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Objective:
To investigate the risk factors for Clostridioides difficile infection (CDI) in patients with ulcerative colitis (UC) during biologic therapy.
Methods:
Patients diagnosed with UC who received Infliximab (IFX) or Vedolizumab (VDZ) were enrolled. Their clinical characteristics and risk factors for CDI were analyzed.
Results:
A total of 110 UC patients treated with IFX (61 cases) or VDZ (49 cases) were included. The overall positive rate of Clostridioides difficile (C. difficile) was 28.2%. Positive Epstein-Barr virus (EBV)-DNA, a modified Mayo score ≥11 points, and a history of glucocorticoids use within 2 months before admission were independent risk factors for CDI in UC patients receiving IFX/VDZ therapy. The incidence of CDI was the highest within 0–3 months after IFX/VDZ treatment.
Conclusion:
Positive EBV-DNA, a modified Mayo score ≥11 points, and a history of glucocorticoids use within 2 months before admission were independent risk factors for CDI in UC patients during IFX/VDZ therapy.
1 IntroductionUlcerative colitis (UC) is an immune-mediated chronic inflammatory bowel disease (IBD) characterized primarily by mucosal leions affecting the rectum and colon. Its therapeutic drugs include aminosalicylate preparations, glucocorticoids, immunosuppressants, biological agents, and small-molecule drugs. Currently, the concept of “step-up” therapy has been downplayed, and biological agents can be used as a first-line treatment regimen for patients with moderate-to-severe active UC (Kucharzik et al., 2021; Inflammatory Bowel Disease Group et al., 2024).The biological agents approved in China for the treatment of UC are Infliximab (IFX) and Vedolizumab (VDZ) (Inflammatory Bowel Disease Group et al., 2024).
Clostridioides difficile (C. difficile) is a normal component of the intestinal flora. When intestinal microecological imbalance occurs, its dormant spores germinate, proliferate, and release toxins, which can cause Clostridioides difficile infection (CDI). This infection not only induces intestinal disorders but also prolongs disease duration or exacerbates the disease. Studies have shown that IBD is an independent risk factor for CDI, with an incidence rate more than five times that of non-IBD patients (Kucharzik et al., 2021). Furthermore, the incidence of CDI in UC patients is higher than that in Crohn’s disease (CD) patients (Khanna, 2021; Spartz et al., 2024). Thus, identifying the risk factors of CDI in UC patients and conducting timely diagnosis and treatment are of great clinical significance.
Therefore, we aimed to explore the clinical characteristics of UC patients and the risk factors for concurrent CDI in the context of biological agent (IFX/VDZ) treatment, so as to improve clinicians’ ability to identify and manage CDI.
2 Methods2.1 Study population and designThis study retrospectively enrolled patients diagnosed with UC in the Department of Gastroenterology, Shengjing Hospital of China Medical University, who received IFX/VDZ treatment from January 2019 to May 2025. Time and dosage of biologic agents: IFX: 5 mg/kg was administered intravenously at weeks 0, 2, and 6, followed by maintenance dosing every 8 weeks thereafter. VDZ: 300 mg was administered intravenously at weeks 0, 2, and 6, followed by maintenance dosing every 8 weeks. The study was approved by the Hospital Ethics Committee (Ethics No: 2024PS1598K). All enrolled patients underwent fecal C. difficile testing. Patients who were pregnant, lactating, or had a history of active malignant tumors were excluded. General patient data, laboratory tests, disease characteristics [Montreal Classification (Silverberg et al., 2005), Modified Mayo Score (Lobatón et al., 2015), Mayo Endoscopic Score (Schroeder et al., 1987)], concurrent medication use within 2 months before admission, and CDI treatment status were collected. Missing data were handled using multiple imputation. Statistical analysis was performed using SPSS 27.0 software to analyze the clinical characteristics of patients, and logistic regression analysis was used to identify the risk factors for CDI. For variables with a missing data rate of ≥30%, they are directly excluded. For variables with a missing rate of <30%, multiple imputation is used to fill in the missing values. The significance level set at P <0.05.
2.2 Diagnostic criteria of C. difficileFecal samples were collected from patients in this study. Referring to the Chinese Guideline of CDI (Chinese Society of Surgery of Chinese Medical AssociationInfectious Diseases Society for Evidence-based and Translational Medicine of Chinese Research Hospital Association, 2024), nucleic acid amplification test (NAAT) and C. difficile toxin B (tcdB) gene detection were performed, and C. difficile binary toxic (CDT) and tcd gene deletion detection were conducted. The result interpretation was as follows: CDI was diagnosed if NAAT (+), tcdB gene (+), and the frequency of diarrhea was ≥3 times/day; C. difficile colonization was diagnosed if NAAT (+), tcdB gene (+), but the frequency of diarrhea was <3 times/day; the presence of a hypervirulent strain was suggested if CDT (+) and tcd gene deletion (+), combined with NAAT (+) and tcdB gene (+); the absence of CDI was determined if all the above four results were (-).
