Clostridium Difficile Colitis: Increasing Incidence, Risk Factors, and Outcomes in Solid Organ Transplant Recipients : Transplantation

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Clinical and Translational Research

Clostridium Difficile Colitis

Increasing Incidence, Risk Factors, and Outcomes in Solid Organ Transplant Recipients

Boutros, Marylise1; Al-Shaibi, Maha1; Chan, Gabriel1; Cantarovich, Marcelo2; Rahme, Elham3; Paraskevas, Steven1; Deschenes, Marc4; Ghali, Peter4; Wong, Philip4; Fernandez, Myriam1; Giannetti, Nadia2; Cecere, Renzo2; Hassanain, Mazen1; Chaudhury, Prosanto1; Metrakos, Peter1; Tchervenkov, Jean1; Barkun, Jeffrey S.1,5

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doi: 10.1097/TP.0b013e31824d34de
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Clostridium difficile-associated diarrhea (CDAD) is an increasingly important diagnosis after solid organ transplantation. It is now recognized as the most common cause of nosocomial antibiotic-associated diarrhea (1–4). Broad-spectrum antimicrobial agents (5–7) have been associated with CDAD; however, not every case of CDAD is preceded by antibiotic therapy (7, 8). Other risk factors for CDAD in the nontransplant population include prolonged hospital stay, advanced age, comorbidities, uremia, and gastrointestinal surgery (9–11). Many of these are inherent to transplantation; however, risk factors specific to the solid organ transplant population have not yet been identified. An “immunocompromised host,” as a general risk category is also reported and includes chemotherapy, acquired immune deficiency syndrome, steroids (12), or transplantation (12–14); however, some authors argue that transplantation is not a clear risk factor for CDAD (15). The presentation of CDAD varies from mild diarrhea to life-threatening systemic toxicity (2, 11, 16, 17). After transplantation, however, diarrhea is a nonspecific complaint with many potential causes. With the exception of a single case report associating tacrolimus with CDAD (18), there has been no clear causative association between CDAD and a specific transplant immunosuppressive medication.

The incidence of CDAD in solid organ transplant recipients has been estimated to be 3.0% to 7.0% in liver (19–23), 3.5% to 16.0% in kidney, 1.5% to 7.8% in kidney-pancreas (19, 20, 24), 9.0% in intestinal (22, 23), 15.0% in heart (19, 25), and 7.0% to 31.0% in lung (12, 19, 26) recipients. CDAD after solid organ transplantation most frequently occurs within the first 3 months likely because of recent hospitalization, intense immunosuppression, and more frequent antimicrobial exposure (19, 21). Late-onset CDAD occurs months to years after transplantation and is usually associated with either antimicrobial exposure or intensified immunosuppression to treat graft rejection (21, 24).

The management of CDAD in the nontransplant population varies widely, but efforts have frequently targeted the identification of groups at risk for complicated C. difficile colitis (CCDC). A single center study identified the factors associated with mortality from CCDC in the general population (27), which included longer pre-CCDC hospital stay, greater Acute Physiology and Chronic Health Evaluation II score, greater American Society of Anesthesiologists class, a lower diastolic blood pressure, preexisting pulmonary and renal disease, steroids, toxic megacolon, leukocytosis, and signs of sepsis or organ dysfunction. Among the general population, the mortality rate associated with colectomy for CCDC was 35.7% (27). However, in the solid organ transplant population, the management and reported mortality of surgery for CCDC is not well characterized. The estimated incidence of fulminant colitis after solid organ transplantation appears higher than in the general population (8.0% of immunocompetent patients and 13.0% of solid organ transplant recipients) (12, 28, 29).

In North America and Europe, a rising incidence of CDAD associated with the North American pulse-field gel electrophoresis type 1 strain of C. difficile has been reported (7). The North American pulse-field gel electrophoresis type 1 strain seems to be responsible for more frequent and severe CCDC resulting in a greater number of emergency colectomies (30) and an attributable mortality of 16.7% (31). This is especially relevant in Quebec, where the number of CDAD cases increased from 3262 in 2001 to 8673 in 2005 (32). These outbreaks were associated with a virulent strain (33), which increased the case-fatality rate of CDAD to 8.0% in Quebec, when compared with 5.7% in Canada (34). The purpose of this study is to describe the incidence, risk factors, and outcomes of colectomy for CDAD after solid organ transplantation.



