Introduction
Asthma is a common and serious bronchopulmonary disorder in the cat and is associated with substantial morbidity and occasional mortality. Feline asthma is likely allergic in nature; that is, it is a type I hypersensitivity reaction against aeroallergens. Once cats become sensitised to an allergen, they are susceptible to a variety of pathologic consequences upon repeated exposure to that same allergen. The hallmark features of naturally occurring asthma include eosinophilic airway inflammation, mucus hypersecretion, bronchoconstriction (both in response to allergenic and non-allergenic stimuli), and airway remodelling (permanent architectural changes in the lungs). Therapy can target any or ideally all of these features.
Current Standard of Therapy
As there currently is no curative treatment for feline asthma, three key components of management consist of environmental modulation, glucocorticoids and bronchodilators. These treatment options focus on decreasing environmental triggers of allergic symptoms, blunting airway inflammation and reducing bronchoconstriction. All are unfortunately achieved once the allergic cascade has already been well established. Environmental modulation consists of avoiding or minimising inhalation of irritants in asthmatic cats, and allergens to which a cat has been sensitized. Irritants might include smoke (cigarette smoke, smoke from wood stoves or fireplaces, aerosols, powders, dusty cat litter, etc.). HEPA filters are useful when cats are indoors. Glucocorticoids are critical for asthma, as they are anti-inflammatory and inflammation drives other pathologic sequelae. Bronchodilators are most important for asthmatic cats with wheeze or episodic respiratory distress; they may not be necessary for asthmatic cats that have cough as the sole clinical manifestation.
Novel Therapies: What Does and Does Not Work
It is appealing to specifically block the physiologic function of mediators released after mast cell degranulation, as there are many drugs available to do this (e.g., antihistaminics, antiserotonergics, leukotriene receptor antagonists). Cetirizine, a 2nd-generation selective histamine receptor 1 antagonist that has effects both dependent and independent of histamine antagonism, was also evaluated for suppression of eosinophilic airway inflammation in experimentally asthmatic cats, with no significant beneficial anti-inflammatory or immunological effects.1 Serotonin is known to cause bronchoconstriction in cats, and cyproheptadine - a serotonin antagonist - was shown in asthmatic cats to block airway smooth muscle constriction ex vivo.2 Additionally, the cysteinyl leukotrienes are implicated as important mediators in human asthma, which is why leukotriene receptor antagonists - e.g., Zafirlukast (Accolate) or Montelukast (Singulair) - help a subpopulation of human asthmatics. However, in experimental studies, neither cyproheptadine nor zafirlukast had an effect on decreasing eosinophilic airway inflammation in asthmatic cats.3 As the pharmacokinetics of cyproheptadine suggest that in some cats a higher dose (8 mg twice daily instead of the standard 2 mg twice daily) may be needed, the higher dose of cyproheptadine was also tested in experimentally asthmatic cats. The results of this study again failed to show benefit of cyproheptadine on eosinophilic airway inflammation.1
There have been a variety of other treatments which have been assessed for use in feline asthma. Dietary omega-3 polyunsaturated fatty acids and luteolin (an antioxidant flavonoid) administered to experimentally asthmatic cats for 4 weeks showed no effect on airway inflammation, but did show a decrease in airway reactivity.4 Importantly, although this prophylactic treatment holds promise to diminish airway hyperresponsiveness, because it does not blunt eosinophilic airway inflammation (which ultimately contributes to worsening airway hyperresponsiveness and airway remodelling), it should not be given as monotherapy to treat feline asthma. An initial study evaluating the effect of a single dose of a peptide feG-COOH which modulates allergic disease by mechanisms which still have not been fully elucidated, prior to allergen challenge by aerosol seemed to hold promise in feline asthma.5 However, chronic administration of feG-COOH (2 weeks, once daily) in established asthma did not diminish airway inflammation, making it poorly suitable as a sole prophylactic treatment for pet cats.6 Inhaled N-acetylcysteine, a mucolytic and antioxidant medication, was also tested in experimental feline asthma and was found to increase airway resistance, putting into question its safety in cats with pre-existing airway disease.7 No studies to date have evaluated the effects of N-acetylcysteine administered either orally or by inhalation on airway inflammation or mucus quality in asthmatic cats.
