II.2.2.2. Ultrasound in the diagnosis and follow-up of patients with inflammatory bowel disease

Dr. Tomás Ripollés Sabater
Hospital Universitari Doctor Peset. Valencia
Dr. Fernando Muñoz
Complejo Asistencial Universitario. Salamanca

INTRODUCTION

The term “inflammatory bowel disease” (IBD) includes Crohn’s Disease (CD) and Ulcerative Colitis (UC) and is primarily characterised by chronicity and a clinical course manifested in outbreaks. IBD peaks in the second and third decades of life, but can occur at any age¹ and approximately 10% of cases are diagnosed with indeterminate colitis because they share characteristics of both pathologies.

UC is characterised by the fact that the disease is confined to the mucosal layer of the colon in a continuous and regular manner, extending proximally from the rectum in a variable distribution. In CD, however, inflammation is transmural and segmental, alternating healthy and diseased intestinal tracts. Although the disease may be located in any section of the digestive tract, the most frequent location is the terminal ileum, which is affected in up to 70% of patients².

Colonoscopy is the gold standard technique for UC, but for patients with CD, it only evaluates inflammatory activity and the extent of disease in the colon and the last few centimetres of the terminal ileum – it does not adequately assess transmural complications. It has been found that colonoscopy is incomplete in up to 20% of cases due to the severity of the disease or the presence of stenosis, or because it extends to inaccessible segments located proximally to the terminal ileum¹.

ULTRASOUND TECHNIQUE

For many years, it was believed that intestinal gas and peristalsis prevented ultrasound evaluation of intestinal loops, as this is often the case in normal intestinal loops. However, in the diseased intestine, the wall is thickened and rigid, with typically decreased peristalsis and a small amount of intraluminal gas. These factors allow satisfactory ultrasound assessment of the affected segments in most patients with IBD. Obesity is also a limitation in ultrasound evaluation; however, IBD patients are usually thin, which favours the use of ultrasound, allowing proper evaluation and interpretation of the findings.

There are several requirements for proper ultrasound examination of the digestive tract: this is a technique that requires skill and a certain amount of experience, both of which can be acquired through prior training; there is a learning curve, so the results obtained improve with experience. Moreover, examination requires a meticulous technique and time, unlike a standard ultrasound to measure the kidneys or detect stones. Another key aspect to ensure a good diagnostic yield is the use of high-frequency probes; an initial general examination of the abdominal cavity can be performed with 3–5 MHz convex probes, but for a detailed examination of the intestinal loops and surrounding tissues, it is essential to use higher frequency (>5 MHz) convex or linear probes, as these provide a higher resolution assessment of the intestinal wall.

In 1986, Puylaert³ described the so-called “gradual compression” technique whereby pressure is gradually increased in order to shift intestinal gas and reduce the distance between the transducer and the area of interest, thus allowing for the use of high-frequency probes with a lower depth of penetration. Fasting before an ultrasound scan makes the examination easier as it reduces gas, but no other special preparation is strictly necessary. Some authors advocate the use of variable amounts (500-700 ml) of nonabsorbable oral isotonic solution for better dilation of the intestinal lumen, although this unduly prolongs the examination. This technique called SICUS (small intestine contrast ultrasonography) is particularly useful in detecting low-grade stenosis. In women, transvaginal ultrasound is ideal for assessing the involvement of the rectosigmoid colon and pelvic intestinal loops.
The procedure used to examine the intestinal loops varies depending on the publication, but it must be thorough and orderly so as not to leave out a single intestinal segment. To ensure a comprehensive assessment, each affected segment of the colon or small intestine should be explored both transversely and longitudinally.
Ultrasound examination of the abdominal cavity must begin with a B-mode examination (greyscale) to detect intestinal segments with a thickened wall, determining the length and distribution of the affected segments. Other parameters to be analysed include the echogenicity of the local fat, transmural complications (fistulas or abscesses) and the presence of stenoses and dilatations. The use of colour Doppler ultrasound as a complement to B-mode ultrasound allows to evaluate parietal vascularisation, a parameter which reflects the degree of inflammation. Lastly, in some cases, ultrasound contrast agents may be used to assess the enhancement of inflamed segments or to differentiate between abscesses and phlegmons.

B-mode ultrasound

• A normal intestine wall has a layered structure; in ideal conditions, up to five layers are visible in the intestinal wall, with the central echogenic layer being the submucosal layer⁴. The morphology of the loop varies during ultrasound examination due to intestinal peristalsis. (Fig. 1).
• Measured from the mid-line to the serosa, the thickness of the normal wall should be less than 3 mm. Ultrasound diagnosis of IBD relies mainly on the detection of wall thickening in an intestinal segment (Fig. 1 and 2).
• In addition to wall thickness, the persistence or loss of the layered structure of the wall, whether its involvement is continuous or discontinuous, whether the involvement is symmetrical or asymmetrical, and the degree of compressibility of the loop should also be analysed.

Colour Doppler ultrasound

• Allows the microscopic vessels of the intestinal loop wall to be visualised. These small vessels are characterised by slow flow and low speeds. In order to evaluate the vascularity of the loops, the colour Doppler parameters must be optimised, setting the ultrasound equipment colour to the maximum sensitivity using a special program preset to maximum sensitivity.
• To reduce inter- and intraobserver variability in the interpretation, settings should be kept the same throughout the examination.
• The vascularity of the intestinal loop wall is measured using the modified Limberg semiquantitative score: no flow (grade 0), weak flow (grade 1) or easily visible flow (grade 2)⁴, or mural flow and enlarged vessels outside the loop wall (grade 3)⁵.

