Download Impact of malignancy on Clostridium difficile infection

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Impact of malignancy on Clostridium difficile infection
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Min Sung Chung*, Jieun Kim*, Jung Oak Kang, Hyunjoo Pai
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* These authors contributed equally to this work.
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Min Sung Chung
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Department of Surgery, Hanyang University College of Medicine, 222-1,
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Wangsimni-ro, Seongdong-gu, Seoul, Korea
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E-mail : [email protected]
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Jieun Kim
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Department of Internal Medicine, Hanyang University College of Medicine,
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222-1, Wangsimni-ro, Seongdong-gu, Seoul, Korea
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E-mail : [email protected]
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Jung Oak Kang
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Department of Laboratory Medicine, Hanyang University College of Medicine,
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222-1, Wangsimni-ro, Seongdong-gu, Seoul, Korea
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E-mail : [email protected]
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Hyunjoo Pai (Corresponding author)
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Department of Internal Medicine, Hanyang University College of Medicine
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222-1, Wangsimni-ro, Seongdong-gu, Seoul, Korea
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TEL: +82-2-2290-8356
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FAX: +82-2-2298-9183
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E-mail: [email protected]
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ABSTRACT
Purpose: The purpose of the study was to investigate the impact of malignancy and chemotherapy on the
clinical and microbiological characteristics of Clostridium difficile infections (CDI).
Methods: CDI patients with a history of malignancy within 5 years were defined as the cancer group. The
characteristics of the patients were compared according to the presence of malignancy.
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Results: Of 580 patients with CDI, 159 (27.4%) belonged to the cancer group and 421 (72.6%) to the non-
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cancer group. More of the patients in the cancer group than of those in the non-cancer group had been hospitalized
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within the prior 2 months (P<0.001). Leukocytosis was more common in the non-cancer group (P = 0.034), while
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infection by PCR ribotype 017 strains was more common in the cancer group, with marginal significance (P =
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0.07). Recurrence was more frequent in the cancer group (20.4% vs. 9.5%, P =0.005) and cancer was an
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independent risk factor for recurrence of CDI (OR=2.66, 95% CI 1.34-5.29, P =0.005). Age also contributed to
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the recurrence of CDI (OR=1.03, 95% CI 1.00-1.06, P =0.026).
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Conclusions: Malignancy and age are independent risk factors for recurrence of CDI. Cancer patients require
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careful observation for recurrence after treatment of CDI.
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Keywords: Clostridium difficile, Malignancy, Clinical outcome, Recurrence
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INTRODUCTION
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Clostridium difficile infection (CDI) is the most common cause of healthcare-associated diarrhea [1]. Due to
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the increased incidence of CDI, mortality, morbidity, length of hospital stay, and healthcare costs have increased
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[2].
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The use of antimicrobial agents is the best-recognized risk factor for CDI [3]. Other risk factors include advanced
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age, admission to a healthcare facility, severe comorbidities, exposure to chemotherapy, immunosuppressive
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therapy, and use of proton pump inhibitors [4].
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The incidence of CDI in cancer patients receiving chemotherapy has been reported to be as high as 7%, compared
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to 1–2 % in the general hospitalized population [5-7]. Cancer patients have multiple risk factors for CDI including
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long-term hospitalization, exposure to broad-spectrum antibiotics, neutropenia, and chemotherapeutic agents. In
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addition, cancer affects an increasingly elderly population, often affected suffering from multiple co-morbidities
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[8]. There have been a few studies of CDI in cancer patients but most were of cancer patients receiving
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chemotherapy or of hematopoietic stem cell transplant patients in single hematology/oncology departments [9-11]
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or single cancer cohorts [12,11].
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To investigate the impact of malignancy and chemotherapy on CDI, we have compared the clinical and
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microbiological characteristics and clinical outcomes of CDI in cancer and non-cancer patients and in cancer
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patients receiving or not receiving chemotherapy.
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MATERIALS AND METHODS
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Setting and study design
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This study was conducted at Hanyang University Hospital, a 900-bed tertiary care facility located in Seoul,
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South Korea. From February 2009 through January 2013, patients above 18 years with healthcare-associated C.
