Peak enhancement in contrast-enhanced ultrasound for assessing endoscopic disease activity in patients with Crohn’s disease: a meta-analysis

Abstract

Background

Contrast-enhanced ultrasound (CEUS) has been proposed as a valuable tool for detecting disease activity in patients with Crohn’s disease (CD). However, previous studies have utilized different parameters, leading to variation in clinical assessment of this technique.

Purpose

To assess the effectiveness of peak enhancement (PE) in CEUS for evaluating endoscopic disease activity in patients with CD.

Material and Methods

Articles were obtained by searching PubMed, Embase, Web of Science, Wanfang, and CNKI databases. Only studies that investigated the effectiveness of PE in CEUS to discriminate endoscopic disease activity in patients with CD were considered. Pooled sensitivity and specificity were then calculated using a random effects model.

Results

Overall, seven studies were included. The endoscopic disease activity of CD was determined based on the simple endoscopic score for Crohn’s disease and Crohn’s Disease Endoscopic Index of Severity scores. Pooled results showed that a high PE was associated with increased detection efficacy for endoscopic disease activity in CD. Pooled sensitivity, specificity, and positive and negative likelihood ratios were 0.88 (95% confidence interval [CI] = 0.71–0.96), 0.88 (95% CI = 0.81–0.93), 7.60 (95% CI = 4.61–12.53), and 0.14 (95% CI = 0.05–0.35), respectively. The pooled receiver operating characteristic was 0.90 (95% CI = 0.87–0.92), suggesting a good discriminating efficacy of PE in CEUS for endoscopic disease activity of patients with CD.

Conclusions

A high PE in CEUS displayed substantial distinguishing accuracy for assessing endoscopic disease activity of patients with CD.

Keywords

Crohn’s disease activity contrast-enhanced ultrasound peak enhancement meta-analysis

Introduction

Crohn’s disease (CD) is a chronic inflammatory intestinal disease that has become more prevalent in recent decades (1,2). The primary pathological characteristic of CD involves inflammation and ulceration that can impact the entire gastrointestinal tract, with the small bowel and colon being the most frequently affected areas (3,4). If left untreated or if not managed effectively, CD can lead to various negative health outcomes, such as stricture formation, intestinal blockages, fistula development, risk of abscesses development within the abdomen, and even colorectal cancer (5 –7). As a result, comprehensive treatments, especially anti-inflammatory therapies for active CD, are essential for reducing inflammation and preventing long-term complications associated with this illness (8).

Assessing disease activity is essential for managing patients with CD (9). The current guidelines recommend regularly and objectively evaluating disease activity every 6–12 months, preferably through endoscopic examination (10,11). Although ileocolonoscopy is the standard for this assessment, conducting repeated colonoscopies presents logistical and economic challenges, and can be burdensome for the patient. In addition, it is not without risk of complications, such as bowel perforation. Therefore, there is still a need for additional practical and dependable objective assessments to repeatedly measure disease activity in patients with CD.

Contrast-enhanced ultrasound (CEUS) is a recently developed ultrasonic method that can detect the passage of an intravenously administered microbubble contrast agent through microvessels, indicating local tissue vascularization and perfusion (12 –14). There is growing evidence to suggest that CEUS may be beneficial in identifying disease activity in patients with CD (15,16). However, previous studies have employed different parameters, resulting in variability in collected data (17). One of the CEUS parameters, known as peak enhancement (PE), can be directly derived from time-intensity curves (TIC), and represents maximal bowel wall microvascularity and the severity of bowel wall inflammation (18). The aim of this meta-analysis was to summarize the efficacy of PE in CEUS for distinguishing endoscopic disease activity in patients with CD.

Materials and Methods

The most recent version of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (19,20) was used when conducting this systematic review and meta-analysis. The study design, execution, and reporting were guided by the recommendations outlined in the Cochrane Handbook (21).

Literature search

According to the aim of this meta-analysis, we used a combined search term to identify the relevant studies by systematic search of the electronic databases, including PubMed (MEDLINE), Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI). The terms that we used were as follows: (i) “ultrasound” OR “sonography” OR “ultrasonography” OR “ultrasonic” OR “US”; (ii) “contrast enhanced” OR “CE” OR “contrast enhancement” OR “echo enhanced” OR “contrast imaging” OR “peak intensity” OR “peak enhancement”; and (iii) “inflammatory bowel disease” OR “crohn disease” OR “crohns disease” OR “regional enteritis” OR “ileocolitis.” We did not apply restrictions for the outcomes reported (disease activity) in our search strategy to retrieve all potentially available studies. The search was limited to studies in humans and published from the index to 15 February 2024. In addition, a manual analysis of the references of the related articles was also performed to identify any possible related studies that had been missed.

