Equine asthma (EA) is arguably one of the most common respiratory diseases of modern-day equids and a condition most equine veterinarians are familiar with.

The term “equine asthma” has only been coined in the past decade to describe a syndrome of chronic allergic airway inflammation that varies in clinical presentation, disease severity and, importantly, reversibility. However, while most veterinarians are familiar with the EA terminology, it remains a dynamic and changing topic as we continue to further define the syndrome and come closer to understanding the exact pathophysiology.

Within the EA syndrome are three primary presentations. The more moderate and reversible condition, which can affect horses of any age and typically responds well to treatment, was formerly termed equine inflammatory airway disease (IAD), with the more severe, irreversible conditions known as recurrent airway obstruction (RAO). Summer pasture-associated recurrent airway obstruction (SPRAO) is the third presentation, with both of the latter associated with marked airway inflammation, exercise intolerance and respiratory distress that can be noted at rest.

However, this still leaves a gap between horses with no overt clinical signs of airway disease that perform poorly and have cytological changes suggestive of chronic inflammation and those with mild clinical signs, such as cough and increased mucous. Hence the suggestion to include “mild”, “moderate” and “severe” classifications into the EA spectrum, where previously only mild and severe EA were described.

Based on this newly proposed terminology, mild EA describes those horses with no discernible clinical signs to link poor performance with airway disease, moderate EA describes those with mild clinical signs only during exercise (formerly classified as mild EA) and severe EA describes horses with clinical signs of airway disease at rest as well as during exercise¹.

Importantly, while a spectrum of disease is noted, EA does not necessarily represent a continuum of disease in which horses with mild EA will progress to severe EA. In fact, many horses with mild and moderate EA recover completely.

Clinically, horses with EA – irrespective of severity – develop lower airway inflammatory changes that include aberrations to the bronchoalveolar lavage fluid (BALF) leukocyte profile, altered respiratory function and varying degrees of poor performance associated with exercise intolerance.

Respiratory problems

Mild-moderate EA is associated with reduced performance that may be clinical (moderate EA) or sub-clinical (mild EA), reduced exercise tolerance, protracted exercise recovery periods and coughing (moderate EA only). However, it is important to note that these clinical signs, with the exception of coughing in some cases, are only evident during exercise^2-4. While auscultation abnormalities rarely feature, the use of a rebreathing bag may induce a cough and/or increased bronchovesicular sounds and subtle wheezes in some horses with moderate EA⁴.

Regardless of the clinical signs exhibited in an individual case, EA diagnosis in a clinical setting is based on the presence of increased tracheobronchial mucous on endoscopy and aberration in the BALF leukocyte profile characterised by increase in any or all of neutrophils, eosinophils and metachromatic cells. In addition to these findings, systemic infection should be ruled out⁴. Phenotypically, various forms of mild-moderate EA are typically seen, with increased mast cell and/or eosinophil counts more commonly seen in young horses, associated with airway hyperresponsiveness and increased interleukin (IL) 4 and IL-5. This compares with neutrophilic forms more typically affecting older horses (aged older than seven years) and commonly associated with cough, increased tracheal mucous, and expression of IL-17 and IL-23 in the BALF⁴.

In contrast to the reversible form of EA, severe EA is an irreversible inflammatory condition more commonly affecting horses older than seven years of age, although clinical remission can occur and should be the treatment goal^4-6. It is associated with exercise intolerance, chronic coughing and an exaggerated respiratory effort, including at rest, due to chronic inflammatory remodelling within the distal airways.

More specifically, bronchiolar collapse occurs secondary to pulmonary remodelling and fibrosis, and leads to air trapping and hyperinflation within the alveoli; hence, respiratory efforts are typically more pronounced on expiration than inspiration.

Likewise, crackles and wheezes may be identified on auscultation in affected horses^3,4,7. Importantly, it is the airway remodelling and fibrosis that results in the irreversibility of severe EA, hence the importance of early intervention to reduce the occurrence of permanent inflammatory change that occurs with both severity and chronicity.

