Inflammatory Airway Disease in the Horse

Melissa Mazan

What Is Inflammatory Airway Disease?

Inflammatory airway disease (IAD), small airway inflammatory disease, small airway disease, and allergic airway disease are often used interchangeably, but the once-fluid definition of IAD is slowly taking form.

The prevalence of IAD is somewhat of a guessing game. One study involving 965 Standardbreds in active racing found that 22% had evidence of mucopus at the trachea or bronchial bifurcation when examined endoscopically, although these horses were diagnosed as having chronic obstructive pulmonary disease (COPD); undoubtedly they properly belong in the IAD group.¹³ Similarly, 27% of actively racing Thoroughbreds in one study had IAD.¹⁴ A remarkable 55% of 2-year-old Thoroughbreds in training could be classified as having lower airway disease on the basis of finding mucus in the trachea on endoscopy and inflammation on examination of tracheal aspirate fluid, and abattoir studies have shown that up to 37% of horses have histopathologic evidence of airway inflammation.^15,16 Because a standard definition of IAD has only recently been agreed on, the prevalence of IAD has varied according to the individual researcher’s case definition. Nonseptic airway inflammation, regardless of whether it causes overt signs of respiratory disease, appears to be very common in performance horses. This discussion adheres to the definitions of IAD and RAO as developed by the International Workshop on Equine Chronic Airway Disease and the recent ACVIM consensus statement on IAD.^1,17 With RAO, horses have demonstrable lower airway obstruction, characterized by peak pleural pressures of at least 15 cm H₂O, induced by an environmental challenge of moldy hay, largely reversible by use of a bronchodilator or return to a nonchallenge environment, and accompanied by an increase in BAL fluid neutrophils during challenge. In contrast, IAD refers to a nonseptic airway disease in athletic horses that does not have a clearly defined allergic cause.

■ Clinical Findings Although most investigators agree that IAD is a disease of younger horses expected to do athletic work, and as such is distinct from the picture of the dyspneic horses with overt RAO, there remains a plethora of clinical signs and case definitions for IAD. One of the most common findings in IAD is exercise intolerance, with or without overt signs of respiratory disease. Of 25 horses referred either for routine physical examination or for poor performance, and without any clinical signs or history of respiratory disease, 76% had evidence of airway inflammation according to an inflammation scoring system based on endoscopy and tracheal wash findings.¹⁸ Subclinical airway disease may result simply in mild abnormalities on auscultation and endoscopy, and occasionally in coughing.¹⁹ Signs such as nostril flaring and excessive abdominal effort at rest, however mild, are usually associated with horses that have true RAO, as clinical signs that can be reliably detected using clinical scoring systems usually are accompanied by significant mechanical dysfunction of the respiratory system.²⁰ The prevalence of cough in horses with IAD is difficult to estimate, as many studies use the presence of cough as an inclusion criterion. Other studies have shown that cough may be seen less than 16% to 50% of the time.^21,22 On endoscopic examination, excessive airway mucus is often seen, ranging from multiple specks to streams of mucus.²³ Other clinical signs that are frequently noticed include prolonged respiratory recovery; respiratory embarrassment at exercise; worsening of signs during hot, humid weather; and inability to perform work during collection.

How does IAD affect performance? The answer depends on the use of the horse and the expectations of the owner. A practitioner with a primarily pleasure-horse practice or with show-hunter clientele might report a very low incidence of IAD in younger horses, primarily because the level of exercise in these horses is not likely to force a diagnosis through signs of exercise intolerance. A racetrack practitioner, on the other hand, would be far more likely to detect exercise intolerance resulting from lower airway disease in young horses because the level of expected athletic output is much higher and the horses have a greater likelihood of being examined endoscopi­cally. Indeed, in a National Hunt racing population, excessive mucus was detected endoscopically in 68% of horses,²⁵ and IAD was one of the top two reasons cited for horses not running.²⁶ As might be expected, cough is more common in sport horses than in racehorses, as is an elevated respiratory rate, reflecting the generally earlier diagnosis in racehorses. Indeed, racehorses with excessive tracheal mucus performed at a lower level than those with no mucus found on endoscopic examination.^11,13

