Elsevier

Clinics in Chest Medicine

Volume 33, Issue 3, September 2012, Pages 459-471
Clinics in Chest Medicine

Biomarkers in Asthma: A Real Hope to Better Manage Asthma

https://doi.org/10.1016/j.ccm.2012.06.007Get rights and content

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The clinical need for biomarkers to inform the care of patients with asthma

Asthma is defined as reversible airflow obstruction in the setting of airway inflammation. Asthma prevalence increased dramatically between 1970 and 2000, with more than 22 million people, of whom over 4.8 million are children, now living with asthma in the United States.1, 2 The increase of asthma has been variously ascribed to improved hygiene worldwide, acetaminophen use, increased exposure to allergens and pollution, and/or increased transmission of respiratory viruses.3 This epidemic has

The eosinophilic or T-helper type 2 high inflammation phenotype: sputum eosinophils, urinary 3-bromotyrosine, and periostin

Asthma phenotyping was first performed based on atopic status (ie, classification of asthma as extrinsic allergic or intrinsic nonallergic).9 Allergic asthma is common, and documentation of this phenotype has been helpful in avoiding allergen triggers and considering immunologic-based therapies. Classification as atopic asthma, which is typified by interleukin (IL)-4, IL-5, and IL-13 cytokines, has traditionally used standard clinical tests, including circulating numbers of eosinophils and

The reducing-oxidizing imbalance phenotype: lipid oxidation and loss of antioxidant superoxide dismutase

Recruitment and activation of inflammatory cells, both eosinophils and neutrophils, causes a respiratory burst in the airways that produces reactive oxygen species and reactive nitrogen species.45, 46, 47, 48 Certain of these species can damage proteins via specific enzyme-catalyzed oxidations or nonspecific oxidation of susceptible molecules. For example, eosinophil peroxidase and neutrophil myeloperoxidase cause halogenation, ie, bromination and chlorination respectively, of tyrosine

The low pH phenotype

During acute exacerbations of asthma, breath condensate pH is decreased.63 This reaction is associated with decreased serum and airway activity of glutaminase, activated downstream of Th1 cytokines associated with viral asthma exacerbations, preventing airway buffering.63, 64 Decreased airway pH promotes ciliary dysfunction, mucus hypersecretion, and cough.63, 64, 65 Recent evidence suggests that this decreased airway pH might be successfully treated with inhaled buffer.36, 44 However, most

Airway remodeling phenotype: airway angiogenic biomarkers

Increased number of blood vessels is universally found in asthmatic airway remodeling of children and adults.67, 68 The mouse model of asthma suggests that the switch to a proangiogenic airway and neovascularization occurs early and well in advance of eosinophilic inflammation.69 This finding suggests that angiogenesis participates in the genesis of asthma. In fact, several lines of evidence indicate that angiogenesis and chronic inflammation are mutually supportive.70 Inflammatory cells

The arginine/NO phenotype: FeNO, arginase, methylarginines

Measure of NO in the exhaled breath has been labeled as a sensitive and reliable biomarker of airway inflammation in adults and children.79, 80, 81, 82, 83, 84 Based on this finding, the U.S. Food and Drug Administration approved FeNO for evaluating antiinflammatory treatment responses of patients with asthma.84 However, FeNO exhibits a broad range of values in these patients85; it is useful for identifying patients characterized by the greatest airflow obstruction and most frequent use of

The leukotriene phenotype: leukotriene E4, lipoxins and protectants

Endogenous lipid mediators can help maintain tissue homeostasis, yet they can also contribute to inflammation and bronchoconstriction.112 Leukotrienes are examples of potent proinflammatory and bronchoconstricting agents. Inhibitors of the cysteinyl leukotriene receptor and the upstream cysteinyl leukotriene synthetic enzyme, 5-lipoxygenase (5-LO), are in clinical use for asthma treatment.113 However, many patients with asthma are not effectively treated with leukotriene receptor antagonists.

Additional considerations for future study

Biologic understanding is improving for several risk factors for severe asthma, including sex, race, obesity, and environmental tobacco exposure. Severe asthma is more prevalent in women after puberty.130, 131 Obesity is associated with asthma severity in adult-onset disease.6 The greater prevalence of severe asthma among obese women may be related to menstrual cycle effects on circulating CD34+CD133+ cells130 or adipose-related factors.132, 133 Additionally, circulating chitinase-like protein

Summary

Asthma occurs in individuals with a broad range of different inflammatory and biochemical phenotypes. Most of these phenotypes have the potential to be targeted with specific treatments. Targeted treatment of the underlying disease process has the potential to be corticosteroid-sparing, particularly in patients with severe asthma. Many biomarkers are being developed to identify these specific phenotypes noninvasively. This development is grounded in a medically meaningful paradigm in which an

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References (139)

  • R.E. Aldridge et al.

    Eosinophil peroxidase produces hypobromous acid in the airways of stable asthmatics

    Free Radic Biol Med

    (2002)
  • B. Gaston et al.

    Bronchodilator S-nitrosothiol deficiency in asthmatic respiratory failure

    Lancet

    (1998)
  • B. Gaston et al.

    Buffering airway acid decreases exhaled nitric oxide in asthma

    J Allergy Clin Immunol

    (2006)
  • E.J. Whalen et al.

    Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2

    Cell

    (2007)
  • A.A. Andreadis et al.

    Oxidative and nitrosative events in asthma

    Free Radic Biol Med

    (2003)
  • S.A. Comhair et al.

    Rapid loss of superoxide dismutase activity during antigen-induced asthmatic response

    Lancet

    (2000)
  • S.A. Comhair et al.

