Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2018 Jul 24.
Published in final edited form as: Immunol Allergy Clin North Am. 2016 Aug;36(3):547–557. doi: 10.1016/j.iac.2016.03.004

Biomarkers in Severe Asthma

Xiao Chloe Wan 1, Prescott G Woodruff 1,*
PMCID: PMC6057475  NIHMSID: NIHMS771132  PMID: 27401625

INTRODUCTION

A biomarker is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”1 Biomarkers useful in respiratory disease can be obtained using several different types of clinical samples (Box 1). In this review, we restrict our discussion to biomarkers that can be measured in blood, sputum, or exhaled gas and those that are cellular, biochemical, or molecular in nature. There are several potential applications of biomarkers in the study and management of severe asthma (Box 2). Of these potential applications, significant advances have been made in biomarkers of endotypes (ie, biologically related subtypes) of asthma and in those that are predictive of response to therapy. In particular, bio-markers of type 2 inflammation (defined as inflammation driven by the Th2-cytokines, interleukin [IL]-4, IL-5, and IL-13) have proven valuable for endotyping in asthma. Here we review the current state of knowledge with respect to biomarkers in severe asthma, stratifying them by those that relate to type 2 inflammation and those that do not.

Box 1. Sample types of biomarker measurement in respiratory disease.

  • Bronchoscopic samples

  • Induced sputum

  • Blood

  • Urine

  • Exhaled gases

Box 2. Potential applications of biomarkers in severe asthma.

  • Understanding the biology

  • Diagnosis and screening

  • Assessment of severity, control, or prognosis

  • Identification of endotypes (biologically related subtypes of disease)

  • Application in clinical trials and safety monitoring

    • Pharmacodynamic biomarkers

    • Predictive of response

BIOMARKERS OF TYPE 2 INFLAMMATION

Sputum Eosinophils

Sputum eosinophils are obtained by sputum induction and are expressed as a percentage of inflammatory cells.2 Upper limit of normal for sputum eosinophil differential is generally defined as approximately 1% to 2%,2–4 with female gender and atopy associated with higher sputum eosinophil counts.3 Sputum eosinophil count is increased in symptomatic individuals with asthma,5 and elevated eosinophils can be found in 50% of corticosteroid-treated patients, and in 70% to 80% of corticosteroid-naive patients.6 Sputum eosinophil count is elevated by allergen challenge and reduced by corticosteroids.7,8 Studies of inhaled corticosteroid (ICS) reduction in patients with asthma show that an increase in sputum eosinophil count may be predictive of asthma exacerbation.9–11

Fractional Exhaled Nitric Oxide Concentration

Nitric oxide (NO) is synthesized by NO synthetases (NOSs).12 Patients with asthma have high levels of NO in their exhaled breath, which is thought to be due to upregulation of inducible NOS (NOS2) in airway epithelial cells secondary to airway inflammation.13 Chemiluminescence analyzers allow the measurement of NO concentration in gas phase.14 A joint American Thoracic Society (ATS) and European Respiratory Society (ERS) guideline (last revised in 2005) recommends that fractional exhaled NO concentration (FeNO) in exhaled breath be expressed as parts per billion (ppb).15 FeNO is elevated in asthma and decreased with inhaled steroids.16 The distribution of FeNO value is skewed to the right with significant overlap between healthy controls and patients with asthma. Current smoking, atopy, and age influence the distribution of FeNO values.17–22 The 2011 ATS clinical practice guideline on the interpretation of FeNO proposes cutoffs for clinical use of FeNO. It suggests that eosinophilic inflammation is unlikely in symptomatic patients with low FeNO (<25 ppb in adults and <20 ppb in children), whereas high FeNO (>50 ppb in adults and >35 ppb in children) suggests airway eosinophilia and steroid-responsive inflammation.13

Blood Eosinophils

There has been growing interest in less-invasive alternatives to sputum induction. Blood eosinophil counts are a potential surrogate biomarker for eosinophilic inflammation in asthma and are relatively easy to obtain. Although studies of blood eosinophil count as predictors of high sputum eosinophils in eosinophilic asthma have yielded somewhat mixed results,23–25 blood eosinophil counts have been useful in selection of patients for eosinophil-targeting agents as described later in this article. The cutoff used in the clinical trials to define high blood eosinophil counts have ranged between 150 and 300 cells/μL.23–27

