Equine asthma (previously called inflammatory airway disease, recurrent airway obstruction or heaves) is an endemic condition in horses and is characterised by non-septic airway inflammation and hyper-reactivity leading to increased mucus production, secretions and a chronic cough, causing poor health and performance (Couëtil et al, 2020). Equine asthma is a global disease that can occur in all climates with increased risk associated with high levels of ambient pollens and moulds, such as in the south of the USA. Equine asthma encompasses a spectrum of clinical presentations from mild to severe, although it is unclear whether the pathogenesis of disease differs between severity levels, and can be a major cause of poor performance (Ivester et al, 2018) and poor quality of life. Mild asthma mostly encompasses the occasional cough (mostly at exercise) with normal breathing at rest, while severe asthma can cause debilitating disease at rest with increases in both respiratory rate and effort, and all forms of equine asthma are the result of a chronic condition lasting from weeks to months, often presenting as a recurrent problem (Couëtil et al, 2020). While treatment with glucocorticosteroids is the most common and reliable pharmaceutical approach to equine asthma, it can be associated with significant systemic side effects and endocrine-related morbidity in at-risk horses (Bailey, 2010). There is a need for the development of new, efficacious treatments of equine asthma because of these deleterious side effects, and current research is heavily focused on novel therapies.
Asthma pathophysiology
Equine asthma is characterised by airway inflammation and hyper-reactivity with a combined environmental and immunological aetiology. The lower airways are exposed to a triggering agent, such as dust, mould spores or other particulates, such as the moulds and pollens found in summer pastures, and, while the response is not necessarily allergic, there is a response by the immune system that results in airway dysfunction (Couëtil et al, 2020). Inflammatory components of equine asthma are likely related to a combination of both the innate and adaptive immune system. Neutrophilic release of pro-inflammatory mediators such as interleukin-8 and −17, neutrophil elastase, reactive oxygen species and neutrophil extracellular traps likely contribute to the bronchoconstriction, mucus hypersecretion and overall pulmonary remodelling that is clinically seen (Couëtil et al, 2020). There is evidence of a Th-1 response with the upregulation of IFN-γ in bronchoalveolar lavage fluid in association with increased inflammatory cells and clinical signs of equine asthma (Hughes et al, 2011; Lavoie et al, 2011; Richard et al, 2014).
Neutrophilic asthma has shown evidence for a Th-17 response with increased interleukin-17 and interleukin-23 expression (Hughes et al, 2011; Beekman et al, 2012). Conversely, a Th-2 response has been detected in mastocytic forms of equine asthma with evidence of increased expression of interleukin-4 and inter-leukin-5, which immunologically closely relates to human ‘allergic’ asthma phenotypes (Lavoie et al, 2011; Beekman et al, 2012). At the more severe end of the spectrum (such as horses with severe equine asthma, or ‘heaves’), pathology includes increased numbers of goblet cells with increased mucus production, and hyperplasia of airway smooth muscle and epithelial tissue along with increased amounts of fibrous tissue (Couëtil et al, 2016). Airway changes have been identified in mild to severe forms of equine asthma; as smaller airways become thickened and narrower, there is increased resistance to airflow in and out of the lungs (Couëtil et al, 2016; Dupuis-Dowd and Lavoie, 2022). These changes are reflected in the clinical signs of wheezing and a decreased ability for adequate airflow during exercise, leading to coughing. Nasal discharge is a common symptom of equine asthma, but its specific characteristics vary between affected horses. Repetitive exposure to the triggering agents causes chronic inflammation of the airway which leads to remodelling, causing irreversible, severe damage (Couëtil et al, 2016; 2020). Recent exploration into the respiratory microbiome in human healthcare literature and its association with several chronic inflammatory airway conditions has led to studies investigating the respiratory microbiome of horses and the changes associated with equine asthma. Evaluation of the respiratory microbiome indicates a unique challenge because of the relatively low biomass of the lower airways, with only one study to date evaluating bronchoalveolar lavage fluid (Fillion-Bertrand et al, 2019); the majority of studies have evaluated nasal and tracheal changes in the microbiota (Bond et al, 2017; Fillion-Bertrand et al, 2019; Bond et al, 2020). All studies identified that significantly different bacterial communities (through evaluation of Bray-Curtis dissimilarity) were present in nasal and tracheal samples of healthy horses and those with mild asthma (Bond et al, 2017).
There is evidence of a dynamic relationship between the upper and lower respiratory tract, as well as between the respiratory tract and the environment, and additional divergences noted between diseased and healthy horses (Fillion-Bertrand et al, 2019). Interestingly, Streptococcus zooepidemicus, a commensal bacteria of the upper respiratory tract, showed an increased relative abundance in mild equine asthma (Bond et al, 2017; Fillion-Bertrand et al, 2019) and positive culture (along with Pasturellaceae spp.) was associated with an increased clinical and tracheal mucus score and airway neutrophilia (Manguin et al, 2020). Microbiological changes are not only restricted to bacteria, as fungal presence in tracheal wash samples (with a positive culture in 55% of horses) was significantly associated with the development of equine asthma (twice greater odds), and the odds of fungi identification was increased with straw bedding and the feeding of dry hay (Dauvillier et al, 2019). However, the specific relationship between equine asthma and changes in the microbiome have yet to be elucidated.
Treatment
Management
Environmental management is the mainstay of treatment for equine asthma and should always be implemented in any treatment protocol. Pharmaceuticals such as glucocorticosteroids are additional therapies to reduce active inflammation or flare-up of clinical signs, but changing the horse's environment is crucial to the reduction of potential triggers, and therefore, the inciting cause of the disease. It is important to note that equine asthma is a manageable, not curable, disease as complete removal of any future exposure to the allergen is impossible.
Turn out for larger portions of the day, or permanent turnout is ideal for horses (unless there is a known summer pasture association). Stabled horses are exposed to an increased amount of dust and debris from feed and bedding, and stables that inherently have reduced ventilation. Limiting overall exposure to dust is essential, especially in arenas and during stable cleaning. Horses should not be present during, and for at least a few hours after, stable cleaning. They should be housed in the most well-ventilated locations (often end stables) and not be housed near hay storage areas or near an indoor arena. Soaking hay will reduce both direct and indirect exposure to particulates associated with hay dust and feeding horses on the ground can be helpful to facilitate the clearance of mucus from their airways.
In contrast, summer-associated equine asthma is linked with horses grazing pasture in hot and humid climates (such as the USA) and hot, dry weather or exposure to dust or crop burning (Couëtil et al, 2020). Management is highly dependent on environmental factors, such as removal from suspected triggering pasture during the warmer seasons.
While environmental management is essential to any equine asthma treatment regimen in reducing exposure to the triggering factors, treatment with glucocorticoids is often necessary to allow a horse to enter remission, as the inflammatory reaction within the lungs has already occurred.
Glucocorticosteroids
Glucocorticosteroids have been the main pharmaceutical therapeutic treatment of asthma in horses since the late 1960s, and are still considered the most effective treatment for severe equine asthma (Couëtil et al, 2020). Glucocorticosteroids directly modulate the gene transcription associated with inflammation, and also have a direct effect in decreasing inflammation, reducing airway smooth muscle contraction and modulating the production of radical oxygen species which are associated with inflammation (Trevor and Deshane, 2014). In cases of mild equine asthma, inhaled steroids can be useful to reduce the amount of systemic corticosteroid the horse is exposed to and reduce the risk of side effects associated with systemic absorption (Mainguy-Seers and Lavoie, 2021). However, when severe inflammation is present, inhaled drugs may be less effective as delivery is inherently poor, and therefore there is a need for systemic (oral, intravenous or intramuscular) treatment. Additionally, in severe cases, nebulisation of corticosteroids has been shown to cause hypothalamic–pituitary–adrenal axis suppression and indicates systemic absorption (Mainguy-Seers and Lavoie, 2021).
Dexamethasone is the most commonly used steroid for the treatment of severe inflammatory and immune conditions including asthma, and has been used orally, intravenously, intramuscularly and through nebulisation (inhaled routes). Studies have shown conflicting data on whether inhaled dexamethasone can cause systemic suppression of the hypothalamic–pituitary axis, which is seen with other routes of steroid administration, but overall data indicate reduced systemic effects following nebulisation (de Wasseige et al, 2021; Mainguy-Seers and Lavoie, 2021). When comparing healthy and severely asthmatic horses, nebulised dexamethasone was shown to suppress the hypothalamic–pituitary axis in horses with severe asthma but have no effect in healthy horses. This is postulated to be as a result of the breakdown in the normal pulmonary epithelial barriers (Mainguy-Seers and Lavoie, 2021). Nebulisation of injectable dexamethasone sodium phosphate did not induce airway inflammation and had minimal systemic bioavailability (likely as a result of absorption happening only within the upper airways) in healthy horses; however, coughing was has been noted in some studies, suggestive of irritation in severely asthmatic horses, nor did the nebulised dexamethasone sodium phosphate improve pulmonary mechanics (Haspel et al, 2018; Mainguy-Seers et al, 2019). When studies have compared oral dexamethasone to nebulised dexamethasone, there is no advantage to giving inhaled dexamethasone compared to oral – however, this is not necessarily the case for other steroids (Mainguy-Seers et al, 2019). Additional research into not only the effectiveness but also the safety of nebulisation of injectable dexamethasone in asthmatic horses is needed.
