Bonet, H

Fung, JJ

Gonzalez-Pinto, I

Kramer, D

Kusne, S

Linden, P

Manez, R

Starzl, TE

English

PubMed

D-Scholarship@Pitt

., I ! ! 0041· 1,33719415701·149$03.0010 TRANSPLANTATION Copyright © 1994 by Williams & Willuns Vol. 57. 149-164. No. 1. Januarv 1994 Prmted In U.S.A Transplantation ® BRIEF COMMUNICATIONS TEMPORARY WITHDRAWAL OF IMMUNOSUPPRESSION FOR LIFE-THREATENING INFECTIONS AFTER LIVER TRANSPLANTATION) The outcome of a transplanted organ depends frequently upon the occurrence of allograft rejection and infection epi-sodes. These 2 events are closely related. On one side, immu-nosuppressive therapy is required to avoid allograft rejection, but on the other side this therapy facilitates the occurrence of infections (1). A better understanding of allograft rejection mechanisms along with new immunosuppressive therapies and antimicrobial prophylaxis has increased graft and pa-tient survival. However, infectious complications continue to be a common cause of morbidity and mortality after organ transplantation: The managements of these infections depend primarily upon identification of infectious causative agents. Specific antibacterial, antiviral, antifungal, and antiprotozoal therapy provides the mainstay in treatment of these infec-tions. However, it also is important to lower the immunosup-pressive background to allow the host immunological re-sponse to these infections, particularly when infections are considered life threatening. Although discontinuation of im-munosuppression is a generally accepted option in these situ-ations of life-threatening infections, no information it is available about graft and patient outcomes in these circum-stances. In kidney transplantation, immunosuppression may be stopped completely in the setting oflife-threatening infec-tions, since return to dialysis and retransplantation is always an option (2, 3). In contrast, in liver transplantation discon-tinuation of immunosuppression is considered "very risky," because it may lead to graft loss and patient death. The following is a report of the circumstances and outcome of patients with life-threatening infectious complications after liver transplantation, all of whom were managed with a tem-porary discontinuation of the immunosuppression therapy. Between 1987 and 1991, 31 patients underwent liver transplantation and developed severe opportunistic infec-tions. The management included, along with the specific anti-infectious therapy, a temporary withdrawal of immuno-suppression for at least 15 days. The patients were on 2 different immunosuppressive protocols, as described previ-ously (4): (1) CsA and steroids (12 patients) and (2) FK506 with low dose steroids (19 patients). Table 1 shows the types of infection seen and the immunosuppression that patients were receiving. The change in their immunosuppression management followed 1 of 2 patterns when infection was diagnosed: total discontinuation of immunosuppressive agents (in 1 CsA and 19 FK506 patients) or a maintenance dose of5 mg/day prednisone only was given (11 CsApatients). 1 This study was presented at the 11th Annual Meeting of the American Society of Transplant Physicians, May 26-27, 1992, Chicago, IL. Thirteen patients (42%; 5 CsA and 8 FK506 patients) died at a median time of 23 days after their immunosuppression therapy was discontinued (range 16-56 days) because of com-plications related to the infections. Autopsy examination was performed in 8 of these patients, with no evidence of allograft rejection in any of them. Eighteen patients (7 CsA and 11 FK506) who survived had their immunosuppression discontinued at a median interval of 140 days (range 44-779) after liver transplantation. They were a median of 17 days (range 15--43) without detectable levels of CsA or FK506. All patients had their baseline im-munosuppression resumed. However, the maintenance dose of either CsA and FK506 was reduced a median of 50% (range 0-89%) in comparison with the baseline immunosuppression before the discontinuation. Only 4 patients (3 CsA, 1 FK506) required reinstitution of immunosuppression because of re-jection. The median interval from liver transplantation to discontinuation of immunosuppression was 129 days (range 44-411) in those patients who had rejection and 143 days (range 53-779) in patients who did not have rejection (NS). The median period with undetectable levels ofCsA or FK506 was 27 days (range 2(43) in those patients who had rejec-tion and 16 days (range 15-27) in patients who did not have it (P=O.Ol). No differences were found in the dose of CsA before the discontinuation among the 3 CsA patients who had rejection and the 4 who did not. In those patients who did reject, all rejection episodes were controlled with the resump-tion of baseline immunosuppression. With a median fol· low-up of 942 days (range 440-2022 days), all patients who survived are alive, none required retransplantation. and only 2 (11%; 1 esA and 1 FK506 patient) have signs of chronic rejection in their liver biopsy (5). The fact that most of the patients reported here had their immunosuppression stopped without emergence of rejection could be explained by more than a single mechanism. On the one hand,. the infection itself may produce immunosuppres-sion, particularly viral infections (CMV or EBV), which are well-known immunosuppressive agents (6, 7). In addition, these