Periostin

Periostin is a matricellular protein that is secreted by bronchial epithelial cells and lung fibroblasts in response to Th2 cytokines, IL-13, and IL-4.28,29 Whether and how periostin may contribute to asthma pathogenesis is still unclear. Although some results are conflicting, mouse models suggest a role of periostin in subepithelial fibrosis, eosinophil recruitment, and mucus production from goblet cells.30–32 A study of sputum and blood eosinophils, periostin, FeNO, and immunoglobulin E (IgE) in patients with severe asthma found that periostin was the strongest biomarker predictor of sputum and tissue eosinophilia.33 The cutoff range to define periostin-high or periostin-low groups for prognostication of treatment response have not been precisely defined, with some clinical studies using the median periostin level of the study population34–36 and others using 50 ng/mL as the cutoff.37

OTHER BIOMARKERS OF TYPE 2 INFLAMMATION

Dipeptidyl peptidase-4 (DPP4) is highly expressed in lung epithelial cells, endothelial cells, and submucosal glands. In rat models, its enzymatic activity increases in bronchoalveolar lavage (BAL) fluid and parenchymal tissue after an allergen challenge.38 Like periostin, the role of DPP4 in asthma is uncertain. DPP4 inhibition has effects on airway inflammation in animal models that depend on the route of administration (oral, aerosolized, topical).39 Studies of DPP4 in human airway inflammation are limited. Other potential biomarkers of type 2 inflammation include urinary bromotyrosine (BrTyr),40,41 monocyte chemoattractant protein-4 (MCP4), and eotaxin-2.42,43

BIOMARKERS UNRELATED TO TYPE 2 INFLAMMATION

Sputum Neutrophil

Using sputum induction and cytology, patients with asthma can be categorized as paucigranulocytic, eosinophilic, neutrophilic, and mixed. Airway neutrophilia is well documented in severe exacerbations of asthma44; however, the prevalence of neutrophilia in severe asthma between exacerbations remains somewhat uncertain.

In healthy subjects, neutrophils and macrophages predominate in the induced sputum (median neutrophil percentage 37% [10th and 90th percentile, 11%–64%]).3 Cigarette smoking, infection, ozone, and endotoxin all increase sputum neutrophil counts.3 In asthma studies, the cutoffs for elevated sputum neutrophil count have ranged between 40% and 76%.25,45,46

Sputum neutrophilia may represent a stable phenotype of severe asthma or, alternatively, could reflect response to therapy. In cluster analyses from the Severe Asthma Research Program (SARP), patients with the worst lung function despite maximal bronchodilator therapy had the highest sputum neutrophil count.46 Conversely, other studies report that ICS use is associated with increased sputum neutrophils47 and that, after tapering ICS, sputum neutrophilia was reduced. Combined increases in sputum eosinophils and neutrophils may identify patients with asthma with low lung function and increased symptoms.45

Interleukin-17

IL-17 can promote neutrophilic inflammation and plays a role in diseases such as psoriasis and ankylosing spondylitis.48–51 Studies measuring IL-17 levels in induced sputum, BAL samples, and bronchial biopsies have found increased IL-17 levels in severe asthma.52–55 Whether IL-17 plays a causative role in severe asthma is less certain, as a randomized trial of IL-17 blockade using Brodalumab, a humanized anti-IL17RA monoclonal antibody, in moderate to severe asthma was negative.56 More recently, IL-17–producing cells and an IL-17–related gene expression signature were observed in severe asthma, and this IL-17 signature was orthogonal to type 2 inflammation.57 One intriguing possibility raised by this data is the airway production of IL-17 may increase as type 2 inflammation is blocked in severe asthma. If so, a strategy that blocks both Th2 cytokines and IL-17 could be beneficial in severe asthma.

Other Non–Type 2 Inflammatory Biomarkers

Several other inflammatory biomarkers that are not associated with type 2 inflammation have been studied in severe asthma, including IL-658 and C-reactive protein.59 Exhaled breath condensate pH may reflect underlying inflammatory process in the airway in asthma, as its levels may correlate with steroid treatment and asthma exacerbation.60 More studies in these markers and others, including tumor necrosis factor α and biomarkers of oxidative stress are needed to better elucidate its role in asthma.

