Asthma is a heterogenous disease characterized by multiple phenotypes driven by different mechanisms. The implementation of precision medicine in the management of asthma requires the identification of phenotype-specific markers measurable in biological fluids. To become useful, these biomarkers need to be quantifiable by reliable systems, reproducible in the clinical setting, easy to obtain and cost-effective.
Using biomarkers to predict asthma outcomes and therapeutic response to targeted therapies has a great clinical significance, particularly in severe asthma. In the last years, significant research has been realized in the identification of valid biomarkers for asthma. This review focuses on the existent and emerging biomarkers with clinical higher applicability in the management of asthma.
Note from the WAF: The WAF editorial board wishes to acknowledge and thank Angelica Tiotiu Pulmonology Department, University Hospital, 9, Rue du Morvan, 54511 Nancy, Vandœuvre-lès-Nancy France National Heart and Lung Institute, Airway Disease Section, Imperial College London, London, UK for their contribution to Asthma education.
Asthma is a heterogeneous disease diagnosed by the presence of intermittent symptoms of wheeze, cough and chest tightness, typically related to a reversible airflow obstruction, usually resolves spontaneously or with asthma treatment [1, 2]. Over the years, clinicians have defined several phenotypes based on the presentation and age of onset of symptoms, the severity of the disease, and the presence of other conditions such as allergy and eosinophilia with different long-terms outcomes and response to therapy with corticosteroids Despite the recognition of these phenotypes of asthma, the approach to the management of asthma recommended by the international Global Initiative for Asthma (GINA) guidelines continues to be based on the severity of the condition, with drugs added on the basis of asthma control
In the era of the personalized medicine, in order to deliver this approach for asthma, it is important to be able to phenotype the condition in an unbiased way and to define biomarkers able to predict the course of the disease and the response to therapy [2, 3]. A biomarker is a measurable indicator that can evaluate a normal or pathological biological processes or pharmacologic response to a therapeutic intervention [2]. A valid biomarker would have several key characteristics: to distinguish between disease and health with high positive and negative predictive values, to provide information about disease prognosis and clinical outcomes, to change with disease progression and “normalize” with successful treatment, to be reliable and reproducible in the clinical setting with little or no day-to-day variation, to be easy to collect in the “real-world” setting, to be quantifiable in an analytical system with well-defined performance, and to be cost-effective
Despite the sustained research efforts during the last years focused on the identification of biomarkers applicable in clinical practice for the management of asthma, only a few biomarkers indicative of T2-high asthma have been described (e.g. IgE, eosinophils in blood and/or sputum, Fractional Exhaled Nitric Oxide [FeNO], periostin), and their utility in diagnosis, prognosis and therapy is still controversial
This review will summarize the recent knowledge about the biomarkers (proteins and related substances) identified of asthma with special focus on those with higher clinical applicability.
Blood cells and serum biomarkers
Using the blood for requiring biomarkers is micro-invasive (the procedure can be painful and difficult in some patients) and easy to realize in the clinical setting, requires minimal patient effort, could be collected across the age spectrum, and it is cost-effective
Blood eosinophil count is not useful for the diagnosis of asthma (GINA), but it can serve as prognostic biomarker and to predict several therapeutic responses in asthmatic patients with type 2 inflammation.
A recent study realized on a large cohort in UK, showed that patients with blood eosinophil counts greater than 400 cells/?L experienced significantly more severe exacerbations (adjusted rate ratio RR 1·42) and acute respiratory events (RR 1·28) than those with counts of 400 cells/ ?L or less and had significantly lower odds of achieving overall asthma control (odds ratio OR 0·74) [7]. Another study found that blood eosinophilia (>?400 cells/ ?L) is a risk factor for airflow obstruction in asthmatic patients (even in those without symptoms) and predicts an enhanced longitudinal decline in lung function, independently of smoking status [8].