Contrast-enhanced ultrasound

• Intravenous ultrasound contrast, unlike those used in CT or MRI, is completely intravascular and does not cross into the interstitium and has recently been introduced into clinical practice. Various histological studies have demonstrated that in diseased intestinal loops, neovascularisation occurs in the early stages of active disease, in the form of small vessels that can be assessed using contrast media⁶.
• Specific image contrast enhancement software must be installed on the ultrasound machine in order to visualise microbubbles after injection of the ultrasound contrast agent. The use of low mechanical indices prevents breakage of the microbubbles and facilitates the evaluation of the enhancement in real time over several minutes.
• We used SonoVue®, a second generation ultrasound contrast agent injected into a peripheral vein as a 2.4 ml bolus through a 20 G catheter, followed by the injection of 10 ml of normal saline (0.9% NaCl). Enhancement of the inflamed intestinal loop wall becomes visible about 15–20 seconds after injection of the contrast agent. The degree of enhancement can be assessed either subjectively or objectively using time-signal intensity curves, measuring enhancement in a region of interest (ROI) in the wall over a specific period of time (Fig. 3 and 4).
• The use of intravenous contrast increases the sensitivity in the detection of the vascularisation of the intestinal wall, compared to the colour Doppler study.
• Ultrasound contrast enhancement assesses parietal microvasculature while colour Doppler evaluates the macroscopic vessels^7,8.

•The contrast agents have other advantages over colour Doppler: the analysis of time-signal intensity curves is more reproducible than the semiquantitative or subjective measurement of the number of vessels; and motion artefacts caused by peristalsis or intestinal contents do not prevent the evaluation of parietal enhancement as is the case with colour Doppler^7,8. The main limitation of the contrast is the heterogeneity of the quantification curves between the different devices, which makes it difficult to compare results.

CROHN’S DISEASE

CD is an inflammatory process that affects all layers of the intestinal wall, frequently presenting changes in the perienteric tissues; for this reason, endoscopy does not assess it adequately as it only allows for visualisation of the mucous. As a result, cross-sectional imaging techniques (ultrasound, CT and MRI) have assumed a central position in the diagnosis and monitoring of patients with CD⁹. A number of systematic reviews, meta-analyses and the latest consensus guidelines by the European Crohn´s and Colitis Organisation (ECCO) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) have shown that the 3 sectional techniques have a similar diagnostic accuracy^9-11.

Crohn´s Disease (CD) is a chronic inflammatory bowel disease characterised by alternating episodes of inflammatory activity and periods of remission. In order to plan treatment, symptomatic patients require repeated assessments of disease activity and intensity, as well as monitoring for transmural complications (abscesses, fistulas, stenoses) that may occur in the clinical course. CD is typically diagnosed in young adults and exhibits a chronic relapsing clinical course, so that where imaging techniques such as CT are used for monitoring purposes, patients are at a significant risk of cumulative exposure to ionising radiation over the course of their lives. Both MRI and ultrasound have been established as the 2 gold standard techniques in daily clinical practice. Both have been used in recent years and have been shown to have similar diagnostic performance and to be well suited to the management of the patient with CD, and both can be used at different times during the course of the disease⁹.

The absence of radiation, cost-effectiveness, high patient acceptance and availability make ultrasonography an attractive technique in the management of this disease. The excellent tolerance of ultrasound allows it to be repeated as often as necessary, which is especially important in monitoring treatment, as the likelihood of achieving the goal (mucosal or transmural healing) increases the more the treatment is adjusted based on the findings of these tests¹². In our hospital, ultrasound is the standard technique used to assess patients with CD.

Along with the medical records, laboratory data and endoscopic data, ultrasound imaging, just like the other 2 cross-sectional imaging techniques, CT or MRI, is helpful in establishing a sound initial diagnosis of CD. The information given by the cross-sectional imaging techniques allows the location, extension (detection of lesions not reachable by the endoscope), inflammatory activity and extent of the disease to be determined, in order to rule out penetrating or stenosing subtypes, or to monitor treatment effectiveness. This information is important to guide the therapeutic strategy and also has prognostic value. The report of an ultrasound examination performed in a patient with CD should include the presence or absence of ultrasound findings, allowing it to be classified into one of the subtypes defined by the Montreal classification, i.e. inflammatory, stenosing or fistulising. However, in clinical practice, more than one disease subtype may be observed in a given intestinal segment or in multiple adjacent segments in the same patient.

Diagnosis of Crohn’s disease

The findings published in the literature show that ultrasound is an accurate technique for the initial diagnosis of patients with suspected CD. In the meta-analyses and systematic reviews conducted to evaluate the accuracy of ultrasound in the detection of IBD, the technique was concluded to be appropriate to either confirm or rule out the diagnosis^10,11. The diagnosis of CD relies primarily on the measurement of wall thickness. Based on the criterion of a wall thickness >3 mm, the published results are: accuracy: 90–93%, sensitivity: 85–97%, and specificity: 83–97%. Sensitivity varies depending on the location of the disease, with higher values for anatomical areas that are easily accessible using ultrasound, such as the terminal ileum (Fig. 2) and the left colon, while lower accuracy was observed in the rectum, the proximal intestinal tracts (jejunum) or those located in the deep pelvis. Sensitivity also decreases in cases with initial mucous lesions or aphthoid ulcers, as these do not cause significant wall thickening. Several studies conducted with ultrasound contrast agents have shown that the presence of enhancement in the wall of intestinal segments with a wall thickness <3 mm increases sensitivity in the diagnosis of CD^7,13.

