>>>Characteristics, Causes, Diagnosis<<<
LPGS Medications and Supplements
Click here to open a Glossary of Terms in a separate window.
Feline Lymphocytic-Plasmacytic Gingivostomatitis (LPGS), by whichever of the many names it goes, is an oral inflammatory disease that, by some of the more generous estimates, will be encountered by owners of about half of all cats infected with FIV and experiencing related symptoms. It is the most common secondary problem associated with FIV infection and is almost universally characterized as difficult to treat.
Chronic Gingivitis in the Cat [Judy Zinn, DVM]
Plasmacytic-Lymphocytic Stomatitis in cats is a chronic condition that results in extreme gingivitis and tooth loss. . . . Cats with stomatitis often have a rancid odor in their mouth, salivate excessively and have difficulty eating. The chronic mouth pain results in a decreased appetite and weight loss. Examination of the teeth and gums reveals extreme gingivitis especially around the upper back molars. The gums will appear raw and bumpy and bleed easily. As the disease progresses the gums will recede from the tooth root and the root will begin to be absorbed resulting in tooth loss. . . .With this degree of inflammation occurring, secondary invasion of bacteria is very common. The bacterial infection results in the rancid
odor. . . .
PLUGS: Cats in the Trenches [Elaine Cebuliak B.V.Sc., Dip.Ed.]
PLS is seen as a severe inflammation of the mucosa, fauces and gingiva of the oral cavity; often causing proliferation of gingiva, intense pain, halitosis, ptyalism, anorexia, lethargy and behaviour changes. There are various degrees of inflammation present, and the distribution within the oral cavity usually is more severe from the upper second premolar distally toward the fauces.
Feline Stomatitis [All Pets Dental Clinic]
Many cats affected by LPS will be unable to eat, develop weight loss, and have excess salivation. Oral examination often reveals a "cobble stone"-like redness in the throat area and severe inflammation where the tooth and gums meet. The premolar and molar areas are usually affected more than the canines and incisors. Intraoral x-rays often reveal moderate to severe periodontal disease. In addition to generalized inflammation, all stages of feline ondontoclastic resorptive lesions may be present.
Inflammation may occur in the gingiva [gums], the fauces [back of the mouth], the buccal [cheek] mucosa, even the tongue. Although stomatitis is the general term used to describe inflammation of nongingival tissue, the specific site of inflammation often provides the terminology of diagnosis and may also indirectly indicate the seriousness of the infection. Faucitis, for instance, would indicate inflammation of the area between the soft palate and throat. When tissue is biopsied, the results of the biopsy often show "lymphocytic-plasmacytic stomatitis." In other words, the two lymphocyte types of the specific immune response are present in abnormal numbers. It is not unusual, though, for the presence of other immune cells (such as neutrophils) in excess to be noted as well.
Not all feline inflammatory oral disease is LPGS. Many cats will suffer from treatable gingivitis related to tartar accumulation. Periodontitis, though generally more severe in cats with LPGS, may occur in any cat as a result of tooth resorption, buccal bone expansion, tooth fractures, and retained roots [Farcas]. Some young cats will suffer from a juvenile gingivitis caused by exfoliating of primary teeth and erupting of adult teeth. "In some cases this is associated with what appears to be gingival hyperplasia, but . . . it is actually inadequate apoptosis (programmed cell death). As the adult teeth erupt, soft tissue over the crowns must die, opening a hole through which the teeth can erupt. As the teeth are erupting, the gingiva is very loosely attached to the tooth so that the tooth can erupt. Until the tooth has erupted completely and the gingiva has died back to an appropriate height, there will be excess gingiva and deeper-than-normal probing depths around the tooth. These false pockets can be plaque-traps and triggers for gingivitis" [Hale].
