Faecal microbiota transplantation the Austrian approach

Transcription

1 REVIEW / Faecal microbiota transplantation the Austrian approach P. K. Kump 1, R. Krause 2, F. Allerberger 3 and C. H ogenauer 1 1) Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, 2) Section of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Medical University of Graz, Graz, and 3) Austrian Agency for Health and Food Safety (AGES), Vienna, Austria 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. Faecal microbiota transplantation (FMT) is aimed at correcting these alterations by delivering faecal microorganisms from a healthy person to the intestines of a patient. At present, recurrent Clostridium difficile 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 long-term safety concerns, is leading to worldwide controversy regarding the use of FMT. Regulations by healthcare 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: Clostridium difficile infection, dysbiosis, faecal microbiota transplantation, guidelines, inflammatory bowel disease, stool transplantation Article published online: 1 October 2014 Clin Microbiol Infect 2014; 20: Corresponding author: C. H ogenauer, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria christoph.hoegenauer@medunigraz.at Introduction The intestinal microbiota has a pivotal role for the human organism in the maintenance of health, especially for defence 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 syndrome, metabolic syndrome, and autoimmune diseases [2 9]. Although there is no generally accepted definition of dysbiosis, most authors consider decreased microbial diversity or an increased abundance of certain pathobionts or opportunistic pathogens as intestinal dysbiosis [5,10 13]. Faecal microbiota transplantation (FMT), also known as stool transplantation, is a therapeutic procedure aimed at restoring the intestinal microbiota by the administration of faecal microorganisms from a healthy donor into the intestinal tract of a patient [10,14 16]. The increasing numbers of reported Clostridium difficile infections (CDIs) since the millennium have resulted in a distinct interest in therapeutic FMT in the medical community, as this method is mainly used to treat recurrent CDI. There is, however, much controversy regarding the use of FMT among physicians, because of potential safety concerns. FMT regulations produced by healthcare authorities vary from very strict, such as those of the Food and Drug Administration in the USA [17], to non-existent in most other countries. The purpose of this review is to describe the situation in Austria, especially with regard to local guidelines recently developed by scientific societies. Clinical Microbiology and Infection ª2014 European Society of Clinical Microbiology and Infectious Diseases

2 CMI Kump et al. FMT the Austrian approach 1107 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 that 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 create a working group of experts from the Austrian Society of Gastroenterology and Hepatology in cooperation with the Austrian Society of Infectious Disease and Tropical Medicine and the Austrian Agency for Health and Food Safety to develop FMT guidelines for Austria. This working group developed a consensus report for the use of FMT in Austria that was approved by both societies and is currently in the publication process 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, including indications, methodology, and donor screening, based on the current medical literature. The guidelines further recommend that FMT may be used only by physicians for certain indications and with safety precautions. In our opinion, FMT self-administration by patients, as has been reported [19 21], or by alternative practitioners should be avoided, owing 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 Vienna, Graz, and Innsbruck, as well as major non-university-associated gastroenterology departments in Vienna, Carinthia, and Upper Austria. We do not know whether FMT has been used in the outpatient setting by practitioners in Austria so far. Indications for FMT 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, on the basis of solid scientific evidence. The European Society for Clinical Microbiology and Infectious Diseases recommends the use of FMT in their current CDI guidelines as preferable to vancomycin or fidaxomicin in patients with at least two CDI recurrences (i.e. three CDI episodes in an single patient) [25]. Austrian guidelines also recommend FMT to treat recurrent CDI, in agreement with European Society for Clinical Microbiology and Infectious Diseases guidelines, and further suggest FMT as a treatment option for severe CDI as an alternative to total colectomy, if standard therapy fails [18]. In Austria, the estimated number of CDI cases is approximately 7000 per year [26]. Assuming a recurrence rate of 20%, as reported in the literature [27], approximately patients with two recurrences (three 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 centres performing FMT would need to treat cases of recurrent CDI per year. So far, we are not aware that these numbers of CDI patients are being 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 centres offering FMT have sufficed 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 treatment of UC have been performed in Austria [28,29] and are still ongoing [30]. Whereas 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 approximately 50% of patients [30]. Owing to a lack of sufficient data at present, 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 CDI FMT is most commonly used for recurrent forms of CDI. There are currently many cohort studies in a large number of 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. Because of a lack of knowledge about the transferability of tumorigenesis or

