Recurrent Airway Obstruction

Also known as: RAO, chronic obstructive pulmonary disease, COPD, heaves.

Do not confuse with: summer pasture associated obstructive pulmonary disease.

Description

Recurrent airway obstruction (RAO) is an inflammatory, obstructive respiratory disease of horses. Disease is induced by the exposure of susceptible animals to organic dust, which gives neutrophil influx to the airways, bronchospasm and mucus accumulation¹. This causes a cough, nasal discharge, and respiratory difficulty. When exposure to the allergen is eliminated, obstruction and clinical signs resolove or attenuate. However, animals are susceptible to reccurent episodes of airway obstruction throughout their lives, and so management is essential.

Since disease required exposure to organic dust, recurrent airway obstruction occurs in stabled horses that are, for example, bedded on straw and fed hay. The condition is therefore most prevalent in the northern hemisphere because horses tend to be stabled for large parts of their lives². Summer pasture-associated obstructive pulmonary disease (SPAOD) is a similar condition that occurs when horses kept on pasture are sensitive to environmental allergens, and may be considered the same disease as RAO but with different inciting factors¹.

Pathogenesis

Organic dusts contain a variety of components that can initiate lung inflammation. These include specific allergens, endotoxin, components of molds such as beta-glucan, and small particulates. Elevated levels of specific IgE in bronchoalveolar lavage fluid (BALF) [8] favor the hypothesis that RAO is initiated by an allergic response to thermophilic molds and actinomycetes such as Faeni rectivirgula. A similar increase in specific IgE could not be documented in horses with SPAOD [9]. More recent studies examining the cytokine responses in both RAO and SPAOD lean toward a TH2 (allergic) immune response [10]. However, it has proved impossible to induce the heaves syndrome simply by administration of molds to susceptible horses [11-13]. Hay and stable dust contains endotoxin [7] and it is known from work in other species that administration of endotoxin into the airways can also induce many of the changes typical of RAO such as neutrophilic inflammation and mucus hypersecretion [14]. Small particles and fibers landing on the surface of the epithelium also can initiate the release of pro-inflammatory cytokines such as IL-8 [15,16]. Because organic dusts contain such a mixture of materials, RAO and SPAOD probably are initiated by several of these factors acting in concert.

Pathophysiology When a horse with a history of RAO is moved from pasture to a stable where it is fed hay, airway inflammation develops [18,19]. Under the influence of IL-8 [20,21] perhaps leukotriene B4, and ICAM-1 [22], neutrophils accumulate in the lung and invade the airway lumen within six to eight hours [23]. Concurrently, airway obstruction develops. This obstruction is a result of bronchospasm, mucus accumulation, and inflammatory changes in the wall of the airway [1]. Inflammatory mediators acting on cholinergic nerves and airway smooth muscle are responsible for bronchospasm [24-27]. Mucus accumulation is due to augmented mucus production and increased mucus viscoelasticity which impairs mucus clearance [28]. Changes in glycosylation of mucus may contribute to its reduced clearability [29]. Inflammatory changes in the airway wall occur both acutely (edema) and chronically (airway wall remodeling). Airway wall remodeling, including mucus metaplasia, smooth muscle hypertrophy, peribronchial fibrosis, and peribronchial inflammation, is responsible for the chronic, intractable development of airway obstruction in RAO [30,31]. This remodeling likely is a result of the repeated bouts of airway inflammation and the accompanying release of proteases [32,33] and other mediators that occur in the RAO-susceptible animal.

One of the characteristic features of horses with RAO is increased non-specific airway hyperresponsiveness [34,35]. This means that airways of RAO-affected horses narrow in an exaggerated fashion in response to a wide variety of stimuli including neurotransmitters [36], inflammatory mediators such as histamine [34,35,37], and non-specific stimuli such as citric acid [36]. The airway hyperresponsiveness is most pronounced during acute exacerbations of RAO when inflammation is most severe and hyperresponsiveness wanes when animals are out at pasture [34,36] and inflammation is less severe. Even quite brief exposure of a RAO-susceptible horse to a stable environment can induce hyperresponsiveness that persists for several days [38]. The causes of the hyperresponsiveness include airway wall thickening, smooth muscle hypertrophy, a reduction in some of the inhibitory mechanisms that limit smooth muscle contraction [39,40] and actions of inflammatory mediators on cholinergic nerves and smooth muscle to facilitate smooth muscle contraction [25,26]. Clinically, airway hyperresponsiveness is important because it means that RAO-susceptible horses are prone to develop bronchospasm in response to levels of stimuli that would not affect a normal horse. Reducing the level of airway inflammation best controls hyperresponsiveness.

Many apparently normal horses develop low levels of airway inflammation when housed in the environment that causes a massive influx of neutrophils into the airways on RAO susceptible animal [41,42]. The reasons for the up-regulation of the inflammatory response following a dust challenge and the persistence of inflammation when RAO susceptible horses are returned to pasture are under active investigation. There is evidence for depletion of endogenous antioxidants in the airways of RAO susceptible animals [43,44] and for prolonged activation of NFkB, a transcription factor that initiates the production of many pro-inflammatory cytokines [22]. Activation of NFkB may be due to a positive feedback loop involving the persistent production of TNFa and IL-1b by neutrophils [45]. Inflammation also persists because apoptosis of neutrophils is delayed [46]. Because of the diffuse obstruction of the peripheral airways, horses with RAO have a mismatching of ventilation and blood flow that leads to inefficient gas exchange and hypoxemia [47]. In order to compensate for the poor gas exchange, RAO-affected horses increase their minute ventilation by increasing respiratory rate [47,48]. Tidal volume does not change. Inhaling the same tidal volume in less time requires that the horse with RAO develop a higher mean airflow rates in the face of airway obstruction [47-49]. This is why, the horse adopts the breathing pattern characteristic of heaves.

Signalment

RAO usually becomes apparent in middle-aged and older horses, and persists for life^allen. There is some evidence that there may be a genetic component to the disease, as many horses do not suffer RAO when they are housed in environments that can provoke clinical disease in others^marti.

Diagnosis

Pathology

COPD (Image sourced from Bristol Biomed Image Archive with permission)

COPD scanning electron micrograph (Image sourced from Bristol Biomed Image Archive with permission)

References

1. Robinson, N E (2001) Recurrent Airway Obstruction. In Equine Respiratory Diseases, IVIS.
2. Robinson N E et al (1995) The pathogenesis of chronic obstructive pulmonary disease of horses. The British Veterinary Journal, 152, 283-306.
3. Merck & Co (2008) The Merck Veterinary Manual (Eighth Edition), Merial.
4. Allen, K and Franklin, S (2007) RAO and IAD: respiratory disease in horses revisited. In Practice, 29(2), 76-82.
5. Marti, E et al (1991) The genetic basis of equine allergic diseases 1. Chronic hypersensitivity bronchitis. The Equine Veterinary Journal, 23, 457-460.
6. McGorum, B et al (2007) Equine respiratory medicine and surgery, Elsevier Health Sciences.
7. Durham, A (2001) Update on therapeutics for obstructive pulmonary diseases in horses. In Practice, 23(8), 474-481.