Download PDF
Semin Respir Crit Care Med 2022; 43(05): 739-751
DOI: 10.1055/s-0042-1750130
Review Article

Phenotyping, Precision Medicine, and Asthma

Arjun Mohan
1   Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
,
Njira L. Lugogo
1   Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

The traditional one-size-fits all approach based on asthma severity is archaic. Asthma is a heterogenous syndrome rather than a single disease entity. Studies evaluating observable characteristics called phenotypes have elucidated this heterogeneity. Asthma clusters demonstrate overlapping features, are generally stable over time and are reproducible. What the identification of clusters may have failed to do, is move the needle of precision medicine meaningfully in asthma. This may be related to the lack of a straightforward and clinically meaningful way to apply what we have learned about asthma clusters. Clusters are based on both clinical factors and biomarkers. The use of biomarkers is slowly gaining popularity, but phenotyping based on biomarkers is generally greatly underutilized even in subspecialty care. Biomarkers are more often used to evaluate type 2 (T2) inflammatory signatures and eosinophils (sputum and blood), fractional exhaled nitric oxide (FeNO) and serum total and specific immunoglobulin (Ig) E reliably characterize the underlying inflammatory pathways. Biomarkers perform variably and clinicians must be familiar with their advantages and disadvantages to accurately apply them in clinical care. In addition, it is increasingly clear that clinical features are critical in understanding not only phenotypic characterization but in predicting response to therapy and future risk of poor outcomes. Strategies for asthma management will need to leverage our knowledge of biomarkers and clinical features to create composite scores and risk prediction tools that are clinically applicable. Despite significant progress, many questions remain, and more work is required to accurately identify non-T2 biomarkers. Adoption of phenotyping and more consistent use of biomarkers is needed, and we should continue to encourage this incorporation into practice.

Keywords

asthma - precision medicine - biomarkers - phenotypes


Publication History

Article published online:
11 October 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Reddel HK. Global Initiative For Asthma (GINA): Global Strategy for asthma management and Prevention. 2021 Accessed August 1, 2021 at: https://ginasthma.org
    PubMedGoogle Scholar
  • 2 Clouthier MM. . 2020 Focused updates to the Asthma Management Guidelines: A report from the National Asthma Education and Prevention Program (NAEPP) Coordinating Committee Expert Panel Working Group; 2020
    PubMed
  • 3 National Research Council. . 2011. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease. Washington, DC. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease; 2011
    PubMed
  • 4 Ginsburg GS, Phillips KA. Precision medicine: from science to value. Health Aff (Millwood) 2018; 37 (05) 694-701
    CrossrefPubMedGoogle Scholar
  • 5 Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol 2004; 113 (01) 101-108
    CrossrefPubMedGoogle Scholar
  • 6 Fitzpatrick AM, Moore WC. Severe asthma phenotypes—how should they guide evaluation and treatment?. J Allergy Clin Immunol Pract 2017; 5 (04) 901-908
    CrossrefPubMedGoogle Scholar
  • 7 Agache IO. From phenotypes to endotypes to asthma treatment. Curr Opin Allergy Clin Immunol 2013; 13 (03) 249-256
    CrossrefPubMedGoogle Scholar
  • 8 Lötvall J, Akdis CA, Bacharier LB. et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011; 127 (02) 355-360
    CrossrefPubMedGoogle Scholar
  • 9 Wenzel SE, Schwartz LB, Langmack EL. et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999; 160 (03) 1001-1008
    CrossrefPubMedGoogle Scholar
