- Email: [email protected]
Response to Drs. Famularo et al.
AJG – July, 2001
4. Schwan A, Sjolin S, Trottestam U, et al. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of homologous feces. Lancet 1983;2(8354):845. 5. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989;1(8648):1156 – 60. 6. Gustafsson A, Lund-Tonnesen A, Berstad A, et al. Faecal short-chain fatty acids in patients with antibiotic-associated diarrhoea, before and after faecal enema treatment. Scand J Gastroenterol 1998;33:721–7. 7. Borody TJ. “Flora power”—fecal bacteria cure chronic C. difficile diarrhea. Am J Gastroenterol 2000;95:3028 –9 (editorial). 8. Banerjee S, Lamont JT. Non-antibiotic therapy for Clostridium difficile infection. Curr Opin Infect Dis 2000;13: 215–9. 9. Campieri M, Gionchetti P. Probiotics in inflammatory bowel disease: New insight to the pathogenesis of the disease or a possible therapeutic alternative? Gastroenterology 1999;116: 1246 –50. 10. Venturi A, Gionchetti P, Rizzello F, et al. Impact on the composition of the faecal flora by a new probiotic preparation: Preliminary data on maintenance treatment of patients with ulcerative colitis. Aliment Pharmacol Ther 1999;13:1103– 8. 11. Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: A double-blind, placebo-controlled trial. Gastroenterology 2000; 119:305–9. 12. Gionchetti P, Rizzello F, Cifone G, et al. In-vivo effect of a highly concentrated probiotic on IL-10 pelvic pouch tissue levels. Gastroenterology 1999;116:A723 (abstract). 13. Famularo G, De Simone C, Gionchetti P, et al. The role of digestive microflora and probiotics in inflammatory bowel disease. Microb Ecol Health Dis 2000;2(suppl 2):138 – 45. Reprint requests and correspondence: Giuseppe Famularo, Department of Medical Sciences, Ospedale San Camillo, Circonvallazione Gianicolense, 00152 Rome, Italy. Received Dec. 26, 2000; accepted Mar. 5, 2001.
Response to Drs. Famularo et al. TO THE EDITOR: We thank Famularo et al. for their well written and erudite letter and are glad that our case study generated some hypotheses. We agree that the fecal flora of each individual are unique and also that fecal bacteriotherapy (because of this reason) may succeed in some individuals, as it did in our patient, and fail in others. It would be preposterously difficult, however, as suggested by the authors, to determine beforehand the bacterial composition of the fecal enema to be used. It has been said it would take one laboratory technician a lifetime to characterize fully the entire bacterial population of feces. Hyperbole? Perhaps, but the point is made. We did not, as stated by Famularo et al., suggest that fecal enemas are “better” than probiotics for the treatment of Clostridium difficile colitis. Indeed, the future in C. difficile treatment belongs to probiotics, and we look forward to “dissection” of the properties of organisms we administer. Since our previous report we have successfully treated
Letters to the Editor
2263
another patient with a 10-month history of recurrent C. difficile infection resistant to conventional therapies. The patient has been asymptomatic for 5 months with negative C. difficile toxin assays after receiving one fecal instillation donated by her husband. Lawrence J. Brandt, M.D. Seth E. Persky, M.D. Division of Gastroenterology Montefiore Medical Center Bronx, New York Reprint requests and correspondence: Lawrence J. Brandt, M.D., Division of Gastroenterology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467. Received Apr. 5, 2001; accepted Apr. 5, 2001.