CD affects the digestive tract in a discontinuous manner; thus, various segments may be affected, with areas of normal intestine between them. When evaluating the exact extent of involvement, namely via intestinal segments, ultrasound results are inferior, with a sensitivity and specificity of 83–88% and 93–95%, respectively, although there are no significant differences with respect to CT or MRI¹¹. From a practical point of view, the detection of more or fewer segments does not generally affect the treatment plan. Nevertheless, it is advisable to perform MR-enterography studies in cases of extensive involvement, suspected lesions of the upper intestine, or when surgery is planned. SICUS with the oral ingestion of nonabsorbable solutions can improve the results of ultrasound in detecting diseased segments¹⁴. The ECCO/ESGAR guidelines support the use of intestinal ultrasound for the study of the extent and location⁹.

Involvement of the appendix in CD is observed in up to 21% of cases in surgical series. Simultaneous involvement of the terminal ileum is nearly always present, whereas caecum thickening is observed in only about 50% of cases. In our experience, the presence of a hyperaemic appendix is very common (73%), with no significant difference with respect to the percentage of cases with hyperaemia found in acute appendicitis¹⁵. In the Emergency Department, when a patient has right iliac fossa pain and thickening of the appendix and of the terminal ileum, the signs suggestive of CD are:

• Involvement of other intestinal segments.
• Fibrofatty proliferation around the ileum.
• Marked and irregular thickening of the submucosal ileum.
• Ileal parietal thickness >5 mm and hyperaemia in the terminal ileum (the presence of the latter two signs had a positive predictive value of 96% and a negative predictive value of 73% for the diagnosis of CD)¹⁵.
  A hyperaemic appendix with no colour Doppler flow in the terminal ileum suggests acute appendicitis.

ULTRASOUND FINDINGS

The main ultrasound findings associated with inflammation in CD include wall thickening, wall ulcers, increased colour Doppler flow, increased enhancement after contrast injection, perienteric inflammation, fistulas, strictures, inflammatory masses and abscesses.

These findings can be classified in four main groups: (1) findings in intestinal wall; (2) mesenteric findings outside the intestinal loop; (3) transmural complications; and (4) stenosis.

1. Wall findings

Bowel wall thickening
Bowel wall thickening is the most solid ultrasound parameter for the diagnosis and evaluation of the activity of the disease, and this finding also shows high interobserver agreement^16,17. The wall thickness should be measured transversely oriented to the intestinal loop, perpendicular to the longitudinal axis. A number of studies have established that setting the threshold for wall thickening in > 3 mm is a good compromise between sensitivity and specificity^18,19. In CD, thickening is usually moderate (5 to 15 mm); the loop involved is normally more rigid, with decreased or absent peristalsis. The thickness of the intestinal wall is significantly greater in patients with active disease than in those with inactive disease^20,21.

Changes in wall echotexture
In the absence of complications, all layers thicken symmetrically and stratification is preserved. Focal or extensive loss of stratification may be seen in severe acute disease (video 1), sometimes accompanied by ulceration (inflammation), although it is rarely observed in very advanced dormant disease, especially in the left colon (severe fibrosis)²². Loss of stratification correlates with disease activity seen at endoscopy and with an increased need for surgery^23-25.

Section II.2.2.2. Video 1: Video of patient with Crohn’s Disease where in addition to bowel wall thickening, a loss of stratification, involvement of perienteric fat and an enteroenteric fistula or sinus tract can be observed.

Hyperaemia with colour Doppler or with contrast dye agents.
While grey scale ultrasound allows for the morphological analysis of the intestinal wall and mesentery, colour Doppler ultrasound and CEUS can better assess inflammation.
Inflamed wall segments generally show increased signal strength in colour Doppler evaluation and in CEUS. Both techniques can be used to visualise and quantify intestinal vascularisation.

The increase of the density of the blood vessels in the intestinal wall in colour Doppler ultrasound correlates positively with the histological activity of the disease and endoscopic activity^{26, 27}. Grade 2 or 3 hyperaemia of the Modified Limberg Score has a diagnostic specificity of over 90% for severe endoscopic disease and a positive predictive value of 97% for the presence of ulcers at endoscopy. Persistence of increased vascularisation despite clinical remission after treatment may suggest a greater risk of relapse²⁸.

Ultrasound contrast predicts endoscopic disease activity better than it does wall thickness or degree of hyperaemia on colour Doppler ultrasound^29,30. Several studies and meta-analysis have shown that CEUS has high sensitivity (87-97%) and specificity (67-91%) to differentiate between active and inactive endoscopic disease^31,32, and the increase in the signal in CEUS correlates with the parietal enhancement on MRI³³. It is particularly useful in patients with pathological wall thickening in which there is no mural hyperaemia on colour Doppler study²¹.

Wall ulcers
The presence of ulcers on the intestinal mucosa is an early macroscopic manifestation of CD. They are characterised as irregularities of the inner wall layer or as hyperechogenic images deepening into the wall to varying degrees (video 2 and 2 bis).
The diagnostic capacity of the ultrasound to detect ulcers could even be greater than that of MRI, as demonstrated by 2 recently published series that reflect a diagnostic accuracy of 81-96%, compared to the combination of colonoscopy and MRI or surgical specimens^34,35.

Section II.2.2.2. Video 2: Patient with Crohn’s Disease where some of the most characteristic findings can be seen: ulcers, wall thickening, adenopathies and increased vascularisation (Limberg 3 out of 4).

Section II.2.2.2. Video 2 Bis: Video of same patient 6 months after starting anti-TNF treatment.

2. Mesenteric findings

Fibrofatty proliferation
The diseased intestinal loops are frequently surrounded by a greater quantity of mesenteric adipose tissue lining the diseased intestinal segment, typically the terminal ileum. It is characterised by the presence of a homogeneous increase in the echogenicity of the fat surrounding an affected intestinal segment with a mass effect that displaces adjacent intestinal loops. This finding is associated with the presence of fistulas and pathological wall thickening³⁶. Nonetheless, this finding can persist in patients in remission³⁶.

