American Journal of Transplantation 2014; 14: 477–480 Wiley Periodicals Inc.
Case Report
C
Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12577
Fecal Microbiota Transplantation for Refractory Clostridium difficile Colitis in Solid Organ Transplant Recipients R. J. Friedman-Moraco, A. K. Mehta, G. M. Lyon and C. S. Kraft* Division of Infectious Diseases, Emory University, Atlanta, GA Corresponding author: Colleen Kraft, [email protected]
Fecal microbiota transplantation (FMT) has been shown to be safe and efficacious in individuals with refractory Clostridium difficile. It has not been widely studied in individuals with immunosuppression due to concerns about infectious complications. We describe two solid organ transplant recipients, one lung and one renal, in this case report that both had resolution of their diarrhea caused by C. difficile after FMT. Both recipients required two FMTs to achieve resolution of their symptoms and neither had infectious complications. Immunosuppressed individuals are at high risk for acquisition of C. difficile and close monitoring for infectious complications after FMT is necessary, but should not preclude its use in patients with refractory disease due to C. difficile. Sequential FMT may be used to achieve cure in these patients with damaged microbiota from antibiotic use and immunosuppression. Keywords: Clostridium difficile, fecal microbiota transplantation, fecal transplant, lung transplant, renal transplant, solid organ transplant Abbreviations: BOS, bronchiolitis obliterans; CDI, Clostridium difficile infection; FEV1, forced expiratory volume; FMT, fecal microbiota transplantation; MDRO, multidrug resistant organism; NJ, nasojejunal; PCR, polymerase chain reaction; SOT, solid organ transplant; UTI, urinary tract infection Received 08 October 2013, revised 07 November 2013 and accepted for publication 11 November 2013
Introduction Clostridium difficile infection (CDI) is the most common cause of infectious healthcare-associated diarrhea (1) with clinical manifestations ranging from asymptomatic coloni-
zation to fulminant colitis (2). The overall incidence of CDI in solid organ transplant (SOT) recipients is higher than that seen in the general hospitalized population; estimated at 1.5–31% depending on organ type compared to a 1.0–2.0% overall incidence in hospitalized patients (3). SOT recipients are at higher risk for CDI for multiple reasons, including frequent antimicrobial use, immune dysregulation and underlying comorbidities. CDI is most common in the first 3 months after SOT due to the level of immunosuppression, healthcare exposures and frequent antibiotics (4). Antibiotic use is an important risk factor in SOT due to the need for antimicrobial prophylaxis and the potential for frequent infectious complications resulting in prolonged courses of antimicrobials (5). Yet, approximately 20% of SOT recipients who develop CDI have no preceding antimicrobial exposure (4), likely related to immune dysfunction in SOT. Impairments of humoral immunity may have the most significant impact on the control of C. difficile (4); in one study, the incidence of CDI in heart transplants decreased after the introduction of immunoglobulin posttransplant (6). Immunosuppressive medications alter the intestinal microbiota further contributing to dysbiosis and C. difficile overgrowth (7). Additionally, SOT recipients with CDI have been shown to have worse outcomes. Fulminant colitis is seen more frequently, with 13.0% in the transplant population versus 8.0% in the general population (3). Pant et al (8) found significant increase in hospital mortality, length of stay, organ complications and colectomy in SOT recipients with CDI. SOT recipients may also have higher rates of recurrent CDI infection. Studies in heart and lung transplant recipients demonstrated that 28.6–33.0% of patients had one or more recurrences, though these were not distinguished from reinfection (7). Given increased incidence of CDI and worsened outcomes in SOT recipients, effective and durable treatment for CDI in SOT recipients is of great importance (4). Fecal microbiota transplantation (FMT) has recently shown to be a safe and effective treatment for recurrent and/or refractory CDI (9), but most case series exclude immunosuppressed patients. In addition, current guidelines for SOT do not include FMT in the treatment algorithm for CDI (4,10). Here, we report on two SOT recipients who received FMT at our institution. 477
Friedman-Moraco et al
