Beyond FEV1: Alveolar Nitric Oxide Within an Integrated, Noninvasive Model for CLAD Surveillance

BACKGROUND: Chronic lung allograft dysfunction (CLAD) remains the major limitation to long-term survival after lung transplantation. Fractional exhaled nitric oxide (FeNO) is a noninvasive marker of airway inflammation, but its clinical role after lung transplantation remains uncertain. This study investigated whether multiple-flow FeNO parameters may support CLAD risk stratification in lung transplant recipients. METHODS: We performed a retrospective observational study of 114 lung transplant recipients. At the time of FeNO assessment, 45 patients had CLAD, 9 had acute cellular rejection, and 60 were clinically stable. FeNO was assessed at multiple expiratory flows to derive proximal and distal nitric oxide parameters. RESULTS: Alveolar nitric oxide concentration (CalvNO) was significantly higher in patients with CLAD than in clinically stable recipients and showed the best discrimination among FeNO-derived variables for prevalent CLAD (area under the curve [AUC], 0.849; optimal cutoff, 7.7 ppb). A model combining CalvNO, diffusing capacity of the lung for carbon monoxide, residual volume/total lung capacity, and forced expiratory volume in 1 s showed good diagnostic performance (AUC, 0.88). Among initially stable recipients, 9 developed CLAD during follow-up. Baseline CalvNO was associated with incident CLAD in exploratory time-to-event analysis (hazard ratio, 1.35 per 1 ppb increase), with an AUC of 0.889 and a cutoff of 7.12 ppb. Microbiological status modified FeNO interpretation, particularly for proximal indices, whereas CalvNO remained more consistently associated with CLAD in colonized and microbiologically negative patients. CONCLUSIONS: Multiple-flow FeNO-derived CalvNO is a biologically plausible and clinically promising noninvasive biomarker for CLAD risk stratification. Its most defensible application is as part of integrated surveillance combining FeNO-derived parameters, pulmonary function, lung volumes, diffusion capacity, and structured assessment of infection or other reversible conditions.