The Long-term Effects of Faecal Microbiota Transplantation for Gastrointestinal Symptoms and General Health in Patients With Recurrent Clostridium Difficile Infection

J. Jalanka; A. Hillamaa; R. Satokari; E. Mattila; V.-J. Anttila; P. Arkkila

Disclosures

Aliment Pharmacol Ther. 2018;47(3):371-379. 

In This Article

Results

Patient Characteristics

The recovery of 84 patients suffering from recurrent Clostrium difficile infection was followed on average for 3.8 years. The range of the follow-up period was very similar in both study groups as well as the number of episodes before the treatment, making the treatment groups comparable. All patients were successfully treated with either FMT (n = 45) or antibiotics (AB, n = 39). The groups were age and gender matched although in both groups the majority of patients were female (77.8% FMT group and 79.5% AB). The demographics of the study population can be seen in Table 1.

The number of episodes before a successful treatment was reviewed from the patient registry as a positive C. difficile culture or toxin test. Positive results that were 14 days or further apart were regarded as separate episodes. The follow-up period was calculated from the last negative C. difficile culture or toxin test or the day of receiving FMT until the date we received the last questionnaires from the patients. There were two patients in the FMT group who consumed antibiotics shortly after the FMT. Both of these patients relapsed and were then treated successfully with a second FMT. The first mistakenly continued to using the prophylactic vancomycin treatment after first FMT treatment (the patient and recovery previously described[28]) and the other patient received antibiotics for an unrelated infection. There were three patients whom were initially selected for the antibiotics group, but it was later found that they had received a FMT in a private health-centre. Therefore, these patients were moved into the FMT group, but as the date of the FMT was not known, their follow-up periods could not be estimated. In addition, there were 26 patients in the FMT group and 28 in the AB group who received antibiotics during the follow-up period for unrelated indication. Two patients in the FMT group and seven in the control group could not estimate the number of antibiotic treatments received in the follow-up period. For those who could make an estimation, the average number of antibiotic treatments was 3.0 (range 1–10) in the FMT group and 3.3 (range 1–10) in the control group. The antibiotics were consumed on average 15.7 months after the treatment (range 3–48 months). These antibiotic treatments did not make the patients more susceptible to another C. difficile infection episode.

Estimation of Potential Long-term Adverse Effects of FMT Compared to Antibiotic Treatment

As the long-term effects of FMT have not been previously validated, our aim was to determine both the intestinal and extra-intestinal symptoms that are potentially associated with FMT treatment and to compare the symptom prevalence between patients treated with either antibiotics or FMT (Table 2). First, the potential increase in body weight after FMT treatment has been speculated. We found no statistical difference in the starting body weight or change in the patients' weight between the groups. On average 80% of the patients gained weight after the treatment (average weight gain 1.9 kg), however, the range of weight gain/loss varied in both groups.

The potential incidence of new allergies has also been speculated due to the drastic modifications in the intestinal microbiota introduced by the condition. We found that there was no statistical difference in the occurrence of allergies before or after the treatment between the groups, although twice as many patients in the AB-group developed new allergies during the follow-up period compared to the FMT group. Majority (6/9) of the new allergies wassensitivities to food components and the patients reported that the allergy symptoms effected their GI function. There were four reported new allergies in the FMT group, which included sensitivity to chemicals, birch pollen and new food allergies. There was one recorded case of coeliac disease prior to the treatment of patients with recurrent C. difficile infection (FMT group) and there were no cases in the AB group. There were no new reported cases of coeliac disease after the treatment.

There were no statistical differences the incidence of more severe disease conditions between the groups. We concentrated in the prevalence of IBD, diabetes, diseases of the nervous system, autoimmune diseases, incidence of gastrointestinal polyps and cancer between the study groups and found that there were no statistical differences in the prevalence of new cases between the groups. In more detail; in this cohort, there were 14 new or worsened cases of nervous system related diseases. The most reported conditions were migraine (8 cases, FMT = 4 and AB = 4) and dementia (6 cases, FMT = 3, AB = 3). There were four cases of new autoimmune diseases, two cases of autoimmune thyroiditis (FMT = 1, AB = 1) and in the AB group one case of psoriasis and one case of rheumatoid arthritis. In patients who were diagnosed with diabetes, there was no change in the symptoms and only one new case of diabetes was diagnosed in the antibiotics group during the follow-up period. There were no new cases of polyps, cancer or IBD in either of the patient groups after the treatment.