Diagnosis of all forms of EA is based on clinical signs (or absence of non-respiratory causes of poor performance in horses with mild EA), clinical history – including exposure to aeroallergens, such as stable bedding or dusty hay, versus pasture-kept horses in SPRAO – and the cytological profile of the BALF. While the approach to performing a bronchoalveolar lavage (BAL) varies among clinicians, a diagnosis of mild-moderate EA or IAD is considered appropriate if BALF cytology shows greater than10 per cent neutrophils, greater than 5 per cent mast cells and/or lower than 5 per cent eosinophils. In contrast, horses with severe EA or RAO typically have a BALF cytology neutrophil count of greater than 25 per cent. An exception to the use of this value as a pseudo “cut-off” for differentiating between mild-moderate and severe EA would be cases of severe EA that are in remission, as BALF cytology values might drop below 25 per cent neutrophils during these periods⁸. The distinction between SPRAO and severe EA/RAO is based on history, housing and temporal factors.

Although arguably less common than the more typical forms of severe EA, SPRAO is a severe, but reversible, form of EA that occurs during warm weather and can be associated with humid climates (common form of SPRAO seen in North America) or dry and dusty periods associated with harvesting of crops or stubble burning (common form of SPRAO seen in the UK)¹.

Altering the environment (that is, isolating the horse from pasture in a stable) typically results in rapid improvement in clinical signs and this response helps to differentiate SPRAO from other forms of EA.

What causes EA forms?

EA is an immune-mediated inflammatory response to exposure to aeroallergens. But why do these horses develop inflammation within the lower airways in the first place? Despite extensive research into this area, debate as to the underlying cause is still taking place. It is well accepted that organic material, such as bacterial and fungal endotoxins and exotoxins, dust mites and ammonia (among other particulate matter present in the respirable zone within stables), effectively induce a predominantly neutrophilic inflammatory response, with migration of neutrophils into the airway lumen within hours of stimulation⁹.

As with other respiratory conditions, neutrophilic inflammation can be detrimental – even pro-inflammatory – when recruitment becomes dysregulated⁹. Hence, these aeroallergens are almost undeniably involved, at least in part, in inciting neutrophilic inflammation in stabled horses^2,10, likely also alongside genetic factors¹¹.

The exact cascade that leads from exposure to the development of EA continues to be investigated; however, components of both type-I and type-2 hypersensitivities feature in the disease process, with both type-1 and type-2 cytokines expressed by affected horses, depending on their stage of disease and chronicity of inflammation⁹.

Irrespective of the sequence of events, the end result of mild-moderate EA is altered respiratory function – including airway hyperresponsiveness, lower airway obstruction and impaired gas exchange with exercise-induced hypoxaemia⁴ – while severe EA is associated with mucous secretion and accumulation, bronchoconstriction and bronchiolitis that results in airway remodelling with chronicity^1,12. Consequently, this progressive airway remodelling, which occurs in both peripheral and central airways¹, results in the development of reduced pulmonary compliance and fibrosis. This is irreversible, hence the importance of early intervention prior to this stage.

However, a debate exists that viral respiratory diseases may act as a trigger for EA¹, as occurs in humans with asthma. While this has yet to be substantiated, initial studies have shown an association between EA and equine rhinitis A virus, as well as equine herpes virus-2 nasal shedding¹³, suggesting further investigation into the potential role of these viruses in inducing or exacerbating EA is warranted.

Despite these findings, it is important to note the association does not equate to causation⁴, and further work is required to determine whether this association is incidental.

Irrespective, neutrophilic inflammation and excessive mucous production is the most common response, and while these cells are important as first-line responders, they can also cause tissue damage themselves via release of reactive oxygen species and neutrophil extracellular traps – particularly when the neutrophilic response becomes dysregulated as previously mentioned – resulting in bronchoconstriction, pulmonary remodelling and hypersecretion of mucous^9,10.

