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SPONSORED BY AN EDUCATIONAL GRANT FROM BOEHRINGER INGELHEIM VETMEDICA clinician’s update ™ Feline Infectious Disease Protection INTRODUCTION The 2013–2014 National Pet Owner Survey reported 37.3% of US households own a total of 95.6 million cats.1 Unfortunately, while cats make up more than half of the pet population, they comprise only 39% of the veterinary patient base.2 Owner misconceptions that indoor cats do not get sick and that cats do not need veterinary care as they age are two factors contributing to this discrepancy in care.2 Compounding this are concerns that have been raised about vaccines and vaccine safety over recent years, leading some cat owners to be less inclined to want to vaccinate their cats, especially if the cat spends all or most of its time indoors. Restricting a cat to the home does not, however, eliminate its risk for infectious disease. The American Association of Feline Practitioners (AAFP) has formulated protective objectives that include vaccinating the greatest number of cats in the population at risk, vaccinating against only those infectious diseases for which a cat is at risk, vaccinating only when potential benefits outweigh potential risks, and vaccinating appropriately for public health protection.3 Toward this end, the AAFP has developed a list of core vaccines recommended for all cats, noncore vaccines for cats in specific risk groups, and vaccines not generally recommended (see AAFP Vaccine Categories). In the following special report, recognized experts in feline medicine discuss some of the most pressing concerns of small animal practitioners with the most up-to-date evidence-based medicine available today. REFERENCES 1. 2013/2014 National Pet Owner Survey. Greenwich, CT: American Pet Products Association, 2013. (americanpetproducts.org) 2. Bayer Veterinary Care Usage Study, 2011. Available at: http://www.ncvei.org/articles/FINAL_BAYER_ VETERINARY_CARE_USAGE_STUDY.pdf 3. The 2006 American Association of Feline Practitioners Feline Vaccine Advisory Report. AAFP Feline Vaccine Advisory Panel. JAVMA 229:1405-1441, 2006. INSIDE: • What you need to know about FeLV and FIV • Risk assessment and creating a vaccine protocol • The latest on feline injection-site sarcoma AAFP Vaccine Categories Core: • Feline panleukopenia virus (FPV) • Feline herpesvirus-1 (FHV-1) • Feline calicivirus (FCV) • Rabies virus Noncore: • Feline leukemia virus (FeLV) • Feline immunodeficiency virus (FIV) • Chlamydophila felis • Bordetella bronchiseptica Generally Not Recommended: • Feline infectious peritonitis (FIP) virus • Feline Giardia Spending all or most of its time indoors does not eliminate a cat's risk for infectious disease. clinician’s update™ • 1 Feline Retroviruses Carrie R. White, DVM, DACVIM VCA Family Animal Hospital Pearl City, Hawaii FELINE LEUKEMIA VIRUS Acute infection with FeLV may follow 1 of 2 main courses. Prevalence & Pathogenesis FeLV is found worldwide. While some slight geographic and local variations exist, overall infection rates are relatively similar and range from 1% to 8% in healthy cats and up to 21% in sick cats.1-5 Kittens (especially <4 months old) are at increased risk for infection; resistance develops with age. However, adult cats may still be at risk. A recent study revealed 67% of adult cats developed persistent FeLV infection after challenge.5 FeLV-negative cats living with FeLV-infected cats are at increased risk for contracting the virus. Males and females are infected with FeLV with equal frequency; however, outdoor cats are more likely to be infected. Cats with abscesses are another high-risk population for FeLV.1 Following infection, FeLV replicates in many tissues, including bone marrow, respiratory epithelium, and salivary glands. Social behaviors (eg, grooming and sharing food bowls) are effective means of transmission. While virus may enter other body fluids and Diagnosis of FeLV Diagnostic Test Sample Detects Interpretation ELISA Plasma or serum, tears, saliva Free soluble p27 antigen Recommended screening test; can have false negative IFA Blood smears, bone marrow Cell-associated Confirmatory test; positive p27 antigen indicates progressive infection (cytoplasm) PCR Blood, bone marrow, lymph nodes, saliva, other tissues Viral RNA, proviral DNA 2 • clinician’s update™ Most sensitive test; may be only way to detect regressive infection; lab dependent secretions, transmission via urine and feces is less likely. Iatrogenic transmission, via contaminated fomites and blood transfusions, can occur. Vertical transmission is possible transplacentally or through the milk. New research suggests most regressor cats actually remain infected for life. Acute infection with FeLV may follow 1 of 2 main courses. An effective immune response can eliminate antigenemia after a few weeks (prior to bone marrow involvement); this is called a regressive infection. Historically, it was believed these