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Knowledge of outcomes of C. difficile infection (CDI) in solid organ transplant (SOT) recipients is limited. To evaluate this population, we undertook a retrospective cohort study of all recipients of kidney and liver transplants diagnosed with CDI at a single center over 14 years. Data pertaining to all episodes of CDI were collected. Multivariate analysis using logistic regression was performed to determine independent predictors of clinical cure. Overall, 170 patients developed 215 episodes of CDI. Among these patients, 162 episodes (75%) were cured, and in 103 episodes (48%), patients were cured within 14 days. In a multivariate analysis, lack of clinical cure at 14 days was predicted by: recurrent episode (0.21, 95% CI 0.06-0.72, p=0.0128), treatment with vancomycin (OR 0.27, 95% CI 0.1-0.74, p=0.011), vasopressor support (OR 0.23, 95% CI 0.07-0.76, p=0.0161), and CDI before the year 2004 (OR 0.44, 95% CI 0.2-0.98, p=0.0446.) The latter three factors are likely markers for severity of illness. In this cohort, 13 patients (8%) died during hospitalization and 49 patients (29%) died within one year. No deaths were attributed to CDI. Recurrent episode was a major predictor of treatment failure, suggesting that research into development of therapeutic options for recurrent disease is needed.
Diarrhea is a common gastrointestinal complication of solid organ transplantation (SOT), affecting up to 50% of liver and kidney recipients.(1, 2) C. difficile infection (CDI) has been increasingly recognized as an important etiology of diarrhea in this population. While only 1-2% of general inpatients develop CDI, 3.5-16% of renal transplant recipients and 3-7% of liver transplant recipients are affected, most frequently in the early post-transplant period.(3-9) This is not surprising given that risk factors for CDI include immunosuppression, healthcare exposure, and antibiotic exposure, all of which are common in the immediate post-transplant period.(10) Previous studies of CDI in SOT have shown higher rates of fulminant colitis compared to non-transplant populations.(11) However, mortality does not appear to be increased among SOT recipients.(12) We retrospectively analyzed liver and kidney transplant recipients from a single center to assess outcomes among this population.
On June 12, 2009, we queried the University of Wisconsin Transplant Database, a prospectively collected data set, to identify all patients receiving liver or kidney transplants between January 1, 1994 and December 31, 2008 who had at least one episode of C. difficile infection (CDI) after transplantation. Due to the low numbers of other intra-abdominal organ transplant types, such as pancreas and intestines, data collection was limited to liver and kidney recipients. Manual chart review was undertaken to identify all episodes in which patients had diarrhea or abdominal pain with one of the following indicators of C. difficile infection: positive toxin assay or culture, pseudomembranous colitis on endoscopy, surgery, or histopathathology. For each episode, the following data were collected: demographics, immunosuppression, comorbid illnesses, recent procedures, CDI treatment, antibiotic exposure, and outcomes, focusing on clinical cure and mortality. Chart review was continued through one year post-CDI diagnosis to ascertain clinical cure and mortality data. Relevant definitions are provided in Table 1. The University of Wisconsin Health Sciences Institutional Review Board approved the study protocol.
All patients were given peri-operative prophylaxis with cefazolin (renal transplant) or ceftriaxone (liver transplant). Selective digestive decontamination was not used. Induction regimens included one of the following: alemtuzumab (for renal transplants, one or two 20 mg doses), basiliximab (2 doses of 20 mg on day 0 or the day of surgery and day 4), daclizumab (1 mg/kg on day 0 and 1 dose every other week for total of 5 doses), or muromonab-CD3, ATG, Thymoglobulin (Genzyme Transplant, Cambridge, MA.) The operating surgeon made the decision to use a particular antibody for induction therapy on the basis of perceived efficacy, side effect profile, and cost. Thymoglobulin was generally preferred for, but not limited to, re-transplants. Thymoglobulin was administered at a dose of 1.5 mg/kg daily starting on day 0 and continued until calcineurin inhibitor levels were therapeutic or a maximum of 14 doses was given. A minimum of 4 doses of Thymoglobulin was given. Muromonab-CD3 (Orthoclone-OKT3; Centocor Ortho Biotech, Horsham, PA) was given at a dose of 5 mg/day for a minimum of 7 doses and maximum of 14 doses. Anti-thymocyte globulin (ATG; Upjohn, Kalamazoo, Mich.) was given at a dose of 15 mg/kg daily for a minimum of 4 and a maximum of 14 doses.
