Risk Factors for Rejection and Infection in Pediatric Liver Transplantation

Rejection and infection are important adverse events after pediatric liver transplantation, not previously subject to concurrent risk analysis. Of 2291 children (<18 years), rejection occurred at least once in 46%, serious bacterial/fungal or viral infections in 52%. Infection caused more deaths than rejection (5.5% vs. 0.6% of patients, p < 0.001). Early rejection (<6 month) did not contribute to mortality or graft failure. Recurrent/chronic rejection was a risk in graft failure, but led to retransplant in only 1.6% of first grafts. Multivariate predictors of bacterial/fungal infection included recipient age (highest in infants), race, donor organ variants, bilirubin, anhepatic time, cyclosporin (vs. tacrolimus) and era of transplant (before 2002 vs. after 2002); serious viral infection predictors included donor organ variants, rejection, Epstein-Barr Virus (EBV) naivety and era; for rejection, predictors included age (lowest in infants), primary diagnosis, donor-recipient blood type mismatch, the use of cyclosporin (vs. tacrolimus), no induction and era. In pediatric liver transplantation, infection risk far exceeds that of rejection, which causes limited harm to the patient or graft, particularly in infants. Aggressive infection control, attention to modifiable factors such as pretransplant nutrition and donor organ options and rigorous age-specific review of the risk/benefit of choice and intensity of immunosuppressive regimes is warranted. Rejection and infection are important adverse events after pediatric liver transplantation, not previously subject to concurrent risk analysis. Of 2291 children (<18 years), rejection occurred at least once in 46%, serious bacterial/fungal or viral infections in 52%. Infection caused more deaths than rejection (5.5% vs. 0.6% of patients, p < 0.001). Early rejection (<6 month) did not contribute to mortality or graft failure. Recurrent/chronic rejection was a risk in graft failure, but led to retransplant in only 1.6% of first grafts. Multivariate predictors of bacterial/fungal infection included recipient age (highest in infants), race, donor organ variants, bilirubin, anhepatic time, cyclosporin (vs. tacrolimus) and era of transplant (before 2002 vs. after 2002); serious viral infection predictors included donor organ variants, rejection, Epstein-Barr Virus (EBV) naivety and era; for rejection, predictors included age (lowest in infants), primary diagnosis, donor-recipient blood type mismatch, the use of cyclosporin (vs. tacrolimus), no induction and era. In pediatric liver transplantation, infection risk far exceeds that of rejection, which causes limited harm to the patient or graft, particularly in infants. Aggressive infection control, attention to modifiable factors such as pretransplant nutrition and donor organ options and rigorous age-specific review of the risk/benefit of choice and intensity of immunosuppressive regimes is warranted. In pediatric liver transplantation, improved patient and graft survival is attributed to advances in surgery and improved immunosuppression regimens (1Colombani PM Dunn SP Harmon WE Magee JC McDiarmid SV Spray TL Pediatric transplantation.Am J Transplant. 2003; 3: 53-63Crossref PubMed Scopus (46) Google Scholar). Advances in immunosuppression have been concentrated on preventing rejection, and indeed the use of such agents has led to a decreased rate of acute cellular rejection and graft loss from rejection (2Martin SR Atkison P Anand R Lindblad AS SPLIT Research GroupStudies of Pediatric Liver Transplantation 2002: Patient and graft survival and rejection in pediatric recipients of a first liver transplant in the United States and Canada.Pediatr Transplant. 2004; 8: 273-283Crossref PubMed Scopus (140) Google Scholar). However, potent immunosuppression imparts a risk for life-threatening infection and other adverse effects. One challenge for the physician managing children after liver transplant is to balance these risks. Outcomes might be improved if modifiable risks are better characterized. Unfortunately, no large-scale studies have concurrently evaluated outcomes and risk factors for both rejection and all types of infection. The imperative for such a study is emphasized by recent data, which suggest that morbidity and mortality from infections in children after liver transplantation may exceed those for rejection (3Utterson EC Shepherd RW Sokol RJ et al.Biliary atresia: Clinical profiles, risk factors, and outcomes of 755 patients listed for liver transplantation.J Pediatr. 2005; 147: 180-185Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar,4Jain A Mazariegos G Kashyap R et al.Pediatric liver transplantation: A single center experience spanning 20 years.Transplantation. 