The clinical, financial & emotional benefits of molecular C. difficile testing

A single Clostridium difficile infection presents an array of challenges for hospitals. A December 2015 study in the American Journal of Infection Control found C. difficile infections can increase hospital costs by 40 percent per case, averaging $7,285 in additional costs. What's more, study authors report hospitalizations due to C. difficile increased by more than 200 percent from 2000 to 2009.

This content is sponsored by Roche Diagnostics

The study also outlines clinical consequences of C. difficile, including an 8.4 percent higher chance of readmission within 30 days, a 55 percent longer hospital stay and a 2.2 percent greater risk of mortality than patients without the infection.

These findings show that efficient detection and proper diagnosis of a C. difficile infection is critical to patients' safety and hospitals' financial stability. Hospital laboratories are increasingly turning to molecular testing to achieve best diagnoses and outcomes.

Ensuring appropriate sample testing
Accurate diagnosis of C. difficile begins with appropriate sample testing. Sending inappropriate samples to the lab can drain resources — time, capital and otherwise — and also result in misdiagnoses. For example, while unformed stools are certainly an indicator of a potential infection, that symptom alone isn't enough to warrant testing a stool sample for C. difficile; loose stools can be caused by any number of reasons.

When assessing a patient for a possible C. difficile infection, evaluating patient history is critically important, says Rodney Arcenas, PhD, clinical scientist of microbiology and molecular testing at Memorial Regional Hospital in Hollywood, Fla. "Many of the symptoms of diarrheal disease overlap," Dr. Arcenas says. "That's where the patient history comes into play with knowing how likely it is that C. difficile is the cause of a patient's diarrhea."

Lance Peterson, MD, director of microbiology and infectious diseases research at Chicago-based NorthShore University HealthSystem and the University of Chicago, agrees. He says more patients have diarrhea than have a C. difficile infection. "About 20 percent of patients coming into the hospital will have loose stools, and it might be from the medication they are on; it might be from the food they're eating. Most of them do not have a C. difficile infection," Dr. Peterson says. "In the hospital setting, maybe five or 10 patients out of 1,000 will actually have a C. difficile infection, whereas 20 percent will have some loose stool."

Typically, a patient producing at least three loose stools in one day is a first indicator of an appropriate sample, but it is a clinician's due diligence to rule out other factors that could contribute to the diarrhea. Like Dr. Peterson said, the patient may be on laxatives for health-related reasons or other medications that cause loose stool. Indicators that a patient's loose stool should be sent to the lab for C. difficile testing include recent antibiotic treatment and if the patient is coming from a nursing home or long-term care facility, Dr. Arcenas says. 

Types of tests
After determining a sample is appropriate for testing, there are multiple ways hospital labs can test the sample for C. difficile. Chris Newhouse, PhD, marketing manager of microbiology at Roche Diagnostics, says the C. difficile testing market is largely split 50/50. Half of labs use the more traditional algorithm of an enzyme immunoassay that detects the toxins responsible for an infection. The other half has adopted polymerase chain reaction testing, or molecular testing, like Roche's cobas® Cdiff Test that is performed on the cobas 4800 system. PCR testing copies small segments of DNA and tests those for the presence of an infection.

The sensitivity levels — how often a test produces a positive C. difficile result — of these two types of tests is often the subject of debate, as some microbiologists suggest molecular testing is actually too sensitive. According to Roche product labeling, the sensitivity of its Cdiff molecular test is 96.7 percent. A technical brief from Cleveland Clinic Laboratories indicates the sensitivity of an enzyme immunoassay is between 61 and 94 percent. That means a hospital lab using an enzyme immunoassay to detect C. difficile infections may only identify six out of 10 patients with the infection.

A study in JAMA Internal Medicine suggests the high sensitivity of molecular testing can produce too many false positive results. However, these types of false positive diagnoses can be avoided from the beginning with the aforementioned appropriate sample testing and adequate discussions regarding patient history.

"Basically you can't just use the test alone in making the diagnosis. The test has to be used in conjunction with patient symptoms, patient history," Dr. Peterson says. "If you aren't careful with who you test, you will think you have a lot more C. difficile infections than you do. That's not a problem with the test; it's a problem with physicians not asking enough questions and taking enough time to make sure their patient that has the symptoms actually has a C. difficile infection."

In fact, experts suggest the high sensitivity is an asset to PCR testing. Roche's Dr. Newhouse says this sensitivity is the No. 1 benefit of their molecular test. "It means for sure you're missing fewer patients."

Sensitivity, specificity and the cost of a diagnosis
While a test's sensitivity rate measures the true positive rate of a diagnosis, specificity measures the true negative rate, or how often a test produces a negative diagnosis for a patient who in fact does not have an infection.

Dr. Newhouse notes that, along with its high sensitivity, the cobas Cdiff test also has a high specificity, which means it produces fewer false positive results than tests with a lower specificity. A positive C. difficile diagnosis is challenging for patients and can take an emotional toll on them, so he says it's critical to ensure that positive diagnoses are accurate.

"There are a lot of implications for patients when they're called positive," Dr. Newhouse says. In addition to starting a strong antibiotic regimen, patients diagnosed with C. difficile are generally placed in full isolation and contact precaution to stop the spread of infection to others, which requires anyone entering the patient room to be fully gowned. Additionally, the number of visitors allowed is restricted.

"There's this emotional trauma because they do feel isolated when they're really sick and they get fewer visitors and fewer nursing staff going into the room," Dr. Newhouse says. "You want to have a highly specific test to know you're accurately treating only those patients you're supposed to be treating."

Isolation precautions require extra gloves and gowns for clinicians, as well as a special cleaning protocol, which incurs extra costs for the hospitals. By minimizing the chance of producing a false positive diagnosis requiring this extra level of care, hospitals can avoid paying for any unnecessary use of these products.

Reducing human error
Automation is another advantage of molecular testing, as it reduces the number of human touchpoints in the lab. The handling, processing and loading of test samples into the traditional immunoassay cartridges introduces opportunities for human errors to skew test results, especially if using a pipette is required.

Dr. Newhouse explains, "The cobas Cdiff test drastically minimizes the amount of manual handling required to run the test. When a stool sample comes into the lab, the technician simply has to take a swab, dip it in the stool sample, transfer it into the cobas PCR Media tube, vortex and then load that tube directly on the system."

"There are no pipetting steps, no manual intervention on the part of the lab technician," says Steven Cagas, PhD, scientific affairs manager within the department of medical and scientific affairs at Roche Diagnostics. "That's a big benefit because it does reduce the number of possibilities of human errors in two ways." Dr. Cagas says automation reduces the possibility of cross-contaminating other samples and contaminating the lab space itself.

Benefits of timely testing
Timeliness is critical when it comes to diagnosing C. difficile; an early, accurate diagnosis has implications on patient safety, care quality and costs. According to Roche, the cobas Cdiff test produces test results in just three hours, which means labs can run multiple tests a day and release results relatively frequently throughout the day.

Unsurprisingly, the earlier a clinician diagnoses and starts treatment for a patient with a C. difficile infection, the greater the likelihood for a positive patient experience and outcome.

"The quicker they get that patient off isolation and start treatment earlier, it's a benefit to the patient and [reduces] the overall burden to the healthcare institution," Dr. Arcenas says. "If you don't start treatment sooner, they're probably going to be in the hospital longer, have a longer length of stay. That patient is occupying a bed. There's a whole domino effect.”

Final thoughts
The advantages of molecular testing are numerous — high sensitivity, specificity, automation and quick turnaround time. And while other C. difficile tests like enzyme immunoassay offer some of these benefits, Dr. Cagas notes that each individual assay generally only offers one or two. "You'll either have good specificity, good sensitivity or a rapid turnaround time," he says. "But with PCR-based molecular assays like the cobas Cdiff test, you get all of those combined."

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