvatore et al. Colon capsule endoscopy in pediatric ulcerative colitis … Endoscopy 2014; 46: 485–492

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486

Original article

Disease extent

Video from Colonoscopy + CCE-2

Disease extent was defined for both procedures according to the Paris classification [20]: E1 = ulcerative proctitis, defined as involvement limited to the rectum (i. e. proximal extent of inflammation distal to the rectosigmoid junction); E2 = left-sided ulcerative colitis, defined as involvement limited to the portion of the colorectum distal to the splenic flexure; E3 = extensive ulcerative colitis, defined as a disease extending proximally to the splenic flexure but distally to the hepatic flexure; and E4 = pancolitis, defined as colitis extending proximally to the hepatic flexure.

Capsule studies were considered to be “complete” when the capsule reached the rectum. The capsule was “excreted” if it was expelled naturally by the patients before the battery life had expired. For cases in which the capsule was not excreted, the Matts score for the segments not reached by the capsule were calculated according to the value given to the proximal segment visualized immediately before.

Sapienza University of Rome

Catholic University of Rome

1st Investigator

3rd Investigator

2nd Investigator

4th Investigator

Interobserver agreement for both procedures at the same center

Interobserver agreement for CCE-2 between two different centers

Fig. 1

Work flow for interobserver agreement evaluation.

Statistical analysis By assuming a 90 % accuracy of CCE-2 in classifying patients according to disease activity, a sample size of 30 was sufficient to achieve an ~±10 % precision of the study estimates. Descriptive statistics of patient demographic characteristics were recorded. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of capsule endoscopy were calculated using colonoscopy as the gold standard for the detection and extent of mucosal inflammation. Confidence intervals at 95 % were calculated according to the Wilson score method. Interobserver agreement between CCE-2 and colonoscopy was computed using Cohen’s kappa (κ) [22]. The Mann – Whitney nonparametric test was used to compare each item of the tolerability score between the two procedures and for assessing superiority of one procedure over the other. An alpha value of 0.05 was used for statistical significance. Statistical analysis was performed using SPSS (SPSS 17.0, Chicago, Illinois, USA).

Colon cleanliness During the video analysis, the overall cleanliness of each colon segment (cecum, ascending, transverse, descending, sigmoid, and rectum) was graded as “poor,” “fair,” “good,” or “excellent” [21]. An overall evaluation of cleansing level was also performed using the same grading system. The grades “poor” and “fair” were considered to be “inadequate,” whereas “good” or “excellent” were considered to be “adequate.”

Interobserver agreement At the end of the recruitment period, the investigators who performed the procedures (S.O. and G.D.N.) and who were blinded to the names of patients, independently performed video analysis of all CCE-2 and optical colonoscopy procedures, in order to assess interobserver agreement for each technique at the same center. For evaluation of interobserver agreement for CCE-2 at two different centers, the results of the first investigator (S.O.) were compared with those provided by two endoscopists from another hospital (C.S. and C.H. at Catholic University of Rome) who " Fig. 1). performed blinded video analysis of the CCE-2 cases (●

Safety The number of serious adverse events related to the CCE-2 procedure or bowel preparation was used to evaluate safety.

Results !

Of the 30 patients enrolled (14 males, 16 females; mean age 14.1 ± 3.2 years; mean duration of colitis 39.1 ± 27.7 months), one patient, who had a prior left-sided colitis and clinical remission at the time of the enrollment, was excluded due to the inability to swallow the capsule, leaving 29 patients available for analysis " Fig. 2; ● " Table 2). A total of 25 patients underwent colonosco(● py in the afternoon of the day of the CCE-2 examination, whereas 4 patients underwent colonoscopy the day after, because the capsule had not been excreted before the end of the battery life.

