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Abstract
A stepwise pharmacological treatment is currently recommended for all asthma patients and is personalized mainly on disease severity, aiming for the lowest disease-controlling step. Nevertheless, asthma comprises several related pathologies with similar clinical manifestations resulting from distinct underlying mechanisms. Therefore novel biomarkers could lead to asthma stratification and thus improve upon the current stepwise approach. The aim of this review is to update the reader with regard to different assays proposed in the recent asthma literature for measuring potential biomarkers for patient stratification and treatment personalization. Promising biomarkers are sputum eosinophils, serum periostin and exhaled nitric oxide. Periostin could differentiate between Th2-high and Th2-low asthma (Th2-high patients are more responsive to glucocorticoids) and the less-defined asthma types which often present a therapeutic challenge. Several other biomarkers, mainly cytokines, leukotrienes and exhaled air components, can be quantified in body fluids and exhaled breath and could also be useful for asthma stratification.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Asthma is a chronic respiratory disorder characterized by episodes of reversible airflow obstruction, manifesting in shortness of breath, wheezing and cough.
Current diagnosis of asthma involves its use as an ‘umbrella term’ that is employed to diagnose groups of similar symptoms; however, asthma is far more diverse and requires greater stratification. To date, inhaled corticosteroids are the most common treatment for asthma. Biomarker discovery is currently looking to stratify asthma endotypes to enable specific drug discovery and personalize treatment.
Eosinophils and neutrophils are closely linked to airway inflammation and are currently measured within induced sputum to stratify asthma into four distinct cellular types; eosinophilic (raised eosinophil levels), neutrophilic (raised neutrophil levels), mixed granulocytic (raised neutrophils and eosinophils) and paucigranulocytic (normal neutrophil and eosinophil levels). Eosinophils are most closely linked to severe asthma and indicate the need for inhaled corticosteroids use.
Periostin is a biomarker directly linked to IL-13 and IL-5 secretion and is elevated in asthmatics with extensive airway remodeling. Elevated periostin can be used to distinguish between Th2-high and Th2-low asthma and again, indicates more severe asthma subtypes for those classified as Th2-high.
Nitric oxide is a short-lived, gaseous free radical that is present in exhaled breath. It can be measured using a range of devices, including an electronic nose, which has the added ability of giving a profile of multiple volatile organic compounds in addition to fractional exhaled nitric oxide from exhaled breath. Asthmatics show elevated levels of fractional exhaled nitric oxide and may show variation in levels depending on the degree of airway inflammation. Multiple studies have found it to be inaccurate for anything more than distinguishing between healthy and asthmatic patients, although researchers are hopeful that it will be refined in conjunction with volatile organic compounds to indicate the risk of exacerbation on a daily basis.
Future asthma biomarkers include exhaled breath profiling of multiple volatile organic compounds for more specific distinctions between asthma subtypes. Simple lipids such as leukotriene E4, which are measurable from urine and have also been found to indicate the responsiveness of a patient to leukotriene receptor antagonists, when elevated. Leukotriene receptor antagonists is used to reduce airway inflammation.
Biomarkers are also merging into genetic testing such as a polymorphism found in CHI3L1, which encodes for a chitin protein YKL-40. The CHI3L1 gene is hypothesized to be indicative of severe, therapy-resistant, childhood asthma when it contains a specific single-nucleotide polymorphism.