Abnormal bowel wall thickness (BWT) is the most important TUS sign of CD and in unselected groups of patients, based on BWT values, sensitivities of 75–94 % with specificities of 67–100 % have been reported [15, 25, 26]. The wide variability of sensitivity and specificity values across studies reflects differences in the study design, size, and characteristics of the study samples and in the different reference standard value as threshold for a positive diagnosis. These methodological issues were evaluated in a meta-analysis [27] that, starting from 44 full-text studies, recognized only 7 prospective and appropriately designed studies (5 case control and 2 cohort studies). The results of this analysis showed that when more than 3 mm cut-off level was applied for abnormality in wall thickness, the sensitivity and specificity of TUS in the diagnosis of CD were 88 % and 93 %, while when a cut-off level of more than 4 mm was used, sensitivity was 75 % and specificity 97 %. The role of US to assess CD has been most extensively investigated for small bowel CD and the highest reported level of diagnostic sensitivity of TUS was achieved in investigations performed in populations mainly affected by known CD located in the terminal ileum [24]. This study, however, lacks a control group and was carried out by qualified investigators with specific expertise in tertiary referral centers. Several studies evaluated the accuracy of TUS in localizing Crohn’s disease lesions and most of them agreed in reporting the highest sensitivity (approximately 90 %) of TUS in detecting CD located in the terminal ileum and the lowest accuracy for those located in the upper small bowel and in the rectum [17, 28]. Few studies have evaluated the diagnostic accuracy of TUS as a screening technique for yet undiagnosed small bowel pathology [17], and most report unsatisfactory sensitivity (74–85 %). The main limit of bowel TUS is its inability to visualize the entire gut that has a virtual lumen and may contain gas making the intestinal wall barely visible. However, the difficulty in visualizing bowel wall is overcome by distending the intestinal lumen with anechoic fluid. After the ingestion of small amounts (250–375 mL) of polyethylene glycol 3,350–4,000 (macrogol) solution [17, 18], the entire small bowel from the duodenal-jejunal angle to ileocecal valve can be visualized with the Small Intestine Contrast US (SICUS). SICUS undertaken in healthy controls in vivo and independent of the volume of oral contrast used, allowed objective normative values of wall thickness (≤ 3 mm) and lumen diameter (≤25 mm) to be defined (Table 2.1, Video 2.1) [19]. These normative values provide useful measurements to discriminate normal from abnormal findings. Based on these normal cut-off values, it has been shown that SICUS is comparable to radiology and superior to standard TUS in detecting intestinal lesions both in patients with undiagnosed small bowel diseases and in those with known CD (Tables 2.2 and 2.3) [17, 20]. Sensitivity of TUS and SICUS were 57 % and 100 % and 87.3 % and 98 %, in the undiagnosed and in known CD patients, respectively. In addition, it has been shown that SICUS is more accurate than TUS in detecting both proximal and distal small bowel CD lesions compared to radiology [17] and surgery [29] (Table 2.4, Video 2.2). These results have subsequently been confirmed by other authors in several studies [30–32].

Notably SICUS enables initial assessment of wall alteration limited to the mucosa and submucosa in CD (Fig. 2.11). The latter is associated with slight thickening of the intestinal wall, which may be missed in absence of the lumen distension by oral contrast (Video 2.3). Furthermore, SICUS allows identification and assessment of the characteristic distribution of intestinal folds (Fig. 2.12) and recognition of endoluminal structures such as polyps from the intestinal wall (Fig. 2.13, Video 2.4).

It has been recently shown that SICUS is a safe, accurate, radiation-free alternative for the assessment of small bowel disease also in pediatric patient population [28]. The reported ability of SICUS to accurately identify the presence of small bowel disease compared to small bowel follow-through (SBFT) and ileocolonoscopy in a pediatric cohort of patients is even higher than in adults with a sensitivity and specificity of 96 % and 100 %, respectively (Table 2.5). In addition, as in adults, this study confirmed that SICUS is as accurate as SBFT in detecting both proximal and distal small bowel lesions, whereas agreement with SBFT was markedly lower for TUS without oral contrast, mainly for the proximal sites lesions (Table 2.5). Although feasibility and reliability of this technique in pediatric clinical practice ought to be confirmed in further studies, the diagnostic accuracy of SICUS, with a considerable negative predictive value and such high level of agreement with radiology, suggests that a normal SICUS at the initial diagnostic workup in a child with suspected CD could avoid radiation exposure and invasive and/or more expensive investigations.

