Thrombotic microangiopathy after lung transplantation.

BACKGROUND: Thrombotic microangiopathy (TMA) is a well-recognized complication after transplantation. The purpose of this study was to describe our center's experience with this complication after lung transplantation. METHODS: We retrospectively reviewed cases of TMA among patients who underwent lung transplantation between January 1, 1999 and December 31, 2003 (n = 257). The cases were characterized and the outcomes were analyzed. Univariate and multivariate Cox regression models were constructed to identify potential risk factors for TMA. RESULTS: Twenty-four cases of TMA developed in 20 recipients. Thirteen cases occurred in the setting of another illness and 11 cases were isolated complications. Multivariate Cox regression models identified female gender, history of TMA, and the immunosuppressive regimen as independent predictors of TMA. Maintenance immunosuppression with the combination of a calcineurin inhibitor and sirolimus carried a significantly higher risk of TMA than a calcineurin inhibitor alone. After the diagnosis of TMA, calcineurin inhibitors were stopped in 18 cases; however, in 6 cases in which the onset of TMA coincided with the addition of sirolimus to a calcineurin inhibitor, only sirolimus was discontinued. Plasmapheresis was performed for severe cases (n = 10). TMA remitted in all cases, and an alternate calcineurin inhibitor was introduced in 14 cases. TMA recurred in 4 recipients, a median 253 days after the initial episode. The median survival after the onset of TMA was 377 days. CONCLUSION: TMA is a serious complication after lung transplantation, and the risk is highest when sirolimus is used in combination with a calcineurin inhibitor.

The significance of a single episode of minimal acute rejection after lung transplantation.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) remains the leading obstacle to better long-term outcomes after lung transplantation. Acute rejection has been identified as the primary risk factor for BOS, but the impact of minimal acute rejection, especially a solitary episode, has usually been discounted as clinically insignificant. METHODS: We performed a retrospective cohort study of 259 adult lung transplant recipients to determine the risk of BOS associated with a single episode of A1 rejection, without recurrence or subsequent progression to a higher grade. The cohort was divided into 3 groups based on the severity of acute rejection (none, single episode of A1, and single episode of A2). We determined the risks of BOS stages 1, 2, 3, and death for each group using univariate and multivariate Cox regression analyses. RESULTS: A solitary episode of A1 rejection was a significant risk factor for BOS stages 1 and 2, but not stage 3 or death, in the univariate analysis. Multivariate Cox regression models confirmed that the risk of BOS attributable to a single episode of A1 rejection was independent of other potential risk factors, such as community acquired respiratory viral infections, number of HLA mismatches, and cytomegalovirus pneumonitis. Likewise, univariate and multivariate analyses demonstrated that a single episode of A2 rejection was a significant risk factor for all stages of BOS but not death. CONCLUSIONS: A single episode of minimal acute rejection without recurrence or subsequent progression to a higher grade is a significant predictor of BOS independent of other risk factors.

Reliability for grading acute rejection and airway inflammation after lung transplantation.

BACKGROUND: The Lung Rejection Study Group (LRSG) created a scheme for grading acute allograft rejection in 1990 and then revised it in 1996, but virtually no studies have evaluated the reliability of this formulation. This investigation assessed the reliability of the current LRSG system by determining inter- and intrareader agreement for grading transbronchial biopsy samples from lung transplant recipients. METHODS: Biopsy samples from a cohort of 204 recipients were reviewed and classified by a single pathologist who was blinded to original interpretations. The "A" and "B" rejection grades from this contemporary review were compared with original grades by the kappa statistic. RESULTS: For "A" grading, weighted kappa was 0.65 (95% confidence interval [CI] 0.60-0.70) for interreader agreement (n = 529 specimens) and 0.65 (95% CI 0.53-0.76) for intrareader agreement (n = 97 specimens). For "B" grading, weighted kappa was 0.26 (95% CI 0.14-0.39) for interreader agreement (n = 164 specimens) and 0.33 (95% CI 0.15-0.51) for intrareader agreement (n = 58 specimens). CONCLUSIONS: On the basis of the analysis of the LRSG scheme, "A" grades exhibit very good reliability, but "B" grades have only fair reliability, and steps to improve this shortcoming should be taken.

Abdominal-pelvic lymphoproliferative disease after lung transplantation: presentation and outcome.

