Aetna considers fecal bacteriotherapy, including capsulized fecal microbiota transplantation, medically necessary for persons with Clostridium difficile infection, with infection confirmed by a positive stool test for C. difficile toxin, that has recurred following at least 1 course of adequate antibiotic therapy (10 or more days of vancomycin at a dose of greater than or equal to 125 mg 4 times per day or 10 or more days of metronidazole at a dose of 500 mg 3 times per day).
Aetna considers fecal bacteriotherapy experimental and investigational for all other indications including the following (not an all-inclusive list):
Fecal bacteriotherapy (FT, also known as fecal microbiota transplantation [FMT], fecal transplant, fecal transfusion, and probiotic infusion) is the transfer of a liquid suspension of stool from a healthy donor to the patient and is proposed for the treatment of Clostridium difficile infection (CDI), which can result in mild diarrhea to life-threatening fulminant pseudomembraneous colitis. Treatment involves discontinuation of the offending antibody and oral administration of metronidazole or vancomycin. In some cases, patients non-responsive to medical management are treated by surgical colectomy which has a motality rate of 35 % to 57 %. One of the risks with FT is the transfer of contagious agents (e.g., fungi, parasites, and viruses) from the donor (You et al, 2008; Bakken et al, 2009).
A randomized controlled clinical trial by van Nood and colleagues (2013) found that infusion of donor feces was significantly more effective for the treatment of recurrent CDI than the use of vancomycin. Included in the study were patients who were at least 18 years of age and who had a life expectancy of at least 3 months and a relapse of CDI after at least 1 course of adequate antibiotic therapy (greater than or equal to 10 days of vancomycin at a dose of greater than or equal to 125 mg 4 times per day or greater than or equal to 10 days of metronidazole at a dose of 500 mg 3 times per day). C. difficile infection was defined as diarrhea (greater than or equal to 3 loose or watery stools per day for at least 2 consecutive days or greate than or eqaul to 8 loose stools in 48 hours) and a positive stool test for C. difficile toxin. Available isolates were characterized by PCR. These investigators randomly assigned patients with recurrent CDI to receive 1 of 3 therapies: (i) an initial vancomycin regimen (500 mg orally 4 times per day for 4 days), followed by bowel lavage and subsequent infusion of a solution of donor feces through a naso-duodenal tube; (ii) a standard vancomycin regimen (500 mg orally 4 times per day for 14 days); or (iii) a standard vancomycin regimen with bowel lavage. The primary end-point was the resolution of diarrhea associated with CDI without relapse after 10 weeks. The study was stopped after an interim analysis. Of 16 patients in the infusion group, 13 (81 %) had resolution of C. difficile-associated diarrhea after the first infusion. The 3 remaining patients received a second infusion with feces from a different donor, with resolution in 2 patients. The investigators reported that resolution of CDI occurred in 4 of 13 patients (31 %) receiving vancomycin alone and in 3 of 13 patients (23 %) receiving vancomycin with bowel lavage (p < 0.001 for both comparisons with the infusion group). No significant differences in adverse events among the 3 study groups were observed except for mild diarrhea and abdominal cramping in the infusion group on the infusion day. After donor-feces infusion, patients showed increased fecal bacterial diversity, similar to that in healthy donors, with an increase in bacteroidetes species and clostridium clusters IV and XIVa and a decrease in proteobacteria species. An accompanying editorial (Kelly, 2013) stated that the study by van Nood et al is an important confirmation of the efficacy of fecal microbiota transplant for recurrent CDI.
Baddour (2013) commented that the findings of this study by van Nood et al will garner much attention and will likely increase the use of fecal transplantation (FT) in the treatment of recurrent CDI. These happenings, coupled with our increasing understanding of the gut microbiome, should markedly advance our understanding of the pathogenesis and treatment of CDI.
This clinical trial is consistent with the results of earlier studies of fecal bacteriotherapy. Guo et al (2012) critically appraised the clinical research evidence on the safety and effectiveness of FT compared with standard care in the treatment of patients with clostridium difficile-associated disease (CDAD). A comprehensive literature search was conducted by a research librarian to identify relevant studies published between 2000 and 2011. The Cochrane Library, PubMed, EMBASE, CINAHL, Biological Abstracts, BIOSIS Previews and Web of Science were searched. Methodological quality of the included case series studies was assessed in terms of patient selection criteria, consecutive recruitment, prospective data collection, reporting of lost to follow-up, and follow-up rates. No controlled studies were found. Based on the weak evidence from 7 full-text case series studies of 124 patients with recurrent/refractory CDAD, FT appears to be a safe and effective procedure. In most cases (83 %) symptoms improved immediately after the first FT procedure, and some patients stayed diarrhea-free for several months or years. The authors concluded that although these results appear to be promising, the treatment effects of FT can not be determined definitively in the absence of a control group. Results from randomized controlled trials (RCTs) that compare FT to oral vancomycin without or with a taper regimen will help to better define the role of FT in the management of recurrent CDAD.