Diagnostic accuracy According to the adopted cutoff of the modified Matts score, 7 patients were classified as normal and 22 had an inflamed colon on CCE-2 (13 with Matts score > 6 – ≤ 12 and 9 with > 12), whereas 6 were classified as normal and 23 with inflammation by colonos" Table 3; copy (14 with > 6 – ≤ 12; 9 with > 12 of Matts score) (● " ● Fig. 2). Only one patient was classified as normal on CCE-2 " Fig. 2). but later found to have inflammation on colonoscopy (● In this case, the capsule did not reach the rectum before the end of the battery life and could not show the area of inflammation, which was located in the distal part of the colon and was correctly identified by colonoscopy. Images of the three classifications " Fig. 3. revealed by the CCE-2 and colonoscopy are shown in the ●

Oliva Salvatore et al. Colon capsule endoscopy in pediatric ulcerative colitis … Endoscopy 2014; 46: 485–492

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Completion and excretion rate

Video from CCE-2

Blinded Evaluation

Tolerability All patients or their parents were asked to evaluate each procedure in terms of ease of swallowing (for CCE), pain or discomfort experienced during and after the examinations, and overall satisfaction with the procedure, using a standardized questionnaire. A parent-report assessment was conducted for children aged 7 – 9 years, and a self-report assessment was performed by children and adolescents aged 10 years or older. Responses were recorded using a modified Likert scale for each procedure. Individual acceptance for each procedure was recorded on a scale from 0 (procedure not acceptable at all) up to 10 (fully acceptable), and pain and discomfort were assessed using a similar scale starting at 0 (pain or discomfort not perceived at all) up to 10 (maximum perception of pain or discomfort) [15].

487

Original article

Assessed for eligibility (n = 30 pediatric ulcerative colitis)

Table 2

Patient demographics and clinical information.

Patients, n

excluded (n = 1) (not able to swallow capsule)

29

Age, median (range), years

14.1 (7 – 18)

Sex, male/female, n

14 /15

Prior known extent of involvement, n (%)

CCE-2 (n = 29)

Proctitis Proctosigmoiditis Left-sided up to splenic flexure

normal (n = 7)

inflamed colon (n = 22) mildly active ulcerative colitis (n = 13)

active ulcerative colitis (n = 9)

Pancolonic disease

3 (10) 10 (35) 14 (48)

Disease duration, median (range), months

39.1 (3 – 96)

Age at diagnosis, median (range), years

11.3 (6 – 17)

Previous medication, n (%) Anti-inflammatory drugs

colonoscopy (n = 29)

2 (7)

11 (38)

Immunomodulators

9 (31)

Biological therapy

5 (17)

No therapy

4 (14)

Disease activity, PUCAI, n (%)

normal (n = 6)

abnormal (n = 1)

inflamed colon (n = 23) mildly active ulcerative colitis (n = 14)

active ulcerative colitis (n = 9)

Inactive

6 (21)

Mild

5 (17)

Moderate Severe

8 (28) 10 (34)

PUCAI, Pediatric Ulcerative Colitis Activity Index.

Fig. 2 Flow chart of study procedures and patients, classified by disease activity.

Fig. 3 Findings by colon capsule endoscopy (PillCam COLON-2; Given Imaging, Yoqneam, Israel; upper panel) and colonoscopy (lower panel) of the three classifications according to the Matts score. a, d Normal or not related to ulcerative colitis; b, e mildly active ulcerative colitis; c, f active ulcerative colitis.

The sensitivity of CCE-2 in detecting disease activity (i. e. modified Matts score > 6) was 96 % (95 %CI 79 – 99) and specificity was 100 % (95 %CI 61 – 100), corresponding to an overall accuracy of 97 % (95 %CI 90 – 100). The PPV and NPV were 100 % (95 %CI 85 – " Table 4). 100) and 85 % (95 %CI 49 – 97), respectively (●

An additional analysis considering the accuracy of the capsule in discriminating between “mild” and “severe” disease (i. e. standard Matts score), showed a perfect accuracy of CCE-2 in classifying patients with “severe” inflammation, with sensitivity of 100 % (95 %CI 70 – 100) and specificity of 100 % (95 %CI 80 – 100). How-

Oliva Salvatore et al. Colon capsule endoscopy in pediatric ulcerative colitis … Endoscopy 2014; 46: 485–492

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488

Original article

CCE-2 Disease activity “modified” Matts score Normal

Inflamed

Total

Normal

6

0

6

Inflamed

1

22

23

Total

7

22

29

489

Table 3 Classification of patients according to disease activity (modified and standard Matts score) and disease extent (Paris classification) for both procedures.

