Feline inflammatory airway diseases
FELINE INFLAMMATORY AIRWAY DISEASES
Carol R. Reinero, DVM, DACVIM (Small Animal Internal Medicine), PhD
University of Missouri
Columbia, MO, USA
There are a number of important inflammatory airway diseases of the cat including asthma, chronic bronchitis, parasitic bronchitis, and secondary bacterial bronchitis. Asthma, a type I hypersensitivity reaction against aeroallergens results in pathologic features of airway eosinophilia, airway hyperresponsiveness and airway remodeling. Chronic bronchitis is characterized by airway neutrophilia with mucus hypersecretion and impaired mucociliary function; the initial trigger of chronic bronchitis is uncommonly identified. Parasitic bronchitis encompasses Aelurostrongylus abstrusus, heartworm associated respiratory disease (HARD) and possibly Toxocara cati. Secondary bacterial infections arise as a sequel to a variety of underlying etiologies and are likely associated with a disrupted lung microbiome (i.e., dysbiosis). This lecture will primarily focus on non-infectious inflammatory disorders in the cat, with brief mention of treatment of the other infectious disorders. All airway diseases to a certain extent can have some overlapping clinical signs and thoracic radiographic features. Thus, discrimination of these disorders requires consideration of signalment, historical signs, physical examination findings, thoracic radiography, testing for infectious causes, analysis of lavage fluid cytology and response to therapeutic trials. There are some similarities in the strategy for management (e.g., relevant parasitic control in at risk environments and environmental modulation to reduce inhaled irritants), there are also some specific treatments especially for allergic asthma.
APPROACH TO INFECTIOUS INFLAMMATORY FELINE AIRWAY DISEASES
Ancillary diagnostics as mentioned above can be helpful to discriminate infectious etiologies of lower airway inflammation. Aelurostrongylus abstrusus, heartworm associated respiratory disease (HARD) and secondary bacterial infections can cause inflammatory airway lesions. Experimentally it has been suggested that Toxocara cati also causes airway-oriented lesions, although the clinical significance of these lesions in pet cats is unknown. Treatment for these diseases may include an anthelmintic, an appropriate year-round heartworm preventative in endemic areas (regardless of whether the cat is indoor only), and an antibiotic ideally based on culture and sensitivity that passes the blood bronchus barrier (e.g., doxycycline), respectively. Short term glucocorticoid therapy may also help resolve inflammation and clinical signs. Chronic infections may predispose to chronic bronchitis, which is not a curable disease, but can be managed with lifelong therapy (see below).
OVERVIEW OF APPROACH TO NON-INFECTIOUS INFLAMMATORY FELINE AIRWAY DISEASES
Ruling out infectious inflammatory airway disease is part of the work up for non-infectious disorders. Ultimately, lavage fluid analysis (cytology and culture) will help discriminate chronic bronchitis from allergic asthma. The hallmark feature of chronic bronchitis is non-degenerate neutrophilic inflammation and of asthma, eosinophilic inflammation. Cultures are generally negative, although secondary bacterial infections can result. Allergen-specific IgE testing may be beneficial for determining relevant aeroallergens and employing avoidance strategies.
For decades, the cornerstone of management for feline asthma and chronic bronchitis has consisted of environmental modulation, glucocorticoids and bronchodilators. Environmental modulation consists of avoiding or minimizing inhalation of irritants or in asthmatic cats, 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) and can trigger non-specific airway hyperresponsiveness. HEPA filters are useful when cats are indoors. Glucocorticoids are critical for both asthma and chronic bronchitis as they are anti-inflammatory. Bronchodilators are most important for asthmatic cats, especially those with wheeze or episodic respiratory distress; they may not be necessary for asthmatic cats that have cough as the sole clinical manifestation or in cats with chronic bronchitis.
Glucocorticoids are the mainstay of therapy for inflammatory airway disease as unchecked inflammation can predispose to airway hyperresponsiveness and remodeling. There are many routes of administration including oral, inhaled, injectable and transdermal, but not all are good therapeutic options because of adverse effects (e.g., injectable repositol forms) or lack of efficacy (transdermal). There are many types of glucocorticoid preparations, most of which have not been studied specifically in cats. The vast majority of the literature on use of glucocorticoids for feline lower airway disease has been in experimental models.
The author prefers to start treatment of asthma and chronic bronchitis with oral prednisolone, which has higher bioavailability than oral prednisone. If oral prednisolone is not effective, oral dexamethasone has been advocated; however, it has greater diabetogenic effects than prednisolone. Inhaled glucocorticoids have all but replaced oral glucocorticoids in humans with asthma as the drug is delivered directly to the site of disease and systemic effects are minimized. In cats, inhaled glucocorticoids have been shown to have minimal systemic immune effects but can suppress the hypothalamic-pituitary-adrenal axis. Inhaled fluticasone can effectively suppress airway inflammation in cats. The exact dose for each type of inhalant steroid for pet cats is not known and many doses are used anecdotally. There is a plateau effect where high doses do not achieve a larger benefit, meaning that more is not always better. Experimentally, very high short term doses of fluticasone have been shown to be as effective as prednisolone in reducing airway inflammation. Transdermal administration of prednisone or prednisolone (2 mg/kg BID X 3 weeks) does not lead to detectable blood concentrations of prednisolone and thus should not be used therapeutically.
