Key results and interpretation
In this multi-center cohort study, we described the real-world experience of FMT procedures for CDI in a heterogeneous national Israeli population during the 5 years since the procedure was approved. We examined the distribution of the various techniques, routes and success rates in 111 FMT procedures.
There was an 85% response to treatment within the first 7 d post-FMT, and the success rates rose to 88% at 2 mo. These rates are compatible with reports and reviews of others[5,7-9,12,15-19]. Comparison of the 3 usual methods of FMT administration, UGI, LGI and capsules, revealed a higher success rates for the capsules and LGI routes over the UGI route although not to a level of statistical significance. Nevertheless, capsules-treated patients had the highest recurrence rates (22% at 6 mo), again not reaching a level of statistical significance. These results can be interpreted in several ways. First, there were higher rates of severe CDI within the UGI group compared with the 2 other groups (Figure 1 and Table 1). Second, previous reports showed lower success rates for the UGI route compared with LGI: one systematic review of 325 cases of FMT for CDI suggested a lower success rate for upper gut administration (76%) compared with colonoscopy (89%) and enema (95%) administration, while Kassam et al reported a trend for higher resolution rates through the LGI route compared with the UGI route. Cure from CDI was associated with a milder disease and undergoing treatment in an outpatient setup. Other factors, such as age, Charlson score, albumin levels, and creatinine levels were not significantly different between the groups, since the study was probably underpowered to detect significant differences in these variables. Multiple infusions were seldom and relatively unsuccessful in our cohort (4 patients, 50% success rate), but the numbers are too low to arrive at any conclusions and the results cannot be compared with those of recent meta analyses which showed increased success rates with multiple FMTs[26,27].
Multivariant analysis revealed that severe CDI (OR = 0.14, P < 0.05) and inpatient FMT (OR = 0.19, P < 0.05) were each independently inversely related to FMT success, while patients’ background illnesses as reflected by the Charlson comorbidity score were not associated with either success or failure of FMT. Similar results were reported by Ianiro et al in their single-center cohort study that showing that severe CDI and inadequate bowel preparation were independent predictors of FMT failure, and by Fischer et al in their multi-center study, in which predictors for FMT failure included severe or severe-complicated CDI, inpatient status during FMT and previous CDI-related hospitalization. Taken together, this data implies that the severe form of CDI is less likely to be successfully treated with FMT, and that future studies are warranted in order to find the optimal treatment. Other factors, including the patients’ comorbidities as determined by the Charlson comorbidity score, did not seem to affect the FMT outcome.
To maintain continuity with a previous report, we compared the outcomes of the patients below and above 60 years of age and found that almost one-third (35/111) of the patients who underwent FMT for treatment of CDI in Israel were below 60 years of age (mean age 37.2 years). These patients had much lower Charlson comorbidity scores, underwent FMT on an ambulatory basis, and tended to have lower rates of severe CDI. Interestingly, there were no differences between the groups regarding hospitalizations in the 3 mo prior to the FMT. In a population-based study from Olmested county, Minnesota, United States, community-acquired CDI accounted for 41% of CDI cases and was characterized by a younger population with less severe disease, which is in line with our findings. We observed a significantly higher percentage (40%) of IBD patients among this group compared to the older group (8%). Interestingly, the waiting period between the first CDI episode to undergoing FMT was longer among the younger patients compared to the older ones, possibly due to a delay in diagnosis or to a lower compliance rate to undergo the procedure, as well as a lower index of suspicion among physicians caring for younger patients with diarrhea compared to older ones leading to a delay in diagnosis. The higher rates of IBD among younger patients might also contribute to the delay in diagnosis, since diarrhea can be attributed to illnesses, such as IBD and other GI disorders other than CDI. Indeed, time to FMT from first CDI in IBD patients tended to be longer compared to non-IBD patients (207.2 and 116.9 d, respectively, P = 0.066). Interestingly, the IBD patients in our study experienced higher success rates than reported in the literature (90% compared to 74.4% reported by Khoruts et al), although the group of IBD patients group in our study is much smaller (n = 20) compared with theirs (n = 272), and that might explain the difference in results.
Finally, severe CDI may be a fatal disease, especially in elderly and frail populations. The patients in our study group who died were much older, had significantly higher Charlson comorbidity scores, and much higher rates of severe CDI than the survivors. The CDI-associated diarrhea had improved significantly in 6 of them, while the condition of the others continued to deteriorate despite broad-spectrum antibiotic coverage treatment and ICU support, including mechanical ventilation and vasopressors. None of the deaths were attributed to the FMT procedure in any of them, which correlates with previous reports[13,19]. Although an approximately 10% mortality rate is quite high for FMT, it represents the natural history of weakened senior patients with multiple comorbidities in a large cohort rather than the FMT itself, as reported earlier[19,32]. Similar numbers can be found in other long follow-up studies, such as the one by Brandt et al which reported the demise of 7 of the 77 patients in their long-term study (mean follow-up 17 mo).
Most of the adverse events were mild and self-resolving, and they included abdominal discomfort, nausea, flatulence and constipation, which can be attributed to the procedure itself (i.e., most of these complications occurred in the LGI group). In addition, they are generally self-limiting and rather common post-colonoscopy events, occurring after up to 33% of colonoscopies. Severe complications were recorded for 2 patients (< 2% of the cohort) who were severely ill in an ICU setting and each suffered post-endoscopy aspirations.
The strength of this study is its ability to capture real-life data from the 5 medical centers throughout Israel that perform FMT through various routes and use different donors with negligible differences in preparing donors’ fecal filtrate. These are important for creating balanced data regarding the efficacy and safety of FMT.
The results of this study correlate with previous works regarding overall success rates[5,7,8,12,15-19], different routes of FMT administration[17,19] and predictors of failure[28,29] (see above), and reflect a multi-center data of heterogenous population from several districts in Israel and from different stool donors, making its results generalizable worldwide.
The corresponding author can provide complete data upon request.
In conclusion, FMT is a safe and effective treatment for CDI, which has been occurring in growing numbers in both older and younger populations. While both LGI and capsule administration of FMT seem to be more efficient than the UGI endoscopic route, FMT via capsules has emerged as a successful and well-tolerated alternative. Severe CDI and inpatient status were related to FMT failure. Prospective and well-powered studies are needed to conclusively determine the best route of administration, regarding patient safety, ease of administration, side effects and costs.