Early alteration of single-breath nitrogen washout (ΔN₂/L) in smokers with preserved spirometry: Association with smoking burden
Keywords:
small-airway disfunction, Single-breath nitrogen washout, Ventilation heterogeneity, Smoking exposureAbstract
Background: Tobacco-related small-airway dysfunction (SAD) may precede spirometric obstruction. The single-breath nitrogen washout (SBW N₂) captures ventilation heterogeneity and may detect early peripheral airway involvement through the phase III slope (ΔN₂/L) and closing volume (CV).
Aim: To describe SBW N₂ indices in smokers with preserved spirometry, examine their relationship with cumulative smoking exposure, and contextualise results against published reference (healthy predicted) values.
Methods: Cross-sectional study of current smokers (n=90) with preserved spirometry (pre-bronchodilator FEV1/FVC ≥0.70). Spirometry followed SEPAR criteria and SBW N₂ followed ERS/ATS recommendations. Associations with pack-years were assessed by Pearson correlations and linear regression. In the absence of a concurrently recruited healthy control group, SBW N₂ outcomes were also expressed as percent-predicted using published reference equations (ΔN₂/L and CV/VC in males aged 30–70 years). To explore sex-related differences in ventilation heterogeneity, we compared key characteristics and size-independent functional indices between men and women (spirometry as % predicted and ratios) and fitted a multivariable OLS model for ΔN₂/L adjusting for pack-years, age and BMI.
Results: Mean age was 42 (11) years and mean smoking exposure 29.01 (16.95) pack-years. Mean ΔN₂/L was 2.674 (1.424) %N2•L⁻¹ and correlated significantly with pack-years (r=0.452, p<0.0001), as did CV/VC (r=0.389, p=0.00015). In external-reference comparisons, ΔN₂/L in males aged 30–70 years (n=42) was markedly elevated (327.1 (165.7)% predicted; p<0.0001), with 83.3% exceeding the proposed ULN (180% predicted). In multivariable regression adjusting for pack-years, age and BMI, male sex remained independently associated with higher ΔN₂/L (β=+0.946 %N2•L⁻¹; 95% CI 0.400 to 1.492; p<0.001).
Conclusions: SBW N₂ indices—particularly ΔN₂/L—show a dose–response relationship with smoking burden and are markedly abnormal relative to healthy predicted values, even in smokers with preserved spirometry. These findings support SBW N₂ as a sensitive tool for detecting early peripheral SAD before spirometric obstruction becomes apparent. Sex-related differences in ΔN₂/L persisted after adjustment for smoking exposure and anthropometrics, suggesting that sex should be considered when extrapolating male-based reference contextualisation to women.
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