For cats with evidence of acute bronchospasm (e.g., cats having “asthma attacks” also called status asthmaticus), bronchodilators are the most important medication to alleviate the airflow limitation. They are perhaps not as critical for cats who only have cough as the chief complaint when glucocorticoids are given to suppress airway inflammation, as resolution of airway inflammation may reduce narrowed lumens and cough. It is the author’s opinion that bronchodilators should not be given as monotherapy to asthmatic cats or cats with chronic bronchitis. The reason is that these are primarily inflammatory diseases and inflammation must be addressed to halt further damage to the airways. Bronchodilators have adverse effects such as hyperexcitability, systemic hypertension and tachycardia; additionally, owner compliance may be poor with oral medications given 2-3 times daily. Thus unless cats have clinically relevant bronchospasm, the emphasis should be placed on glucocorticoids to manage inflammation.
Short acting beta 2 agonists (SABA) are the most important lifesaving therapy for a cat with status asthmaticus as they work quickly and are potent. Interestingly, there is evidence that chronic inhaled use of SABA may paradoxically exacerbate airway inflammation and airway hyperresponsiveness. In humans this is known as the beta agonist paradox and is responsible for increasing mortality associated with over use of SABA alone. In an experimental model of feline asthma, inhaled racemic albuterol which is a 1:1 mixture of R- and S-albuterol given twice daily for 2 weeks led to significant increases in airway eosinophilia; the R-isomer alone did not. Thus, the author recommends racemic albuterol to be used predominantly as a rescue medication at home and ideally no more than twice weekly. If sustained use of a SABA is needed, inhaled levalbuterol, a commercially available form of R-albuterol, or oral bronchodilators (SABA or methylxanthines) may be administered. Inhaled long acting beta 2 agonists (LABA) are thought to have similar paradoxical reactions, although these effects have not been specifically studied in cats. Overall, LABA (salmeterol) is thought to have weak but more sustained bronchodilatory effects in healthy cats but does not appear to be an effective bronchodilator in asthmatic cats. If given the choice of an injectable or inhaled SABA for an asthmatic cat in crisis, the author will preferentially use an injectable medication as with severe bronchospasm inhaled medications may not adequately reach the target airways. In other words, cat in distress are unable to breathe sufficiently deeply or for long enough periods for inhalant medications to reach their targets.
There have been a variety of other medications have been investigated in experimental asthma models for potential bronchodilatory and anti-inflammatory properties. These include nebulized lidocaine, anticholinergics, cysteinyl leukotriene antagonists, anti-serotonergics and anti-histaminics. Nebulized 2% lidocaine 2mg/kg TID for 2 weeks had no anti-inflammatory effects but significantly reduced AHR compared with placebo. The anticholinergic ipratropium has synergistic bronchodilatory effects with albuterol. There has been no evidence to suggest that the other aforementioned classes of drugs including zafirlukast, cyproheptadine or cetirizine beneficially reduce AHR or airway inflammation.
OTHER ASTHMA THERAPEUTICS
Dietary omega-3 polyunsaturated fatty acids and luteolin (an antioxidant flavinoid) administered to experimentally asthmatic cats for 4 weeks showed no effect on airway inflammation, but did show a decrease in airway reactivity. 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 remodeling), it should not be given as monotherapy to treat feline asthma. 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 preexisting airway disease. 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.
Since allergic asthma is thought to be driven by a T helper 2 lymphocytic process leading to a type I hypersensitivity reaction, modulating Th2 lymphocyte activity seems like a rational target. Treatments which function by altering T cell activity which have been tested in experimental models include cyclosporine, allergen-specific immunotherapy, receptor and non-receptor tyrosine kinase inhibitors and 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 remodeling. Because of the need for therapeutic monitoring and the potential side effects of cyclosporine, it is NOT advocated for routine management of feline asthma, but may be considered in severe or refractory cases. Other potential therapies being evaluated for the treatment of feline asthma include allergen-specific immunotherapy (“allergy shots”). Allergen-specific immunotherapy is most commonly administered to humans with allergic rhinitis, but has also been used in the treatment of asthma. There is evidence that an abbreviated form of conventional immunotherapy, called rush immunotherapy, may dampen eosinophilic inflammation in experimental feline asthma. Addition of an adjuvant (CpG immunostimulatory sequences which polarize the immune response towards a T helper 1 and away from a T helper 2 response) demonstrated good safety and efficacy. Comparing the subcutaneous route of injection with topical mucosal delivery of allergen-specific rush immunotherapy was also performed in experimental feline asthma. 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. Concurrent use of oral glucorticoids during immunotherapy diminishes its efficacy; however, inhaled steroids do not alter beneficial effects of immunotherapy. The major difference between allergen-specific immunotherapy and other forms of treatment (eg, steroids and bronchodilators) is that immunotherapy has the potential for cure of the disease by re-training 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. Masitinib had beneficial effects on the asthmatic phenotype; however, adverse effects were common and limiting. Toxicity of these small molecule inhibitors is 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. Allogeneic adipose-derived mesenchymal stem cells have been assessed in experimental feline asthma. These are different from commercial autologous stem cells many of which are really “stromovascular fraction” that likely have few stem cells. While with the protocol used there was no reduction of airway inflammation or AHR, airway remodeling assessed by computed tomographic changes was dampened compared with placebo. Additional study of stem cell protocols is warranted.