Incidence and risk factors of Clostridioides difficile infection in liver transplant recipients: A comprehensive literature review

INTRODUCTION

Clostridioides difficile infection (CDI) has recently emerged as a cause of rising morbidity and mortality in hospitalized patients in North America.¹ CDI is seen in 3%–7% of liver transplant recipients (LTRs) and is noted to complicate the course of these patients² frequently. Despite its impact on LTR, limited data are available evaluating its incidence, risk factors, and outcomes.²

Gut microbiota plays a crucial role in CDI through immune response, intestinal morphology, and biliary tract metabolism.³ Alteration in the composition of the intestinal microbiome is known as gut dysbiosis.⁴ Gut dysbiosis increases the gastrointestinal barrier permeability, thereby aiding the reach of bacterial byproducts to the liver through the portal system; it can subsequently perturb the homeostatic balance of intestinal microbes, the immune system, and ultimately, the gut-liver axis.^5,6 The gastrointestinal tract is colonized by numerous commensals with different roles in health and disease; any alteration in the barrier or the flora that resides there has the potential to cause changes in health. Since the portal vein drains the blood from parts of the digestive tract through the liver, toxic compounds or dietary constituents may act as a stressor or pathogen to the liver. Thus, the gut-liver axis involves bidirectional communication between the gastrointestinal tract and the liver, regulating inflammation and infections.⁷ Disruption of this axis, mainly through intestinal barrier damage, is paramount in the development of hepatic inflammation, affecting morbidity in LTRs.⁷

Given the scarcity of published data, we aim to discuss existing research regarding the incidence, risk factors, and outcomes of C. difficile infection in LTRs.

METHODS

A comprehensive literature search was conducted using PubMed, MEDLINE, Cochrane Library, Embase, and CINAHL. These databases were searched from inception to July 2023 for cohort studies, case-control studies, and cross-sectional assessments of relationships, outcomes, and incidence of CDI in LTRs.

Variations of the following keywords were used in our search: Liver disease, Liver transplant recipients, and C. difficile infection. All human studies published in English were assessed for eligibility. Retrieved results were then scanned based on their title and abstract. The authors, Tooba Laeeq and Kyaw Min Tun, independently evaluated the eligibility of the studies. No date of publication, location, or demographic limitations were placed.

RESULTS

Table 1 summarizes the main findings of the included studies with a detailed discussion below. A strong association was noted between CDI in LTRs along with higher mortality associated with it.

TABLE 1.

Summary of the studies analyzed in this review

References	Type of study/year of enrollment/location	Objective	Year of enrollment	Number of subjects and patient population	Length of follow-up	Results
Mittal et al2	Retrospective cohort study/2014/Detroit, Michigan, USA	Report rates of CDI and mortality in hospitalized patients undergoing liver transplant	Patients who were LTRs from 2000 to 2010 at a tertiary hospital in Detroit	970 LTRs with positive EIA for C. difficile toxins A/B	Date of LTR-death or until December 31, 2011	Prevalence of CDI pretransplant (3.3%), posttransplant (16.7%), overall prevalence (18.9%). Mortality rate (p=0.003) of the entire population (27.8%), CDI population (35%), non-CDI population (26%)
Ali et al8	Retrospective cross-sectional study/2012/Wisconsin, USA	Prevalence of CDI and effect of CDI on patient mortality in patients undergoing transplant	HCUP-NIS patients from 2004 to 2008	193,714 discharges with LTR diagnosis and age 50–64 y similar in terms of gender, race, and insurance provider	Hospital stay only	LTRs were noted to have a higher prevalence of CDI infection (2.7% vs. 0.9%) and higher mortality (5.5% vs. 2.3%) as compared to the nonliver transplant population (p<0.001)
Rogala et al9	Retrospective case-control study/2016/Philadelphia, Pennsylvania, USA	Analyze risk factors among LTRs for CDI	Patients who were LTRs from January 2008 to December 2012	65 patients who were LTRs with classification of C. difficile infection by either positive toxin A/B EIA or glutamate dehydrogenase EIA and PCR within 1 y of transplantation	1-y after transplantation	Incidence of CDI 23% with risk factors including previous history of CDI (p=0.001), exposure to PPIs (p=0.015), antimicrobial therapy before transplantation (p=0.039), prolonged hospitalization before transplantation (p=0.028), and chronic kidney disease (p=0.011).
Kortt et al10	Case-control study/2021/New South Wales, Australia	LT recipients were examined for prevalence and long-term outcomes with and without CDI	Patients who were LTRs from 2007 to 2017	649 patients who underwent deceased-donor LT	1 y	4.9% of the patients undergoing LT developed CDI with no difference in mortality (p=0.08) among patients with CDI and without CDI undergoing LT.
Gomez-Simmonds et al11	Longitudinal cohort study/2022/Michigan, USA	Development of CDI in LT cohort with 1 y of transplant	2022	197 patients undergoing LT during the study period	(1, 3, 6) months, and 1 y	9.1% of the patients developed CDI within 1 y of LT. Factors significantly associated with CDI included pre-LT Child-Pugh class C liver disease, postoperative biliary leak, and the use of broad-spectrum antibiotics.
Sullivan et al12	Retrospective cross-sectional study/2016/New York, USA	Evaluation of potential risk factors for CDI infection in patients undergoing LT	January 2011 to April 2013	192 patients who underwent LT	Mean follow-up time of 1.8 y	14% of the LTRs developed CDI. An association between MELD score (>20) (p=0.01) and living donor transplant (p=0.006) was also seen with CDI.
Amjad et al13	Retrospective case-control study/2021/Massachusetts, USA	Assessment and predictors of readmission in patients who are LTRs with CDI	Readmission data from 2010 to 2017	310,222 LTR with CDI infection subjects	Hospital length of stay	CDI in the LTR population was associated with higher 30-day readmission
Niemczyk et al14	Retrospective cross-sectional study/2005/Warsaw, Poland	Incidence of CDI in solid organ transplant recipients	2003	Liver transplantation and kidney transplantation recipients/16 patients	6 mo	During the analyzation period (6 mo) 88% of transplant recipients developed CDI out of which 37% were LTRs