For kidney transplants, maintenance immunosuppression in all groups consisted of either tacrolimus or cyclosporine started when serum creatinine level declined to less than 3.0 mg/dL. The choice of cyclosporine or tacrolimus was at the discretion of the transplant physician. Mycophenolate mofetil (MMF) was used in all patients starting on day 1 at a dose of 1000 mg twice daily and reduced for symptoms of diarrhea or white blood cell count less than 3.0 × 103/μL. In patients not treated with alemtuzumab, methylprednisolone was administered at a dose of 500 mg intravenously on day 0 and 250 mg intravenously on day 1. Subsequent steroids consisted of prednisone 90 mg orally on day 2, 60 mg on day 3, 30 mg on day 4 and 30 mg daily thereafter. Prednisone was tapered to 10 mg by 3 months in patients without rejection.
For liver transplants, maintenance immunosuppression consisted of tacrolimus with or without a second immunosuppressant such as MMF at a dose of 2 to 3 grams per day in two divided doses. The tacrolimus doses were adjusted to maintain levels of 5-10 ng/ml.
Treatment of rejection was initiated with high dose corticosteroids. For steroid refractory rejection, muromonab-CD3 was used.
Antifungal prophylaxis included clotrimazole troches or nystatin swish and swallow for 3 months. Fluconazole antifungal prophylaxis was not routinely used at our institution for any of these organ transplant groups. Cytomegalovirus (CMV) prophylaxis in kidney recipients was based on donor/recipient status (D/R). If basiliximab was used as the induction agent, patients at highest risk (D+/R) received valganciclovir 900 mg daily, while D−/R− received acyclovir 400 mg twice daily and D−/R+ received acyclovir 800 mg four times daily. If alemtuzumab or anti-thymocyte globulin was used, valganciclovir 900 mg daily replaced acyclovir. Preemptive therapy or monitoring was not employed at our institution. Liver transplant recipients received valganciclovir 900 mg daily for CMV prophylaxis. In the years before valganciclovir became available, oral ganciclovir was used. The duration of CMV prophylaxis was 90 days following transplantation.
Data on predictors of mortality for patients who died and those who did not was compared using the χ2 or Fisher's exact test for categorical variables and the Wilcoxon Rank Sum test for continuous variables. Multivariate analysis of factors associated with mortality was performed using stepwise multiple logistic regression modeling with generalized estimating equations. We chose to model the correlation of the repeated measures on some of the individuals with a compound symmetry covariance structure. While age and gender were always included in the model, the criterion for entry into the model for the remaining predictors was significance at α = .20, whereas the criterion for remaining in the model was significance at α = .10. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated. Model fit was assessed using the Hosmer-Lemeshow goodness-of-fit statistic, and all models fit the data well. Analyses were repeated using clinical cure as the outcome. Analyses were conducted using the R statistical computing environment (Version 2.11, 2010.)
During the time period of January 1, 1994 through December 31, 2008, 1,036 patients underwent liver transplant and 3,630 patients underwent kidney transplant Overall, 170 patients with 215 episodes of CDI formed the cohort, including 63 liver recipients with 83 episodes and 107 kidney recipients with 132 episodes. 80% of patients had a single episode of CDI and 16% had two episodes. The remainder had 3 or more episodes (range 3-7.) There were 106 (62%) men and 64 (38%) women. The mean age at the time of CDI was 55 years (SD 10.93, range 25-77). Most patients, 139 (82%) had a single transplant, 25 (15%) underwent re-transplantation and 6 (4%) had a third or fourth transplant. Ninety-nine percent of patients received prednisone. Seventy percent (111) of patients received induction treatment with a monoclonal antibody. The monoclonal antibody used was alemtuzumab in 28 patients (16%), basiliximab in 60 (35%), muromonab in 4 (2%) and daclizumab in 4 (2%). ATG was used in 16 patients (9%). For maintenance immunosuppression, tacrolimus was used in 82 (49%) of patients, MMF in 143 (84%), cyclosporine in 70 (41%), and azathioprine in 5 (3%).
In assessing potential risk factors for CDI, 20 patients (12%) had malignancy and 23 (14%) had non-C. difficile colitis. Eighteen liver patients (29%) had renal dysfunction and 4 kidney patients (<1%) had liver disease. Overall, 37 (22%) patients were receiving hemodialysis. Use of acid suppressants, including proton pump inhibitors or H2-blockers, was recorded in 173 (80%) of the episodes. Antibiotic use at the time of CDI diagnosis was documented in 106 episodes, while antibiotics preceded 152 episodes within 30 days. Lastly, in 105 episodes, patients underwent an abdominal surgery or procedure within 30 days preceding diagnosis with CDI.
