Objectives of the Presentation

The presentation will discuss the inflammatory component of two common feline diseases, chronic gingivostomatitis and idiopathic cystitis.

Overview of the Issue

Inflammation in the Oral Cavity

In a recent survey of the health status of over 31,000 dogs and over 15,000 cats examined at veterinary practices in the United States, the most commonly reported disorders were dental calculus (20.5% prevalence in dogs; 24.2% in cats) and gingivitis (19.5% prevalence in dogs; 13.1% in cats).[1] Inflammation of the oral cavity, ranging from mild to severe, is a common finding in cats and may be increasing in frequency. Gingivitis is inflammation confined to the gingiva, and stomatitis is inflammation that extends beyond the mucogingival junction. Chronic inflammatory oral disease has been given many names, such as lymphoplasmacytic stomatitis, lymphocytic-plasmacytic gingivitis-stomatitis, plasmacytic stomatitis, plasma cell gingivitis-stomatitis-pharyngitis, chronic ulcerative stomatitis, chronic gingivitis-stomatitis-faucitis, and feline chronic gingivostomatitis.(GS)

Chronic GS is a condition characterized by persistent inflammation and sometimes ulceration of the oral mucosa. The disease varies in severity and may include faucitis, pharyngitis, or palatitis. Clinical signs include drooling, bleeding gingiva, oral sensitivity, and partial anorexia and weight loss. It can be debilitating, frustrating to treat, and in some cases may result in euthanasia. Quality of life can only be achieved in some cats with the extraction of all molar and premolar teeth.[2]

The pathogenesis of oral inflammatory disease in the cat is not well understood and may be multifactorial. The histopathologic characteristics indicate that an inappropriate immunologic response occurs. Abnormalities in the immune system may alter the individual cat's response to either infectious or non-infectious antigens, contributing to the chronic nature of the problem. The immune system responds to chronic stimulation with the production of immunoglobulins by mature plasma cells, often resulting in a monoclonal gammopathy. Some of these immunoglobulins are specific for oral microorganisms. The most common pattern seen on examination of biopsy samples of cats with GS is an inflammatory reaction primarily consisting of plasma cells, but also neutrophils, lymphocytes, and macrophages. While often unrewarding, attempts to establish the etiology may allow for focused treatment to eliminate the stimulus for the immune response.

Several infectious agents have been associated with chronic oral inflammatory disease in cats, such as Bartonella, plaque bacteria, calicivirus, herpesvirus, feline leukemia virus (FeLV), and feline immunodeficiency virus (FIV). Other important contributing conditions include chronic endocrine disease (e.g., diabetes mellitus), immunological response to food proteins, and even the effect of domestication.[3] Oral inflammatory disease appears to be more common in some cat breeds, indicating there may be a genetic predisposition.

Many studies have evaluated the potential contribution of various infectious agents to GS in cats, sometimes with conflicting results. All the candidate agents may be found in both clinically healthy cats and cats with GS, making confirmation of causality difficult. In one study, oral mucosal swabs were collected from 25 cats with GS and 24 cats with periodontal disease for virus culture.[4] Shedding of calicivirus and herpesvirus was found in 88% of cats with chronic GS compared to 21% of cats without chronic oral inflammation (classical periodontal disease). In a case study of a cat with chronic GS, calicivirus shedding was monitored for 22 months.[5] The cat was treated with thalidomide and lactoferrin, as well as a change in diet. After 11 months of treatment, clinical signs began to resolve and coincided with cessation of calicivirus shedding.

However, calicivirus isolated from cats with GS and then inoculated into specific pathogen free cats will not reliably reproduce GS, suggesting that other factors contribute to the development of oral inflammation. Development of GS is more likely associated with the host immune response to chronic calicivirus infection rather than particular calicivirus strains. The high success rate of tooth extraction in cats with GS suggests that it may be the sum of the total antigenic stimulation from plaque bacteria and viruses that is significant for the development of GS.[6]

The objective of another study was to determine the prevalence of Bartonella DNA in blood and B. henselae serum antibodies in 34 client-owned cats with histopathologically documented GS as well as 34 age- and geographically-matched healthy control cats.[7] All cats were also tested for FeLV antigen and FIV antibody. No significant differences in the prevalence rates for PCR-positive cats or for antibody-positive cats between affected and control cats were found. An earlier study performed in Europe found that cats seropositive for Bartonella showed an increased incidence of GS.[8] One of the difficulties in evaluating the role of Bartonella is the high prevalence rates of antibody-positive animals within the healthy population and variations in test methodologies.

A colony of cats in southern California including 9 cats with active GS and 36 unaffected cats were evaluated for FeLV, FIV, calicivirus, herpesvirus and Bartonella with blood and throat swabs.[9] Evidence of infection with these agents was not overrepresented in the cats with GS. Many factors affect the results of these studies, including sampling, shipping and storage factors, assay methods, clearance or latency of the organisms, presence of subsets of GS, and potential variations in organism virulence.