It would seem rational to design therapy which could block the effects of the allergic asthmatic cascade. Modulation of T lymphocyte activity, cytokine inhibition, antibody blockade (especially IgE), small molecule inhibition (e.g., tyrosine kinases), and other immunomodulators are thought to be rationale targets. Not all of these have been evaluated in cats, and the therapies mentioned below that have been tested have been done so in experimental models of feline allergic asthma.
Since allergic asthma is thought to be driven by a T helper 2 lymphocytic process, modulating Th2 lymphocyte activity would seem to hold promise for therapy. The treatments which have been tested that function by altering T cell activity include cyclosporine, allergen-specific immunotherapy and possible tyrosine kinase inhibitors and/or stem cells. In experimental feline asthma, cyclosporine did not inhibit the early phase response to allergen challenge (mediated in large part by mast cells), but it was effective at blunting airway hyperresponsiveness to acetylcholine and airway remodelling.8,9 CpG immunostimulatory sequences which polarise the immune response toward a T helper 1 and away from a T helper 2 response demonstrated good safety and efficacy.11 Comparing the subcutaneous route of injection with topical mucosal delivery of allergen-specific rush immunotherapy was also performed in experimental feline asthma.12 The latter route of administration more closely mimics the natural route of exposure to aeroallergens. Both routes of administration of allergen-specific immunotherapy decreased eosinophilic airway inflammation and were generally associated with minimal side effects; either could be used. However, the subcutaneous protocol demonstrated more consistent resolution of scored clinical signs after allergen challenge by aerosol. The major difference between allergen-specific immunotherapy and other forms of treatment (e.g., steroids and bronchodilators) is that immunotherapy has the potential for cure of the disease by retraining the immune system to be tolerant to allergens. This has not yet been tested in pet cats with asthma, and there are differences in the protocol used in this model versus conventional immunotherapy - a clinical trial in pet cats still needs to be performed.
Inhibition of tyrosine kinases, a group of proteins which regulate cell survival, growth and differentiation, has more recently been of interest for treatment of asthmatic patients. Tyrosine kinase inhibitors are small molecule inhibitors which block the ATP binding sites of kinases. In asthma, the c-KIT receptor has been associated with proliferation and degranulation of mast cells and eosinophils in humans and mice and seems to be a logical target for therapeutic intervention. The tyrosine kinase inhibitor masitinib showed efficacy in reduction of airway inflammation and improvement in a measure of pulmonary mechanics in an experimental model of feline asthma.13 Toxicity of this small molecule inhibitor was a concern, and the side effects must be carefully weighed against the potential benefits on airway inflammation and airflow limitation.
Stem cell therapy has been advocated for use in a number of chronic lung disorders, including asthma. A pilot study suggested allogeneic adipose-derived mesenchymal stem cells had a delayed benefit in an acute model of feline asthma.14 Very few cats present to veterinarians immediately after asthma has developed - the majority of cases we see are cats with chronic established asthma. In a subsequent study using a chronic feline asthma model, no effect on airway inflammation or airway hyperresponsiveness were noted; however, airway remodelling was attenuated.15 Without additional stem cell treatment, airway remodelling progressed, suggesting repeated dosing over long periods of time would likely be necessary.
Neurogenic inflammation is thought to contribute to pathologic features of allergic asthma. Inhibition of the neurokinin-1 receptor (NK-1R) is an interesting novel strategy. Treatment of experimentally asthmatic cats with acute asthma given a single injection of an NK-1R antagonist showed no benefit on reduction of airflow limitation or airway inflammation.16 Similarly, when chronically administered an oral NK-1R antagonist for 2 weeks, there was also no beneficial effect on the asthmatic phenotype.17 Other targets for neurogenic inflammation have yet to be studied.
