Fecal microbiota transplantation (FMT) is an accepted procedure for managing recurrent Clostridioides difficile infection (CDI). FMT is generally considered safe and well-tolerated - even in high-risk patients. Most short-term risks are mild and known to be associated with delivery methods. Long-term side effects have not been established, and no signs of harm have been found to date. However, causality for several microbiome-disease associations should be established.

In this review, we discuss the adverse events associated with FMT, as well as its safety, based on clinical studies and systematic reviews on treatment for CDI.

FMT is usually considered safe, and the common side effects are minor adverse events, including transient diarrhea, abdominal cramps or pain, low-grade fever, bloating, flatulence, and constipation (Table 1) [1]. However, we should consider the possible uncommon severe side effects following FMT.

The safety of FMT in high-risk patients has not been established, as almost all FMT trials excluded those patients. A recent systematic review of 44 studies on FMT for CDI showed an 88% treatment success rate in 303 immunocompromised patients (almost all patients used immunosuppressive medication), [13] of which 2 patients died, 2 patients had colectomies, 5 patients had treatment-related infections, and 10 patients were subsequently hospitalized. Based on the findings of that study, FMT in immunocompromised patients seems to have comparable safety to that in immunocompetent patients [13]. However, the transmission of live microorganisms to recipients with underlying illnesses presents a greater potential risk [14,15]. For example, clinicians should consider the possible transmission of the Epstein-Barr virus and cytomegalovirus from donors in immunosuppressed FMT recipients, for which recent guidelines recommend additional donor screening [16]. Several risks are mitigated by implementing a careful selection and screening process for prospective donors. Luo et al. suggested a higher incidence of adverse events in high-risk patients, including immunocompromised patients, patients with inflammatory bowel disease (IBD), and patients with fulminant colitis [17]. Particularly, clinicians should consider the risk of IBD flare-ups in patients with IBD. Another systematic review of FMT for the treatment of IBD showed bothersome serious side effects: 7% of FMT participants, compared with 5% of controls, had severe adverse events (relative risk, 1.4; 95% confidence interval, 0.5-3.6) [18]. However, this should be interpreted with caution, because the adverse event reports were not standardized. In solid-organ transplant recipients who underwent FMT for the treatment of CDI, adverse events occurred in 22.3%, and relatively mild adverse events, such as nausea, abdominal pain, diarrhea, and severe adverse events occurred in 3.2% of patients, suggesting that FMT is safe in solid-organ transplant recipients [19]. Table 2 summarizes the safety of FMT in high-risk patients.

With the outbreak of the coronavirus disease 2019 (COVID-19), several centers have decreased the volume of routine diagnostic or elective procedures to avoid potential transmission of the virus. Several studies have reported a longer excretion of severe acute respiratory syndrome coronavirus 2 through feces than through the nasopharyngeal route [21]. Therefore, several FMT centers and stool banks have suspended the active performance of FMT and the recruitment of FMT donors. Recently, the FDA recommended only FMT products generated from donated stool before December 2019 [21]. However, FMT plays a major role in the management of recurrent CDI and cannot be postponed, especially in patients with life-threatening conditions. Therefore, during this COVID-19 pandemic, FMT should be considered a nonpostponable treatment modality, especially in patients with severe and/or recurrent CDI. A recent study demonstrated the possible application of FMT in patients with recurrent CDI during the COVID-19 pandemic by adopting specific changes in the workflow [22]. Recent guidelines have proposed a very strict workflow of stool donation, in which positivity of polymerase chain reaction for nasopharyngeal swabs, stool, and/or Immunoglobulin M serology should be an absolute contraindication for donation [21].

Even though FMT is generally considered safe, a severe adverse event has been reported to be associated with its product manufactured under a protocol that did not involve screening for multi-drug resistant organisms. Therefore, rigorous donor screening and testing should be mandated to minimize the risks of FMT, especially during the COVID-19 pandemic.

FMT is generally considered safe, and a recent study suggested that it is well-tolerated in high-risk patients. Rigorous donor screening and testing should be mandated to minimize the risk of FMT, especially during the COVID-19 pandemic.