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difficile infections (HA-CDIs) were enrolled. Only the first episode of HA-CDI was included. The study was
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approved by the institutional review board of Hanyang University Hospital (HYUH IRB 2013-07-016), and
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informed consent was waived.
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Definitions
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Diarrhea was defined as unformed stool more than 3 times per day on consecutive days, or 6 times within 36
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hr. CDI was defined when the isolates from stool cultures were positive for toxin genes (tcdA, tcdB, cdtA, or cdtB)
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by multiplex PCR, positive in assays for toxins A & B with a commercial kit (VIDAS® C. difficile Toxin A & B;
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BioMerieux SA, Marcyl’Etoile, France), and/or pseudomembranes were observed during endoscopy or histology.
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CDI patient who developed diarrhea at least 72 hr after hospitalization or within 2 months of their last discharge
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were considered as HA-CDI [13].
Those with a history of malignancy within 5 years were defined as the ‘cancer
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group’, and, within the cancer group, patients who received chemotherapy within 2 months were defined as the
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‘chemotherapy subgroup’ and those not receiving chemotherapy as the ‘conservative group’.
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Neutropenia was defined when the WBC count was < 1,000 cells/mm3. Recurrence was defined as growth of C.
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difficile (as defined above) with resurgence of symptoms, at least 10 days and < 60 days after the first episode
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[14]. Death related to CDI was defined as death within 30 days after diagnosis if CDI was either the primary or a
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contributory cause [15].
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White blood cell (WBC) count and albumin level were checked within 24 hr of enrollment to assess disease
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severity. To assess disease severity, two method was applied. Age > 60 yr, temperature > 38.3°C, albumin level <
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2.5 mg/dL, or WBC count > 15,000 cells/mm3 got 1 point each; the sum of the points was taken as the severity
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score for CDI and the CDI was considered to be severe when scores were ≥ 2 points [16]. The other method
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defined by SHEA/IDSA, and white blood cell count ≥ 15,000 cells/mL or serum creatinine ≥1.5 times the
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premorbid level was regarded as severe CDI [17].
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Collection of data
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Age, sex, body mass index (BMI), length of stay in hospital, admission history and medication history within
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the previous 2 months, and underlying disease including Charlson’s score were obtained as demographic and
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clinical data by review of medical records. Use of antibiotics and chemotherapy within 2 months has been studied
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as a risk factor for CDI [18]. We also noted whether antibiotics for non-CDI were continued or discontinued after
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diagnosis of CDI.
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Isolation and characterization of C. difficile isolates
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Stool specimens were grown anaerobically on cycloserine–cefoxitin–taurocholate agar (Oxoid Ltd., Cambridge,
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UK) supplemented with 7% horse blood after alcohol shock treatment [19]. Colonies of C. difficile were identified
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with an API® Rapid ID 32A system (bioMérieux SA, Lyon, France). Using DNA from each isolate, multiplex
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PCR for toxin genes and agar gel electrophoresis were performed as described elsewhere with minor modifications
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[20]. PCR-ribotyping was also performed as described [21].
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Statistical methods
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SPSS version 21.0 for Windows (SPSS, Chicago, IL, USA) was used for statistical analysis. Categorical
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variables were analyzed by Pearson’s chi-square test or Fisher’s exact test. Continuous variables were analyzed
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by independent t-test or the Mann-Whitney U-test. A P value of < 0.05 in a two-tailed test was considered
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statistically significant.
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RESULTS
During the study period, 580 cases were diagnosed as initial, non-recurrent HA-CDI. 159 cases (27.4%) were
in the cancer group and 421 (72.6%) in the non-cancer group.
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Characteristics related to malignancy in the cancer group
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Of the 159 cancer cases, 144 (90.6%) had solid malignancies and 15 (9.4%) had hematologic malignancies.
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The most common type of solid malignancy was gastrointestinal (76, 52.8%), followed by pulmonary (27, 18.8%),
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urologic (10, 6.9%), gynecologic (6, 4.2%), head and neck (5, 3.5%) and breast (4, 2.8%). Sixty-nine of the 159
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patients (43.4 %) received chemotherapy. The most commonly employed regimens were platinum (35, 50.7%)
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followed by 5-FU/5-FU prodrugs (18, 26.1%), topoisomerase inhibitors, and taxane and tyrosine kinase inhibitor
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(TKI)-based regimens used in combination.
