Both infection and colonization with Clostridium difficile are common in patients with hematologic malignancy; 10%–29% of patients are positive by culture on admission.Reference Bruminhent, Wang and Hu 1 , Reference Jain, Croswell and Urday-Cornejo 2 However, while there is increasing recognition that molecular-based polymerase chain reaction (PCR) testing for C. difficile toxin lacks specificity for detecting infection as opposed to colonization,Reference Dubberke, Han and Bobo 3 , Reference Truong, Schroeder and Gaur 4 determining true infection in patients with hematologic malignancy may be particularly difficult given the high prevalence of diarrhea due to other etiologies (eg, chemotherapy or antibiotics)Reference Akahoshi, Kimura and Nakano 5 , Reference Stein, Voigt and Jordan 6 and the absence of typical signs and symptoms of infection such as leukocytosis or fever due to the effect of disease and/or therapy. Similarly, while studies have suggested lower rates of both characteristics predictive of infection and poor outcomes in patients with PCR versus enzyme immunoassay (EIA) positive tests,Reference Polage, Gyorke and Kennedy 7 , Reference Origuen, Corbella and Orellana 8 it is unknown whether these findings apply to patients with hematologic malignancy. Therefore, we aimed to compare clinical characteristics and outcomes between patients with EIA- versus PCR-positive C. difficile test results in a cohort of inpatients with hematologic malignancy.
METHODS
We performed a retrospective cohort study of patients admitted to the Hospital of the University of Pennsylvania (HUP), a 776-bed tertiary-care medical center from January 1, 2015, to March 31, 2017. Patients with active hematologic malignancy and a positive C. difficile test during hospitalization were included.
Stool samples ordered for C. difficile testing were processed by the HUP Clinical Microbiology Laboratory. The testing algorithm uses a commercial EIA for detection of toxin A, B, and glutamate dehydrogenase (GDH) (C Diff Quik Check Complete, Alere, Waltham, MA). Samples that are negative for toxin A and B but positive for GDH are subsequently tested using PCR for toxin genes (BD MAX Cdiff Assay, Becton Dickinson, Franklin Lakes, NJ).
Clinical data were collected using medical record review, including demographics, comorbidities, antibiotic use in the previous month, clinical signs and symptoms (including fever, diarrhea, number of bowel movements, abdominal pain, and imaging evidence of colitis), and medication use in the 72 hours prior to the positive test. Clinical outcomes were also collected, including toxic megacolon, colectomy, recurrent C. difficile disease in the 90 days after index testing, as well as all-cause intensive care unit (ICU) transfer, in-hospital mortality, and hospital readmission. Clinical characteristics and outcomes of patients with EIA- versus PCR-positive C. difficile test results were compared using the χ2 or the Fischer exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables using Stata version 14.2 software (StataCorp, College Station, TX). For all calculations, a 2-tailed P value <.05 was considered significant.
RESULTS
Over the 27-month study period in the hospital’s dedicated hematology oncology units, 11.6% of C. difficile tests were positive. Of the 182 patients admitted with hematologic malignancy who had a positive C. difficile test result, 101 patients (55%) had a PCR(+)/EIA(−) result, and 81 patients (45%) had an EIA(+) result. Among patients without neutropenia, leukocytosis (white blood cell count >15,000 cells/mm3) at the time of testing was significantly more common in the EIA(+) group (ie, 26%) versus the PCR(+)/EIA(−) group (ie, 11%; P=.02) (Table 1). There was no difference in rates of severe CDI,Reference Surawicz, Brandt and Binion 9 fever, diarrhea, or imaging evidence of colitis between the 2 groups. Stool output trended towards being higher in the PCR(+)/EIA(−) group, with a median of 4 bowel movements per 24 hours compared to a median of 3 bowel movements per 24 hours in the EIA(+) group (P=.15).
TABLE 1 Clinical Characteristics of Patients With Hematologic Malignancy With EIA- Versus PCR-Positive C. difficile Test Results
NOTE. IQR, interquartile range; EIA, enzyme immunoassay; PCR, polymerase chain reaction
a Median, interquartile range (IQR).
b A positive C. difficile test by PCR or EIA within the prior year.
c Within the prior 30 days.
d Graft-versus-host disease, inflammatory bowel disease (Crohn’s disease or ulcerative colitis), irritable bowel syndrome, short gut syndrome.
e Absolute neutrophil count <500 cells/mm3 within 72 h of the index C. difficile test.
f Total white blood cell count (WBC) >15,000 cells/mm3 among nonneutropenic patients.
g Temperature >38°C (100.4°F).
h Within 72 h (n=110).
i Serum albumin <3 g/dL plus WBC ≥15,000 cells/mm3 or abdominal tenderness.
j Listed as diarrhea or liquid stool by provider.
k Highest number of stools per 24-h period over 72 h prior to the testing date.
l Within the previous 72 h of the testing date.
m Includes sennosides, polyethylene glycol, milk of magnesia, bisacodyl, lactulose.
n Cefepime, meropenem, piperacillin-tazobactam, and levofloxacin.
