Human vs Equine Asthma : phenotypes, diagnostic and treatments

Human asthma has been extensively explored using a range of phenotyping approaches. Cluster analysis of clinical and laboratory features, sputum transcriptomics and proteomics have provided unequivocal evidence of a heterogeneous pathology. Approximately 50% of asthmatics can be clearly categorized as being T2 in nature, based on the findings of elevated immunoglobulin E, a high prevalence of prick skins test positivity for common aeroallergens, blood and sputum eosinophilia. T2 immunity is a term derived from the profile of cytokines expressed by CD4 T cells, namely interleukin-4, IL-5 and IL-13. These cytokines are responsible for promoting IgE synthesis, eosinophilia and airway hyperresponsiveness to inhalation challenge with methacholine and other contractile agonists (1). Non-T2 asthma has fewer of these features and is less responsive to inhaled corticosteroids (2). T cells that express interleukin-17 have been linked to steroid-resistant induced asthma in mice (3). The Th1 cytokine interferon-γ likewise has been found to be expressed in the airways of severe asthmatics (4).

In recent years there has emerged another lymphoid cell that participates in host responses to mucosal injury. These lineage negative innate lymphoid cells they express similar panels of cytokines to the T helper subsets and are labelled groups 1, 2, and 3 innate lymphoid cells (ILC) (5). They are rapidly activated by epithelial signals such as thymic stromal lymphopoietin (TSLP), interleukins 25 and 33, released when the epithelium is damaged and hence are termed alarmins. The secretion of IL-5 and IL-13 by ILC2 may lead to a pattern of inflammation previously interpreted as Th2. These cells are less steroid sensitive. Additionally, alarmins prime cells such as dendritic cells and therefore have a role in adaptive immunity as well as innate immune responses. Viral infection of epithelial cells or damage by irritants is likely to give rise to inflammation mediated by ILCs. Their roles are not fully explored.

Transcriptomic analysis of sputum has revealed three patterns of inflammation and gene signatures consistent with both Th2 and ILC2 driven inflammation and oxidative stress (6). The descriptions of molecular mechanisms of inflammation are still just a deeper form of phenotyping. However, the application of novel biologics to treat asthma is now implicating certain pathways in disease and therefore is providing us with true disease endotypes. Most of the progress in the identification of treatable traits has related to the T2 phenotype. Biologics targeting IgE (omalizumab), IL-5 and therefore the eosinophil (mepolizumab, benrazilumab, rezlizumab) and the T2 cytokines (dupilumab) have all demonstrated efficacy in reducing exacerbations of asthma. Recent results of studies targeting the alarmin TSLP have confirmed efficacy against acute attacks of asthma (7). Promising results are also published for anti-IL-33 (8). Both are claimed to be useful for T2- low asthma but the data are unconvincing. Oxidative stress in asthma has not been specifically addressed.

A problematic form of asthma is that associated with airway remodeling and fixed airway obstruction. The association with mucus plugging and eosinophilic inflammation has been recently identified as a potential factor in long term impaired airway function (9).

Irritant asthma is associated with airway neutrophilia but is also accompanied by an element of eosinophilic inflammation. Given the biological effects of alarmins it seems inevitable that some degree, however minor, of eosinophilic inflammation is likely to be present. However, non- T2 asthma or T2-low asthma remains a form of asthma for which no targeted therapy is available. Severe equine asthma is typically a neutrophilic form of asthma although expression of T2 cytokines has been described (10). There is also evidence that IL- 17 is expressed in equine asthma and its effects on neutrophil survival are steroid-insensitive. Although neutrophilic human asthma is less steroid-sensitive than the eosinophilic phenotype, severe equine asthma is responsive to steroid treatment despite the presence of neutrophilic inflammation. Severe equine asthma shares the structural remodeling of the airways with human asthma and a part of the remodeling change is reversible with steroid treatment as well as withdrawal from the inciting stimulus. Neutrophilia is correlated with pathological features of the airway in equine asthma (11) whereas its role in human asthma is unclear. In contrast to the field of equine asthma there is a lack of clinical trials addressing key components of airway remodeling in human asthma such as increased airway smooth muscle mass. Thus, there are significant features in common between human and equine asthma although the focus of investigation and the experimental approaches available to both communities of researchers differ and had led to different research emphasis. [...]