Elsevier

Disease-a-Month

Volume 61, Issue 5, May 2015, Pages 181-206
Disease-a-Month

Pseudomembranous colitis

https://doi.org/10.1016/j.disamonth.2015.01.006Get rights and content

Introduction

Pseudomembranous colitis (PMC) is a manifestation of severe colonic disease that is usually associated with Clostridium difficile infection, but can be caused by a number of different etiologies. Prior to the use of broad-spectrum antibiotics, PMC was more frequently related with ischemic disease, obstruction, sepsis, uremia, and heavy metal poisoning.1 The list of associated etiologies is vast, although Clostridium difficile infection (CDI) is still the most common cause.

On endoscopic examination, PMC is characterized by elevated yellow–white nodules or plaques that form pseudomembranes on the mucosal surfaces of the colon (Fig.).2, 3 Endothelial damage from the initial event or disease process causes small areas of necrosis in the surface epithelium. The eruption of neutrophils, nuclear debris, and other inflammatory elements from the lamina propria onto the epithelium then leads to pseudomembrane formation.4, 5 Pseudomembranes can be up to two centimeters in diameter, scattered among areas of normal or erythematous mucosa; however, confluent pseudomembranes that cover the entirety of the mucosa can be seen in severe disease.4, 6

Classification of pseudomembranous lesions can be made based on the degree and depth of inflammatory changes, with grading of lesions from type 1 (“summit lesions,” focal surface epithelial inflammation, or necrosis) to type 3 (complete mucosal necrosis and significant inflammatory debris).1, 6, 7 Histologic examination of biopsy samples vary based on the underlying cause, disease severity, and time course of the disease, which can make identification of the inciting trigger challenging.

This article will review the many diverse etiologies of PMC (Table). Although CDI is the most common cause, other less common etiologies of PMC will be described. These include ischemic colitis, collagenous colitis, inflammatory bowel disease, viral infection with cytomegalovirus (CMV), numerous bacterial and parasitic organisms, and multiple drugs and toxins. The purpose of this comprehensive review is to aid the general practitioner in the diagnosis of both typical (C. difficle) and atypical (non-C. difficile) causes of PMC.

Clostridium difficile was first described in 1935, but its association with antibiotics and PMC was not described until the 1970s, corresponding with an increased use of broad-spectrum antibiotics.7 C. difficile is an obligate anaerobic organism and toxin-producing gram-positive rod with the ability to form spores.8 This latter characteristic lends itself to acquisition from the environment, particularly in nosocomial settings. It has been identified as the causative agent in 15–30% of antibiotic-associated diarrhea and as the primary cause of antibiotic-associated colitis.9

The clinical presentation of CDI is highly variable, ranging from the asymptomatic carrier to the patient with PMC, fulminant colitis, and toxic megacolon.5, 10, 11 Accompanying signs and symptoms include fever, leukocytosis, abdominal cramping, and non-specific radiographic findings of colitis or megacolon. Severe cases can present with profound leukocytosis (with reports of white blood cell counts up to 100,000 per mm3), hypovolemia, hypotension, hypoalbuminemia/protein-losing enteropathy, renal dysfunction, and reactive arthritis.3, 9, 10, 11, 12 It is estimated that 3–8% of patients with CDI develop fulminant infection, which includes severe ileus, toxic megacolon, colonic perforation with subsequent peritonitis, and septic shock; many of these patients require colectomy and have an overall high mortality.13

The pathophysiology of CDI has been studied extensively and appears to progress in a particular sequence. The common first step is the disruption of the normal colonic flora with subsequent C. difficile colonization. This is usually precipitated by the use of antibiotics, but can also follow the use of chemotherapeutic drugs and immunosuppressive therapy.5, 14

