Biomarkers in asthma
In the past decades, it has been increasingly recognized that asthma is a highly heterogeneous disorder with different underlying mechanisms and pathways translating into variable responses to standard treatment across the different subsets or clinical phenotypes.23,24 Unbiased approaches and cluster analyses identified four major clinical phenotypes, i.e .: (1) early-onset allergic asthma, (2) early-onset allergic moderate-to-severe asthma, (3) late-onset non-allergic eosinophilic asthma, and (4) late-onset non-allergic non-eosinophilic asthma.25 The late-onset subsets tend to present as more severe or more difficult-to-treat than early onset asthma. To promote an adequate treatment strategy, asthma can be subdivided into Type 2 (high) and non-Type 2 (or Type 2 low) endotypes based on their underlying inflammatory pathways.26 As part of a more general syndrome often including nasal polyps with or without NSAID-Exacerbated Respiratory Disease (NERD),27,28 Type2 asthma currently comprises the best defined asthma subset(s) in terms of underlying immunopathology, corresponding biomarkers 8 and targeted treatment options with biologicals and small molecules.13,29,30
In parallel with the available (targeted) treatment options, biomarkers have been validated along the corresponding inflammatory pathways aimed for pheno/endotyping and to guide treatment for Type 2 asthma.8Clinically applicable point-of-care biomarkers include blood eosinophils, or whenever feasible, sputum eosinophil counts, serum specific IgE and FeNO.8,31 Although overlapping in type 2 biomarkers may occur within patients, all biomarkers represent different aspects of the type2 inflammatory pathways with IgE associating to allergy, while FeNO is linked to the IL-13 pathway and epithelium-derived inflammation.8 Based on these point-of-care biomarkers in combination with clinical characteristics (age of onset, comorbidities, exacerbations, need for maintenance systemic corticosteroids) and physiological parameters (lung function, airway hyperresponsiveness, etc.), current guidelines have now adapted algorithms which can help to predict a response to (targeted) treatments and/or can be used to monitor the subsequent treatment response.23,32,33 In this context, some confounders have been recognized for the existing point-of-care biomarkers,i.e ., for FeNO mainly related to ICS use, smoking, dietary nitrate intake, virus infections and bronchoconstriction, while for blood eosinophils circadian variation, parasites and systemic corticosteroids were found to be the most common perturbing factors.23,34 In this context, a clinically relevant issue has been raised, i.e ., whether ‘’true” non-Type 2 (non-eosinophilic) asthma really exists among patients with severe asthma, given the fact that high-dose inhaled and oral corticosteroids may potentially mask pre-existing Type 2 inflammation interfering with its biomarkers, especially blood eosinophils and FeNO.35,36 Currently ongoing corticosteroid-tapering studies (RASP-UK) in patients with non-Type 2 severe asthma should answer this question. Alternatively, airway neutrophilia (‘’neutrophilic asthma”) may often reflect (subclinical) airway infection.36-38
In contrast, for non-Type 2 asthma which is by default defined as asthma without type2 biomarkers, underlying pathways and, hence, clinically applicable biomarkers and targeted treatment options are still largely under exploration.36,39 Apart from most patients with mild clinically stable asthma,26,40 clinical phenotypes frequently associated with non-Type 2 asthma include very late-onset asthma (women), obesity-associated asthma, smoking-associated neutrophilic asthma and pauci-granulocytic asthma. Although generally based on increased sputum neutrophils or absence of normal levels of (sputum) eosinophils and neutrophils (paucigranulocytic) with normal levels of other Type 2 markers, the diagnosis of non-type2 asthma is difficult to establish as often based on cross-sectional data potentially affected by confounders including respiratory infections or anti-inflammatory therapies.36 In the absence of targeted biologicals, in non-Type 2 asthma treatable traits should be targeted,41-43 e.g.: obesity, smoking habits, psychological aspects, neutrophilia as a potential indicator of respiratory infection and airway narrowing or airway hyperresponsiveness as an indicator of ASM dysfunction, while corticosteroids may not be effective and should be tapered off (Figure 1).23
In conclusion, despite substantial progress in our understanding, applicable biomarkers and targeted treatment options for Type 2 asthma, further characterization of molecular pathways by omics technologies,44-46 sophisticated imaging47 and innovative anatomical approaches48 should help to further unravel the complexity of asthma and to define reliable (composite) biomarkers and therapeutic strategies for patients non-responsive to currently available (targeted) treatment options including non-Type 2 asthma.