It should be pointed out that compared to standard TUS, SICUS is a time-consuming technique, the duration of the examination being on average 45 min. Although SICUS may appear to be a more expensive technique than traditional TUS, the lack of radiation actually makes it a cost-effective alternative to the less available and more expensive MRI. When considering colonic CD, US is more accurate in the assessment of intestinal wall pathology located in the sigmoid/descending colon, followed by the cecum/ascending, and transverse colon, while accuracy for rectal disease is poor [33]. A systematic review of 6 studies investigating US for assessment of ileo-colonic CD found sensitivities ranging from 63 to 100 % and specificities from 77 to 100 % [27]. The accuracy of standard ultrasound compared to endoscopy in the assessment of presence and severity of CD located in the colon improves markedly with hydrocolonic sonography [34], but these findings have not been reproduced.

The effectiveness of intravenous contrast agents in the detection of Crohn’s disease remains, despite some positive findings, largely uninvestigated [21].

To date few studies have assessed the accuracy of ultrasound to assess extension of CD intestinal involvement and reports have been equivocal regarding the correlation of TUS with radiology and intraoperative findings [33, 35–37]. Two studies [33, 35] performed in the same group of patients reported a significant correlation (r = 0.51) between TUS and small bowel enema in the assessment of CD lesion extension. However, this finding was not confirmed by a study that, while not contradicting such correlation, showed that when an appropriate test of comparative analysis is employed, (i.e., ANOVA), the accuracy of TUS in the assessment of extension of small bowel lesions is lower than that observed at SICUS and confirmed by SBFT or surgery [17, 29].

The use of oral contrast improves ultrasound accuracy in assessing extension of small bowel CD lesions in both adults and children independent of the site of lesions (Figs. 2.14 and 2.15).

These findings are of clinical relevance in patients with suspected CD, as well as in those with a previously established diagnosis, to help address follow-up and appropriate management of a progressive disease.

Assessment of inflammatory activity is a central component of the management of Crohn’s disease patients. Measurement of disease activity has traditionally involved a combination of clinical, biochemical (ESR, CRP, α1-antitrypsin, fecal calprotectin), imaging, and endoscopic methods; although no ideal reference standard currently exists [38]. Clinical scoring systems such as the CDAI have been shown to have low correlation with mucosal inflammation, poor inter-observer reproducibility and, more relevantly, may not detect asymptomatic inflammation [39]. Laboratory parameters are not specific and endoscopy, including double balloon enteroscopy, is invasive and limited to mucosal assessment. Computed tomography (CT) involves the use of ionizing radiation whereas magnetic resonance (MR) imaging is expensive and time consuming. Several studies evaluated the relationship between CD activity assessed as CDAI and/or with biochemical parameters, and TUS features of the bowel wall with equivocal results [40–42]. Previous studies have shown significant but weak correlation between the degree of bowel wall thickening and its extent and clinical (CDAI) and biochemical parameters (ESR, CRP) [40]. As such, an ultrasound index of intestinal inflammatory activity has been developed based on the wall thickness and stratification of the diseased gut demonstrating a strong correlation with the endoscopic and radiological score but a weak correlation with clinical (CDAI) and biological indices of inflammation [41].

The introduction of second-generation ultrasound contrast agents in combination with low mechanical index harmonic ultrasound allows accurate imaging and analysis of bowel wall microvascularity that takes part in the pathogenesis of CD inflammation [43]. Several studies have examined both qualitative and quantitative measures of bowel wall enhancement obtained from CEUS as a means of assessing inflammatory activity in Crohn’s disease with inconsistent results [44–49]. Some studies have demonstrated a significant relationship between measurements obtained from CEUS and clinical or endoscopic indices of disease activity [44, 45] while others have failed to confirm similar results [46, 47], suggesting that mural microvascularity may be variably increased in active disease. Experimental data have previously shown that regional blood flow is, in fact, reduced in Crohn’s disease and associated to microvascular ischaemia [49].