Abbreviations: C, difficile, Clostridioides difficile; CDI, Clostridioides difficile infection; EIA, enzyme immunoassay; HCUP-NIS, health care cost and utilization project-nationwide inpatient sample; LT, liver transplant; LTR, liver transplant recipient(s); MELD, Model for End-Stage Liver Disease; PPI, proton pump inhibitors.

Ali et al’s⁸ analysis of patients with concomitant CDI discharge diagnosis codes of LT and CDI was identified. The study defined CDI as an independent risk factor predicting mortality in patients who are LTRs (OR: 1.7; CI: 1.3–2.2). They also found that although renal transplant recipients and LTRs were both at increased risk of CDI, LTR prevalence was higher. Mittal et al’s² study also demonstrated a strong relationship between CDI and liver transplant with a higher incidence of posttransplant versus pretransplant infections as well as mortality; specific statistically significant predictors for posttransplant CDI included White race (p=0.035), higher Model for End-Stage Liver Disease (MELD) scores >20 (p<0.001), year of transplant (p<0.001), and increased length of stay for transplant (p<0.001). They noted that over 10 years, about one-sixth of their patients who were LTRs developed CDI.

In Rogala et al’s⁹ study, statistically significant associations were found between the incidence of infection and risk factors of chronic kidney disease and proton pump inhibitor use before transplantation. This study used a 2-step C. difficile testing methodology, increasing their rate of detection and incidence. Kortt et al¹⁰ evaluated LTRs who received deceased donor transplants in 11 years and the incidence of CDI over the first year following the transplant. They described no difference in overall survival among LTRs with and without CDI; decreased risk of infection was seen with the use of rifaximin (p=0.0); increased risk was seen with antibiotic use, especially penicillins (p=0.03) along with length of stay after LT (p=0.02). Gomez-Simmond et al¹¹ found an interesting association between the enriched presence of Enterococcus faecium in fecal samples of patients with CDI with abundant non-faecium Enterococcus in patients who did not develop an infection. They also noted that there were significant but transient reductions in alpha diversity in the 1-month posttransplant period. This time association with increased risk of CDI suggests some role in gut microbial diversity and the development of CDI in LTRs. They also noticed a linkage between high Child-Pugh scores (p=0.02) and postoperative biliary leak (p=0.02) with CDI in LTRs.¹¹

Sullivan et al’s¹² study evaluated patients diagnosed with CDI within 2 months before LT. It disclosed a higher incidence of CDI in LTRs with higher MELD scores (p=0.04), metabolic associated fatty liver disease (p=0.031), and coinfection with hepatitis C and HIV (p=0.021) showing MELD score of 20 or greater along with a living donor transplant posing a higher risk. This was thought to be related to MELD, which is related to advanced illness. Interestingly, LTRs receiving a living donor were more likely to develop CDI. Amjad et al¹³ evaluated readmission data to evaluate CDI in LTRs. Their study solidified CDI as the most common cause of 30-day readmission in LTRs, as well as the admissions frequently being recurrence in infection, along with higher mortality (p <0.001) in this population.