  • 10 Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol 2015; 15 (01) 57-65
    CrossrefPubMedGoogle Scholar
  • 11 Moore WC, Meyers DA, Wenzel SE. et al; National Heart, Lung, and Blood Institute's Severe Asthma Research Program. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010; 181 (04) 315-323
    CrossrefPubMedGoogle Scholar
  • 12 Haldar P, Pavord ID, Shaw DE. et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008; 178 (03) 218-224
    Google Scholar
  • 13 Shaw DE, Sousa AR, Fowler SJ. et al; U-BIOPRED Study Group. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J 2015; 46 (05) 1308-1321
    CrossrefPubMedGoogle Scholar
  • 14 Loza MJ, Djukanovic R, Chung KF. et al; ADEPT (Airways Disease Endotyping for Personalized Therapeutics) and U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcome Consortium) investigators. Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study. Respir Res 2016; 17 (01) 165
    CrossrefPubMedGoogle Scholar
  • 15 Silkoff PE, Strambu I, Laviolette M. et al. Asthma characteristics and biomarkers from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) longitudinal profiling study. Respir Res 2015; 16: 142
    CrossrefPubMedGoogle Scholar
  • 16 Kaur R, Chupp G. Phenotypes and endotypes of adult asthma: moving toward precision medicine. J Allergy Clin Immunol 2019; 144 (01) 1-12
    CrossrefPubMedGoogle Scholar
  • 17 Opina MT, Moore WC. Phenotype-driven therapeutics in severe asthma. Curr Allergy Asthma Rep 2017; 17 (02) 10
    CrossrefPubMedGoogle Scholar
  • 18 Lefaudeux D, De Meulder B, Loza MJ. et al; U-BIOPRED Study Group. U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics. J Allergy Clin Immunol 2017; 139 (06) 1797-1807
    CrossrefPubMedGoogle Scholar
  • 19 Chupp GL, Bradford ES, Albers FC. et al. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med 2017; 5 (05) 390-400
    CrossrefPubMedGoogle Scholar
  • 20 Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology 2006; 11 (01) 54-61
    CrossrefPubMedGoogle Scholar
  • 21 Yan X, Chu JH, Gomez J. et al. Noninvasive analysis of the sputum transcriptome discriminates clinical phenotypes of asthma. Am J Respir Crit Care Med 2015; 191 (10) 1116-1125
    CrossrefPubMedGoogle Scholar
  • 22 Moore W. Reproducibility and stability of severe asthma research program (SARP) clinical cluster phenotypes in SARP3. Eur Respir J 2016; 48: OA3033
    PubMedGoogle Scholar
  • 23 Oppenheimer J, Hoyte FCL, Phipatanakul W, Silver J, Howarth P, Lugogo NL. Allergic and eosinophilic asthma in the era of biomarkers and biologics: similarities, differences and misconceptions. Ann Allergy Asthma Immunol 2022; 129 (02) 169-180
    CrossrefPubMedGoogle Scholar
  • 24 Shrimanker R, Keene O, Hynes G, Wenzel S, Yancey S, Pavord ID. Prognostic and predictive value of blood eosinophil count, fractional exhaled nitric oxide, and their combination in severe asthma: a post hoc analysis. Am J Respir Crit Care Med 2019; 200 (10) 1308-1312
    CrossrefPubMedGoogle Scholar
  • 25 Brusselle G, Germinaro M, Weiss S, Zangrilli J. Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils. Pulm Pharmacol Ther 2017; 43: 39-45
    CrossrefPubMedGoogle Scholar
  • 26 Howarth P, Chupp G, Nelsen LM. et al. Severe eosinophilic asthma with nasal polyposis: a phenotype for improved sinonasal and asthma outcomes with mepolizumab therapy. J Allergy Clin Immunol 2020; 145 (06) 1713-1715
    CrossrefPubMedGoogle Scholar
  • 27 Canonica GW, Harrison TW, Chanez P. et al. Benralizumab improves symptoms of patients with severe, eosinophilic asthma with a diagnosis of nasal polyposis. Allergy 2022; 77 (01) 150-161
    CrossrefPubMedGoogle Scholar