Antibiotics, such as clindamycin, penicillins, fluoroquinolones, and cephalosporins, are typically associated with CDI, but disease can occur with almost any anti-bacterial agent, including vancomycin and metronidazole, which are commonly used for treatment.5, 7 Furthermore, fluoroquinolones have been linked with the highly resistant and virulent North American pulsed-field gel electrophoresis type 1, restriction endonuclease analysis group BI, polymerase chain reaction (PCR) ribotype 027 (NAP1/BI/027) strain of C. difficile, responsible for a number of highly morbid, nosocomial outbreaks in North America and Europe.15, 16 Various studies have estimated the median time from C. difficile exposure to CDI to be 2–3 days, although symptoms can be delayed by up to 3 months and can occur even after a single dose of an antimicrobial or chemotherapeutic agent.9, 14 Proton pump inhibitors have also been shown to increase the risk of acquiring CDI, although the relationship remains unclear.17

Following initial colonization, clinically significant infection is mediated by toxin production. Most disease-causing strains produce two large protein exotoxins, toxins A and B.5, 15 Once released in the colon, the toxins bind to cell surface receptors and are internalized within the targeted cells.5 Inside the cell, they cause glycosylation of small proteins involved in cell signaling and regulating pathways. This, in turn, leads to cytoskeleton disruption, causing cell morphologic changes, cytokine activation, and eventual cell death.8, 10, 15, 18 In addition, tight junctions between neighboring colonic cells are affected, allowing infiltration by neutrophils and causing an inflammatory response characteristic of colitis.8 Pseudomembranes form via this influx of neutrophils into the mucosa and further activation of the native immune system by the toxins. Activation of macrophages and monocytes causes the release of pro-inflammatory cytokines like interleukin (IL)-1, IL-8, tumor necrosis factor (TNF), and leukotriene B4, which lead to additional mucosal injury and focal microabscess and pseudomembrane formation.19

Toxin A was widely believed to be the main causative agent of CDI, as it possesses both enterotoxic and cytotoxic properties. Nonetheless, more recent studies have reported disease associated with toxin A-negative, toxin B-positive strains.5, 8 An in vitro disease study in 2009 using hamster models demonstrated that toxin B, not toxin A, was the essential virulence factor in CDI.20 This was later refuted in another hamster model study published in 2010, where mutant strains of C. difficile producing either toxin A or B were found to be just as likely as wild-type strains to cause significant disease. In addition, double-mutant strains producing neither toxin were found to be avirulent.21 Given the variability of published findings, it is prudent to focus on diagnostic testing that can identify the presence of both toxins.

Endoscopy is not routinely recommended in patients with typical CDI symptoms and positive laboratory testing due to its inherent risks and cost. However, it can be valuable in patients with consistent symptoms and negative testing, failure of conventional CDI therapy, or inability to obtain stool samples due to ileus.3 Endoscopy should be avoided when fulminant colitis or toxic megacolon is suspected, given the procedural risk of perforation and subsequent peritonitis.2

Endoscopic findings in the colon vary in CDI, although PMC appears to be the most commonly described finding. Pseudomembranes can develop very early in the course of CDI with only mild symptoms. A small single-center prospective study published in 1985 identified 149 C. difficile-positive patients very early in the course of symptomatic disease. Of the endoscopic examinations performed in 96 of these patients, 39 patients (41%) had PMC.22 Several patients only underwent flexible sigmoidoscopy, which may have underestimated the true incidence of PMC, since up to one-third of patients have disease limited to the right colon.23 As a result, colonoscopy is preferred when endoscopy is needed for diagnosis.

