- Email: [email protected]
Feline Asthma
RESPIRATORY MEDIONE AND SURGERY
0195-5616/00 $15.00
+ .00
FELINE ASTHMA Diagnosis and Treatment Philip Padrid, RN, DVM
Asthma in human beings is a chronic inflammatory disease within the lower airways (bronchi and bronchioles) that causes cough, wheeze, and exercise intolerance. These clinical signs are the result of a decrease in airflow through airways that are narrowed from excessive mucus secretion, airway wall edema, and bronchoconstriction. "Feline asthma" is a remarkably similar condition that has been recognized in the veterinary literature since at least 1906, when HilF described cats with increased airway mucus, airway inflammation, and the clinical signs of labored breathing and wheezing. DIAGNOSIS
There are no clinical signs or laboratory tests available in routine veterinary clinical practice that are pathognomonic for asthma in cats. The tests we can perform are most valuable to exclude other common causes of (acute) dyspnea, wheeze, and cough, including chronic bronchitis, heart failure, pneumonia, pulmonary malignancy, respiratory parasitism, and inhaled foreign bodies. Fortunately, except for chronic bronchitis, these other disorders do not routinely cause clinical signs similar to asthma in an otherwise healthy cat. As a result, we can usually make the correct diagnosis of feline asthma if we examine only a few clinical signs and radiographic findings, including:
From the Section of Pulmonary/Critical Care Medicine, University of Chicago, Chicago, Illinois; and the Veterinary Centers of America, Los Angeles, California
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME30•NUNrnER6•NOVEMBER2~
1279
1280
PADRID
1. There is a history of sudden onset of labored breathing that is quickly relieved (usually) with some combination of oxygen, bronchodilators, and steroids. 2. In some cases, however, the only clinical problem is a chronic cough. Cats with chronic bronchitis have the clinical symptom of daily cough, and this can mimic feline asthma. Fortunately, cats with chronic bronchitis should be treated similarly as cats with asthma (daily, mild or moderate [see classification scheme below]). As a result, the distinction between chronic bronchitis and asthma is not always critical. 3. The most important radiographic finding is bronchial wall thickening. These changes are usually described as "doughnuts" and "tramlines." Air trapping may be assumed if there is flattening of the diaphragm and the dorsal crus of the diaphragm is near intercostal space 12 to 13 on multiple views of the thorax. This is a less common but significant finding. 4. When airway cytology is available, cats with asthma usually have evidence of airway inflammation, including large numbers of eosinophils recovered from tracheobronchial secretions. This is not specific for asthma, however, as many healthy cats also have large numbers of eosinophils within their respiratory tract. 19 In contrast, the neutrophil is the predominant inflammatory cell in tracheobronchial secretions from cats with chronic bronchitis. These clinical and laboratory findings are also found in human asthma. Histologic fe9-tures of feline asthma, including hyperplasia and hypertrophy of the mucus-secreting apparatus, airway smooth muscle thickening, and epithelial erosion associated with an eosinophilic infiltrate, also closely parallel the human condition (Fig. 1). Finally, "airway hyper-reactivity," a defining feature of human asthma, has recently been demonstrated in cats with clinical signs of asthma. 3 Thus, cats do get asthma in the same way as we understand this disorder in human beings. Although the clinical signs of asthma may seem straightforward, the classification of the disease has not been as clear. Even in human respiratory medicine, it has historically been easier to recognize the clinical signs of asthma than it has been to precisely define the condition. Thus, the purpose of this article is to (1) review our current understanding of the pathophysiology of asthma in cats; (2) suggest a straightforward and clinically oriented classification scheme for diagnosing and treating cats with asthma; and (3) introduce the practical use of inhaled medications to treat asthmatic cats with mild, moderate, or severe disease. PATHOPHYSIOLOGY OF ASTHMA IN CATS
Although there are many potential causes of asthma, the airways respond to inhaled irritants or immunologic stimuli in a limited number of ways:
FELINE ASTHMA
1281
Figure 1. Naturally occurring feline asthma. Medium-sized bronchus from a 9-year-old Siamese Cat with a 4-year history of cough and wheeze. Note the invagination of airway mucus from bronchoconstriction, luminal exudate, thickened smooth muscle, and hypertrophied submucosal glands. (From Padrid P: Feline asthma: Pathophysiology and treatment. Waltham Focus 9:17-22, 1999; with permission.)
1. Airway epithelium may thicken (hypertrophy), evolve to a differ-
ent structure (metaplastic change), or simply become damaged (erode or ulcerate). 2. The structures responsible for producing mucus (goblet cells and submucosal glands) may enlarge and produce excessive amounts of a particularly thick form of mucus. 3. Bronchial smooth muscle often spasms and may become hypertrophied. These changes are associated with cellular infiltration of the bronchial mucosa and submucosa, and this tissue m ay also become edematous. The resulting clinical signs of cough, wheeze, difficulty in breathing, and decreased exercise capacity are due to airway narrowing (and airflow reduction) from excessive mucus secretions, airway edem a, airway narrowing from cellular infiltrates, and airway smooth muscle constriction. Cough may also result from stimulation of inflamed and contracted cough mechanoreceptors located in airway epithelium. This is an important concept, because even a small degree of airway narrowing can produce dramatic changes in clinical signs. For example, a 50% reduction in the radius of an airway results in a 16-fold reduction in the amount
1282
PADRID
Figure 2. Effect of airway size on air flow. A, Normal-sized airway. B, Asthmatic airway, in which the airway is partially obstructed (50%) with mucus and cellular debris. This obstruction results in a 16-fold reduction in air flow through that airway. (From Padrid P: Feline asthma: Pathophysiology and treatment. Waltham Focus 9:17-22, 1999; with permission.)
of air that flows through that airway (Fig. 2). It is easy to imagine why any movement that requires an increase in the depth of breathing such as chasing a mouse is tremendously altered if there is a 16-fold decrease in the amount of air that comes into the lungs during normal respiration. The important take-home message is that small changes in airway size result in dramatic changes in airflow through that airway. The clinical implications of this finding are twofold. First, relatively small amounts of mucus or bronchoconstriction can partially occlude airways and cause a dramatic fall in airflow. Conversely, therapy that results in relatively small increases in airway size may cause a dramatic improvement in clinical signs. An important advance in our understanding of this relation between airway structure and function is the recent discovery that human asthmatic airways are chronically inflamed whether or not the patient is symptomatic (this has not been confirmed in cats). It has also been recognized for some time that eosinophils seem to play a primary role in chronic asthmatic airway inflammation in human beings and cats. Highly charged cationic proteins within eosinophil granules are released into airways and cause epithelial disruption and sloughing. Additionally, these granular proteins can make airway smooth muscle more " twitchy" and prone to contraction after exposure to low levels of stimulation (airway hyper-reactivity). 6• zo Eosinophil-T Lymphocyte Interactions
The pathogenesis of asthmatic airway hyper-reactivity is complex. Recent studies suggest that the interaction between activated T lympho-
FELINE ASTHMA
1283
cytes and eosinophils within airways may play a particularly important role in the generation of eosinophilic airway inflammation and airway hyper-reactivity in human asthma. Cytokines, including interleukin-5 secreted from the T-helper-2 subset of activated CD4 + T cells, promote eosinophil survival, activation, and recruitment into airways. 5 Recent experimental studies using transgenic and "knockout" mice to overexpress or delete activated T lymphocytes or T cell-specific cytokine products in antigen-challenged mice continue to support the role of activated T lymphocytes and eosinophils in the development of asthmatic airway inflammation. 11' 17 WHAT DO WE KNOW ABOUT CATS WITH ASTHMA?
