Phenotyping immune sensitization reveals pattern-based association with post-lung transplant complications

Immune sensitization is an important contributor to adverse outcomes after lung transplantation, including impaired pulmonary function, increased risk of chronic lung allograft dysfunction (CLAD), and reduced survival. Prior studies have examined individual immunologic features, such as panel reactive antibodies (PRA), donor-specific antibodies (DSA), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). However, existing literature has evaluated each of these in isolation, creating a gap in understanding regarding the potential for synergistic and overlapping effects. In this retrospective cohort study, we developed 5 immune sensitization phenotypes based on perioperative patterns of immune injury observed before and after transplantation: non-sensitized, pre-transplant humoral sensitization, post-transplant humoral sensitization, cellular-mediated sensitization, and mixed sensitization. A total of 502 adult lung transplant recipients were classified into these phenotypes and compared with respect to initial post-transplant FEV₁, CLAD risk, and overall survival. Across outcomes, the mixed sensitization phenotype was generally associated with worse post-transplant lung function and greater mortality, while CLAD onset was directionally similar but remained statistically nonsignificant. Within the mixed sensitization group, the AMR subtype demonstrated significant associations with adverse lung outcomes. These findings suggest that immune sensitization may be better understood as overlapping patterns of immune injury that develop over time after transplant. These findings provide an exploratory framework for describing longitudinal immune injury patterns that may guide future studies of post-transplant surveillance and enable tailored immunomodulatory strategies.