Low-grade nonseptic airway inflammation was found to have a negative impact on ventilatory capacity, but this was more pronounced in racehorses. Moreover, using bronchiolar biopsy, this group also demonstrated that oxygen uptake and pulmonary ventilation correlated inversely with the morphologic grade of small airway disease and the height of the bronchiolar epithelium—the last finding suggesting that the extent of 27 obstruction may determine the extent of exercise impairment.²' Racehorses with IAD have impaired gas exchange during exercise.³ However, other studies have found that horses with obvious evidence of airway inflammation do not necessarily have a history of exercise intolerance.²⁸ However, this may reflect the difficulty of diagnosing low-grade respiratory impairment and the trainer’s failure to recognize poorer performance than nature intended, rather than the benign nature of the underlying disease.

■ Diagnosis

BRONCHOALVEOLAR LAVAGE. Varying levels of specificity are used when documenting the presence of airway inflam­mation. The least specific is the documentation of mucus in the trachea, although it is the method that best lends itself to large studies in the field. However, visualization of mucus in the trachea gives little information as to the nature and the exact origin of the inflammation. Many workers have used and continue to use tracheal aspirate cytology to describe the nature of inflammation in IAD. Although tracheal aspiration can be used to explore the presence of inflammation and has been used to document neutrophilia, mastocytosis, and eosinophilia in young performance horses, the question of the nature and exact origin again presents itself.²⁹ Studies have shown poor correlation between tracheal aspiration and BAL cytology in horses.^30,31 Whereas tracheal aspiration harvests primarily neutrophils and epithelial cells, BAL yields primarily alveolar macrophages and lymphocytes in normal horses. Moreover, there is no evidence of correlation between tracheal wash findings and performance. Consequently, to avoid the problem of neutrophil count sensitivity to the collection method, BAL is the best choice for sampling respiratory secretions in horses with IAD.

Different pictures of inflammation emerge from various BAL studies, leading to speculation that different genetic predispositions and environmental exposures are important to the inflammatory phenotype. In comparison with healthy horses, BAL cytology in horses with IAD has shown, variably, neu­trophils, mast cells, eosinophils, or lymphocytes. In general, horses with IAD have airway inflammation that may involve increases in nucleated cells or may also involve lymphocytosis. This is distinguished from RAO by the relatively low percentage of abnormal cells in IAD; whereas horses with RAO may exhibit almost entirely neutrophils in the BAL fluid, horses with IAD seldom have more than 2% to 15% neutrophils.¹ It is prob­lematic that all BALs are not created equal.

Histopathology. a recent study has given us insight into the inflammation that exists in the lower airways even of horses that have not been identified to have respiratory disease.³³ Inflammatory cell infiltrates (primarily CD3+ T cells) and smooth muscle hyperplasia were identified in most of the horses, although epithelial changes were not noted. Bronchiolar biopsies of athletic young horses with lower airway inflammation have shown inflammatory mucosal cellular infiltrates and luminal exudates, bronchiolar hyperplasia, and goblet cell metaplasia.⁸ It is interesting to note that 80% of supposedly normal horses had minimal evidence of peribronchiolitis; this raises the question of what constitutes normal. O’Callaghan, while directing his concern to exercise-induced pulmonary hemor­rhage (EIPH), nevertheless found plentiful evidence of multifo­cal, small airway-centered disease on postmortem examination of young racehorses.³⁴ These findings included thickened walls caused by increased quantities of mucosal and peribronchiolar connective tissue, mononuclear bronchiolar cuffs, and extension of nonciliated bronchiolar epithelial cells into alveolar ducts.³⁴ Lakritz,³⁵ looking at lung tissue of clinically normal, young Thoroughbred horses in training, found evidence of increased collagen, disruption of the epithelial basement membrane, and duplication of the epithelial basement membrane, suggesting previous airway inflammation and epithelial injury, which correlate with an increased interstitial pattern on radiographs. An ultrastructural study of young horses with “mild COPD” in one study found a decreased number of typical Clara cell granules and goblet cell metaplasia before the bronchioles began to show signs of inflammation typical of RAO.³⁶ Although the authors state that there was good correlation between histopathology and the results of a battery of PFTs, auscultation, bronchoscopy, blood gas analysis, and BAL in these horses, it is a lasting disappointment that the results of the ancillary testing remain unpublished. These data, in sum, suggest that the histopathologic lesion of IAD is not only local bronchiolar inflammation but also remodeling and thickening of the bronchioles themselves, which lends itself to at least low-grade airway obstruction.

