Case–Control Study of Inflammatory Bowel Disease Patients with and without Clostridium difficile Infection and Poor Outcomes in Patients Coinfected with C. difficile and Cytomegalovirus

Clostridium difficile (C. difficile), a gram-positive spore-forming anaerobe, is the most commonly reported pathogen, causing 12.1% of healthcare-associated infections in the USA [1]. Studies have demonstrated an increasing incidence of C. difficile infection (CDI) in patients with inflammatory bowel disease (IBD) who commonly had a more severe course of disease than the non-IBD population [2‐5]. Traditional risk factors for CDI include recent antibiotic use or hospital exposure, older age, comorbidity, immunosuppression, and underlying IBD [6]. However, CDI has been associated with certain risk factors, including younger age, colonic IBD, active colitis, community acquisition, and use of corticosteroids or infliximab, in patients with IBD [3, 5, 7]. In addition, CDI has been found to complicate the course of IBD and has been reported to be associated with poor prognosis, including increased colectomy, higher mortality, and longer length of hospital stay [7].

The exact epidemiology of CDI has been hindered by a lack of global reporting and surveillance programs. To date, there are limited data describing the epidemiology and prognosis of CDI in IBD patients in China [8, 9]. One study reported that the incidence of CDI (19.3%) in patients with ulcerative colitis (UC) was higher than that (12.7%) in patients with Crohn’s disease (CD) in South China [8]. The other retrospective study reported that CDI was diagnosed in 5% (13 cases) of 260 patients with IBD in one tertiary hospital in Shanghai, China, from 2013 to 2015 [9]. The incidence, temporal change in incidence, risk factors, and prognosis of CDI in Chinese IBD patients are still poorly characterized. Therefore, we performed this study with the following aims: (1) to investigate the proportion of CDI for a longer duration and detect the temporal change in the proportion; (2) to identify the risk factors of CDI in patients with IBD; and (3) to explore the outcome of CDI in IBD patients.

CDI in patients with IBD has been recognized as an essential clinical problem due to the growing incidence, increasing prevalence, and worsening outcome. IBD is proven to be an independent risk factor of CDI. A population-based study revealed that individuals with IBD were approximately five times more likely to develop CDI than individuals without IBD [5]. In the present study, we have shown the following: (1) CDI cases and its proportion in hospitalized IBD patients are increasing in our tertiary IBD center in recent years; (2) the use of steroids and recent (within 1 month) hospitalization are associated with CDI; and (3) CMV coinfection is independently associated with IBD-related colectomy after CDI in IBD patients.

The presumed incidence CDI in hospitalized patients with IBD at our center has increased from 1.18% in 2010 to 8.29% in 2015, and the highest number (12.99%) occurred in 2014. The prevalence of CDI is 7.41% in our tertiary IBD center. Most studies reported the prevalence of CDI in hospitalized IBD patients ranging from 1 to  10% [2‐4, 14]. Furthermore, several studies from single centers reported in 2007 [15, 16] and studies using national hospitalization databases reported in 2008 [2, 14] have shown a temporal increase in the proportion of IBD hospitalizations complicated by CDI. A nationwide temporal increase in CDI in IBD hospitalizations from 1998 to 2007 was reported [4]. Although two studies have reported the prevalence of CDI in Chinese IBD patients, our present study is the first to show the temporal change in the proportion of CDI in hospitalized IBD patients. Due to the retrospective nature of this study, we have no data on the percentage of patients underwent testing for C. difficile toxin each year. Bias from physicians’ awareness was introduced in this study. In 2012, the publication of Chinese consensus on IBD management which emphasized opportunistic infection screening may explain the prominent increase of incidence from 2012. A more recent study describing the incidence of CDI in IBD patients found a decreasing trend [17]. In the UK, the incidence of CDI in IBD patients decreased from 8.7% in 2007/2008 to 0.4% in 2012/2013 [17]. Potential explanations for these observations are as follows: (1) better and prompt management of IBD in recent years, i.e., the early introduction of anti-TNFα agents to improve mucosal function and thereby reduce C. difficile colonization and (2) improved awareness of CDI and infection control practices in healthcare providers. In our study, we also observed a decrease in the proportion of detected CDI cases between 2014 (12.99%) and 2015 (8.29%). Ongoing monitoring of the temporal changes will reveal whether China exhibits a trend of CDI incidence similar to the recent study from the UK.

Endoscopy rarely detects pseudo-membranes and is therefore ineffective at diagnosing CDI in patients with IBD [15, 18]. It was reported that endoscopic pseudo-membranes were found in 13% of patients with IBD and CDI and that these patients more commonly presented with fever (P = 0.02) than patients without pseudo-membranes [19]. In our study, fewer endoscopic pseudo-membranes were found, with 6.3% in patients with UC and CDI and 0% in patients with CD and CDI. Therefore, the diagnosis of CDI is predominantly based on C. difficile toxin tests. The CDI diagnostic conundrum has been resolved by the development of molecular assays for toxigenic C. difficile that utilize real-time PCR to detect the tcdB gene encoding toxin B in fecal specimens, and these new assays have a higher sensitivity and specificity than the conventional enzyme-linked immunosorbent assay (ELISA)-based assays [20, 21]. Given the relatively lower sensitivity of ELISA-based assays, the incidence and prevalence of CDI reported in our study may be underestimated.

Which IBD patients are at the greatest risk of acquiring C. difficile infection? Risk factors for CDI in patients with IBD are different from those of non-IBD patients, such as younger age and fewer predisposing non-IBD-related comorbidities [2, 14]. Moreover, risk factors for CDI in non-IBD patients, such as antibiotic use or PPI use, are less common in patients with IBD [15]. Consistent with the known epidemiology of CDI in patients with IBD, our study found that recent hospitalization or use of steroids remained one of the strongest risk factors for CDI. Data from IBD cohorts did not consistently demonstrate the independent associations between medication use (including immunomodulators, anti-TNF agents, and 5-ASA) and risk of CDI [15], and our findings confirmed this lack of association. In a population-based IBD cohort from British Columbia, the use of corticosteroids tripled the risk of CDI in a manner that was independent of dose or duration [22]. However, in our study, we found a higher risk of CDI in patients administered a dosage of prednisone over 37.5 mg/day.

Higher plasma calcifediol [25(OH)D] was found to be associated with reduced risk of C. difficile infection in patients with IBD [23]. This study suggested a role for vitamin D in the pathogenesis of CDI in patients with IBD. Vitamin D stimulates the production of cathelicidin, which is an antimicrobial peptide that is widely expressed in neutrophils, natural killer cells, and intestinal epithelium, and has antibacterial activity against a spectrum of bacterial pathogens [24]. Furthermore, it was recently reported that cathelicidin inhibits the effect of C. difficile toxin [25]. However, our study did not find an association between plasma 25(OH)D levels and the risk of CDI. However, because only half (n = 31) of the patients with CDI had available 25(OH)D levels prior to CDI, the small sample size may weaken the power of this finding. Further studies investigating the association between 25(OH)D and the risk of CDI as well as the role of vitamin D adjunctive treatment in IBD patients to reduce the risk of CDI are imperative.

CDI was reported to worsen the outcome of patients with IBD and was associated with mortality, colectomy, and health resource utilization [2, 7, 8, 15]. However, studies reporting the impact of CDI on the risk of colectomy are inconsistent. Some single-center and nationwide studies failed to find an association between colectomy following CDI [2, 26]. Our study added evidence of no association between CDI alone and the subsequent colectomy. However, we found that the occurrence of CDI and CMV coinfections in patients strongly associated with the subsequent colectomy. We also found that CMV infection was more common in IBD patients with CDI. A recent study reported that CDI occurred more frequently in IBD patients with CMV reactivation and was associated with poor outcomes [27]. Conversely, our study revealed a higher rate of CMV coinfection in IBD patients with CDI and the association with poorer outcomes. A review article reported clinical scenario of coexisting cytomegalovirus infection in immunocompetent patients with CDI [28]. In cases of coexisting CMV and C. difficile colitis, ganciclovir therapy for CMV colitis in time may circumvent the unnecessary second-line therapeutic method for CDI, supposing that persistent diarrhea was not due to treatment failure for C. difficile [28]. In our clinical practice, coinfection is mostly seen in severe patients or those who received consequent or joined immunosuppressive medications. The severity of IBD itself may also contribute to the vulnerability of coinfections and poorer outcome. Although most of IBD patients with CDI-CMV coinfections were treated with antiviral therapy (15/18), but mostly the outcome of colectomy was still not prevented. Delayed diagnosis or initiation of antiviral therapy may not be the reason for poor outcome. Other more aggressive, novel, or adjunctive therapy such as using fecal microbiota transplantation, fidaxomicin, and anti-CMV immunoglobulin may need further investigation. Being aware of the poor outcomes of patients with coinfections, physicians should promptly test and aggressively manage these high-risk patients.