Accepted Article
Received Date : 05-Jul-2014 Revised Date : 19-Aug-2014 Accepted Date : 11-Sep-2014 Article type : Invited Review
Fecal microbiota transplantation – the Austrian approach Patrizia K. Kump1, Robert Krause2, Franz Allerberger3, Christoph Högenauer1 1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Austria 2. Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, Austria 3. Austrian Agency for Health and Food Safety (AGES), Vienna, Austria
Running title: FMT – The Austrian Approach
Corresponding Author: ao Univ. Prof. Dr. Christoph Högenauer Division of Gastroenterology and Hepatology Department of Internal Medicine Medical University of Graz Auenbruggerplatz 15 A-8036 Graz Austria Tel: +43-316-385-14388 Fax: +43-316-385-12648 E-Mail: [email protected] Abstract The intestinal microbiome is essential for maintaining human health and defending against intestinal pathogens. Alterations of the intestinal microbiota, also termed dysbiosis, play a pivotal role in the pathogenesis of various human diseases. Fecal microbiota transplantation (FMT) aims on correcting these alterations by delivering fecal microorganisms from a healthy person to the intestines of a patient. Up to now, This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1469-0691.12801 This article is protected by copyright. All rights reserved.
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recurrent Clostridium difficile (CDI) infection is the only indication supported by solid scientific evidence, but many ongoing studies are investigating FMT in other dysbiosis-related diseases such as inflammatory bowel disease. As there are no systematic methodological investigations, several questions about techniques, donor screening and safety issues remain. This shortage of evidence, especially on longterm safety concerns, is leading to worldwide controversy on the use of FMT. Regulations by health care authorities vary among different countries. This review reflects the Austrian situation and its FMT guidelines concerning indications, techniques and donor screening, recently developed by local scientific societies.
Keywords:
fecal microbiota transplantation (FMT); stool transplantation; dysbiosis; Clostridium difficile infection; inflammatory bowel disease; guidelines. Introduction Intestinal microbiota have a pivotal role for the human organism in maintenance of health, especially for defense against pathogenic microorganisms [1]. Specific alterations in the intestinal microbiota, termed dysbiosis, seem to be involved in the pathogenesis of a variety of intestinal and extra-intestinal diseases, such as intestinal infections, inflammatory bowel disease (IBD), irritable bowel disease, metabolic syndrome and autoimmune diseases. [2-9]. Although there is no generally accepted definition for dysbiosis, most authors consider a decreased microbial diversity or an increased abundance of certain pathobionts or opportunistic pathogens as intestinal dysbiosis [5, 10-13]. Fecal microbiota transplantation (FMT), also known as stool transplantation, is a therapeutic procedure aimed at restoring altered intestinal microbiota by administrating stool microorganisms from a healthy donor into the intestinal tract of a patient [10, 14-16]. The increasing numbers of reported Clostridium difficile infections (CDI) since the millennium have resulted in a distinct interest in therapeutic FMT in the medical community, since this method is mainly used to treat recurrent CDI. There is, however, much controversy on the use of FMT among physicians because of potential safety concerns. FMT regulations by health care authorities vary from very strict, such as by the FDA in the US [17], to none in most other countries. The purpose of this review is to describe the situation
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in Austria, especially the aspect of local guidelines recently developed by scientific societies.
Guidelines and regulation for FMT in Austria The Austrian Federal Office for Safety in Health Care, which executes federal policy in areas of infectious disease control and pharmaceuticals, sees FMT as a therapeutic intervention which should not be considered a pharmaceutical drug and therefore not be regulated by the Austrian Medicines Act. FMT is also not subject to the Medical Devices Act or to the Austrian Transplantation Act. To avoid a legally precarious state for physicians who want to use FMT to treat their patients, the Austrian federal ministry of health was contacted about developing national guidelines. The Austrian federal ministry of health saw no reason to act and based the decision on the current state of knowledge.
In order to prevent an unclear situation for physicians, scientific societies in this field decided to launch a working group of experts from the Austrian society of gastroenterology and hepatology (ÖGGH) in cooperation with the Austrian society of infectious disease and tropical medicine (ÖGIT) and the Austrian Agency for Health and Food Safety (AGES) to develop FMT guidelines for Austria. This working group developed a consensus report for the use of FMT in Austria which was approved by both societies and has currently been submitted for publication in the official organ of the Austrian society of gastroenterology and hepatology [18]. This consensus is intended to provide instructions for physicians who want to use FMT, giving indications, methodology and donor screening, based on current medical literature. The guidelines further recommend that FMT may be used only by physicians for certain indications and under safety precautions. In our opinion, FMT “selfadministration” by patients as has been reported [19-21] or by alternative practitioners should be avoided due to potential risks. The latter situation would be the case if FMT were restricted too rigorously by medical authorities.
So far in Austria FMT has been mainly used by gastroenterologists working at departments of gastroenterology and hepatology, including the university hospitals in This article is protected by copyright. All rights reserved.
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Vienna, Graz and Innsbruck as well as major non-university associated gastroenterology departments in Vienna, Carinthia and Upper Austria. We are not aware if FMT has been used in the outpatient setting by practitioners in Austria so far.