Mesenteric inflammation
Mesenteric inflammation is common in CD patients. Seen on colour Doppler ultrasound or CEUS as the “comb sign”, increased mesenteric blood flow can be seen in multiple intestinal processes, however, in the context of CD, it is identified in intestinal segments with active inflammation.

Lymph nodes
It is a finding that is identified in up to approximately 25% of patients with CD^37,38. Nevertheless, presence and number is more frequent during childhood, at the onset of the disease, as well as in patients with fistulas and abscesses. However, these lymphadenopathies may disappear after treatment³⁸. Reactive lymph nodes are typically observed as round or oval hypoechoic nodules in the mesentery adjacent to the diseased intestinal loop.

Sinus tracts and fissures
As the disease progresses, inflammation often spreads deep into the layers of the affected intestinal wall. Linear ulcers observed as echogenic tracts in the intestinal wall pass through the intestinal wall and extend beyond the external surface, becoming extramural. Initially seen as subtle hypoechoic irregularities (fissures) at the outer margin of the loop or serosa, the discontinuity of the serosa promotes inflammation of the adjacent soft tissue^37,39-41. Fissures may extend into hyper- or hypoechoic tracts through the mesentery, and are known as sinus tracts when they end blindly in the mesentery^19,39,42. The fissures and the sinus tracts reflect severe transmural inflammation and are probably the result of microperforations.

3. Transmural complications

Fistulas
Although the inflammatory phonotype is the most common presentation of CD, up to a third of patients develop a penetrating disease⁴³. The differentiation between fissure and fistula is purely academic as they have the same biological behaviour. The term fistula implies communication between organs covered by epithelium or skin; fistulas may occur between loops, especially the ileum and caecum (enteroenteral – fig 5 & 6) or involve adjacent structures, such as the bladder (enterovesical) (video 3), abdominal wall (enterocutaneous) or psoas muscle (retroperitoneal). They look like hypoechoic tracts, but when they contain gas bubbles, they are identified as echogenic lines in the mesenteric fat. In very advanced penetrating disease, a cluster of inflamed bowel loops may be interconnected by multiple fistulous tracts (starfish sign).

Section II.2.2.2. Video 3: Transmural involvement in a patient with CD. B-mode ultrasound of the minor pelvis showing a hypoechoic thickened intestinal loop (transverse section) surrounded by echogenic fat, located cranial to the bladder. Deep to the thickened loop, multiple blind hypoechoic tracts can be seen, representing fissures, and others superiorly communicating with other loops in relation to entero-enteral fistula. A hypoechoic tract can also be seen leading to the upper part of the bladder showing wall thickening, in relation to enterovesical fistula.

The diagnostic precision of ultrasound to detect fistulas is similar to that of CT or MRI, with a sensitivity between 67 and 87% and a specificity between 90 and 100%¹¹. In the ECCO-ESGAR consensus guidelines for the diagnosis and follow-up of inflammatory bowel disease, ultrasound is one of the recommended imaging techniques to evaluate fistula complications⁹.

Inflammatory masses (phlegmons and abscesses)
As a result of “covered perforations” caused by fissures or fistulas, inflammatory masses or phlegmons develop in the mesentery adjacent to the intestinal loop, which may contain fluid collections or abscesses. Abscesses appear on ultrasound as well-defined, thick-walled hypo- or anechoic masses without internal vessels, which may contain gas. Phlegmons are seen as hypoechoic masses with poorly defined margins, no identifiable wall, with internal vessels on colour Doppler^37,41,44. However, abscesses and phlegmons may have a similar appearance on B-mode ultrasound. The differentiation between the 2 pathologies is important to decide on medical (antibiotics with or without percutaneous drainage) or surgical treatment. It also helps in the introduction of disease-specific treatments, e.g. before starting biological treatment, abscesses must be ruled out because of the risk of septic complications.

The use of ultrasound contrast agents safely differentiates them, as phlegmons show diffuse enhancement of the lesion whereas abscesses show peripheral enhancement and an avascular central portion⁴⁵. The use of contrast agents does not increase the detection of inflammatory masses, but it improves the specificity of the diagnosis of abscess, preventing false positives. It also defines more precisely the size of the abscess, which can be important when deciding whether the collection requires drainage⁴⁵. Therefore, when an inflammatory mass is detected at ultrasound, it should be evaluated with contrast ultrasound. Contrast may also be useful in monitoring the evolution of abscess resolution^8,16,46 (fig. 7 and 8).

The sensitivity of ultrasound for the diagnosis of abdominal abscesses varies between 81% and 100%, with specificities of 92-94%, similar to CT and MRI. However, certain anatomical areas, such as the pelvis, are difficult to assess by ultrasound because of the depth and presence of gas that can obscure lesions unless a vaginal transducer is used^16,46,47. Ultrasound may be used as the initial imaging method, restricting CT or MRI to diagnostic uncertainties or in centres without adequate ultrasound expertise.

4. Estenosis

Stenoses occur in 12–54% of patients with CD and are associated with increased morbidity and decreased quality of life. Several systematic reviews and consensus documents state that ultrasound, CT and MRI have high sensitivity and specificity for the diagnosis of small bowel and colon stenosis, with similar diagnostic yields^9,11. In a recently published systematic review, the sensitivity of ultrasound was 80% (95% CI, 75.2%–84.2%) and specificity was 95% (95% CI, 89.7%–99.8%)¹⁶. The use of oral contrast agents (SICUS) significantly improved the sensitivity of the technique for diagnosing low-grade stenosis²⁴.

