Small airway dysfunction is common even in mild asthma and suggests increased exacerbation risk

I read with great interest the article entitled "Assessing asthma control by impulse oscillometry and fractional expiratory nitric oxide in children with normal spirometry,"1Yun H.-J. Eom S.-Y. Hahn Y.-S. Assessing asthma control by impulse oscillometry and fractional expiratory nitric oxide in children with normal spirometry.J Allergy Clin Immunol Pract. 2023; 11: 2822-2829Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar which convincingly showed that impulse oscillometry (IOS) metrics indicating small airway dysfunction (SAD) effectively identifies patients with asthma that is not well controlled (NWC). Identification was improved when SAD was combined with elevated FeNO levels in children with asthma with preserved spirometry. Although this observation with SAD was previously reported in adults,2Cottini M. Bondi B. Bagnasco D. Braido F. Passalacqua G. Licini A. et al.Impulse oscillometry defined small airway dysfunction in asthmatic patients with normal spirometry: prevalence, clinical associations, and impact on asthma control.Respir Med. 2023; 218107391Abstract Full Text Full Text PDF Scopus (6) Google Scholar this study further illustrates the importance of SAD determined by IOS reference equations previously described3Galant S.P. Fregeau W. Padelonio M. Morphew T. Tirakitsoontorn P. Standardized IOS reference values define peripheral airway impairment-associated uncontrolled asthma risk across ethnicity in children.J Allergy Clin Immunol Pract. 2020; 8: 2698-2706Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar as a potential clinical biomarker for many children with asthma. However, to ascribe the IOS-defined SAD potential mainly to identifying NWC asthma underestimates the clinical value of SAD. Small airway dysfunction also is associated with more severe airway hyperreactivity and is a significant predictor of previous2Cottini M. Bondi B. Bagnasco D. Braido F. Passalacqua G. Licini A. et al.Impulse oscillometry defined small airway dysfunction in asthmatic patients with normal spirometry: prevalence, clinical associations, and impact on asthma control.Respir Med. 2023; 218107391Abstract Full Text Full Text PDF Scopus (6) Google Scholar and future exacerbations4Kraft M. Richardson M. Hallmark B. Billheimer D. Van den Berge M. Fabbri L.M. et al.The role of small airway dysfunction in airway control and exacerbations: a longitudinal observational analysis using data from the ATLANTIS study.Lancet Respir Med. 2022; 10: 661-668Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar that, if recurrent, can result in airway remodeling. The recent longitudinal ATLANTIS study4Kraft M. Richardson M. Hallmark B. Billheimer D. Van den Berge M. Fabbri L.M. et al.The role of small airway dysfunction in airway control and exacerbations: a longitudinal observational analysis using data from the ATLANTIS study.Lancet Respir Med. 2022; 10: 661-668Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar showed that the IOS-determined SAD ordinal scores for the difference between resistance at 5 and 20 Hz, area of reactance, and X5, reactance at 5 Hz were independently related to an increase in the exacerbation rate. Thus, the importance of SAD as a significant risk factor for future exacerbation suggests that the presence of SAD could be clinically important not only for those with NWC, but also for those with well-controlled (WC) asthma. As suggested by the studies of Yung et al1Yun H.-J. Eom S.-Y. Hahn Y.-S. Assessing asthma control by impulse oscillometry and fractional expiratory nitric oxide in children with normal spirometry.J Allergy Clin Immunol Pract. 2023; 11: 2822-2829Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and Cottini et al,2Cottini M. Bondi B. Bagnasco D. Braido F. Passalacqua G. Licini A. et al.Impulse oscillometry defined small airway dysfunction in asthmatic patients with normal spirometry: prevalence, clinical associations, and impact on asthma control.Respir Med. 2023; 218107391Abstract Full Text Full Text PDF Scopus (6) Google Scholar the presence of SAD is frequently present in those with NWC asthma, but the authors fail to mention the potential importance of SAD in patients with WC asthma characterized by few symptoms and preserved spirometry. Table I compares the presence of SAD by several IOS metrics in those with asthma that is WC and with asthma that is with that is NWC. We selected three studies to illustrate this point: the study by Yun et al regarding children with asthma, the study by Cottini et al in adults,2Cottini M. Bondi B. Bagnasco D. Braido F. Passalacqua G. Licini A. et al.Impulse oscillometry defined small airway dysfunction in asthmatic patients with normal spirometry: prevalence, clinical associations, and impact on asthma control.Respir Med. 2023; 218107391Abstract Full Text Full Text PDF Scopus (6) Google Scholar both of which had preserved spirometry, and study by Galant et al study3Galant S.P. Fregeau W. Padelonio M. Morphew T. Tirakitsoontorn P. Standardized IOS reference values define peripheral airway impairment-associated uncontrolled asthma risk across ethnicity in children.J Allergy Clin Immunol Pract. 