The Utility of Contrast Enhanced Ultrasound and Elastography in the Early Detection of Fibro-Stenotic Ileal Strictures in Children with Crohn’s Disease

Crohn’s disease (CD) is a chronic, and often relapsing inflammatory bowel disease (IBD) that can affect any portion of the gastrointestinal tract [1]. In pediatrics, CD is estimated to be diagnosed in up to 8.5 per 100,000 children living in North America most frequently affecting the terminal ileum and proximal colon [2]. Children and adolescents with CD may present with either abdominal pain, weight loss and loose stools or with less specific symptoms, including fatigue, decreased oral intake, and growth failure [3]. Medical management is aimed at early diagnosis and aggressive medical therapy to enable mucosal healing and to maintain adequate growth and development [4]. If left untreated, acute inflammation will progress to chronic inflammation with the excessive deposition of collagen and fibronectin within the bowel wall. This attempt by the body to repair the injured tissue results in fibrotic stricture formation, reactive muscular hypertrophy of the muscularis and either partial or complete intestinal obstruction. Failure to identify and surgically treat these fibrotic strictures can lead to intestinal fistulae, intra-abdominal abscess formation, and bowel perforation. While biological therapy has proven efficacy in healing tissue inflammation, fibrotic intestinal strictures can only be managed surgically [5].

Contrast-Enhanced Ultrasound (CEUS) is an imaging modality that utilizes an intravenous microbubble-based contrast agent to amplify the diagnostic scope of ultrasound; and by adding this image enhancement technique, it can also provide a pharmacokinetic measurements of tissue perfusion. CEUS has been utilized throughout Europe with the use of SonoVue^® (Bracco Diagnostics Inc.) contrast. In 2016, the United States Food and Drug Administration approved the use of Lumason^® (Bracco Diagnostics Inc.) contrast for the CEUS of adult and pediatric liver and bladder under specific dosing and application guidelines that have been previously described [6, 7]. Although there have been few reports of severe anaphylactic reactions to Lumason^® (Bracco Diagnostics Inc.), most adverse side-effects are described as mild and transient [8, 9, 10]. The scope of use for pediatric CEUS continues to expand, as more studies have demonstrated its utility in identifying and monitoring liver lesions, in the diagnosis of blunt abdominal trauma, the monitoring of solid organ transplant grafts, and in the diagnosis of IBD [11, 12]. Studies in adult patients with CD have shown that CEUS can be a useful diagnostic tool in delineating inflammatory from fibro-stenotic strictures [13, 14, 15]. The application of CEUS in children has been limited to either individual case reports or small case series [16, 17].

The primary aim of this prospective study was to investigate the role of CEUS in identifying fibrotic strictures of the terminal ileum in children and adolescents with CD. The study also aims to correlate CEUS kinetics and shear wave elastography (SWE) with histopathologic fibrosis and hypertrophy of the muscular propria in those patients that required surgical resection. We hypothesized that there would be a significant difference in the CEUS kinetic values between inflammatory and fibrotic terminal ileum strictures. Presumably, the inflammatory lesions would show increased CEUS kinetic values due to presumed greater tissue perfusion in the setting of ongoing inflammation, as shown in a previous adult study [15].

Twenty-five patients underwent CEUS and SWE with no reported side-effects. Kinetic measurements were not able to be obtained in 3 of the patients studied, and as such, 22 patients with a median (range) Pediatric Crohn’s Disease Activity Index (PCDAI) of 45 (30–60) at diagnosis were included in the statistical analysis. The mean age (standard deviation) of the surgically and medically managed patients was 15.2 (3.2) and 15.9 (2.6) years, respectively. Among the 11 patients medically responsive to induction followed maintenance infliximab therapy, CEUS was performed after a median (range) of 16 (8–26) weeks from the time of diagnosis. In this group, the median (range) PCDAI at the time of the CEUS was 15 (10–25). In comparison, among the 11 patients with medically refractory disease that ultimately required surgical resection, the CEUS was performed after a median (range) of 4 (2–12) weeks from the time of diagnosis. In these patients, the median (range) PCDAI at the time the CEUS was performed was 55 (20–60).

Based on each patient’s clinical history and exam, medical therapy was maximized whenever possible, including escalation to biologic therapy, as clinically indicated. All patients were closely monitored by their primary pediatric gastroenterologist to determine if clinical improvement occurred with the change in medical therapy. Those patients who demonstrated obstructive symptoms (inability to tolerate PO, severe abdominal pain, or worsening proximal bowel dilation on abdominal imaging) despite presumed optimized medical therapy were referred for surgical intervention at the discretion of their primary gastroenterologist.

Patients who required ileocecectomy were found to have significantly elevated mean area under the curve (medical 311.5 dB sec, surgical 762.6 dB sec, p=0.03) on CEUS when compared to those patients whose ileal disease responsive to medical therapy (Table 1). There was no significant difference found between the time to peak intensity, mean wash-in-slope, peak intensity, or elastography between the two groups.