Inclusion and exclusion criteria

We applied the following criteria to identify relevant studies: full-length articles published in English or Chinese; involving patients with CD; no age limitations; assessment of PE accuracy derived from TIC analysis using CEUS for discriminating endoscopic disease activity of CD; disease activity judged by endoscopic results according to original study criteria and used as a reference test for detecting CD activity; and reporting of essential data on true-positive, false-positive, true-negative, and false-negative values or estimations for creating a standard 2 × 2 table. Studies that utilized a clinical activity index as the reference standard were excluded because these tools have limited correlation with inflammatory disease activity in CD (22). Studies were excluded from the meta-analysis if they were reviews, if they did not include patients with CD or if they included patients with ulcerative colitis alongside patients with CD, if they did not report PE in CEUS, or if they did not base disease activity on endoscopic findings. If two studies included potentially overlapping patient populations, only the one with the largest sample size was included in the meta-analysis.

Data collection and quality assessment

Two separate researchers conducted a review of the existing literature, gathered data, and assessed the quality of studies based on specific criteria. Any inconsistencies between the two were resolved through mutual agreement between the authors for final decision-making. Information about the study, patient characteristics, reference standard details, software used for PE calculation in CEUS, PE cutoffs, as well as true-positive and false-positive values were collected from each study. The Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) scale (23) was employed to evaluate the quality of the included studies. Each study was classified as having a low, high, or uncertain risk of bias across the different domains based on identified biases and protocol applicability.

Statistical methods

The sensitivity, specificity, and positive and negative diagnostic likelihood ratios were combined from the 2 × 2 tables and summarized with the corresponding 95% confidence interval (CI). In addition, the diagnostic odds ratio (OR), which signifies the odds of a correct diagnosis compared to the odds of a misdiagnosis (24), was also computed to demonstrate the effectiveness of diagnosis. The discriminative accuracy of PE versus CEUS for endoscopic disease activity of CD was assessed by summarizing the area under the receiver operating characteristic curve (AUC) using data pooled from each included study. The degree of heterogeneity between studies was examined using the Cochrane Q test and an estimation of the I² statistic (21). An I²> 50% indicates substantial heterogeneity (25). A random-effect model was employed in this analysis as an approach to incorporate the potential between-study heterogeneity. Deeks’ funnel plots were generated, and asymmetry tests were conducted to assess the risk of publication bias. STATA 12.0 software was utilized for statistical analyses. A P value <0.05 was considered statistically significant.

Results

Results of literature searches

The initial database search yielded 810 studies (Fig. 1), of which 602 remained after duplicates were removed. Upon analyzing the titles and abstracts, a further 580 studies were excluded due to lack of relevance to the objective of the meta-analysis. After a thorough review of full texts, 15 out of the remaining 22 studies were excluded for reasons detailed in Fig. 1. Ultimately, seven studies (26 –32) were included in the meta-analysis.

Fig. 1.

Flow chart representing the process of study screening and identification.

Study characteristics and quality assessment

The features of the included studies are summarized in Table 1. These studies were performed in Italy, the Netherlands, Spain, Portugal, Slovenia, and China, and were published between 2012 and 2023. Five of the studies were prospective studies (26 –29,31) and two were retrospective (30,32). Overall, a total of 438 patients with CD were included. The sample sizes of the included studies were in the range of 36–94. The mean ages of the patients were in the range of 14–46 years, and the proportion of male patients was in the range of 42%–72%. In all the included studies, PE derived from the TIC analysis in CEUS was used for the detection of endoscopic disease activity in CD. The software and cutoff for the analysis of PE varied among the included studies. Endoscopic results evaluated via the simple endoscopic score for Crohn’s disease (26,27,29 –32) or the Crohn’s Disease Endoscopic Index of Severity (28) scores were used as the reference test to validate the endoscopic disease activity. Accordingly, 316 patients were classified with active CD and 122 patients were classified with inactive CD based on the endoscopic findings. Details of the quality evaluation of the included studies via the QUADAS-2 criteria are shown in Table 2. For two of the included studies (30,32), the risk of bias for patient selection was deemed to be of unclear risk as the patients were not consecutively or randomly selected in these studies. In addition, the interval of CEUS and endoscopic examinations were not described in three of the selected studies (28,30,31), for which they were judged to be of unclear risk in the domain of flow and timing. For all the other domains, all the included studies were judged to be of low risk of bias.

