Abstract
Background:
Clostridioides difficile infection (CDI) is a significant complication in patients with acute severe ulcerative colitis (ASUC).
Objectives:
To assess the clinical outcomes of hospitalized ASUC patients with CDI.
Design:
Retrospective, single-center study.
Methods:
Medical records of ASUC patients admitted from December 1, 2008, to June 1, 2018, were reviewed. Primary outcomes included hospital duration, in-hospital colectomy rates, and escalation of immunosuppression at discharge. Secondary outcomes included readmission rates and use of salvage therapy.
Results:
Among 410 ASUC patients, 67 tested positive for CDI. No significant differences in hospital duration, colectomy rates, or readmission rates were found between CDI-positive and CDI-negative groups. CDI-positive patients were less likely to receive intravenous corticosteroids.
Conclusion:
A positive CDI test in ASUC patients does not correlate with worse clinical outcomes. Based on these results, CDI should be ruled out and treated in hospitalized patients with severe ulcerative colitis without delaying ASUC management.
Plain language summary
The paper investigates the clinical outcomes of hospitalized patients with acute severe ulcerative colitis (ASUC) who test positive for Clostridioides difficile (C. difficile) infection (CDI). C. difficile is known to cause a range of illnesses from mild diarrhea to severe colitis, especially in patients with inflammatory bowel disease (IBD). This study specifically looks at how CDI affects the treatment and prognosis of ASUC patients. The study included patients over 18 years old with ASUC admitted to the hospital between December 1, 2008, and June 1, 2018. Clinical data such as CDI test results, disease location, CRP and albumin levels, and prior treatments were collected. The primary outcomes analyzed were hospital length of stay, inhospital colectomy rates, and the need for increased immunosuppression at discharge. Secondary outcomes included readmission rates, colectomy within 90 days, and use of intravenous (IV) corticosteroids and salvage therapies during hospitalization. Out of 410 patients, 391 had stool C. difficile PCR test results, and 67 tested positive. The results showed that a positive CDI test did not significantly impact hospital stay duration, in-hospital colectomy rates, or the need for salvage therapy or increased immunosuppression. However, ASUC patients with CDI were less likely to receive IV corticosteroids during their hospital stay. There were no differences in readmission rates between those who tested positive and those who did not. The findings suggest that a positive CDI test does not necessarily worsen the clinical outcomes for hospitalized ASUC patients, except for a lower initiation rate of IV corticosteroids. This study underscores the importance of diagnosing and treating CDI in ASUC patients without delaying aggressive treatment for ulcerative colitis. Future research should involve larger, multi-center studies to validate these findings and further explore the interactions between ASUC and CDI.
Introduction
Clostridioides difficile (C. difficile) is a spore-forming, toxin-producing, anaerobic bacterium that can cause a spectrum of disease from mild diarrhea to severe colitis, with potential complications such as toxic megacolon, colonic perforation, and sepsis. Patients with inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis (UC), are at increased risk for C. difficile infection (CDI). While typical risk factors for CDI in the general population include advanced age, recent hospitalizations, and antibiotic use, IBD patients are often younger and have higher rates of community-acquired CDI. Colonic involvement and frequent healthcare exposures, along with disease flares, often requiring antibiotics, further elevate the risk of CDI in this population. 1 Pre-existing alterations in gut microbiota in IBD patients may also predispose them to CDI, even in the absence of recent antibiotic use, as demonstrated in murine models. 2
Acute severe ulcerative colitis (ASUC) is the most critical presentation of UC, defined by the Truelove and Witts criteria as having more than six bloody stools per day along with one or more of the following: body temperature >37.8°C, heart rate >90 bpm, hemoglobin <10.5 g/dL, erythrocyte sedimentation rate >30 mm/h, and C-reactive protein (CRP) >3 mg/L. 3 ASUC often requires hospitalization and may not respond to intravenous (IV) steroid therapy, necessitating salvage treatments. The risk of colectomy is significantly increased in patients with ASUC, with rates reported as high as 10%–15%.3,4
Despite the known risks and complications associated with CDI in patients with UC, the specific clinical impact of CDI (confirmed by polymerase chain reaction testing) on the management and outcomes of hospitalized ASUC patients remains underexplored. This retrospective study aims to characterize the clinical outcomes of hospitalized patients with ASUC who test positive for CDI, focusing on the utilization of inpatient medical therapies and overall patient prognosis.
