A UC Davis clinical research study that cautions against racing too quickly toward new diagnostic technologies has been named one of the nation’s three most impactful

A nonprofit association of leading academic health centers has chosen a UC Davis study — a cautionary tale about racing too fast to embrace new diagnostic technologies — among the top three examples of high-impact work that the group is highlighting in 2016 to drive support for American clinical and translational research.

Christopher Polage, an associate professor of pathology and infectious diseases at UC Davis Health System and director of its clinical microbiology laboratory, received a prestigious Distinguished Clinical Research Award from the Washington, D.C.-based Clinical Research Forum this April for his innovative study, which found popular molecular tests may overdiagnose Clostridium difficile infections by up to 50 percent.

The results are relevant to multiple national health issues such as antibiotic resistance, quality improvement and overreliance on technology — and also weigh in powerfully on a long-simmering national debate within laboratory science and infection control circles.

And ultimately, the board of directors of the Clinical Research Forum — including research leaders from highly endowed private universities such as Yale, Stanford and Case Western — ranked the work among the three papers it reviewed for 2016 that “represent the best and brightest work in the field, and lead to advancements in medicine that change lives and patient outcomes worldwide.”

“Being among these studies of the highest national importance is an indication of the quality of research going on here at UC Davis,” said Lars Berglund, the senior associate dean for research at UC Davis School of Medicine, and director of UC Davis’ National Institutes of Health-funded Clinical and Translational Science Center (CTSC) that helped support Polage’s research in its early stages. “It also points at the value of the clinical enterprise being linked to the academic mission, and how this is of great advantage to us.

“The study highlights a principle — realizing that when we are getting methods of screening and analysis that are perceived as cutting-edge, it doesn’t necessarily mean they differentiate who needs treatment. It’s a bit of a wake-up call to make sure that you put what you’re measuring in the context of the disease and the overall picture.”

Founded in 1996 by a Harvard endocrinologist, the Clinical Research Forum brings together leading U.S. academic research institutions to discuss best practices and promote wider understanding and support for clinical and translational research. In a given year members can collectively account for a significant portion of the NIH extramural research budget.

The forum’s awards program highlights returns on the nation’s investment in research by identifying and sharing major advances that emerge. Forum members annually honor the 10 most outstanding studies nominated or submitted from across the nation, and flag three for additional recognition.

Winning papers for 2016 were chosen from a pool of more than 40 nominations from 30 research and academic health centers nationwide. Berglund represents UC Davis Health System on the 16-member CRF board and nominated Polage’s study, which has been widely discussed in clinical microbiology and infectious disease circles nationally. Berglund cannot vote for the study.

“I feel extremely honored to have received this award and be recognized among such an esteemed group of researchers,” Polage said. “It’s really a testament to the training and environment at UC Davis and the years of planning and work in this area by our whole team.”

‘Like night and day’

C. difficile is the one of the most common causes of infection in hospitals in the U.S., leading to diarrheal illness, colitis and potentially deadly complications in susceptible patients. But most patients act simply as carriers — similar to other bacteria like staph — without illness or complications, making it important to distinguish colonization from clinical disease.

Making this distinction is particularly challenging in hospitals, where many patients have symptoms that mimic C. difficile infection from other causes and C. difficile carriage is also common. This is where Polage’s study comes in.

There has been long-standing debate about the best test to diagnose C. difficile infection and predict the need for treatment, Polage said. The debate took on a new urgency when more sensitive molecular tests were approved for market in 2009 and widely adopted in health care settings with little investigation of the consequences. The impetus for the new tests was a concern that occasional infections were being missed; however, the new tests were so different that after they were adopted, the number of patients diagnosed with C. difficile infection doubled nearly overnight.

“These tests gave dramatically different results than the traditional toxin tests, and the difference was like night and day — not grey, but a stark difference between the two,” Polage said. “That caused me and others to become concerned that we were headed too far in the opposite direction and starting to overdiagnose patients with colonization and symptoms from other causes.

“We decided to do a study to find out which test correlated more closely with clinical disease.”

Overdiagnosed and overtreated

Dr. Polage’s team evaluated 1,416 hospitalized patients tested for C. difficile at UC Davis, tracking patient outcomes and symptom severity according to results of the traditional toxin tests — which look for the toxins that cause disease — versus molecular tests, which look for bacterial DNA regardless of toxin production.

The two-year study concluded that the molecular tests cannot distinguish infected patients who need treatment from patients who are colonized and do fine without treatment. As a result, many patients — likely tens of thousands each year, Polage said — are presumably being overdiagnosed and overtreated at hospitals where molecular tests are used as the sole determinant of C. difficile infection.

These erroneous diagnoses can delay recognition of other medical conditions, and unnecessary treatment may cause antibiotic resistance, damage to beneficial bacteria in the gut, increased health-care costs and — ironically — an increased chance of C. difficile after the antibiotics are stopped.

“If you only detect DNA or the presence of the organism, you haven’t necessarily proven that the organism is what’s causing symptoms,” Polage said. “Yet, doctors routinely assume that all patients with positive molecular test results are infected and treat everyone with antibiotics, even when patients might be better off left alone.”

Right place, right time

Polage recommends that physicians and laboratories move back in a direction of defining C. difficile disease based on the detection of toxins, and use molecular tests for screening as in the United Kingdom.

More provocatively, he wonders if regulators should consider requiring clinical outcomes studies of diagnostic tests before approving them for clinical use, especially when new tests are novel or differ substantially from others. Clinical outcome studies of diagnostic tests are quite rare compared to the process for evaluating and approving new pharmaceuticals, Polage said.

UC Davis Medical Center has historically relied on the more traditional toxin test for clinical diagnosis of C. difficile, and continues to rely on it to guide treatment decisions after this study. However, Polage and colleagues are also leveraging the new molecular tests to good effect in a program to decrease new C. difficile infections in hospitalized patients by identifying carriers, similar to strategies which aim to prevent other hospital-acquired infections like methicillin resistant Staphylococcus aureus.

“We’re doing leading-edge work in multiple areas to ensure that diagnosis and treatment are as accurate as possible, while minimizing the number of patients who contract a C. difficile infection here too,” Polage said. “We’re taking a multidisciplinary, multifaceted approach to deal with important patient safety issues, like C. difficile infection, that all hospitals face worldwide.”

Polage was first author of the study, which included participation by representatives then or now based at UC Davis School of Medicine, University of Michigan Medical School, Yolo County Health Department, Memorial Sloan Kettering Cancer Center, First Affiliated Hospital of Sun Yat-sen University and Weill Medical College of Cornell University.

Read more:

Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era. JAMA Internal Medicine, November 2015