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Demographic and clinical characteristics of the CDI patients
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Table 1 presents the demographic and clinical characteristics of the CDI patients according to presence of
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malignancy. Age, BMI, and antibiotics history were similar in the two groups. In the cancer group, there were
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significantly fewer females (P=0.009), more patients were hospitalized within the previous 2 months (45.3% vs.
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27.4%, P <0.001), and the mean Charlson`s score was significantly higher. Median WBC counts was higher in
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the non-cancer group (8,000/mm3 vs 9,900/mm3, P<0.001), as was leukocytosis (13.2% vs. 20.9%, P = 0.034).
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Other factors reflecting disease severity such as old age, fever, and hypoalbuminemia did not differ.
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Pseudomembranous colitis was observed during endoscopy in 26.3% (10/38) and 38.0% (41/108) of the cancer
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and non-cancer patients, respectively.
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The patients in the conservative treatment subgroup were on average older than those in the chemotherapy
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subgroup (p<0.001) (Table 1). Admissions were more frequent in the chemotherapy subgroup (p=0.005), but
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antibiotic exposure was more frequent in the conservative subgroup (p=0.004). Higher WBC counts and lower
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albumin levels were observed in the conservative subgroup (p<0.001, p=0.023, respectively), but there was no
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difference in severity score. A similar proportion of the patients in each group were treated.
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Clinical outcomes
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The clinical outcomes of CDI were compared in those cancer and non-cancer patients receiving treatment for
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CDI (93 and 274 patients, respectively), and between the chemotherapy and conservative subgroups who received
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treatment for CDI (38 and 55, respectively) (Table 2).
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Of the 367 treated patients, 22 (6.0%) received vancomycin as first line therapy (3.2% in the cancer vs. 6.9% in
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the non-cancer group; P=0.193). The recurrence rate was significantly higher in the cancer group than the non-
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cancer group (20.4% vs. 9.5%, P=0.005). Although not statistically significant, the cancer patients had a higher
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in-hospital mortality rate (23.9% vs. 8.0%, P=0.161); however, CDI-related deaths were more frequent in the non-
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cancer group (0 vs. 1.8%, P=0.335).
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There were no statistically significant differences in clinical outcomes including recurrence rate between the
cancer subgroups.
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Microbiologic characteristics
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PCR-ribotyping was performed on 400 of 421 isolates (95%) from the non-cancer group and 150 of 159 isolates
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(94.3%) from the cancer group (Table 1). In the non-cancer group, PCR-ribotype 018 was the most frequent type,
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whereas, PCR ribotype 017 was the most common type in the cancer group; the latter appeared to be more
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common in the cancer group than the non-cancer group (P=0.07). A total of 15 binary toxin-producing strains
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were identified, 2 in the cancer group and 13 in the non-cancer group; one of the strains was PCR ribotype 267
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and the others had no matching reference strains. PCR ribotype 027 was not encountered.
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There was no statistically significant association between PCR ribotype and toxinotype and exposure to
chemotherapy.
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Risk factors for recurrence of CDI
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In a univariate analysis there was a significant difference between the recurrence rates in the cancer and non-
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cancer group (Table 1). We therefore performed a multivariate logistic regression analysis to establish whether
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presence of malignancy remained a risk factor for recurrence after adjusting other variables. Age, sex, history of
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malignancy, admission history and leukocytosis were included in the analysis. Because of multicollinearity
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between malignancy and Charlson’s score, we excluded the latter from the analysis. Presence of malignancy
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within 5 years was found to be a significant risk factor for recurrence (OR=2.665, 95% CI 1.343-5.289, P=0.005).
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Age also had a statistically significant effect (OR=1.032, 95% CI 1.004-1.060, P=0.026) (Table 3).
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DISCUSSION
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In this study the clinical characteristics, outcomes and microibiological characteristics of CDI in patients with
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malignancies and those receiving anticancer chemotherapy were investigated. Recurrence of CDI was more
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frequent in the cancer patients than in the non-cancer patients, but chemotherapy did not significantly effect the
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clinical outcomes.
