The Patient with Diarrhea

Issue: January 2017

The Case: A 49-year-old woman was diagnosed with Clostridium difficile infection 5 weeks ago and treated with a 14-day course of metronidazole, 500 mg 3 times daily. Although her symptoms resolved, she again developed several watery stools daily 10 days after stopping her initial treatment. She has no fever, abdominal pain, blood or mucus in the stools, and has taken no other medications.

Physical examination reveals her to be afebrile with no other abnormalities.

CBC reveals a leukocyte count of 9800/µL, with normal glucose, renal function, electrolytes, and transaminases.

Stool specimen is negative for ova, parasites, and occult blood. Stool assay is positive for C. difficile toxin.

Key Supporting Information

Intestinal infections with Clostridium difficile, a spore-forming gram-positive anaerobic bacillus, are among the most common and serious health care-related infections in the United States. The number of hospital infections due to C. difficile infections has more than doubled since 2001, increasing from 4.5/1000 in 2001 to 8.2/1000 in 2010. The incidence of C. difficile infection has increased since 2000, with hypervirulent strains, such as restriction enzyme analysis type BI, polymerase chain reaction (PCR) ribotype 027 (NAP1/BI/027 strain), and North American Pulsed Field type 1 (NAP1) being reported. The NAP 1 strain can produce larger quantities of toxins A and B, with low cure rates as well as high recurrence and mortality rates. Widespread use of fluoroquinolone antibiotics may have played a role in the proliferation of the NAP1 hypervirulent strain, which has been associated with the most serious sequelae of C. difficile infection.

Colitis, due to colonization by this organism, arises from a disruption of the normal, colonic bacterial flora with subsequent release of 2 endotoxins: toxin A, an entertoxin, and toxin B, a cytotoxin. Both toxins are high-molecular weight proteins capable of binding to specific intestinal cell mucosal receptors, producing mucosal inflammation and damage. Receptor-bound toxins gain intracellular entry by catalyzing alterations of Rho proteins, small glutamyl transpeptidase-binding proteins, that assist in cell movement, actin polymerization, and cytoskeletal architecture. These toxins are the key to pathogenesis, disrupting the integrity of the epithelial surface of the colonic mucosa, by means of cell–cell tight junctions and microtubules, releasing mediators of inflammation, such as IL-8, resulting in epithelial necrosis, fluid shift-inducing diarrhea, and mucosal infiltrates. Infection with this organism can result in pseuodmembranous colitis, colonic perforations, toxic megacolon, recurrent diarrhea, leukocytosis, and sepsis.

Transmission of the disease is fecal–oral, with C. difficile cells being killed by gastric acid, but the surviving acid-resistant spores are transmitted to the small bowel, where they germinate into the toxin-producing vegetative form.

Various factors are associated with an increased risk for C. difficile induced colitis, including: prolonged use of antibiotics, proton pump inhibitors, chronic renal disease, older age, chemotherapy, prolonged hospitalization, and feeding tubes. Community acquired infections have also been reported, usually in younger females with fewer comorbidities and less likely to have been taking antibiotics.

Symptoms of C. difficile colitis often include fever, nausea, malaise, loss of appetite, abdominal pain, and mild-to-moderate watery diarrhea that is rarely bloody. The symptoms usually occur within the first 7 days of antibiotic therapy, but can originate from the first day to as late as 10 weeks after antibiotic therapy is discontinued. Severity of infection may range from asymptomatic carrier states to fulminant, relapsing, fatal colitis, with recurrent diarrhea. Asymptomatic carriers tend to have high levels of antitoxin A and/or B, while those with recurrent disease have low antibody titers. Ultimately, the virulence of the C. difficile strain and host susceptibility determine outcome infection. Extraintestinal manifestations have also been described, including: osteomyelitis, reactive arthritis, splenic abscesses, and bacteremia. Physical examination may demonstrate lower abdominal and rebound tenderness, as well as clinical signs of dehydration.

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The mucosa of the colon is populated with pseudomembranous, raised, 2 mm to 10 mm plaques that appear yellow on endoscopic examination, easily dislodged initially, but progressing to larger areas that can coalesce to involve the entire colon, but usually more severe in the rectosigmoid area. Endoscopic examination findings may be normal in some patients with mild disease or may demonstrate nonspecific colitis in moderate cases. Abdominal CT scanning is the imaging modality of choice, especially if other complications or intra-abdominal pathology is suspected.

Testing for infection should be considered for those patients who have had at least 3 unformed stools within 24 hours. Because laboratory testing cannot distinguish between asymptomatic colonization and symptomatic infection, diagnostic testing should be utilized only on symptomatic patients. In addition, guidelines from the American College of Gastroenterology recommend testing all patients hospitalized with a flare-up of inflammatory bowel disease. Diagnosis focuses on detecting either the causative organism by glutamate dehydrogenase antigen detection and bacterial culture or the A and B toxins by PCR assay, tissue toxin assay, and enzyme immunoassay.

The C. difficile glutamate dehydrogenase antigen detection test has demonstrated good sensitivity but poor specificity, is fast and widely available, but should not be used exclusively, requiring a follow-up PCR or toxin assay due to its high false positivity. Stool cultures, often used as the gold standard for detection and utilized in clinical trials of performance, require a 3- to 4-day turnaround in most laboratories and can result in false positives due to the presence of nontoxigenic strains. Toxigenic cultures are time intensive, requiring specialized equipment and trained personnel, resulting in diagnostic delays, and impacting treatment decisions and infection control protocols.

Molecular PCR assays for detecting the gene-encoding toxin B have high specificity and sensitivity with a negative predictive value, representing the most preferred of the toxin detection modalities, as recommended by the American College of Gastroenterology. The toxin enzyme immunoassay can detect both toxins A and B, is fast, widely available with specificity up to 99%, but lower sensitivity (approximately 75% to 95%) as well as a high false-negative result in cases with low toxin levels. The tissue cytotoxin assay has a high specificity and sensitivity, but possesses a relatively slow turnaround time.

Key Diagnostic Criteria for Establishing the Diagnosis

Three unformed stools in 24 hours
Positive stool for toxigenic C. difficile or its toxins
Colonoscopic and/or histopathologic evidence of pseudomembranous colitis
Multistep polymerase chain reaction (PCR) for toxin gene(s)
Single-step PCR of liquid stool samples.

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Learning Objectives

Upon successful completion of this educational activity, participants should be better able to assess the diagnosis and management of Clostridium difficile infection.

Overview

Author(s)/Faculty: Ronald A. Codario, MD, FACP, FNLA, RPVI, CCMEP
Source: Healio Infectious Disease Education Lab
Type: Monograph
Articles/Items: 4
Release Date: 2/15/2016
Expiration Date: 2/15/2017
Credit Type: CME
Number of Credits: 0.25
Cost: Free
Provider: Vindico Medical Education

CME Information

Provider Statement: This continuing medical education activity is provided by Vindico Medical Education.
Support Statement: No commercial support for this activity.
Target Audience: This activity is designed for infectious disease specialists and other health care professionals involved in the treatment of patients with infectious diseases.