LPGS itself is a blanket term to describe a condition that may proceed from different underlying conditions. Not all cats with LPGS suffer from immunosuppressive viral disease. A number of sources [e.g. Addie, Wolf] insist that LPGS is not particularly associated with FIV infection and is distributed throughout the feline population--a conclusion that begs the question of why so many FIV+ cats suffer from significant oral inflammation and why other studies have found a clear correlation. A 1993 study of a colony of mixed FIV+ and FIV- cats reported, "The gingivitis was generally more severe in the cats infected with both [calici and feline immunodeficiency] viruses, suggesting that feline immunodeficiency virus may make cats infected with calicivirus more susceptible to chronic gingivitis"[Waters]. A 2006 study of nearly nine thousand cats found that cats with retroviral infection (FIV and FeLV) suffered from oral disease generally and stomatitis in particular at many times their representative percentage of the feline population [Bellows2]. A recent study of over 5,000 cats in 150 clinics and shelters concluded that FIV infection was a significant risk factor in development of oral inflammatory disease, particularly in cats under 10 years old, with retroviral infection (FIV or FeLV) and particularly in the form of stomatitis, as distinct from gingivitis or periodontitis [Little]. Data presented at the 2011 ACVIM Forum estimated FIV+ cats 4 to 6 times more likely that FIV- cats to suffer from oral inflammatory disease [Levy].
While immune suppression appears to be a factor in expression of the disease, immune hyperactivation is at least as important a feature. A more
comprehensive view might be this one offered by Judy Rochette: "The oral tissues are constantly exposed to bacterial pathogens and antigenic proteins. In a healthy mouth, a balance is maintained between progression of disease and the host's immune system. Humoral and cellular immunity invokes the presence in the oral tissues of neutrophils, lymphocytes, plasma cells, interleukins, cytokines, prostaglandins, histamine, complement, kinins, helper and suppressor T-cells, natural killer cells, and antibodies. Any imbalance in the interactions involved in this complex protective mechanisms results in a disease state. Both inadequate and exuberant host responses have been identified as causes of stomatitis." In FIV+ cats, the skewing of immune response is already a feature of the disease, which is perhaps a reason why acquired LPGS seems particularly refractory in them.
Not only is the underlying cause of LPGS unknown, but there is a general belief that a complex of causes are involved. Veterinary dentists seem inclined to approach the problem from a more narrowly dental point of view, emphasizing interaction of teeth and tooth environment. Veterinary nondentists tend to see the problem more broadly, emphasizing the state of immune response. A number of characteristics are seen in case after case, but part of the problem lies in deciphering which characteristics are causes and which are effects of prior causes.
Bacterial Infection. Gram-negative anaerobes present in plaque are thought to be a major contributing factor to LPGS [Klein]. According to some dental vets, most cases of feline gingivitis/stomatitis syndrome involve an exaggerated oral immune system response to these plaque bacteria and perhaps others [Carmichael]. One dental vet has hypothesized a polymicrobial infection extending to the bone tissue [DeForge]. Other vets argue, however, that the bacterial explanation is too narrow and does not account for the presence of lesions in other sites of the oral cavity. One writer has noted that the bacteriods found in the oral tissue of felines with severe LPGS are similar to those found in humans and canines with milder gingivitis, suggesting that there is something peculiarly exaggerated about the feline reaction to them [Cebuliak]. FIV+ status may make a difference in the bacterial aspect of LPGS, at least in regard to some bacterial populations. Several studies have found that the oral microbiota of FIV+ cats differ from those of FIV- cats. One recent study found statistically significant over-representation of various genera in cats with FIV, genera that tend to be rare in uninfected cats [Weese]. An earlier study found that FIV- cats with gingivostomatitis have different strains of Staphylococcus sp. than cats with FIV. Moreover, cats with gingivitis and infected by FIV have higher numbers of bacteria compared to those not infected by FIV and Corynebacterium sp. Streptococcus sp., Proteusmirabilis sp., Klebsiella pneumoniae and Pseudomonas sp. predominate, a significantly different population of gingival bacterial population than found in cats without FIV [Daniel]. The more recent study likewise singled out staphylocci, finding a clear over-representation of that genus. Immunosuppression-induced overgrowth of opportunistic pathogens residing in the oral cavity that are normally kept in check may be at least one element in the FIV-LPGS equation.