patients were by definition iatrogenically "overimmu-nosuppressed," as none of the 8 who came to an autopsy had evidence of rejection; for those who survived, a 50% reduction in baseline maintenance immunosuppression when this was resumed did not lead to rejection. A second explanation for the ability to stop treatment is that the first stage of donor recipient nonreactivity was well underway. This tolerance induction, which has been associ-ated with cell migration and chimerism (8-10), allowed glo-bal immunologic recovery without rejection of the graft. The variable and unpredictable completeness of this process of "graft acceptance" was evident even at such an early time. 149 1;30 BRIEF COMMUNICATIONS Vol. 57, No.1 TABLE 1. Infection, immunosuppression, and outcome in the 31 patients" PatIent Infection Immunosuppression Outcome 1 CMV retinitis FK Alive 2 CVM retinitis FK Alive 3 CMV retinitis FK Alive 4 CMV pneumonitis FK Died (28 days i 5 CMV pneumonitis CSA Alive 6 CMV + PCP pneumonitis FK Died (18 days) 7 Disseminated CMV FK Died (27 days) 8 Disseminated CMV FK Died (16 days) 9 Disseminated CMV + PTLD FK Died (21 days) 10 Disseminated TB FK Alive 11 Dissemmated TB CSA Alive 12 PCP pneumonia FK Alive 13 PCP pneumonia FK Alive 14 Aspergillosis FK Alive 15 Aspergillosis FK Died (30 days) 16 Aspergillosis FK Died (50 days) 17 Cryptococcal meningitis FK Died (56 days) 18 Cryptococcal meningitis CSA Died (21 days) 19 Cryptococcal meningitis CSA Died (23 days) 20 PTLD CSA Died (20 days) 21 PTLD CSA Died (25 days) 22 PTLD CSA Died (23 days) 23 PTLD CSA Alive 24 PTLD CSA Alive 25 PTLD CSA Alive 26 PTLD CSA Alive 27 PTLD CSA Alive 28 PTLD FK Alive 29 PTLD FK Alive 30 PTLD FK Alive 31 PTLD FK Alive a PCP, Pneumocystis carinii pneumonia; PTLD, posttransplant lymphoproliferative disorder. Rejection emerged in 4 of the 18 survivors when reinstitution of treatment was withheld beyond 2 weeks, by freedom of this complication in the other 14. However, even in the recipients who developed rejection, secondary rescue therapy at a lower level of immunosuppression was successful in all cases. Reyes et al. (11) have shown that some recipients in a similar series of cases could be left permanently drug free, but which recipients cannot be predicted. In summary, we have shown here that in selected patients after liver transplantation, temporary withdrawal of immu-nosuppression therapy may be indicated in the management of severe infectious complications, without the development of immediate rejection. Reinstitution of immunosuppression in reduced doses at a later time can be done on a case to case basis to prevent the emergence of rejection. RAFAEL MA:NEZ2 SHIMON KUSNE2,3 PETER ifkab~ IGNACIO GoNZALEZ-PIN'r02 eAoovBo~ DAVID KRAMER4 JOHN J. FuNG2 THOMAS E. STARZL 2,5 Departments of Surgery, Medicine, and Anesthesiology / CCM University of Pittsburgh School of Medicine The Veterans Administration Medical Center Pittsburgh, Pennsylvania 2 Department of Surgery. 3 Department of Medicine. 4 Department of Anesthesiology/CCM. S Address correspondence to: Thomas E. Stanl, MD, PhD, Depart-ment of Surgery, 3601 Fifth Avenue, Falk Clinic 5C, Pittsburgh, PA 15213. REFERENCES 1. Rubin RH. The compromised host as a sentinel chicken. N Engl J Med 1987; 317: ll51. 2. Scherbaum W A, Zanker B. lnfectious complications in immuno-suppressed patients after kidney transplantation. lmmun In-fekt 1988; 16: 6. 3. Bass M. Infection in renal transplantation. Crit Care Nurs Clin North Am 1990; 2: 133. 4. Fung J, Abu-Elmagd K, Jain A, et al. A randomized trial of primary liver transplantation under immunosuppression with FK506 vs cyclosporine_ Transplant Proc 1991; 23: 2977. 5. Demetris A.J, Fung J, Todo S, et al. Conversion ofliver allograft recipients from cyclosporine to FK506 immunosuppressive therapy: a clinicopathologic study of96 patients. Transplanta-tion 1992; 53: 1056. 6. Rouse BT, Horohov DW. Immunosuppression in viral infections. Rev Infect Dis 1986; 8: 850. 7. Kaposi K, Rice GPA. Cytomegalovirus infection of peripheral blood mononuclear cells: effects on interleukin-l and -2 pro-duction and responsiveness. J Virol 1988; 62: 3603. 8. Starzl TE, Demetris A.J, Murase N, lldstad S, Ricordi C, Trucco M. Cell migration, chimerism, and graft acceptance. Lancet 1992; 339: 1579. 9. Starzl TE, Demetria A.J, Trucco M, et al. Chimerism after liver transplantation for type IV glycogen storage disease and Type I Gaucher's disease. N Engl J Med 1993; 328: 745. 10. Starzl TE, Demetris AJ, Trucco M, et al. Cell migration and gonuo~ 1994 BRIEF COMMUNICATIONS 151 chimerism after whole organ transplantation: the basis of graft acceptance. Hepatology 1993; 17: ll27. 11. Reyes J, Tzakis A, Zeevi A, et a1. Chimerism and the frequent achievement of a drug free state after orthotopic liver trans-plantatIOn. Abstracts ofthe 19th Annual Meeting of the Ameri-can Society of Transplant Surgeons, Houston, TIC, May 19-2l. 1993. Received 22 April 1993. Accepted 20 May 1993. 

Temporary withdrawal of immunosuppression for life-threatening infections after liver transplantation

Name not available

http://d-scholarship.pitt.edu/5027/1/31735062125814.pdf

Temporary withdrawal of immunosuppression for life-threatening infections after liver transplantation

Abstract

Similar works

Full text

Available Versions

D-Scholarship@Pitt

Name not available

Name not available