Table 1.

Characteristics of the included studies.

Study	Country	Design	No. of patients	Mean age (years)	Men (%)	Reference standard for CD activity	Software for calculation of PE in CEUS	Cutoff of PE in CEUS	TP	FP	FN	TN
De Franco (2012)	Italy	Prospective	54	35	72	Endoscopic (SES-CD)	QLAB	24 VI	35	3	1	15
Horjus (2015)	The Netherlands	Prospective	94	33	44	Endoscopic (SES-CD)	Qontrast	10%	82	1	0	11
Quaia (2017)	Italy	Prospective	65	42	62	Endoscopic (CDEIS)	Built-in software	11.83	26	2	14	23
Ripolles (2021)	Spain	Prospective	72	46	50	Endoscopic (SES-CD)	Built-in software	18	42	4	8	18
Freitas (2022)	Portugal	Retrospective	50	34	46	Endoscopic (SES-CD)	EZU-CH8	8.2	22	4	8	16
Ponorac (2023)	Slovenia	Prospective	36	14	42	Endoscopic (SES-CD)	CHI Q	6.9 AU	22	0	6	8
Zhang (2023)	China	Retrospective	67	31	66	Endoscopic (SES-CD)	Built-in software	8.5 dB	39	0	11	17

AU, arbitrary unit; CD, Crohn's disease; CDEIS, Crohn's Disease Endoscopic Index of Severity; CEUS, contrast-enhanced ultrasound; dB, decibel; PE, peak enhancement; SES-CD, simple endoscopic score for Crohn's disease; FN, false negative; FP, false positive; TN, true negative; TP, true positive; VI, video intensity.

Table 2.

Quality evaluation for the included studies with QUADAS-2 scores.

Study	Risk of bias				Applicability concerns
Study	Patient selection	Index test	Reference standard	Flow and timing	Patient selection	Index test	Reference standard
De Franco (2012)	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Horjus (2015)	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Quaia (2017)	Low risk	Low risk	Low risk	Unclear	Low risk	Low risk	Low risk
Ripolles (2021)	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Freitas (2022)	High risk	Low risk	Low risk	Unclear	Low risk	Low risk	Low risk
Ponorac (2023)	Low risk	Low risk	Low risk	Unclear	Low risk	Low risk	Low risk
Zhang (2023)	High risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk

Meta-analysis results

Overall, the pooled results of nine datasets showed that a high PE derived from CEUS was associated with a satisfying level of discriminating efficacy for endoscopic disease activity of CD, with pooled sensitivity, specificity, and positive and negative likelihood ratios of 0.88 (95% CI = 0.71–0.95, I²= 84%) (Fig. 2a), 0.88 (95% CI = 0.81–0.93, I²= 38%) (Fig. 2b), 7.60 (95% CI = 4.61–12.53), and 0.14 (95% CI = 0.05–0.35), respectively. The pooled receiver operating characteristic (AUC) was 0.90 (95% CI = 0.87–0.92) (Fig. 3), suggesting a good discriminating efficacy of PE in CEUS for assessing endoscopic disease activity of patients with CD.

Fig. 2.

Forest plots for the summarized efficacy of PE in CEUS for distinguishing endoscopic activity in patients with CD. (a) Summarized sensitivity; (b) summarized specificity. CD, Crohn’s disease; CEUS, contrast-enhanced ultrasound; PE, peak enhancement.

Fig. 3.

Summarized ROC curves for the efficacy of PE in CEUS for distinguishing endoscopic activity in patients with CD. CD, Crohn’s disease; CEUS, contrast-enhanced ultrasound; ROC, receiver operating characteristic.

Publication bias

Deeks’ funnel plots of the meta-analysis are shown in Fig. 4, and the asymmetry test showed a low risk of publication bias (P = 0.41).

Fig. 4.

Deeks' funnel plots evaluating possible publication bias underlying the performance efficacy of PE in CEUS for distinguishing endoscopic activity in patients with CD. CD, Crohn’s disease; CEUS, contrast-enhanced ultrasound; PE, peak enhancement.

Discussion

In this meta-analysis, we combined the findings of seven studies and discovered that an elevated PE, as assessed by CEUS, demonstrated a strong ability to differentiate endoscopic disease activity in patients with CD, with a summarized sensitivity, specificity, and AUC of 0.88, 0.88, and 0.90, respectively. Considering the safety, non-invasive nature, and repeatability of the procedure, these results validate the clinical adoption of PE derived from CEUS as an unbiased method for assessing disease activity in patients with CD.

