Risk Factors for Acute Rejection in the First Year after Lung Transplant. A Multicenter Study

Abstract

Rationale: Acute rejection, manifesting as lymphocytic inflammation in a perivascular (acute perivascular rejection [AR]) or peribronchiolar (lymphocytic bronchiolitis [LB]) distribution, is common in lung transplant recipients and increases the risk for chronic graft dysfunction.Objectives: To evaluate clinical factors associated with biopsy-proven acute rejection during the first post-transplant year in a present-day, five-center lung transplant cohort.Methods: We analyzed prospective diagnoses of AR and LB from over 2,000 lung biopsies in 400 newly transplanted adult lung recipients. Because LB without simultaneous AR was rare, our analyses focused on risk factors for AR. Multivariable Cox proportional hazards models were used to assess donor and recipient factors associated with the time to the first AR occurrence.Measurements and Main Results: During the first post-transplant year, 53.3% of patients experienced at least one AR episode. Multivariable proportional hazards analyses accounting for enrolling center effects identified four or more HLA mismatches (hazard ratio [HR], 2.06; P ≤ 0.01) as associated with increased AR hazards, whereas bilateral transplantation (HR, 0.57; P ≤ 0.01) was associated with protection from AR. In addition, Wilcoxon rank-sum analyses demonstrated bilateral (vs. single) lung recipients, and those with fewer than four (vs. more than four) HLA mismatches demonstrated reduced AR frequency and/or severity during the first post-transplant year.Conclusions: We found a high incidence of AR in a contemporary multicenter lung transplant cohort undergoing consistent biopsy sampling. Although not previously recognized, the finding of reduced AR in bilateral lung recipients is intriguing, warranting replication and mechanistic exploration.

Keywords: acute rejection; lung transplantation; lymphocytic bronchiolitis.

Figure 1.

Forest plot of multivariable associations from the Cox regression model evaluating the impact of donor and recipient factors on the time to development of the first acute perivascular rejection event in the first year after lung transplantation. The enrolling center is included in the model as a random effect. Acute perivascular rejection–free survival was censored for death, retransplant, study termination, and the end of first post-transplant year. CI = confidence interval; CMV = cytomegalovirus; LAS = lung allocation score; PGD = primary graft dysfunction; UNOS = United Network for Organ Sharing.

Figure 2.

Descriptive Kaplan-Meier plots illustrating the time to development of the first acute perivascular rejection event in the first year after lung transplantation as stratified by presence or absence of identified clinical risk factor. (A) Fewer than four versus four or more HLA mismatches. (B) Single versus bilateral lung transplant recipient. Acute perivascular rejection–free survival was censored for death, retransplant, study termination, and the end of first post-transplant year.

Figure 3.

Distribution of normalized acute perivascular rejection scores over the first year after lung transplantation as stratified by the presence or absence of identified clinical risk factors. (A) Fewer than four versus four or more HLA mismatches. (B) Single versus bilateral lung transplant recipient. AR = acute perivascular rejection.