Crohn's disease (CD) is an inflammatory bowel disease characterized by transmural inflammation that can occur throughout the gastrointestinal tract. However, the terminal ileum is the most frequently involved location. The prevalence of CD among children less than 20 years of age is 43 per 100,000 [1]. In most cases, CD is associated with periods of worsening inflammation and, over time, leads to complications like strictures and fistulas [2]. Intestinal inflammation can typically be managed with medical therapy, however, fibrotic strictures often require surgical or endoscopic treatments like resection or dilation [23]. Therefore, characterization of the bowel wall to determine the extent of inflammation and/or fibrosis is necessary to guide proper clinical management and to assess the response to therapy in these patients.

Ultrasound (US) is a well-established imaging modality that is useful in detecting CD. US parameters such as bowel wall thickness, vascularity, abdominal free fluid, bowel stenosis, and the presence of fistulas or abscesses are considered to be specific markers for CD. However, the ability of conventional grayscale US and Doppler to assess disease activity remains controversial [4]. Contrast-enhanced US (CEUS) allows for qualitative and quantitative assessment of kinetic perfusion parameters in the bowel. Lumason® (Bracco Diagnostics, Inc., Monroe Township, NJ, USA) is an US contrast agent available in the United States and is approved by the Food and Drug Administration for the evaluation of liver and vesicoureteral reflux in the pediatric population. However, off-label uses of US contrast agents in evaluating many conditions in adults and children have been well established in the literature [5]. Some studies have utilized CEUS for distinguishing active and inactive CD, demonstrating a sensitivity of 93.5% and a specificity of 93.7% [6]. Quantitatively, these studies have demonstrated that a shorter time-to-peak intensity and a higher peak enhancement correlates with increased disease activity in these patients [7]. However, other studies have demonstrated no significant association of these same parameters with disease activity [8].

Another useful US technique is elastography, which can be used to map tissue stiffness. Shear wave elastography (SWE) utilizes an acoustic radiation force to excite a region of interest for evaluation. The technology works by a measuring the speed of the shear waves that travel away from this region, which are proportional to tissue elasticity [910]. A few studies have utilized elastography to assess fibrotic from inflammatory strictures in CD. In both, elastography was useful in distinguishing fibrotic from non-fibrotic strictures [1112]. However, because strictures in CD can involve both fibrotic and inflammatory tissue, distinguishing fibrosis from inflammation remains challenging.

Here we present three cases where CEUS and elastography were used to evaluate disease activity in patients with CD. These patients had a spectrum of disease activity including acute inflammation, chronic inflammation with stricture formation, and a post-surgical fibrotic stricture. In all three patient cases, CEUS and elastography were useful in demonstrating the degree of inflammation and presence of fibrosis. We also discuss interpreting CEUS kinetic parameters and elastography values in the evaluation of CD activity.

In this case series, we discuss three patients presenting with abdominal pain in the setting of CD, in which CEUS and elastography were useful in detecting the degree of inflammation and fibrosis in the bowel. A few studies have demonstrated the utility of CEUS in evaluating CD activity in the pediatric population. A study by Pallotta et al. [15] demonstrated that CEUS had a sensitivity and specificity for detecting undiagnosed CD of 100% and 100%, compared to a sensitivity and specificity of 75% and 100%, respectively, for conventional transabdominal US alone. However, few studies have used quantification parameters derived from CEUS to evaluate CD activity in the pediatric population. The first study to do so, by Kljucevsek et al. [16], utilized CEUS derived quantification parameters to optimize medical therapy in a 13-year-old boy with CD. The researchers in this study demonstrated that a high intensity of enhancement and a short time-to-peak enhancement were associated with active inflammation of the small bowel, and subsequently optimized the patient's medical therapy, leading to clinical improvement and normalization of the bowel on a subsequent US examination [16]. However, most published studies utilizing CEUS derived kinetic parameters to evaluate CD were performed in adults. Other studies have demonstrated the value of elastography to evaluate children with CD. A study by Fufezan et al. [17] created an elastography scoring system for the assessment of CD inflammation and fibrosis. This classification system demonstrated that elastography could predict increased levels of disease activity markers, like C-reactive protein and erythrocyte sedimentation rate, and could predict disease complications [17]. However, there is a paucity of research that utilizes CEUS and elastography together to assess CD activity in the pediatric population.

