Reduced lung fluid club cell secretory protein informs chronic lung allograft dysfunction risk

Rationale Lung transplant recipients with lower club cell secretory protein (CCSP) levels in the bronchoalveolar lavage fluid (BALF) early posttransplantation are at increased risk for chronic lung allograft dysfunction (CLAD). For CLAD risk stratification, we previously identified a potential risk threshold for reduced CCSP (protein-normalized CCSP <8.63 ng·µg −1 ). Here, we aim to validate this association in an independent patient set from a prospective observational cohort. Methods Total protein and CCSP were quantified in 1481 BALF samples collected over the first posttransplant year from 353 patients (validation cohort). A Cox model tested the association between time to first CCSP <8.63 ng·µg −1 and CLAD. If this threshold did not validate, we pre-specified combining the discovery and validation cohorts to rederive a reduced CCSP risk threshold considering a larger number of CLAD events. In a subset, gene expression analyses were performed on allograft biopsies to examine molecular alterations at the time of reduced CCSP. Results BALF CCSP <8.63 ng·µg −1 in the first posttransplant year was not significantly associated with CLAD in the validation cohort (HR 1.41, p=0.208). However, in the combined cohort, a dense grid search, including the previously identified threshold of 8.63 ng·µg −1 , revealed that the threshold of 8.63 ng·µg −1 had the largest hazard ratio for CLAD. Iterative resampling demonstrated robust reproducibility of the association between BALF CCSP <8.63 ng·µg −1 and CLAD risk across the combined cohort. Biopsies corresponding to CCSP <8.63 ng·µg −1 had a proinflammatory profile. Conclusions Early posttransplant reductions in BALF CCSP identify lung recipients at increased CLAD risk and may associate with heightened allograft inflammation.