In mild cases of CDI, only signs of non-specific colitis may be seen, including erythematous, inflamed, or friable mucosa. Pseudomembranes may be absent or too small for visualization by endoscopy. In such cases, where clinical suspicion for CDI is high, biopsy is indicated to seek characteristic histologic findings of PMC.3, 24 Focal pseudomembranes can also coalesce to involve large areas of mucosa as the disease progresses, although the interposing mucosa will usually appear normal or only mildly erythematous or inflamed.7

Radiographic studies can also be advantageous in the diagnosis of CDI, given the wide spectrum of findings and choice of radiologic tests. Plain radiography of the abdomen may show evidence of colonic ileus, small bowel ileus, ascites, nodular thickening, or “thumbprinting,” a finding of wide-transverse bands associated with haustral thickening. Severe disease may be demonstrated by marked colonic dilatation, perforation, or pneumoperitoneum.2, 7 Computed tomography (CT) is more commonly used given the lower sensitivity of plain radiography. CT findings in CDI include colonic wall thickening and nodularity, bowel wall stranding and edema, ascites, the “accordion” sign (ingested oral contrast becomes trapped between thickened haustral folds), and the “double-halo” sign (submucosal edema indicated by two or three concentric rings in the large bowel seen on transverse imaging).2, 7, 23, 25 A single-center retrospective review comparing the CT scans of 54 C. difficile-positive and 56 C. difficile-negative patients, all with symptoms, found that CT imaging alone had a sensitivity of 52–70% and specificity of 93% in diagnosing C. difficile colitis. Sensitivity varied based on the criteria used for diagnosis and generally favored the combination of both colonic wall thickening and another sign. Of particular note was a positive predictive value of 88%, meaning that those with positive diagnostic criteria by CT had an 88% chance of testing positive on a stool assay. This raises the possibility of CT imaging being used for rapid diagnosis in those awaiting the results of stool assay testing.25

Initial testing in patients with non-specific gastrointestinal (GI) and/or infectious symptoms often includes a complete blood count (CBC). As previously discussed, leukocytosis is a prominent feature of CDI. A retrospective study of 70 hospitalized patients found a significant difference in the white blood cell (WBC) counts of C. difficile-positive and C. difficile-negative patients (15,800 per mm3 vs. 7700 per mm3), demonstrating the utility of a frequently obtained lab marker in initial suspicion and subsequent diagnosis of CDI.26, 27

Specific laboratory testing for CDI has evolved greatly since it was first discovered as the main causative agent in PMC. In general, only stools from patients with diarrhea should be tested for C. difficile; one caveat to this recommendation is that when CDI is suspected in a patient with ileus, either solid stool or rectal swabs can be submitted for testing.28 The C. difficile cytotoxin neutralization assay (CCNA) and toxigenic culture (TC) have both been called gold standard tests, although TC has been shown to detect one-third more cases of CDI when compared to CCNA. CCNA detects the cytopathic effect of toxin B on cells (cell rounding) and then neutralization of the effect with antitoxin. TC involves standard stool culture for C. difficile (this will identify both toxigenic and non-toxigenic strains), followed a confirmatory test to detect the presence of toxin genes or actual toxin proteins.27 Recently, both methods have been abandoned in standard clinical practice because results are often not available for several days.13, 27 Nonetheless, because of their high sensitivities and specificities, they are still used in epidemiologic studies and in trials comparing the efficacy of newer testing methods.28

For many years, the most frequently used diagnostic tests were enzyme immunoassays (EIA) for toxins A and/or B; however, more recent evidence has questioned the utility of EIA in single-step testing algorithms. One prospective study in 1993 compared gold standard testing (cytotoxin assay and toxigenic culture) to three different commercially available EIA (one detected toxins A and B, and two detected monoclonal antibodies directed against toxin A) using 285 stool samples from patients with suspected CDI. The results showed excellent sensitivity and specificity for cytotoxin assay and toxigenic culture, but poor sensitivity (75.5% for EIA detecting toxin A and B and 65.4% for EIA only detecting toxin A) and excellent specificity (97.8–100%) for all three EIA.29 As previously discussed, toxin A-only EIA is more likely to have a false-negative result given the existence of toxin A-negative, toxin B-positive disease-producing strains; consequently, the most commercial available EIA can now detect both toxins.28, 30 A systematic review of rapid toxin detection kits for both toxins A and B, including EIA and similar testing modalities, reported overall sensitivities and specificities as 75–95% and 83–98%, respectively, when compared to CCNA.30 Given these results, efforts have been made to standardize two- or three-step diagnostic algorithms or further the use of more accurate one-step tests.

