Biomarkers in Asthma: A Real Hope to Better Manage Asthma
Section snippets
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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Cited by (18)
GEMA 5.3. Spanish Guideline on the Management of Asthma
2023, Open Respiratory ArchivesThe emerging roles of eosinophils: Implications for the targeted treatment of eosinophilic-associated inflammatory conditions
2022, Current Research in ImmunologyCitation Excerpt :In the field of precision medicine, the different biology of eosinophil subtypes should be taken into account, and a truly targeted therapeutic intervention should be ideally able to distinguish between rEos and iEos. Second, a better characterization of the predominant pathway underlying the eosinophilic inflammation in the single patient could help: there are cases in which asthmatic patients have a modest hypereosinophilia and increased FeNO, or a normalization of peripheral eosinophils during anti-IL-5 treatment with suboptimal asthma control and increased FeNO, suggesting a predominance of IL-13 activation that might respond better to IL-13 targeted treatment (Erzurum and Gaston, 2012). Similarly, high circulating IgE levels (in addition to eosinophilia) in asthmatic patients, may suggest an hyperactivation of IL-4 pathway.
GEMA<sup>4.0.</sup> Guidelines for Asthma Management
2015, Archivos de BronconeumologiaChildhood asthma biomarkers: Present knowledge and future steps
2015, Paediatric Respiratory ReviewsCitation Excerpt :However, the invasiveness of these procedures limits their use in daily clinical practice [2]. Sputum induction is also considered too invasive and technically complex, especially in children under eight years old [2,5]. When working with children, it becomes particularly important to devise non-invasive methods for studying and monitoring asthma-related inflammation.
Diagnostic value of IL-6 for patients with asthma: a meta-analysis
2023, Allergy, Asthma and Clinical ImmunologySevere uncontrolled asthma
2021, Journal of Investigational Allergology and Clinical Immunology
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.