Horses with severe EA typically have increased airway smooth muscle mass, and accumulation of collagen and elastic fibre within the lamina propria of the peripheral airways¹. Consequently, it is important to control neutrophilic inflammation early in the disease process before irreversible damage occurs.

The pathophysiology of development of SPRAO has been less well classified and is still under investigation, with specific pasture-associated agents yet to be identified. However, it is thought that grass pollens elicit a Th2 response and this, along with chronic exposure to sensitising antigens, results in a Th17 response and neutrophilic inflammation, although this chronic neutrophilic inflammation can also be replicated with fungal asthma models, supporting a biotropic pasture-fungi relationship as the inciting cause¹.

However, as with other forms of EA, irrespective of the inciting allergen, it is the inflammatory response that results in the clinical disease, as described previously.

Innovations in treatment

While environmental management is undoubtedly the cornerstone of effective management and long-term control of EA, it alone is often not sufficient to induce remission during exacerbations of EA. As such, therapeutic interventions are often necessary to bring the inflammation under control.

The use of dietary supplementation, such as omega-3 polyunsaturated fatty acids, has been suggested to be of benefit in horses with lower airway inflammation when used in conjunction with environmental management⁵. However, in the author’s experience, dietary manipulations and supplementations alone are insufficient to manage acute exacerbations of asthma. As such, treatment with corticosteroids and bronchodilators should be considered the treatment of choice in cases of EA.

Systemic administration of corticosteroids, such as dexamethasone or prednisolone, remains the most effective treatment for acute exacerbations of severe EA^2,14. However, long-term treatment with systemic corticosteroids is not without risk due to the immunosuppression associated with this treatment, as well as the anecdotal risk of laminitis. As such, an initial treatment period for systemic corticosteroids of two to four weeks with or without tapering of the dose², followed by switching to inhaled corticosteroid therapy as soon as possible, is encouraged^15,16.

A meta-analysis performed in 2018 concluded corticosteroids effectively improve EA irrespective of the route of administration (systemic versus inhaled). However, a difference was seen in the rate of response, with systemic administration resulting in a more rapid response¹⁴, hence the recommendation for systemic administration in the short term. The most common inhaled treatments include nebulised dexamethasone and inhaled fluticasone via metered dose inhalers, and these are arguably the most critical therapeutic component of long-term control – particularly of severe EA.

One study investigating the efficacy of nebulised dexamethasone showed that both systemically administered and nebulised dexamethasone induced a reduction in neutrophil percentage of BALF, while the nebulised dexamethasone had the added advantage of not inducing suppression of the hypothalamic pituitary adrenal axis due to minimal systemic bioavailability¹⁵. The nebulised dose used in this study was 0.01mg/kg, which is lower than the typical systemic dose of 0.05mg/kg dexamethasone.

Another study found that both systemic dexamethasone and inhaled fluticasone resulted in reduced airway hypersensitivity and hyperreactivity after a two-week course. However, effects on BALF cytology were minimal¹⁷, and the residual effect of treatment beyond three weeks of discontinuation was minimal to none¹⁷. Irrespective, management with inhaled corticosteroids is preferable and effective in many cases – once the acute exacerbation has been controlled.

Bronchodilators have long been used in the treatment of EA – often alongside corticosteroids – and these drugs are indicated initially in the management of asthma, both to facilitate delivery of drug to the distal airways during inhalational therapy and to improve ventilation in the lower airways.

Indeed, during acute and severe exacerbations, bronchodilators play a critical role as rescue therapy to rapidly induce bronchodilation. In this scenario, treatments such as N-butylscopalamine and atropine are appropriate choices, with effects noted within five minutes of parenteral administration, albeit with a short half-life^2,6.

