Treatable traits of small airway dysfunction in children with asthma and advances in small airway-targeted therapeutic research: a narrative review

Introduction

Asthma is a predominant chronic respiratory disease in childhood, and its prevalence has continued to rise in recent years. The disease substantially impairs quality of life and psychosocial development in affected children and imposes a considerable burden on society (1,2). Despite continuous advances in diagnostic and therapeutic strategies, a proportion of pediatric patients still fail to achieve adequate disease control (3,4). Traditionally, asthma assessment and management have focused primarily on airflow limitation in the large airways, with clinical evaluation of disease severity and treatment response relying largely on indices such as forced expiratory volume in one second (FEV₁) (1). Emerging evidence, however, underscores the critical role of the small airways in asthma initiation, progression, and persistence (5).

Under physiological conditions, the small airways are numerous and have a large total cross-sectional area, contributing minimally to overall airway resistance; they have therefore been referred to as the “silent zone” of the lung (6). In the context of inflammation and structural remodeling, however, they become a major site of airflow obstruction, leading to a marked increase in resistance. Pathological studies have demonstrated that during asthma exacerbations, inflammatory cell infiltration and airway remodeling involve both large and small airways throughout the bronchial tree. The small airways may exhibit mucosal edema, smooth muscle spasm, and thickening of the airway wall (7,8). Given their narrower caliber, children are particularly vulnerable to ventilation impairment caused by small-airway pathology (6).

The application of techniques such as impulse oscillometry (IOS) and fractional exhaled nitric oxide (FeNO) measurement in recent years has further corroborated the high prevalence and clinical significance of small-airway involvement in pediatric asthma. Studies have shown that small airway dysfunction (SAD) is closely associated with poor asthma control, an increased risk of acute exacerbations, and progressive decline in lung function with age, making it a key determinant of long-term prognosis in children with asthma (9-11). Accordingly, clinical management has gradually shifted from an exclusive focus on large airways to a more integrated approach that encompasses both, with the small airways emerging as a critical therapeutic target. Concurrently, advances in pharmaceutical formulations and inhalation delivery technologies have further facilitated the clinical translation of small airway-targeted therapies.

Against this backdrop, the “treatable traits” (TTs) concept has been introduced and refined. This framework emphasizes identifying measurable and modifiable disease drivers in individual patients to enable personalized, multi-target treatment strategies (12). Applying this paradigm to pediatric asthma management may facilitate the integration of SAD into routine assessment and treatment. While previous reviews on SAD have primarily addressed its pathophysiology and assessment, this narrative review aims to synthesize current evidence on both inhaled and systemic therapeutic strategies targeting the small airways. Furthermore, within the TTs framework, we propose a conceptual clinical pathway for the individualized management of SAD in children with asthma. Our goal is to provide a synthesized evidence base and a practical hypothesis to inform future research and support more precise therapeutic decisions. We present this article in accordance with the Narrative Review reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0251/rc).

Methods

This article is a narrative review that aims to synthesize and discuss the current evidence regarding SAD as a TT in pediatric asthma, and to propose a related clinical management framework. To inform this discussion, a literature search was conducted in PubMed, Embase, the Cochrane Library, and China National Knowledge Infrastructure (CNKI) to comprehensively identify relevant publications. The search strategies for all databases were designed to capture key studies using terms related to “asthma”, “children”, “small airway dysfunction”, and “treatable traits”.

A summary of the search parameters and the guiding principles for literature consideration is provided in Table 1. The detailed, step-by-step search strategies for each database are provided in Tables S1-S4.

Titles and abstracts of retrieved records were reviewed for relevance. The literature selection for this narrative synthesis prioritized original research articles (e.g., randomized controlled trials, cohort studies) and seminal review articles that offered foundational or contemporary insights into the pathophysiology, assessment, or management of SAD in children with asthma. The criteria in Table 1 served as guiding principles for this selection process. Full texts of articles deemed pertinent were obtained and reviewed to develop the clinical insights and conceptual pathway presented herein.