Table 1
Mean CEUS kinetic values for patients treated medically and surgically

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Histopathologic fibrosis scoring of resected ileocecal specimens are detailed in Table 2. Among the 9 resected surgical specimens that underwent fibrosis scoring, all had either high grade acute and/or chronic inflammation. All specimens were also found to have irreversible fibrosis in the submucosa and muscularis propria, ranging from 10–60% of the tissue depth. Among these, 6 specimens were found to have 30% or greater fibrosis in the submucosa and muscularis propria at the most narrowed portion of the stricture. Increasing amounts of fibrosis were found to correlate significantly with increasing thickness of the muscularis propria, reflecting a reactive muscular hypertrophy due to chronic obstruction (r_xy =0.74, p<0.01) (Fig. 1).

Table 2
Histopathologic scores of resected ileal strictures

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Fig. 1
Degree of hypertrophy of muscularis propria and percent of fibrosis in ileal strictures.

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This is the first pediatric study to demonstrate the utility of CEUS in identifying those patients with CD and obstructive fibrosing disease of the terminal ileum that would be amenable to early surgical therapy. All of the surgically managed patients were found to have histopathology proven fibrosis and reactive muscular hypertrophy of the muscularis indicating the presence of high grade obstructive mixed fibrotic and inflammatory stricture of the terminal ileum. The reactive muscular hypertrophy correlated with increased tissue perfusion (AUC). In comparison, patients with medically responsive small bowel disease had less tissue perfusion noted on CEUS, thereby reflecting less inflammation and hypertrophy of the muscularis propria.

The study was not designed to validate CEUS in demonstrating clinical responsiveness to therapy, since only patients with obstructive symptoms were recruited into the study. Our initial hypothesis was that SWE would allow us to best delineate tissue fibrosis refractory to therapy. But in the end, SWE showed no correlation with the degree of fibrosis among those patients that required surgical intervention. Moreover, the increased tissue perfusion as defined by the markedly elevated AUC among those patients with refractory disease that went on to receive surgery proved to be secondary to an hypertrophy of the muscularis propria in response to the significant resistance imposed by the mixed inflammatory and fibrotic obstructive lesions within the terminal ileum.

In pediatric CD, the ileum is the most commonly, and frequently most severely affected region of bowel [1]. Failure to identify and appropriately treat fibrotic strictures in a timely manner leads to CD complications, including fistula and abscess formation. While medical therapy can be used to treat inflammation, most medications, including anti-tumor necrosis factor are unlikely to resolve fibrotic intestinal strictures [20, 21]. The early identification and management of patients with CD complicated by fibrotic intestinal stricture holds significant clinical implications, including the need to closely follow patients with obstructive symptoms, and in limiting the use of corticosteroids. Most importantly, these patients should be referred for surgical resection.

Most diagnostic modalities have not been shown to detect the presence of fibrosis in intestinal strictures that have required surgical resection. Although computerized tomography enterography and fluorodeoxyglucosepositron emission tomography identify strictures by demonstrating luminal narrowing with proximal dilation, these studies require significant radiation exposure and are unable to discriminate between acute inflammation and fibrosis within the affected bowel wall [22]. Similarly, magnetic resonance imaging (MRI) including MR enterography and gadolinium-enhanced MRI offer radiation-free, cross-sectional imaging can identify intestinal strictures but cannot delineate between fibrotic and inflammatory strictures [23]. Moreover, these radiological techniques are lengthy and costly exams that often require sedation in pediatric patients. Traditional abdominal ultrasound offers a fast, radiation-free, sedation-free bedside mode of detecting terminal ileum strictures in CD, but again does not provide an assessment of bowel wall fibrosis. CEUS expands the role of traditional ultrasound and allows for enhanced characterization of targeted tissues [18]. It can be extrapolated that the significantly increased measure of AUC in those patients who underwent surgical resection reflected an enhanced level of tissue perfusion within the hypertrophied muscularis in the setting of tissue fibrosis. Indeed, a reactive hypertrophy of the muscularis in the setting of severe obstructive fibro-stenotic disease. Our observations are in contrast to our initial hypothesis that predicted that acute inflammation would result in increased local tissue perfusion and higher CEUS kinetic values, as concluded from a prior adult study [24]. Our study would suggest that through CEUS enhanced tissue perfusion, as quantified by AUC kinetics may be used as a surrogate marker of reactive muscular hypertrophy and fibrosis. The limitations of this study include: a small sample size, and a selection bias, as only those patients presenting with obstructive symptoms were recruited into the study. Moreover, expertise in performing CEUS is limited to a small number of well-trained personnel.

In conclusion, CEUS is particularly useful in children with CD due it being a non-invasive, radiation-free, sedation-free radiological exam ideally suited for the pediatric patient population. Our study shows that CEUS is helpful in identifying bowel wall fibrosis that would be amenable to early surgical intervention, especially in patients that are presumed refractory to conventional therapy. Further research is needed in-order to validate these study results, and to support the notion of using CEUS as a Point of Care radiological tool that could be used to non-invasively monitor patient responsiveness to medical therapy. The clinical application of CEUS in the evaluation of patients with isolated colonic CD remains to be determined.