These treatments are directed at relieving bronchospasm, and in doing so enable resolution of bronchoconstriction and facilitating lower airway clearance of mucous plugs and obstruction². Once initial rescue therapy has been implemented, more appropriate bronchodilators for short-term use (two to four weeks) would include β2-agonists, such as salbutamol and clenbuterol. However, response to treatment may become refractory with sole therapy and/or prolonged treatment with bronchodilators¹⁸, and as such their use is most appropriate during the first two to four weeks of treatment – and should be in conjunction with both corticosteroid treatment and environmental management.

A new product to the market (Aservo EquiHaler; Boehringer Ingelheim) that delivers ciclesonide, a potent corticosteroid to the lower airways with minimal systemic absorption, has shown good results in the management of EA. Ciclesonide is a pro-drug for des-ciclesonide, which is activated on contact with the respiratory epithelium and has a high affinity for glucocorticoid receptors. Anecdotally, the reports on this product are good, although – as with other treatments for EA – multiple courses are often required to control EA.

Frustratingly, while the Aservo EquiHaler delivers a soft mist that is considered superior for delivery to the lower airways, the spacer is unable to be reused or used with other medications, and as such the whole unit must be purchased for each treatment course. As this product has only been released for around six months, its efficacy in large numbers of clinical cases remains to be seen.

Some evidence in preliminary studies suggests that immunomodulatory inhalation therapies, such as cytosine-phosphate-guanosine oligodeoxynucleotides delivered via gelatine nanoparticles to the airways, may help to reduce airway inflammation via activation of regulatory T cells and restoration of T helper cell balance¹⁹. However, further work is required before this becomes a clinically applicable and available treatment.

Diagnosis

The initial step in diagnosing EA is recognition of the clinical signs. Early recognition is the key to a good outcome, as it enables early implementation of treatment and management changes prior to the occurrence of airway remodelling. Arguably, severe EA is more easily recognised; however, education of owners to consider respiratory disease in horses with subtle poor performance may help to encourage early diagnosis.

The 2019 Havemeyer Workshop suggested that, as a minimum database for diagnosis of EA, practitioners should have a good history (it is often sufficient to have a good index of suspicion of EA, particularly in more severe cases). It also suggested to apply the 23-point modified clinical score to differentiate mild, moderate and severe cases; the use of bronchodilation as a diagnostic test in severe cases may also be helpful; and, importantly, a BAL or tracheal wash (TW) be performed. Bronchial biopsies, radiography and ultrasonography were not considered part of a minimum database for diagnosis of EA¹.

The diagnostic test with the highest sensitivity and specificity for identification of EA is cytological evaluation of BALF, and as such this should be the diagnostic test of choice for confirmation of EA^2,8,20,21. In addition, endoscopic evaluation of TW and bacterial culture of TW samples can also assist in both the diagnosis/grading of EA and identification of concurrent opportunistic bacterial tracheitis respectively, the latter of which can influence response to treatment of EA.

Despite the superiority of BALF cytology over TW cytology for diagnosis of EA, a reluctance to perform BAL in field settings continues among some clinicians. While neutrophilic inflammation may be adequately identified in tracheal secretions, it is unlikely that metachromatic cases will be identified given the rarity of mast cells within tracheal secretions²².

In cases of infectious lung disease, such as pneumonia, a TW is considered the most appropriate diagnostic test as the disease process typically affects a focal segment of lung – the secretions of which will eventually be delivered to the trachea to be coughed up, for example.

As a BAL samples the airway distal to the bronchus the tube lodges in (typically, this is the right caudal lung lobe when passed blindly), the cytological picture of this sample may not be representative of the infectious lung disease if that segment is unaffected. However, in contrast, EA is typically a diffuse disease, and as such, the cytological profile from BALF correlates most accurately²³.

Occasionally, in horses with severe EA a neutrophil percentage lower than 20 per cent may be seen, and is likely reflective of paucigranulocytic asthma²³ whereby the tissue inflammation is marked – in the absence of marked luminal accumulation of inflammatory cells.