LUNG FUNCTION TESTING. The esophageal balloon and pneumotach method for measuring lung function tends not to detect airway obstruction even in horses with RAO in remission.³⁷ However, use of the forced oscillatory technique and forced expiratory maneuvers has shown the existence of low-grade obstruction of the small airways of some horses with IAD.^3,38 The mechanical behavior of the respiratory system has been shown to differ with sampling frequencies in asthmatic humans,³⁹ and a pattern of decreasing respiratory system resistance (RSR) with increasing frequency has been termed negative frequency dependence of resistance and has been interpreted as evidence of underlying small airway obstruction despite baseline measurements within the expected range. Similarly, horses with IAD as a group have significantly higher values for RSR at the lower frequencies (1 to 3 Hz) and mild frequency dependence of resistance compared with controls,^40,41 although the baseline measurement of RSR may still frequently fall within the normal range. A study finding that lower oxygen uptake capacity and tidal volume correlated to a reduced diameter of the bronchiolar lumen owing to epithelial hyperplasia is strongly supportive of the existence of airway obstruction in IAD.²⁷ Likewise, lung resistance decreases with increasing minute ventilation in control horses but not in horses with IAD.⁴² Consequently, without dynamic, frequency­dependent tests of lung function, forced maneuvers, or bronchoprovocation, it seems that researchers are simply failing to document a common feature of small airway obstruction in horse with IAD because testing devices are not sufficiently sensitive to these changes.

AIRWAY RESPONSIVENESS. Horses with clinical signs compatible with IAD also exhibit signs of airway hyperrespon­siveness (the threshold at which horses react) and hyperreactivity (the slope, which correlates to the magnitude, of the response) when they are exposed to nonspecific agents such as histamine aerosol. The basis for airway hyperresponsiveness remains hotly debated among pulmonary physiologists. It is likely a multifacto­rial phenomenon that has been associated with airway wall thickening undetectable by conventional lung function testing, airway inflammation, and autonomic nervous system dysfunc­tion.⁴³ There is a paucity of information concerning the mediators of airway hyperresponsiveness in horses with IAD. In our laboratory, horses with a clinical history and signs compatible with IAD have significantly greater airway reactivity than controls, although some control horses display airway hyperresponsiveness (AWHR) as well. A study in Standardbred racehorses with unexplained poor performance or cough showed a discordance in some horses between positive BAL findings and positive airway hyperreactivity,⁴⁴ raising the idea that without testing for AWHR, some horses affected with IAD will be missed. This nonspecific airway hyperresponsiveness has been seen in humans and is associated with a greater risk of eventual development of asthma.⁴⁵ Although nonspecific airway hyperresponsiveness has been noted both in adult horses without signs of respiratory disease and in foals, the significance of this finding remains unclear.

Although radiography can be useful in helping exclude septic causes of lower respiratory tract disease, such as pneumonia, lung abscess, or pleuropneumonia, its sensitivity in IAD is too low for it to be useful for identification of this disease. Moreover, no correlation exists among thoracic radiographs, airway hyperresponsiveness, and BAL cytology.⁴⁶ However, the more frequent finding of a bronchial pattern on thoracic radiographs supports the existence of airway obstruction in these horses.

ENDOSCOPY. Tracheal endoscopy is convenient and easily performed, and lower airway scoring correlates with lower airway inflammation; moreover, particulate levels in the air have been correlated with endoscopically visible mucus in the trachea. Thickening of the septum has been shown to be useful in distinguishing horses with RAO from horses with IAD. The accumulation of mucus in the trachea has been shown to correlate with neutrophil percentages, but there was no such 4749

correlation with thickening of the septum.⁴' ⁴⁹

BIOMARKERS. Although there was no utility found in using the circulating acute phase proteins C-reactive protein, hap­toglobin, or serum amyloid A (SAA) to distinguish IAD from other causes of unexplained poor performance in racehorses,⁵⁰ SAA was found to be useful in distinguishing horses with IAD from those with infectious airway diseases, thus demonstrating the use of SAA in ruling out subclinical infectious disease.⁵¹