3 1108 Clinical Microbiology and Infection, Volume 20 Number 11, November 2014 CMI autoimmune, metabolic and neuropsychiatric diseases, the long-term side effects are unknown. In principle, donors genetically related to FMT recipients show similarities in their intestinal microbiota [31]. Donors and recipients living in the same household and/or in a sexual relationship are largely exposed to the same infectious risk factors. Therefore, the possibility of transmitting infectious agents via faeces from related donors is assumed to be reduced. However, FMT has also been successfully performed with donor faeces from unrelated healthy volunteers [32]. The success rates of FMT for recurrent CDI are comparable for related and unrelated donors (89.5% vs. 90.7%) [33]. The appropriateness or advantage of donor faeces in terms of relationship status for indications other than CDI (e.g. UC and metabolic syndrome) remains uncertain. There are different screening procedures for donors. Recommendations about the 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). Potential donors present as healthy adults or adolescents (optional body mass index between 17 and 35) lacking any evidence of acute or chronic disease (e.g. autoimmune disease, malignancy, and chronic IBDs). They should confirm no antibiotic therapy within the last 3 months, no diarrhoea within the last 3 months, no intravenous drug abuse or other risk behaviour for transmissible diseases, and no significant gastrointestinal (GI) surgery (e.g. Whipple procedure and total colectomy). In Austria, laboratory tests comprise various TABLE 1. Austrian guidelines for screening stool donors History Serological tests Analysis of faeces Healthy adult or adolescent Optionally: BMI >17 and <35 Negative for acute or chronic diseases (autoimmune disease, IBD, malignant disease, etc.) Negative for transmittable diseases No antibiotics within the last 3 months No diarrhoea within the last 3 months Negative for intravenous drug abuse No significant gastrointestinal surgery (e.g. total colectomy) Hepatitis A antibodies (IgM), hepatitis B antigens and antibodies (anti-hbc), hepatitis C antibodies (IgG) HIV antigens or antibodies Treponema pallidum haemagglutination assay Pathogenic intestinal bacteria (Clostridium difficile, Salmonella species, Campylobacter species, EHEC, Yersinina species, Shigella species) Microscopic examination for ova and parasites Giardia lamblia and Cryptosporidium antigen Norovirus and rotavirus antigen or PCR Calprotecin (optional in CDI; recommended for indication IBD) BMI, body mass index; CDI, Clostridium difficile infection; CMV, cytomegalovirus; EHEC, enterohaemorrhagic Escherichia coli; HIV, human immunodeficiency virus; IBD, inflammatory bowel disease. immunological and microbiological parameters, as listed in Table 1. Since feacal transmission of cytomegalovirus infection has not been reported, the Austrian guidelines discuss cytomegalovirus antibodies only to be performed as an optional screening in donors for immunocompromised recipients, such as patients with negative cytomegalovirus IgG antibodies and the presence of chronic IBDs, wasting disease, or immunosuppression, including prednisolone >20 mg daily, and a history of solid organ or stem cell transplantation. Stool analysis for calprotectin is optional in FMT for recurrent CDI, but is recommended in the application of FMT for chronic IBD. Donors repeatedly used for FMT should be retested every 6 months, and sooner in the case of certain risks for infectious diseases (e.g. vacation in countries with a high risk for GI infections). In cases 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], the donor screening and infectious work-up as described above seems to have been sufficient so far. Method FMT 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, there have been no comparative methodical studies, so clinicians have to rely on experience and expert opinions. According to empirical data, donor faeces should be fresh, i.e. not older than 6 h, and stored in airtight vessels at +6 C to +8 C to avoid bacterial overgrowth. Faecal bacteria are classified as biohazard level 2, which requires the wearing of water-repellent garments, gloves, facemasks, protective goggles, or shields; the use of a biological safety cabinet is optional. Depending on faecal consistency the entire faecal donation will be diluted with ml of sterile saline (0.9% NaCl) or water and homogenized in a household blender or similar device, especially designated for this purpose (Fig. 1a). There are, however, no standardized data on the total weight of faeces to be used; g seems to be appropriate [4]. In the next step, the faecal suspension will be filtered in order to remove solid components (Fig. 1b). Gauze pads, paper or steel filters and sieves can serve as filters (such as are commonly used in households). Some authors recommend coffee filters to separate faecal debris but, in our

