Update on feline asthma (Proceedings)

Feline bronchopulmonary disease (FBPD), often referred to as "feline asthma" actually encompasses a group of common, but poorly understood, airway diseases. It is estimated that bronchopulmonary disease affects 1% of the general cat population and > 5% of the Siamese breed. Cats of any age can be affected and there is no clear gender predisposition.

Pathophysiology

Airways have a limited number of ways of responding to inhaled irritants or immunologic stimuli. The airway walls usually become thickened and edematous. These thickened airways then experience a greater degree of narrowing in response to a given amount of smooth muscle contraction, resulting in a smaller luminal diameter. Submucosal glands may become hyperplastic and secrete excessive amounts of thick mucus. These physiologic changes result in narrowed airways and increased airway resistance. Initially, reversible airflow obstruction may be seen (which can respond to medications); however, with time, airway remodeling may occur, resulting in a "fixed" airway obstruction.

In humans, hyperreactivity of the airways is a hallmark of clinical asthma; this has been documented in some cats. True asthma results from an IgE mediated hypersensitivity to airborne allergens. Helper T cells produce a variety of interleukins and direct the release of inflammatory mediators. In humans, asthma often has a genetic component.

Infection with Mycoplasma may also have a role in the generation of feline bronchopulmonary disease. Mycoplasma is an extracellular pathogen which attaches to and destroys ciliated epithelial cells. Mycoplasma infection has been shown to produce airway inflammation and hyperreactivity in mice. In humans, infection with M. pneumoniae has been found to be significantly associated with asthma. Studies have shown that 50% of children experiencing their first asthmatic attack were also infected with M. pneumoniae. Furthermore, those children suffering from mycoplasmal infections were far more likely to suffer from recurrences of asthma. In cats, approximately 25% of feline patients evaluated for bronchopulomonary disease culture positive for Mycoplasma.

Heartworm infection is being increasingly recognized as a cause of bronchial disease in cats. Cats are inherently more resistant to heartworm (HW) infection and tend to have smaller, less frequent infections. However, in ~50% of cats who are exposed to HW but who are able to reject the infection still develop respiratory disease. Exposure to heartworm, even in cats who never are truly infected with adult worms, can still result in proliferative changes in the pulmonary arteries and arterioles, bronchioles and lung parenchyma, leading to "heartworm-associated respiratory disease (HARD)". Potentially up to three-quarters of cats with adult HW infection develop clinical signs.

Another potential cause of feline bronchopulmonary disease is the use of bromide to treat seizures. Two separate studies found that approximately one-third of feline patients treated with bromide began coughing and showing evidence of lower airway disease. In some of these cats, the bronchopulmonary changes were so severe as to result in euthanasia. In cats receiving bromide, eosinophilia was found in the bronchoalveolar fluid.

Clinical Signs

Affected cats typically have intermittent respiratory distress and may be without clinical signs between episodes. In some cats, FBPD can result in severe, potentially fatal respiratory distress. With time, progressive airway changes can develop that result in more severe clinical disease and diminished quality of life. Cats typically display coughing and wheezing. Owners may mistake coughing for gagging or vomiting. An increase in respiratory rate and/or effort is usually present during episodes. Signs may progress to more overt dyspnea wherein the cat may become cyanotic and display open-mouth breathing.

During the physical examination, harsh lung sounds, crackles or wheezes may be ausculted. The clinician may note a prolonged expiratory phase to respiration. An abdominal effort may be noted during respiration. During more severe episodes, the cat may be cyanotic and open-mouth breathing.

Differential diagnoses

There are many differential diagnoses to consider for a cat presenting for coughing, wheezing or respiratory difficulty. In addition to feline asthma and other inflammatory, noninfectious bronchopulmonary disease, infectious causes including viral, fungal, protozoal, bacterial or parasitic agents; cardiac disease, pleural space disease (chylothorax, pyothorax, pneumothorax, hemothorax), neoplasia, upper airway disease, respiratory tract foreign bodies and pulmonary thromboembolism should be considered. Clinicians should also keep in mind that the cat may actually be vomiting or gagging and the client is mistaken in presenting the cat for coughing.

Diagnosis

A minimum database (CBC, chemistry profile, urinalysis) may be more beneficial for ruling out causes other than FBPD for coughing and respiratory distress. In feline bronchopulmonary disease, the CBC may reveal eosinophilia in approximately 20% of the cases. Neutrophilia and/or a stress leukogram may also be present. Hyperproteinemia or hemoconcentration may also be noted. Fecal analysis (floatation, Baermann, sedimentation) is recommended to rule out parasites.

Heartworm testing, although fraught with complications, should be undertaken. Antigen-positive cats usually have adult HW infections. Cats who do not develop adult worms may be antibody-positive, antigen-negative. Approximately 50% of those cats will develop HARD.

Thoracic radiographs usually display many abnormalities in cats suffering from bronchopulmonary disease. A bronchial pattern, described as "doughnuts" and "tramlines", is frequently present. Peribronchial cuffing is also seen. Other radiographic findings may include flattening of the diaphragm, atelectasis of the right middle lung lobe and air trapping. Rarely, radiographs may be normal.

Airway cytology, obtained through either tracheal wash or bronchoscopy, reveals inflammation. In healthy cats, the predominant cell type (80%-90%) is the alveolar macrophage. In cats suffering from bronchopulmonary disease, increased numbers of eosinophils and/or neutrophils are found. Airway eosinophilia is considered to be more consistent with true asthma whereas airway neutrophilia may be seen more with chronic bronchitis. It is important that samples are handled appropriately and in a timely manner. A recent study by DeClue and Reinero found that storage of samples for greater than 48 hours affected the cellular composition.

Either bronchoalveolar lavage fluid or tracheal wash fluid can be submitted for bacterial and mycoplasma culture. It can be difficult to distinguish between true bacterial infections versus colonization of the airways. Growth of a single organism without the use of enrichment broth is consistent with a true infection. Isolation of Mycoplasma is always of clinical significance because Mycoplasma is not recovered from the airways of healthy cats. Additionally, the destructive effects of Mycoplasma upon the respiratory epithelium makes isolation of it of note.

Endothelin-1 is expressed in the lungs and has been implicated in causing inflammatory airway disease. Endothelin-1 is pro-inflammatory, profibrotic, and causes bronchoconstriction. In cats with experimentally induced asthma, greater amounts of endothelin-1 were found in their BAL fluid as compared to normal cats. Further work is needed on the usefulness of this assay in cats with naturally occurring disease as well as whether serum concentrations could be beneficial in the diagnosis of asthma.

Bronchoscopy allows visualization of the airways. Increased secretions as well as edema may be seen. Complication rates for bronchoscopy in cats range from 25%-40%; however, most complications are considered minor.

In humans, pulmonary function testing is usually done as part of the work-up for a suspected asthmatic or bronchitic patient as well as in monitoring the response to treatment. In veterinary medicine, pulmonary function testing is usually limited to teaching hospitals and large referral centers. Noninvasive tests such as tidal breathing flow volume loops and barometric whole body plethysmography have been used in cats. Tidal breathing flow volume loops (TBFVL) measure air flow and volume during both inspiration and expiration. In healthy cats, peak flow occurs during late inspiration and early expiration. Decreased expiratory flow rates are seen in feline bronchopulmonary disease, resulting in a flattening of the curve. Barometric whole body plethysmography (BWBP) is another noninvasive measurement of pulmonary function that can be done on nontrained cats. The patient is placed into an airtight, ventilated chamber. Pressure changes are measured as the cat inspires and expires. During bronchoconstriction, the major alteration is seen in early expiration.

Research is currently underway evaluating the usefulness of evaluation of Exhaled Breath Condensation (EBC) for the diagnosis of asthma in cats. In human patients with asthma, a difference in metabolomics (profiling of metabolic pathway intermediates) can be used in diagnosis. More work is needed to see if this methodology will be useful in cats with naturally occurring disease.

Treatment

The acute crisis

Asthmatic cats may present in true respiratory distress (open-mouth breathing, cyanotic) which may prove to be fatal. It is crucial to stabilize these cats without causing them undue stress. Oxygen needs to be supplemented in a fashion that does not make the cat anxious or induce panic. If it is available, the cat should be placed into an oxygen cage. Both bronchoconstriction and inflammation need to be addressed. Bronchodilators include both beta-2 agonists such as terbutaline and methylxanthines such as aminophylline and theophylline. If available, inhalational bronchodilators such as the beta-2 agonist albuterol may provide more immediate relief than if given by injection. If an inhalational bronchodilator is not available, injectable bronchodilators should be used. Epinephrine should be considered as a last resort. A systemically acting corticosteroid such as dexamethasone should be administered during the acute attack as inhalational corticosteroids do not reach full efficacy for a period of time.

Chronic therapy

Glucocorticoids

Glucocorticoids (GC) are an essential tool in the management of feline bronchopulmonary disease. GC are necessary for treating the inflammatory component, thus preventing progression of the disease. Oral GC should be used in the initial management of cats with bronchopulmonary disease. GC should be tapered to the lowest effective dose to minimize side-effects if possible. In minimally affected cats, i.e. very intermittent clinical signs, GC therapy may be halted when clinical signs are not present (after an appropriate period of tapering off of medication).

An alternate delivery method of GC is via inhalation. This allows for more immediate delivery to the target organ with fewer systemic side-effects. It has been proven that untrained cats will have deposition of inhaled materials in their lower airways. Inhaled GC have been shown to reduce bronchial reactivity and eosinophilia. Minimal impact on the immune system is seen with inhaled GC. They do produce some changes in the hypothalamic-pituitary-adrenal axis, but the clinical significance of these alterations is not known. Inhalational therapy is strongly recommended for cats suffering from additional conditions such as heart disease or diabetes where systemic glucocorticoids should be avoided. Inhalational GC therapy should initially be administered concurrently with oral GC because it can take up to 10 days for the inhaled medication to reach full effect. Fluticasone (Flovent) 110 mcg/actuation is a commonly used inhaled GC in veterinary patients.

Using Inhaled Medications

Equipment

The two major classes of medications used in the treatment of feline asthma, corticosteroids and bronchodilators, are available as metered-dose inhalers (MDI). MDI deliver a specific amount of medication per actuation (puff). The actuation of the MDI is supposed to be coordinated with a slow, deep inhalation. The timing of this breath has proven difficult in humans and impossible in veterinary patients. For this reason, the use of a spacer is strongly recommended. In humans, spacers have been shown to potentially double the amount of medication reaching the lower airways. Additionally, in humans with asthma, the use of spacers appears to reduce the systemic effects of inhaled glucocorticoids. The spacer serves as a storage area for the medication until the patient breathes it in. A veterinary specific spacer, Aerokat®, is available (www.aerokat.com). The Aerokat® has a built-in facemask that will fit most cats and small dogs on one end and an opening on the other end that fits the MDI device. Spacers meant for human use can also be used. They will need to be used with an appropriate facemask.

Technique

     1. Shake the MDI 3-4 times, then remove the cap and insert the MDI into the appropriate end of the spacer.

     2. Place the facemask gently over the cat's face, making sure the nose is covered.

     3. Actuate the MDI.

     4. Hold the mask in place for 7-10 seconds.

     5. If 2 actuations of the same medication are prescribed, wait 30-60 seconds in-between repeating administration. Start again at step 1, shaking the MDI.

     6. If using both a bronchodilator and a corticosteroid, use the bronchodilator first, wait for 5 minute, then administer the corticosteroid. The bronchodilation achieved will allow for deeper deposition of the corticosteroid into the lungs.

     7. Follow manufacturers' recommendations for cleaning.

     8. The owner needs to monitor the number of actuations administered to know when the MDI needs to be replaced. The number of actuations contained within the MDI is listed on the canister. The owner can divide the total number of actuations by the number to be administered daily to know how many days the MDI will last for. Fluticasone at 1 actuation twice daily will last for 2 months. It is inaccurate to see if the MDI floats in water as a judge of whether or not the canister is empty.

Bronchodilators

Bronchodilators are also available in both oral and inhaled formulations. Bronchodilators such as albuterol are crucial during the acute asthmatic crisis. Inhaled albuterol can be administered every ½ hour for up to 4 hours during a crisis. Bronchodilators are also useful in the management of chronic disease but should not be used as the sole therapy. Bronchodilators are not anti-inflammatory and do nothing to prevent airway remodeling. There is some concern that chronic albuterol administration can actually result in airway inflammation. Bronchodilators should be administered during times of increased symptoms or to decrease the amount of GC administered, not as a monotherapy.

Antibiotics

Antibiotics are rarely indicated in the treatment of feline asthma, with the exception of treating Mycoplasma infections. If Mycoplasma is isolated, an appropriate antibiotic such as doxycycline should be administered at the usual dose. Other bacterial infections only warrant treatment if culture suggests a true infection (growth of a single agent) rather than colonization of the airways.

Serotonin inhibitors

Cyproheptadine, a serotonin inhibitor, has been advocated as an additional therapeutic for asthma. Serotonin mediates smooth muscle contractility in feline airways. Studies have not shown consistent benefit. It may be that higher doses are necessary.

Cyclosporine

Asthma is mediated by T helper 2 cells so suppressing T cells may be of benefit. Cyclosporine decreases IL-2 production resulting in inhibition of T cell proliferation. Experimentally, cyclosporine reduces airway reactivity & remodeling. However, cyclosporine is expensive and can cause gastrointestinal upset. Further investigation into the use of cyclosporine for treating feline asthma is necessary.

Immunotherapy

"Allergy shots", such as are used to treat atopic skin disease, are another consideration in the treatment of feline asthma. The mechanism by which immunotherapy works is still poorly understood. There is little correlation between allergens determined by skin tests and allergens seen on blood panels. There is also no correlation between the number of reacting allergens (a high number suggesting a very allergic patient) and the amount of airway eosionophilia. When compared to normal cats, cats with airway disease do have a greater number of positive allergen reactions, regardless of the test methodology. Immunotherapy involves exposing the patient to a known allergen and thus carries the risk of inducing an anaphylactic reaction. Studies on cats with naturally occurring disease are needed before this therapy can be safely recommended.

Omega 3 Fatty Acids

Omega 3 Fatty Acids as found in fish oil have received a lot of attention due to their potent antioxidant and anti-inflammatory effects. One study did not find any decrease in bronchial reactivity or change in airway cytology. A decrease in pulmonary oxidative stress was noted however.

Environmental Modification

One of the simplest yet most often overlooked as aspects of managing feline asthma is modifying the environment. Inhaled particles can act as irritants as well as potentially inducing allergic reactions. If an offending allergen can be identified and removed from the cat's environment, then the asthma could be potentially be completely resolved. Unfortunately, it is usually impossible to remove all allergens from the environment even if the allergen(s) can be identified. It is still important to reduce the amount of airborne allergens and irritants. HEPA filters and air cleaners should be used. Common household airway irritants include dusty cat litter, tobacco smoke and aerosols.