Overview of SAD

Small airways are typically defined as distal conducting airways with an internal diameter of <2 mm, located beyond the 8th generation of branching, and lacking cartilaginous support. These structures primarily include terminal bronchioles, respiratory bronchioles, and alveolar ducts. SAD generally refers to a spectrum of pathophysiological abnormalities arising from inflammatory and structural alterations in the small airways, including increased small airway resistance, airway closure, and ventilation heterogeneity. These changes ultimately result in functional impairment due to narrowing or obstruction of the distal airways (13).

In children with asthma, SAD is highly prevalent. A retrospective analysis by Yi et al. (14) of 851 preschool-aged asthmatic children reported an SAD detection rate of 19.5%. Small airway involvement is even more common in children with moderate-to-severe asthma. Azaldegi et al. (15) included 100 children with moderate-to-severe asthma and found that among those who completed multiple small airway assessments, 77.78% exhibited abnormality in at least one small airway parameter. The reported prevalence of SAD varies considerably across studies, which likely reflects heterogeneity in study populations (e.g., differences in age, asthma severity, or phenotype) and, importantly, the lack of a standardized operational definition leading to the use of diverse diagnostic criteria and tool thresholds (6).

Risk factors and prognostic relevance of SAD

The development of SAD is closely linked to early-life biological factors and environmental exposures. Adverse antenatal and early-life factors such as fetal growth restriction, prematurity, and low birth weight can impair alveolar and small airway development, thereby establishing a reduced lung function trajectory from early life (16). During infancy and early childhood, recurrent or severe viral lower respiratory tract infections are linked to reduced lung function and an increased risk of asthma in school-age years. These infections may further disrupt distal airway structure and function through mechanisms including persistent inflammation, epithelial barrier damage, and dysregulation of airway developmental processes (17,18).

Furthermore, long-term exposure during childhood to environmental factors like tobacco smoke and indoor/outdoor air pollution is associated with impaired lung function and adverse respiratory health outcomes in children. These exposures can amplify airway inflammation and impair ventilation distribution (19). A retrospective cohort study introduced the concept of persistent small airway dysfunction (p-SAD) and identified its association with factors such as earlier asthma onset, delayed initiation of regular treatment, prolonged duration of inhaled therapy, and poorer asthma control (20).

SAD not only affects short-term asthma control but is also closely associated with long-term respiratory outcomes. Cross-sectional studies indicate that SAD, as assessed by IOS, shows a significant correlation with suboptimal asthma control in children (9). From a long-term perspective, persistent small airway inflammation and ventilation heterogeneity may impair lung growth and hinder the achievement of optimal peak lung function. Suboptimal peak lung function, in turn, is associated with an increased risk of developing chronic obstructive pulmonary disease (COPD) in adulthood (21). Therefore, early identification and targeted intervention for SAD in childhood may not only improve current symptoms and disease control but also optimize long-term respiratory outcomes and reduce the risk of persistent asthma or early lung function decline in adulthood.

SAD management from the TTs perspective

Overview of TTs

Traditional asthma management typically classifies patients as having mild, moderate, or severe disease based on symptom frequency and lung function levels, subsequently applying a stepwise treatment approach. However, even within the same severity classification, significant heterogeneity exists among children in terms of phenotypes and endotypes, leading to considerable variability in treatment responses. This variability limits the precision of the traditional “one-size-fits-all” stepwise management strategy (12).

To address this limitation, the TTs model has been increasingly proposed and adopted in recent years. This model emphasizes the identification, at the individual level, of measurable, modifiable, and clinically relevant factors that contribute to disease development or exacerbation, followed by the implementation of multi-targeted, personalized interventions. A trait is generally considered a TT if it fulfills three core elements: clinical relevance, measurability, and treatability (22). In the field of asthma, TTs are often categorized into three groups: pulmonary traits, extrapulmonary comorbidities, and behavioral/psychological factors. This framework shifts the management paradigm from simple severity classification to the construction of an individualized problem list for targeted intervention (23). The strength of this model lies in its departure from the traditional severity-based treatment framework, enabling more precise and intensified intervention for patients whose overall severity classification may not be high but who exhibit prominent issues in specific domains.

Integrating SAD as a pulmonary TT in childhood asthma

Within the TT framework, SAD in children with asthma is increasingly being explored as a potential trait that may meet the fundamental criteria for being considered an independent therapeutic target.