From January 1999 to March 2010, there were 1331 solid organ transplant recipients, who received 1465 organs including 430 liver (none living related), 814 kidney, 109 pancreas, 112 heart allografts (of which there were 29 retransplants), and 105 combined organ transplants (88 kidney-pancreas, 10 kidney-heart, and seven kidney-liver allograft). Of these 1331 patients, 165 patients (12.4%) developed CDAD in their posttransplantation course, for respective incidences of 11.3% in kidney, 9.0% in kidney-pancreas, 19.0% in liver, and 8.0% in heart transplantation (Fig. 1). The median age was 53 years, ranging from 15 to 75 years, and 72.0% were men.

Incidence of Clostridium difficile-associated diarrhea (CDAD) in our population during the study period (1999–2010).

Incidence and Mortality

Mirroring the Quebec pandemic of C. difficile infections, the annual incidence of CDAD increased significantly from 4.5% in 1999 to 21.1% in 2005 and then stabilized at 9.5% in 2010. Of the 165 patients with CDAD, 14 patients suffered recurrence (8.5%), five of whom had more than two episodes of CDAD. Sixteen percent of patients with CDAD progressed to CCDC. The all-cause mortality rate for all organ groups confounded within 90 days from a CDAD episode was 8.5% (Table 1). The peak frequency of CDAD was found to be 6 to 10 days posttransplantation (Fig. 2).

Peak frequency of Clostridium difficile-associated diarrhea (CDAD) at 6 to 10 days posttransplantation.
Incidence and mortality of CDAD in solid organ transplant recipients during the study period (1999–2010)

Risk Factors for Developing CDAD

On chi-square analysis, age more than 55 years was significantly associated with developing a CDAD event posttransplant. Allograft type was predictive of CDAD: an incidence of 11.3% among kidney-alone allograft recipients versus 18.7% in all other allograft recipients (P<0.008). Living-related or deceased-donor kidney allograft did not impact risk of CDAD. Conversely, 19.0% of liver allograft recipients suffered a CDAD event, when compared with 12.7% of all other graft recipients (P<0.007). Combined organ transplants, when compared with single organ transplants, were not significantly associated with CDAD. Antithymocyte globulin (ATG) induction was also associated with development of CDAD (P<0.002) (Table 2). Neither inpatient versus outpatient status before transplantation nor pretransplant episode of CDAD were significant predictors of posttransplant CDAD on univariate analysis. Furthermore, presence of specific comorbidities, including diabetes, hypertension, coronary artery disease, human immunodeficiency virus, inflammatory bowel disease, or cytomegalovirus infection was not significantly associated with CDAD.

Significant risk factors associated with CDAD on univariate analysis and the results of multivariate analysis

On multivariate analysis, the risk of CDAD associated with liver allograft and retransplantation could be explained by higher rates of ATG use in these cohorts. Thus, ATG induction remained as an independent predictor of CDAD (hazard ratio [HR]: 1.43, confidence interval [CI]: 1.07–1.94, P=0.002). Similarly, age more than 55 years remained an independent predictor of CDAD (HR: 1.47, CI: 1.16–1.81, P=0.001), and kidney allograft type was independently associated with a decreased risk of CDAD posttransplantation, when compared with all other organ groups (HR: 0.71, CI: 0.52–0.95, P=0.002) (Table 2).

Risk Factors for Developing CCDC

Twenty-six of 165 patients developed CCDC (15.8%). All 26 patients had fulminant CDAD as defined by a systemic inflammatory response and hypotension requiring fluid resuscitation or hemodynamic instability requiring intensive care admission. Six patients underwent total abdominal colectomy with end ileostomy: five of whom survived (83%). The median time from CDAD to colectomy was 7 days ranging from 2 to 42 days. Five patients underwent colectomy between 2 and 12 days from diagnosis of CDAD. These patients presented with fulminant CDAD within a median of 2 days from CDAD diagnosis; however, one patient had a 30-day history of mild CDAD, followed by a 12-day worsening course of symptoms leading to fulminant CDAD before colectomy. The diagnosis of CDAD was confirmed in all pathological specimens. One patient lost her kidney graft before the colectomy. One patient died with a functioning kidney graft. Twenty patients received medical treatment alone. Of these, seven patients survived but lost their graft within 1 month of CDAD diagnosis. The other 13 patients with CDAD died within 90 days of the CDAD diagnosis; five of these patients had lost their grafts before the time of death (Fig. 3). The decision to undergo surgical or medical management for fulminant CDAD was discussed at a multidisciplinary service meeting, including transplant surgeons and physicians. Factors considered included C. difficile disease severity, improvement with medical therapy (vital signs, physical examination, computed tomography (CT) scan results, laboratory tests, and graft status), need for intensive care monitoring, postoperative ability for rehabilitation, and quality of life, in addition to the patient’s own wishes. Patients who had worsening disease despite optimal medical therapy, increasing support requirements, or indicators of threatened graft viability were strongly considered for colectomy.