Special Considerations in Children

Periostin is a product of bone turnover and is elevated in children.61 Thus, whether it will be useful as a biomarker of asthma in children is uncertain. Two recent studies show significantly higher periostin levels in children with asthma compared with healthy controls, suggesting that periostin may still have some value in this age group, although more studies are needed.61,62 One study showed poor correlation between blood eosinophils and airway eosinophilia in children with severe asthma on high-dose ICS.63 A BAL study of 69 children suggest that severe therapy-resistant asthma in children is characterized by eosinophilic, rather than neutrophilic predominant airways. However, there were no elevated cytokines in the BAL fluid suggestive of type 2 inflammation (IL-4, IL-5, IL-13) in these children compared with the control group.64

UTILITY IN SEVERE ASTHMA

Diagnosis

As asthma is heterogeneous with respect to type 2 inflammation, biomarkers such as FeNO are supportive rather than definitive for diagnosis of asthma.13

Prognosis

A study in SARP found no difference in FeNO level in severe as compared with non-severe asthma; however, when the groups were subdivided further, high FeNO levels in severe asthma identified those with greatest airflow limitation and reversibility, highest sputum eosinophils, and most emergency department visits and intensive care unit admissions, suggesting that FeNO may be used to risk stratify.65 Elevated sputum neutrophils with or without concurrent sputum eosinophilia have been associated with a more severe asthma phenotype.66 In a multivariable analysis of 224 patients with asthma on ICS, high baseline serum periostin level (≥95 ng/mL) was an independent risk factor for greater decline of lung function.67 Furthermore, elevated levels of periostin have been found in aspirin-exacerbated respiratory disease and were again associated with more severe and eosinophilic asthma.68

Establishing a Baseline and Monitoring Control

How variable airway eosinophilia may be over time is uncertain. In one longitudinal study over 5 years, 70% of those with eosinophilic asthma (sputum eosinophils ≥2%) and 96% of those with noneosinophilic asthma retained their sputum phenotype.69 However, one pro-con debate cited data from 40 patients with severe asthma, which showed that 60% of the patients changed their classification from eosinophilic (sputum eosinophils ≥2%) to noneosinophilic and vice versa.70

Endotyping

The observation that biomarkers of type 2 inflammation mark patients who have distinct immune cell infiltration, histological changes, and treatment response suggests that type 2 inflammation defines an endotype of asthma.71 Formally, an endotype can be defined as patients who share a common underlying biology, and one review article suggested that investigation of a series of shared features could define an endotype (see Box 2).72 Many of these proposed criteria for an endotype have been met for type 2 inflammation asthma, including association with treatment response. Those criteria that still require some investigation include studies of genetic predisposition and shared epidemiology.

Guiding Choice of Therapy in Severe Asthma

The concept of an endotype can inform precision medicine has been key in developing new therapies for severe asthma, especially because new therapies can be expensive and cumbersome and can have adverse effects.

The first example of using biomarkers to predict therapy in severe asthma comes from the development of mepolizumab, a humanized monoclonal antibody against IL-5. The first clinical trial of mepolizumab (in moderate asthma) did not use eosinophilia as inclusion criteria and failed to show benefit.73 Subsequently, 2 studies in severe asthma that selected patients based on persistent sputum eosinophilia showed a remarkable benefit in reduction of exacerbations with mepolizumab.74,75 Subsequent larger trials confirmed these observations, informed the use of blood eosinophils as a surrogate for sputum eosinophils, and identified optimized threshold values for prediction of clinical response. In the DREAM study, mepolizumab, reduced exacerbations in patients with severe asthma who had sputum eosinophil count ≥3%, FeNO ≥50 ppb, or blood eosinophil count ≥300 cells/μl. Furthermore, baseline blood eosinophil count correlated with the reduction in exacerbations.76 Post hoc analysis of the DREAM study showed that blood eosinophils ≥150 cells/μl predicted response to mepolizumab and that a single measurement was predictive of future elevated blood eosinophil levels.27 Mepolizumab also reduced exacerbations, improved asthma symptoms, and had oral steroid-sparing effects in patients with eosinophilic inflammation (prerandomization blood eosinophil count ≥300 cells/μl, or 150 cells/μl during optimization phase) who required chronic oral steroids for their asthma.77 In November 2015, the Food and Drug Administration approved mepolizumab for treatment of severe asthma in patients 12 years and older with an eosinophilic phenotype. Similarly, reslizumab, an anti-IL5 humanized monoclonal antibody, has also been demonstrated to improve lung function and quality of life in poorly controlled asthma with sputum eosinophilia ≥ 3% or blood eosinophil count ≥400/μL.78,79

An alternative approach to using biomarkers of type 2 inflammation to guide the use of biologics for severe asthma was the development of periostin as a predictive biomarker for response to lebrikizumab, an anti-IL-13 humanized monoclonal antibody. In a phase II study (MILLY study), lebrikizumab significantly improved lung function but not exacerbation rates when stratifying patients by elevated periostin levels.35 Subsequently, 2 pooled phase IIb studies (LUTE and VERSE studies) demonstrated both improved lung function and reduced exacerbation in patients with periostin-high severe asthma.37 The efficacy of lebrikizumab in mild asthma is less clear, as a study of patients with mild asthma not on ICS showed no significant clinical benefit with lebrikizumab.36 Similarly, a phase IIb study of tralokinumab, a humanized anti-IL-13 monoclonal antibody, in severe asthma showed no decrease in asthma exacerbations, except in post hoc subgroup analysis, in which asthma exacerbations decreased in those with high periostin level and lung function improved in those with elevated DPP-4 level.80