To our knowledge, only one comprehensive analysis has been conducted to assess the use of CEUS in determining disease activity in patients with CD (17). This particular analysis incorporated eight studies published before 2015 and indicated that CEUS demonstrated good sensitivity and moderate specificity in identifying active CD (17). However, these studies encompassed various CEUS parameters such as enhancement presence, relative enhancement, TIC AUC, and PE, leading to substantial clinical diversity (17). In addition, there was limited inclusion of PE data, which only came from a small study with 54 participants (17). Moreover, the reference tests used also included endoscopic findings and clinical measurements, which could confound the results (17). This is due to the limited correlation between clinical tools like the Crohn’s Disease Activity Index and inflammatory disease activity in CD (22). In contrast to this previous meta-analysis, our analysis possesses several methodological strengths. We performed an extensive search for recent English and Chinese literature databases resulting in more studies that were published after the prior meta-analysis (2015). In addition, we specifically focused on studies reporting on the role of PE in CEUS for detecting disease activity to provide a summarized efficacy of this specific parameter for differentiating active CD cases. Moreover, endoscopic findings were exclusively used as reference tests, which minimized the potential bias of the results by introducing different reference tests. Technically, PE is a parameter that measures tissue contrast perfusion by assessing the maximum signal intensity over time in the bowel wall region of interest (18). This measurement reflects the microvascularity of the area and therefore indicates the severity of inflammation in the bowel wall (18). Our results demonstrate effective discriminative capability of PE compared to CEUS for active CD. Given its technical feasibility and non-invasive nature, these findings endorse utilizing PE in CEUS to assess disease activity in patients with CD.

Besides PE, accumulating evidence suggests that two other parameters from the time intensity curves in CEUS may also be potential predictors of the disease activity in CD, including the reduced time-to-peak enhancement and the area under time–intensity enhancement curve (AUC). We chose PE as the parameter of interest in this study because this parameter is most often used in previous studies, and previous studies evaluating the predictive efficacy of the other two parameters were limited. In one of the included studies, it was found that the AUC during wash-in was slightly superior to PE as the best discriminator of disease activity (29). However, the AUC data were not collected and analyzed in the other included studies. Accordingly, more studies are needed in the future to record these main parameters and assess their value for predicting the endoscopic disease activity of CD.

The present study has some limitations. One limitation is the heterogeneity among the included studies, which could be due to the differences in patients’ demographic characteristics, co-morbidities, the analytic software used for PE, and the cutoff points used for PE detection of active CD. However, at the current stage, it is impossible to estimate the impacts of these factors on the meta-analyses’ outcome due to the limited number of available studies. For example, in CEUS, it is important to delineate the submucosal layer since almost all perfusion can be seen in this layer. However, none of the included studies described the details for delineating the submucosal layer, and instead indicated that CEUS procedure occurred according to standard protocols. It may be explained by the fact that all the patients had CD, which is associated with different degrees of transmural inflammation. In addition, the difference in software and cutoffs for PE analysis varied among the included studies, which is likely to be a major contributor to the heterogeneity and different results in the included studies. At the current stage, no consensus has been reached regarding the standard software or optimal cutoff for defining a high PE in CEUS for patients with CD. Also, due to the limited studies included, we were unable to determine the influences of the above factors on the predictive performance of PE in CEUS for disease activity of CD. Moreover, two of the included studies did not involve consecutive or random patient selection methods, potentially leading to selection bias and confounding of overall results (30,32). Therefore, there remains a need for high-quality prospective studies to confirm these findings. Another limitation is that only English and Chinese language publications were considered; this may have led to relevant studies that were non-published or studies in other languages that were overlooked. However, according to the Deeks’ plots and asymmetry test results, there appears to be a low risk of publication bias.

In conclusion, the findings of this meta-analysis indicate that PE obtained from CEUS shows a satisfactory ability to distinguish endoscopic disease activity in patients with CD. While larger, high-quality prospective studies are necessary to establish the best analysis method and optimal cutoff values, utilizing PE in CEUS could be an alternatively feasible and reliable strategy for the early prediction of endoscopic disease activity in patients with CD.

Footnotes

Availability of data and materials

The authors confirm that the data supporting the findings of this study are available within the article. Further inquiries can be directed to the corresponding author.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Deyin Zhai

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