Introduction: the single breath nitrogen (SBN₂) test explores the function of small airways, and its relationships with pulmonary diffusing capacity for carbon monoxide (DLCO) is poorly studied in population-based longitudinal studies.

Aim: to evaluate whether the SBN₂ test could be a predictor of the decline in DLCO over an 8-yr follow-up.

Methods: 712 adults (20+ years old) from the prospective Po River Delta epidemiological study underwent SBN₂ test at baseline and DLCO test at both baseline and follow-up. Multiple regression models were used to assess associations between the slope of phase 3 or alveolar plateau (N2-slope) from SBN₂ test and rates of DLCO or DLCO/alveolar volume (KCO) decline (i.e., difference between follow-up and baseline values divided by the duration of individual follow-up time in years), after adjusting for sex, and baseline age, height, DLCO (or KCO) and smoking status.

Results: 712 adults (54.6% males, mean age 37.0 (±11.1) years, 48.7% smokers, 17% ex-smokers) showed a mean DLCO decline of -0.12±0.75 mL/mmHg/min/year and a mean KCO decline of -0.03±0.12 mL/mHg/min/L/year. N2-slope was significantly associated with the rate of DLCO decline (-0.133 mL/mmHg/min/year for a one-unit change in N2-slope, p<0.001) and KCO decline (-0.013 mL/mHg/min/L/year, p=0.017).

Conclusion: N2-slope from the SBN₂ test is a significant predictor of DLCO decline over an 8-year follow-up. Initial impairment of small airways might predict a more extensive functional involvement of lung parenchyma (including alveolar and interstitial spaces) over the long run.