2020; 8: 2698-2706Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar in children with asthma not restricted to preserved spirometry. Although there are obvious differences in SAD between those with WC asthma and those with NWC asthma, SAD was found in those with WC asthma at 11.9% to 45.6%, and thus at potential risk for future exacerbations. This points to the importance of establishing the presence of SAD with oscillometry in patients with persistent asthma, because spirometry is much less sensitive,2Cottini M. Bondi B. Bagnasco D. Braido F. Passalacqua G. Licini A. et al.Impulse oscillometry defined small airway dysfunction in asthmatic patients with normal spirometry: prevalence, clinical associations, and impact on asthma control.Respir Med. 2023; 218107391Abstract Full Text Full Text PDF Scopus (6) Google Scholar and owing to the recognition that SAD is associated with an increased risk of future exacerbations even in those with supposedly WC asthma.Table ISmall airway dysfunction defined by resistance at 5 Hz, difference between resistance at 5 and 20 Hz, area of reactance, and resonant frequency >95th percentile, and <5th percentile for X5 in patients with well-controlled (WC) not well-controlled (NWC) asthmaVariableWell controlled (% small airway disease)Not well controlled (% small airway disease)Impulse oscillometry metric123123Resistance at 5 Hz15.335.4NT57.448.1NTDifference between resistance at 5 and 20 Hz11.945.629.965.466.7100%Area of reactanceNT38.0NTNT73.9NTX527.125.7NT59.463.8NTResonant frequency40.7NTNT80.2NTNTNT, not tested.Study 1 by Jung et al,1Yun H.-J. Eom S.-Y. Hahn Y.-S. Assessing asthma control by impulse oscillometry and fractional expiratory nitric oxide in children with normal spirometry.J Allergy Clin Immunol Pract. 2023; 11: 2822-2829Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar study 2 by Galant et al,3Galant S.P. Fregeau W. Padelonio M. Morphew T. Tirakitsoontorn P. Standardized IOS reference values define peripheral airway impairment-associated uncontrolled asthma risk across ethnicity in children.J Allergy Clin Immunol Pract. 2020; 8: 2698-2706Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar and study 3 by Cottini et al.2Cottini M. Bondi B. Bagnasco D. Braido F. Passalacqua G. Licini A. et al.Impulse oscillometry defined small airway dysfunction in asthmatic patients with normal spirometry: prevalence, clinical associations, and impact on asthma control.Respir Med. 2023; 218107391Abstract Full Text Full Text PDF Scopus (6) Google Scholar Asthma control was determined by Asthma Control Questionnaire 6 for study 1; National Heart, Lung, and Blood Institute for study 2; and Global Initiative for Asthma for study 3. Open table in a new tab NT, not tested. Study 1 by Jung et al,1Yun H.-J. Eom S.-Y. Hahn Y.-S. Assessing asthma control by impulse oscillometry and fractional expiratory nitric oxide in children with normal spirometry.J Allergy Clin Immunol Pract. 2023; 11: 2822-2829Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar study 2 by Galant et al,3Galant S.P. Fregeau W. Padelonio M. Morphew T. Tirakitsoontorn P. Standardized IOS reference values define peripheral airway impairment-associated uncontrolled asthma risk across ethnicity in children.J Allergy Clin Immunol Pract. 2020; 8: 2698-2706Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar and study 3 by Cottini et al.2Cottini M. Bondi B. Bagnasco D. Braido F. Passalacqua G. Licini A. et al.Impulse oscillometry defined small airway dysfunction in asthmatic patients with normal spirometry: prevalence, clinical associations, and impact on asthma control.Respir Med. 2023; 218107391Abstract Full Text Full Text PDF Scopus (6) Google Scholar Asthma control was determined by Asthma Control Questionnaire 6 for study 1; National Heart, Lung, and Blood Institute for study 2; and Global Initiative for Asthma for study 3. How then should one deal with the patient with asthma with SAD that is WC at the time of the office visit? Because of the potential of SAD-associated future exacerbations even in this type of patient, one should strongly consider stepping up therapy. Small airway dysfunction is a treatable trait that has been shown to respond well to extra-fine inhaled corticosteroids with improvement in both clinical asthma and SAD.5Galant S.P. Komarow H.D. Shin H.-W. Siddiqui S. Lipworth B.J. The case for impulse oscillometry in the management of asthma in children and adults.Ann Allergy Asthma Immunol. 2017; 118: 664-671Abstract Full Text Full Text PDF PubMed Google Scholar,6Hozawa S. Terada M. Hozawa M. Comparison of budesonide/formoterol Terbuhaler with fluticasone/salmeterol Diskus for treatment effects on small airway impairment and airway inflammation in patients with asthma.Pulm Pharmacol Ther. 2011; 24: 571-576Crossref PubMed Scopus (0) Google Scholar Additional randomized clinical trials are needed to characterize potential morbidities of the WC SAD asthma phenotype and establish the effectiveness of extra-fine inhaled corticosteroids in this cohort. Assessing Asthma Control by Impulse Oscillometry and Fractional Expiratory Nitric Oxide in Children With Normal SpirometryThe Journal of Allergy and Clinical Immunology: In PracticeVol. 11Issue 9PreviewBecause spirometric parameters fail to address current status of asthma in some patients, additional tests are required for better evaluation of asthma. Full-Text PDF Reply to "Small airway dysfunction is common even in mild asthma, suggests increased exacerbation risk"The Journal of Allergy and Clinical Immunology: In PracticeVol. 12Issue 7PreviewThank you for forwarding the correspondence regarding our article, "Assessing asthma control by impulse oscillometry and fractional expiratory nitric oxide in children with normal spirometry."1 We appreciate the opportunity to discuss further the findings and implications of our research in the context of recent advances in the field. Full-Text PDF