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CMV, EBV, HHV6, and HHV7 infections after intestinal transplantation without specific antiviral prophylaxis
CMV, EBV, HHV6, and HHV7 Infections After Intestinal Transplantation Without Specific Antiviral Prophylaxis A. Pascher, J. Klupp, R.J. Schulz, A. Dignass, and P. Neuhaus ABSTRACT Purpose. To analyze the incidence and relevance of viral infections after intestinal transplantation (ITx) without specific antiviral prophylaxis. Methods. Eleven patients (median age 34 years; range 26 to 58 years) who underwent ITx received no CMV/EBV prophylaxis but rather preemptive treatment. Viral monitoring for CMV or EBV polymerase chain reactions (PCR) in peripheral blood and graft biopsies, for HHV6-, and HHV7-PCR; for adeno-/rotavirus antigen and serology was performed based on clinical indications. Results. Median time under risk was 19 months (range 2 to 39). CMV: The donor (D)-to-recipient (R) status prior to ITx was: D⫹/R⫹ (4); D⫹/R⫺ (3); D⫺/R⫺ (2); D⫺/R⫹ (2). Eight patients showed no positive CMV-PCR. Three episodes of tissue invasive CMV disease occurred in two patients. There were two asymptomatic CMV infections but no episodes of CMV disease. None of the R(⫺) recipients developed CMV infection or enteritis irrespective of the donor status. EBV: Four patients experienced six episodes of transient significant EBV-viremia. Two patients developed EBV enteritis concurrently with CMV enteritis during acute rejection. There were no PTLD. CMV and EBV enteritis only occured during or immediately after steroid and OKT3 therapy. None of the patients developed significant HHV6 and HHV7 infection or viremia. There was one episode of adeno- and rotavirus enteritis. Conclusions. Despite witholding specific antiviral prophylaxis against CMV and EBV, we observed no such infections in 60% to 80% of patients. Donor-recipient matching regarding CMV was not predictive for the occurence of CMV-related complications. HHV6 and HHV7 have not contributed to posttransplant morbidity.
B
ECAUSE OF THE HIGH incidence of viral infections after intestinal transplants (ITx), physicians have proposed aggressive and prolonged prophylaxis regimens against cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection. However, these regimens are associated with the potential threat of nephrotoxicity, myelotoxicity, or development of resistance. Herein we report low viral infection rates after ITx despite not using specific, highdose, or prolonged anitviral prophylaxis.
MATERIALS AND METHODS Until September 2003, isolated ITx was performed in 11 adult patients for the indications of short bowel syndrome (median residual length 10 cm), owing to mesenterial infarction/ischemia (n ⫽ 5), nonrotation (n ⫽ 2), recurrent bowel obstruction after appendicitis (n ⫽ 1), volvolus (n ⫽ 2), and Gardner’s syndrome © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 381–382 (2004)
plus desmoid tumor (n ⫽ 1). Grafts were treated by immunonutrition and lactobacilli prior to explantation. All patients received postoperative prostaglandins IV and early enteral immunonutrition via a nasogastric feeding tube 6 hours posttransplantation. Immunonutrition, glutamine, and lactobacilli were administered until month 6 when the ileostomy was removed. Induction immunosuppression included tacrolimus, sirolimus, prednisolone, a sin-
From the Departments of General and Transplantation Surgery (A.P., J.K., P.N.), Department of Internal Medicine (R.J.S., A.D.), Division of Hepatology and Gastroenterology, Charite´, Campus Virchow Clinic, Berlin, Germany. Address reprint requests to Andreas Pascher, MD, Department of Surgery, Charite´, Campus Virchow, Augustenburgerplatz 1, 13353 Berlin, Germany. E-mail: andreas.pascher@ charite.de 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.01.080 381
382 gle preoperative dose of ATG (8 mg/kg) and daclizumab. Median time follow-up was 19 months (range 2 to 39).
Viral Monitoring Polymerase chain reaction (PCR) monitoring was conducted once weekly until month 6 and once fortnightly thereafter. CMV- and EBV-PCR were performed on peripheral blood and graft biopsies and HHV6 and HHV7 PCR on blood. Adeno-/rotavirus antigen and serology were obtained whenever indicated. The severity of infection was graded as: (I) infection (PCR-positive only), (II) noninvasive disease (clinical symptoms, fever, leukopenia), and (III) tissue-invasive disease (transplant enteritis or other organ manifestation).
Treatment Patients received no CMV/EBV prophylaxis but rather preemptive antiviral therapy. In cases of infection without evidence of disease, the immunosuppression was first reduced. Unless a significant improvement was seen, preemptive therapy was initiated with oral valganciclovir. Criteria for the onset of therapy were two sequentially positive CMV PCRs or two sequentially and significantly elevated quantitative EBV PCRs (⬎1000 copies). Noninvasive and invasive disease were treated with ganciclovir IV for 14 days plus immunoglobulin for initial 5 days.
