Abstract
Background
Clostridioides difficile infection (CDI, formerly Clostridium difficile infection) is the leading cause of healthcare-associated diarrhea. Secondary bile acids inhibit C. difficile germination in vitro and confer resistance to CDI in animals. Cholecystectomy (CCY) alters gut bile acid composition, with increased fecal levels of secondary bile acids. This study tested the hypothesis that remote CCY confers protection against CDI by increasing gut levels of secondary bile acids.
Methods
This was a retrospective case control study with two control groups. Adults hospitalized between January 2010 and June 2017 at our institution were included in the study. CDI cases were defined as a positive stool PCR followed by appropriate anti-CDI treatment and were matched 1:1:1 with two controls groups (those who tested negative for CDI and those who were not tested for CDI) by sex, age group, body mass index, and exposure to antibiotics during the index hospital admission. Remote CCY was defined as a history of CCY at least 6 months prior to the index C. difficle test or the index admission date in the untested controls. Conditional logistic regression modeling was used to estimate the relationship between remote CCY and risk for CDI.
Results
The final study population was 7,077 (2,359 CDI cases, 2,359 matched controls without CDI, and 2,359 matched controls not tested for CDI). Rates of remote CCY did not differ among the three groups (14.4% vs. 15.5% vs. 14.2%) and this result was unchanged after adjusting for additional clinical factors (adjusted OR 0.90, 95% CI 0.76–1.06 comparing CDI cases vs. matched controls without CDI; adjusted OR 1.04, 95% CI 0.78–1.39 comparing CDI cases vs. matched controls not tested for CDI).
Conclusions
There was no association between remote CCY and risk for CDI. Either gut bile acid content is not a major driver of CDI in humans or CCY impacts gut bile acids less than previously believed.
INTRODUCTION
Clostridioides difficile infection (CDI, formerly Clostridium difficile infection) is the leading cause of healthcare-associated diarrhea (1). While the incidence of healthcare-associated CDI may be leveling off (2), it remains important to understand risk factors associated with CDI in order to appropriately target high-risk patients for prevention.
For decades it has been known that conjugated primary bile acids stimulate C. difficile spore germination in culture. The media used to grow C. difficile was frequently enriched in the primarily bile acid taurocholate to promote outgrowth of spores (3). In recent years, it has been shown that secondary bile acids, primarily deoxycholic acid (DCA) and lithocholic acid (LCA), provide resistance to CDI in culture (4). Colonic anaerobes convert primary into secondary bile acids and, in animal models of CDI, the bacterial species responsible for generating secondary bile acids are protective against CDI (5). Cholecystectomy (CCY) results in continuous hepatic bile acid secretion into the small intestine and an alteration of both total and secondary bile acid levels, resulting in bile salt diarrhea in a subset of patients (6, 7). Most notably, fecal excretion of DCA is doubled in post-CCY patients compared to patients with an intact gallbladder (7).
The purpose of this study was to evaluate the relationship between remote CCY and subsequent risk for CDI. Specifically, our a priori hypothesis was that remote CCY would confer protection against CDI by increasing fecal levels of DCA and other secondary bile acids (Figure).
Figure 1.
Schematic of the study.
METHODS
Study Population
This was a retrospective case: control: control study. Adult inpatients hospitalized between 1 January 2010 and 30 June 2017 at our institution were included in the study. For patients with multiple inpatient stool tests for C. difficile, the first test was chosen. Patients were excluded from the study if they tested positive for C. difficile but were not treated for CDI. Patients with CCY within 6 months of index C. difficile PCR testing were also excluded so that the long-term effects of CCY could be distinguished from short-term peri-operative factors. The Institutional Review Board of Columbia University Medical Center approved this study.
Case Definition
Cases of incident CDI were defined as patients with a positive diarrheal stool PCR test for the C. difficile toxin B gene, who received anti-CDI treatment within 24 hours of test positivity with metronidazole or oral vancomycin. Fidaxomicin was not used for incident CDI during the study period. All other patients within the study population were eligible as controls.
