Immune-mediated Respiratory Disease
World Small Animal Veterinary Association World Congress Proceedings, 2007
Rance K. Sellon, DVM, PhD

Introduction

Like the skin and intestinal tract, the respiratory system is constantly exposed to a variety of potential allergens. It is no surprise then that the respiratory system of dogs and cats can be the site of immunologically-mediated respiratory disease, which are seen primarily in the form of airway diseases. This paper will discuss feline asthma and canine eosinophilic bronchopneumopathy (EB), formerly known as pulmonary infiltrates with eosinophils (PIE) as the typical immune-mediated respiratory diseases. While not considered strictly "immune-mediated," canine chronic bronchitis is discussed because it is an important canine respiratory disease.

Feline Asthma Syndrome

Feline asthma is believed to represent a type I hypersensitivity reaction to allergens, possibly inhaled. There is little definitive evidence of this pathogenesis for spontaneous disease in cats, but this pathogenesis is supported by experimental models of feline asthma. Circumstantial evidence from necropsy, as well as clinical observations supports this proposed etiology. While the specific allergic or environmental factors that trigger clinical signs in cats have not been determined, most evidence suggests that the pathogenesis of the feline asthma syndrome likely parallels that of human asthma.

Clinical signs of "asthma" in cats typically include cough, tachypnea and sometimes episodes of severe respiratory difficulty. Affected cats are usually young to middle-aged, although clinical signs can occur in cats of any age. Clinical signs can be present for weeks to months prior to examination, and can wax and wane.

Physical examination abnormalities in affected cats can include wheezes, tachypnea, cough, and sometimes prominent expiratory effort. Occasional cats may have normal respiratory sounds. Fever is also possible.

A diagnosis of feline asthma is based on supportive thoracic radiographic findings, laboratory results, airway fluid cytology, and response to therapy. Thoracic radiographs help exclude other differential diagnoses for cough and respiratory distress. Bronchial patterns, interstitial patterns, or a combination of bronchial and interstitial patterns are the most commonly observed radiographic abnormalities. Alveolar patterns, often patchy in distribution, and collapse of the right middle lung lobe may be seen as can lung hyper-inflation and aerophagia. Lung lobe torsion has been reported in association with feline asthma. Thoracic radiographs can be normal in some cats.

Results of laboratory tests in cats with feline asthma syndrome can be variable. Eosinophilia may support the diagnosis, but its absence would not exclude a diagnosis of feline asthma. In retrospective studies, affected cats were more likely to have normal eosinophil counts than to have eosinophilia. Results of serum biochemical profiles are usually normal, although hyperglobulinemia is seen in a fraction of cats. Urinalysis results should be normal unless there is concurrent disease.

Results of bronchial fluid cytology, obtained by either transtracheal aspiration, endotracheal tube washings, or bronchoscopy, may show eosinophils as the predominant cell type to specimens in which neutrophils are the predominant cell type, especially if obtained from chronically diseased cats. Mixed populations of eosinophils, neutrophils, macrophages and lymphocytes are possible. Positive microbial cultures of wash fluid may be seen in some cats; microbes are not thought to play a major role in the pathogenesis of clinical signs, but when recovered, they usually prompt treatment with antibiotics.

Therapy for cats with feline asthma hinges on administration of corticosteroids and bronchodilators. In acute episodes requiring rapid relief, intravenous administration of prednisolone sodium succinate (1-2 mg/kg) or dexamethasone (0.2-0.5 mg/kg) is useful, while oral or inhaled formulations are more appropriate for less severely affected cats or for maintenance therapy. Reported beneficial effects of corticosteroids in cats with asthma include anti-inflammatory properties, increased sensitivity to ß2 adrenergic agonists, and decreased mucus secretion (people). The goal of glucocorticoid therapy is to maintain affected cats symptom free with the least amount of medication required. Some cats will remain symptom free for extended periods following dose taper and cessation of steroid therapy and require only intermittent treatment while other may require life-long administration.