Finally, post hoc analysis of a clinical trial of omalizumab, a widely used anti-IgE monoclonal antibody, identified potential biomarkers of response (reduction in exacerbations).81 This is particularly interesting in that patients were already selected for those with a positive skin test or in vitro response to a relevant perennial aeroallergen. The investigators found that FeNO and blood eosinophils at baseline predicted response to omalizumab and that there was a trend for improved response in those with increased baseline levels of serum periostin.

Guide Dosing of Inhaled Corticosteroid

Randomized trials have demonstrated that the use of sputum eosinophil to guide ICS therapy can reduce asthma exacerbations without increasing the total amount of ICS used.82,83 One meta-analysis showed that the use of sputum eosinophils to titrate asthma treatment reduced exacerbations, whereas the use of FeNO reduced ICS dose in adults but failed to show significant improvement in asthma control.84 In children with severe asthma, the use of sputum eosinophils to guide management was not shown to decrease asthma exacerbations or overall control compared with standard symptom-based management.85 The use of FeNO to guide therapy in children resulted in somewhat higher ICS use without significant improvement in clinical outcomes.84,86 The ATS/ERS guideline on severe asthma recommends that in adults, clinical criteria and sputum eosinophil counts, but not FeNO, be used for guiding therapy.87

Assess Adherence

According to collective experience of investigators in the ATS guideline, one of the most common causes of persistently elevated FeNO despite therapy is likely poor compliance.13

SUMMARY

Biomarkers have been critical for studies of disease pathogenesis and the development of new therapies in severe asthma. In particular, biomarkers of type 2 inflammation have proven valuable for endotyping and targeting new biological agents. Because of these successes in understanding and marking type 2 inflammation, lack of knowledge regarding non–type 2 inflammatory mechanisms in asthma will soon be the major obstacle to the development of new treatments and management strategies in severe asthma. Biomarkers can play a role in these investigations as well by providing insight into the underlying biology in human studies of patients with severe asthma.

KEY POINTS.

  • Asthma biomarkers can be broadly categorized as those that relate to type 2 inflammation and those that relate to other biological processes.

  • Biomarkers of type 2 inflammation include sputum and blood eosinophils, exhaled nitric oxide levels, and serum periostin.

  • In severe asthma, biomarkers are particularly useful in defining endotypes (ie, biologically related subtypes) and in predicting response to therapy.