Similarly, in a pediatric cohort [9], blood eosinophilia (? 300 cells/?L) is associated with asthma severity (p?=?0.036), high atopy (p?=?0.001), more exacerbations (p?=?0.022), FEV1/FVC (p?=?0.004), and bronchial hyperresponsiveness (p?=?0.002).
Blood eosinophils counts can predict responsiveness to corticosteroid therapy. In atopic asthmatic children with blood eosinophilia (? 300 cells/?L), daily inhaled corticosteroids use is associated with more asthma control days and lower exacerbations rate [10]. Previous data showed that blood eosinophils count could be useful to monitor the response to oral corticosteroids because the adjustment of dose to maintain blood eosinophilia ?61% [68]. Sputum neutrophilia is associated with asthma severity and poor response to corticosteroids [64, 69]. Macrolide treatment could be a possible therapeutic intervention for these patients. Clarithromycin administration (500?mg twice daily) in patients with refractory asthma reduced the airway neutrophil counts and improved the quality of life in patients undergoing active treatment. A subgroup analysis in patients with sputum neutrophilia of >?61% showed that they had greater improvements in quality of life scores compared with those without sputum neutrophilia [70]. A more recent trial (AMAZES) [71] confirmed the benefice of the macrolide treatment with a reduction in exacerbation rate and an improvement of quality of life in patients with refractory asthma who took azithromycin 500?mg three times per week for 48?weeks. Prior data suggested that activation of CXCR2 resulted in increased airway neutrophilia, thus contributing to the pathogenesis of non-eosinophilic asthma, but a recent trial with a CXCR2 antagonist in severe neutrophilic asthma (sputum neutrophils >?40%) not showed a significant improvement in asthma outcomes despite the reduction of sputum neutrophilia [72].
Recent data found that changes in sputum eosinophil count over time reflect fluctuations in clinical asthma control [73]. The high level of Group 2 ILC in the sputum is corelated with severe asthma whose airway eosinophilia is greater than 3%, despite normal blood eosinophil numbers (Discussion
In asthma, and particularly in the severe asthma, many biomarkers have been investigated but only few of them, so far, can be easily used in clinical practice [121]. The Table 1 summarizes the advantages, the limits and the utility in the clinical setting of major biomarkers.
Table 1
Summary of major biomarkers’ characteristics
Biomarker Advantages Limits Utility
Blood eosinophils -Minimal invasive
-Minimal patient effort
-Easy to measure and collect in the clinical setting
-Correlates with sputum eosinophilia -Painful and difficult in some patients
-Varying cut-offs used to determine predictive characteristics
-Can be elevated due to other causes, such as parasitic infection -Defines the inflammatory phenotype
-Predicts exacerbations, poor asthma control and greater airway obstruction
-Predicts therapeutic responses to corticosteroids and biotherapies
Serum IgE -Easy to measure
-Identifies patients who may be candidates for Anti-IgE therapy -Not predictive of response to Anti-IgE
-Outperformed by other markers of T2 inflammation and allergen specific IgE -Associated with asthma severity and airway remodelling
Serum periostin -Marker of Il-13 activity and T2 airway inflammation -Not currently realised in the clinical setting
-Can be elevated in growing children -Predicts a greater airway obstruction and decline of lung function
-Predicts therapeutic responses to biotherapies
Sputum eosinophils -Non invasive
-Reflects the upper airways -Difficult to collect
-Not all patients can provide adequate samples
-Not universally available
-Requires specialized training, equipment, laboratory -Defines the inflammatory phenotype
-Predicts responses to corticosteroids and biotherapies
FeNO -Non invasive
-Minimal patient effort
-Easy to collect in the clinical setting -Multiple confounders
-Requires specialized equipment -Identifies airways inflammation
-Predicts exacerbations and airways hyperreactivity
-Predicts responses to corticosteroids and several biotherapies
An ideal biomarker should be suitable to identify the disease as well the specific endotype/phenotype, useful in the monitoring of the disease and to determine the prognosis, easily to obtain with minimum discomfort or risk to the patient [3, 4, 121].
