Chronic Lung Allograft Dysfunction with Expiratory Flow Limitation: A Novel Sub-Phenotype Associated with Increasing Small Airway Resistance and CLAD Severity

Purpose Expiratory flow limitation (EFL) during tidal breathing is a major determinant of dynamic hyperinflation, dyspnoea and exercise limitation in obstructive lung disease. Within breath respiratory system reactance, measured by oscillometry, accurately detects EFL. The aim of this study is to assess predictors of EFL in recipients with chronic lung allograft dysfunction (CLAD). Methods A cross-sectional study was performed on bilateral lung transplant (LTx) recipients with persistent lung allograft dysfunction at 2 Australian centres between Jan-20 and Jun-21. Spirometry and oscillometry (TremoFlo C-100) were performed to obtain FEV1, FVC and Xrs at 5Hz, R5-19 respectively. EFL was defined as [mean inspiratory - mean expiratory Xrs (∆Xrs)] > 2.53. Patients with CLAD, based on 2019 Consensus criteria and phenotyping, were included. Recipients with non-CLAD causes of lung allograft dysfunction were excluded. Logistic regression measured the association between demographic and physiologic predictors and risk of EFL. Results A total of 110 bilateral lung transplant recipients with persistent lung allograft dysfunction were enrolled. 20 patients were excluded and 90 with confirmed CLAD were included for final analysis. EFL was observed in 16 (17.8%) patients. The median (IQR) ∆Xrs in recipients with EFL was 3.40 (2.10) compared to -0.14 (1.37) in those without. In univariable analysis, reduced concurrent FEV1/FVC (OR 0.01 95%CI 0.00-0.43, p=0.018), reduced concurrent FEV1 as %-baseline (OR 0.02 95%CI 0.00-0.72, p=0.03) and increased R5-19 Z-Score (OR 1.30 95%CI 1.11-1.52, p=0.001) were associated with an increased risk of EFL. Recipient BMI (OR 1.07 95%CI 0.99-1.16, p=0.09) was positively correlated with EFL with a weak association. CLAD BOS phenotype (BOS OR 0.82 95%CI 0.25-2.64, p=0.73) was not associated with an increased risk of EFL compared to other phenotypes. Conclusion EFL occurs in a minority of patients with CLAD, and occurs both in BOS and non-BOS phenotypes. Increasing airflow obstruction, CLAD severity and small airway resistance (R5-19) are associated with an increased risk of EFL. Advanced fibroproliferative small airway obstruction likely explains these associations. CLAD with EFL may be associated with poor outcomes and routine monitoring with oscillometry may be beneficial. Expiratory flow limitation (EFL) during tidal breathing is a major determinant of dynamic hyperinflation, dyspnoea and exercise limitation in obstructive lung disease. Within breath respiratory system reactance, measured by oscillometry, accurately detects EFL. The aim of this study is to assess predictors of EFL in recipients with chronic lung allograft dysfunction (CLAD). A cross-sectional study was performed on bilateral lung transplant (LTx) recipients with persistent lung allograft dysfunction at 2 Australian centres between Jan-20 and Jun-21. Spirometry and oscillometry (TremoFlo C-100) were performed to obtain FEV1, FVC and Xrs at 5Hz, R5-19 respectively. EFL was defined as [mean inspiratory - mean expiratory Xrs (∆Xrs)] > 2.53. Patients with CLAD, based on 2019 Consensus criteria and phenotyping, were included. Recipients with non-CLAD causes of lung allograft dysfunction were excluded. Logistic regression measured the association between demographic and physiologic predictors and risk of EFL. A total of 110 bilateral lung transplant recipients with persistent lung allograft dysfunction were enrolled. 20 patients were excluded and 90 with confirmed CLAD were included for final analysis. EFL was observed in 16 (17.8%) patients. The median (IQR) ∆Xrs in recipients with EFL was 3.40 (2.10) compared to -0.14 (1.37) in those without. In univariable analysis, reduced concurrent FEV1/FVC (OR 0.01 95%CI 0.00-0.43, p=0.018), reduced concurrent FEV1 as %-baseline (OR 0.02 95%CI 0.00-0.72, p=0.03) and increased R5-19 Z-Score (OR 1.30 95%CI 1.11-1.52, p=0.001) were associated with an increased risk of EFL. Recipient BMI (OR 1.07 95%CI 0.99-1.16, p=0.09) was positively correlated with EFL with a weak association. CLAD BOS phenotype (BOS OR 0.82 95%CI 0.25-2.64, p=0.73) was not associated with an increased risk of EFL compared to other phenotypes. EFL occurs in a minority of patients with CLAD, and occurs both in BOS and non-BOS phenotypes. Increasing airflow obstruction, CLAD severity and small airway resistance (R5-19) are associated with an increased risk of EFL. Advanced fibroproliferative small airway obstruction likely explains these associations. CLAD with EFL may be associated with poor outcomes and routine monitoring with oscillometry may be beneficial.