Increased airway smooth muscle in preschool wheezers who have asthma at school age Ruth O'Reilly, MBChBBAO, Nicola Ullmann, MD, Samantha Irving, BSc,

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Increased airway smooth muscle in preschool wheezers who have asthma at school age Ruth O'Reilly, MBChBBAO, Nicola Ullmann, MD, Samantha Irving, BSc, Cara J. Bossley, MBChB, Samatha Sonnappa, PhD, Jie Zhu, PhD, Timothy Oates, BSc, Winston Banya, BSc, Peter K. Jeffery, DSc, Andrew Bush, MD, Sejal Saglani, MD Journal of Allergy and Clinical Immunology Volume 131, Issue 4, Pages 1024-1032.e16 (April 2013) DOI: 10.1016/j.jaci.2012.08.044 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Flow diagram showing follow-up at school age (2009-2010) and tests performed in previously recruited preschool children. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Preschool airway pathology and its relationship to preschool wheeze and asthma at school age. A, No difference in ASM area fraction between preschool wheezers and control subjects. B, Increased preschool ASM area fraction in school-aged asthmatic subjects. C, Increased RBM thickness in preschool wheezers. D, No difference in preschool RBM thickness in school-aged asthmatic subjects. E, Increased subepithelial eosinophil numbers at preschool age. F, No difference in preschool subepithelial eosinophil numbers in school-aged asthmatic subjects. G, No difference in ASM mast cell numbers between preschool wheezers and control subjects. H, No difference in ASM mast cell numbers in school-aged asthmatic subjects. Analysis was performed with the Mann-Whitney U test. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Area under the receiver operating characteristics curve (AUC) for ASM area fraction in preschool wheezers for the diagnosis of asthma at school age was 0.88 (SE, 0.08; 95% CI, 0.66-0.98; P < .0001). CIs are represented by the broken line, and the area under the curve is represented by the continuous line. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Correlation between Feno50 values and RBM thickness at school age (i) and ASM area fraction (ii) in preschool children with severe wheeze. There is a positive correlation between Feno50 values and ASM area fraction. There is no correlation between RBM thickness and Feno50 values. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Smooth muscle bundles were traced with a computer mouse, and then the area was calculated by using computer-aided analysis. ASM was represented as a fraction of the total subepithelial area (scale not shown: image shown for illustration purposes). Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Smooth muscle volume fraction was quantified by using point and line intersection counting. A Weibel grid (M168) was overlaid at the section, and ASM was measured at ×200 magnification. The length between 2 points was 68 μm. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 A Bland-Altman plot of ASM area fraction measurements between observer 1 and observer 2. Good repeatability between ASM area fraction measurements was shown between observer 1 and observer 2. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 A, No difference in smooth muscle proliferation between wheezers and control subjects. B, No difference in smooth muscle proliferation between children with and without asthma at school age. Smooth muscle proliferation was assessed by quantifying the proportion of proliferating cell nuclear antigen (PCNA)–positive smooth muscle cells per square millimeter of smooth muscle. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 There was no difference between ASM area fraction in confirmed (CW) and reported (RW) wheezers (A) or in multiple-trigger or episodic (viral) wheezers (B) at preschool age. The Mann-Whitney U test was used. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 ASM area fraction is increased in preschool wheezers with asthma at school age (A), but there was no difference in RBM thickness (B) or subepithelial eosinophil numbers (C) between preschool wheezers who did and did not have asthma at school age. The Mann-Whitney U test was used. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Receiver operating characteristics curve for ASM volume fraction measured by using point and line intersection counting in preschool wheezers related to asthma at school age (area under the curve [AUC], 0.79; SE, 0.08; 95% CI, 0.61-0.91; P = .0008). CIs are represented by the broken line, and the area under the curve was represented by the continuous line. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 Receiver operating characteristics curve for wheeze severity score related to asthma at school age (area under the curve [AUC], 0.7; SE, 0.08; 95% CI, 0.53-0.84; P = .01) in preschool wheezers recruited from the Royal Brompton Hospital from 2002-2005. CIs are represented by the broken line, and the area under the curve was represented by the continuous line. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E9 No difference in volume fraction of ASM indexed to surface area of RBM between preschool wheezers and control subjects (A) and children with and without asthma at school age (B). The Mann-Whitney U test was used. V/S, Volume fraction of smooth muscle indexed to surface area of RBM. Journal of Allergy and Clinical Immunology 2013 131, 1024-1032.e16DOI: (10.1016/j.jaci.2012.08.044) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions