Usefulness of patency capsule prior to small-bowel capsule endoscopy in clinical practice: Validity of the modied method of patency judgement

In 2012, Japan approved the use of a tag-less patency capsule (PC), which evaluates gastrointestinal patency before small-bowel capsule endoscopy (SBCE). This study aimed to evaluate the validity of our modication on the passage criteria for this PC in clinical practice. We retrospectively enrolled 326 consecutive patients who underwent PC examination before SBCE. If X-ray could not reveal the PC in the body during the judgement time (30–33 h after ingestion), we dened it as ‘estimated patency’ and performed SBCE. We employed plain computed tomography (CT) for the second judgement, as needed. The overall patency rate was 95.1%. By X-ray, 41 (12.6%) patients were judged to have ‘estimated patency’, and SBCE could be safely performed. Plain CT judgement was necessary in 32.5%. One PC case had a residual coating lm associated with stenosis in a patient with Crohn’s disease (CD), and one (0.3%) SBCE case had capsule retention resulting from false CT judgement. Multivariate analysis revealed that established CD and inpatient were factors related to patency loss. In conclusion, PC is useful for examining gastrointestinal patency, keeping in mind CT misjudgement. If PC was not found in the body via X-ray, performing SBCE as ‘estimated patency’ seemed appropriate.


Introduction
Since small-bowel capsule endoscopy (SBCE) was introduced by Iddan et al. in 2000 [1], it has been widely used because of its noninvasiveness and ability to visualise the entire small-bowel mucosa for diagnosing small-bowel pathologies, such as obscure gastrointestinal bleeding (OGIB), small-bowel tumour and in ammation, including Crohn's disease (CD) and NSAID-induced small intestinal injury [2][3][4][5][6]. However, SBCE occasionally results in capsule retention proximal to stenosis in the gastrointestinal tract [7,8]. Capsule retention incidence was reported to be 1.4%, 7.4% and 6.3% in OGIB, established CD and suspected CD cases, respectively [9]. Balloon-assisted enteroscopy or surgery should be performed to retrieve the capsule [10,11]. The Agile TM patency capsule (PC), an ingestible and dissolvable capsule with an external scanner, was developed and used in western countries to assess the functional patency of the small bowel while avoiding capsule retention [12][13][14].
In Japan, the PillCam TM PC was initially available in 2012 as a tag-less Agile TM PC for safer gastrointestinal evaluation [3,15,16]. Passage criteria, which include judging the passage of PillCam TM PC within 30-33 h after ingestion, are recommended in the enteroscopy practice guidelines [17]. Upon excretion, the medical professional should inspect and palpate the PC to con rm an intact capsule or intact body. If the PC remains in the body but is detected in the large bowel via X-ray, the gastrointestinal tract is considered patent. However, the entry of the PC into the large bowel should be further veri ed by computed tomography (CT) [18], X-ray tomography [19] or abdominal ultrasonography [20], as necessary.
Recently, its safety and usefulness have been reported in larger-scale prospective studies in Japan [21]. However, the methods may need to be modi ed in daily clinical practice. In fact, some modi cations of the passage criteria suitable for daily clinical use were reported to increase the possibility to perform SBCE safely [22,23].
However, the insights into how to deal with invisible PC excretion via X-ray during the judgement time (30-33 hour after ingestion) and which imaging modality should be used for the second examination after con rming PC location by X-ray remain unknown. In this study, if PC was not detected in the body via X-ray during the judgement time, we considered it as 'estimated patency' before performing SBCE. Plain CT was used as the second imaging tool for judgement. We aimed to evaluate the validity of our modi cation on the passage criteria suitable for daily clinical practice and evaluated the safety and usefulness of PC in our consecutive cases.