Newer advances in the diagnosis of CDI include nucleic acid amplification tests (NAAT), such as polymerase chain reaction (PCR), and stool testing for glutamate dehydrogenase (GDH). NAAT appears to be much more sensitive than EIA (>90% vs. 40–80%) with high specificity, when compared against gold standard.27 NAAT also appears to have a generally high negative predictive value, further supporting its use as a single-step test.11, 28 In addition, NAAT results are readily available when compared to TC or CCNA. However, as with most molecular testing, NAAT detects genes associated with toxin production rather than the presence of actual toxin in the stool. Given the number of colonized, asymptomatic patients, especially in the nosocomial and long-term care settings, there is potential for false-positive results.11, 27 Finally, NAAT is expensive and there is only limited data to suggest that rapid diagnosis of CDI by an accurate test is more cost-effective in the long term.27, 31

GDH is an enzyme produced by C. difficile, both in toxigenic and non-toxigenic strains. Thus, testing for GDH is sensitive, but not specific for CDI, with the potential for high false-positive rates but very high negative predictive value. This has made it a useful screening test in multiple-step testing sequences.9, 11, 28, 32 Examples include EIA for GDH, followed by EIA for toxins A and B, CCNA, or NAAT; such approaches can have sensitivities of 75–100% and very high specificities, with rapid time to results.9, 23, 27, 31 Further evaluation of these approaches, including head-to-head testing and cost-benefit analyses, will determine which, if any of these methods, will become the new gold standard in diagnosis.

Finally, numerous clinical practice guidelines have recommended against repeat testing during the same episode of illness after a negative result. Repeat testing after a negative result is positive in less than 5% of samples and greatly increases the chances of false-positive results.9, 28 In addition, testing for cure after symptom resolution and treatment completion is not advised; stool can remain positive for both toxins and bacteria as long as 30 days after symptoms resolve.9, 11, 28, 32 Positive results during that period may lead to unnecessary CDI treatment and related complications.

Once diagnosis of CDI is confirmed, it is important to immediately identify responsible antibiotic or chemotherapy agents and discontinue these drugs as soon as possible. The next step is to individualize the agent of choice for each case. Fidaxomicin and oral vancomycin are the only agents approved by the U.S. Food and Drug Administration (FDA) for treatment of CDI, although metronidazole has been used as a first-line agent since the late 1970s–1980s.9, 32 Numerous studies have demonstrated equal or near-equal efficacy of vancomycin and metronidazole when treating initial and/or mild-to-moderate episodes of CDI.13

To choose the correct treatment, it is important to classify the severity of disease. Mild-to-moderate disease is typically defined as CDI with diarrhea and other symptoms not consistent with severe illness; recommended treatment is oral metronidazole for 10–14 days or oral vancomycin for 10–14 days if the patient cannot tolerate or does not improve significantly while on metronidazole.9, 11, 28, 32 Important adverse reactions of metronidazole therapy include nausea, vomiting, taste disturbances, and dose-dependent neurotoxicity.9 Of note, fidaxomicin, a macrolide antibiotic, was approved for the treatment of mild-moderate CDI in 2011. Two separately conducted phase III, randomized, double-blinded trials demonstrated non-inferiority when compared to oral vancomycin; further analysis proposed that fidaxomicin might be superior in preventing recurrences in non-NAP1/BI/027 strains, although the small number of trials and short duration of follow-up limit additional conclusions. Moreover, fidaxomicin is much more expensive than vancomycin, and it is unclear if its proposed benefits outweigh the cost.28, 33, 34, 35

