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Transplantation in the face of severe donor sepsis: Pushing the boundaries?
CASE REPORT
Transplantation in the Face of Severe Donor Sepsis: Pushing the Boundaries? Robert P. Pauly, MD, David Rayner, MD, Allan G. Murray, MD, Susan M. Gilmour, MD, and Dennis Y. Kunimoto, MD ● Most current transplantation guidelines suggest that bacteremia or bacterial sepsis precludes organ donation. However, various investigators report good outcomes when donor bacteremia was discovered incidentally posttransplant or when bacteremia was cleared before organ retrieval. The authors present the case of a donor who underwent surgical repair of a congenital heart defect complicated by refractory septic shock with positive blood cultures for cloxacillin-sensitive Staphylococcus aureus until time of death. Hemorrhagic and necrotic foci were noted on the renal capsules at time of organ retrieval. The donor liver appeared grossly unremarkable. One year after transplantation, the 3 recipients continue to do well with no known sequelae of having received organs from a Staphylococcus aureus–septic donor. The authors conclude that with appropriate perioperative antibiotics targeted at an organism with known sensitivities and consideration of a modified immunosuppressive protocol, even organs from individuals with known severe sepsis at the time of retrieval may be appropriate for donation. Am J Kidney Dis 44:E64-E67. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Transplantation; sepsis; bacteremia.
T
RANSMISSION of infection from donor to recipient has traditionally been a feared complication of transplantation in the setting of an immunosuppressed recipient. This is undoubtedly warranted with regard to certain viral pathogens such as the human immunodeficiency virus, hepatitis B and C viruses, or even opportunistic fungi and parasites1; however, emerging data suggest that bacteremia or even bacterial sepsis may not be an absolute contraindication for organ donation.2-7 Given the disparity between the number of people awaiting transplantation and the inadequate supply of donors, expanding the donor pool to include marginal donors, particularly those organs from septic individuals, could constitute an appreciable increase in available organs. We report a case of successful kidney
From the Departments of Medicine and Pathology; Division of Nephrology, Department of Medicine; Department of Pediatrics; and Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Received February 20, 2004; accepted in revised form June 23, 2004. Address reprint requests to Dennis Y. Kunimoto, MD, FRCPC, Department of Medicine, 2F1 Walter MacKenzie Centre, 8440 112 St, Edmonton, Alberta, Canada, T6G 2B7. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4404-0029$30.00/0 doi:10.1053/j.ajkd.2004.06.026
e64
and liver transplants from a donor with documented severe sepsis syndrome at the time of organ procurement. CASE REPORT An 8-year-old boy with Down’s syndrome underwent surgical revision of a congenital heart defect in March 2002. Although the immediate postoperative period was uneventful, on day 8 the patient had fever and diarrhea. On day 10, cloxacillin-sensitive Staphylococcus aureus was reported growing from his blood and rotavirus from his feces, and he was started on cloxacillin (700 mg every 4 hours) and gentamicin (40 mg every 8 hours); he continued on these antibiotics until death. On day 10 he was taken back to the operating room for sternal wound debridement when purulent drainage, which grew S aureus, was detected from the mediastinum. Vasopressor support was required, and a second mediastinotomy was performed the following day for irrigation and insertion of temporary epicardial pacemaker wires. Two days later, 13 days after the original surgery, the patient died secondary to sudden intracranial bleeding and septic shock. Daily blood cultures until time of death continued to grow S aureus and, despite refractory septic shock, this patient’s kidneys and liver were accepted for organ donation. The last creatinine and alanine aminotransferase levels on the day of death were 1.22 mg/dL (108 mol/L) and 107 U/L, respectively. A number of hemorrhagic and necrotic foci were noted on the renal capsules at the time of organ retrieval. Wedge biopsy of these areas confirmed microabscesses and tissue necrosis, although pathologic interpretation was not available at the time of implantation (Fig 1). Subsequent review of donor autopsy results revealed purulent pericarditis with Gram-positive cocci, septic thromboemboli and microabscesses in the right lung, mixed bacterial and fungal tracheobronchitis, and visceral lymphadenopathy. There was no evidence of endocarditis on either the
American Journal of Kidney Diseases, Vol 44, No 4 (October), 2004: E64-E67
TRANSPLANTATION AND SEVERE DONOR SEPSIS
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Fig 1. Donor kidney biopsy shows necrosis with hemorrhage and abscess formation (hematoxylin and eosin, original magnification ⴛ125). (Inset) Clustered Gram-positive cocci in macrophages (Gram, original magnification ⴛ500).