Patient characteristics
We enrolled 326 patients, with 198 males and 128 females (  LDA, low-dose aspirin; NSAIDs, nonsteroidal anti-in ammatory drugs; OGIB, obscure gastrointestinal bleeding; SD, standard deviation Patency evaluation Figure 1 presents the ow diagram of the study. We found that 46.9% of the participants excreted a visually intact PC within 30 h and that 32.5% needed plain CT judgement when the PC was con rmed inside the body within 30-33 h after ingestion by X-ray (judgement time). The con rmed patency rate was 82.5%. In 41 (12.6%) patients, the PC could not be detected via X-ray during the judgement time, thereby judged as 'estimated patency'. The overall patency rate was 95.1%, whereas the no-patency rate was 4.9% (Table 2).  Table 3. Univariate analysis showed that age, OGIB, inpatient, diabetes mellitus, haemodialysis and constipation signi cantly contributed to excretion inability within 30 h (P < 0.05). In multivariate analysis, eight factors were analysed, and among them, age, female and inpatient were the independently in uencing factors associated with PC excretion within 30 h (P < 0.05) ( Table 3). Factors associated with patency loss We found 16 patients whose PC did not con rm patency. Table 4 summarises the patient characteristics, and Supplementary Table S1 lists the details of individual clinical information. Eight patients had established CD. Univariate analysis showed that established CD was signi cantly associated with patency loss (P < 0.05). In multivariate analysis, six factors were analysed, and among them, established CD and inpatient were the independently in uencing factors associated with patency loss (P < 0.05) ( Table 5).

Discussion
In this study, we examined the validity of our modi cation on the passage criteria suitable for daily clinical practice and evaluated the safety and usefulness of PC in our consecutive patients. Our main ndings were as follows. The overall patency rate was 95.1%, 41 (12.6%) patients were judged as having estimated patency, and SBCE was performed safely. In addition, 32.5% of the participants needed CT judgement. According to our passage criteria, one (0.3%) SBCE case resulted in capsule retention because of a false CT judgement. Multivariate analysis revealed that established CD and inpatient were the factors independently related to patency loss (P < 0.05). Therefore, our modi cation on the passage criteria tailored for daily clinical practice seemed to be reasonable, keeping in mind CT misjudgement.
One of the main purposes of this study was to determine whether 'estimated patency' without retesting is valid in identifying patency for SBCE. Premature dissolution of the Agile TM patency device was reported to occur, with at least an incidence of 1.3% in Europe, possibly the cause of unexpected capsule retention [24]. This event was recognised by the detection of a persistent radiofrequency signal after radiological imaging had failed to identify the patency device. In Japan, patients who need to undergo a patencytesting procedure can avail insurance if an intact capsule or intact body with an eroded timer plug is directly detected or if PC entry into the colon is con rmed by X-ray or another imaging modality at 30-33 h after ingestion [17]. However, PC retesting is clinically di cult because it impairs the proper timing of the examination and patient acceptability. In this study, no case of SBCE retention in 'estimated patency' was found, suggesting the validity of our judgement method.
Another purpose of this study was to determine the validity of plain CT judgement after con rming the location of the PC inside the body. Candidates for the second imaging modality include plain or contrastenhanced CT [25], low-dose CT [18], X-ray tomography [19], abdominal ultrasonography [20], air enema and magnetic resonance imaging. Among them, plain CT is an objective method and is the easiest to use in Japan, although it exposes patients to radiation. In this study, capsule retention occurred in one (0.3%) patient. This result seems to agree with the results of a recent large-scale multicentre study in Japan [21]. Our results suggested that the choice of plain CT as the second imaging modality is nearly valid.
However, a misjudgement of CT was observed in one case. Other studies also revealed that CT misjudgement would be a non-negligible reason for SBCE retention after PC examination [21,23]. Physicians performing PC examinations should be aware of this issue.
Moreover, multivariate analysis indicated that age, female and inpatient were the factors independently associated with PC excretion within 30 h, and established CD and inpatient were the factors independently related to patency loss (P < 0.05). CD is a recognised factor related to patency loss, consistent with our results [26]. However, many reports indicated that inpatients are related to transit time but not to patency loss. Although the exact reason for this discrepancy remains unknown, our results showed that inpatients were more likely to have organic disorders, such as radiation enteritis and NSAIDinduced small-bowel mucosal injury. In addition, patients with impaired functional passage of the upper gastrointestinal tract might have been included. Physicians should also be aware that SBCE has a longer small-bowel transit time in the elderly and women, regardless of having patency loss.
Although the safety and usefulness of PC have been reported in larger-scale prospective studies in Japan [5], the methods may need to be modi ed in daily clinical practice. Watanabe et al. reported that extending the time to con rm functional patency to 72 h might be acceptable and increase the possibility to perform CE safely [23]. Meanwhile, Omori et al. reported that the 24-hour assessment method can be handled more easily and more useful clinically [22]. Our modi cation in this study also proposes a highly feasible use of PC in daily practice.
This study has several limitations. Firstly, it is a single-centre, single-arm, retrospective study, although the participants were consecutive patients in clinical practice. Secondly, the overall patency rate was high in this study because we included many patients with OGIB in addition to CD. Therefore, the number of cases might be statistically insu cient for the analysis of factors related to patency loss. Despite some limitations, our study certainly suggests that our modi ed criteria play a role in the real-world use of PCs in actual clinical practice. A prospective comparative study with a larger sample size and in multiple centres is required to verify these issues.