A recently published consensus document reports that stenosis can be defined when there is a thickened (>4 mm), rigid, narrow lumen intestinal segment followed by a distended intestinal segment preceding that segment⁴⁸. Oral contrast is defined as when the lumen of the affected intestinal segment has a diameter of less than 1 cm, measured at maximum loop distension⁴⁶ (fig 9 & 10).

When obstruction is clinically suspected in a patient with CD, a CT scan is usually performed, especially in Emergency settings. However, according to a meta-analysis, if the sensitivity of ultrasound imaging in the diagnosis of intestinal obstruction is >85%, in these patients, therefore, where obstruction is suspected, a preliminary ultrasound should be performed19, taking into account that the assessment of the inner diameter of the intestinal loops does not require a great deal of experience (video 4). CT scans ordered by non-specialist doctors in an Emergency Department and/or carried out by radiologists with no experience in ultrasound are one of the main contributors to irradiation in CD patients⁵⁰.

Section II.2.2.2. Video 4. Stenosis in a patient with CD. 18-year-old patient with known CD and suspected obstruction from the Emergency Department. Dilation of small intestine loops in a supravesical location, continuing the ultrasound scan towards the right iliac fossa where slight, concentric and continuous thickening of the walls of the terminal ileum is observed. A few centimeters from the ileocecal valve you can see a segment with intestinal stenosis.

In the event of obstruction, it is important to determine whether the stenosis is predominantly inflammatory or fibrotic (scar tissue), as the former responds to medical treatment while the latter may require surgery, strictureplasty or endoscopic dilation. Although colonoscopy is considered the gold standard to assess stenosis, this technique only provides information on the mucosa; in many cases, it cannot reach the stenotic area when located in the small intestine. Most stenoses are mixed, and only a small percentage are purely inflammatory or fibrotic⁴⁸.

Ultrasound assessment of the inflammatory component of a stenosis is performed by B-mode, colour Doppler or contrast ultrasound, while the degree of fibrosis is assessed by elastography. Several studies have shown that layer destructuring and moderate-severe hyperaemia with colour Doppler or CEUS correlate with a higher degree of inflammation in the histology of surgical specimens^{16,27,46,51-54}. The enhancement parameters that correlate most strongly with the degree of inflammation are a higher peak brightness intensity or a higher percentage of enhancement; and with the degree of fibrosis, a lengthened time to peak^16,46. The absence of signs of inflammatory activity in a stenosis that causes bowel dilation indirectly suggests fibrosis.

Elastography is a new technique that makes it possible to assess tissue stiffness by means of specific programmes included in ultrasound equipment. A recent systematic review has shown a correlation between the degree of wall stiffness of the stenosis measured by elastography and the degree of histological fibrosis, with higher values in segments with fibrosis⁵⁵. Two recent studies have shown sensitivities of 70-75% and specificities of 92-100% for the detection of fibrosis in the stenosed segment^56,57.

In short, elastography and colour Doppler or contrast can be used to assess bowel stiffness and inflammation, respectively, providing a differentiation between active bowel wall inflammation, fibrosis and vascularisation found in chronic diseases to improve selection between medical therapy and surgery.

Evaluation of inflammatory disease activity

CD is characterised by a chronic recurrent course; therefore, for an appropriate therapeutic approach, periodic evaluations of inflammatory activity is required. This can be done based on clinical or laboratory tests, or macroscopic data, measured either by endoscopy or imaging tests.

A high correlation between various ultrasound parameters and endoscopic or histological activity has been demonstrated in the literature. Wall thickness, colour Doppler grade or parietal enhancement after contrast injection, ulcers or destructuring of the parietal layers are all parameters with a significant positive correlation with the degree of endoscopic activity^11,16. The presence of transmural complications, fistulas or abscesses are also signs of inflammatory activity. According to Panés et al., based on 6 studies reviewed in the literature, the sensitivity of ultrasound for the detection of disease activity ranged from 63 and 100% (total 85%), and specificity from 77 and 100% (total 91%)¹¹.

Monitoring of Crohn’s Disease with ultrasound

We have seen how useful ultrasound is in diagnosing CD, in assessing the extension of the affected area and detecting complications, but to determine if it is useful in monitoring the disease, it needs to be able to detect changes with treatment, quantify them and the findings need to be of prognostic interest in order to justify treatment adjustments.

Can it detect changes? And these changes, do they have prognostic value, or in other words, would they justify a change in treatment?

Among the initial studies to assess the use of this technique in the monitoring of CD is the study by Ripollés et al.⁵⁸, which includes 51 patients with CD treated with anti-TNF and followed up prospectively for 52 weeks. The ultrasound tests were performed at 12 and 52 weeks in addition to the baseline ultrasound. It was observed that 85% of patients experienced improvements in the ultrasound parameters at week 12 and that these findings were predictive of outcomes at week 52, so only 11% of patients with improvement required intensification or surgery compared to 65% of those who did not experience early improvement. However, normalisation of ultrasound parameters was achieved in only 14% of patients by week 12 and in 30% one year after the start of treatment, so this is a difficult goal to achieve. many studies were later published that show the capacity of the technique in to detect changes induced by the treatment^38,59-63 (fig 11).

The prognostic value of the ultrasound findings is highlighted in a number of studies, of which we will mention that of Rispo et al.⁶⁴, which retrospectively included 100 patients and identified as independent predictors of surgery, in addition to endoscopic findings and the presence of complications, the following variables (phenotypes B2 or B3) to two ultrasound parameters such as extension and thickness of wall. Based on these variables, a risk matrix ranging from a 15% to 87.5% chance of surgery per year is established⁶⁴. Another noteworthy study that supports the prognostic value of the ultrasound findings is the one by Alloca et al.⁵⁹, in which they found faecal calprotectin and ultrasound findings with an increased risk of progression or treatment escalation in a cohort of 225 CD patients as predictors of poor outcome or treatment escalation with an OR of 6.97 (2.87-16.9; p<0.001) and 8.7 (3.6-21.2; p<0.001) respectively.