RESULTS CMV
The donor (D)-to-recipient (R) status prior to ITx was: D⫹/R⫹ (4); D⫹/R⫺ (3); D⫺/R⫺ (2); D⫺/R⫹ (2). Eight patients had no positive CMV PCR. Three episodes of tissue invasive CMV disease occurred in two patients. There were two asymptomatic CMV infections, but no episodes of CMV disease. None of the R(⫺) recipients developed CMV infection or enteritis irrespective of the donor status. Invasive CMV disease was restricted to recipients with a positive serostatus at the time of transplantation. Hence, donor-recipient CMV matching was not predictive for the occurence of CMV-related complications. EBV
Four patients had six episodes of transient but significant EBV viremia. During acute rejection episodes two patients developed EBV enteritis concurrently with CMV enteritis. There were no cases of posttransplant lymphoproliferative disease and none of the EBV infections accompanied by increased numbers of CD19 (⫹) cells as sign of B-cell proliferation. Tissue invasive CMV and EBV disease (enteritis) oc-
PASCHER, KLUPP, SCHULZ ET AL
cured only during or immediately after steroid and OKT3 therapy. Fifty percent of CMV and 40% of EBV reactivations remitted spontaneously upon reduction of immunosuppression. The other infections responded adequately to oral valganciclovir. All episodes of noninvasive and invasive disease responded to IV treatment with ganciclovir. There was no CMV- or EBV-associated mortality and graft loss. Other Viral Infections
None of the patients developed significant HHV6 and HHV7 infection or viremia and there was no correlation with CMV and EBV infections. There was one episode of adeno- and rotavirus enteritis, triggering severe acute cellular rejection in one patient. DISCUSSION
Viral infections have been recognized as a major cause of morbidity after intestinal transplantation, accounting for up to 60% of graft losses.1 Particularly in children, the high incidence of EBV infections and its correlation with the development of PTLD represent a major side effect of potent immunosuppression. Aggressive prophylaxis and preemptive therapy have been proposed2 to reduce the rate of complications associated with viral infections after intestinal transplantation. Progress in the early detection of invasive CMV/EBV disease3 led to new prophylaxis and treatment strategies, especially early after the onset of preemptive therapy. The presented data suggest that moderate to low viral infection rates may be achieved without aggressive prophylaxis, which may itself cause harm to the patient. Early onset of preemptive antiviral therapy was of crucial importance. Donor-recipient matching regarding CMV was not predictive for the occurrence of CMV-related complications and thus may not be mandatory to reduce CMV-related complications.2 Since HHV6 and HHV7 did not contribute to morbidity after intestinal transplantation in this limited number of patients, aggressive monitoring of these viral infections does not seem to be necessary. REFERENCES 1. Thompson JS: Intestinal transplantation. Experience in the United States. Eur J Pediatr Surg 9:271, 1999 2. Bueno J, Green M, Kocoshis S, et al: Cytomegalovirus infection after intestinal transplantation in children. Clin Infect Dis 25:1078, 1997 3. Kusne S, Manez R, Frye BL, et al: Use of DNA amplification for diagnosis of cytomegalovirus enteritis after intestinal transplantation. Gastroenterology 112:1121, 1997
B
ECAUSE OF THE HIGH incidence of viral infections after intestinal transplants (ITx), physicians have proposed aggressive and prolonged prophylaxis regimens against cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection. However, these regimens are associated with the potential threat of nephrotoxicity, myelotoxicity, or development of resistance. Herein we report low viral infection rates after ITx despite not using specific, highdose, or prolonged anitviral prophylaxis.
MATERIALS AND METHODS Until September 2003, isolated ITx was performed in 11 adult patients for the indications of short bowel syndrome (median residual length 10 cm), owing to mesenterial infarction/ischemia (n ⫽ 5), nonrotation (n ⫽ 2), recurrent bowel obstruction after appendicitis (n ⫽ 1), volvolus (n ⫽ 2), and Gardner’s syndrome © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 381–382 (2004)
plus desmoid tumor (n ⫽ 1). Grafts were treated by immunonutrition and lactobacilli prior to explantation. All patients received postoperative prostaglandins IV and early enteral immunonutrition via a nasogastric feeding tube 6 hours posttransplantation. Immunonutrition, glutamine, and lactobacilli were administered until month 6 when the ileostomy was removed. Induction immunosuppression included tacrolimus, sirolimus, prednisolone, a sin-
From the Departments of General and Transplantation Surgery (A.P., J.K., P.N.), Department of Internal Medicine (R.J.S., A.D.), Division of Hepatology and Gastroenterology, Charite´, Campus Virchow Clinic, Berlin, Germany. Address reprint requests to Andreas Pascher, MD, Department of Surgery, Charite´, Campus Virchow, Augustenburgerplatz 1, 13353 Berlin, Germany. E-mail: andreas.pascher@ charite.de 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.01.080 381
382 gle preoperative dose of ATG (8 mg/kg) and daclizumab. Median time follow-up was 19 months (range 2 to 39).
