**1. Introduction**

According to the concurrent paradigm, asthma should not be regarded as a single disease, but rather as a complex of multiple, overlapping syndromes. The heterogeneity of asthma has been

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recognised already for over a century, for instance, as intrinsic and extrinsic ("allergic") asthma [1].

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

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 pathways interrelate.

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 currently used in the management of asthma.