For measurability, advances in detection technologies are transforming SAD from a silent pathological process into a detectable and quantifiable clinical phenotype (24). In conventional spirometry, maximal mid-expiratory flow (MMEF) and other small airway flow indices serve as sensitive indicators for suggesting SAD in children with asthma (25). IOS, a low-effort-dependent technique with excellent applicability in pediatrics, has been shown by Beinart et al. (26) to demonstrate high sensitivity in detecting SAD and strong predictive value for moderate-to-severe exacerbations and poor asthma control. Furthermore, measurement of FeNO, particularly alveolar nitric oxide (CaNO), can be used to assess peripheral airway inflammatory burden and has been associated with persistent SAD (p-SAD) in childhood asthma (20).

For treatability, expert reviews suggest that several strategies may potentially intervene in SAD. These include optimizing distal deposition using extrafine-particle inhaled corticosteroids (ICS), adding a long-acting muscarinic antagonist (LAMA) to medium-to-high dose ICS-long-acting β₂-agonist (LABA) therapy to improve distal airway dilation, and employing biologics in specific phenotypes (27). However, the evidence base, particularly from pediatric-specific randomized controlled trials, requires further strengthening.

For clinical relevance, SAD is closely associated with the level of asthma symptom control and the risk of acute exacerbations (28). This association supports the rationale for considering SAD as a TT.

However, operationalizing SAD as a validated TT in children faces several challenges. First, there is no universally accepted operational definition of pediatric SAD. Second, the diagnostic tools discussed have inherent limitations regarding variability, standardization, and age-specific reference values. Third, while therapeutic strategies targeting the small airways exist, high-level evidence from pediatric-focused studies, especially those using SAD-specific outcomes as primary endpoints, remains relatively limited. Much of the supporting evidence is extrapolated from adult studies or expert consensus. Consequently, while conceptualizing SAD as a TT is a promising and logical step towards precision medicine, it should currently be viewed as a hypothesis-generating framework that necessitates rigorous validation through well-designed, prospective pediatric studies.

A proposed clinical pathway for small airway management based on the TTs framework

Building on the TT principle of precise management, we propose a preliminary clinical pathway for targeted small airway management in childhood asthma. This pathway is conceptualized as a hypothesis-generating framework to aid in risk stratification, dynamic monitoring, and individualized treatment strategies (Table 2). It is important to note that this pathway requires prospective validation in pediatric populations. Importantly, the application of this pathway must be adapted to the child’s developmental stage, as the feasibility of assessment tools and the availability of treatments vary significantly with age.

Step 1: screening children potentially at high risk for SAD

A high index of suspicion for SAD may be considered for children with early-onset recurrent wheezing, those with comorbid allergic conditions such as allergic rhinitis or atopic dermatitis, elevated peripheral blood eosinophil counts or FeNO levels, and those with poor asthma control despite standard therapy.

Step 2: assessing small airway function

In the absence of a universally accepted gold standard for diagnosing SAD, clinical practice relies on a composite assessment integrating multiple physiological and inflammatory indicators. Regarding spirometry, the Chinese expert consensus [2021] on the assessment and treatment of SAD in childhood asthma suggests that SAD can be defined when FEV₁ and FEV₁/FVC% are within the normal range, but any two of the following parameters are <65% of predicted values: FEF25–75%, forced expiratory flow at 50% of FVC (FEF50%), and forced expiratory flow at 75% of FVC (FEF75%) (29) (this threshold is based on expert consensus and not universally validated). It is important to note that the fixed threshold of 65% predicted, while pragmatic, is a departure from the statistically more rigorous use of the lower limit of normal (LLN) advocated in international spirometry guidelines. The evidence base specifically validating this 65% cut-off for predicting clinical outcomes in children is limited, highlighting the need for future standardization. Crucially, reliable spirometry performance typically requires a developmental age of 6 years and above, limiting its utility in preschool children.

