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doi:10.1111/jgh.12488
GASTROENTEROLOGY
High sensitivity of quick view capsule endoscopy for detection of small bowel Crohn’s disease Morten Lee Halling,* Torben Nathan,† Jens Kjeldsen† and Michael Dam Jensen† *Department of Internal Medicine, Hospital of Southwest Denmark, Esbjerg, and †Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark
Key words capsule endoscopy, Crohn’s disease, quick view, sensitivity and specificity, small intestine. Accepted for publication 21 November 2013. Correspondence Dr Michael Dam Jensen, Department of Medical Gastroenterology, Odense University Hospital, Sdr. Boulevard 29, Odense DK-5000, Denmark. Email: [email protected] Conflicts of interest: There are no conflicts of interest for any author. The study was initiated, planned and undertaken by the investigators without funding from companies providing endoscopic equipment. The authors alone are responsible for the content and writing of the paper.
Abstract Background and Aim: Capsule endoscopy (CE) has a high sensitivity for diagnosing small bowel Crohn’s disease, but video analysis is time-consuming. The quick view (qv) function is an effective tool to reduce time consumption. The aim of this study was to determine the rate of missed small bowel ulcerations with qv-CE compared with standard view and the diagnostic accuracy of qv-CE in suspected Crohn’s disease. Methods: This study consisted of two parts: (i) 12 small bowel segments with Crohn’s disease of varying severity were selected for a detailed analysis of the number and type of lesions visualized with CE and qv-CE, and (ii) a blinded study of the diagnostic accuracy of qv-CE including 40 patients with suspected Crohn’s disease. Ileocolonoscopy and CE served as gold standard. Results: Part 1: CE visualized 171 ulcerations compared with 102 detected with qv-CE (miss rate 40%, P = 0.02). Part 2: qv-CE identified 15 of 16 patients with small bowel Crohn’s disease corresponding to a 94% sensitivity, and overall, 39 out of 40 patients were classified correct (diagnostic accuracy 98%). Qv-CE was false negative in one patient because of a leap of 3 min and 20 s in the terminal ileum. Reading times varied from 5 to 18 min (median 10). Conclusion: Despite a significant number of missed lesions, qv-CE is a safe and timereducing method for diagnosing small bowel Crohn’s disease. To avoid false negative cases, we recommend viewing the terminal ileum in standard view.
Introduction Capsule endoscopy (CE) provides at detailed view of the entire small bowel mucosa and has become a leading modality for diagnosing non-complicated small bowel Crohn’s disease (CD).1 Several studies have confirmed CE’s superiority for detection of lesions consistent with CD,2 and in a recent study, CE had a higher sensitivity and specificity compared with magnetic resonance imaging enterography (MRE) and computed tomography enterography (CTE).3 A significant limitation with CE, however, is the time consumption required for video analysis. In previous series, reading times above 40 min were reported.4–6 However, software to reduce time consumption is now available. The quick view (qv) function provided by Given Imaging’s RAPID Reader 6 filters the number of images shown, that is with a sampling rate of 10% (default setting), 10% of images from the original videos is shown. Images are filtered according to a specific algorithm developed by the manufacturer, and sampling rates between 5% and 80% can be chosen. Several studies have compared qv-CE with standard view CE. Time consumption is significantly reduced but at the expense of 992
missed lesions.7–10 Hence, qv-CE is recommended only when large lesions or widespread small bowel disease is suspected, for example CD or celiac disease.7,9,10 Qv-view needs further validation, and the sensitivity for detection of small bowel CD remains to be clarified. The purpose of this study was to determine (i) the rate of missed small bowel ulcerations with qv-CE compared with standard view and (ii) the diagnostic accuracy of qv-CE in patients with suspected CD.
Methods Capsule endoscopies from patients with suspected CD who participated in a prospective blinded multicenter study of the diagnostic validity of MRE, CTE, and CE were used in this analysis (ClinicalTrials.gov Identifier NCT01019460). Criteria for inclusion and exclusion are described in detail elsewhere.3 All patients had a standardized work-up including medical history, physical examination, blood samples, stool samples for enteropathogenic bacteria, fecal calprotectin, ileocolonoscopy, CE, MRE, and CTE. CEs were assessed by experienced gastroenterologists blinded to the results of ileocolonoscopy and other small bowel examinations.3
Journal of Gastroenterology and Hepatology 29 (2014) 992–996 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
ML Halling et al.
This study consisted of two parts: 1 Qv-CE miss rate: A detailed and non-blinded analysis of the number and type of lesions detected with CE and qv-CE. 2 Diagnostic accuracy of qv-CE for detection of small bowel CD. Study of qv-CE miss rate. Capsule endoscopies from patients with small bowel CD were searched by the last author, and segments of interest were marked with Given Imaging’s RAPID Reader (Yoqneam, Israel). Segments were selected according to the number and severity of lesions varying from few minor lesions to extensive severe inflammation. Segments were meticulously analyzed by the first author in standard and qv mode separately and non-blinded. The following settings were used: single view, maximally 5 frames/s and standard image enhancement settings. Lesions were counted and classified as aphthous lesions, isolated ulcers/fissures, or cobblestone appearance. Study of diagnostic accuracy. Patients with and without small bowel CD and a complete ileocolonoscopy and CE were selected, anonymized with RAPID Reader, and viewed in qv mode by the last author in a random order. After placing anatomical landmarks, the stomach and small bowel were analyzed with dual view, 10–15 frames/s and standard image enhancement settings. The following findings were recorded: time consumption during qv-CE reading, times to passage of the pylorus, and the ileocecal valve, CD (yes/no), localization (duodenum/jejunum, ileum, and/or terminal ileum), aphthous lesions, large or irregular ulcerations, and stenosis.