Which ultrasound parameters are modified with the treatment?

The German prospective study TRUST³⁸ best answers this question. A prospective follow-up study was carried out on 234 patients with active CD (HBI ≥ 7) for whom anti-TNF treatment was intensified, with ultrasound scans being performed at baseline and in months 3, 6 and 12. All the ultrasound parameters analysed: wall thickness, Doppler signal, fibro-fatty proliferation, adenopathy or stenosis, improved significantly with treatment at the first 3-month check-up compared to baseline values. In this study, the probability of reaching normality in ultrasound parameters was 58%, considerably higher than in previous years, being less likely to be achieved in the ileum than in the colon segments.

Beyond anti-TNF, ultrasound has also proven to be useful in monitoring the effect of other drugs. Maybe the most relevant study in this regard is the one by Calabrese et al.⁶⁰, also prospective and multicentre, with ultrasound scans at baseline and at 3, 6 and 12 months performed on 188 CD patients about to start different biologics. With all the drugs (adalimumab, infliximab, vedolizumab and ustekinumab), improvement in ultrasound parameters was demonstrated, with normality being achieved in 27.5% of patients at 1-year follow-up. Again, in the ileal location it was more difficult to achieve and basal thickness was a predictive factor at both 3 months and 12 months, so the higher the basal thickness, the lower the likelihood of returning to normal. Ultrasound has also been included in the assessment of the response in a clinical trial, such as Stardust⁶³, where again, improvement of the different parameters is observed with treatment – in this case ustekinumab, with normality being more difficult to achieve in the ileal location as in previous studies.

Can we quantify these studies? One of the limits in implementing the technique in research is the absence of properly validated and easy-to-apply quantitative indices, unlike in the case of MRI⁶⁵. A recent review of ultrasound indices in CD concludes that, despite the large number of indices described, the risk of bias is high in 92% of them⁶⁶. However, several points of consensus on the use of ultrasound have been established⁶⁷. At least 3 validated indices have been published since this review, so it is possible that one of them will be used in future research. Among the new indices mentioned, both the Simple US Score (SUSS)⁶⁸ and the BUSS (Bowel Ultrasound Score)⁵⁹ include wall thickness and Doppler signal as the only variables. The SUSS is based on a Spanish prospective multicentre study and is currently in the validation phase. The BUSS has internal but not external validation, and its sensitivity to change has also been assessed⁶⁹. Two more partially validated indices should be highlighted because some of them have the potential to become the most widely used index. The first is the SUS-CD (Simple Ultrasound Activity Score) which includes as variables thickness and Doppler of the 5 usual segments, not only the most affected one; therefore, it gives a global idea of the activity of the disease⁷⁰. The last index we will discuss is the IBUS-SAS (International Bowel Ultrasound Segmental Activity Score) developed to try to reduce interobserver variability, achieving excellent agreement (ICC=0.97) and includes, in addition to thickness and Doppler, fat involvement and loss of wall stratification⁷¹.

Why use it? What are its advantages and limits?

The advantages over colonoscopy are clear, not only in terms of patient tolerance and acceptance, but also because it assesses areas that colonoscopy cannot reach. Furthermore, even in patients where colonoscopy is normal, alterations in imaging techniques can be observed in up to 50% of them, with clear prognostic implications⁷².

When evaluating the different meta-analyses, the diagnostic yield of ultrasound is similar to other imaging techniques such as MRI or CT. However, it should be noted that most of the evidence included in these meta-analyses has limitations as they are mostly retrospective studies. On the other hand, the gold standard technique is not always the most appropriate (usually colonoscopy), the interval between examinations is not always short enough and there is usually no central assessment or blinding. There is a prospective, multicentre, blinded British study involving 284 patients who underwent the 2 scans, showing the MRI slightly superior to ultrasound in the ileal location (sensitivity (SE) and specificity (SP) for the presence of CD: 80% and 95% vs 70% and 81% respectively)⁷³. The problem of this study is that most of the technicians were MRI experts with only 1 experienced sonographer. The Allocca et al. Study³⁴ includes 60 patients with CD who underwent both techniques, in a single centre, blinded and with an interval of only 1 week between colonoscopies. The cost-effectiveness of ultrasound, under these conditions of expert scanners in both techniques, is very good in detecting CD, sensitivity 88%, specificity 96% and in showing activity with a sensitivity and specificity of 92% and 100% respectively. Therefore, the diagnostic performance of ultrasound is excellent. Nevertheless, both techniques have advantages and disadvantages over the other. Ultrasound has a greater capacity to detect ulcers in the bowel wall than MRI (SE and SP: 94.7% and 66.7% compared to 83.3% and 33.3% respectively), i.e. it has a higher resolution in the assessment of the affected loop³⁵. Nevertheless, when estimating the involvement, MRI is superior, so ultrasound can underestimate the affected length when the segment is longer than 30 cm⁷⁴. In other words, the spatial resolution of MRI is higher and avoids the inconvenience of ultrasound assessment of bowel loops located in the deep pelvis. The example is the rectum where performance is clearly worse⁷⁵. One of the limitations classically attributed to ultrasound was the detection of proximal disease in CD. Nonetheless, MRI also has a lower performance in this location and, in fact, in the published meta-analysis where they are compared to capsule endoscopy, the performance is similar⁷⁶. Obesity also limits the quality of the ultrasound technique, as does pregnancy, above all in the third trimester.