native tissue or the ventricular-pulmonary artery conduit graft. All organ recipients (or the parents of the liver recipient) were informed of the sepsis status of the donor and the potential risk of receiving infected organs as part of the transplant consent process. All 3 recipients were relatively young and free of diabetes. The first recipient was a 41-year-old woman with endstage renal disease from focal sclerosis. Pretransplant, the recipient was given cloxacillin, and postoperatively a steroidfree regimen of tacrolimus, mycophenolate mofetil, and daclizumab was initiated and cloxacillin continued. Posttransplant, there was delayed graft function requiring 1 hemodialysis session and several boluses of methylprednisolone (Solu-Medrol). On posttransplant day 13, she was readmitted with fever and chills and a white blood cell count of 24,000/L; she had surgical drainage of a perinephric fluid collection around the transplanted graft, which grew mycoplasma. Cloxacillin subsequently was discontinued on posttransplant day 21, and the patient received 17 days of clindamycin and doxycycline. No further bacteriologic complications have been noted, and there has been no evidence of organ rejection. Her creatinine level at 1 year was 1.54 mg/dL (136 mol/L). The second kidney was transplanted into a 23-year-old woman with end-stage renal disease secondary to idiopathic glomerulonephritis. Her immunosuppression consisted of
the same regimen as described above, she had satisfactory graft function, and she was treated for a total of 4 weeks of cloxacillin. The patient was readmitted to the hospital in June 2002, 8 weeks after finishing cloxacillin, for persistent nausea, vomiting, and diarrhea; she was found to have evidence of a cytomegalovirus infection on colonic biopsy, which was treated with ganciclovir, No further infectious complications have subsequently been documented, and there has been no evidence of organ rejection. Her creatinine level at 1 year was 1.74 mg/dL (154 mol/L). The liver recipient was a 2-year, 10-month-old boy with biliary atresia and failing Kasai portoenterostomy. His immunosuppression included preoperative methylprednisolone and a postoperative regimen of tacrolimus and prednisone. He received 7 days of intravenous cloxacillin. His postoperative course was complicated by an enterococcus urinary infection and Clostridium difficile toxin-associated diarrhea. Both were treated and quickly cleared with standard therapy. Ten days posttransplant, during a period of low tacrolimus levels, the patient experienced acute cellular rejection with a Banff score of 6/9. The patient was treated with methylprednisolone for 3 days and rapamycin for 6 weeks before resuming dual therapy of tacrolimus and tapering doses of steroid. He was readmitted on 2 occasions, September and November 2002, for intravenous antibiotics for culturenegative cholangitis, secondary to a small subsegmental
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PAULY ET AL
biliary stricture. At 1 year, his alanine aminotransferase level was 120 U/L, the prothrombin time international normalized ratio was 1.0, and the total bilirubin level was 0.6 mg/dL (11 mol/L). Nearly 2 years after transplantation, all 3 recipients continue to do well with no known sequellae of having received organs from an S aureus–septic donor.