Viral Monitoring Polymerase chain reaction (PCR) monitoring was conducted once weekly until month 6 and once fortnightly thereafter. CMV- and EBV-PCR were performed on peripheral blood and graft biopsies and HHV6 and HHV7 PCR on blood. Adeno-/rotavirus antigen and serology were obtained whenever indicated. The severity of infection was graded as: (I) infection (PCR-positive only), (II) noninvasive disease (clinical symptoms, fever, leukopenia), and (III) tissue-invasive disease (transplant enteritis or other organ manifestation).
Treatment Patients received no CMV/EBV prophylaxis but rather preemptive antiviral therapy. In cases of infection without evidence of disease, the immunosuppression was first reduced. Unless a significant improvement was seen, preemptive therapy was initiated with oral valganciclovir. Criteria for the onset of therapy were two sequentially positive CMV PCRs or two sequentially and significantly elevated quantitative EBV PCRs (⬎1000 copies). Noninvasive and invasive disease were treated with ganciclovir IV for 14 days plus immunoglobulin for initial 5 days.
RESULTS CMV
The donor (D)-to-recipient (R) status prior to ITx was: D⫹/R⫹ (4); D⫹/R⫺ (3); D⫺/R⫺ (2); D⫺/R⫹ (2). Eight patients had no positive CMV PCR. Three episodes of tissue invasive CMV disease occurred in two patients. There were two asymptomatic CMV infections, but no episodes of CMV disease. None of the R(⫺) recipients developed CMV infection or enteritis irrespective of the donor status. Invasive CMV disease was restricted to recipients with a positive serostatus at the time of transplantation. Hence, donor-recipient CMV matching was not predictive for the occurence of CMV-related complications. EBV
Four patients had six episodes of transient but significant EBV viremia. During acute rejection episodes two patients developed EBV enteritis concurrently with CMV enteritis. There were no cases of posttransplant lymphoproliferative disease and none of the EBV infections accompanied by increased numbers of CD19 (⫹) cells as sign of B-cell proliferation. Tissue invasive CMV and EBV disease (enteritis) oc-
PASCHER, KLUPP, SCHULZ ET AL
cured only during or immediately after steroid and OKT3 therapy. Fifty percent of CMV and 40% of EBV reactivations remitted spontaneously upon reduction of immunosuppression. The other infections responded adequately to oral valganciclovir. All episodes of noninvasive and invasive disease responded to IV treatment with ganciclovir. There was no CMV- or EBV-associated mortality and graft loss. Other Viral Infections
None of the patients developed significant HHV6 and HHV7 infection or viremia and there was no correlation with CMV and EBV infections. There was one episode of adeno- and rotavirus enteritis, triggering severe acute cellular rejection in one patient. DISCUSSION
Viral infections have been recognized as a major cause of morbidity after intestinal transplantation, accounting for up to 60% of graft losses.1 Particularly in children, the high incidence of EBV infections and its correlation with the development of PTLD represent a major side effect of potent immunosuppression. Aggressive prophylaxis and preemptive therapy have been proposed2 to reduce the rate of complications associated with viral infections after intestinal transplantation. Progress in the early detection of invasive CMV/EBV disease3 led to new prophylaxis and treatment strategies, especially early after the onset of preemptive therapy. The presented data suggest that moderate to low viral infection rates may be achieved without aggressive prophylaxis, which may itself cause harm to the patient. Early onset of preemptive antiviral therapy was of crucial importance. Donor-recipient matching regarding CMV was not predictive for the occurrence of CMV-related complications and thus may not be mandatory to reduce CMV-related complications.2 Since HHV6 and HHV7 did not contribute to morbidity after intestinal transplantation in this limited number of patients, aggressive monitoring of these viral infections does not seem to be necessary. REFERENCES 1. Thompson JS: Intestinal transplantation. Experience in the United States. Eur J Pediatr Surg 9:271, 1999 2. Bueno J, Green M, Kocoshis S, et al: Cytomegalovirus infection after intestinal transplantation in children. Clin Infect Dis 25:1078, 1997 3. Kusne S, Manez R, Frye BL, et al: Use of DNA amplification for diagnosis of cytomegalovirus enteritis after intestinal transplantation. Gastroenterology 112:1121, 1997