BACKGROUND:Achieving simultaneous 'dual remission' in both upper and lower airways is the clinical goal for comorbid asthma and chronic rhinosinusitis with nasal polyps (CRSwNP). This multicentric observational study evaluated the 24-month real-world effectiveness of dupilumab in reaching these stringent endpoints. METHODS:A retrospective study of 205 adult patients was conducted. Remission was defined by SANI criteria for asthma and modified EPOS/EUFOREA-DUPIREAL benchmarks for CRSwNP. Complete recovery required dual remission plus normosmia restoration. RESULTS:At 24 months, 77.4% of patients with severe asthma achieved CRSwNP remission, significantly higher than the 61.8% in the moderate asthma group (p = 0.0309). Dual remission was reached by 22.9% of the overall cohort. High baseline FeNO (≥50 ppb) was the strongest predictor for dual remission (34.5%) and normosmia restoration (19.2%). Prior surgery did not hinder long-term outcomes; surgical patients achieved complete recovery significantly faster at 12 months (16.7% vs. 3%, p = 0.0115). A higher surgical burden positively predicted olfactory restoration (OR = 4.0 per revision, p = 0.045). CONCLUSIONS:Dupilumab is highly effective over the long term, exhibiting a structural 'catch-up" effect. While high baseline Type 2 biomarkers and surgical history are positive prognostic indicators, the persistent "clinical-functional gap' suggests earlier intervention is critical to prevent irreversible neuroepithelial damage. CLINICAL TRIAL REGISTRATION:www.clinicaltrials.gov identifier is NCT07574294.

BACKGROUND:Obesity is associated with poorer asthma outcomes and an increased risk of exacerbations, but the underlying mechanisms remain incompletely understood. Small airway dysfunction (SAD) may represent a key mechanistic link between excess body weight and adverse asthma outcomes. METHODS:In this multicenter observational study, adult patients with asthma underwent clinical characterization, spirometry and impulse oscillometry (IOS). SAD was defined using a composite criterion based on peripheral airway resistance (R5-20), reactance area (AX) and the ratio of peripheral to total airway resistance (R5-20)/R5. Associations between body mass index (BMI), SAD and severe asthma exacerbations were assessed using multivariable regression models. Non-linear relationships were explored using generalized additive models and mediation analyses quantified the contribution of SAD to the obesity-exacerbation association. FINDINGS:Among 1169 patients, IOS-defined SAD was significantly more prevalent in individuals with BMI≥30 kg·m-2. Increasing BMI was associated with worse oscillometric parameters (p<0.0001), following a non-linear pattern with steeper deterioration beyond BMI values of approximately 28-30 kg·m-2. SAD was independently associated with obesity (adjusted OR 2.11, 95% CI 1.56-2.86) and with severe asthma exacerbations in the previous year (adjusted OR 2.01, 95% CI 1.53-2.65, both p<0.0001). Mediation analyses showed that SAD accounted for 26%-41% of the association between obesity and exacerbation risk (p=0.004 and 0.03). Spirometric indices provided limited additional information. INTERPRETATION:Oscillometry-defined small airways dysfunction (SAD) represents a non-linear functional trait underlying the association between obesity and severe asthma exacerbations, supporting its clinical relevance in obese patients with asthma and identifying SAD as a potential treatable trait.

The management of chronic obstructive lung diseases, particularly severe asthma, chronic obstructive pulmonary disease (COPD) and non-cystic fibrosis bronchiectasis, is complicated by frequent overlap syndromes such as asthma-bronchiectasis overlap and bronchiectasis-COPD overlap syndrome. These overlapping phenotypes are characterized by severe symptoms, frequent exacerbations, accelerated lung function decline and increased mortality, driven by a common, destructive endotype: persistent, neutrophil-dominant airway inflammation. This inflammation is fuelled by the overactivity of neutrophil serine proteases, notably neutrophil elastase, which drives the self-perpetuating 'vicious vortex' of structural damage and infection. Traditional therapies, including inhaled corticosteroids and type 2 (T2) inflammation-targeted biologics, are often ineffective against this non-T2, neutrophilic inflammation. Brensocatib, a first-in-class, oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), offers a novel, targeted strategy. By inhibiting DPP1 - the master activator of neutrophil serine proteases in the bone marrow - brensocatib effectively 'disarms' neutrophils before they reach the lungs. The phase III ASPEN trial in non-cystic fibrosis bronchiectasis demonstrated its disease-modifying potential, showing a significant reduction in the annualized rate of exacerbations and, critically, a statistically significant slowing of the decline in forced expiratory volume in 1 second in the 25 mg arm (a benefit not observed with the 10 mg dose). Subgroup analysis confirmed consistent efficacy in the high-risk bronchiectasis-COPD overlap syndrome population. These findings validate DPP1 inhibition as a first potential disease-modifying therapy. This strategy is poised to fundamentally shift clinical focus from symptom control to the preservation of lung function for patients with severe, neutrophilic-driven neutrophilic overlap syndromes.