Although coughing and wheezing cats have been identified by owners and veterinarians for more than 90 years, it is only in the last 5 years that we have begun to study the disorder in earnest. Doctors at the University of Illinois School of Veterinary Medicine have identified pulmonary function abnormalities in cats with signs of chronic lower airway inflammation. Some of these cats have increased lung resistance that resolves after treatment with terbutaline (a !32 agonist), indicating the presence of reversible bronchoconstriction in these patients. 3' 12 Additionally, some of these cats experience dramatic bronchoconstriction after exposure to low levels of methacholine, a drug that has minimal effects on pulmonary function when used in equivalent doses in nonasthmatic cats. This is an important finding as the first demonstration of spontaneous and naturally occurring airway hyper-reactivity in a nonhuman species. Even more recently, Hoffman and associates8 at Tufts School of Veterinary Medicine have validated the use of the Buxco noninvasive plethysmograph (Buxco Electronics, Sharon, CT) to study pulmonary function in awake nonrestrained cats. Use of this device may greatly speed the generation of knowledge regarding pulmonary function in asthmatic cats and lead to objective means of evaluating current and future drug therapies for these patients, HOW SHOULD WE CLASSIFY CATS WITH ASTHMA?
In veterinary medicine, feline asthma has been referred to as feline lower airway disease, feline allergic asthma, extrinsic asthma, feline allergic bronchitis, chronic obstructive pulmonary disease, eosinophilic bronchitis, acute allergic bronchitis, chronic bronchitis, and immunemediated airway disease. 2' 3, 12, 13, 15, 16 These multiple definitions of asthma in cats reflect a widespread confusion in the veterinary community regarding respiratory disease in general and respiratory disease in cats in particular. This confusion, in turn, has inhibited the development of generally accepted rational standards of care for feline asthma. What follows is an attempt to clarify the notion of feline asthma by simplifying
1284
PADRID
the way we classify cats with this disease and proposing a standard of treatment for these animals. Obviously, the clinician should be reasonably certain of the diagnosis. Once the diagnosis is made, the first step is to determine if the clinical signs are intermittent or if they occur daily. If symptoms occur daily, the next step is to decide if the clinical signs are mild, moderate, or severe. 1. Mild symptoms: In these cases, the symptoms do not affect the way in which the cat conducts its business (quality of life). In these cases, between "attacks/' the cat eats, drinks, and plays as if nothing is wrong. 2. Moderate symptoms: In these cases, the asthmatic condition sometimes affects the way the cat conducts its business (e.g., it may tire easily, it may wake up at night coughing). Symptoms are not constant, and the cat does not have obvious difficulty when breathing at rest most times of the day. 3. Severe symptoms: In these cases, the asthmatic condition is continual and clearly limits the eat's ability to conduct its business. These cats are not comfortable at rest, and the symptoms occur for most of each day. In summary, to classify cats with asthma, we take the following steps: (1) determine if the signs are intermittent or daily, and (2) determine the severity of daily symptoms. These two steps are the beginning of a rational treatment plan.
HOW SHOULD WE TREAT CATS WITH ASTHMA?
The primary signs of asthma include cough and wheeze, and these signs are frequently caused by airway smooth muscle contraction. It is tempting to treat these signs of asthma by using bronchodilators to reverse the airway smooth muscle spasm, and, in fact, this is the logical treatment for cats with intermittent symptoms. It is critically important to remember that human (feline?) asthmatic airways show evidence of chronic ongoing inflammation whether or not the patient is symptomatic. As a result, for cats with daily symptoms, treatment strategies are most successful if they are directed toward decreasing the underlying inflammatory component of the disease. Corticosteroids are the most effective long-term treatment of feline asthma. Corticosteroids have many beneficial effects in this setting, including inhibiting the synthesis of genes for cytokines that are important in generating airway inflammation. Nevertheless, the side effects of chronic high-dose oral steroid treatment in cats are well known and include pancreatitis, insulin resistance (diabetes), and significant behavioral changes in addition to polyuria, cystitis, and inappropriate urination. Fortunately, inhaled steroids are now available that do not
FELINE AS1HMA
1285
cause systemic side effects, and this treatment has greatly enhanced our ability to successfully treat cats with asthma. Inhaled Medications
Corticosteroids and bronchodilators can now be given effectively by inhalation to cats with asthma (Table 1). Both classes of drugs are available as metered dose inhalers (MDis) (Fig. 3) for human patients with asthma. Proper use of an MDI requires the patient to coordinate inhaling with the actuation of the device, and this has proven to be surprisingly difficult for most patients. This is also not realistic for infants and young children. An alternative was developed to allow these individuals to use the MDis without the need to coordinate their breathing. Thus, the MDI is used in conjunction with a "spacer" designed for use in infants and small children and a face mask specifically made for cats. The spacer is a plastic chamber the size of a cardboard Table 1. DRUGS AVAILABLE AS METERED DOSE INHALERS, USED WITH SPACERS AND FACE MASKS TO TREAT DOGS AND CATS WITH RESPIRATORY DISEASE* Drug Class
Bronchodilator (~-2 agonist)
Drug Name
Albuterol (Ventolin, Proventil) Pirbuterol (Maxair) Bitolterol (To malate) Salmeterol (Serevent)
Indication
Important Points
Immediate relief of bronchoconstriction Immediate relief of bronchoconstriction Immediate relief of bronchoconstriction Long-term (12 h) control of bronchoconstriction
Effect is short-lived (<4 h) Not studied in dogs and cats Not studied in dogs and cats Takes > 1 h to take effect
Anticholinergic
Ipratropium bromide (Atrovent)
Additive bronchodilation with ~-2 agonists
Not studied in dogs and cats
Anti-inflammatory corticosteroid
Fluticasone propionate (Flovent) Flunisolide (AeroBid) Budesonide (Pulmocort) Beclomethasone dipropionate (Beclovent, Vanceril)
Long-term control of inflammation Long-term control of inflammation Long-term control of inflammation Long-term control of inflammation
Takes 10-14 days to reach peak effects Not studied in dogs and cats Not studied in dogs and cats Not studied in dogs and cats
Cromolyn sodium (Intal)
Long-term control of inflammation
Not studied in dogs and cats
Nedocromil sodium (Tilade)
Long-term control of inflammation
Not studied in dogs and cats
Mechanisms unclear (inhibits mast cell degranulation)
*See text for specific indications.