Disease activity “standard” Matts score Mildly active

Active

Total

6

0

0

6

Mildly active

1

13

0

14

Active

0

0

9

9

Total

7

13

9

29 Total

Disease extension – Paris classification Normal

E1

E2

E3

E4

Normal

6

0

0

0

0

6

E1

1

2

0

0

0

3

E2

0

0

4

0

0

4

E3

0

0

1

6

0

7

E4

0

0

0

0

9

9

Total

7

2

5

6

9

29

CCE, colon capsule endoscopy. Paris classification: E1 = ulcerative proctitis; E2 = left-sided ulcerative colitis; E3 = extensive ulcerative colitis; E4 = pancolitis.

CCE-2 Number of patients, n

29

Diagnostic accuracy (normal vs. inflamed colon), %

Colonoscopy

95 %CI, or P value

29

Table 4 Results at CCE-2 and colonoscopy.

Reference 90 – 100

Overall accuracy

97

Sensitivity

96

79 – 99

Specificity

100

61 – 100

PPV

100

85 – 100

NPV

85

49 – 97

Extent of disease, % E1 Sensitivity

67

21 – 94

Specificity

100

84 – 100

E2 Sensitivity

100

51 – 100

Specificity

95

75 – 99

E3 Sensitivity

86

49 – 97

Specificity

100

81 – 100

E4 Sensitivity

100

70 – 100

Specificity

100

79 – 100

Overall tolerability, mean ± SD

8.9 ± 1.2

Completion rate, %

97

Excretion rate, %

86

4.7 ± 1.9

P < 0.05

Bowel preparation grade, % Excellent

17

21

Good

45

41

Fair

24

28

Poor

14

10

Interobserver agreement, κ From single center 1st vs. 2nd investigator

0.90

1.0

0.77 – 1.00

From different centers 1st vs. 3 rd investigator

0.90

0.77 – 1.00

1st vs. 4th investigator

0.89

0.75 – 0.97

CCE-2, colon capsule endoscopy (second generation); CI, confidence interval; PPV, positive predictive value; NPV, negative predictive value.

Oliva Salvatore et al. Colon capsule endoscopy in pediatric ulcerative colitis … Endoscopy 2014; 46: 485–492

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Colonoscopy

Normal Normal

Original article

Colonoscopy

CCE-2

Ingestion of capsule was no problem

N/A

9.8 ± 0.2

I would undergo the capsule procedure again

N/A

9.5 ± 0.6

P value1

Individual tolerability scale 2 1. Ease of swallowing

Table 5 Patient questionnaire assessing tolerability of the procedures (based on modified Likert scale).

2. Wearing the data recorder Wearing the data recorder was no problem

N/A

8.9 ± 3.7

Wearing the data recorder significantly reduced scale of operations

N/A

6.1 ± 3.2

4.7 ± 1.9

8.9 ± 1.2

P < 0.05

5.3 ± 2.5

1.2 ± 0.9

P < 0.05

5.6 ± 2.1

2.1 ± 0.5

P < 0.05

3. Overall tolerability of the procedure I tolerated the procedure Pain and discomfort scale 3 4. Pain experienced during the procedure Abdominal pain occurred within 12 hours after the procedure 5. Discomfort caused by the procedure

N/A, not assessed; CCE, colon capsule endoscopy. 1 P value from the Mann – Whitney U test. 2 Tolerability scale, where 0 = not acceptable at all, and 10 = fully acceptable. 3 Pain and discomfort scale, where 0 = pain or discomfort not perceived at all, and 10 = maximum perceptionof pain or discomfort.

ever, CCE-2 was less precise in evaluating “mild” inflammation, especially in the distal part of colon, where sensitivity was 93 % (95 %CI 69 – 99) and specificity was 94 % (95 %CI 79 – 100).

For colonoscopy, the bowel preparation was considered to be excellent in 6 (21 %), good in 12 (41 %), fair in 8 (28 %), and poor in 3 " Table 4). No significant differences were observed for (10 %) (● bowel cleanliness between CCE-2 and colonoscopy.