Case Report The first patient is a 73-year-old female with a history of deceased donor renal transplantation for hypertensive nephrosclerosis, on tacrolimus, azathioprine and prednisone. Her posttransplant course was complicated by recurrent urinary tract infections (UTIs)/pyelonephritis and recurrent CDI that was moderate in severity. Her initial CDI occurred 2 months posttransplant and was treated with oral vancomycin 125 mg QID for 14 days. She had recurrences in posttransplant months 3, 7 and 8 that were treated with the same dose and duration of vancomycin. Recurrences of CDI were in the setting of repeated antibiotic administration for UTIs and were confirmed by positive C. difficile polymerase chain reaction (PCR; tcdB gene) testing. Nine months posttransplant, she was treated with a prolonged vancomycin taper of 125 mg QID for 2 weeks, then reduced every 5 days to: 125 mg TID, 125 mg BID, 125 mg daily and finally 125 mg every other day. Ten months posttransplant, she was treated with oral vancomycin and 2 weeks of rifaximin, followed by two additional CDI recurrences that were treated with oral vancomycin 125 mg for 14 days. Nineteen months posttransplant, she had another recurrence in the setting of a resistant Pseudomonas aeruginosa UTI treated simultaneously with a 7-day course of colistin and oral vancomycin for an additional 1 week. She underwent FMT with stool prepared from her daughter via nasojejunal (NJ) Dobhoff tube without complications, and had clinical improvement in her diarrhea. She was readmitted 2 weeks later with altered mental status attributed to CDI recurrence, though had not received any antibiotics after the FMT. She was treated with 4 days of oral vancomycin, and then underwent a second FMT, via colonoscopy, utilizing the same donor. She had no infectious complications after the procedure, but her hospital course was complicated by an ischemic cerebral vascular event. Prior to FMT her urine culture demonstrated P. aeruginosa resistant to all antibiotics tested with the exception of intermediate susceptibility to colistin, amikacin and ceftazidime. She did not receive any antibiotics until 5 months post-FMT, when her urine culture grew pansensitive Klebsiella pneumoniae for which she received a 14-day course of ciprofloxacin. Seven months post-FMT, her urine culture grew P. aeruginosa that was susceptible to colistin and tobramycin, which was not treated. One year after the second FMT, she has had no further recurrences of CDI, and her urine cultures post-FMT demonstrated organisms with significantly decreased drug resistance than prior to FMT. The second patient was a 65-year-old female with a history of bilateral lung transplant for alpha-1-antitrypsin deficiency/ emphysema, maintained on tacrolimus, mycophenolic acid and prednisone. She initially developed CDI 27 months posttransplant, treated with oral metronidazole for 14 days with improvement. She was hospitalized 2 months later with dyspnea related to bronchiolitis obliterans (BOS) and CDI for which she was treated with oral vancomycin 478
125 mg QID for 14 days. Her diarrhea initially improved, but recurred soon after stopping vancomycin. Five months later, she was prescribed a 4-week course of oral vancomycin 125 mg QID that resulted in resolution of her diarrhea. Two months later, she was hospitalized with suspected diverticulitis and started on broad-spectrum antibiotics which led to another recurrence. FMT was discussed; however, she initially declined and was treated with an oral vancomycin taper of 125 mg QID for 3 weeks, then 7 days each of: 125 mg TID, 125 mg BID, 125 mg daily and finally 125 mg every other day with resolution of diarrhea. She was hospitalized 2 months later due to progressive BOS and was treated with high dose steroids and photopheresis. She received no antibiotics except for dapsone prophylaxis. CDI recurred while she was hospitalized, and she was treated again with the same taper as above, but reported recurrence of diarrhea once her vancomycin dose was tapered to less than three times a day. Throughout this time period she had a 26-kg weight loss, and she was unable to tolerate needed photopheresis therapy for her BOS due to refractory diarrhea and dehydration. She underwent FMT with stool prepared from a standard donor via outpatient colonoscopy that was without complication. She had recurrence of diarrhea 3 weeks after initial FMT while hospitalized again for failure to thrive. She underwent a second FMT via NJ Dobhoff tube with stool from a different standard donor which resulted in resolution of her diarrhea. She was transitioned to hospice care 5 days after second FMT given declining forced expiratory volume (FEV1) and CO2 retention consistent with progressive BOS and ultimately died, but remained diarrhea-free at time of transfer to hospice.
