Multi-omics characterises early immune divergence associated with infection-related deterioration after lung transplantation.

BACKGROUND

Early adverse outcomes after lung transplantation often manifest as infection-associated clinical deterioration. Such events are closely intertwined with dysregulated perioperative immune reconstitution and are influenced by immunosuppressive therapy. A systematic characterisation of the perioperative immune landscape and potentially actionable pathways may facilitate understanding of early trajectory divergence and inform perioperative monitoring and management.

METHODS

We conducted longitudinal sampling and immune profiling at predefined perioperative time points in lung transplant recipients. A deeply profiled discovery cohort was constructed using multi-omics approaches including single-cell transcriptomics, B-cell receptor sequencing, plasma proteomics, and flow cytometry, and key findings were externally validated in an independent validation cohort. Healthy donors provided reference baselines for peripheral immune states.

RESULTS

Outcome-associated immune divergence was detectable early and became more apparent by post-operative Day 7 (T2). At baseline (T0), recipients who later died tended to show a higher burden of CD177⁺ neutrophils, which may reflect a subclinical inflammatory state and a propensity for NETs-related activity. By T2, the Death group more frequently exhibited persistent inflammatory and infection-related deterioration with features of maladaptive humoral reconstitution, including plasmablast/plasma cell expansion, naïve B-cell depletion, skewed BCR clonality with restricted somatic hypermutation, and heightened BAFF/NETs activity alongside IgA-biased responses. The Live group generally showed a more resolving inflammatory course with relative preservation of B-cell homeostasis.

CONCLUSIONS

These data suggest that CD177⁺ neutrophil–linked NETs–BAFF activity may contribute to early adverse trajectories after lung transplantation and may be informative for perioperative risk stratification. A composite assessment at T0 and T2 integrating CD177⁺ neutrophils, BAFF/NETs readouts, B-cell dynamics and immunoglobulin profiles may help identify recipients at risk of infection-related deterioration and nominate the first post-operative week as a potential window for carefully timed immune modulation.