BACKGROUND:Mild asthma is considered a low-risk condition because symptoms are infrequent and lung function is preserved. However, severe exacerbations may still occur in such patients. Small airway dysfunction (SAD) is recognized as an important contributor to exacerbation risk, even in adults with mild asthma. Less is known in adolescents, a vulnerable population because of transition-related issues. OBJECTIVE:To investigate whether SAD, identified by impulse oscillometry, is associated with prior exacerbations in adolescents with Global Initiative for Asthma (GINA)-defined mild asthma, good symptom control, and normal spirometry. METHODS:SAD was determined by the concomitant presence of abnormal z-score values for peripheral airway resistance between 5 and 20 Hz (R5-R20) and the area under the reactance curve (>+1.645) and peripheral airway reactance at 5 Hz (<-1.645). Associations between SAD, fractional exhaled nitric oxide (FeNO), and blood eosinophil count (BEC) with previous exacerbations were assessed using multivariable logistic regression. RESULTS:SAD was present in 28% of participants. Adolescents with SAD exhibited higher type-2 inflammatory biomarkers and significantly more frequent exacerbations than those without SAD (79% vs 20%, P < .0001). In multivariable analysis, SAD, FeNO greater than or equal to 25 parts per billion, and BEC greater than or equal to 300 cells/μL were independently associated with previous exacerbations; SAD remained an independent predictor even after adjusting for both elevated FeNO and BEC (adjusted odds ratio, 5.07; 95% CI, 1.52-18.43; P = .008). Mediation analysis suggested that SAD significantly mediated the association between type-2 inflammation and exacerbations. CONCLUSION:Among adolescents with mild, controlled asthma and normal spirometry, impulse oscillometry-defined SAD is strongly associated with exacerbation susceptibility. Objective assessment of peripheral airway function may help refine risk stratification in this population.

BACKGROUND:Spirometry remains central to the assessment of asthma but may fail to detect small airways dysfunction (SAD), which contributes to considerable symptoms and exacerbation risk. OBJECTIVE:We investigated whether integrating oscillometry with spirometry improves physiological phenotyping and risk stratification in asthma. METHODS:In this retrospective, multicenter study, data from 1497 adults with asthma were analyzed from the Oscillometry Asthma Registry. SAD was defined using the ratio of resistance heterogeneity between 5 and 20 Hz to resistance at 5 Hz ≥19% and airflow obstruction as forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) <70%. Participants were categorized into 4 mutually exclusive groups: (1) group 1-normal oscillometry and normal spirometry, (2) group 2-abnormal oscillometry with normal spirometry, (3) group 3-normal oscillometry with abnormal spirometry, and (4) group 4-abnormal oscillometry and abnormal spirometry. Associations with symptom control, exacerbations, and type 2 inflammatory biomarkers were assessed using multivariable logistic regression. RESULTS:For ≥1 exacerbation, the adjusted odds ratios (aORs) (95% confidence intervals) for group 4 were as follows: versus group 1, 3.19 (2.31, 4.42); versus group 2, 1.99 (1.46, 2.74); and versus group 3, 1.59 (1.07, 2.37). Corresponding aOR values for group 3 were as follows: versus group 2, 1.26 (0.85, 1.86), and versus group 1, 2.01 (1.37, 2.94). The aOR for ≥1 exacerbation for group 2 versus group 1 was 1.60 (1.18, 2.16). Results were similar when using FEV1/FVC <lower limit of normal instead of traditional predicted values. CONCLUSIONS:The combined use of oscillometry and spirometry identifies distinct physiological phenotypes of asthma with clinically meaningful differences in symptom burden and exacerbation risk.

