Small-bowel capsule endoscopy: A ten-point contemporary review

Table 1 Available types of small-bowel capsule endoscopes and operating characteristics

Capsule device	Company	Country	Field of view (°)	Lens	LEDs	Image sensor	Transmission	Frames per second (fps)	Dimensions (mm)	Weight (g)	Battery life (h)	Real-time imager	FDA approval	Reviewing software	Optical enhancements
PillCam®SB2	Given®Imaging, Yokneam	Israel	156	Multi-element	4	CMOS	Radiofrequency	2-41	11 × 26	3.45	9->11.52	Yes	Yes	Rapid®v7	Blue-mode FICE 1,2,3
MiroCam®v2	IntroMedic® Co., Seoul	South Korea	170	N/A	4	CMOS	EFP	3	ø11 × 24	3.2	12	Yes	Yes	MiroView®v2	ALICE colour-mode
EndoCapsule®	Olympus© Co., Tokyo	Japan	145	N/A	4	CCD	Radiofrequency	2	ø11 × 26	3.45	10	Yes	Yes	OLYMPUS®WS-1	Contrast imaging
OMOM® (SmartCapsule)	Chongding Jinshan Science and Technology Co., Beijing	China	140	N/A	4	CCD	Radiofrequency	2 (variable)	13 × 27.9	6	8	Yes	No	OMOM® workstation	N/A
CapsoCam®SV1	CapsoVision® Inc., Saratoga	United States	360	N/A	16	N/A	On-board EPROM flash memory (USB)	16 (4 per camera)	11 × 31	N/A	15	No	No	CapsoView®	N/A

¹PillCam^®SB2 (L) captures 2 fps - PillCam^®SB2-4 captures 4 fps;

²PillCam^®SB2 (L) battery life > 11.5 h - PillCam^®SB2-4 battery life 8 h. LED: Light emitting diode; N/A: Not available; CMOS: Complementary metal-oxide-semiconductor; CCD: Charge-coupled device; EFP: Electric field propagation; EPROM: Erasable programmable read-only memory; USB: Universal Serial Bus; FDA: Food and Drug Administration; FICE: Fujinon Intelligent Chromo Endoscopy; ALICE: A Large Ion Collider Experiment.

Table 2 Head-to-head trials of small-bowel capsule endoscopy systems

Ref.	Country	Centre	Objective(s)	Study type	Design	CE type	Outcome(s)	Conclusion
Hart-mann et al[7]	Germany	Single centre	Head-to-head evaluation of technical performance and DY of two CE systems (PillCam®SB vs EndoCapsule®)	Prospective	►OGIB pts;	►PillCam®SB (Given®Imaging, Yoqneam, Israel);	►Pts enrolled: 40;	►Statistically non-significant trend for EndoCapsule® to detect more bleeding sources in pts with suspected small-bowel bleeding than PillCam®SB;
					►Pts randomized to undergo 2 CEs using different CE in random order		►CR: PillCam®SB 33/40 (82%); EndoCapsule® 40/40 (100%); P = NS;
							►Overall DY: PillCam®SB 26/50 (52%); EndoCapsule® 29/50 (58%); P = NS;
						►Pts randomized to undergo 2 CEs using different CE in random order	►DY (SB P2): PillCam®SB 22/50 (44%), EndoCapsule® 25/50 (50%), P = NS;
							►In all discordant SB P2findings (not detected by the PillCam®SB but detected by EndoCapsule®), PillCam®SB examinations were incomplete	►This is (likely) due to the longer recording time with EndoCapsule®
Cave et al[8]	United States	Multi-centre (4 centres)	Comparison of performance (DY in pts with OGIB): EndoCapsule®vs PillCam®SB	Prospective	►OGIB pts;	►EndoCapsule® (Olympus© America, Allentown, PA);	►Pts with OGIB (transfused or with haematocrit < 31%) (males) or < 28% (females): 63;	►Both devices are safe and have comparable DY within the previously reported range;
					►EndoCapsule® and PillCam®SB swallowed by each participant 40 min apart;		►Available data 51/63; 9 pts excluded for technical reasons + 3 pts for protocol violation;
							►24 videos read as normal, 14 as abnormal (from both CEs). Disagreement occurred in 13;	►Subjective difference in image quality favouring the EndoCapsule®;
					►Ingestion of CEs in randomized order;	►PillCam®SB (Given®Imaging, Yoqneam, Israel)	►No adverse events reported for either CE. Overall agreement: 38/51 (74.5%), κ = 0.48, P = 0.008;
					►Head-to-head comparison of CEs		Limitations: Although ingestion randomized, videos reading not blind (different shape of the image margin)	►Lack of electromechanical interference between 2 different CE
Kim et al[9]	South Korea	Single centre	Head-to-head evaluation of technical performance DY and of two capsule systems (PillCam®SB vs MiroCam®)	Prospective	►Pts referred to CE for various indications;	►MiroCam® (IntroMedic Co. Ltd., Seoul, South Korea);	►Pts enrolled: 24;	►MiroCam shows a longer operating time and a higher CR;
					►Each pt was randomly assigned to swallow 1 of 2 CEs, the second CE was swallowed once fluoroscopy indicated that first CE had reached the SB		►Mean operating time: MiroCam® 702 min; PillCam®SB 446 min, P < 0.001;
							►CR: MiroCam® 20/24 (83%); PillCam®SB 14/24 (59%), P = 0.031;	►Nevertheless, the 2 capsule systems showed comparable efficiency;
						►PillCam®SB (Given®Imaging, Yoqneam, Israel)	►DY: MiroCam® 11/24 (45.8%); PillCam®SB 10/24 (41.7%), P = 1.0;
							►DY (additive of both capsules): 12/24 (50%);	►Sequential capsule endoscopy with the MiroCam and PillCam SB produced slight (but NS) increase in DY
							►Concordance of findings among the two capsule systems 87.5%, κ = 0.74
Pioche et al[10]	France	Multi-centre	Head-to-head evaluation of the diagnostic concordance (κ value): PillCam®SB SB2 vs MiroCam®	Prospective	►OGIB pts;	►MiroCam®; (IntroMedic Co. Ltd., Seoul, South Korea);	►83 pts; drop-outs explained (10 technical issues), 73 pts/videos analysed;	►MiroCam® showed a slightly higher DY, difference not statistically significant;
					►Each pt ingested 2 CEs at a 1 h interval in a random order;		►31 concordant (-) ve cases (42.4%) and 30 concordant (+) ve cases (41.1%);
							►Satisfactory diagnostic concordance between the 2 systems (κ = 0.66);	►The 2 CE systems showed comparable efficiency for the diagnosis of OGIB
					►Videos read in a random order by 2 experienced (> 200 CEs) readers;	►PillCamSB2 (Given®Imaging, Yoqneam, Israel)	►DY similar among the 2 CE systems(PillCam®SB 2 vs MiroCam®: 46.6% vs 56.2%, respectively; P = 0.02);
					►Image-by-image review of cases of disagreement between the readers was performed by 3 expert readers		►SBTT longer with MiroCam®vs PillCam®SB (mean SBTT: 268 vs 234 min, < 0.05);
							►Reading time longer with MiroCam®vs PillCam®SB (mean reading time 40 vs 23 min, P < 0.05);
							►(+) ve diagnosis obtained in 46.6% vs 56.2% of pts with PillCam®SB2 vs MiroCam®, respectively;
							►PillCam®SB2 vs MiroCam®CEs identified 78.6% vs 95.2% of (+) ve cases, respectively, P = 0.02
Dolak et al[11]	Austria	Single centre	Head-to-head comparison (MiroCam®vs EndoCapsule®) of: CR of SB examinations, DY in SB disease	Prospective	►Pts referred to CE for various indications;	►MiroCam® (IntroMedic Co. Ltd., Seoul, South Korea);	►Pts enrolled: 50;	►The two capsule endoscopy systems were not statistically different with regards to CR and DY;
					►Each pt was randomly assigned to swallow either MiroCam® first, followed by the EndoCapsule® 2 h later, or vice versa;		►CR: MiroCam® 48/50 (96%) vs EndoCapsule® 45/50 (90%); P = 0.38;
							►DY in SB: MiroCam® 25/50 (50%) vs EndoCapsule® 24/50 (48%); P > 0.99;
						►EndoCapsule® (Olympus America, Allentown, PA)	►Concordance of findings among the two CE systems: 68%; κ = 0.50	►Moderate concordance, mainly caused by missed pathological findings (which affected both devices), needs consideration in clinical practice
					►All videos analysed by two investigators independently

DY: Diagnostic yield; CE: Capsule endoscopy; OGIB: Obscure gastrointestinal bleeding; pts: Patients; CR: Completion rate; NS: Not significant (statistically); SB: Small-bowel; P2: Refers to grading of angioectasias; SBTT: Small-bowel transit time.