Capsule endoscopy in Crohn’s Disease
was predefined as a superficial and pale mucosal break surrounded by a red rim. An ulcer was defined as a pale lesion within a crater representing a visible loss of mucosal substance and fissures as longitudinal ulcers. Cobblestone appearance was defined as connected longitudinal and transversal fissures. Erythema, red spots, and nodularity were considered non-diagnostic. The terminal ileum was defined as the distal 20 cm of the ileum. Anatomical distinctions among jejunum, ileum, and terminal ileum were not predefined. Ethical considerations. The study was approved by the local ethics committee of Southern Denmark (S-20070072) and the Danish Data Protection Agency (journal number: 2007–20410675). All patients gave informed consent before participation. Before inclusion of adolescents between 15 and 17 years of age, both parents gave informed consent. Statistical analyses. Demographic data were analyzed using descriptive statistics. Differences in detection rates between CE and qv-CE were tested for statistical significance in a clustered linear regression model with 12 clusters (corresponding to 12 segments) accounting for observer dependency within segments. Sensitivity and specificity of qv-CE was calculated from 2 × 2 contingency tables. Anatomical landmarks placed with qv-CE were compared with CE reports from the initial diagnostic study.3 Intraclass correlation coefficients were used to assess the intermodality reliability and coefficients were calculated in a oneway analysis of variance model.
Results Gold standard. Ileocolonoscopy with biopsies and CE served as gold standard for the presence and location of CD. Ileocolonoscopy procedures are described in detail elsewhere.3 CE procedures. CE was performed with Pillcam SB from Given Imaging and did not include bowel preparation or the use of prokinetic drugs. The day before the examination, patients were instructed to ingest liquid foods from noon and to fast from 10 pm. Patients attended the outpatient clinic at 8 am. The sensor array was attached to the patient and connected to the data recorder. After checking for technical malfunctions, the patients ingested the capsule with half a glass of water. Patients were allowed to ingest liquids after 3 hours and a light meal after 5 h.
Qv-CE miss rate. A total of 12 segments with CD were selected for analyses (jejunum 1, ileum 3, terminal ileum 8). Segment lengths varied from 10 to 70 min (median 27). Qv-CE visualized lesions consistent with CD in all segments (Table 1). A total of 118 aphthous lesions were detected with CE compared with 75 with qv-CE (P = 0.13). CE and qv-CE identified 53 and 27 ulcers/fissures, respectively (P = 0.01), and cobblestone appearance was detected by both modalities in three patients. Overall, CE detected 171 ulcerations compared to 102 identified with qv-CE (miss rate 40 %, P = 0.02).
Observers. The first author has 2 years of experience in upper endoscopy and had CE training before this study was initiated. The last author has 6 years of experience in gastrointestinal endoscopy and more than 75 previous CE readings.
Diagnostic accuracy. Baseline characteristic of 40 patients with suspected CD selected for the study of diagnostic accuracy are listed in Table 2. The gold standard diagnosed CD in 18 patients, and 16 patients had findings consistent with CD in the small bowel (jejunum 5, ileum 10, terminal ileum 16). Qv-CE detected small bowel CD in 15 patients corresponding to a 94% sensitivity (CI 70–100), and overall, 39 out of 40 patients were classified correct (diagnostic accuracy 98%, Table 3). Qv-CE was false negative in one patient because of a leap of 3 min and 20 s in the terminal ileum (Fig. 1).
Definitions. The presence of more than 3 ulcerations (aphthous lesions or ulcers) or stenosis caused by fibrosis or inflammation was diagnostic of small bowel CD.1 An aphthous lesion
Anatomical landmarks. The mean times to passage of the pylorus were not significantly different with CE and qv-CE (34.5 and 34.7 min, respectively, P = 0.95), and the intraclass correlation
Software. Analyses were carried out with the RAPID Reader 6 Software Platform, Given diagnostic system. Default settings were used for qv analyses (10% sampling rate).
Journal of Gastroenterology and Hepatology 29 (2014) 992–996 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Table 1 Lesions detected with standard view capsule endoscopy (CE) and quick view capsule endoscopy in a detailed analysis of 12 small bowel segments with Crohn’s disease
Segment
Aphthae
Standard view CE Ulcers/fissures
Cobblestoning
Aphthae
Quick view CE Ulcers/fissures
Cobblestoning
1 2 3 4 5 6 7 8 9 10 11 12 Total
6 0 0 0 6 4 7 72 0 0 23 0 118
7 0 1 6 0 3 5 0 11 13 2 5 53
0 1 1 1 0 0 0 0 0 0 0 0 –
4 0 0 0 4 1 3 46 0 0 17 0 75
4 0 0 0 0 3 0 0 7 7 2 4 27
0 1 1 1 0 0 0 0 0 0 0 0 –
CE, capsule endoscopy.