Response to Drs. Famularo et al. TO THE EDITOR: Persky and Brandt (1) may have generated hypotheses— one reason case reports are published— but did not set out to prove anything, as asserted by Famularo et al. Rather, they alerted us to a mechanism of action of fecal flora that now demands further study to answer the many questions this case report generated. In their letter the authors raise the issue of “fecal heterogeneity” and then state that fecal enemas from different individuals cannot be standardized. No one will disagree with this view, but similarly, it has long been known that blood transfusion cannot be standardized, as different blood groups occur—yet, generally blood transfusions give the same result, and this seems to hold true for fecal enemas. Unlike the authors’ unfounded claims, published reports suggest that feces from subjects A, B, and C are indeed likely to prove effective against Clostridium difficile (2). This is probably because feces possess antibiotic activity, a property that can be abolished by heat treatment (3). Furthermore, rather than failing “in a substantial proportion of a statistically significant sample of patients” or showing a “marginal effectiveness” in C. difficile colitis, the published results are totally opposite. Famularo et al. attempt to support their statement by quoting Bowden et al. (4), Schwan et al. (5), Tvede and Rask-Madsen (6), and Gustafsson et al. (7). Here, the authors need to be taken to task, because upon rereading these papers it is clear that results of fecal bacteriotherapy quoted in these articles are anything but “marginal.” Bowden et al. (4) state in their abstract that “the patients responded dramatically.” In pseudomembranous colitis at the time of Bowden’s series the death rate was around 74% (8). Meanwhile, 13 of 16 patients in Bowden’s series were cured very rapidly, and the three who died may have been cured had the treatment not been delayed. In fact, two of these three did not have a pseudomembrane at death, and one had involvement of the small bowel where a fecal enema did not reach. Schwan and
2264
Letters to the Editor
colleagues’ (5) patient recovered completely and was also cured of an accompanying irritable bowel syndrome. Gustafsson et al. (7) state that in 31 patients “clinically, most enema-treated patients recovered within days and had no relapses within 18 months.” Tvede and Rask-Madsen (6) cured one of two patients, albeit using two low volume fecal enemas. The true situation is that far from having a “marginal” effectiveness, fecal bacteriotherapy is overwhelmingly successful. Famularo et al. next suggest that bacterial composition of the fecal enema should have been reported. Unfortunately, reliable methods for obtaining such a composition are not generally available, and such a report would have contributed little to the case report. More to the point, the donor stools were found to be free of pathogens, and after all, the treated patient did remain well for ⱖ5 yr after the therapy. Though the potential for transmitting pathogenic organisms to the recipient does exist, if the donor is a spouse or a close relative with negative stool tests the risk has been minimized. Indeed, if a prospective donor has been a healthy person with negative stool tests and had this “natural probiotic” within his or her bowel for many years, this in itself suggests safety. Because fecal bacteriotherapy is not being promoted for widespread use but as a therapy of last resort, the fact remains that risk of transmission of infection is negligible, with no reported transmitted infections to date (2). The article by Persky and Brandt (1) and the accompanying editorial (2) are in no way misleading. Neither of the articles suggests that fecal bacteriotherapy has been demonstrated to be better than probiotics for treatment of intestinal diseases. The converse, however, is also true. It is also an incontrovertible fact that fecal bacteriotherapy utilizes the “ultimate probiotic,” which can never be copied by use of cultured bacteria that ultimately originate from human feces. Some probiotics, especially Lactobacillus GG, have been more effective in trials than placebos but have never been trialed against fecal bacteriotherapy in chronic relapsing C. difficile diarrhea or colitis. Until such a trial is carried out, the Persky and Brandt article and accompanying editorial stand. There is growing interest and research in the use of single and mixed probiotics in intestinal diseases. These at best copy the fecal flora but have not been shown to implant long term. Ideally, we all would like to come up with probiotics for gut disorders, and our center has an interest in the development of this technology (9). It appears, therefore, that our research efforts are similar to those of Famularo et al. We would all dearly like to dissect out the metabolic, functional, and enzymatic properties of various bacteria and have a product that could reproduce the power of fecal infusions. However, as with blood transfusions and bone marrow transplants, we still have not dissected out their components to create artificial blood and artificial bone
