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Evolutionary experience with immunosuppression in pediatric intestinal transplantation
Journal of Pediatric Surgery (2005) 40, 274 – 280
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Evolutionary experience with immunosuppression in pediatric intestinal transplantation Geoffrey J. Bond, George V. Mazariegos, Rakesh Sindhi, Kareem M. Abu-Elmagd, Jorge Reyes* Thomas E Starzl Transplantation Institute, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA Index words: Intestinal transplantation; Intestinal failure; Immunosuppression; Monotherapy; Steroid-free
Abstract Background/Purpose: Intestinal transplantation has developed to become the standard of care for patients with irreversible intestinal failure who are not responding to total parenteral nutrition. Once considered experimental, it has taken time and much effort for the procedure to become a clinical reality, with final acceptance primarily because of the vastly improved outcomes. Advances and novel modifications in immunosuppression have been at the forefront of these improvements. The authors review their evolutionary experience with intestinal transplantation, particularly relating changes in immunosuppression protocols to improved outcomes. Methods: From July 1990 to December 2003, 122 children received 129 intestinal containing allografts (70 liver/intestine, 42 isolated intestine, 17 multivisceral). Mean age was 5.3 F 5.2 years, and 55% were boys. Indications for transplantation were mostly short gut syndrome. The allografts were cadaveric, ABO identical (except one), with no immunomodulation. Bone marrow augmentation was used in 29% of the recipients since 1995. T-cell lymphoctytotoxic crossmatch was positive in 24% cases. Immunosuppression protocols can be divided into 3 categories: (i) maintenance tacrolimus and steroids (n = 52, 1990-1995, 1997-1998); (ii) addition of induction therapy with cyclophosphamide (n = 16, 1995-1997) then daclizumab (n = 24, 1998-2001). A third immunosuppressive agent was added in either group where increased immunosuppression was indicated; (iii) pretreatment/induction with antilymphocyte conditioning and steroid-free posttransplantation tacrolimus monotherapy (n = 37, 2002-2003). In this later group, if clinically stable at 60 to 90 days posttransplantation, and no recent rejection, the tacrolimus was weaned by decreasing frequency of dosing. Results: The overall Kaplan-Meier patient/graft survival was 81%/76% at 1 year, 62%/60% at 3 years, and 61%/51% at 5 years. Survival continues to improve, with 1-year patient/graft survival being 71%/62%, 77%/75%, and 100%/100% for groups (i), (ii), and (iii), respectively. Acute intestinal allograft rejection has decreased markedly in group (iii). The rate of infectious diseases, such as cytomegalovirus and Epstein-Barr virus, is lowest in group (iii). Graft-versus-host disease has not significantly increased with the latest protocol. Most importantly, the overall level of immunosuppression requirements has decreased markedly, with most patients in group (iii) being
Presented at the 35th Annual Meeting of the American Pediatric Surgical Association, Ponte Vedra, Florida, May 27-30, 2004. * Corresponding author. Tel.: +1 412 692 7867; fax: +1 412 692 6116. E-mail address: [email protected] (J. Reyes). 0022-3468/05/4001-0049$30.00/0 D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2004.09.020
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on monotherapy. Of these, most had their monotherapy weaned down to spaced doses, something never systematically attempted or achieved in pediatric intestinal transplantation. Conclusions: Intestinal transplantation has progressed markedly over the last 13 years. Although there have been modifications in all aspects of the procedure, the story of intestinal transplantation has been the evolution of successful immunosuppression regimens. Our latest pretreatment/ induction conditioning and posttransplantation monotherapy strategy improves graft acceptance and lowers subsequent immunosuppression dosing requirements. It is expected this will overcome many of the complications related to the previously high immunosuppression requirements. Minimization of immunosuppression with avoidance of steroid therapy offers profound long-term benefits, especially in the pediatric population. The patients still remain challenging and complex in every aspect; however, these advances offer significant hope to both patients and caregivers alike. D 2005 Elsevier Inc. All rights reserved.
The intestine is the last solid abdominal organ to successfully be transplanted. Although it was initially included in multivisceral grafts in the 1960s [1], the outcomes were uniformly poor, most likely related to the immunogenicity of the lymphocyte-rich intestinal allograft and the limited immunosuppressants available to control the immune response. Up to the late 1980s there were only sporadic unsuccessful attempts at transplanting the intestine [2- 4]. The only long-term survivor from that era was an isolated intestine transplanted by the French group in 1989 under cyclosporin immunosuppression [5]. The introduction of tacrolimus in 1990 [6] allowed for routine successes with intestinal transplantation [7,8]. With this drug, the balance of host-versusgraft reaction could be controlled. The early days though were fraught with many difficulties, mostly related to infectious complications from initial over–immunosuppression or the need to treat rejection episodes with even stronger immunosuppressants (OKT3, a monoclonal antibody) [9]. With increasing experiences in intestinal transplantation, advances occurred in all aspects of the transplantation including the donor and recipient operation [10-12], monitoring of the allograft [13,14] and for infectious complications, [15] and immunosuppression management [16-19]. As newer immunosuppressive agents became available, these were added to various regimens which overall resulted in heavier immunosuppression. Although acute cellular rejection was better controlled and treated, there still were significant problems with infectious complications [15,20,21], chronic rejection [22], and drug toxicities. To this end, a new strategy in tolerance induction [23] was initiated with a goal to minimize the posttransplantation immunosuppression requirements. In this paper we outline the changes in the immunosuppression management over the last 13 years that have brought intestinal transplantation from what was previously considered an experimental procedure to the now accepted standard of care for patients with irreversible intestinal failure.
1. Materials and methods From July 1990 to December 2003, 122 children received 129 intestinal containing allografts at the Children’s Hospital of Pittsburgh. The mean age at transplantation was 5.3 F 5.2 years, ranging from 0.5 to 18 years. Of these 55% were boys and 45% girls. The indications for transplantation were short gut syndrome in 73%, dysmotility disorders (such as intestinal pseudoobstruction and Hirschsprung’s disease) in 17%, intestinal dysfunction (such as microvillus inclusion disease) in 7%, neoplasm (such as familial polyposis) in 2%, and hepatoportomesenteric thrombosis in 1%. The most common causes of short gut syndrome were volvulus (33%), gastroschisis (32%), intestinal atresia (15%), necrotizing enterocolitis (15%), and trauma (3%). The types of transplants were combined liver and intestine (54%), isolated intestine (33%), and multivisceral (13%) (stomach, duodenum, pancreas, intestine with liver [n = 13] and without liver [n = 4]). All donor grafts were cadaveric and ABO identical except one (O to A compatible). HLA matching was random and uniformly poor. There was no immune modulation of the allograft with either in vivo antilymphocyte therapy to the donor or ex vivo intestinal allograft irradiation. Donor bone marrow augmentation (n = 27) was used in 29% of the grafts from 1995 onwards. The T-cell lymphoctytotoxic crossmatch was positive in 24% of cases. Because of size disparity and the paucity of small organs for the younger recipients, allograft reduction (liver and/or intestine) has been used more recently. Immunosuppression regimens over the period can be divided into 3 basic groups: (i)
Tacrolimus and steroid maintenance therapy (n = 52, 1990-1995, 1997-1998). Steroids (solumedrol/prednisone) were given in high doses in the perioperative period and then tapered down over time to a single daily maintenance dose. The tacrolimus was commenced as a continuous intravenous infusion after reperfusion of the allograft and converted to a twice a day oral dosing upon restitution of alimentary function.