  • 28 Harrison TW, Chanez P, Menzella F. et al; ANDHI study investigators. Onset of effect and impact on health-related quality of life, exacerbation rate, lung function, and nasal polyposis symptoms for patients with severe eosinophilic asthma treated with benralizumab (ANDHI): a randomised, controlled, phase 3b trial. Lancet Respir Med 2021; 9 (03) 260-274
    CrossrefPubMedGoogle Scholar
  • 29 Holgate ST, Wenzel S, Postma DS, Weiss ST, Renz H, Sly PD. Asthma. Nat Rev Dis Primers 2015; 1: 15025
    Google Scholar
  • 30 Fricker M, Heaney LG, Upham JW. Can biomarkers help us hit targets in difficult-to-treat asthma?. Respirology 2017; 22 (03) 430-442
    CrossrefPubMedGoogle Scholar
  • 31 Rupani H, Fong WCG, Kyyaly A, Kurukulaaratchy RJ. Recent insights into the management of inflammation in asthma. J Inflamm Res 2021; 14: 4371-4397
    CrossrefPubMedGoogle Scholar
  • 32 Lugogo NL, Kreindler JL, Martin UJ, Cook B, Hirsch I, Trudo FJ. Blood eosinophil count group shifts and kinetics in severe eosinophilic asthma. Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, &. Immunology 2020; 125: 171-176
    PubMedGoogle Scholar
  • 33 Toledo-Pons N, van Boven JFM, Muncunill J. et al. Impact of blood eosinophil variability in asthma: a real-life population study. Ann Am Thorac Soc 2022; 19 (03) 407-414
    CrossrefPubMedGoogle Scholar
  • 34 Bleecker ER, FitzGerald JM, Chanez P. et al; SIROCCO study investigators. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016; 388 (10056): 2115-2127
    CrossrefPubMedGoogle Scholar
  • 35 FitzGerald JM, Bleecker ER, Nair P. et al; CALIMA study investigators. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2016; 388 (10056): 2128-2141
    CrossrefPubMedGoogle Scholar
  • 36 Couillard S, Laugerud A, Jabeen M. et al. Derivation of a prototype asthma attack risk scale centred on blood eosinophils and exhaled nitric oxide. Thorax 2022; 77 (02) 199-202
    Google Scholar
  • 37 King GG, James A, Harkness L, Wark PAB. Pathophysiology of severe asthma: We've only just started. Respirology 2018; 23 (03) 262-271
    CrossrefPubMedGoogle Scholar
  • 38 Pizzichini E, Pizzichini MM, Efthimiadis A, Dolovich J, Hargreave FE. Measuring airway inflammation in asthma: eosinophils and eosinophilic cationic protein in induced sputum compared with peripheral blood. J Allergy Clin Immunol 1997; 99 (04) 539-544
    CrossrefPubMedGoogle Scholar
  • 39 Kim H, Ellis AK, Fischer D. et al. Asthma biomarkers in the age of biologics. Allergy Asthma Clin Immunol 2017; 13: 48
    CrossrefPubMedGoogle Scholar
  • 40 Lugogo N, Green CL, Agada N. et al. Obesity's effect on asthma extends to diagnostic criteria. J Allergy Clin Immunol 2018; 141 (03) 1096-1104
    CrossrefPubMedGoogle Scholar
  • 41 Wagener AH, de Nijs SB, Lutter R. et al. External validation of blood eosinophils, FE(NO) and serum periostin as surrogates for sputum eosinophils in asthma. Thorax 2015; 70 (02) 115-120
    CrossrefPubMedGoogle Scholar
  • 42 Pavord ID, Afzalnia S, Menzies-Gow A, Heaney LG. The current and future role of biomarkers in type 2 cytokine-mediated asthma management. Clin Exp Allergy 2017; 47 (02) 148-160
    CrossrefPubMedGoogle Scholar
  • 43 Chipps BE, Jarjour N, Calhoun WJ. et al. A comprehensive analysis of the stability of blood eosinophil levels. Ann Am Thorac Soc 2021; 18 (12) 1978-1987
    Google Scholar
  • 44 Corren J, Du E, Gubbi A, Vanlandingham R. Variability in blood eosinophil counts in patients with eosinophilic asthma. J Allergy Clin Immunol Pract 2021; 9 (03) 1224-1231.e9
    CrossrefPubMedGoogle Scholar
  • 45 Busby J, Khoo E, Pfeffer PE, Mansur AH, Heaney LG. The effects of oral corticosteroids on lung function, type-2 biomarkers and patient-reported outcomes in stable asthma: a systematic review and meta-analysis. Respir Med 2020; 173: 106156
    CrossrefPubMedGoogle Scholar
  • 46 Sidhu SS, Yuan S, Innes AL. et al. Roles of epithelial cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci U S A 2010; 107 (32) 14170-14175