Table 3 Available meta-analyses and systematic reviews in the field of small-bowel capsule endoscopy

Ref.	Title	Search (start - end date)	Type	Subject	Data extractors	Total titles found	Titles entered meta-analysis	Individuals included	Outcome/conclusion
Liao et al[13]	Indications, detection, completion, and retention rates of SBCE: A systematic review	2000 - Jan 2009	Systematic review of evidence base	Indications, DR, CR and RR of SBCE	2	227	227	22753 Pts; 22840 CE	►Most common indications: OGIB (66.0%); investigation of clinical symptoms (10.6%); definite/suspected CD (10.4%);
									►Pooled DRs for overall, OGIB, CD, neoplasia: 59.4%, 60.5%, 55.3%, 55.9%, respectively;
									►Commonest cause for OGIB: angiodysplasia (50.0%);
									►Pooled CRs (overall): 83.5%; breakdown 83.6% (OGIB), 85.4% (clinical symptoms), 84.2% (CD);
									►Pooled RRs (overall): 1.4%; breakdown 1.2% (OGIB), 2.6% (clinical symptoms), 2.1% (CD);
									►Hence, most common indication for SBCE is OGIB, with high DR and low RR;
									►A relatively high RR is associated with definite/suspected CD and neoplasms
Marmo et al[17]	Meta-analysis: Capsule enteroscopy vs conventional modalities in diagnosis of SB diseases	Jan 1966 - Mar 2005	Meta-analysis of diagnostic test accuracy	DY/safety of SBCE vs alternative modalities (PE, SBBaR or enteroclysis) in SB disease	2	187	17	526 pts (289 OGIB and 237 CD)	►17 studies (526 patients) met inclusion criteria;
									►Overall, the rate difference for SB disease (i.e., the absolute pooled difference in the rate of positive findings) of SBCE vs alternative modalities was 41% (95%CI: 35.6-45.9);
									►For OGIB, 37% (95%CI: 29.6-44.1) for Crohn's disease 45% (95%CI: 30.9-58.0);
									►Incomplete SBCE occurred in 13%, more often in OGIB (17%) than in pts with CD (8%) (P < 0.006);
									►Adverse events: 29 pts (6%);
									►Capsule retention more frequent in pts with CD (3% vs 1%, OR 4.37)
Triester et al[18]	A meta-analysis of the yield of CE compared to other diagnostic modalities in patients with OGIB	N/A - April 2005	Meta-analysis of diagnostic test accuracy	IY (yield of CE-yield of comparative modality) and 95%CI of CE over comparative modalities	2	80	14	396 CE-PE; 88 CE-SBBaR	►14 studies (n = 396) compared DY CE vs PE in OGIB, 63% vs 28%, respectively (IY = 35%, P < 0.00001, 95%CI: 26%-43%);
									►For clinically significant findings (n = 376) DY was 56% (CE) vs 26% (PE), IY = 30%, P < 0.00001, 95%CI: 21%-38%;
									►3 studies (n = 88) compared DY of CE vs SBBaR, 67% vs 8%, respectively (IY = 59%, P < 0.00001, 95%CI: 48%-70%);
									►For clinically significant findings DY was 42% (CE) vs 6% (SBBaR); IY = 36%, P < 0.00001, 95%CI: 25%-48%;
									►NNT to yield one additional clinically significant finding with CE over either modality: 3 (95%CI: 2-4);
									►1 study compared DY (significant findings) of CE vs intraoperative enteroscopy (n = 42, IY = 0%, P = 1.0, 95%CI: -16%-16%);
									►1 study compared DY (significant findings) of CE vs CT enteroclysis (n = 8, IY = 38%, P = 0.08, 95%CI: -4%-79%);
									►1 study compared DY (significant findings) of CE vs mesenteric angiogram (n = 17, IY = -6%, P = 0.73, 95%CI: -39%-28%);
									►1 study compared DY (significant findings) of CE vs SB MRI (n = 14, IY = 36%, P = 0.007, 95%CI: 10%-62%);
									►CE-DY vs PE (vascular lesions): 36% vs 20% (IY = 16%, P < 0.00001, 95%CI: 9%-23%);
									►CE-DY vs PE (inflammatory lesions): 11% vs 2% (IY = 9%, P = 0.0001, 95%CI: 5%-13%);
									►CE-DY vs PE (tumours or "other" findings): no difference
Leighton et al[19]	Capsule endoscopy: A meta-analysis for use with OGIB and CD	N/A - April 2005	Meta-analysis of diagnostic test accuracy	DY and safety of SBCE vs alternative modalities (PE, SBBaR or enteroclysis) in SB disease	2	80	20	537 pts	►CE superior to PE/SB radiography for diagnosing SB pathology in pts with OGIB (yield comparable to intraoperative endoscopy);
									►Incremental yield of CE over PE/SB radiography is > 30% for clinically significant findings, due to visualization of additional vascular, inflammatory lesions by CE;
									►CE was also superior to SB radiography, C + IL, CT enterography, PE for diagnosing non-stricturing SBCD;
									►Marked improvement in yield with the use of CE over all other methods in pts who had established CD and were evaluated for SB recurrence;
									►Unknown whether these results will translate into improved pt outcomes with the use of CE vs alternate methods
Leighton et al[19]	Capsule endoscopy: A meta-analysis for use with OGIB and CD	N/A - April 2005	Meta-analysis of diagnostic test accuracy	DY and safety of SBCE vs alternative modalities (PE, SBBaR or enteroclysis) in SB disease	2	80	20	537 pts	►CE superior to PE/SB radiography for diagnosing SB pathology in pts with OGIB (yield comparable to intraoperative endoscopy);
									►Incremental yield of CE over PE/SB radiography is > 30% for clinically significant findings, due to visualization of additional vascular, inflammatory lesions by CE;
									►CE was also superior to SB radiography, C + IL, CT enterography, PE for diagnosing non-stricturing SBCD;
									►Marked improvement in yield with the use of CE over all other methods in pts who had established CD and were evaluated for SB recurrence;
									►Unknown whether these results will translate into improved pt outcomes with the use of CE vs alternate methods
Triester et al[20]	A meta-analysis of the yield of CE compared to other diagnostic modalities in patients with non-stricturing SB Crohn’s disease	N/A - Aug 2005	Meta-analysis of diagnostic test accuracy		2	82	9	250 pts	►9 studies (n = 250) compared DY CE vs SBBaR in CD: 63% vs 23%, respectively (IY = 40%, P < 0.001, 95%CI: 28%-51%);
									►4 studies (n = 114) compared DY CE vs C + IL in CD: 61% vs 46%, respectively (IY = 15%, P = 0.02, 95%CI: 2%-27%);
									►3 studies (n = 93) compared DY CE vs CT enterography/enteroclysis: 69% vs 30%, respectively (IY = 38%, P = 0.001, 95%CI: 15%-60%);