Matching
CDI cases were matched 1:1:1 with controls without replacement by sex, age group (18–55 years, 56–75 years, or ≥ 76 years), BMI (normal/underweight, overweight, obese, or missing data), and antibiotic exposure (none, low-risk for CDI, or high-risk for CDI). Specifically, we first performed matching between CDI cases and controls who tested negative for CDI. This first round of matching generated CDI cases and the negative controls that were included in the study. Second, we matched these cases to anotherset of controls admitted during the study period who were not tested for CDI (same matching parameters).
Primary Exposure
The primary exposure was defined as a history of remote CCY at least 6 months prior to index C. difficile PCR test (CDI cases and matched controls without CDI), or 6 months prior to index admission date (matched controls not tested for CDI). History of remote CCY was identified by manual chart review. Overall, the case:control:control design was selected over a cohort study design in part because manual chart review was necessary to accurately ascertain distant CCY.
Covariates
Using automated electronic queries, the following potential risk factors for CDI were extracted and examined: demographics; comorbidities; body mass index; vital signs and laboratory values immediately prior to index C. difficile PCR testing (classified categorically based on standard cut-points or using our institutional laboratory reference range). For the matched controls not tested for CDI, the first set of vital signs/laboratory values from the index admission was used. Medication exposure prior to C. difficile PCR test during the index admission was also extracted, including antibiotics, proton pump inhibitor (oral or intravenous PPI at any dose or duration) and immunosuppressants (systemic steroids at a minimum daily dose of 5mg prednisone or equivalent, calcineurin inhibitors, anti-metabolites, anti-TNFα agents, or mycophenolic acid). High-risk antibiotics were defined based on previous studies indicating risk for CDI. Specifically, these were antibiotics within the following classes: clindamycin, fluoroquinolones, cephalosporins, extended-spectrum penicillins, monobactams, and carbapenems. Low-risk antibiotics were antibiotics within all other classes, excluding topical antibiotics. All medication exposures were classified based on documented receipt of the medication in the electronic provider order entry system.
Statistical Approach
Categorical variables were compared using the χ2 test. The final multivariable model was performed using conditional logistic regression (conditioned based on matching). To construct the model, a full model was first built containing all covariates which had an independent relationship with CDI (p≤0.10). A reduced model was then produced through stepwise subtraction of variables, retaining in the final/reduced model those that showed an independent relationship with CDI (p<0.05) or which altered the β-coefficient representing remote CCY by 10% or more. Within this final model, several secondary analyses were performed. To assess for a duration-based effect, we conducted stratified analyses assessing risk for CDI among those whose CCY was relatively recent (6 months to 1 year prior to CDI testing) versus relatively long-term (1–5 years, and >5 years prior to CDI testing). To explore the effect of antibiotics on the model, we adjusted for antibiotic use that was within 90 days but not during the index admission. Additionally, a restriction analysis was performed to include only patients with antibiotics exposure within the past 14 days from the index CDI testing. We also conducted an analysis excluding cases of community-associated CDI (defined as a diagnosis of CDI within 72 hours of the index hospital admission) (8, 9). All statistical testing was done on STATA 15 (StataCorp, College Station, TX) and all analyses were performed at the alpha 0.05 level of significance except as mentioned above.
RESULTS
Patient Characteristics
The final study population was 7,077 including 2359 CDI cases, 2359 matched controls without CDI, and 2359 matched controls not tested for CDI. Cases and controls did not differ based on any of the matching variables (sex, age, BMI, or exposure to antibiotics) (Table 1).
Table 1.
Baseline and hospital patient characteristics, stratified by C. difficile infection status.
| Baseline Characteristics | CDI Cases n=2359 |
Matched Controls Without CDI n=2359 |
Matched Controls Not Tested for CDI n=2359 | |
|---|---|---|---|---|
| all (%) | n (%) | n (%) | n (%) | |
| Sex (Matched) | ||||
| Female | 3504 (50) | 1168 (50) | 1168 (50) | 1168 (50) |
| Male | 3573 (50) | 1191 (50) | 1191 (50) | 1191 (50) |
| Age (Matched) | ||||
| 18–55 years | 2154 (30) | 718 (30) | 718 (30) | 718 (30) |
| 56–75 years | 2913 (41) | 971 (41) | 971 (41) | 971 (41) |
| ≥ 76 years | 2010 (28) | 670 (28) | 670 (28) | 670 (28) |
| Body mass index (Matched) | ||||
| Obese (>30%) | 1542 (22) | 514 (22) | 514 (22) | 514 (22) |
| Overweight (>25%) | 1746 (25) | 582 (25) | 582 (25) | 582 (25) |
| Normal/underweight(< 24.9%) | 2802 (40) | 934 (40) | 934 (40) | 934 (40) |
| Missing | 987 (14) | 329 (14) | 329 (14) | 329 (14) |
| Race/ethnicity | ||||
| White | 2220 (31) | 788 (33) | 740 (31) | 692 (29) |
| Black | 760 (11) | 270 (11) | 249 (11) | 241 (10) |
| Hispanic | 1326 (19) | 362 (15) | 470 (20) | 494 (21) |
| Other/Unclassified | 2771 (39) | 939 (40) | 900 (38) | 932 (40) |
| Charlson comorbidity index | ||||
| 0–2 points | 2560 (36) | 767 (33) | 857 (36) | 936 (40) |
| 3–4 points | 2121 (30) | 768 (33) | 718 (30) | 635 (27) |
| ≥ 5 points | 2396 (34) | 824 (35) | 784 (33) | 788 (33) |
| Hospital Characteristics | ||||
| Vital signs | ||||
| Temperature (<35°C, >38°C) | 310 (5) | 108 (6) | 115 (6) | 87 (4) |
| Heart rate (<60, >100) | 1395 (23) | 481 (25) | 465 (23) | 449 (21) |
| MAP (<65 mm Hg) | 267 (4) | 119 (6) | 97 (5) | 51 (2) |
| Lab results | ||||
| White blood cell count (<3.12 or >8.44 × 10(3)/uL) |
4475 (65) | 1597 (69) | 1541 (66) | 1337 (58) |
| Hematocrit (<37.2%) | 5144 (74) | 1946 (84) | 1900 (82) | 1298 (56) |
| Platelet count (<156 ×10(3)/uL) | 1794 (26) | 669 (29) | 708 (30) | 417 (18) |
| Direct bilirubin (>0.3 mg/Dl) | 1398 (23) | 528 (25) | 585 (27) | 285 (15) |
| Indirect bilirubin (>0.9 mg/dL) | 647 (12) | 215 (12) | 240 (13) | 192 (12) |
| Alkaline phosphatase (>129 U/L) | 1306 (21) | 492 (23) | 474 (21) | 340 (18) |
| Creatinine(>1.3 mg/dL) | 2341 (34) | 934 (40) | 826 (34) | 608 (27) |
| Medication exposures during index admission | ||||
| Antibiotics (Matched) | ||||
| High risk antibiotics1 | 4185 (59) | 1395 (59) | 1395 (59) | 1395 (59) |
| Low risk antibiotics2 | 420 (6) | 140 (6) | 140 (6) | 140 (6) |
| No antibiotics | 2472 (35) | 824 (35) | 824 (35) | 824 (35) |
| PPIs | 3268 (46) | 1196 (51) | 1161 (49) | 911 (39) |
| Immunosuppressants | 1848 (26) | 683 (29) | 681 (29) | 484 (21) |
| Length of stay at time of CDI testing/entire length of stay | ||||
| Tertile 1 (0–6 days) | 2835 (40) | 591 (25) | 690 (29) | 1554 (66) |
| Tertile 2 (7–16 days) | 2302 (33) | 857 (36) | 825 (35) | 620 (26) |
| Tertile 3 (≥ 17 days) | 1940 (27) | 911 (39) | 844 (36) | 185 (8) |
| Medical ICU stay | 931 (13) | 381 (16) | 403 (17) | 147 (6) |
High-risk antibiotics: clindamycin, fluoroquinolones, cephalosporins, extended-spectrum penicillins, monobactams, and carbapenems.