In IOS, parameters such as R5–R20, X5, and AX are more sensitive indicators of small airway resistance heterogeneity and peripheral lung elasticity changes. Some studies propose R5–R20 >0.07 kPa/L·s as indicative of increased peripheral resistance, and an elevated AX suggests abnormal peripheral reactivity, serving as a clinical reference (26) (pediatric-specific reference values are still evolving). The threshold of R5–R20 >0.07 kPa/L·s is frequently cited but primarily derives from adult studies and expert opinion; robust, age-specific reference values and validation studies linking this specific threshold to meaningful clinical outcomes in children are still evolving. The reactance at 5 Hz (X5) is another important parameter reflecting peripheral elastic properties; however, established and widely validated age-specific reference values for clinical interpretation in children are currently lacking. The application of IOS in clinical practice faces several challenges. These include the lack of globally standardized, age-specific reference values for children, the requirement for operator expertise and good patient cooperation (e.g., maintaining a tight seal, relaxed posture), and the potential for results to be influenced by upper airway resistance. Despite these challenges, IOS is a low-effort technique and can often be successfully applied in children as young as 3–4 years of age, making it a valuable tool for assessing preschool children with suspected SAD.

For assessing inflammation, it is crucial to differentiate the sites reflected by different measurements. FeNO measured at a standard flow rate (e.g., 50 mL/s) primarily reflects type 2 inflammatory activity in the central airways. The 2021 Chinese expert consensus on FeNO measurement suggests that FeNO at an expiratory flow of 200 mL/s (FeNO200) >10 ppb and/or CaNO >5 ppb may indicate a high peripheral airway inflammatory load (30). CaNO, derived from multiple-flow measurements, is theoretically considered a potential marker of peripheral airway/alveolar inflammation. These thresholds are not strict diagnostic criteria but serve as supportive indicators in clinical practice. However, it is important to acknowledge the current limitations. The consensus-based thresholds (FeNO200 >10 ppb, CaNO >5 ppb) are not directly equivalent to cut-offs established in international guidelines like those from the American Thoracic Society and/or the European Respiratory Society. CaNO measurement and interpretation are less standardized than those for FeNO, and there is ongoing debate regarding the optimal mathematical model and flow rates for its calculation, especially in children. Furthermore, FeNO values themselves exhibit age-dependent variability. Therefore, these values should be interpreted as part of a composite assessment rather than as definitive diagnostic criteria. The feasibility of obtaining valid multi-flow measurements for CaNO calculation is often lower in very young children.

Step 3: implementing targeted treatment adjustment

If assessment suggests SAD, treatment strategies favoring small airway delivery could be prioritized within the stepwise therapy framework. This may involve selecting extrafine-particle ICS as a first-line consideration (supported primarily by adult data and expert consensus), ensuring adequate dosing, and considering earlier initiation of combination therapy with LABA (preferably extrafine-particle ICS-LABA) in moderate-to-severe cases. If control remains inadequate, adding LAMA as an add-on therapy (where age and indications permit) may be considered to further improve small airway resistance (extrapolated from adult and mixed-population studies; pediatric-specific randomized controlled trial (RCT) data are limited) (29). The use of LAMAs such as tiotropium is approved for children of specific ages (e.g., ≥6 years for asthma in many regions), and this must be considered in treatment decisions. For difficult-to-treat cases, eligibility for biologic therapies should be evaluated. Appropriate escalation to biologic therapy can help reduce distal airway inflammation. The age indications for biologics vary: omalizumab is approved for children ≥6 years, dupilumab and mepolizumab for severe asthma are indicated for children ≥6 years, and age thresholds for other agents (e.g., benralizumab, tezepelumab) should be checked per local guidelines, particularly for adolescents versus younger school-age children. Concurrently, relevant triggers (e.g., environmental allergen exposure, passive smoking) should be systematically identified and minimized.

Step 4: follow-up and dynamic adjustment

Given the dynamic nature of small airway involvement, trend monitoring using a consistent methodology is recommended during treatment. If objective indicators worsen, inhalation technique, treatment adherence, and exposure to triggers should be reassessed prior to therapy escalation. Step-down therapy can be considered once overall control is stable. Monitoring for adverse effects is crucial for children on high-dose ICS or long-term intensive therapy (31).

This proposed pathway highlights SAD as a potentially modifiable trait. Future research is urgently needed to standardize definitions, validate the proposed diagnostic and treatment thresholds, and prospectively test the efficacy of this TT-based management approach, thereby generating higher-quality evidence for precision management in childhood asthma.