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G.J. Bond et al. expected to be less than 10 ng/mL and may well be unrecordable. In all groups, acute cellular rejection was diagnosed pathoclinically, with endoscopic monitoring and histopathologic examination of the allograft biopsy being the gold standard. Early and mild acute cellular rejection was treated with a steroid bolus and recycle, whereas more severe rejection and steroid-resistant rejection were treated with antibody therapy (OKT3 or rATG). In groups (i) and (ii) a third agent may then be added to the immunosuppression management. In the weaning patients (group [iii]), careful monitoring of immune activation in the allograft was essential. Rejection was treated according to its severity, and the patient placed on maintenance therapy (tacrolimus twice a day and daily steroids) until stability returned.
Fig. 1
Pediatric patient survival.
Target tacrolimus trough levels were 20 ng/mL initially, then 15 ng/mL after several months. (ii) Induction therapy, initially with cyclophosphamide (n = 16, 1995-1997) and subsequently with the interleukin-2 blocker daclizumab (n = 24, 1998-2001), in addition to the tacrolimus and steroid maintenance therapy as described above. Daclizumab was given as a 1 – to 2 – mg/kg body weight infusion for 5 doses, the first at the time of transplantation and the next 4 doses given every 2 weeks after transplantation. A third immunosuppressive agent (azathioprine [n = 16], mycophenolate mofetil [n = 2], or sirolimus [n = 16]) was added in both groups (i) and (ii) where considered necessary. (iii) Pretreatment/induction with antilymphocyte conditioning and steroid-free posttransplantation tacrolimus monotherapy (n = 37, 2002-2003). The rabbit antithymocyte globulin (rATG) was given as a 5-mg/kg body weight infusion in the perioperative period. In the pediatric population it was technically difficult to infuse the whole dose before reperfusion of the allograft; hence, the dose was divided and given pre and post reperfusion of the allograft. Steroids (10 mg/ kg body weight) were given at the time of infusion to control systemic side effects of the infusion. Immunosuppression posttransplantation was tacrolimus monotherapy alone, starting 24 hours after transplantation with an oral dose twice daily, aiming for tacrolimus trough levels of 10 to 15 ng/mL. At 60 to 90 days posttransplantation, if the recipient has been stable with no recent rejection episode, the dosing frequency of tacrolimus is weaned down, initially to once-a-day dosing, then every other day, then 3 times a week as tolerated. At this stage tacrolimus trough levels are
2. Results For the entire experience, with follow-up until March 2004, 69 of the 122 recipients (57%) were alive. Seven patients required retransplantation for acute rejection (n = 2), chronic rejection (n = 1), allograft liver failure secondary to native pancreatitis (n = 1), allograft dysfunction (n = 1), posttransplant lymphoproliferative disease (PTLD) (n = 1), and pseudoaneurysm of the aortic graft (n = 1). Five from group (i) were retransplanted, 4 under the same immunosuppression regimen, and 1 in group (ii). Two from group (ii) were retransplanted using the regimen of group (iii). The overall Kaplan-Meier patient/allograft survival is 81%/76% at 1 year, 62%/60% at 3 years, and 61%/51% at 5 years, respectively (Figs. 1 and 2). Induction
Fig. 2
Pediatric graft survival.
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sepsis (patient on FK single-dose monotherapy) and 1 with PTLD (patient treated with steroids for rejection episodes). Of the remaining 35 recipients, 18 are on tacrolimus monotherapy and 2 on sirolimus monotherapy, both converted because of complications of tacrolimus (1 for FKinduced hemolysis, 1 for FK neurotoxicity). One patient is on daily dosing of both FK and sirolimus with no steroids (patient with intestinal rejection but also renal dysfunction). A further 4 are on a once-a-day dosing of tacrolimus and lowdose daily steroids, 3 for GVH, and 1 for bhepaticQ changes in the liver allograft suggestive of mild rejection. Nine patients are on FK twice a day and steroids (daily [n = 7] or every other day [n = 2]), 3 having failed the attempted weaning process. One patient was unable to tolerate steroid treatment of liver rejection (gastrointestinal bleeding) and is currently on FK twice a day and azathioprine.
2.3. Weaning protocol Fig. 3
Pediatric patient survival induction vs noninduction.
therapies (groups [ii] and [iii]) showed marked improvements over maintenance therapy alone (group [i]) for both patient and allograft survival (Figs. 3 and 4). Strikingly, the 1-year patient/allograft survival is 71%/62%, 77%/75%, and 100%/100% for groups (i), (ii), and (iii), respectively.
2.1. Rejection rate The incidence of intestinal rejection within the first 90 days posttransplantation was 77% in group (i) and 78% in group (ii) (81% with cyclophosphamide, 75% with daclizumab). In group (iii) the rejection rate dropped to 49%. Similarly, the incidence of severe rejection, which was 38% in group (i) and 55% for group (ii), has decreased to 27% for group (iii). In the composite allografts (liver included), rejection of the liver occurred in 41%, 15%, and 29% in groups (i), (ii), and (iii), respectively. Rejection of the stomach and pancreas was rarely seen in any group. Chronic intestinal allograft rejection was encountered in 8% of group (i), 13% of group (ii), and as yet no cases in group (iii).
The criteria for weaning was met in 21 of the 37 recipients. Of these, 13 are on once-a-day dosing of tacrolimus with 4 on low-dose prednisone (3 for GVH and 1 for mild liver rejection). Two are on every other day dosing (1 on tacrolimus, 1 sirolimus), and 2 on 3 times a week dosing (1 on tacrolimus, 1 sirolimus). A patient on tacrolimus once a day unfortunately died of presumed line sepsis. The remaining 3 patients were on tacrolimus once a day (n = 2) or 3 times a week (n = 1) when the intestine rejected. All 3 required treatment with OKT3; however, no grafts were lost to rejection, and the patients are on tacrolimus twice-a-day therapy and prednisone. Interestingly, 11 of the 21 patients undergoing the weaning trial (52%) had intestinal allograft rejection within the first 60 days. All were successfully treated and subsequently able to participate in the weaning protocol. Of the 11, all but 1 are successfully
2.2. Immunosuppression dosing The remaining functional allografts in group (i) (n = 14, 27%) and (ii) (n = 18, 45%) are all still being treated with tacrolimus (FK) twice a day (aiming for trough levels of 1015 ng/mL) and daily steroids. In addition, 37% of groups (i) and (ii) were placed on a third immunosuppressive agent. In contrast, all the patients in group (iii) were commenced only on tacrolimus monotherapy. Steroids were only added briefly for biopsy-proven rejection of the intestine, rejection of the liver, or other immunologic reasons (graft versus host [GVH]). Currently, 35 of the 37 patients/allografts (95%) in group (iii) are surviving with only 2 deaths, 1 from line
Fig. 4
Pediatric graft survival induction vs noninduction.