Low-risk antibiotics: all antibiotics excluding high-risk antibiotics. Topical antibiotics excluded.
Remote Cholecystectomy
There were a total of 1, 041 (14.7%) patients in the study with remote CCY. Patients with remote CCY were more likely to be female, older, and obese (BMI≥30) compared to patients without history of CCY (Supplemental Table 2).
Relationship between Remote CCY and CDI
In the crude analysis, there was no association between remote CCY and CDI. Among patients with CDI, a total of 340 (14.4%) had remote CCY compared to 366 (15.5%) among patients without CDI, and 335 (14.2%) among patients not tested for CDI (p=0.39). This result was unchanged after adjusting for additional clinical factors (adjusted OR 0.90, 95% CI 0.76–1.06 comparing CDI cases vs. matched controls without CDI; aOR 1.04, 95% CI 0.78–1.39 comparing CDI cases vs. matched controls not tested for CDI; aOR 0.96, 95% CI 0.83–1.11 comparing CDI cases vs. both groups of controls; see Table 2 and Table 3). The CCY-CDI relationship, and the final multivariable model, were substantially unchanged after adjusting for exposure to antibiotics and the other matching variables.
Table 2.
Multivariable model for the relationship between remote cholecystectomy and risk for subsequent development of C. difficile infection (comparing CDI cases versus matched controls without CDI).
| Risk Factors | Full model (Odds Ratio, 95% CI) |
Reduced model (Odds Ratio, 95% CI) |
|---|---|---|
| Remote cholecystectomy | 0.93 (0.76–1.13) | 0.90 (0.76–1.06) |
| Comorbidities | ||
| Liver disease | 1.07 (0.96–1.19) | --- |
| Chronic kidney disease | 1.11 (0.98–1.25) | --- |
| CVA/TIA | 0.69 (0.52–0.91) | 0.74 (0.58–0.94) |
| Peripheral vascular disease | 1.35 (0.97–1.89) | --- |
| Charlson comorbidity index | ||
| 0–2 | Reference | Reference |
| 3–4 | 1.23 (1.02–1.56) | 1.31 (1.10–1.56) |
| >/=5 | 1.06 (0.82–1.37) | 1.25 (1.04–1.52) |
| Length of hospital stay at time of CDI testing (days) | ||
| Tertile 1 (0–6 days) | Reference | Reference |
| Tertile 2 (7–16 days) | 1.21 (1.00–1.47) | 1.18 (1.01–1.37) |
| Tertile 3 (≥17 days) | 1.21 (0.99–1.48) | 1.26 (1.08–1.49) |
| Vitals/Laboratory values at time of CDI testing | ||
| MAP (< 65 mm Hg) | 1.23 (0.91–1.65) | --- |
| WBC (< 3.1, > 8.4 × 103/uL) | 1.10 (0.94–1.29) | --- |
| Hematocrit (< 37.2%) | 1.07 (0.87–1.32) | --- |
| Creatinine (>1.3 mg/dL) | 1.19 (1.01–1.39) | 1.25 (1.11–1.43) |
Table 3.
Multivariable model for the relationship between remote cholecystectomy and risk for subsequent development of C. difficile infection (comparing CDI cases versus matched controls not tested for CDI).