AJG – Vol. 96, No. 7, 2001
marrow, and such dreams with probiotics are yet a little way off. Thomas J. Borody, M.D., F.R.A.C.P., F.A.C.G. Centre for Digestive Diseases Sydney, Australia
REFERENCES 1. Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile–associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol 2000;95: 3283–5. 2. Borody TJ. “Flora power”—fecal bacteria cure chronic C. difficile diarrhea. Am J Gastroenterol 2000;95:3028 –9 (editorial). 3. Percival AK. Incidence and mechanisms of transfection of R-factors in bacteria. Melbourne: The Alfred Hospital, 1975 (thesis). 4. Bowden TA, Mansberger AR, Lykins LE. Pseumoembranous enterocolitis—mechanism for restoring floral homeostasis. Am Surg 1981;47:178 – 83. 5. Schwan A, Sjolin S, Trottetam U. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of homologous faeces. Lancet 1983;2(8354):845. 6. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989; 1(8648):1156 – 60. 7. Gustafsson S, Lund-Tonnesen S, Berstad A, et al. Faecal shortchain fatty acids in patients with antibiotic-associated diarrhoea, before and after faecal enema treatment. Scand J Gastroenterol 1998;33:721–7. 8. Eisenman B, Silen W, Bascom G, Kauvar A. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958;44:854 –9. 9. Pearce L, Bampton P, Borody T, Shortis N. Modifications of the colonic microflora using probiotics: The way forward? Gut 1997;41(suppl 3):A63. Reprint requests and correspondence: Thomas J. Borody, M.D., Centre for Digestive Diseases, 144 Great North Road, Five Dock, Sydney, NSW 2046, Australia. Received Feb. 19, 2001; accepted Apr. 5, 2001.
Herpes Simplex Virus Esophagitis in an Immunocompetent Host With Sepsis TO THE EDITOR: We have read with interest the review written by Ramanathan et al. entitled “Herpes Simplex Virus Esophagitis in the Immunocompetent Host” (1). We also had an immunocompetent patient who was referred to our center with acute pyelonephritis, who had sepsis and later herpes simplex virus esophagitis (HSVE). HSVE generally develops in patients whose cellular immunity is compromised, especially patients with AIDS (2). In these cases, it is thought that factors that caused trauma to tissues, like gastroesophageal reflux, nasogastric drainage, and ingestion of caustics, were predisposing (3). To our knowledge, this is the first report describing the development of HSVE in an immunocompetent patient with sepsis.
4. Schwan A, Sjolin S, Trottestam U, et al. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of homologous feces. Lancet 1983;2(8354):845. 5. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989;1(8648):1156 – 60. 6. Gustafsson A, Lund-Tonnesen A, Berstad A, et al. Faecal short-chain fatty acids in patients with antibiotic-associated diarrhoea, before and after faecal enema treatment. Scand J Gastroenterol 1998;33:721–7. 7. Borody TJ. “Flora power”—fecal bacteria cure chronic C. difficile diarrhea. Am J Gastroenterol 2000;95:3028 –9 (editorial). 8. Banerjee S, Lamont JT. Non-antibiotic therapy for Clostridium difficile infection. Curr Opin Infect Dis 2000;13: 215–9. 9. Campieri M, Gionchetti P. Probiotics in inflammatory bowel disease: New insight to the pathogenesis of the disease or a possible therapeutic alternative? Gastroenterology 1999;116: 1246 –50. 10. Venturi A, Gionchetti P, Rizzello F, et al. Impact on the composition of the faecal flora by a new probiotic preparation: Preliminary data on maintenance treatment of patients with ulcerative colitis. Aliment Pharmacol Ther 1999;13:1103– 8. 11. Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: A double-blind, placebo-controlled trial. Gastroenterology 2000; 119:305–9. 12. Gionchetti P, Rizzello F, Cifone G, et al. In-vivo effect of a highly concentrated probiotic on IL-10 pelvic pouch tissue levels. Gastroenterology 1999;116:A723 (abstract). 13. Famularo G, De Simone C, Gionchetti P, et al. The role of digestive microflora and probiotics in inflammatory bowel disease. Microb Ecol Health Dis 2000;2(suppl 2):138 – 45. Reprint requests and correspondence: Giuseppe Famularo, Department of Medical Sciences, Ospedale San Camillo, Circonvallazione Gianicolense, 00152 Rome, Italy. Received Dec. 26, 2000; accepted Mar. 5, 2001.