DISCUSSION
A number of previous investigators have reported the success of transplanting donor-infected organs without an increased incidence of subsequent infections in recipients. In the mid1980s Odenheimer et al7 documented a case series of 15 patients receiving cadaveric kidneys in which cultures from donor urine, blood, wound, or flush solution were found to be positive after the organ was already transplanted. However, there was no information on the clinical status of the donors, and 40% of isolates were Staphylococcus epidermidis, which may have represented contamination or colonization rather than true infection. With broad-spectrum perioperative antibiotics and tailored antimicrobial coverage after culture results became available, transmission of infection from donor to recipient was avoided in all cases. Freeman et al4 reported good recipient outcomes with 95 known bacteremic heart, lung, liver, and kidney donors and the outcomes of the 212 recipients. Similar results were reported by Lumbreras et al2 in their case-control study of 29 unrecognized donor bacteremia in heart and liver recipients and by Satoi et al,3 who found no difference in survival among recipients from 33 donors with bacterial meningitis versus matched controls. In these studies, donors typically received empiric or culture-specific antibiotics before procurement as did the recipients after transplantation. Because of the retrospective nature of these studies, there is no indication why organs from some bacteremic donors were accepted for transplantation while others were not. Presumably, the sickest bacteremic individuals were rejected for organ retrieval or never identified as potential donors, thus introducing a selection bias into the study populations. A number of groups have suggested guidelines to govern the use of organs from bacteremic donors. The transplant unit in Barcelona proposes that sterilization of donor blood is essential, that donor organs be infection free, and that
consideration be given to the virulence of the infectious agent and to the antibiotic regimen for both the donor and the recipient.5,6 Rubin and Fishman8 suggest that bacteremia owing to organisms that are cleared easily from the blood stream by bactericidal agents should be treated for 5 days with confirmation by negative blood cultures; patients with infected fluid collections should be treated longer regardless of organism. Donors with S aureus, Pseudomonas aeruginosa, or streptococcal species with decreased sensitivity to penicillin should be treated for 2 weeks with bactericidal antibiotics before donation is considered. Finally, donors with blood stream or tissue infection caused by Group A streptococci, vancomycin-resistant enterococci, Streptococcus milleri, Salmonella, fungi, nocardia, or active mycobacteria should not be considered for transplantation at all. The case we present is unique in that the donor was selected despite overwhelming sepsis and pathologic evidence of tissue necrosis and microabscesses in the donor kidneys at the time of death. Since transplantation, none of the 3 recipients have had cultures from any site growing S aureus or any clinical evidence of S aureus infection. Although we do not advocate the indiscriminate use of septic donors with infected organs as a means of expanding the organ pool, we do propose that with a perioperative bactericidal antibiotic regimen targeted at an organism with known sensitivities, and consideration of a modified (steroid-free) immunosuppressive protocol, even organs from the sickest individuals may be appropriate for retrieval. This continues to challenge the view that severe sepsis and septic emboli to potentially transplantable organs are absolute contraindications to organ donation. REFERENCES 1. Schaffner A: Pretransplant evaluation for infections in donors and recipients of solid organs. Clin Inf Dis 33:S9S14, 2001 (suppl 1) 2. Lumbreras C, Sanz F, Gonzalez A, et al: Clinical significance of donor-unrecognized bacteremia in the outcome of solid-organ transplant recipients. Clin Inf Dis 33:722726, 2001 3. Satoi S, Bramhall SR, Solomon M, et al: The use of liver grafts from donors with bacterial meningitis. Transplantation 72:1108-1113, 2001 4. Freeman RB, Giatras I, Falagas ME, et al: Outcome of
TRANSPLANTATION AND SEVERE DONOR SEPSIS
transplantation of organs procured from bacteremic donors. Transplantation 68:1107-1111, 1999 5. Caballero F, Lopez-Navidad A, Domingo P, Sola R, Guirado L, Figueras J: Successful transplantation of organs retrieved from a donor with enterococcal endocarditis. Transpl Int 11:387-389, 1998 6. Lopez-Navidad A, Domingo P, Caballero F, Gonzalez C, Santiago C: Successful transplantation of organs re-
e67
trieved from donors with bacterial meningitis. Transplantation 64:365-368, 1997 7. Odenheimer DB, Matas AJ, Tellis VA, et al: Donor cultures reported positive after transplantation: A clinical dilemma. Transplantation Proc 18:465-466, 1986 8. Rubin RH, Fishman JA: A consideration of potential donors with active infection—Is this a way to expand the donor pool? Transpl Int 11:333-335, 1998
