How to solve your C. Difficile diagnosis challenges

It's among the most challenging problems in modern healthcare: Clostridium difficile (C. difficile, C. diff), the spore-forming bacterium, infects thousands of patients in hospitals every year. According to a study by the New England Journal of Medicine,¹ toward the end of the last century the incidence of C. difficile infection (CDI) in hospitals in the United States “remained stable" at less than 40 cases per 100,000 patients. By 2001, however, these numbers started to climb, and by 2005 the infection rate had more than doubled.

In 2011, according to the U.S. Centers for Disease Control and Prevention (CDC), nearly 500,000 patients were infected with the diarrhea-causing bacterium, including 29,000 who died within 30 days of their C. diff diagnosis.² “C. difficile has become the most common microbial cause of healthcare-associated infections in U.S. hospitals," the agency announced when it released its study in 2015. Estimates today peg the cost of C. difficile infection (CDI) at somewhere in the neighborhood of $5 billion annually.³

Below, find background on this perennial health hazard and an overview of the tools microbiologists can use to fight it.

Given how often C. diff  is found in U.S. hospitals, it may help to understand how this bacterium causes disease. Most strains of C. diff produce two toxins: TcdA (toxin A), an enterotoxin that attracts neutrophils and stimulates their release of cytokines; and TcdB (toxin B), a cytotoxin that increases permeability of the intestinal wall. While both toxins are inflammatory, toxin B is the one that causes diarrhea and is therefore the focus of CDI tests. The emergence, in 2000, of an epidemic C. difficile strain (BI/NAP1/027) that includes a binary toxin in addition to toxins A and B has been blamed for much of the uptick in CDI rates and severity between 2000 and 2011.

Because C. diff is shed in human feces, any contaminated surface (food, hands, countertops, etc.) within a hospital can potentially harbor its spores. Most people are able to fight off infection even if they come into contact with C. diff, but certain patients with ware more susceptible to its effects. Among the major risk factors for CDI, according to the CDC, are antibiotic exposure, long length of stay in a healthcare setting, and a weakened immune system. Those patients most likely to have CDI, the agency notes, are “older adults, who take antibiotics and also get medical care." Symptoms of CDI, which tend to cause complications like colitis and dehydration far more often than a fatality, include watery diarrhea, fever, and abdominal pain.³

While the stats surrounding C. diff can be severe, it's the trouble clinicians have diagnosing CDI that really alarms healthcare executives. The issue, as one recent study in the Journal of Clinical Microbiology (JCM) points out,⁴ involves the high prevalence of C. diff colonization. Anywhere from 4.4% to 21% of patients in U.S. hospitals are asymptomatically colonized with toxigenic C. diff, the researchers note. This can lead to over-diagnosis of CDI if hospitals test for C. diff in patients who don't have “clinically significant diarrhea" (having diarrhea three or more times over 24 hours, without the use of laxitives).

Furthermore, testing itself can be problematic, depending on the method a facility decides to use. For healthcare organizations focused on value-based purchasing and the impact—through safety ratings—their CDI rates may have on reimbursement, the inability to identify positive cases of CDI efficiently and effectively may have real repercussions for the bottom line.

So how should institutions go about the work of differentiating CDI from C. difficile colonization? First of all, because of the potential for false-positive results, testing for C. diff is only recommended when patients have frequent diarrhea or watery stools. From there, the various tests clinicians have at their disposal include toxin targeted toxigenic stool cultures, cytotoxicity assays, and enzyme immunoassays (EIA) and combination GDH and Toxin immunoassays. They also include approaches like real-time polymerase chain reaction (PCR) that employ nucleic acid amplification technology. The gold standard tests for CDI diagnosis are Culture and Cell Culture Cytotoxicity Neutralization Assay (CCNA), however due to their need for highly trained staff and long turn around times, these tests are no longer used in regular clinical practice.

Here's a look at the most commonly used diagnostic tests—and the possible benefits and drawbacks associated with each:

Toxigenic stool cultures: Stool culture has long been considered a “gold standard" for CDI diagnosis, but it can also lead to false-positive results in the event of C. difficile colonization. In addition, stool cultures tend to be labor intensive and time-consuming, and so are relatively more expensive than other testing methods.

Cytotoxicity assays (CYTAs): CYTAs detect toxin B only, and are therefore capable of distinguishing CDI from mere C. difficile colonization. Like toxigenic stool cultures, however, CYTAs are expensive and difficult to perform, and require multiple days to get results.

Enzyme immunoassays (EIAs): EIAs can detect both C. diff toxins, and can do so rapidly and relatively inexpensively. The problem with EIAs is their relative lack of sensitivity, which can lead to false-negative results. Due to this, labs that used this technology were typically doing testing from three separate patient samples before being confident that negative results were truly negative.

