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. 2019 Jan;143(1):104-113.e14.
doi: 10.1016/j.jaci.2017.12.1009. Epub 2018 Mar 7.

Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids

Michael C Peters  1 , Sheena Kerr  1 , Eleanor M Dunican  1 , Prescott G Woodruff  1 , Merritt L Fajt  2 , Bruce D Levy  3 , Elliot Israel  3 , Brenda R Phillips  4 , David T Mauger  4 , Suzy A Comhair  5 , Serpil C Erzurum  5 , Mats W Johansson  6 , Nizar N Jarjour  7 , Andrea M Coverstone  8 , Mario Castro  9 , Annette T Hastie  10 , Eugene R Bleecker  10 , Sally E Wenzel  2 , John V Fahy  11 ; National Heart, Lung and Blood Institute Severe Asthma Research Program 3
Affiliations

Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids

Michael C Peters et al. J Allergy Clin Immunol. 2019 Jan.

Abstract

Background: Airway type 2 inflammation is usually corticosteroid sensitive, but the role of type 2 inflammation as a mechanism of asthma in patients receiving high-dose inhaled corticosteroids (ICSs) is uncertain.

Objective: We sought to determine whether airway type 2 inflammation persists in patients treated with ICSs and to evaluate the clinical features of patients with steroid-resistant airway type 2 inflammation.

Methods: We used quantitative PCR to generate a composite metric of type 2 cytokine gene expression (type 2 gene mean [T2GM]) in induced sputum cells from healthy control subjects, patients with severe asthma receiving ICSs (n = 174), and patients with nonsevere asthma receiving ICSs (n = 85). We explored relationships between asthma outcomes and T2GM values and the utility of noninvasive biomarkers of airway T2GM.

Results: Sputum cell T2GM values in asthmatic patients were significantly increased and remained high after treatment with intramuscular triamcinolone. We used the median T2GM value as a cutoff to classify steroid-treated type 2-low and steroid-resistant type 2-high (srT2-high) subgroups. Compared with patients with steroid-treated type 2-low asthma, those with srT2-high asthma were older and had more severe asthma. Blood eosinophil cell counts predicted srT2-high asthma when body mass index was less than 40 kg/m2 but not when it was 40 kg/m2 or greater, whereas blood IgE levels strongly predicted srT2-high asthma when age was less than 34 years but not when it was 34 years or greater.

Conclusion: Despite ICS therapy, many asthmatic patients have persistent airway type 2 inflammation (srT2-high asthma), and these patients are older and have more severe disease. Body weight and age modify the performance of blood-based biomarkers of airway type 2 inflammation.

Keywords: Severe asthma; biomarkers; steroid resistance; type 2 inflammation.

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Conflict of interest statement

Disclosure of potential conflict of interest: M. C. Peters reports consultancy fees from Merck and Genentech. P. G. Woodruff reports consultancy fees from AstraZeneca, Theravance, Regeneron, Sanofi, Genentech, Novartis, and Janssen. B. D. Levy reports institutional National Institutes of Health (NIH) funding and consultancy fees from AstraZeneca, Merck, Pieris Pharmaceuticals, and Sanofi. E. Israel reports personal fees from AstraZeneca, Novartis, Philips Respironics, Regeneron Pharmaceuticals; fees from Research in Real Life (RiRL); personal fees and other from TEVA Specialty Pharmaceuticals; grants from Genentech; nonfinancial support from Boehringer Ingelheim, GlaxoSmithKline, Merck, Sunovion, and TEVA; grants from Sanofi; personal fees from Bird Rock Bio, Nuvelution Pharmaceuticals, and Vitaeris; grants from Boehringer Ingelheim; nonfinancial support from TEVA Specialty Pharmaceuticals; personal fees from Sanofi, Merck, Entrinsic Health Solutions, and Glaxo-SmithKline; other funds from Vorso; and personal fees from Pneuma Respiratory outside the submitted work. D. T. Mauger reports institutional grant funding from the NIH. S. C. Erzurum reports institutional NIH funding and has pending NIH grants and is Chair of the ABIM Pulmonary Disease Board and reports travel support from them. M. W. Johansson’s institution reports grant funding from the NIH, and he has grants pending from Hoffman-LaRoche, is a member of the Genentech Advisory Board, and received speaking fees from them. N. N. Jarjour reports consulting fees from Teva, Daiichi Sankyo, and AstraZeneca, and his institution reports NIH grant funding. A. M. Coverstone reports institutional NIH grants (U10 HL109257 and UL1 TR00448), and she has grant funding from Orbex (5U01HL3004502) and the Inner City Asthma Consortium (5UM1Al11427104 and 5UM1Al11427103). M. Castro reports grants from the NIH and ALA during the conduct of the study; personal fees from Aviragen, Boehringer-Ingelheim, Boston Scientific, Elsevier, Genentech, GlaxoSmithKline, Holaira, and Teva; and grants from Amgen, Boehringer-Ingelheim, Genentech, Gilead, GlaxoSmithKline, Invion, Medimmune, Sanofi-Aventis, and Vectura, all outside the submitted work. A. T. Hastie reports grants from the National Heart, Lung and Blood Institute (NHLBI) during the conduct of the study. E. R. Bleecker reports undertaking clinical trials through his employer, Wake Forest School of Medicine, and the University of Arizona and has also served as a paid consultant outside the submitted work. S. E. Wenzel has received consultancy fees from AstraZeneca (Anti-IL-5R/TSLP), Sanofi (anti–IL-4R), Genentech, and Teva (anti–IL-5) and her institution has grant funding pending from GlaxoSmithKline (anti–IL-33), Boehringer Ingelheim (anti–IL-23), and received funds from AstraZeneca (anti–IL-5R trials), GlaxoSmithK-line (anti–IL-5 trials), Sanofi (anti–IL-4R trials), and Novartis (CRTH2 antagonist trial). J. V. Fahy reports consultant fees from Boehringer Ingelheim, Dynavax, Medimmune, Theravance, Pieris, and Entrinsic Health Solutions; his institution has received NIH grant funding and has grants from NHLBI, Pfizer, Genentech, and Vitaeris, and the institution also received biomedical patents in which he was the named inventor (for the National Heart, Lung and Blood Institute Severe Asthma Research Program 3). The rest of the authors declare that they have no relevant conflicts of interest.