On average, CDI occurred 653 days post-transplant. Of the 215 episodes, 29 were recurrences (14 liver, 15 kidney.) Data regarding location of symptom onset were available for 189 episodes. Among these, 106 episodes were hospital-acquired and 56 were community-onset, healthcare-associated. Patients were hospitalized specifically for CDI in 59 episodes. Signs and symptoms were abstracted from the chart for the 48 hours prior to diagnosis of CDI. Among all episodes, 48 patients (22%) had fever, 33 (15%) were hypothermic, 67 (31%) were hypotensive, and 37 (17%) were tachycardic. Eleven (5%) were cared for in the ICU due to infection with C. difficile. The average white blood cell count at diagnosis among all episodes was 9.8 × 103/μl. One hundred seventy cases (79%) were diagnosed by C. difficile toxin enzyme immunoassay with the remainder being diagnosed by culture, cytotoxicity assay, and/or visualization of pseudomembranous colitis via endoscopy or surgery.
Metronidazole was the initial therapy in 174 episodes (81%), while 29 episodes (13%) were first treated with oral vancomycin. Among those first treated with oral vancomycin, 9 were a recurrent episode of CDAD. The remaining episodes were treated with rifaximin or specific treatment was unknown. The median duration of initial therapy was 10 days (SD 9). In 22 episodes (10%), patients were initially treated with metronidazole and later switched to vancomycin. Using the scoring system developed by Zar, et al., the average severity of illness was 1 (SD 1.) (13)
Overall, 162 episodes (75%) were cured, 62 episodes (75%) in liver recipients and 100 episodes (76%) in kidney recipients. In 103 episodes (48%), patients were cured within 14 days. In the remaining 53 episodes, 9 episodes were not cured (symptoms persisted or re-treatment was undertaken) and 44 episodes had incomplete data. Thirteen patients died (8%) died during hospitalization. In this study, no patients were treated with colectomy and no deaths were attributed to CDI.
We compared features of patients who were cured in 14 days to those who were not cured to determine predictors of successful treatment. Table 2 shows features of patients who were cured versus those who were not. Clinical cure was achieved less frequently in patients with recurrent CDI and liver disease, as well as those treated with vancomycin. We constructed regression models to identify independent predictors of clinical cure in 14 days. The following variables were associated with a reduced likelihood of cure: use of vancomycin (OR 0.27, 95% CI 0.1-0.74, p=0.011), recurrent episode (OR 0.21, 95% CI 0.06-0.72, p=0.0128), vasopressor support (OR 0.23, 95% CI 0.07-0.76, p=0.0161), and CDI before the year 2004 (OR 0.44, 95% CI 0.2-0.98, p=0.0446.)
We compared features of patients with CDI who died within 1 year of a CDI episode to those who did not die to determine predictors of mortality (Table 4). Renal disease was more common amongst patients who died within 1 year. Additionally, the 1-year mortality rate was higher among patients with healthcare-onset CDI and prior ICU care. Multivariate analysis to determine independent predictors of mortality was not performed due to the low number of deaths.
With incidence ranging from 3-16% among intra-abdominal solid organ transplant recipients, CDI is a significant problem in terms of morbidity and cost.(10) Fulminant colitis has been reported in up to 13% of SOT recipients and previous retrospective analysis showed that as many as 27% of SOT recipients with CDI required colectomy.(11, 12) Despite the apparent increased severity of disease among SOT recipients, all-cause mortality among SOT recipients with CDI is low, ranging 0.7% to 10.3%.(12,14,15) Our study had similar results with all-cause one-year mortality of 7.6% and no deaths attributed to CDI. There are several possible explanations for discordant assessments of disease severity and mortality. The most important issue is that of assessing disease severity. There is no validated scoring system for severity of illness specifically in transplant recipients. As studies of CDI include a diverse population of inpatients and outpatients, assessing severity of illness is challenging. In our study, we attempted to address this by reviewing surrogate markers, including vital signs, location of care (intensive care unit versus general care), and need for vasopressor support. Additionally, we included calculation of the scoring system used by Zar, et al to assess severity of CDI.(13) Vasopressor support independently predicted treatment failure, suggesting a relationship between severity of illness and outcome. However, no other surrogate marker predicted clinical cure. Development of a severity of underlying illness instrument to allow for adequate adjustment of this important variable is needed.