BACKGROUND: Lymphoproliferative disease (LPD) is a well-recognized complication after lung transplantation. However, its presentation in the abdomen and pelvis has not been previously detailed. METHODS: We retrospectively identified cases of abdominal-pelvic LPD in lung transplant recipients. The cases were characterized clinically, and the outcomes were analyzed. RESULTS: Abdominal-pelvic LPD was identified in 19 of 603 adult patients who underwent lung or heart-lung transplantation at Barnes-Jewish Hospital between July 1, 1988 and December 31, 2001. The median time from transplantation to the onset of LPD was 5.8 years. Three cases presented early after transplantation (median, 175 days), and 16 cases presented late (median, 2,255 days). The time to diagnosis of LPD was significantly shorter for Epstein-Barr virus (EBV)-seronegative than for EBV-seropositive recipients (median, 175 vs. 2255 days; log-rank, P<0.001). Seventeen cases were non-Hodgkin's lymphomas, one was a Burkitt's lymphoma, and one was an atypical lymphoid proliferation. Among the 19 cases, 12 involved the gastrointestinal tract and 7 occurred in other sites. Immunosuppressive therapy was decreased in all patients. Eleven underwent surgical resection, and nine received chemotherapy. Sixteen patients have died, and 14 deaths were attributable to LPD. The median time from the diagnosis of LPD to death was 68 days. CONCLUSIONS: Abdominal-pelvic LPD is typically a late complication after lung transplantation; however, when it occurs early, it may be related to a primary EBV infection. This form of LPD is most frequently a non-Hodgkin's lymphoma, and despite aggressive therapy, the prognosis is poor.

Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation.

BACKGROUND: Because the development of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) after lung transplantation has been associated with acute and chronic rejection, we implemented a clinical protocol to screen all transplant recipients for DSA and preemptively treat those who developed DSA with rituximab and intravenous immune globulin (IVIG), or IVIG alone. METHODS: We conducted a prospective observational study of this protocol and used the LABScreen Single Antigen assay to detect DSA after transplantation. We compared the incidence of acute rejection, lymphocytic bronchiolitis, and bronchiolitis obliterans syndrome (BOS) between those who developed DSA and those who did not using Cox proportional hazards models. We used the Kaplan-Meier method to compare freedom from BOS and survival between those who had persistent DSA and those who had successful depletion of DSA. RESULTS: Among 116 recipients screened, DSA developed in 65 during the study period. Those who developed DSA and received antibody-directed therapy had a similar incidence of acute rejection, lymphocytic bronchiolitis, and BOS as those who did not develop DSA. Furthermore, recipients who had successful depletion of DSA had greater freedom from BOS and better survival than those who had persistent DSA. Finally, those treated for DSA had a similar incidence of infectious complications as those who did not develop DSA. CONCLUSIONS: The development of DSA is surprisingly common after lung transplantation. Antibody-directed therapy may reduce the risk of rejection associated with DSA, but a randomized controlled trial is necessary to critically evaluate the efficacy of this treatment protocol.

Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome.

RATIONALE: Primary graft dysfunction is a common complication after lung transplantation and a significant risk factor for short- and long-term mortality. OBJECTIVE: We examined the impact of primary graft dysfunction on bronchiolitis obliterans syndrome. METHODS: We performed a retrospective cohort study of 334 adult lung transplant recipients at our program and graded the severity of primary graft dysfunction according to the International Society for Heart and Lung Transplantation definition. We evaluated the impact of primary graft dysfunction on acute rejection, lymphocytic bronchitis, and bronchiolitis obliterans syndrome stage 1, using univariable and multivariable Cox proportional hazards models. MAIN RESULTS: Among the 334 recipients, 65 did not have primary graft dysfunction (grade 0), 130 had grade 1, 69 had grade 2, and 70 had grade 3. In the univariable analysis, all grades of primary graft dysfunction were associated with a significantly increased risk of bronchiolitis obliterans syndrome stage 1 (grade 1: relative risk [RR] = 1.73; grade 2: RR = 2.13; and grade 3: RR = 2.53, compared with grade 0). The multivariable model demonstrated that the increased risk of bronchiolitis obliterans syndrome associated with primary graft dysfunction was independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections. However, there was no association between primary graft dysfunction and acute rejection or lymphocytic bronchitis. CONCLUSIONS: Primary graft dysfunction is associated with an increased risk of bronchiolitis obliterans syndrome independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections, and this risk is directly related to the severity of primary graft dysfunction.

A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation.