References

  • 1.Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95. doi: 10.1067/mcp.2001.113989. [DOI] [PubMed] [Google Scholar]
  • 2.Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European Respiratory Society Statement: asthma control and exacerbations. Am J Respir Crit Care Med. 2009;180(1):59–99. doi: 10.1164/rccm.200801-060ST. [DOI] [PubMed] [Google Scholar]
  • 3.Belda J, Leigh R, Parameswaran K, et al. Induced sputum cell counts in healthy adults. Am J Respir Crit Care Med. 2000;161(2 Pt 1):475–8. doi: 10.1164/ajrccm.161.2.9903097. [DOI] [PubMed] [Google Scholar]
  • 4.Spanevello A, Confalonieri M, Sulotto F, et al. Induced sputum cellularity. Am J Respir Crit Care Med. 2000;162(3):1172–4. doi: 10.1164/ajrccm.162.3.9908057. [DOI] [PubMed] [Google Scholar]
  • 5.Pizzichini E, Pizzichini MM, Efthimiadis A, et al. Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med. 1996;154(2 Pt 1):308–17. doi: 10.1164/ajrccm.154.2.8756799. [DOI] [PubMed] [Google Scholar]
  • 6.Haldar P, Pavord ID. Noneosinophilic asthma: a distinct clinical and pathologic phenotype. J Allergy Clin Immunol. 2007;119(5):1043–52. doi: 10.1016/j.jaci.2007.02.042. quiz: 1053–4. [DOI] [PubMed] [Google Scholar]
  • 7.Pin I, Freitag AP, O’Byrne PM, et al. Changes in the cellular profile of induced sputum after allergen-induced asthmatic responses. Am Rev Respir Dis. 1992;145(6):1265–9. doi: 10.1164/ajrccm/145.6.1265. [DOI] [PubMed] [Google Scholar]
  • 8.Pizzichini MM, Pizzichini E, Clelland L, et al. Sputum in severe exacerbations of asthma: kinetics of inflammatory indices after prednisone treatment. Am J Respir Crit Care Med. 1997;155(5):1501–8. doi: 10.1164/ajrccm.155.5.9154849. [DOI] [PubMed] [Google Scholar]
  • 9.Leuppi JD, Salome CM, Jenkins CR, et al. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med. 2001;163(2):406–12. doi: 10.1164/ajrccm.163.2.9912091. [DOI] [PubMed] [Google Scholar]
  • 10.Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am J Respir Crit Care Med. 2000;161(1):64–72. doi: 10.1164/ajrccm.161.1.9809100. [DOI] [PubMed] [Google Scholar]
  • 11.Deykin A, Lazarus SC, Fahy JV, et al. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin Immunol. 2005;115(4):720–7. doi: 10.1016/j.jaci.2004.12.1129. [DOI] [PubMed] [Google Scholar]
  • 12.Stuehr DJ. Mammalian nitric oxide synthases. Biochim Biophys Acta. 1999;1411(2–3):217–30. doi: 10.1016/s0005-2728(99)00016-x. [DOI] [PubMed] [Google Scholar]
  • 13.Dweik RA, Boggs PB, Erzurum SC, et al. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011;184(5):602–15. doi: 10.1164/rccm.9120-11ST. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Gustafsson LE, Leone AM, Persson MG, et al. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun. 1991;181(2):852–7. doi: 10.1016/0006-291x(91)91268-h. [DOI] [PubMed] [Google Scholar]
  • 15.American Thoracic Society, European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005;171(8):912–30. doi: 10.1164/rccm.200406-710ST. [DOI] [PubMed] [Google Scholar]
  • 16.Silkoff PE, McClean P, Spino M, et al. Dose-response relationship and reproducibility of the fall in exhaled nitric oxide after inhaled beclomethasone dipropionate therapy in asthma patients. Chest. 2001;119(5):1322–8. doi: 10.1378/chest.119.5.1322. [DOI] [PubMed] [Google Scholar]
  • 17.Jackson DJ, Virnig CM, Gangnon RE, et al. Fractional exhaled nitric oxide measurements are most closely associated with allergic sensitization in school-age children. J Allergy Clin Immunol. 2009;124(5):949–53. doi: 10.1016/j.jaci.2009.07.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Kovesi T, Kulka R, Dales R. Exhaled nitric oxide concentration is affected by age, height, and race in healthy 9- to 12-year-old children. Chest. 2008;133(1):169–75. doi: 10.1378/chest.07-1177. [DOI] [PubMed] [Google Scholar]
  • 19.Steerenberg PA, Janssen NAH, de Meer G, et al. Relationship between exhaled NO, respiratory symptoms, lung function, bronchial hyperresponsiveness, and blood eosinophilia in school children. Thorax. 2003;58(3):242–5. doi: 10.1136/thorax.58.3.242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Schilling J, Holzer P, Guggenbach M, et al. Reduced endogenous nitric oxide in the exhaled air of smokers and hypertensives. Eur Respir J. 1994;7(3):467–71. doi: 10.1183/09031936.94.07030467. [DOI] [PubMed] [Google Scholar]
  • 21.Kharitonov SA, Robbins RA, Yates D, et al. Acute and chronic effects of cigarette smoking on exhaled nitric oxide. Am J Respir Crit Care Med. 1995;152(2):609–12. doi: 10.1164/ajrccm.152.2.7543345. [DOI] [PubMed] [Google Scholar]
