ORIGINAL ARTICLE: GASTROENTEROLOGY
Fecal Transplant for Recurrent Clostridium difficile Infection in Children With and Without Inflammatory Bowel Disease
George H. Russell, Jess L. Kaplan, yIlan Youngster, Mariah Baril-Dore, Lili Schindelar, z Elizabeth Hohmann, and Harland S. Winter
ABSTRACT Ten children at our institution received single-infusion fecal microbiome transplant (FMT) using healthy, related screened donor stool to treat recurrent Clostridium difficile infection (RCDI) via nasogastric tube (2 patients) or colonoscopic delivery. Nine of the 10 (90%) children had resolution of their symptoms after a single-infusion FMT with follow-up of 1 month to 4 years. No concerning related adverse events were recognized during short- or longterm follow-up. Three of these children had concomitant inflammatory bowel disease and 2 of these 3 (66%) patients cleared RCDI with no clinical change in their underlying inflammatory bowel disease clinical activity as assessed by Physician’s Global Assessment. All of the patients who had clinical improvement of gastrointestinal symptoms of RCDI while treated with antibiotics had lasting return of baseline health after FMT. Key Words: Crohn disease, fecal microbiome transplant, inflammatory bowel disease, recurrent Clostridium difficile infection, ulcerative colitis
(JPGN 2014;58: 588–592)
A
fter initial Clostridium difficile infection (CDI), up to onethird of adult patients and one-fifth of children will experience a symptomatic recurrent CDI (RCDI) with discontinuation of antibiotic therapy (1,2). Fifty percent to 65% of patients with RCDI experience multiple recurrences (3). Few established evidence-based therapies are available to the practitioner taking care of children with RCDI. Accepted antibiotic therapies such as metronidazole and vancomycin further perturb the gut flora that may protect against colonization with C difficile, resulting in reduced gut microbial diversity, depletion of Bacteroidetes and Firmicutes, and increased prominence of Proteobacteria that may predispose patients to recurrent infection (4). Fecal microbiome transplant (FMT) is emerging as an effective therapy for the treatment of RCDI. Eiseman et al (5) first described FMT as curative in 4 adults with pseudomembranous
Received July 29, 2013; accepted December 13, 2013. From the Division of Pediatric Gastroenterology & Nutrition, MassGeneral Hospital for Children, the yDivision of Pediatric Infectious Diseases, Children’s Hospital Boston, and the zDivision of Infectious Disease, Massachusetts General Hospital, Boston, MA. Address correspondence and reprint requests to George H. Russell, MD, MS, Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, 175 Cambridge St, CPZ-S5, Boston, MA 02114 (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000283
colitis in 1958. Retrospective review of >300 published cases of FMT for the treatment of adults with RCDI shows a success rate of approximately 90% (6–12). A recent prospective doubleblind randomized placebo-controlled trial showed superiority of FMT to vancomycin to treat RCDI with a success rate of 93% without any short-term safety concerns (13). We report our single-center experience using FMT to treat RCDI in children.
METHODS Retrospective review of the medical record was completed to describe our patient population with RCDI treated with singleinfusion FMT from 2009 to 2013 at the MassGeneral Hospital for Children. Eleven patients underwent single-infusion FMT for RCDI. One family whose child received FMT for RCDI and for whom RCDI cleared successfully by this method specifically declined to include their child in any research efforts at the time of his care and is not described fully herein. Three of 10 patients reported had concomitant IBD. All of the patients had at least 3 recurrences of a diarrheal process of at least 2 to 3 daily loose, watery, and/or bloody stools with evidence of C difficile on laboratory testing that resolved or improved with CDI treatment. All of the patients continued antibiotics until 36 to 48 hours before FMT. Donors (who were all parents) completed a donor health screening questionnaire, were screened for sexually transmitted diseases, and had their stools tested for known pathogens based on previously published screening protocols (14). Thirty to forty grams of fresh donor stool was blended with 250 mL of sterile and preservativefree normal saline and filtered with sterile gauze to decrease particulate matter. The mixture was delivered into the stomach via nasogastric tube or into the cecum via colonoscope following previously published protocols (14). When appropriate, IBD disease activity was measured by Physician’s Global Assessment (15). During the time reviewed in this case series, the Partners Healthcare institutional review board had approved FMT for the treatment of RCDI following established protocols with written informed consent. Once the US Food and Drug Administration established the suggestion for an Investigational New Drug (IND) Application for the use of FMT to treat RCDI in children, we complied with those requirements (expanded access IND 15199– 03). Institutional review board approval (2013 P001294) was obtained to complete this retrospective case series.