The association of vancomycin and lack of clinical cure was an unexpected finding in this study and in all likelihood reflects confounding by indication or confounding by disease severity. Prior work by Zar, et al. showed similar clinical outcomes with vancomycin and metronidazole in mild CDI and improved outcomes with vancomycin in severe CDI.(13) As our study was not randomized, treatment was selected by individual providers. Patients with more severe CDI were likely given vancomycin as the initial treatment thus representing confounding by indication and disease severity. As a result, this finding cannot be interpreted as a suggestion to change clinical practice. Recently, another therapeutic option for CDI, fidaxomicin, a macrocyclic antibiotic with activity against C. difficile has become available and should be studied further for its efficacy in the solid organ transplant population.(16)
The remaining predictors for lack of cure included recurrent episode and treatment before 2004. Risk factors for recurrence, including inadequate antitoxin antibody response, persistent disruption of the colonic flora, advanced age, antibiotic exposure, long hospital stays, and concomitant receipt of gastric acid-suppressing medication, are common among SOT recipients.(17) These risks often cannot be modified in SOT recipients; thus, the finding of increased treatment failure in recurrent disease is biologically plausible. We analyzed our cohort based on treatment of CDI pre- and post-2004 based on the potential for hypervirulent BI/NAP1/027 strain to result in different outcomes.(5) We hypothesized that treatment failure would occur more frequently in the years after identification of the hypervirulent epidemic strain. However, in multivariate analysis, treatment before 2004 predicted treatment failure. As strain typing was not routinely done at our institution, we cannot determine whether or not any of the patients had disease caused by the epidemic strain or not. Routine antibiotic prophylaxis regimens were unchanged during the study period. We propose that the unexpected finding of improved outcomes post-2004 is related to improvements in transplant surgical techniques that decrease complications and length of stay, as well as enhanced medication regimens that minimize the degree of immune suppression. Further investigation into the etiology of improved CDI outcomes over the past decade could yield improved identification and treatment of CDI among this patient population.
Data on outcomes on CDI in transplant patients is limited but growing.(10,18) The incidence of CDI varies greatly across studies likely due to differences in study populations, type of transplant, comorbid illnesses, antibiotic use and site specific characteristics, including location and immunosuppression.(19) A recent retrospective study in lung transplant recipients reported a 22% incidence of CDI following lung transplantation and a higher risk of death in those patients.(20) In a large study from Spain, 26 of 4472 SOT patients had CDI between 2003 to 2006 for an incidence of 0.9%. There were no deaths related to CDI.(21) In another recent analysis, the authors found an incidence of CDI of 2.7% using the United States Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality 2009 database. CDI was associated with greater in hospital mortality especially in the lung transplant group and increased need for colectomy. However the impact of CDI treatment on these outcomes was not assessed.(22) Our study supports current literature and extends the knowledge on this topic by examining the impact of treatment on outcomes. Future studies should examine the reported disparity across studies in outcomes of CDI, with some finding an independently increased risk of mortality and colectomy, and others such as ours reporting favorable outcomes for SOT patients with CDI.
Limitations of our study included lack of data regarding cost or duration of hospitalization in transplant patients with CDI. Additionally, we did not assess outcomes of CDI in non-transplant patients at our center to use as a comparison. These are potential areas for future investigation.
In summary, we found that treatment with vancomycin, recurrent episode, need for vasopressor support, and treatment before the year 2004 predicted lack of CDI cure within 14 days. No mortality attributed to CDI was seen in this cohort and all-cause mortality approximated that of prior studies. Based on this retrospective analysis, outcomes of SOT recipients with CDI appear to be similar to non-SOT patients with CDI. Further research is needed to assess severity of illness in transplant populations and to identify better therapeutic options for CDI, especially recurrent disease.
Hsu JL, Enser JJ, McKown T, Leverson GE, Pirsch LD, Hess TM, Safdar N. Outcomes of Clostridium difficile infection in recipients of solid abdominal organ transplants.
All authors participated in the research design; J.L.H., J.J.E., T.M., N.S. participated in the performance of the research; J.L.H., G.L., T.M.H., N.S. participated in data analysis; J.L.H., J.J.E., T.M., J.D.P., and N.S. participated in the writing of the manuscript.