  • 22.Robbins RA, Millatmal T, Lassi K, et al. Smoking cessation is associated with an increase in exhaled nitric oxide. Chest. 1997;112(2):313–8. doi: 10.1378/chest.112.2.313. [DOI] [PubMed] [Google Scholar]
  • 23.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(2):115–20. doi: 10.1136/thoraxjnl-2014-205634. [DOI] [PubMed] [Google Scholar]
  • 24.Hastie AT, Moore WC, Li H, et al. Biomarker surrogates do not accurately predict sputum eosinophil and neutrophil percentages in asthmatic subjects. J Allergy Clin Immunol. 2013;132(1):72–80. doi: 10.1016/j.jaci.2013.03.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Schleich FN, Manise M, Sele J, et al. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med. 2013;13:11. doi: 10.1186/1471-2466-13-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Nadif R, Siroux V, Oryszczyn M-P, et al. Heterogeneity of asthma according to blood inflammatory patterns. Thorax. 2009;64(5):374–80. doi: 10.1136/thx.2008.103069. [DOI] [PubMed] [Google Scholar]
  • 27.Katz LE, Gleich GJ, Hartley BF, et al. Blood eosinophil count is a useful biomarker to identify patients with severe eosinophilic asthma. Ann Am Thorac Soc. 2014;11(4):531–6. doi: 10.1513/AnnalsATS.201310-354OC. [DOI] [PubMed] [Google Scholar]
  • 28.Takayama G, Arima K, Kanaji T, et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol. 2006;118(1):98–104. doi: 10.1016/j.jaci.2006.02.046. [DOI] [PubMed] [Google Scholar]
  • 29.Sidhu SS, Yuan S, Innes AL, et al. Roles of epithelial cell-derived periostin in TGF-β activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci U S A. 2010;107(32):14170–5. doi: 10.1073/pnas.1009426107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Gordon ED, Sidhu SS, Wang Z-E, et al. A protective role for periostin and TGF-β in IgE-mediated allergy and airway hyperresponsiveness. Clin Exp Allergy. 2012;42(1):144–55. doi: 10.1111/j.1365-2222.2011.03840.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Sehra S, Yao W, Nguyen ET, et al. Periostin regulates goblet cell metaplasia in a model of allergic airway inflammation. J Immunol. 2011;186(8):4959–66. doi: 10.4049/jimmunol.1002359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Blanchard C, Mingler MK, McBride M, et al. Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses. Mucosal Immunol. 2008;1(4):289–96. doi: 10.1038/mi.2008.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Jia G, Erickson RW, Choy DF, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol. 2012;130(3):647–54. e10. doi: 10.1016/j.jaci.2012.06.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Scheerens H, Arron JR, Zheng Y, et al. The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge. Clin Exp Allergy. 2014;44(1):38–46. doi: 10.1111/cea.12220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365(12):1088–98. doi: 10.1056/NEJMoa1106469. [DOI] [PubMed] [Google Scholar]
  • 36.Noonan M, Korenblat P, Mosesova S, et al. Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. J Allergy Clin Immunol. 2013;132(3):567–74. e12. doi: 10.1016/j.jaci.2013.03.051. [DOI] [PubMed] [Google Scholar]
  • 37.Hanania NA, Noonan M, Corren J, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015;70(8):748–56. doi: 10.1136/thoraxjnl-2014-206719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Schade J, Stephan M, Schmiedl A, et al. Regulation of expression and function of dipeptidyl peptidase 4 (DP4), DP8/9, and DP10 in allergic responses of the lung in rats. J Histochem Cytochem. 2008;56(2):147–55. doi: 10.1369/jhc.7A7319.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Stephan M, Suhling H, Schade J, et al. Effects of dipeptidyl peptidase-4 inhibition in an animal model of experimental asthma: a matter of dose, route, and time. Physiol Rep. 2013;1(5):e00095. doi: 10.1002/phy2.95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Cowan DC, Taylor DR, Peterson LE, et al. Biomarker-based asthma phenotypes of corticosteroid response. J Allergy Clin Immunol. 2015;135(4):877–83. e1. doi: 10.1016/j.jaci.2014.10.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Wedes SH, Wu W, Comhair SAA, et al. Urinary bromotyrosine measures asthma control and predicts asthma exacerbations in children. J Pediatr. 2011;159(2):248–55. e1. doi: 10.1016/j.jpeds.2011.01.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Provost V, Larose M-C, Langlois A, et al. CCL26/eotaxin-3 is more effective to induce the migration of eosinophils of asthmatics than CCL11/eotaxin-1 and CCL24/eotaxin-2. J Leukoc Biol. 2013;94(2):213–22. doi: 10.1189/jlb.0212074. [DOI] [PubMed] [Google Scholar]