Figures

FIG. 1
FIG. 1
Sputum gene expression measures in 30 healthy control subjects, 259 asthmatic patients receiving ICSs before intramuscular injection of triamcinolone (Pre-CS), and 283 asthmatic patients receiving ICSs after a 40-mg intramuscular injection of triamcinolone (Post-CS). A–C, Measures of IL4, IL5, and IL13 are greater in asthmatic patients receiving ICSs compared with healthy control subjects and remain increased after triamcinolone injection. D, T2GM values (a summary metric of IL-4, IL-5, and IL-13 sputum gene expression) are significantly greater in asthmatic patients receiving ICSs than in healthy subjects at baseline and remains significantly greater after the triamcinolone injection. Asthmatic patients with values greater than the median T2GM value (Pre-CS) were classified as having srT2-high asthma, and patients with values of less than this median value were classified as having stT2-low asthma. E and F, Measures of IFNG and IL17 are no different in asthmatic patients compared with those in healthy control subjects. G, Kernel density plot demonstrating T2GM values are lower in healthy control subjects (black line) compared with patients with nonsevere asthma (blue line) or patients with severe asthma (red line; P < .01). T2GM measures are significantly greater in patients with severe asthma compared with those in patients with non-severe asthma (P < .01). *Significantly different from healthy control subjects: P < .05.
FIG. 2
FIG. 2
A, T2GM measures a gradual increase in older subjects. Age quintiles: 1, 18 to 33.7; 2, 33.8 to 45.1; 3, 45.3 to 52.9; 4, 52.9 to 61.6; and 5, 62.0 to 84.4. B, T2GM measures do not change in more obese subjects. WHO, World Health Organization.
FIG. 3
FIG. 3
A, ROC curves for type 2 biomarkers for the outcome of srT2-high asthma. Eos, Eosinophils. B, Performance characteristics of blood eosinophil cell counts for predicting srT2-high asthma. *Blood eosinophil cell counts of 189 cells/μL or greater had the highest specificity and sensitivity for differentiating stT2-high asthma from stT2-low asthma. LR, Likelihood ratio.
FIG. 4
FIG. 4
A, Relationship between serum IgE levels and T2GM values is modified by age (Wald test for interaction, P = .004). Five linear regression lines demonstrate the relationship between log-transformed serum IgE levels and T2GM values subgrouped by age quintiles. Asthmatic patients in the youngest quintile have serum IgE levels that strongly correlate with airway T2GM measures (red line), whereas this relationship decreases in the older quintiles (green, blue, maroon, and orange lines). B, Relationship between blood eosinophil counts and T2GM values is modified by BMI (Wald test for interaction, P = .02). Five linear regression lines demonstrate the relationship between log-transformed blood eosinophil counts and T2GM values subgrouped by World Health Organization (WHO) BMI categories. Although asthmatic patients in BMI categories of less than 40 kg/m2 have blood eosinophil counts that correlate to airway T2GM measures (green, blue, maroon, and orange lines), this relationship decreases in patients with BMI of 40 kg/m2 or greater (red line). dy/dx, Marginal effect of serum IgE levels on T2GM values stratified by age quintiles or the marginal effect of blood eosinophil counts on T2GM values stratified by BMI WHO classification. P values are for (1) comparison of average marginal effects of the 4 oldest age quintiles compared with the youngest (reference) quintile and (2) comparison of average marginal effects of the 4 lowest BMI WHO categories compared with the highest (reference) BMI WHO category.
FIG. 5
FIG. 5
A, Maximal response to bronchodilators (BD-Response) is greater in patients with srT2-high asthma compared with those with stT2-low asthma. B, Absolute change in FEV1 percentage 2 weeks after a triamcinolone injection is greater in patients stT2-high asthma compared with those with stT2-low asthma. C, ROC curves demonstrating T2GM values as a superior predictor of a 5% absolute change in FEV1 percentage 2 weeks after a triamcinolone injection compared with other biomarkers of airway type 2 inflammation. *P < .05 for the T2GM AUC compared with other biomarkers. Eos, Eosinophils.
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