Crohn disease (CD) is a chronic relapsing inflammatory bowel disease (IBD) that may progressively and destructively involve various parts of the gastrointestinal tract,[1,2] causing irreversible transmural bowel damage that is mainly characterized by stricture and penetration. Imaging modalities assessing the site, number, extent, and complications of bowel inflammatory lesions are essential in the establishment of a detailed diagnosis of CD.[4,5]
Although endoscopy provides a direct vision of bowel lesions, only the intraluminal vision can be shown. Transabdominal ultrasonography (TUS) overcomes some of the drawbacks of first-line imaging modalities in CD assessment, but the presence of gas in the intestinal loops often results in suboptimal visualization of the surrounding organs, such as pancreas, duodenal tract, and the extrahepatic bile ducts.[8–10]
By applying a small amount of oral contrast fluid to CD patients, small intestine contrast ultrasonography (SICUS) provides a comprehensive depiction about both intramural and extraluminal bowel lesions with a high contrast ratio.[11,12] Moreover, SICUS has shown its potential in locating the sites of lesion, representing the typical cobblestone-like changing of small-bowel wall and depicting enlarged lymph nodes and swelling mesenteric tissue without radiation exposure. As sufferers of CD are mainly at reproductive ages, and they generally need frequent and long-term monitoring due to the relapsing nature of CD, frequent radiation exposure should be avoided. An article analyzing the diagnostic ionizing radiation exposure in a large IBD patients cohort showed that patients with CD received 2.46 times higher total cumulative effective radiation dose than patients with ulcerative colitis, potentially leading to a higher risk of cancer.
SICUS might be a potential modality in CD assessment with its low-cost, noninvasive, radiation-free nature. In this meta-analysis, we analyzed all eligible published studies to evaluate the use of SICUS in detecting CD or its complications in clinical practice.
2.1 Literature search
We searched PubMed database for relevant studies published before April 24, 2016, using “Crohn or Crohn's” and “contrast or contrast-enhanced” and “ultrasound or ultrasonography or sonography or ultrasound” as our search keywords. We also manually examined the references listed in retrieved eligible articles. As this was a meta-analysis, no ethical approval was required.
2.2 Study selection
Two investigators reviewed and selected studies independently according to the inclusion and exclusion criteria set before the selection, and when disagreements came up, we made a consensus by discussion. The inclusion and exclusion criteria were as follows:
Inclusion criteria: articles assessed the accuracy of SICUS for the detection of sites or complications in CD; the contrast agent was taken orally and was nonabsorbable; the gold standard of CD diagnosis was biopsy, surgical findings, or imaging findings; and articles reported true positives (TP), false positives (FP), true negatives (TN), and false negatives (FN) directly, or the data in the article was sufficient enough to extract a 2 × 2 table of TP, FP, TN, FN manually. For example, Calabrese E2 reported the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the total number of patients, and we calculated TP, FP, FN, and TN based on these data.
Exclusion criteria: the gold standard of CD diagnosis was not valid enough, such as using C-reactive protein only; the contrast agent was not taken orally or was absorbable; and articles without enough data to extract TP, FP, FN, and TN.
2.3 Data extraction
Two investigators independently extracted data from eligible articles. When any discrepancy appeared, we made a consensus by discussion. The following items were extracted from each article: author, year of publication, number of patients, sex, median age, ultrasound system, duration, contrast agents, gold standard, TP, FP, FN, and TN, and so forth.
2.4 Statistical methods
To evaluate the accuracy of SICUS for CD diagnosis and CD complication assessment, we integrated TP, FP, FN, TN into the pooled estimates of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR), all given with 95% confidence intervals (CIs).
The heterogeneity of all the eligible studies was assessed using the χ2 test (heterogeneity χ2-Qexp) and the consistency index (I2). When significant heterogeneity existed, the random-effect model was applied, otherwise we used the fixed-effect model (Mantel–Haenszel method). The pooled DOR was calculated as (TP × TN)/(FP × FN).
Publication bias was examined by Deeks’ funnel plot asymmetry test, and P > 0.05 was considered as no potential publication bias. All the above statistical analyses were conducted using STATA 12.0 (STATA Corporation, College Station, TX) and Meta-Disc 1.4 (Cochrane Colloquium, Barcelona, Spain).
2.5 Quality assessment
A quality assessment tool for diagnostic accuracy studies, Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2), was used to assess the quality of the included studies. Each item is rated “yes,” “no,” or “unclear.” The assessment was measured using Review Manager 5.3 (Copenhagen, Sweden).
3.1 Included studies
As is shown in Fig. 1, the initial search yielded a total of 279 articles. After screening titles and abstracts, we excluded 260 because they were either review articles (n = 47), letter to the editor (n = 2), case reports (n = 2), irrelevant to SICUS (n = 209). After the full-text review of the remaining 19 potential candidate studies, 6 were ruled out for insufficient data. Finally 13 articles were considered eligible.[2,11–13,22–30]
3.2 Study characteristics
We listed the main characteristics of the 13 eligible studies in Table 1. The articles were published between 2001 and 2015. The number of the patients in each study ranged from 13 to 148. The contrast agent of all the 13 studies was polyethylene glycol (PEG), which was nonabsorbable and was taken orally. Intestinal wall thickness was the main diagnostic variable for all studies. Of the 13 studies, 12 used 3 mm as the cutoff value while Parente et al used 4 mm.