Oral disease may be a marker for more serious systemic disease in cats. In a 2006 nationwide study of 8,982 cats with oral disease, 14.2% were retrovirus positive (J. Bellows and IDEXX Laboratories, data on file). This is much higher than the general population rate of about 3% in the United States.[10] Knowing the retrovirus status of a cat is essential for optimal assessment, wellness management, and treatment.

Chronic gingivostomatitis is often refractory to treatment. No conservative treatment, including dental cleaning, home care, antibiotics (e.g., metronidazole, clindamycin, azithromycin), or corticosteroids, is likely to provide long-term (>6 months) resolution for moderate to severely affected cats. The only treatment shown to provide long-term relief in a majority of cats without further intervention is caudal (all teeth behind the canines) or whole mouth dental extractions. In the only published study on the efficacy of dental extractions for chronic gingivostomatitis, 60% of cats had significant improvement, 20% had some improvement, and 20% had little or no improvement.[2]

Inflammation in the Bladder

Feline idiopathic cystitis (FIC) is a sterile, inflammatory process causing signs of lower urinary tract disease (LUTD). It affects 1.5% of cats presented to primary care veterinarians.[1] It is the most common diagnosis for young cats with LUTD (the second most common being urolithiasis). FIC is important not only because of the pain and distress it causes patients, but also because it is highly associated with housesoiling (periuria), the leading cause of relinquishment of cats to shelters.

FIC appears to be a modern disease, having first been mentioned in the early 1990s when it was discovered that no specific diagnosis could be made in over 50% of cats with LUTD.[11] Diet and environment may therefore play important roles. Terminology can be confusing with this disease. "Interstitial cystitis" is a term best reserved for that subset of FIC patients with chronic or frequent signs and cystoscopic findings similar to humans with interstitial cystitis. Idiopathic cystitis is a more generic, umbrella term for those cats with acute or chronic signs of LUTD where cystoscopy has not been performed or has not revealed changes associated with interstitial cystitis.

Approximately 60-70% of cats under 10 years of age with signs of LUTD have no specific cause identified, and are referred to as having FIC. In one study of 109 cats with signs of LUTD, 64% were determined to have FIC.[12] Several studies have shown that less than 2% of cats with LUTD signs have bacterial urinary tract infection (UTI). Recently, however, a study of 134 Norwegian cats with clinical signs of lower urinary tract disease found 33% had bacteriuria.[13] Cats with FIC are generally young to middle-aged when diagnosed; FIC is less likely as a new diagnosis in geriatric cats and other causes of LUTD should be pursued aggressively in this age group.

Most patients are 2-6 years of age at diagnosis; FIC is uncommon in cats under 1 year of age. Certain factors have been associated with increased risk in several studies:

 Breed: lower in Siamese, higher in Persians

 Gender: neutered male and spayed female

 Age at neutering not important

 Increased body weight, decreased activity

 Multiple cat households

 Exclusive dry food diet[12]

 Indoor lifestyle

In one questionnaire-based study of 31 cats with FIC compared to 24 normal housemates and 125 other normal cats,[14] certain risk factors were identified: male gender, being overweight, pedigreed breed, and stress factors, especially conflict with another cat in the home.

The most common sign associated with FIC is urination in inappropriate places (periuria). Other common clinical signs include:

 Pollakiuria

 Dysuria

 Vocalizing during attempts to urinate

 Hematuria

 Bilateral inguinal alopecia, often with self-excoriation

These clinical signs are not specific to FIC, and can also be seen in cats with other causes of LUTD disease, such as cystic calculi, UTI, crystalluria, mass lesions, etc. The clinical signs typically wax and wane, and are usually self-limiting and of short duration (3-7 days). Some cats will have chronic persistent clinical signs or frequent recurrences. It is unknown if this represents an extreme on the spectrum of cats with FIC, or whether it is due to another etiology. Some male cats with FIC will suffer a urethral blockage due mucus plugs that consist of serum proteins, crystals, cells and debris.

The pathophysiology of FIC is not well understood, although advances have been made in recent years. It is thought that FIC involves complex interaction between the central nervous system and the endocrine system. Cats with FIC are described by investigators at Ohio State University as "sensitive cats in a provocative environment." These cats may be unusually sensitive to changes in their environment and diet.

The sympathetic nervous system plays an important role by releasing catecholamines such as norepinephrine (NE) and epinephrine. Stress and pain stimulate increased sympathetic nervous system outflow. Cats with FIC have an increased release of NE and other catecholamine metabolites during stress compared to normal cats.[15] This appears to upregulate the inflammatory response. The neurotransmitter substance P and its receptors are increased in the bladder of cats with FIC, further fueling the inflammatory response. In addition, cats with FIC have significantly decreased serum cortisol responses compared to normal cats and have smaller adrenal glands.[16]

Essentially, FIC is an exaggerated sympathetic nervous system response to stress with a blunted endocrine response. Stress appears to be a very important factor in flare-ups of FIC and often precedes a cat's first episode. The involvement of the central nervous system may explain why therapies directed only at the bladder have a high failure rate.