2002; 73: 941-947Crossref PubMed Scopus (116) Google Scholar). All children receiving their first transplant enrolled in the SPLIT Registry between 1995 and 2006 were included in this data analysis. All SPLIT centers have Institutional Review Board approval and individual informed consent is obtained from parents and/or guardians (5Hollenbeak CS Alfrey EJ Sheridan K Burger TL Dillon PW Surgical site infections following pediatric liver transplantation: Risks and costs.Transpl Infect Dis. 2003; 5: 72-78Crossref PubMed Scopus (43) Google Scholar, 6Quiros-Tejeira RE Ament ME McDiarmid SV et al.Late-onset bacteremia in uncomplicated pediatric liver-transplant recipients after a febrile episode.Transpl Int. 2002; 15 (Epub 2002 Sep 19.): 502-507Crossref Scopus (2) Google Scholar, 7Their M Holmberg C Lautenschlager I Hockerstedt K Jalanko H Infections in pediatric kidney and liver transplant patients after perioperative hospitalization.Transplantation. 2000; 69: 1617-1623Crossref PubMed Scopus (30) Google Scholar). Coded information is submitted to the SPLIT data-coordination center at the time of listing for liver transplant (LT). Follow-up data were submitted on a biannual basis pre- and post-LT in the first 2 years and yearly, thereafter. There is long-term reporting of data related to events such as LT, death, allograft rejection, posttransplant complications, including infections and serious viral infection [symptomatic Epstein-Barr Virus (EBV) and cytomegalovirus (CMV) disease and EBV-related posttransplant lymphoproliferative disease (PTLD)]. For this study, database elements pertaining to deaths and graft losses due to infection and rejection were analyzed and causes of death and graft failure tabulated, including probability of posttransplant patient and graft survival, probability of rejection, probability of bacterial and fungal infection in the first 30 days and probability of serious viral infection in the first 15 months posttransplant. These time periods were chosen for the purposes of the detailed risk analyses for infections, as they represent the peak periods for the development of these types of infections (5Hollenbeak CS Alfrey EJ Sheridan K Burger TL Dillon PW Surgical site infections following pediatric liver transplantation: Risks and costs.Transpl Infect Dis. 2003; 5: 72-78Crossref PubMed Scopus (43) Google Scholar, 6Quiros-Tejeira RE Ament ME McDiarmid SV et al.Late-onset bacteremia in uncomplicated pediatric liver-transplant recipients after a febrile episode.Transpl Int. 2002; 15 (Epub 2002 Sep 19.): 502-507Crossref Scopus (2) Google Scholar, 7Their M Holmberg C Lautenschlager I Hockerstedt K Jalanko H Infections in pediatric kidney and liver transplant patients after perioperative hospitalization.Transplantation. 2000; 69: 1617-1623Crossref PubMed Scopus (30) Google Scholar, 8George DL Arnow PM Fox A et al.Patterns of infection after pediatric liver transplantation.Am J Dis Child. 1992; 146: 924-929PubMed Google Scholar, 9Sokal EM Antunes H Beguin C et al.Early signs and risk factors for the increased incidence of Epstein-Barr virus-related posttransplant lymphoproliferative diseases in pediatric liver transplant recipients treated with tacrolimus.Transplantation. 1997; 64: 1438-1442Crossref PubMed Scopus (161) Google Scholar, 10Mellon A Shepherd RW Faoagali JL et al.Cytomegalovirus infection after liver transplantation in children.J Gastroenterol Hepatol. 1993; 8: 540-544Crossref PubMed Scopus (24) Google Scholar). Infants are defined as <1 year of age. Rejection was listed as occurrence of hyperacute, acute cellular or chronic rejection requiring specific treatment at any time after transplant. Serious infection was defined by culture-proven bacterial and fungal infections and culture, seroconversion on sequential serology or polymerase chain reaction-proven CMV disease, EBV disease and biopsy-confirmed PTLD. A wide range of potential demographic, illness severity, surgical and immunological risk factors were selected to be evaluated in a risk analysis for both rejection and infection, as defined above, including assessment of an era effect (before 2002 vs. after 2002). Patients were grouped into proportions experiencing each event. Kaplan–Meier probability estimates were used to predict patient and graft survival after LT. Univariate and multivariate analyses were performed using the aforementioned risk factors for rejection and infection. The Cox proportional hazards model was used to test univariate and multivariate associations for rejection and for viral infections. The Logistic regression model was used for evaluating risk factors associated with bacterial/fungal infections. Factors significant at a p-value of 0.1 for bacterial, fungal or viral infections and 0.15 for