Methods
Patients over the age of 18 with a diagnosis of ASUC and admitted to the University of Chicago hospital between December 1, 2008, and June 1, 2018, were retrospectively identified and reviewed under IRB 18-0918. Patient data were deidentified such that the identity of the patients may not be ascertained in any way. Patients who had a stool C. difficile test performed upon admission were included in the study. Clinical variables and laboratory values were extracted from medical records. The variables included CDI PCR results, demographic data, disease location, admission CRP and albumin levels, disease duration, Mayo scores, and prior use of steroids, immunomodulators, mesalamine, and biologic drugs.
The primary outcomes assessed were hospital length of stay, in-hospital colectomy rates, and escalation of immunosuppression at discharge, defined as an increase or addition of oral steroids. Secondary outcomes included 30-day readmission rates for CDI and 90-day readmission rates for CDI (defined as readmission between 30 and 90 days), colectomy within 90 days of admission, use of IV corticosteroids during admission, and use of salvage therapy (such as cyclosporine, tacrolimus, anti-tumor necrosis factor (TNF) drugs, and other biologics, including tofacitinib) during admission. Continuous variables were analyzed using the unpaired t test, while categorical data were analyzed using the Chi-square test of independence and Fisher’s exact test, as appropriate. Additionally, a multivariable logistic regression analysis was performed to evaluate the impact of CDI on clinical outcomes while controlling for disease location, Mayo endoscopy score at presentation, and prior use of biologics.
Results
The study analyzed charts of 410 hospitalized patients with ASUC, of whom 391 had stool C. difficile PCR testing results available. Among these, 67 patients tested positive for CDI. Treatment regimens for CDI included oral vancomycin alone in 56 patients, oral vancomycin combined with IV metronidazole in 4 patients, IV metronidazole alone in 5 patients, and a combination of oral vancomycin, IV metronidazole, and oral fidaxomicin in 1 patient. The median Mayo score for patients testing positive for C. difficile was 2 (interquartile range 2–3), while the median Mayo score for those testing negative was 3 (interquartile range 2–3). Notably, 19% of patients initially testing positive and treated for CDI were symptomatic and tested positive again at 8 weeks. Similarly, 11% were symptomatic and tested positive again at 6 months.
Two clinically significant differences in clinical traits were identified between ASUC patients with and without CDI. Patients without CDI were more likely to have a Mayo endoscopic sub-score of 0 (p < 0.05; Table 1), and a higher proportion of patients with CDI during admission for ASUC had tested positive for the infection within 8 weeks prior to their initial admission (p < 0.05; Table 1). Univariable analysis revealed that ASUC patients with CDI were less likely to receive IV corticosteroids during hospitalization (p = 0.0018, odds ratio = 0.3, 95% confidence interval = 0.14–0.65, Table 2). A positive C. difficile test was not associated with increased hospitalization duration, in-hospital colectomy rates, colectomy within 90 days of admission, use of salvage therapy during hospitalization, or escalation of immunosuppression at discharge (p > 0.05; Table 2). Furthermore, a positive C. difficile test during hospitalization did not predict 30-day or 90-day readmission rates (p > 0.05; Table 2).
Clinical traits and demographics.
CDI, C. difficile infection; CI, confidence interval; CRP, C-reactive protein; PTA, prior to admission.
Univariable analysis of outcomes based on Clostridioides difficile status.
CDI, C. difficile infection; CI, confidence interval; CRP, C-reactive protein; PTA, prior to admission; TNF, tumor necrosis factor.
Multivariable logistic regression analysis was performed to evaluate the impact of CDI on clinical outcomes while controlling for disease location, Mayo endoscopy score at presentation, and prior use of biologics (Table 3). CDI was not significantly associated with colectomy during the admission (OR 1.0, p = 0.31) or within 90 days (OR 0.4, p = 0.39). Similarly, no significant associations were observed between CDI and length of stay >6 days (OR 0.68, p = 0.33), 30-day readmission (OR 0.49, p = 0.27), or 90-day readmission (OR 0.89, p = 0.83). CDI also did not significantly influence the initiation of IV corticosteroids during admission (OR 1.04, p = 0.97), escalation of immunosuppression at discharge (OR 0.83, p = 0.66), or the use of anti-TNF agents (OR 1.12, p = 0.41) or cyclosporine/tacrolimus (OR 0.53, p = 0.55) during admission as salvage therapies.
