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.