Ramsey R. Hachem

Abstract:  Background:  The use of induction immunosuppression after lung transplantation remains controversial. In this study, we examined the impact of induction on survival after lung transplantation.Methods:  We performed a retrospective cohort study of 3970 adult lung transplant recipients reported to the ISHLT Registry. We divided the cohort into three groups based on the use of induction: none, interleukin‐2 receptor antagonists (IL‐2 RA), and polyclonal antithymocyte globulins (ATG). We estimated graft survival using the Kaplan‐Meier method and constructed a multivariable Cox proportional hazards model to examine the impact of induction on graft survival in the context of other variables.Results:  During the study period, 2249 patients received no induction, 1124 received IL‐2 RA, and 597 received ATG. Four years after transplantation, recipients treated with IL‐2 RA had better graft survival (64%) than those treated with ATG (60%) and those who did not receive induction (57%; log rank p = 0.0067). This survival advantage persisted in the multivariable model for single and bilateral recipients treated with IL‐2 RA compared to those who did not receive induction (RR = 0.82, p = 0.007). Similarly, bilateral recipients treated with ATG had a survival advantage over bilateral recipients who did not receive induction (RR = 0.78, p = 0.043), but single lung recipients treated with ATG did not have a survival advantage over single lung recipients who did not receive induction (RR = 1.06, p = 0.58).Conclusions:  Induction with lL‐2 RA for single and bilateral lung recipients and induction with ATG for bilateral recipients are associated with a survival benefit, independent of other variables that might impact survival.

Purpose of review The purpose of induction immunosuppression is to minimize the risk of early acute rejection, but its use after lung transplantation remains controversial. The purpose of this review is to examine the previous studies evaluating the impact of induction immunosuppression on clinical outcomes after lung transplantation. Recent findings There is a dearth of randomized controlled trials investigating the use of induction therapy after lung transplantation. Most studies have reported that induction therapy reduces the incidence of acute rejection and some have suggested that certain agents may reduce the incidence of chronic rejection. In addition, most studies have suggested that induction immunosuppression does not increase the risk of infectious or malignant complications. Summary Based on the available evidence, induction therapy after lung transplantation appears to reduce the incidence of acute rejection, but if this translates into a better long-term survival is unclear. Randomized controlled trials are needed to provide better insights into the efficacy and safety of induction therapy 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.

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. 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. 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. 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.

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 FEV1 criterion for stage 0-p had a positive predictive value of 79% and a negative predictive value of 82%. In contrast, the FEF25–75% 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 FEV1 criterion progressed to stage 1 within 1 year, whereas only 37% of those who developed stage 0-p by the FEF25–75% criterion progressed to stage 1 within 1 year. We conclude that the FEV1 criterion for stage 0-p is a reasonable predictor of BOS stage 1 after bilateral lung transplantation, but the FEF25–75% criterion for stage 0-p is not predictive of BOS stage 1 after bilateral lung transplantation.