278 weaning. The other 2 patients who failed the weaning did not have prior rejection.
2.4. Bone marrow augmentation We have previously reported at the 2003 International Small Bowel Symposia that attempts at developing chimerism and enhanced graft acceptance with the infusion of 3 to 5 108 donor bone marrow cells/kg recipient body weight has not resulted in any significant improvements in rejection rates or survival. Once again this was confirmed in this pediatric group when comparing those who received bone marrow augmentation and those that did not.
2.5. Opportunistic infections The infectious complication rate has markedly decreased over time. The cytomegalovirus (CMV) rate was highest with cyclophosphamide (56%), but down to 4% with daclizumab, giving an overall rate of 25% for group (ii). Likewise, the early rate for CMV in group (i) was 23%, and 11% for the later cohort, giving an overall rate of 19%. The lowest rate of CMV was in group (iii), with an incidence of 5%. The incidence of PTLD also decreased from 42% in group (i) to 18% in group (ii) to 3% in group (iii).
2.6. Graft versus host Graft versus host disease (GVHD) has not proven to be as significant a complication as was originally feared. The incidence of histologically documented GVHD was 12% in group (i), 4% in group (ii), and 8% in group (iii). However, GVH-type reaction (spurious mild fevers and rashes not diagnostic of GVHD) appears to be slightly more prevalent in the recent recipients (group iii). It has not caused any fatalities and has been treated with modifications in immunosuppression, mostly the addition of steroids for symptomatic rashes. Based on previous reports of chimerism and its impact on tolerance [24], the patients exhibiting this reaction were considered most likely to develop tolerance and an effort was made to wean these patients and minimize their immunosuppression early.
2.7. Nutritional assessment Nutritional autonomy (cessation of total parenteral nutrition) with good allograft function was rapidly and successfully achieved in 96% of the recipients. In group (iii) all patients are off total parenteral nutrition. Overall, in most patients, growth was maintained or improved toward what was normal for the patient’s age.
3. Discussion Intestinal and multivisceral transplantation has progressed significantly since 1990 [25-28]. Many factors are responsible for this improvement, but rapidly changing protocols and
G.J. Bond et al. major advances in both medical and surgical treatments make comparable statistical analysis difficult. However, modifications in immunosuppression have been at the forefront. The various immunosuppression regimen used in this experience were determined both by drug development and availability, as well as conceptual thoughts regarding intestinal transplantation immunology. This is reflected in the evolution of our protocols. No longer content with successful implantation and early results, it became important to focus on long-term outcomes. Avoidance of immunosuppression complications, especially those related to steroid therapy in children, by developing a strategy to minimize the requirements was the key. In fact, it could be said that the bartQ of successful intestinal transplantation is the management of immunosuppression from which stems most subsequent events, both beneficial and harmful. With tacrolimus, a more potent immunosuppressant than cyclosporin, intestinal transplantation became a reality. However, both rejection and infectious complications were common early on (group [i]). In an attempt to control rejection, more immunosuppression (induction therapy with cyclophosphamide and daclizumab, group [ii]) was added, which resulted in improved survival although rates of rejection did not improve. Concurrent advances in monitoring and preemptive treatment assisted in lowering the infectious complication rate. However, long-term outcomes were still unsatisfactory, and complication rates still unacceptably high. Recently, there has been a significant change in mentality toward the application of immunosuppression strategies [2931]. It has been suggested by Starzl and others [32-34], based on previous experimental and clinical experience, that the mechanism of clonal exhaustion and deletion is responsible for allograft acceptance. The key therapeutic principles are conditioning of the recipient with antibody pretreatment and minimal posttransplantation immunosuppression. This is diametrically opposed to the way immunosuppression management had been progressing with increasingly heavier immunosuppression resulting in immunologic unresponsiveness (groups [i] and [ii]). In our recent cohort of patients (group [iii]), the above key principles were adhered to with recipient pretreatment (rATG) and minimal posttransplantation immunosuppression (tacrolimus monotherapy). This did not prevent immune reactivity, as evidenced by continued rejection and high levels of microchimerism and GVH-type reaction in some patients. It did allow for improved graft acceptance, whereby patients were weaned in their immunosuppression requirements to levels never previously seen or considered systematically achievable. Initial early results with the latest protocol have been very encouraging, with no patient or graft lost in the first year of its use and 95% of patients and allografts currently surviving since the inception of the protocol 24 months ago. It is important to note that this protocol allows for alloreactivity to occur in an attempt to promote allograft
Evolutionary experience with immunosuppression in pediatric intestinal transplantation acceptance rather than prevent rejection through recipient immune inactivation from heavy immunosuppression as done previously. As alloreactivity can tip into frank rejection, careful monitoring and experience will help determine destructive immunity and the need to modify therapy sooner than later. This is especially the case in those patients undergoing weaning; however, to date, no patients or grafts have been lost in this group, and it is possible they may even undergo reweaning once stabilized. Importantly, infectious complications are at their lowest rates. Long-term outcomes await, especially the expectant extraorgan benefits from decreased levels of immunosuppression. Regardless of current improvements, this group of patients still remains very complex and extremely challenging to manage. However, as advancements continue, like those seen in immunosuppression, the outcome can only be beneficial to both the patients and those caring for them.
References [1] Starzl TE, Kaupp Jr HA, Brock DR, et al. Homotransplantation of multiple visceral organs. Am J Surg 1962;103:219 - 29. [2] Grant D, Wall W, Mimeault R, et al. Successful small-bowel/liver transplantation. Lancet 1990;335:181. [3] Starzl TE, Rowe MI, Todo S, et al. Transplantation of multiple abdominal viscera. JAMA 1989;261:1149 - 457. [4] Abu-Elmagd K. The history of intestinal transplantation. In: Hakim NS, Papalcis VE, editors. History of organ and cell transplantation. London, England7 Imperial College Press; 2003. p. 171 - 93 [Chapter 8]. [5] Goulet O, Revillon Y, Brousse N, et al. Successful small bowel transplantation in an infant. Transplantation 1992;53(4):940 - 3. [6] Todo S, Tzakis AG, Abu-Elmagd K, et al. Cadaveric small bowel and small bowel liver transplantation in humans. Transplantation 1992;53(2):369 - 76. [7] Todo S, Tzakis AG, Abu-Elmagd K, et al. Intestinal transplantation in composite visceral grafts or alone. Ann Surg 1992;216:223 - 34. [8] Starzl TE, Todo S, Tzakis AG, et al. The many faces of multivisceral transplantation. Surg Gynecol Obstet 1991;172:335 - 44. [9] Todo S, Reyes J, Furukawa H, et al. Outcome analysis of 71 intestinal transplantations. Ann Surg 1995;222:270 - 82. [10] DeVille D, Goyet J, Mitchell A, et al. En block combined reduced liver and small bowel transplants: from large donors to small children. Transplantation 2000;69:555 - 9. [11] Bueno J, Abu-Elmagd K, Mazariegos G, et al. Composite liver-small bowel allografts with preservation of donor duodenum and hepatic biliary system in children. J Pediatr Surg 2000;35:291 - 5. [12] Abu-Elmagd K, Fung J, Bueno J, et al. Logistics and technique for procurement of intestinal, pancreatic, and hepatic grafts from the same donor. Ann Surg 2000;232(5):680 - 7. [13] Kato T, O’Brien CB, Berho M, et al. Improved rejection surveillance in intestinal transplant recipients with frequent use of zoom video endoscopy. Transplant Proc 2000;32:1200. [14] Pappas PA, Saudubray JM, Tzakis AG, et al. Serum citrulline and rejection in small bowel transplantation: a preliminary report. Transplantation 2001;72(7):1212 - 6. [15] Green M, Bueno J, Sigurdsson L, et al. Unique aspects of the infectious complications of intestinal transplantation. Curr Opin Organ Transpl 1999;4:361 - 7. [16] Abu-Elmagd K, Reyes J, Bond G, et al. Clinical intestinal transplantation: a decade of experience at a single center. Ann Surg 2001;234(4):404 - 17.
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[17] Reyes J, Mazariegos G, Bond G, et al. History of pediatric organ transplantation: pediatric intestinal transplantation: historical notes, principles and controversies. Pediatr Transplant 2002;(6): 193 - 207. [18] Abu-Elmagd K, Reyes J, Todo S, et al. Clinical intestinal transplantation: new perspectives and immunologic considerations. J Am Coll Surg 1998;186(5):512 - 27. [19] Pinna AD, Weppler D, Nery JR, et al. Induction therapy for clinical intestinal transplantation: comparison of four different regimens. Transplant Proc 2000;32:1193. [20] Manez R, Kusne S, Green M, et al. Incidence and risk factors associated with the development of cytomegalovirus disease after intestinal transplantation. Transplantation 1995;59:1010 - 4. [21] Bueno J, Green M, Kocoshis S, et al. Cytomegalovirus infection after intestinal transplantation in children. Clin Infect Dis 1997;25: 1078 - 83. [22] Parizhskaya M, Redondo C, Demetris A, et al. Chronic rejection of small bowel grafts: a pediatric and adult study on risk factors and morphologic progression. Pediatr Dev Pathol 2003;6(3):240 - 50. [23] Abu-Elmagd K, Bond GJ, Murase N, et al. Tolerance for human intestinal transplantation. Transplantation 2002;74:38. [24] Murase N, Starzl TE, Tanabe M, et al. Variable chimerism, graftversus-host disease, and whole tolerance after different kinds of cell and whole organ transplantation from Lewis to Brown Norway rats. Transplantation 1995;60(2):158 - 71. [25] Grant D. Intestinal transplantation: 1997 report of the international registry. Intestinal transplant registry. Transplantation 1999;67:1061 - 4. [26] Reyes J, Bueno J, Kocoshis S, et al. Current status of intestinal transplantation in children. J Pediatr Surg 1998;33:243 - 54. [27] Abu-Elmagd K, Bond G, Reyes J, et al. Intestinal transplantation: a coming of age. Adv Surg 2002;36(4):65 - 101. [28] Grant D, Abu-Elmagd K, Reyes J, et al. 2003 report of the intestine transplant registry. A new era has dawned. Ann Surg 2004 [in press]. [29] Starzl TE, Murase N, Abu-Elmagd K, et al. Tolerogenic Immunosuppression for organ transplantation. Lancet 2003;361(9368):1502 - 10. [30] Tzakis AJ, Kato T, Nishida S, et al. Preliminary experience with campath (ClH) in intestinal and liver transplantation. Transplantation 2002;74:33. [31] Calne RY, Friend P, Moffat S, et al. Prope tolerance, perioperative campath1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet 1998;351:1701 - 2. [32] Starzl TE, Zinkernagel RM. Antigen localization and migration in immunity and tolerance. NEJM 1998;339:1905 - 13. [33] Starzl TE, Zinkernagel RM. Transplantation tolerance from a historical perspective. Nat Rev Immunol 2001;1(3):233 - 9. [34] Starzl TE, Demetris AJ, Trucco M, et al. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 1993;17:1127 - 52.
Discussion R. Meyers (Salt Lake City, UT): I just wanted to ask you about your current protocols for the management of your PTLD. Although your preconditioning has reduced the incidence, it is still a big problem in this patient population. I just wondered if you could comment on your standard approach to management. G. Bond (response): In the intestinal transplant community there are two ways of doing it, either preemptive treatment or monitoring and then treat when it arrives. I think the monitoring has really helped us to define that patient who is at risk. We put them on intravenous
280 DHPG (ganciclovir) routinely up to 2 to 3 months posttransplant and then wean it down to oral dosing and may finally stop, and then as we follow their EBV PCR levels if we notice a rise, we will reinstitute it or go from oral to IV, and if there is a further rise we will add CytoGam as well. M. Langham (Gainesville, FL): Thank you very much, Dr Bond. This is terrific work and documents the improvement in the results of intestinal transplantation to a point that is similar to where liver transplant was in the early 1980s which is light-years better than it has been in the past. How many of the patients that you have that are listed as both patient and graft survival are free of TPN, since the functional aspect of this is one thing that is important? Also, can you tell us whether or not selection of donors that are CMV and EBV negative has something
G.J. Bond et al. to do with the lower rates of those infections after transplant? G. Bond (response): Sure. Two very good questions. I flew through it very quickly. Almost all our patients are off TPN, 96%, so functionally they do very well. In our most recent group they are all off TPN. Some, however, are still requiring some IV fluids, although the vast majority are not. As far as CMV/EBV goes, we in the earlier period did avoid placing grafts, a CMV-positive graft into a CMVnegative recipient, up until just recently. We now believe with our monitoring and our better treatment, we can start to even break our own rule. If a very good organ comes up, we will now put a CMV-positive graft into a CMVnegative recipient, but I think the previous policy also did help the decreased CMV rate.
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Evolutionary experience with immunosuppression in pediatric intestinal transplantation Geoffrey J. Bond, George V. Mazariegos, Rakesh Sindhi, Kareem M. Abu-Elmagd, Jorge Reyes* Thomas E Starzl Transplantation Institute, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA Index words: Intestinal transplantation; Intestinal failure; Immunosuppression; Monotherapy; Steroid-free
Abstract Background/Purpose: Intestinal transplantation has developed to become the standard of care for patients with irreversible intestinal failure who are not responding to total parenteral nutrition. Once considered experimental, it has taken time and much effort for the procedure to become a clinical reality, with final acceptance primarily because of the vastly improved outcomes. Advances and novel modifications in immunosuppression have been at the forefront of these improvements. The authors review their evolutionary experience with intestinal transplantation, particularly relating changes in immunosuppression protocols to improved outcomes. Methods: From July 1990 to December 2003, 122 children received 129 intestinal containing allografts (70 liver/intestine, 42 isolated intestine, 17 multivisceral). Mean age was 5.3 F 5.2 years, and 55% were boys. Indications for transplantation were mostly short gut syndrome. The allografts were cadaveric, ABO identical (except one), with no immunomodulation. Bone marrow augmentation was used in 29% of the recipients since 1995. T-cell lymphoctytotoxic crossmatch was positive in 24% cases. Immunosuppression protocols can be divided into 3 categories: (i) maintenance tacrolimus and steroids (n = 52, 1990-1995, 1997-1998); (ii) addition of induction therapy with cyclophosphamide (n = 16, 1995-1997) then daclizumab (n = 24, 1998-2001). A third immunosuppressive agent was added in either group where increased immunosuppression was indicated; (iii) pretreatment/induction with antilymphocyte conditioning and steroid-free posttransplantation tacrolimus monotherapy (n = 37, 2002-2003). In this later group, if clinically stable at 60 to 90 days posttransplantation, and no recent rejection, the tacrolimus was weaned by decreasing frequency of dosing. Results: The overall Kaplan-Meier patient/graft survival was 81%/76% at 1 year, 62%/60% at 3 years, and 61%/51% at 5 years. Survival continues to improve, with 1-year patient/graft survival being 71%/62%, 77%/75%, and 100%/100% for groups (i), (ii), and (iii), respectively. Acute intestinal allograft rejection has decreased markedly in group (iii). The rate of infectious diseases, such as cytomegalovirus and Epstein-Barr virus, is lowest in group (iii). Graft-versus-host disease has not significantly increased with the latest protocol. Most importantly, the overall level of immunosuppression requirements has decreased markedly, with most patients in group (iii) being
Presented at the 35th Annual Meeting of the American Pediatric Surgical Association, Ponte Vedra, Florida, May 27-30, 2004. * Corresponding author. Tel.: +1 412 692 7867; fax: +1 412 692 6116. E-mail address: [email protected] (J. Reyes). 0022-3468/05/4001-0049$30.00/0 D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2004.09.020
Evolutionary experience with immunosuppression in pediatric intestinal transplantation
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on monotherapy. Of these, most had their monotherapy weaned down to spaced doses, something never systematically attempted or achieved in pediatric intestinal transplantation. Conclusions: Intestinal transplantation has progressed markedly over the last 13 years. Although there have been modifications in all aspects of the procedure, the story of intestinal transplantation has been the evolution of successful immunosuppression regimens. Our latest pretreatment/ induction conditioning and posttransplantation monotherapy strategy improves graft acceptance and lowers subsequent immunosuppression dosing requirements. It is expected this will overcome many of the complications related to the previously high immunosuppression requirements. Minimization of immunosuppression with avoidance of steroid therapy offers profound long-term benefits, especially in the pediatric population. The patients still remain challenging and complex in every aspect; however, these advances offer significant hope to both patients and caregivers alike. D 2005 Elsevier Inc. All rights reserved.
The intestine is the last solid abdominal organ to successfully be transplanted. Although it was initially included in multivisceral grafts in the 1960s [1], the outcomes were uniformly poor, most likely related to the immunogenicity of the lymphocyte-rich intestinal allograft and the limited immunosuppressants available to control the immune response. Up to the late 1980s there were only sporadic unsuccessful attempts at transplanting the intestine [2- 4]. The only long-term survivor from that era was an isolated intestine transplanted by the French group in 1989 under cyclosporin immunosuppression [5]. The introduction of tacrolimus in 1990 [6] allowed for routine successes with intestinal transplantation [7,8]. With this drug, the balance of host-versusgraft reaction could be controlled. The early days though were fraught with many difficulties, mostly related to infectious complications from initial over–immunosuppression or the need to treat rejection episodes with even stronger immunosuppressants (OKT3, a monoclonal antibody) [9]. With increasing experiences in intestinal transplantation, advances occurred in all aspects of the transplantation including the donor and recipient operation [10-12], monitoring of the allograft [13,14] and for infectious complications, [15] and immunosuppression management [16-19]. As newer immunosuppressive agents became available, these were added to various regimens which overall resulted in heavier immunosuppression. Although acute cellular rejection was better controlled and treated, there still were significant problems with infectious complications [15,20,21], chronic rejection [22], and drug toxicities. To this end, a new strategy in tolerance induction [23] was initiated with a goal to minimize the posttransplantation immunosuppression requirements. In this paper we outline the changes in the immunosuppression management over the last 13 years that have brought intestinal transplantation from what was previously considered an experimental procedure to the now accepted standard of care for patients with irreversible intestinal failure.
1. Materials and methods From July 1990 to December 2003, 122 children received 129 intestinal containing allografts at the Children’s Hospital of Pittsburgh. The mean age at transplantation was 5.3 F 5.2 years, ranging from 0.5 to 18 years. Of these 55% were boys and 45% girls. The indications for transplantation were short gut syndrome in 73%, dysmotility disorders (such as intestinal pseudoobstruction and Hirschsprung’s disease) in 17%, intestinal dysfunction (such as microvillus inclusion disease) in 7%, neoplasm (such as familial polyposis) in 2%, and hepatoportomesenteric thrombosis in 1%. The most common causes of short gut syndrome were volvulus (33%), gastroschisis (32%), intestinal atresia (15%), necrotizing enterocolitis (15%), and trauma (3%). The types of transplants were combined liver and intestine (54%), isolated intestine (33%), and multivisceral (13%) (stomach, duodenum, pancreas, intestine with liver [n = 13] and without liver [n = 4]). All donor grafts were cadaveric and ABO identical except one (O to A compatible). HLA matching was random and uniformly poor. There was no immune modulation of the allograft with either in vivo antilymphocyte therapy to the donor or ex vivo intestinal allograft irradiation. Donor bone marrow augmentation (n = 27) was used in 29% of the grafts from 1995 onwards. The T-cell lymphoctytotoxic crossmatch was positive in 24% of cases. Because of size disparity and the paucity of small organs for the younger recipients, allograft reduction (liver and/or intestine) has been used more recently. Immunosuppression regimens over the period can be divided into 3 basic groups: (i)
Tacrolimus and steroid maintenance therapy (n = 52, 1990-1995, 1997-1998). Steroids (solumedrol/prednisone) were given in high doses in the perioperative period and then tapered down over time to a single daily maintenance dose. The tacrolimus was commenced as a continuous intravenous infusion after reperfusion of the allograft and converted to a twice a day oral dosing upon restitution of alimentary function.
