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Corresponding author at: Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. Fax: +49 391 6713105.
Fecal microbiota transplantation (FMT) is a valuable treatment modality for recurrent Clostridium difficile (C. difficile) colitis. Multiple questions including the best delivery route and volume remain unanswered. Here, we report a case series of high-volume FMT using endoscopic jejunal application route.
Methods
In prospective observational study, FMT was performed using fresh specimen from healthy unrelated donors to the patients with recurrent or refractory C. difficile colitis. Selection of the route was based on the patient's preferences. Specimens of at least 50 g were dissolved in 500 ml of electrolyte solution and administered using endoscope directly in jejunum.
Results
All procedures led to cure of C. difficile colitis. With exception of one case the procedure was well tolerated. In two cases, we observed FMT-reflux into the stomach despite deep jejunal application and in single case the FMT-reflux led to tracheal aspiration and severe pneumonia.
Conclusions
High-volume FMT via endoscopic jejunal route is an effective treatment option that is well tolerated and easy to perform. Nevertheless, aspiration is potential life-threatening event that needs to be kept in mind during the FMT-procedure.
]. The therapy aims to restore a balanced physiological microbiota composition of the bowel. The existing clinical experience supports the clinical benefit and efficacy of FMT [
]. “Quality” of the donor feces, art of the preparation of feces, amount of living microbiota and the optimal route of application vary between different centers and may all influence the efficacy of FMT [
]. Although, no head to head studies are available, few meta-analyses and systematic reviews concluded that the upper GI route has a slightly lower success rate compared to lower GI route [
]. The data are mostly based on case-controlled studies using low volume of feces for upper GI route and therefore the comparison appears inappropriate. The upper GI application route is supported by the keystone randomized clinical trial where the authors showed overwhelming superiority of FMT administered through nasoduodenal tube compared to vancomycin for the treatment of recurrent C. difficile [
The best application route and necessary amount of feces remains uncertain. The currently available recommendations provide only low level evidence to support one over the other route of application [
Empfehlungen zur Anwendung der fäkalen Mikrobiotatransplantation “Stuhltransplantation”: Konsensus der Österreichischen Gesellschaft für Gastroenterologie und Hepatologie (ÖGGH) in Zusammenarbeit mit der Österreichischen Gesellschaft für Infektiologie und.
Empfehlungen zur Anwendung der fäkalen Mikrobiotatransplantation “Stuhltransplantation”: Konsensus der Österreichischen Gesellschaft für Gastroenterologie und Hepatologie (ÖGGH) in Zusammenarbeit mit der Österreichischen Gesellschaft für Infektiologie und.
]. The preference for FMT application route is strongly dependent on center experience and the personal preference of the individual patient. Majority of patients with recurrent C. difficile are of the older age with multiple comorbidities and limited performance status and at increased risk for FMT-related procedural complications [
]. However, the scientific evidence for the additional benefit of the bowel lavage is rather questionable suggesting that upper GI application route may be performed without bowel preparation, better patients comfort and shorter procedure time.
Here, we report a case series of six patients who underwent jejunal application of high volume FMT using endoscopy for recurrent and/or refractory C. difficile colitis and discuss potential pitfalls, safety concerns and limitations of this method.
2. Material and methods
2.1 Study design
The prospective study was approved by the ethical board of the Otto-von-Guericke University (Study Number 109/14). All patients suffered from recurrent or refractory C. difficile colitis with ≥3 unformed stools/24 h and positive C. difficile toxin. The primarily infection and the causing antibiotic treatment was terminated prior to FMT. C. difficile-antibiotic therapy (metronidazol, vancomycin, fidaxomycin) were terminated at least 24 h prior to FMT. All patients provided written informed consent and underwent recto-sigmoidoscopy to determine the severity of colitis. Study endpoint was the resolution of C. difficile defined by a short-term improvement/normalization of the symptoms and long-term cure 90 days following FMT.