									►2 studies compared DY CE vs PE: (IY = 38%, P < 0.001, 95%CI: 26%-50%);
									►1 study compared DY CE vs SBMRI (IY = 22%, P = 0.16, 95%CI: -9%-53%);
									Sub-analysis (pts with suspected CD): no difference in DY CE vs SBBaR (P = 0.09), C + IL (P = 0.48), CT enterography (P = 0.07) or PE (P = 0.51);
									Sub-analysis (pts with established CD): difference in DY CE vs SBBaR (P < 0.001 C + IL (P = 0.002), CT enterography (P < 0.001) and PE (P < 0.001)
Pasha et al[21]	DBE and CE have comparable DY in SB disease: A meta-analysis	N/A - Dec 2006	Meta-analysis of diagnostic test accuracy	Comparison of DY of CE vs DBE	2	113	11	397 pts	►Pooled DY CE vs DBE: 60% vs 57% (IYW = 3%, 95%CI: -4%-10%, P = 0.42, FEM);
									►Pooled DY CE vs DBE (vascular findings, 10 studies): 24% vs 24% (IYW = 0%, 95%CI: -5%-6%, P = 0.88, REM);
									►Pooled DY CE vs DBE (inflammatory findings, 9 studies): 18% vs 16% (IYW = 0%, 95%CI: -5%-6%, P = 0.89, FEM);
									►Pooled DY CE vs DBE (polyps/tumours, 9 studies): 11% vs 11% (IYW = -1%, 95%CI: -5%-4%, P = 0.76, FEM);
									►SB disease: CE vs DBE have comparable DY, including OGIB, CE should be the initial diagnostic test for determining the insertion route of DBE
Niv[22]	Efficiency of bowel preparation for capsule endoscopy examination: A meta-analysis	N/A - July 2007	Meta-analysis of RCTs and cohort studies	Purgative use vs fasting alone for SBCE	1	6	8	130 bowel prep; 107 fasting	►237 pts, 130 with and 107 without preparation;
									►Seven out of 8 studies included a comparison of GTT, SBTT and CR;
									►SBCE CR: 76% in pts with preparation vs 68% without prep (difference did not reach statistical significance);
									►No statistically significant difference between CEs performed with or without preparation in GTT (pooled effect size, -0.054; 95%CI: -0.418-0.308) or SBTT (pooled effect size, -0.327; 95%CI: -1.419 - -0.765)
El-Matary et al[23]	Diagnostic characteristics of given video capsule endoscopy in diagnosis of celiac disease: A meta-analysis		Meta-analysis of diagnostic test accuracy	Coeliac and CE	2	N/A	3	107 pts	►3 studies (n = 107, 63 pts with CD/44 without) met inclusion criteria;
									►Pooled SBCE (overall) Sens and Spec: 83% (95%CI: 71%-90%) and 98% (95%CI: 88%-99.6%), respectively;
									►No major complications reported;
									►Costs mentioned only in 1 study. Overall, diagnostic characteristics of SBCE, could not justify the routine use of SBCE as alternative to biopsy
Chen et al[24]	A meta-analysis of the yield of CE compared to DBE in pts with SB diseases	N/A - Feb 2007	Meta-analysis of diagnostic test accuracy	Comparison of DY of CE vs DBE	2	163	8	277 pts	►8 studies (n = 277 pts) prospectively compared the yield of CE and DBE were included;
									►No difference between the yield of CE and DBE (170/277 vs 156/277, OR 1.21, 95%CI: 0.64-2.29);
									►Sub analysis: yield of CE significantly higher than that of DBE without combination of oral+anal insertion approaches (137/219 vs 110/219, OR 1.67, 95%CI: 1.14-2.44, P < 0.01), but not superior to the yield of DBE with combination of the two insertion approaches (26/48 vs 37/48, OR 0.33, 95%CI: 0.05-2.21, P < 0.05);
									►Focused meta-analysis of the fully published articles concerning OGIB showed similar results wherein the yield of CE was significantly higher than that of DBE without combination of oral + anal insertion approaches (118/191 vs 96/191, fixed model: OR 1.61, 95%CI: 1.07-2.43, P < 0.05) and the yield of CE was significantly lower than that of DBE by oral+ anal combinatory approaches (11/24 vs 21/24, fixed model: OR 0.12, 95%CI: 0.03-0.52, P < 0.01)
Rokkas et al[25]	Does purgative preparation influence the diagnostic yield of small bowel video capsule endoscopy? A meta-analysis	N/A - Feb 2008	Meta-analysis of RCTs and cohort studies	Purgative use vs fasting alone for SBCE	2	194	12	718 pts purgative; 444 controls	►12 eligible studies (6 prospective/6 retrospective), including 16 sets of data;
									►Significant difference in DY between pts prepared with purgatives (n = 263) vs pts prepared with clear liquids (n = 213): OR = 1.813 (95%CI: 1.251-2.628, P = 0.002);
									►Significant difference in SBVQ between pts prepared with purgatives (n = 404) vs pts prepared with clear liquids (n = 249): OR = 2.113 (95%CI: 1.252-3.566, P = 0.005); There was no statistically significant difference regarding CR rate. Purgatives did not affect VCE GTT or VCE SBTT
Dionisio et al[26]	CE has a significantly higher DY in patients with suspected and established small-bowel CD: A meta-analysis	2000 - May 2009	Meta-analysis of diagnostic test accuracy	DY of CE vs modalities in patients with suspected/ established CD	2	291	12	428 pts	►8 studies (n = 236 pts) compared CE vs C + IL, 4 (n = 119 pts) CE vs CTE, 2 (n = 102 pts) vs PE, 4 (n = 123 pts) vs MRE;
									►For suspected CD, several comparisons met statistical significance; Yields in this subgroup were: CE vs SBR: 52% vs 16% (IYw = 32%, P < 0.0001, 95%CI: 16%-48%), CE vs CTE: 68% vs 21% (IYw = 47%, P < 0.00001, 95%CI: 31%-63%), CE vs C + IL: 47% vs 25% (IYw = 22%, P = 0.009, 95%CI: 5%-39%);
									►For established CD, statistically significant yields for CE vs an alternate diagnostic modality in patients were seen: CE vs PE: 66 vs 9% (IYw = 57%, P < 0.00001, 95%CI: 43-71%), CE vs SBR: 71 vs 36% (IYw = 38%, P < 0.00001, 95%CI: 22%-54%), CE vs CTE: 71 vs 39% (IYw = 32%, P ≤ 0.0001, 95%CI: 16%-47%)
Wu et al[27]	Systematic review and meta-analysis of RCTs of Simethicone for GI endoscopic visibility	N/A- Nov 2009	Meta-analysis of RCTs	Simethicone and CE	2	128	4	121 pts	►Adequate or excellent/good SB mucosa visualization in pts receiving Simethicone vs those who did not (66.1% vs 37.2%);
									►Pooled OR = 2.84 (95%CI: 1.74-4.65, P = 0.00); no significant heterogeneity (P = 0.16, I2 = 38.8%) or publication bias (P = 0.251);
