Measuring the Cost of Overtesting and Overdiagnosis of C Measuring the Cost of Overtesting and Overdiagnosis of C. difficile Infection Division of Infectious Diseases & International Health Department of Medicine, School of Medicine Gregory R. Madden, MD Costi D. Sifri, MD McIntire School of Commerce David C. Smith, PhD

C. difficile Infection Asymptomatic Colonization Predisposing antibiotics Toxins A/B Spore-forming bacteria Leading cause of healthcare-associated infection -As an infectious diseases fellow, I think C. difficile might be the perfect hospital pathogen -it colonizes the gut of around 15% of hospitalized patients so that they serve as a reservoir for transmission to other patients but also to lays in wait until you’re on antibiotics (which we use a lot of in hospitals) when it can take over your disrupted microbiome. -And then it turns on its toxin production that causes diarrhea and even more spreading around the hospital. -When in the environment, it forms spores that resist our alcohol hand gels and conventional cleaning agents. -As a result C. diff is the leading cause of healthcare associated infection. Jose S, Madan R. Neutrophil-mediated inflammation in the pathogenesis of Clostridium difficile infections. Anaerobe. 2016;41:85-90. Yang Z, Zhang Y, Huang T, Feng H. Glucosyltransferase activity of Clostridium difficile Toxin B is essential for disease pathogenesis. Gut Microbes. 2015;6(4):221-224. Image: David Goulding, Wellcome Trust / Flickr cc

The Cost of C. difficile C. difficile infection costs the US $5.4 Billion annually1,2 $7,286-$11,285 per hospitalized case3,4 Additional 5 days length of stay3 -And C. difficile is expensive. -It costs the US healthcare system an estimated 1 border wall with mexico each year, or about 5 billion dollars. -If you are merely diagnosed with C. difficile in the hospital, it is estimated this adds on average 7 to 11 thousand dollars and an additional 5 days to your hospital stay. Polage CR, et al. JAMA Intern Med 2015; 175:1792-1801 Desai K, et al. BMC Infect Dis 2016; 16:303 Magee G, et al. Am J Infect Control 2015; 43:1148-53 Zimlichman E, et al. JAMA Intern Med 2013; 173:2039-46

C. difficile Colonization + Toxin B Gene PCR C. difficile Negative ~15% of Hospitalized Patients C. difficile Colonization C. difficile Infection >25% of Hospitalized Patients -But believe it or not, because of this issue of colonization, we don’t have a reliable way of identifying who’s infected and who’s not. There is no FDA approved test which tells us. -If you consider in hospitals, about 15% of asymptomatic patients are colonized with C. diff and will have a positive PCR test -(Most hospitals, including UVA, use this PCR test for C. diff because it’s the most sensitive.) -these colonized patients outnumber infected patients about 5 to 1. -And diarrhea doesn’t help us because a quarter of hospitalized patients will have diarrhea of one cause or another during their hospitalization. -And as a result of all of this, it’s estimate that half or more of hospitalized patients who test positive, may not require any C. diff treatment. Diarrhea

C. difficile Colonization C. difficile Negative C. difficile Colonization What is the Cost of Overdiagnosis? -But no one has tried to directly quantify the cost of this donut: patients incorrectly diagnosed with C. difficile infection who are really are just colonized. We call these false positives, or overdiagnosis. -But I just told you that our conventional tests for C. difficile are flawed, so how do we identify these patients?

C. difficile PCR Cycle Threshold -The approach we took is to leverage the information we have at hand -Every time you run a real-time PCR test, you get curve that looks like one these. -The RT PCR test looks for C. diff DNA and copies and amplifies it in a series of cycles -The number of cycles it takes for the machine to detect the DNA at a certain threshold is called the cycle threshold, which is a proxy that can tell help us estimate the number of organisms present in the stool. -A low cycle threshold or CT means you had a lot of C. diff present in the stool to begin with. -A high cycle threshold means you had barely enough to detect. GeneXpert CT Maximum Cutoff = 37.0. Estimated limit of detection of 1,657 colony-forming units.

Receiver Operating Characteristic (ROC) The cool thing about cycle threshold being now a continuous measure instead of a binary positive or negative test, is that you can tweak the test characteristics by choosing a CT cutoff.

Low PCR CT (≤26.0 - 28.0): +Toxin EIA, +CCNA1 Low PCR Cycle Threshold = Likely Infected Low PCR CT (≤26.0 - 28.0): +Toxin EIA, +CCNA1 ↑ Symptoms (duration of diarrhea, pain)2 clinically severe CDI1,3 The idea is that a low CT has been shown to correlate with tests that are more specific for clinical C. difficile infection And if you have a low CT, you’re more likely to have symptoms consistent with C diff infection like ab pain, longer duration of diarrhea, and others measures of disease severity. Thus, patients with a low CT are more likely to be truly infected. Kamboj M, et al. J Infect. 2018; 76:369-75 Pollock NR. J Clin Microbiol. 2016; 54:259-64 Garvey MI, et al. Antimicrob Resist Infect Control. 2017; 6:217

High PCR CT (≥30.85) is associated with: High PCR Cycle Threshold = Likely Colonized High PCR CT (≥30.85) is associated with: >98% negative predictive value for 3 other (more specific tests) combined. -Conversely if you have a high CT > 30.85, it has >98% negative predictive value for 3 other more specific tests, combined, including one that is considered the current gold standard test, this one called a CCNA. -Suggesting these patients are likely colonized and not infected. Adapted from: Senchyna F, Gaur RL, Gombar S, Truong CY, Schroeder LF, Banaei N. Clostridium difficile PCR Cycle Threshold Predicts Free Toxin. Tang Y-W, editor. J Clin Microbiol. American Society for Microbiology; 2017 Sep;55(9):2651–60. 

Measuring the Cost of Overtesting and Overdiagnosis of C Measuring the Cost of Overtesting and Overdiagnosis of C. difficile infection. And we have validated these data at UVA using a different test called a toxin enzyme immunoassay and found similar results.

Measuring the Cost of Overtesting and Overdiangnosis of C Measuring the Cost of Overtesting and Overdiangnosis of C. difficile infection. Aim: What are the costs associated with C. difficile overtesting and overdiagnosis? leverage PCR cycle threshold data to differentiate true infection versus colonization and identify determinants of costs in these groups Along with my research mentor Costi Sifri, who is the hospital epidemiologist and David Smith from the McIntire School of Commerce, we want to use cycle threshold as a tool to answer the question: what are the costs associated with C. difficile overtesting and overdiagnosis

C. difficile Real-Time PCR Cycle Threshold ~1,800 positive tests (Jan 2014-June 2018) So we are able to look at the cycle threshold data from over 1800 patients diagnosed with C. difficile here at UVA Health System.

>30.85 (>98% NPV for (-) CCNA)2 Measuring the Cost of Overtesting and Overdiagnosis of C. difficile infection. ≤28.0 (81% PPV for (+) CCNA)1 = Likely “True” Infection   >30.85 (>98% NPV for (-) CCNA)2 =Likely Colonization -What we know about cycle threshold allows us to categorize these patients into those with likely “true” infection, likely “colonized”, and we can exclude these really indeterminate cases in the middle. -We hypothesized that patients with C. difficile colonization will incur significantly higher costs than patients with negative tests but not higher than those with true infection.

Preliminary Data -Our Preliminary data are not what we expected. -These are box and whisker plots showing a true C. difficile diagnosis adds about 4.5 thousand dollars to the total hospital cost compared to a negative result -but a misdiagnosis of colonization actually adds 16 thousand; that’s over a 50% increase. -Now, these are unadjusted comparisons, so whether these differences represent factors that we should adjust for (such as comorbidity burden) or whether these differences could be accounted for a, say, misdiagnosis and thus mistreatment of patients’ diarrhea are open questions. -We asked Dr. Smith here to help us with a propensity score analysis to find out...

Measurement issue: Selection bias Patients testing as “Colonized” could be more expensive to treat independent of outcome of Real-Time PCR Test Confounding patient characteristics that could be correlated with “Colonized” grouping and also raise costs: Age Antibiotic Exposure Charlson Comorbidity Index (CCI) Length of Stay ICU Location at Time of Diagnosis Sepsis Acute Kidney Injury Elevated WBC Count To account for confounding factors, will employ a propensity score matching estimator as a multivariate and nonlinear control for confounding factors