Is inhaled immunotherapy more effective than environmental management when treating equine asthma?

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Appraisal, application and reflection

There are currently no studies directly comparing inhaled immunotherapy with environmental modification for the management of equine asthma, and only limited studies exploring the use of inhaled immunotherapy. Papers that directly investigated the effect of inhaled immunotherapy on clinical signs of asthma in horses were included. Five papers were found that investigated the use of inhaled CpG. Comparators used included placebos, inhaled corticosteroid or varying doses of CpG. There are no reports of adverse effects to CpG inhalation.

Due to the incomplete understanding of the pathophysiology of equine asthma (Couëtil et al., 2016) it is difficult to assess the effect of specific interventions on disease modification. The different studies measured a variety of outcomes. Bronchoscopy and BAL fluid analysis, clinical exam scoring, and arterial blood gas analysis were used in all 5 studies. Other outcomes investigated included pulmonary function tests, immunologic analysis of tracheal washes and serum, and owner questionnaires.

The length of these studies ranged; the longest being Klier et al. (2019) which assessed the horses 8 weeks after the treatment period. Therefore, none of these studies is able to determine the long-term effect of inhaled immunotherapy on disease modification.

Four studies found inhaled CpG to improve the clinical signs associated with equine asthma (Klier et al., 2019; Klier et al., 2017; Klier et al., 2015; and Klier et al., 2012). A significant improvement in clinical score was found following treatment with CpG compared to beclomethasone inhalation in the one study that assessed this (Klier et al., 2019). Allergen-specific inhaled immunotherapy was found to be of no significant benefit over inhaled CpG (Klier et al., 2017).

Two studies investigated the effects of CpG inhalation on immunomodulation. CpG inhalation was found to significantly increase IL-10 and IFN- γ (Klier et al., 2012) although the clinical benefits of this are yet to be assessed. CpG inhalation significantly reduced the expression of MMP-2, MMP-9, TIMP-1 and TIMP-2 and IL-4 in tracheal wash fluid (Barton et al., 2019). The authors suggest this indicates CpG may be able to prevent the formation of pulmonary fibrosis and be effective in modifying the disease course of equine asthma.

The five studies investigating the effects of immunotherapy together provide mild evidence supporting the use of inhaled immunotherapy as a treatment for equine asthma.

Due to the lack of papers with a direct comparison relevant to the PICO, papers comparing environmental modification with an alternative treatment for equine asthma were included in this Knowledge Summary. Seven papers were identified that investigated the effect of environmental management on horses with asthma.

Three papers found that environmental modification by outdoor turnout with no access to hay improved lung function and the clinical signs associated with equine asthma (Jackson et al., 2010; Couëtil et al., 2005; and Leclere et al., 2012). There was no significant improvement in clinical scores of asthmatics or pulmonary function when inhaled fluticasone or oral prednisone were used alongside environmental modification (Couëtil et al., 2005). Leclere et al. (2012) found that inhaled corticosteroids improved pulmonary function of asthmatics more quickly than environmental modification alone, but after 6 months of either treatment there was no significant difference in pulmonary function between groups.

Leclere et al. (2010) found a significant negative impact of poor environmental management (stabled with access to hay for 30 days) on pulmonary function of asthmatic horses when compared to healthy horses.

Two papers investigated the effect of environmental management on airway smooth muscle mass (ASM). It was found that horses with heaves had a significantly increased ASM compared to healthy horses, both prior to antigen exposure and after 30 days of antigen exposure (Leclere et al., 2011). Leclere et al. (2012) found a significant decrease in ASM of horses with heaves after 12 months of environmental management or inhalation of corticosteroids. There was no significant difference in ASM between the groups, but inhaled corticosteroids resulted in a faster reduction of ASM.

Auger and Moore-Coyler (2017) identified that dry hay and straw result in a higher concentration of airborne respirable dust (ARD) and showed that by modifying the stable environment, concentrations of ARD can be significantly reduced.

Miskovic et al. (2008) found that after 6 years of outdoor environmental management with no access to hay, horses with RAO had a significantly lower forced expiratory flow than age-matched healthy horses. Vandeput et al. (1998) found that contact with dry hay can bring horses with COPD out of remission and result in development of clinical signs. These studies provide moderate evidence that environmental management alone is insufficient to permanently cure RAO.

The papers reviewed in this Knowledge Summary all had major limitations. Firstly, the management of horses was heterogenous within studies, horses were kept in their normal environments, with different types and quality of bedding and forage material used, as well as different stable designs and levels of ventilation. This makes it difficult to assess the effect of treatment as the environments of individual horses will also have affected the clinical study results. All of the studies had low study populations and no details were given about power calculations, decreasing the statistical power of results. Other major limitations are the lack of controls in some studies which is likely to affect the clinical significance of each study. The immunotherapy papers share many of the same authors, and there are no publications available from a separate research group, which may create author bias.

Alternative treatments for asthma, that can be used alongside environmental management, are needed. There is the potential for poor owner compliance in maintaining appropriate environmental modifications (Simoes et al., 2020) and in horses with underlying or a history of endocrinopathy, systemic corticosteroid use may be unsuitable (Cornelisse & Robinson, 2011). Recent research has identified inhaled ciclesonide as an effective treatment for equine asthma without affecting serum cortisol (Lavoie et al., 2019), however further research is needed to compare the effect of inhaled ciclesonide with environmental management for equine asthma.

In conclusion, there is low level evidence to support the use of inhaled immunotherapy, alongside environmental modification, as a treatment for equine asthma. The long-term effect of immunotherapy is yet to be assessed, but these papers find it to be effective for up to 8 weeks following a treatment period. There is also the need for further research into the effect of immunotherapy when environmental factors including housing, bedding and forage are controlled, in order to determine if immunotherapy can be recommended as a sole treatment for equine asthma.

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