Reduced Clostridioides difficile Tests Among Solid Organ Transplant Recipients Through a Diagnostic Stewardship Bundled Intervention

Background

Clostridioides difficile (formerly Clostridium difficile) is the major pathogen causing healthcare-associated infection (HAI) in the USA, leading to significant morbidity, mortality, and cost [1]. Solid organ transplant (SOT) recipients suffer a higher incidence of C. difficile infection (CDI) compared to other hospitalized and postoperative patients [2,3]. CDI in SOT patients occurs most frequently during the first 3 months following transplantation, when antimicrobial use and immunosuppression tend to be highest [3,4].

Molecular detection of C. difficile toxin genes through highly-sensitive nucleic acid amplification testing (NAAT) is a common diagnostic approach for CDI. However, since NAAT can also detect toxigenic C. difficile in samples from asymptomatic carriers (patients who are colonized with C. difficile but do not have CDI), and CDI overdiagnosis is thought to be common. Recent studies suggest that up to 50% of hospitalized patients with a positive NAAT for C. difficile may not benefit from treatment [5,6]. To our knowledge, whether this is true in SOT recipients has not been reported. Positive tests in colonized patients who are not infected could lead to overtreatment and increased healthcare expenditures. Additionally, for SOT patients, unnecessary CDI treatment may lead to downstream drug reactions, immunosuppressant disruption, prolonged hospitalization, and promote antimicrobial resistance such as vancomycin-resistant enterococci [7].

CDI overdiagnosis could be explained by inappropriate testing of patients who are colonized with C. difficile and have low pretest probability for infection. Improvement of diagnostic utilization using diagnostic stewardship is an increasingly recognized approach that hospitals use to reduce diagnostic error and cost [8]. Computerized clinical decision support (CCDS) systems, incorporated in the computerized physician order entry system, are one method to guide diagnostic decision-making.

Here we report a successful CCDS-based intervention used to decrease inappropriate C. difficile testing in a SOT recipient population.

Material and Methods

INTERVENTION:

The CCDS tool was designed as part of a system-wide effort to address C. difficile infection and improve test utilization based on established institutional criteria for appropriate C. difficile testing [9]. The 2-part CCDS first presented a duplicate order alert screen that listed any C. difficile result within 28-days. Next, algorithmized questions were presented to the ordering providers in a step-wise fashion that were designed to encourage appropriate testing based on the 2010 Infectious Diseases Society of America (IDSA) C. difficile guidelines [10]. The ordering provider was encouraged to complete an order when they could attest that the patient had diarrhea (defined as ≥3 liquid stools within 24 hours) and either signs or symptoms of C. difficile infection (e.g., fever, abdominal discomfort, leukocytosis) or risk factors for infection (e.g. recent antibiotic exposure, abdominal surgery, age >60 years). This process would also be consistent with the recently updated 2017 IDSA and Society for Healthcare Epidemiology of America (SHEA) C. difficile guidelines which recommend NAAT testing alone (versus a multistep algorithm) and should only be performed on stool submitted from patients that meet “preagreed institutional criteria” for diagnostic testing [11]. A test was allowed to be ordered regardless of responses. Per laboratory protocol, non-liquid stool specimens would be rejected, and a test would not be performed. NAAT was done using the GeneXpert platform (Cepheid, Sunnyvale, CA, USA). In addition, during the intervention period, peroxyacetic acid/hydrogen peroxide-based cleaner was adopted hospital-wide, and antimicrobial stewardship performed CDI case reviews with feedback to providers; no other C. difficile or SOT-specific infection prevention measures were implemented during the study period.

The CCDS was bundled with educational efforts involving all nurses and other licensed independent practitioners (including flyers, a demonstration video, and emails) and a quality improvement project lead by graduate medical education (GME) house staff [9]. A C. difficile electronic display was produced for the institutional patient safety and quality dashboard that depicted real-time testing rates (including positive, duplicate, and prevented test attempts). The dashboard was visible to all hospital staff and administration with specific service line ascriptions, including transplant.