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G.J. Bond et al. expected to be less than 10 ng/mL and may well be unrecordable. In all groups, acute cellular rejection was diagnosed pathoclinically, with endoscopic monitoring and histopathologic examination of the allograft biopsy being the gold standard. Early and mild acute cellular rejection was treated with a steroid bolus and recycle, whereas more severe rejection and steroid-resistant rejection were treated with antibody therapy (OKT3 or rATG). In groups (i) and (ii) a third agent may then be added to the immunosuppression management. In the weaning patients (group [iii]), careful monitoring of immune activation in the allograft was essential. Rejection was treated according to its severity, and the patient placed on maintenance therapy (tacrolimus twice a day and daily steroids) until stability returned.
Fig. 1
Pediatric patient survival.
Target tacrolimus trough levels were 20 ng/mL initially, then 15 ng/mL after several months. (ii) Induction therapy, initially with cyclophosphamide (n = 16, 1995-1997) and subsequently with the interleukin-2 blocker daclizumab (n = 24, 1998-2001), in addition to the tacrolimus and steroid maintenance therapy as described above. Daclizumab was given as a 1 – to 2 – mg/kg body weight infusion for 5 doses, the first at the time of transplantation and the next 4 doses given every 2 weeks after transplantation. A third immunosuppressive agent (azathioprine [n = 16], mycophenolate mofetil [n = 2], or sirolimus [n = 16]) was added in both groups (i) and (ii) where considered necessary. (iii) Pretreatment/induction with antilymphocyte conditioning and steroid-free posttransplantation tacrolimus monotherapy (n = 37, 2002-2003). The rabbit antithymocyte globulin (rATG) was given as a 5-mg/kg body weight infusion in the perioperative period. In the pediatric population it was technically difficult to infuse the whole dose before reperfusion of the allograft; hence, the dose was divided and given pre and post reperfusion of the allograft. Steroids (10 mg/ kg body weight) were given at the time of infusion to control systemic side effects of the infusion. Immunosuppression posttransplantation was tacrolimus monotherapy alone, starting 24 hours after transplantation with an oral dose twice daily, aiming for tacrolimus trough levels of 10 to 15 ng/mL. At 60 to 90 days posttransplantation, if the recipient has been stable with no recent rejection episode, the dosing frequency of tacrolimus is weaned down, initially to once-a-day dosing, then every other day, then 3 times a week as tolerated. At this stage tacrolimus trough levels are
2. Results For the entire experience, with follow-up until March 2004, 69 of the 122 recipients (57%) were alive. Seven patients required retransplantation for acute rejection (n = 2), chronic rejection (n = 1), allograft liver failure secondary to native pancreatitis (n = 1), allograft dysfunction (n = 1), posttransplant lymphoproliferative disease (PTLD) (n = 1), and pseudoaneurysm of the aortic graft (n = 1). Five from group (i) were retransplanted, 4 under the same immunosuppression regimen, and 1 in group (ii). Two from group (ii) were retransplanted using the regimen of group (iii). The overall Kaplan-Meier patient/allograft survival is 81%/76% at 1 year, 62%/60% at 3 years, and 61%/51% at 5 years, respectively (Figs. 1 and 2). Induction
Fig. 2
Pediatric graft survival.
Evolutionary experience with immunosuppression in pediatric intestinal transplantation
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sepsis (patient on FK single-dose monotherapy) and 1 with PTLD (patient treated with steroids for rejection episodes). Of the remaining 35 recipients, 18 are on tacrolimus monotherapy and 2 on sirolimus monotherapy, both converted because of complications of tacrolimus (1 for FKinduced hemolysis, 1 for FK neurotoxicity). One patient is on daily dosing of both FK and sirolimus with no steroids (patient with intestinal rejection but also renal dysfunction). A further 4 are on a once-a-day dosing of tacrolimus and lowdose daily steroids, 3 for GVH, and 1 for bhepaticQ changes in the liver allograft suggestive of mild rejection. Nine patients are on FK twice a day and steroids (daily [n = 7] or every other day [n = 2]), 3 having failed the attempted weaning process. One patient was unable to tolerate steroid treatment of liver rejection (gastrointestinal bleeding) and is currently on FK twice a day and azathioprine.
2.3. Weaning protocol Fig. 3
Pediatric patient survival induction vs noninduction.
therapies (groups [ii] and [iii]) showed marked improvements over maintenance therapy alone (group [i]) for both patient and allograft survival (Figs. 3 and 4). Strikingly, the 1-year patient/allograft survival is 71%/62%, 77%/75%, and 100%/100% for groups (i), (ii), and (iii), respectively.
2.1. Rejection rate The incidence of intestinal rejection within the first 90 days posttransplantation was 77% in group (i) and 78% in group (ii) (81% with cyclophosphamide, 75% with daclizumab). In group (iii) the rejection rate dropped to 49%. Similarly, the incidence of severe rejection, which was 38% in group (i) and 55% for group (ii), has decreased to 27% for group (iii). In the composite allografts (liver included), rejection of the liver occurred in 41%, 15%, and 29% in groups (i), (ii), and (iii), respectively. Rejection of the stomach and pancreas was rarely seen in any group. Chronic intestinal allograft rejection was encountered in 8% of group (i), 13% of group (ii), and as yet no cases in group (iii).
The criteria for weaning was met in 21 of the 37 recipients. Of these, 13 are on once-a-day dosing of tacrolimus with 4 on low-dose prednisone (3 for GVH and 1 for mild liver rejection). Two are on every other day dosing (1 on tacrolimus, 1 sirolimus), and 2 on 3 times a week dosing (1 on tacrolimus, 1 sirolimus). A patient on tacrolimus once a day unfortunately died of presumed line sepsis. The remaining 3 patients were on tacrolimus once a day (n = 2) or 3 times a week (n = 1) when the intestine rejected. All 3 required treatment with OKT3; however, no grafts were lost to rejection, and the patients are on tacrolimus twice-a-day therapy and prednisone. Interestingly, 11 of the 21 patients undergoing the weaning trial (52%) had intestinal allograft rejection within the first 60 days. All were successfully treated and subsequently able to participate in the weaning protocol. Of the 11, all but 1 are successfully
2.2. Immunosuppression dosing The remaining functional allografts in group (i) (n = 14, 27%) and (ii) (n = 18, 45%) are all still being treated with tacrolimus (FK) twice a day (aiming for trough levels of 1015 ng/mL) and daily steroids. In addition, 37% of groups (i) and (ii) were placed on a third immunosuppressive agent. In contrast, all the patients in group (iii) were commenced only on tacrolimus monotherapy. Steroids were only added briefly for biopsy-proven rejection of the intestine, rejection of the liver, or other immunologic reasons (graft versus host [GVH]). Currently, 35 of the 37 patients/allografts (95%) in group (iii) are surviving with only 2 deaths, 1 from line
Fig. 4
Pediatric graft survival induction vs noninduction.