Viral Infection. There is a generally held belief that a major component of LPGS in many or most cases is stimulation of immune response caused by chronic, carrier-state infections. Research on virus-bacteria interactions in human oral inflammatory disease has suggested a synergistic relationship in which each furthers the pathogenicity of the other [Slots]. Cases where other pathogens cannot be isolated suggest that FIV itself may provide sufficient viral stimulus. However, chronic infection with upper respiratory viruses is more often than not an important component of LPGS. Feline calici virus infection is widely accepted as playing a major role; feline herpesvirus has a more ambiguous association, but is clearly involved in some feline inflammatory oral disease. In one study, eighty-eight per cent of cats with chronic gingivostomatitis were shedding both viruses, compared to 21% of cats without [Lommer]. Cats with chronic gingivostomatitis are significantly more likely to concurrently shed both feline calicivirus and feline herpesvirus than are cats with classical periodontal disease. Feline herpesvirus has been documented as associated with a unique ulcerative and often persistent facial dermatitis or stomatitis syndrome. This syndrome is believed to be relatively common [Hargis]. Calici virus has been isolated in nearly 100% of chronic gingivostomatitis cases in some studies and is particularly marked by the presence of caudal lesions [Hennet]. Primary calici infection is itself associated with a transient and recognizable stomatitis. However, the chronic carrier state sees the emergence of antigenically distinct and distant viruses from the infective wild type [Poulet] and may therefore have a unique disease causing role in the emergence of LPGS, although this premise has been called into doubt [Southerden]. FIV, however, introduces a separate element in the LPGS equation. A 1991 Cal Davis study found that while cats infected with calici virus alone did not have a higher likelihood of developing inflammatory oral disease than other cats, those cats coinfected with FIV and FCV had the highest prevalence of oral cavity infections and the most severe lesions [Tenorio]. In a British study, 92% of chronic stomatitis cases in a hospital setting (79% in general practice) tested positive for calici virus, compared to 19 per cent of controls in both cases. In the same study, FeLV prevalence was low in all chronic stomatitis populations, but a significantly higher prevalence of antibody to FIV was found (81 per cent) compared with time-matched controls (16 per cent) [Knowles]. The prevalence of LPGS in FIV+ cats coinfected with other viruses, particularly calici virus, may involve the double whammy of chronic immune stimulation by two carrier-state infections and both immunosuppression and a characteristically skewed immune response associated with FIV infection. FIV has been shown to result in more serious acute infections of calici and herpes; perhaps it is also responsible for a more pathogenic carrier state.
[***Bartonella***]. A virus-like immune-stimulating role has been suggested in recent years for the bacterium Bartonella henselae. "Feline Bartonella are Gram-negative bacilli that possess pili which are hair-like structures found on the bacteria’s surface. Bartonella have a strong tendency to stick or clump together in tissues and in culture and to stick to, and penetrate, RBCs and endothelial cells. . . . The ability to adhere to each other, and to the membranes of RBCs and endothelial cells, leads to the wide and varied tissue pathogenesis observed in cats, dogs and people. Pili and a protein called deformin are probably responsible for the sticky properties. The wide tissue specificity of Bartonella is due to the adhesion to endothelial cells which are the constituents of capillaries. Experimental data show that B. henselae interaction with macrophages . . . induce[s] proliferation of endothelial cells. Bartonella proteins stimulate endothelial cells to proliferate causing neovascularization or angiogenesis and an outpouring of inflammatory cytokines which recruit inflammatory cells such as lymphocytes,plasma cells and
macrophages. Thus, Bartonella induce chronic lymphocyticplasmacytic granulomatous inflammatory reactions in highly vascular tissues throughout the infected animal’s body" [Hardy] . The mounting "evidence" for Bartonella involvement in LPGS and other feline illnesses has its naysayers. One skeptic has questioned why, if a bacterium is responsible for the underlying problem, antibiotics are not able to eradicate it [Wolf1]. According to Alice Wolf, “Recent studies by Dr. Mike Lappin and the infectious disease group at Colorado State University have shown no statistical differences in Bartonella
seropositivity between cats with and without uveitis, oral cavity disease, and central nervous system disease (ACVIM 2005)” [Wolf2]. Since Bartonella DNA can be recovered from cats who have 'cleared" the infection, according to available tests, the book is still being written on what Bartonella does and does not do.