2.2 FMT preparation protocol
The fecal sample preparation protocol and method of application was slightly modified according to available studies [
]. The donor samples were provided from two healthy unrelated donors who were carefully selected through clinical examination, personal history, exclusion of high-risk life-style, good physical condition, BMI between 20 and 30 kg/m2, unremarkable blood routine blood testing and exclusion of potentially transmissible diseases. The donor selection protocol is based on the study from van Nood et al. [
]. Microbiological testing of donor feces was extended by testing for vancomycin-resistant enterococcus infection and multi drug-resistant gram negative rods (MDRGN bacteria). Fresh donor stool was obtained on the day of the procedure and kept in tightly closed plastic box 1 h prior to application at 4 °C. The sample was weighted (≥50 g) and homogenized in 500 ml of sterile saline solution, filtered and stored in a glass bottle.
2.3 Application of FMT
All patients were asked for preferred route of application (jejunal application using endoscope or nasojejunal tube, or lower GI via colonoscopy following bowel lavage). Upper GI route was the preferred route in all cases. Endoscopy was performed under local anesthesia of the thought and i.v. sedation (Table 1). Standard or long colonoscope (Fuji EC 580RD-L) was used to access jejunum as deep as possible. Application was performed under endoscopic view through a working channel using 100 ml syringe (Fig. 1A). The last portion of the FMT-mix was flashed with water. Metoclopramide was optional to stimulate the peristaltic. Following endoscopy all patients were allowed to drink once the local anesthesia was reversed and were allowed to take food 4 h after procedure.
Table 1Characteristics of patients and fecal microbiota transplantation data.
The same patients as 1 with recurrence of C. difficile following 2 courses of antibiotic therapy due to urosepsis despite prophylactic treatment with metronidazol.
The same patients as 1 with recurrence of C. difficile following 2 courses of antibiotic therapy due to urosepsis despite prophylactic treatment with metronidazol.
Recto-sigmoidoscopy was performed in all subjects and endoscopically visible pseudomembranes were documented. Abbreviations: M: metronidazol, V: vancomycin, F: fidaxomycin, Mid: midazolam, Prop: propofol, CHD: coronary heart disease, DM: diabetes mellitus, RA: rheumatoid arthritis, CKD: chronic kidney disease, pAOD: peripheral arterial occlusive disease, CVI: cerebrovascular insult, COPD: chronic obstructive pulmonary disease, SAS: sleep apnea syndrome, DVT: deep vein thrombosis, ACVB: arteria coronary vein bypass.
Yes
No
Yes
Yes
Yes
Yes
CDI-antibiotics prior FMT
V-24h
V-48h
V-24h
V-24h
V-24h
V-24h
Stool dose (g)
85
150
90
130
130
60
FMT volume (ml)
500
500
500
500
500
500
Sedation
Mid
Mid, Prop
Mid, Prop
Mid, Prop
Mid
Mid, Prop
Duration (min)
15
18
20
20
20
22
Adverse events
Stool-mix in stomach
No
No
Stool-mix in stomach
No
Fecal aspiration, sepsis
Short-term improvement
Yes
Yes
Yes
Yes
Yes
Yes
Long-term cure
Yes
Yes
Yes
Yes
Yes
Yes
a The same patients as 1 with recurrence of C. difficile following 2 courses of antibiotic therapy due to urosepsis despite prophylactic treatment with metronidazol.
b Recto-sigmoidoscopy was performed in all subjects and endoscopically visible pseudomembranes were documented.Abbreviations: M: metronidazol, V: vancomycin, F: fidaxomycin, Mid: midazolam, Prop: propofol, CHD: coronary heart disease, DM: diabetes mellitus, RA: rheumatoid arthritis, CKD: chronic kidney disease, pAOD: peripheral arterial occlusive disease, CVI: cerebrovascular insult, COPD: chronic obstructive pulmonary disease, SAS: sleep apnea syndrome, DVT: deep vein thrombosis, ACVB: arteria coronary vein bypass.