Guidelines on Clostridium difficile infection from the American College of Gastroenterology (Surawicz, et al., 2013) state that, if there is a third recurrence of Clostridium difficile after a pulsed vancomycin regimen, fecal microbiota transplant (FMT) should be considered. This is a conditional recommendation based upon moderate-quality evidence.
Brandt and Reddy (2011) stated that with the increasing prevalence of recurrent/refractory CDI, alternative treatments to the standard antibiotic therapies are being sought. One of the more controversial of such alternative treatments is fecal microbiota transplantation (FMT). Although the notion of FMT is foreign -- even startling -- and not esthetic to most people, the concept has been around for many decades. Its benefit and effectiveness dated back more than 50 years to its use for staphylococcal pseudomembranous colitis, and now FMT is showing a great promise as an inexpensive, safe, and highly efficient treatment for recurrent and refractory CDI. Moreover, with a better understanding of the intricacies of the colonic microbiome and its role in colonic pathophysiology, FMT has the potential to become the standard of care for CDI treatment, and a potential answer to other intestinal disorders in years to come.
Smits et al (2013) stated that there has been growing interest in the use of fecal microbiota for the treatment of patients with chronic gastro-intestinal infections and inflammatory bowel diseases (IBD). Lately, there has also been interest in its therapeutic potential for cardio-metabolic, autoimmune, and other extra-intestinal conditions that were not previously considered to be associated with the intestinal microbiota. Although it is not clear if changes in the microbiota cause these conditions, these researchers reviewed the most current and best methods for performing FMT and summarized clinical observations that have implicated the intestinal microbiota in various diseases. They also discussed case reports of FMT for different disorders, including CDI, irritable bowel syndrome, IBD, insulin resistance, multiple sclerosis, and idiopathic thrombocytopenic purpura. There has been increasing focus on the interaction between the intestinal microbiome, obesity, and cardio-metabolic diseases, and these investigators explored these relationships and the potential roles of different microbial strains.
Kump et al (2013) examined if patients with ulcerative colitis (UC) would benefit from FMT and if dysbiosis can be reversed. A total of 6 patients with chronic active UC non-responsive to standard medical therapy were treated with FMT by colonoscopic administration. Changes in the colonic microbiota were assessed by 16S rDNA-based microbial community profiling using high-throughput pyro-sequencing from mucosal and stool samples. All patients experienced short-term clinical improvement within the first 2 weeks after FMT. However, none of the patients achieved clinical remission. Microbiota profiling showed differences in the modification of the intestinal microbiota between individual patients after FMT. In 3 patients, the colonic microbiota changed toward the donor microbiota; however, this did not correlate with clinical response. On phylum level, there was a significant reduction of proteobacteria and an increase in bacteroidetes after FMT. The authors concluded that FMT by a single colonoscopic donor stool application is not effective in inducing remission in chronic active therapy-refractory UC. Changes in the composition of the intestinal microbiota were significant and resulted in a partial improvement of UC-associated dysbiosis. They stated that the results of this small study suggested that dysbiosis in UC is at least in part a secondary phenomenon induced by inflammation and diarrhea rather than being causative for inflammation in this disease.
Zhang et al (2013) stated that the concept of FMT has been used in traditional Chinese medicine at least since the 4th century. Evidence from recent human studies strongly supports the link between intestinal bacteria and IBD. These investigators proposed that standardized FMT might be a promising rescue therapy for refractory IBD. However, there were no reports of FMT used in patients with severe Crohn's disease (CD). These researchers reported the successful treatment of standardized FMT as a rescue therapy for a case of refractory CD complicated with fistula, residual barium sulfate and formation of intra-peritoneal large inflammatory mass. The authors concluded that this was the first case of severe CD treated using FMT through mid-gut.
