Airway obstruction alters the FENO threshold for detecting airway inflammation
Published online June 4, 2025
Asthma is a heterogeneous disease involving inflammatory pathways, notably so-called type-2 processes involving cytokines such as interleukin (IL)-13 and -5. Fractional exhaled nitric oxide (FENO) has emerged as a non-invasive biomarker of type-2 airway inflammation, primarily reflecting IL-13 activity Thresholds have been proposed for the use of FENO in asthma management. For example, the GINA guidelines proposed that a FENO value of ≥ 25 ppb indicates persistent type-2 inflammation in asthma. This threshold also predicts the effectiveness of certain anti-type-2 biologics such as dupilumab in the treatment of severe type-2 asthma and is used to obtain reimbursement for these medications. However, it has been previously shown that airway calibre reduction lowers FENO, so this threshold may not be suitable for patients with significantly impaired lung function, as it does not account for reduced airway calibre.
In this study from The Journal of Allergy and Clinical Immunology: In Practice, Michils et al. sought to determine whether, in addition to airway IL-13, the calibre of the airways also influences FENO values in asthma. They also examined how airway calibre reduction impacts FENO thresholds for detecting type-2 airway inflammation. FENO and forced expiratory volume in one second (FEV1-reflecting airway calibre) measurements as well as sputum induction were performed in 120 asthma patients (ranging from severe to mild) and 13 controls. Elevated sputum IL-13, IL-5, or eosinophils, compared to controls, identified patients with type-2 airway inflammation. In these patients, the relative contributions of IL-13 and FEV1 to FENO were assessed, and the FENO thresholds that discriminate between patients with and without type-2 airway inflammation were determined for different levels of airway obstruction.
The study indicates that airway calibre, assessed by FEV1, and type-2 airway inflammation, assessed by IL-13, are both important factors influencing FENO values in asthma. As a result, in patients with a lower FEV1, the FENO thresholds for detecting type 2 airway inflammation are lowered. For example, in asthmatic patients with an FEV1 <70% of the predicted value, which is common in severe asthma, the discriminating threshold for FENO decreases to 11 ppb. This means that such patients with a FENO between 11 and 25 ppb may be denied treatment with anti-type-2 biologics that require a FENO test for reimbursement, despite the presence of type-2 airway inflammation. The next step is to determine the FENO thresholds that would appropriately reflect type 2 airway inflammation in asthmatic patients, now considering the impact of airway obstruction on FENO in larger cohorts of patients.
The Journal of Allergy and Clinical Immunology: In Practice is an official journal of the AAAAI, focusing on practical information for the practicing clinician.
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