3 Results3.1 Clinical characteristics of the study populationA total of 110 patients with UC were enrolled in this study. The positive rate of C. difficile was 28.2%, including a C. difficile infection rate of 23.6% and a colonization rate of 4.5%. Among all infected patients, only one case was infected with a hypervirulent strain. According to the type of biological agent used, 61 patients received IFX and 49 received VDZ.
The clinical characteristics of the patients were as follows: 71 males and 39 females, with a male-to-female ratio of 1.82:1; the age ranged from 14 to 82 years, with a mean age of 48.43 ± 16.39 years; the mean length of hospital stay was 10.98 ± 7.67 days; the mean BMI was 20.23 ± 3.28 kg/m²; the mean disease duration was 61.85 ± 62.07 months. There were 28 smokers and 28 drinkers; 16 patients had hypertension, 7 had diabetes, and 26 (23.6%) had a previous history of CDI. Seventy-six patients (69.1%) were treatment-naïve, and 34 had received prior biologic therapy. In terms of clinical manifestations, 81 patients (73.6%) had abdominal pain, 82 (74.5%) had bloody stools, while only 13 patients (11.8%) presented with fever. In total, 14 patients tested positive for EBV-DNA. Regarding disease-related data: 54.5% (60 patients) had severe disease activity according to the modified Mayo score; 85.5% of UC patients had a Mayo endoscopic subscore of 3 (severe active phase); extensive colonic involvement was observed in 80.6% (89 patients) of cases. Within 2 months before admission, the most frequent combination medication was corticosteroids, used in 32 patients (29.1%). Detailed data are shown in Table 1.
ItemsTotal(n=110)CDI groupComparison of clinical characteristics between patients in CDI group and non-CDI group.
In the between-group comparison (see Table 1 for details): the length of hospital stay was significantly longer in the CDI group than in the non-CDI group. The proportion of patients with fever (26.9%) was significantly higher in the CDI group than in the non-CDI group (7.1%). In addition, the percentage of patients with positive EBV-DNA was also significantly higher in the CDI group. In terms of disease characteristics, 76.9% of patients in the CDI group had severe disease activity based on the modified Mayo score. With regard to medication history, the proportion of patients with corticosteroids use within 2 months before admission was higher in the CDI group than in the non-CDI group, with P < 0.05.
3.2 Analysis of risk factors for CDI in UC patients treated with IFX/VDZResults of univariable analysis showed that positive EBV-DNA, a modified Mayo score ≥11 points, and a history of glucocorticoids use within 2 months before admission might increase the risk of CDI. For UC patients receiving IFX or VDZ treatment who developed concurrent CDI, the condition might lead to prolonged hospital stays and fever. Considering that prolonged hospital stay and fever were merely outcomes of CDI, only positive EBV-DNA, a modified Mayo score ≥11 points, and a history of glucocorticoids use within 2 months before admission were included in the multivariable analysis. Multivariable analysis revealed that positive EBV-DNA, a modified Mayo score ≥11 points, and a history of glucocorticoids use within 2 months before admission were independent risk factors for CDI in UC patients treated with IFX/VDZ. For details, see Table 2.
VariablesUnivariable AnalysisMultivariable AnalysisOdds Ratio(95%CI)P ValueOdds Ratio(95%CI)P ValueLength of hospital stay2.88(1.17-7.10)0.022Symptom-fever4.79(1.44-15.90)0.011Positive EBV-DNA4.05(1.27-12.95)0.0184.416(1.26-15.80)0.020A modified Mayo score ≥11 points3.67(1.34-10.05)0.0123.56(1.22-10.39)0.020History of glucocorticoids within 2 months before admission3.42(1.36-8.61)0.0093.10(1.16-8.28)0.024Analysis of risk factors for CDI in UC patients treated with IFX/VDZ.
The length of hospital stay was set with <10 days as the reference; Fever was set with no fever as the reference; Positive EBV-DNA was set with negative EBV-DNA as the reference; A modified Mayo score ≥11 points was set with <11 points as the reference;History of glucocorticoids use within 2 months before admission was set with no glucocorticoids use as the reference.