    CrossrefPubMedGoogle Scholar
  • 47 Suresh V, Mih JD, George SC. Measurement of IL-13-induced iNOS-derived gas phase nitric oxide in human bronchial epithelial cells. Am J Respir Cell Mol Biol 2007; 37 (01) 97-104
    CrossrefPubMedGoogle Scholar
  • 48 Menzies-Gow A, Flood-Page P, Sehmi R. et al. Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics. J Allergy Clin Immunol 2003; 111 (04) 714-719
    CrossrefPubMedGoogle Scholar
  • 49 Khatri SB, Iaccarino JM, Barochia A. et al; American Thoracic Society Assembly on Allergy, Immunology, and Inflammation. Use of fractional exhaled nitric oxide to guide the treatment of asthma: an Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 2021; 204 (10) e97-e109
    Google Scholar
  • 50 Korevaar DA, Westerhof GA, Wang J. et al. Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Respir Med 2015; 3 (04) 290-300
    CrossrefPubMedGoogle Scholar
  • 51 Hershey GK. IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin Immunol 2003; 111 (04) 677-690 , quiz 691
    CrossrefPubMedGoogle Scholar
  • 52 Dressel H, de la Motte D, Reichert J. et al. Exhaled nitric oxide: independent effects of atopy, smoking, respiratory tract infection, gender and height. Respir Med 2008; 102 (07) 962-969
    CrossrefPubMedGoogle Scholar
  • 53 Komakula S, Khatri S, Mermis J. et al. Body mass index is associated with reduced exhaled nitric oxide and higher exhaled 8-isoprostanes in asthmatics. Respir Res 2007; 8: 32
    CrossrefPubMedGoogle Scholar
  • 54 Gratziou C, Lignos M, Dassiou M, Roussos C. Influence of atopy on exhaled nitric oxide in patients with stable asthma and rhinitis. Eur Respir J 1999; 14 (04) 897-901
    CrossrefPubMedGoogle Scholar
  • 55 Buchvald F, Baraldi E, Carraro S. et al. Measurements of exhaled nitric oxide in healthy subjects age 4 to 17 years. J Allergy Clin Immunol 2005; 115 (06) 1130-1136
    CrossrefPubMedGoogle Scholar
  • 56 Taylor DR, Mandhane P, Greene JM. et al. Factors affecting exhaled nitric oxide measurements: the effect of sex. Respir Res 2007; 8: 82
    CrossrefPubMedGoogle Scholar
  • 57 Castro M, Corren J, Pavord ID. et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med 2018; 378 (26) 2486-2496
    Google Scholar
  • 58 Menzies-Gow A, Corren J, Bourdin A. et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med 2021; 384 (19) 1800-1809
    Google Scholar
  • 59 Corren J, Parnes JR, Wang L. et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med 2017; 377 (10) 936-946
    CrossrefPubMedGoogle Scholar
  • 60 Nagase H, Ueki S, Fujieda S. The roles of IL-5 and anti-IL-5 treatment in eosinophilic diseases: asthma, eosinophilic granulomatosis with polyangiitis, and eosinophilic chronic rhinosinusitis. Allergol Int 2020; 69 (02) 178-186
    CrossrefPubMedGoogle Scholar
  • 61 Johansson SG. Raised levels of a new immunoglobulin class (IgND) in asthma. Lancet 1967; 2 (7523): 951-953
    CrossrefPubMedGoogle Scholar
  • 62 Sharma S, Kathuria PC, Gupta CK, Nordling K, Ghosh B, Singh AB. Total serum immunoglobulin E levels in a case-control study in asthmatic/allergic patients, their family members, and healthy subjects from India. Clin Exp Allergy 2006; 36 (08) 1019-1027
    CrossrefPubMedGoogle Scholar
  • 63 Denton E, Price DB, Tran TN. et al. Cluster analysis of inflammatory biomarker expression in the International Severe Asthma Registry. J Allergy Clin Immunol Pract 2021; 9 (07) 2680-2688.e7
    CrossrefPubMedGoogle Scholar
  • 64 Tanaka A, Jinno M, Hirai K. et al. Longitudinal increase in total IgE levels in patients with adult asthma: an association with poor asthma control. Respir Res 2014; 15: 144
    CrossrefPubMedGoogle Scholar
  • 65 Tsolakis N, Jacinto T, Janson C, Borres M, Malinovschi A, Alving K. Relationship between longitudinal changes in type-2 inflammation, immunoglobulin E sensitization, and clinical outcomes in young asthmatics. Clin Transl Allergy 2021; 11 (07) e12066