Nevertheless, it has clear advantages such as easy availability, cost-effectiveness and, above all, excellent tolerance. In fact, when patients are questioned about tolerance in surveys, ultrasound is listed above blood tests and is significantly higher than MRI with similar perceived usefulness^77,78. In the aforementioned Alloca study³⁴, where 60 patients were examined, 83% preferred ultrasound compared to 17% who preferred MRI, and 97% thought that the former was the better tolerated technique. This would allow us to repeat it as many times as necessary, both in terms of tolerance and cost. On the other hand, the great advantage of ultrasound is the immediacy, i.e. it can be carried out in the same consultation room or patient’s room, thus speeding up the decision-making process, known as POCUS or POCBUS (Point-Of-Care (Bowel) Ultrasonography)⁷⁹.

When should it be carried out?

The ECCO consensus places MRI and ultrasound on the same level in the initial diagnosis of CD, in monitoring treatment (it establishes a timeframe of 6 months to perform it, although the level of evidence is low), in following up the symptomatic patient and in detecting complications, although when it comes to abscesses or fistulas located in the pelvis, MRI probably has a certain advantage. However, the gold standard technique for diagnosing post-surgical complications is CT, because of speed, availability and performance, although at times a preliminary ultrasound scan may eliminate the need to carry it out. In monitoring colic involvement and recurrence, colonoscopy is the gold standard, although ultrasound could eliminate the need for examinations⁹.

Evaluating the response to a specific treatment early is essential either to optimise it or to switch to another line in case of ineffectiveness. In this regard, 6 months seems too wide an interval; in fact, in a recent consensus, the most voted intervals for ultrasound scanning are at 8, 26 and 54 weeks⁶⁷. Nonetheless, there is little data on the cost-effectiveness of ultrasound before 3 months of age assessed in the TRUST study. In the Stardust study with ustekinumab, an ultrasound assessment was made at 4 weeks, in which a significant decrease in wall thickness was already observed with respect to baseline values, although the percentage of ultrasound response was relatively low (26.7%) with respect to that achieved at week 48 (46.3%), which is not sufficient to take a specific therapeutic approach⁶³. A recent study⁸⁰ performs serial ultrasound scans on 54 consecutive CD patients with no previous exposure to biologics, who initiate infliximab at weeks 0, 2, 6 and 12 together with colonoscopy at the last follow-up. In week 2 there were already significant differences with respect to baseline values in thickness and especially in IV contrast parameters (especially peak intensity and area under the curve) in a way that would allow early discrimination of patients with response. Two recent studies confirm that early testing in the first 2⁶¹ or 4⁶² weeks, significant changes can already be detected.

How often should it be performed? We have already mentioned that according to the ECCO recommendations, 6 months is established as the time to assess the effect of treatment on imaging techniques, and the recent consensus also suggests 52 weeks as an alternative. Logically if lesions persist that require treatment adjustments, the ultrasound or MRI will be repeated after 3 months. In the case of normalising the ultrasound parameters, it is not clear how often carrying this out is advisable. The rationale for this is that faecal calprotectin is of more limited utility in small bowel involvement than in colon involvement. In this regard, algorithms have been published that advise it should be carried out every 6-12 months^81,82 in conjunction with regular biomarker measurement, in particular faecal calprotectin, as they would have independent prognostic value⁸³. In any case, the determination of biomarkers alone is insufficient as it has a low sensitivity (73%) and specificity (71.4%) for the detection of ultrasound lesions or especially complications⁸⁴.

Does it really change how we manage CD?

Several studies try to answer this question. In the most classic, Novak et al.⁸⁵, clinical, biological and endoscopic information on 49 CD patients is provided to 2 physicians who give their opinion on the approach to be taken. Subsequently, after providing the ultrasound findings, both physicians changed their approach in 60% of patients, either therapeutically or by performing further examinations. An important point of this study is that ultrasound carried out in the consultation or POCUS, so the change of attitude was taken at the same time as the patient was assessed, with no waiting time. Other later studies confirm these findings, with management changes with POCUS around 60%^86,87.

One of the problems of carrying out on-the-spot ultrasound is the difficulty in making ultrasound scanners available in all speciality practices. The introduction of new affordable handheld devices, if they prove useful, could overcome this drawback. Few studies have been published, but with handheld devices (not POCUS), attitudinal changes of 40% with a sensitivity of 94% and a specificity of 71% have been described comparing the technique with colonoscopy⁸⁸. Recently a study comparing MRI with handheld ultrasound in 85 patients with suspected CD, using colonoscopy and MRI as benchmark examinations, has been reported. The results with the portable ultrasound in diagnosing CD are similar to those achieved by MRI with a sensitivity of 87% and a specificity of 91%⁸⁹. Nevertheless, MRI is superior in defining the extent of the disease or detecting complications.

Therefore, ideally ultrasound should be scheduled in asymptomatic patients or for treatment monitoring, but in symptomatic patients or those with clearly elevated biomarkers, on-the-spot ultrasound or POCUS should ideally be performed⁷⁹.

A distinctive situation in the monitoring of CD patients is the surveillance of recurrence after surgery. In this situation the choice technique is colonoscopy, but ultrasound has proven to have a good diagnostic performance. In the Rispo et al. meta-analysis⁹⁰, which includes 536 patients in 10 studies, the sensitivity of ultrasound in detecting recurrence was 94% with a specificity of 84%. The fundamental problem and the reason why specificity is lower is mild recurrence or Rutgeerts 2, so that for grades >i3 the specificity increases to 97.7%.

When compared with MRI or capsule endoscopy in a systemic review, the area below the curve of the capsule was 90% compared to 98% of the MRI and 93% of ultrasound.