Table 2
Baseline characteristics of 40 patients included in the study of diagnostic accuracy of quick view capsule endoscopy
Gender
Male Female
Age Symptoms
Median (range) Abdominal pain Diarrhea Weight loss > 3 kg Fever > 37.8°C
Use of NSAID Disease status after ileocolonoscopy and CE Montreal classification
Fecal calprotectin† C-reactive protein‡ CDAI§ Bowel resection prior to inclusion
11 (28%) 29 (72%)
Clinically suspected CD and normal pan-endoscopy Newly diagnosed CD Disease distribution Ileal (L1) Colonic (L2) Ileocolonic (L3) Upper small bowel (L4) Disease behavior Non-stricturing, non-penetrating (B1) Stricturing (B2) Penetrating (B3) Perianal disease (p) Non-CD: median (range) Newly diagnosed CD: median (range) Median (range) Median (range)
26 (15–74) 38 (95%) 33 (83%) 17 (43%) 1 (3%) 0 (0%) 22 (55%) 18 (45%)
n
years n
n n n
5 (28%) 2 (11%) 11 (61%) 5 (28%) 18 (100%) 0 (0%) 0 (0%) 0 (0%) 23 (20–53) 835 (31–1994) 6 (1–35) 179 (48–310) 0 (0%)
mg/g mg/L n
†
Fecal calprotectin was measured in 36 patients. C-reactive protein was measured in 39 patients. § Crohn’s Disease Activity Index was calculated in 14 patients with newly diagnosed Crohn’s disease. n, number of patients; CE, capsule endoscopy; CD, Crohn’s disease; NSAID, non-steroidal anti-inflammatory drug. ‡
coefficient was almost perfect (0.97 CI 0.95–0.99). In three patients, disagreements of more than 5 min were recorded. The mean times to passage of the ileoceacal valve were not significantly different between modalities (265.0 and 264.5 min, P = 0.92) and the intraclass correlation coefficient was almost perfect (0.98 CI 0.97–0.99). In six patients, disagreements of more than 5 min were recorded. 994
Placing anatomical landmarks did not affect the diagnosis of small bowel CD with qv-CE. Time consumption. Qv-CE reading times varied from 5 to 18 min (median 10). The mean time consumption was identical in patients with and without small bowel CD (10.5 vs 10.3 min, P = 0.96). Journal of Gastroenterology and Hepatology 29 (2014) 992–996
© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Capsule endoscopy in Crohn’s Disease
Table 3 Diagnostic accuracy of quick view capsule endoscopy (qv-CE) in 40 patients with suspected Crohn’s disease. Gold standard: Ileocolonoscopy + standard view capsule endoscopy
Gold standard CD Gold standard normal
qv-CE CD
qv-CE normal
15 0 15
1 24 25
16 24 40
Prevalence of CD: 40% Sensitivity: 94% (CI 70–100); Positive predictive value: 100% (CI 78–100) Specificity: 100% (CI 86–100); Negative predictive value: 96% (CI 80–100) CE, capsule endoscopy; CD, Crohn’s disease; CI, 95% confidence intervals.
Figure 1 False negative quick view capsule endoscopy (qv-CE). Due to a leap of 3 min and 20 s at the ileocecal junction, 6 frames shown in standard view were missed with qv-CE. Ileocolonoscopy and CE revealed fissures consistent with small bowel Crohn’s disease. CE also detected four apthous lesions, of which one was visualized with qv-CE but misinterpreted as debris.
Discussion Small bowel imaging is often required to visualize CD outside the reach of the colonoscope.11,12 Compared with radiological techniques, CE is superior for diagnosing small bowel CD,2,3 but video analysis is time-consuming. Hence, ways to reduce CE reading times without affecting the diagnostic accuracy would be helpful in clinical practice. Reading times are reduced by viewing two of four images simultaneously (doubleview or quadview) or with qv. However, altering reading times may affect detection rates, and the optimal mode for CE reading remains to be established. This study con-
firms a high diagnostic sensitivity of qv-CE in patients with suspected CD despite a significant rate of missed ulcerations. Missed lesions. In a recent study comparing single view at a speed of 10 frames/s with quadview at 20 frames/s, the mean reading time was reduced from 22 min to 11.9 min.13 However, detection rates of angiodysplasias, erosions, ulcers, and polyps were lower with quadview. Similarly, Shiotani et al. found decreased reading times with quadview compared with single view but no significant difference in detection rates among three investigators.14 Shiotani et al. examined how different sampling rates affect detection rates of qv-CE.8 A variety of preselected lesions were included in the study. With a 5% sampling rate, 39% of lesions were missed, which is comparable with this study. However, with a 25% sampling rate, only 7% of lesions were missed, and the reading time was reduced by approximately 50%. This setting was considered a proper trade-off between reading times and detection rates. Data on patients with CD are scarce. In the present study of qv-CE with a 10% sampling rate, 40% of small bowel ulcerations were missed compared with standard view. Miss rates were roughly comparable for lesions of different severity, that is 36% and 49% for aphthous ulcerations and ulcers/fissures, respectively. Our results do not confirm findings in a recent study in which primarily small ulcerations were missed.9 In a study of 81 patients with suspected or known CD, 155 and 71 ulcerations were detected with CE and qv-CE (35% sampling rate), respectively, corresponding to a miss rate of 54%.9 Studies on mixed populations have reported lower miss rates, but isolated data for patients with suspected or known CD are not available.15,16 Hence, it is possible to reduce reading times with quadview or qv but at the expense of lower detection rates. Diagnostic sensitivity. CD is characterized by the presence multiple ulcerations (aphthous, punched out, or irregular), and despite no diagnostic criterion for small