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With regard to CDI in cancer patients, either cancer itself or anticancer chemotherapy could influence the course
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of CDI. Chemotherapeutic agents could induce colonic inflammation, decrease the repair capacity of the mucosal
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epithelium or promote an anaerobic enviroment, which favors CDI [7]. In a review of CDI in cancer patients, it
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was noted that several specific chemotherapeutic agents such as 5-fluorouracil, DNA topoisomerase inhibitors,
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cisplatin, paclitaxel, and carboplatin among others were associated with the occurrence of CDI [7,22]. In a
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previous study, patients with gastrointestinal cancer had a lower probability of developing CDI than patients with
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other types of cancer [9]. Because the present study was retrospective, we could not estimate the true incidence
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and prevalence of CDI in the varios types of cancer or in response to chemotherapy. However, most of the cancer
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patnts in this study had solid tumors, and gastrointestinal cancer was actually the most common (47.8%) type
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among the CDI patients.
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There were no differences between the groups in clinical characteristics. Although WBC count was higher in the
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non-cancer group than the cancer group, and in the subgroup receiving conservative treament than in the subgroup
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receiving chemotherapy, severity scores and mortality did not differ between the groups. There were a total of 9
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neutropenia patients and most of them received chemotherapy, but neutropenia followed by chemotherapy was
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not associated with a poor outcome of CDI. Therefore, in the cancer group, and especially in the cancer patients
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receiving chemotherapy, leukocytosis did not predict the clinical course of CDI, which supports the view that
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other factors influence the CDI severity score in cancer patients [10].
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The estimated recurrence rate of CDI among initially treated CDI patients has been reported to be as high as
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35%, and this increases in the case of hypervirulent BI/NAP1/027 C. difficile infections [23-25]. The recurrence
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rate in Korea, where the prevalent PCR ribotypes are 017 and 018, has been reported to be 10-20%, lower than in
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Europe or North America [26,27]. In this study, recurrence was defined as a second episode at least 10 days and
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no more than 60 days after the first one. The overall recurrence rate was 12.3%, and 20.4% of cancer patients
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experienced recurrence. The risk factors for recurrent CDI described in previous studies include inadequate
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antitoxin antibody response, persistent disruption of colonic flora, age over 65 years, continuation of non-
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C.difficile antimicrobial therapy, long hospital stay, and concomitant receipt of antacid medication [28]. The
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presence of severe underlying disease was also associated with an increased risk of recurrence [29]. In our study,
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malignancy itself was found to be an independent risk factor for recurrent CDI regardless of exposure to
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chemotherapy within 2 months, or hospital admission. The profound immunological changes associated with
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cancer itself may increase the risk of recurrence [30,31,7].
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PCR ribotype 017 strains were the most common C. difficile ribotype infecting cancer patients. These strains are
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toxin A-negative and toxin B-positive strains endemic in Korea, especially in healthcare settings [32]. Frequent
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hospitalization probably increased the chance of infection by endemic C. difficile strains, but chemotherapy itself
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did not favor the acquisition of any particular C. difficile PCR ribotype. Because PCR ribotype 017 infections are
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reported to be more likely to recur in Korea than other PCR ribotype infections [33], infection by this ribotype
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may contribute to the higher recurrence rate in cancer patients.
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This study has several limitations. Because it was retrospective, we could not investigate the incidence of CDI
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among the totatality of cancer patients admitted to our hosipital, or establish which type of cancer or chemothrapy
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was most frequently associated with CDI. Second, because the study was conducted in a single-center, the types
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of cancers in patients and the prevalent strains of C. difficile could differ between hospitals, and conclusions must
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be generalized with care. However, our findings provide a basis for larger multicenter prospective studies of CDI
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in patients with malignancies.
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In conclusion, malignancy and old age are independent risk factors for recurrence of CDI. CDI patients
suffering from cancer should be kept under careful observation for recurrence after the initial treatment.
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Acknowledgments
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Funding : none
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Conflict of Interest : none
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Ethical approval : approved by the institutional review board of Hanyang University Hospital (HYUH IRB 2013-
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07-016)
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Informed consent : waived.
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Parts of this study present as a poster at ASM microbe 2016 (poster number 2207, June 16-20, 2016, Boston, US)
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