STUDY DESIGN:

A quasi-experimental retrospective cohort study was done to analyze inpatient rates of C. difficile tests among patients that received a SOT between January 2014 and December 2017 at University of Virginia Health System (UVAHS), before and after introduction of a CCDS tool. The UVAHS Charles O. Strickler Transplant Center is a comprehensive transplant program that performed on average 185 adult SOTs per year (range 137–239) during the study period (49% kidney, 33% liver, 10% lung, 6% heart, 2% kidney/pancreas, and <1% pancreas). Monthly rates of NAAT orders, results, and order attempts prevented by the CCDS occurring over a 24-month pre-intervention period (December 2014 to November 2016) were compared to a 13-month post-intervention period (December 2016 to December 2017) after CCDS implementation on December 5, 2016.

OUTCOMES:

Our primary outcomes were the relative reduction in the rate of C. difficile tests and National Healthcare Safety Network (NHSN) reported CDI events. CDI events included combined community-onset (occurring on hospital day ≤3 in a patient not hospitalized within 28 days), community-onset healthcare facility-associated (CO-HCFA) (occurring on hospital day ≤3 in a patient hospitalized within 28 days), and healthcare facility-onset (occurring on hospital day ≥4) [12]. Secondary outcomes included all-cause mortality and 30-day readmission rates. Quantitative real-time polymerase chain reaction (qRT-PCR) cycle threshold values of positive results were also analyzed as a marker of pathogen burden in each group [5,13].

ANALYSIS:

Orders were labeled as prevented if providers initiated a NAAT order but aborted the order before it was electronically submitted. Baseline characteristics, all-cause mortality, 30-day readmission, and monthly rates of testing and CDI events were compared between the intervention groups [12].

Tests and CDI events were dated by order and collection date, respectively. Monthly rates were calculated using hospitalized patient-days for the cohort. P values were obtained using χ² test for categorical variables, independent samples t-test for continuous variables with normal distributions (2-tailed, equal variances not assumed), and Mann-Whitney U test for variables without a normal distribution (time from transplant to test, tests per patient, cycle threshold). In addition, interrupted time series analyses were performed using quasi-Poisson models to assess change in total test and CDI events between pre- and post-intervention periods, using an offset of patient days. Statistical software R, version 3.4.1 (R Core Team, Vienna, Austria) was used to perform analyses. This study received approval from the UVa Internal Review Board (#20082) with a waiver of consent.

Results

CHARACTERISTICS OF THE STUDY POPULATION:

Among the cohort of 769 patients, a total of 14 944 and 8822 SOT inpatient days were measured throughout the pre- and post-intervention periods, respectively. 27% (211 out of 769) of the cohort was tested at least once for C. difficile during the period of observation (139 individual patients during pre-intervention, 87 patients during post-intervention), resulting in a total of 491 inpatient tests (322 pre-intervention, 169 post-intervention). Baseline characteristics of patients at the time of each test were similar between groups, with the exceptions of older age, a higher percentage of liver transplants and lower percentages of kidney and pancreas transplants in the pre-intervention group (Table 1).

PRIMARY OUTCOMES:

The CCDS bundled intervention was accompanied by a 33% reduction in the rate of C. difficile tests (189 results per 10 000 patient days pre-intervention versus 124 per 10 000 patient days post-intervention; P<0.001) (Table 2). There was a trend towards reduced LabID CDI events (including NHSN-defined community-onset, community-onset healthcare facility-associated, and healthcare facility-onset) that was not statistically significant (35 per 10 000 patient days pre-intervention versus 17 positives per 10 000 patient days post-intervention; P=0.113) [12]. Quasi-Poisson models of testing rates and CDI events demonstrated similar findings (P<0.001 and P=0.122, respectively) (Figure 1).

Out of 169 test attempts during the intervention period, 38 tests (22.5%) were prevented by the CCDS and 12 tests (7.1%) were rejected by the laboratory. Specific CCDS provider responses for prevented tests were not recorded; however, among the 119 orders completed during the intervention period, 7 tests (5.9%) were ordered despite guidance by the CCDS indicating an inappropriate test (3 for lack of diarrhea, 3 for lack of signs/symptoms of CDI, and no CDI risk factors, and 1 test for a duplicate of negative test).