FMT Procedure The FMT procedure has been approved at Emory Healthcare by the Medical Practices, Infection Control, Antibiotic Utilization and the Pharmacy and Therapeutics Committees since July 2012. The related donor and the standard donors were screened for the following serologies: hepatitis A IgM antibody, HIV-1 antigen/antibody, RPR, hepatitis-B surface antigen, hepatitis-B core antibody and hepatitis-C antibody. Stool samples from all donors were screened based on published guidelines with a PCR for C. difficile, routine bacterial culture for Campylobacter, Shigella, Salmonella species and ova and parasite exam (11). At our institution, standard donors had additional testing for vancomycinresistant Enterococcus and carbapenemase-producing Enterobacteriaceae. Screening for the Helicobacter pylori stool antigen was added to the protocol prior to the second case. Stool specimens from the donors were processed within 2 h of voiding in the clinical microbiology laboratory. Thirty grams of stool per 30 mL saline was emulsified in 50 mL conical tubes, vortexed for 30 s and filtered. The stool solution was placed in 60 mL syringes and labeled ‘‘FOR ENTERAL USE ONLY.’’ The volume instilled during the first transplant via NJ tube for the renal SOT recipient American Journal of Transplantation 2014; 14: 477–480
Fecal Microbiota Transplantation in Solid Organ Transplant Recipients
was 80 mL; the second FMT via colonoscopy was 250 mL. The lung transplant patient received 325 mL via colonoscopy for the first FMT and 100 mL via NJ for the second FMT. These differences reflect the different routes of administration: for NJ administration, 80–100 mL is instilled; for colonoscopy, 250–300 mL.
Discussion CDI is a significant disease in SOT recipients. These patients are at high risk for acquisition of CDI, morbidity from CDI, and recurrence after initial infection. We present two patients with refractory diarrhea due to multiply recurrent CDI that was incurable using oral vancomycin. These patients consented to FMT and had resolution of diarrhea after repeated FMT. Current treatment guidelines for an initial episode and first relapse of CDI in SOT recipients are the same as the general population (4,10,12). For multiple CDI relapses, vancomycin taper is currently recommended. FMT has been shown to be safe and effective for treatment of refractory/relapsed CDI and preventing further CDI recurrences; however, study into this field has previously excluded immunosuppressed patients (9). Concern has been raised that FMT may pose an infection risk in SOT recipients (4). In these two patients described, there were no infectious complications, though further research with larger numbers of patients is clearly needed. Both patients did have serious adverse events (first patient with cerebral vascular event, the second went to hospice for BOS), but these were considered unrelated to FMT. Of note, both patients in this report had initial improvement, followed by relapsed diarrhea within a couple weeks of the first FMT; however, both ultimately achieved a lasting treatment response after a second FMT procedure. Weingarden et al (13) reported the use of sequential FMT to treat severe antibiotic refractory CDI. A retrospective case series of 66 immunocompromised adults and children was presented at the October 2013 American College of Gastroenterology meeting which included 14 SOT patients, and found an overall 79% success rate with initial FMT (14). SOT recipients likely have more severe alterations in intestinal microbiota, and sequential FMT may be necessary to correct dysbiosis. There are other considerations in these patients in addition to the resolution of diarrhea. The restoration of the microbiota to a homeostatic state allows symptomatic CDI to resolve, and the normal predominance of anaerobic bacteria to return (15). This is likely also the case for FMT as it pertains to multidrug resistant organisms (MDRO) (16), where restoration of a normal microbiome will allow less virulent but drug-resistant organisms to be eradicated. This seemed to have occurred in the urinary tract of the renal transplant American Journal of Transplantation 2014; 14: 477–480