    CrossrefPubMedGoogle Scholar
  • 66 Hanania NA, Wenzel S, Rosén K. et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med 2013; 187 (08) 804-811
    Google Scholar
  • 67 Wan XC, Woodruff PG. Biomarkers in severe asthma. Immunol Allergy Clin North Am 2016; 36 (03) 547-557
    CrossrefPubMedGoogle Scholar
  • 68 Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012; 18 (05) 716-725
    CrossrefPubMedGoogle Scholar
  • 69 Gauthier M, Ray A, Wenzel SE. Evolving concepts of asthma. Am J Respir Crit Care Med 2015; 192 (06) 660-668
    CrossrefPubMedGoogle Scholar
  • 70 Gauvreau GM, Sehmi R, Ambrose CS, Griffiths JM. Thymic stromal lymphopoietin: its role and potential as a therapeutic target in asthma. Expert Opin Ther Targets 2020; 24 (08) 777-792
    Google Scholar
  • 71 Berry M, Morgan A, Shaw DE. et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax 2007; 62 (12) 1043-1049
    Google Scholar
  • 72 Louis R, Lau LC, Bron AO, Roldaan AC, Radermecker M, Djukanović R. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med 2000; 161 (01) 9-16
    CrossrefPubMedGoogle Scholar
  • 73 Zhang XY, Simpson JL, Powell H. et al. Full blood count parameters for the detection of asthma inflammatory phenotypes. Clin Exp Allergy 2014; 44 (09) 1137-1145
    CrossrefPubMedGoogle Scholar
  • 74 Schleich FN, Manise M, Sele J, Henket M, Seidel L, Louis R. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med 2013; 13: 11
    CrossrefPubMedGoogle Scholar
  • 75 Kim RY, Horvat JC, Pinkerton JW. et al. MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase-mediated suppression of histone deacetylase 2. J Allergy Clin Immunol 2017; 139 (02) 519-532
    CrossrefPubMedGoogle Scholar
  • 76 Maes T, Cobos FA, Schleich F. et al. Asthma inflammatory phenotypes show differential microRNA expression in sputum. J Allergy Clin Immunol 2016; 137 (05) 1433-1446
    CrossrefPubMedGoogle Scholar
  • 77 Popović-Grle S, Štajduhar A, Lampalo M, Rnjak D. Biomarkers in different asthma phenotypes. Genes (Basel) 2021; 12 (06) 12
    CrossrefPubMedGoogle Scholar
  • 78 Watanabe T, Asai K, Fujimoto H, Tanaka H, Kanazawa H, Hirata K. Increased levels of HMGB-1 and endogenous secretory RAGE in induced sputum from asthmatic patients. Respir Med 2011; 105 (04) 519-525
    CrossrefPubMedGoogle Scholar
  • 79 Bafadhel M, McCormick M, Saha S. et al. Profiling of sputum inflammatory mediators in asthma and chronic obstructive pulmonary disease. Respiration 2012; 83: 36-44
    CrossrefPubMedGoogle Scholar
  • 80 Peters MC, McGrath KW, Hawkins GA. et al; National Heart, Lung, and Blood Institute Severe Asthma Research Program. Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med 2016; 4 (07) 574-584
    CrossrefPubMedGoogle Scholar
  • 81 Gao P, Gibson PG, Baines KJ. et al. Anti-inflammatory deficiencies in neutrophilic asthma: reduced galectin-3 and IL-1RA/IL-1β. Respir Res 2015; 16: 5
    CrossrefPubMedGoogle Scholar
  • 82 Dusser D, Montani D, Chanez P. et al. Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations. Allergy 2007; 62 (06) 591-604
    CrossrefPubMedGoogle Scholar
  • 83 McGrath KW, Icitovic N, Boushey HA. et al; Asthma Clinical Research Network of the National Heart, Lung, and Blood Institute. A large subgroup of mild-to-moderate asthma is persistently noneosinophilic. Am J Respir Crit Care Med 2012; 185 (06) 612-619
    Google Scholar
  • 84 Krishnan JA, Lazarus SC, Blake KV. et al. Biomarkers to predict response to ICS and LAMA in adolescents and adults with mild persistent asthma. Ann Am Thorac Soc 2022; Mar; 19 (03) 372-380
    CrossrefPubMedGoogle Scholar
  • 85 Chipps BE, Newbold P, Hirsch I, Trudo F, Goldman M. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy, Asthma Immunol 2018; 120: 504-511 e4
    CrossrefPubMedGoogle Scholar