278 weaning. The other 2 patients who failed the weaning did not have prior rejection.
2.4. Bone marrow augmentation We have previously reported at the 2003 International Small Bowel Symposia that attempts at developing chimerism and enhanced graft acceptance with the infusion of 3 to 5 108 donor bone marrow cells/kg recipient body weight has not resulted in any significant improvements in rejection rates or survival. Once again this was confirmed in this pediatric group when comparing those who received bone marrow augmentation and those that did not.
2.5. Opportunistic infections The infectious complication rate has markedly decreased over time. The cytomegalovirus (CMV) rate was highest with cyclophosphamide (56%), but down to 4% with daclizumab, giving an overall rate of 25% for group (ii). Likewise, the early rate for CMV in group (i) was 23%, and 11% for the later cohort, giving an overall rate of 19%. The lowest rate of CMV was in group (iii), with an incidence of 5%. The incidence of PTLD also decreased from 42% in group (i) to 18% in group (ii) to 3% in group (iii).
2.6. Graft versus host Graft versus host disease (GVHD) has not proven to be as significant a complication as was originally feared. The incidence of histologically documented GVHD was 12% in group (i), 4% in group (ii), and 8% in group (iii). However, GVH-type reaction (spurious mild fevers and rashes not diagnostic of GVHD) appears to be slightly more prevalent in the recent recipients (group iii). It has not caused any fatalities and has been treated with modifications in immunosuppression, mostly the addition of steroids for symptomatic rashes. Based on previous reports of chimerism and its impact on tolerance [24], the patients exhibiting this reaction were considered most likely to develop tolerance and an effort was made to wean these patients and minimize their immunosuppression early.
2.7. Nutritional assessment Nutritional autonomy (cessation of total parenteral nutrition) with good allograft function was rapidly and successfully achieved in 96% of the recipients. In group (iii) all patients are off total parenteral nutrition. Overall, in most patients, growth was maintained or improved toward what was normal for the patient’s age.
3. Discussion Intestinal and multivisceral transplantation has progressed significantly since 1990 [25-28]. Many factors are responsible for this improvement, but rapidly changing protocols and
G.J. Bond et al. major advances in both medical and surgical treatments make comparable statistical analysis difficult. However, modifications in immunosuppression have been at the forefront. The various immunosuppression regimen used in this experience were determined both by drug development and availability, as well as conceptual thoughts regarding intestinal transplantation immunology. This is reflected in the evolution of our protocols. No longer content with successful implantation and early results, it became important to focus on long-term outcomes. Avoidance of immunosuppression complications, especially those related to steroid therapy in children, by developing a strategy to minimize the requirements was the key. In fact, it could be said that the bartQ of successful intestinal transplantation is the management of immunosuppression from which stems most subsequent events, both beneficial and harmful. With tacrolimus, a more potent immunosuppressant than cyclosporin, intestinal transplantation became a reality. However, both rejection and infectious complications were common early on (group [i]). In an attempt to control rejection, more immunosuppression (induction therapy with cyclophosphamide and daclizumab, group [ii]) was added, which resulted in improved survival although rates of rejection did not improve. Concurrent advances in monitoring and preemptive treatment assisted in lowering the infectious complication rate. However, long-term outcomes were still unsatisfactory, and complication rates still unacceptably high. Recently, there has been a significant change in mentality toward the application of immunosuppression strategies [2931]. It has been suggested by Starzl and others [32-34], based on previous experimental and clinical experience, that the mechanism of clonal exhaustion and deletion is responsible for allograft acceptance. The key therapeutic principles are conditioning of the recipient with antibody pretreatment and minimal posttransplantation immunosuppression. This is diametrically opposed to the way immunosuppression management had been progressing with increasingly heavier immunosuppression resulting in immunologic unresponsiveness (groups [i] and [ii]). In our recent cohort of patients (group [iii]), the above key principles were adhered to with recipient pretreatment (rATG) and minimal posttransplantation immunosuppression (tacrolimus monotherapy). This did not prevent immune reactivity, as evidenced by continued rejection and high levels of microchimerism and GVH-type reaction in some patients. It did allow for improved graft acceptance, whereby patients were weaned in their immunosuppression requirements to levels never previously seen or considered systematically achievable. Initial early results with the latest protocol have been very encouraging, with no patient or graft lost in the first year of its use and 95% of patients and allografts currently surviving since the inception of the protocol 24 months ago. It is important to note that this protocol allows for alloreactivity to occur in an attempt to promote allograft
Evolutionary experience with immunosuppression in pediatric intestinal transplantation acceptance rather than prevent rejection through recipient immune inactivation from heavy immunosuppression as done previously. As alloreactivity can tip into frank rejection, careful monitoring and experience will help determine destructive immunity and the need to modify therapy sooner than later. This is especially the case in those patients undergoing weaning; however, to date, no patients or grafts have been lost in this group, and it is possible they may even undergo reweaning once stabilized. Importantly, infectious complications are at their lowest rates. Long-term outcomes await, especially the expectant extraorgan benefits from decreased levels of immunosuppression. Regardless of current improvements, this group of patients still remains very complex and extremely challenging to manage. However, as advancements continue, like those seen in immunosuppression, the outcome can only be beneficial to both the patients and those caring for them.