Outcomes of complicated Clostridium difficile colitis (CCDC) with and without colectomy.

Age, gender, recurrent CDAD, retransplantation, allograft type, and use of ATG were not significant predictors of a complicated course of CDAD. On the other hand, four clinical markers were identified on univariate analysis to differentiate CCDC from CDAD. Patients with CCDC had a mean peak leukocyte count of 25,100/μL, when compared with 15,700/μL (P<0.001) in CDAD. CCDC cases had a mean platelet count nadir of 82,000/μL, versus a mean of 136,000/μL (P<0.014) in uncomplicated cases. A rise in baseline (1 month before CDAD) creatinine by 61.1 μmol/L regardless of allograft type (P<0.006) was also significantly associated with CCDC. Finally, CT scans demonstrated pancolitis in 60.0% of patients with CCDC, in comparison with only 11.6% of patients with CDAD (P<0.003) (Table 3).

Significant clinical markers associated with CCDC on univariate analysis and the results of multivariate analysis

On Cox regression, only two of these associations remained significant: peak leukocyte count and a finding of pancolitis on CT scan (P<0.011with HR: 1.08, CI: 1.02–1.15, and P<0.015 with HR: 2.52, CI: 1.19–5.35, respectively) (Table 3). Using the regression model, one can estimate that a patient with CDAD who has a peak leukocyte count of only 10,000/μL and a CT scan without pancolitis has a 14.4% calculated risk of developing CCDC. However, a leukocytosis of 20,000/μL with confirmation of pancolitis on CT scan is associated with a 42.2% risk of CCDC. Finally, if a patient’s leukocyte count rises to 40,000/μL and a CT scan demonstrates pancolitis, the predicted risk of CCDC rises to 76.0% (Table 4).

Logistic regression model predicting risk of CCDC


The most important finding of our study was that patients older than 55 years, with a transplant other than kidney alone and receiving ATG induction are at higher risk of experiencing CDAD. In addition, white blood cell (WBC) count more than 25,000/μL and evidence of pancolitis on CT scan are independent significant predictors of CCDC.

In our series, the incidence of CDAD of 4.5% in 1999 is comparable with published incidences; however, the highest incidence of 21.1% in 2005 is fourfold higher, which is in keeping with the observed Quebec-wide outbreak, which prompted precautions and hospital-based infection control efforts across the whole province. Our series reflects both the change in incidence and severity of the disease, as reflected by the increasing number of cases and requirement for inpatient treatment of the infection. The incidence of CDAD in 2010 (9.5%) reflects the fact that the rate of CDAD has stabilized but is still not the same as before the outbreak.

The reported timing of CDAD after solid organ transplantation has been variable in past reports. In a few reports of kidney and kidney-pancreas recipients, the peak frequency was between 4 and 12 months posttransplantation, whereas in liver transplantation, CDAD was reported as an early cause of diarrhea at a median time of 1 month postliver transplant (35). Including the described changes which occurred in 2005, we found that CDAD seems to be occurring sooner in the early posttransplant period, more specifically peaking at 6 to 10 days postoperatively. This early in-hospital CDAD can be due to a more aggressive strain, whereas the delayed presentation reported in the earlier literature (24, 36) may have been associated with milder infections. This should be used to guide posttransplant care: with increased surveillance being one of our best clinical tools, suspicion for CDAD during the early posttransplant period should be great.

No risk factor for developing CDAD posttransplantation has been previously published. The multivariable analysis of this series identified three independent risk factors for the development of CDAD posttransplantation. First, age more than 55 years, which is in keeping with findings in nontransplant patients. However, the age of increased risk reported in those populations is described to be more than 65 to 90 years (11). The second risk factor was receiving a nonkidney allograft, when compared with kidney allografts. The reason for decreased CDAD rates among kidney allograft recipients is not known, and it is not related to the type of donation (living related vs. deceased donor). This risk may be due to increased gastrointestinal complications postliver transplantation such as ileus and narcotic use. The third risk factor for developing CDAD is the use of ATG for induction. In our center, ATG has historically been the principle induction regimen in the majority of liver, pancreas, and nonliving-related kidney patients. It is especially used in patients who cannot receive calcineurin inhibitors in the early postoperative period because of postoperative acute kidney injury or renal failure in nonrenal and slow or delayed graft function in kidney transplant recipients, respectively. Thus, the association between ATG and CDAD may be due to either drug effects or a reflection of the physiologic status of the patient.