The first patient presented with acute inflammation that responded to treatment with infliximab. MRE demonstrated the presence of inflammation, which correlated with US findings. At that time, CEUS demonstrated avid contrast enhancement of the terminal ileum, suggestive of acute inflammation. Quantitatively, compared to the jejunum, the terminal ileum was noted to have more prompt wash-in, increased peak intensity, and increased area under the curve. These findings also favor the presence of active inflammation. The average elastography value in the terminal ileum was 0.64 m/s, suggestive of less stiff and less fibrotic tissue. Our results are consistent with a number of studies that have demonstrated increased contrast enhancement by qualitative and quantitative measures in inflammatory CD [1819]. A number of studies have correlated contrast enhancement and CD activity both histologically and endoscopically in these patients [192021]. A study by Ripollés et al. [20] demonstrated that inflammatory lesions had greater contrast enhancement when compared to fibrotic lesions. Additionally, our patient had a low elastography value, which was consistent with previous studies that demonstrate decreased tissue stiffness associated with acute inflammation when fibrosis is not present [192223]. Together, these findings suggest acute inflammation without the presence of fibrosis. These findings are supported by her clinical improvement with infliximab.

The second patient had minimal inflammation, and her fibrotic surgical anastomosis was most likely the source of her pain. The MRE findings of postsurgical versus mild inflammatory changes without evidence of a high-grade inflammatory stricture correlated with US findings. CEUS demonstrated that the anastomosis had minimal enhancement, suggestive of none to minimal inflammation. Quantitatively, the small values of the peak enhancement and area under the curve also suggested the presence of minimal inflammation. Additionally, the mean elastography value was 1.57 m/s which is suggestive of the presence of a stiffer tissue, containing a more fibrotic component. Taken together, these findings correlate with the fibrotic surgical anastomosis noted on a previous endoscopy.

The third patient underwent an elective bowel resection. The CEUS findings of minimal contrast uptake suggested a lack of acute inflammation. The terminal ileum had an elastography value of 1.58 m/s denoting an increased level of stiffness. These findings were consistent with surgical findings of fibrosis and histological findings of active chronic inflammation with stricture formation in this patient.

In these last two patients, CEUS and elastography were useful in ruling out acute inflammation of the bowel. However, the ability to differentiate fibrotic from inflammatory strictures with CEUS remains controversial. Quaia et al. [24] demonstrated that area under the curve and peak enhancement could be used to differentiate predominantly fibrotic from predominantly inflammatory strictures. However, another study using an animal model demonstrated that quantitative perfusion parameters cannot detect the degree of fibrosis in CD when inflammation is also present. They found that no quantitative parameter could reliably detect fibrosis [23]. Strictures often contain both inflammatory and fibrotic components, and as such, CEUS perfusion parameters are predominantly affected by the degree of inflammation [23]. Our results are consistent with this study, as CEUS effectively identified the presence of acute inflammation, but a lack of contrast enhancement was common to both the surgical fibrotic stricture and the chronic inflammation with stricture formation. Indeed, the quantitative CEUS findings were similar in these two patients. A previous study by Quaia et al. [25] suggested that elastography could complement CEUS in distinguishing the presence of fibrosis, regardless of the degree of inflammation. In our study, elastography demonstrated the presence of a fibrotic stricture in both patients. The elastography value for the patient with active chronic inflammation with stricture formation was comparable to the patient with a surgical fibrotic anastomosis. The increased tissue stiffness in both patients is likely due to underlying fibrosis in the bowel wall, which is present in most ileal strictures, even those with inflammatory infiltrate on histology review [25].

In conclusion, our study demonstrates that CEUS and elastography combined are valuable tools in monitoring disease activity in patients with CD. CEUS is most useful in determining the degree of acute inflammation, and quantitative parameters are not as useful in assessing bowel wall fibrosis. However, elastography can identify bowel wall fibrosis through an evaluation of tissue stiffness. Used together, these techniques allow for a better characterization of the degree of fibrosis and inflammation in bowel strictures in patients with CD. CEUS and elastography offer promise in improving the assessment of CD activity and response to treatment.