Background Small airways dysfunction (SAD) is increasingly recognised as a treatable trait in severe asthma and may influence the likelihood of achieving clinical remission. Objective To investigate whether oscillometry defined SAD parameters were associated with remission following biologic or standard-of-care treatment. Methods Data from 237 adults with GINA-defined severe asthma were retrospectively collected at a tertiary specialist centre. 127 received add on biologic therapy (Benralizumab, Dupilumab or Tezepelumab) and 110 received standard of care alone. Spirometry, oscillometry, fractional exhaled nitric oxide (FeNO), blood eosinophil count (BEC), exacerbation frequency and Asthma Control Questionnaire (ACQ) scores were collected. Three component remission (3CR: no exacerbations, no maintenance OCS,ACQ <1.5) and four component remission (4CR: 3CR plus stable lung function defined as FEV₁) were assessed. Multivariable logistic regression was used to identify predictors of remission, adjusted for age, sex, BMI, ICS dose and smoking status. Results Biologic therapy significantly improved lung function, oscillometry indices, type 2 biomarkers, exacerbation frequency and ACQ scores. In the biologics group, 50.4% achieved 3CR and 34.6% achieved 4CR, compared with 42.6% and 25.0% respectively in the standard-of-care group. Baseline FeNO ≥25ppb and ≥50ppb were associated with higher odds of achieving remission following biologic therapy. An improvement in FEV₁ ≥100mL was strongly associated with both 3CR and 4CR. Importantly, improvement in oscillometry-derived area under the reactance curve (AX) ≥0.65kPa/L, corresponding to the minimal clinically important difference, was significantly associated with 4CR (adjusted OR 2.61 [1.02-6.65], p<0.05). In the standard-of-care group (3CR: 42.6%; 4CR: 25%), higher baseline AX ≥1.0 kPa/L was associated with a lower likelihood of achieving 3CR (adjusted OR 0.36 [0.14-0.93], p<0.05). Conclusion Improvements in peripheral airway compliance measured using oscillometry are associated with clinical remission in severe asthma following biologic therapy. These findings support SAD as an important physiological correlate and potential treatable trait in achieving asthma remission.

Background: “Remission” is a primary therapeutic goal in severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), though definitions vary regarding olfactory function. We evaluated “Dual Remission” kinetics in patients treated with dupilumab over 24 months. Methods: This single-center retrospective study analyzed 28 patients with comorbid severe asthma and CRSwNP. Dual Remission was defined as simultaneous asthma remission (ACT ≥ 20, no exacerbations, no OCS and stable lung function) and CRSwNP remission (SNOT-22 < 40, NPS ≤ 1). We additionally analyzed “Complete Recovery” by applying a stricter composite definition requiring the restoration of normosmia (Sniffin’ Sticks score ≥ 12). Results: At baseline, patients exhibited uncontrolled disease (median ACT 19, NPS 6). Treatment led to rapid asthma remission (85.7% at 12 months, 100% at 24 months). CRSwNP remission was slower but progressive, rising from 57% at 12 months to 88% at 24 months, demonstrating a significant “catch-up” phenomenon. Consequently, Dual Remission rates increased from 54% to 88% by month 24. When applying the stricter “Complete Recovery” criteria requiring normosmia, only 32% met the goal. Conclusion: Dupilumab is highly effective, enabling 88% of patients to achieve Dual Remission after 24 months. However, full olfactory restitution is distinct from structural polyp regression and harder to achieve, likely due to persistent neuroepithelial damage.

BACKGROUND:Clinical remission is an emerging goal in severe asthma (SA) management. While tezepelumab demonstrates broad efficacy, its real-world impact on remission-specifically in the context of small airway dysfunction (SAD)-remains incompletely defined. METHODS:This prospective, multicentre study enrolled 39 adults with SA treated with tezepelumab for 12 months. Clinical remission was defined by SANI criteria: complete oral corticosteroid (OCS) withdrawal, zero severe exacesrbations, Asthma Control Test score ≥20, and stable/improved FEV1. SAD remission required normalization of oscillometric parameters. RESULTS:At baseline, 44% of patients exhibited SAD. Tezepelumab eliminated severe exacerbations and achieved complete OCS withdrawal in 100% of evaluable patients. At 12 months, 77.4% of the overall evaluable cohort and 80.0% of those with baseline SAD achieved clinical remission. However, SAD remission was not observed; these patients maintained persistent oscillometric abnormalities despite reaching all clinical goals. CONCLUSION:Tezepelumab enables high rates of clinical remission regardless of baseline small airway status. In the SAD phenotype, symptomatic and inflammatory recovery dissociates from physiological SAD remission. Persistent mechanical abnormalities highlight the necessity of oscillometry to identify hidden residual disease in patients who otherwise appear to be in remission.