  • 43.Lamkhioued B, Garcia-Zepeda EA, Abi-Younes S, et al. Monocyte chemoattractant protein (MCP)-4 expression in the airways of patients with asthma. Am J Respir Crit Care Med. 2000;162(2):723–32. doi: 10.1164/ajrccm.162.2.9901080. [DOI] [PubMed] [Google Scholar]
  • 44.Ordoñez CL, Shaughnessy TE, Matthay MA, et al. Increased neutrophil numbers and IL-8 levels in airway secretions in acute severe asthma. Am J Respir Crit Care Med. 2000;161(4):1185–90. doi: 10.1164/ajrccm.161.4.9812061. [DOI] [PubMed] [Google Scholar]
  • 45.Hastie AT, Moore WC, Meyers DA, et al. Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes. J Allergy Clin Immunol. 2010;125(5):1028–36. e13. doi: 10.1016/j.jaci.2010.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am J Respir Crit Care Med. 2010;181(4):315–23. doi: 10.1164/rccm.200906-0896OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Cowan DC, Cowan JO, Palmay R, et al. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax. 2010;65(5):384–90. doi: 10.1136/thx.2009.126722. [DOI] [PubMed] [Google Scholar]
  • 48.Chesné J, Braza F, Mahay G, et al. IL-17 in severe asthma. Where do we stand? Am J Respir Crit Care Med. 2014;190(10):1094–101. doi: 10.1164/rccm.201405-0859PP. [DOI] [PubMed] [Google Scholar]
  • 49.Krueger JG, Fretzin S, Suárez-Fariñas M, et al. IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis. J Allergy Clin Immunol. 2012;130(1):145–54. e9. doi: 10.1016/j.jaci.2012.04.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Baeten D, Baraliakos X, Braun J, et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382(9906):1705–13. doi: 10.1016/S0140-6736(13)61134-4. [DOI] [PubMed] [Google Scholar]
  • 51.Mease PJ, Genovese MC, Greenwald MW, et al. Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med. 2014;370(24):2295–306. doi: 10.1056/NEJMoa1315231. [DOI] [PubMed] [Google Scholar]
  • 52.Nanzer AM, Chambers ES, Ryanna K, et al. Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion. J Allergy Clin Immunol. 2013;132(2):297–304. e3. doi: 10.1016/j.jaci.2013.03.037. [DOI] [PubMed] [Google Scholar]
  • 53.Irvin C, Zafar I, Good J, et al. Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J Allergy Clin Immunol. 2014;134(5):1175–86. e7. doi: 10.1016/j.jaci.2014.05.038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Kim HY, Lee HJ, Chang Y-J, et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med. 2014;20(1):54–61. doi: 10.1038/nm.3423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Bullens DMA, Truyen E, Coteur L, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir Res. 2006;7:135. doi: 10.1186/1465-9921-7-135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti–IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013;188(11):1294–302. doi: 10.1164/rccm.201212-2318OC. [DOI] [PubMed] [Google Scholar]
  • 57.Choy DF, Hart KM, Borthwick LA, et al. TH2 and TH17 inflammatory pathways are reciprocally regulated in asthma. Sci Transl Med. 2015;7(301):301ra129. doi: 10.1126/scitranslmed.aab3142. [DOI] [PubMed] [Google Scholar]
  • 58.Konno S, Taniguchi N, Makita H, et al. Distinct phenotypes of cigarette smokers identified by cluster analysis of patients with severe asthma. Ann Am Thorac Soc. 2015;12(12):1771–80. doi: 10.1513/AnnalsATS.201507-407OC. Available at. [DOI] [PubMed] [Google Scholar]
  • 59.De Lima Azambuja R, da Costa Santos Azambuja LS, Costa C, et al. Adiponectin in asthma and obesity: protective agent or risk factor for more severe disease? Lung. 2015;193(5):749–55. doi: 10.1007/s00408-015-9793-8. [DOI] [PubMed] [Google Scholar]
  • 60.Kostikas K, Koutsokera A, Papiris S, et al. Exhaled breath condensate in patients with asthma: implications for application in clinical practice. Clin Exp Allergy. 2008;38(4):557–65. doi: 10.1111/j.1365-2222.2008.02940.x. [DOI] [PubMed] [Google Scholar]
  • 61.Anderson WC, 3rd, Szefler SJ. New and future strategies to improve asthma control in children. J Allergy Clin Immunol. 2015;136(4):848–59. doi: 10.1016/j.jaci.2015.07.007. [DOI] [PubMed] [Google Scholar]
  • 62.Song J-S, You J-S, Jeong S-I, et al. Serum periostin levels correlate with airway hyper-responsiveness to methacholine and mannitol in children with asthma. Allergy. 2015;70(6):674–81. doi: 10.1111/all.12599. [DOI] [PubMed] [Google Scholar]
  • 63.Ullmann N, Bossley CJ, Fleming L, et al. Blood eosinophil counts rarely reflect airway eosinophilia in children with severe asthma. Allergy. 2013;68(3):402–6. doi: 10.1111/all.12101. [DOI] [PubMed] [Google Scholar]