RESULTS Patient 1 was previously reported as the index case for treating RCDI in a child with FMT (16). Our findings are summarized in Table 1. We have included other supplementary
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5
6
15
12
2 1
5
11
19
2
3
4
5
6 7
8
9
10
F
M
M
M M
F
M
F
M
F
Sex
Cephalexin for MRSA cellulitis
Community acquired
Community acquired
Community acquired Community acquired
Infected during hospitalization Cephalosporin for UTI
Penicillins and cephalosporins for otitis media Cephalexin for oral abscess Cephalexin for skin cellulitis
Precipitating event for initial CDI
UC
Crohn ileocolitis
Chronic constipation IgG subclass deficiency, non-IgE-mediated milk intolerance IBD-U
Visceral hypersensitivity, chronic pain, IBS None
None
None
None
Comorbid diagnoses
M, V, VPT6, V and N
V
V, LGG, SB
M, N, V, VPT6 Routine bimonthly IVIG, M, V, VPT6
M, M, V, VPT6, SB, VSL#3 M, N, V, VPT6, SB
M, V, VPT, V and R, IVIG 3
M, V, V and R, V then M, V then N then R, VPT6, LGG, SB V, VPT8, N, SB
Treatment before FMT
3 EIA, 2þ clinical recurrences afterward
2 EIA, 2þ clinical recurrences afterward
4 PCR
4 EIA positive followed by 2 clinical recurrences afterward 5 PCR 2 EIA and 5þ clinical recurrences afterward
4 PCR
7 EIA and PCR
4 EIA
6 EIA
No. recurrences
Colonoscopy
Colonoscopy
Colonoscopy
Colonoscopy Colonoscopy
Colonoscopy
Colonoscopy
Colonoscopy
NGT
NGT
Route of FMT delivery
Gassiness, bloating, cramping, bloody stool None
Diarrhea, abdominal pain, blood in stool
None Diarrhea, abdominal pain
Abdominal pain, cramping Gassiness
Bloating, cramping, loose stools
None
None
Short-term adverse events
None
None
None
None None
None
Self-limited mucoid stools 2 weeks after FMT None
None
None
Long-term adverse events
Immediate
No resolution of initial symptoms
No resolution of initial symptoms
Immediate 2-3 Days
26
Lost to follow-up after 4 mo 2
12 6
15
At least 2
13
Immediate
No resolution of initial symptoms Immediate
26
53
CDI free follow-up, mo
Immediate
Immediate
Days to resolution of symptoms
Volume 58, Number 5, May 2014
CDI ¼ Clostridium difficile infection; EIA ¼ enzyme immunoassay; FMT ¼ fecal microbiome transplant; IBS ¼ irritable bowel syndrome; IBD-U ¼ IBD-undetermined; IVIG ¼ intravenous immunoglobulin infusion; LGG ¼ Lactobacillus GG; M ¼ metronidazole; MRSA ¼ methicillin-resistant Staphylococcus aureus; N ¼ nitazoxanide; NGT ¼ nasogastric tube; PCR ¼ polymerase chain reaction amplification assay; R ¼ rifamixin; SB ¼ Saccharomyces boulardii; UC ¼ ulcerative colitis; V ¼ vancomycin; VPT6 ¼ vancomycin pulse and taper during 6 weeks; VPT8 ¼ vancomycin pulse and taper during 8 weeks.
2
1
Age, y
Patient
TABLE 1. Summary of patients with recurrent CDI treated with FMT
JPGN Fecal Transplant for Recurrent Clostridium difficile Infection
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Russell et al relevant details for specific patients below only when tabular representation of the clinical data was insufficient.
Patient 4 This 15-year-old boy had underlying diarrhea and chronic abdominal pain that led to a hospitalization for diagnostic laparoscopy, where it was believed he contracted an initial nosocomial CDI assessed by polymerase chain reaction (PCR) DNA amplification assay. His symptoms reportedly improved with antibiotic administration, but his baseline intermittent diarrhea and chronic abdominal pain never changed. He had several more episodes of worsening of baseline diarrhea and pain that was associated with persistent positive PCR testing that improved with antibiotics, but did not improve his baseline symptoms. His baseline chronic abdominal pain did not improve after FMT. Two months after FMT, his local care team at another institution documented the absence of CDI by enzyme immunoassay (EIA) for C difficile toxins, but has not reassessed for the presence of CDI thereafter. He continues to have chronic abdominal pain and diarrhea that are believed to be functional and he is being treated locally by a multidisciplinary pain clinic.
Patient 6 This 5-year-old boy with a history of constipation was considered appropriate for FMT because he had reported improvement of baseline diarrhea when treated with antibiotics for presumed RCDI based on PCR testing. The colonoscopy showed a tortuous and capacious colon consistent with constipation but was otherwise normal. Following FMT, we initiated aggressive treatment for chronic constipation and functional fecal retention and he had resolution of symptoms.
Patient 8 This patient was a 5-year-old boy with failure to thrive and a chronic diarrheal process that was responsive to vancomycin. His diarrheal symptoms began after developing a presumed infectious colitis while travelling in India. He was endoscopically evaluated previously and was believed to have IBD-undetermined but had 3 diarrheal episodes with RCDI detected by PCR assay. On 2 additional occasions, he had bloody and mucoid diarrhea episodes without the documentation of CDI that improved empirically with vancomycin treatment. Near the time of FMT, he had diarrhea and CDI presence was assessed at an outside hospital by PCR assay. At the time of FMT delivery, colonoscopy showed moderately active ileocolitis and a granuloma in the left colon. Although his bloody diarrhea never resolved, he remained EIA toxin free for 4 months following FMT. Within 1 month of FMT, he initiated immunosuppressants for his Crohn disease with better control of symptoms.
Patient 9 This 11-year-old boy with moderately active granulomatous Crohn ileocolitis diagnosed at age 5 years had recurrent IBD symptoms consistently responsive to vancomycin therapy with 2 documented CDIs by EIA. He was unable to taper or discontinue vancomycin without prompt resumption of diarrhea and abdominal pain. He was intolerant to 6-mercaptopurine and was maintained in remission, by parents’ report, by 5-aminosalicylates and vancomycin. At the time of FMT delivery, colonoscopy showed obvious signs of ileocolitis and a stricture in the sigmoid colon. Eight weeks
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after FMT, while hospitalized for the symptoms of Crohn disease, he developed CDI by EIA toxin identification that was successfully treated with vancomycin. He ultimately required systemic corticosteroids as a bridge to methotrexate therapy for Crohn disease.
Patient 10 This patient was a 19-year-old girl with ulcerative colitis treated with adalimumab who developed RCDI after developing a methicillin-resistant Staphylococcus aureus cellulitis requiring multiple antibiotic courses. During vancomycin taper, she developed acute severe colitis requiring hospitalization with CDI that was refractory to vancomycin and nitazoxanide therapy. She had 12 bloody stools and was anemic and hypoalbuminemic. Colonoscopy showed diffuse and severe pancolitis without pseudomembranes. After FMT, diarrhea completely resolved for 5 days and her stools tested negative for the presence of C difficile toxin. Six days after FMT, she redeveloped acute severe colitis symptoms without return of CDI. She was unresponsive to high-dose steroids for 5 days and she underwent colectomy.