Indications for FMT Clostridium difficile infection (CDI) FMT is most commonly used for recurrent forms of Clostridium difficile infection (CDI). There are currently many cohort studies in a large number of patients and a randomized controlled trial showing a dramatic effect of FMT for this indication [14, 15, 22-24]. Therefore FMT is recommended by international medical societies for the treatment of recurrent CDI based on solid scientific evidence. The European society for clinical microbiology and infectious diseases (ESCMID) recommends the use of FMT in their current CDI guidelines as preferable to vancomycin or fidaxomicin in patients with at least 2 CDI recurrences (i.e. 3 CDI episodes in an single patient) [25]. Austrian guidelines also recommend FMT to treat recurrent CDI in agreement with ESCMID guidelines and further suggest FMT as a treatment option for severe CDI as an alternative to total colectomy, failing positive results of standard therapy [18].
In Austria, the estimated number of CDI cases is approximately 7,000 per year [26]. Assuming a recurrence rate of 20% as reported in the literature [27], about 250-300 patients with 2 recurrences (3 episodes) of CDI would need to be treated with FMT according to these guidelines in Austria. If cases were evenly distributed, this would mean that the current centers performing FMT would need to treat 40-50 cases of recurrent CDI per year. So far we are not aware that these numbers of CDI patients are treated with FMT at any hospital in Austria. This suggests that physicians in Austria still hesitate to choose FMT as an early treatment option for recurrent CDI. Obviously the current centers offering FMT suffice so far for the number of patients requiring this form of therapy.
Other indications Other potential indications for the use of FMT are the treatment of inflammatory bowel diseases, especially ulcerative colitis (UC). Studies using FMT for the This article is protected by copyright. All rights reserved.
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treatment of UC have been performed in Austria [28, 29] and are still ongoing [30]. While a single application of FMT as is recommended for patients with CDI seems to be without major benefit for UC patients [28, 29], a protocol using repeated FMT has shown a clinical response in about 50% of patients [30]. Due to lack of sufficient data at the current time, Austrian guidelines only recommend the use of FMT to treat UC or indications other than CDI in clinical studies with appropriate safety measures.
Recommended donor screening in Austria The selection of possible donors is one of the key points in executing FMT. The definition of potentially transmittable diseases in this context remains unclear. Considering lack of knowledge about the transferability of tumorgenesis or autoimmune, metabolic, neuropsychiatric diseases, long term side effects are unknown. In principle, donors genetically related to FMT recipients show similarities of intestinal microbiota [31]. Donors and recipients living in the same household and/or in sexual relationship are largely exposed to the same infectious risk factors. Therefore the possibility of transmitting infectious agents via stool from related donors is assumed to be reduced. However, FMT has also been successfully performed with donor stool from unrelated healthy volunteers [32]. Success rates of FMT for recurrent CDI are comparable for related and unrelated donors (89.5% vs. 90.7%) [33].Appropriateness or advantage of donor feces in terms of relation status for indications other than C. difficile (e.g. ulcerative colitis, metabolic syndrome) remains uncertain.
There are different screening procedures for stool donors. Recommendations about parameters to be tested for donor screening are inconsistent among various institutions and countries and are mainly based on theoretical estimations of risk assessment. The following screening procedure reflects the Austrian consensus [18] and is mainly based on expert opinions. Donor screening comprises adequate history, physical examination, laboratory tests and microbiological investigations (Table 1).
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Potential donors present as healthy adults or adolescents (optional BMI between 17 and 35) lacking any evidence of acute or chronic disease (e.g. autoimmune disease, malignancy, chronic inflammatory bowel diseases). They should confirm no antibiotic therapy within the last 3 months, no diarrhea within the last 3 months, no intravenous drug abuse or other risk behavior for transmissible diseases and no significant gastrointestinal surgery (e.g. Whipple procedure, total colectomy). In Austria laboratory tests comprise various immunological and microbiological parameters as listed in Tab. 1. The Austrian guidelines discuss CMV antibodies only to be performed in recipients with negative CMV IgG antibodies and presence of chronic inflammatory bowel diseases, wasting disease, or immunosuppression including prednisolone >20mg/d as well as a history of solid organ or stem cell transplantation. Stool analysis for calprotectin is optional in FMT for recurrent CDI but recommended in application of FMT for chronic inflammatory bowel disease.
Donors repeatedly used for FMT should be retested every 6 months, and sooner in case of certain risks for infectious diseases (e.g. vacation in countries with a high risk for gastrointestinal infections). In case of emergency and proposed FMT in fulminant CDI, relatives or sexual partners may be used as donors without the testing described above [34].
Despite or just because of the great awareness of potential FMT induced injury, reports about severe side effects are rare. However, considering reported cases of successfully and safely performed FMT in immunosuppressed patients [35] donor screening and infectious workup as described above seems to be sufficient so far.
