Feline immunodeficiency virus and FeLV are retroviruses endemic among cats throughout the world.1–3 Feline immunodeficiency virus is most commonly acquired from bite wounds sustained in fights among cats and is therefore most prevalent in sexually intact males.4 Cats infected with FIV may remain healthy or may develop progressive CD4 T-lymphocytopenia, neutropenia, hyperglobulinemia, and organ dysfunction such as encephalopathy, stomatitis, enteritis, and nephropathy.1 Cats seroconvert 3 to 6 weeks after FIV infection and remain antibody positive for life.1 Clinical signs during the acute phase are characterized by mild transient fever, lethargy, and malaise. After several days or weeks, a clinically silent phase begins during which cats appear healthy but immunocompetence gradually wanes. This period may last for several years and, in some cases, leads to the third and final phase of infection, which is characterized by opportunistic infections, neurologic disease, and neoplasia.1
Feline leukemia virus is spread by exchange of saliva or other secretions through shared water bowls, sneezing, mutual grooming, and biting as well as vertically between a queen and kittens.1,5 Infection with FeLV results in diverse outcomes depending on the viral subtype, age of the cat at the time of infection, and nature of the immune response to FeLV.5 Insight derived from application of quantitative PCR assays suggests that progressive, regressive, abortive, and focal infection occur but that only progressive FeLV infection is associated with persistent antigenemia and a high likelihood of clinical disease.6 Clinical disease in FeLV-infected cats may consist of neoplasia (eg, lymphoma), myelosuppression such as anemia and thrombocytopenia, immunosuppression, neurologic disease, and other conditions.1
Inflammatory oral disease in cats is a complex, multifactorial condition primarily consisting of localized or widespread inflammation with or without ulceration.7 Many terms have been applied to various types and locations of lesion, including gingivitis and periodontitis that affect particular regions of the mouth and stomatitis that comprises more generalized inflammation of the mouth. Feline chronic gingivostomatitis is a term used to describe extensive and persistent inflammation of the mucosa throughout the mouth, including the gingiva.7 Many factors, including oral bacterial flora, dietary factors, hypersensitivity to plaque antigens, viral infection, and immune status, have been suggested as potential contributors to inflammatory oral disease in cats.8–13 However, the exact pathogenesis of this condition remains unclear.
Histopathologically, a wide range of inflammatory cell types have been identified in FCGS, and a relative abundance of CD8+ lymphocytes suggests that cytotoxic T-cell immune responses may be a key component of the condition.10 Feline calicivirus has been identified at an increased frequency in stomatitis lesions, but the lesions could not be replicated in experimental infections.9,11–14
The link between inflammation and immune dysregulation in oral disease raises questions as to whether immunosuppressive viruses such as FIV or FeLV contribute, directly or indirectly, to oral inflammatory disease in cats. Seropositivity for FIV has been significantly associated with presence of oral inflammatory disease in several studies.14–16 Concurrent infection with FIV, FCV, or FHV has been found in cats with FCGS.15–18 Furthermore, oral inflammatory lesions and signs of pain improved with antiviral interferon-ω treatment in 2 studies.19,20 Odontoclastic resorptive lesions, also known as tooth resorptions, are common but poorly understood oral conditions often associated with gingival and periodontal inflammation in cats. On the basis of visual scores, it was suggested that odontoclastic resorptive lesions were more common in FIV-infected cats than in matched FIV-uninfected cats when both groups were free of other pathogens such as FeLV, FCV, and FHV, although dental radiography is considered essential to diagnose tooth resorption.21 In other studies,9,11,22 a positive association between oral inflammatory disease or odontoclastic resorptive lesions and seropositivity for FIV or FeLV was not identified.
The effect of FIV or FeLV infection is more likely to be indirect via systemic immunosuppression rather than through mediators released by retrovirus-infected leukocytes that have migrated into the oral mucosa.1 Thus, a possible link between specific types of inflammatory oral disease and naturally occurring retroviral infection remains to be fully explored. The objective of the study reported here was to determine whether positive test results for retroviruses were associated with naturally occurring gingivitis, periodontitis, or stomatitis in male and female cats of various ages and neuter status.