Transplantation in the Face of Severe Donor Sepsis: Pushing the Boundaries? Robert P. Pauly, MD, David Rayner, MD, Allan G. Murray, MD, Susan M. Gilmour, MD, and Dennis Y. Kunimoto, MD ● Most current transplantation guidelines suggest that bacteremia or bacterial sepsis precludes organ donation. However, various investigators report good outcomes when donor bacteremia was discovered incidentally posttransplant or when bacteremia was cleared before organ retrieval. The authors present the case of a donor who underwent surgical repair of a congenital heart defect complicated by refractory septic shock with positive blood cultures for cloxacillin-sensitive Staphylococcus aureus until time of death. Hemorrhagic and necrotic foci were noted on the renal capsules at time of organ retrieval. The donor liver appeared grossly unremarkable. One year after transplantation, the 3 recipients continue to do well with no known sequelae of having received organs from a Staphylococcus aureus–septic donor. The authors conclude that with appropriate perioperative antibiotics targeted at an organism with known sensitivities and consideration of a modified immunosuppressive protocol, even organs from individuals with known severe sepsis at the time of retrieval may be appropriate for donation. Am J Kidney Dis 44:E64-E67. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Transplantation; sepsis; bacteremia.
T
RANSMISSION of infection from donor to recipient has traditionally been a feared complication of transplantation in the setting of an immunosuppressed recipient. This is undoubtedly warranted with regard to certain viral pathogens such as the human immunodeficiency virus, hepatitis B and C viruses, or even opportunistic fungi and parasites1; however, emerging data suggest that bacteremia or even bacterial sepsis may not be an absolute contraindication for organ donation.2-7 Given the disparity between the number of people awaiting transplantation and the inadequate supply of donors, expanding the donor pool to include marginal donors, particularly those organs from septic individuals, could constitute an appreciable increase in available organs. We report a case of successful kidney
From the Departments of Medicine and Pathology; Division of Nephrology, Department of Medicine; Department of Pediatrics; and Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Received February 20, 2004; accepted in revised form June 23, 2004. Address reprint requests to Dennis Y. Kunimoto, MD, FRCPC, Department of Medicine, 2F1 Walter MacKenzie Centre, 8440 112 St, Edmonton, Alberta, Canada, T6G 2B7. E-mail: [email protected] © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4404-0029$30.00/0 doi:10.1053/j.ajkd.2004.06.026
e64
and liver transplants from a donor with documented severe sepsis syndrome at the time of organ procurement. CASE REPORT An 8-year-old boy with Down’s syndrome underwent surgical revision of a congenital heart defect in March 2002. Although the immediate postoperative period was uneventful, on day 8 the patient had fever and diarrhea. On day 10, cloxacillin-sensitive Staphylococcus aureus was reported growing from his blood and rotavirus from his feces, and he was started on cloxacillin (700 mg every 4 hours) and gentamicin (40 mg every 8 hours); he continued on these antibiotics until death. On day 10 he was taken back to the operating room for sternal wound debridement when purulent drainage, which grew S aureus, was detected from the mediastinum. Vasopressor support was required, and a second mediastinotomy was performed the following day for irrigation and insertion of temporary epicardial pacemaker wires. Two days later, 13 days after the original surgery, the patient died secondary to sudden intracranial bleeding and septic shock. Daily blood cultures until time of death continued to grow S aureus and, despite refractory septic shock, this patient’s kidneys and liver were accepted for organ donation. The last creatinine and alanine aminotransferase levels on the day of death were 1.22 mg/dL (108 mol/L) and 107 U/L, respectively. A number of hemorrhagic and necrotic foci were noted on the renal capsules at the time of organ retrieval. Wedge biopsy of these areas confirmed microabscesses and tissue necrosis, although pathologic interpretation was not available at the time of implantation (Fig 1). Subsequent review of donor autopsy results revealed purulent pericarditis with Gram-positive cocci, septic thromboemboli and microabscesses in the right lung, mixed bacterial and fungal tracheobronchitis, and visceral lymphadenopathy. There was no evidence of endocarditis on either the
American Journal of Kidney Diseases, Vol 44, No 4 (October), 2004: E64-E67
TRANSPLANTATION AND SEVERE DONOR SEPSIS
e65
Fig 1. Donor kidney biopsy shows necrosis with hemorrhage and abscess formation (hematoxylin and eosin, original magnification ⴛ125). (Inset) Clustered Gram-positive cocci in macrophages (Gram, original magnification ⴛ500).
native tissue or the ventricular-pulmonary artery conduit graft. All organ recipients (or the parents of the liver recipient) were informed of the sepsis status of the donor and the potential risk of receiving infected organs as part of the transplant consent process. All 3 recipients were relatively young and free of diabetes. The first recipient was a 41-year-old woman with endstage renal disease from focal sclerosis. Pretransplant, the recipient was given cloxacillin, and postoperatively a steroidfree regimen of tacrolimus, mycophenolate mofetil, and daclizumab was initiated and cloxacillin continued. Posttransplant, there was delayed graft function requiring 1 hemodialysis session and several boluses of methylprednisolone (Solu-Medrol). On posttransplant day 13, she was readmitted with fever and chills and a white blood cell count of 24,000/L; she had surgical drainage of a perinephric fluid collection around the transplanted graft, which grew mycoplasma. Cloxacillin subsequently was discontinued on posttransplant day 21, and the patient received 17 days of clindamycin and doxycycline. No further bacteriologic complications have been noted, and there has been no evidence of organ rejection. Her creatinine level at 1 year was 1.54 mg/dL (136 mol/L). The second kidney was transplanted into a 23-year-old woman with end-stage renal disease secondary to idiopathic glomerulonephritis. Her immunosuppression consisted of
the same regimen as described above, she had satisfactory graft function, and she was treated for a total of 4 weeks of cloxacillin. The patient was readmitted to the hospital in June 2002, 8 weeks after finishing cloxacillin, for persistent nausea, vomiting, and diarrhea; she was found to have evidence of a cytomegalovirus infection on colonic biopsy, which was treated with ganciclovir, No further infectious complications have subsequently been documented, and there has been no evidence of organ rejection. Her creatinine level at 1 year was 1.74 mg/dL (154 mol/L). The liver recipient was a 2-year, 10-month-old boy with biliary atresia and failing Kasai portoenterostomy. His immunosuppression included preoperative methylprednisolone and a postoperative regimen of tacrolimus and prednisone. He received 7 days of intravenous cloxacillin. His postoperative course was complicated by an enterococcus urinary infection and Clostridium difficile toxin-associated diarrhea. Both were treated and quickly cleared with standard therapy. Ten days posttransplant, during a period of low tacrolimus levels, the patient experienced acute cellular rejection with a Banff score of 6/9. The patient was treated with methylprednisolone for 3 days and rapamycin for 6 weeks before resuming dual therapy of tacrolimus and tapering doses of steroid. He was readmitted on 2 occasions, September and November 2002, for intravenous antibiotics for culturenegative cholangitis, secondary to a small subsegmental
e66
PAULY ET AL
biliary stricture. At 1 year, his alanine aminotransferase level was 120 U/L, the prothrombin time international normalized ratio was 1.0, and the total bilirubin level was 0.6 mg/dL (11 mol/L). Nearly 2 years after transplantation, all 3 recipients continue to do well with no known sequellae of having received organs from an S aureus–septic donor.