Method Fecal microbiota transplantation can be performed either via the upper or the lower GI tract; for both routes of application, different techniques have been described. However, to date no comparative methodical studies exist, thus clinicians can only rely on experience and expert opinions. According to empirical data, donor stool
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should be fresh, not older than 6 hours, and stored in airtight vessels at +6 to +8 C° to avoid bacterial overgrowth.
Fecal bacteria are classified as biohazard level 2, which implicates wearing water repellent garments, gloves as well as face masks, protection goggles or shields; the use of a biological safety cabinet is optional. Depending on stool consistency the entire fecal donation will be diluted with 100-500 ml sterile saline (NaCl 0.9%) and homogenized in a household blender or similar device, especially designated for this purpose (Fig. 1a). There is, however, no standardized data about the total stool weight to be used; 50 to 150 g seem to be appropriate [4]. In the next step the stool suspension will be filtered in order to remove solid components (Fig. 1b). Gauze pads, paper or steel filters as well as sieves can serve as filters (such as commonly used in households). Some authors recommend coffee filters to separate stool debris but in our experience, coffee filters, at least the ones available in Austria, tend to clog rapidly. The objective of filtration is to refine the stool suspension by removing roughage, which might hamper stool application by blocking a tube or the working channel of the endoscope.
Depending on the route of administration, the diluted, homogenized and filtered suspension will be apportioned into 20 to 50 ml syringes (Fig. 1c) and administered to the patient within the next 2 hours (Fig. 1d). In our view, processing the stool rapidly in a possible closed system is essential to protect anaerobic bacteria from oxygen.
Recent publications reported successful transplantation of previously frozen fecal suspension, which had specially been prepared with glycerol [32, 36, 37]. These experiences are based on small case series therefore we only recommend the application of prior frozen microbiota in certain cases, such as increased urgency or donor drop out. In such cases, fecal samples should be stored at -80 °C and gently reheated in a 37 °C warm water bath over a period of 2 hours [32, 36, 37].
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Preparation of the Patient The preparation of the patient depends on the route of administration as well as on indication for FMT.
In case of recurrent CDI patients receive an antibiotic pretreatment either with vancomycin or fidaxomicin for at least 4 days in order to repress the abundance of intestinal C. difficile. Antibiotics should be stopped 36 to 48 hours prior to FMT.
For application in the lower GI tract, patients receive a conventional colon lavage routinely given prior to colonoscopy. As the colon lavage significantly reduces the patient`s microbiota [38] it is also reasonable to perform it for administration in the upper GI tract. To extend retention time of the donor microbiota in the patient`s intestines, loperamid can be provided after successful FMT; however, in our experience this might aggravate post-interventional side effects like bloating and abdominal pain or may lead to nausea and emesis.
In case of FMT via upper GI tract, prokinetic therapy might reduce the risk of aspiration. Also proton pump inhibitors (PPI) can have a positive impact on the viability of the transplanted bacteria [34].
Route of administration Different routes of administration are described in the literature. Stool application can be performed by colonoscopy to the terminal ileum and portion-wise further downstream in the colon (Fig. 1d) or exclusively to the left colon either via endoscope or enema, depending on the patient’s condition and what is available locally. Whereas 200-500 ml fecal suspension can be placed in the lower GI tract [4, 14, 22], transplantation volumes in the upper GI tract are limited due to the risk of possible aspiration.. If the donor stool is placed in the upper GI-tract, nasogastric – or nasojejunal tubes can be used; endoscopic applications via gastroscopy are also described. The total volume of inserted bacterial suspension is usually much lower, about 25 – 50 ml [39], but also transplanted volumes of up to 500 ml via nasojejunal tubes (2-3 minutes/50 ml) have been reported [15]. Nasoduodenal application as the mode of FMT application has been used in the only randomized controlled study [15], This article is protected by copyright. All rights reserved.
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Physicians must be aware of increasing risks of severe side effects according to transplantation volumes in the upper GI tract.On the occasion of a recently published case of pneumoperitoneum and septic shock with lethal outcome after FMT via nasojejunal tube [40], we highly recommend to confirm the correct tube position by xray before installing donor stool in the upper GI tract [41].
The authors of this review decidedly recommend the lower GI tract as preferable route of administration due to safety reasons and the larger amounts of transplantable volume. Cases of severe C. difficile infection with paralytic ileus have also been successfully treated with FMT by colonoscopy without any serious infectious side events as well as patients receiving immunosuppressive therapy [28, 35, 42]. A recently published review revealed a non-significant advantage of FMT for recurrent C. difficile infection via colonoscopy compared to FMT in the upper GI tract via nasogastric or jejunal tubes. (91.4% vs 82.3%) [33].
The route of administration has to be chosen depending on the phenotype of the disease as well as comorbidities of the patient and remains an individualized decision. However, assessing risks and benefits, FMT via colonoscopy seems to be effective and safe and in the authors’ view is therefore the preferable route of administration.
Conclusion Fecal microbiota transplantation is a new treatment option for patients with dysbiosis- induced diseases [2-8]., as well as for patients with recurrent CDI. Due to lack of treatment alternatives for some of these patients, we believe that FMT is a major improvement in the therapeutic arsenal for physicians. We further believe that too strict regulations for FMT by medical authorities would prevent this form of therapy for many patients who could benefit. Furthermore this would displace this method to an alternative medicine sector resulting in even more potential safety risks for patients. Scientific societies in other counties are therefore called to develop FMT guidelines which are practicable for most physicians in this field.