Disease extent According to the Paris classification, the disease was E1 in 2 (9 %), E2 in 5 (23 %), E3 in 6 (27 %), and E4 in 9 (41 %) on CCE-2, and E1 in 3 (13 %), E2 in 4 (17 %), E3 in 7 (30 %), and E4 in 9 (39 %) on colo" Table 3). noscopy (● Sensitivity and specificity values of CCE-2 in detecting disease extent were: 67 % (95 %CI 21 – 94) and 100 % (95 %CI 84 – 100) for E1; 100 % (95 %CI 51 – 100) and 95 % (95 %CI 75 – 99) for E2; 86 % (95 % CI 49 – 97) and 100 % (95 %CI 81 – 100) for E3; 100 % (95 %CI 70 – " Table 4). 100) and 100 % for E4 (95 %CI 79 – 100) (●

Tolerability In almost all patients, ingestion of the CCE-2 was comfortable (mean score 9.8), and a possible further investigation by capsule " Tawas acceptable to most of the patients (mean score 9.5) (● ble 5). Wearing of the data recorder was widely accepted (score 8.9), although a minority of patients complained of a significant reduction in their range of activities (score 6.1). The overall tolerability was significantly higher for CCE-2 than for colonoscopy (P < 0.05), and both pain and discomfort were worse for colonosco" Table 5). py than for CCE-2 (P < 0.05) (●

Completion and excretion rate The bowel preparation and booster regimen used in the study resulted in 25 capsules (86 %) being excreted in 6 hours. Four (14 %) capsules were not excreted before the battery expired; however, three of these reached the rectum, thus enabling a complete evaluation of the colon, and in the remaining patient, the battery expired at the level of the sigmoid colon. From these data, comple" Tation and excretion rate were 97 % and 86 %, respectively (● ble 4).

Colon cleanliness Bowel preparation with PEG solution and sodium phosphate boosters was considered to be excellent in 5 (17 %), good in 13 " Table 4). Indeed, (45 %), fair in 7 (24 %), and poor in 4 (14 %) (● two-thirds (62 %) were adequate and one-third (38 %) was inadequate.

Interobserver agreement. Interobserver agreement in evaluating disease activity (Matts score > 6) for both procedures between two investigators at the same center was very high (κ = 1.0, 95 %CI 1.00 for colonoscopy; κ = 0.90, 95 %CI 0.77 – 1.00 for CCE-2). There was also an excellent agreement for CCE-2 between the investigators at two different centers in assessing disease activity (κ = 0.90, κ = 0.89, CI95 % 77 – " Ta100) and disease extent (κ = 0.91, κ = 0.86, CI95 % 75 – 97) (● ble 4). Regarding the reading time, the mean time required to evaluate one CCE-2 examination was 1.03 hours (range 0.43 – 1.41 hours).

Safety No serious adverse event related to the CCE procedure or bowel preparation was reported. Only one episode of vomiting was reported in one patient.

Discussion !

This is the first pilot diagnostic study using CCE-2 in pediatric patients with ulcerative colitis. Using a modified Matts score, CCE-2 was accurate in evaluating disease activity and extent in patients. The procedure was also highly safe and tolerable. Indeed, monitoring disease activity by CCE-2 may provide endoscopic visualization equivalent to colonoscopy in pediatric patients. The findings are of utmost interest for several reasons. First, the good diagnostic accuracy makes CCE-2 a potential alternative and valuable tool in defining disease activity in pediatric ulcerative colitis. Second, CCE-2 showed a satisfactory concordance with colonoscopy in assessing disease extent in patients with widespread inflammation. Third, the good tolerability means that CCE-2 is a comfortable evaluation procedure for pediatric patients, and therefore may increase adherence to endoscopic follow-up and management of patients according to the mucosal status. This is of clinical value in children with ulcerative colitis because of the long life course of their disease, which requires repeated endoscopic procedures. Moreover, due to the low risk of

Oliva Salvatore et al. Colon capsule endoscopy in pediatric ulcerative colitis … Endoscopy 2014; 46: 485–492