Immune Dysfunction. Since some cats with LPGS test negative for all chronic pathogens, immune dysfunction of unknown origin must be listed as an independent cause. Sorting out which kinds of immune dysfunction are causes or effects of others becomes a knotty chicken-and-egg proposition. Hyperstimulation, dysregulation, and loss of immune response have all been strongly implicated in LPGS. (For discussion of components of the immune system, see the pages Bud's Therapeutic Guidelines, Determining Immune Status, and FIV and the CBC.) In one study, the cats with LPGS "tended to demonstrate generalized and progressive up regulation of cytokine expression as the lesion severity increased. The similarity of the cytokine profile in lesions from different cats supports the view that a similar pathogenesis underlies all cases." Cytokines (many of them "interleukens," or IL) are immunoregulatory proteins commonly secreted by immune cells, including T-Helper Type 1 cells [cytokines IFN-γ, IL-2, IL-12] and T-Helper Type 2 cells [Cytokines IL-4, IL-5, IL-6, IL-10]. TH-1 cytokines, which invoke cell-mediated immunity, predominate in healthy feline oral tissue. Th-2 cytokines invoke antibody-mediated, or humoral, immune responses. Cats with LPGS show a mixed TH1/TH2 pattern. "IFN-γ, IL-2, IL-12 . . ., and IL-10 were detected in the majority of nondiseased faucal-tissue samples. In contrast, IL-6 was found in only a small proportion of the samples, while neither IL-4 or IL-5 was detected in any samples from nondiseased analysis. . . . In contrast, the relative levels of IL-2, IL-4, IL-6, IL-10, IL-12 . . . ,and IFN-γ mRNA expression were all significantly higher in the diseased population. . . . The results also suggest that IL-6 expression is induced early in the pathogenesis of the disease,whereas expression of IL-4 is a late event and is mainly confined to established lesions. This would imply that the underlying immunological bias switches from a predominantly classical type 1 to a mixed type 1-type 2 response as the lesion progresses" [Harley1]. Deducing a logical disease process from these findings is not simple. Cell-mediated (TH 1-induced) immunity is particularly associated with combating viruses and bacteria that have already infected cells. It is possible that an initial increase in inflammatory TH1 cytokines (IFN-γ, IL-2, IL-12) is provoked by chronic viruses invading the oral cavity (or by other causes in cases where no viral infection exists) and that the nature of these viruses upsets normal homeostasis within the mouth and spurs production of inflammatory immunoglobulins (the latter part of the TH2 response [Medan]). IL-10, which normally shuts down the cell-mediated response, does not in cats with stomatitis. Excessive quantities of cytotoxic T cells (CTL's) -- killers of infected cells activated as part of the TH 1 response -- continue to be found in large quantities within inflammatory lesions [Medan]. It has been noted that populations of the specific subset of T cells that normally shut down CTL response (T Regulatory Cells, or TREGs) are notably reduced in stomatitis lesions, a doubly curious finding in FIV+ cats since TREGs exist in unusually large numbers elsewhere in their immune system.
Abnormalities in antibody production have also been noted in cats with LPGS. "The cats with chronic gingivostomatitis had significantly higher salivary concentrations of IgG, IgM and albumin, and higher serum concentrations of IgG, IgM and IgA, but significantly lower salivary concentrations of IgA than the healthy cats" [Harley2]. IgA "neutralises pathogens and toxins in the oral cavity, inhibits the adherence or growth of microorganisms on the oral mucosa or teeth and enhances non-specific defence factors. It is unclear whether the Ig pattern described is a cause or a result of the inflammatory disease" [Southerden]. IgA, by contrast to IgG, is a non-inflammatory cytokine that ordinarily competes with IgG for binding sites, and its absence seems clearly important to resulting oral inflammation. Why, moreover, IL-6 should tend to precede IL-4 in excess is a mystery, since, in the ordinary course, IL-4, which promotes differentiation of TH2 Helper T cells, subsequently induces them to secrete IL-6, which promotes formation of antibody excreting plasma cells from B cells.