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Figure Legend Figure 1. A. Dilution and homogenization of donor stool with 0.9% NaCl in a blender. B. Subsequent filtration of homogenized and diluted stool suspension with a metal sieve in order to remove debris. C. Fecal suspension portioned into 20 ml syringes prior to application. D. Application of fecal suspension into the working channel of a colonoscope for fecal microbiota transplantation into the lower GI tract.
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Lawley TD, Walker AW. Intestinal colonization resistance. Immunology. 2013; 138: 1-11. Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M. Therapeutic potential of fecal microbiota transplantation. Gastroenterology. 2013; 145: 946-953. Khoruts A, Weingarden AR. Emergence of fecal microbiota transplantation as an approach to repair disrupted microbial gut ecology. Immunol Lett. 2014. Brandt LJ, Aroniadis OC. An overview of fecal microbiota transplantation: Techniques, indications, and outcomes. Gastrointest Endosc. 2013; 78: 240-249. Gevers D, Kugathasan S, Denson LA, et al. The treatment-naive microbiome in new-onset crohn's disease. Cell Host & Microbe. 2014; 15: 382-392. Jalanka-Tuovinen J, Salojarvi J, Salonen A, et al. Faecal microbiota composition and host-microbe cross-talk following gastroenteritis and in postinfectious irritable bowel syndrome. Gut. 2013. Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the fecal microbiome in recurrent clostridium difficile-associated diarrhea. J Infect Dis. 2008; 197: 435-438. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012; 489: 242-249. Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012; 143: 913-916 e917. Song Y, Garg S, Girotra M, et al. Microbiota dynamics in patients treated with fecal microbiota transplantation for recurrent clostridium difficile infection. PLoS One. 2013; 8: e81330. Knights D, Lassen KG, Xavier RJ. Advances in inflammatory bowel disease pathogenesis: Linking host genetics and the microbiome. Gut. 2013; 62: 15051510. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009; 9: 313-323. Schneditz G, Rentner J, Roier S, et al. Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis. Proc Natl Acad Sci U S A. 2014; in press. Borody TJ, Campbell J. Fecal microbiota transplantation: Techniques, applications, and issues. Gastroenterol Clin North Am 2012; 41: 781.
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van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent clostridium difficile. N Engl J Med. 2013; 368: 407-415. Seekatz AM, Aas J, Gessert CE, et al. Recovery of the gut microbiome following fecal microbiota transplantation. mBio. 2014; 5: e00893-00814. Kelly CR, Kunde SS, Khoruts A. Guidance on preparing an investigational new drug application for fecal microbiota transplantation studies. Clin Gastroenterol Hepatol. 2014; 12: 283-288. Kump P, Krause R, Steininger C, et al. 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 Tropenmedizin (OEGIT). Z Gastroenterol. 2014; submitted for publication. Swaminath A. The power of poop: Patients getting ahead of their doctors using self-administered fecal transplants. Am J Gastroenterol. 2014; 109: 777-778. Silverman MS, Davis I, Pillai DR. Success of self-administered home fecal transplantation for chronic clostridium difficile infection. Clin Gastroenterol Hepatol. 2010; 8: 471. Hohmann EL, Ananthakrishnan AN, Deshpande V. Case 25-2014. Case records of the massachusetts general hospital. N Engl J Med. 2014; 371: 668-675. Mattila E, Uusitalo-Seppala R, Wuorela M, et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent clostridium difficile infection. Gastroenterology. 2012; 142: 490. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent clostridium difficile infection. Clin Infect Dis. 2011; 53: 994. Lee CH, Belanger JE, Kassam Z, et al. The outcome and long-term follow-up of 94 patients with recurrent and refractory clostridium difficile infection using single to multiple fecal microbiota transplantation via retention enema. Eur J Clin Microbiol Infect Dis. 2014. Debast SB, Bauer MP, Kuijper EJ. European society of clinical microbiology and infectious diseases: Update of the treatment guidance document for clostridium difficile infection. Clin Microbiol Infect. 2014; 20 Suppl 2: 1-26. Wenisch JM, Schmid D, Kuo HW, et al. Hospital-acquired clostridium difficile infection: Determinants for severe disease. Eur J Clin Microbiol Infect Dis.. 2012; 31: 1923-1930. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for clostridium difficile infection. N Engl J Med. 2011; 364: 422-431. Kump PK, Grochenig HP, Lackner S, et al. Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis. Inflamm Bowel Dis. 2013; 19: 2155-2165. Angelberger S, Reinisch W, Makristathis A, et al. Temporal bacterial community dynamics vary among ulcerative colitis patients after fecal microbiota transplantation. Am J Gastroenterol. 2013; 108: 1620-1630. Kump PK, Gröchenig HP, Spindelböck W, et al. Preliminary clinical results of repeatedly fecal microbiota transplantation (fmt) in chronic active ulcerative colitis UEG Journal 2013; 1 (Suppl 1): A57. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut microbiome in obese and lean twins. Nature. 2009; 457: 480-484.