Proposed criteria for severe disease include WBC count greater than 15,000 per mm3, elevated creatinine (greater than 1.5 times baseline), advanced age, and/or hypoalbuminemia (serum albumin less than 3.0 g/dL). Recommended treatment for severe disease is oral vancomycin (125 mg four times daily) for 10–14 days.9, 11, 15, 24, 28 A prospective, randomized, double-blinded, placebo-controlled trial published in 2007 compared the efficacy of metronidazole and vancomycin in mild and severe CDI in 150 patients. There was no significant difference in treatment with metronidazole and vancomycin in mild disease; however, vancomycin was found to be superior in achieving cure for severe disease.36

Criteria used to define severe and complicated CDI have varied and have included admission to an intensive care unit, hypotension that may or may not require vasopressors, fever greater than 38.5°C, ileus, megacolon, altered mental status, severe leukocytosis (WBC count greater than 35,000 per mm3) or leukopenia (WBC count less than 2000per mm3), elevated serum lactate, and/or end-organ damage. Recommended treatment is oral vancomycin (500 mg four times daily) in conjunction with intravenous metronidazole and rectal vancomycin enemas in cases of severe ileus.9, 11, 24, 28

In fulminant, CDI refractory to medical therapy or with complications (toxic megacolon, perforation with peritonitis, or septic shock), surgical intervention, including hemicolectomy or subtotal colectomy, may be necessary. Several retrospective cohort studies have found a survival benefit with early surgical intervention, particularly in patients undergoing total colectomy; nevertheless, overall morbidity and mortality in fulminant CDI is very high despite surgery, with mortality rates up to 80% reported.9, 28, 37, 38, 39, 40 In one retrospective observational cohort study of 165 patients with complicated or fulminant CDI, colectomy appeared more beneficial in patients meeting certain criteria, including age greater than 65 years, leukocytosis (WBC count greater than 20,000 per mm3), serum lactate level between 2.2 and 4.9 mmol/L, and immunocompetence. Independent predictive factors of 30-day mortality included severe leukocytosis (WBC count greater than 50,000 per mm3), serum lactate levels equal to or greater than 5 mmol/L, age equal to or greater than 75 years, immunosuppressed state, or septic shock requiring vasopressor support.38 Early surgical consultation is advised in these settings.

Recurrent CDI is defined by the complete resolution of presenting symptoms on appropriate therapy, with subsequent relapse and return of symptoms after completion of treatment; this may be very difficult to distinguish from re-infection. Reported recurrence rates in small studies and review articles range from 5% to 66%, although 20–25% is often cited as an average rate.9, 17, 41, 42 Risk factors for recurrent disease include advanced age, female gender, additional courses of antibiotics and/or chemotherapy, the use of GI medications or procedures, prolonged hospital stays, and prior episodes of recurrent CDI. In patients with a history of one recurrence, the rate of additional recurrences increases to 40–65%.13, 17, 41, 42

The first episode of recurrent CDI is typically treated with the same agent that was used initially, either with oral metronidazole or oral vancomycin. Exceptions to this recommendation are markers of increasing disease severity, including leukocytosis (WBC count greater than 15,000per mm3), rising serum creatinine or baseline renal insufficiency, or other signs of systemic illness. In this setting, treatment with oral vancomycin (500 mg/day) is recommended.9, 13, 28, 43 A subset analysis of one of two phase III clinical trials evaluating the use of fidaxomicin in treatment of CDI found that fidaxomicin was an effective therapy for recurrent CDI when compared to standard of care, oral vancomycin (500 mg/day) for 10 days. In addition, fidaxomicin was associated with a lower rate of further recurrence within 28 days of treatment completion when compared to oral vancomycin.44 One proposed mechanism for this finding is the improved preservation of normal colonic flora in those treated with fidaxomicin, thereby preventing relapse from residual C. difficile spores (within 14 days of treatment completion). Recurrences secondary to suspected re-infection (after 14 days from time of therapy completion) did not appear to vary significantly.44 As previously discussed, the high cost of fidaxomicin limits its widespread use in initial disease, although it should be considered in recurrent CDI.