recipient described here, where the MDRO Pseudomonas in her urine was replaced by a sensitive Klebsiella and a less drug-resistant Pseudomonas strain after the second FMT, but this could also be due to less antibiotic pressure during that time. The lung transplant recipient described here had concomitant BOS with CDI that led to her death. There may be a relation between BOS and chronic inflammation triggered by CDI. In one study, all (n ¼ 7) lung transplant recipients who had early CDI (within 90 days of transplant) went on to develop BOS (17). Also it was noted in that study that lung transplant recipients (n ¼ 8) who received treatment for CDI had significant improvement in their FEV1 compared to pretreatment (17). Early intervention with FMT may lead to decreased number of CDI recurrences and thus reduce chronic inflammation that may lead to BOS in the posttransplant setting. Again, this report describes only two patients, and further research into this area is needed. Alterations in the microbiota may also have an impact on alloimmunity, as recently reviewed (18). As the study of the interplay between the microbiome and immune system, and in particular alloimmunity, is still in its infancy, it is unclear how the altered microbiota SOT recipients, and of FMT recipients, affect the graft. In conclusion, FMT in these two SOT recipients was safe and effective for treating multiply recurrent CDI. We recommend the consideration of FMT in SOT recipients with refractory CDI with vigilance for infectious complications. Given the severity of the disruption of the microbiota in immunosuppressed individuals, practitioners should have a low threshold to repeat FMT in these patients if CDI recurs.
Acknowledgments This work was supported by CSK—NIH/NCRR KL2 TR000455 and UL1TR000454.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
References 1. Mylonakis E, Ryan ET, Calderwood SB. Clostridium difficileassociated diarrhea: A review. Arch Intern Med 2001; 161: 525– 533. 2. Bartlett JG, Clinical practice. Antibiotic-associated diarrhea. N Engl J Med 2002; 346: 334–339. 3. Riddle DJ, Dubberke ER. Clostridium difficile infection in solid organ transplant recipients. Curr Opin Organ Transplant 2008; 13: 592–600.
479
Friedman-Moraco et al 4. Dubberke ER, Burdette SD. Clostridium difficile infections in solid organ transplantation. Am J Transplant 2013; 13 (Suppl 4): S42– S49. 5. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998; 338: 1741–1751. 6. Carbone J, Sarmiento E, Palomo J, et al. The potential impact of substitutive therapy with intravenous immunoglobulin on the outcome of heart transplant recipients with infections. Transplant Proc 2007; 39: 2385–2388. 7. Collini PJ, Bauer M, Kuijper E, Dockrell DH. Clostridium difficile infection in HIV-seropositive individuals and transplant recipients. J Infect 2012; 64: 131–147. 8. Pant C, Anderson MP, O’Connor JA, Marshall CM, Deshpande A, Sferra TJ. Association of Clostridium difficile infection with outcomes of hospitalized solid organ transplant recipients: Results from the 2009 Nationwide Inpatient Sample database. Transpl Infect Dis 2012; 14: 540–547. 9. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol 2012; 107: 1079–1087. 10. Mehta AK. Suggested therapy of Clostridium difficile colitis after transplantation. In: Lombard GA, LaPlace SG, Taylor DE, Valentine VG, eds. The AST handbook of transplant infections. Hoboken, NJ: Blackwell Publications, 2011, p. 80. 11. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: Case series involving 18 patients treated with donor stool
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12.
13.
14.
15.
16.
17. 18.
administered via a nasogastric tube. Clin Infect Dis 2003; 36: 580– 585. Kumar D, Humar A, Ebrary, Inc., American Society of Transplantation. Infectious Diseases Community of Practice. The AST handbook of transplant infections. Hoboken, NJ: Blackwell Publications, 2011. Weingarden AR, Hamilton MJ, Sadowsky MJ, Khoruts A. Resolution of severe Clostridium difficile infection following sequential fecal microbiota transplantation. J Clin Gastroenterol 2013; 47: 735–737. Ihunnah C. Fecal microbiota transplantation (FMT) for treatment of Clostridium difficile infection (CDI) in immunocompromised patients. Paper presented at the 2013 ACG Governors Award Recipients for Excellence in Clinical Research; ACG 2013 Annual Scientific Meeting; October 11–16; San Diego, CA. Khoruts A, Dicksved J, Jansson JK, Sadowsky MJ. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol 2010; 44: 354–360. Tosh PK, McDonald LC. Infection control in the multidrug-resistant era: Tending the human microbiome. Clin Infect Dis 2012; 54: 707– 713. Gunderson CC, Gupta MR, Lopez F, et al. Clostridium difficile colitis in lung transplantation. Transpl Infect Dis 2008; 10: 245–251. Alegre ML, Bartman C, Chong AS. Microbes and allogeneic transplantation. Transplantation 2014; 9: 5–11.