TABLE 2 Outcomes of Patients With Hematologic Malignancy and EIA- Versus PCR-Positive Clostridium difficile Test Results
NOTE. EIA, enzyme immunoassay; PCR, polymerase chain reaction; ICU, intensive care unit; GVHD, graft-versus-host disease; GI, gastrointestinal.
a Within 90 days.
b Within 30 days.
c Patients may have received >1 antibiotic for treatment.
Receipt of medications associated with an increased risk for CDI, including acid suppressants (52%) and systemic antibiotics (80%), were similar in both groups. There were relatively high rates of recent use of laxatives (30%), but this was not significantly different between the 2 groups.
We observed high rates of adverse outcomes in the cohort, including an in-hospital mortality rate of 18% and an ICU transfer rate of 25%, but these were similar between the 2 groups (Table 2). Toxic megacolon was uncommon but occurred in 2 patients (2%) in the PCR(+)/EIA(−) group compared to zero in the EIA(+) group (P=.20). Most patients received treatment with oral vancomycin (59%). Two patients in the PCR(+)/EIA(−) group did not receive treatment; neither developed a measured adverse outcome.
DISCUSSION
We compared clinical characteristics and outcomes in patients with hematologic malignancy and an EIA- versus PCR-positive C. difficile test result after positive GDH screening. We have demonstrated that clinical characteristics and outcomes are similar in this cohort, whether results are positive by EIA or PCR. In addition, the results of our study highlight the significant morbidity and mortality of patients with C. difficile in this population, with high rates of ICU transfer and death.
Particularly in a population characterized by high rates of colonization with C. difficile,Reference Bruminhent, Wang and Hu 1 , Reference Jain, Croswell and Urday-Cornejo 2 it is important to differentiate infection versus colonization. However, our results suggest that among patients with hematologic malignancy, the testing modality (ie, EIA vs PCR) cannot be used to reliably distinguish between C. difficile infection and colonization. Specifically, clinical factors typically associated with active or more severe infectionReference Surawicz, Brandt and Binion 9 were similar between the 2 groups. Complicating the appropriate diagnosis of CDI in this population, there was a high rate of use of laxative and stool softeners in the 72 hours prior to C. difficile testing in both groups.
Clinical outcomes were also similar between hematologic malignancy patients with PCR(+)/EIA(−) versus EIA(+) C. difficile test results. Morbidity and mortality were high, likely reflecting the overall complexity and severity of illness of patients hospitalized with hematologic malignancy. However, those outcomes specific to CDI were also similar between both groups, with rates of recurrent CDI of 12% within 90 days and cases of toxic megacolon identified in the PCR(+)/EIA(−) group.
Our results differ from studies of general medical patients that have found those with toxin EIA(+) C. difficile results to have both a greater prevalence of CDI clinical characteristics and worse outcomes compared to those with PCR(+)/EIA(−) results.Reference Polage, Gyorke and Kennedy 7 , Reference Origuen, Corbella and Orellana 8 A prospective study without GDH screening found those with PCR(+)/EIA(−) results to have a lower prevalence of leukocytosis, fewer number of stools, and lower rates of adverse outcomes, including mortality and recurrent CDI.Reference Polage, Gyorke and Kennedy 7 However, the 30-day mortality of 0.6% in the PCR(+)/EIA(−) group in this study compared to 15% in our study highlights the significant difference in study populations. Another recent study also demonstrated higher rates of leukocytosis, fever, and severe CDI as well as recurrent CDI with an EIA(+) result versus PCR(+)/EIA(−) result after GDH screening, but these results showed no difference in mortality between the groups.Reference Origuen, Corbella and Orellana 8 Notably, our study included only samples collected through routine clinical care and were tested via a multistage process, which included a C. difficile GDH screening test. While we compared EIA and PCR test results, these tests were conducted for patients who had had a positive GDH screen. In a multicenter study comparing clinical outcomes among general medical patients, GDH screening was shown to perform similarly to cytotoxigenic culture and had similar sensitivity to PCR.Reference Planche, Davies and Coen 10 However, it is possible that our results differ somewhat from prior studies where GDH screening was not performed.
Our study has potential limitations. First, given the relatively limited sample size available for clinical outcomes, we were unable to perform a multivariable analysis for the association between C. difficile testing method and patient outcomes. Additionally, our study focused on the care of hematology oncology patients at an academic institution and may not be generalizable to populations with different characteristics.
In conclusion, our findings highlight the importance of evaluating the characteristics and performance of C. difficile testing algorithms specifically in high-risk populations. Additionally, considering the high morbidity and mortality associated with C. difficile in this population, future studies are needed focusing on optimal methods of differentiating colonization versus infection, as well as preventing C. difficile disease in patients with hematologic malignancy.Reference Chakrabarti, Lees, Jones and Milligan 11
ACKNOWLEDGMENTS
Financial support: This work was supported by the National Institutes of Health (grant no. T32-AI055435 to M.Z. and grant no. K01-AI103028 to J.H.H.) and by a CDC Cooperative Agreement, FOA#CK16-004-Epicenters for the Prevention of Healthcare Associated Infections. The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
Potential conflicts of interest: All authors report no conflicts of interest relevant to this study.