3.3 Detection of small-bowel lesions
The pooled sensitivity and specificity of the eligible studies were 0.883 (95% CI 0.847–0.913) and 0.861 (95% CI 0.828–0.890), respectively (Fig. 2A and B). The PLR and NLR for SICUS were 5.593 (95% CI 3.317–9.430, I2 = 77.5%) and 0.186 (95% CI 0.106–0.326, I2 = 77.3%), respectively (Fig. 2C and D). The pooled DOR was 39.123 (95% CI 20.014–76.476) (Fig. 2E). Summary receiver operating characteristic (SROC) curves for the diagnostic value of SICUS in the detection of small-bowel lesions are illustrated in Fig. 3. The overall area under the curve (AUC) of SROC was 0.9273 (standard error: 0.0152).
3.4 Subgroup analysis
Of the 13 studies enrolled in our meta-analysis, 2 studies[27,30] assessed recurrence of CD, 2 studies[24,25] detected active small-bowel CD. The pooled sensitivity and specificity of SICUS in detecting recurrence of CD were 0.899 (95% CI 0.817–0.953) and 0.808 (95% CI 0.606–0.934), respectively. The pooled sensitivity and specificity for the assessment of active small-bowel CD were 0.885 (95% CI 0.698–0.976) and 0.864 (95% CI 0.651–0.971).
Data from 2 studies[11,24] were detailed enough for us to divide the sites of CD bowel lesions into proximal and distal small intestine subgroup. The pooled sensitivities of SICUS in detecting proximal and distal small intestine lesions were 0.903 (95% CI 0.742–0.980) and 0.968 (95% CI 0.833–0.999). Pooled specificities were 0.929 (95% CI 0.827–0.980) and 0.857 (95% CI 0.572–0.982).
Another subgroup analysis was performed for the accuracy of SICUS for the differentiation of CD-related complications. We analyzed the differentiation accuracy of SICUS in CD complications, including stricture (n = 5), dilation above stricture (n = 3), abscess (n = 4), and fistula (n = 4). The pooled sensitivity and specificity were 0.816 and 0.818 in the definition of stricture, 0.895 and 0.683 for detecting dilation, 0.875 and 0.962 for abscess assessment, and 0.778 and 0.942 for fistula detection (Table 2).
3.5 Quality assessment
The quality of the 13 eligible studies, as assessed according to the QUADAS criteria, is reported in Fig. 4A and B.
3.6 Publication bias
The evaluation of publication bias of the eligible studies was performed using STATA 12.0 (Fig. 5). Results showed that no significant publication bias existed.
To the best of our knowledge, this is the first study to evaluate the diagnostic accuracy of SICUS for the detection and assessment of CD. Unlike other inflammatory bowel disease, CD may involve any part of the digestive tract, from oral cavity to rectum, and small intestine is the most predilection site of CD. Lesions of CD are discontinuous and jumpy. Therefore, it is important to detect sites and numbers of lesion precisely, especially for surgical purpose. The sensitivity, specificity, and DOR of SICUS in detecting small-bowel lesions were 0.883, 0.861, and 39.123, respectively, and the area under the curve (AUC) of SROC was 0.9273, which indicated that it is reliable in assessing small-bowel lesions. Moreover, SICUS represented substantial sensitivity and specificity in proximal and distal small-intestine lesion according to our subgroup analyses.
One of the most significant characteristics of CD is its high recurrence rate. Rutgeerts’ studies[31,32] showed that CD patients suffered from a recurrence rate of 50% to 90% 1 year after surgery, and what makes CD an intractable disease to manage is that recurrence may happen earlier before clinical symptoms shows up. Therefore, early detection of the recurrence is essential. Negative SICUS findings could help prove that the patients are unlikely to have recurrence regarding the substantial sensitivity of SICUS, and also prevent the patients from excess radiation exposure.[33,34]
Apart from high recurrence rate, CD is always accompanied by various complications such as stenosis, dilation, fistula, and abscess. Management strategies of CD patients with different kinds of complications differ a lot. Accurate locating, characterizing, numbering, and grading of the complications are quite crucial for preoperative schemes making. Such assessment is also a necessity before endoscopic examination to avoid unnecessary extra trauma or even the retention of capsule endoscopy. According to our analysis, SICUS turns out to be a reliable modality in CD complication assessment. Of all the complications, SICUS shows a prominent ability in abscess assessment with relatively higher sensitivity and specificity, and if detected, abscess should be handled either by surgery or pharmaceuticals.[37,38]
SICUS has some merits over the first-line imaging modalities. As we all know, endoscopy is the most direct equipment to visualize small-bowel lesion, and is considered to be the golden standard for intestinal disease diagnosis. However, the invasiveness might increase the risk of penetration of bowel wall and the extremely discomfort experience might lead to lack of cooperation of patients with relapsing diseases such as CD, who need regular follow-up. Also, endoscopy examination could not be accomplished if strictures exist. Most importantly, transmural condition such as bowel wall thickness and stiffness, and perienteric condition such as lymph nodes and mesenteric tissue could not be represented by endoscopy.[41,42] Compared with computed tomography and magnetic resonance imaging, SICUS provides a dynamical real-time visualization of small-bowel lesions,[2,39,43] and the amount of oral contrast agent taken by the patients for SICUS is far less. Therefore, it is worthwhile to recommend SICUS in clinical application of CD assessment.
There are still some limitations of our study. Firstly, the proper application of SICUS is to a high degree user-dependent which relies on the personal expertise of operators, but the introduction of the oral contrast seems to increase the accuracy of diagnosis. Secondly, more large-sampled, multicentered researches are still expected in the future to confirm our results.
To sum up, SICUS is not only accurate enough but also informative enough to make a complete assessment about the location, extent, number, and almost all kinds of complications in CD small-bowel lesions. What is more, considering the noninvasiveness, radiation-free, well-toleration, and relatively low cost characteristics of SICUS, SICUS is also the most suitable choice in frequent CD follow-up.
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Keywords:Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
Crohn disease; meta-analysis; SICUS