Clostridium difficile, a gram-positive, spore-forming bacteria, is a normal component of gut flora. When the competing gut flora are eliminated by antibiotics, Clostridium difficile may proliferate and result in Clostridium difficile infection (CDI), with disease symptoms ranging from Clostridium difficile–associated diarrhea to pseudomembranous colitis and toxic megacolon. Recent studies suggest an incidence of CDI of 4 to 9 per 1,000 days of hospital stay.Reference McFarland, Mulligan, Kwok and Stamm 1 – Reference Lessa, Gould and McDonald 4 CDI is the most common cause of infectious diarrhea in hospitalized patients.Reference Gursoy, Guven and Arikan 5 The recent increase in CDI has been attributed to the NAP-1 strain. Among the 300,000 patients diagnosed in the United States with CDI annually, ~14,000 patients die due to CDI-related complications.Reference Lucado, Gould and Elixhauser 3 , 6 – Reference McDonald, Killgore and Thompson 8
Epidemiological studies evaluating the incidence of and morbidity and mortality due to CDI in hematopoietic stem cell transplant (SCT) recipients are limited. The results of a multi-institutional survey in the United States demonstrated increased pooled rates of CDI in cancer patients. Patients with known malignancy were twice as likely to acquire CDI than the noncancer population (15.8 vs 7.4 per 10,000 patient days, respectively).Reference Kamboj, Son and Cantu 9 Several factors make SCT patients more susceptible to CDI: chemotherapy-related neutropenia, susceptibility to infectious complications necessitating use of broad-spectrum antibiotics, prolonged hospitalization, altered integrity of the intestinal mucosa due to chemotherapy induced gut injury, graft-versus-host disease (GVHD),Reference Chakrabarti, Lees, Jones and Milligan 10 , Reference Alonso, Treadway and Hanna 11 and inability to mount a humoral response to C. difficile–specific toxins.Reference Aronsson, Granstrom, Mollby and Nord 12 , Reference Kyne, Warny, Qamar and Kelly 13 To date, varying prevalence rates of CDI have been reported in SCT patients, ranging from 3.5% to 27% in allogeneic SCT (allo-SCT) patients and 6.5% to 9% among autologous SCT (auto-SCT) patients.Reference Alonso and Marr 14 Because infectious complications comprise a major portion of treatment-related mortality in SCT patients, identifying the most common infectious causes of death and attempting to decrease their prevalence with appropriate interventions may favorably impact survival after SCT. A retrospective analysis by Morris et alReference Morris, Jobe, Stoney, Sheppard, Deveney and Deveney 15 demonstrated that the incidence of CDI has increased by ~30% compared with the data from the prior 10 years. During the same period, CDI-related mortality increased from 3.5% to 15.3%, suggesting the need for interventions to decrease the incidence of CDI and to reduce its devastating consequences.Reference Morris, Jobe, Stoney, Sheppard, Deveney and Deveney 15
Previous single-institution trials evaluating CDI in SCT patients identified the following risk factors for CDI: elderly patients, myeloablative conditioning regimen, use of total body irradiation ≥12 Gy in the conditioning regimen, duration of neutropenia, length of hospital stay (LOS), lower gastrointestinal acute GVHD, use of antibiotics, overall number of antibiotics, and use of proton-pump inhibitors.Reference Alonso, Treadway and Hanna 11 , Reference Slimings and Riley 16 – Reference Paul, Yahav, Fraser and Leibovici 19 We employed a large national database to address questions regarding the overall prevalence rates of CDI among SCT patients and to compare differences in prevalence of CDI-related mortality among auto-SCT and allo-SCT patients. Our analysis represents the largest hospital-based study to date that has independently examined risk factors for CDI among auto-SCT and allo-SCT patients.