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Received Date : 05-Jul-2014 Revised Date : 19-Aug-2014 Accepted Date : 11-Sep-2014 Article type : Invited Review
Fecal microbiota transplantation – the Austrian approach Patrizia K. Kump1, Robert Krause2, Franz Allerberger3, Christoph Högenauer1 1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Austria 2. Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, Austria 3. Austrian Agency for Health and Food Safety (AGES), Vienna, Austria
Running title: FMT – The Austrian Approach
Corresponding Author: ao Univ. Prof. Dr. Christoph Högenauer Division of Gastroenterology and Hepatology Department of Internal Medicine Medical University of Graz Auenbruggerplatz 15 A-8036 Graz Austria Tel: +43-316-385-14388 Fax: +43-316-385-12648 E-Mail: [email protected] Abstract The intestinal microbiome is essential for maintaining human health and defending against intestinal pathogens. Alterations of the intestinal microbiota, also termed dysbiosis, play a pivotal role in the pathogenesis of various human diseases. Fecal microbiota transplantation (FMT) aims on correcting these alterations by delivering fecal microorganisms from a healthy person to the intestines of a patient. Up to now, This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1469-0691.12801 This article is protected by copyright. All rights reserved.
Accepted Article
Serological tests
Stool analysis
hepatitis B antigens and antibodies (anti-HBc) hepatitis C antibodies (IgG) HIV** antigens or antibodies Treponema pallidum hemagglutination assay (TPPH) CMV*** antibodies (IgG, IgM) (optional in IBD*, wasting diseases, prednisolon >20mg/d, and in patients with previous solid organ or stem cell transplantation) pathogenic intestinal bacteria (Clostridium difficile, Salmonella sp., Campylobacter sp., EHEC, Yersinina sp., Shigella sp.) microscopic examination for ova and parasites Giardia lamblia and Cryptosporidium antigen norovirus and rotavirus antigen or PCR calprotecin (optional in CDI****, obligatory in unrelated donors and IBD*)
*
IBD: inflammatory bowel disease **HIV: human immunodeficiency virus ***CMV: cytomegalovirus CDI: Clostridium difficile infection
****
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Received Date : 05-Jul-2014 Revised Date : 19-Aug-2014 Accepted Date : 11-Sep-2014 Article type : Invited Review
Fecal microbiota transplantation – the Austrian approach Patrizia K. Kump1, Robert Krause2, Franz Allerberger3, Christoph Högenauer1 1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Austria 2. Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, Austria 3. Austrian Agency for Health and Food Safety (AGES), Vienna, Austria
Running title: FMT – The Austrian Approach
Corresponding Author: ao Univ. Prof. Dr. Christoph Högenauer Division of Gastroenterology and Hepatology Department of Internal Medicine Medical University of Graz Auenbruggerplatz 15 A-8036 Graz Austria Tel: +43-316-385-14388 Fax: +43-316-385-12648 E-Mail: [email protected] Abstract The intestinal microbiome is essential for maintaining human health and defending against intestinal pathogens. Alterations of the intestinal microbiota, also termed dysbiosis, play a pivotal role in the pathogenesis of various human diseases. Fecal microbiota transplantation (FMT) aims on correcting these alterations by delivering fecal microorganisms from a healthy person to the intestines of a patient. Up to now, This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1469-0691.12801 This article is protected by copyright. All rights reserved.
Accepted Article
recurrent Clostridium difficile (CDI) infection is the only indication supported by solid scientific evidence, but many ongoing studies are investigating FMT in other dysbiosis-related diseases such as inflammatory bowel disease. As there are no systematic methodological investigations, several questions about techniques, donor screening and safety issues remain. This shortage of evidence, especially on longterm safety concerns, is leading to worldwide controversy on the use of FMT. Regulations by health care authorities vary among different countries. This review reflects the Austrian situation and its FMT guidelines concerning indications, techniques and donor screening, recently developed by local scientific societies.
Keywords:
fecal microbiota transplantation (FMT); stool transplantation; dysbiosis; Clostridium difficile infection; inflammatory bowel disease; guidelines. Introduction Intestinal microbiota have a pivotal role for the human organism in maintenance of health, especially for defense against pathogenic microorganisms [1]. Specific alterations in the intestinal microbiota, termed dysbiosis, seem to be involved in the pathogenesis of a variety of intestinal and extra-intestinal diseases, such as intestinal infections, inflammatory bowel disease (IBD), irritable bowel disease, metabolic syndrome and autoimmune diseases. [2-9]. Although there is no generally accepted definition for dysbiosis, most authors consider a decreased microbial diversity or an increased abundance of certain pathobionts or opportunistic pathogens as intestinal dysbiosis [5, 10-13]. Fecal microbiota transplantation (FMT), also known as stool transplantation, is a therapeutic procedure aimed at restoring altered intestinal microbiota by administrating stool microorganisms from a healthy donor into the intestinal tract of a patient [10, 14-16]. The increasing numbers of reported Clostridium difficile infections (CDI) since the millennium have resulted in a distinct interest in therapeutic FMT in the medical community, since this method is mainly used to treat recurrent CDI. There is, however, much controversy on the use of FMT among physicians because of potential safety concerns. FMT regulations by health care authorities vary from very strict, such as by the FDA in the US [17], to none in most other countries. The purpose of this review is to describe the situation
This article is protected by copyright. All rights reserved.