Study design
This single-centre, retrospective study conformed to the principles of the Declaration of Helsinki. In accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects (Ministry of Education, Culture, Sports, Science and Technology and Ministry of Health, Labour and Welfare, Japan), informed consent was omitted, and study information, including the objectives, was disclosed on our hospital website with an opt-out approach. The Ethics Committee of Hamamatsu University School of Medicine in Japan reviewed and approved the study protocol .
We enrolled consecutive patients who underwent PC before SBCE between September 2012 and February 2020 in our hospital. All patients provided written informed consent for PC prior to SBCE. The inclusion criteria were patients with suspected small-bowel stenosis scheduled for PC-based evaluation before SBCE. Physicians reviewed the small-bowel stenosis according to the patients' medical records and interview. In particular, patients with stenotic symptoms but with unclear stenosis on imaging studies were enrolled. The exclusion criteria included patients with ongoing small-bowel obstruction, barium allergy and dysphagia.

PC and SBCE procedures
We used the tag-less PillCam TM PC (Covidien Japan, Medtronic, Japan), which has the same size and components as the conventional Agile TM PC with a radiofrequency identi cation tag. After 12 h of fasting, patients swallowed the PC with water at 9 AM. After 2 h, drinking water was allowed, and in the next 2 h, a meal was provided. Excretion of the PC was con rmed visually using a PC recovery kit during bowel movement until their outpatient visit the following evening. Small-bowel patency was con rmed with a PC 30-33 h after its ingestion. 'Con rmed patency' was de ned as the visual veri cation of an intact capsule (body and timer plugs are virtually intact) or intact body (body is intact and hard, but timer plugs have eroded) once excreted within 30 h, or the entry of an intact capsule into the large bowel con rmed by plain X-ray examination and further examination by plain CT, as necessary. Furthermore, 'estimated patency' was de ned as the lack of PC evidence in the body via X-ray during the judgement time (30-33 h after ingestion). Within 7 d, patients with con rmed and estimated patency underwent SBCE (PillCam TM SB, Covidien Japan, Medtronic, Japan).

Endpoints
The primary endpoint was the 'con rmed patency' and 'estimated patency' rates evaluated by smallbowel examination with PC, and then the SBCE retention rate. The secondary endpoints were the CT judgement rate, adverse events, factors associated with patency loss and factors associated with excretion within 30 h.

Statistical analysis
All statistical data were analysed using SPSS for Windows, version 16.0 (SPSS Inc., Chicago, Illinois, USA) and EZR (Saitama Medical Centre, Jichi Medical University, Saitama, Japan). Categorical data were evaluated using χ 2 -test and Fisher's exact test. Factors associated with the noncon rmation of PillCam TM PC-based gastrointestinal patency were identi ed by univariate and multivariate logistic regression analyses, and the results are expressed as crude and adjusted odds ratios (ORs) with 95% con dence intervals (CIs). The relationship between the period of time from PC ingestion to patency con rmation and the total enteroscopy rate was analysed using the Mann-Whitney U test. Differences were considered signi cant if their P values were less than 0.05. PC is useful for examining gastrointestinal patency prior to SBCE in clinical practice. In the judgement of patency, if the PC cannot be detected in the body by X-ray, performing SBCE as 'estimated patency' seems appropriate. Although plain CT is commonly used after PC detection via X-ray, physicians should be aware that the PC is di cult to locate accurately.

Declarations
Funding: This research was supported by Grants-in-Aid for Scienti c Research (C) 19K08466 from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Competing interests:
The authors declare no competing interests.     Colonoscopic image con rms ileocecal valve stenosis, which was treated with balloon dilatation (D).