bowel CD with CE has been validated, a threshold of more than three ulcerations is commonly used.1 A key question is whether the reported miss rate translates to at reduced diagnostic sensitivity using this diagnostic criterion. Westerhof et al. investigated the influence of the small-bowel transit time on the diagnostic yield in patients who were given prokinetics.17 They found decreased diagnostic yield in patients with low transit times. However, this concerned all indications for CE except suspected CD. This is probably due to the multiple and widespread small bowel lesions usually seen in CD. In the present study, qv-CE visualized lesions consistent with CD in all small bowel segments included in the non-blinded analysis (part 1). Furthermore, in a blinded assessment of qv-CE, the diagnostic sensitivity was 94% with only one false negative examination (part 2). This patient had small bowel CD confined to a short segment in the terminal ileum, which was only visualized in 6 frames with standard view. Other studies came to similar conclusions. Kyriakos et al. reported that CD was detected in 23 patients with both CE and qv-CE corresponding to a 100% sensitivity,10 and in the study by Koulaouzidis et al., missed lesions at qv-CE would have changed the diagnosis in only 1 of 15 patients with suspected CD.9
Journal of Gastroenterology and Hepatology 29 (2014) 992–996 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Hence, despite a significant miss rate, the diagnostic sensitivity of qv-CE seems to be high, which probably reflects the diffuse inflammation seen in CD. Anatomical landmarks. We have previously shown that misinterpretation of anatomical landmarks can affect the diagnosis of small bowel CD with CE.18 In the present study, we found no significant differences in placing anatomical landmarks with qv-CE and CE. Time consumption. In agreement with other studies, we found that qv-CE markedly reduces time consumption.7,10,15 The median time consumption for analyzing qv-CE was 10 min, which is one fifth of the time reported by the last author in a previous study.18 Similarly, Saurin et al. analyzed 106 CEs in qv mode with a mean time consumption of 11.6 min (range 2–27).15 Limitations. The analysis of the qv-CE miss rate was nonblinded, which could have biased results. Counting and classifying lesions can be difficult because of technical limitations. Frequently, lesions are seen only briefly in 1 or 2 frames or in the image periphery and the distinction between aphthous lesions, and debris on the mucosal surface can be difficult. We chose to compare modalities directly in order to secure a uniform classification of lesions and avoid counting lesions twice if they were shown repeatedly. Furthermore, disagreements when classifying lesions were minimized by predefining the characteristics. The strength of this study is the well-characterized population. Patients were thoroughly examined with CE and colonoscopy with biopsies, which is the accepted gold standard for diagnosing ileocolonic CD.11 However, the study is limited by the size of the population and more studies are needed to confirm our findings.
Conclusion In the present study, qv-CE missed 40% of small bowel ulcerations compared with standard view. However, the diagnostic sensitivity remained high, and qv-CE seems to be a safe and time-reducing method for detection of small bowel CD. In the majority of patients, CD is located in the terminal ileum and to avoid false negative cases, we recommend viewing this area in standard view.
Acknowledgments None.
Author contributions MLH, TN, JK, and MDJ designed the research. MLH and MDJ performed the data collection, data analysis, and drafted the article. JK and TN critically revised the article. MLH, TN, JK and MDJ approved the final version to be published.
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References 1 Bourreille A, Ignjatovic A, Aabakken L et al. Role of small-bowel endoscopy in the management of patients with inflammatory bowel disease: an international OMED-ECCO consensus. Endoscopy 2009; 41: 618–37. 2 Dionisio PM, Gurudu SR, Leighton JA et al. Capsule endoscopy has a significantly higher diagnostic yield in patients with suspected and established small-bowel Crohn’s disease: a meta-analysis. Am. J. Gastroenterol. 2009; 105: 1240–8. 3 Jensen MD, Nathan T, Rafaelsen SR, Kjeldsen J. Diagnostic accuracy of capsule endoscopy for small bowel Crohn’s disease is superior to that of MR enterography or CT enterography. Clin. Gastroenterol. Hepatol. 2011; 9: 124–9. 4 Levinthal GN, Burke CA, Santisi JM. The accuracy of an endoscopy nurse in interpreting capsule endoscopy. Am. J. Gastroenterol. 2003; 98: 2669–71. 5 Niv Y, Niv G. Capsule endoscopy examination—preliminary review by a nurse. Dig. Dis. Sci. 2005; 50: 2121–4. 6 Pennazio M. Capsule endoscopy: where are we after 6 years of clinical use? Dig. Liver Dis. 2006; 38: 867–78. 7 Westerhof J, Koornstra JJ, Weersma RK. Can we reduce capsule endoscopy reading times? Gastrointest. Endosc. 2009; 69: 497–502. 8 Shiotani A, Honda K, Kawakami M et al. Analysis of small-bowel capsule endoscopy reading by using Quickview mode: training assistants for reading may produce a high diagnostic yield and save time for physicians. J. Clin. Gastroenterol. 2012; 46: e92–5. 9 Koulaouzidis A, Smirnidis A, Douglas S, Plevris JN. QuickView in small-bowel capsule endoscopy is useful in certain clinical settings, but QuickView with Blue Mode is of no additional benefit. Eur. J. Gastroenterol. Hepatol. 2012; 24: 1099–104. 10 Kyriakos N, Karagiannis S, Galanis P et al. Evaluation of four time-saving methods of reading capsule endoscopy videos. Eur. J. Gastroenterol. Hepatol. 