    Superoxide dismutase inactivation in pathophysiology of asthmatic airway remodeling and reactivity

    Am J Pathol

    (2005)
  • L. Liu et al.

    Determinants of exhaled breath condensate pH in a large population with asthma

    Chest

    (2011)
  • M. Hashimoto et al.

    Quantitative analysis of bronchial wall vascularity in the medium and small airways of patients with asthma and COPD

    Chest

    (2005)
  • S. Psarras et al.

    Vascular endothelial growth factor-mediated induction of angiogenesis by human rhinoviruses

    J Allergy Clin Immunol

    (2006)
  • I. Puxeddu et al.

    Human peripheral blood eosinophils induce angiogenesis

    Int J Biochem Cell Biol

    (2005)
  • S.A. Kharitonov et al.

    Increased nitric oxide in exhaled air of asthmatic patients

    Lancet

    (1994)
  • F.L. Ricciardolo et al.

    Acid stress in the pathology of asthma

    J Allergy Clin Immunol

    (2004)
  • P.E. Silkoff et al.

    The Aerocrine exhaled nitric oxide monitoring system NIOX is cleared by the US Food and Drug Administration for monitoring therapy in asthma

    J Allergy Clin Immunol

    (2004)
  • S.J. Szefler et al.

    Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial

    Lancet

    (2008)
  • B.V. Nelson et al.

    Expired nitric oxide as a marker for childhood asthma

    J Pediatr

    (1997)
  • E. Ceylan et al.

    Evaluation of oxidative-antioxidative status and the L-arginine-nitric oxide pathway in asthmatic patients

    Respir Med

    (2005)
  • H. Li et al.

    Genetic polymorphisms in arginase I and II and childhood asthma and atopy

    J Allergy Clin Immunol

    (2006)
  • N. Zimmermann et al.

    The arginine-arginase balance in asthma and lung inflammation

    Eur J Pharmacol

    (2006)
  • B.P. Yawn et al.

    Assessment of asthma severity and asthma control in children

    Pediatrics

    (2006)
  • National Heart Lung and Blood Institute. Expert panel report 3: guidelines for the diagnosis and management of asthma...
  • S. Wenzel et al.

    The mouse trap: it still yields few answers in asthma

    Am J Respir Crit Care Med

    (2006)
  • M. Masoli et al.

    The global burden of asthma: executive summary of the GINA dissemination Committee report

    Allergy

    (2004)
  • K. Paull et al.

    Do NHLBI lung function criteria apply to children? A cross-sectional evaluation of childhood asthma at National Jewish Medical and Research Center, 1999-2002

    Pediatr Pulmonol

    (2005)
  • ATS Workshop Proceedings: exhaled nitric oxide and nitric oxide oxidative metabolism in exhaled breath condensate: executive summary

    Am J Respir Crit Care Med

    (2006)
  • W.C. Moore et al.

    Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program

    Am J Respir Crit Care Med

    (2010)
  • A.M. Fitzpatrick et al.

    Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program

    J Allergy Clin Immunol

    (2010)
  • R. Polosa et al.

    Sputum eosinophilia is more closely associated with airway responsiveness to bradykinin than methacholine in asthma

    Eur Respir J

    (1998)
  • R. Louis et al.

    The relationship between airways inflammation and asthma severity

    Am J Respir Crit Care Med

    (2000)
  • P.G. Gibson

    Use of induced sputum to examine airway inflammation in childhood asthma

    J Allergy Clin Immunol

    (1998)
  • M. Berry et al.

    Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma

    Thorax

    (2007)
  • A.T. Hastie et al.

    Analyses of asthma severity phenotypes and inflammatory proteins in subjects stratified by sputum granulocytes

    J Allergy Clin Immunol

    (2010)
  • P.G. Woodruff et al.

    T-helper type 2-driven inflammation defines major subphenotypes of asthma

    Am J Respir Crit Care Med

    (2009)
  • J. Corren et al.

    Lebrikizumab treatment in adults with asthma

    N Engl J Med

    (2011)
  • J.C. MacPherson et al.

    Eosinophils are a major source of nitric oxide-derived oxidants in severe asthma: characterization of pathways available to eosinophils for generating reactive nitrogen species

    J Immunol

    (2001)
  • V.J. Erpenbeck et al.

    Local release of eosinophil peroxidase following segmental allergen provocation in asthma

    Clin Exp Allergy

    (2003)
  • W. Wu et al.

    3-Bromotyrosine and 3,5-dibromotyrosine are major products of protein oxidation by eosinophil peroxidase: potential markers for eosinophil-dependent tissue injury in vivo

    Biochemistry

    (1999)
  • H. Mita et al.

    Urinary 3-bromotyrosine and 3-chlorotyrosine concentrations in asthmatic patients: lack of increase in 3-bromotyrosine concentration in urine and plasma proteins in aspirin-induced asthma after intravenous aspirin challenge

    Clin Exp Allergy

    (2004)
  • S.H. Wedes et al.

    Urinary bromotyrosine measures asthma control and predicts asthma exacerbations in children

    J Pediatr

    (2011)
  • L.G. Que et al.

    Protection from experimental asthma by an endogenous bronchodilator

    Science

    (2005)
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    Funding sources: Dr Erzurum: National Heart Lung Blood Institute, American Asthma Foundation, Cardiovascular Medical Research Education Foundation, and Asthmatx Inc. Dr Gaston: National Heart Lung and Blood Institute: P01HL101871; U10HL109250; R01 HL59337.

    Conflict of interests: Dr Erzurum: None. Dr Gaston: Intellectual property and minority shareholder in Respiratory Research, Inc, and In Airbase Pharmaceuticals. Intellectual property in N30 Pharma.

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