■ Etiology No single cause of IAD has been identified, although there has been plentiful speculation about the role of environment, viral disease, infection, air pollution, and genetic predisposition. Although horses with IAD do not seem to experience bouts of overt airway obstruction on exposure to an allergenic environment, organic dust associated with stabling likely contributes to the initial inflammation. Sweeney noted that the racehorses in her study lived in conditions of poor ventilation, and she speculated that covert IAD may be instigated by the organic dusts, especially mold, in hay.⁵² Others have noted that there is more mucopus in the tracheas of horses kept in poorly ventilated conditions, and in one study Thor­oughbred racehorses in training, housed on straw, were found to be twice as likely to suffer from lower airway disease as those kept on shredded paper.²³ More recently, Holcombe and colleagues⁵³ showed that yearlings had a significantly higher number and percentage of neutrophils (polymorphonuclear neutrophils as high as 18%) in BAL fluid when they were stabled versus when they were at pasture. In support of this finding, endotoxin concentrations are, as expected, higher in stables than at pasture.^54,55 Although none of these horses had any clinical signs of respiratory disease or evidence of exercise intolerance, they were not in work, and subtle signs of per­formance impairment could easily have gone undetected. Dust levels in the horse's breathing zone can be as high as 25 mg/m³ (a level that would be considered unacceptable in any human workplace), which can explain the development of airway neutrophilia as a nonspecific response to high levels of particulates.⁵⁶ It is also likely that increased levels of endotoxin in hay and grain dust contribute to the development of airway neutrophilia,^57-59 which is supported by the finding that hay eating is a risk factor for increased tracheal mucus in pleasure horses.²⁸ A recent study of Thoroughbred racehorses in training confirmed that feeding hay from a net resulted in a significantly higher concentration of particulates and respirable endotoxin in the horse's breathing zone as well as an increase in eosinophil numbers in the BAL fluid.⁶⁰ In addition, the horse's position in the stable may affect development of IAD. In one study there was a significant association between the presence of visible accumulation of mucus in the trachea and the stable, stall, and particulate concentration and numbers.⁶¹ Moreover, even when unaffected horses are exposed to stable dust, the neutrophil chemoattractant, IL-8, increases in the BAL fluid.⁶²

Previous viral disease is commonly invoked as a predisposing factor in the development of IAD, and the evidence needed to implicate virus is increasing. As in humans with asthma, viral respiratory disease has been shown to cause AWHR for a period of time after infection, perhaps because of denuding of the respiratory epithelium. In one study various equine herpesviruses were found with greater frequency in the tracheal aspirate of poorly performing horses with signs compatible with IAD,⁶³ and more recently both EHV-2 DNA and equine rhinitis B virus RNA were found in the tracheal fluid but not in the nasal fluid of young racehorses with cough.⁶⁴ Similarly, in a different laboratory, horses with IAD had higher titers to equine rhinitis A virus, and there was a significant association between nasal shedding of EHV-2 DNA and diagnosis of IAD.⁶⁵ Moreover, both alphaherpesviruses (EHV-1 and EHV-4) and gammaherpesvirus (EHV-2d) have been associated with more long-lasting airway inflammation.⁶⁶

The role of bacterial infection in IAD, particularly in young racehorses, is unclear. In several studies there was a strong relationship between inflammation of the lower respiratory tract and the presence of streptococcal species; horses with greater evidence of airway inflammation on tracheal aspiration and endoscopy had higher mean bacterial counts in tracheal aspirate,²³ and horses with bacteria found in the tracheal aspirate had a greater tendency to cough.¹⁵ Recently, it has been shown that the respiratory microbiota differs between horses with IAD and those without respiratory disease, with streptococcal species being increased in horses with IAD. Moreover, treatment with dexamethasone exacerbated this difference.⁶⁷ However, it is important to remember that association is not necessarily causation, and so increased numbers of bacteria may reflect impaired airway clearance rather than a causative role for bacteria. The role of bacterial and viral infection in IAD remains unclear at this time.

