Edited by: Jose Antonio Castro-Rodriguez, Pontifical Catholic University of Chile, Chile
Reviewed by: Elisabetta Calamelli, University of Bologna, Italy; Paolo Maria Matricardi, Charité Medical University of Berlin, Germany
This article was submitted to Pediatric Pulmonology, a section of the journal Frontiers in Pediatrics
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Biomarkers are essential to determine different phenotypes of childhood asthma, and for the prediction of response to treatments. In young preschool children with asthma, aeroallergen sensitization, and blood eosinophil count of 300/μL or greater may identify those who can benefit from the daily use of inhaled corticosteroids (ICS). We propose that every preschool child who is considered for ICS treatment should have these two features measured as a minimum before a decision is made on the commencement of long-term preventive treatment. In practice, IgE-mediated sensitization should be considered as a quantifiable variable, i.e., we should use the titer of sIgE antibodies or the size of skin prick test response. A number of other blood biomarkers may prove useful (e.g., allergen-specific IgG/IgE antibody ratios amongst sensitized individuals, component-resolved diagnostics which measures sIgE response to a large number of allergenic molecules, assessment of immune responses to viruses, level of serum CC16, etc.), but it remains unclear whether these can be translated into clinically useful tests. Going forward, a more integrated approach which takes into account multiple domains of asthma, from the pattern of symptoms and blood biomarkers to genetic risk and lung function measures, is needed if we are to move toward a stratified approach to asthma management.
Asthma is a heterogeneous condition with a myriad of definitions in the literature (
After decades of improvements, in the past 10–15 years little progress has been made against key outcomes in asthma such as hospital admissions and mortality rate (
Biomarkers are needed both to determine the subtype of asthma, and for prediction of response to treatments. This review will focus on the importance of blood biomarkers, most notably serum IgE levels and blood eosinophil counts, and will mainly focus on childhood asthma. Longitudinal trajectories of allergic sensitization during childhood and their relevance to asthma-related conditions will be discussed, as well as different types of modeling required to uncover such trajectories. A further blood biomarker of interest is serum periostin, shown in a recent study to be a better predictor of airway eosinophilia than IgE levels or blood eosinophils (
Moving beyond blood biomarkers, we present the reader with an overview of further asthma domains, from lung function measurements to genetic findings. Put together, all of this knowledge points to a need for the integration of all aspects of this complex condition, combined with methodological development, as the way forward to a complete understanding of the underlying endotypes and the development of mechanism-based stratified treatments (
The presence of specific IgE antibodies measured in blood or by SPTs defines allergic sensitization, and is one of the strongest associates of asthma in epidemiological studies (
Total level of IgE was also shown to be an important predictor of asthma in population-based studies; this association persists after adjusting for specific IgE levels against several core allergens (dust mite, cat, timothy grass, fungi, and plants) (
A clearer picture about the association between sensitization and asthma can emerge when responses to specific allergens are taken into account (
We will return to the relevance of specific allergens and the methodological developments that have helped identify the association between different sensitization patterns and asthma in the next section. However, since a large portion of sensitized individuals do not develop asthma (
Of note, control mechanisms mediated via allergen-specific IgG may also play an important role, and may help differentiate between benign sensitization (i.e., sensitization without symptoms of allergic disease) and pathologic sensitization (i.e., sensitization leading to clinical symptoms) (
The presence of elevated eosinophil counts in blood or sputum is of considerable importance, as these cells are central effectors at the site of allergic inflammation (
A recent study which investigated the relationship between phenotypic features and biomarkers in relation to response profiles to asthma medication in young children between the ages of 12 and 59 months on the step two of asthma management identified a subgroup of patients who benefitted from the daily use of ICS. The features that predicted preferential response to regular ICS were aeroallergen sensitization and blood eosinophil counts of 300/μL (
To better understand the heterogeneity of childhood asthma and allergic sensitization, researchers are increasingly turning toward birth cohorts (
Early attempts for phenotype classification were investigator-led, and ascribed labels based on observing simple patterns (
Other machine learning approaches can allow us to better represent the underlying structure of the data. For example, we can use Hidden Markov Models (HMMs) as graphical models: a simple picture showing the relationships between different variables at different ages can be turned into a probabilistic clustering method (
Traditionally, whole allergen extracts have been used to diagnose allergic sensitization (
Further studies investigated temporal changes of component-specific IgE responses (
A more recent approach applied network analysis to investigate interactions and connectivity patterns between component-specific IgE to 112 allergenic molecules from more than 50 sources on a CRD array and related these to the presence of asthma (
Summarizing the discussion of blood biomarkers of asthma, we would highlight the report of the expert group commissioned by the US National Institutes of Health (NIH), which recommended a multi-allergen screening to define atopy as the only core biomarker for asthma (
The UK National Institute of Health and Care Excellence (NICE) proposed a diagnostic algorithm for childhood asthma in children with symptoms presenting to health-care professionals, which includes the sequential use of four measures of lung function and inflammation: spirometry (forced expiratory volume in 1 s [FEV1]/forced vital capacity [FVC] ratio), bronchodilator reversibility, fractional exhaled nitric oxide (FeNO), and peak flow variability (
Measurement of FeNO is considered a supplemental biomarker by the NIH due to its close tracking with eosinophilic inflammation and responsiveness to corticosteroids (
A further opportunity to identify biomarkers for childhood asthma may lie in discovering genetic associates, and consistent association of asthma with variants on chromosome 17q21 has been reported (
Many environmental factors play a role in the disease trajectory (
Overall, an elaborate multitude of interactions points to the necessity of an integrated approach to facilitate the move toward a more personalized approach to allergy and asthma (
Given the multitude of potentially relevant biomarkers discussed thus far, it seems apparent that viewing any of them in isolation does not give us sufficient information to move toward patient stratification. While the identification of phenotypes in birth cohorts using data-driven approaches gives us an insight into the structure at the population level, it has been shown that associations with risk factors can be inconsistent across studies (
Thus, it remains unlikely that purely data-driven identification of clusters on a subset of symptoms can identify true endotypes of this complex disease. We propose that integrating across a more comprehensive range of the available data (
A range of different biomarkers can help us disaggregate the disease via domain integration and combining data-driven models with expert clinical knowledge.
In conclusion, we urgently need better biomarkers to determine different subtypes of childhood asthma, and to predict the response to treatments. Aeroallergen sensitization and blood eosinophil count ≥300/μL may identify young pre-school children who benefit from the daily use of inhaled corticosteroids, and we suggest that every pre-school child who is considered for a long-term preventative asthma treatment should have these features measured as a minimum before the decision is made on which drug to prescribe. Several other blood biomarkers may prove useful (e.g., allergen-specific IgG/IgE antibody ratios amongst sensitized individuals, component-resolved diagnostics which measures sIgE response to a large number of allergenic molecules, level of serum CC16, etc.), but it remains unclear whether these can be translated into clinically useful tests.
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
AC reports personal fees from Novartis, personal fees from Regeneron/Sanofi, personal fees from Thermo Fisher Scientific, personal fees from Boehringer Ingelheim, personal fees from Novartis, personal fees from Philips, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.