Bronchiolitis obliterans syndrome (BOS), the clinical correlate of chronic rejection after lung transplantation, is the leading obstacle to better long-term outcomes. We previously instituted a clinical protocol to screen for donor-specific human leukocyte antigen (HLA) antibodies (DSA) and a preemptive antibody-directed therapy protocol consisting of rituximab and/or intravenous immune globulin. In this study, we retrospectively analyzed serum samples from lung transplant recipients (n = 108) for antibodies to self-antigens (K-α 1 tubulin and collagen V) before and after antibody-directed therapy and correlated the results with the subsequent development of BOS. Seventy-two of the 108 recipients developed antibodies to self-antigens. There was a correlation between the development of antibodies to self-antigens and DSA. Sixteen of the 54 patients who had antibodies to self-antigens and were treated with antibody-directed therapy cleared the antibodies, and they were significantly less likely to develop BOS than those who had persistent antibodies. Furthermore, those who cleared DSA after treatment but had persistent antibodies to self-antigens were significantly more likely to develop BOS than those who cleared these antibodies. We conclude that antibodies to self-antigens are an important risk factor for the development of BOS.

These data suggest that BOS is the result of an immune process, that differences at the HLA-A locus may play an important role in this process, and antibody-mediated injury may play a role in BOS.

Background: Lung transplant (LTx) recipients have low long-term survival and a high incidence of bronchiolitis-obliterans syndrome (BOS). However, few long-term, multicenter, and precise estimates of BOS-free survival (a composite outcome of death and BOS) incidence exist. Methods: This retrospective cohort study of primary LTx recipients (1994–2011) reported to the ISHLT Thoracic Transplant Registry assessed outcomes through 2012. For the composite primary outcome of BOS-free survival, we used Kaplan-Meier survival and Cox proportional hazards regression, censoring for loss-to-follow-up, end-of-study, and retransplantation. While standard Registry analyses censor at the last consecutive annual complete BOS status report, our analyses allowed for partially missing BOS data. Results: Due to BOS reporting standards, 99.1% of the cohort received LTx in North America. During 79,896 person-years of follow-up, single LTx (6,599/15,268; 43%) and bilateral LTx (8,699/15,268; 57%) recipients had a median BOS-free survival of 3.16 (95% CI, 2.99–3.30) years and 3.58 (95% CI, 3.53–3.72) years, respectively. Almost 90% of the single and bilateral LTx recipients developed the composite outcome within 10 years of transplantation. Standard Registry analyses “overestimated” median BOS-free survival by 0.42 years and “underestimated” the median survival after BOS by about a half-year for both single and bilateral LTx (p<0.05). Conclusions: A majority of LTx recipients die or develop BOS within 4 years, and very few remain alive and free from BOS at 10 years post-transplantation. Less inclusive Registry analytic methods tend to overestimate BOS-free survival. The Registry would benefit from improved international reporting of BOS and other chronic lung allograft dysfunction (CLAD) events.

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The incidence of hyperammonemia syndrome in LTx patients was approximately 1%. Future research is needed to determine the efficacy of treatment, including hemodialysis, bowel decontamination, antibiotics, and the use of nitrogen scavenging agents in lung recipients with hyperammonemia.