3.3 Comparison of the epidemiology of CDI and the onset time following the administration of biologic agents between the VDZ group and the IFX groupThere were 61 cases in the IFX group and 49 cases in the VDZ group. In the IFX group, the C. difficile positivity rate was 23% and the infection rate was 18%; in the VDZ group, the C. difficile positivity rate was 34.7% and the infection rate was 30.6%. No statistically significant differences were observed in either the positivity rate or the infection rate between the two groups. Analysis of the onset time of CDI in patients of the two groups showed that among UC patients, the incidence of CDI was the highest within 0–3 months after the initiation of VDZ/IFX treatment; however, this difference was not statistically significant. For details, see Table 3.
ItemsVDZ GroupIFX Groupχ²P ValueC. difficile Positivity RatePositive 31/110/(28.2%)17/49(34.7%)14 /61(23%)1.8510.174C. difficile Infection RateInfection 26/110(23.6%)15/49(30.6%)11/61(18%)2.3820.123Onset Time of CDI n(%)≤3 months 19/26(73.1%)Comparison of the epidemiology of CDI and the onset time following the administration of biologic agents between the VDZ group and the IFX group.
3.4 Treatment details of CDIA total of 31 patients with positive C. difficile test results were included in this study, consisting of 26 patients with confirmed infection (CDI) and 5 patients with colonization. Among the CDI patients, 23 received oral vancomycin treatment; 1 patient was switched to oral metronidazole due to vancomycin intolerance; 1 patient with recurrent CDI underwent fecal microbiota transplantation (FMT) after evaluation; another patient was discharged against medical advice without treatment due to personal reasons. Among the colonized patients, 2 received no treatment; 3 received oral vancomycin.
When stratified by infection type: 21 cases (80.8%) were primary CDI; 19 received oral vancomycin, 1 was switched to oral metronidazole due to vancomycin intolerance, and 1 was discharged against medical advice without treatment; 5 cases (19.2%) were recurrent CDI; 1 underwent FMT, and the remaining 4 all received oral vancomycin treatment.
4 DiscussionA real-world study showed the incidence of CDI was 20.6% in the IFX group and 4.8% in the VDZ group among UC patients (Zhao, 2024); another study indicated the incidence of CDI after VDZ treatment was only 6.2% (Li et al., 2025). Additionally, foreign scholars demonstrated the C. difficile positivity rate in IBD patients who had used IFX within 1 year was 34.8% (Anderson et al., 2017), and existing studies have confirmed that UC patients treated with VDZ had a lower CDI risk than those treated with anti-tumor necrosis factor agents (Chen et al., 2024). In this study, the C. difficile positivity rate in IFX-treated UC patients was consistent with previous studies; however, that in VDZ-treated patients was significantly higher, conflicting with previous research conclusions. The putative reasons include this study’s small sample size, the inclusion of patients with a previous history of CDI (increasing the risk of reinfection), and regional differences in baseline characteristics and diagnosis or treatment practices.
The manifestations of IBD complicated with CDI are highly similar to those of active IBD, making clinical differentiation often difficult. In this study, when comparing clinical manifestations and laboratory indicators, patients in the CDI group had a longer length of hospital stay and a higher proportion of fever. This conclusion was consistent with previous clinical experience. Furthermore, this study confirmed that positive EBV-DNA was a risk factor for CDI in UC patients receiving biologic agents. When IBD patients present with aggravated diarrhea accompanied by systemic symptoms such as fever and pharyngitis, EBV infection warrants attention; a high or dynamically increasing EBV-DNA load can serve as an indicator. To date, no studies have reported the association between the two. EBV infection may indirectly increase the risk of CDI by inducing immune dysfunction, exacerbating the underlying disease, or disrupting intestinal microecological balance. However, this study did not further investigate the impact of EBV infection on disease severity and immune status. The potential association and molecular mechanisms between them still need to be further clarified with an expanded sample size and combined basic experiments. Although studies have shown that IBD patients complicated with CDI exhibited characteristic differences in the species composition of intestinal flora (Yu et al., 2023), this study only preliminarily determined the presence of intestinal dysbiosis by detecting the Gram staining characteristics of patients’ intestinal flora, and no statistically significant difference was observed between the two groups. To analyze the structure and changes of intestinal flora more accurately, further studies using molecular biological techniques such as rRNA sequencing are required.