2012; 24: 1276–80. 11 Van Assche G, Dignass A, Panes J et al. The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: definitions and diagnosis. J. Crohns. Colitis. 2010; 4: 7–27. 12 Jensen MD, Nathan T, Rafaelsen SR, Kjeldsen J. Ileoscopy reduces the need for small bowel imaging in suspected Crohn’s disease. Dan. Med. J. 2012; 59: A4491. 13 Gunther U, Daum S, Zeitz M, Bojarski C. Capsule endoscopy: comparison of two different reading modes. Int. J. Colorectal Dis. 2012; 27: 521–5. 14 Shiotani A, Honda K, Kawakami M et al. Evaluation of RAPID((R)) 5 Access software for examination of capsule endoscopies and reading of the capsule by an endoscopy nurse. J. Gastroenterol. 2011; 46: 138–42. 15 Saurin JC, Lapalus MG, Cholet F et al. Can we shorten the small-bowel capsule reading time with the “Quick-view” image detection system? Dig. Liver Dis. 2012; 44: 477–81. 16 Appalaneni V, Glenn T, Hoffman BJ. Video capsule endoscopy: accuracy of quick-view. Gastrointest. Endosc. 2007; 65: AB313. 17 Westerhof J, Koornstra JJ, Hoedemaker RA, Sluiter WJ, Kleibeuker JH, Weersma RK. Diagnostic yield of small bowel capsule endoscopy depends on the small bowel transit time. World J. Gastroenterol. 2012; 18: 1502–7. 18 Jensen MD, Nathan T, Kjeldsen J. Inter-observer agreement for detection of small bowel Crohn’s disease with capsule endoscopy. Scand. J. Gastroenterol. 2010; 45: 878–84.
Journal of Gastroenterology and Hepatology 29 (2014) 992–996 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
doi:10.1111/jgh.12488
GASTROENTEROLOGY
High sensitivity of quick view capsule endoscopy for detection of small bowel Crohn’s disease Morten Lee Halling,* Torben Nathan,† Jens Kjeldsen† and Michael Dam Jensen† *Department of Internal Medicine, Hospital of Southwest Denmark, Esbjerg, and †Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark
Key words capsule endoscopy, Crohn’s disease, quick view, sensitivity and specificity, small intestine. Accepted for publication 21 November 2013. Correspondence Dr Michael Dam Jensen, Department of Medical Gastroenterology, Odense University Hospital, Sdr. Boulevard 29, Odense DK-5000, Denmark. Email: [email protected] Conflicts of interest: There are no conflicts of interest for any author. The study was initiated, planned and undertaken by the investigators without funding from companies providing endoscopic equipment. The authors alone are responsible for the content and writing of the paper.
Abstract Background and Aim: Capsule endoscopy (CE) has a high sensitivity for diagnosing small bowel Crohn’s disease, but video analysis is time-consuming. The quick view (qv) function is an effective tool to reduce time consumption. The aim of this study was to determine the rate of missed small bowel ulcerations with qv-CE compared with standard view and the diagnostic accuracy of qv-CE in suspected Crohn’s disease. Methods: This study consisted of two parts: (i) 12 small bowel segments with Crohn’s disease of varying severity were selected for a detailed analysis of the number and type of lesions visualized with CE and qv-CE, and (ii) a blinded study of the diagnostic accuracy of qv-CE including 40 patients with suspected Crohn’s disease. Ileocolonoscopy and CE served as gold standard. Results: Part 1: CE visualized 171 ulcerations compared with 102 detected with qv-CE (miss rate 40%, P = 0.02). Part 2: qv-CE identified 15 of 16 patients with small bowel Crohn’s disease corresponding to a 94% sensitivity, and overall, 39 out of 40 patients were classified correct (diagnostic accuracy 98%). Qv-CE was false negative in one patient because of a leap of 3 min and 20 s in the terminal ileum. Reading times varied from 5 to 18 min (median 10). Conclusion: Despite a significant number of missed lesions, qv-CE is a safe and timereducing method for diagnosing small bowel Crohn’s disease. To avoid false negative cases, we recommend viewing the terminal ileum in standard view.
Introduction Capsule endoscopy (CE) provides at detailed view of the entire small bowel mucosa and has become a leading modality for diagnosing non-complicated small bowel Crohn’s disease (CD).1 Several studies have confirmed CE’s superiority for detection of lesions consistent with CD,2 and in a recent study, CE had a higher sensitivity and specificity compared with magnetic resonance imaging enterography (MRE) and computed tomography enterography (CTE).3 A significant limitation with CE, however, is the time consumption required for video analysis. In previous series, reading times above 40 min were reported.4–6 However, software to reduce time consumption is now available. The quick view (qv) function provided by Given Imaging’s RAPID Reader 6 filters the number of images shown, that is with a sampling rate of 10% (default setting), 10% of images from the original videos is shown. Images are filtered according to a specific algorithm developed by the manufacturer, and sampling rates between 5% and 80% can be chosen. Several studies have compared qv-CE with standard view CE. Time consumption is significantly reduced but at the expense of 992
missed lesions.7–10 Hence, qv-CE is recommended only when large lesions or widespread small bowel disease is suspected, for example CD or celiac disease.7,9,10 Qv-view needs further validation, and the sensitivity for detection of small bowel CD remains to be clarified. The purpose of this study was to determine (i) the rate of missed small bowel ulcerations with qv-CE compared with standard view and (ii) the diagnostic accuracy of qv-CE in patients with suspected CD.