DISCUSSION Emerging toxigenic and hypervirulent strains of C difficile (NAP1/B1/027) can cause RCDI in children even in the absence of traditional risk factors (17,18). Culture-independent sequencing techniques have identified at least 17 bacterial families and >500 species that constitute the complicated and dynamic commensal ecosystem that exists in the healthy gut (19–22). This ecosystem is altered in patients with RCDI, and antibiotic therapy for RCDI further perturbs the infected gut microflora’s ecological equilibrium that defines human health and prevents colonization with pathogens such as C difficile (4,23,24). This may help explain why some patients develop RCDI that becomes more difficult to eradicate with continued antibiotic exposure. Almost no prospectively studied therapies exist for children with RCDI. FMT has been shown to be successful in the treatment of RCDI in adults (25). The mechanisms responsible for FMT effect are incompletely understood but possibly include restoration of a more diverse and healthy gut microflora ecosystem that is resistant to continued colonization by C difficile. In general, FMT results in an increase in Bacteroidetes, which are often absent during RCDI, and relative engraftment of healthy donor microflora (26,27). Soluble factor(s) in the donor stool may also play a role in clearance of RCDI. Work by Gustafson et al suggests, for instance, that transplantation of short-chain fatty acids may help maintain the health of the gut (28,29). The transplanted healthy donor microbiome theoretically may out-compete RCDI for nutrients or receptors, upregulate innate immune function, or promote intestinal barrier function resulting in tissue repair. Within this context, we report our single-center case series showing FMT as an effective treatment for eradicating RCDI in children. Our successful cure rate of RCDI by FMT for patients without IBD was 100%. Our overall cure rate of RCDI was 90% when including patients with concomitant IBD. Patient 4 seemed to resolve RCDI, at least for 2 documented months, but his baseline chronic diarrhea and abdominal pain never improved and it is unclear whether C difficile was a colonizer or a pathogen in this case. For the purposes of reporting effectiveness of eradicating CDI, we have included this case as a ‘‘cure.’’ Patient 6 improved significantly after FMT, but this may have been because the bowel lavage preparation treated his constipation aggressively and mitigated withholding symptoms or because FMT treated underlying constipation instead. Indeed, his baseline diarrhea may have represented fecal loading with overflow diarrhea in the first place. www.jpgn.org
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Although patient 6 had several diarrheal illnesses where CDI was detected on PCR testing, C difficile may have only been a colonizer in this case. Interestingly, both of these patients had CDI confirmed by PCR assay, which assesses the presence of C difficile in the host with great sensitivity but does not definitely confirm CDI. The safety profile of this pediatric case series matches that of the retrospective review of the adult experience (6). Short-term adverse effects were determined in the 3-day period following FMT. In those patients receiving FMT by colonoscopy, short-lived symptoms did not differ from typical postcolonoscopy adverse events: bloating, flatulence, cramping, and mild abdominal pain. There were no short-term adverse events in patients receiving FMT via nasogastric tube. At last follow-up, there were no long-term complications believably attributable to FMT. These findings are consistent with those of van Nood et al (13), who prospectively documented diarrhea and cramping on the day of FMT but did not report dissimilar adverse effects experienced by the patients randomized to antibiotic therapy. All of our patients stated they would undergo FMT again if they developed CDI before re-initiating standard antibiotic therapies for CDI. Although the evidence is generally retrospective and lacks placebo-controlled trials, FMT has potential promise for the treatment of IBD (30). Bennet and Brinkman first published the improvement of a patient with refractory ulcerative colitis (UC) symptoms with FMT by large-volume fecal enema, and Borody et al (31) published his uncontrolled experience in successfully treating UC by fecal enema for 5 days. Kunde et al (32) recently published a phase 1 pilot study of FMT in pediatric UC that showed overall safety and clinical improvement in 7 of 9 children with mild-tomoderate UC treated with daily fecal enema for 5 days. Because patients with IBD are at increased risk for CDI, particularly after antibiotic exposure, and have worse outcomes with CDI (33,34), these patients may represent a population that would benefit from FMT. In our experience, FMT effectively cleared CDI in 2 of 3 patients with concomitant IBD; however, in this limited case series, FMT did not seem to meaningfully or sustainably alter the underlying IBD disease activity when measured by Physician’s Global Assessment. Only a single FMT was performed in our subjects, and these results cannot be compared with the work of Borody et al and Kunde et al wherein multiple FMTs were administered, but they support the recently published report by Kump et al that single FMT does not induce remission in patients with IBD (35); however, our limited experience supports the safety of FMT in individuals with IBD. None of the patients with CDI and IBD had sustained change in IBD activity. The patient with IBD-undetermined (patient 8) was diagnosed as having Crohn ileocolitis during the colonoscopy for FMT, and his bloody diarrhea never appreciably changed until his Crohn disease was more effectively managed. The PCR assay documenting presumed RCDI may have suggested colonization with C difficile and not true CDI. After the FMT, the family accepted more aggressive therapy for his underlying IBD. Patient 9 initially cleared CDI but developed a recurrence of CDI 8 weeks after FMT during hospitalization for the symptoms of Crohn disease. We did not consider him ‘‘cured’’ for the purposes of this report. The 19-year-old woman with severe UC (patient 10) cleared RCDI and improved substantially for 5 days before having recurrence of severe colitis in the absence of CDI. She eventually underwent total colectomy and ileoanal pull-through. In regard to patients with IBD and CDI/RCDI, it is also possible that all symptoms represented IBD flare activity with unrelated colonization with C difficile. Improvement of underlying Crohn activity with antibiotic treatment may be unrelated to the presence of C difficile. Similarly, in non-IBD patients in whom www.jpgn.org
Fecal Transplant for Recurrent Clostridium difficile Infection underlying symptoms could be explained by a comorbid condition, colonization with C difficile, rather than actual RCDI, is possible. For all non-IBD patients in whom treatment of conventional CDI returns the patient to a healthy normal baseline but who develop RCDI after antibiotics are stopped, FMT appears to be a safe and reasonable therapeutic option. We observed that in non-IBD patients in whom diarrhea may be caused by a comorbidity and PCR testing may have reflected colonization with C difficile, FMT did not appear effective. In these patients, even when families press the provider to perform FMT because RCDI may explain ongoing diarrhea, realistic anticipatory guidance that RCDI may not be the cause of the ongoing complaints is advised. Regulatory, safety, and ethical concerns remain regarding the future use of FMT. At the time of writing this case series, the US Food and Drug Administration recommends an IND for the use of FMT for RCDI in the pediatric population but does not require it. Clear clinical and diagnostic criteria to differentiate the presence of RCDI from colonization with C difficile need to be established, particularly because anxious families clamor for this treatment modality when their baseline complaints are not always clearly related to RCDI. Information regarding selection of donors, handling of the donor specimens, optimal delivery methods, and long-term follow-up of recipients is lacking. Prospective clinical trials in children are needed to establish short- and long-term efficacy and safety of FMT for RCDI in children. This case series represents a retrospective and anecdotal report of a single-center experience with FMT for RCDI. The lack of a control group and blinding of the practitioners or patients make the likelihood of a placebo response higher. The families of patients seeking care for RCDI with FMT at a major academic medical center are likely not generalizable to a standard pediatric population with RCDI.
CONCLUSIONS FMT of screened healthy donor stool appears to be a safe and effective method to eradicate RCDI in children and young adults, with success rates of at least 90% in patients without concomitant IBD, similar to the cure rates reported in the literature regarding adult patients. Although FMT successfully cleared CDI in 66% of children with concomitant IBD, in this case series it did not appear to alter the IBD disease activity. Prospective studies using standardized FMT protocols will provide the evidence to support safety and efficacy of this novel therapy. Clear clinical and diagnostic criteria are needed to differentiate RCDI from potential colonization with C difficile. Registries should be started to monitor the long-term safety.
REFERENCES 1. Pepin J. Improving the treatment of Clostridium difficile-associated disease: where should we start? Clin Infect Dis 2006;43:553–5. 2. Khanna S, Baddour LM, Huskins WC, et al. The epidemiology of Clostridium difficile infection: a population based study. Clin Infect Dis 2013;56:1401–6. 3. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002;97:1769–75. 4. Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the fecal microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis 2008;197:435–8. 5. Eiseman B, Silen W, Bascom GS, et al. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958;44:854–9. 6. Brandt L, Reddy S. Fecal microbiota transplant for recurrent Clostridium difficile infection. J Clin Gastroenterol 2011;45 (suppl):S159–67. 7. 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;36:580–5.
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Russell et al 8. Borody TJ. ‘‘Flora power’’—fecal bacteria cure chronic C. difficile diarrhea. Am J Gastreonterol 2000;95:3028–9. 9. van Nood E, Speelman P, Kuijper EJ, et al. Struggling with recurrent Clostridium difficile infections: is donor faeces the solution? Euro Surveill 2009;14:ii:19316. 10. Rohlke F, Surawicz CM, Stollman N. Fecal flora reconstitution for recurrent Clostridium difficile infection: results and methodology. J Clin Gastroenterol 2010;44:567–70. 11. Garborg K, Waagsb B, Stallemo A, et al. Results of faecal donor instillation therapy for recurrent Clostridium difficile-associated diarrhea. Scand J Infect Dis 2010;42:857–61. 12. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis 2011;53:994–1002. 13. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013;368: 407–15. 14. Bakken J, Borody T, Brandt L, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011;9:1044–9. 15. Improve Care Now Collaborative. PGA definitions. https://improvecarenow.org/care-providers/pga-definitions. Accessed December 11, 2013. 16. Russell G, Kaplan J, Ferraro M, et al. Fecal bacteriotherapy for relapsing Clostridium difficile infection in a child: a proposed treatment protocol. Pediatrics 2010;126:e239–42. 17. Centers for Disease Control and Prevention. Severe Clostridium difficile-associated disease in populations previously at low risk: four states. MMWR Morb Mortal Wkly Rep 2005;54:1201–5. 18. Zilberberg MD, Tillotson GS, McDonald C. Clostridium difficile infections among hospitalized children, United States, 1997–2006. Emerg Infect Dis 2010;16:604–9. 19. Backhed F, Ley RE, Sonnenburg JL, et al. Host-bacterial mutualism in the human intestine. Science 2005;307:1915–20. 20. Dethlefsen L, Huse S, Sogin ML, et al. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol 2008;6:e280. 21. Yang F, Polk DB. Commensal bacteria in the gut: learning who our friends are. Curr Opin Gastoenterol 2004;20:565–71.
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22. Hopkins MJ, Macfarlane GT. Changes in predominant bacterial populations in human feces with age and with Clostridium difficile infection. J Med Microbiol 2002;51:448–54. 23. Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 2009;7:526–36. 24. Preidis GA, Versalovic J. Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era. Gastroenterology 2009;136:2015–31. 25. Kassam Z, Lee CH, Yuan Y, et al. Fecal microbiota transplant for Clostridium difficile infection: systemic review and meta-analysis. Am J Gastroenterol 2013;108:500–8. 26. Grehan MJ, Borody TJ, Leis SM, et al. Durable alteration of the colonic microbiota by the administration of donor fecal flora. J Clin Gastroenterol 2010;44:551–61. 27. Khoruts A, Sadowsky MJ. Therapeutic transplantation of the distal gut microbiotia. Mucosal Immunol 2011;4:4–7. 28. Gustafsson A, Lund-Tonnesen S, Berstad A, et al. Fecal short chain fatty acids in patients with antibiotic-associated diarrhea, before and after fecal enema treatment. Scand J Gastroenterol 1998;33:721–7. 29. Gustafsson A, Berstad A, Lund-Tonnesen S, et al. The effect of fecal enema on five microflora-associated characteristics in patients with antibiotics associated diarrhea. Scand J Gastroenterol 1999;34:580–6. 30. Anderson JL, Edny RJ, Whelan K. Systematic review: faecal microbiota transplant in the management of inflammatory bowel disease. Aliment Pharmacol Ther 2012;36:503–16. 31. Borody TJ, Warren EF, Leis S, et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol 2003;37:42–7. 32. Kunde S, Pham A, Bonczyck S, et al. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr 2013;56:597–601. 33. Reddy SS, Brandt LJ. Clostridium difficile infection and inflammatory bowel disease. J Clin Gastroenterol 2013;47:666–71. 34. Mir SA, Kellermayer R. Clostridium difficile infection in newly diagnosed pediatric inflammatory bowel disease in the mid-southern United States. J Pediatr Gastroenterol Nutr 2013;57:487–8. 35. 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;19:2155–65.
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Fecal Transplant for Recurrent Clostridium difficile Infection in Children With and Without Inflammatory Bowel Disease
George H. Russell, Jess L. Kaplan, yIlan Youngster, Mariah Baril-Dore, Lili Schindelar, z Elizabeth Hohmann, and Harland S. Winter
ABSTRACT Ten children at our institution received single-infusion fecal microbiome transplant (FMT) using healthy, related screened donor stool to treat recurrent Clostridium difficile infection (RCDI) via nasogastric tube (2 patients) or colonoscopic delivery. Nine of the 10 (90%) children had resolution of their symptoms after a single-infusion FMT with follow-up of 1 month to 4 years. No concerning related adverse events were recognized during short- or longterm follow-up. Three of these children had concomitant inflammatory bowel disease and 2 of these 3 (66%) patients cleared RCDI with no clinical change in their underlying inflammatory bowel disease clinical activity as assessed by Physician’s Global Assessment. All of the patients who had clinical improvement of gastrointestinal symptoms of RCDI while treated with antibiotics had lasting return of baseline health after FMT. Key Words: Crohn disease, fecal microbiome transplant, inflammatory bowel disease, recurrent Clostridium difficile infection, ulcerative colitis
(JPGN 2014;58: 588–592)
A
fter initial Clostridium difficile infection (CDI), up to onethird of adult patients and one-fifth of children will experience a symptomatic recurrent CDI (RCDI) with discontinuation of antibiotic therapy (1,2). Fifty percent to 65% of patients with RCDI experience multiple recurrences (3). Few established evidence-based therapies are available to the practitioner taking care of children with RCDI. Accepted antibiotic therapies such as metronidazole and vancomycin further perturb the gut flora that may protect against colonization with C difficile, resulting in reduced gut microbial diversity, depletion of Bacteroidetes and Firmicutes, and increased prominence of Proteobacteria that may predispose patients to recurrent infection (4). Fecal microbiome transplant (FMT) is emerging as an effective therapy for the treatment of RCDI. Eiseman et al (5) first described FMT as curative in 4 adults with pseudomembranous
Received July 29, 2013; accepted December 13, 2013. From the Division of Pediatric Gastroenterology & Nutrition, MassGeneral Hospital for Children, the yDivision of Pediatric Infectious Diseases, Children’s Hospital Boston, and the zDivision of Infectious Disease, Massachusetts General Hospital, Boston, MA. Address correspondence and reprint requests to George H. Russell, MD, MS, Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, 175 Cambridge St, CPZ-S5, Boston, MA 02114 (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000283
colitis in 1958. Retrospective review of >300 published cases of FMT for the treatment of adults with RCDI shows a success rate of approximately 90% (6–12). A recent prospective doubleblind randomized placebo-controlled trial showed superiority of FMT to vancomycin to treat RCDI with a success rate of 93% without any short-term safety concerns (13). We report our single-center experience using FMT to treat RCDI in children.
METHODS Retrospective review of the medical record was completed to describe our patient population with RCDI treated with singleinfusion FMT from 2009 to 2013 at the MassGeneral Hospital for Children. Eleven patients underwent single-infusion FMT for RCDI. One family whose child received FMT for RCDI and for whom RCDI cleared successfully by this method specifically declined to include their child in any research efforts at the time of his care and is not described fully herein. Three of 10 patients reported had concomitant IBD. All of the patients had at least 3 recurrences of a diarrheal process of at least 2 to 3 daily loose, watery, and/or bloody stools with evidence of C difficile on laboratory testing that resolved or improved with CDI treatment. All of the patients continued antibiotics until 36 to 48 hours before FMT. Donors (who were all parents) completed a donor health screening questionnaire, were screened for sexually transmitted diseases, and had their stools tested for known pathogens based on previously published screening protocols (14). Thirty to forty grams of fresh donor stool was blended with 250 mL of sterile and preservativefree normal saline and filtered with sterile gauze to decrease particulate matter. The mixture was delivered into the stomach via nasogastric tube or into the cecum via colonoscope following previously published protocols (14). When appropriate, IBD disease activity was measured by Physician’s Global Assessment (15). During the time reviewed in this case series, the Partners Healthcare institutional review board had approved FMT for the treatment of RCDI following established protocols with written informed consent. Once the US Food and Drug Administration established the suggestion for an Investigational New Drug (IND) Application for the use of FMT to treat RCDI in children, we complied with those requirements (expanded access IND 15199– 03). Institutional review board approval (2013 P001294) was obtained to complete this retrospective case series.
RESULTS Patient 1 was previously reported as the index case for treating RCDI in a child with FMT (16). Our findings are summarized in Table 1. We have included other supplementary
588 JPGN Volume 58, Number 5, May 2014 Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
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5
6
15
12
2 1
5
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3
4
5
6 7
8
9
10
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M
M M
F
M
F
M
F
Sex
Cephalexin for MRSA cellulitis
Community acquired
Community acquired
Community acquired Community acquired
Infected during hospitalization Cephalosporin for UTI
Penicillins and cephalosporins for otitis media Cephalexin for oral abscess Cephalexin for skin cellulitis
Precipitating event for initial CDI
UC
Crohn ileocolitis
Chronic constipation IgG subclass deficiency, non-IgE-mediated milk intolerance IBD-U
Visceral hypersensitivity, chronic pain, IBS None
None
None
None
Comorbid diagnoses
M, V, VPT6, V and N
V
V, LGG, SB
M, N, V, VPT6 Routine bimonthly IVIG, M, V, VPT6
M, M, V, VPT6, SB, VSL#3 M, N, V, VPT6, SB
M, V, VPT, V and R, IVIG 3
M, V, V and R, V then M, V then N then R, VPT6, LGG, SB V, VPT8, N, SB
Treatment before FMT
3 EIA, 2þ clinical recurrences afterward
2 EIA, 2þ clinical recurrences afterward
4 PCR
4 EIA positive followed by 2 clinical recurrences afterward 5 PCR 2 EIA and 5þ clinical recurrences afterward
4 PCR
7 EIA and PCR
4 EIA
6 EIA
No. recurrences
Colonoscopy
Colonoscopy
Colonoscopy
Colonoscopy Colonoscopy
Colonoscopy
Colonoscopy
Colonoscopy
NGT
NGT
Route of FMT delivery
Gassiness, bloating, cramping, bloody stool None
Diarrhea, abdominal pain, blood in stool
None Diarrhea, abdominal pain
Abdominal pain, cramping Gassiness
Bloating, cramping, loose stools
None
None
Short-term adverse events
None
None
None
None None
None
Self-limited mucoid stools 2 weeks after FMT None
None
None
Long-term adverse events
Immediate
No resolution of initial symptoms
No resolution of initial symptoms
Immediate 2-3 Days
26
Lost to follow-up after 4 mo 2
12 6
15
At least 2
13
Immediate
No resolution of initial symptoms Immediate
26
53
CDI free follow-up, mo
Immediate
Immediate
Days to resolution of symptoms
Volume 58, Number 5, May 2014
CDI ¼ Clostridium difficile infection; EIA ¼ enzyme immunoassay; FMT ¼ fecal microbiome transplant; IBS ¼ irritable bowel syndrome; IBD-U ¼ IBD-undetermined; IVIG ¼ intravenous immunoglobulin infusion; LGG ¼ Lactobacillus GG; M ¼ metronidazole; MRSA ¼ methicillin-resistant Staphylococcus aureus; N ¼ nitazoxanide; NGT ¼ nasogastric tube; PCR ¼ polymerase chain reaction amplification assay; R ¼ rifamixin; SB ¼ Saccharomyces boulardii; UC ¼ ulcerative colitis; V ¼ vancomycin; VPT6 ¼ vancomycin pulse and taper during 6 weeks; VPT8 ¼ vancomycin pulse and taper during 8 weeks.
2
1
Age, y
Patient
TABLE 1. Summary of patients with recurrent CDI treated with FMT
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Russell et al relevant details for specific patients below only when tabular representation of the clinical data was insufficient.
Patient 4 This 15-year-old boy had underlying diarrhea and chronic abdominal pain that led to a hospitalization for diagnostic laparoscopy, where it was believed he contracted an initial nosocomial CDI assessed by polymerase chain reaction (PCR) DNA amplification assay. His symptoms reportedly improved with antibiotic administration, but his baseline intermittent diarrhea and chronic abdominal pain never changed. He had several more episodes of worsening of baseline diarrhea and pain that was associated with persistent positive PCR testing that improved with antibiotics, but did not improve his baseline symptoms. His baseline chronic abdominal pain did not improve after FMT. Two months after FMT, his local care team at another institution documented the absence of CDI by enzyme immunoassay (EIA) for C difficile toxins, but has not reassessed for the presence of CDI thereafter. He continues to have chronic abdominal pain and diarrhea that are believed to be functional and he is being treated locally by a multidisciplinary pain clinic.
Patient 6 This 5-year-old boy with a history of constipation was considered appropriate for FMT because he had reported improvement of baseline diarrhea when treated with antibiotics for presumed RCDI based on PCR testing. The colonoscopy showed a tortuous and capacious colon consistent with constipation but was otherwise normal. Following FMT, we initiated aggressive treatment for chronic constipation and functional fecal retention and he had resolution of symptoms.
Patient 8 This patient was a 5-year-old boy with failure to thrive and a chronic diarrheal process that was responsive to vancomycin. His diarrheal symptoms began after developing a presumed infectious colitis while travelling in India. He was endoscopically evaluated previously and was believed to have IBD-undetermined but had 3 diarrheal episodes with RCDI detected by PCR assay. On 2 additional occasions, he had bloody and mucoid diarrhea episodes without the documentation of CDI that improved empirically with vancomycin treatment. Near the time of FMT, he had diarrhea and CDI presence was assessed at an outside hospital by PCR assay. At the time of FMT delivery, colonoscopy showed moderately active ileocolitis and a granuloma in the left colon. Although his bloody diarrhea never resolved, he remained EIA toxin free for 4 months following FMT. Within 1 month of FMT, he initiated immunosuppressants for his Crohn disease with better control of symptoms.
Patient 9 This 11-year-old boy with moderately active granulomatous Crohn ileocolitis diagnosed at age 5 years had recurrent IBD symptoms consistently responsive to vancomycin therapy with 2 documented CDIs by EIA. He was unable to taper or discontinue vancomycin without prompt resumption of diarrhea and abdominal pain. He was intolerant to 6-mercaptopurine and was maintained in remission, by parents’ report, by 5-aminosalicylates and vancomycin. At the time of FMT delivery, colonoscopy showed obvious signs of ileocolitis and a stricture in the sigmoid colon. Eight weeks
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after FMT, while hospitalized for the symptoms of Crohn disease, he developed CDI by EIA toxin identification that was successfully treated with vancomycin. He ultimately required systemic corticosteroids as a bridge to methotrexate therapy for Crohn disease.
Patient 10 This patient was a 19-year-old girl with ulcerative colitis treated with adalimumab who developed RCDI after developing a methicillin-resistant Staphylococcus aureus cellulitis requiring multiple antibiotic courses. During vancomycin taper, she developed acute severe colitis requiring hospitalization with CDI that was refractory to vancomycin and nitazoxanide therapy. She had 12 bloody stools and was anemic and hypoalbuminemic. Colonoscopy showed diffuse and severe pancolitis without pseudomembranes. After FMT, diarrhea completely resolved for 5 days and her stools tested negative for the presence of C difficile toxin. Six days after FMT, she redeveloped acute severe colitis symptoms without return of CDI. She was unresponsive to high-dose steroids for 5 days and she underwent colectomy.
DISCUSSION Emerging toxigenic and hypervirulent strains of C difficile (NAP1/B1/027) can cause RCDI in children even in the absence of traditional risk factors (17,18). Culture-independent sequencing techniques have identified at least 17 bacterial families and >500 species that constitute the complicated and dynamic commensal ecosystem that exists in the healthy gut (19–22). This ecosystem is altered in patients with RCDI, and antibiotic therapy for RCDI further perturbs the infected gut microflora’s ecological equilibrium that defines human health and prevents colonization with pathogens such as C difficile (4,23,24). This may help explain why some patients develop RCDI that becomes more difficult to eradicate with continued antibiotic exposure. Almost no prospectively studied therapies exist for children with RCDI. FMT has been shown to be successful in the treatment of RCDI in adults (25). The mechanisms responsible for FMT effect are incompletely understood but possibly include restoration of a more diverse and healthy gut microflora ecosystem that is resistant to continued colonization by C difficile. In general, FMT results in an increase in Bacteroidetes, which are often absent during RCDI, and relative engraftment of healthy donor microflora (26,27). Soluble factor(s) in the donor stool may also play a role in clearance of RCDI. Work by Gustafson et al suggests, for instance, that transplantation of short-chain fatty acids may help maintain the health of the gut (28,29). The transplanted healthy donor microbiome theoretically may out-compete RCDI for nutrients or receptors, upregulate innate immune function, or promote intestinal barrier function resulting in tissue repair. Within this context, we report our single-center case series showing FMT as an effective treatment for eradicating RCDI in children. Our successful cure rate of RCDI by FMT for patients without IBD was 100%. Our overall cure rate of RCDI was 90% when including patients with concomitant IBD. Patient 4 seemed to resolve RCDI, at least for 2 documented months, but his baseline chronic diarrhea and abdominal pain never improved and it is unclear whether C difficile was a colonizer or a pathogen in this case. For the purposes of reporting effectiveness of eradicating CDI, we have included this case as a ‘‘cure.’’ Patient 6 improved significantly after FMT, but this may have been because the bowel lavage preparation treated his constipation aggressively and mitigated withholding symptoms or because FMT treated underlying constipation instead. Indeed, his baseline diarrhea may have represented fecal loading with overflow diarrhea in the first place. www.jpgn.org
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Although patient 6 had several diarrheal illnesses where CDI was detected on PCR testing, C difficile may have only been a colonizer in this case. Interestingly, both of these patients had CDI confirmed by PCR assay, which assesses the presence of C difficile in the host with great sensitivity but does not definitely confirm CDI. The safety profile of this pediatric case series matches that of the retrospective review of the adult experience (6). Short-term adverse effects were determined in the 3-day period following FMT. In those patients receiving FMT by colonoscopy, short-lived symptoms did not differ from typical postcolonoscopy adverse events: bloating, flatulence, cramping, and mild abdominal pain. There were no short-term adverse events in patients receiving FMT via nasogastric tube. At last follow-up, there were no long-term complications believably attributable to FMT. These findings are consistent with those of van Nood et al (13), who prospectively documented diarrhea and cramping on the day of FMT but did not report dissimilar adverse effects experienced by the patients randomized to antibiotic therapy. All of our patients stated they would undergo FMT again if they developed CDI before re-initiating standard antibiotic therapies for CDI. Although the evidence is generally retrospective and lacks placebo-controlled trials, FMT has potential promise for the treatment of IBD (30). Bennet and Brinkman first published the improvement of a patient with refractory ulcerative colitis (UC) symptoms with FMT by large-volume fecal enema, and Borody et al (31) published his uncontrolled experience in successfully treating UC by fecal enema for 5 days. Kunde et al (32) recently published a phase 1 pilot study of FMT in pediatric UC that showed overall safety and clinical improvement in 7 of 9 children with mild-tomoderate UC treated with daily fecal enema for 5 days. Because patients with IBD are at increased risk for CDI, particularly after antibiotic exposure, and have worse outcomes with CDI (33,34), these patients may represent a population that would benefit from FMT. In our experience, FMT effectively cleared CDI in 2 of 3 patients with concomitant IBD; however, in this limited case series, FMT did not seem to meaningfully or sustainably alter the underlying IBD disease activity when measured by Physician’s Global Assessment. Only a single FMT was performed in our subjects, and these results cannot be compared with the work of Borody et al and Kunde et al wherein multiple FMTs were administered, but they support the recently published report by Kump et al that single FMT does not induce remission in patients with IBD (35); however, our limited experience supports the safety of FMT in individuals with IBD. None of the patients with CDI and IBD had sustained change in IBD activity. The patient with IBD-undetermined (patient 8) was diagnosed as having Crohn ileocolitis during the colonoscopy for FMT, and his bloody diarrhea never appreciably changed until his Crohn disease was more effectively managed. The PCR assay documenting presumed RCDI may have suggested colonization with C difficile and not true CDI. After the FMT, the family accepted more aggressive therapy for his underlying IBD. Patient 9 initially cleared CDI but developed a recurrence of CDI 8 weeks after FMT during hospitalization for the symptoms of Crohn disease. We did not consider him ‘‘cured’’ for the purposes of this report. The 19-year-old woman with severe UC (patient 10) cleared RCDI and improved substantially for 5 days before having recurrence of severe colitis in the absence of CDI. She eventually underwent total colectomy and ileoanal pull-through. In regard to patients with IBD and CDI/RCDI, it is also possible that all symptoms represented IBD flare activity with unrelated colonization with C difficile. Improvement of underlying Crohn activity with antibiotic treatment may be unrelated to the presence of C difficile. Similarly, in non-IBD patients in whom www.jpgn.org
Fecal Transplant for Recurrent Clostridium difficile Infection underlying symptoms could be explained by a comorbid condition, colonization with C difficile, rather than actual RCDI, is possible. For all non-IBD patients in whom treatment of conventional CDI returns the patient to a healthy normal baseline but who develop RCDI after antibiotics are stopped, FMT appears to be a safe and reasonable therapeutic option. We observed that in non-IBD patients in whom diarrhea may be caused by a comorbidity and PCR testing may have reflected colonization with C difficile, FMT did not appear effective. In these patients, even when families press the provider to perform FMT because RCDI may explain ongoing diarrhea, realistic anticipatory guidance that RCDI may not be the cause of the ongoing complaints is advised. Regulatory, safety, and ethical concerns remain regarding the future use of FMT. At the time of writing this case series, the US Food and Drug Administration recommends an IND for the use of FMT for RCDI in the pediatric population but does not require it. Clear clinical and diagnostic criteria to differentiate the presence of RCDI from colonization with C difficile need to be established, particularly because anxious families clamor for this treatment modality when their baseline complaints are not always clearly related to RCDI. Information regarding selection of donors, handling of the donor specimens, optimal delivery methods, and long-term follow-up of recipients is lacking. Prospective clinical trials in children are needed to establish short- and long-term efficacy and safety of FMT for RCDI in children. This case series represents a retrospective and anecdotal report of a single-center experience with FMT for RCDI. The lack of a control group and blinding of the practitioners or patients make the likelihood of a placebo response higher. The families of patients seeking care for RCDI with FMT at a major academic medical center are likely not generalizable to a standard pediatric population with RCDI.
CONCLUSIONS FMT of screened healthy donor stool appears to be a safe and effective method to eradicate RCDI in children and young adults, with success rates of at least 90% in patients without concomitant IBD, similar to the cure rates reported in the literature regarding adult patients. Although FMT successfully cleared CDI in 66% of children with concomitant IBD, in this case series it did not appear to alter the IBD disease activity. Prospective studies using standardized FMT protocols will provide the evidence to support safety and efficacy of this novel therapy. Clear clinical and diagnostic criteria are needed to differentiate RCDI from potential colonization with C difficile. Registries should be started to monitor the long-term safety.
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22. Hopkins MJ, Macfarlane GT. Changes in predominant bacterial populations in human feces with age and with Clostridium difficile infection. J Med Microbiol 2002;51:448–54. 23. Rupnik M, Wilcox MH, Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 2009;7:526–36. 24. Preidis GA, Versalovic J. Targeting the human microbiome with antibiotics, probiotics, and prebiotics: gastroenterology enters the metagenomics era. Gastroenterology 2009;136:2015–31. 25. Kassam Z, Lee CH, Yuan Y, et al. Fecal microbiota transplant for Clostridium difficile infection: systemic review and meta-analysis. Am J Gastroenterol 2013;108:500–8. 26. Grehan MJ, Borody TJ, Leis SM, et al. Durable alteration of the colonic microbiota by the administration of donor fecal flora. J Clin Gastroenterol 2010;44:551–61. 27. Khoruts A, Sadowsky MJ. Therapeutic transplantation of the distal gut microbiotia. Mucosal Immunol 2011;4:4–7. 28. Gustafsson A, Lund-Tonnesen S, Berstad A, et al. Fecal short chain fatty acids in patients with antibiotic-associated diarrhea, before and after fecal enema treatment. Scand J Gastroenterol 1998;33:721–7. 29. Gustafsson A, Berstad A, Lund-Tonnesen S, et al. The effect of fecal enema on five microflora-associated characteristics in patients with antibiotics associated diarrhea. Scand J Gastroenterol 1999;34:580–6. 30. Anderson JL, Edny RJ, Whelan K. Systematic review: faecal microbiota transplant in the management of inflammatory bowel disease. Aliment Pharmacol Ther 2012;36:503–16. 31. Borody TJ, Warren EF, Leis S, et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol 2003;37:42–7. 32. Kunde S, Pham A, Bonczyck S, et al. Safety, tolerability, and clinical response after fecal transplantation in children and young adults with ulcerative colitis. J Pediatr Gastroenterol Nutr 2013;56:597–601. 33. Reddy SS, Brandt LJ. Clostridium difficile infection and inflammatory bowel disease. J Clin Gastroenterol 2013;47:666–71. 34. Mir SA, Kellermayer R. Clostridium difficile infection in newly diagnosed pediatric inflammatory bowel disease in the mid-southern United States. J Pediatr Gastroenterol Nutr 2013;57:487–8. 35. 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;19:2155–65.
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