Table 1.

Features of asthma phenotypes in humans and IAD/RAO in horses, appropriateness of equine asthma model, and areas identified for future research

Asthma phenotype	Features in humans	Features supporting phenotype model in horses	Equine model appropriate?	Areas identified for future equine research
Allergic asthma	Allergenic trigger associated with respiratory symptoms/expiratory airflow limitation Often commences in childhood Past/family history of allergic disease (eczema/allergic rhinitis/food or drug allergy) Sputum often reveals eosinophilic airway inflammation Usually respond well to ICS treatment Th‐2 CD4+ lymphocyte response—IL‐5–mediated eosinophil recruitment IL4Rα gene associated with the development of asthma, skin allergies and parasite defense	IAD Antigenic triggers central to development of lower airway inflammation Stabling exposes horses to high levels of airborne particulates (eg, dust, endotoxin, fungi, molds, ultrafine particles, noxious gases), and is a risk factor for IAD Antigenic triggers (eg, dust, mold spores) associated with increased neutrophil/mast cell% in BALF Antigenic triggers associated with clinical signs (eg, coughing, poor performance) Often occurs in young horses Eosinophilic phenotype associated with dust exposure in young horses Usually respond well to ICS treatment Th‐2 response—Increase in IL‐4 and IL‐5 in BALF linked with mastocytic phenotype	Yes	Eosinophil involvement in pathogenesis of IAD Effect of BALF phenotype on performance Role of IgE in IAD and RAO Longitudinal and cross‐sectional studies investigating an “atopic march” in horses Comprehensive study investigating the effect of various allergenic triggers on both lower airway pathology and clinical signs (ie, investigate causality rather than association)
		RAO Allergenic trigger (molds ± LPS) associated with clinical signs and pathology (increased neutrophil % in BALF, increased respiratory effort at rest) Associated with multiple hypersensitivities in some families of horses (insect bite hypersensitivity, urticaria, increased parasite resistance) Good response to ICS Association between IL4Rα and RAO IL4Rα upregulates IL‐4 expression during disease exacerbation, which promotes isotype switching from IgM to IgE Increased IgE in BALF in horses with RAO	Yes
Non‐allergic asthma	Not associated with allergy Sputum can be neutrophilic eosinophilic or paucigranulocytic Often respond less well to ICS Chronically activated mast cells in bronchial mucosa (can be associated with non‐allergenic stimulus) Th‐1 response—cell‐mediated immunity and phagocyte‐dependent inflammation	IAD BALF can reveal neutrophilia and/or eosinophilia and/or mast cells accumulation Th‐1 response—mRNA encoding TNF‐α, IL‐1β, and IFN‐γ in BALF Th‐17 response—Increase in IL‐17 and IL‐23 linked with increased neutrophil % in BALF Often respond less well to ICS	Yes	Role of neutrophil/mast cell activation in the development of lower airway inflammation
		RAO BALF can be neutrophilic or paucigranulocytic (in severe cases where BALF return is low) Chronic innate immune activation ‐ chronic activation of peripheral neutrophils Often respond less well to ICS	Yes
Late‐onset asthma	Initial presentation as adult (particularly women) Less likely to be atopic Decreased baseline pulmonary function Often refractory to ICS/require higher doses for control	IAD Insufficient evidence	No	Disease progression from IAD to RAO over time Correlation between inflamm‐aging and development of chronic inflammatory airway disease
		RAO Decreased baseline pulmonary function during disease exacerbation Mature/older animals Can require higher doses for control	Yes
Asthma with fixed airflow limitation	Chronic asthma patients with fixed airflow limitation; thought to be because of airway wall remodeling Increased airway smooth muscle mass and extracellular matrix at all levels of bronchial tree Postbronchodilator FEV1 < 70% (predicted)	IAD Insufficient evidence	No	Airway remodeling in IAD Reversibility of airway remodeling in human asthmatics/horses with IAD/horses with RAO; there is limited data studying airway remodeling of the peripheral airways of human asthmatics and reversibility in response to therapy, and limited data available in horses with RAO
		RAO Tissue remodeling is reversible—long‐term antigen avoidance strategies and corticosteroid therapy decrease airway smooth muscle mass and subepithelial collagen area	Insufficient evidence
Asthma in obese patients	Dyspnea on exertion Requires objective measurement of variable airflow limitation—Obesity‐associated respiratory symptoms can mimic asthma Little eosinophilic airway inflammation	Correlation between body condition score and body fat (%) and increased expression of IL‐1 and TNF‐α in plasma	Insufficient evidence	Expression of inflammatory cytokines in BALF or increased pulmonary resistance in obese/equine metabolic syndrome horses

Abbreviations: BALF, bronchoalveolar lavage fluid; FEV₁, forced expiratory volume in 1 s; IAD, inflammatory airway disease; ICS, inhaled corticosteroid; RAO, recurrent airway obstruction, TNF, tumor necrosis factor.