**7. Conclusions**

have measurable levels of serum periostin, thus other systemic sources of periostin than IL-13

Overall, blood eosinophils, serum periostin and FeNO reflect "type 2" airway inflammation in different ways and are only weakly correlated; therefore, combinations of these biomarkers obtained with minimally or non-invasive samplings may further enable optimisation of

Recently, application of "omics" technologies to peripheral blood and invasive sampling with unsupervised clustering are yielding crucial data to capture the complexity of various asthma phenotypes and add new insights on asthma endotypes and treatment response. Given its maturity, transcriptomics analysis using microarrays is the current state-of-the-art method for asthma signature discovery [60]. For instance, gene expression profiling of bronchial epithe‐ lium identified distinct subtypes of patients with asthma with "Th2-high" or "Th2-low" phenotype [5], supported the involvement of endotoxin and macrophage activation in corticosteroid resistance, and suggested that corticosteroids also exert their beneficial effects through activity on bronchial smooth muscle [60]. "Omics" technologies developments, with data comparison and validation, will lead to the integration of composite signature biomarkers in phenotyping asthma and improvements in our understanding of asthma. Ultimately, breakthroughs in asthma treatment may be reached through the development of innovative

Non-invasive procedures for biomarker analysis form the backbone for day-to-day clinical asthma management. However, invasive tests may provide important information to pheno‐ type and direct therapy in patients with severe refractory asthma [88]. These techniques bring significant additional knowledge in asthma research that needs to be integrated with noninvasive procedures outcomes to allow truly innovative steps in biomarker discovery for

In general, milder asthma phenotypes respond well to standard therapy with corticosteroids (with or without long-acting beta2-agonists), while those with more severe disease urged the development of new therapeutic modalities. To enable the development of effective (targeted) therapies, it is crucial to understand the pathophysiological mechanisms driving these subsets of asthmatic patients. Haldar et al. performed a cluster analysis on baseline data of 184 patients with mild to moderate asthma coming from different general practitioners (GP) and baseline data of 187 patients with refractory disease from specialist settings [3]. Additionally, a third dataset comprised baseline and longitudinal data of 68 patients with refractory disease followed for 12 months. Hierarchical cluster analysis revealed five different clusters, with some overlapping features between patients from GP and specialist origins. Most importantly, patients with concordant symptoms and (eosinophilic) inflammation (based on sputum analysis) were mostly coming from GP and were characterised by overall milder, often atopic, well-controlled disease, with a benign disease course. Alternatively, patients with uncontrol‐

**6. Asthma phenotypes based on cluster analyses**

need to be explored [82].

30 Asthma - From Childhood Asthma to ACOS Phenotypes

treatment benefit [82, 86, 87].

targeted therapies [12, 60].

asthma management.

The complex heterogeneity and dynamics of asthma with varying response to standard treatment is driving the search for distinct asthma phenotypes and endotypes. While in‐ haled corticosteroids can effectively control asthma, therapeutic responses are individual‐ ised (though clinical manifestations may match), can be incomplete in a significant number of patients and no curative treatment exists.

In this setting, biomarkers are needed to innovate asthma management. As indicators of pathophysiologic processes or pharmacologic responses, biomarkers can be useful for asth‐ ma diagnosis and phenotyping, prediction of future risk or treatment selection or evaluation of response. Non-invasive sampling has the advantage of being patient-friendly and allow‐ ing repeatable measurements across all age and severity groups. More direct airway or dis‐ tant assessment non-invasive sampling and analysis are currently possible, yielding molecular, cellular, functional and imaging potentially clinically useful biomarkers.

For the promise of delivering valuable new biomarkers to the clinic to come forward, it is mandatory that standard optimised procedures are set for sample collection and analysis, and that resulting data are critically processed, explored and cut-off values are well-defined. This will allow comparison of results and replication, with external validation in different population settings.

Though relevant single biomarkers have been found in asthma, increasing evidence shows that biomarker panels do better and composite signatures may indeed soon be integrated in phenotyping/endotyping of asthma. Multiscale, high-dimensional biological, together with standard clinical measures are adding new relevant knowledge. This systems medicine ap‐ proach is helping to generate new hypotheses and (re)discover pathways and related bio‐ markers, linking phenotypes to endotypes and ultimately leading to truly innovative treatments for patients with asthma syndromes.