NAATs and GDH/EIA/PCR algorithms: The American College of Gastroenterology (ACG), in its 2013 “Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile infections,"⁵ offers three initial recommendations around laboratory testing for the bacterium: First, the ACG notes, echoing other authorities on the matter, it's important to only test the stools of patients with diarrhea. Beyond that, two different testing procedures are equally appropriate: A) nucleic acid amplification tests (NAATs); or B) glutamate dehydrogenase (GDH) screening tests used in two- or three-step algorithms with subsequent EIA testing for toxins A and B. In the latter case, GDH-positive samples “must undergo additional testing for C. difficile either by NAAT or by EIA testing followed by NAAT if the EIA results are discordant," the guidelines recommend.

In its discussion around NAATs, the ACG guidelines note that “evidence suggests" they are “good stand-alone tests for toxigenic C. diff." Indeed, research shows that real-time PCR permits direct toxin gene detection from fecal samples; is relatively rapid and easy to implement; simplifies reporting, because it's a single test without algorithms; and has both high analytical sensitivity and specificity and high clinical sensitivity. The only real drawback associated with NAATs occurs when labs test samples from patients who don't exhibit clinically significant diarrhea. “Because [NAATs] do not distinguish [CDI] as asymptomatic C. diff carriage, the diagnostic value of NAATs is limited when used in patients with low probability of CDI," explains Larry Kociolek, MD, MSCI, in a 2017 JCM article.⁶ In the updated "Clinical Practice Guidelines for C. diff Infection in Adults and Children" published in 2018, use of a NAAT alone or a multi-step algorithm approach is recommended when there are preagreed institutional criteria for patient stool submission.⁷

There are other complications surrounding C. diff testing aside from the problem of colonized patients. For one, note Christopher Polage and Mark Wilcox in a recent “Point-Counterpoint" article in JCM,⁸ there is “no reliable clinical or laboratory definition for CDI that accurately distinguishes true CDI from non-CDI-related symptoms in all patients." And then there's the issue of physicians requesting C. diff tests hoping the results will provide a level of clarity. They may fully understand that a lack of diarrhea is a sign that CDI is highly unlikely, but they also may want a way to further rule it out to help minimize the chance they'll miss a positive case.

The question for microbiologists, then, is this: What can you do if you work in an organization where CDI is a concern? Is there anything that can be done to help drive down CDI rates without the risk of over-diagnosing? The answer, if you follow the example of at least one institution—Toledo Mercy Health-St. Anne Hospital in Ohio—is a resounding “yes."

In an article for the CDC's “Safe Healthcare Blog,"⁹ Lisa Beauch, BSN, RN, CAPA, CPAN, CIC, the Regional Infection Prevention Manager at Mercy Health-St. Anne, explains how her team used a “multi-component strategy" to reduce their CDI rates to zero. CDI is “a complex and evolving battle," Beauch writes. “But it's a battle that can be won."

Beauch explains that prior to launching their CDI initiative, the 100-bed hospital's infection rate was 40% higher than would have been predicted for a facility of its type and size. Hoping to bring that number down, Beauch and her colleagues began by having each unit in the hospital share daily reports on CDI-related data, including information about confirmed and suspected cases. Next, they started tracking the locations of CDI cases and determined that nearly all originated in the intensive care unit. Knowing that, Beauch says, she and her team changed their approach to cleaning in the ICU, scrubbing down surfaces with bleach, for example, and using UV light to ensure thorough disinfection. And then they dove into staff education: Personnel were taught about “appropriate testing, the accuracy of PCR testing, and proper specimen collection," Beauch writes. “We then implemented policies to assess for diarrhea and C. diff risk factors at the time of admission." If a patient reported having diarrhea prior to their admission, and also had another risk factor like recent antibiotic use, he or she would be isolated and a stool test would be administered. “Isolation was discontinued only if C. diff was not detected by PCR, or if the patient did not have watery stool in a 24-hour period," Beauch notes.

Beauch's team led the charge for other changes to hospital policy, as well: A new antimicrobial stewardship program (ASP) was implemented to encourage the appropriate use of antibiotics, for example, and written reminders about policies around the use of protective gowns and gloves were placed outside of rooms of patients with CDI. In 2016, Beauch reports, her facility brought down its CDI cases to 55% less than was predicted, and in 2017 they did even better: As of last November, when she wrote her article, Mercy Health-St. Anne hadn't seen a single case of CDI.

The good news for providers and patients alike is that the most recent national data from the CDC shows an 8% decrease in CDI between 2011 and 2014.¹⁰ And facilities like Mercy Health-St. Anne, which Beauch estimates has avoided $150,000 in costs through its CDI-reduction program thus far, have shown that infection rates can be cut even more.

The take-home message for anyone with a role in the ongoing fight against C. difficile? If you take a holistic approach to combatting C. diff—combining clinician education, departmental collaboration, and sensitive and accurate testing with PCR—there's a very good chance you're going to win.