  • 86 Lazarus SC, Krishnan JA, King TS. et al; National Heart, Lung, and Blood Institute AsthmaNet. Mometasone or tiotropium in mild asthma with a low sputum eosinophil level. N Engl J Med 2019; 380 (21) 2009-2019
    CrossrefPubMedGoogle Scholar
  • 87 Gleich GJ, Adolphson CR, Leiferman KM. The biology of the eosinophilic leukocyte. Annu Rev Med 1993; 44: 85-101
    CrossrefPubMedGoogle Scholar
  • 88 Hanania NA, Alpan O, Hamilos DL. et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med 2011; 154 (09) 573-582
    CrossrefPubMedGoogle Scholar
  • 89 Busse W, Spector S, Rosén K, Wang Y, Alpan O. High eosinophil count: a potential biomarker for assessing successful omalizumab treatment effects. J Allergy Clin Immunol 2013; 132 (02) 485-6.e11
    CrossrefPubMedGoogle Scholar
  • 90 Ortega HG, Yancey SW, Mayer B. et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med 2016; 4 (07) 549-556
    CrossrefPubMedGoogle Scholar
  • 91 Castro M, Mathur S, Hargreave F. et al; Res-5-0010 Study Group. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med 2011; 184 (10) 1125-1132
    CrossrefPubMedGoogle Scholar
  • 92 Bleecker ER, Wechsler ME, FitzGerald JM. et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J 2018; 52 (04) 52
    CrossrefPubMedGoogle Scholar
  • 93 FitzGerald JM, Bleecker ER, Menzies-Gow A. et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med 2018; 6 (01) 51-64
    Google Scholar
  • 94 Wenzel S, Castro M, Corren J. et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet 2016; 388 (10039): 31-44
    CrossrefPubMedGoogle Scholar
  • 95 Tajiri T, Matsumoto H, Gon Y. et al. Utility of serum periostin and free IgE levels in evaluating responsiveness to omalizumab in patients with severe asthma. Allergy 2016; 71 (10) 1472-1479
    CrossrefPubMedGoogle Scholar
  • 96 Djukanović R, Wilson SJ, Kraft M. et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med 2004; 170 (06) 583-593
    CrossrefPubMedGoogle Scholar
  • 97 Flood-Page P, Swenson C, Faiferman I. et al; International Mepolizumab Study Group. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007; 176 (11) 1062-1071
    CrossrefPubMedGoogle Scholar
  • 98 Haldar P, Brightling CE, Hargadon B. et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360 (10) 973-984
    CrossrefPubMedGoogle Scholar
  • 99 Laviolette M, Gossage DL, Gauvreau G. et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol 2013; 132 (05) 1086-1096.e5
    CrossrefPubMedGoogle Scholar
  • 100 Wenzel S, Ford L, Pearlman D. et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013; 368 (26) 2455-2466
    CrossrefPubMedGoogle Scholar
  • 101 Rabe KF, Nair P, Brusselle G. et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med 2018; 378 (26) 2475-2485
    Google Scholar
  • 102 Kirenga B, Chakaya J, Yimer G. et al. Phenotypic characteristics and asthma severity in an East African cohort of adults and adolescents with asthma: findings from the African severe asthma project. BMJ Open Respir Res 2020; 7 (01) 7
    CrossrefPubMedGoogle Scholar
  • 103 Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 2003; 167 (02) 199-204
    CrossrefPubMedGoogle Scholar
  • 104 Hastie AT, Moore WC, Meyers DA. et al; National Heart, Lung, and Blood Institute Severe Asthma Research Program. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol 2010; 125 (05) 1028-1036.e13
    CrossrefPubMedGoogle Scholar
  • 105 Green RH, Brightling CE, McKenna S. et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360 (9347): 1715-1721
    CrossrefPubMedGoogle Scholar
  • 106 Jayaram L, Pizzichini MM, Cook RJ. et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 2006; 27 (03) 483-494
    CrossrefPubMedGoogle Scholar
  • 107 Kraft M, Brusselle G, FitzGerald JM. et al. Patient characteristics, biomarkers and exacerbation risk in severe, uncontrolled asthma. Eur Respir J 2021; 58 (06) 58