Accepted Article
in Austria, especially the aspect of local guidelines recently developed by scientific societies.
Guidelines and regulation for FMT in Austria The Austrian Federal Office for Safety in Health Care, which executes federal policy in areas of infectious disease control and pharmaceuticals, sees FMT as a therapeutic intervention which should not be considered a pharmaceutical drug and therefore not be regulated by the Austrian Medicines Act. FMT is also not subject to the Medical Devices Act or to the Austrian Transplantation Act. To avoid a legally precarious state for physicians who want to use FMT to treat their patients, the Austrian federal ministry of health was contacted about developing national guidelines. The Austrian federal ministry of health saw no reason to act and based the decision on the current state of knowledge.
In order to prevent an unclear situation for physicians, scientific societies in this field decided to launch a working group of experts from the Austrian society of gastroenterology and hepatology (ÖGGH) in cooperation with the Austrian society of infectious disease and tropical medicine (ÖGIT) and the Austrian Agency for Health and Food Safety (AGES) to develop FMT guidelines for Austria. This working group developed a consensus report for the use of FMT in Austria which was approved by both societies and has currently been submitted for publication in the official organ of the Austrian society of gastroenterology and hepatology [18]. This consensus is intended to provide instructions for physicians who want to use FMT, giving indications, methodology and donor screening, based on current medical literature. The guidelines further recommend that FMT may be used only by physicians for certain indications and under safety precautions. In our opinion, FMT “selfadministration” by patients as has been reported [19-21] or by alternative practitioners should be avoided due to potential risks. The latter situation would be the case if FMT were restricted too rigorously by medical authorities.
So far in Austria FMT has been mainly used by gastroenterologists working at departments of gastroenterology and hepatology, including the university hospitals in This article is protected by copyright. All rights reserved.
Accepted Article
Vienna, Graz and Innsbruck as well as major non-university associated gastroenterology departments in Vienna, Carinthia and Upper Austria. We are not aware if FMT has been used in the outpatient setting by practitioners in Austria so far.
Indications for FMT Clostridium difficile infection (CDI) FMT is most commonly used for recurrent forms of Clostridium difficile infection (CDI). There are currently many cohort studies in a large number of patients and a randomized controlled trial showing a dramatic effect of FMT for this indication [14, 15, 22-24]. Therefore FMT is recommended by international medical societies for the treatment of recurrent CDI based on solid scientific evidence. The European society for clinical microbiology and infectious diseases (ESCMID) recommends the use of FMT in their current CDI guidelines as preferable to vancomycin or fidaxomicin in patients with at least 2 CDI recurrences (i.e. 3 CDI episodes in an single patient) [25]. Austrian guidelines also recommend FMT to treat recurrent CDI in agreement with ESCMID guidelines and further suggest FMT as a treatment option for severe CDI as an alternative to total colectomy, failing positive results of standard therapy [18].
In Austria, the estimated number of CDI cases is approximately 7,000 per year [26]. Assuming a recurrence rate of 20% as reported in the literature [27], about 250-300 patients with 2 recurrences (3 episodes) of CDI would need to be treated with FMT according to these guidelines in Austria. If cases were evenly distributed, this would mean that the current centers performing FMT would need to treat 40-50 cases of recurrent CDI per year. So far we are not aware that these numbers of CDI patients are treated with FMT at any hospital in Austria. This suggests that physicians in Austria still hesitate to choose FMT as an early treatment option for recurrent CDI. Obviously the current centers offering FMT suffice so far for the number of patients requiring this form of therapy.
Other indications Other potential indications for the use of FMT are the treatment of inflammatory bowel diseases, especially ulcerative colitis (UC). Studies using FMT for the This article is protected by copyright. All rights reserved.
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treatment of UC have been performed in Austria [28, 29] and are still ongoing [30]. While a single application of FMT as is recommended for patients with CDI seems to be without major benefit for UC patients [28, 29], a protocol using repeated FMT has shown a clinical response in about 50% of patients [30]. Due to lack of sufficient data at the current time, Austrian guidelines only recommend the use of FMT to treat UC or indications other than CDI in clinical studies with appropriate safety measures.
Recommended donor screening in Austria The selection of possible donors is one of the key points in executing FMT. The definition of potentially transmittable diseases in this context remains unclear. Considering lack of knowledge about the transferability of tumorgenesis or autoimmune, metabolic, neuropsychiatric diseases, long term side effects are unknown. In principle, donors genetically related to FMT recipients show similarities of intestinal microbiota [31]. Donors and recipients living in the same household and/or in sexual relationship are largely exposed to the same infectious risk factors. Therefore the possibility of transmitting infectious agents via stool from related donors is assumed to be reduced. However, FMT has also been successfully performed with donor stool from unrelated healthy volunteers [32]. Success rates of FMT for recurrent CDI are comparable for related and unrelated donors (89.5% vs. 90.7%) [33].Appropriateness or advantage of donor feces in terms of relation status for indications other than C. difficile (e.g. ulcerative colitis, metabolic syndrome) remains uncertain.
