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Observational Study
. 2022 Jul;10(7):661-668.
doi: 10.1016/S2213-2600(21)00536-1. Epub 2022 Mar 2.

The role of small airway dysfunction in asthma control and exacerbations: a longitudinal, observational analysis using data from the ATLANTIS study

Monica Kraft  1 , Matthew Richardson  2 , Brian Hallmark  3 , Dean Billheimer  3 , Maarten Van den Berge  4 , Leonardo M Fabbri  5 , Thys Van der Molen  6 , Gabriele Nicolini  7 , Alberto Papi  5 , Klaus F Rabe  8 , Dave Singh  9 , Chris Brightling  2 , Salman Siddiqui  10 ; ATLANTIS study group
Collaborators, Affiliations
Observational Study

The role of small airway dysfunction in asthma control and exacerbations: a longitudinal, observational analysis using data from the ATLANTIS study

Monica Kraft et al. Lancet Respir Med. 2022 Jul.

Abstract

Background: Although small airway disease is a feature of asthma, its association with relevant asthma outcomes remains unclear. The ATLANTIS study was designed to identify the combination of physiological and imaging variables that best measure the presence and extent of small airway disease in asthma, both cross-sectionally and longitudinally. In this longitudinal analysis, we evaluated which small airway parameters studied were most strongly associated with asthma control, exacerbations, and quality of life.

Methods: In this observational cohort study, participants with mild, moderate, or severe stable asthma were recruited between June 30, 2014, and March 3, 2017, via medical databases and advertisements in nine countries worldwide. Eligible participants were aged 18-65 years with a clinical asthma diagnosis for at least 6 months. Participants were followed up for 1 year, with visits at baseline, 6 months, and 12 months. Physiological tests included spirometry, lung volumes, impulse oscillometry, multiple breath nitrogen washout (MBNW), and percentage decrease in forced vital capacity during methacholine challenge. CT densitometry was performed to evaluate small airway disease. We examined the associations between these measurements and asthma exacerbations, asthma control, and quality of life using univariate and multivariate analyses. A composite ordinal score comprising percent predicted R5-20 (resistance of small-to-mid-sized airways), AX (area of reactance), and X5 (reactance of more central, conducting small airways at 5 Hz) was constructed.

Findings: 773 participants (median age 46 years [IQR 34-54]; 450 [58%] female) were included in this longitudinal study. Univariate analyses showed that components of impulse oscillometry, lung volumes, MBNW, and forced expiratory flow at 25-75% of FVC were significantly correlated with asthma control and exacerbations (Spearman correlations 0·20-0·25, p<0·0001 after Bonferroni correction). As a composite of impulse oscillometry, the ordinal score independently predicted asthma control and exacerbations in a multivariate analysis with known exacerbation predictors. CT parameters were not significantly correlated with asthma control, exacerbation, or quality of life.

Interpretation: Small airway disease, as measured by physiological tests, is longitudinally associated with clinically important asthma outcomes, such as asthma control and exacerbations.

Funding: Chiesi Farmaceutici.

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Conflict of interest statement

Declaration of interests MK reports grants paid to their institution for their research from the National Institutes of Health, American Lung Association, Chiesi Farmaceutici (for support of this study), AstraZeneca and Sanofi-Regeneron; personal fees for consultancies from Chiesi Farmaceutici, Genentech (Roche), GSK, Sanofi Regeneron, and AstraZeneca; speaker fees from Chiesi Farmaceutici; personal fees from participation in a data safety and monitoring board for AstraZeneca and ALung; and leadership in the American Thoracic Society. MVdB receives grants paid to their institution from Chiesi Farmaceutici (for this study), Sanofi, Genentech, GSK, and Roche. LMF reports personal fees for consultancies from Chiesi Farmaceutici; speaker fees from participation in advisory boards for Chiesi Farmaceutici, AstraZeneca, GSK, Alfasigma, Novartis, and Verona Pharma; travel expense reimbursement from Chiesi Farmaceutici, Novartis, and Menarini; and personal fees from participation in a data safety and monitoring board for Novartis. TVdM reports part-time employment with GSK and personal fees for consultancies from Chiesi Farmaceutici. GN reports being employed by Chiesi Farmaceutici. AP reports funding by Chiesi Farmaceutici (for this and other studies), AstraZeneca, GSK, Boehringer Ingelheim, Pfizer, Teva, and Sanofi paid to their institution; personal fees for consulting from Chiesi Farmaceutici, AstraZeneca, GSK, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceutic, and ALS; personal fees for lectures and presentations from Chiesi Farmaceutici, AstraZeneca, GSK, Boehringer Ingelheim, Menarini, Novartis, Zambon, Mundipharma, Teva, Sanofi, Edmond Pharma, Iqvia, MSD, Avillion, Elpen Pharmaceutic, ALS. KFR reports support from Chiesi Farmaceutici paid to their institution for this study; speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Novartis, Sanofi/Regeneron, GlaxoSmithKline, Berlin Chemie, and Roche Pharma; personal fees from participation in a data safety and monitoring board for AstraZeneca, Boehringer Ingelheim, and Sanofi/Regeneron; and a leadership or fiduciary role for the German Center for Lung Research, the German Chest Society, and the American Thoracic Society. DS reports personal fees for consulting from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Cipla, CSL Behring, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Teva, Theravance, and Verona. CB reports support paid to their institution from Chiesi Farmaceutici for this study; grants paid to their institution from GSK, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi Farmaceutici, Sanofi, Genetech, Merck, Mologic, 4DPharma, and Gossamer; and personal fees for consulting from GSK, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi Farmaceutici, Sanofi, Genentech, Merck, Mologic, 4DPharma, Gossamer, TEVA, Regeneron, Roche, and CSL Behring. SS reports funding paid to their institution from Chiesi Farmaceutici for support of this study; personal fees from GSK, Novartis, ERT Medical, AstraZeneca, Knopp Biotech, Owlstone Medical, Mundipharma, CSL Behring, and Boehringer Ingelheim; and personal fees for lectures from Chiesi Farmaceutici. All other authors declare no competing interests.

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