Distal Airway Inflammation Is Linked to Small Airway Dysfunction in Asthma

Background/Objectives: Airway inflammation and small airway dysfunction (SAD) are key features of asthma. Inflammation can be assessed by blood eosinophil count (Eos) and exhaled nitric oxide (NO) parameters, including fractional exhaled nitric oxide (FeNO), bronchial NO flux (J'awNO), and alveolar NO concentration (CANO), the latter reflecting distal airway inflammation. We aimed to evaluate the association between Eos and the degree of airway inflammation as specified by exhaled NO parameters and to assess the relationships between exhaled NO parameters and small airway dysfunction using spirometric and plethysmographic indices. Methods: We conducted an observational study of asthmatic outpatients who underwent spirometry, plethysmography, and exhaled NO measurements. Multivariable regression models were used to estimate associations between Eos and FeNO, J'awNO, CANO, and spirometric/plethysmographic indices, adjusting for age, sex, body mass index, and relevant covariates. Results: The analytic cohort included 121 patients (49 men; 72 women; median age 54.2 years). Small airway obstruction and a range of airway inflammation severity were observed. Mean (SD) or median [IQR] values, as appropriate, were: FEF₇₅ z-score -0.62 (0.96); FEF_25-75 z-score -1.27 (1.29); RV z-score 1.26 (0.94); RV/TLC z-score 1.60 (1.10); J'awNO 60.20 nL/min (102.80); FeNO 23.61 ppb (37.61); CANO 3.80 ppb (4.12); and Eos 260 cells/µL (430). Log-transformed Eos (log[Eos]) was associated with FeNO, J'awNO, and CANO (adjusted marginal slope [95% CI]: 12.11 [9.35-14.69], 33.56 [25.34-41.19], and 1.14 [0.84-1.43], respectively). Log(Eos) was also positively associated with RV and RV/TLC, but negatively associated with FEF_25-75, FEF₇₅, and FEV₁. Similarly, CANO was positively associated with RV and RV/TLC and inversely associated with FEF_25-75 and FEF₇₅. No significant associations were observed for FeNO or J'awNO. Conclusions: Blood eosinophils were independently associated with all exhaled NO parameters. The association between CANO and small airway ventilatory function indices supports a link between distal airway inflammation and SAD in asthma.