rejection in the univariate analyses were used in the multivariate model. Next, a backward-elimination procedure was performed to obtain those risk factors that were significant at a p-value of 0.05 from the multivariate analysis. The likelihood-ratio test was used to test significance, and model simplification continued until the reduced model yielded significant worsening of fit at a p-value of 0.05 (SAS System for Windows, v 9.1; SAS Institute, Cary, NC). Of 2291 patients enrolled in SPLIT who received their first transplant between January 1994 and May 2006, 9% (n = 200) died after their first transplant and 10% (n = 236) were retransplanted (Table 1). Of those receiving two to five transplants, a further 74 died (31% of retransplants). Thus, overall 274 patients have died (12% of total) and 2017 (88%) have survived. Actuarial patient survival after the first transplant, irrespective of the number of retransplants was 89.8% and 87.9% at 1 and 2 years, respectively (Figure 1A). After a second transplant these were 73.8% and 70.2% at 1 and 2 years, respectively (data not shown). Actuarial graft survival was 84.0% at 1 year and 77.3% at 4 years (Figure 1B).Table 1Mortality after liver transplantation in children, particularly with respect to rejection and infectionTransplants (number)12345TotalPatients229123632212291Deaths200631001274 (12% of patients)Causes of DeathInfection (total)50173070, 26% of deaths (3.1% of patients)Bacterial2511339, 56% of infection deathsFungal5207, 10% of infection deathsPTLD92011 PTLD, 16% of infection deathsEBV Disease300CMV disease010Other810Total viral infection deaths = 13 (19% of infection deaths)Multiorgan failure20141136 (13% of deaths)Cardiopulmonary257234 (12% of deaths)Renal failure1Graft failure409150 (18% of deaths)Primary non-function9413 (26% of deaths from graft)Hepatic Artery Thrombosis99 (18% of deaths from graft)Recurrent disease9110 (20% of deaths from graft)Other liver failure94114 (28% of deaths from graft)Acute rejection22 (4% of deaths from graft)Chronic rejection22 (4% of deaths from graft)Brain injury275234 (12% of deaths)GI surgical complications4318 (3% of deaths)Malignancy14115 (5% of deaths)Other206Primary causes of death after first and in 2291 children as listed in the SPLIT as number and of deaths after each transplant. that infection caused more deaths than rejection in a causes of death after first and in 2291 children as listed in the SPLIT as number and of deaths after each transplant. that infection caused more deaths than rejection 1 the primary of death following first or Infection was the of death, listed as the primary of death in patients (3.1% of all the due to bacterial with viral and fungal infections for and 10% of infection Infection for of first transplant of second transplant deaths and of transplant Infection was listed as to death in 74 patients primary of death was failure, failure or graft failure (data not shown). Infection or to the deaths of of patients, for of In rejection or to the deaths of of all patients, for of Rejection was the primary of death graft failure in only 4 patients overall of all patients, of rejection may have to the death of patients, rejection was the for retransplant in patients, of died after retransplant univariate rejection was not a risk in including rejection in the first months after transplant, and or of or of rejection overall hazards and = and was a risk of death from infection than from rejection (3.1% vs. of patients or vs. of p < 0.001). causes of death (Table included failure and failure (n = of all graft failure first or second the of further retransplant (n = (n = and (n = in of patients receiving a primary graft retransplants for graft failure, with or surgical and primary graft for the and retransplants were to infection in the graft Rejection was a for graft failure and retransplant in of the first of these for chronic that of the rejection was with only 1.6% of all patients requiring retransplant for graft failure due to of to after first and in 2291 children as listed in the SPLIT for graft and liver that of second transplants, rejection for only of the primary graft There are patients with primary for the second transplant and with primary for the transplant. in a that of second transplants, rejection for only of the primary graft There are patients with primary for the second transplant and with primary for the transplant. univariate the occurrence of rejection in the first months after transplant or a of 1 of rejection graft survival hazards p = and p = and of rejection, the hazards was p = In those patients receiving two or more retransplants for any only two patients further graft due to rejection and of due to Thus, rejection in the first months and single of rejection did not contribute