									►Sens analysis: studies stratified by factors such as bowel preparation (purgative vs fasting): Significant results for bowel preparation + fasting (OR = 4.43, 95%CI: 1.82-10.76, P = 0.00) with P = 0.78, I2 = 0.0%, No significant results for bowel preparation + purgative (OR = 1.59, 95%CI: 0.78-3.27, P = 0.203) with P = 0.20, I2 = 38.9%
Rokkas et al[25]	Does purgative preparation influence the diagnostic yield of small bowel video capsule endoscopy? A meta-analysis	N/A - Feb 2008	Meta-analysis of RCTs and cohort studies	Purgative use vs fasting alone for SBCE	2	194	12	718 pts purgative; 444 controls	►12 eligible studies (6 prospective/6 retrospective), including 16 sets of data;
									►Significant difference in DY between pts prepared with purgatives (n = 263) vs pts prepared with clear liquids (n = 213): OR = 1.813 (95%CI: 1.251-2.628, P = 0.002);
									►Significant difference in SBVQ between pts prepared with purgatives (n = 404) vs pts prepared with clear liquids (n = 249): OR = 2.113 (95%CI: 1.252-3.566, P = 0.005); There was no statistically significant difference regarding CR rate. Purgatives did not affect VCE GTT or VCE SBTT
Dionisio et al[26]	CE has a significantly higher DY in patients with suspected and established small-bowel CD: A meta-analysis	2000 - May 2009	Meta-analysis of diagnostic test accuracy	DY of CE vs modalities in patients with suspected/ established CD	2	291	12	428 pts	►8 studies (n = 236 pts) compared CE vs C + IL, 4 (n = 119 pts) CE vs CTE, 2 (n = 102 pts) vs PE, 4 (n = 123 pts) vs MRE;
									►For suspected CD, several comparisons met statistical significance; Yields in this subgroup were: CE vs SBR: 52% vs 16% (IYw = 32%, P < 0.0001, 95%CI: 16%-48%), CE vs CTE: 68% vs 21% (IYw = 47%, P < 0.00001, 95%CI: 31%-63%), CE vs C + IL: 47% vs 25% (IYw = 22%, P = 0.009, 95%CI: 5%-39%);
									►For established CD, statistically significant yields for CE vs an alternate diagnostic modality in patients were seen: CE vs PE: 66 vs 9% (IYw = 57%, P < 0.00001, 95%CI: 43-71%), CE vs SBR: 71 vs 36% (IYw = 38%, P < 0.00001, 95%CI: 22%-54%), CE vs CTE: 71 vs 39% (IYw = 32%, P ≤ 0.0001, 95%CI: 16%-47%)
Wu et al[27]	Systematic review and meta-analysis of RCTs of Simethicone for GI endoscopic visibility	N/A - Nov 2009	Meta-analysis of RCTs	Simethicone and CE	2	128	4	121 pts	►Adequate or excellent/good SB mucosa visualization in pts receiving Simethicone vs those who did not (66.1% vs 37.2%);
									►Pooled OR = 2.84 (95%CI: 1.74-4.65, P = 0.00); no significant heterogeneity (P = 0.16, I2 = 38.8%) or publication bias (P = 0.251);
									►Sens analysis: studies stratified by factors such as bowel preparation (purgative vs fasting): Significant results for bowel preparation + fasting (OR = 4.43, 95%CI: 1.82-10.76, P = 0.00) with P = 0.78, I2 = 0.0%, No significant results for bowel preparation + purgative (OR = 1.59, 95%CI: 0.78-3.27, P = 0.203) with P = 0.20, I2 = 38.9%
Cohen et al[28]	Use of CE in diagnosis and management of pediatric patients, based on meta-analysis	Jan 2001 - May 2010	Systematic review of evidence base	Systematic compilation of data on indications and outcomes of CE in paediatric patients	2	N/A	15	740 examinations; 723 pts	►Most common indication for CE (in pts < 18 yr): suspicion or evaluation of IBD (overall 54%), Breakdown: suspected CD (34%), known CD (16%), UC (1%), indeterminate colitis (3%)
									►CR and RR: 86.2% (95%CI: 81.5-90.3%) and 2.6% (95%CI: 1.5-4.0%), respectively;
									►CE RR (gastric and SB): 0.5% and 1.9%, respectively, similar to those of adults, by indication;
									►CE with positive findings: 65.4% (95%CI: 54.8%-75.2%);
									►CE resulting in new diagnosis: 69.4% (95%CI: 46.9%-87.9%); CE leading to change in therapy: 68.3% (95%CI: 43.6%-88.5%)
Teshima et al[29]	DBE and CE for OGIB: An updated meta-analysis	N/A - June 2010	Meta-analysis of diagnostic test accuracy	OGIB; CE or DBE	2	147	10	651 CE; 642 DBE	►Pooled DY for CE: 62% (95%CI: 47.3%-76.1%)
									►Pooled DY for DBE 56% (95%CI: 48.9%-62.1%); OR for CE vs DBE of 1.39 (95%CI: 0.88-2.20; P = 0.16);
									Subgroup analyses
									►DBE-DY after (+)ve CE: 75.0% (95%CI: 60.1%-90.0%)
									►DBE-DY after (-)ve CE: 27.5% (95%CI: 16.7%-37.8%)
									►DBE-OR (for successful diagnosis after (+)ve CE) compared with DBE: 1.79 (95%CI: 1.09-2.96, P = 0.02)
									►In OGIB CE and DBE have similar DY, DBE-DY significantly higher when performed in pts with prior positive CE
Belsey et al[30]	Meta-analysis: efficacy of SB preparation for SBCE	Jan 2000 - Dec 2010	Meta-analysis of RCTs	Purgative use vs fasting alone for SBCE	2	33	8	291 PEG; 133 NaP; 322 fasting	►8 studies, using PEG or NaP-based bowel cleansing regimens;
									►Any form of purgative significantly better visibility than fasting alone (OR = 2.31; 95%CI: 1.46-3.63, P < 0.0001);
									►Similar results on DY (OR = 1.88; 95%CI: 1.24-2.84; P = 0.023);
									Subgroup analyses (per cleansing regimen used):
									►PEG-based regimens showed benefit (OR = 3.11; 95%CI: 1.96-4.94, P < 0.0001);
									►NaP-based regimens no significant difference from fasting alone (OR = 1.32; 95%CI: 0.59-2.96, P < 0.0001);
									►Use of purgatives (alongside fasting) is recommended in SBCE; PEG-based regimens offer a clear advantage over NaP;
									►Lower volume PEG regimens as efficacious as higher volumes traditionally used for colonoscopy preparation
Rokkas et al[31]	The role of video CE in the diagnosis of coeliac disease: A meta-analysis	N/A - April 2011	Meta-analysis of diagnostic test accuracy	Coeliac and CE	2	461	6	166 pts	►Pooled CE Sens: 89% (95%CI: 82%-94%) and Spec: 95% (95%CI: 89%-98%), AuROC: 0.9584;
									►Although not as accurate as pathology, CE a reasonable alternative method of diagnosing coeliac disease
Koulaouzidis et al[32]	Diagnostic yield of SBCE in patients with IDA: A systematic review	Jan 2001 - Nov 2011	Systematic review of evidence base	IDA and CE	2	1225	24	1960 pts	►Pooled SBCE-DY in IDA: 47% (95%CI: 42%-52%), with significant heterogeneity among included studies (I2 = 78.8%, P < 0.0001);

CE: Capsule endoscopy; N/A: Not available or not applicable; Sens: Sensitivity; Spec: Specificity; AuROC: Area under Receiver operation characteristics curve; DBE: Double-balloon enteroscopy; OGIB: Obscure gastrointestinal bleeding; DY: Diagnostic Yield; pts: Patients; IY: Incremental yield; GTT: Gastric transit time; SBTT: Small bowel transit time; SBCE: Small-bowel capsule enteroscopy; OR: Odds ratio; RR: Relative risk; C + IL: Colonoscopy with ileoscopy; PE: Push enteroscopy; SBCD: Small bowel Crohn's disease; CT: Computed tomography; IDA: Iron deficiency anemia; FEM: Fixed effect model.

Table 4 Studies evaluating the clinical application of faecal calprotectin in the setting of small-bowel capsule endoscopy

Ref.	Country	Centre	Study type	Design	Participants	FC	CE	Objective(s)	Outcome(s)
Goldstein et al[41]	United States	Multi-centre	Prospective	Double-blind, triple-dummy, placebo controlled	334 healthy subjects	N/A	M2A®; Given®Imaging, Yokneam, Israel	Evaluate incidence of SB injury and correlation with FC in healthy subjects on celecoxib or ibuprofen + omeprazole	►Mean increase in FC higher in subjects on ibuprofen+omeprazole compared with celecoxib alone (P < 0.001);
									►No correlation between FC and SB mucosal breaks
Hawkey et al[42]	Germany, United Kingdom	Multi-centre	Prospective	Double-blind, double-dummy, placebo controlled	139 healthy subjects	Phical Calprotectin Test Kit NovaTec Immunodiagnostica, GmbH Dietzenbac, Germany	M2A®; Given®Imaging, Yokneam, Israel	Investigate SB injury lumiracoxib reduces vs naproxen + omeprazole	►More SB mucosal breaks on naproxen+omeprazole (77.8% vs 40.4%, P < 0.001);
									►Furthermore, higher FC vs placebo (96.8 vs 14.5 μg/g, P < 0.001);
									►27.7% on lumiracoxib had SB mucosal breaks (vs placebo, P = 0.196; vs naproxen, P < 0.001)
									►No increase in FC (-5.7 μg/g; vs placebo, P = 0.377; vs naproxen, P < 0.001)
Smecuol et al[43]	Argentina, Spain, Canada	Multi-centre	Prospective	Non-blinded study	20 healthy subjects	Calprest® Eurospital SpA, Trieste, Italy	M2A®; Given®Imaging, Yokneam, Israel	Determine SB damage by low-dose ASA (on a short-term basis)	►Short-term administration of low-dose ASA associated with mucosal abnormalities of the SB mucosa;
									►Median baseline FC (6.05 μg/g; range: 1.9-79.2 μg/g) increased significantly after ASA use
Werlin et al[44]	United States, Israel, United Kingdom	Multi-centre	Prospective	N/A	42 pts with CF* (aged 10-36 yr); 29 had pancreatic insufficiency	Calprest® Eurospital SpA, Trieste, Italy	PillCam®SB; Given®Imaging, Yokneam, Israel	Examine the SB of pts with CF without overt evidence of GI disease using CE	►Varying degrees of diffuse areas of inflammatory findings in the SB: oedema, erythema, mucosal breaks and frank ulcerations;
									►No adverse events recorded;
									FC markedly high in pts with pancreatic insufficiency, 258 μg/g (normal < 50)
Koulaouzidis et al[45]	United Kingdom	Single centre	Retrospective	Chart review	70 pts with suspected CD and (-) ve bi-directional endoscopy	CALPRO NovaTec Immunodiagnostica GmbH, Dietzenbac, Germany	(1) PillCam®SB; Given®Imaging, Yokneam, Israel; (2) MiroCam®; IntroMedic Co., Seoul, South Korea	Value of FC as selection tool for further investigation of the SB with SBCE, in a cohort of pts with suspected CD	►FC = 50-100 μg/g: normal SBCE, despite symptoms suggestive of IBD;
									►FC > 100 μg/g: good predictor of positive SBCE;
									►FC > 200 μg/g: associated with higher SBCE DY (65%); confirmed CD in 50%;
									►Measurement of FC prior SBCE: useful tool to select patients for referral. If FC < 100 μg/g: SBCE is not indicated (NPV 1.0)
Jensen et al[46]	Denmark	Single centre	Prospective	Blinded study	83 pts from GI OPD clinics with suspected CD	Calprotectin ELISA, BÜHLMANN Laboratories AG, Basel, Switzerland	PillCam®SB; Given®Imaging, Yokneam, Israel	Determine FC levels in CD restricted to SB compared to colonic CD, in pts on first diagnostic work-up; Assess the Sens and Spec of FC in suspected CD	►In pts with SB or colonic CD FC is equal: median 890 μg/g vs 830 mg/kg, respectively (P = 1.0);
									►FC cut-off = 50 μg/g: 92% and 94% Sens for SB and colonic CD, respectively;
									►Overall, Sens and Spec for FC: 95% and 56%;
									►CD was ruled out with NPV of 92%;
									►In suspected CD, FC is effective marker to r/o CD and select patients for endoscopy
Koulaouzidis et al[47]	United Kingdom	Single centre	Retrospective	Chart review	49 pts; known or suspected CD	CALPRO NovaTec Immunodiagnostica GmbH, Dietzenbac, Germany	PillCam®; Given®Imaging, Yokneam, Israel; MiroCam®; IntroMedic Co., Seoul, South Korea	Assess performance of 2 SBCE inflammation scoring systems (LS and CECDAI) correlating them with FC; Define threshold levels for CECDAI	►LS performs better than CECDAI in describing SB inflammation, especially at FC < 100 μg/g
									►CECDAI levels of 3.8 and 5.8 correspond to LS thresholds of 135 and 790, respectively
Sipponen et al[48]	Finland	Single centre	Prospective	Blinded study	84 pts; known or suspected CD	Calprest® Eurospital SpA, Trieste, Italy	PillCam®; Given®Imaging, Yokneam, Israel; MiroCam®; IntroMedic Co., Seoul, South Korea	Study the role of FC and S100A12 in predicting SB inflammatory lesions	►CE abnormal in 35/84 (42%) pts: 14 CD, 8 NSAID-enteropathy, 8 angioectasias, 4 polyps/tumours, 1 ischemic stricture
									►Median FC/S100A12: 22 μg/g (range: 2-342 μg/g)/0.048 μg/g (range: 0.003-1.215 μg/g)
									►FC significantly higher in CD pts (median 91, range: 2-312) compared with pts with normal CE or other abnormalities (P = 0.008)
									►Faecal S100A12 (0.087 μg/g, range: 0.008-0.896 μg/g): no difference between the groups (P = 0.166)
									►Sens, Spec, PPV, NPV in detecting SB inflammation; FC (cut-off 50 μg/g): 59%, 71%, 42%, 83%; S100A12 (cut-off 0.06 μg/g): 59%, 66%, 38%, 82%, respectively

CF: Cystic Fibrosis; CD: Crohn’s disease; GI: Gastrointestinal; OPD: Out-Patient Department; SB: Small-bowel; FC: Faecal calprotectin; ASA: Acetyl-salycylic acid; CE: Capsule endoscopy/e; Pts: Patients; Sens: Sensitivity; Spec: Specificity; SBCE: Small-bowel capsule endoscopy; LS: Lewis score; CECDAI: Capsule endoscopy Crohn’s disease activity index; NPV: Negative predictive value; PPV: Positive predictive value; N/A: Not available or not applicable; NSAID: Non-steroidal anti-inflammatory drug.

Table 5 Studies looking at the identification rate of the ampulla in capsule endoscopy

Ref.	CE	Type of CE model; Company	AoV seen, n (%)	Reviewers	Reviewing speed (fps)	Frames AoV visible2	Comments
Wijeratne et al[53]1	138	NS	9 (6.0)	1	NS	NS	4 FAP patients (AoV not seen)
Kong et al[54]	110	M2A®; Given®Imaging Ltd.	48 (43.6)	2	15	3.5 ± 2.5
Clarke et al[55]	125	M2A®; Given®Imaging Ltd.	13 (10.4)	2	5	NS
Iaquinto et al[56]	23	PillCam®SB; Given®Imaging Ltd.	0 (0.0)	2	NS	N/A	FAP patients (11/23 had duodenal polyps)
Metzger et al[57]	20	PillCam®SB1; Given®Imaging Ltd.	1 (5.0)	NS	NS	NS	Repeat examinations
		PillCam®SB2; Given®Imaging Ltd.	5 (25.0)	NS	NS	NS
Katsinelos et al[58]	14	NS	0 (0.0)	1	NS	N/A	FAP patients
Nakamura et al[59]	96	PillCam®SB1; Given®Imaging Ltd.	18 (18.0)	2	10	NS
Karagiannis et al[60]	10	PillCam®Colon; Given®Imaging Ltd.	6 (60.0)	NS	NS	NS	Two-headed PillCam®
Lee et al[61]1	30	PillCam®SB; Given®Imaging Ltd.	13 (43.3)	NS	NS	NS
	30	PillCam®SB2; Given®Imaging Ltd.	15 (50.0)	NS	NS	NS
	50	PillCam®SB1; Given®Imaging Ltd.	0 (0.0)	2	NS	N/A
Selby et al[62]	50	PillCam®SB2; Given®Imaging Ltd.	9 (18.0)	2	NS	NS
	8	PillCam®ESO1; Given®Imaging Ltd.	0 (0.0)	2	NS	N/A	Two-headed PillCam®
	12	PillCam®ESO2; Given®Imaging Ltd.	1 (8.0)	2	NS	NS	Two-headed PillCam®
Koulaouzidis et al[63]	11	PillCam®ESO1; Given®Imaging Ltd.	4 (36.4)	1	7	NS	Two-headed PillCam®
	7	PillCam®ESO2; Given®Imaging Ltd.	1 (14.3)	1	9	NS	Two-headed PillCam®
Park et al[64]	30	PillCam®SB; Given®Imaging Ltd.	13 (43.3)	6	7	3.1 ± 1.1
	30	PillCam®SB2; Given®Imaging Ltd.	15 (50.0)	6	9	3.1 ± 1.5
	262	PillCam®SB1; Given®Imaging Ltd.	28 (10.7)	1	6	36.35 ± 73.24
Koulaouzidis et al[65]	148	PillCam®SB2; Given®Imaging Ltd.	13 (8.8)	1	6	42.46 ± 69.3
	209	MiroCam®; IntroMedic Ltd.	18 (8.6)	1	6	87.20 ± 248.4
Friedrich et al[66]	25	CapsoCam®SV1; Capsovision Ltd.	22 (71)	3	NS	3.1 ± 1.8

¹Published only as abstracts;

²mean ± SD. CE: Capsule endoscopy; NS: Not stated; N/A: Not available or not applicable; AoV: Ampulla of Vater; fps: Frames per second; FAP: Familial adenomatous polyposis syndrome.

Table 6 Case reports of aspiration of capsule endoscopes

Ref.	Case (age/gender)	Comorbidities	CE model/company	Swallowing difficulties	No. of attempts to swallow CE/gagging or coughing	Aspiration time/where in bronchial tree CE seen	Capsule removal (if employed)	Final diagnosis
Schneider et al[72]	64/male	Mechanical MV on phenprocoumon, BMI 15.5	M2A®; Given®Imaging Ltd.	No Hx of dysphagia	4/gagging and spitting capsule - last attempt recurrent coughing (aspiration presumed)	2 min/trachea-bronchi	Spontaneous resolution	NS
Fleischer et al[73]	76/male	HHT	M2A®; Given®Imaging Ltd.	No Hx of dysphagia	1/lodged in his throat - no respiratory difficulty, could talk, vital signs normal	60 min/cricopharyngeus	Endoscopy-Roth net; 6 d post-dilation, patient ingested capsule with no problem	Spasticity, prominence of cricopharyngeus; endoscopy and oesophageal dilation 1 wk later
Sinn et al[74]	69/female	On phenprocoumon	M2A®; Given®Imaging Ltd.	No Hx of dysphagia	1/coughed several times	50 s/bifurcation of the trachea	Spontaneous resolution	NS
Tabib et al[75]	87/female	Recent onset IDA, CHF, IHD, AF, bladder cancer, CRF	M2A®; Given®Imaging Ltd.	No Hx of dysphagia, pre-CE barium meal	2/choking, dyspnoea, CE felt lodged in the throat	NS/right main-stem bronchus - bronchus intermedius	Rigid bronchoscopy	NS
Buchkremer et al[76]	74/male	Recent diagnosis of coeliac disease; past Hx of ankylosing spondylitis	M2A®; Given®Imaging Ltd.	No Hx of dysphagia	NS/dyspnoea started after CE ingestion	NS/right main-stem bronchus	Flexible bronchoscopy	NS
Rondonotti et al[77]	NS	NS	M2A®; Given®Imaging Ltd.	NS	NS/coughed several times	NS/NS	Spontaneous resolution	NS
Nathan et al[78]	93/male	No significant past medical Hx	M2A®; Given®Imaging Ltd.	No Hx of dysphagia	1/coughed hours post-ingestion	Approximately 8 h/bronchial tree	Spontaneous resolution	NS
Shiff et al[79]	75/male	NS	M2A®; Given®Imaging Ltd.	No Hx of dysphagia	2/some coughing	NS/bronchi	Spontaneous resolution	NS
							Eventually, CE endoscopic placement
Sepehr et al[80]	67/male	HTN, DM, CVA	NS	Hx of dysphagia (intermittent)	1/coughing, tachypnoea, and tachycardia	NS/trachea	Endoscopy-Roth net	NS
Koulaouzidis et al[81]	76/male	NS	PillCam®SB; Given®Imaging Ltd.	No Hx of dysphagia	1/coughed weakly	15 s/trachea	Spontaneous resolution	NS
Guy et al[82]	90/male	Ischaemic CVA	NS	No Hx of dysphagia	NS/no symptoms	NS/bronchial tree	Rigid bronchoscopy - stone retrieval basket	NS
Leeds et al[83]	85/male	NS	NS	No Hx of dysphagia	NS/difficulty swallowing CE, slightly painful	8 h/lobar bronchus	Spontaneous resolution	NS
Bredenoord et al[84]	65/male	Sigmoid colectomy for diverticulae; Ileal carcinoid resected	NS	Hx of dysphagia	Lengthy swallowing attempt/coughing noted	NS/right main bronchus	Spontaneous resolution, eventually, CE was swallowed on same session	Normal small-bowel
Choi et al[85]	75/male	Prior CVA	PillCam®SB; Given®Imaging Ltd.	No Hx of dysphagia	NS/coughed several times	2 h/left main bronchus	Flexible Bronchoscopy-Roth net and bronchial wall irrigation to induce cough	NS, patient declined further investigations
Depriest et al[86]	90/male	IHD, AF, PVD (warfarin + clopidogrel)	PillCam®SB; Given®Imaging Ltd.	No Hx of dysphagia	NS/some cough	NS/left main bronchus, then right main bronchus	Chest percussive therapy + postural drainage; Flexible bronchoscopy + extraction basket + Roth net	NS
Depriest et al[86]	90/male	IHD, AF, PVD (warfarin + clopidogrel)	PillCam®SB; Given®Imaging Ltd.	No Hx of dysphagia	NS/some cough	NS/left main bronchus, then right main bronchus	Chest percussive therapy + postural drainage; flexible bronchoscopy + extraction basket + Roth net	NS
Kurtz et al[87]	73/male	Renal cell cancer, MV (bovine), hyperlipidaemia, melaena	NS	No Hx of dysphagia	Sips of water, 1st attempt, 2 min later non-productive cough (20 s)	Level of carina; then right main stem bronchus	Bronchoscopy-retrieval basket (multiple spontaneous ejections from trachea prior bronchoscopy)	NS
Lucendo et al[88]	80/male	Advanced PD, DM, walking + speech difficulties	PillCam®SB; Given®Imaging Ltd.	No Hx of dysphagia	Several attempts/persistent coughing and some dyspnoea	20 s/tracheobronchial tree	Spontaneous resolution	Oesophageal ulcer + ileal ulcer
Pezzoli et al[89]	82/male	Unexplained anemia, HTN	NS	No Hx of dysphagia	NS/asymptomatic (minimal cough)	3 d/in the right bronchus	Spontaneous resolution	NS
Parker et al[90]	77/female	Hysterectomy	NS	No Hx of dysphagia	Initial attempt unsuccessful/chocking episode, CE coughed-up	NS/NS	Spontaneous resolution, endoscopic placement with AdvanCE® device	Patient suffered intracranial bleed, eventually succumbed
Despott et al[91]	65/male	COPD, cirrhosis, pancreatitis	NS	No Hx of dysphagia	NS/asymptomatic	NS/right main bronchus	Rigid bronchoscopy-Roth net	Endoscopic placement with AdvanCE® device
	73/male	COPD	NS	NS	NS/brief coughing	NS/left main bronchus	Bronchoscopy-snare + Roth net	Endoscopic placement with AdvanCE® device
	81/male	NS	NS	NS	NS/fleeting choking sensation	NS/right main bronchus	Rigid bronchoscopy-crocodile grasping forceps	NS
Girdhar et al[92]	83/male	COPD, GORD	PillCam®SB; Given®Imaging Ltd.	No Hx of dysphagia	Difficult, requiring multiple sips of water/some cough, after 1 h mild shortness of breath	NS/left main bronchus	Flexible bronchoscopy + rat-tooth alligator forceps + stiff-wire basket with a pin-vise handle	NS
Poudel et al[93]	80/male	AF, IHD, CVA on anti-coagulants, anaemia + melaena	M2A®; Given®Imaging Ltd.	NS	NS	24 h/left main stem bronchus; then right bronchus	Flexible bronchoscopy + net + snare forceps + tripod; eventually, grasped with basket	NS

MV: Mitral valve; BMI: Body mass index; HHT: Hereditary haemorrhagic telangiectasia; IDA: Iron deficiency anaemia; CHF: Chronic heart failure; IHD: Ischaemic heart disease; AF: Atrial fibrillation; CRF: Chronic renal failure; Hx: History; Ns: Not stated; HTN: Hypertension; DM: Diabetes mellitus; CVA: Cerebrovascular accident; PVD: Peripheral vascular disease; PD: Parkinson’s disease; COPD: Chronic obstructive pulmonary disease; GORD: Gastro-oesophageal reflux disease; CE: Capsule endoscopy.

Table 7 Studies looking at the clinical validity of Suspected Blood Indicator, feature of capsule endoscopy reading software, in small-bowel capsule endoscopy