References [1] Starzl TE, Kaupp Jr HA, Brock DR, et al. Homotransplantation of multiple visceral organs. Am J Surg 1962;103:219 - 29. [2] Grant D, Wall W, Mimeault R, et al. Successful small-bowel/liver transplantation. Lancet 1990;335:181. [3] Starzl TE, Rowe MI, Todo S, et al. Transplantation of multiple abdominal viscera. JAMA 1989;261:1149 - 457. [4] Abu-Elmagd K. The history of intestinal transplantation. In: Hakim NS, Papalcis VE, editors. History of organ and cell transplantation. London, England7 Imperial College Press; 2003. p. 171 - 93 [Chapter 8]. [5] Goulet O, Revillon Y, Brousse N, et al. Successful small bowel transplantation in an infant. Transplantation 1992;53(4):940 - 3. [6] Todo S, Tzakis AG, Abu-Elmagd K, et al. Cadaveric small bowel and small bowel liver transplantation in humans. Transplantation 1992;53(2):369 - 76. [7] Todo S, Tzakis AG, Abu-Elmagd K, et al. Intestinal transplantation in composite visceral grafts or alone. Ann Surg 1992;216:223 - 34. [8] Starzl TE, Todo S, Tzakis AG, et al. The many faces of multivisceral transplantation. Surg Gynecol Obstet 1991;172:335 - 44. [9] Todo S, Reyes J, Furukawa H, et al. Outcome analysis of 71 intestinal transplantations. Ann Surg 1995;222:270 - 82. [10] DeVille D, Goyet J, Mitchell A, et al. En block combined reduced liver and small bowel transplants: from large donors to small children. Transplantation 2000;69:555 - 9. [11] Bueno J, Abu-Elmagd K, Mazariegos G, et al. Composite liver-small bowel allografts with preservation of donor duodenum and hepatic biliary system in children. J Pediatr Surg 2000;35:291 - 5. [12] Abu-Elmagd K, Fung J, Bueno J, et al. Logistics and technique for procurement of intestinal, pancreatic, and hepatic grafts from the same donor. Ann Surg 2000;232(5):680 - 7. [13] Kato T, O’Brien CB, Berho M, et al. Improved rejection surveillance in intestinal transplant recipients with frequent use of zoom video endoscopy. Transplant Proc 2000;32:1200. [14] Pappas PA, Saudubray JM, Tzakis AG, et al. Serum citrulline and rejection in small bowel transplantation: a preliminary report. Transplantation 2001;72(7):1212 - 6. [15] Green M, Bueno J, Sigurdsson L, et al. Unique aspects of the infectious complications of intestinal transplantation. Curr Opin Organ Transpl 1999;4:361 - 7. [16] Abu-Elmagd K, Reyes J, Bond G, et al. Clinical intestinal transplantation: a decade of experience at a single center. Ann Surg 2001;234(4):404 - 17.
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[17] Reyes J, Mazariegos G, Bond G, et al. History of pediatric organ transplantation: pediatric intestinal transplantation: historical notes, principles and controversies. Pediatr Transplant 2002;(6): 193 - 207. [18] Abu-Elmagd K, Reyes J, Todo S, et al. Clinical intestinal transplantation: new perspectives and immunologic considerations. J Am Coll Surg 1998;186(5):512 - 27. [19] Pinna AD, Weppler D, Nery JR, et al. Induction therapy for clinical intestinal transplantation: comparison of four different regimens. Transplant Proc 2000;32:1193. [20] Manez R, Kusne S, Green M, et al. Incidence and risk factors associated with the development of cytomegalovirus disease after intestinal transplantation. Transplantation 1995;59:1010 - 4. [21] Bueno J, Green M, Kocoshis S, et al. Cytomegalovirus infection after intestinal transplantation in children. Clin Infect Dis 1997;25: 1078 - 83. [22] Parizhskaya M, Redondo C, Demetris A, et al. Chronic rejection of small bowel grafts: a pediatric and adult study on risk factors and morphologic progression. Pediatr Dev Pathol 2003;6(3):240 - 50. [23] Abu-Elmagd K, Bond GJ, Murase N, et al. Tolerance for human intestinal transplantation. Transplantation 2002;74:38. [24] Murase N, Starzl TE, Tanabe M, et al. Variable chimerism, graftversus-host disease, and whole tolerance after different kinds of cell and whole organ transplantation from Lewis to Brown Norway rats. Transplantation 1995;60(2):158 - 71. [25] Grant D. Intestinal transplantation: 1997 report of the international registry. Intestinal transplant registry. Transplantation 1999;67:1061 - 4. [26] Reyes J, Bueno J, Kocoshis S, et al. Current status of intestinal transplantation in children. J Pediatr Surg 1998;33:243 - 54. [27] Abu-Elmagd K, Bond G, Reyes J, et al. Intestinal transplantation: a coming of age. Adv Surg 2002;36(4):65 - 101. [28] Grant D, Abu-Elmagd K, Reyes J, et al. 2003 report of the intestine transplant registry. A new era has dawned. Ann Surg 2004 [in press]. [29] Starzl TE, Murase N, Abu-Elmagd K, et al. Tolerogenic Immunosuppression for organ transplantation. Lancet 2003;361(9368):1502 - 10. [30] Tzakis AJ, Kato T, Nishida S, et al. Preliminary experience with campath (ClH) in intestinal and liver transplantation. Transplantation 2002;74:33. [31] Calne RY, Friend P, Moffat S, et al. Prope tolerance, perioperative campath1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet 1998;351:1701 - 2. [32] Starzl TE, Zinkernagel RM. Antigen localization and migration in immunity and tolerance. NEJM 1998;339:1905 - 13. [33] Starzl TE, Zinkernagel RM. Transplantation tolerance from a historical perspective. Nat Rev Immunol 2001;1(3):233 - 9. [34] Starzl TE, Demetris AJ, Trucco M, et al. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 1993;17:1127 - 52.
Discussion R. Meyers (Salt Lake City, UT): I just wanted to ask you about your current protocols for the management of your PTLD. Although your preconditioning has reduced the incidence, it is still a big problem in this patient population. I just wondered if you could comment on your standard approach to management. G. Bond (response): In the intestinal transplant community there are two ways of doing it, either preemptive treatment or monitoring and then treat when it arrives. I think the monitoring has really helped us to define that patient who is at risk. We put them on intravenous
280 DHPG (ganciclovir) routinely up to 2 to 3 months posttransplant and then wean it down to oral dosing and may finally stop, and then as we follow their EBV PCR levels if we notice a rise, we will reinstitute it or go from oral to IV, and if there is a further rise we will add CytoGam as well. M. Langham (Gainesville, FL): Thank you very much, Dr Bond. This is terrific work and documents the improvement in the results of intestinal transplantation to a point that is similar to where liver transplant was in the early 1980s which is light-years better than it has been in the past. How many of the patients that you have that are listed as both patient and graft survival are free of TPN, since the functional aspect of this is one thing that is important? Also, can you tell us whether or not selection of donors that are CMV and EBV negative has something
G.J. Bond et al. to do with the lower rates of those infections after transplant? G. Bond (response): Sure. Two very good questions. I flew through it very quickly. Almost all our patients are off TPN, 96%, so functionally they do very well. In our most recent group they are all off TPN. Some, however, are still requiring some IV fluids, although the vast majority are not. As far as CMV/EBV goes, we in the earlier period did avoid placing grafts, a CMV-positive graft into a CMVnegative recipient, up until just recently. We now believe with our monitoring and our better treatment, we can start to even break our own rule. If a very good organ comes up, we will now put a CMV-positive graft into a CMVnegative recipient, but I think the previous policy also did help the decreased CMV rate.