Materials and Methods
Animals—Cats of any age, breed, or sex were eligible for inclusion in the study if they had no known history of vaccination against FIV. Oral examinations were a noninvasive procedure, and blood samples were collected for medically indicated diagnostic testing; hence, institutional approval or client consent was not required.
Procedures—An invitation with an incentive to participate (equivalent of $5 in manufacturer's points/test) was sent to primary care veterinary clinics and animal shelters throughout North America between September 2012 and May 2013. Participating veterinarians were required to complete online training (ie, a webinar) that included a review of representative photographs of oral lesions in cats (Figure 1). Information in the webinar was based on guidelines of the American Veterinary Dental College. The same photographs were also provided to participating veterinarians as hardcopy images.
Representative photographs of the mouths of cats with gingivitis (A), periodontitis (B), and stomatitis (C).
Citation: Journal of the American Veterinary Medical Association 245, 8; 10.2460/javma.245.8.916
Veterinarians then classified each participating cat with regard to oral health status (orally healthy or gingivitis, periodontitis, stomatitis, or another oral condition as the predominant lesion). Inflammatory lesions consistent with FCGS were included in stomatitis. Other oral conditions included dental disease such as resorptive lesions, calculi, or traumatic tooth damage or oral cancer such as squamous cell carcinoma. Age, sex, and neuter status of each cat were recorded. A serum sample was obtained and an ELISAa (conducted in-house by each veterinarian or at a reference laboratoryb) was used to test for FeLV and FIV infection status. Confirmatory testing was not performed as part of the study. All information was recorded on a form, verified by the participating veterinarian, and returned for entry into a data spreadsheet.
Data analysis—Statistical analysis was performed by use of a generalized linear mixed models procedure in statistical software.c Data were categorized into groups on the basis of test results for FIV (seropositive vs seronegative) and FeLV (seropositive vs seronegative). Effects of age, sex, and oral health on retrovirus test results were determined by type 3 tests of fixed effects.c Within the group seropositive for FIV, an interaction between age and oral health was found; therefore, to allow assessment of changing disease prevalence with age, the relation of FIV test result and oral health was examined for cats in the following 6 age quantiles: < 0.4 years (10th percentile), < 0.5 years (25th percentile), 2 years (median), 3.6 years (mean), < 5 years (75th percentile), and < 10 years (90th percentile). In the group seropositive for FeLV, there were no significant interactions of age or sex with oral health; therefore, cats were treated as a single cohort. Data were analyzed by use of a standard logistic regression with binary outcome to determine risk of disease in each group of cats. The ORs were calculated between cats of each oral health status. Results were considered significant at values of P < 0.05.
Results
Animals—Requests for participation were sent to 11,833 veterinary clinics and 1,250 animal shelters. Information was returned for 5,179 cats from 125 veterinary clinics and 25 animal shelters. Mean age of all cats was 3.6 years (median, 2.0 years). Mean and median age of seropositive and seronegative cats for each retrovirus and sex category were plotted on a graph (Figure 2).
Box-and-whisker plots of age distribution in cats seropositive (+) and seronegative (−) for FIV and FeLV and of various sex and neuter status. Boxes represent 25th to 75th percentiles, the solid line in each box is the median, the dashed line in each box is the mean, and the whiskers represent the range. F = Female. FS = Spayed female. M = Male. MN = Neutered male.
Citation: Journal of the American Veterinary Medical Association 245, 8; 10.2460/javma.245.8.916
Retrovirus seroprevalence—Seroprevalence of FIV infection in the study population was 237 of 5,179 (4.6%). Interactions between FIV status and both age and sex were identified. Hence, data were categorized into 6 quantiles on the basis of cat age, and results for each age group were analyzed separately without application of correction factors. Prevalence of FIV seropositivity in all groups of cats, except for spayed females, increased from birth until 5 years of age, but then decreased in older cats (Figure 3). Seroprevalence in spayed females was low for all age groups and decreased with increasing age, although there were no significant differences in FIV seroprevalence among age groups. Although there was no significant difference in FIV seroprevalence between sexes in young (< 0.4 years old) cats, seroprevalence in cats < 5 years old was significantly higher for sexually intact males (242/816 [29.7%]) than for sexually intact females (113/836 [13.5%]; P = 0.001), neutered males (104/984 [10.6%]; P < 0.001), and spayed females (21/825 [2.5%]; P < 0.001). Among the oldest (> 5.0 years old) cats, FIV seroprevalence was significantly different only between spayed (78/412 [1.9%]) and sexually intact (40/419 [9.6%]) female cats and between spayed female and neutered male (42/492 [8.5%]) cats.