Fig. 1Schematic presentation of fecal microbiota transplantation (FMT) via upper GI-tract using endoscopic application in jejunum. (A) Fresh high weight fecal specimens were obtained from healthy donors and administered in large volume via endoscopy. (B) Application was performed directly in jejunum of patients with C. difficile infection. (C) High weight and volume FMT led to cure of all patients, although in one of the cases, FMT-application led to aspiration with severe pneumonia. Representative images show sigmoid colon mucosa bevor and 2 weeks after FMT.
We performed six procedures using direct endoscopic application of FMT in jejunum (Fig. 1B). The application route was preferred choice of all patients since no bowel lavage was necessary and the FMT application would be performed during endoscopy in sedation. The data describing patients and FMT-related characteristics are presented in Table 1. All patients had multiple comorbidities, with reduced overall performance and status (Karnofsky performance 40 to 50). Primary short-term improvement and long-term cure were achieved in all subjects following FMT.
3.1 Patient's characteristics
Four patients presented with recurrent and two patients with refractory C. difficile colitis. Systematic evaluation revealed the presence of pseudomembranous form in 5 patients, while one patient had only less severe form. Most patient were severely disabled and needed nursing care. All of them had antibiotic-associated cause of C. difficile colitis with history of multiple antibiotic treatments. One of the patients had history of gastrectomy with Billroth's II situs. All of the patients were symptomatic and suffered from diarrhea, abdominal pain.
3.2 FMT-procedure and complication
During the retraction of endoscope, we observed FMT-reflux into the stomach in 3 out of 6 patients (50%). FMT was suctioned in two patients without any clinical adverse events. In one case, FMT-reflux reached esophagus, pharynx and trachea. The visible stool was suctioned and patients underwent immediate bronchoscopy with bronchial lavage. Despite immediate lavage and antibiotic treatment, the patient developed septic shock with respiratory insufficiency (Fig. 1C). During the 48 h period his condition worsened and high dose of catecholamine's were required. Antibiotic treatment with meropenem and linezolid were further extended through antimycotics (caspofungin) that lead to steady improvement of his severe septic conditions during next days. Blood culture revealed E. coli and Candida albicans sepsis supporting the treatment of choice. Initially metronidazole and further oral vancomycin (4 × 250 mg) was added to the antibiotic treatment to prevent C. difficile recurrence despite missing signs of diarrhea and negative testing for C. difficile in feces. The patient was discharged three weeks later for his rehabilitation.
4. Discussion
In this study, we observed a high therapeutic efficacy following a single high-volume FMT via endoscopic jejunal application route. Five out of six procedures were without any adverse events despite endoscopic evidence for FMT-reflux into stomach. In one case FMT-reflux led to tracheal aspiration with severe pneumonia.
FMT is considered as a relatively safe therapeutic option with very low frequency of infectious diseases related to FMT as well as low procedure-related complication rate. Thirty-nine deaths have been reported until now and only two deaths were directly related to FMT [
]. Aspiration is probably the most feared FMT-related complication. Both FMT-related deaths occurred following aspiration of the stomach content during colonoscopy during FMT-application in one case, and following FMT-reflux during duodenal FMT-application despite general anesthesia [
]. Summarizing the existing publication to endoscopic FMT via upper GI tract, the aspiration has been reported including our data in 2 cases in total 74 reported procedures. Even though the number of 74 procedures might strongly underestimate existing practice; however, those 2 events would estimate the aspiration complication of 2.7% [
]. Multiple factors may contribute to the aspiration risk during procedure including volume of the feces, application speed, co-morbidities of the patients. The majority of FMT's through upper GI route via endoscopy were performed using low weight/volume FMT. As we mentioned above, several meta-analyses suggested slightly lower cure rates for upper vs. lower GI application routes [
]. This was the rational for us to use high weight and volume FMT to improve the efficacy of upper GI FMT. In our series, we observed high cure rates although the life-threatening complication appeared in one cases. Van Nood et al. demonstrated that high weight/volume FMT using nasojejunal tube was safe and no severe adverse events occurred [
]. Since our FMT-application protocol (including speed) was similar to the study from van Nood et al. it is rather doubtful that one of those factors may led to aspiration. Endoscopic-assisted application of FMT via upper GI route has several advantages over nasojejunal tube. Direct visualization of FMT-application, possibility of suctioning of FMT-reflux from the stomach that may reduce the risk for aspiration in case of vomiting and the comfort for the patients are few to mention. Taking to account currently missing reports to aspiration during FMT-application via nasogastric or nasojejunal tube, we believe that the sedation, which is required during endoscopy, may probably be the main risk factor for aspiration.