Because horses sample the ambient air on a continual basis, it seems logical that air pollution might contribute to the development of IAD. In one study, clinically normal horses exposed to ozone had significant increases in the glutathione redox ratio as well as total iron levels in the pulmonary epithelial lining fluid (both markers of exposure to oxidizing agents), and there was a strong correlation between airway inflammation score and the glutathione redox ratio in horses examined for poor performance but without overt airway disease.⁶⁸ In contrast, horses living in urban environments have been shown to have less airway reactivity, although greater levels of iron in the BAL fluid, than do horses living in rural environments.⁶⁹

There are multiple other possible contributors to the development of IAD. Cold air exposure is an important risk factor for the development of asthma in human athletes, and cold air exposure has been shown to be a risk factor for develop­ment of tracheal mucus accumulation in some horses.²⁸ In support of this observation, exposure of equine airways to cold air resulted in altered immunologic responses for at least 48 hours. Exercise may also play a role in the development of IAD, in that neutrophils are increased in the BAL fluid for at least 48 hours after exercise, and there is a corresponding increased late-phase expression of IL-8 and TNF-α in the BAL fluid.⁷⁰,⁷¹

There is no convincing evidence of an allergic response in horses with IAD. However, the presence of increased numbers of mast cells in the BAL fluid of horses with poor performance,² the association of BAL mastocytosis with AWHR,⁷² and immunohistochemistry studies showing more IgA-containing cells and occasionally increased numbers of IgM- and IgG- containing cells are suggestive of a degree of allergic response and a heightened immune response. Anyone looking at recent studies of gene expression profiles in the BAL fluid of horses with IAD should take note of whether the horses were diagnosed as having IAD on the basis of a generalized increase in inflam­matory cells or if the study group was parsed more thoroughly into horses with increased mast cells or horses with increased neutrophils. One study of horses with a generalized increase in inflammatory cells revealed an upregulation of IL-1β, IL-23, and TNF-α but no evidence of a polarized cytokine response.⁷³ On the other hand, when horses are stratified into mast cell versus neutrophil groups, mRNA for IL-4 correlated with mast cells but not neutrophils, whereas for all groups, similar to the previous study, TNF-α and IL-1β were increased.^74,75 It is most likely that multiple factors contribute to the development of IAD in individual horses; a critical level of risk factors or exposure is probably necessary for the disease to manifest itself. Recently, measurement of cytokine concentrations in BAL fluid suggested that neutrophilic IAD involved activation of the innate immune system and a Th1 polarized response; at the same time, the study supported other emerging findings that different cytologic profiles are likely associated with dif­fering immunologic pathways.⁷⁶

■ Differential Diagnoses The diagnosis of IAD often requires the exclusion of other diseases that may have a similar clinical picture. Whereas horses with RAO (heaves) or summer pasture-associated RAO (SPARAO) in remission may be very difficult to distinguish from horses with IAD, horses with RAO or SPARAO have a history of episodes of obvious breathing difficulty associated with exposure to either moldy hay or summer pasture. Upper airway disease, such as sinus infection or guttural pouch infection, may cause cough and nasal dis­charge, and both static and dynamic upper airway obstructions may cause poor performance and poor recovery from exercise. These may be largely ruled out by endoscopy. Horses with pneumonia, bronchopneumonia, or lung abscess commonly have abnormalities suggesting systemic disease, such as abnormal findings on CBC, recent history of fever, weight loss, or inap­petence. In these cases tracheal wash can be very helpful in determining a septic cause of disease. Thoracic radiographs or ultrasound will also aid in the detection of these septic respiratory diseases. EIPH may be seen in conjunction with IAD, but the presence of epistaxis, blood on endoscopy of the trachea, or red cells or hemosiderophages on BAL confirm the diagnosis of EIPH. Overt viral respiratory disease is difficult to confuse with IAD, as it usually manifests with fever and malaise, but horses with viral respiratory disease may exhibit prolonged cough and AWHR for weeks to months after resolu­tion of the primary disease.

■ Therapy There is remarkably little evidence-based support for any particular therapy in treating IAD. However, the main­stay of treatment has become a combination of environmental remediation, corticosteroid therapy, and bronchodilators.