Other factors undoubtedly further promote mucosal inflammation. As a result of inflammation, breaching of the epithelial barrier that protects mucosae exposes the latter to antigens that may perpetuate a vicious cycle of inflammation via allergy or intolerance. Compromised immunity may be an exacerbating factor in cats with FIV. One study suggests that a dearth of T-Helper cell numbers rather than T-Helper type-bias is responsible for a recently observed excess of IL-8 in lesions of FIV+ cats with severe oral inflammation [Zuccari]. Both FIV and HIV infections, it has been noted, result in defective neutrophil development. ". . . we observed that neutrophils from HIV-infected patients have a profound defect in chemotaxis in response to endogenous (IL-8) . . . which was directly correlated with peripheral CD4+ [Helper-T] lymphocyte levels." Chemotaxis in this case refers to the ability to respond to recruitment cues. "A similar chemotactic defect was observed in the feline immunodeficiency virus (FIV) model of HIV infection" [Heit]. Neutrophils, as major antibacterial immune cells, are essential to control of pathogenic oral bacteria.
Dietary Allergy/Sensitivity. Although there have been no studies to confirm it, there is a long-standing suspicion that elements of prepared feline diets play a role in feline LPGS. Human studies have confirmed that certain dietary substances can cause or worsen oral inflammation. What the offending substances might be in cats is speculative. Canned and dry cat foods have a variety of additives intended
to enhance flavor (e.g., cinnaminase/ cinnamaldehyde and benzoin), consistency, and freshness. Grain and soy products used as filler and protein boost have often been singled out for attention in the case of feline bowel disease and could conceivably have a role in feline oral disease. Human studies suggest that high levels of vegetable polyunsaturated fatty acids lead to elevated levels of proinflammatory markers [Ferrucci]. Retrospective examination of feline skulls from museum collections revealed in one study a much lower incidence of FORLs (resorptive, or "neck," lesions caused by immune attack on the tooth) prior to 1960 than is the case today [Klein]. FORLs have a known connection to FIV+ status [Hofmann-Lehmann], may and probably will occur concurrently with LPGS, but are a separate pathology. The researchers have speculated that either dietary changes or vaccination protocols are the most obvious areas to look for an explanation. Several successful treatment programs have involved carefully controlled dietary intake, but since other therapies were used concurrently, they provide no "smoking gun" that dietary change by itself is significant. Diane Addie does mention, "In addition, after dentistry, cats fed on Hills a/d diet gained more weight and had smaller lesions than those fed on a control diet (Theyse et al, 2003)." The reference is to field study presented at the Hills European symposium on Oral Care, Amsterdam, 2003. The study is unavailable for inspection.
Diagnosis, properly done [Carmichael], is likely to be at least a two-part process involving two visits to the vet.
● A thorough physical exam, including examination of the teeth and oral cavity for evidence of tartar, for location of any FORLS (with particular attention to those that may be hidden by overgrowth of inflamed gingival tissue), and for notation of the location of any sites of inflammation and inflammatory lesions. "Many of the more severely affected cats will have very proliferative and painful hyperplastic tissue in the fauces of the mouth. Lesions are usually bilateral which will help to distinguish this condition from neoplasia" [Wolf1]
● A CBC and serum chemistry. In the case of LPGS, hyperglobulinemia (overactive antibody response) is a common finding in the serum chemistry. (It is also a common finding in serum chemistries of FIV+ cats generally, indicating a hyperactive antibody response to the virus.)
● If evidence upon examination suggests a significant pattern of inflammatory disease, FIV and FeLV testing will be done, unless the cat's status in this regard is already known.
● A return visit scheduled for further examination and dentistry and dental prophylaxis under anaesthesia.
● Polishing and scaling under anaesthesia. Any teeth that need to be removed will be removed.
● Radiographs taken (if teeth have been removed) for any evidence of root tips and fragments.
● Individual biopsy samples taken from lesions at sites of inflammation and sent off for analysis. One writer cautions of the importance of retrieving samples from deeply rather than superficially in the lesion.
The Biopsy Analysis
Analysis is likely to return a finding of lymphocytic plasmacytic stomatitis. Some would argue that this finding is so inevitable and so uninformative that biopsy is hardly necessary [Hale]. Others suggest it is important to eliminate results that might alter treatment: e.g.,eosinophilic granuloma, autoimmune diseases such as pemphigus, several types of cancer [Carmichael], or cyrptococcosis [Cebuliak]. As can be seen in the following example, biopsy results can also provide cues for possible future developments that will require close monitoring.