to graft failure, rejection was a risk rejection to graft failure and in only of all of patients at least of rejection months of transplant, serious bacterial or fungal infections and serious viral infections months after liver transplant. There was a significant in both infection and rejection The rejection rate was in those as with vs. patient p < the time to first rejection days vs. days was not significant = the bacterial or fungal infection rate was in and in vs. p < as was the viral infection rate vs. p = Of the bacterial infections were infections, were were bacterial were infections, were infections, were and were Of the fungal infections, were were were and were infections. For serious viral infections, the overall CMV disease rate was and the EBV disease rate was with a rate of those with CMV disease more in the first 30 days this the first 30 of those with EBV disease occurred 30 days posttransplant. caused or illness in (n = univariate age was a significant risk in the development of CMV or EBV disease (data not and the rate was in patients as to that in vs. p < 0.001). CMV and EBV at the time of transplant was in for CMV and for Of were and were children at the time of transplant. Of those <1 year of were patients, on may have Of the patients, of those CMV at transplant and of those EBV at transplant viral infection or EBV the first 15 months posttransplant. Of the potential risk factors for rejection analyzed in the univariate model (data not factors significant at 0.15 included age at transplant, primary diagnosis, primary immunosuppression vs. tacrolimus), use of or era of transplant (before 2002 vs. after donor-recipient time, use in the first days posttransplant and Factors not to be significant included race, factors the time, patient at transplant and a range of immunological factors, including donor age and donor recipient or In the multivariate only age at transplant, primary diagnosis, use in the first era of transplant and immunosuppression as risk factors (Table Of is that liver transplantation in has a rejection risk of other analysis of risk factors for rejection, bacterial/fungal infection and serious viral infections after liver transplantation in children (n = risk patients in A have risk of with risks and the are for other factors in the = or liver blood use the first of fungal of anhepatic of recipient EBV is defined as treated bacterial or fungal infections as culture-proven infections in the first 30 and serious viral infections as Epstein-Barr disease or lymphoproliferative Of risk factors evaluated by univariate those significant at a p-value of 0.1 for bacterial, fungal or viral infections and 0.15 for rejection were used in the multivariate and a backward-elimination procedure was performed to obtain those significant risk factors risk patients in A have risk of with risks and the are for other factors in the = in a Rejection is defined as treated bacterial or fungal infections as culture-proven infections in the first 30 and serious viral infections as Epstein-Barr disease or lymphoproliferative Of risk factors evaluated by univariate those significant at a p-value of 0.1 for bacterial, fungal or viral infections and 0.15 for rejection were used in the multivariate and a backward-elimination procedure was performed to obtain those significant risk factors For bacterial infections, significant factors in the univariate analysis included a wide range of factors race, primary and era of factors and and bilirubin, and at transplant, time on the patient surgical factors donor organ anhepatic and immunological factors donor age and vs. at In the multivariate analysis (Table race, year of transplant, and organ donor type were significant risk Of for bacterial infections than who received donor or liver were at The are more to be in this risk in this age For viral infections, in the univariate significant risk factors included and were including rejection, cyclosporin use and era of transplant. disease factors were not but as for bacterial infections, those who received donor or liver were at Of these significant factors in the univariate only rejection risk era of transplant and organ donor were significant in the multivariate analysis (Table analysis of data, from the of pediatric liver outcomes and risk factors in to rejection and infection, both important and adverse events after liver There is no concurrent analysis with which to these data, which a of outcomes centers in analyses from the database this concurrent study (2Martin SR Atkison P Anand R Lindblad AS SPLIT Research GroupStudies of Pediatric Liver Transplantation 2002: Patient and graft survival and rejection in pediatric recipients of a first liver transplant in the United States and Canada.Pediatr Transplant. 