Pharmacotherapy targeting small airways

Pharmacotherapy targeting small airways encompasses a range of strategies with distinct mechanisms and varying levels of evidence. To provide a clear overview and comparison, the mechanisms of action, target populations, and supporting evidence for the major drug classes are systematically summarized in Table 3 and illustrated in Figure 1.

Figure 1 Mechanisms of small airway-targeted therapies in childhood asthma. Schematic overview of therapeutic strategies targeting the small airways. The left panel illustrates the mechanisms of inhaled therapies: extrafine-particle ICS/LABA (combining anti-inflammatory and bronchodilation) and add-on LAMA (reducing cholinergic tone). The central panel depicts structural abnormalities in asthmatic small airways, including inflammation, wall thickening, and smooth muscle constriction. The right panel shows how biologic agents (e.g., anti-IgE, anti-IL-5/IL-5R, anti-IL-4R) target key mediators of type 2 inflammation, reducing peripheral airway inflammation. ICS, inhaled corticosteroids; IgE, immunoglobulin E; IL, interleukin; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist.

Extrafine-particle ICS and ICS-LABA

ICS remain the cornerstone of long-term asthma management in children. Given the substantial contribution of small airways to the total surface area of the bronchial tree and the widespread expression of glucocorticoid-related molecular targets in distal lung regions and small airways (30), ensuring adequate ICS delivery to these areas is crucial for achieving comprehensive anti-inflammatory control.

Compared with standard fine-particle ICS formulations [with a mass median aerodynamic diameter (MMAD) of approximately 2–5 µm], extrafine-particle formulations can achieve comparable overall efficacy at lower nominal doses and may confer specific advantages in improving small airway function (31). However, it is important to note that current evidence for the superiority of extrafine-particle formulations in children is still predominantly derived from adult studies and expert opinion, with a relative scarcity of high-quality randomized controlled trials specifically designed for and conducted in children ≤12 years of age. Notably, studies have observed that patients with SAD, as defined by IOS, are less likely to be prescribed extrafine-particle formulations than those without SAD (32). This indirectly suggests that small airway-targeted therapy may be underutilized in clinical practice. When asthma control remains suboptimal with medium-dose ICS, the treatment strategy typically follows a stepwise approach by adding a LABA, resulting in ICS-LABA combination therapy. For children with SAD, ICS-LABA not only provides synergistic anti-inflammatory and bronchodilatory effects, but the LABA component may also enhance intrapulmonary distribution and peripheral deposition of ICS, thereby enhancing delivery to distal airways. A domestic study found that in children with p-SAD, ICS-LABA resulted in greater improvement in small airway parameters compared with ICS monotherapy (20).

Thus, extrafine-particle ICS and their combination regimens represent key components of small airway-targeted therapy, enhancing drug deposition in distal airways and thereby improving asthma control and quality of life.

LAMA triple therapy

LAMAs exert sustained bronchodilation by antagonizing muscarinic M receptors and inhibiting vagally mediated airway smooth muscle contraction. In asthma management, LAMAs are typically positioned as add-on therapy in patients with inadequately controlled disease.

A randomized controlled trial that included both children (6–18 years) and adults with moderate-to-severe persistent asthma demonstrated that triple therapy (ICS-LABA-LAMA), compared to dual therapy (ICS-LABA), reduced the risk of severe acute exacerbations [risk ratio (RR) =0.83; 95% confidence interval (CI): 0.77–0.90] and provided modest improvement in asthma control (33). It is crucial to recognize that this study was conducted in a mixed pediatric-adult population. Specific efficacy data and safety profiles for the pediatric subgroup, particularly for younger children, are more limited and require further confirmation in dedicated pediatric trials. The Global Initiative for Asthma (GINA) reports that adding a LAMA to ICS-LABA provides modest improvements in lung function and reduces exacerbation risk to a limited extent (24).

From an SAD perspective, the potential benefit of LAMAs may stem from their ability to further relieve constriction in distal airways, particularly in patients whose small airway smooth muscle spasm responds insufficiently to conventional β₂-agonists. Additionally, the prolonged duration of action of agents such as tiotropium helps maintain airway patency during nocturnal periods and reduces vagally mediated airway narrowing.