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490

dysplasia in pediatric patients [5], histological analysis is not always necessary, and the quick software mode for evaluating CCE-2 examinations, results in a reduction of the reading time by 20 minutes. CCE-2 showed good reproducibility between investigators from different centers, which makes it a simple and nonoperator-dependent technique. This is the first study to use PEG and sodium phosphate bowel preparation in a pediatric population. There were no serious adverse events related to the preparation. However, only 62 % patients had an optimal score (“excellent” or “good”). The quality of bowel preparation did not seem to affect the overall tolerability of the procedure or visualization of the mucosal inflammation, which was still possible with only a fair preparation, although the visualization of the colonic mucosa and the localization of disease extent may have been rendered more difficult. This is also the first experience of this bowel preparation for capsule endoscopy in a pediatric population. The majority of inadequate preparations occurred in cases with extensive inflammation, probably as a result of reduced motility in the inflamed colon. Future studies should focus on methods of improving bowel preparation in order to enhance the performance of CCE-2, particularly in pediatric gastroenterology. The safety of CCE-2 was confirmed in the study: none of the patients complained of discomfort related to the procedure itself, and most adverse events were related to bowel preparation, particularly the sodium phosphate boosters. The study has certain limitations that need to be taken into account when considering its contribution. First, the diagnostic accuracy was calculated using a modified Matts score, consisting of a dichotomous assessment of disease activity (normal or active) on a small sample. Indeed, when the standard Matts score was used, CCE-2 appeared to be less precise in discriminating mild inflammation and distal location of the disease. Second, the bowel preparation was chosen based on adult data and it was not always optimal for mucosal visualization or capsule excretion, especially in pancolitis. However, it should be noted that in the setting of ulcerative colitis in pediatric patients, the relevance of a suboptimal cleansing level might be considered marginal, as no subtle and/or focal mucosal abnormalities need to be detected, rather an overall mucosal evaluation needs to be made. Moreover, not all children will be able to swallow the capsule, although only one patient from the current study was excluded for this reason. This latter limitation cannot be easily overcome because endoscopic insertion is not rational and miniaturization would not suffice, as the inability to swallow is not necessarily related to the object’s size. Third, the tolerability of CCE-2 was higher for all parameters, but it is also true that a nonstandardized scale for evaluation of pain in children was used (modified Likert scale), which could be an additional limitation. Indeed, a parent-report assessment was conducted for children aged 7 – 9 years, whereas a self-report assessment was performed by children and adolescents aged 10 years and older. It is usually difficult to evaluate pain in children under the age of 4 years, for whom appropriate scales are required; however, the current population ranged from 7 to 18 years (with a median age of 14 years) and, thus, this limitation would not seem to be present. Finally, in calculating disease extent, the sample size became even smaller (only 23 patients with active inflammation) and therefore the results may not be very reliable. Nevertheless, the results are better than those of previous studies [13 – 16], particularly for the left-sided colon. It is conceivable that CCE-2 has a

more favorable colonic transit time in pediatric patients compared with adults, either due to more efficient motility or a shorter length of the colon. However, a relative weakness of CCE-2 in evaluating proctitis or left-sided colitis was confirmed. Indeed in this study, the only patient classified as normal by the CCE-2 and as mildly active by colonoscopy had a proctitis, and the capsule failed to reach the distal segments, thus missing the lesions. The possibility of the capsule failing to reach the rectum and missing distal lesions is another potential limitation of the technique; however, the majority of pediatric patients with ulcerative colitis have an extensive disease distribution, and thus only a few cases would be expected to be missed by the capsule. Previous reports on CCE monitoring of ulcerative colitis have been described in adults. Using the first-generation CCE, Sung et al. reported sensitivity, specificity, PPV, and NPV values of 89 %, 75 %, 93 %, and 65 % in 96 patients analyzed in two different centers. However, the study did not include a second evaluation of CCE and colonoscopy recordings by blinded readers in order to determine the interobserver agreement [13]. Two other studies using the first-generation CCE, showed a significant correlation between CCE and colonoscopy in assessing severity and extent of disease, but the diagnostic accuracy was not calculated and the sample sizes were very small [14, 15]. Finally, the only other study using the second-generation device, which was performed by Hosoe et al. and included 29 adults with ulcerative colitis, found a strong correlation in Matts scores between colonoscopy and CCE-2 (κ = 0.797), which became slightly lower when only the left-sided colon was considered (κ = 0.673) [16]. In conclusion, this study indicates that CCE-2 in future can play an important role in monitoring mucosal inflammation in pediatric ulcerative colitis, without invasiveness or discomfort and with a good level of diagnostic accuracy and tolerability. However, future multicenter studies are recommended, and indeed mandatory, before considering CCE-2 as an alternative technique in the follow-up of pediatric ulcerative colitis. Competing interests: Drs. Hassan and Spada are consultants for Given Imaging. All other authors have no competing interests. Given Imaging supported this study by providing 30 capsules.

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Second-generation colon capsule endoscopy vs. colonoscopy in pediatric ulcerative colitis: a pilot study.

Second-generation colon capsule endoscopy (CCE-2) may overcome the invasiveness of colonoscopy in the evaluation of mucosal inflammation, especially i...
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