| Risk Factors | Full model (Odds Ratio, 95% CI) |
Reduced model (Odds Ratio, 95% CI) |
|---|---|---|
| Remote cholecystectomy | 0.82 (0.58–1.17) | 1.04 (0.78–1.39) |
| Comorbidities | ||
| Liver disease | 1.16 (0.96–1.42) | --- |
| Congestive heart failure | 1.73 (1.25–2.39) | 1.60 (1.24–2.06) |
| Connective tissue disease | 0.29 (0.09–0.86) | 0.47 (0.18–1.28) |
| Diabetes | 1.19 (0.97–1.47) | --- |
| Hemiplegia | 1.83 (1.11–3.02) | 2.07 (1.36–3.10) |
| Malignancy | 0.83 (0.74–0.94) | 0.81 (0.74–0.88) |
| Myocardial infraction | 0.42 (0.25–0.70) | 0.39 (0.25–0.61) |
| Peripheral vascular disease | 1.54 (0.88–2.67) | --- |
| Charlson comorbidity index | ||
| 0–2 | Reference | Reference |
| 3–4 | 1.23 (0.89–1.68) | --- |
| >/=5 | 0.79 (0.52–1.20) | --- |
| Length of hospital stay at time of CDI testing (days) | ||
| Tertile 1 (0–6 days) | Reference | Reference |
| Tertile 2 (7–16 days) | 3.08 (2.34–4.03) | 3.91 (3.12–4.92) |
| Tertile 3 (≥17 days) | 13.55 (9.18–20.01) | 15.66 (11.42–21.48) |
| Vitals/Laboratory values at time of CDI testing | ||
| MAP (< 65 mm Hg) | 1.99 (1.06–3.76) | 1.91 (1.13–3.25) |
| Hematocrit (< 37.2%) | 4.41 (3.34–5.81) | 4.01 (3.20–5.01) |
| Platelet (<156 ×10(3)/uL) | 1.56 (1.18–2.06) | 1.57 (1.24–1.98) |
| Recent medication exposures | ||
| PPI | 1.18 (0.92–1.49) | --- |
| MICU stay | 0.74 (0.51–1.07) | --- |
Secondary Analyses
Several secondary analyses were performed, focusing on the comparison between those who tested positive for CDI versus those who tested negative. First, the relationship between remote CCY and risk for CDI was reexamined based on the duration since CCY. Remote CCY compared to no CCY was not associated with CDI when remote CCY was redefined as occurring within 6 months to < 1 year (n= 283 CCYs, aOR 0.99, 95% CI 0.77–1.29), when it was redefined as within 1–5 years (n= 129 CCYs, aOR 0.99, 95% CI 0.81–1.21), or when it was redefined as over 5 years prior to date of CDI testing (n= 294 CCYs, aOR 0.92, 95% CI 0.85–1.01). Second, antibiotic exposure was redefined as occurring within 14 days of CDI testing (aOR for CCY 1.01, 95% CI 0.78–1.31). Third, the final multivariable model was adjusted for antibiotics exposure within 90 days prior to CDI testing but not during the index admission (aOR for CCY 0.90, 95% CI 0.76–1.06). Fourth, a restriction analysis was performed to exclude 1256 patients with community-acquired CDI (aOR for CCY 0.88, 95% CI 0.68–1.15). These results were all similar when CDI cases were compared to untested controls.
DISCUSSION
In this large case: control: control study conducted among hospitalized patients tested for CDI, we found no association between remote CCY and risk for subsequent CDI. The case:control:control design selected for the study addresses two related but distinct questions. First, following a CDI test, is a positive result more likely in those with a distant CCY? Second, are patients with a distant CCY more likely to subsequently test positive for CDI? In neither case were distant CCY and CDI associated, and this null association remained through multiple sensitivity analyses.
Two previous studies have investigated the relationship between CCY and CDI. The first found that, among U.S. patients hospitalized from 1993 to 2003 for a general surgical procedure, those undergoing CCY had among the lowest rates of CDI during the immediate post-operative period (0.41%) (10). In the second study, Qazi et al. assessed risk for CDI associated with remote CCY compared to remote appendectomy from 2005 to 2014 (11). After a mean follow-up time of over 6 years, patients who had remote CCY were slightly more likely to be tested for CDI compared to those who had remote appendectomy (27% vs 21% respectively). Because of the era in which this study was performed, most patients were tested for CDI using the toxin enzyme-linked immunoassay (EIA). Interestingly, the authors observed that CDI rates were similar among patients tested by EIA (4.5% CCY vs. 2.5% appendectomy) but significantly differed among patients tested by PCR (7% vs. 2% respectively). Because PCR positive EIA negative patients are often colonized but not actually infected (12), these results were interpreted as suggesting that CCY was associated with increased long-term testing rates due to bile salt diarrhea but was not associated with increased risk for CDI. Our null findings are in line with this interpretation.