INTRODUCTION:Despite significant advances in precision medicine, managing severe asthma remains a major clinical challenge. Small airway dysfunction (SAD) is a crucial determinant of poor symptom control, airway remodeling, and frequent exacerbations. While conventional spirometry primarily assesses large airway mechanics, airway oscillometry (AO) provides a highly sensitive, effort-independent evaluation of peripheral resistance and reactance during normal breathing. AREAS COVERED:This review synthesizes current evidence from major biomedical databases (PubMed, Embase, Scopus, and Web of Science; 2000-2026) regarding the physiological role of SAD across severe asthma phenotypes (eosinophilic vs. non-eosinophilic). Furthermore, it systematically evaluates the specific impact of targeted biological therapies (anti-IgE, anti-IL-5/IL-5 R, anti-IL-4/13 Rα, and anti-TSLP) on distal respiratory mechanics. EXPERT OPINION:SAD represents a vital treatable trait in severe asthma. Biologics exert distinct physiological effects on peripheral parameters, with upstream modulators such as dupilumab and tezepelumab demonstrating superior efficacy in reversing distal mucus plugging and frequency-dependent resistance abnormalities. Incorporating AO into routine clinical algorithms alongside T2 inflammatory biomarkers is essential to refine endophenotyping, improve overall risk stratification, guide personalized biologic selection, and accurately monitor functional therapeutic responses in patients with severe refractory asthma.

INTRODUCTION:Notwithstanding considerable progress in asthma management, a significant proportion of patients continue to demonstrate suboptimal control. Research has identified small airways dysfunction (SAD) as a critical site for airflow limitation and an independent risk factor of exacerbations, with airway oscillometry (AO) playing a pivotal role in this field. AREAS COVERED:Spirometry is widely accepted as the gold standard for evaluating respiratory function. However, it is primarily sensitive to large airway obstruction… AO has emerged as a valuable tool for quantifying SAD, and recent studies have established strong correlations between AO, advanced imaging techniques and type 2 biomarkers. We conducted a review of the English-language literature from the beginning of the databases reviewed through June 2025. EXPERT OPINION:In recent years, a substantial body of literature has emerged, leading to a resurgence of interest in the role of AO in asthma management. It is recommended that AO be utilized as a primary diagnostic tool for the early detection of SAD, even when spirometric values are within normal limits. The identification of patients with asthma in accordance with the criteria of defined severe SAD-oscillometry signifies the culmination of the evolution of AO from a research tool to a clinical tool.

The small airways comprise generations 8 to 23 of the bronchial tree, consist of airways with an internal diameter < 2 mm, and are classically difficult to assess and treat in persistent asthma. Small airways dysfunction (SAD) is integral to the asthma management paradigm because it is associated with poorer symptom control and greater levels of type 2 inflammation, and it has been proposed as a potentially treatable asthma trait. Although identification of SAD based on oscillometry has been found to be clinically useful in managing asthma, very few physicians, including specialists, use this technique as part of standard or adjunct evaluation of lung function to diagnose asthma, grade severity of airway obstruction, ascertain disease control or the risk for future exacerbations, or to make management decisions. To rectify the unrecognized value of oscillometry in the asthma community, a consortium of authors who are investigators with knowledge and experience of oscillometry wished to address the most important clinical questions raised by our colleagues who are considering using this technique, including its clinical utility. In this article, we discuss integral concepts, including applicability of oscillometry as a predictive tool for asthma exacerbations and disease control, adequacy of spirometry and oscillometry in assessing SAD, potential limitations of oscillometry, and treatment options for SAD.

BACKGROUND:Although current guidelines for asthma diagnosis and management have proven relatively successful, many patients with asthma continue to experience poor asthma control and exacerbations. This may be due to a failure to recognize that patients with mild, well-controlled asthma commonly have small airway dysfunction (SAD), which is associated with a significant exacerbation risk. OBJECTIVE:We aimed to better characterize how well SAD, determined by impulse oscillometry, is associated with prior exacerbations in the Global Initiative for Asthma-defined mild, well-controlled asthma phenotype. METHODS:In 170 adults with mild, well-controlled asthma, we determined the presence of SAD by impulse oscillometry metrics of peripheral airway resistance between 5 and 20 Hz and peripheral airway reactance as the area under the reactance curve at cut points of 0.10 kPa/L per second and 1.0 kPa/L, respectively. We also assessed the associations among SAD, FEV1, FeNO, blood eosinophilia, and extra-fine inhaled corticosteroids (ICS) with prior exacerbations. A multivariate analysis evaluated which variables were independently associated with prior exacerbations. RESULTS:Small airway dysfunction was present in 27.6% of the population, and prior exacerbations in 34.1%. Exacerbations were greater in those with SAD (82.9% vs 15.4%; P < .001) and lower in those receiving extra-fine ICS (27.7% vs 55.3%; P < .05). Small airway dysfunction and extra-fine ICS were both independently associated with prior exacerbations; SAD increased and extra-fine ICS decreased exacerbation risk. CONCLUSIONS:In the patient with mild, well-controlled asthma, SAD and prior exacerbations are common. Small airway dysfunction and extra-fine ICS are respectively independently associated with increased or decreased exacerbations. Detecting SAD could result in early extra-fine ICS intervention, potentially preventing future exacerbations in this phenotype.