There are different screening procedures for stool donors. Recommendations about parameters to be tested for donor screening are inconsistent among various institutions and countries and are mainly based on theoretical estimations of risk assessment. The following screening procedure reflects the Austrian consensus [18] and is mainly based on expert opinions. Donor screening comprises adequate history, physical examination, laboratory tests and microbiological investigations (Table 1).
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Potential donors present as healthy adults or adolescents (optional BMI between 17 and 35) lacking any evidence of acute or chronic disease (e.g. autoimmune disease, malignancy, chronic inflammatory bowel diseases). They should confirm no antibiotic therapy within the last 3 months, no diarrhea within the last 3 months, no intravenous drug abuse or other risk behavior for transmissible diseases and no significant gastrointestinal surgery (e.g. Whipple procedure, total colectomy). In Austria laboratory tests comprise various immunological and microbiological parameters as listed in Tab. 1. The Austrian guidelines discuss CMV antibodies only to be performed in recipients with negative CMV IgG antibodies and presence of chronic inflammatory bowel diseases, wasting disease, or immunosuppression including prednisolone >20mg/d as well as a history of solid organ or stem cell transplantation. Stool analysis for calprotectin is optional in FMT for recurrent CDI but recommended in application of FMT for chronic inflammatory bowel disease.
Donors repeatedly used for FMT should be retested every 6 months, and sooner in case of certain risks for infectious diseases (e.g. vacation in countries with a high risk for gastrointestinal infections). In case of emergency and proposed FMT in fulminant CDI, relatives or sexual partners may be used as donors without the testing described above [34].
Despite or just because of the great awareness of potential FMT induced injury, reports about severe side effects are rare. However, considering reported cases of successfully and safely performed FMT in immunosuppressed patients [35] donor screening and infectious workup as described above seems to be sufficient so far.
Method Fecal microbiota transplantation can be performed either via the upper or the lower GI tract; for both routes of application, different techniques have been described. However, to date no comparative methodical studies exist, thus clinicians can only rely on experience and expert opinions. According to empirical data, donor stool
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should be fresh, not older than 6 hours, and stored in airtight vessels at +6 to +8 C° to avoid bacterial overgrowth.
Fecal bacteria are classified as biohazard level 2, which implicates wearing water repellent garments, gloves as well as face masks, protection goggles or shields; the use of a biological safety cabinet is optional. Depending on stool consistency the entire fecal donation will be diluted with 100-500 ml sterile saline (NaCl 0.9%) and homogenized in a household blender or similar device, especially designated for this purpose (Fig. 1a). There is, however, no standardized data about the total stool weight to be used; 50 to 150 g seem to be appropriate [4]. In the next step the stool suspension will be filtered in order to remove solid components (Fig. 1b). Gauze pads, paper or steel filters as well as sieves can serve as filters (such as commonly used in households). Some authors recommend coffee filters to separate stool debris but in our experience, coffee filters, at least the ones available in Austria, tend to clog rapidly. The objective of filtration is to refine the stool suspension by removing roughage, which might hamper stool application by blocking a tube or the working channel of the endoscope.
Depending on the route of administration, the diluted, homogenized and filtered suspension will be apportioned into 20 to 50 ml syringes (Fig. 1c) and administered to the patient within the next 2 hours (Fig. 1d). In our view, processing the stool rapidly in a possible closed system is essential to protect anaerobic bacteria from oxygen.
Recent publications reported successful transplantation of previously frozen fecal suspension, which had specially been prepared with glycerol [32, 36, 37]. These experiences are based on small case series therefore we only recommend the application of prior frozen microbiota in certain cases, such as increased urgency or donor drop out. In such cases, fecal samples should be stored at -80 °C and gently reheated in a 37 °C warm water bath over a period of 2 hours [32, 36, 37].
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Preparation of the Patient The preparation of the patient depends on the route of administration as well as on indication for FMT.
In case of recurrent CDI patients receive an antibiotic pretreatment either with vancomycin or fidaxomicin for at least 4 days in order to repress the abundance of intestinal C. difficile. Antibiotics should be stopped 36 to 48 hours prior to FMT.
For application in the lower GI tract, patients receive a conventional colon lavage routinely given prior to colonoscopy. As the colon lavage significantly reduces the patient`s microbiota [38] it is also reasonable to perform it for administration in the upper GI tract. To extend retention time of the donor microbiota in the patient`s intestines, loperamid can be provided after successful FMT; however, in our experience this might aggravate post-interventional side effects like bloating and abdominal pain or may lead to nausea and emesis.
In case of FMT via upper GI tract, prokinetic therapy might reduce the risk of aspiration. Also proton pump inhibitors (PPI) can have a positive impact on the viability of the transplanted bacteria [34].