Methods Capsule endoscopies from patients with suspected CD who participated in a prospective blinded multicenter study of the diagnostic validity of MRE, CTE, and CE were used in this analysis (ClinicalTrials.gov Identifier NCT01019460). Criteria for inclusion and exclusion are described in detail elsewhere.3 All patients had a standardized work-up including medical history, physical examination, blood samples, stool samples for enteropathogenic bacteria, fecal calprotectin, ileocolonoscopy, CE, MRE, and CTE. CEs were assessed by experienced gastroenterologists blinded to the results of ileocolonoscopy and other small bowel examinations.3
Journal of Gastroenterology and Hepatology 29 (2014) 992–996 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
ML Halling et al.
This study consisted of two parts: 1 Qv-CE miss rate: A detailed and non-blinded analysis of the number and type of lesions detected with CE and qv-CE. 2 Diagnostic accuracy of qv-CE for detection of small bowel CD. Study of qv-CE miss rate. Capsule endoscopies from patients with small bowel CD were searched by the last author, and segments of interest were marked with Given Imaging’s RAPID Reader (Yoqneam, Israel). Segments were selected according to the number and severity of lesions varying from few minor lesions to extensive severe inflammation. Segments were meticulously analyzed by the first author in standard and qv mode separately and non-blinded. The following settings were used: single view, maximally 5 frames/s and standard image enhancement settings. Lesions were counted and classified as aphthous lesions, isolated ulcers/fissures, or cobblestone appearance. Study of diagnostic accuracy. Patients with and without small bowel CD and a complete ileocolonoscopy and CE were selected, anonymized with RAPID Reader, and viewed in qv mode by the last author in a random order. After placing anatomical landmarks, the stomach and small bowel were analyzed with dual view, 10–15 frames/s and standard image enhancement settings. The following findings were recorded: time consumption during qv-CE reading, times to passage of the pylorus, and the ileocecal valve, CD (yes/no), localization (duodenum/jejunum, ileum, and/or terminal ileum), aphthous lesions, large or irregular ulcerations, and stenosis.
Capsule endoscopy in Crohn’s Disease
was predefined as a superficial and pale mucosal break surrounded by a red rim. An ulcer was defined as a pale lesion within a crater representing a visible loss of mucosal substance and fissures as longitudinal ulcers. Cobblestone appearance was defined as connected longitudinal and transversal fissures. Erythema, red spots, and nodularity were considered non-diagnostic. The terminal ileum was defined as the distal 20 cm of the ileum. Anatomical distinctions among jejunum, ileum, and terminal ileum were not predefined. Ethical considerations. The study was approved by the local ethics committee of Southern Denmark (S-20070072) and the Danish Data Protection Agency (journal number: 2007–20410675). All patients gave informed consent before participation. Before inclusion of adolescents between 15 and 17 years of age, both parents gave informed consent. Statistical analyses. Demographic data were analyzed using descriptive statistics. Differences in detection rates between CE and qv-CE were tested for statistical significance in a clustered linear regression model with 12 clusters (corresponding to 12 segments) accounting for observer dependency within segments. Sensitivity and specificity of qv-CE was calculated from 2 × 2 contingency tables. Anatomical landmarks placed with qv-CE were compared with CE reports from the initial diagnostic study.3 Intraclass correlation coefficients were used to assess the intermodality reliability and coefficients were calculated in a oneway analysis of variance model.
Results Gold standard. Ileocolonoscopy with biopsies and CE served as gold standard for the presence and location of CD. Ileocolonoscopy procedures are described in detail elsewhere.3 CE procedures. CE was performed with Pillcam SB from Given Imaging and did not include bowel preparation or the use of prokinetic drugs. The day before the examination, patients were instructed to ingest liquid foods from noon and to fast from 10 pm. Patients attended the outpatient clinic at 8 am. The sensor array was attached to the patient and connected to the data recorder. After checking for technical malfunctions, the patients ingested the capsule with half a glass of water. Patients were allowed to ingest liquids after 3 hours and a light meal after 5 h.
Qv-CE miss rate. A total of 12 segments with CD were selected for analyses (jejunum 1, ileum 3, terminal ileum 8). Segment lengths varied from 10 to 70 min (median 27). Qv-CE visualized lesions consistent with CD in all segments (Table 1). A total of 118 aphthous lesions were detected with CE compared with 75 with qv-CE (P = 0.13). CE and qv-CE identified 53 and 27 ulcers/fissures, respectively (P = 0.01), and cobblestone appearance was detected by both modalities in three patients. Overall, CE detected 171 ulcerations compared to 102 identified with qv-CE (miss rate 40 %, P = 0.02).
Observers. The first author has 2 years of experience in upper endoscopy and had CE training before this study was initiated. The last author has 6 years of experience in gastrointestinal endoscopy and more than 75 previous CE readings.