1286
PADRlD
Figure 3. Metered dose inhaler (MDI) used to treat respiratory disease in human beings. This device requires a coordinated effort by the patient to inhale immediately after actuation of the device and is not suitable, by itself, for use in animals.
FELINE ASTHMA
1287
Figure 4. A, The spacer device connected to an MDI. B, The spacer connected to an MDI and a self-sealing mask commonly used for induction of anesthesia. The spacer acts as a reservoir for the inhaled medication, so that the animal breathes the drug into its airways whenever it breathes through the face mask.
1288
PADRID
Figure 5. The attachment on the spacer for the face mask has been removed to show the thin rubber gasket that acts as a one-way valve. On inspiration the gasket moves toward the mouth and opens, allowing the medication within the spacer to be inhaled. The gasket closes on exhalation, preventing the medication from escaping.
inner roll of toilet paper. The MDI fits into one end of the spacer, and the other end of the spacer has an attachment for the face mask (Fig. 4). The end of the spacer that connects with the face mask has an inner rubber gasket that acts as a one-way valve so that the medication within the spacer can only leave the spacer during an inhalation (Fig. 5). The client first attaches the MDI and the face mask to the spacer and then actuates (presses) the MDI twice to fill the spacer with medication. The client then places the face mask gently over the eat's mouth and nose. The cat is allowed to breath in and out 7 to 10 times with the mask in place, and the treatment is completed. Specific Treatment for Cats with Asthma
Treatment of Feline Asthma if Symptoms Are Intermittent (Do Not Occur Daily)
In these cases, I prescribe an albuterol inhaler with instructions to use "as needed." The assumption in these cases is that cats with symp-
FELINE ASTHMA
1289
toms that do not occur daily do not have significant chronic ongoing inflammation that requires daily anti-inflammatory therapy. When acute signs do occur (e.g., cough, wheeze, difficulty in breathing), they can usually be effectively and quickly treated with the inhaled bronchodilator. If signs become more frequent, the cat should be re-evaluated to determine if more aggressive treatment should be initiated (see next step). Treatment of Feline Asthma if Symptoms Occur Daily
Mild Daily Symptoms. These cats have daily symptoms but in between the coughing and wheezing, they are generally unaffected by their disorder. For these cats, I prescribe 220 f..Lg of Flovent twice daily. I also prescribe an albuterol inhaler as needed for those times when symptoms are particularly troublesome. Because inhaled Flovent takes about 7 to 10 days before its maximum effect is seen, these cats continue to be symptomatic for an additional week or so. Clients should be supported through this period and encouraged that their pet is going to begin to improve after the first week of therapy. Moderate Daily Symptoms. These cats have daily symptoms that have a negative effect on their quality of life, but their cough, wheeze, or dyspnea is not constant. For these cases, I prescribe 220 f..Lg of Flovent twice daily and albuterol as needed. I also prescribe 1 mg/kg of prednisone administered orally twice daily for 5 days and then daily for 5 additional days. After 10 days of combined oral and inhaled steroids, the cat has generally shown great improvement, and the oral prednisone can be discontinued without taper. Oral prednisone is used in this setting because significant daily symptoms suggest the presence of a more aggressive inflammatory component that should be more aggressively treated. Severe Daily Symptoms. These cats are symptomatic and uncomfortable at rest and require aggressive early management. I begin with 2 mg/kg of dexamethasone administered intravenously and inhaled albuterol every 30 minutes for up to 4 hours. This frequency of albuterol treatment generally does not cause side effects or might cause slight muscle tremor. These cats are also given 40% to 100% oxygen either by nasal cannula or oxygen cage. Once these patients are stabilized (their symptoms are dramatically improved), they can be discharged with 220 f..Lg of Flovent administered twice daily and albuterol administered four times daily as needed. Some of these cats with severe symptoms may also require intermittent lower doses of oral prednisone, but this is tailored for the individual patient. ADDITIONAL TREATMENTS Antibiotics
There is no objective evidence that bacterial infections play a significant role in the cause or continuation of feline asthma. Similarly,
1290
PADRID
there is little objective evidence that antibiotic therapy has any effect on the duration or intensity of signs displayed by the cat with asthma. 1' 3, 19 It is important to remember that the clinical signs of asthma frequently wax and wane in severity as well as in frequency of occurrence. There are anecdotal reports describing the therapeutic effect of antibiotics in controlling asthmatic symptoms; however, the author believes that these reports are consistent with the "waxing and waning" nature of the symptoms in nontreated cases. A positive culture result obtained from a tracheobronchial wash does not necessarily demonstrate a clinically significant airway infection and should not automatically prompt the clinician to start antibiotic therapy. Remember, there is a revolving population of commensal bacteria that live in the respiratory tract in cats and other species, and these organisms are not disease-producing. 3, 19 In general, antibiotics are rarely indicated for cats with asthma and are appropriate only when there is good evidence of superimposed airway infection. A true infection may be assumed if the positive culture was obtained after growing the organisms in culture without using an enrichment broth such as thioglycolate. (Your reference laboratory can tell you if enrichment broth was used or if your samples were subcultured.) This is because the concentration of aerobic bacteria recovered from the airways of healthy cats rarely exceeds 5 X 103 organisms per milliliter. In contrast, growth of a single organism recovered without the use of enrichment broth implies more than 105 organisms per milliliter, and this is consistent with an "infected" airway. 3' 19 Antibiotic therapy is then based on sensitivity data. Prophylactic or long-term antibiotic therapy is not indicated unless there is documentation of a chronic airway infection. Documented chronic airway infection is extraordinarily uncommon in feline asthma. There is a possible exception to these statements. Mycoplasma species have been isolated from the airway of as many as 25% of cats with signs of lower airway disease. 16 In contrast, Mycoplasma species are not cultured from the airway of healthy cats. For this reason, and because Mycoplasma species have the potential to cause significant structural damage to airway epithelium, it may be prudent to treat any cat with a Mycoplasma-positive airway culture with an appropriate antibiotic. 4 Cyproheptadine
Cyproheptadine is an antihistamine and antiserotonin compound that has been used in feline medicine to increase appetite. Our laboratory demonstrated that mast cells within feline airways contain serotonin and that serotonin can cause smooth muscle constriction within feline airways. These studies were performed with isolated lung tissue in vitro and were intended to encourage further studies in vivo to determine the effectiveness (or lack of effectiveness) of cyproheptadine in cats with asthma. 18 Although there have been many anecdotal reports that cypro-
FELINE ASTHMA
1291
heptadine is sometimes helpful in these cases, the author does not routinely prescribe this drug for these cats. Antileukotriene (or Receptor) Drugs