ENVIRONMENTAL REMEDIATION. The barn environment is a hotbed of particulate matter, respirable endotoxins, molds, and volatile gases such as ammonia. The worst offenders appear to be hay and straw. A study looking at different management systems showed that when hay and straw bedding were replaced by pelleted feed and wood shavings, the respirable particulate levels were remarkably reduced.⁵⁵ Further improvements can be made by using cardboard bedding to reduce dust and mold levels.⁷⁷ Indoor arenas present another high-dust challenge to the horse, with respirable particulate levels 20 times the level recognized to cause respiratory dysfunction in humans.⁶¹ Other fairly common-sense strategies can be used. We make the following recommendations to owners in addition to the suggestion to change to low-dust feeds and beddings:

• Sprinkle aisles with water before sweeping.

• Avoid storing hay overhead. If unavoidable, lay a tarp under the hay to avoid dust raining down on the horses.

• Use a humectant or hygroscopic agent to reduce dust in the indoor and outdoor arenas.

• Remove horses from the barn while cleaning stalls or moving hay.

• Do not use blowers to clean aisles.

• Wet hay before feeding or use Dengie or other baked hay products.

• Remove cobwebs and other dust collectors routinely.

A recent study demonstrated that environmental control was by far the most important means of treating airway inflam­mation and dysfunction in horses with heaves (RAO), a more severe disease than IAD, and feeding hay in a net was shown to be the most important factor in high breathing zone par­ticulate levels.^60,78 It is logical therefore to suppose that environmental management is equally important in the treat­ment of IAD.

CORTICOSTEROID THERAPY. Either parenteral or inhaled corticosteroids form the mainstay of drug therapy for IAD. Although the utility of corticosteroids for preventing or ameliorating airway remodeling in human asthma is debated, corticosteroids have recently been demonstrated to prevent airway smooth muscle thickening in mice with experimental asthma.^79,80 The degree of efficacy in decreasing BAL neutro­philia is not completely known. Some studies show an obvious benefit of dexamethasone in improving clinical signs and lung function and reducing BAL neutrophilia,⁸¹ whereas others show improvement primarily in lung function with little effect on BAL cytology for dexamethasone only or for both dexametha­sone and fluticasone.^78,82 Corticosteroid treatment certainly causes adrenocortical dysfunction, but this is less pronounced with inhaled therapy versus systemic.⁸¹ Although concerns about precipitating laminitis with corticosteroid therapy are frequently expressed, the actual risk of laminitis with cortico­steroid therapy is completely unknown.⁶ In our clinic we frequently treat with an initial course of parenteral corticoster­oids, typically a 4-week decreasing course of prednisolone followed by inhaled corticosteroids. A recent study demonstrated that fluticasone propionate is detectable in blood and urine after delivery by inhalation.⁸³

BRONCHODILATOR THERAPY. Bronchodilators, especially the inhaled form, appear to be efficacious in treating IAD in conjunction with corticosteroids. The most commonly used bronchodilators in IAD include aerosolized β-adrenergics, such as albuterol, and aerosolized parasympatholytics, such as ipratropium. β-Adrenergic drugs such as albuterol also increase mucociliary transport. The use of systemic β-adrenergics such as clenbuterol is not advised, as the extent of bronchoconstriction in IAD does not warrant risking the adverse effect of cardiovas­cular remodeling, which has been shown to occur in horses.⁸⁴ Moreover, a recent study demonstrated that when clenbuterol is given to horses with AWHR, tachyphylaxis associated with increased airway reactivity develops by 21 days of treatment,⁷ whereas no such increase in AWRH was noted when horses were given aerosolized albuterol over a 10-day period.⁸⁵

MAST CELL INHIBITORS. Sodium cromoglycate can be effica­cious in treating known mast cell-mediated IAD⁹ but will not be of use for treating the majority of horses with neutrophil- mediated disease. The use of sodium cromoglycate requires considerable owner compliance, as the maximum response to this drug occurs at 1 to 2 weeks after beginning treatment.

