Lower Limit of Normal of Pulmonary Function to Define Baseline Lung Allograft Dysfunction

Subnormal lung function after lung transplantation (LTx) has increasingly been recognized as an independent risk factor for mortality. Historically, baseline lung allograft dysfunction (BLAD) has been defined using the fixed "< 80% predicted" threshold from population-wide reference equations, which disregards age- and sex-related variability in spirometric values and can lead to systematic overdiagnosis, particularly in older and female recipients. While the lower limit of normal (LLN), derived from Global Lung Initiative reference equations, has been accepted as technical standard in spirometry, it has not yet been applied to define BLAD.

A retrospective multicenter study included LTx recipients transplanted between 2014 and 2018. Lung function trajectories and allograft survival were followed-up until August 2024. The association of BLAD defined by forced expiratory volume in 1 s (FEV1) or forced vital capacity (FVC) < LNN as time-dependent variable with graft loss was studied using time-dependent Cox proportional hazard models.

We analyzed 726 patients after LTx including 102 unilateral LTx recipients, of whom 470 (65%) of the cohort achieved normal baseline lung function defined as FEV1 and FVC ≥ LLN. Two hundred thirty-six patients experienced graft loss (n = 2 redo LTx) and 179 developed chronic lung allograft dysfunction. After adjusting for age, disease, transplant type, and chronic lung allograft dysfunction, baseline FEV1 or FVC < LLN was associated with graft loss (hazard ratio, 1.822; 95% confidence interval, 1.372-2.418; P < 0.001).

BLAD defined by concurrent baseline FEV1 or FVC below the LLN was strongly associated with increased risk of graft loss. These findings extend prior studies that used the fixed 80% threshold by demonstrating that an LLN-based, age- and sex-adjusted definition of BLAD identifies lung transplant recipients at risk, thereby avoiding fixed cutoff associated age- and sex-bias.