Seroprevalence for FIV in cats of various sex and neuter status, analyzed on the basis of 6 quantiles in age. In cats of all sexual statuses, except spayed females, seroprevalence increased with age until the oldest cohort. In spayed females, prevalence decreased with age. Values reported are observed percentage and 95% CI. See Figure 2 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 245, 8; 10.2460/javma.245.8.916
Overall FeLV seroprevalence was 186 of 5,179 (3.6%) and ranged from 53 of 1,476 (3.6%) in neutered males to 106 of 1,225 (8.7%) in sexually intact males (Figure 4), although seroprevalence did not differ significantly between these groups. Seroprevalence for FeLV was higher in younger cats, with a mean decrease in seroprevalence of 6%/y after 1 year of age. Interactions between age and sex were not identified for FeLV seroprevalence.
Seroprevalence for FeLV in cats of various sex and neuter status. Values reported are observed percentage and 95% CI. See Figure 2 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 245, 8; 10.2460/javma.245.8.916
Coinfection with both viruses was uncommon. Seroprevalence for both FIV and FeLV was 12 of 5,179 (0.2%).
Oral disease prevalence—Among all 5,179 cats, 3,075 (59.4%) were classified as orally healthy, 1,073 (20.7%) had gingivitis, 576 (11.1%) had periodontitis, 203 (3.9%) had stomatitis, and 252 (4.9%) had other oral conditions; thus, overall oral disease prevalence was 2,104 of 5,179 (40.6%) cats. Among the 4,768 retrovirus-seronegative cats, 978 (20.5%) had gingivitis, 488 (10.2%) had periodontitis, 162 (3.4%) had stomatitis, and 226 (4.8%) had other oral conditions, for an overall oral disease prevalence of 1,854 of 4,768 (38.9%) cats. Among the 411 retrovirus-seropositive cats, 93 (22.6%) had gingivitis, 88 (21.4%) had periodontitis, 41 (10.0%) had stomatitis, and 24 (5.8%) had other oral conditions, for an overall oral disease prevalence of 246 of 411 (59.9%) cats. Median age of cats with gingivitis, periodontitis, stomatitis, and other oral conditions and orally healthy cats was 4.8, 2.7, 4.3, 3.3, and 1.1 years, respectively (Figure 5). There were significant differences in the ages of cats with various categories of oral disease. Odds were significant that orally healthy cats would be younger than cats with gingivitis, periodontitis, stomatitis, and other oral conditions, and odds were also significant that cats with gingivitis would be younger than cats with periodontitis, stomatitis, and other oral conditions (Table 1).
Box-and-whisker plots of age of cats with various types of oral health. Other oral conditions (OC) included dental disease such as resorptive lesions, calculi, or traumatic tooth damage or oral cancer such as squamous cell carcinoma. GV = Gingivitis. OH = Orally healthy. PT = Periodontitis. ST = Stomatitis. See Figure 2 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 245, 8; 10.2460/javma.245.8.916
The OR that cats with a specific oral health status would be older than cats with another specific oral health status.
| Oral health status comparison* | OR | 95% CI | P value† |
|---|---|---|---|
| Gingivitis vs periodontitis | 0.559 | 0.500–0.624 | < 0.001 |
| Gingivitis vs stomatitis | 0.616 | 0.527–0.719 | < 0.001 |
| Gingivitis vs orally healthy | 2.424 | 2.256–2.604 | < 0.001 |
| Gingivitis vs other oral conditions | 0.808 | 0.697–0.937 | 0.005 |
| Periodontitis vs stomatitis | 1.102 | 0.931–1.304 | 0.259 |
| Periodontitis vs orally healthy | 4.334 | 3.930–4.778 | < 0.001 |
| Periodontitis vs other oral conditions | 1.445 | 1.230–1.699 | < 0.001 |
| Stomatitis vs orally healthy | 3.932 | 3.396–4.553 | < 0.001 |
| Stomatitis vs other oral conditions | 1.311 | 1.079–1.594 | 0.006 |
| Orally healthy vs other oral conditions | 0.333 | 0.290–0.383 | < 0.001 |
Other oral conditions included dental disease such as resorptive lesions, calculi, or traumatic tooth damage or oral cancer such as squamous cell carcinoma.