METHODS
Description of Dataset
We analyzed adult SCT patients (≥18 years of age) who received inpatient SCT in 10 years of National Inpatient Sample (NIS) data between January 2001 and December 2010. 20 Each year, the NIS provides information on approximately 8 million inpatient stays from ~1,000 hospitals in states participating in the Healthcare Cost and Utilization Project (HCUP). It is designed to approximate a 20% sample of US community non-federal, short-term, general, and specialty hospitals. SCT recipients were identified using principal procedure International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes for auto-SCT or allo-SCT. Thus, our study population included patients who had an SCT during this hospitalization and not just a history of stem cell transplantation. The demographic variables used for our analyses included gender (female as reference group), race (white as reference group), age group (<40 years, 40–65 years [reference group], >65 years), LOS (LOS ≤ median as the reference group) and in-hospital mortality (IHM). Other clinical variables were also used for our analysis: (diagnosis of multiple myeloma (MM), Hodgkin’s disease (HL), non-Hodgkin’s lymphoma (NHL), leukemia and others), history of radiation, other hospitalization complications of septicemia, respiratory failure, diabetes, and comorbidities.
The database does not describe the type of chemotherapy used in the preparative regimen, but it does indicate whether radiation was administered during the hospitalization. While the dataset does not distinguish between localized versus total-body irradiation (TBI), we classified the use of any inpatient radiation as a TBI-based conditioning regimen. We used the comorbidity software to identify and tabulate comorbidities based on ICD-9 diagnosis coding as reported by Elixhauser et al.Reference Elixhauser, Steiner, Harris and Coffey 21 Comorbidity was stratified into 2 groups: ≤1 comorbidity or ≥2 comorbidities.
Next, we used the clinical classification software (CCS) developed by HCUP to identify the clinical variables for our analyses.Reference Elixhauser, Steiner and Palmer 22 We performed a Breslow Day test to assess for interaction and logistic regression to adjust for confounding factors. Since the likelihood ratio test was found to be significant, we dropped 1 interaction term at a time to reach a final model with significant interaction terms and relevant confounders. All statistical analyses were conducted using SAS version 9.3 for Windows (SAS, Cary, NC). A P value<.05 was considered statistically significant.
RESULTS
The NIS contained data on a total of 98,684 patients who were admitted for SCT during the study period. Of these admissions, 86,261 (87.4%) had complete data available and were included in the current analysis. Moreover, 53,072 patients (61.5%) underwent auto-SCT and 33,189 patients (38.5%) underwent allo-SCT for the indications listed in Table 1. Multiple myeloma was the most common indication for auto-SCT (43%), followed by NHL (29.7%), HL (11.1%), and leukemia (6.9%). In contrast, leukemia patients formed the majority (63.8%) of the allo-SCT recipients, while 14.8% of allo-SCT recipients had a diagnosis of NHL. Multiple myeloma and HL comprised small portions of the allo-SCT group: 4.4% and 3.3%, respectively.
TABLE 1 Characteristics of Stem Cell Transplant Patients
NOTE. CDI, Clostridium difficile infection; auto-SCT, autologous stem cell transplant; allo-SCT, allogeneic stem cell transplant.
Among the 53,072 auto-SCT recipients, 58.3% were male and most (64.5%) were aged 40–65 years. Similarly, among the 33,189 allo-SCT recipients, most (58.6%) were male, and 64.6% were aged 40–65 years. The allo-SCT recipients were younger, with 29.2% in the 18–39-year age group (vs 18.9% of auto-SCT patients). The proportion of whites in the auto-SCT group was 74.5% (vs 78% of the allo-SCT group), whereas blacks comprised 10.3% (vs 4.8% of the allo-SCT group). In addition, 4.4% of auto-SCTs and 21.9% of allo-SCTs received radiation as part of the preparative regimen. The allo-SCT group had lower comorbidity scores than the auto-SCT group (≤1: 41.4% of allo-SCTs vs 54.6% of auto-SCTs; P=.0007). Auto-SCT patients had lower rates for several risk factors analyzed: length of stay (18 days for auto-SCTs vs days 26 for allo-SCTs), IHM (2.2% of auto-SCTs vs 9.1% of allo-SCTs), in hospital complications of septicemia (15.7% of auto-SCTs vs 20.4% of allo-SCTs), and respiratory failure (3% of auto-SCTs vs 9.4% of allo-SCTs) (P<.0001). Leukemia patients were also more likely to develop septicemia than other pateints among both auto-SCT and allo-SCT recipients. In-hospital mortality was higher among leukemia patients in both auto- and allo-SCT groups.
