In an Adult Horse With Severe Asthma (Previously Recurrent Airway Obstruction) Does Using Inhaled Corticosteroids Result in an Equal Improvement in Clinical Signs When Compared to Systemic Corticosteroids?

a Knowledge Summary by

Natasha A Jocelyn MA VetMB MRCVS ^1*

¹ The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire, AL9 7TA
^*Corresponding Author (njocelyn@rvc.ac.uk)

Clinical scenario

A 12-year-old cob mare presents to you with increased respiratory effort and rate at rest. Radiographs and ultrasound of the lungs are unremarkable. A bronchoalveolar lavage indicates inflammation and neutrophilia (>20% neutrophils) with no evidence of bacterial infection. You diagnose equine severe asthma (previously called recurrent airway obstruction) and need to decide the best treatment option for the mare. The owner is concerned with the potentially long term use of systemic steroids and wants to know if other routes of administration for steroid treatment are effective.

The evidence

Following refinement of the initial search and exclusion of unsuitable publications, four studies were found that were directly applicable to the PICO question (Rush et al. 1998; Couëtil et al. 2005; Couëtil et al. 2006; Robinson et al. 2009). All four were clinical trials, with three  being crossover in design (Rush et al. 1998; Couëtil et al. 2006; Robinson et al. 2009). Three were blinded (Rush et al. 1998; Couëtil et al. 2005; Couëtil et al. 2006). None of the studies were completely comparable because each had slightly different interventions and outcomes but overall the evidence was of high quality.

Summary of the evidence

Appraisal, application and reflection

Three out of the four studies (Rush et al. 1998; Couëtil et al. 2006; Robinson et al. 2009) used a very similar design which involved inducing clinical disease by exposure to hay and or straw, using highly controlled environments and comparing inhaled and systemic corticosteroids to a control. The studies used clinical scoring systems for assessment of clinical signs, and used other similar outcome measures such as BAL cytology and pulmonary function testing, which allowed comparison between studies. All three of the above studies used pleural pressure changes to initiate the start of the treatment period, with the cut off value being equivalent in Rush et al. (1998) and Couëtil et al. (2006), and similar in Robinson et al. (2009). The populations were different and geographical location also varied. As is often the case, the clinical trials used small numbers of animals and relatively short study periods Treatment protocols varied from three days to four  weeks with the largest and longest study (Couëtil et al. 2005) being the least controlled. Couëtil et al. (2005) differed in methodology to the other papers but, importantly, it was not crossover in design and still employed clinical scores, pulmonary function and cytology to compare the groups.

Two different inhaled corticosteroids were investigated (beclomethasone and fluticasone) in all four studies, but at different doses. Two studies (Rush et al. 1998; Robinson et al. 2009) used systemic dexamethasone at the same dose for varying lengths of time. The two studies that compared systemic dexamethasone to the inhaled steroids found them to be broadly equivalent at specific doses except that the onset of beneficial actions was slower with the inhaled steroids.

The other two studies found that the systemic corticosteroid used, either oral prednisone (Couëtil et al. 2005) or a long-acting intramuscular preparation of dexamethasone (Couëtil et al. 2006), was not effective. The low bioavailability of prednisone in horses makes its use in the Couëtil et al. 2005 paper highly questionable.  Couëtil et al. (2005) also modified the environment for all animals. This had a significant effect on outcome, which may have confounded the results. Two studies used the same inhaler device (Hand held metered device 3M^TM) for administering beclomethasone (Rush et al. 1998; Couëtil et al. 2006) whereas the other two used different devices, thus adding a further potential variable when comparing the studies.

Only one study (Rush et al. 1998) observed significant differences in airway cytology, specifically reduction in BAL neutrophilia, as a result of corticosteroid treatment. BAL is widely used for diagnosis and monitoring of equine severe asthma but the evidence from the other three of these studies suggests it may not be a useful outcome for monitoring response to treatment.

The available evidence is of sufficient quality that clinicians should be able to apply the findings to clinical scenarios. The most effective inhaled corticosteroid appears to be fluticasone at 6mg BID which seems to be able to prevent exacerbation of asthma in horses moving from pasture to a stabled environment. The use of IV dexamethasone may be preferable in the acute case as the onset of clinically-apparent action was reported in these studies to be faster. The literature is lacking comparison of inhaled corticosteroids and prednisolone. Prednisolone is a widely used oral corticosteroid in the UK with a product licensed for equine asthma specifically. Since these studies were published, ultrasonic nebulisers (which provide an alternative to metered dose inhalers as a means of delivering inhalation therapy) have come to the market in the UK and these also warrant comparison in clinical settings.

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts 1973- week 29 2017 Pubmed 1900- week 29 2017
Search terms:	Equine or horse and recurrent airway obstruction or RAO or equine asthma and corticosteroids or corticoids
Dates searches performed:	19/07/2017

Exclusion / Inclusion Criteria
No limitations regarding study design, setting, sample size or study population were imposed.
Exclusion:	Articles not relevant to the PICO question, in vitro studies, book chapters or conference proceedings.
Inclusion:	Relevant to PICO question, more than 1 animal, in vivo

Search Outcome
Database	Number of results	Excluded – irrelevant to PICO question	Excluded – duplicates	Excluded – conference proceedings or review articles	Excluded – in vitro studies	Total relevant papers
CAB Abstracts	23	20	0	2	0	1
PubMed	37	30	1	0	3	3
Total relevant papers when duplicates removed						4

The authors declare no conflicts of interest.

1. Couëtil, L.L. et al., 2006. Effect of beclomethasone dipropionate and dexamethasone isonicotinate on lung function, bronchoalveolar lavage fluid cytology, and transcription factor expression in airways of horses with recurrent airway obstruction. Journal of veterinary internal medicine / American College of Veterinary Internal Medicine, 20(2), pp.399–406. doi: http://dx.doi.org/10.1111/j.1939-1676.2006.tb02875.x
2. Couëtil, L.L. et al., 2005. Randomized, controlled study of inhaled fluticasone propionate, oral administration of prednisone, and environmental management of horses with recurrent airway obstruction. American journal of veterinary research, 66(10), pp.1665–1674. doi: http://dx.doi.org/10.2460/ajvr.2005.66.1665
3. Robinson, N.E. et al., 2009. Fluticasone Propionate Aerosol is More Effective for Prevention than Treatment of Recurrent Airway Obstruction. Journal of Veterinary Internal Medicine, 23(6), pp.1247–1253. doi: http://dx.doi.org/10.1111/j.1939-1676.2009.0382.x
4. Rush, B.R. et al., 1998. Pulmonary function in horses with recurrent airway obstruction after aerosol and parenteral administration of beclomethasone dipropionate and dexamethasone, respectively. American journal of veterinary research, 59(8), pp.1039–1043.