The “hay challenge” has been discussed and used in research settings as a form of bronchoprovocation for diagnosis of severe EA; however, it is not an acceptable method of identifying airflow variability in clinical cases, and instead, the response to bronchodilation should be used¹. This typically involves administration of N-butylscopalamine or atropine systemically, or alternatively inhaled salbutamol or albuterol.

Contrary to other airway disease, administration of bronchodilators to horses with severe EA often results in rapid improvement in respiratory effort that is visible to the clinician, although in some cases pulmonary function testing may be required to identify this.

Additional methods of diagnosis have also been evaluated, such as identification of allergen-specific immunoglobulins (specifically IgE) in serum. In theory, this technique enables tailored immunotherapy to the specific allergen in an individual case²⁴. However, such assays currently remain ancillary tests and do not replace cytological evaluation of BALF in the diagnosis of EA. Of interest, though, the identification of latex as a potentially detrimental substance to airway health in one study warrants further investigation²⁴.

Exhaled breath condensate has also been investigated as a potential diagnostic tool to identify markers of lower airway inflammation^25,26, although – in the author’s experience – the procedure of collecting exhaled breath condensate is more arduous than performing a BAL and, as such, unless proven to be far superior this method of diagnosis is unlikely to be widely performed.

Prevention

Unfortunately, EA cannot always be prevented, and in those predisposed animals vigilant management of the environment and early treatment of episodes or “flare-ups” is critical to reducing the risk of progression to severe EA.

As no practical way of identifying predisposed individuals prior to the development of EA exists, it is prudent to encourage implementation of environmental and feeding practices that reduce the exposure to respirable aeroallergens, irrespective of the presence of current cases of EA at the time. This is arguably of benefit to the well-being of all equids, regardless of whether predisposed to EA.

As such, the mainstay of prevention is ensuring horses are exposed to minimal amounts of dust in their environment, which requires ensuring good ventilation to the stable/barn, provision of low-dust stable bedding, low-dust feeds or dampening feeds to reduce aerosolisation of any dust present and working horses on a low-dust surface or not directly behind other horses.

Additional practices that can help with reducing exposure to aeroallergens include removing the horse from the stable prior to mucking out/turning over the stable, spraying the bedding down with water twice daily to settle dust during periods of hot weather, steaming hay to reduce dust within the feed and wetting feed down.

Importantly, feed should always be provided from the ground so that dust from the process of eating/pulling apart hay (this is often inevitable, even with high-quality hay unless the hay is wet) is not wafted into the respirable zone. While not always possible or practical, particularly during inclement weather, housing horses on pasture rather than in stables is the best means of reducing their exposure to aeroallergens, unless they suffer from SPRAO.

Preventing exposure to inciting pastures during periods of warm weather is also important in SPRAO and is most effectively achieved by stabling, contrary to other forms of EA¹.

Some evidence suggests management of comorbidities, such as obesity and insulin dysregulation, may influence the risk of developing EA and/or the severity of EA. A direct link between obesity and EA has not currently been established. However, the direct influence of obesity on respiratory physiology is well understood, with both increased work of respiration and an increase in the demand for ventilation²⁷.

Arguably we should consider management of these important comorbidities equally critical, regardless of their influence on EA. However, as evidence exists that obesity and insulin dysregulation result in an increased risk of development of asthma in people, it is likely a similar link may be identified in horses in time²⁷.

Conclusion

EA is an important cause of morbidity and mortality in horses worldwide, and while gaps in our knowledge of this condition remain, research into the topic is ongoing and our understanding of the condition continues to grow.

Irrespective of the severity of disease, the take-home messages remain focused on improving the environment to reduce exposure to aeroallergens. While this is critical for horses that already suffer from EA, it should be the goal of all equine environments, irrespective of whether they have previously suffered from EA.

However, during periods of acute exacerbation, therapeutic interventions are likely to be required and corticosteroids remain the most effective means of controlling lower airway inflammation.