The prevalence of CDI among all SCT recipients was 6.8%, with a higher prevalence of CDI among allo-SCT recipients than among auto-SCT recipients (8.5% of allo-SCTs vs 5.8% of auto-SCTs; P<.0001). Among both auto-SCT and allo-SCT recipients, the prevalence of CDI differed depending on the underlying diagnosis. Leukemia patients were the group most likely to acquire CDI, regardless of transplant type.
Among auto-SCT recipients, risk factors for CDI included older age (40–65 years vs 18–39 years; OR, 1.37; 95% CI, 1.08–1.74; and >65 years versus 18–39 years; OR, 1.67; 95% CI, 1.3–2.16), male gender (OR, 1.25; 95% CI, 1.08–1.37), and the presence of ≥2 comorbidities (≥2 vs ≤1 comorbidity; OR, 1.39; 95% CI, 1.16–1.67). Auto-SCT patients who had a LOS longer than the median (≤18 days vs >18 days; OR, 2.76; 95% CI, 2.23–3.41), who received a TBI-based regimen (yes vs no; OR, 1.48; 95% CI, 1.08–2.01), who developed septicemia (yes vs no; OR, 2.16; 95% CI, 1.77–2.63), or who had respiratory failure (yes vs no; OR, 2.33; 95% CI, 1.61–3.38) were more likely to develop CDI. In the multivariate analyses, the presence of ≥2 comorbidities (OR, 1.32; 95% CI, 1.11–1.57), developing septicemia (OR, 1.64; 95% CI, 1.35–2), longer-than-median LOS (≤18 days vs >18 days; OR, 2.81; 95% CI, 2.29–3.45) were independently associated with CDI in auto-SCT patients (Table 2).
TABLE 2 AnalysesFootnote a for Different Covariates and the Risk of Developing Clostridium difficile Infection (CDI) Among Autologous Stem Cell Transplant PatientsFootnote b
NOTE. Ref, reference.
a Multivariate analysis was adjusted for age, race, gender, comorbidities, diabetes, radiation, septicemia, respiratory failure, and length of stay.
b N=53,072.
c P value for interaction, >0.05.
d P value for interaction, <0.05.
Among the allo-SCT patients, patients with NHL were less likely to develop CDI (OR, 0.64; 95% CI, 0.5–0.82), whereas young patients (aged 18–39 years; OR, 1.36; 95% CI, 1.08–1.5), male gender (OR, 1.36; 95% CI, 1.18–1.57), and patients with ≥2 comorbidities (OR ≥2 vs ≤1 comorbidity, 1.18; 95% CI, 0.97–1.44) were more likely to develop CDI. Allo-SCT patients that had a longer-than-median LOS (>26 days vs ≤26 days; OR, 3.06; 95% CI, 2.44–3.84), received a TBI-based regimen (yes vs no; OR, 1.36; 95% CI, 1.09–1.69), developed septicemia (yes vs no; OR, 2.16; 95% CI, 1.76–2.66), or had respiratory failure (yes vs no; OR, 1.61; 95% CI, 1.29–2.0) were more likely to develop CDI than those without. On the multivariate analysis, presence of ≥2 comorbidities (OR, 1.18; 95% CI, 1.00–1.40), developing septicemia (OR, 1.69; 95% CI, 1.36–2.1), longer-than-median LOS (OR, 2.63; 95% CI, 2.15–3.22) were independently associated with CDI (Table 3).
TABLE 3 Stratified Odds Ratio Estimates for Different Indications Among Autologous Stem Cell Transplant Patients
We conducted a multivariate analysis in which adjustment was made for age, race, gender, comorbidities, diabetes, radiation, septicemia, respiratory failure, and LOS. Among auto-SCTs, there was significant correlation between age and diagnostic indication (Table 4).
TABLE 4 AnalysesFootnote a for Different Covariates and the Risk of Developing Clostridium difficile Infection Among Allogeneic Stem Cell Transplant PatientsFootnote b
NOTE. Ref, reference.
a Multivariate analysis was adjusted for age, race, gender, comorbidities, diabetes, radiation, septicemia, respiratory failure and LOS.
b N=33,189.
DISCUSSION
Using data from close to 1,000 hospitals (20% of US community hospitals) over a 10-year period, our study is the first of its kind to evaluate the risk factors for CDI among SCT recipients. Current literature about the epidemiology of CDI among SCT recipients is limited to single-institution–based publications, in which the incidence of CDI widely fluctuates. Our study, using data from in-hospital admissions for SCT obtained from the NIS aimed not only to understand the prevalence of CDI among the autologous and allogeneic SCT patients but also to elucidate the CDI-associated risk factors and to identify SCT patient subsets at higher risk for developing CDI. We found that the prevalence of CDI among the auto-SCT patients was lower than that among the allo-SCT patients, and we analyzed each subset separately. The clinical characteristics of patients in the NIS database were similar to findings reported elsewhere, indicating that these data are representative of SCT activities during this period. Multiple myeloma was the most common indication for auto-SCT, and leukemias were the most common indication for allo-SCT, similar to findings reported by the Center for International Blood and Marrow Transplant Research (CIBMTR). Furthermore, other patient and treatment characteristics were in line with findings that would be expected based on available registry data, so we believe that this analysis can yield general conclusions regarding risk for CDI that can be extrapolated to the general SCT population in the United States.
Based on the most common indication for auto-SCT and allo-SCT, we used MM patients (aged 40–65 years) and leukemia patients (aged 18–39 years) as reference groups for auto-SCT and allo-SCT, respectively, when conducting multivariate analyses. The prevalence of CDI among all SCT recipients was 6.8% (auto-SCT vs allo-SCT recipients: 5.8% vs 8.5%, respectively; P<.0001). Our study corroborates findings from previous studies showing a higher rate of CDI among allo-SCT recipients than their auto-SCT counterparts.Reference Kamboj, Son and Cantu 9 , Reference Alonso, Treadway and Hanna 11 , Reference Trifilio, Pi and Mehta 17 , Reference Chopra, Chandrasekar, Salimnia, Heilbrun, Smith and Alangaden 23 The prevalence of CDI was highest for leukemia patients, whether they received auto- or allo-SCT. Several factors may explain a higher rate of CDI in leukemia patients: more intensive therapy and extensive hospitalization prior to the transplant maneuver, increased transplant admission LOS, more common use of TBI-based conditioning,Reference Willems, Porcher and Lafaurie 18 and increased risk of septicemia and respiratory failure. On multivariate analyses, younger patients with any of the different diagnostic indications were at lower risk of developing CDI than the reference group. Notably, older allo-SCT patients were at a lower risk of developing CDI than younger allo-SCT patients, which could be due to the greater use of reduced-intensity conditioning regimens in older patients.