In the first randomized clinical trial on FMT by colonoscopy vs. vancomycin, Cammarota et al. clearly shown the effectivity of FMT via colonoscopy [
Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection.
Alimentary Pharmacology and Therapeutics.2015; 41: 835-843
Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection.
Alimentary Pharmacology and Therapeutics.2015; 41: 835-843
]. Colonoscopy is relatively safe procedure without risk for FMT-aspiration, however, bowel preparation and colonoscopy may be associated with other adverse events in critically ill patients with severe colitis. As mentioned above, several deaths have been reported following colonoscopy. Even though that majority of deaths were linked to C. difficile infection and not to colonoscopy, the potentially safety concerns are still insufficiently studied. FMT-application using enema may be an appropriate alternative, but the efficacy with up to 5 applications needed to achieve the cure rates of 85–90% is low [
Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile Infection: a randomized clinical trial.
Journal of the American Medical Association.2016; 315: 142-149
]. Longer hospital stay may be associated with additional risk for nosocomial infection, higher costs and the most effective and easy to perform procedure without high pre-procedural preparation (such as bowel cleaning) may be most beneficial. The use of lower GI route may have advantage for the evaluation of pseudomembranous colitis, however, the recto-sigmoidoscopy is performed in our clinical practice in all patients with recurrent C. difficile infection prior to planning of FMT to estimate the severity of colitis and confirm the diagnosis.
Recently, several other indications for FMT, including metabolic syndrome, chronic inflammatory bowel diseases, have been proposed [
]. Similarly to C. difficile infection, the advantage of upper GI FMT may be due to the ease of procedure, unnecessary bowel cleaning. However, the risk of aspiration should not be underestimated in those young patients and additional clinical studies are needed. One of the solutions to obtain the long-term safety data may be using the global registries (for example MicroTrans Registry in Germany).
Overall, we show in this series that high-weight and -volume FMT is a very effective treatment modality in recurrent or refractory C. difficile. Aspiration is a potential life-threatening event that may appear during the upper GI application route. Sedation during endoscopy may be one of most important risk factor for aspiration. According to our experience, FMT application using nasojejunal tube may be an alternative method specifically if upper GI route was selected as preferred option. High risk subjects for example with insufficient cough/swallowing reflex or history of esophageal, gastric or duodenal surgery, the lower GI application route may be another safe option. To address the application-related safety, further methodological data are urgently needed.
Conflict of interest
None declared.
Acknowledgements
The authors thank healthy donors for providing the specimens. This clinical study has been registered at DRKS and WHO with the number DRKS00006810.
References
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Mellow M.
Tierney W.M.
Fecal microbiota transplantation in the treatment of Clostridium difficile infections.
Empfehlungen zur Anwendung der fäkalen Mikrobiotatransplantation “Stuhltransplantation”: Konsensus der Österreichischen Gesellschaft für Gastroenterologie und Hepatologie (ÖGGH) in Zusammenarbeit mit der Österreichischen Gesellschaft für Infektiologie und.
Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection.
Alimentary Pharmacology and Therapeutics.2015; 41: 835-843
Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile Infection: a randomized clinical trial.
Journal of the American Medical Association.2016; 315: 142-149
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