By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A retrospective cohort study found that for patients taking immunosuppressing medications, the greatest risk for C. difficile infection occurred for those receiving calcineurin inhibitors and those taking drugs from multiple immunosuppressant classes.
SOURCE: Varma S, Greendyke WG, Li J, Freedberg DE. Class-specific relationship between use of immunosuppressants and risk for community-acquired Clostridioides difficile infection. Clin Infect Dis 2022;74:793-801.
It is evident that patients taking immunosuppressing medications are at increased risk for developing Clostridioides difficile infection (CDI). However, the degree of risk for specific immunosuppressing medications is not yet clear. Varma and colleagues aimed to determine the risk for CDI across multiple classes of immunosuppressant drugs.
The study was a retrospective cohort analysis from a single hospital in New York City. Patients were included who were 18 years of age or older and tested positive for community-acquired CDI (CA-CDI), defined as stool C. difficile toxin testing within 72 hours of hospital admission, between 2010 and 2019. The primary outcome was a diagnosis of CA-CDI. The exposure of interest was the home use of immunosuppressant medications at the time of hospital admission. Immunosuppressant medications were characterized by class and included systemic steroids, calcineurin inhibitors, anti-metabolites, anti-tumor necrosis factor (TNF) agents, anti-CD20 antibody, and all others. This latter category included interleukin inhibitors, interferon-γ, CTLA-4 inhibitors, JAK kinase inhibitors, and integrase inhibitors.
There were 1,795 patients with CDI included in the analysis, of whom 485 (27%) were taking one or more classes of immunosuppressant. The most common class was steroids, followed by calcineurin inhibitors and antimetabolites. After adjustments were made for demographic and clinical characteristics, only calcineurin inhibitors were independently associated with an increased risk for CA-CDI (adjusted odds ratio [aOR], 1.19; 95% confidence interval [CI], 1.01-1.44). Furthermore, as the number of immunosuppressant classes increased, so did the risk for CA-CDI (aOR, 1.22, 1.53, and 2.40 for two, three, and four or more classes, respectively). Solid organ transplantation also was associated with a higher risk for CA-CDI (aOR, 1.25%; 95% CI, 1.08-1.45). No association was found between any specific immunosuppressive medicine class and CDI among patients who received antibiotics. Finally, outpatient care variables did not have a significant impact on the relationship between immunosuppression and CA-CDI incidence.
COMMENTARY
CA-CDI continues to be a major cause of morbidity and mortality for patients and drains significant resources from healthcare systems. Thus, a more nuanced understanding of risk factors for CA-CDI potentially may lead to earlier testing and treatment, along with reducing its incidence. Therefore, the study by Varma et al is important because it sheds light on the impact of a specific class of immunosuppressant medications, calcineurin inhibitors, and the risk for CA-CDI. Calcineurin inhibitors are immunosuppressants used in the management of multiple conditions, including lupus nephritis, interstitial lung disease, idiopathic inflammatory myositis, atopic dermatitis, and solid organ transplants. Common examples include cyclosporine, tacrolimus, and pimecrolimus. They are known to damage the gastrointestinal mucosa, reduce gut microbial diversity, alter the host immune response in the gastrointestinal tract, and affect genetic susceptibility. These factors likely have an impact on the risk of developing CDI and its severity. Furthermore, calcineurin inhibitors attenuate IL-2 production, which plays an important role in T-cell expansion and B-cell function. Higher levels of tacrolimus lead to lower IL-6, so an unresolved question is whether lower trough levels of tacrolimus are associated with a reduced risk for CDI.
Recent or current use of antibiotics is the main risk factor for CDI. In this study, antibiotics themselves were not associated with CA-CDI. This was surprising and may be due to ascertainment bias. Patients who report recent antibiotic use are more likely to be tested for CDI, even when other clinical features of CDI (e.g., fever and elevated white blood cell count) are absent. Thus, the true risk for CA-CDI from antibiotics may have been underestimated by the design of the study.
There are a number of other limitations to the study. First, unmeasured confounding variables could have affected the results because of the retrospective observational design. Second, the study was conducted at a large, quaternary, single center in New York City, so its findings might not be generalizable to other healthcare settings and geographic areas. Third, the investigators did not have information on the duration of immunosuppression or drug levels. They relied on the medicine reconciliation form at the time of hospitalization, which previous studies have shown might not be accurate. Fourth, because only a positive stool C. difficile toxin polymerase chain reaction (PCR) test was used to identify patients, the investigators were not able to differentiate CDI from colonization. Finally, no attempts were made to assess microbiome or immunologic impacts in individual patients.
The study highlights the increased risk for CA-CDI for patients on calcineurin inhibitors. It should remind clinicians to have a high clinical suspicion for CA-CDI in these patients, even when other traditional risk factors such as recent antibiotic exposure are absent. More data regarding specific medications and their risk for CA-CDI are required to mitigate the harm caused by this common affliction.
A retrospective cohort study found that for patients taking immunosuppressing medications, the greatest risk for C. difficile infection occurred for those receiving calcineurin inhibitors and those taking drugs from multiple immunosuppressant classes.
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