Niemczyk et al¹⁴ discussed that by modifying antibiotic use, cleaning and disinfecting rooms of infected patients, and early identification and isolation of patients with suspected infection, they were able to decrease their frequency of infection by 2-fold (from 4.5/1000 patient days to 2.2/1000 patient days). They found that 62.5% of infections occurred in the first 6 months, with 37.5% occurring in the first month. This suggested that patients who had recent transplants received immunosuppressive drugs in high doses and whose transplanted organs had not received optimal function were at special risk.

DISCUSSION

Despite recent advances in surgical techniques and immunosuppression in solid organ transplantations, there remains a significant risk for C. difficile infection. In a 2022 study by Gomez-Simmonds et al,¹¹ patients undergoing solid organ transplant had a 5-fold increase in CDI incidence compared to other hospitalized adults. While immunosuppressed patients, such as patients undergoing transplant, have an increased incidence and recurrence rate of C. difficile infection up to 40%, there is no strong data linking the increase to immunosuppression type. The increase is believed to be secondary to more frequent antimicrobial use, increased health care settings, and the prevalence of colonization.¹ C. difficile remains the leading cause of nosocomial antibiotic-associated diarrhea; antibiotics alter the indigenous microbiome and bile acid metabolism, hence promoting the growth of C. difficile in the gut.¹⁵ Bile acids are key in maintaining gut microbiota through enterohepatic circulation.¹⁶ Gastrointestinal manipulation and the postbiliary leak are also associated with taxonomic changes in the gut microbiome, leading to changes predisposing it to CDI.¹¹ Recent studies have established the relationship of bile acids with bacterial resistance and local and distant immune reactions.¹⁶ Bacteria such as Anaorotignum, Blautia, Lactonifactor, and Monoglobus, which are protective and aid in bile and fiber metabolism, are also noted to be decreased in the CDI population.¹¹

Moreover, age >65 is considered to be a risk factor for CDI owing to the impaired immune response and comorbidities in this group.¹⁷ Gastric acid suppression has also been associated with an increased incidence of CDI.¹⁸ Tariq et al’s¹⁸ meta-analysis studies 7703 subjects, with 22.1% developing recurrent CDI in the gastric acid suppression group compared to 17% in the control group. The presumed reason is weakened defense mechanisms due to suppressing gastric acid, promoting C. difficile colonization and infection.¹⁷ In LTRs, high rates of hospital readmissions, infectious complications requiring antibiotics, and stress ulcer prophylaxis through proton pump inhibitors all serve as independent risk factors for CDI.¹³ Among other risk factors, pretransplant higher MELD >20 is also considered a significant risk factor for the development of posttransplant CDI.¹² Furthermore, postoperative patients with higher Child-Pugh scores and higher MELD scores were noted to have increased overall microbial diversity in follow-up periods than patients with lower scores.¹⁹

In conclusion, LTRs are at high risk for developing nosocomial and community-acquired C. difficile infection. Risk factors can be modified, potentially leading to lower rates of infections. A conservative immunosuppression rather than an aggressive approach can prevent opportunistic and nosocomial infections like CDI. Patients with chronic diseases that cause baseline immunosuppression, such as diabetes or chronic kidney disease, may benefit from a lessened immunosuppression regimen to decrease CDI incidence and recurrence. However, as the individual immunosuppression of each patient may differ, further studies are needed to evaluate additional immunotherapy and the risk of transplant rejection in immune-compromised patients. Furthermore, replenishing protective gut microbiota through fecal microbiota transplant can be implemented to prevent CDI and its associated mortality in LTRs. On top of that, the cautious use of proton pump inhibitors and antibiotics, along with efforts to reduce the duration of hospitalization, can imaginably contribute toward decreased incidence of CDI in light of the above arguments. Emphasis on preventative measures for C. difficile, including contact precautions, hand hygiene before and after seeing the patients, and assessing CDI risk factors play a paramount role in disease prevention. Strategies such as gene therapy and immunotherapy with Treg expansion are underway. These advances may prevent the need for lifelong immunosuppression and decrease the risk of CDI in some patients requiring liver transplants.