This study confirmed that a modified Mayo score ≥11 points was an independent risk factor for CDI in UC patients receiving IFX/VDZ treatment. This was consistent with the conclusions of previous studies that patients with active IBD have a higher risk of CDI (Consensus Expert Group of Journal of Modern Digestion & Intervention, 2019; Drozdinsky et al., 2023). The possible mechanism is that the intestinal barrier is impaired during the active phase, which facilitates the colonization of C. difficile. Although meta-analyses have indicated that colonic involvement is a risk factor for CDI in IBD patients (Balram et al., 2019; Zhang, 2020), there was no significant difference in the proportion of colonic involvement between the two groups in this study. This is presumably related to the relatively severe overall condition of the patients included in this study. In the future, the sample size needs to be expanded to further reduce selection bias and explore the association between the two more accurately.
This study indicated that the use of glucocorticoids within 2 months before admission increased the risk of CDI in patients with UC, which was consistent with the conclusions of previous studies (Jakubowska et al., 2024). However, although it is widely accepted that the combination of biologics with antibiotics and immunosuppressants significantly increases the risk of CDI (Zhang et al., 2017; Gholam-Mostafaei et al., 2020), and that PPI use is also associated with an elevated risk of CDI (Eeuwijk et al., 2024; Finke et al., 2025), but this study did not observe any association between these factors and CDI. This may be due to the limited sample size, recall bias, and documentation bias. Future large-sample, multicenter prospective studies with standardized, real-time, and comprehensive medical records are warranted to collect accurate information on patients.
There are few specific studies on the onset time of CDI in IBD patients after initiating biologic therapy at home and abroad, but relevant studies can provide references: the risk of infection was the highest in the early stage of anti-TNF agent use (Ma et al., 2023), and the risk of opportunistic infection in rheumatoid arthritis patients receiving biologic therapy in the short term (< 6 months) was higher than that in the long-term stage (Hashimoto et al., 2017).These findings lay an important foundation for this study. This study showed that among UC patients receiving IFX/VDZ treatment, the incidence of CDI was the highest within 0–3 months after the start of treatment. This was basically consistent with the conclusions of previous studies. This result also sounds an alarm for clinical practice: in the early stage of biologic therapy, it is necessary to strengthen the monitoring of CDI to detect and take intervention measures in a timely manner.
The treatment of CDI in this study mainly focused on vancomycin, metronidazole, and fecal microbiota transplantation. The Chinese guideline (Chinese Society of Surgery of Chinese Medical AssociationInfectious Diseases Society for Evidence-based and Translational Medicine of Chinese Research Hospital Association, 2024) acknowledges the efficacy of vancomycin and metronidazole; The 2021 IDSA guideline (Johnson et al., 2021) recommends fidaxomicin and vancomycin for the treatment of CDI, with metronidazole as an alternative option. FMT is recommended for patients with ≥2 recurrences or those who have failed antibiotic therapy. Domestic and international guidelines are generally consistent. Although the Chinese guideline also recognizes the efficacy of fidaxomicin, its limited availability in China restricts its use to patients with recurrence or at risk of recurrence only when the drug is accessible. Therefore, fidaxomicin was not used in our hospital.
This study was a single-center retrospective study with certain limitations. The late implementation of routine testing for C. difficile in our hospital resulted in a limited sample size, which may affect the stability and representativeness of the findings. During the follow-up period of biologic therapy, infection-related screenings such as C. difficile and EBV-DNA testing were not performed at every hospital admission, which may lead to missing data. In addition, this study only included patients who underwent CDI testing, while those who did not receive CDI testing were excluded, resulting in selection bias that may impact the study results. Future multicenter, large-sample prospective studies are warranted to further validate and refine the conclusions of this study, and improve the reliability and generalizability of the results.
5 ConclusionsPositive EBV-DNA, a modified Mayo score ≥11 points, and a history of glucocorticoids use within 2 months before admission were independent risk factors for CDI in UC patients during IFX/VDZ therapy.
StatementsData availability statementThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics statementThe studies involving humans were approved by Shengjing Hospital of China Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because This study is a retrospective study with minimal risks, which would not compromise the rights and interests of participants, and adequate measures were taken to protect patients’ privacy. Therefore, the written informed consent was waived by the hospital’s Ethics Committee.
Author contributionsTX: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. YX: Supervision, Writing – review & editing.
FundingThe author(s) declared that financial support was not received for this work and/or its publication.
AcknowledgmentsFirst and foremost, I would like to express my sincere gratitude to my supervisor, Ying Xie, for providing valuable guidance and constant encouragement throughout the course of my research. Her profound professional knowledge in the field of IBD and rigorous academic attitude have laid the foundation for the smooth implementation of this study. Secondly, I would like to thank the clinical team of Shengjing Hospital of China Medical University for providing crucial clinical data for this research, which has enabled the successful completion of the study.
Conflict of interestThe author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statementThe author(s) declared that generative AI was not used in the creation of this manuscript.
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