Route of administration Different routes of administration are described in the literature. Stool application can be performed by colonoscopy to the terminal ileum and portion-wise further downstream in the colon (Fig. 1d) or exclusively to the left colon either via endoscope or enema, depending on the patient’s condition and what is available locally. Whereas 200-500 ml fecal suspension can be placed in the lower GI tract [4, 14, 22], transplantation volumes in the upper GI tract are limited due to the risk of possible aspiration.. If the donor stool is placed in the upper GI-tract, nasogastric – or nasojejunal tubes can be used; endoscopic applications via gastroscopy are also described. The total volume of inserted bacterial suspension is usually much lower, about 25 – 50 ml [39], but also transplanted volumes of up to 500 ml via nasojejunal tubes (2-3 minutes/50 ml) have been reported [15]. Nasoduodenal application as the mode of FMT application has been used in the only randomized controlled study [15], This article is protected by copyright. All rights reserved.
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Physicians must be aware of increasing risks of severe side effects according to transplantation volumes in the upper GI tract.On the occasion of a recently published case of pneumoperitoneum and septic shock with lethal outcome after FMT via nasojejunal tube [40], we highly recommend to confirm the correct tube position by xray before installing donor stool in the upper GI tract [41].
The authors of this review decidedly recommend the lower GI tract as preferable route of administration due to safety reasons and the larger amounts of transplantable volume. Cases of severe C. difficile infection with paralytic ileus have also been successfully treated with FMT by colonoscopy without any serious infectious side events as well as patients receiving immunosuppressive therapy [28, 35, 42]. A recently published review revealed a non-significant advantage of FMT for recurrent C. difficile infection via colonoscopy compared to FMT in the upper GI tract via nasogastric or jejunal tubes. (91.4% vs 82.3%) [33].
The route of administration has to be chosen depending on the phenotype of the disease as well as comorbidities of the patient and remains an individualized decision. However, assessing risks and benefits, FMT via colonoscopy seems to be effective and safe and in the authors’ view is therefore the preferable route of administration.
Conclusion Fecal microbiota transplantation is a new treatment option for patients with dysbiosis- induced diseases [2-8]., as well as for patients with recurrent CDI. Due to lack of treatment alternatives for some of these patients, we believe that FMT is a major improvement in the therapeutic arsenal for physicians. We further believe that too strict regulations for FMT by medical authorities would prevent this form of therapy for many patients who could benefit. Furthermore this would displace this method to an alternative medicine sector resulting in even more potential safety risks for patients. Scientific societies in other counties are therefore called to develop FMT guidelines which are practicable for most physicians in this field.
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Figure Legend Figure 1. A. Dilution and homogenization of donor stool with 0.9% NaCl in a blender. B. Subsequent filtration of homogenized and diluted stool suspension with a metal sieve in order to remove debris. C. Fecal suspension portioned into 20 ml syringes prior to application. D. Application of fecal suspension into the working channel of a colonoscope for fecal microbiota transplantation into the lower GI tract.
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Received Date : 05-Jul-2014 Revised Date : 19-Aug-2014 Accepted Date : 11-Sep-2014 Article type : Invited Review
Fecal microbiota transplantation – the Austrian approach Patrizia K. Kump1, Robert Krause2, Franz Allerberger3, Christoph Högenauer1 1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Austria 2. Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, Austria 3. Austrian Agency for Health and Food Safety (AGES), Vienna, Austria
Running title: FMT – The Austrian Approach
Corresponding Author: ao Univ. Prof. Dr. Christoph Högenauer Division of Gastroenterology and Hepatology Department of Internal Medicine Medical University of Graz Auenbruggerplatz 15 A-8036 Graz Austria Tel: +43-316-385-14388 Fax: +43-316-385-12648 E-Mail: [email protected] Abstract The intestinal microbiome is essential for maintaining human health and defending against intestinal pathogens. Alterations of the intestinal microbiota, also termed dysbiosis, play a pivotal role in the pathogenesis of various human diseases. Fecal microbiota transplantation (FMT) aims on correcting these alterations by delivering fecal microorganisms from a healthy person to the intestines of a patient. Up to now, This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1469-0691.12801 This article is protected by copyright. All rights reserved.
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Serological tests
Stool analysis
hepatitis B antigens and antibodies (anti-HBc) hepatitis C antibodies (IgG) HIV** antigens or antibodies Treponema pallidum hemagglutination assay (TPPH) CMV*** antibodies (IgG, IgM) (optional in IBD*, wasting diseases, prednisolon >20mg/d, and in patients with previous solid organ or stem cell transplantation) pathogenic intestinal bacteria (Clostridium difficile, Salmonella sp., Campylobacter sp., EHEC, Yersinina sp., Shigella sp.) microscopic examination for ova and parasites Giardia lamblia and Cryptosporidium antigen norovirus and rotavirus antigen or PCR calprotecin (optional in CDI****, obligatory in unrelated donors and IBD*)
*
IBD: inflammatory bowel disease **HIV: human immunodeficiency virus ***CMV: cytomegalovirus CDI: Clostridium difficile infection
****
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