2004; 8: 273-283Crossref PubMed Scopus (140) Google EC Shepherd RW Sokol RJ et al.Biliary atresia: Clinical profiles, risk factors, and outcomes of 755 patients listed for liver transplantation.J Pediatr. 2005; 147: 180-185Abstract Full Text Full Text PDF PubMed Scopus (163) Google SV Anand R SPLIT Research GroupStudies of Pediatric Liver Transplantation A of the 2003; Scholar). infection and rejection are but these data that the risk from infection far exceeds that from rejection, particularly in a that detailed analysis. Rejection to and was not a risk in and the risk of graft failure from rejection was limited to chronic or rejection, which in was of rejection and rejection in the first months were not predictors of graft failure, that acute cellular rejection was In infection was the of death and caused more morbidity than age was an important risk for infections, but a risk for rejection, and the rate of rejection, the rate of bacterial or fungal infection and the rate of with These overall risk analysis were of the in the risks of both rejection and infection 2002 after 2002 = which may be by improved immunosuppression and and the to and immunosuppression SV Anand R Lindblad AS SPLIT Research GroupStudies of Pediatric Liver 2002 of and immunosuppressive in pediatric liver transplantation in the United States and Canada.Pediatr Transplant. 2004; 8: PubMed Scopus Google Scholar). risk factors for bacterial and fungal infections included recipient of illness factors and surgical and for serious viral infections, the primary immunosuppression used and rejection increased these data the that choice and/or intensity of primary immunosuppression are modifiable risk factors for infection, particularly for serious viral infections, and particularly for infants. by and blood and use at least in this age be Infants are in a of are more CMV and EBV but of a for organ failure due to rejection, and from immunosuppression Thus, a rigorous age-specific review of the choice and intensity of the risk of rejection is in pediatric liver Of to these data is the development and use of more potent immunosuppressive regimens SV Anand R Lindblad AS SPLIT Research GroupStudies of Pediatric Liver 2002 of and immunosuppressive in pediatric liver transplantation in the United States and Canada.Pediatr Transplant. 2004; 8: PubMed Scopus Google Scholar, SV Anand R Lindblad AS and of the of Pediatric Liver Transplantation Research of a pediatric liver disease to predict in children liver 2002; PubMed Scopus Google Scholar, A A in pediatric liver and transplantation: A at the Gastroenterol 2005; Scopus Google Scholar, JC C induction associated with has better with in pediatric donor liver 2005; PubMed Scopus Google Scholar, R Pediatric liver transplantation with 2003; PubMed Scopus Google Scholar, R A A M of induction immunosuppression in pediatric liver transplant Transplant. 2005; PubMed Scopus Google Scholar, A in pediatric organ transplantation: and Transplant. PubMed Scopus Google for induction or and is that studies that use these agents an rejection but have not included a detailed of infection risk JC C induction associated with has better with in pediatric donor liver 2005; PubMed Scopus Google Scholar, R Pediatric liver transplantation with 2003; PubMed Scopus Google Scholar, R A A M of induction immunosuppression in pediatric liver transplant Transplant. 2005; PubMed Scopus Google Scholar). For of by such as may be as a for patients with but their use in long-term studies in particularly with to the risk of serious and other infections A in pediatric organ transplantation: and Transplant. PubMed Scopus Google M et in transplant PubMed Scopus Google Scholar). In age and risk evaluating the use of For the use of or induction agents may be in their risk of rejection and more of the of their In all age potent immunosuppressive regimens have other A in pediatric organ transplantation: and Transplant. 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PubMed Scopus Google be particularly to the risk of these in or is a risk particularly in (3Utterson EC Shepherd RW Sokol RJ et al.Biliary atresia: Clinical profiles, risk factors, and outcomes of 755 patients listed for liver transplantation.J Pediatr. 2005; 147: 180-185Abstract Full Text Full Text PDF PubMed Scopus (163) Google modifiable by Shepherd RW et in children with liver disease for liver transplantation: to Gastroenterol Hepatol. 5: PubMed Scopus Google Shepherd RW et in children with liver A of a J 1992; PubMed Scopus Google Scholar). For that are not the type of donor organ donor and donor organ vs. to be a in both bacterial and viral infections, but not Surgical from the use of these may the potential for bacterial and fungal infections. 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