DISCUSSION
A number of previous investigators have reported the success of transplanting donor-infected organs without an increased incidence of subsequent infections in recipients. In the mid1980s Odenheimer et al7 documented a case series of 15 patients receiving cadaveric kidneys in which cultures from donor urine, blood, wound, or flush solution were found to be positive after the organ was already transplanted. However, there was no information on the clinical status of the donors, and 40% of isolates were Staphylococcus epidermidis, which may have represented contamination or colonization rather than true infection. With broad-spectrum perioperative antibiotics and tailored antimicrobial coverage after culture results became available, transmission of infection from donor to recipient was avoided in all cases. Freeman et al4 reported good recipient outcomes with 95 known bacteremic heart, lung, liver, and kidney donors and the outcomes of the 212 recipients. Similar results were reported by Lumbreras et al2 in their case-control study of 29 unrecognized donor bacteremia in heart and liver recipients and by Satoi et al,3 who found no difference in survival among recipients from 33 donors with bacterial meningitis versus matched controls. In these studies, donors typically received empiric or culture-specific antibiotics before procurement as did the recipients after transplantation. Because of the retrospective nature of these studies, there is no indication why organs from some bacteremic donors were accepted for transplantation while others were not. Presumably, the sickest bacteremic individuals were rejected for organ retrieval or never identified as potential donors, thus introducing a selection bias into the study populations. A number of groups have suggested guidelines to govern the use of organs from bacteremic donors. The transplant unit in Barcelona proposes that sterilization of donor blood is essential, that donor organs be infection free, and that
consideration be given to the virulence of the infectious agent and to the antibiotic regimen for both the donor and the recipient.5,6 Rubin and Fishman8 suggest that bacteremia owing to organisms that are cleared easily from the blood stream by bactericidal agents should be treated for 5 days with confirmation by negative blood cultures; patients with infected fluid collections should be treated longer regardless of organism. Donors with S aureus, Pseudomonas aeruginosa, or streptococcal species with decreased sensitivity to penicillin should be treated for 2 weeks with bactericidal antibiotics before donation is considered. Finally, donors with blood stream or tissue infection caused by Group A streptococci, vancomycin-resistant enterococci, Streptococcus milleri, Salmonella, fungi, nocardia, or active mycobacteria should not be considered for transplantation at all. The case we present is unique in that the donor was selected despite overwhelming sepsis and pathologic evidence of tissue necrosis and microabscesses in the donor kidneys at the time of death. Since transplantation, none of the 3 recipients have had cultures from any site growing S aureus or any clinical evidence of S aureus infection. Although we do not advocate the indiscriminate use of septic donors with infected organs as a means of expanding the organ pool, we do propose that with a perioperative bactericidal antibiotic regimen targeted at an organism with known sensitivities, and consideration of a modified (steroid-free) immunosuppressive protocol, even organs from the sickest individuals may be appropriate for retrieval. This continues to challenge the view that severe sepsis and septic emboli to potentially transplantable organs are absolute contraindications to organ donation. REFERENCES 1. Schaffner A: Pretransplant evaluation for infections in donors and recipients of solid organs. Clin Inf Dis 33:S9S14, 2001 (suppl 1) 2. Lumbreras C, Sanz F, Gonzalez A, et al: Clinical significance of donor-unrecognized bacteremia in the outcome of solid-organ transplant recipients. Clin Inf Dis 33:722726, 2001 3. Satoi S, Bramhall SR, Solomon M, et al: The use of liver grafts from donors with bacterial meningitis. Transplantation 72:1108-1113, 2001 4. Freeman RB, Giatras I, Falagas ME, et al: Outcome of
TRANSPLANTATION AND SEVERE DONOR SEPSIS
transplantation of organs procured from bacteremic donors. Transplantation 68:1107-1111, 1999 5. Caballero F, Lopez-Navidad A, Domingo P, Sola R, Guirado L, Figueras J: Successful transplantation of organs retrieved from a donor with enterococcal endocarditis. Transpl Int 11:387-389, 1998 6. Lopez-Navidad A, Domingo P, Caballero F, Gonzalez C, Santiago C: Successful transplantation of organs re-
e67
trieved from donors with bacterial meningitis. Transplantation 64:365-368, 1997 7. Odenheimer DB, Matas AJ, Tellis VA, et al: Donor cultures reported positive after transplantation: A clinical dilemma. Transplantation Proc 18:465-466, 1986 8. Rubin RH, Fishman JA: A consideration of potential donors with active infection—Is this a way to expand the donor pool? Transpl Int 11:333-335, 1998