Ref.	Country	Centre	Objective(s)	Study type	Design	CE type	Outcome(s)	Conclusions
Gross et al[96]	United States	Single centre	Accuracy of SBI to number of blood transfusions	Retrospective	►Gold standard for lesions detected by experienced CE reviewer	M2A; Given® Imaging Ltd.	►Gold standard: 72 pts;	Pts receiving blood transfusions are more likely to have a positive SBI correlating with the localization of active bleeding
							►pts received blood transfusions ranging between 0-16 units;
							►Overall: A total of 17 pts had positive SBI. Active bleeding in 16 pts, who were transfused an average of 8 units before the study;
							►55 pts had a negative SBI and no active bleeding was seen on their capsule studies. In this group, the average number of PRBC transfused was 1 unit. There was one patient who had a false positive SBI with no active bleeding seen in the capsule study review
Liangpunsakul et al[97]	United States	Single centre	Assess accuracy of SBI	Retrospective	►Gold standard for lesions detected by experienced CE reviewer;	M2A; Given® Imaging Ltd.	►Gold standard: 109 lesions;	SBI has good Sens and PPV for actively bleeding SB lesions
							►SBI: 31 potential areas of blood; correctly identified lesions: 28;
					►Significant lesions considered AVMs, ulcers, erosions, active bleeding;		►Overall: SBI (Sens, PPV, accuracy): 25.7%, 90%, 34.8%, respectively;
							►For actively bleeding SB lesions only: SBI (Sens, PPV, accuracy): 81.2%, 81.3%, 83.3%, respectively
					►Reviewing speed: 15fps
D'Halluin et al[98]	France	Multi-centre (7 centres)	Assess Sens/Spec of SBI (in OGIB)	Retrospective	►Gold standard for lesions detected by experienced CE reviewer, SBI tags marked by another investigator;	M2A; Given® Imaging Ltd.	►156 SBCE recordings evaluated: In 83 (normal): either no lesion (n = 71) or P0 lesion (n = 12); in 73 abnormal: P2 (n = 114) and P1 (n = 92) lesions;	►SBI-based detection of SB lesions (with bleeding potential) is of limited clinical value
					►Significant lesions considered Bleeding or having a bleeding potential: high (P2), low (P1), or absent (P0);		►154 red tags analysed: SBI (Sens, Spec, PPV, NPV) for P2 or P1: 37%, 59%, 50%, 46%, respectively
					►Concordance: same time code in frames selected by expert reader and those tagged by SBI;
					►Reviewing speed: NS
Singnorelli et al[99]	Italy	Single centre	Assess Sens/Spec of SBI per lesion, overall, according to red findings (identified by the reader), and per patient	Retrospective	►Gold standard for lesions detected by four experienced CE reviewers;	M2A; Given® Imaging Ltd.	►95 patients; 209 red findings;	►SBI has low Sens/Spec in per-lesion and per-patient SBCE evaluation;
							►Overall Sens: 28%;
					►Outcomes: Sens, Spec and accuracy calculated both per lesion/patient;		►Sens higher for identification of blood (61%) than for nonbleeding “red” findings, e.g., AVMs (26%);
					►Reviewing speed: NS		►Per-patient Sens, Spec: 41%, 70%, respectively	►Complementary/rapid screening tool;
								►Complete review of the recordings is still necessary
Ponferrada et al[100]	Spain	Single centre	Assess accuracy/performance of SBI	Prospective	►Gold standard for lesions detected by experienced CE reviewers	M2A; Given® Imaging Ltd.	►57 consecutive patients;
							►Indications: OGIB (64.9%), CD (14%), malabsorption (14%), suspicion of SB tumour (7.1%);
							►SBI Sens, Spec, PPV, NPV: 58.3%, 75.5%, 38.8%, 87.2%, respectively
Buscaglia et al[101]	United States	Single centre	Assess accuracy/performance of SBI according to CE indications	Retrospective	►Gold standard for lesions detected by experienced CE reviewer;	M2A; Given® Imaging Ltd.	►CE indications: OGIB (n = 112), suspected CD (n = 122), anaemia of unknown origin (n = 53), other (n = 4);	►SBI performance characteristics suboptimal/insufficient to screen for SB lesions with bleeding potential;
					►Significant lesions:AVMs, varices, venous ectasias, red spots, ulcers, erosions, blood, blood clots		►221 lesions with bleeding potential;
							►Overall: SBI (Sens, Spec, PPV, NPV): 56.4%, 33.5%, 24.0%, 67.3%, respectively;
					►Concordant and discordant findings between CE reviewer and SBI;
							►For actively bleeding lesions: SBI (Sens, PPV): 58.3%, 70%, respectively;	►Even in pts with active intestinal bleeding, SBI Sens was only < 60%
					►Reviewing speed: 8-15 fps		►For suspected CD: SBI (Sens, NPV): 64%, 80.4%, respectively;
							►For OGIB: SBI Sens 58.3%;
							►For anaemia: SBI Sens 41.3%;
Park et al[102]	South Korea	Single centre	Investigate whether SBI is affected by background colour and CE velocity	Experimental	►Paper-made phantom SB models in a variety of colours to simulate the background colours observed in CE;	M2A; Given® Imaging Ltd.	►SBI red spots detection rate differed significantly per background colour of SB model, P < 0.001;	►SBI Sens affected by background colour and capsule passage velocity in the models
							►SBI red spots detection rate highest for very pale magenta, burnt sienna, yellow background;
					►Red spots were attached inside them;
					►CE manually passed through models;
					►SBI red spots detection rate was evaluated based on colours of SB models and CE velocities (0.5, 1, 2 cm/s)		►SBI red spots detection rate lowest for dark brown, very pale yellow background

PRBC: Pack red blood cells; fps: Frames per second; SBI: Suspected Blood Indicator; CE: Capsule endoscopy; AVM: Arterio-venous malformations; SB: Small-bowel; Sens: Sensitivity; Spec: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; OGIB: Obscure gastrointestinal bleeding; CD: Crohn’s disease.

Table 8 Studies looking at the clinical validity of QuickView, feature of capsule endoscopy reading software, in small-bowel capsule endoscopy

Ref.	QuickView sampling rate	QuickView reading frame mode/reading speed (fps)	Average reading time (mean)	Comparison with/reading frame mode/reading speed used (fps)	Rapid®Reader version	Reviewers	Cases					QuickView		Lesions missed
							Total	OGIB	CD	Polyposis	Other	Sensitivity (%)	Specificity (%)
Ponferrada et al[100]	NS	25, 15, 5	NS	Conventional/NS/15, 15, 5		2	57	37	8	N/A	12	96.5 (5 fps)	NS	NS
Schmelkin[104]	NS	NS	NS	NS	4.0	1	47	47	N/A	N/A	N/A	100	100	N/A
Appalaneni et al[105]	NS	Single frame, 25	3 min	NS	NS	2	50	NS	NS	NS	NS	NS	NS	2
Westerhof et al[106]	High (17)	NS	4.4 min (median)	Conventional/dual view/18	4.0	2	100	56	30	2	12	NS	NS	13
Shiotani et al[107]	High (17)	Single, 6	17.9 min	NS	5.0	3	44	NS	NS	NS	14	NS	NS	10
Hosoe et al[108]	Normal	NS	NS	NS	5.0	3	45	NS	NS	NS	14	NS	NS	NS
Saurin et al[109]	NS	NS	11.6 min	Conventional/NS/NS	5.0	12	106	106	N/A	N/A	N/A	89.2	Jul-84	8
Shiotani et al[110]	5, 15, 25, 35	Single, NS	NS	NS	6.5	4	87	NS	NS	NS	NS	NS	NS	NS
Koulaouzidis et al[111]	35	Dual view (WL + BM)	475 s (QuickView WL)	Conventional/single or dual view/12-20	7.0	1	200	106	81	4	9	92.3 (QVWL P1 + P2)	96.3 (QVWL P1 + P2)
		18	450 s (QuickView BM)									91 (QVBM P1+P2)	96 (QVBM P1 + P2)
Kyriakos et al[112]	NS	NS, 3	16.3 min (6.7)	Conventional/NS/NS	5.0	2	100	55	22	3	20	NS	NS	12

NS: Not stated; NA: Not applicable; fps: Frames per second; QVWL; QuickView with white light; QVBM: QuickView with blue mode; OGIB: Obscure gastrointestinal bleeding; CD: Crohn’s disease; P1, P2: Classification as per probability of bleeding.

Table 9 Studies looking at the clinical validity of Fujinon^® intelligent chromoendoscopy enhancement/Blue mode, feature of capsule endoscopy reading software, in small-bowel capsule endoscopy