SECONDARY OUTCOMES:

Duplicate-negative results (defined as any negative result ≤3 days after a previous negative) decreased from 8.4 per 10 000 patient-days (13 duplicate negatives) pre-intervention to 1.3 per 10 000 patient-days (1 duplicate negative) post-intervention (P=0.004). Duplicate positive results (≤14 days after prior positive) decreased from 3.3 per 10 000 patient-days (5 duplicate positives) pre-intervention to 0 duplicate positives post-intervention (P=0.023). The rate of laboratory rejection of stool samples was unchanged post-intervention (15.4 per 10 000 patient days versus 14.4 per 10 000 patient days; P=0.878). All-cause mortality rate was not statistically different between groups (31.2 per 10 000 patient days pre-intervention versus 37.4 per 10 000 patient days post-intervention; P=0.742) and there was a nonsignificant trend towards fewer 30-day readmissions (367.7 per 10 000 patient days pre-intervention versus 324.7 per 10 000 patient days post-intervention; P=0.081). Cycle thresholds were not statistically different between groups.

An in-depth review of prevented test patients identified 3 instances in 2 patients in which a subsequent positive result occurred within a week of the prevented test. A full clinical summary is provided in Table 3. In the first instance, a patient with aspiration pneumonia had a positive C. difficile NAAT 1 day after a prevented test. The Infectious Diseases consult team concluded that the test was likely to be a false positive and recommended that C. difficile treatment be withheld. The patient clinically improved and diarrhea stopped without CDI-specific treatment. Of note, the cycle threshold value for the test was 27.8.

Patient 2 had 2 different instances in which a prevented test was followed by a positive result for C. difficile within the subsequent week. In the first instance, an increase in diarrhea and abdominal cramping prompted reconsideration for testing 3 days after a prevented test. Interestingly, the cycle threshold was just below the maximum cycle threshold cutoff of 37.0, suggesting that patient was likely colonized but not infected with C. difficile at that time. In the second instance, a duplicate C. difficile test was not indicated, because the patient had a positive C. difficile test at another facility 2 days prior and had already begun treatment for recurrent CDI. The cycle threshold for this result was 25.3.

Discussion

LIMITATIONS:

Our study offers a unique understanding of the impact of a particular diagnostic stewardship approach to C. difficile testing in a high-risk population. To our knowledge, this is the first report of the effects of CCDS-based diagnostic stewardship amongst SOT recipients. However, there are several limitations. As a quasi-experimental study, we could not account for time-varying confounding variables apart from the intervention and the longer-term durability of these findings is unknown. While the prevention of 38 tests could be linked to the CCDS tool, the overall reduced rate of testing may be attributed to our overlapping efforts. Impacts of individual aspects of our bundled intervention (CCDS tool, trainee involvement, provider education, electronic dashboard) could not be separately analyzed.

The reduction in CDI events theoretically represents hindrance of potential false-positives but could also reflect improved infection control efforts or prevention of appropriate testing. CCDS has not been associated with patient harm due to delayed or missed CDI treatment; however, many C. difficile diagnostic stewardship studies have not systematically addressed patient safety [24,25]. Furthermore, SOT patients are at higher risk for CDI and CDI-related complications compared to other patient populations and CDI doubles the risk of graft loss [2,3,26]. The lack of specific encounter-level baseline data such as medications and comorbidities were a significant limitation to our study. Although complicated outcomes related to potential missed or delayed CDI diagnoses were not systematically examined in our SOT cohort, it is reassuring that 30-day readmission and all-cause mortality were not significantly increased post-intervention. Further, the 6.1% mortality rate among patients identified as having at least 1 prevented test (2 deaths/33 patients) was similar compared to the 7.9% cohort mortality rate. In addition, no instance could be identified in which prevention of a test led to delayed C. difficile diagnosis with adverse outcomes. Patient 1 was felt to have had a false positive result and clinically improved without CDI-directed treatment. An increase in gastrointestinal symptoms for Patient 2 led to reconsideration of testing in one instance, and repeat testing while being treated for CDI occurred in the second instance. However, it is possible that patients with a prevented test had CDI but were never tested in our institution and/or did not meet either of the primary adverse outcomes – all-cause mortality or 30-day readmission.

Future studies for CDI and other healthcare-associated infections (HAI)-related diagnostic stewardship should ideally involve measures of outcomes of patients at highest risk for potential complications, such as those with prevented tests [8].

Conclusions

Clinical criteria play a key role in the accurate interpretation of C. difficile tests [27]. One way to improve C. difficile diagnostic accuracy is to prevent tests from occurring that are clinically irrelevant or in patients that have low pretest probability for disease [8].

CCDS-based diagnostic stewardship may be helpful and cost effective in reducing unnecessary testing among patients at high risk for disease, such as SOT patients [28]. Additional studies are required to establish efficacy, safety, and the optimal diagnostic stewardship approach for this and other high-risk populations.