The most commonly used bronchodilators for treatment of acute episodes are ß2 agonists such as terbutaline (0.01 mg/kg IM or SC q4-8h), albuterol and others. In emergency situations, administration of epinephrine (0.1 mg) may be valuable, but its bronchodilatative properties are balanced by some bronchoconstrictive properties mediated by α-adrenergic receptor stimulation; it is not advised for cats with pre-existing hypertension or heart disease. More chronic bronchodilation may be achieved with methylxanthines such as theophylline (25 mg/kg PO q24h), or terbutaline (0.625 mg PO q12h). Cyproheptadine (2 mg/kg PO q12h) may benefit some cats. Leukotriene receptor antagonists are not considered useful.

Canine Allergic Lung Disease

Like feline asthma, canine EB is considered manifestation of a type I hypersensitivity reaction. Proposed sources of antigenic stimulation have included inhaled allergens, parasitic larvae migrating through the lungs, and heartworms in endemic areas. There has also been some suggestion that food allergens may also have a role in the development of eosinophilic lung disease. The true cause is rarely identified.

EB is characterized clinically by a history of chronic antibiotic unresponsive cough, increased respiratory effort, and exercise intolerance. Fever, lethargy, anorexia, and weight loss may be seen in some dogs. The cough may sound "moist," and may be very productive. Miscellaneous complaints in dogs with EB have included pruritus and skin lesions. Physical examination abnormalities reflect respiratory system disease including inducible cough, wheezes and crackles.

The diagnosis of EB is supported by history and physical examination, and by results of appropriate diagnostic tests. Results of a CBC may show neutrophilic leukocytosis and variably present eosinophilia. Results of biochemical profile and urinalysis are usually normal unless there is concurrent disease. The most common radiographic abnormalities in dogs with EB are interstitial and peribronchial infiltrates. Patchy alveolar infiltrates or lung lobe consolidation can also be seen. Radiographic changes are not specific for eosinophilic pulmonary disease.

Additional diagnostic tests that can be helpful include bronchoscopy and cytological examination of respiratory wash fluid. Bronchoscopic abnormalities typically include the presence of abundant amounts of greenish or greenish-yellow mucus, mucosal erythema and nodular hyperplasia. There is an abundance of eosinophils in respiratory wash specimens, although a predominance of neutrophils may be present in some. Bacterial culture of wash fluid is usually negative.

A diagnosis of EB is based on exclusion of other potential causes of eosinophilic pulmonary infiltrates such as heartworm infection, and pulmonary parasites (Oslerus and others), pulmonary neoplasia and bacterial or fungal infections. The diagnostic approach to these patients thus also includes screening tests for heartworm disease and fecal examinations.

Treatment for EB centers around elimination of exposure to allergens if candidates are identified, and administration of immunosuppressive dosages glucocorticoids. Treatment with high glucocorticoid doses should continue until remission is achieved as determined by resolution of clinical signs and improvement in radiographic appearance. Glucocorticoids are then tapered after clinical remission has been accomplished. Relapses may be seen, and patients are candidates for long-term therapy with glucocorticoids at the minimal dose needed to control clinical signs. The role of allergy testing and hyposensitization needs to be explored as some dogs appear to achieve remission with lower doses of glucocorticoids if also hyposensitized based on allergy testing. The prognosis is generally good, but dogs with severe disease should be considered to have a guarded prognosis.

Canine Chronic Bronchitis

Chronic canine bronchitis is a syndrome defined as a cough that occurs on most days of two or more consecutive months in the absence of other active or causative disease. The etiology in most cases is never determined, but chronic airway inflammation in response to an inhaled inflammatory stimulus defines the proposed pathogenesis. Canine chronic bronchitis is characterized by excess mucus production in airways and concomitant airway inflammation. Most cases of chronic bronchitis are seen in dogs over 8 years of age, with small and toy breed dogs over-represented. The typical history is a harsh, chronic cough; affected animals may gag or retch at the end of the cough. Exercise intolerance is common, but affected animals are typically normal in other respects.