References
1. Schooley E, McGee Turner J, Jiji R, et al. Effects of cyproheptadine and cetirizine on eosinophilic airway inflammation in cats with experimentally induced asthma. Am J Vet Res. 2007;68:1265–1271.
2. Padrid P, Mitchell R, Ndukwu I, et al. Cyproheptadine-induced attenuation of type-I immediate-hypersensitivity reactions of airway smooth muscle from immune-sensitized cats. Am J Vet Res. 1995;56:109–115.
3. Reinero C, Decile K, Byerly J, et al. Effects of drug treatment on inflammation and hyperreactivity of airways and on immune variables in cats with experimentally induced asthma. Am J Vet Res. 2005;66:1121–1127.
4. Leemans J, Cambier C, Chandler T, et al. Prophylactic effects of omega-3 polyunsaturated fatty acids and luteolin on airway hyperresponsiveness and inflammation in cats with experimentally-induced asthma. Vet J. 2010;184:111–114.
5. DeClue A, Schooley E, Nafe L, et al. feG-COOH blunts eosinophilic airway inflammation in a feline model of allergic asthma. Inflamm Res. 2009;58:457–462.
6. Eberhardt J, DeClue A, Reinero C. Chronic use of the immunomodulating tripeptide feG-COOH in experimental feline asthma. Vet Immunol Immunopath. 2009;132:175–180.
7. Reinero C, Lee-Fowler T, Dodam J, et al. Endotracheal nebulization of N-acetylcysteine increases airway resistance in cats with experimental asthma. J Feline Med Surg. 2011;13:69–73.
8. Mitchell R, Cozzi P, Ndukwu I, et al. Differential effects of cyclosporine A after acute antigen challenge in sensitized cats in vivo and ex vivo. Br J Pharmacol. 1998;123:1198–1204.
9. Padrid P, Cozzi P, Leff A. Cyclosporine A inhibits airway reactivity and remodeling after chronic antigen challenge in cats. Am J Repir Crit Care Med. 1996;154:1812–1818.
10. Reinero CR, Byerly JR, Berghaus RD, et al. Rush immunotherapy in an experimental model of feline allergic asthma. Vet Immunol Immunopathol. 2006;110:141–153.
11. Reinero C, Cohn L, Delgado C, et al. Adjuvanted rush immunotherapy using CpG oligodeoxynucleotides in experimental feline allergic asthma. Vet Immunol Immunopath. 2008;121(3–4):241–250.
12. Lee-Fowler T, Cohn L, DeClue A, et al. Evaluation of subcutaneous versus mucosal (intranasal) allergen-specific rush immunotherapy in experimental feline asthma. Vet Immunol Immunopathol. 2009;129:49–56.
13. Lee-Fowler T, Guntur V, Dodam J, et al. The tyrosine kinase inhibitor masitinib blunts airway inflammation and improves associated lung mechanics in a feline model of chronic allergic asthma. Int Arch Allergy Immunol. 2012;158:369–374.
14. Trzil JE, Masseau I, Webb TL, et al. Intravenous adipose-derived mesenchymal stem cell therapy for the treatment of feline asthma: a pilot study. J Feline Med Surg. 2015, pii: 1098612X15604351.
15. Trzil JE, Masseau I, Webb TL, et al. Long term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma. Clin Exp Allergy. 2014;44(12):1546–1557.
16. Grobman M, Krumme S, Outi H, et al. Acute neurokinin-1 receptor antagonism fails to dampen airflow limitation or airway eosinophilia in an experimental model of feline asthma. J Feline Med Surg. 2016;18(2):176–181.
17. Grobman M, Graham A, Outi H, et al. Chronic neurokinin-1 receptor antagonism fails to ameliorate clinical signs, airway hyper-responsiveness or airway eosinophilia in an experimental model of feline asthma. J Feline Med Surg. 2016;18(4):273–279.