Diagnostic accuracy. Baseline characteristic of 40 patients with suspected CD selected for the study of diagnostic accuracy are listed in Table 2. The gold standard diagnosed CD in 18 patients, and 16 patients had findings consistent with CD in the small bowel (jejunum 5, ileum 10, terminal ileum 16). Qv-CE detected small bowel CD in 15 patients corresponding to a 94% sensitivity (CI 70–100), and overall, 39 out of 40 patients were classified correct (diagnostic accuracy 98%, Table 3). Qv-CE was false negative in one patient because of a leap of 3 min and 20 s in the terminal ileum (Fig. 1).
Definitions. The presence of more than 3 ulcerations (aphthous lesions or ulcers) or stenosis caused by fibrosis or inflammation was diagnostic of small bowel CD.1 An aphthous lesion
Anatomical landmarks. The mean times to passage of the pylorus were not significantly different with CE and qv-CE (34.5 and 34.7 min, respectively, P = 0.95), and the intraclass correlation
Software. Analyses were carried out with the RAPID Reader 6 Software Platform, Given diagnostic system. Default settings were used for qv analyses (10% sampling rate).
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Table 1 Lesions detected with standard view capsule endoscopy (CE) and quick view capsule endoscopy in a detailed analysis of 12 small bowel segments with Crohn’s disease
Segment
Aphthae
Standard view CE Ulcers/fissures
Cobblestoning
Aphthae
Quick view CE Ulcers/fissures
Cobblestoning
1 2 3 4 5 6 7 8 9 10 11 12 Total
6 0 0 0 6 4 7 72 0 0 23 0 118
7 0 1 6 0 3 5 0 11 13 2 5 53
0 1 1 1 0 0 0 0 0 0 0 0 –
4 0 0 0 4 1 3 46 0 0 17 0 75
4 0 0 0 0 3 0 0 7 7 2 4 27
0 1 1 1 0 0 0 0 0 0 0 0 –
CE, capsule endoscopy.
Table 2
Baseline characteristics of 40 patients included in the study of diagnostic accuracy of quick view capsule endoscopy
Gender
Male Female
Age Symptoms
Median (range) Abdominal pain Diarrhea Weight loss > 3 kg Fever > 37.8°C
Use of NSAID Disease status after ileocolonoscopy and CE Montreal classification
Fecal calprotectin† C-reactive protein‡ CDAI§ Bowel resection prior to inclusion
11 (28%) 29 (72%)
Clinically suspected CD and normal pan-endoscopy Newly diagnosed CD Disease distribution Ileal (L1) Colonic (L2) Ileocolonic (L3) Upper small bowel (L4) Disease behavior Non-stricturing, non-penetrating (B1) Stricturing (B2) Penetrating (B3) Perianal disease (p) Non-CD: median (range) Newly diagnosed CD: median (range) Median (range) Median (range)
26 (15–74) 38 (95%) 33 (83%) 17 (43%) 1 (3%) 0 (0%) 22 (55%) 18 (45%)
n
years n
n n n
5 (28%) 2 (11%) 11 (61%) 5 (28%) 18 (100%) 0 (0%) 0 (0%) 0 (0%) 23 (20–53) 835 (31–1994) 6 (1–35) 179 (48–310) 0 (0%)
mg/g mg/L n
†
Fecal calprotectin was measured in 36 patients. C-reactive protein was measured in 39 patients. § Crohn’s Disease Activity Index was calculated in 14 patients with newly diagnosed Crohn’s disease. n, number of patients; CE, capsule endoscopy; CD, Crohn’s disease; NSAID, non-steroidal anti-inflammatory drug. ‡
coefficient was almost perfect (0.97 CI 0.95–0.99). In three patients, disagreements of more than 5 min were recorded. The mean times to passage of the ileoceacal valve were not significantly different between modalities (265.0 and 264.5 min, P = 0.92) and the intraclass correlation coefficient was almost perfect (0.98 CI 0.97–0.99). In six patients, disagreements of more than 5 min were recorded. 994
Placing anatomical landmarks did not affect the diagnosis of small bowel CD with qv-CE. Time consumption. Qv-CE reading times varied from 5 to 18 min (median 10). The mean time consumption was identical in patients with and without small bowel CD (10.5 vs 10.3 min, P = 0.96). Journal of Gastroenterology and Hepatology 29 (2014) 992–996
© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
ML Halling et al.
Capsule endoscopy in Crohn’s Disease
Table 3 Diagnostic accuracy of quick view capsule endoscopy (qv-CE) in 40 patients with suspected Crohn’s disease. Gold standard: Ileocolonoscopy + standard view capsule endoscopy
Gold standard CD Gold standard normal
qv-CE CD
qv-CE normal
15 0 15
1 24 25
16 24 40
Prevalence of CD: 40% Sensitivity: 94% (CI 70–100); Positive predictive value: 100% (CI 78–100) Specificity: 100% (CI 86–100); Negative predictive value: 96% (CI 80–100) CE, capsule endoscopy; CD, Crohn’s disease; CI, 95% confidence intervals.
Figure 1 False negative quick view capsule endoscopy (qv-CE). Due to a leap of 3 min and 20 s at the ileocecal junction, 6 frames shown in standard view were missed with qv-CE. Ileocolonoscopy and CE revealed fissures consistent with small bowel Crohn’s disease. CE also detected four apthous lesions, of which one was visualized with qv-CE but misinterpreted as debris.
