**2. Do we need biomarkers in asthma?**

Given the heterogeneity of asthma and the evidence that standard therapy is not (fully) effective in all patients, especially in those with more severe disease and those at risk for frequent exacerbations, the need for appropriate biomarkers allowing the identification and subsequent targeted treatment of these patients has been increasingly recognised. Since asthma is multidimensional and thus presents at several different levels including clinical, physio‐ logical, histological, cytological and molecular, various approaches have been developed to identify effective biomarkers (**Table 1**) [10]. In addition, given the complexity of the disease, (unbiased) biomarker clustering within different asthma populations has been performed by several research groups, which revealed different disease subphenotypes with varying disease course and/or response to treatment [3, 4].


BAL: bronchoalveolar lavage; CRP: C-reactive protein; eNose: electronic nose; IgE: immunoglobulin E; SNP: single nucleotide polymorphism

**Table 1.** Clinical and biological biomarkers in asthma.

recognised already for over a century, for instance, as intrinsic and extrinsic ("allergic") asthma

The introduction and subsequent validation of hypertonic saline-induced sputum analysis revealed different inflammatory asthma phenotypes: i.e. eosinophilic versus non-eosinophilic [2]. Asthma phenotypes comprise shared similar observable characteristics, produced by the interactions of an individual's genetic make-up and the environment that can be affected by several triggers and respond to treatment. However, phenotypes may vary over time and do not directly link to the underlying pathophysiology. Factor analyses involving various disease characteristics and biomarkers, including fractional exhaled nitric oxide (FeNO) levels and

In the 1990s, in analogy with animal models, asthma was thought to be a typical T-helper (Th)2 and immunoglobulin E (IgE)-driven disease, and hence, the proof of clinical effectiveness of potential asthma therapeutics was tested in the allergen challenge model. More recently, genomics and other sophisticated "omics" techniques enabled further characterisation of various inflammatory cells and other biomarkers, and helped to link asthma subphenotypes or endotypes to specific cellular and molecular pathways. For instance, gene expression profiling revealed two major subtypes: i.e. "Th2-high" and "Th2-low" asthma providing evidence for responders and non-responders to Th2-targeted therapies [5, 6]. Apart from the involvement of the adaptive immune responses, pathognomonic for parasites and allergens, more recent insight showed the major involvement of the innate system (ILC2s: innate lymphoid type 2 cells) in some asthma endotypes [7]. Interestingly, both Th2 cells and ILC2s produce type 2 cytokines (i.e. interleukin (IL)-4, IL-5 and IL-13) and these type 2 responses are mainly mediated by eosinophils. However, the underlying "upstream" mechanisms differ: while allergens mainly drive Th2-responses [8], viruses and pollutants are common triggers for ILC2-mediated type 2 responses that involve epithelial cells and IL-25, IL-33 and thymic stromal lymphopoietin [9]. Presently, it is not fully clarified how exactly both type 2 response

Apart from disease typing, the discovery of new inflammatory pathways and related bio‐ markers resulted into the development of endotype-specific, individualised asthma treatment. In this review, we aim to highlight the key non-invasive and semi-invasive biomarkers

Given the heterogeneity of asthma and the evidence that standard therapy is not (fully) effective in all patients, especially in those with more severe disease and those at risk for frequent exacerbations, the need for appropriate biomarkers allowing the identification and subsequent targeted treatment of these patients has been increasingly recognised. Since asthma is multidimensional and thus presents at several different levels including clinical, physio‐

sputum cell differentials, helped to further define asthma (sub)phenotypes [3, 4].

[1].

16 Asthma - From Childhood Asthma to ACOS Phenotypes

pathways interrelate.

currently used in the management of asthma.

**2. Do we need biomarkers in asthma?**

Using a systems biology approach in large cohorts of patients, researchers within the Innova‐ tive Medicines Initiative Severe Asthma Project U-Biopred have been collecting data, including molecular analyses, tissue, exhaled air and blood samplings, as well as clinical and lung function data, and patient-reported symptoms [11]. By combining this information, the researchers aimed to generate a "handprint", i.e. a combination of clinical and biological characteristics (biomarkers) indicative of a specific asthma subphenotype/endotype. Subse‐ quent studies are being undertaken to test if one's "handprint" can predict the disease course and can indicate a response to (targeted) asthma treatments. This approach will provide a key step to personalised medicine [12–14].

Generally, an ideal biomarker should possess the following key characteristics: clinical relevance, adequate sensitivity and specificity for (targeted) treatment effects, repeatability, simplicity and cost-effectiveness [10].
