Introduction
Background
Pseudomembranous colitis (PMC) is a descriptive term for colitides defined by the presence of pseudomembranes on the colonic or small intestinal mucosa.1 Although small intestine can be involved in PMC, most cases encountered in the modern era involve only the colon. Clostridium difficile infection is responsible for virtually all cases of PMC and for as many as 20% of cases of antibiotic-induced diarrhea without colitis.2
The etiology of antibiotic-associated diarrhea and colitis not caused by C difficile is poorly understood, and a variety of other organisms have been implicated as causative agents, including Staphylococcus aureus, Candida species , Clostridium perfringens, and salmonellosis.3
Pseudomembranous lesions in the intestinal tract, originally reported in 1893, were thought to be caused by S aureus on the basis of its recovery in the stool samples of affected patients. With time, S enterocolitis (involving both small intestine and colon) became an accepted entity. Widespread antibiotic use made PMC a common problem, and it became apparent that the disease primarily involved the colon and only rarely involved the small intestine. In 1977, C difficile was recognized as the pathogen responsible for the development of PMC.
Pathophysiology
PMC is a descriptive term for colitides associated with pseudomembrane formation on the colonic mucosa (see Images 1-2). Pseudomembrane production is not always related to antibiotic administration; it may also may result from mucosal ischemia. However, the most common cause of PMC is C difficile overgrowth secondary to antibiotic therapy.
Other causative factors for PMC are abdominal surgery, colonic obstruction, uremia, and prolonged hypotension causing hypoperfusion of the bowel. PMC also has been described with lymphoma, leukemias, and advanced HIV infection.4 Key steps in the pathogenesis of C difficile — mediated diarrhea and colitis include the following:
- Disruption of colonic flora by an antibiotic or antineoplastic agent with antibacterial activity
- Colonization with C difficile
- Elaboration of toxin A and toxin B, both of which mediate cytoskeletal derangement in target cells
- Mucosal injury and inflammation3
Although clindamycin and lincomycin classically have been linked to PMC, virtually all antibiotics can cause PMC. Cephalosporins and ampicillin may be the most common antibiotics associated with PMC on the basis of their widespread use.1 Most cases of PMC are associated with oral rather than parenteral administration of antibiotics.1 PMC can begin within days after initiation of antibiotic therapy or can occur up to 6 weeks after discontinuation.
The basic mechanism in pathogenesis of PMC is overgrowth of C difficile and toxin production by the organism that causes a wide spectrum of illnesses ranging from mild diarrhea to life-threatening PMC. The anaerobes that are normally present in the colon control colonization by C difficile; therefore, antibiotics that are most active against anaerobic organisms are more commonly associated with PMC. Toxin-mediated direct endothelial damage is the accepted theory for pathogenesis of PMC. Production of at least 2 types of toxins by the C difficile organism is required for clinical expression. Toxin A is an enterotoxin, while toxin B is a cytotoxin.
Frequency
United States
Antibiotic use is commonly associated with diarrhea without colitis. Overall rates of antibiotic-associated diarrhea in hospitals range from 3.2-29%. As many as 25% of patients develop self-limiting diarrhea following ampicillin or clindamycin administration. Of hospitalized patients, 15% of those receiving beta-lactam antibiotics and approximately 10-25% receiving clindamycin develop diarrhea. Few of these patients actually develop PMC. C difficile is responsible for development of antibiotic-associated diarrhea in 20-30% of patients and in more than 90% of patients who develop antibiotic-associated PMC.3
Mortality/Morbidity
Mortality rates of PMC in various series vary from 1.1-3.5%.4 PMC causes significant morbidity because of its variable and nonspecific clinical manifestations at presentation, potentially difficult endoscopic diagnosis, and delayed results of stool assays. Approximately 5% of patients may present with features suggestive of acute abdomen or sepsis with resultant unwarranted laparotomy.4 Overall morbidity and economic burden of antibiotic-associated diarrhea are difficult to quantify; however, various studies have demonstrated significantly higher death rates and increased hospital costs.3
Age
Definite age-related susceptibility is observed with C difficile, with adults being more susceptible than children. Neonates can harbor the organism and its toxin without apparent consequence. In addition, older children, despite frequent antibiotic use, rarely develop PMC. The exact cause of such age-related susceptibility is not clear. It may be secondary to lack of mature enterocytic membrane receptor for the toxin, preventing binding of the toxin to the bowel wall and subsequent production of PMC.1
Presentation
Infection with toxigenic C difficile causes a spectrum of diseases ranging from the asymptomatic carrier state, particularly in neonates, to a fulminant relapsing and occasionally fatal colitis.3 The typical clinical presentation is diarrhea, abdominal pain, fever, leukocytosis, and an often-overlooked history of recent/concurrent use of antibiotics. Hospital inpatients may be asymptomatic or may only have mild-to-moderate symptoms.4 In severe cases, life-threatening colitis may develop, progressing to toxic megacolon and subsequent perforation.
In rare cases, extraintestinal manifestations occur, including bacteremia, osteomyelitis, and splenic abscess. Other clinical manifestations that have been described are reactive arthritis and tenosynovitis. As with other reactive arthritides following enteric infections, many patients are positive for human leukocyte antigen (HLA)-B27.3 Nonspecific symptomatology of PMC mimics features of acute abdomen, especially sepsis or intra-abdominal infection and abscess.
Most of these patients undergo ultrasound or CT examination without clinical suspicion of PMC.1 Thus, it is important for radiologists to recognize the radiologic features of PMC, since the radiologist is often the first physician to suggest the diagnosis.
Preferred Examination
It is important to note that even though the diagnosis of PMC may be suggested by imaging, it is not the method of choice for establishing the diagnosis. This is done by stool assays for C difficile toxins or colonoscopy.
Limitations of Techniques
Of patients with PMC, 90% or more demonstrate either C difficile or its toxins in stool samples.3 A variety of enzyme-linked immunosorbent assay (ELISA) tests that detect toxin A or B are available. When strict diagnostic criteria that include clinical diarrhea, positive cytotoxin assay, and positive culture are used, a sensitivity of 63-94% and specificity of 75-100% can be achieved.3
Flexible sigmoidoscopy alone without the use of colonoscopy may not detect up to 10% of cases of PMC. When PMC is not accompanied by pseudomembrane formation, endoscopic findings are relatively nonspecific, but a biopsy may reveal changes typical of PMC.3 Colonoscopy characteristically demonstrates 2- to 10-mm adherent yellow plaques; however, colonoscopy may be negative or nonspecific in 25-70% of patients.1
Differential Diagnoses
Appendicitis
Colitis, Ischemic
Colon, Diverticulitis
Crohn Disease
Typhlitis
Ulcerative Colitis
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References
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Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med. Jan 27 1994;330(4):257-62. [Medline].
Thielman NM. Pseudomembranous colitis. In: Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. 5th ed. 2000:1111-1126.
Kawamoto S, Horton KM, Fishman EK. Pseudomembranous colitis: spectrum of imaging findings with clinical and pathologic correlation. Radiographics. Jul-Aug 1999;19(4):887-97. [Medline].
Boland GW, Lee MJ, Cats A, Mueller PR. Pseudomembranous colitis: diagnostic sensitivity of the abdominal plain radiograph. Clin Radiol. Jul 1994;49(7):473-5. [Medline].
Boland GW, Lee MJ, Cats AM, et al. Antibiotic-induced diarrhea: specificity of abdominal CT for the diagnosis of Clostridium difficile disease. Radiology. Apr 1994;191(1):103-6. [Medline].
Downey DB, Wilson SR. Pseudomembranous colitis: sonographic features. Radiology. Jul 1991;180(1):61-4. [Medline].
Brook I. Pseudomembranous colitis in children. J Gastroenterol Hepatol. Feb 2005;20(2):182-6. [Medline].
Jung SW, Jeon SW, Do BH, Kim SG, Ha SS, Cho CM. Clinical aspects of rifampicin-associated pseudomembranous colitis. J Clin Gastroenterol. Jan 2007;41(1):38-40. [Medline].
Ramachandran I, Sinha R, Rodgers P. Pseudomembranous colitis revisited: spectrum of imaging findings. Clin Radiol. Jul 2006;61(7):535-44. [Medline].
Wolf PL, Kasyan A. Images in clinical medicine. Pseudomembranous colitis associated with Clostridium difficile. N Engl J Med. Dec 8 2005;353(23):2491. [Medline].
Further Reading
Keywords
clostridium difficile disease, PMC
