Reply to Erdem Topal

To the Editor,

We read with interest the correspondence by Yılmaz, Özer, and Topal ¹ regarding our recently published study on the relationship between bronchodilator response (BDR), asthma control, and systemic inflammatory profiles in children with moderate‐to‐severe asthma. ² We appreciate their engagement with our work and welcome the opportunity for further discussion. However, we note that all of the points raised in their commentary, particularly regarding study limitations and future research directions, were already explicitly acknowledged and discussed in our original manuscript. ² Before addressing the specific comments raised in the correspondence, we believe it is worthwhile to revisit these points for the benefit of the scientific community and to further clarify the context of our findings.

First, regarding the cross‐sectional design, Yılmaz et al. reiterate our own statement that this precludes causal inference. To expand upon this from a potential mechanistic perspective, the relationship between BDR and asthma severity in children already treated with inhaled corticosteroids (ICS) could be a consequence of underlying airway hyperresponsiveness. As we reported, the elevation of interleukin‐4 (IL‐4), IL‐13, matrix metalloproteinase‐1 (MMP‐1), and other markers in these patients suggests that high BDR is linked to a distinct molecular profile rather than acting merely as a transient functional marker. While longitudinal studies are indeed necessary, as we originally proposed, their primary value will be in evaluating whether these BDR‐related inflammatory signatures can predict long‐term clinical outcomes and treatment responsiveness, helping to definitively establish whether BDR represents a stable phenotypic marker or a fluctuating indicator of the disease activity and the inflammatory status.

Second, the authors also repeat our caution that serum cytokines may not fully mirror local airway inflammation. While induced sputum remains the gold standard for assessing the airway compartment, its routine clinical application in pediatrics is restricted by procedural complexity and the potential to provoke bronchospasm in susceptible children. ³ , ⁴ Therefore, our strategic focus on systemic inflammatory profiling was designed specifically to bridge this practical gap. In pediatric moderate‐to‐severe asthma, demonstrating that a simple, non‐invasive physiological marker like BDR correlates with a systemic inflammatory signature provides actionable clinical value. It helps identify patients who might benefit from systemic biologic therapies targeting the IL‐4/IL‐13 pathway despite ICS compliance. At the same time, our findings provide a rationale for future studies investigating the relationship between BDR and airway‐specific inflammatory profiles in childhood asthma.

Third, while Yılmaz et al. point out the small sample size of the high BDR group (n = 30), this limitation must be contextualized clinically. Severe asthma is relatively uncommon in children, accounting for approximately 3% (95% CI: 1–6) of pediatric asthma cases in Europe. ⁵ However, the disproportionate clinical burden of this condition necessitates multi‐center efforts to actively recruit and investigate this subgroup, as we accomplished in the SysPharmPediA study. ⁶ Recruiting a pediatric cohort with moderate‐to‐severe asthma—particularly one already adherent to GINA Step 3 or higher therapies—is inherently difficult. Identifying a high BDR phenotype within such a heavily medicated cohort is even more challenging, as inhaled corticosteroid (ICS) treatment generally suppresses both airway hyperresponsiveness and T2 cytokine expression. Therefore, detecting robust, statistically significant differences in inflammatory mediators despite a limited sample size is a notable strength, underscoring the resilience of this biological signal.

Finally, the correspondence suggests the incorporation of oscillometry, which perfectly aligns with the future directions we already explicitly recommended in our manuscript. Because oscillometry can help assess central (proximal) airway resistance and peripheral small‐airway dysfunction (albeit not with perfect specificity), ⁷ applying it in conjunction with BDR and inflammatory profiling may provide complementary insights into pediatric asthma phenotyping and further improve our understanding of the mechanisms underlying high BDR.

We appreciate that the authors concur with the limitations and future research priorities identified in our study. Advancing precision medicine in pediatric asthma will require moving beyond the recognition of methodological constraints and toward a deeper understanding of the interplay between airway physiology and immunologic mechanisms. We hope that our findings stimulate further collaborative research in this important area.

AUTHOR CONTRIBUTIONS

Nariman K. A. Metwally: Conceptualization; writing – review and editing. Simone Hashimoto: Conceptualization; writing – review and editing. Mahmoud I. Abdel‐Aziz: Writing – original draft; conceptualization. Anke H. Maitland‐van der Zee: Writing – review and editing; conceptualization.

CONFLICT OF INTEREST STATEMENT

Anke H. Maitland‐van der Zee (AHMZ) disclosed receiving grants as the PI of the P4O2 consortium sponsored by Health Holland, involving private partners (AbbVie, Boehringer Ingelheim, Breathomix, Fluidda, Ortec Logiqcare, PeXA, Philips, Quantib‐U, Smartfish, Clear, SODAQ, Thirona, Roche, TopMD, Novartis, RespiQ), an unrestricted research grant from Boehringer Ingelheim, and a Vertex Innovation Award grant; her institution received consulting honoraria from Boehringer Ingelheim and Astra Zeneca; and she serves as the Chair of a DSMB of a study on BPD in neonates. All other authors report no conflict of interest to disclose.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.