Fractional Exhaled Nitric Oxide (FeNO) as a Biomarker of Lower Airway Eosinophilic Inflammation: Benefits and Limitations

Fractional exhaled nitric oxide (FeNO) has progressively consolidated its role in the assessment of type 2 (T2) airway inflammation, on the strength of standardized methodology, two decades of evidence in asthma and growing data in chronic obstructive pulmonary disease (COPD) and bronchiectasis. The clinical interpretation of the measurement, however, remains uneven, partly because the underlying biology is often condensed into the shorthand of an eosinophilic biomarker. FeNO is generated by the airway epithelium through inducible nitric oxide synthase, whose transcription is driven primarily by interleukin-13 acting through STAT6, with interleukin-4 in a supporting role. The interleukin-5/eosinophil pathway runs in parallel and is not directly captured by FeNO. This single distinction explains the moderate correlation between FeNO and sputum eosinophils, the sensitivity of the measurement to inhaled corticosteroids, smoking, atopy and infection, and the differential magnitude of FeNO suppression observed under biologic therapies that target distinct points of the T2 cascade. Drawing on a non-systematic search of MEDLINE/PubMed up to early 2026, with priority given to society guidelines, position papers and randomized trials with their biomarker analyses, the present narrative review reframes FeNO around its actual biological substrate and traces the implications for diagnosis, phenotyping, prediction of corticosteroid responsiveness, adherence assessment, exacerbation risk and biologic treatment selection across T2-high asthma, severe asthma referred for biologic therapy, eosinophilic COPD, eosinophilic bronchiectasis, chronic cough and the unified airway. Limitations are discussed alongside interpretation, since each constraint maps onto a specific bedside rule. Future directions converge on personalized reference intervals, multiple-flow analysis, breathomics and remote monitoring, and on a shift in the operational unit of decision-making from the isolated cut-off to the longitudinal trajectory interpreted within an integrated biomarker algorithm.