Values are significant at P < 0.05.
Association between retrovirus status and oral disease—Seroprevalence of FIV infection increased until cats were 5 years old, but there was no significant interaction between sex and oral health status. In all groups of cats < 5 years old, the presence of periodontitis or stomatitis was associated with an increased OR for FIV seropositivity, whereas in cats ≥ 10 years old, there was no association between oral health status and FIV status. The OR that cats with stomatitis would be seropositive for FIV was similar to that for cats with periodontitis in any age group. For all age groups, cats with periodontitis or stomatitis had a significantly higher OR of being seropositive for FIV than did cats with gingivitis (Figure 6; Table 2).
Seroprevalence of FIV in cats with various types of oral health, analyzed on the basis of 6 quantiles in age. Values reported are observed percentage and 95% CI. See Figures 2 and 5 for remainder of key.
Citation: Journal of the American Veterinary Medical Association 245, 8; 10.2460/javma.245.8.916
The OR that cats in a specific age quantile with a specific type of oral health status would be seropositive for FIV.
| Age quantile (y) | Oral health status comparison* | OR | 95% CI |
|---|---|---|---|
| < 0.4 | Periodontitis vs orally healthy | 9.515 | 5.206–17.392 |
| Stomatitis vs orally healthy | 10.990 | 5.028–24.022 | |
| Stomatitis vs gingivitis | 6.494 | 2.747–15.385 | |
| Periodontitis vs gingivitis | 5.618 | 11.364–2.801 | |
| < 0.5 | Periodontitis vs orally healthy | 9.245 | 5.101–16.754 |
| Stomatitis vs orally healthy | 10.735 | 4.963–23.218 | |
| Periodontitis vs gingivitis | 5.525 | 2.778–10.989 | |
| Stomatitis vs gingivitis | 6.410 | 2.747–14.925 | |
| 2.0 | Periodontitis vs orally healthy | 5.994 | 3.712–9.678 |
| Stomatitis vs orally healthy | 7.548 | 4.032–14.130 | |
| Periodontitis vs gingivitis | 4.219 | 2.421–7.353 | |
| Stomatitis vs gingivitis | 5.319 | 2.667–10.526 | |
| 3.6 | Periodontitis vs orally healthy | 3.831 | 2.574–5.702 |
| Stomatitis vs orally healthy | 5.245 | 3.119–8.821 | |
| Periodontitis vs gingivitis | 3.185 | 2.033–5.000 | |
| Stomatitis vs gingivitis | 4.367 | 2.481–7.692 | |
| < 5.0 | Periodontitis vs orally healthy | 2.519 | 1.725–3.680 |
| Stomatitis vs orally healthy | 3.731 | 2.300–6.052 | |
| Periodontitis vs gingivitis | 2.457 | 1.623–3.717 | |
| Stomatitis vs gingivitis | 3.636 | 2.174–6.098 |
All ORs were significant (P < 0.001).
See Table 1 for remainder of key.
A standard logistic regression was used to estimate population seroprevalence in groups of cats. Seroprevalence for FeLV was 5.3% (95% CI, 4.0% to 7.0%) in cats with gingivitis, 8.1% (95% CI, 5.6% to 11.7%) in cats with periodontitis, 10.2% (95% CI, 6.1% to 16.3%) in cats with stomatitis, 4.1% (95% CI, 2.0% to 8.1%) in cats with other diseases, and 2.2% (95% CI, 1.8% to 2.8%) in orally healthy cats. Presence of any type of inflammatory oral disease (gingivitis, periodontitis, or stomatitis) was associated with a significantly higher OR of being seropositive for FeLV (Figure 7; Table 3).