BACKGROUND:Most physiological production of Fractional exhaled Nitric Oxide (FeNO) occurs in the small airways, but studies on the relationship between FeNO and small airway dysfunction (SAD) in asthma are scant. OBJECTIVE:To investigate the relationship between asthma control, changes of FeNO in relation to airway bronchodilation (BD), and SAD. METHODS:Baseline conventional spirometry, impulse oscillometry, and FeNO pre- and post-BD (salbutamol 400 μg) were tested on consecutive community-treated adult patients with asthma. Results were stratified by FeNO response (change in FeNO [ΔFeNO]), being FeNO "responder" if the increase is greater than 10% post-BD compared with the basal values and "nonresponder" if less than or equal to 10%. RESULTS:When measured, post-BD FeNO greater than 25 parts per billion was found in an additional 31.5% of patients. Of the 92 patients included, 61% were classified as FeNO "responders" and 39% as "nonresponders." A significant moderate-to-strong correlation was observed between ΔFeNO and R5R20, a functional marker of SAD (R = 0.52, P < .0001), whereas the correlations between spirometry markers and ΔFeNO were not significant (P > .05). Both R5R20 and ΔFeNO inversely correlated with asthma control (P < .0001). Using causal mediation analysis modeling, the effect of asthma control on ΔFeNO was mediated by SAD, with a strong indirect effect of asthma control on ΔFeNO mediated by SAD (β value: -7.04, 95% CI: -11.80 to -3.53, P < .0001), without a significant direct effect (β value: -4.96, 95% CI: -9.15 to 0.11, P = .056). CONCLUSION:Changes in FeNO values pre-/post-BD can improve the identification of patients with "TH2 high" asthma. The relationship between ΔFeNO and asthma control is mainly mediated by SAD, highlighting its contribution to asthma control.

Monoclonal antibodies targeting interleukin (IL)-5 pathways have revolutionized the treatment expectations for eosinophilic-associated conditions, particularly in patients with respiratory involvement. Mepolizumab (IL-5 antagonist monoclonal antibody), benralizumab (IL-5 receptor blocker monoclonal antibody), and reslizumab (IL-5 antagonist monoclonal antibody) have collectively contributed to the overall improvement of the disease burden in various conditions. Eosinophilic asthma currently boasts the most robust evidence across all age groups: all three biologics are approved for adults (aged ≥18 years); mepolizumab is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) also in children (aged ≥ 6 years), while bernalizumab was recently approved by the FDA for patients aged ≥6 years in the USA. In chronic rhinosinusitis with nasal polyps, subcutaneous mepolizumab is the only anti-IL-5 therapy approved so far and can be used in adult patients (aged ≥18 years). For eosinophilic esophagitis, conflicting evidence surrounds both mepolizumab, reslizumab, and benralizumab, leading to non-approval of these agents by the FDA/EMA. Recently, mepolizumab was approved for eosinophilic granulomatosis with polyangiitis patients aged ≥6 years or older and for hypereosinophilic syndrome adult patients. A phase III trial proving noninferiority of benralizumab versus mepolizumab in eosinophilic granulomatosis with polyangiitis has been recently published, while evidence on reslizumab is scant. Overall, current evidence on anti-IL-5 biologics for eosinophilic-associated disorders is mostly focused on adults, whereas data for individuals aged under 18 years and over 65 years are scarce, resulting in a lack of evidence, particularly regarding efficacy, for the use of anti-IL-5 agents in these specific patient populations. This review addresses high-quality evidence from randomized controlled trials and real-world post-marketing studies regarding the use of anti-IL-5 therapies for eosinophilic-associated disorders across all age groups, spanning childhood, adulthood, and older age.