In most patients, CDAD resolves after medical treatment; however, in our population, 26 patients went on to develop progressive symptoms despite timely and appropriate medical therapy. A common clinical picture for all 26 CCDC patients was the need for fluid resuscitation or pressors in a monitored setting. In addition, the multidisciplinary team would recommend decreased immunosuppressive therapy in such a situation, which included ATG being held, cessation of mycophenolate mofetil, reduced calcineurin inhibitors aiming for the lower range, and tapered steroids to 5 to 10 mg/day when possible. Taken together, these parameters validate the definition of the CCDC composite outcome. The prevalence of CCDC was thus 15.8%, which is the first reported rate of CCDC in solid organ transplant recipients. This is significantly greater than the reported rate of 8% for fulminant C. difficile colitis reported in the general population (29).

In any patient with CCDC, the time between onset of symptoms and fulminant disease may vary from hours to weeks. Predicting which patients will fail medical therapy in the nontransplant population has been difficult, so that reliable early warning signals are invaluable (12). We found in our transplant population that demographic, allograft-related, or medication-related variables were predictive of developing CCDC. Notably, the markers that predicted CCDC were also found to be different from the risk factors for CDAD. On multivariate analysis, there were only two independent and significant clinical markers for CCDC: peak leukocyte count and pancolitis on CT scan. We observed that patients with a WBC count above 25,100/μL were at significantly increased risk of CCDC. This is an important clinical finding because leukocytosis usually precedes findings of clinically fulminant colitis such as hypotension and vasopressor requirement (12); leukocytosis may thus be an earlier warning sign for CCDC although this will need prospective validation. The second independent predictor of CCDC is a finding of pancolitis on CT scan, whereas a finding of segmental colitis was common but not predictive of a CCDC outcome. CT scans were typically performed during the early phase of establishing a diagnosis for lack of improvement in the patient’s clinical status and were mostly performed with intravenous contrast infusion reflecting the lack of renal failure at this time point. This association with the finding of pancolitis on CT was not identified as a predictor of worsening C. difficile colitis in the nontransplant population (37) and may either be specific to transplant patients or reflect infection with a new more aggressive strain. We would thus recommend that, CDAD that is neither improving nor worsening in a patient with a rising leukocyte count may be a good indication for an abdominal CT scan. On logistic regression, the combined effects of a rising leukocyte count and findings of pancolitis on CT were dramatic: a peak leukocyte count from 10,000/μL to 25,000/μL, accompanied by CT scan findings of pancolitis, raised the risk of CCDC from 14.4% to 42.2%.

Although the outcomes of colectomy for CCDC in solid organ transplant recipients have not been well studied, the results of colectomy for fulminant disease in nontransplant patients have often been disappointing, with death rates reported from 43% to 80% (19, 38–40). We, however, retrospectively report excellent outcomes with aggressive and early surgical intervention for CCDC: 83% patient survival and 80% graft survival. Lamontagne et al. (42) report similar benefits of colectomy in nontransplant patients in Quebec during the same era. In their recent study of patients with C. difficile requiring intensive care unit admission, patients who underwent colectomy had improved survival compared with those who were managed medically (odds ratio=0.22). One possible explanation for these results may be a recently increased index of suspicion for CCDC and more aggressive approach to the overall CCDC management in our hospital in addition to the short median time from diagnosis to surgery (7 days). To our knowledge, the rate of colectomy for CCDC in the nontransplant population has not been reported; thus, it is unclear whether this 24% colectomy rate truly represents a more aggressive surgical approach. However, the median time to surgery of 7 days is clearly shorter than previously reported. Furthermore, as the frequency of CCDC increased in our population, guidelines for timing and threshold for colectomy became more clear (42).

In summary, CDAD is an increasingly common and important diagnosis after solid organ transplantation. We report the changing epidemiology of this disease: a more aggressive and earlier onset after solid organ transplantation. Aggressive early measures to confirm the diagnosis and treat the infection are imperative, especially in patients older than 55 years, with a transplant other than kidney alone, who are receiving ATG. Furthermore, surgical intervention should be considered in patients who demonstrate clinically worsening disease, a leukocyte count above 25,000/μL,or a finding of pancolitis on CT scan. Finally, when assessing patients at risk of requiring a total abdominal colectomy for CCDC, judicious early intervention may be associated with good outcomes.