Seroprevalence of FeLV in cats with various types of oral health. Values reported are observed percentage and 95% CI.
Citation: Journal of the American Veterinary Medical Association 245, 8; 10.2460/javma.245.8.916
The OR that cats with a specific type of oral health status would be seropositive for FeLV.
| Oral health category comparison* | OR | 95% CI | P value† |
|---|---|---|---|
| Gingivitis vs orally healthy | 2.453* | 1.681–3.580 | < 0.001 |
| Periodontitis vs orally healthy | 3.894* | 2.439–6.217 | < 0.001 |
| Stomatitis vs orally healthy | 4.983* | 2.752–9.023 | < 0.001 |
| Other condition vs orally healthy | 1.890 | 0.889–4.089 | 0.094 |
| Periodontitis vs gingivitis | 1.590 | 0.991–2.545 | 0.054 |
| Stomatitis vs gingivitis | 2.033 | 1.115–3.704 | 0.021 |
| Stomatitis vs periodontitis | 1.280 | 0.683–2.398 | 0.441 |
| Gingivitis vs other oral conditions | 1.292 | 0.600–2.781 | 0.512 |
| Periodontitis vs other oral conditions | 2.051 | 0.927–4.538 | 0.076 |
| Stomatitis vs other oral conditions | 2.625 | 1.092–6.312 | 0.031 |
See Table 1 for key.
Seroprevalence of FIV for all age groups was estimated to be 2.1% (95% CI, 1.2% to 3.6%) in cats with gingivitis, 10.8% (95% CI, 6.5% to 17.6%) in cats with periodontitis, 12.3% (95% CI, 6.2% to 2.3%) in cats with stomatitis, 4.9% (95% CI, 2.0% to 11.0%) in cats with other oral conditions, and 1.3% (95% CI, 0.1% to 1.7%) in orally healthy cats. There were marked differences in FIV seroprevalence among age groups (Figure 6).
For comparisons between groups, cats with any inflammatory oral disease were significantly more likely to be seropositive for FeLV than were orally healthy cats; however, specific categories of oral disease were not significantly associated with differences in the risk of retrovirus infection (Table 3). Although the prevalence of retrovirus infection decreased in older cats, there was no significant interaction between age and oral health status. Overall retrovirus seropositivity rates among cats with gingivitis, periodontitis, and stomatitis were estimated to be 7.7% (95% CI, 5.2% to 10.6%), 18.9% (95% CI, 12.6% to 33.9%), and 22.5% (95% CI, 12.3% to 27.3%), respectively.
Discussion
The prevalence of retrovirus seropositivity in the present study was similar to that reported previously in cats in North America.2,3 Typically, FIV infection is subclinical for several years with no overt signs of illness and hence infection is often not diagnosed until middle age.1 With increasing age, there is higher potential lifetime retroviral exposure, which enhances the likelihood of detecting infection. This is likely the reason that FIV-seropositive cats were older than FIV-seronegative cats. Seropositivity for FIV increased with age in cats of all sexual statuses, except spayed females. This may have indicated that spayed cats had a lower risk of acquiring FIV infection. However, a similar pattern in the rate of seropositivity was not observed for neutered males, for which higher FIV seropositivity rates might reflect an older age at adoption and neutering.23 Sexually intact male cats, despite their younger mean age, had much higher rates of FIV seropositivity than did sexually intact females or neutered cats, which probably was related to the higher likelihood of exposure to FIV-positive blood and saliva during fighting, even in young males.2,3
On the other hand, cats with FeLV infection are more likely to manifest with illness soon after infection, which may explain the younger mean age of seropositive cats.1 Although the prevalence of FeLV infection has decreased over the past decades, most likely as a result of testing and vaccination, there appear to have been no further reductions in recent years.2,24,25 Seroprevalence for FeLV was slightly higher in sexually intact males than in cats of other sexual statuses, which may also have indicated viral acquisition associated with biting or sexual behavior. Age at neutering was not considered in the present study.
Prevalence of oral inflammatory disease differed with age. Cats with gingivitis and stomatitis were older than were cats with periodontitis, but all types of oral inflammatory disease were much more common in older cats than in young cats. In light of the mean and median age of 3.6 and 2.0 years, respectively, in the study population, these values reflect a high prevalence of inflammatory oral disease in relatively young cats. Retrovirus seropositivity rates were significantly higher in cats with inflammatory oral disease.