On multivariate analysis, independent risk factors for developing CDI in both the auto-SCT and the allo-SCT cohorts were septicemia, ≥2 comorbidities, and longer LOS. From this database, we were not able to assess whether longer LOS is part of the etiology of CDI or a consequence of CDI. Septicemia as a risk factor for developing CDI has been previously reported in multiple studies,Reference Halabi, Nguyen, Carmichael, Pigazzi, Stamos and Mills 24 possibly related to prolonged use of broad-spectrum antibiotics. Although it may be intuitive to think that diabetic patients are more likely to develop CDI due to increased risk of immunosuppression, as shown by Hassan et al,Reference Hassan, Rahman, Huda, Wan Bebakar and Lee 25 our results did not show a difference in CDI between diabetics and nondiabetics. Because CDI is relatively common among mechanically ventilated patientsReference Halabi, Nguyen, Carmichael, Pigazzi, Stamos and Mills 24 , Reference Micek, Schramm and Morrow 26 and the NIS dataset does not allow us to specifically identify ventilated patients, we used respiratory failure as a surrogate marker. On univariate analyses, respiratory failure was a risk factor for CDI in both auto-SCT and allo-SCT patients but was not statistically significant in the multivariate analyses.
Although this large dataset allows us to evaluate the prevalence and risk factors for CDI, the NIS data have certain limitations. First, individual patients may not be followed longitudinally over time. Second, because it is discharge-level data, cause and effect cannot be ascertained and our results can show associations only. Third, the dataset does not provide detailed information to explore specific aspects of treatment that have been shown in previous studies to be associated with CDI, such as the type of conditioning regimen, previous lines of therapy, disease status, type of antibiotic prophylaxis, time to engraftment, occurrence of neutropenic fever, and development of GVHD after allo-SCT.Reference Alonso, Treadway and Hanna 11 , Reference Trifilio, Pi and Mehta 17 We used broad categories for indications of SCT, making it impossible to tease out nuances of risk that may be associated with specific disease subgroups (eg, AML vs ALL) or rare disease indications for transplantation. This study included a population over 10 years, and we did not take into account the change in testing practices for detection of C. difficile. Using ICD-9 codes, it is difficult to assess whether C. difficile was detected using culture or toxigenic culture or toxin A+B enzyme immunoassay or nucleic acid amplification.Reference Surawicz, Brandt and Binion 27 The testing methods used to diagnose CDI are unavailable in the NIS database; therefore, we relied on the ICD-9 codes to identify patients. Our data rely on accurate coding of a diagnosis of CDI; aggressive coding practices could lead to coding of colonization as infection. Prior studies have found a good correlation between ICD-9 codes and toxin assays, establishing this as an acceptable method for the identification of CDI.Reference Scheurer, Hicks, Cook and Schnipper 28 , Reference Dubberke, Reske, McDonald and Fraser 29 Despite these limitations, our study establishes CDI rates in auto-SCT and allo-SCT recipients, and it indicates the broad groups of patients at risk for developing CDI, potentially identifying subgroups that could benefit from prophylactic strategies for preventing CDI. Currently, the mainstays of CDI prevention include antimicrobial stewardship and infection control practices such as barrier precautions and environmental cleaning. Despite the implementation of these measures in SCT practices, CDI rates remain high; therefore, alternative strategies for prevention are needed. Studies including multifaceted interventionsReference Koll, Ruiz and Calfee 30 , Reference Davis, Yin, Blomberg and Fung 31 have shown promise and need to be tested at the multi-institutional level for certain high-risk groups. Davis et alReference Davis, Yin, Blomberg and Fung 31 tested the impact of a 5-component bundle that included antibiotic drug management, early detection, cleaning, practice, and people bundle. The current study helps identify higher-risk groups for such clinical interventions. Among allo-SCT recipients, interventions to reduce or treat gut GVHD could also impact CDI rates. The impact of fecal microbiota transplantation among patients with gut GVHD was studied recently.Reference Kakihana, Fujioka and Suda 32 It would be interesting to study its impact on CDI. Many topics of study remain to be explored in the prevention of CDI among SCT patients. This group could certainly benefit from more interventions to reduce mortality and morbidity. Since its inception in 1939, stem cell transplant has advanced considerably. Certainly, further interventions to improve outcomes, such as reducing the rate of C. difficile infection, are needed.
ACKNOWLEDGMENTS
Financial support: No financial support was provided relevant to this article.
Potential conflicts of interest: All authors report no conflicts of interest relevant to this article.
