Recurrent airway obstruction
Recurrent airway obstruction (RAO) is defined as an inflammatory reaction due to hypersensitivity of the small airway which leads to reversible obstruction of the airway (Allen, et al., 2007; Robinson, et al., 1996). The condition can be known as heaves or broken wind due to the increased respiratory effort with the severe form of the disease (Robinson, et al., 1996).
Recurrent airway obstruction should be a differential if an animal presents with occasional coughing and exercise intolerance (Allen, et al., 2007). At the moderate disease stage the cough becomes more frequent, with paroxysmal bouts of coughing. Clinical signs include elevated respiratory rate and occasionally mucopurulent nasal discharge. Once the disease is severe then there will be clear signs of respiratory distress even when at rest. Finally, the horse will lose body condition and, due to hypertrophy of the external abdominal oblique muscle, develops a ‘heave' line.
Recommended therapy involves reducing the allergen concentrations within the environment with management changes. If this alone is not sufficient to control the disease or the horse has severe disease then bronchodilators can be used with or without a steroid inhaler. A short course of systemic corticosteroids can be used to cause a rapid improvement in clinical signs. Antibiotic therapy is only required to treat secondary bacterial infections.
An eleven year old, welsh crossbreed mare presented with an increased respiratory rate and effort, and occasional coughing after being stabled. The horse had been seen twice in the last month and had been dispensed Trimethoprim and sulphadiazine (30mg/kg SID Trimediazine plain oral powder, Vetoquinol UK LTD) for seven days. An improvement to clinical signs was seen following each course of antibiotics for a few days and then the horse relapsed.
Clinical examination by the veterinary surgeon identified an increased respiratory rate of 40 breaths per minute (normal rate eight to 16 breaths a minute) and increased abdominal effort with no heave line. Auscultation identified an increase of lung sounds over all lung fields and wheezing particularly noticeable in the lower right lung field. There was no coughing during the examination. Mucous membranes were pink and moist with a capillary refill time of less than two seconds. Cardiac auscultation revealed rhythm and normal rate of 32. The horse was 3/5 condition score. There was a bilateral mild serous discharge from the nostrils. The horse was afebrile which suggested any secondary bacterial infection had been controlled by Trimethoprim sulphdiazine.
A diagnosis of RAO was made based on clinical signs and history of similar episodes. The owner was advised to change the management to reduce the allergen levels in the environment. The pony has laminitis which means turnout time has to be restricted and the owner cannot use haylage. However, the routine can be modified so the horse lives outside on a barren small area of land, muzzled if necessary and has hay soaked for at least twenty minutes or a low calorie haylage alternative. When stabled use minimal shavings bedding in the stable and avoid straw.
The first aim of treatment was to control with management the environmental factors. If this strategy fails to reduce clinical signs the owner could use a bronchodilator and corticosteroid systemically or topically.
The average age of onset of RAO is nine years old (Allen, et al., 2007; The Merck Veterinary Manual, 2008) although around 12% of middle-aged to older horses suffer some degree of lower airway inflammation due to allergens (The Merck Veterinary Manual, 2008). There is no gender or breed predilection but there may be a hereditary component.
The underlying pathophysiology of RAO is an inflammatory reaction to a specific allergen. In the Northern hemisphere the weather conditions mean horses are stabled to manage their workload (Robinson, et al., 1996) this leads to high levels of exposure to allergens.
The hypersensitivity reaction to the allergens results in increased mucus production, bronchoconstriction and increased neutrophils in the lumen. The reduction in performance occurs when the diffuse airway obstruction and mucus plugs block the bronchioles preventing oxygen entering the alveoli. This leads to a ventilation/perfusion mismatch and hypoxaemia (Robinson, et al., 1996). Neutrophil accumulations lead to proteases, oxygen radicals and increased inflammatory mediators in the pulmonary tissue (K.J. Rickards, 2000) and this can lead to chronic pathology of the bronchiolar walls (Davis, et al., 2002). The reactive oxygen species reduce the amount of nitric oxide which is needed to operate the inhibitory response to smooth muscle contraction in the trachea and larger bronchi (Robinson, et al., 1996) exacerbating the ventilation/perfusion mismatch. Lymphocytes are the predominating leukocyte in the pulmonary submucosa. The CD4+ lymphocyte is often elevated in horses suffering from COPD (Watson, et al., 1997). The CD4+ lymphocytes are of the T helper 2 phenotype and are responsible for release of interleukins leading to an increase in IgE antibody production and neutrophil recruitment (Davis, et al., 2002). An increase in neutrophils is evident in normal horses but the increase is exaggerated in COPD horses supporting the inflammatory response hypothesis of COPD (Robinson, et al., 1996).
Research has shown a genetic predilection to RAO and genetic susceptibility could explain the sporadic nature of the disease when horses are stabled in the same conditions (Robinson, et al., 2009). Another underlying cause could be viral infection of the respiratory system which causes epithelial damage and reduces mucociliary clearance of accumulations. This has been suggested as a cause of COPD particularly if the horse is not rested post-infection. However, whilst this is likely to increase the risk of COPD in susceptible horses alone it is unlikely to trigger COPD.
In this case, as with many in practice, diagnosis was made on clinical signs and history. Further diagnostic tests may have included the following. Bronchoalveolar lavage (BAL) fluid in RAO sufferers includes increased pulmonary neutrophils (from 15-85%) and Curschmann's spirals (Davis, et al., 2002) compared to BAL from normal horses which contains mainly lymphocytes and macrophages (Robinson, et al., 1996). Neutrophil levels are elevated in the BAL fluid from four to five hours post-exposure to an allergen (Watson, et al., 1997). Endoscopy can be used to directly visualise the increased mucus, tracheal hyperaemia and narrowing of the airways. Arterial blood gas analysis is a simple procedure but the results are not pathognomic of RAO and values for PaO2 of 50mmHg or less are indicative of severe disease but not the underlying cause. Lung biopsies are an invasive and time-consuming technique but can provide useful information for prognosis (Davis, et al., 2002). A commercial test is available for determining alteration in pleural pressure via intrathoracic oesophageal pressure but the test is only useful if the horse is already showing clinical signs and is probably better used as a research tool.