Following is a case history demonstrating the diagnostic procedure
"A 12-year-old, neutered male, domestic shorthair was presented due to difficulty in eating, pawing at the face, and weight loss. Three years earlier, the cat had undergone a dental prophylaxis for mild gingivitis and tartar accumulation. On physical examination (day 1), mild dental tartar, severe gingivitis, and stomatitis involving the caudal part of the dental arcades, the commisures of the lips, and under the tongue on both sides were apparent. A complete blood (cell) count (CBC) and serum biochemical profile revealed mild decreases in albumin and alanine aminotransferase (ALT). An enzyme-linked immunosorbent assay (ELISA) (SNAP FeLV/FIV antigen test; IDEXX, Toronto, Ontario) was negative. . . .
"On the day of surgery . . . the cat was maintained under general anesthesia with isoflurane (Isoflurane; Vetoquinol) in order to perform a dental scaling and gingival biopsy. A complete scaling and polishing was performed on all of the teeth. Two teeth, numbers 309 and 409, were extracted. Although teeth numbers 107, 108, 207, 208, 308, and 408 were not removed at this time, a note was made to examine the gingiva around these teeth biannually for a worsening or improvement of the current clinical presentation. Two 5-mm by 5-mm biopsies were taken from an area of gingival hyperplasia in the right ventral quadrant. The biopsy samples were preserved in 10% buffered solution and sent for histopathologic examination
(Histovet, Guelph, Ontario). Histological examination of these samples revealed marked hyperplasia of the gingival epithelium with severe inflammation of the lamina propria. Some areas of each biopsy contained a predominantly lymphoplasmacytic infiltrate, while others showed significant eosinophilic inflammation. Focal areas of epithelial dysplasia were evident, as well as suppurative lesions associated with gingival ulceration. The lesions were considered consistent with the syndrome known as lymphoplasmacytic stomatitis (LPS). Eosinophilic inflammation is not only suggestive of hypersensitivity disease, but in combination with the epithelial dysplasia, it has been shown to predispose to subsequent development of carcinoma" [Baird].
Chronic pathogens play a major role in the pathology of much LPGS. In some instances, FIV alone may occupy that role. In others, additional (or, in the case of FIV- cats, alternative) pathogens are players. There is a case to be made for extending the diagnostic procedure to testing for the presence of these pathogens.
Bartonella testing has, evidently, become more common in clinical practice. This may, in part, be because it is treatable with antibiotic therapy. However, Bartonella is frequently a relapsing infection and often is not cleared by antibiotics. The various treatment protocols for Bartonella are not dealt with in these pages because they are complex and involve many uncertainties. Four-week courses of azithromycin are the most common prescription. Skeptics say a positive test result is of questionable value because exposure to Bartonella is so common.
Testing for herpesvirus and calicivirus in connection with oral inflammatory disease does not seem to occur much in clinical practices. Some have actively argued against it on the grounds that treatment would remain unchanged despite the result. That is a questionable view since herpesvirus is generally more responsive to treatment than calici. Addie-Radford proposed, on the basis of their one-cat study model, testing repeatedly for calici virus during the course of feline interferon therapy, when the object is to eradicate the virus as an inciting cause of immune dysfunction. How adaptable their laboratory model is to an actual clinical situation is hard to say, but for someone already paying for, say, feline interferon, repeat testing might be particularly worthwhile. Serum testing is generally not fruitful since most cats express antibodies because of either vaccination or previous exposure. Idexx laboratory, which has a new PCR program using the Taqman PCR system for DNA detection, now offers reasonably priced assays for herpes and calici viruses individually, as well as a one-price panel for all of the major upper respiratory viruses: herpes, calici, chlamydia, bordetella, and mycoplasma. If "know your enemy to the maximum extent possible" is good advice, this or similar assays might be worth the investment. Caveats to keep in mind are: (1) Shedding of herpesvirus is intermittent and may affect presence of DNA in blood. (2) While shedding of calicivirus is more or less continuous, genetic variability has historically affected the reliability of PCR results.
Next >>>Medications and Supplements (LPGS)>>>