There has been a great deal of recent interest in drugs that block production of leukotrienes (LTC.v LTD4 ) or ligation of these molecules to their receptor(s). In general, these drugs have limited but significant effectiveness in treating some human asthmatics with moderate to severe disease. 9• 10 Leukotrienes increase mucus production, induce cellular edema, and promote airway smooth muscle constriction in human beings and other species, so it is reasonable to think that antileukotriene drugs might have a role in the therapy of feline asthma. Perhaps it is not surprising that Zyflo, Accolate, and Singulair have all been used to treat cats with asthma even though there are no safety or efficacy studies of these drugs in the feline species. We have found that LTE.v the metabolic product of LTC 4 and LTD4 metabolism, is found in increased amounts in urine of cats with asthma but not in normal cats or cats with nonasthmatic disorders such as kidney failure or pancreatitis. We have also found similar increases in prostaglandins (PGF 2., PGI2 ) and thromboxane A 2 (TXA 2 ) in bronchoalveolar lavage fluid of cats with experimentally induced asthma (unpublished studies). This suggests that leukotrienes and other products of the arachadonic acid cascade are manufactured in increased amounts in cats with asthma. Interestingly, a more recent study by Mellema et aP 4 did not support our finding but instead found no increase in urinary LTE 4 in 20 cats with signs of lower airway disease. Additionally, direct instillation of LTC4 into the airways of normal cats has no adverse effect on feline airway structure or function. It is probable that increased leukotriene production, like prostaglandin production, is a clinically nonsignificant byproduct of the general inflammation in asthma. There are no current data that suggest that antileukotriene drugs have an important role in the treatment of cats with asthma. Most importantly, the author strongly believes that correct diagnosis and aggressive therapy of cats with asthma as outlined in this article minimize the need to explore untested and variably effective human drugs in these feline patients. SUMMARY AND CONCLUSIONS
Human asthma is not a curable disease, although spontaneous resolution is common in adult asthmatics who developed asthma in childhood. We do not know if this is true or not for cats with asthma. We do know that some cats may be only mildly and intermittently symptomatic and that others may suffer life-threatening illness. An important new development in our understanding of this disease is the occurrence of airway inflammation even when patients are symptom-
1292
PADRID
free. It is therefore crucial that we direct our therapeutic attention toward the underlying chronic inflammation that causes the acute clinical signs of cough, wheeze, and increased respiratory effort. Client education is also critical so that our clients develop realistic expectations of the effectiveness of these treatments for their pets. A great deal still needs to be learned regarding the pathogenesis of feline asthma and the optimal approach( es) to treating cats with this sometimes debilitating and potentially fatal respiratory syndrome. There is great hope and anticipation that ongoing research can bring new treatments for human and feline asthmatics alike. References 1. Corcoran BM, Foster DJ, Fuentes VL: Feline asthma syndrome: A retrospective study of the clinical presentation in 29 cats. J Small Anim Pract 36:481--488, 1995 2. Dye JA: Feline bronchopulmonary disease. Vet Clin North Am Small Anim Pract 22:1187-1201, 1992 3. Dye JA, McKiernan BC, Rozanski EA, et al: Bronchopulmonary disease in the cat: Historical, physical, radiographic, clinicopathologic, and pulmonary functional evaluation of 24 affected and 15 healthy cats. J Vet Intern Med 10:385--400, 1996 4. Foster SF, Barrs VR, Martin P, et al: Pneumonia associated with Mycoplasma spp in three cats. Aust Vet J 76:460--464, 1998 5. Gleich GJ: Mechanisms of eosinophil-associated inflammation. J Allergy Clin Immunol 105:651-663, 2000 6. Hamann KJ, Strek ME, Baranowski SL, et al: Effects of activated eosinophils cultured from human umbilical cord blood on guinea pig trachealis. Am J Physiol 265:1301307, 1993 7. Hill JW: Diseases of the respiratory organs. In Jenkins WR (ed): The Diseases of the Cat. New York, 1906, pp 11-21 8. Hoffman AM, Dhupa N, Cimetti L: Airway reactivity measured by barometric wholebody plethysmography in healthy cats. Am J Vet Res 60:1487-1492, 1999 9. Leff AR: Role of leukotrienes in bronchial hyperresponsiveness and cellular responses in airways. Am J Respir Crit Care Med 161(suppl):S125-32, 2000 10. Lofdahl CG, Reiss TF, Leff JA, et al: Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ 319:87-90, 1999 11. Mathur M, Herrmann K, Qin Y, et al: CD28 interactions with either CD80 or CD86 are sufficient to induce allergic airway inflammation in mice. Am J Respir Cell Mol Bioi 21:498-509, 1999 12. McKiernan B, Johnson L: Clinical pulmonary function testing in dogs and cats. Vet Clin North Am Small Anim Pract 22:1087-1101, 1992 13. McKiernan BC, Dye JA, Rozanski EA: Tidal breathing flow-volume loops in healthy and bronchitic cats. J Vet Intern Med 7:388-393, 1993 14. Mellema, et al: [abstract]. In Proceedings of American College of Veterinary Internal Medicine, 1999 15. Moise NS, Spaulding GL: Feline bronchial asthma: Pathogenesis, pathophysiology, diagnostics and therapeutic consideration. Compend Contin Educ Pract Vet 3:10911101, 1981 16. Moise NS, Weidenkeller D, Yeager AE, et al: Clinical radiographic and bronchial cytologic features of cats with bronchial disease: 65 cases (1980-1986). JAVMA 194:1467-1473, 1989 17. Padrid PA, Mathur M, Li X, et al: CTLA4Ig inhibits airway eosinophilia and hyperresponsiveness by regulating the development of Th1/Th2 subsets in a murine model of asthma. Am J Respir Cell Mol Biol18:453--462, 1998
FELINE AS1HMA
1293
18. Padrid PA, Mitchell RW, Ndukwu IM, et al: Cyproheptadine-induced attenuation of
type-I immediate-hypersensitivity reactions of airway smooth muscle from immunesensitized cats [published erratum appears in Am J Vet Res 56:402, 1995]. Am J Vet Res 56:109-115, 1995 19. Padrid PA, Feldman BF, Funk K, et al: Cytologic, microbiologic, and biochemical analysis of bronchoalveolar lavage fluid obtained from 24 healthy cats. Am J Vet Res 52:1300--1307, 1991 20. Strek ME, Williams FS, Gleich GJ, et al: Mechanisms of smooth muscle contraction elicited by cationic proteins in guinea pig trachealis. Am J Physiol 270:L133-140, 1996
Address reprint requests to Philip Padrid, RN, DVM University of Chicago Section of Pulmonary/Critical Care Medicine MC 1030 Attn: Animal Resources Center 5841 South Maryland Avenue Chicago, IL 60637 e-mail: [email protected]
0195-5616/00 $15.00
+ .00
FELINE ASTHMA Diagnosis and Treatment Philip Padrid, RN, DVM
Asthma in human beings is a chronic inflammatory disease within the lower airways (bronchi and bronchioles) that causes cough, wheeze, and exercise intolerance. These clinical signs are the result of a decrease in airflow through airways that are narrowed from excessive mucus secretion, airway wall edema, and bronchoconstriction. "Feline asthma" is a remarkably similar condition that has been recognized in the veterinary literature since at least 1906, when HilF described cats with increased airway mucus, airway inflammation, and the clinical signs of labored breathing and wheezing. DIAGNOSIS
There are no clinical signs or laboratory tests available in routine veterinary clinical practice that are pathognomonic for asthma in cats. The tests we can perform are most valuable to exclude other common causes of (acute) dyspnea, wheeze, and cough, including chronic bronchitis, heart failure, pneumonia, pulmonary malignancy, respiratory parasitism, and inhaled foreign bodies. Fortunately, except for chronic bronchitis, these other disorders do not routinely cause clinical signs similar to asthma in an otherwise healthy cat. As a result, we can usually make the correct diagnosis of feline asthma if we examine only a few clinical signs and radiographic findings, including:
From the Section of Pulmonary/Critical Care Medicine, University of Chicago, Chicago, Illinois; and the Veterinary Centers of America, Los Angeles, California
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME30•NUNrnER6•NOVEMBER2~
1279
1280
PADRID
1. There is a history of sudden onset of labored breathing that is quickly relieved (usually) with some combination of oxygen, bronchodilators, and steroids. 2. In some cases, however, the only clinical problem is a chronic cough. Cats with chronic bronchitis have the clinical symptom of daily cough, and this can mimic feline asthma. Fortunately, cats with chronic bronchitis should be treated similarly as cats with asthma (daily, mild or moderate [see classification scheme below]). As a result, the distinction between chronic bronchitis and asthma is not always critical. 3. The most important radiographic finding is bronchial wall thickening. These changes are usually described as "doughnuts" and "tramlines." Air trapping may be assumed if there is flattening of the diaphragm and the dorsal crus of the diaphragm is near intercostal space 12 to 13 on multiple views of the thorax. This is a less common but significant finding. 4. When airway cytology is available, cats with asthma usually have evidence of airway inflammation, including large numbers of eosinophils recovered from tracheobronchial secretions. This is not specific for asthma, however, as many healthy cats also have large numbers of eosinophils within their respiratory tract. 19 In contrast, the neutrophil is the predominant inflammatory cell in tracheobronchial secretions from cats with chronic bronchitis. These clinical and laboratory findings are also found in human asthma. Histologic fe9-tures of feline asthma, including hyperplasia and hypertrophy of the mucus-secreting apparatus, airway smooth muscle thickening, and epithelial erosion associated with an eosinophilic infiltrate, also closely parallel the human condition (Fig. 1). Finally, "airway hyper-reactivity," a defining feature of human asthma, has recently been demonstrated in cats with clinical signs of asthma. 3 Thus, cats do get asthma in the same way as we understand this disorder in human beings. Although the clinical signs of asthma may seem straightforward, the classification of the disease has not been as clear. Even in human respiratory medicine, it has historically been easier to recognize the clinical signs of asthma than it has been to precisely define the condition. Thus, the purpose of this article is to (1) review our current understanding of the pathophysiology of asthma in cats; (2) suggest a straightforward and clinically oriented classification scheme for diagnosing and treating cats with asthma; and (3) introduce the practical use of inhaled medications to treat asthmatic cats with mild, moderate, or severe disease. PATHOPHYSIOLOGY OF ASTHMA IN CATS
Although there are many potential causes of asthma, the airways respond to inhaled irritants or immunologic stimuli in a limited number of ways:
FELINE ASTHMA
1281
Figure 1. Naturally occurring feline asthma. Medium-sized bronchus from a 9-year-old Siamese Cat with a 4-year history of cough and wheeze. Note the invagination of airway mucus from bronchoconstriction, luminal exudate, thickened smooth muscle, and hypertrophied submucosal glands. (From Padrid P: Feline asthma: Pathophysiology and treatment. Waltham Focus 9:17-22, 1999; with permission.)
1. Airway epithelium may thicken (hypertrophy), evolve to a differ-
ent structure (metaplastic change), or simply become damaged (erode or ulcerate). 2. The structures responsible for producing mucus (goblet cells and submucosal glands) may enlarge and produce excessive amounts of a particularly thick form of mucus. 3. Bronchial smooth muscle often spasms and may become hypertrophied. These changes are associated with cellular infiltration of the bronchial mucosa and submucosa, and this tissue m ay also become edematous. The resulting clinical signs of cough, wheeze, difficulty in breathing, and decreased exercise capacity are due to airway narrowing (and airflow reduction) from excessive mucus secretions, airway edem a, airway narrowing from cellular infiltrates, and airway smooth muscle constriction. Cough may also result from stimulation of inflamed and contracted cough mechanoreceptors located in airway epithelium. This is an important concept, because even a small degree of airway narrowing can produce dramatic changes in clinical signs. For example, a 50% reduction in the radius of an airway results in a 16-fold reduction in the amount
1282
PADRID
Figure 2. Effect of airway size on air flow. A, Normal-sized airway. B, Asthmatic airway, in which the airway is partially obstructed (50%) with mucus and cellular debris. This obstruction results in a 16-fold reduction in air flow through that airway. (From Padrid P: Feline asthma: Pathophysiology and treatment. Waltham Focus 9:17-22, 1999; with permission.)
of air that flows through that airway (Fig. 2). It is easy to imagine why any movement that requires an increase in the depth of breathing such as chasing a mouse is tremendously altered if there is a 16-fold decrease in the amount of air that comes into the lungs during normal respiration. The important take-home message is that small changes in airway size result in dramatic changes in airflow through that airway. The clinical implications of this finding are twofold. First, relatively small amounts of mucus or bronchoconstriction can partially occlude airways and cause a dramatic fall in airflow. Conversely, therapy that results in relatively small increases in airway size may cause a dramatic improvement in clinical signs. An important advance in our understanding of this relation between airway structure and function is the recent discovery that human asthmatic airways are chronically inflamed whether or not the patient is symptomatic (this has not been confirmed in cats). It has also been recognized for some time that eosinophils seem to play a primary role in chronic asthmatic airway inflammation in human beings and cats. Highly charged cationic proteins within eosinophil granules are released into airways and cause epithelial disruption and sloughing. Additionally, these granular proteins can make airway smooth muscle more " twitchy" and prone to contraction after exposure to low levels of stimulation (airway hyper-reactivity). 6• zo Eosinophil-T Lymphocyte Interactions
The pathogenesis of asthmatic airway hyper-reactivity is complex. Recent studies suggest that the interaction between activated T lympho-
FELINE ASTHMA
1283
cytes and eosinophils within airways may play a particularly important role in the generation of eosinophilic airway inflammation and airway hyper-reactivity in human asthma. Cytokines, including interleukin-5 secreted from the T-helper-2 subset of activated CD4 + T cells, promote eosinophil survival, activation, and recruitment into airways. 5 Recent experimental studies using transgenic and "knockout" mice to overexpress or delete activated T lymphocytes or T cell-specific cytokine products in antigen-challenged mice continue to support the role of activated T lymphocytes and eosinophils in the development of asthmatic airway inflammation. 11' 17 WHAT DO WE KNOW ABOUT CATS WITH ASTHMA?