Treatment starts with management ideally turnout to pasture or at least based on reducing dust and allergens in the stable environment (Robinson, et al., 1996). Management aims to reduce the exposure to dust and mould by controlling aerosol (reduced bedding, soaked hay) and to improve ventilation systems. Faenia rectivirgula, Thermoactinomyces vulgaris and Aspergillus fumigatus have both been suggested as possible allergens for RAO horses. These organisms are found in poor quality hay and straw (McGorum, 1998). If hay becomes wet before baling then the humid and warm centre of the bale is the perfect environment for proliferation of the thermophilic moulds and actinomycetes and this increases the risk of spores small enough to be inhaled deep into the lung when feeding the horse (Robinson, et al., 1996). Endotoxins can accumulate in the stable to high levels and maybe a primary or secondary cause of inflammation and RAO. Forage mites in hay and straw can be antigens directly or through digested spores in the faeces but there has been little research confirming their effect in RAO. The allergens accumulate in the breathing zone (around the nose) due to the feeding behaviour of the horse with dust concentrations reaching up to 35 fold (Davis, et al., 2002; Robinson, et al., 1996). Therefore, for environmental changes to be effective the aim is a very low antigen environment in the stable to reduce the accumulation in the breathing zone. Owners can become frustrated believing a misdiagnosis or treatment failure due to inadequate changes to management.
If necessary corticosteroids and bronchodilators can be used. The drugs alone will not prevent recurrence, often two to four days after finishing treatment, if management changes are not made. Corticosteroids prevent cytokine release, which reduces the level of the pulmonary neutrophils. These can be administered systemically such as triamcinolone acetonide, dexamethasone or topically using inhalational devices with beclomethasone or fluticasone propionate. Systemic prednisolone is an easy option for owners to give in food. However, the effect is limited by the bioavailability and some research even suggests there is no benefit at all from oral prednisolone in RAO cases (Couetil, et al., October 2005). Therefore, higher then desired doses are given and can cause unwanted side-effects. In this case, although the debate about corticosteroids and laminitis continues, the laminitis makes systemic corticosteroid use undesirable. The topical administration has an advantage of accumulating in high levels in the affected area if not prevented by the airway constriction and mucus plugs (Durham, September 2001). Topical beclomethasone has a greater suppressive effect on the adrenal glands compared to flucticasone. The newer drug flucticasone reduced systemic effect by reducing the amount absorbed when swallowed from nasopharynx and extensive first-pass metabolism by the liver (Couetil, et al., October 2005). Flucticasone has more benefits when given topically to a horse with severe airway obstruction (Couetil, et al., October 2005). If necessary and based on a clinical assessment of severity of signs then the drugs can be used on a short term basis to provide comfort whilst other changes are being put into action. The drug therapy could be used prophylactically when exposure to the allergen is unavoidable. Corticosteroids are ineffective in the later stages of disease when the normal pulmonary tissue is replaced by fibrosis.
Bronchodilators include anticholinergics, beta-2 agonists and theophylline. Anticholinergic drugs act by preventing acetylcholine activating muscarinic receptors responsible for bronchoconstriction by contracting smooth muscle (Robinson, et al., 1996). However, the use is best limited to quick relief from an acute episode as resistance of the receptors can develop in five days. Clenbuterol, a non-steroidal beta-2 agonist, causes smooth muscle relaxation leading to bronchodilation and increases mucociliary transport (Turgut, et al., 1989). Ventipulmin granules, Boehringer Ingelheim Ltd contain clenbuterol and are commonly administered in feed to horses suffering from moderate RAO. Another drug sodium cromoglycate, a mast cell stabiliser, has been used to prevent clinical signs by reducing pulmonary inflammation for several days at high exposure in COPD horses (Clayton, et al., 1980). Histamine is released when a mast cell degranulates and this causes bronchoconstriction. Histamine levels have been found to elevate in RAO cases and there maybe benefit using drug therapy to control the degranulation (Hare, et al., 1998), however, this drug is not commonly used in practice (Cunningham, et al., 2008).
Human research has identified phosphodiesterase type 4 (PDE4) as the predominant isoenzyme in human neutrophil populations of asthma sufferers. Similarly, research into equine neutrophils has identified an elevated presence of PDE4 in COPD horses (K.J. Rickards, 2000). There could be beneficial effects of limiting the PDE4 present by using a selective PDE4 drug. The drug rolipram has been studied by K J Richards et al (2000) and shown to reduce levels of PDE4 in both COPD affected and normal controls. This could reduce the chronic lung pathology and help to improve the speed of return of a RAO horse during an acute episode to in remission.
In this case the owner could soak the hay without worrying about the reduced nutritional value as it would aid the laminitis. However, during a laminitic episode the horse is advised to stand on a deep bedding to reduce the pain. This increases the risk to the horse of RAO due to increased dust and provides a difficult dilemma. The horse could be given prophylactic drug therapy as discussed, however, long-term this is not an ideal solution and signs of RAO can return two to four days after the end of the course if management has not altered. The corticosteroid administration is a possible risk factor for laminitis, therefore, the other drugs discussed need to be considered.
In conclusion, RAO is a multifactorial disease with many areas of drug therapy to consider and the individual treatment plan must be designed to suit the owner, temperament of the horse and severity of signs of the horse. However, the lynch pin to successful treatment is definitely environmental management.