Studies of Naturally Occurring Disease

Feline bronchial disease has been recognized for over a century. In 1906 Hill described cats with increased airway mucus, airway inflammation, labored breathing, and wheezing (Hill, 1906). In this monograph, airway reactivity was suggested (“ammoniacal odors [urine? in the barn?] excited the symptoms”). However, only in the last 15 years have veterinarians begun to study the disorder in earnest. Dye and associates (1996) identified pulmonary function abnormalities in cats with signs of chronic lower airway inflammation. Some of these cats had increased pulmonary resistance that resolved after treatment with terbutaline, a β₂-agonist, which indicated the presence of reversible bronchoconstriction. In addition, some of these cats experienced dramatic bronchoconstriction after exposure to low levels of methacholine, a drug with minimal effects on pulmonary function when used in equivalent doses in nonasthmatic cats. This was the first demonstration of spontaneous, naturally occurring airway hyperreactivity and reversible bronchoconstriction in a nonhuman species. In addition, histologic changes in airway specimens from asthmatic cats include epithelial erosion, goblet cell and submucosal gland hyperplasia and hypertrophy, and an increased mass of smooth muscle, which are features of human asthmatic airways. Additional reviews have demonstrated the variation in clinical findings, radiographic patterns, and responses to therapy in cats with bronchitis and asthma (Foster et al, 2004). This likely is a result of differences in the staging of these disorders and the confusion caused by other respiratory disorders such as pulmonary fibrosis and occult heartworm infection (Cohn et al, 2004).

Experimentally Induced Feline Asthma

Experimental models of feline asthma have been developed to elucidate the immunologic mechanisms and objectively determine responses to therapy. The first model of feline asthma involved antigen sensitization and long-term aerosol challenge with Ascaris suum. These cats developed persistent airway eosinophilia and hyperresponsiveness to nebulized acetylcholine along with typical morphologic changes observed in spontaneous bronchial disease of cats. These studies suggested mast cell–derived serotonin as a primary mediator contributing to airway smooth muscle contraction (Padrid et al, 1995). This mediator is absent in human, equine, and canine airways. According to this hypothesis, inhaled antigens promote mast cell degranulation, with the release of preformed serotonin precipitating the acute asthmatic attack through contraction of airway smooth muscle. The role of histamine is less certain given the variable effects of nebulized histamine, which range from bronchoconstriction to airway dilation. In clinical practice, antihistamine drugs do not demonstrate a beneficial effect in the treatment of cats with chronic bronchitis or asthma. Leemans and colleagues (2012) also have used the feline A. suum model of airway inflammation to demonstrate that inhaled fluticasone propionate was as effective as oral prednisolone in dampening eosinophilia in bronchoalveolar lavage (BAL) fluid and allergen-induced airway reactivity.

Reinero and colleagues (2005) developed an experimental feline model in which cats were sensitized and recurrently challenged with either Bermuda grass allergen (BGA) or house dust mites to mimic well-recognized antigenic triggers of human asthma. These cats showed enhanced production of allergen-specific immunoglobulin E (IgE); allergen-specific serum and BAL fluid IgG or IgA; airway hyperreactivity; airway eosinophilia; an acute helper T cell type 2 cytokine profile in peripheral blood mononuclear cells and BAL fluid cells; and histologic evidence of airway remodeling. This model has been particularly helpful in evaluating specific immunomodulating treatment strategies. For example, when cats sensitized and challenged with BGA were then treated with rush immunotherapy (high parenteral doses of BGA), eosinophil counts decreased significantly. Norris and associates (2003) used CpG motifs (microbial oligodeoxynucleotide products that modulate activity in human and murine lymphocytes) in cats with BGA-induced airway inflammation and hyperreactivity. This approach dampened the eosinophilic response normally seen in these antigen-sensitized and -challenged cats; however, the hyperactivity within airways was unaffected. More recently, this group has shown that allergen-specific immunotherapy (with or without a CpG adjuvant) can suppress BAL fluid eosinophilia and that irrelevant antigen can dampen the eosinophilic response (Reinero et al, 2009b). This latter finding is significant because the offending antigens that play a role in the pathogenesis of naturally occurring feline asthma have not been identified. Finally, IgE, nitric oxide, interleukin-4, interferon-γ, and tumor necrosis factor all have been identified and measured in BAL fluid or serum in this model, but none of the levels of these biomarkers has been elevated significantly enough to be recommended for diagnostic purposes in clinical practice (Delgado et al, 2010; Nafe et al, 2010).