    CrossrefPubMedGoogle Scholar
  • 108 Zeiger RS, Schatz M, Li Q. et al. High blood eosinophil count is a risk factor for future asthma exacerbations in adult persistent asthma. J Allergy Clin Immunol Pract 2014; 2 (06) 741-750
    CrossrefPubMedGoogle Scholar
  • 109 Price DB, Rigazio A, Campbell JD. et al. Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. Lancet Respir Med 2015; 3 (11) 849-858
    Google Scholar
  • 110 Malinovschi A, Fonseca JA, Jacinto T, Alving K, Janson C. Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects. J Allergy Clin Immunol 2013; 132 (04) 821-827.e1 , 5
    CrossrefPubMedGoogle Scholar
  • 111 Dweik RA, Sorkness RL, Wenzel S. et al; National Heart, Lung, and Blood Institute Severe Asthma Research Program. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med 2010; 181 (10) 1033-1041
    CrossrefPubMedGoogle Scholar
  • 112 Pavord ID, Holliday M, Reddel HK. et al; Novel START Study Team. Predictive value of blood eosinophils and exhaled nitric oxide in adults with mild asthma: a prespecified subgroup analysis of an open-label, parallel-group, randomised controlled trial. Lancet Respir Med 2020; 8 (07) 671-680
    CrossrefPubMedGoogle Scholar
  • 113 Hancox RJ, Pavord ID, Sears MR. Associations between blood eosinophils and decline in lung function among adults with and without asthma. Eur Respir J 2018; 51 (04) 51
    CrossrefPubMedGoogle Scholar
  • 114 Sverrild A, Porsbjerg C, Thomsen SF, Backer V. Airway hyperresponsiveness to mannitol and methacholine and exhaled nitric oxide: a random-sample population study. J Allergy Clin Immunol 2010; 126 (05) 952-958
    CrossrefPubMedGoogle Scholar
  • 115 Matsunaga K, Hirano T, Oka A, Ito K, Edakuni N. Persistently high exhaled nitric oxide and loss of lung function in controlled asthma. Allergol Int 2016; 65 (03) 266-271
    CrossrefPubMedGoogle Scholar
  • 116 DiMango E, Rogers L, Reibman J. et al. Risk factors for asthma exacerbation and treatment failure in adults and adolescents with well-controlled asthma during continuation and step-down therapy. Ann Am Thorac Soc 2018; 15 (08) 955-961
    CrossrefPubMedGoogle Scholar
  • 117 Kimura H, Konno S, Makita H. et al; Hi-CARAT investigators. Prospective predictors of exacerbation status in severe asthma over a 3-year follow-up. Clin Exp Allergy 2018; 48 (09) 1137-1146
    CrossrefPubMedGoogle Scholar
  • 118 Bourdin A, Bjermer L, Brightling C. et al. ERS/EAACI statement on severe exacerbations in asthma in adults: facts, priorities and key research questions. Eur Respir J 2019; 54 (03) 54
    CrossrefPubMedGoogle Scholar
  • 119 Sundh J, Wireklint P, Hasselgren M. et al. Health-related quality of life in asthma patients—a comparison of two cohorts from 2005 and 2015. Respir Med 2017; 132: 154-160
    CrossrefPubMedGoogle Scholar
  • 120 Castillo JR, Peters SP, Busse WW. Asthma exacerbations: pathogenesis, prevention, and treatment. J Allergy Clin Immunol Pract 2017; 5 (04) 918-927
    CrossrefPubMedGoogle Scholar
  • 121 Price DB, Bosnic-Anticevich S, Pavord ID. et al. Association of elevated fractional exhaled nitric oxide concentration and blood eosinophil count with severe asthma exacerbations. Clin Transl Allergy 2019; 9: 41
    CrossrefPubMedGoogle Scholar
  • 122 Chlumský J, Striz I, Terl M, Vondracek J. Strategy aimed at reduction of sputum eosinophils decreases exacerbation rate in patients with asthma. J Int Med Res 2006; 34 (02) 129-139
    CrossrefPubMedGoogle Scholar
  • 123 Petsky HL, Li A, Chang AB. Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev 2017; 8: CD005603
    PubMedGoogle Scholar
  • 124 Wark PA, McDonald VM, Gibson PG. Adjusting prednisone using blood eosinophils reduces exacerbations and improves asthma control in difficult patients with asthma. Respirology 2015; 20 (08) 1282-1284
    CrossrefPubMedGoogle Scholar