In vitro assays and animal models of CDI stress the importance of local bile acid composition in the pathogenesis of CDI. Primary bile acids are associated with C. difficile spore germination in culture and secondary bile acids suppress vegetative growth of C. difficile (4, 13, 14). It has been proposed that in a healthy host, after C. difficile spore ingestion, spores can survive and germinate in the distal small bowel where the concentrate of primary bile acids are relatively high but that the relatively high colonic concentration of secondary bile acids prevents vegetative growth of C. difficile (14, 15). The role of secondary bile acids in suppressing CDI was validated by Buffie et al., who found that Clostridium scindens, the colonic anaerobe most responsible for the production of secondary bile acids, conferred resistance to CDI in a secondary bile acid dependent fashion in mice (5). In a parallel observational cohort study of patients undergoing allogeneic bone marrow transplant, C. scindens was associated with a similar protective effect in humans. It is also well established that CCY changes luminal bile acid composition leading, in some individuals, to bile salt diarrhea. Cholecystectomy is associated with increased continuous bile flow into the intestine and increased bacterial conversion of secondary bile acids with an alteration of commensal fecal microbiota (16–18). Cholecystectomy has even been identified as a possible risk factor for colorectal cancer due to higher levels of secondary bile acids (18, 19).
Why then do our results differ from what might be expected based on in vitro assays and animal models? Overall, there are two potential explanations. First, the studies that established the suppressive effect of secondary bile acids on CDI were based primarily on mouse models which may not translate well to humans. There are intrinsic differences between human and mouse gut microbiota, bile acid production (20), and dietary patterns (21). The vast majority of bacterial genera found in the mouse gut microbiota are not present in humans and the capability of mouse models to recapitulate the human gut microbiota shifts in disease state may be more limited than we would wish (22, 23). Second, it is possible that CCY does not lead to major changes in the secondary bile acid profile. Two studies that followed patients who underwent cholecystectomy showed no expansion in secondary bile acid pool using isotope dilution technique, both in the short term (3 months) and in the long term (5–8 years) (24, 25). Conversion of primary bile acids to secondary bile acids requires 7α-dehydroxylation, a multi-step intracellular enzymatic process performed by only a few anaerobic species, representing less 0.0001% of the total colonic microbiota (26). It is unclear how C. scindens or other species with 7α-dehydroxylation capability can respond to CCY by expanding to convert secondary bile acids. A related possibility is that CCY causes a change in bile acids in the proximal colon but not the distal colon, where CDI tends to be the most active clinically. In our own previous prospective study, we found that microbiome changes predisposing to CDI were not accompanied by changes in total fecal bile acids or in the ratio of primary to secondary fecal bile acids (27).
Our study has multiple strengths. It utilized two distinct control groups, was large, and classified remote CCY through manual chart review. We adjusted for the most important established predictors of CDI, and conducted multiple secondary analyses to identify potential effect modification. Our study also has limitations. It was retrospective and thus unable to directly measure post-CCY fecal bile acid content. While it accounted for established predictors of CDI, the presence of unmeasured differences between study groups remains possible in this study, as in any retrospective study. CDI was classified in this study as a positive diarrheal stool PCR followed by appropriate anti-CDI treatment. This approach may improve the specificity of CDI but does not exclude the possibility that some colonized patients were misclassified as infected. CDI test results performed at other institutions prior to the index testing date were not available, and may have resulted in recurrent CDI misclassified as incident CDI. Last, although relatively large, the study was unable to completely exclude a very modest protective effect associated with remote CCY. Such an effect, if it does indeed exist, would be so small that it would be unlikely to play a clinically meaningful role in CDI.
In conclusion, there was no association between remote CCY and subsequent risk for CDI in this large retrospective case: control: control study. As expected, patients with CDI had more baseline comorbidities and longer hospital stays. Secondary bile acids may not be a major driver of CDI in humans and novel therapeutics that aim to treat CDI through manipulation of secondary bile acid levels may not be beneficial.
Supplementary Material
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