Ref.	Country	Centre	Study type	Objective(s)	Design	Images	FICE	CE	Outcome(s)
Imagawa et al[114]	Japan	Single centre	Retrospective	Assess whether visualization of SB lesions improves with FICE	►5 experienced readers compared CE-WL images to their FICE counterparts	►Angiectasis (n = 23);	FICE 1,2,3	PillCam®SB1; Given®Imaging Ltd.	►FICE 1: AVMs: improvement in 87% (20/23) cases; erosion/ulceration: improvement 53.3% (26/47) cases; tumour images: improvement 25.3% (19/75) cases;
						►Erosion/ulcers (n = 47);
									►FICE 2: AVMs: improvement in 87% (20/23) cases; erosion/ulceration: improvement in 25.5% (12/47) cases; tumour images: improvement in 20.0% (15/75) cases;
						►Tumour (n = 75)
									►FICE 3: All images groups: only equivalence achieved in all cases; intra-observer agreement: good to satisfactory (5.4 or higher)
Imagawa et al[115]	Japan	Single centre	Prospective	Assess whether FICE improves detection rate of SB lesions in CE	►A CE reader reviewed CE-WL videos;	50 pts	FICE 1,2,3	PillCam®SB1; Given®Imaging Ltd.	►Angioectasias detection: CE-WL: 17 AVMs; CE-FICE 1: 48 AVMs; CE-FICE 2: 45 AVMs; CE-FICE 3: 24 AVMs; significant CE-FICE 1 and 2 (P = 0.0003 and P < 0.0001, respectively)
					►Another reader, reviewed CE-FICE videos with FICE 1,2,3
									►Detection rate for erosion, ulceration and tumour did not differ statistically between CE-WL and CE-FICE 1,2,3;
Gupta et al[116]	Belgium	Single centre	Retrospective	Assess potential benefit of FICE for SB lesion detection in patients with OGIB	CE videos analysed by 2 GI fellows with and without FICE 1,2,3;	60 pts with OGIB	FICE 1,2,3	PillCam®SB1; Given®Imaging Ltd.	►Overall, 157 lesions diagnosed with CE-FICE vs 114 with CE-WL (P = 0.15);
									►For P2 lesions; CE-FICE Sens/Spec: 94%/95% vs CE-WL Sens/Spec: 97%/96%, respectively; 5/55 AVMs better characterized with CE-FICE than CE-WL
					Reference standard: Senior consultant described findings as P0, P1 and P2 lesions
									►More P0 diagnosed by CE-FICE than CE-WL (39 vs 8, P < 0.001);
									►Intra-class kappa correlations between fellows and reference: CE-FICE vs CE-WL for P2 lesions: 0.88 vs 0.92; CE-FICE vs CE-WL for P1 lesions: 0.61 vs 0.79
Krystallis et al[117]	United Kingdom	Single centre	Retrospective	Assess FICE and Blue mode visualisation of SB lesions in CE	►2 experienced reviewers CE-WL images to FICE/Blue mode counterparts	►Angioectasias (n = 18);	Blue mode; FICE 1,2,3	Pillcam®SB1/SB2; Given®Imaging Ltd.	►Total of 167 images, for all lesion categories:
						►Erosion/ulcers (n = 60);			►Blue mode vs WL: image improvement in 83%; κ = 0.786
						►Villi oedema (n = 17);			►FICE 1 vs WL: image improvement in 34%; κ = 0.646
						►Cobblestone (n = 11);			►FICE 2 vs WL: image improvement in 8.6%; κ = 0.617
						►Blood lumen (n = 15);			►FICE 3 vs WL: image improvement in 7.7%; κ = 0.669
						►LICS/other (n = 46)
Duque et al[118]	Portugal	Single centre	Prospective	Assess reproducibility and diagnostic accuracy of CE-FICE	►4 physicians reviewed 150 FICE images;	20 patients with OGIB	Blue mode; FICE 1,2,3	PillCam®SB2; Given®Imaging Ltd.	►Concordance between the 4 gastroenterologists: 0.650;
									►CE-WL identified 75 findings and the CE-FICE 95;
					►2 experienced physicians analysed 20 CE; 1 interpreted CE-WL; the other, CE-FICE videos				►CE-FICE did not miss any lesions identified by CE-WL and allowed the identification of a higher number of AVMs (35 vs 32) and erosions (41 vs 24)
Nakamura et al[119]	Japan	Single centre	Prospective	Assess preview of angioectasias by CE-FICE preview (compared to CE-WL)	►One experienced physician analysed CEs in QuickView mode;	50 pts with angiodysplasia were randomly assigned to 2 equally sized groups of CE-WL reading and CE-FICE reading	SBI; Blue mode; FICE 1,2,3	PillCam®SB2; Given®Imaging Ltd.	►Mean reading time: 14min for both CE-WL and CE-FICE reading;
									►The two previews for angiodysplasia were significantly superior to the function of SBI (P < 0.01);
					►Mean reading time, sensitivity and specificity for angiodysplasia detection were evaluated including SBI
									►Sens and Spec of CE-WL: 80% and 100%, respectively;
									►Sens and Spec of CE-FICE: 91% and 86%, respectively;
									►FICE reading was superior in Sens, while it resulted in more false (+) ve lesion findings and lower Spec
Sakai et al[120]	Japan	Single centre	Prospective	►Assess whether CE-FICE improves detectability of SB lesions by CE trainees and if it contributes to reducing the bile-pigment effect;	►4 gastroenterology trainees interpreted 12 CE videos with WL and FICE 1,2,3;	►60 AVMs; ►82 erosions/ulcers	FICE 1,2,3	PillCam®SB2; Given®Imaging Ltd.	►60 angioectasias; CE trainees identified: 26 by CE-WL, 40 by CE-FICE1, 38 by CE-FICE2, 31 by CE-FICE3;
									►82 erosions/ulcerations, CE trainees identified: 38 by CE-WL, 62 by CE-FICE1, 60 CE- FICE2, 20 by CE-FICE3;
					►Lesion detection rate under each of the three FICE settings was compared with that by conventional CE-WL
									►CE-FICE 1 and 2 significantly improved detectability of angioectasias (P = 0.0017 and P = 0.014, respectively) and erosions/ulcers (P = 0.0012 and P = 0.0094, respectively);
				►Evaluate whether poor bowel preparing affects the accuracy of lesion recognition by FICE					►Detectability of SB lesions by CE-FICE1 was not affected (P = 0.59) by the presence of bile-pigments;
									►Detectability of SB lesions by CE-WL (P = 0.020) and CE-FICE2 (P = 0.0023) was reduced by the presence of bile-pigments;
									►In poor bowel visibility conditions, CE-FICE yielded a high rate of false-positive findings

FICE: Fujinon^® Intelligent chromoendoscopy enhancement; CE: Capsule endoscopy; SB: Small bowel; WL: White light; OGIB: Obscure gastrointestinal bleeding; SBI: Suspected Blood Indicator; AVM: arterio-venous malformation; κ: Inter-observer agreement; LICS: Lesions of indeterminate clinical significance; Sens: Sensitivity; Spec: Specificity.

Table 10 Experimental and models in development for capsule-endoscopy the future?

Ref.	Project	Status	Active actuation	Magnetic propulsion	Therapeutic capabilities
Johannessen et al[124]	IDEAS: A miniature lab-in-a-pill multi-Sens or microsystem	Prototype	No	Yes	Yes
Karagozler et al[125]	Miniature endoscopy capsule robot using biomimetic micro-patterned adhesives	Prototype	Yes	No	No
Quirini et al[126]	An approach to capsular endoscopy with active motion	Prototype	Yes	No	No
Valdastri et al[127]	Wireless therapeutic endoscopic capsule: in vivo experiment	Prototype	No	Yes	Yes
Glass et al[128]	A legged anchoring mechanism for capsule endoscopes using micro-patterned adhesives	Prototype	Yes	No	No
Valdastri et al[129]	An endoscopic capsule robot: a meso-scale engineering case study	Concept	Yes	No	No
Tortora et al[130]	Propeller-based wireless device for active capsular endoscopy in the gastric district	Prototype	Yes	No	No
Valdastri et al[131]	A magnetic internal mechanism for precise orientation of the camera in wireless endoluminal applications	Prototype	No	Yes	No
Ciuti et al[132]	Robotic magnetic steering and locomotion of capsule endoscope for diagnostic and surgical endoluminal procedures	Prototype	No	Yes	Yes
Bourbakis et al[133]	Design of new-generation robotic capsules for therapeutic and diagnostic endoscopy	Concept	Yes	No	Yes
Gao et al[134]	Design and fabrication of a magnetic propulsion system for self-propelled capsule endoscope	Concept	No	Yes	No
Simi et al[135]	Design, fabrication, and testing of a capsule with hybrid locomotion for gastrointestinal tract exploration	Concept	No	Yes	No
Morita et al[136]	A further step beyond wireless capsule endoscopy	Concept	No	Yes	No
Yang et al[137]	Autonomous locomotion of capsule endoscope in gastrointestinal	Concept	Yes	No	No
Filip et al[138]	Electronic stool (e-Stool): A novel self-stabilizing video capsule endoscope for reliable non-invasive colonic imaging	Prototype	Yes	No	No
Yim et al[139]	Design and rolling locomotion of a magnetically actuated soft capsule endoscope	Prototype	Yes	No	No
Kong et al[140]	A robotic biopsy device for capsule endoscopy	Prototype	Yes	No	Yes
Woods et al[141]	Wireless capsule endoscope for targeted drug delivery: Mechanics and design considerations	Prototype	Yes	No	Yes