For patients with a second recurrence of CDI, there are limited data for the optimal treatment regimen. Metronidazole should not be used after the first recurrent episode, given the risk for cumulative neurotoxicity with repeated therapy.9, 28 A case cohort study from the placebo arm of two trials evaluating the use of a probiotic in conjunction with standard treatment for CDI, found a significant reduction in further episodes of recurrent CDI with the use of tapered and pulsed-dose regimens of oral vancomycin. Recurrence rates in patients receiving oral vancomycin for 10–14 days, tapered regimens, or pulsed-dose regimens were 54%, 31%, and 14%, respectively.41 Consensus guidelines suggest a combined tapered/pulsed-dose regimen of vancomycin 125 mg four times a day for 10–14 days, 125 mg two times a day for 7 days, 125 mg once a day for 7 days, and 125 mg once every 2–3 days for 2–8 weeks.9 There are minimal data for the use of rifampin or rifaximin to treat recurrent CDI, further limited by evidence of increasing resistance to rifampin in certain strains of C. difficile.9, 28

In a patient with three or more recurrences despite treatment with a tapered/pulsed-dose oral vancomycin regimen, fecal microbiota transplant (FMT) should be considered.9, 28 FMT is the delivery of a liquid suspension of donor stool from a healthy individual to an infected recipient with the goal of restoring normal gut flora and clinical cure of recurrent CDI. Techniques for FMT delivery vary, with success described using retention enemas, colonoscopy, and nasogastric tube.45 Two systematic reviews, published in 2011 and 2013, reported resolution rates after FMT of 89–92%, with the 2013 review reporting a non-significant difference favoring lower rather than upper GI delivery of stool.46, 47 A small, open-label, randomized, controlled trial of 43 patients, published in 2013, compared rates of resolution in recurrent CDI with three different treatment modalities—oral vancomycin (2 g/day) for 4 days followed by bowel lavage and FMT, oral vancomycin alone (2 g/day) for 14 days, and oral vancomycin (2 g/day) for 14 days with bowel lavage on day 4 or 5. The study was terminated early when results showed a cure rate of 81% in the donor feces infusion group after one infusion (94% overall after a second infusion in two patients achieved cure), compared to 31% in those receiving oral vancomycin alone and 23% of patients receiving oral vancomycin and bowel lavage. The significant difference between the groups may be explained by failure of oral vancomycin (in standard, tapered, and pulses-dose regimens) in many of these patients prior to study inclusion or by the dramatic success of FMT.48 A multi-center long-term follow-up study of 77 patients at five different U.S. medical centers found an overall cure rate of 91% within 90 days after FMT. Of the seven patients who failed FMT, six achieved symptom resolution with repeat FMT or oral vancomycin therapy, with a secondary cure rate of 98%.49 FMT remains a viable option in patients with multiple relapses of CDI, although further studies are required to establish a more uniform protocol to optimize delivery method, amount of stool used, method and materials used in preparation, and time to repeat FMT.

Section snippets

Ischemic colitis

Previously recognized as gangrene, ischemic colitis (IC) was first described as reversible vascular occlusion of the colon in 1963.50 IC encompasses a wide and heterogeneous spectrum of disease that includes mild and reversible colopathy, acute colitis (including PMC), chronic colitis, chronic disease with stricture, gangrenous bowel, and fulminant pancolitis.51, 52, 53 It is the most common form of GI ischemic disease, comprising 50–60% of reported episodes, and is also a common cause of lower