Therefore, triple therapy may offer additional benefit for children with elevated small airway resistance who experience persistent symptoms or recurrent exacerbations despite ICS-LABA therapy (34). It is important to emphasize that LAMAs primarily target airway smooth muscle tone and have limited effects on eosinophilic inflammation-driven airway remodeling; thus, they should be regarded as adjunctive rather than substitutive therapy to ICS-based treatment.

Leukotriene receptor antagonists (LTRAs) and other oral agents

Leukotrienes are key lipid mediators of allergic inflammation and airway hyperresponsiveness in asthma, synthesized from arachidonic acid via the 5-lipoxygenase pathway. They contribute to bronchoconstriction, mucus hypersecretion, increased vascular permeability, and type 2 (T2) inflammatory responses. As these effects occur throughout the airway tree, intervention in the leukotriene pathway is considered a potential strategy to influence inflammatory and constrictive phenotypes in airways, including distal bronchioles (35). Consequently, blocking this pathway represents an adjunctive strategy for the management of SAD.

LTRAs primarily inhibit leukotriene-mediated bronchoconstriction and inflammation by antagonizing the CysLT1 receptor. In the long-term management of childhood asthma, montelukast has been shown to improve symptoms; however, its overall efficacy is generally inferior to that of ICS. Systematic reviews and meta-analyses also indicate that ICS is superior to montelukast for symptom control (36); therefore, LTRAs are often considered alternative or add-on controller medications. Critically, direct evidence from pediatric randomized controlled trials specifically demonstrating that LTRAs improve small airway function parameters (e.g., IOS indices) in children with asthma is currently lacking. It is crucial to note that montelukast has been associated with neuropsychiatric adverse events; therefore, potential risks should be carefully discussed with caregivers prior to initiation, and patients should be closely monitored for behavioral and mood changes during treatment.

Beyond receptor antagonists, the 5-lipoxygenase inhibitor zileuton inhibits leukotriene synthesis at an upstream level. Theoretically, this offers broader suppression of leukotriene-mediated pathways may offer an advantage for refractory small airway inflammation (37). However, its use equires routine liver function monitoring and remains limited in clinical practice. Robust pediatric data supporting its efficacy for SAD are lacking.

While theophylline exerts bronchodilatory effects and possesses modest immunomodulatory and anti-inflammatory properties, its narrow therapeutic window, risk of drug interactions, and potential for adverse effects have substantially limited its role in contemporary asthma management. Regarding a specific effect on SAD in children, robust modern evidence is not well-established. Recent reviews tend to position it as a highly individualized option in selected cases, emphasizing the importance of therapeutic drug monitoring (38). Evidence for its specific effect on pediatric SAD is not well-established in modern literature.

For adolescents with severe refractory disease, persistent SAD, and inadequate response to other therapies, maintenance oral corticosteroids may be considered as a last-resort option. However, long-term oral corticosteroid use in children should be avoided whenever possible due to significant adverse effects on growth and development.

Biologic therapies

Biologic agents, which target immunoglobulin E (IgE) or key mediators of type 2 (T2) inflammation—such as interleukin (IL)-5/IL-5Rα, IL-4/IL-13, and thymic stromal lymphopoietin (TSLP)—to interrupt the inflammatory cascade, have become a crucial step-up option for children with severe asthma who remain uncontrolled despite optimized inhaled therapy. As most biologics are administered systemically, they can theoretically reach and affect the peripheral small airways. Recent studies also indicate that certain biologics can improve functional indices associated with small airway involvement (39), thereby offering an advanced treatment option for children with SAD. However, the level and specificity of evidence vary significantly between adult and pediatric populations.

Anti-IgE (omalizumab), which primarily neutralizes circulating IgE and downregulates IgE-mediated allergic inflammation, is an approved add-on therapy for children aged 6–11 years with severe allergic asthma (40). Regarding small airway-related outcomes, adult studies suggest that parameters such as FEF25–75% may demonstrate greater sensitivity to change compared with FEV₁ following biologic therapy (39). However, in pediatric populations, existing evidence has predominantly focused on exacerbation reduction, overall asthma control, and steroid-sparing effects (41). More high-quality studies with SAD-specific endpoints are needed to clarify its direct impact on small airway function in children.