General Well-being and Gastrointestinal Symptoms in the Patients After Treatment

It has been estimated that 25% of the patients with previous C. difficile infection suffer from IBS like symptoms after the infection has been cleared.[29] Therefore, we aimed to investigate whether there are differences in the incidence of functional gastrointestinal disorders, specifically symptoms associated with irritable bowel syndrome and symptoms of dyspepsia between the FMT and AB treated patients. The subjects in the AB group recorded more frequently that their bowel function had become worse and more irregular after clearing the infection as compared to FMT treated patients (FMT = 11.1%, AB = 35.9%, P = .034). In contrast, the subjects in FMT group most often recorded that their bowel function had become better and more regular after the treatment (FMT = 53.3%, AB = 25.6%, P = .016, Figure 1). Moreover, we noted that a lower proportion of the patients treated with FMT (77.8%) experienced gastrointestinal symptoms related to IBS, whereas 92.3% of antibiotic treated patients recorded these symptoms with borderline statistical significance (Figure 2, P = .06). The experience of individual gastrointestinal symptoms did not differ between the treatment groups (P > .05, Figure 2). The most commonly experienced symptom in both groups was flatulence (FMT = 55.6%, AB = 69.2%). Other common intestinal symptoms in the FMT group were urgency to defecate (53.3%) and loose stools (51.1%). In the AB treated group other common GI symptoms included abdominal pain (56.4%), bloating (53.9%) and loose stools (51.3%).

Figure 1.

The number of patients reporting changes in their GI-tract function after treatment. The antibiotic treated patients had worse and more irregular GI function when compared to before treatment whereas the FMT treated patients reported to have less better and more regular GI-function. Significant changes indicated with an asterisk

Figure 2.

The number of patients reporting IBS-like gastrointestinal symptoms between the treatment groups

In addition to the gastrointestinal symptoms, there was a statistically significant difference in how the patients experienced their mental well-being. Although majority (on average 45.7%) of the patients reported no change in their mental well-being, 31.1% of the FMT group and 8.9% of the AB group reported improvement of their mental health after the treatment with border line statistical significance (P = .06, Figure 3).

Figure 3.

The number of patients reporting differences in their mental well-being after the treatment. The FMT treated patients reported significantly more often to have improvement in their mental health after the treatment than the AB-group patients. Significant changes indicated with an asterisk

Symptoms of Upper Intestinal Tract After the Treatments

Enteric infections and antibiotics use have been linked to increased risk of developing functional gastrointestinal disorders also effecting the upper intestinal tract.[30] We aimed to study if there were alterations in the incidence of these symptoms in our patient cohort. Here, the patients treated with antibiotics were experiencing statistically significantly more symptoms of the upper intestinal tract than the FMT treated patients (prevalence AB = 51.3%, FMT = 31.1%, P = .045, Figure 4). The most frequently recorded symptom in both groups was pain in the upper GIT, where the prevalence was 25.6% in the AB group and 11.1% in the FMT group (P = .06). In addition, there was a significant difference in the recorded experience of feeling bothersome fullness after a meal between the study groups (FMT = 4.4%, AB = 18.0%, P = .05). We also surveyed the intensity of upper intestinal tract symptoms and recorded that 5 patients in the FMT group reported decreased symptoms, compared to 1 in the AB group. However, the majority of patients in both groups reported no change in symptoms, although the difference between FMT and antibiotic treated patients was significant (FMT = 75.6%, AB = 64.1%, P = .04, Figure S1).

Figure 4.

The number of patients reporting symptoms of upper intestinal tract between the patient groups. The FMT treated patient group included significantly more patients with no upper intestinal tract symptoms and less patients reported to have symptoms of feeling of fullness after a meal when compared to the AB group. Significant changes indicated with an asterisk

Response and Readiness for FMT

The willingness for a patient to undergo FMT treatment has been discussed previously and we aimed to retrospectively address the patients' views on the treatment and willingness to undergo FMT treatment in the future. In this cohort 97.6% of the FMT treated patients would prefer FMT as their initial treatment instead of antibiotics (P = 1.21*10−5, Figure 5) in the future. This preference was also detected in the AB group, where 60% of the patients would also want FMT as the initial treatment. In this same group of patients 33.3% would be willing to try it if antibiotics gave no results, and only 6.7% would accept solely antibiotic treatment.

Figure 5.

The number of patients reporting to willingness to undergo FMT treatment in the future if fallen ill with recurrent Clostridium difficile again. Majority of patients in both groups would consider FMT as firs line of treatment. The numbers indicate the number of patients in each category

We also wanted to estimate if there were differences in the recovery rates between the treatment groups by asking the patients how well they recovered from the given treatment. The recovery of the FMT treated patients was significantly faster than that recorded by the antibiotic treated patients (Figure 6). In the FMT group, 77.8% of the patients reported to have been cleared from all symptoms of C. difficile infection within 3 days or less, whereas only 23.1% of the AB treated patients reported the same (P = 8.95*10−9).

Figure 6.

The number of patients reporting their rate of recovery in both groups. The FMT treated patients reported significantly more often to be recovered from the Clostridium difficile infection within 24 hours or 2–3 days. The antibiotic treated patients reported significantly more often that the recover from the infection took longer than a week. Significant changes indicated with an asterisk

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