Inflammatory bowel disease

PMC has been reported in patients with Crohn’s disease and ulcerative colitis. Pseudomembranes can be seen in patients with inflammatory bowel disease (IBD) during a flare that may be related or unrelated to coexistent infections like CDI or CMV.76, 77, 78 A study included patients with IBD and CDI who underwent lower endoscopy. A total of 93 patients were identified. PMC was documented in 13% of the patients. The only factor associated with presence of pseudomembranes was fever at the time of

Microscopic colitis (collagenous and lymphocytic colitis)

Collagenous colitis (CC) was first described in 1976 in a middle-aged woman with abdominal cramping and chronic watery diarrhea.80 It is a chronic inflammatory condition of the colon that falls under the larger category of microscopic colitis (MC). MC, initially described in 1980, is characterized by the presence of grossly normal-appearing mucosa with abnormal biopsy findings of lymphocytic inflammatory infiltrate within the lamina propria.81 Now expanded to include CC, it is differentiated

Behcet’s disease

Behcet’s disease is a systemic vasculitis that can involve small, medium, and large vessels. It is characterized by the presence of mucocutaneous apthous ulcers and ocular inflammation. It can affect any organ including the central nervous system.94 Clinical presentation includes fever, malaise, painful chronic or recurrent oral, and urogenital ulcers, a great variety of cutaneous lesions (acneiform, papules, pustular, nodules, erythema nodosum, and palpable purpura), ocular involvement

Drugs and toxins

Medications, drugs, and chemicals can cause PMC by localized ischemia and/or inflammation. Examples include alosetron, a selective serotonin antagonist used in the treatment of irritable bowel syndrome (IBS), cocaine, dextroamphetamine, gold, and glutaraldehyde, a disinfecting solution used to clean endoscopes.4, 66, 98, 99, 100, 101 An isolated case report of paraquat (herbicide) toxicity causing PMC was published in 1981, but it is unclear what testing was pursued to make the diagnosis. It

Cytomegalovirus colitis

CMV is a common human herpes viral pathogen, in which clinical disease can affect nearly all organ systems. Initial infection in healthy individuals is usually asymptomatic or mild, after which CMV typically enters a latency phase.112 Clinically significant infection is often secondary to reactivation of latent disease. It is most frequently reported in immunocompromised patients, but illness due to reactivation or primary infection can also occur in otherwise immunocompetent individuals.113

CMV

Clostridium ramosum

Clostridium ramosum is a frequent enteric anaerobe that is usually a commensal organism in the GI tract but occasionally can be a pathogen. It is commonly isolated from stool samples of children but has been associated with infections in different systems and bacteremia.127 There are reports of C. ramosum causing cerebellar abscess, acute otitis media, lung abscess, spondylodiscitis, and gas gangrene. The associated risks factors include immunosuppression and extremes of age, although it has

Entamoeba histolytica

Entamoeba histolytica is an anaerobic parasitic protozoan that can be found worldwide but is endemic to a number of developing nations. E. histolytica has a relatively simple life cycle within the human host, existing as either infectious cysts or trophozoites, which form after cysts are ingested and have reached the terminal ileum or colon.165, 166 The spectrum of disease includes asymptomatic infection with or without eventual clearance, mild diarrhea, amebic colitis with occult-blood

Conclusion

PMC is an inflammatory condition of the colon that is most often a manifestation of CDI. If confirmed endoscopically and testing for CDI is negative, other less common etiologies should be entertained in order to identify the culprit. Ischemic colitis, inflammatory bowel disease, microscopic colitis, medications, chemicals, vasculitis, and multiple infectious pathogens can be responsible for non-C. difficile PMC. Repeat testing is not recommended when initial CDI testing is negative.

Acknowledgments

We thank Dr. Jean-Pierre Raufman (Professor of Medicine and Division Head, Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine) for additionally editing and reviewing our manuscript.

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    Financial support: Nathalie H. Urrunaga, MD, MS was supported by Grant no. 5 T32 DK067872-07 from the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Disease (NIDDK). This document was also supported by the Intramural Research Program of the NIDDK at NIH.

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