Anti-IL-5/anti-IL-5Rα agents (mepolizumab, benralizumab) target eosinophilic inflammation by inhibiting eosinophil maturation, recruitment, or inducing depletion, making them suitable for children with severe, eosinophilic or T2-high asthma. Given that eosinophilic inflammation is also associated with small airway inflammation and increased airway resistance heterogeneity (39), these agents are mechanistically promising for improving SAD. The IMPOSE study, conducted in adults with severe eosinophilic asthma, demonstrated significant improvements in small airway function as early as one month after initiation of mepolizumab, with sustained benefits in parameters such as R5–R20, AX, and FEF25–75% at 6 months, aligning with improved asthma control and quality of life (42). This suggests that the small airway benefits of biologics can manifest early in treatment. Similar robust pediatric studies focusing on SAD outcomes are awaited.

Anti-IL-4Rα (dupilumab) blocks the IL-4/IL-13 signaling pathway and is indicated for children over 6 years of age with moderate-to-severe T2-high asthma. A randomized controlled trial in children aged 6–11 years with uncontrolled moderate-to-severe asthma showed that add-on dupilumab significantly reduced exacerbations and improved lung function and control, providing high-level evidence for its use in this population (43). Further studies in adults using IOS as the primary assessment tool indicate that 12 weeks of dupilumab treatment significantly improves small airway-related markers such as R5–R20, AX, and FEF25–75%, alongside improvements in asthma control (44). Pediatric data specifically evaluating SAD improvement with IOS are more limited but emerging.

Anti-TSLP agents TSLP, blocking its receptor interaction and thereby inhibiting upstream T2 inflammatory signaling. These are indicated for patients with severe asthma and elevated eosinophils or FeNO levels. In a large randomized controlled trial including adolescents aged ≥12 years, tezepelumab significantly reduced exacerbations and improved lung function and asthma control (45). Studies evaluating adult patients on tezepelumab using oscillometry/spirometry ratios have also suggested potential improvements in small airway function (46).

Beyond currently approved biologics, interventions targeting upstream inflammatory mediators (e.g., IL-33) and pathways related to airway remodeling remain under investigation. While biologics have shown potential benefits for the small airway phenotype in adult asthma, direct and high-level evidence in children, particularly from trials using SAD-specific parameters as primary endpoints, remains relatively limited. Future research should prioritize prospective studies and randomized controlled trials with pediatric SAD-specific endpoints, in order to clarify optimal patient selection, treatment duration, and combination strategies, as well as to evaluate their impact on airway remodeling and long-term lung function trajectories.

Conclusions

The small airways have become an increasingly important therapeutic target that should not be overlooked in asthma management. Strategies such as extrafine-particle ICS, triple therapy incorporating LAMA, and biologic agents have shown promise in improving SAD. Viewing SAD through the lens of TTs provides a new framework for individualized and precision-based management in childhood asthma.

Looking ahead, further elucidation of the underlying pathophysiological mechanisms of SAD will likely facilitate the development of more specific and targeted therapeutic approaches. Concurrently, the broader implementation and standardization of small airway assessment techniques, such as IOS and FeNO, are essential. Efforts should be made to improve the accessibility and standardized use of these non-invasive modalities in clinical practice, thereby enabling earlier detection and dynamic monitoring of SAD.

Furthermore, the TTs-based management model requires refinement. A more detailed, practical, and actionable management pathway for SAD in children should be established, taking into account developmental stages, specifying age-appropriate assessment frequencies, treatment adjustment thresholds, and long-term follow-up strategies.

Through the integrated advancement of basic and clinical research, it is anticipated that overall asthma control in children can be improved, the risk of long-term lung function impairment reduced, and the quality of life and long-term prognosis of affected children further optimized.

Acknowledgments

The authors sincerely thank all contributors to this study.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0251/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0251/prf

Funding: This work was supported by the Guizhou Provincial Science and Technology Plan Project of China (No. 202542924776X30008), and Guizhou Provincial Basic Research Program (Natural Science) {No. QKH-ZK[2023]-General 347}.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0251/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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