In a pilot study, Cui and colleagues (2015) evaluated the safety, feasibility and effectiveness of FMT through mid-gut for refractory CD. These researchers established standardized laboratory protocol and clinical work-flow for FMT. Only refractory CD patients with Harvey-Bradshaw Index (HBI) score greater than or equal to 7 were enrolled for this study. All included patients were treated with single FMT through mid-gut and assessed during follow-up. Meta-genomics analysis showed a high concordance between feces sample and purified fecal microbiota from same donors. Standardized fecal microbiota preparation and clinical flow significantly simplified the practical aspects of FMT. A total of 30 patients were qualified for the present analysis. The rate of clinical improvement and remission based on clinical activity at the 1st month was 86.7 % (26/30) and 76.7 % (23/30), respectively, which was higher than other assessment points within 15-month follow-up. Patients' body weight increased after FMT, and the lipid profile improved as well. Fecal microbiota transplantation also showed a fast and continuous significant effect in relieving the sustaining abdominal pain associated with sustaining CD. The authors concluded that these findings demonstrated that FMT through mid-gut might be a safe, feasible, and efficient rescue therapy for refractory CD.
van Nood et al (2014) reviewed the current evidence on FMT for recurrent CDIs, metabolic syndrome and IBD. These investigators noted that recently, a randomized trial confirmed the effectiveness of this treatment strategy in patients with recurrent CDI. For other disorders, evidence is still limited. To-date, studies have been performed to try and influence the course of metabolic syndrome and IBD. The authors concluded that there is increasing interest in the role of altered microbiota in the development of a myriad of diseases. Together with new insights comes an interest in influencing this altered microbiota as a potential target for therapy. Fecal microbiota transplantations are effective against recurrent CDI. Restoration of intestinal flora and thereby restoration of colonization resistance is thought to be the mechanism responsible for cure. With the developments in FMT and the extension of this treatment modality to both intestinal and extra-intestinal diseases, a new field of targeted therapy awaits. The authors concluded that currently, FMT should only be given in a strict experimental setting for other conditions than CDI.
Colman and Rubin (2014) conducted a systematic review and meta-analysis to evaluate the effectiveness of FMT as treatment for patients with IBD. A systematic literature search was performed through May 2014. Inclusion criteria required FMT as the primary therapeutic agent. Clinical remission (CR) and/or mucosal healing were defined as primary outcomes. Studies were excluded if they did not report clinical outcomes or included patients with infections. A total of 18 studies (9 cohort studies, 8 case studies and 1 RCT) were included. A total of 122 patients were described (79 UC; 39 CD; 4 IBD unclassified). Overall, 45 % (54/119) of patients achieved CR during follow-up. Among the cohort studies, the pooled proportion of patients that achieved CR was 36.2 % (95 % confidence interval [CI]: 17.4 % to 60.4 %), with a moderate risk of heterogeneity (Cochran's Q, p = 0.011; I2 = 37 %). Subgroup analyses demonstrated a pooled estimate of CR of 22 % (95 % CI: 10.4 % to 40.8 %) for UC (p = 0.37; I2 = 0 %) and 60.5 % (95 % CI: 28.4 % to 85.6 %) for CD (p = 0.05; I2 = 37 %); 6 studies performed microbiota analysis. The authors concluded that this analysis suggested that FMT is a safe, but variably effective treatment for IBD. They stated that more RCTs are needed and should investigate frequency of FMT administration, donor selection and standardization of microbiome analysis.
Almeida and colleagues (2015) stated that as knowledge of the composition and function of the intestinal microbiota continues to expand, there is new interest in using these developments to tailor FMT and microbial ecosystem therapeutics (MET) for a variety of diseases. The potential role of FMT and MET in the treatment of CDI -- currently the leading nosocomial gastro-intestinal infection -- has proven highly effective for recurrent CDI, and has emerged as a paradigm shift in the treatment of this disease. These investigators summarized the key aspects of CDI, and introduced the essential frame-work and challenges of FMT, as is currently practiced. Microbial ecosystem therapeutics represents the progression of conventional bacteriotherapy that fundamentally capitalizes on the restorative properties of intestinal bacterial communities and may be viewed as the culmination of a rationally designed therapeutic modality. The authors concluded that as the understanding of the composition and function of the intestinal microbiota evolves, it will likely drive next-generation microbiota therapies for a range of medical conditions, such as IBD, metabolic syndrome, and obesity.
