Colon: Non Neoplastic Disease: Pseudomembranous Colitis: Spectrum of Imaging Findings with Clinical and Pathological Correlation

Abstract

Pseudomembranous colitis (PMC) is an acute infectious colitis caused by a toxin or toxins produced by an unopposed proliferation of Clostridium difficile bacteria. With increased use of prophylactic and broad spectrum antibiotics, PMC has emerged as a significant medical problem. It is characterized pathologically by the presence of elevated yellowish white plaques forming pseudomembranes on the colonic mucosa. These plaques can also be visualized at endoscopy. As patient presentation varies widely, the radiologist may be the first to suggest the diagnosis of PMC. Plain films, contrast enemas and CT are useful radiographic techniques for evaluation of these patients.

Imaging findings will vary with the severity of the disease. Plain abdominal radiographs can demonstrate polypoid mucosal thickening, thumb-printing, wide transverse bands, haustral fold thickening or gaseous distention of the colon. The appearance of a toxic megacolon with distention and occasionally pneumoperitoneum may occur in the most severe cases which have resulted in perforation. In mild cases, small nodular filling defects representing the mucosal plaques are the main findings. With more severe colonic involvement, the plaques are larger and coalescent causing an irregular bowel wall margin. Mural thickening and wide haustral folds may also be seen due to intramural edema. Contrast enema is contraindicated due to the danger of perforation. In patients with severe PMC. CT findings include wall thickening, low attenuation of the mural thickening corresponding to mucosal and submucosal edema, the "accordion sign", the "target sign" or "double halo sign", pericolonic stranding, and ascites.

Introduction

Pseudomembranous Colitis (PMC) is an acute infectious colitis caused by toxins produced by an unopposed proliferation of Clostridium difficile bacteria in the colon [1]. C. difficile infection is responsible for virtually all cases of PMC and for up to 20% of cases of antibiotic-associated diarrhea without colitis [1]. Over the last few decades, it has emerged as a significant medical problem, largely due to the increased use of prophylactic and broad spectrum antibiotics. The incidence of PMC continues to rise steadily in the United States with recent epidemic outbreaks reported at a number of institutions [2].

PMC can result in significant patient morbidity and mortality, especially if the condition is not diagnosed early. Overall mortality rate of PMC has been reported between 1.1% to 3.5% [3,4]. It is important for the radiologists to be aware of this potentially life-threatening condition and to recognize its imaging findings early, as the radiologist may be the first to suggest the diagnosis.

Etiology

C. difficile is a nosocomial hospital-acquired infection and can be epidemic or endemic in hospitals or nursing homes [5]. PMC usually occurs as a complication of antibiotic use, but it is also associated with abdominal surgery, colonic obstruction, uremia, prolonged hypotension or hypoperfusion of bowel. PMC also occurs with increased frequency in patients with severe debilitating disease such as lymphoma, leukemia [6,7] and advanced human immunodeficiency virus infection [8]. PMC is a toxin mediated disease that requires production of 2 toxins by the C. difficile organisms for clinical expression. Toxin A is an enterotoxin and toxin B is a cytotoxin [5]. Although many laboratories only assay for one of these toxins, both are present, and by testing for both, sensitivity increases. [9].

Clinical Presentation and Diagnosis

The clinical presentation of C. difficile infection includes, in increasing order of severity, asymptomatic carriers, antibiotic-associated colitis without pseudomembrane formation, PMC, and fulminant colitis.

The majority of hospital inpatients infected with C. difficile are asymptomatic carriers [1] or only mildly or moderately ill [10]. The clinical features of PMC include diarrhea, abdominal tenderness, fever, dehydration, and leukocytosis. Occasionally, patients with C. difficile colitis present or progress to a fulminant, life-threatening colitis. Such patients are acutely ill, with lethargy, fever, tachycardia, and abdominal pain [1,11], and may progress to toxic megacolon and colonic perforation resulting from full-thickness colonic necrosis [3].

As its presentation may be variable, PMC is not always recognized by the attending physician. For example, approximately 5% of patients with PMC may present with signs and symptoms suggestive of an acute abdomen or abdominal sepsis [3,12] and may result in an unwarranted laparotomy [3,13].

The diagnosis of PMC depends on the demonstration of C. difficile toxins in stool or characteristic adherent yellow plaques that vary in diameter from 2 to 10 mm by proctosigmoidoscopy or colonoscopy [1].

Treatment

The treatment of PMC consists of oral metronidazole or vancomycin. Most patients respond well to oral metronidazole or vancomycin within 3 to 4 days [10]. Prior to the introduction of metronidazole or vancomycin for the treatment of PMC, medical therapy failed in 22% of patients, resulting in the need for surgical intervention [3]. Today, PMC is essentially a "medical" disease, with less than 1% of patients requiring surgery [10]. However, in patients with a fulminant and toxic form of PMC who fail to respond to medical therapy, surgical intervention (usually subtotal colectomy with a temporary diverting ileostomy) can be lifesaving [1,14].

Pathological Findings

PMC caused by C. difficile infection is restricted to the colon, except in patients with ileostomies or defunctionalized loops of small bowel.[5,15]. On gross inspection, there are classically multiple, elevated yellowish white plaques on the colonic mucosa forming "pseudomembranes"[5] (Figure 1). Histologically, these pseudomembranes typically arise from a point of superficial ulceration and are accompanied by an acute or chronic inflammatory infiltrate in the lamina propria. They are composed of fibrin, mucin, sloughed mucosal epithelial cells, and acute inflammatory cells and can vary in size from a few millimeters to 20 mm. With advanced disease, pseudomembranes may coalesce and eventually slough to leave large denuded areas [5].

In patients with severe acute PMC requiring surgical resection, massive transmural edema has also been observed extending through the submucosa into the muscularis propria of the colon (Figure 2). Although mural edema can be present in acute colitis of any cause, it is typically confined to the mucosa and submucosa [16]. Therefore, a marked degree of transmural edema involving the colon is probably most typical of severe C. difficile colitis.

Endoscopic Findings

Endoscopy can establish the diagnosis of PMC by demonstrating characteristic adherent yellow plaques . The rectum and sigmoid colon are typically involved, but in approximately 10% of cases, colitis is confined to the more proximal colon and therefore may be missed during sigmoidoscopy [17]. In fulminant colitis, sigmoidoscopy or colonoscopy should be avoided because of the risk of perforation. But proctoscopy, with minimal insufflation of air, may be a useful diagnostic tool [1].

Radiographic Findings

With the increased use of radiologic imaging studies today, it is important for the radiologists to recognize PMC and help direct the correct course of management. Although radiologic imaging is typically not considered the method of choice for the diagnosis of PMC, the increased use of CT in recent years for the evaluation of acute abdominal pathology has resulted in its increasing role in suggesting the diagnosis, often before it is even considered clinically. It is therefore important for the radiologist to be aware of the spectrum of imaging findings of PMC.

Plain Films

Boland et al. reported plain film abnormalities were observed in 32% of 152 hospitalized patients with positive stool toxin assay, including colonic ileus (32%), small bowel ileus (20%), ascites (7%) and nodular haustral thickening (18%) [18] presumably representing the plaque-like pseudomembranous plaques protruding into the air containing lumen. Plain film findings in PMC vary depending on the severity and extent of disease.

In severe cases of PMC, plain abdominal radiographs can demonstrate polypoid mucosal thickening, presumedly representing the plaque-like pseudomembranous plaques protruding into the air containing lumen . "Thumb-printing", unusual wide transverse bands associated with thickening of the haustral folds, and gaseous distention of the colon can also be identified. [19-22]. Segmental dilatation of the colon may be in the same area as the thumb-printing or remote from this area [20]. The appearance of toxic megacolon with distention [20], and even colonic perforation [22] with pneumoperitoneum may occur in the most severe cases.

Although plain films may suggest the diagnosis of PMC, they are not sensitive and even when positive may underestimate the extent and severity of disease [23] .

Contrast Enema

With the advent of cross-sectional imaging, contrast enema now plays a limited role in the diagnosis of PMC [24]. In patients with severe PMC, an enema is contraindicated due to the danger of perforation [6,25]. It may be performed only on patients in whom the clinical and plain radiographic findings are equivocal or misleading [25].

Contrast enema findings in PMC also vary depending on the severity and extent of disease. In mild cases, small nodular filling defects representing the mucosal plaques are the main findings . With more severe colonic involvement, the plaques are larger and coalescent causing an irregular bowel wall margin [6,7,25]. The serrated outline of the barium column represents barium interposed between the plaque like membranes rather than true ulceration with surrounding edema [26]. Mural thickening and wide haustral folds may also be seen due to intramural edema [19,21] .

CT

CT has proved useful in the diagnosis of PMC [27-31], especially in cases where it is clinically unsuspected. CT findings in a group of 26 patients with PMC [31] revealed that the scan was abnormal in 23. Common CT findings include wall thickening, low attenuation of the mural thickening corresponding to mucosal and submucosal edema, the "accordion sign", the "target sign" or "double halo sign", pericolonic stranding, and ascites. Although the accordion sign is very suggestive of PMC, the other findings such as wall thickening, pericolonic standing, and scites are not very specific and can be seen in a variety of inflammatory/ infectious disease of the colon [32]. In addition, approximately 5% of patients with PMC present with signs and symptoms suggestive of an acute abdomen or abdominal sepsis [3,12]. In these cases, CT can help suggest the diagnosis and therefore prevent unwarranted laparotomy.

• Wall thickening

The most common CT finding in patients with PMC is colonic wall thickening, usually ranging from 3 to 32 mm (average 14.7 mm) [31]. Mural thickening may be circumferential (Figure 9), eccentric , smooth, irregular or polypoid in appearance. On CT, the wall thickening in PMC is often more irregular and shaggy compared to Crohn's disease which is usually symmetric and homogenous [31].

Inflamed mucosa and colon wall may show significant contrast enhancement following bolus intravenous contrast administration . The "double-halo sign", or "target sign" consisting of two or three concentric rings of different attenuation, originally described in ulcerative colitis and Crohn's disease has also been reported in PMC [33] . It indicates mucosal hyperemia and submucosal edema or inflammation [34]. The different ring attenuations are better appreciated during the arterial phase of enhancement.

• The accordion sign

The accordion sign is a result of oral contrast material trapped between markedly thickened haustral folds. This gives the appearance of alternating bands of high attenuation (contrast) and low attenuation (edematous haustra) [31,35]. It is highly suggestive of PMC, although it is usually seen only in advanced cases. This appearance may be variable depending upon the degree of edema of the haustral folds and the amount of contrast material trapped between the folds [35]. With marked fold enlargement, deep tracking of barium between markedly thickened folds may simulate intramural tracts [23].

• Extent of the disease

CT examination may reveal pancolitis or segmental colitis. In a series of 26 patients with PMC, abnormal bowel wall thickening most commonly involved the entire colon (12/26) , but also presented as disease limited to the sigmoid colon (3/26) ,or either the right or the transverse colon (7/26) [31] . More localized involvement of PMC may also be encountered . By determining the extent and location of colonic involvement, CT can aid the endoscopist. For instance, if the disease is not present in rectosigmoid colon, proctoscopy and sigmoidoscopy may fail to make the diagnosis.

• Pericolonic stranding

Pericolonic stranding may be identified, but is usually mild, reflecting the primary mucosal and submucosal nature of this disease [24]. The relative paucity of pericolonic inflammation in this disorder in association with marked colonic wall thickening helps differentiate PMC from other colitides [29].

• Ascites

Ascites is occasionally a direct complication of PMC, which tends to occur in severe cases (Figure 26). However, it may also be due to coexisting conditions such as portal hypertension, congestive heart failure and sepsis [36] . Since ascites is uncommon in other inflammatory bowel disease, it may be a helpful clinical finding. However, ascites has also been reported in patients with Crohn's colitis, infectious colitis and vasculitis, and is therefore not specific for PMC [32].

• Other CT findings

Colonic intramural gas or pneumatosis coli with or without intrahepatic portal venous air have been reported in severe cases [12,30]. Small pleural effusions and subcutaneous edema are also commonly seen in patients with severe PMC, although both findings may relate to the primary pathology or debilitated state.

Pitfalls and Caution

Radiological imaging studies including plain radiographs, barium enema, and CT may suggest the diagnosis of PMC. However, the imaging findings in PMC are not specific, and can be simulated by other disorders that result in focal or diffuse bowel wall thickening. For example, PMC can be confused with the acute stage of ulcerative and granulomatous colitis, inflammatory colitides, and ischemic colitis. Entities that cause thickening of the colon unrelated to colitis such as hemorrhage, colonic lymphangiectasia, leukemic infiltration and diverticulitis should also be considered as differential diagnoses [24].

A retrospective study of 64 patients with C. difficile disease and 30 control patients with diarrhea and negative for C. difficile disease revealed that sensitivity and specificity of CT for the detection of colonic abnormalities was 85% and 48%, respectively [37].

Although CT changes do not necessarily correlate with clinical severity, and negative CT findings do not exclude the disease [38], it is important to rise the index of suspicion of PMC since the increased mortality has been associated with a delay in diagnosis. Once PMC is suspected, diagnosis of PMC can be confirmed by the presence of toxins in stool assays and supported endoscopically by direct visualization of the pseudomembranous plaques.

Conclusion

PMC is an acute infectious colitis caused by a toxin or toxins produced by an unopposed proliferation of C. difficile, and usually occurs as a complication of antibiotic use. The clinical presentation of C. difficile infection is variable from asymptomatic carriage to fulminant colitis. Although many of imaging features of PMC are often nonspecific, they may be the first study to suggest the diagnosis. With the increase use of imaging studies in the evaluation of the patients with abdominal pain, it is important to recognize the imaging findings that may suggest the diagnosis. Early diagnosis and treatment are important to prevent progression to more serious conditions.

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