Physical examination of dogs with chronic bronchitis is fairly unremarkable in most cases except thoracic auscultation; the most commonly heard abnormality is coarse crackles in most lung fields. Because of the dog breeds commonly affected, auscultation of left and/or right sided murmurs is common in dogs with chronic bronchitis. To allow differentiation of the origin of the cough (cardiac or respiratory) in such cases, it is critical to make note of the dog's heart rate: dogs with chronic cough due to chronic bronchitis commonly have normal to low heart rates, while dogs with cough from congestive heart failure would be expected to have an increased heart rate. It is common for dogs with chronic bronchitis to be referred for cardiac evaluation because of the presence of murmur in a dog with a history of chronic cough, or treated without success for heart failure.

Results of routine laboratory test results in dogs with chronic bronchitis are usually normal. Hypoxemia, which can be profound (PaO2 < 60 mm Hg), can be found on arterial blood gas analysis even in dogs that exhibit little evidence of respiratory difficulty.

The most common thoracic radiographic abnormality in dogs with chronic bronchitis is thickened bronchial walls; one report of dogs with chronic bronchitis observed a high proportion of dogs with bronchial calcification. Thoracic radiographs of dogs with chronic bronchitis can also appear normal.

Bronchoscopy is and bronchoalveolar lavage cytology are useful techniques for establishing a more definitive diagnosis of canine chronic bronchitis. A hallmark bronchoscopic feature is excess mucus in airways. Airways will often appear reddened, roughened and can assume a granular appearance. Intrathoracic airway collapse during expiration can also be observed during bronchoscopy.

Bronchopulmonary cytology is helpful in eliminating other causes of lung disease that may appear radiographically similar to chronic bronchitis. Neutrophils are the most commonly observed cell type in dogs with chronic bronchitis, and unless seen with intracellular bacteria, should not be interpreted as reflecting current or recent infection. Lymphocytes, eosinophils and airway epithelial cells are other cells that may be seen, though usually not in the same abundance as neutrophils. If fluid specimens were collected by alveolar lavage, there may be a high proportion of alveolar macrophages, which is considered a normal finding. Fluid obtained during bronchoscopic examination can also be used for bacterial culture and sensitivity testing, though it is uncommon to recover pathogens.

Therapy for dogs with chronic bronchitis is similar to that for cats with asthma, with administration of glucocorticoids, either alone or with bronchodilators, the cornerstone of therapy. Administration of glucocorticoids is done with the goal of decreasing airway inflammation, and secondarily decreasing the stimulus for cough mediated by irritated airway nerve endings. Glucocorticoids may also decrease the amount of mucus production in airways. As is the case with feline asthma, doses of corticosteroids are initially high (prednisone 0.5-1 mg/kg q12h, usually for 5-7 days), then tapered to the least amount required to control clinical signs. A recent report has shown that dogs can fare well with inhaled glucocorticoids.

Bronchodilators may also be of benefit to some dogs with chronic bronchitis. Recommended bronchodilators for dogs with chronic bronchitis include albuterol, terbutaline, and theophylline. If a positive clinical response has not been observed within 14 days, then it is likely that no benefits can be expected from bronchodilators. If clinical response is not seen in response to treatment with theophylline, measurement of serum theophylline concentrations can be determined to be certain that therapeutic concentrations are achieved before abandoning use of the drug.

The administration of antibiotics to dogs with chronic bronchitis should be made on a case by case basis based on culture/sensitivity testing. Response to antibiotics should be appreciated within a week if given as sole therapy, but since these patients are often treated concurrently with other medications, attributing clinical improvement to a specific component may prove a guessing game.

Occasionally, cough suppressants such as hydrocodone (0.22 mg/kg PO q6-12h) or butorphanol (0.25-1 mg/kg PO q6-12h) are necessary in dogs with chronic bronchitis. They are most indicated when coughing persists because of bronchial collapse, or when coughing is unrelenting and exhausting to the pet in the face of therapy glucocorticoids alone or with other drugs (bronchodilators, antibiotics). Because coughing is important for clearing the respiratory tract of mucus, cough suppressants are used judiciously, and owners should be instructed to the effect that some coughing in a dog with chronic bronchitis is acceptable.

Summary

The immune mediated respiratory diseases carry good to fair prognoses with appropriate treatment. Chronic anti-inflammatory therapy may be needed to control clinical signs in some patients.

References

References are available upon request.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Rance K. Sellon, DVM, PhD
Washington State University
Washington, USA


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