For all ages, cats with periodontitis and stomatitis had a significantly higher risk than orally healthy cats of being seropositive for FIV. In particular, stomatitis was associated with the highest risk of FIV seropositivity. The results for stomatitis are in agreement with previous findings in cats naturally and experimentally infected with FIV.14–16 Periodontitis was not previously associated with a higher risk of FIV infection, but it should now also be considered a clinical finding associated with FIV seropositivity.
Presence of any inflammatory oral disease was significantly associated with an increased risk of a positive test result for FeLV infection. Similar to results for FIV infection, the OR of a positive test result for FeLV was highest for stomatitis.7 Interestingly, oral conditions other than inflammation were not significantly associated with an increased risk of retroviral infection. Gingivitis, periodontitis, and stomatitis are conditions with extensive inflammation, whereas dental lesions and oral cancer may induce only transient localized neutrophilic inflammation in areas of ulceration.7 Retroviral-induced functional changes might be more likely to affect lymphocyte function than neutrophil function because only the former are infected by retroviruses.1,26
It could be speculated that oral inflammation in retrovirus-infected cats results from aberrant or insufficient immune responses that allow for increased replication of agents such as FCV and increased severity of inflammation, but there is a paucity of studies directly comparing systemic retroviral load to lesion viral load with agents implicated in oral inflammation. Although there appears to be a link between oral inflammation and viral status, most types of oral inflammation, such as that associated with tooth resorption, occur in cats in the absence of FIV, FeLV, FCV, and FHV, which suggests additional etiologic factors.21,22 It is challenging to diagnose FCV infection because serum antibodies do not persist; thus, it may be necessary to determine viral load within lesions.11,12 Investigators in 1 study8 identified unusual bacterial phylotypes in the oral flora of cats with FCGS. However, the control samples originated from FIV-infected cats, which may not reflect findings in healthy cats. Additional studies will be necessary to define the bacterial flora in healthy and diseased oral cavities of cats.
The present study had several limitations. Although the ELISA for both retroviruses are highly accurate, false-positive results are possible in populations with low infection prevalence; hence, test results ideally should have been confirmed with additional tests. Opinions differ with regard to ideal confirmatory tests, but among commercially available tests, western blot and repeated ELISA for FIV and PCR assay for FeLV have been suggested for use,24,27,28 and positive results of a retrovirus ELISA for cats with oral disease should be confirmed by such tests. Other study limitations pertained to use of a young population of cats, with a high proportion of cats lacking oral disease. Oral lesions were scored by general veterinary practitioners rather than by board-certified veterinary dentists, which may have led to misclassification of some lesions. Examination by board-certified veterinary dentists likely would have yielded greater specificity of lesion identification; however, the number of cats included in the study made it difficult to obtain the participation of such experts. Furthermore, an objective of the study included determining the association between viral status and lesions identified by general practitioners during a brief oral examination.
The response rate to the invitation to participate in the present study was low but within expected rates for surveys of this nature.29 Reasons for the low response rate are unknown, but they may have related to general factors concerning awareness about the study and perceived relevance in addition to limited professional resources, given that veterinarians were required to initially attend a webinar and subsequently assist with scoring of oral lesions.29 Therefore, the limited response may have been a potential source of bias toward certain veterinary practices or animal shelters. An overall low number of retrovirus-positive samples were identified. However, the study was intended as a survey of the frequency with which cats with various types of oral health are seropositive for retroviruses. Future studies may focus more specifically on the types of oral disease in cats seropositive for FIV or FeLV.
ABBREVIATIONS
| CI | Confidence interval |
| FCGS | Feline chronic gingivostomatitis |
| FCV | Feline calicivirus |
| FHV | Feline herpesvirus |
SNAP FeLV/FIV ELISA combo test, IDEXX Laboratories, Westbrook, Me.
IDEXX Reference Laboratories, Westbrook, Me.
PROC GLIMMIX, SAS, version 9.2, SAS Institute Inc, Cary, NC.
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