Coughing and wheezing cats (Proceedings)

Lower respiratory tract disease produces typical clinical signs in cats, including chronic cough and wheeze as well as dyspnea that may have a sudden onset. Owners may report an increase in respiratory rate (>30-40 breaths per minute), increased expiratory effort and lethargy. Clinical signs may be mild to severe and may be chronic or intermittent.

Diagnosis involves a thorough history and physical examination as well as a minimum database (complete blood count, serum chemistries, urinalysis, and retrovirus serology). Other diagnostic tests for feline lower airway disease include feline heartworm serology, thoracic radiographs, bronchoscopy and/or bronchoalveolar lavage with cytology and culture, and fecal analysis. Differential diagnoses include heartworm disease, viral, bacterial or fungal infection, inhaled foreign body, cardiac disease, thoracic disease, neoplasia, and pulmonary parasites (ascarids, lungworms, lung flukes). Essentially, a diagnosis of feline asthma is a diagnosis of exclusion.

Feline Asthma

Feline asthma is one of a spectrum of conditions under the umbrella of chronic lower airway disease or bronchopulmonary disease that also includes chronic bronchitis. Feline asthma may also be called allergic airway disease or allergic bronchitis.

Since feline asthma is characterized by airway inflammation and bronchoconstriction, therapy is aimed at reversing these changes. There are many treatments for feline asthma, including some experimental modalities borrowed from human medicine. Many of these treatments have not been well evaluated in the cat.

Heartworm Associated Respiratory Disease (HARD)

The cat is considered a resistant, yet susceptible host for Dirofilaria immitis. Worm burdens are much lower in cats than in dogs (average 15 worms in dogs and 1-3 in cats in endemic areas) and about 1/3 of feline infections involve worms of the same sex. Feline heartworm (HW) was first described in the 1920s; awareness has increased greatly since the introduction of Heartgard for cats in 1997 and the associated marketing campaign. Feline HW remains a difficult to diagnose, yet fully preventable disease.

Cats are infected with HW in the same way as dogs, but far fewer larvae mature to adulthood. It is difficult to estimate prevalence of feline HW for several reasons – there is no ideal test, inapparent infections go unnoticed, and some cats die acutely without a diagnosis. The prevalence of immature infections is higher than the adult infection rate. Based on necropsy surveys of shelter cats, feline HW is thought to be present at about 5-15% of the canine rate in endemic areas. Certainly wherever canine heartworm is found, feline HW is present as well.

Many cats will have no clinical signs of HW disease and they will spontaneously eliminate the infection without incident. Other cats may have clinical signs associated with infection at two possible time points:

1) Upon arrival of immature worms (L5s) in the pulmonary arteries and arterioles in the 3 to 6 month post-infection period. The high mortality of immature worms stimulates a severe vascular and parenchymal inflammatory response. Pulmonary lesions may be long-lasting. The clinical response in the cat is termed HARD because respiratory signs predominate (dyspnea, tachypnea, and cough). The clinical signs may be transient or intermittent. Clinical signs subside as the worms mature. Many cats with HARD are misdiagnosed as having asthma or bronchitis.

2) Upon death of adult worms, with release of antigens and toxins leading to pulmonary inflammation and thromboembolism. Clinical signs include rapid onset of respiratory compromise or sudden death (occurs in 10% or more of HW infected cats). Even the death of 1 adult worm can be lethal by causing circulatory collapse and respiratory failure. Adult worms are able to suppress pulmonary intravascular macrophage activity and so actually induce little inflammation until they die in 1 to 2 years.

Nonspecific clinical signs associated with feline HW include chronic vomiting (present in 25-33% of cases), lethargy, anorexia, and weight loss. Less common signs due to aberrant migration include ascites, pneumothorax, chylothorax, neurological signs (ataxia, seizures, syncope, collapse, blindness, vestibular signs), and hemoptysis. Signs of cardiac disease or failure are very uncommon in cats with HW.

Our understanding of the role of Wolbachia, an endosymbiont Rickettsial bacterium found in D. immitis in feline HW disease is evolving. HW infected cats may be exposed to Wolbachia when larvae or adult worms die, and probably at other times in the worm's life cycle. A strong antibody response against Wolbachia surface protein has been demonstrated in HW infected cats. Wolbachia may play a role in the inflammatory response seen in HARD; raising the possibility that treatment with antibiotics such as doxycycline may help reduce clinical signs in cats with HARD. Research is currently underway to define the exact relationship between Wolbachia and pulmonary inflammation in cats.

Diagnosis of feline HW may be difficult. Cats are rarely microfilaremic so filtration or IFA testing for microfilaria is not recommended. No single diagnostic test can detect feline HW at all life stages of the worm. Combining antigen and antibody testing achieves higher sensitivity than either test alone, but may generate more false positives.

A positive HW antibody test documents exposure to early stage infection but not necessarily current infection, and a negative test does not rule out infection. The different tests available also vary widely in sensitivity and specificity, as each brand may detect a different stage of larval development. Interestingly, up to 30% of cats on HW prevention may become antibody positive although they are not at risk for HARD.

HW antigen testing detects proteins associated with the reproductive tract in mature female worms, so that a positive test confirms the presence of at least one adult female HW. A negative antigen test does not rule out infection with adult worms as antigen levels may be below the detection threshold of the test. Antigen tests miss the early stages of HW infection and don't detect the immature worms that cause HARD. While sensitivities and specificities of the various tests vary, false positives should be uncommon.

The American Heartworm Society (www.heartwormsociety.org) guidelines for testing cats:

• Screen healthy cats with both antigen (for adult worms) and antibody (for immature worms) tests

• For cats with clinical signs compatible with HARD, use both an antigen and antibody test, and thoracic radiography

• Testing may be used to monitor the progress of cats previously diagnosed with HW

• Testing cats before administering preventative medication helps increase awareness about local risk potential and will establish a baseline reference in case the cat must be retested

• A positive test does not preclude administration of chemoprophylaxis in order to prevent additional infections

Thoracic radiography can also provide evidence for HW disease independent of serology. Radiography is also valuable for assessing severity of disease and monitoring progression or resolution. The most characteristic radiographic features of feline HW disease are a subtle enlargement of the pulmonary arteries (especially the caudal lobar), loss of taper and sometimes tortuosity in the caudal lobar branches. These characteristics are best seen with a ventrodorsal view and may only be visible in the right hemithorax. They may be found in about 50% of HW positive cats. A common secondary feature is a bronchointerstitial lung pattern that is not unique to feline HW disease. In fact, feline asthma and feline HW disease may have a very similar radiographic appearance.

Interpretation of HW tests in cats (after Nelson, 2007)

Echocardiography is useful for antigen positive cats. Heartworms are most often found in the main and right lobar branch of the pulmonary artery. The body wall of an adult HW is strongly echogenic, producing a signature sign with echocardiography. With an experienced sonographer and good quality equipment, there may be a greater chance of finding adult HW in infected cats than in infected dogs. Quantification of the worm burden is difficult, however.

Only 4% of cat owners give HW preventatives, compared to 59% of dog owners. Even indoor cats in endemic areas should be on HW prevention. In one North Carolina study, 28% of HW positive cats were considered indoor only. Four drugs are currently licensed for prevention of feline HW by preventing development of L3 and L4 in subcutaneous tissues. Two products are oral: ivermectin (Heartgard; Merial), milbemycin (Milbemax, Interceptor; Novartis); and two are topical: selamectin (Revolution; Pfizer), moxidectin (Advocate; Bayer),

Treatment of Asthma or HW Patients with Acute Clinical Signs

Patients in acute respiratory distress may be unstable and should be examined and treated with great care. Some drugs may cause a temporary increase in heart and respiratory rate. When using combination drug therapy, be aware of the risk of arrhythmia in stressed, hypoxic cats. Some very anxious and stressed dyspneic cats may benefit from mild sedation with a low dose of acepromazine (0.05 mg/kg, IM, SQ).

First line therapy

• Supplemental oxygen: Preferably using an oxygen cage

• Bronchodilators: Best via nebulizer or metered dose inhaler as the effects are seen within 5 minutes (versus 15-30 minutes by injection); give 2-4 puffs of inhaled drugs such as albuterol every 20 minutes; repeat injectable drugs in 15 minutes if required

• Short-acting corticosteroid: Intravenous dexamethasone or prednisolone sodium succinate; may take 3-6 hours for maximum effect; useful in cats on chronic oral bronchodilator therapy to reverse down-regulation of airway β-adrenergic receptors causing drug tolerance

Second line therapy

• Anticholinergics: Atropine, glycopyrrolate; block vagal input causing bronchoconstriction and decrease bronchial secretions; not useful for long term therapy as these drugs will cause increased viscosity of airway mucus

Third line therapy

• Epinephrine: α- and β-agonist, can reverse bronchoconstriction; may cause arrhythmia

Treatment of HW Positive Cats

Heartworm positive cats with no clinical signs of disease, but with radiographic evidence of pulmonary vascular/interstitial disease, should be monitored every 6 to 12 months with repeat antigen and antibody testing, and radiography. Recovery is indicated by improvement in radiographic signs and seroconversion of a positive antigen test to negative. It may be prudent to administer prednisone to cats with radiographic signs of disease whether or not they have clinical signs of illness, although this is controversial. Whenever antibody or antigen positive cats have clinical signs, prednisone should be administered on a decreasing dose schedule (2 mg/kg/day, decreasing to 0.5 mg/kg/day every other day by 2 weeks, discontinuing after an additional 2 weeks). The effect of treatment should be assessed by clinical response and radiographs. Cats with recurrent signs can be retreated.

Adulticide therapy is rarely indicated in cats. No safe and efficacious adulticides are available for cats. Removal of adult worms via right jugular venotomy or left thoracotomy has been described when worms can be identified ultrasonographically, but extraction procedures can result in acute shock and death if the worm cuticle is damaged.

Treatment of Chronic Asthma

Corticosteroids are the cornerstone of treatment for feline asthma as control of inflammation leads to clinical control. Inflammation exists even in the absence of clinical signs. Treatments can be combined to create tailored regimes. In general, the simpler and easier the treatment regime is, the more likely owner compliance will be achieved.

Feline asthma patients should be re-evaluated every 3 to 6 months and owners should be instructed to alert the veterinarian promptly if respiratory distress develops or the cat's clinical signs worsen.

Oral Therapy

• Antibiotic therapy: Not usually indicated for treatment of feline asthma. However, Mycoplasma has been isolated from the airways of 25% of cats with lower airway disease, while it is not found in the airways of clinically healthy cats. It may be reasonable to treat feline asthma patients for Mycoplasma with doxycycline for 14 days if they do not respond to corticosteroid treatment within 5 days.

• Corticosteroids: Appropriate for long-term oral therapy but must monitor for adverse effects, especially diabetes mellitus. The dose should be tapered carefully, with many cats achieving alternate or every third day therapy in the long term. Repository corticosteroid injections are more likely to cause adverse effects and cats may become refractory to corticosteroid treatment more readily with this approach. In general, repository corticosteroids should be reserved for very fractious cats or non-compliant owners. Frequency of administration should be not more often than every 2 months.

• Bronchodilators:

•Methylxanthines: Weak bronchodilators, narrow therapeutic window; adverse effects include vomiting and diarrhea, hyperactivity, muscle tremors. Oral aminophylline is not recommended as adverse effects are common. Only the sustained-release forms of theophylline produced by Inwood Laboratories should be used in cats.

•β-agonists: Effective bronchodilators, primary side effects are tachycardia and hypertension, β2-agonists have fewer cardiac side effects (e.g. terbutaline); drug

Inhalant Therapy

The administration of inhaled steroids and bronchodilators via metered dose inhalers (MDIs) has revolutionized treatment of feline asthma. Using a nebulized radiopharmaceutical, it has been shown that inhaled medications can be distributed to the lower airways in cats. With use of inhaled medications, systemic side effects can be effectively minimized or eliminated.

In cats with moderate to severe asthma, oral corticosteroids are recommended for the first few weeks of therapy, and the dose can be tapered as the cat responds to the inhaled medications. If a patient is being switched from oral therapy to inhaled therapy, the transition should occur over a period of at least one week. Some severely asthmatic cats require every second day oral corticosteroid dosing concurrent with inhaled medications.

Each inhaler delivers a set dose per actuation ("puff") and contains a fixed number of doses. MDIs require slow, deep inhalation on the part of the patient. This type of inspiration is not possible for infants and animals, so a spacer and mask must be used. Spacers decrease the amount of drug deposited in the oropharynx.

A spacer and facemask is available for veterinary patients (AeroKat™, Trudell Medical International, http://www.trudellmed.com/Animal_Health/ah_aerokat_fac.asp). The spacer and mask must be applied to the cat within 5 seconds of actuating the MDI to avoid losing the medication, or place the mask and spacer on the cat's face before the MDI is actuated. This is a superior system for use with cats as it has been optimized for the smaller feline tidal volume.

The most commonly used inhaled corticosteroid is fluticasone, but others are sometimes available (e.g. beclomethasone) and may be less expensive (although potentially less effective). A corticosteroid inhaler used twice daily should be the cornerstone of therapy. A typical starting dose is 1 puff twice daily using 110 mcg fluticasone.

Inhalers containing bronchodilators are also widely used and are inexpensive. A bronchodilator inhaler may be used two to four times daily initially, but for most patients, they should be reserved for occasional use in acute bronchoconstriction to avoid development of tolerance. It has alos bee demonstrated that long term use of inhaled albuterol may exacerbate inflammation. Patients with mild intermittent disease may be treated with a bronchodilator alone on an as-needed basis.

Albuterol (salbutamol) is a short acting β2-agonist that relaxes smooth muscle and increases airflow within five minutes of administration. The effect of albuterol will last four to six hours.

Inhaled medications are more expensive than oral medications, and a certain cost is associated with purchase of the spacer and mask. However, for cats that are difficult to medicate orally and for owners who wish to minimize long-term effects of oral corticosteroids, MDIs are a good choice. Most cats readily learn to tolerate the spacer and mask after some initial training. Owners must be carefully instructed on care and use of the spacer, mask and MDI.

Other Control Measures for Cats with Asthma

Certain measures can help reduce or prevent acute attacks, such as avoiding contact with cats showing signs of upper respiratory tract infection, and prevention or treatment of excess weight gain. Avoidance of known aerosol triggers may also be prudent, such as dusty or scented cat litter, air fresheners and room deodorizers, cleaning agents, fumigants, cigarette and wood fire smoke, etc. HEPA filters can help reduce aeroallergens. A few cats with asthma will respond favourably to a hypoallergenic diet, so a 4 to 8 week trial may be justified.

Websites for cat owners:

http://www.felineasthma.org/

http://www.knowheartworms.org/

References

Atkins, C., T. DeFrancesco, et al. Heartworm infection in cats: 50 cases (1985-1997). J Amer Vet Med Assoc 217(3): 355-358, 2000

Atkins, C. E. Reassessing the definition of heartworm infection in cats. J Am Vet Med Assoc 231(9): 1338, 2007

Berdoulay, P., J. K. Levy, et al. Comparison of serological tests for the detection of natural heartworm infection in cats. J Am Anim Hosp Assoc 40(5): 376-84, 2004

Browne LE, Carter TD, Levy JK, et al. Pulmonary arterial disease in cats seropositive for Dirofilaria immitis but lacking adult heartworms in the heart and lungs. Am J Vet Res 66: 1544–1549, 2005

Foster, S., G. Allan, et al. Twenty-five cases of feline bronchial disease (1995-2000). J Fel Med Surg 6(3): 181-188, 2004

Guenther-Yenke, C. L., B. C. McKiernan, et al. Pharmacokinetics of an extended-release theophylline product in cats. J Am Vet Med Assoc 231(6): 900-6, 2007

Litster, A. L. and R. B. Atwell. Feline heartworm disease: a clinical review. J Feline Med Surg. In Press

Morchon, R., A. C. Ferreira, et al. Specific IgG antibody response against antigens of Dirofilaria immitis and its Wolbachia endosymbiont bacterium in cats with natural and experimental infections. Vet Parasitol 125(3-4): 313-21, 2004

Nelson, C.T., R.L. Seward, et al. 2007 Guidelines for the diagnosis, prevention and management of heartworm (Dirofilaria immitis) infection in cats. Available from: www.heartwormsociety.org/article.asp?id=47

Norris, C., K. Decile, et al. Effects of an inhaled steroid and a leukotriene receptor antagonist in experimental feline asthma. 21st Amer Coll Vet Intern Med Forum, Charlotte, NC, 2003

Padrid, P. Feline asthma: diagnosis and treatment. Vet Clin North Amer 30(6): 1279-1293, 2000

Randolph, J., N. Moise, et al. Prevalence of mycoplasmal and ureaplasmal recovery from tracheobronchial lavages and of mycoplasmal recovery from pharyngeal swab specimens in cats with or without pulmonary disease. Am J Vet Res 54(6): 897-900, 1993

Schulman, R., S. Crochik, et al. Investigation of pulmonary deposition of a nebulized radiopharmaceutical agent in awake cats. Am J Vet Res 65(6): 806-809, 2004

Snyder, P., J. Levy, et al. Performance of serologic tests used to detect heartworm infection in cats. J Amer Vet Med Assoc 216(5): 693-700, 2000