Many similarities between FIC and interstitial cystitis in humans have been found:[17-19]

 Cystoscopic changes such as submucosal hemorrhage, edema

 Decreased urinary glycosaminoglycan excretion

 Increased bladder permeability, allowing constituents of urine to access bladder submucosa and cause inflammation

Treatment is problematic although environmental enrichment is proving to be a powerful tool to help decrease sympathetic overdrive, reduce stress, and prolong time between episodes of FIC. In a recent study of 46 client-owned cats,[20] multimodal environmental modification (MEMO) was instituted and the cats were followed for 10 months. The components of MEMO are available for owners and veterinarians on the website of the Indoor Cat Initiative (www.indoorcat.org). Significant decreases were documented in signs of LUTD, fearfulness, nervousness and aggressive behavior. As well, owners reported decreases in clinical signs referable to the respiratory and gastrointestinal tracts.

Summary

Some of the most frustrating conditions to treat in feline medicine are those with a strong inflammatory component. While corticosteroids have been the mainstay of traditional anti-inflammatory therapy, newer approaches are required that take into account the inciting causes, whether they be infectious, environmental, or genetic.

References

1.  Lund, E., et al., Health status and population characteristics of dogs and cats examined at private veterinary practices in the United States. J Amer Vet Med Assoc, 1999. 214(9): p. 1336-1341.

2.  Hennet, P., Chronic gingivo-stomatitis in cats: long-term follow-up of 30 cases treated by dental extractions. J Vet Dent, 1997. 14(1): p. 15-21.

3.  Lyon, K., Gingivostomatitis. The Veterinary clinics of North America. Small Animal Practice, 2005. 35(4): p. 891-911.

4.  Lommer, M.J. and F.J. Verstraete, Concurrent oral shedding of feline calicivirus and feline herpesvirus 1 in cats with chronic gingivostomatitis. Oral Microbiol Immunol, 2003. 18(2): p. 131-4.

5.  Addie, D., et al., Cessation of feline calicivirus shedding coincident with resolution of chronic gingivostomatitis in a cat. J Small Anim Pract, 2003. 44(4): p. 172-176.

6.  Southerden, P. and C. Gorrel, Treatment of a case of refractory feline chronic gingivostomatitis with feline recombinant interferon omega. J Small Anim Pract, 2007. 48(2): p. 104-6.

7.  Dowers, K.L. and M.R. Lappin, The association of Bartonella species infection with chronic stomatitis in cats (abstract). J Vet Intern Med, 2005. 19(3): p. 471.

8.  Glaus, T., et al., Seroprevalence of Bartonella henselae infection and correlation with disease status in cats in Switzerland. J Clin Microbiol, 1997. 35(11): p. 2883-5.

9.  Quimby, J.M., et al., Evaluation of the association of Bartonella species, feline herpesvirus 1, feline calicivirus, feline leukemia virus and feline immunodeficiency virus with chronic feline gingivostomatitis. J Feline Med Surg, 2008. 10(1): p. 66-72.

10. Levy, J., et al., Seroprevalence of feline leukemia virus and feline immunodeficiency virus infection among cats in North America and risk factors for seropositivity. J Amer Vet Med Assoc, 2006. 228(3): p. 371-376.

11. Kruger, J.M., et al., Clinical evaluation of cats with lower urinary tract disease. J Am Vet Med Assoc, 1991. 199(2): p. 211-6.

12. Buffington, C.A., et al., Clinical evaluation of cats with nonobstructive urinary tract diseases. J Am Vet Med Assoc, 1997. 210(1): p. 46-50.

13. Eggertsdottir, A.V., et al., Bacteriuria in cats with feline lower urinary tract disease: a clinical study of 134 cases in Norway. J Feline Med Surg, 2007. 9(6): p. 458-65.

14. Cameron, M.E., et al., A study of environmental and behavioural factors that may be associated with feline idiopathic cystitis. J Small Anim Pract, 2004. 45(3): p. 144-7.

15. Westropp, J.L., P.H. Kass, and C.A. Buffington, Evaluation of the effects of stress in cats with idiopathic cystitis. Am J Vet Res, 2006. 67(4): p. 731-6.

16. Westropp, J.L., K.A. Welk, and C.A. Buffington, Small adrenal glands in cats with feline interstitial cystitis. J Urol, 2003. 170(6 Pt 1): p. 2494-7.

17. Buffington, C., D. Chew, and S. DiBartola, Lower urinary tract disease in cats: is diet still a cause? JAVMA, 1994. 205(11): p. 1524-1527.

18. Buffington, C.A., et al., Decreased urine glycosaminoglycan excretion in cats with interstitial cystitis. J Urol, 1996. 155(5): p. 1801-4.

19. Pereira, D.A., et al., Changes in cat urinary glycosaminoglycans with age and in feline urologic syndrome. Biochim Biophys Acta, 2004. 1672(1): p. 1-11.

20. Buffington, C.A., et al., Clinical evaluation of multimodal environmental modification (MEMO) in the management of cats with idiopathic cystitis. J Feline Med Surg, 2006. 8(4): p. 261-8.