The administration of IV contrast can improve to a degree diagnostic performance. In the study by Martinez et al.³⁴ involving 108 patients prospectively undergoing conventional and IV contrast-enhanced ultrasound, the highest diagnostic performance corresponds to a combination of parameters including the percentage of enhancement (thickness, Doppler, enhancement) and reaches 90.7%. Nonetheless, the thickness of the wall considered separately achieves a sensitivity of 95% but a specificity of only 72.2%, but what we are really interested in is a high sensitivity because most of the time we will confirm it with colonoscopy.

What is its scope?

Currently the most challenging treatment target is mucosal healing⁹¹ and ultrasound has shown an excellent correlation, with areas under the curve ranging between 0.86 and 0.97^68,70,83,92. However, in the Stardust study the correlation found is clearly lower with a kappa of 0.21 at 48 weeks⁶³. The correlation probably depends on the characteristics of the patients included, so more superficial lesions may go unnoticed on ultrasound and, on the other hand, ultrasound lesions (thickening, fat, etc.) may correspond to mucosal healing on endoscopy. In other words, they measure different and probably complementary things. In this direction, in a prospective series⁹³ with 116 patients monitored for 1 year, mucosal healing (MH) after starting anti-TNF is achieved in 59.5%, while transmural healing (TH) is reached in 38.8% (measured by MRI), both in the situation of MH without TH and 24.1% of TH without MH, although with a lower frequency (3.4%). Therefore, TH seems like a harder goal to achieve than MH.

The Stride II Consensus does not include transmural healing (with the problem of multiple definitions)⁹⁴ as a treatment objective, mainly because, as we have seen, it is a difficult goal to achieve⁹¹. Nevertheless, it does not detract from the prognostic value of this objective. As, for example, in the study by Castiglione et al.⁹⁵ the likelihood of surgery, hospitalisation or recurrence is significantly higher in patients who achieved mucosal healing but with persistence of lesions on ultrasound than in those with transmural healing. These findings have also been confirmed in other studies^96,97 highlighting that up to 61% of patients in clinical remission have lesions on ultrasound⁹⁷, and that partial TH is probably not sufficient⁹⁸. However, there is a significant percentage of patients with residual lesions who have an excellent prognosis and it may be necessary to establish the criteria for so-called transmural healing beyond complete normalisation. Finally, rather than achieving mucosal or transmural healing it is likely to be a combination of both as the prognosis would still be better^99,100.

In order to standardise the ultrasound targets to be achieved, a consensus has recently been published stating that TH would be defined as a thickness of 3 mm or less together with the absence of Doppler signal, while the ultrasound response includes one of the following criteria: 2 mm reduction in thickness from baseline, 1 mm reduction together with a decrease in Doppler signal by at least 1 degree, or a reduction in thickness greater than 25%¹⁰¹.

Ulcerative Colitis

Is it useful in ulcerative colitis?

In UC, the burden of monitoring falls on biomarkers, especially faecal calprotectin and colonoscopy; however, ultrasound may have an important role to play in supporting these techniques. The ultrasound findings in Ulcerative Colitis (UC) are similar to those described in CD (fig 12-14), i.e. increased wall thickness, increased vascularisation, loss of stratification in layers, etc.¹⁰², perhaps point to the loss of haustration as a characteristic feature of colic involvement. The role of surveillance of UC is analysed in the study by TRUST&CU¹⁰³, which includes 224 patients with UC prospectively followed up with ultrasound at baseline and at 2, 6 and 12 weeks after initiation of treatment at the discretion of the attending physician. They find, as early as week 2, a significant decrease in all parameters analysed. Thus, 89% of patients had a thickness >4 mm in the sigma (cut-off point in sigma vs. 3 mm in all other segments) at baseline compared to 32% at week 12. In addition, thickness at week 2 predicted response to treatment at week 12. One of the main limitations of this study is the absence of endoscopy and the exclusion of patients with exclusive rectal involvement. In a recent trial with 30 patients treated with tofacitinib¹⁰⁴ observed a good correlation between endoscopic response and remission and ultrasound findings and proposed cut-off points of 3.9 mm and 2.8 mm respectively, with areas under the curve of 0.92 and 0.87.

The limited sensitivity of ultrasound in assessing the rectum⁷⁵ is particularly relevant when it is the most affected area or when the disease is limited to this location. To overcome this problem, transperineal ultrasound has been proposed with good results¹⁰⁵, although it is true that a rectoscopy can also be performed quickly and without preparation.

Three ultrasound indices have been mentioned¹⁰⁶, of which only the MUC (Milan Ultrasound Criteria) is valid^107,108, showing good ability to discriminate between active and inactive disease. However, its sensitivity to change has not been assessed, nor can it discriminate between different degrees of inflammation, so its use is not yet widespread.

In what situations can it be of help?

Once again, Point-of-Care Ultrasound (POCUS) can help us make a complementary assessment to the clinical diagnosis or biomarkers if available, providing us with more information for treatment decisions or for the indication of further examinations, mainly colonoscopy or rectoscopy. It also allows us to assess the extension of the disease in situations where colonoscopy is incomplete because of stenosis or lack of training, or not recommended due to the severity of the outbreak¹⁰⁹. Its possible role in predicting response to treatment in a severe UC outbreak should be highlighted. Ilvemark et al.¹¹⁰ include 56 patients in this situation, performing baseline and 24-72 hour ultrasound scans and finding that a decrease of 20% or more in basal thickness is associated with a favourable response to intravenous corticosteroids, with a sensitivity of 84.2% and specificity of 78.4%. In this study the baseline ultrasound values did not predict the subsequent course, unlike in the work of Smith with just 10 patients where a basal thickness greater than 6 mm predicted treatment failure¹¹¹. In any case, they are promising preliminary studies that need to be expanded.

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