Several glucocorticosteroids have been designed specifically for inhalation therapy, including budesonide and ciclesonide. What makes these different to glucocorticosteroids designed for systemic use is that they target the lung tissue specifically and have a much reduced ability to cross the blood–bronchial barrier. Multiple studies have shown improvement in patient lung function testing, but not necessarily airway cytology, and low doses spared hypothalamic–pituitary axis function (Couëtil et al, 2006; Haspel et al, 2018; Lavoie et al, 2019a; Bond et al, 2020). Ciclesonide (Aservo) is currently the only inhaled steroid that is not associated with hypothalamic–pituitary axis suppression, and improves lung function testing and clinical signs. It has been associated with improvement in owner quality of life assessments compared to a placebo (with the caveat that 50% of the placebo horses also displayed treatment success) (Lavoie et al, 2019b; Pirie et al, 2021).
Overall, glucocorticosteroids have been reliable in reducing clinical signs, with or without improvement in diagnostic testing (including lung function and airway cytology), but have a variable systemic effect on the hypothalamic–pituitary axis and therefore, variable risks for unwanted systemic side effects.
Bronchodilators
Bronchodilators are often used in conjunction with glucocorticosteroids (systemic or inhaled), and are particularly useful during episodes of acute exacerbation, where they have been shown to improve lung mechanics. Muscarinic agonists (parasympatholytic) such as N-butyl-scopolamine bromide (Buscopan), atropine and ipratropium block smooth muscle constriction, inducing bronchodilation. Ipratropium is poorly absorbed within the respiratory tract, minimising systemic effects (which are often associated with atropine), and it exhibits an effect within 30 minutes and lasts 4–6 hours with improved lung mechanics at rest but minimal improvement during exercise (Murphy et al, 1980; Pearson and Riebold, 1989; Robinson et al, 1993; Bayly et al, 2002; de Lagarde et al, 2014).
Buscopan has caused improvement in clinical and pulmonary function testing within 10 minutes (with a duration of 30–60 minutes) with no adverse side effects (Couëtil et al, 2012; de Lagarde et al, 2014). β2-adrenergic agonists produce smooth muscle relaxation of bronchioles, and aerosolised treatment permits direct delivery and reduction of unfavourable side effects. Albuterol sulfate improves pulmonary function by 60–70% but requires frequent administration, and is often used in rescue protocols (Derksen et al, 1999; Arroyo et al, 2016). Clenbuterol has historically been used; however, this is no longer advised as a result of the increased risk of cardiovascular remodelling which has been shown in horses, as well as evidence of tachyphylaxis with prolonged treatment which has not been noted with albuterol (Erichsen et al, 1994; Sleeper et al, 2002; Thompson et al, 2011; Mazan et al, 2014).
Nebulised lidocaine
Lidocaine is an amide derivative that aids in blocking sodium channels and is primarily used as a local anaesthetic, anti-arrhyth-mic and gastrointestinal prokinetic. In humans, topical lidocaine used for aid of respiratory sampling in studies was found to have immunomodulatory effects, similar to the patterns shown in glucocorticosteroids in the lower airways (Ohnishi et al, 1996). Since its discovery, it has shown similar efficacy to inhaled beclomethasone (an inhaled steroid) and bronchodilators at suppressing coughing in humans (Chong et al, 2005; Honarmand and Safavi, 2008). Lidocaine is well suited for nebulisation as a result of favourable properties such as osmolality and droplet size (Cohen et al, 2011). Safety studies in humans showed that local drug delivery reduces the risk of systemic side effects with only mild, and self-limiting, adverse effects including an unpleasant taste and oral irritation (Lim et al, 2013). However, it is important to note that a reflex bronchoconstriction has been observed in a subset of humans with reactive airways, the effects of which were minimised with bronchodilators and overall showed little clinical significance (Lv et al, 2011).
Recent evaluation of nebulised lidocaine shows potential for the treatment of equine asthma. Nebulisation of preservative-free (4%) lidocaine has been shown to be safe for administration in clinically asthmatic horses, and an efficacy study in adult horses with equine asthma over a 2-week trial period comparing lidocaine to budesonide showed improved clinical and tracheal mucus scoring and bronchoalveolar lavage neutrophil numbers, but no improvement in baseline lung function testing (Mahalingam-Dhingra et al, 2022). Evaluation of the pharmacokinetics of nebulised lidocaine in healthy horses showed no immediate adverse effects or effect on airway sensitivity (Minuto et al, 2022). Lidocaine reached a therapeutic concentration in the lower airways but showed no immediate impact on lower airway cytology in healthy horses (Minuto et al, 2022). It is interesting to note that Mahalingam-Dhingra et al (2022) indicated a poor response to nebulised saline in two control horses with noted exacerbation in clinical disease. Anecdotally, current research evaluating preservative-containing lidocaine compared to nebulised saline (as a control) in healthy, non-asthmatic horses has shown no adverse effects following treatment. In human asthma, hypertonic (3%) saline has been shown to be a promising short-term therapy for adults with asthma (Forouzan et al, 2017). Therefore, saline nebulisation may itself pose as a promising area of further study.
