Occupational asthma contribution in phenotyping adult asthma by using age-of-asthma onset clustering

Response to: Tan DJ, Walters EH, Perret JL, et al. Age-of-asthma onset as a determinant of different asthma phenotypes in adults: a systematic review and meta-analysis of the literature. Expert Rev Respir Med 2015;9:109-23

Identification of phenotypes of asthma has received considerable attention, particularly in the last decade, in the attempt to identify sub-groups who could optimally respond to selected therapeutic agents. This objective could also be imagined as a consequence of a better and homogeneous characterization of sub-groups of asthmatics with a more similar genetic susceptibility to external agents causing symptoms of asthma. However, the strategy to reach the best possible characterization of these phenotypes remains under constant investigation. The most commonly used methods include the so-called ‘biased’ and ‘un-biased’ approaches [1,2]. The ‘biased’ approach is based on a number of clinical or lung functional characteristics that define a priori the asthmatic populations under investigation [1,2]. These clinically defined ‘phenotypes’ require subsequent confirmation of their specific characteristics through the identification of the related endotypes (biological markers, cytokine patterns). The higher is the association of the pre-defined phenotypes and related endotypes, the more consistent is the identification of a well defined phenotype [1,2]. One such ‘phenotype-endotype’ has been identified in the response to corticosteroid treatment [1,2]. In contrast, the ‘un-biased’ approach is mainly based on the use of large numbers of non-clinically characterized asthmatics for which the genomic and proteomic approach is used for identification of clusters (phenotypes) of asthmatics showing specific gene or post-transcriptional protein similarities identifying clinically defined sub-groups (phenotypes) of asthmatics [2]. Occupational asthma has long been considered a relatively homogeneous group of asthmatics showing cellular and molecular (endotypes) characteristics similar to allergic asthma [3,4]. We refer to a detailed review for more specific notions on this topic [4]. The systematic review and meta-analysis recently published by Tan and colleagues [5] shows that age-of-asthma onset can be used to distinguish different adult asthma phenotypes. Age 12 was more frequently used to differentiate the two age of onset phenotypes. In the early onset group atopy was more frequently found, while in the late onset group a higher fixed airflow obstruction, smoking habit and female sex prevalence were observed. Severe asthma was similarly observed in both phenotypes [5]. These authors [5] critically suggest that in spite of the identification of clinical and functional differences characterizing these two phenotypes, a more detailed approach is needed to clarify the potential clinical implications of this investigation [5]. To this purpose a useful notion could be gained by considering occupational asthma. Isocyanates, used by car painters, are a group of low molecular weight chemicals causing occupational asthma [3,4,6] with a divergent disease free periods of exposure ranging from 1 to 30 years of exposure before sensitization to toluene diisocyanate (TDI) [3,4,6]. In our previous work we observed that there was a prevalence of two distinct groups of sensitized subjects, one group who developed TDI induced asthma after an average of 2.4 years of exposure (mean ± SE age, 32 ± 3), and another group who developed asthma after a very long period of exposure (on average 21.6 years) (mean ± SE age, 45 ± 2) [7]. Duration of asthma symptoms, baseline FEV1 (% predicted) values, PD₂₀FEV1 (mg methacholine), maximal fall in FEV1 (%) after TDI challenge, were all similar in the two subgroups of asthmatics studied [7]. TDI exposure levels were not formally measured, but on the basis of work regimens, a similar TDI/year quantitative exposure could be supposed [6,7]. Interestingly, looking at bronchial biopsy inflammatory cells (endotype) prevalence in the two groups, we observed a significant increase of mast cells infiltration in epithelium and lamina propria of early onset TDI asthmatics compared to late onset ones [7]. Also eosinophils were somewhat increased in the early onset group [7]. Numbers of mast cells in the lamina propria were inversely correlated with the length of exposure to TDI before onset of asthma (years) (R = -0.81, p < 0.001). These data suggest that quite distinct genetic susceptibilities in developing asthma symptoms are present in TDI asthmatics, that this different susceptibility is associated with different endotypes, confirming a prevalent Th2 type inflammation, related to early onset asthma and atopy, similar to that recently reported for the general population of mild asthmatics [1,2]. Interestingly, the TDI induced asthma model supports the notion that a clear grouping of early and late onset adult asthmatics could be recognized after TDI stimulation. Extending this notion to the general population of asthmatic subjects, the 12 year cut-off value separating the early and late groups of asthmatics appears to be clearly insufficient for the definition of an early onset and a late onset group of asthmatics. Childhood asthma should also be clearly excluded from this attempt of clustering adult asthmatics. A more appropriate late onset defining criterion should be an age greater than 40 years old. At present, there is a broad heterogeneity of definitions have been adopted in different published works. Tan and Coauthors, in their interesting systematic review of the literature found 2921 records from which only 12 studies showed eligibility criteria sufficiently standardized to be accepted in the inclusion criteria for meta-analysis [5]. In agreement with Tan and Coauthors, we believe that a more detailed approach is required to better characterize early and late onset phenotypes in the general population of asthmatics. To reach this objective, the early and late onset groups should be clearly separated on the basis of: age of onset of asthma; comparable duration of symptoms; and severity of the disease. A step by step approach involving the analysis of endotypes and the use of genomic and proteomic methods should also be adopted in order to define the genetic and biological manifestations developing in association of early and late onset groups of adult asthmatics in the attempt to confirm (or deny) the clinically defined phenotypes adopted in our studies. This pathway could help us to establish more clearly the role of early and late onset subgroups (phenotypes) of adult asthmatics and their potential clinical and therapeutic relevance.

Acknowledgments

We wish to thank George Cremona MD, PhD, for inspiring this work and for contributing to its final form.

Financial & competing interests disclosure

This work was supported by a Fondazione Salvatore Maugeri, IRCCS, Ricerca Corrente. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.