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

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.

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.

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.

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.