Although coughing and wheezing cats have been identified by owners and veterinarians for more than 90 years, it is only in the last 5 years that we have begun to study the disorder in earnest. Doctors at the University of Illinois School of Veterinary Medicine have identified pulmonary function abnormalities in cats with signs of chronic lower airway inflammation. Some of these cats have increased lung resistance that resolves after treatment with terbutaline (a !32 agonist), indicating the presence of reversible bronchoconstriction in these patients. 3' 12 Additionally, some of these cats experience dramatic bronchoconstriction after exposure to low levels of methacholine, a drug that has minimal effects on pulmonary function when used in equivalent doses in nonasthmatic cats. This is an important finding as the first demonstration of spontaneous and naturally occurring airway hyper-reactivity in a nonhuman species. Even more recently, Hoffman and associates8 at Tufts School of Veterinary Medicine have validated the use of the Buxco noninvasive plethysmograph (Buxco Electronics, Sharon, CT) to study pulmonary function in awake nonrestrained cats. Use of this device may greatly speed the generation of knowledge regarding pulmonary function in asthmatic cats and lead to objective means of evaluating current and future drug therapies for these patients, HOW SHOULD WE CLASSIFY CATS WITH ASTHMA?
In veterinary medicine, feline asthma has been referred to as feline lower airway disease, feline allergic asthma, extrinsic asthma, feline allergic bronchitis, chronic obstructive pulmonary disease, eosinophilic bronchitis, acute allergic bronchitis, chronic bronchitis, and immunemediated airway disease. 2' 3, 12, 13, 15, 16 These multiple definitions of asthma in cats reflect a widespread confusion in the veterinary community regarding respiratory disease in general and respiratory disease in cats in particular. This confusion, in turn, has inhibited the development of generally accepted rational standards of care for feline asthma. What follows is an attempt to clarify the notion of feline asthma by simplifying
1284
PADRID
the way we classify cats with this disease and proposing a standard of treatment for these animals. Obviously, the clinician should be reasonably certain of the diagnosis. Once the diagnosis is made, the first step is to determine if the clinical signs are intermittent or if they occur daily. If symptoms occur daily, the next step is to decide if the clinical signs are mild, moderate, or severe. 1. Mild symptoms: In these cases, the symptoms do not affect the way in which the cat conducts its business (quality of life). In these cases, between "attacks/' the cat eats, drinks, and plays as if nothing is wrong. 2. Moderate symptoms: In these cases, the asthmatic condition sometimes affects the way the cat conducts its business (e.g., it may tire easily, it may wake up at night coughing). Symptoms are not constant, and the cat does not have obvious difficulty when breathing at rest most times of the day. 3. Severe symptoms: In these cases, the asthmatic condition is continual and clearly limits the eat's ability to conduct its business. These cats are not comfortable at rest, and the symptoms occur for most of each day. In summary, to classify cats with asthma, we take the following steps: (1) determine if the signs are intermittent or daily, and (2) determine the severity of daily symptoms. These two steps are the beginning of a rational treatment plan.
HOW SHOULD WE TREAT CATS WITH ASTHMA?
The primary signs of asthma include cough and wheeze, and these signs are frequently caused by airway smooth muscle contraction. It is tempting to treat these signs of asthma by using bronchodilators to reverse the airway smooth muscle spasm, and, in fact, this is the logical treatment for cats with intermittent symptoms. It is critically important to remember that human (feline?) asthmatic airways show evidence of chronic ongoing inflammation whether or not the patient is symptomatic. As a result, for cats with daily symptoms, treatment strategies are most successful if they are directed toward decreasing the underlying inflammatory component of the disease. Corticosteroids are the most effective long-term treatment of feline asthma. Corticosteroids have many beneficial effects in this setting, including inhibiting the synthesis of genes for cytokines that are important in generating airway inflammation. Nevertheless, the side effects of chronic high-dose oral steroid treatment in cats are well known and include pancreatitis, insulin resistance (diabetes), and significant behavioral changes in addition to polyuria, cystitis, and inappropriate urination. Fortunately, inhaled steroids are now available that do not
FELINE AS1HMA
1285
cause systemic side effects, and this treatment has greatly enhanced our ability to successfully treat cats with asthma. Inhaled Medications
Corticosteroids and bronchodilators can now be given effectively by inhalation to cats with asthma (Table 1). Both classes of drugs are available as metered dose inhalers (MDis) (Fig. 3) for human patients with asthma. Proper use of an MDI requires the patient to coordinate inhaling with the actuation of the device, and this has proven to be surprisingly difficult for most patients. This is also not realistic for infants and young children. An alternative was developed to allow these individuals to use the MDis without the need to coordinate their breathing. Thus, the MDI is used in conjunction with a "spacer" designed for use in infants and small children and a face mask specifically made for cats. The spacer is a plastic chamber the size of a cardboard Table 1. DRUGS AVAILABLE AS METERED DOSE INHALERS, USED WITH SPACERS AND FACE MASKS TO TREAT DOGS AND CATS WITH RESPIRATORY DISEASE* Drug Class
Bronchodilator (~-2 agonist)
Drug Name
Albuterol (Ventolin, Proventil) Pirbuterol (Maxair) Bitolterol (To malate) Salmeterol (Serevent)
Indication
Important Points
Immediate relief of bronchoconstriction Immediate relief of bronchoconstriction Immediate relief of bronchoconstriction Long-term (12 h) control of bronchoconstriction
Effect is short-lived (<4 h) Not studied in dogs and cats Not studied in dogs and cats Takes > 1 h to take effect
Anticholinergic
Ipratropium bromide (Atrovent)
Additive bronchodilation with ~-2 agonists
Not studied in dogs and cats
Anti-inflammatory corticosteroid
Fluticasone propionate (Flovent) Flunisolide (AeroBid) Budesonide (Pulmocort) Beclomethasone dipropionate (Beclovent, Vanceril)
Long-term control of inflammation Long-term control of inflammation Long-term control of inflammation Long-term control of inflammation
Takes 10-14 days to reach peak effects Not studied in dogs and cats Not studied in dogs and cats Not studied in dogs and cats
Cromolyn sodium (Intal)
Long-term control of inflammation
Not studied in dogs and cats
Nedocromil sodium (Tilade)
Long-term control of inflammation
Not studied in dogs and cats
Mechanisms unclear (inhibits mast cell degranulation)
*See text for specific indications.
1286
PADRlD
Figure 3. Metered dose inhaler (MDI) used to treat respiratory disease in human beings. This device requires a coordinated effort by the patient to inhale immediately after actuation of the device and is not suitable, by itself, for use in animals.
FELINE ASTHMA
1287
Figure 4. A, The spacer device connected to an MDI. B, The spacer connected to an MDI and a self-sealing mask commonly used for induction of anesthesia. The spacer acts as a reservoir for the inhaled medication, so that the animal breathes the drug into its airways whenever it breathes through the face mask.
1288
PADRID
Figure 5. The attachment on the spacer for the face mask has been removed to show the thin rubber gasket that acts as a one-way valve. On inspiration the gasket moves toward the mouth and opens, allowing the medication within the spacer to be inhaled. The gasket closes on exhalation, preventing the medication from escaping.
inner roll of toilet paper. The MDI fits into one end of the spacer, and the other end of the spacer has an attachment for the face mask (Fig. 4). The end of the spacer that connects with the face mask has an inner rubber gasket that acts as a one-way valve so that the medication within the spacer can only leave the spacer during an inhalation (Fig. 5). The client first attaches the MDI and the face mask to the spacer and then actuates (presses) the MDI twice to fill the spacer with medication. The client then places the face mask gently over the eat's mouth and nose. The cat is allowed to breath in and out 7 to 10 times with the mask in place, and the treatment is completed. Specific Treatment for Cats with Asthma
Treatment of Feline Asthma if Symptoms Are Intermittent (Do Not Occur Daily)
In these cases, I prescribe an albuterol inhaler with instructions to use "as needed." The assumption in these cases is that cats with symp-
FELINE ASTHMA
1289
toms that do not occur daily do not have significant chronic ongoing inflammation that requires daily anti-inflammatory therapy. When acute signs do occur (e.g., cough, wheeze, difficulty in breathing), they can usually be effectively and quickly treated with the inhaled bronchodilator. If signs become more frequent, the cat should be re-evaluated to determine if more aggressive treatment should be initiated (see next step). Treatment of Feline Asthma if Symptoms Occur Daily
Mild Daily Symptoms. These cats have daily symptoms but in between the coughing and wheezing, they are generally unaffected by their disorder. For these cats, I prescribe 220 f..Lg of Flovent twice daily. I also prescribe an albuterol inhaler as needed for those times when symptoms are particularly troublesome. Because inhaled Flovent takes about 7 to 10 days before its maximum effect is seen, these cats continue to be symptomatic for an additional week or so. Clients should be supported through this period and encouraged that their pet is going to begin to improve after the first week of therapy. Moderate Daily Symptoms. These cats have daily symptoms that have a negative effect on their quality of life, but their cough, wheeze, or dyspnea is not constant. For these cases, I prescribe 220 f..Lg of Flovent twice daily and albuterol as needed. I also prescribe 1 mg/kg of prednisone administered orally twice daily for 5 days and then daily for 5 additional days. After 10 days of combined oral and inhaled steroids, the cat has generally shown great improvement, and the oral prednisone can be discontinued without taper. Oral prednisone is used in this setting because significant daily symptoms suggest the presence of a more aggressive inflammatory component that should be more aggressively treated. Severe Daily Symptoms. These cats are symptomatic and uncomfortable at rest and require aggressive early management. I begin with 2 mg/kg of dexamethasone administered intravenously and inhaled albuterol every 30 minutes for up to 4 hours. This frequency of albuterol treatment generally does not cause side effects or might cause slight muscle tremor. These cats are also given 40% to 100% oxygen either by nasal cannula or oxygen cage. Once these patients are stabilized (their symptoms are dramatically improved), they can be discharged with 220 f..Lg of Flovent administered twice daily and albuterol administered four times daily as needed. Some of these cats with severe symptoms may also require intermittent lower doses of oral prednisone, but this is tailored for the individual patient. ADDITIONAL TREATMENTS Antibiotics
There is no objective evidence that bacterial infections play a significant role in the cause or continuation of feline asthma. Similarly,
1290
PADRID
there is little objective evidence that antibiotic therapy has any effect on the duration or intensity of signs displayed by the cat with asthma. 1' 3, 19 It is important to remember that the clinical signs of asthma frequently wax and wane in severity as well as in frequency of occurrence. There are anecdotal reports describing the therapeutic effect of antibiotics in controlling asthmatic symptoms; however, the author believes that these reports are consistent with the "waxing and waning" nature of the symptoms in nontreated cases. A positive culture result obtained from a tracheobronchial wash does not necessarily demonstrate a clinically significant airway infection and should not automatically prompt the clinician to start antibiotic therapy. Remember, there is a revolving population of commensal bacteria that live in the respiratory tract in cats and other species, and these organisms are not disease-producing. 3, 19 In general, antibiotics are rarely indicated for cats with asthma and are appropriate only when there is good evidence of superimposed airway infection. A true infection may be assumed if the positive culture was obtained after growing the organisms in culture without using an enrichment broth such as thioglycolate. (Your reference laboratory can tell you if enrichment broth was used or if your samples were subcultured.) This is because the concentration of aerobic bacteria recovered from the airways of healthy cats rarely exceeds 5 X 103 organisms per milliliter. In contrast, growth of a single organism recovered without the use of enrichment broth implies more than 105 organisms per milliliter, and this is consistent with an "infected" airway. 3' 19 Antibiotic therapy is then based on sensitivity data. Prophylactic or long-term antibiotic therapy is not indicated unless there is documentation of a chronic airway infection. Documented chronic airway infection is extraordinarily uncommon in feline asthma. There is a possible exception to these statements. Mycoplasma species have been isolated from the airway of as many as 25% of cats with signs of lower airway disease. 16 In contrast, Mycoplasma species are not cultured from the airway of healthy cats. For this reason, and because Mycoplasma species have the potential to cause significant structural damage to airway epithelium, it may be prudent to treat any cat with a Mycoplasma-positive airway culture with an appropriate antibiotic. 4 Cyproheptadine
Cyproheptadine is an antihistamine and antiserotonin compound that has been used in feline medicine to increase appetite. Our laboratory demonstrated that mast cells within feline airways contain serotonin and that serotonin can cause smooth muscle constriction within feline airways. These studies were performed with isolated lung tissue in vitro and were intended to encourage further studies in vivo to determine the effectiveness (or lack of effectiveness) of cyproheptadine in cats with asthma. 18 Although there have been many anecdotal reports that cypro-
FELINE ASTHMA
1291
heptadine is sometimes helpful in these cases, the author does not routinely prescribe this drug for these cats. Antileukotriene (or Receptor) Drugs
There has been a great deal of recent interest in drugs that block production of leukotrienes (LTC.v LTD4 ) or ligation of these molecules to their receptor(s). In general, these drugs have limited but significant effectiveness in treating some human asthmatics with moderate to severe disease. 9• 10 Leukotrienes increase mucus production, induce cellular edema, and promote airway smooth muscle constriction in human beings and other species, so it is reasonable to think that antileukotriene drugs might have a role in the therapy of feline asthma. Perhaps it is not surprising that Zyflo, Accolate, and Singulair have all been used to treat cats with asthma even though there are no safety or efficacy studies of these drugs in the feline species. We have found that LTE.v the metabolic product of LTC 4 and LTD4 metabolism, is found in increased amounts in urine of cats with asthma but not in normal cats or cats with nonasthmatic disorders such as kidney failure or pancreatitis. We have also found similar increases in prostaglandins (PGF 2., PGI2 ) and thromboxane A 2 (TXA 2 ) in bronchoalveolar lavage fluid of cats with experimentally induced asthma (unpublished studies). This suggests that leukotrienes and other products of the arachadonic acid cascade are manufactured in increased amounts in cats with asthma. Interestingly, a more recent study by Mellema et aP 4 did not support our finding but instead found no increase in urinary LTE 4 in 20 cats with signs of lower airway disease. Additionally, direct instillation of LTC4 into the airways of normal cats has no adverse effect on feline airway structure or function. It is probable that increased leukotriene production, like prostaglandin production, is a clinically nonsignificant byproduct of the general inflammation in asthma. There are no current data that suggest that antileukotriene drugs have an important role in the treatment of cats with asthma. Most importantly, the author strongly believes that correct diagnosis and aggressive therapy of cats with asthma as outlined in this article minimize the need to explore untested and variably effective human drugs in these feline patients. SUMMARY AND CONCLUSIONS
Human asthma is not a curable disease, although spontaneous resolution is common in adult asthmatics who developed asthma in childhood. We do not know if this is true or not for cats with asthma. We do know that some cats may be only mildly and intermittently symptomatic and that others may suffer life-threatening illness. An important new development in our understanding of this disease is the occurrence of airway inflammation even when patients are symptom-
1292
PADRID
free. It is therefore crucial that we direct our therapeutic attention toward the underlying chronic inflammation that causes the acute clinical signs of cough, wheeze, and increased respiratory effort. Client education is also critical so that our clients develop realistic expectations of the effectiveness of these treatments for their pets. A great deal still needs to be learned regarding the pathogenesis of feline asthma and the optimal approach( es) to treating cats with this sometimes debilitating and potentially fatal respiratory syndrome. There is great hope and anticipation that ongoing research can bring new treatments for human and feline asthmatics alike. References 1. Corcoran BM, Foster DJ, Fuentes VL: Feline asthma syndrome: A retrospective study of the clinical presentation in 29 cats. J Small Anim Pract 36:481--488, 1995 2. Dye JA: Feline bronchopulmonary disease. Vet Clin North Am Small Anim Pract 22:1187-1201, 1992 3. Dye JA, McKiernan BC, Rozanski EA, et al: Bronchopulmonary disease in the cat: Historical, physical, radiographic, clinicopathologic, and pulmonary functional evaluation of 24 affected and 15 healthy cats. J Vet Intern Med 10:385--400, 1996 4. Foster SF, Barrs VR, Martin P, et al: Pneumonia associated with Mycoplasma spp in three cats. Aust Vet J 76:460--464, 1998 5. Gleich GJ: Mechanisms of eosinophil-associated inflammation. J Allergy Clin Immunol 105:651-663, 2000 6. Hamann KJ, Strek ME, Baranowski SL, et al: Effects of activated eosinophils cultured from human umbilical cord blood on guinea pig trachealis. Am J Physiol 265:1301307, 1993 7. Hill JW: Diseases of the respiratory organs. In Jenkins WR (ed): The Diseases of the Cat. New York, 1906, pp 11-21 8. Hoffman AM, Dhupa N, Cimetti L: Airway reactivity measured by barometric wholebody plethysmography in healthy cats. Am J Vet Res 60:1487-1492, 1999 9. Leff AR: Role of leukotrienes in bronchial hyperresponsiveness and cellular responses in airways. Am J Respir Crit Care Med 161(suppl):S125-32, 2000 10. Lofdahl CG, Reiss TF, Leff JA, et al: Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients. BMJ 319:87-90, 1999 11. Mathur M, Herrmann K, Qin Y, et al: CD28 interactions with either CD80 or CD86 are sufficient to induce allergic airway inflammation in mice. Am J Respir Cell Mol Bioi 21:498-509, 1999 12. McKiernan B, Johnson L: Clinical pulmonary function testing in dogs and cats. Vet Clin North Am Small Anim Pract 22:1087-1101, 1992 13. McKiernan BC, Dye JA, Rozanski EA: Tidal breathing flow-volume loops in healthy and bronchitic cats. J Vet Intern Med 7:388-393, 1993 14. Mellema, et al: [abstract]. In Proceedings of American College of Veterinary Internal Medicine, 1999 15. Moise NS, Spaulding GL: Feline bronchial asthma: Pathogenesis, pathophysiology, diagnostics and therapeutic consideration. Compend Contin Educ Pract Vet 3:10911101, 1981 16. Moise NS, Weidenkeller D, Yeager AE, et al: Clinical radiographic and bronchial cytologic features of cats with bronchial disease: 65 cases (1980-1986). JAVMA 194:1467-1473, 1989 17. Padrid PA, Mathur M, Li X, et al: CTLA4Ig inhibits airway eosinophilia and hyperresponsiveness by regulating the development of Th1/Th2 subsets in a murine model of asthma. Am J Respir Cell Mol Biol18:453--462, 1998
FELINE AS1HMA
1293
18. Padrid PA, Mitchell RW, Ndukwu IM, et al: Cyproheptadine-induced attenuation of
type-I immediate-hypersensitivity reactions of airway smooth muscle from immunesensitized cats [published erratum appears in Am J Vet Res 56:402, 1995]. Am J Vet Res 56:109-115, 1995 19. Padrid PA, Feldman BF, Funk K, et al: Cytologic, microbiologic, and biochemical analysis of bronchoalveolar lavage fluid obtained from 24 healthy cats. Am J Vet Res 52:1300--1307, 1991 20. Strek ME, Williams FS, Gleich GJ, et al: Mechanisms of smooth muscle contraction elicited by cationic proteins in guinea pig trachealis. Am J Physiol 270:L133-140, 1996
Address reprint requests to Philip Padrid, RN, DVM University of Chicago Section of Pulmonary/Critical Care Medicine MC 1030 Attn: Animal Resources Center 5841 South Maryland Avenue Chicago, IL 60637 e-mail: [email protected]