4 CMI Kump et al. FMT the Austrian approach 1109 (a) (b) (d) (c) FIG. 1. (a) Dilution and homogenization of donor faeces with 0.9% NaCl in a blender. (b) Subsequent filtration of the homogenized and diluted faecal suspension with a metal sieve in order to remove debris. (c) Faecal suspension apportioned into 20-mL syringes prior to application. (d) Introduction of faecal suspension into the working channel of a colonoscope for faecal microbiota transplantation into the lower gastrointestinal tract. experience, coffee filters, at least those available in Austria, tend to clog rapidly. The objective of filtration is to refine the faecal suspension by removing roughage, which might hamper application of faeces 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 mL syringes (Fig. 1c) and administered to the patient within the next 2 h (Fig. 1d). In our view, processing the faeces rapidly, possibly in a closed system, is essential to protect anaerobic bacteria from oxygen. Recent publications reported successful transplantation of previously frozen faecal 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 dropout. In such cases, faecal samples should be stored at 80 C and gently reheated in a 37 C warm water bath over a period of 2 h [32,36,37]. Preparation of the Patient The preparation of the patient depends on the route of administration and on the indication for FMT. In cases of recurrent CDI, patients receive an antibiotic pretreatment with either vancomycin or fidaxomicin for at least 4 days in order to reduce the abundance of intestinal C. difficile. Antibiotics should be stopped h 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 the 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-intervention side effects, such as bloating and abdominal pain, or may lead to nausea and emesis. In cases of FMT via the upper GI tract, prokinetic therapy might reduce the risk of aspiration. Also, proton-pump inhibitors 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. Application of faeces 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, via either endoscope or enema, depending on the patient s condition and what is available locally. Whereas ml of faecal suspension can be placed in the lower GI tract [4, 14, 22], transplantation volumes in the upper GI tract are limited, owing to the risk of aspiration. If the donor faeces are placed in the upper GI tract, nasogastric or nasojejunal tubes can be used; endoscopic applications via gastroscopy have also been described. The total volume of inserted

5 1110 Clinical Microbiology and Infection, Volume 20 Number 11, November 2014 CMI bacterial suspension is usually much lower, approximately ml [39], but transplanted volumes of up to 500 ml via nasojejunal tubes (2 3 min/50 ml) have also been reported [15]. Nasoduodenal application has been used in the only randomized controlled study [15]. Physicians must be aware of increasing risks of severe side effects according to transplantation volumes in the upper GI tract. Given a recently published case of pneumoperitoneum and septic shock with a lethal outcome after FMT via a nasojejunal tube [40], we highly recommend confirmation of the correct tube position by X-ray before donor faeces are installed in the upper GI tract [41]. The authors of this review definitely recommend the lower GI tract as the preferable route of administration, for safety reasons and because of the larger transplantable volume. Cases of severe CDI with paralytic ileus, and patients receiving immunosuppressive therapy, have also been successfully treated with FMT by colonoscopy, without any serious infectious side events [28,35,42]. A recently published review revealed a non-significant advantage of FMT for recurrent CDI via colonoscopy over 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 according to the phenotype of the disease and comorbidities of the patient, and remains an individualized decision. However, given the 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 FMT is a new treatment option for patients with dysbiosis-induced diseases [2 8], and for patients with recurrent CDI. Because of the lack of treatment alternatives for some of these patients, we believe that FMT is a major improvement in the therapeutic arsenal for physicians. We also believe that too strict regulations for FMT from 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 on to develop FMT guidelines that are practicable for most physicians in this field. Transparency Declaration The authors declare no conflict of interest. References 1. Lawley TD, Walker AW. Intestinal colonization resistance. Immunology 2013; 138: Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M. Therapeutic potential of fecal microbiota transplantation. Gastroenterology 2013; 145: Khoruts A, Weingarden AR. Emergence of fecal microbiota transplantation as an approach to repair disrupted microbial gut ecology. Immunol Lett doi: /j.imlet Brandt LJ, Aroniadis OC. An overview of fecal microbiota transplantation: techniques, indications, and outcomes. Gastrointest Endosc 2013; 78: Gevers D, Kugathasan S, Denson LA et al. The treatment-naive microbiome in new-onset Crohn s disease. Cell Host Microbe 2014; 15: 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 2014; 63: 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: Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489: 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: 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: e Knights D, Lassen KG, Xavier RJ. Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome. Gut 2013; 62: Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 2009; 9: Schneditz G, Rentner J, Roier S et al. Enterotoxicity of a nonribosomal peptide causes antibiotic-associated colitis. Proc Natl Acad Sci USA 2014; 111: Borody TJ, Campbell J. Fecal microbiota transplantation: techniques, applications, and issues. Gastroenterol Clin North Am 2012; 41: van Nood E, Vrieze A, Nieuwdorp M et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013; 368: Seekatz AM, Aas J, Gessert CE et al. Recovery of the gut microbiome following fecal microbiota transplantation. mbio 2014; 5: e00893 e Kelly CR, Kunde SS, Khoruts A. Guidance on preparing an investigational new drug application for fecal microbiota transplantation studies. Clin Gastroenterol Hepatol 2014; 12: Kump P, Krause R, Steininger C et al. Empfehlungen zur Anwendung der f akalen Mikrobiotatransplantation Stuhltransplantation : Konsensus der Osterreichischen Gesellschaft f ur Gastroenterologie und Hepatologie ( OGGH) in Zusammenarbeit mit der Osterreichischen Gesellschaft f ur Infektiologie und Tropenmedizin (OEGIT). Z Gastroenterol (in press). 19. Swaminath A. The power of poop: patients getting ahead of their doctors using self-administered fecal transplants. Am J Gastroenterol 2014; 109: Silverman MS, Davis I, Pillai DR. Success of self-administered home fecal transplantation for chronic Clostridium difficile infection. Clin Gastroenterol Hepatol 2010; 8:

6 CMI Kump et al. FMT the Austrian approach Hohmann EL, Ananthakrishnan AN, Deshpande V. Case Case records of the Massachusetts general hospital. N Engl J Med 2014; 371: Mattila E, Uusitalo-Seppala R, Wuorela M et al. Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection. Gastroenterology 2012; 142: Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011; 53: 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; 33: 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): 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: Louie TJ, Miller MA, Mullane KM et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011; 364: 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: 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: Kump PK, Gr ochenig HP, Spindelb ock W et al. Preliminary clinical results of repeatedly fecal microbiota transplantation (FMT) in chronic active ulcerative colitis. United European Gastroenterol J 2013; 1(suppl 1): A Turnbaugh PJ, Hamady M, Yatsunenko T et al. A core gut microbiome in obese and lean twins. Nature 2009; 457: Youngster I, Sauk J, Pindar C et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis 2014; 58: Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol 2013; 108: Bakken JS, Borody T, Brandt LJ et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011; 9: Kelly CR, Ihunnah C, Fischer M et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am J Gastroenterol 2014; 109: Hamilton MJ, Weingarden AR, Sadowsky MJ, Khoruts A. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. Am J Gastroenterol 2012; 107: Hamilton MJ, Weingarden AR, Unno T, Khoruts A, Sadowsky MJ. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes 2013; 4: Gorkiewicz G, Thallinger GG, Trajanoski S et al. Alterations in the colonic microbiota in response to osmotic diarrhea. PLoS ONE 2013; 8: e Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003; 36: Solari PR, Fairchild PG, Noa LJ, Wallace MR. Tempered enthusiasm for fecal transplantation. Clin Infect Dis 2014; 59: H ogenauer C, Kump P, Krause R. Tempered enthusiasm for fecal transplantation. Clin Infect Dis 2014; 59: Friedman-Moraco RJ, Mehta AK, Lyon GM, Kraft CS. Fecal microbiota transplantation for refractory Clostridium difficile colitis in solid organ transplant recipients. Am J Transplant 2014; 14: