Molecular Testing Makes All the (C.) Diff

Clostridium difficile infection (CDI) is a significant cause of illness in hospital inpatients; worryingly incidence rates have increased by over 200 percent in the last 15 years alone. Hypervirulent strains are suspected to play a part in this, but could overdiagnosis also be a key factor? A team of US researchers certainly think so, in fact, they believe that up to half of patients diagnosed with CDI using molecular testing alone could be overdiagnosed, leading to unnecessary treatment.

Traditionally, immunoassays to detect C. diff toxin were the standard for identifying CDI because they provided faster, more reliable results than bacterial culture. The advent of molecular diagnostics, however, coupled with the FDA approval of the first CDI molecular test in 2009 has led to widespread uptake of the technique for CDI diagnosis in hospitals (1). Though methods like PCR provide fast and sensitive results, there is one major flaw – similar to culture, PCR does not detect the bacterial toxins which correlate with clinical disease, but rather the toxin-producing genes.

Since switching to molecular testing, some hospitals have reported increases in CDI detection of 50 to 100 percent (2). But because they don’t detect toxins, are molecular tests detecting disease or simply C. diff colonization, and could the increase in CDI incidence be partly attributed to the introduction of these tests rather than a rising incidence? These were the questions researchers at the University of California Davis Medical Center, sought to answer. Using both PCR and toxin they tested 1,416 hospitalized adults with diarrhea and suspected CDI, and assessed duration of diarrhea, complications, and CDI-related deaths. What they found was that toxin-negative, PCR-positive patients had similar health outcomes to patients who returned negative results on both tests, showing less inflammation and milder symptoms even with little or no treatment. This strongly suggested that those patients did not need treatment for CDI, and that their nosocomial diarrhea had another cause (3).

Overall, 55.6 percent of the patients with a positive PCR result had no toxin present using immunoassay, implying that molecular testing alone could overdiagnose as many as one in every two patients. The authors concluded that relying on molecular tests to provide a diagnosis is likely to lead to overdiagnosis, unneeded treatments and increased costs, and recommend that there should be more focus on developing reliable ways to distinguish between active infection and bacterial colonization. The results serve as a reminder that, even as molecular techniques continue to become more commonplace, DNA testing isn’t always the best approach.