Response to Drs. Famularo et al. TO THE EDITOR: We thank Famularo et al. for their well written and erudite letter and are glad that our case study generated some hypotheses. We agree that the fecal flora of each individual are unique and also that fecal bacteriotherapy (because of this reason) may succeed in some individuals, as it did in our patient, and fail in others. It would be preposterously difficult, however, as suggested by the authors, to determine beforehand the bacterial composition of the fecal enema to be used. It has been said it would take one laboratory technician a lifetime to characterize fully the entire bacterial population of feces. Hyperbole? Perhaps, but the point is made. We did not, as stated by Famularo et al., suggest that fecal enemas are “better” than probiotics for the treatment of Clostridium difficile colitis. Indeed, the future in C. difficile treatment belongs to probiotics, and we look forward to “dissection” of the properties of organisms we administer. Since our previous report we have successfully treated
Letters to the Editor
2263
another patient with a 10-month history of recurrent C. difficile infection resistant to conventional therapies. The patient has been asymptomatic for 5 months with negative C. difficile toxin assays after receiving one fecal instillation donated by her husband. Lawrence J. Brandt, M.D. Seth E. Persky, M.D. Division of Gastroenterology Montefiore Medical Center Bronx, New York Reprint requests and correspondence: Lawrence J. Brandt, M.D., Division of Gastroenterology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467. Received Apr. 5, 2001; accepted Apr. 5, 2001.
Response to Drs. Famularo et al. TO THE EDITOR: Persky and Brandt (1) may have generated hypotheses— one reason case reports are published— but did not set out to prove anything, as asserted by Famularo et al. Rather, they alerted us to a mechanism of action of fecal flora that now demands further study to answer the many questions this case report generated. In their letter the authors raise the issue of “fecal heterogeneity” and then state that fecal enemas from different individuals cannot be standardized. No one will disagree with this view, but similarly, it has long been known that blood transfusion cannot be standardized, as different blood groups occur—yet, generally blood transfusions give the same result, and this seems to hold true for fecal enemas. Unlike the authors’ unfounded claims, published reports suggest that feces from subjects A, B, and C are indeed likely to prove effective against Clostridium difficile (2). This is probably because feces possess antibiotic activity, a property that can be abolished by heat treatment (3). Furthermore, rather than failing “in a substantial proportion of a statistically significant sample of patients” or showing a “marginal effectiveness” in C. difficile colitis, the published results are totally opposite. Famularo et al. attempt to support their statement by quoting Bowden et al. (4), Schwan et al. (5), Tvede and Rask-Madsen (6), and Gustafsson et al. (7). Here, the authors need to be taken to task, because upon rereading these papers it is clear that results of fecal bacteriotherapy quoted in these articles are anything but “marginal.” Bowden et al. (4) state in their abstract that “the patients responded dramatically.” In pseudomembranous colitis at the time of Bowden’s series the death rate was around 74% (8). Meanwhile, 13 of 16 patients in Bowden’s series were cured very rapidly, and the three who died may have been cured had the treatment not been delayed. In fact, two of these three did not have a pseudomembrane at death, and one had involvement of the small bowel where a fecal enema did not reach. Schwan and
2264
Letters to the Editor
colleagues’ (5) patient recovered completely and was also cured of an accompanying irritable bowel syndrome. Gustafsson et al. (7) state that in 31 patients “clinically, most enema-treated patients recovered within days and had no relapses within 18 months.” Tvede and Rask-Madsen (6) cured one of two patients, albeit using two low volume fecal enemas. The true situation is that far from having a “marginal” effectiveness, fecal bacteriotherapy is overwhelmingly successful. Famularo et al. next suggest that bacterial composition of the fecal enema should have been reported. Unfortunately, reliable methods for obtaining such a composition are not generally available, and such a report would have contributed little to the case report. More to the point, the donor stools were found to be free of pathogens, and after all, the treated patient did remain well