Incidence and Prevalence

Currently there are no reliable data regarding the incidence and prevalence of asthma in cats. The prevalence of lower airway disease in the general adult cat population is estimated to be approximately 1%; prevalence in the Siamese breed may be 5% or higher as also suggested by an informal survey at a website (www.fritzthebrave.com) devoted to feline asthma (Hopper, n.d.).

Clinical Signs

Clinical signs are variable. Cats with bronchitis have a daily cough and may be absolutely free of signs between episodes of cough. Alternatively, they may be tachypneic at rest. This is different from dogs with chronic bronchitis, in which tachypnea is rare, and suggests that cats with chronic bronchitis should be treated aggressively early in the course of the disease. Asthmatic cats may cough, wheeze, and struggle to breath on a daily basis. In mild cases, signs may be limited to occasional and brief coughing. Some cats with asthma may be asymptomatic for weeks or months between occasional episodes of acute airway obstruction. Severely affected cats may have a persistent daily cough and experience repeated episodes of life-threatening acute bronchoconstriction.

As previously noted, in a cat with chronic coughing, it is difficult to distinguish chronic bronchitis from asthma as the underlying cause. Although these two disorders are frequently lumped together under the title of chronic bronchial disease or lower airway disease, different therapeutic approaches are needed and the disorders carry dissimilar prognoses. For example, asthmatic but not bronchitic cats may benefit from bronchodilator treatment.

Physical Examination Findings

There are no consistent physical examination findings on which to base a diagnosis of asthma. Importantly, cats with bronchitis or asthma may have normal physical examination findings at rest. When respiratory distress is evident, it occurs during expiration, which is a hallmark finding of both disorders in cats. Adventitious sounds including crackles often are heard. Wheezes are more characteristic of feline asthma.

• A history that includes one or more of these chronic persistent or intermittent clinical signs: acute wheeze, tachypnea, or respiratory distress, including labored, open-mouth breathing. These signs are usually relieved quickly with some combination of oxygen, bronchodilators, and corticosteroids. The diagnosis of chronic bronchitis requires the presence of a daily cough. But many cases of asthma also present with daily or intermittent chronic cough as the only problem.

• Findings on routine survey chest radiographs may be normal, and this result does not rule out asthma. However, frequently radiographs demonstrate diffuse prominent bronchial markings consistent with inflammatory airways (“doughnuts and tram lines”). Air trapping may be evidenced by hyperinflated airways. This is seen most prominently on the lateral view and can be appreciated by recognizing the position of the diaphragmatic crus at approximately the level of L1-L2. In the author’s experience approximately 10% of radiographs in cats with bronchial disease have increased density within the right middle lung lobe associated. This may be associated with a mediastinal shift to the right. This is evidence of atelectasis. It is usually easier to see this pattern on a dorsoventral or ventrodorsal exposure because the right middle lung lobe silhouettes with the cardiac silhouette on the lateral view. Atelectasis with or without bronchial stenosis most commonly occurs in the right middle lung lobe (Johnson and Vernau, 2011) because of mucus accumulation within the bronchus. This lobe is involved most commonly because its bronchus demonstrates a dorsoventral orientation and is more susceptible to gravitational influences.

• In more extreme cases, fluffy, ill-defined heavy interstitial infiltrates in multiple lung lobes may be appreciated. These changes may stem from multiple small areas of atelectasis associated with diffuse small mucus plugs. This presents a diagnostic challenge because this radiographic change is consistent with a number of disorders, including neoplasia and diffuse interstitial pneumonitis.

• Clinicopathologic evidence of airway inflammation is found, including the recovery of large numbers of eosinophils from tracheobronchial secretions in asthmatic airways and nonseptic neutrophils in bronchitic airways. Interestingly, until the 1980s it was generally assumed that eosinophils played only a beneficial role in the immune system by protecting against parasitic infection. However, within the last 30 years it has become clear that the presence of these cells in the wrong place at the wrong time can result in significant cellular and tissue damage. Therefore it is of great interest that eosinophils (often 20% to 25% of total count) can be recovered in large numbers from the tracheobronchial washings of many healthy cats (Padrid et al, 1991), and these cells appear to cause no damage to the local tissue environment. Their presence should not be assumed to indicate allergy or parasitism. Thus eosinophil counts can be somewhat confusing because of this normally high value. Similarly, alveolar macrophages are a normal cell within the lung parenchyma and are the most common cells recovered from BAL fluid obtained from healthy cats. These cells should not be interpreted as granulomatous or histiocytic inflammation when obtained in BAL fluid from bronchitic or asthmatic cats. These cells may also be resistant to eradication with corticosteroid therapy (Cocayne et al, 2011).