Patient data were collected using the prospective McGill University Health Centre Solid Organ Transplant database, which is maintained by a dedicated database manager according to proven validation and reliability protocols. Solid organ transplant recipients from January 1999 to March 2010 were identified who had CDAD, as defined by diarrhea and a positive cytotoxin assay as per criteria of the U.S. Centres for Disease Control and Prevention (43). The incidence rate of CDAD was calculated by dividing the number of new cases of CDAD each year by the overall number of new transplant patients for that same year.

Cell culture cytotoxin assays were used to detect toxin B by standard methods (44). The institutional protocols for immunosuppression included induction regimen of intravenous ATG (Genzyme, Mississauga, Ontario, Canada), 76% use in our population, followed by a rapid steroid taper in combination with a calcineurin inhibitor (either cyclosporine microemulsion or tacrolimus) and an antimetabolite (either azathioprine or mycophenolate mofetil). Patients who did not receive ATG, received either daclizumab (Zenapax, Hoffman LaRoche, Missisauga, Ontario, Canada) or basixilimab (Simulect, Novartis Pharma Canada Inc., Dorval, Quebec, Canada) for induction. All patients received, on protocol, a preoperative dose of antibiotics: liver transplant patients received tircacillin-clavulanate 3.1 g intravenously and all other patients received cefazolin 1 g intravenously. Postoperative antibiotics were only given for treatment of diagnosed or presumed infections. Postoperative prophylaxis comprised oral nystatin, trimethoprim-sulfamethaxazole, and cytomegalovirus prophylaxis where indicated. CDAD was initially treated with metronidazole 500 mg three times per day (oral or intravenous). If there was an inadequate response, oral vancomycin 500 mg four times per day was added. Recurrent CDAD was treated with oral vancomycin 500 mg four times per day and occasionally with additional agents including cholestyramine and intravenous immunoglobulin if the clinical response remained inadequate.

Patients at our center initially stayed in multipatient rooms. However, in 2005, as part of a hospital-wide initiative to control the C. difficile epidemic, the transplant program was moved to a different hospital area with 94% single- and 6% double-occupancy rooms with private toilets. Any patient with suspected CDAD or CCDC was immediately placed in isolation with enforced hand-washing precautions. In addition, the treating team would see the patients with suspected or documented C. difficile infections separately during morning rounds.

Variable Definitions

In searching for clinical risk factors associated with CDAD and CCDC, we defined several variables with the intention to capture the most representative values. Peak WBC count was defined as the highest value from 1 week before CDAD diagnosis to 14 days after CDAD diagnosis. Similarly, platelet nadir was defined as the lowest platelet count from 1 week before CDAD diagnosis to 14 days after CDAD diagnosis. A rise in baseline creatinine was defined by subtraction of two variables: baseline creatinine which is the value of the patient’s creatinine 1 month before CDAD diagnosis and peak creatinine defined as the highest value for creatinine from 1 week before CDAD diagnosis to 14 days after CDAD diagnosis.

Outcome Definitions

Graft loss was defined as insulin dependence postpancreas transplant, hemodialysis postrenal transplant, or retransplantation postheart or liver transplant. CCDC was defined as an episode of CDAD that progressed to a fulminant disease state resulting in total abdominal colectomy, graft loss (within 30 days of CDAD diagnosis), or death (within 90 days of CDAD diagnosis, to be as conservative as possible). This composite outcome definition was chosen because each of these clinical states results from the infection itself and the associated need to reduce or stop immunosuppression as part of the treatment plan. Recurrent CDAD was defined as two clinical episodes of CDAD (with positive cytotoxin assay) more than 2 months apart (45).

Statistical Methods

Five groups of allograft recipients were considered: kidney alone, liver alone, pancreas alone, heart alone, and combined-organ (kidney-heart, kidney-liver, and kidney-pancreas) transplants. Data are expressed as a mean and standard deviation or median (range) for skewed distributions. Chi-square test and Student’s t test were used for univariate analyses as appropriate. Multivariate Cox regression models were used to identify risk factors for CDAD among all study patients. Independent variables considered were age, sex, allograft type, deceased donor vs. living-related donor status, retranplantation, and use of ATG. Variables that were significant in univariate analyses at the 0.25 significance level were included in the multivariable model. A variable was kept in the multivariable model if it was significant at the 0.05 significance level. Predictors of CCDC were also identified using multivariable logistic regression modeling. For those who had multiple episodes of CDAD, the earliest episode after transplant was used. Statistical analyses were performed using SYSTAT Software Inc. (version 10.2, San Jose, CA, 2002).


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C. difficile colitis; Diarrhea; Colectomy; Solid organ transplant

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