AEROSOLIZED THERAPY. Aerosolized therapy using a combination of inhaled corticosteroids and bronchodilators is well established clinically in the treatment of IAD; however, there are no clinical trials establishing the efficacy of these drugs. When using inhaled drugs, we use a spacer and mask in order to improve delivery of the drug. Regardless of the type of mask and spacer device used, actual delivery of particles to the lower airways is poor in horses, as indeed it is even in humans, and the least efficacious means of delivering aerosolized drugs is by nebulization.^86,87 Unfortunately, strategies that we know improve lung deposition of aerosolized drugs in humans, such as slow deep breathing and breath holding, are not practical in horses. Devices currently on the market include the Aerohip­pus (Trudell Medical, Inc., London, Canada), the Equine Haler (Equine Health Care, Inc., Horsholm, Denmark), and the Flexineb® (Nortev Ltd., Galway, Ireland). Individual horse and owner preference determines which device should be used. Inhaled corticosteroids commonly used in the treatment of IAD include beclomethasone and fluticasone.

Although there are no reported clinical trials using corticosteroids in horses with IAD, horses with RAO treated with 3750 μg of beclomethasone dipropionate twice daily showed improvement in both clinical signs and lung function.⁸⁸ Smaller doses (500 to 1500 μg twice daily) were shown to be efficacious in horses with heaves, and we commonly use small doses (500 to 1000 μg twice daily) with good clinical effect in horses with IAD.

Fluticasone is a more potent corticosteroid than beclometha- sone and has been shown to be efficacious in treating horses with heaves when administered using a delivery device that is no longer on the market at a dose of 2000 μg twice daily.⁸⁹ Unlike with beclomethasone, fluticasone did not cause adre­nocortical dysfunction.⁸⁹ We use a decreasing-dose regimen, starting at 1500 to 2000 μg twice daily, working down to 1000 μg once daily or every other day. The lowest dose is reached over a 3- to 4-week period. Although we previously advised use of a short-acting bronchodilator, such as inhaled albuterol, 5 to 15 minutes before treatment with inhaled corticosteroid to increase deposition of the latter by fully opening the small airways, the accepted practice in human medicine currently is to avoid this practice. The logic behind this is that it is important to get the most useful and costly drug administered first before compliance decreases. It is important that the owner understand that even with the higher doses of inhaled corticosteroid, it may require 1 to 2 months for the best therapeutic effects to be achieved.

The most commonly used inhaled bronchodilator is albuterol, a β₂-specific adrenergic drug. The onset of effect with albuterol is quite rapid, with maximum bronchodilation being seen within 15 minutes. However, it is important to note that the maximum effect lasts for only an hour in some horses, and there are side effects (such as anxiety, nervousness, trembling, and tachycardia) with higher doses of the drug, even in the inhaled form. There is no evidence to suggest that the oral form of albuterol is even absorbed in the horse, and it is not suggested as appropriate therapy. Longer-acting β₂- adrenergic agonists, such as salmeterol and formoterol, can also be used, with bronchodilation lasting for 6 to 8 hours. Parasympatholytic drugs such as ipratropium have a slower onset of action but longer duration (at least 6 hours) than albuterol and lack the severe side effects of parenteral use of drugs such as atropine. It is important to remember that these bronchodilators are symptomatic drugs only; they do not treat the underlying inflammation and therefore are unsuitable for single-drug therapy.

Mast cell inhibitors that can be administered by metered dose inhaler include Intal (cromolyn) and Tilade (nedocromil sodium). They are discussed in earlier sections. Many putative ancillary treatments have been touted as efficacious in the treatment of airway inflammation in the horse. The only one with good evidence for efficacy is the use of omega-3 fatty acids in the feed.⁹⁰

In summary, IAD is a disease characterized by nonseptic inflammation, visible on BAL cytology as excessive neutrophils, mast cells, or eosinophils, and involving low-grade airway obstruction and AWHR. Clinical signs include variable cough, nasal discharge, and poor performance. Excessive amounts of mucus may also be visualized in the trachea during endoscopic examination. The cause of IAD is unknown, but the disease is probably best avoided by achieving a low-dust and low- endotoxin environment. Treatment logically begins with environmental remediation and is supplemented by anti­inflammatory drug therapy using systemic or inhaled corticosteroids and inhaled bronchodilators. IAD that involves an excess of mast cells in the airways can be further treated with inhaled mast cell inhibitors.