Research is currently being undertaken for the evaluation of the safety of preservative-containing (2%) lidocaine, which is more readily accessible, as well as its short-term effects on pulmonary function testing and bronchoalveolar lavage cytology, and its effects on airway immunomodulation of anti-inflammatory and inflammatory cytokines.
Other emerging therapies
Immunomodulation therapies are growing in popularity and equine asthma is no exception. Studies have evaluated the administration of autologous (self) mesenchymal stem cells for the treatment of severe equine asthma with the rationale of anti-in-flammatory effects mediated directly through cytokine regulation (Adamič et al, 2022). A randomised, controlled, blinded field study compared horses with severe equine asthma who received 100 million mesenchymal stem calls endoscopically delivered to the right accessory lobe, or a tapering dose of dexamethasone. Horses who received the mesenchymal stem cells showed a decrease in clinical score and pro-inflammatory cytokines (interleukin-1β, interleukin-4 and TNFα), and an improvement in pulmonary function, consistent with a modest improvement that was not inferior to the effect of treatment with corticosteroids at 3 weeks. Long term outcomes showed fewer exacerbations over the one year follow up period compared to corticosteroids (Adamič et al, 2022).
Inhaled nanoparticle-bound cytosine phosphate-guanosine immunotherapy has been shown to cause a reduction in the Th-2 immune response and activation of T-regulatory cells in humans (Barton et al, 2019). This therapy assumes that a Th-2 response is associated with equine asthma, and studies showed that inhaled cytosine phosphate-guanosine may be an effective non-glucocor-ticoid therapy for equine asthma; however, commercial products are not currently available (Klier et al, 2019). Further studies evaluating allergic (Th-2) and non-allergic (non-Th-2) phenotypes within equine asthma, like phenotypic variation within human asthma (Bond et al, 2018), and investigation regarding the roles of allergens and triggers of the immune system is necessary before instigation of specific immunological target treatments.
Tamoxifen is a selective oestrogen receptor modulator that reduced neutrophil chemotactic response and neutrophil death (apoptosis), and was therefore theoretically expected to decrease airway neutrophilia (Mainguy-Seers et al, 2018). However, there were no clinically significant changes in pulmonary function testing and bronchoalveolar lavage cytology, and dexamethasone remained superior in normalising lung function but not cytologic neutrophilia (Mainguy-Seers et al, 2018).
Future immunologic targets for the treatment of equine asthma include myristoylated alanine rich C kinase substrate protein, which has shown to be altered in naturally occurring asthma in horses (Davis and Sheats, 2020) and monoclonal antibodies, for example targeting interleukin-6 (Calzetta et al, 2022). Immunomodulation is at the forefront of several proposed therapeutic strategies in human and veterinary medicine; however, much more research is needed for its use in the treatment of equine asthma.
Conclusions
The mainstay of treatment for equine asthma remains a combination of environmental remediation for prevention, systemic and inhaled glucocorticosteroids to decrease inflammation and bronchodilators to temporarily reverse bronchospasm. Glucocorticosteroids have important deleterious side effects and there is a dire need for alternative therapies that are effective at controlling the disease, reducing exacerbation and repeat episodes. Nebulised lidocaine is one of the newest therapeutics in equine asthma that holds promise for management of the disease and avoidance of glucocorticosteroids and their side effects. Immunomodulatory therapy also holds promise and further research is necessary in both areas, and gives hope for new, safer therapies for the treatment of horses with this possibly progressive and debilitating disease.
KEY POINTS
- Equine asthma is an endemic condition characterised by non-infectious airway inflammation leading to chronic poor performance and poor health.
- Glucocorticosteroids remain the mainstay of therapy for treatment of equine asthma. However, they are associated with significant systemic side effects and endocrine-related morbidity in at-risk horses.
- Nebulised lidocaine holds promise for the treatment of equine asthma, and studies have shown safety for use in horses and promising results for improvement in clinical signs.
- Immunomodulatory therapies are emerging for the treatment of equine asthma; however, more research is necessary for application in equine asthma.