Discussion Small bowel imaging is often required to visualize CD outside the reach of the colonoscope.11,12 Compared with radiological techniques, CE is superior for diagnosing small bowel CD,2,3 but video analysis is time-consuming. Hence, ways to reduce CE reading times without affecting the diagnostic accuracy would be helpful in clinical practice. Reading times are reduced by viewing two of four images simultaneously (doubleview or quadview) or with qv. However, altering reading times may affect detection rates, and the optimal mode for CE reading remains to be established. This study con-
firms a high diagnostic sensitivity of qv-CE in patients with suspected CD despite a significant rate of missed ulcerations. Missed lesions. In a recent study comparing single view at a speed of 10 frames/s with quadview at 20 frames/s, the mean reading time was reduced from 22 min to 11.9 min.13 However, detection rates of angiodysplasias, erosions, ulcers, and polyps were lower with quadview. Similarly, Shiotani et al. found decreased reading times with quadview compared with single view but no significant difference in detection rates among three investigators.14 Shiotani et al. examined how different sampling rates affect detection rates of qv-CE.8 A variety of preselected lesions were included in the study. With a 5% sampling rate, 39% of lesions were missed, which is comparable with this study. However, with a 25% sampling rate, only 7% of lesions were missed, and the reading time was reduced by approximately 50%. This setting was considered a proper trade-off between reading times and detection rates. Data on patients with CD are scarce. In the present study of qv-CE with a 10% sampling rate, 40% of small bowel ulcerations were missed compared with standard view. Miss rates were roughly comparable for lesions of different severity, that is 36% and 49% for aphthous ulcerations and ulcers/fissures, respectively. Our results do not confirm findings in a recent study in which primarily small ulcerations were missed.9 In a study of 81 patients with suspected or known CD, 155 and 71 ulcerations were detected with CE and qv-CE (35% sampling rate), respectively, corresponding to a miss rate of 54%.9 Studies on mixed populations have reported lower miss rates, but isolated data for patients with suspected or known CD are not available.15,16 Hence, it is possible to reduce reading times with quadview or qv but at the expense of lower detection rates. Diagnostic sensitivity. CD is characterized by the presence multiple ulcerations (aphthous, punched out, or irregular), and despite no diagnostic criterion for small bowel CD with CE has been validated, a threshold of more than three ulcerations is commonly used.1 A key question is whether the reported miss rate translates to at reduced diagnostic sensitivity using this diagnostic criterion. Westerhof et al. investigated the influence of the small-bowel transit time on the diagnostic yield in patients who were given prokinetics.17 They found decreased diagnostic yield in patients with low transit times. However, this concerned all indications for CE except suspected CD. This is probably due to the multiple and widespread small bowel lesions usually seen in CD. In the present study, qv-CE visualized lesions consistent with CD in all small bowel segments included in the non-blinded analysis (part 1). Furthermore, in a blinded assessment of qv-CE, the diagnostic sensitivity was 94% with only one false negative examination (part 2). This patient had small bowel CD confined to a short segment in the terminal ileum, which was only visualized in 6 frames with standard view. Other studies came to similar conclusions. Kyriakos et al. reported that CD was detected in 23 patients with both CE and qv-CE corresponding to a 100% sensitivity,10 and in the study by Koulaouzidis et al., missed lesions at qv-CE would have changed the diagnosis in only 1 of 15 patients with suspected CD.9
Journal of Gastroenterology and Hepatology 29 (2014) 992–996 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Hence, despite a significant miss rate, the diagnostic sensitivity of qv-CE seems to be high, which probably reflects the diffuse inflammation seen in CD. Anatomical landmarks. We have previously shown that misinterpretation of anatomical landmarks can affect the diagnosis of small bowel CD with CE.18 In the present study, we found no significant differences in placing anatomical landmarks with qv-CE and CE. Time consumption. In agreement with other studies, we found that qv-CE markedly reduces time consumption.7,10,15 The median time consumption for analyzing qv-CE was 10 min, which is one fifth of the time reported by the last author in a previous study.18 Similarly, Saurin et al. analyzed 106 CEs in qv mode with a mean time consumption of 11.6 min (range 2–27).15 Limitations. The analysis of the qv-CE miss rate was nonblinded, which could have biased results. Counting and classifying lesions can be difficult because of technical limitations. Frequently, lesions are seen only briefly in 1 or 2 frames or in the image periphery and the distinction between aphthous lesions, and debris on the mucosal surface can be difficult. We chose to compare modalities directly in order to secure a uniform classification of lesions and avoid counting lesions twice if they were shown repeatedly. Furthermore, disagreements when classifying lesions were minimized by predefining the characteristics. The strength of this study is the well-characterized population. Patients were thoroughly examined with CE and colonoscopy with biopsies, which is the accepted gold standard for diagnosing ileocolonic CD.11 However, the study is limited by the size of the population and more studies are needed to confirm our findings.
Conclusion In the present study, qv-CE missed 40% of small bowel ulcerations compared with standard view. However, the diagnostic sensitivity remained high, and qv-CE seems to be a safe and time-reducing method for detection of small bowel CD. In the majority of patients, CD is located in the terminal ileum and to avoid false negative cases, we recommend viewing this area in standard view.
Acknowledgments None.
Author contributions MLH, TN, JK, and MDJ designed the research. MLH and MDJ performed the data collection, data analysis, and drafted the article. JK and TN critically revised the article. MLH, TN, JK and MDJ approved the final version to be published.
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Journal of Gastroenterology and Hepatology 29 (2014) 992–996 © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