BACKGROUND: The optimal maintenance immunosuppressive regimen after lung transplantation is uncertain. METHODS: We conducted a randomized controlled trial of tacrolimus versus cyclosporine in combination with azathioprine and prednisone after lung transplantation. Ninety adults were randomized to tacrolimus (n = 44) or cyclosporine (n = 46). The primary end point was a composite of a cumulative acute rejection A score of 3 or higher, a cumulative lymphocytic bronchitis B score of 4 or higher, or the onset of bronchiolitis obliterans syndrome (BOS) stage 0-p. RESULTS: Recipients randomized to cyclosporine were significantly more likely to develop the primary end point than those randomized to tacrolimus. During the study period, the primary end point developed in 39 of 46 cyclosporine subjects compared with 24 of 44 tacrolimus subjects (p = 0.002); acute rejection or lymphocytic bronchitis end points developed in 29 of 46 cyclosporine subjects compared with 18 of 44 tacrolimus subjects (p = 0.036). Furthermore, BOS stage 0-p was more likely to develop in the cyclosporine group than in the tacrolimus group, but this was not statistically significant (log-rank p = 0.1). In addition, there was a trend to a higher incidence of diabetes among those in the tacrolimus group, but there was no significant difference in graft survival or the total number of infections, or in the incidence of hypertension, chronic kidney disease, or cancer between the 2 groups. CONCLUSIONS: Tacrolimus is associated with a lower burden of acute rejection and lymphocytic bronchitis and a trend to a greater freedom from BOS stage 0-p than cyclosporine after lung transplantation.

A comparison of basiliximab and anti-thymocyte globulin as induction agents after lung transplantation.

BACKGROUND: Interleukin-2 receptor antagonists have supplanted polyclonal antibody preparations as the most frequently used induction agents after lung transplantation, but the relative efficacy of these agents has not been firmly established. METHODS: We retrospectively analyzed the efficacy of basiliximab compared with antithymocyte globulin among 157 adult lung transplant recipients at our center. RESULTS: At 3, 6, and 12 months after transplantation, the median cumulative acute rejection A scores for the basiliximab group (2, 2, and 3, respectively) were significantly higher than those for the anti-thymocyte globulin group (1, 1, and 2, respectively; p = 0.003, 0.004, and 0.033, respectively). In addition, basiliximab recipients were more likely to develop acute rejection grade > or = A2 than anti-thymocyte globulin recipients; in fact, 60% of basiliximab recipients compared with 38% of anti-thymocyte globulin recipients developed their first episode of acute rejection grade > or = A2 in the first 100 days after transplantation (log-rank p = 0.04). Furthermore, basiliximab recipients were more likely to develop bronchiolitis obliterans syndrome than anti-thymocyte globulin recipients (log-rank p = 0.036). Two years after transplantation, 36% of basiliximab recipients and 26% of anti-thymocyte globulin recipients developed bronchiolitis obliterans syndrome. However, there were no significant differences in the incidences of cytomegalovirus viremia and pneumonitis between the 2 groups (p = 0.86 and 0.89, respectively). CONCLUSIONS: Induction with anti-thymocyte globulin is associated with a lower burden of acute rejection and bronchiolitis obliterans syndrome compared with basiliximab, without a significant difference in the incidence of cytomegalovirus infections.

The predictive value of bronchiolitis obliterans syndrome stage 0-p.

Bronchiolitis obliterans syndrome (BOS) remains the main cause of graft loss after lung transplantation. Stage 0-p was recently added to the staging criteria to detect early deterioration in allograft function that might presage BOS stage 1. We assessed the predictive value of stage 0-p by retrospectively analyzing spirometric data for 203 adult bilateral lung transplant recipients. The FEV(1) criterion for stage 0-p had a positive predictive value of 79% and a negative predictive value of 82%. In contrast, the FEF(25-75%) criterion for stage 0-p had a positive predictive value of 52% and a negative predictive value of 72%. Fifty-seven percent of subjects who developed stage 0-p by the FEV(1) criterion progressed to stage 1 within 1 year, whereas only 37% of those who developed stage 0-p by the FEF(25-75%) criterion progressed to stage 1 within 1 year. We conclude that the FEV(1) criterion for stage 0-p is a reasonable predictor of BOS stage 1 after bilateral lung transplantation, but the FEF(25-75%) criterion for stage 0-p is not predictive of BOS stage 1 after bilateral lung transplantation.