American Journal of Transplantation 2014; 14: 477–480
Case Report
C
Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12577
Fecal Microbiota Transplantation for Refractory Clostridium difficile Colitis in Solid Organ Transplant Recipients R. J. Friedman-Moraco, A. K. Mehta, G. M. Lyon and C. S. Kraft* Division of Infectious Diseases, Emory University, Atlanta, GA Corresponding author: Colleen Kraft, [email protected]
Fecal microbiota transplantation (FMT) has been shown to be safe and efficacious in individuals with refractory Clostridium difficile. It has not been widely studied in individuals with immunosuppression due to concerns about infectious complications. We describe two solid organ transplant recipients, one lung and one renal, in this case report that both had resolution of their diarrhea caused by C. difficile after FMT. Both recipients required two FMTs to achieve resolution of their symptoms and neither had infectious complications. Immunosuppressed individuals are at high risk for acquisition of C. difficile and close monitoring for infectious complications after FMT is necessary, but should not preclude its use in patients with refractory disease due to C. difficile. Sequential FMT may be used to achieve cure in these patients with damaged microbiota from antibiotic use and immunosuppression. Keywords: Clostridium difficile, fecal microbiota transplantation, fecal transplant, lung transplant, renal transplant, solid organ transplant Abbreviations: BOS, bronchiolitis obliterans; CDI, Clostridium difficile infection; FEV1, forced expiratory volume; FMT, fecal microbiota transplantation; MDRO, multidrug resistant organism; NJ, nasojejunal; PCR, polymerase chain reaction; SOT, solid organ transplant; UTI, urinary tract infection Received 08 October 2013, revised 07 November 2013 and accepted for publication 11 November 2013
Introduction Clostridium difficile infection (CDI) is the most common cause of infectious healthcare-associated diarrhea (1) with clinical manifestations ranging from asymptomatic coloni-
zation to fulminant colitis (2). The overall incidence of CDI in solid organ transplant (SOT) recipients is higher than that seen in the general hospitalized population; estimated at 1.5–31% depending on organ type compared to a 1.0–2.0% overall incidence in hospitalized patients (3). SOT recipients are at higher risk for CDI for multiple reasons, including frequent antimicrobial use, immune dysregulation and underlying comorbidities. CDI is most common in the first 3 months after SOT due to the level of immunosuppression, healthcare exposures and frequent antibiotics (4). Antibiotic use is an important risk factor in SOT due to the need for antimicrobial prophylaxis and the potential for frequent infectious complications resulting in prolonged courses of antimicrobials (5). Yet, approximately 20% of SOT recipients who develop CDI have no preceding antimicrobial exposure (4), likely related to immune dysfunction in SOT. Impairments of humoral immunity may have the most significant impact on the control of C. difficile (4); in one study, the incidence of CDI in heart transplants decreased after the introduction of immunoglobulin posttransplant (6). Immunosuppressive medications alter the intestinal microbiota further contributing to dysbiosis and C. difficile overgrowth (7). Additionally, SOT recipients with CDI have been shown to have worse outcomes. Fulminant colitis is seen more frequently, with 13.0% in the transplant population versus 8.0% in the general population (3). Pant et al (8) found significant increase in hospital mortality, length of stay, organ complications and colectomy in SOT recipients with CDI. SOT recipients may also have higher rates of recurrent CDI infection. Studies in heart and lung transplant recipients demonstrated that 28.6–33.0% of patients had one or more recurrences, though these were not distinguished from reinfection (7). Given increased incidence of CDI and worsened outcomes in SOT recipients, effective and durable treatment for CDI in SOT recipients is of great importance (4). Fecal microbiota transplantation (FMT) has recently shown to be a safe and effective treatment for recurrent and/or refractory CDI (9), but most case series exclude immunosuppressed patients. In addition, current guidelines for SOT do not include FMT in the treatment algorithm for CDI (4,10). Here, we report on two SOT recipients who received FMT at our institution. 477
Friedman-Moraco et al
Case Report The first patient is a 73-year-old female with a history of deceased donor renal transplantation for hypertensive nephrosclerosis, on tacrolimus, azathioprine and prednisone. Her posttransplant course was complicated by recurrent urinary tract infections (UTIs)/pyelonephritis and recurrent CDI that was moderate in severity. Her initial CDI occurred 2 months posttransplant and was treated with oral vancomycin 125 mg QID for 14 days. She had recurrences in posttransplant months 3, 7 and 8 that were treated with the same dose and duration of vancomycin. Recurrences of CDI were in the setting of repeated antibiotic administration for UTIs and were confirmed by positive C. difficile polymerase chain reaction (PCR; tcdB gene) testing. Nine months posttransplant, she was treated with a prolonged vancomycin taper of 125 mg QID for 2 weeks, then reduced every 5 days to: 125 mg TID, 125 mg BID, 125 mg daily and finally 125 mg every other day. Ten months posttransplant, she was treated with oral vancomycin and 2 weeks of rifaximin, followed by two additional CDI recurrences that were treated with oral vancomycin 125 mg for 14 days. Nineteen months posttransplant, she had another recurrence in the setting of a resistant Pseudomonas aeruginosa UTI treated simultaneously with a 7-day course of colistin and oral vancomycin for an additional 1 week. She underwent FMT with stool prepared from her daughter via nasojejunal (NJ) Dobhoff tube without complications, and had clinical improvement in her diarrhea. She was readmitted 2 weeks later with altered mental status attributed to CDI recurrence, though had not received any antibiotics after the FMT. She was treated with 4 days of oral vancomycin, and then underwent a second FMT, via colonoscopy, utilizing the same donor. She had no infectious complications after the procedure, but her hospital course was complicated by an ischemic cerebral vascular event. Prior to FMT her urine culture demonstrated P. aeruginosa resistant to all antibiotics tested with the exception of intermediate susceptibility to colistin, amikacin and ceftazidime. She did not receive any antibiotics until 5 months post-FMT, when her urine culture grew pansensitive Klebsiella pneumoniae for which she received a 14-day course of ciprofloxacin. Seven months post-FMT, her urine culture grew P. aeruginosa that was susceptible to colistin and tobramycin, which was not treated. One year after the second FMT, she has had no further recurrences of CDI, and her urine cultures post-FMT demonstrated organisms with significantly decreased drug resistance than prior to FMT. The second patient was a 65-year-old female with a history of bilateral lung transplant for alpha-1-antitrypsin deficiency/ emphysema, maintained on tacrolimus, mycophenolic acid and prednisone. She initially developed CDI 27 months posttransplant, treated with oral metronidazole for 14 days with improvement. She was hospitalized 2 months later with dyspnea related to bronchiolitis obliterans (BOS) and CDI for which she was treated with oral vancomycin 478
125 mg QID for 14 days. Her diarrhea initially improved, but recurred soon after stopping vancomycin. Five months later, she was prescribed a 4-week course of oral vancomycin 125 mg QID that resulted in resolution of her diarrhea. Two months later, she was hospitalized with suspected diverticulitis and started on broad-spectrum antibiotics which led to another recurrence. FMT was discussed; however, she initially declined and was treated with an oral vancomycin taper of 125 mg QID for 3 weeks, then 7 days each of: 125 mg TID, 125 mg BID, 125 mg daily and finally 125 mg every other day with resolution of diarrhea. She was hospitalized 2 months later due to progressive BOS and was treated with high dose steroids and photopheresis. She received no antibiotics except for dapsone prophylaxis. CDI recurred while she was hospitalized, and she was treated again with the same taper as above, but reported recurrence of diarrhea once her vancomycin dose was tapered to less than three times a day. Throughout this time period she had a 26-kg weight loss, and she was unable to tolerate needed photopheresis therapy for her BOS due to refractory diarrhea and dehydration. She underwent FMT with stool prepared from a standard donor via outpatient colonoscopy that was without complication. She had recurrence of diarrhea 3 weeks after initial FMT while hospitalized again for failure to thrive. She underwent a second FMT via NJ Dobhoff tube with stool from a different standard donor which resulted in resolution of her diarrhea. She was transitioned to hospice care 5 days after second FMT given declining forced expiratory volume (FEV1) and CO2 retention consistent with progressive BOS and ultimately died, but remained diarrhea-free at time of transfer to hospice.
FMT Procedure The FMT procedure has been approved at Emory Healthcare by the Medical Practices, Infection Control, Antibiotic Utilization and the Pharmacy and Therapeutics Committees since July 2012. The related donor and the standard donors were screened for the following serologies: hepatitis A IgM antibody, HIV-1 antigen/antibody, RPR, hepatitis-B surface antigen, hepatitis-B core antibody and hepatitis-C antibody. Stool samples from all donors were screened based on published guidelines with a PCR for C. difficile, routine bacterial culture for Campylobacter, Shigella, Salmonella species and ova and parasite exam (11). At our institution, standard donors had additional testing for vancomycinresistant Enterococcus and carbapenemase-producing Enterobacteriaceae. Screening for the Helicobacter pylori stool antigen was added to the protocol prior to the second case. Stool specimens from the donors were processed within 2 h of voiding in the clinical microbiology laboratory. Thirty grams of stool per 30 mL saline was emulsified in 50 mL conical tubes, vortexed for 30 s and filtered. The stool solution was placed in 60 mL syringes and labeled ‘‘FOR ENTERAL USE ONLY.’’ The volume instilled during the first transplant via NJ tube for the renal SOT recipient American Journal of Transplantation 2014; 14: 477–480
Fecal Microbiota Transplantation in Solid Organ Transplant Recipients
was 80 mL; the second FMT via colonoscopy was 250 mL. The lung transplant patient received 325 mL via colonoscopy for the first FMT and 100 mL via NJ for the second FMT. These differences reflect the different routes of administration: for NJ administration, 80–100 mL is instilled; for colonoscopy, 250–300 mL.
Discussion CDI is a significant disease in SOT recipients. These patients are at high risk for acquisition of CDI, morbidity from CDI, and recurrence after initial infection. We present two patients with refractory diarrhea due to multiply recurrent CDI that was incurable using oral vancomycin. These patients consented to FMT and had resolution of diarrhea after repeated FMT. Current treatment guidelines for an initial episode and first relapse of CDI in SOT recipients are the same as the general population (4,10,12). For multiple CDI relapses, vancomycin taper is currently recommended. FMT has been shown to be safe and effective for treatment of refractory/relapsed CDI and preventing further CDI recurrences; however, study into this field has previously excluded immunosuppressed patients (9). Concern has been raised that FMT may pose an infection risk in SOT recipients (4). In these two patients described, there were no infectious complications, though further research with larger numbers of patients is clearly needed. Both patients did have serious adverse events (first patient with cerebral vascular event, the second went to hospice for BOS), but these were considered unrelated to FMT. Of note, both patients in this report had initial improvement, followed by relapsed diarrhea within a couple weeks of the first FMT; however, both ultimately achieved a lasting treatment response after a second FMT procedure. Weingarden et al (13) reported the use of sequential FMT to treat severe antibiotic refractory CDI. A retrospective case series of 66 immunocompromised adults and children was presented at the October 2013 American College of Gastroenterology meeting which included 14 SOT patients, and found an overall 79% success rate with initial FMT (14). SOT recipients likely have more severe alterations in intestinal microbiota, and sequential FMT may be necessary to correct dysbiosis. There are other considerations in these patients in addition to the resolution of diarrhea. The restoration of the microbiota to a homeostatic state allows symptomatic CDI to resolve, and the normal predominance of anaerobic bacteria to return (15). This is likely also the case for FMT as it pertains to multidrug resistant organisms (MDRO) (16), where restoration of a normal microbiome will allow less virulent but drug-resistant organisms to be eradicated. This seemed to have occurred in the urinary tract of the renal transplant American Journal of Transplantation 2014; 14: 477–480
recipient described here, where the MDRO Pseudomonas in her urine was replaced by a sensitive Klebsiella and a less drug-resistant Pseudomonas strain after the second FMT, but this could also be due to less antibiotic pressure during that time. The lung transplant recipient described here had concomitant BOS with CDI that led to her death. There may be a relation between BOS and chronic inflammation triggered by CDI. In one study, all (n ¼ 7) lung transplant recipients who had early CDI (within 90 days of transplant) went on to develop BOS (17). Also it was noted in that study that lung transplant recipients (n ¼ 8) who received treatment for CDI had significant improvement in their FEV1 compared to pretreatment (17). Early intervention with FMT may lead to decreased number of CDI recurrences and thus reduce chronic inflammation that may lead to BOS in the posttransplant setting. Again, this report describes only two patients, and further research into this area is needed. Alterations in the microbiota may also have an impact on alloimmunity, as recently reviewed (18). As the study of the interplay between the microbiome and immune system, and in particular alloimmunity, is still in its infancy, it is unclear how the altered microbiota SOT recipients, and of FMT recipients, affect the graft. In conclusion, FMT in these two SOT recipients was safe and effective for treating multiply recurrent CDI. We recommend the consideration of FMT in SOT recipients with refractory CDI with vigilance for infectious complications. Given the severity of the disruption of the microbiota in immunosuppressed individuals, practitioners should have a low threshold to repeat FMT in these patients if CDI recurs.
Acknowledgments This work was supported by CSK—NIH/NCRR KL2 TR000455 and UL1TR000454.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
References 1. Mylonakis E, Ryan ET, Calderwood SB. Clostridium difficileassociated diarrhea: A review. Arch Intern Med 2001; 161: 525– 533. 2. Bartlett JG, Clinical practice. Antibiotic-associated diarrhea. N Engl J Med 2002; 346: 334–339. 3. Riddle DJ, Dubberke ER. Clostridium difficile infection in solid organ transplant recipients. Curr Opin Organ Transplant 2008; 13: 592–600.
479
Friedman-Moraco et al 4. Dubberke ER, Burdette SD. Clostridium difficile infections in solid organ transplantation. Am J Transplant 2013; 13 (Suppl 4): S42– S49. 5. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998; 338: 1741–1751. 6. Carbone J, Sarmiento E, Palomo J, et al. The potential impact of substitutive therapy with intravenous immunoglobulin on the outcome of heart transplant recipients with infections. Transplant Proc 2007; 39: 2385–2388. 7. Collini PJ, Bauer M, Kuijper E, Dockrell DH. Clostridium difficile infection in HIV-seropositive individuals and transplant recipients. J Infect 2012; 64: 131–147. 8. Pant C, Anderson MP, O’Connor JA, Marshall CM, Deshpande A, Sferra TJ. Association of Clostridium difficile infection with outcomes of hospitalized solid organ transplant recipients: Results from the 2009 Nationwide Inpatient Sample database. Transpl Infect Dis 2012; 14: 540–547. 9. Brandt LJ, Aroniadis OC, Mellow M, et al. Long-term follow-up of colonoscopic fecal microbiota transplant for recurrent Clostridium difficile infection. Am J Gastroenterol 2012; 107: 1079–1087. 10. Mehta AK. Suggested therapy of Clostridium difficile colitis after transplantation. In: Lombard GA, LaPlace SG, Taylor DE, Valentine VG, eds. The AST handbook of transplant infections. Hoboken, NJ: Blackwell Publications, 2011, p. 80. 11. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: Case series involving 18 patients treated with donor stool
480
12.
13.
14.
15.
16.
17. 18.
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