Clinical and Laboratory Characteristics of Clostridium difficile Infection in Patients with Discordant Diagnostic Test Results

Abstract

The aim of this study was to compare the clinical and laboratory characteristics of Clostridium difficile infection (CDI) in patients with discordant test results for the cytotoxin assay (CYT) and PCR assays. A retrospective study from May to August 2008 and March to May 2010 was performed. CDI was diagnosed in 128 patients. PCR increased the yield of C. difficile cases by 2-fold compared to that of the CYT assay. Fifty-six cases (44%) were detected by PCR only (CYT negative). Forty-nine percent of patients with non-NAP1 strains were detected by PCR only, compared to 28% of those infected with NAP1 strains (P < 0.05). No significant differences were found in the clinical severity of illness and outcome among patients that tested positive for CDI by both tests (CYT and PCR) compared to those that tested positive by PCR only. Clostridium difficile has been implicated in up to 25% of antibiotic-associated diarrhea and nearly all bacterial cases of hospital-acquired diarrhea (6, 10). The spectrum of disease can range from uncomplicated diarrhea to pseudomembranous colitis, toxic megacolon, sepsis with associated organ failure, and even death. North American hospitals began to experience an increased incidence of a particularly virulent strain of C. difficile in the early part of the decade, characterized by recurrent infection and increased mortality, especially in the elderly (3,8,11,14,20).The increase in the incidence of C. difficile infection (CDI) has been attributed in part to the emergence of a predominant strain, known as North American pulsed-field type 1 (NAP1), of ribotype 027 and group BI. The characteristics of the NAP1 strain include fluoroquinolone resistance, production of binary toxin in addition to toxins A and B, and various polymorphisms in the tcdC gene (13). Louie et al. were recently able to demonstrate both an increased severity of illness due to the NAP1 strain and lower incidence of relapse in those treated with fidaxomicin who were infected with non-NAP1 strains, suggesting that knowledge of the infecting strain may have a significant impact on treatment decisions (9). One of the FDA-cleared PCR diagnostic assays for the detection of C. difficile, the Xpert (Cepheid, Sunnyvale, CA), is able to identify NAP1 strains in a timely fashion; although only FDA cleared for infection control purposes, such results may potentially be used to make therapeutic decisions.Toxigenic culture has been considered the gold standard for the diagnosis of C. difficile, and its use is supported by the most recent practice guidelines issued by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) (4). However, toxicogenic culture is time consuming and labor intensive. Alternative enzyme immunoassay (EIA)-based tests are more frequently used for routine diagnostic use, but sensitivities for EIAs have been reported to be as low as 30% (15). PCR-based detection of C. difficile is increasingly being used in many centers. PCR is rapid and highly sensitive but d...

Impact of Changes in Clostridium difficile Testing Practices on Stool Rejection Policies and C. difficile Positivity Rates across Multiple Laboratories in the United States

“…Concerns about detection of colonized patients with NAAT have been raised and emphasize the importance of testing patients with clinically significant diarrhea in order to avoid false-positive tests and unnecessary treatments (16)(17)(18). In our study, the majority (85%) of the laboratories adopted more-stringent stool rejection policies after NAAT implementation.…”

Point-Counterpoint: What Is the Optimal Approach for Detection of Clostridium difficile Infection?

“…Many of these studies also have significant sources of bias, which likely contributed to the authors' conclusions, including clinical reporting or reviewer knowledge of NAAT results and automatic classification of patients with a positive NAAT or culture as having CDI regardless of disease status (11, 15-17, 42, 48). Another common problem is failure to acknowledge that many clinical signs and outcomes seen in patients tested for CDI are common and nonspecific in hospitals and so are not necessarily indicative of, or related to, CDI (e.g., diarrhea, leukocytosis, intensive-care unit care) (11,16,48). Preanalytic issues can also cause negative results.…”

“…Immunocompromised hosts are at increased risk for CDI, and at least some studies suggest comparable clinical severities of CDI in immunocompromised patients with positive toxin assays and those with a positive NAAT only (15,48). However, as I advocate the use of a NAAT to diagnosis CDI in all patients, immunocompromised patients do not require a special testing approach.…”

“…Most of these studies were not adequately designed or powered to detect a statistical difference in rare clinical outcomes, such as CDI-related complications or mortality, and erroneously interpret a nonsignificant P value as evidence that differences do not exist (a type II statistical error) (11,(15)(16)(17)48). Many of these studies also have significant sources of bias, which likely contributed to the authors' conclusions, including clinical reporting or reviewer knowledge of NAAT results and automatic classification of patients with a positive NAAT or culture as having CDI regardless of disease status (11, 15-17, 42, 48).…”

Clostridium difficile PCR Cycle Threshold Predicts Free Toxin

“…These studies indicate that PCR is linked to overdiagnosis of patients colonized with C. difficile, triggering unnecessary antibiotic therapy. However, not all studies support this view (9)(10)(11)(12). Some experts recommend using highly sensitive PCR to avoid missing toxin Ϫ /PCR ϩ CDI cases because EIA toxin is less sensitive compared with cell cytotox-icity neutralization assay (CCNA), which is the gold standard for fecal free toxin but takes several days to perform (3).…”