According to the presence of assessable biomarkers of T2 mediated airway inflammation, the cluster-analysis identified several asthma phenotypes. The T2-high phenotype includes the classical allergic one (mild blood eosinophilia, high levels of FeNO, high level of serum total IgE) and the late-onset, nonallergic but highly eosinophilic one, frequently associated to chronic rhinosinusitis with nasal polyps (high FeNO but serum total IgE normal or elevated but probably with a lower etiopathogenetical importance) [1, 121]. The eosinophilic phenotype is associated with an intense production of IL-5 and IL-13. The T2-low phenotypes are more diversified and less well defined, with predominant neutrophilic airway inflammation, higher frequency of recurrent airway infections, higher prevalence of obesity and cigarette smoking. The mechanisms implicated in these phenotypes are the TNF? and IL-17 inflammatory pathways [69].
Unfortunately, at the moment, an ideal biomarker doesn’t exist and the overlap between the biomarkers is a reality. Using panels of biomarkers could improve probably the identification of asthma endotypes in the era of the precision medicine.
Other desired characteristics of a biomarker are the easiness and non-invasiveness of assessment. The development of point-of-care testing and non-invasive devices (one validated recently for the blood eosinophil count, others in study for the assessment of serum IgE and periostin) could accelerate the path leading to a precision medicine approach and clinical management of severe asthma [121].
Biomarkers, in addition to their role in defining phenotypes and endotypes may also have a predictive value for the response to biologic treatments. Serum total IgE is used in practice to verify that a patient with severe allergic asthma could be a candidate for omalizumab therapy and blood eosinophils count (usually ?300 cells/?L) to prescribe biological agents such as anti-IL5 antibody in the eosinophilic refractory severe asthma. If in the last 10?years, only omalizumab was available, followed by mepolizumab, we will move in the next few years to a situation in which we will have to choose one monoclonal antibody among many (benralizumab, an IL-5 receptor antagonist; dupilumab, an IL-4 receptor alpha antagonist; tezepelumab, an anti-thymic stromal lymphopoietin antibody). This implies the need of more selective biomarkers (or panels of them) in order to identify the right biologic therapy for each single patient, in a more personalized and precise medicine approach to the disease treatment [2, 121].
Conclusions
The implementation of the precision medicine in the management of asthma in clinical practice requires the detection of valid biomarkers. A variety of biomarkers have been used clinically to predict the response to steroid therapy, and in the clinical trial setting to identify patients that will respond to biologic therapies, but currently available biomarkers are limited in number and precision. At the moment, for a patient with a severe allergic asthma (high level of serum total IgE, high FeNO, normal or mild blood eosinophilia) uncontrolled despite a Step 4 or 5 treatment of GINA guideline, omalizumab seems to be the most adapted therapeutic option. If failure, another biologic therapy such as mepolizumab or reslizumab could be prescribe if blood eosinophilia (? 300 cells/?L, respectively ?400 cells/?L). In the refractory eosinophilic asthma without atopic background (high blood eosinophilia, high FeNO, normal IgE), an anti-IL5 antibody seems to be the most appropriate. Macrolides could be an interesting therapeutic option for the patients with severe uncontrolled asthma with T2-low inflammatory pattern, as well the bronchial termoplasty in patients with airways remodeling.
Further research and validation of emerging biomarkers are needed to define the molecular phenotype of asthma, particularly in the non-T2 pathways, to predict outcomes and therapeutic response to more specific targeted therapies. The use of omics data from multiple platforms (transcriptomics, proteomics, or metabolomics) appears as a promising tool to obtain endotypes. Viewing the heterogeneity of asthma, to predict therapeutic response, the development of composite biomarkers from blood, urine and exhaled breath seams to be a more appropriate solution in practice.