Fractional exhaled nitric oxide in monitoring biological treatment for severe asthma in adults: Clinical implications and future perspectives

Severe asthma (SA) is a heterogeneous disease that remains uncontrolled despite optimized, high-dose inhaled therapy. It is also associated with substantial morbidity, corticosteroid exposure, and a significant healthcare burden. The advent of targeted biologic therapies has transformed SA management, making accurate biomarker-guided phenotyping essential. Fractional exhaled nitric oxide (FeNO), a noninvasive biomarker of IL-4/IL-13-driven airway inflammation, is widely used in asthma; however, interpreting its levels in SA is complex. This narrative review provides a biology-driven analysis of FeNO in SA, focusing on mechanistic foundations, interpretive limitations, and biologic-specific behavior. Chronic exposure to high-dose inhaled or systemic corticosteroids, overlap with reference ranges in healthy populations, and common SA comorbidities, such as obesity, chronic rhinosinusitis with nasal polyps, and bronchiectasis, can substantially modify FeNO levels. This limits the usefulness of fixed cutoffs. We summarize the available evidence on FeNO dynamics across biologic classes, highlighting the rapid and pronounced suppression observed with anti-IL-4Rα and anti-TSLP therapies. This is in contrast to the variable and often modest changes seen with anti-IL-5/IL-5R agents. We also review data linking baseline FeNO values and early FeNO trajectories to clinical outcomes and asthma remission. FeNO should be integrated with blood eosinophils, IgE, sputum cytology, and clinical features to guide biologic selection and longitudinal monitoring, rather tham being used in isolation. Key evidence gaps include the need for prospective FeNO-guided biologic trials, harmonized SA-specific FeNO thresholds, and integration with multi-omics approaches to fully realize the full potential of FeNO as a precision biomarker in SA.