  • 64.Bossley CJ, Fleming L, Gupta A, et al. Pediatric severe asthma is characterized by eosinophilia and remodeling without TH2 cytokines. J Allergy Clin Immunol. 2012;129(4):974–82. e13. doi: 10.1016/j.jaci.2012.01.059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Dweik RA, Sorkness RL, Wenzel S, et al. 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):1033–41. doi: 10.1164/rccm.200905-0695OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Moore WC, Hastie AT, Li X, et al. Sputum neutrophil counts are associated with more severe asthma phenotypes using cluster analysis. J Allergy Clin Immunol. 2014;133(6):1557–63. e5. doi: 10.1016/j.jaci.2013.10.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Kanemitsu Y, Matsumoto H, Izuhara K, et al. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J Allergy Clin Immunol. 2013;132(2):305–12. e3. doi: 10.1016/j.jaci.2013.04.050. [DOI] [PubMed] [Google Scholar]
  • 68.Kim M-A, Izuhara K, Ohta S, et al. Association of serum periostin with aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 2014;113(3):314–20. doi: 10.1016/j.anai.2014.06.014. [DOI] [PubMed] [Google Scholar]
  • 69.Van Veen IH, Ten Brinke A, Gauw SA, et al. Consistency of sputum eosinophilia in difficult-to-treat asthma: a 5-year follow-up study. J Allergy Clin Immunol. 2009;124(3):615–7. 617.e1–2. doi: 10.1016/j.jaci.2009.06.029. [DOI] [PubMed] [Google Scholar]
  • 70.Peters SP. Counterpoint: is measuring sputum eosinophils useful in the management of severe asthma? No, not for the vast majority of patients. Chest. 2011;139(6):1273–5. doi: 10.1378/chest.11-0627. discussion: 1275–8. [DOI] [PubMed] [Google Scholar]
  • 71.Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2–driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180(5):388–95. doi: 10.1164/rccm.200903-0392OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Lötvall J, Akdis C, Bacharier L, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127(2):355–60. doi: 10.1016/j.jaci.2010.11.037. [DOI] [PubMed] [Google Scholar]
  • 73.Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176(11):1062–71. doi: 10.1164/rccm.200701-085OC. [DOI] [PubMed] [Google Scholar]
  • 74.Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 2009;360(10):973–84. doi: 10.1056/NEJMoa0808991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360(10):985–93. doi: 10.1056/NEJMoa0805435. [DOI] [PubMed] [Google Scholar]
  • 76.Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):651–9. doi: 10.1016/S0140-6736(12)60988-X. [DOI] [PubMed] [Google Scholar]
  • 77.Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371(13):1189–97. doi: 10.1056/NEJMoa1403291. [DOI] [PubMed] [Google Scholar]
  • 78.Castro M, Mathur S, Hargreave F, et al. Reslizumab for poorly controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2011;184(10):1125–32. doi: 10.1164/rccm.201103-0396OC. [DOI] [PubMed] [Google Scholar]
  • 79.Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355–66. doi: 10.1016/S2213-2600(15)00042-9. [DOI] [PubMed] [Google Scholar]
  • 80.Brightling C, Chanez P, Leigh R, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3(9):692–701. doi: 10.1016/S2213-2600(15)00197-6. [DOI] [PubMed] [Google Scholar]
  • 81.Hanania N, Wenzel S, Rosén K, et al. Exploring the effects of omalizumab in allergic asthma. Am J Respir Crit Care Med. 2013;187(8):804–11. doi: 10.1164/rccm.201208-1414OC. [DOI] [PubMed] [Google Scholar]
  • 82.Jayaram L, Pizzichini MM, Cook RJ, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006;27(3):483–94. doi: 10.1183/09031936.06.00137704. [DOI] [PubMed] [Google Scholar]
  • 83.Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715–21. doi: 10.1016/S0140-6736(02)11679-5. [DOI] [PubMed] [Google Scholar]
  • 84.Petsky HL, Cates CJ, Lasserson TJ, et al. A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils) Thorax. 2012;67(3):199–208. doi: 10.1136/thx.2010.135574. [DOI] [PubMed] [Google Scholar]
  • 85.Fleming L, Wilson N, Regamey N, et al. Use of sputum eosinophil counts to guide management in children with severe asthma. Thorax. 2012;67(3):193–8. doi: 10.1136/thx.2010.156836. [DOI] [PubMed] [Google Scholar]
  • 86.Lu M, Wu B, Che D, et al. FeNO and asthma treatment in children: a systematic review and meta-analysis. Medicine. 2015;94(4):e347. doi: 10.1097/MD.0000000000000347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Chung K, Wenzel S, Brozek J, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2013;43(2):343–73. doi: 10.1183/09031936.00202013. [DOI] [PubMed] [Google Scholar]

RESOURCES