Oral, Capsulized, Frozen Fecal Microbiota Transplantation:
In an open-label, single-group, preliminary feasibility study, Youngster et al (2014) evaluated the safety and rate of resolution of diarrhea following administration of frozen FMT capsules from pre-screened unrelated donors to patients with recurrent CDI. This study was conducted from August 2013 through June 2014 at Massachusetts General Hospital, Boston. A total of 20 patients (median age of 64.5 years; range of 11 to 89 years) with at least 3 episodes of mild-to-moderate CDI and failure of a 6- to 8-week taper with vancomycin or at least 2 episodes of severe CDI requiring hospitalization were enrolled. Healthy volunteers were screened as potential donors and FMT capsules were generated and stored at -80° C (-112° F). Patients received 15 capsules on 2 consecutive days and were followed-up for symptom resolution and adverse events for up to 6 months. The primary end-points were safety, assessed by adverse events of grade 2 or above, and clinical resolution of diarrhea with no relapse at 8 weeks. Secondary end-points included improvement in subjective well-being per standardized questionnaires and daily number of bowel movements. No serious adverse events attributed to FMT were observed. Resolution of diarrhea was achieved in 14 patients (70 %; 95 % CI: 47 % to 85 %) after a single capsule-based FMT. All 6 non-responders were re-treated; 4 had resolution of diarrhea, resulting in an overall 90 % (95 % CI: 68 % to 98 %) rate of clinical resolution of diarrhea (18/20). Daily number of bowel movements decreased from a median of 5 (interquartile range [IQR] of 3 to 6) the day prior to administration to 2 (IQR of 1 to 3) at day 3 (p = 0.001) and 1 (IQR of 1 to 2) at 8 weeks (p < 0.001). Self-ranked health scores improved significantly on a scale of 1 to 10 from a median of 5 (IQR of 5 to 7) for overall health and 4.5 (IQR of 3 to 7) for gastrointestinal-specific health on the day prior to FMT to 8 (IQR of 7 to 9) after FMT administration for both overall and gastro-intestinal health (p = 0.001). Patients needing a second treatment to obtain resolution of diarrhea had lower pre-treatment health scores (median of 6.5 [IQR of 5 to 7.3] versus 5 [IQR of 2.8 to 5]; p = 0.02). The authors concluded that this preliminary study among patients with relapsing CDI provided data on adverse events and rates of resolution of diarrhea following administration of FMT using frozen encapsulated inoculum from unrelated donors. They stated that larger studies are needed to confirm these results and to evaluate long-term safety and effectiveness. The main drawbacks of this study were its small sample size and the lack of placebo or active comparator.
Commenting on the study by Youngster et al, Rex (2014) noted that “The oral use of frozen encapsulated fecal material for FMT seems to be a major improvement over current methods of treating relapsing C. difficile infection -- for a number of obvious reasons. The major risks seem to be vomiting and aspiration, which did not occur in this small, non-placebo-controlled trial. Pending commercialization of frozen encapsulated fecal material, or development of safe, reliable protocols for institutions to create their own frozen encapsulated feces, colonoscopy will likely remain the primary means of FMT administration”.
An UpToDate review on “Fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection” (broody et al, 2015) states that “In an open label, single group feasibility study, 20 patients with at least three episodes of mild to moderate C. difficile infection and failure of a six- to eight-week taper with vancomycin taper or at least two episodes of severe C. difficile infection requiring hospitalization were treated with up to 30 frozen FMT capsules on two consecutive days. Diarrhea resolved following initial treatment in 14 of 20 patients and 4 of 6 non-responders who were retreated. No serious adverse events were noted during six months follow-up. However, larger studies are needed to confirm these results and to evaluate long-term safety and effectiveness”.
|CPT Codes / HCPCS Codes / ICD-10 Codes|
|Information in the [brackets] below has been added for clarification purposes.  Codes requiring a 7th character are represented by "+":|
|ICD-10 codes will become effective as of October 1, 2015:|
|CPT codes covered if selection criteria are met :|
|44705||Preparation of fecal microbiota for instillation, including assessment of donor specimen|
|HCPCS codes covered if selection criteria are met:|
|G0455||Preparation with instillation of fecal microbiota by any method, including assessment of donor specimen|
|ICD-10 codes covered if selection criteria are met:|
|A04.7||Enterocolitis due to Clostridium difficile|
|ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):|
|D69.3||Immune thrombocytopenic purpura [idiopathic thrombocytopenic purpura]|
|E88.81||Metabolic syndrome [insulin resistance]|
|K50.00 - K50.919||Crohn's disease [regional enteritis]|
|K51.00 - K51.919||Ulcerative colitis|
|K52.0 - K52.9||Other and unspecified noninfectious gastroenteritis and colitis [inflammatory bowel diseases]|
|K58.0 - K58.9||Irritable bowel syndrome|