for ⱖ5 yr after the therapy. Though the potential for transmitting pathogenic organisms to the recipient does exist, if the donor is a spouse or a close relative with negative stool tests the risk has been minimized. Indeed, if a prospective donor has been a healthy person with negative stool tests and had this “natural probiotic” within his or her bowel for many years, this in itself suggests safety. Because fecal bacteriotherapy is not being promoted for widespread use but as a therapy of last resort, the fact remains that risk of transmission of infection is negligible, with no reported transmitted infections to date (2). The article by Persky and Brandt (1) and the accompanying editorial (2) are in no way misleading. Neither of the articles suggests that fecal bacteriotherapy has been demonstrated to be better than probiotics for treatment of intestinal diseases. The converse, however, is also true. It is also an incontrovertible fact that fecal bacteriotherapy utilizes the “ultimate probiotic,” which can never be copied by use of cultured bacteria that ultimately originate from human feces. Some probiotics, especially Lactobacillus GG, have been more effective in trials than placebos but have never been trialed against fecal bacteriotherapy in chronic relapsing C. difficile diarrhea or colitis. Until such a trial is carried out, the Persky and Brandt article and accompanying editorial stand. There is growing interest and research in the use of single and mixed probiotics in intestinal diseases. These at best copy the fecal flora but have not been shown to implant long term. Ideally, we all would like to come up with probiotics for gut disorders, and our center has an interest in the development of this technology (9). It appears, therefore, that our research efforts are similar to those of Famularo et al. We would all dearly like to dissect out the metabolic, functional, and enzymatic properties of various bacteria and have a product that could reproduce the power of fecal infusions. However, as with blood transfusions and bone marrow transplants, we still have not dissected out their components to create artificial blood and artificial bone
AJG – Vol. 96, No. 7, 2001
marrow, and such dreams with probiotics are yet a little way off. Thomas J. Borody, M.D., F.R.A.C.P., F.A.C.G. Centre for Digestive Diseases Sydney, Australia
REFERENCES 1. Persky SE, Brandt LJ. Treatment of recurrent Clostridium difficile–associated diarrhea by administration of donated stool directly through a colonoscope. Am J Gastroenterol 2000;95: 3283–5. 2. Borody TJ. “Flora power”—fecal bacteria cure chronic C. difficile diarrhea. Am J Gastroenterol 2000;95:3028 –9 (editorial). 3. Percival AK. Incidence and mechanisms of transfection of R-factors in bacteria. Melbourne: The Alfred Hospital, 1975 (thesis). 4. Bowden TA, Mansberger AR, Lykins LE. Pseumoembranous enterocolitis—mechanism for restoring floral homeostasis. Am Surg 1981;47:178 – 83. 5. Schwan A, Sjolin S, Trottetam U. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of homologous faeces. Lancet 1983;2(8354):845. 6. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet 1989; 1(8648):1156 – 60. 7. Gustafsson S, Lund-Tonnesen S, Berstad A, et al. Faecal shortchain fatty acids in patients with antibiotic-associated diarrhoea, before and after faecal enema treatment. Scand J Gastroenterol 1998;33:721–7. 8. Eisenman B, Silen W, Bascom G, Kauvar A. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery 1958;44:854 –9. 9. Pearce L, Bampton P, Borody T, Shortis N. Modifications of the colonic microflora using probiotics: The way forward? Gut 1997;41(suppl 3):A63. Reprint requests and correspondence: Thomas J. Borody, M.D., Centre for Digestive Diseases, 144 Great North Road, Five Dock, Sydney, NSW 2046, Australia. Received Feb. 19, 2001; accepted Apr. 5, 2001.
Herpes Simplex Virus Esophagitis in an Immunocompetent Host With Sepsis TO THE EDITOR: We have read with interest the review written by Ramanathan et al. entitled “Herpes Simplex Virus Esophagitis in the Immunocompetent Host” (1). We also had an immunocompetent patient who was referred to our center with acute pyelonephritis, who had sepsis and later herpes simplex virus esophagitis (HSVE). HSVE generally develops in patients whose cellular immunity is compromised, especially patients with AIDS (2). In these cases, it is thought that factors that caused trauma to tissues, like gastroesophageal reflux, nasogastric drainage, and ingestion of caustics, were predisposing (3). To our knowledge, this is the first report describing the development of HSVE in an immunocompetent patient with sepsis.