Multivariable logistic regression.
ORs represent the impact of CDI on each outcome of interest when controlled for disease location, Mayo endoscopy score at presentation, and use of biologics prior to admission.
CI, confidence interval; IV, intravenous; OR, odds ratio; TNF, tumor necrosis factor.
Discussion
In this single tertiary center study, hospitalized patients with ASUC who tested positive for C. difficile by PCR exhibited similar outcomes to those who tested negative. The only statistically significant difference observed was that patients with a negative test were more frequently initiated on IV corticosteroids during their hospitalization compared to those with a positive test. There were no significant differences between the two groups in terms of initiating salvage therapy, escalating immunosuppression, colectomy rates, hospital duration, or readmission rates.
Patients with IBD who acquire CDIs generally have poorer outcomes compared to those without IBD, particularly in hospitalized settings. Previous studies have reported increased rates of complications such as toxic megacolon and colonic perforation, longer hospitalizations, higher rates of in-hospital procedures, higher recurrence rates of CDI, and increased mortality among IBD patients with CDI. 5 For instance, a 2009 study found that hospitalized UC patients with CDI had higher rates of colectomy within a year following admission and increased UC-related hospitalizations, though no differences were observed in short-term outcomes like hospital duration and cyclosporine use. 6 Similarly, a 2022 study found higher mortality rates 3 months post-infection and increased need for IBD therapy intensification within 1 year in UC patients with CDI. 7 In contrast, a 2018 study from Korea found no differences in demographic data, length of hospital stay, or colectomy rates between UC patients with and without CDI despite higher CDI rates among those hospitalized for a UC flare. 8
Our study showed no differences in the initiation of salvage therapy, escalation of immunosuppression, colectomy rates, hospital duration, or readmission rates between ASUC patients with and without CDI. One possible explanation could be the younger age of our ASUC cohort (mean age <40), as CDI tends to be more severe in older individuals, particularly those over 65.
IV corticosteroids remain a cornerstone therapy in ASUC. 4 Our study uniquely observed higher rates of IV corticosteroid initiation in CDI-negative patients. In ASUC patients with concurrent CDI, the use of corticosteroids may warrant careful consideration. While corticosteroids are essential for controlling inflammation in patients with ASUC, their immunosuppressive effects may theoretically exacerbate CDI by impairing the host immune response to the infection. However, our findings suggest that the presence of CDI does not lead to worse short-term outcomes, such as increased colectomy rates or prolonged hospital stays. These results highlight the need for close monitoring of ASUC patients with CDI to balance the risks and benefits of corticosteroid use. Earlier CDI testing in hospitalized ASUC patients could expedite diagnosis and enable timely initiation of targeted therapies. Practitioners might also consider adjusting corticosteroid dosing and closely monitoring ASUC patients with CDI to minimize potential risks.
This study has some limitations. The single-center design of this study limits the generalizability of this study to broader populations or other institutions due to variations in healthcare practices and patient demographics. Future multicenter studies with larger sample sizes and different health care settings would be needed to validate our findings and enhance their external validity. This study also utilizes retrospective data, which is dependent on the accuracy and completeness of our electronic medical record system. Additionally, our study center utilizes only PCR-based testing for CDIs. Future studies could benefit from analyzing ASUC patients testing positive for CDI through enzyme immunoassay testing for the presence of C. difficile antigen and/or toxin. This can distinguish between those infected with the toxigenic strain of C. difficile and those colonized with the bacteria.
This study demonstrates that, in the context of ASUC, a positive C. difficile test does not correlate with worse clinical outcomes. However, these findings do not undermine the significance of CDI in ASUC patients. It remains crucial to rule out and appropriately treat CDI in all patients with ASUC, ideally using toxin-based testing. The presence of CDI should not delay the prompt and aggressive treatment of ASUC. Future research should focus on larger, multi-center studies, and prospective designs to validate these findings and further elucidate the complex interactions between ASUC and CDI.