patients had cleared the virus; however, new research suggests most actually remain infected for life. While these cats have no serologic evidence of infection, the virus persists in circulation, and provirus can be detected by PCR. They are unlikely to develop FeLV-associated diseases or shed virus in saliva but could be infectious to other cats via blood transfusion or organ transplantation. Rarely, regressor cats may have a recurrence of viremia, resulting in clinical disease. The second main outcome is progressive infection, which results from an ineffective immune response. In this case, there is extensive virus replication, first in the lymphoid, mucosal, and glandular epithelial tissues, followed by the bone marrow. Cats in this group remain persistently viremic and antigenemic, thus positive by all testing methods (ELISA, IFA, PCR), and are infectious to other cats. Many go on to develop FeLV-associated diseases, often within the first few years following infection. Two very rare stages of FeLV infections also exist: abortive infections, characterized by the absence of virus, antigen, and provirus Pathogenesis: Stages of FeLV Viremia Remember that infection is not the same as clinical illness; FeLV- and FIV-infected cats can live for many years with appropriate management, including twice yearly veterinary examinations. FeLV Exposure Ineffective Immune Response Effective Immune Response Progressive Infection Regressive Infection Extensive virus replication in lymphoid tissues, bone marrow Persistent viremia, antigenemia FeLV-associated diseases Abortive Exposure Focal Infection Virus localized in tissues FeLV antigen, virus detectable in blood for 2–3 weeks after exposure Cats maintain proviral DNA but are not antigenemic long term Unlikely to develop FeLV-associated disease Rare recurrence of viremia, clinical disease clinician’s update™ • 3 FeLV Diagnostic Algorithm ELISA Negative Retest if <12 weeks old or if recently exposed. Consider PCR to rule out regressive or early infection The AAFP now recommends vaccinating all kittens against FeLV, regardless of risk for infection. Positive IFA or PCR Retest in 6–8 weeks Positive Negative Progressive Infection Retest in 60 days (ELISA, IFA) after initial infection, and focal infections, which are restricted to tissues such as the spleen, lymph nodes, small intestine, or mammary gland. Clinical Signs FeLV infection can cause variable clinical signs. In a study of over 8,000 FeLV positive cats, the most common presenting signs were various infections,6 followed by anemia, lymphoma, leukopenia or thrombocytopenia, and leukemia or myeloproliferative disorders. FeLV infection can also cause various malignancies, most commonly lymphoma and leukemia; however, other tumors have been reported as well. Hematopoietic disorders, particularly cytopenias, can occur as a result of bone marrow suppression. Approximately 10% A negative FeLV test result is more reliable than a positive result; it is important to consider the history and clinical signs when interpreting all results. 4 • clinician’s update™ of FeLV-associated anemias are regenerative, most often resulting from immunemediated hemolytic anemia or concurrent mycoplasma infection, but most are nonregenerative, resulting from myelosuppression, myelodestruction, myeloproliferative disease, neoplasia, or chronic inflammatory disease. Immunosuppression resulting from FeLV infection accounts for a large portion of the morbidity and mortality of infected cats, due either to lymphopenia or abnormal lymphocyte function. Other disorders, such as glomerulonephritis and reproductive disorders, have also been reported. Diagnosis Available diagnostic tests for FeLV have a high negative predictive value (99% to 100%), but a lower positive predictive value (91% to 100%). Thus, a negative result is more reliable than a positive result; it is important to consider the history and clinical signs when interpreting all results. The ELISA test, which detects free soluble FeLV–p27 antigen in plasma or serum, is the recommended screening test. Cats become ELISA positive in the first phase of viremia, which is within the first weeks following infection; experimentally, most test positive within 28 days. The ELISA test is very sensitive but can yield false positive results. Additionally, regressor cats or cats with acute infection can test negative. Immunofluorescent antibody testing (IFA) detects cell-associated p27 antigen in blood cells, primarily neutrophils and platelets. Cats become positive only after bone marrow infection, which occurs after at least 3 weeks of viremia. A positive IFA result indicates bone marrow infection, thus progressive infection. Negative IFA results can be seen either with regressive infection or initial stages of viremia. PCR can be used to detect the FeLV virus and is currently being offered by several commercial laboratories. Technical errors, which can result from a lack of standardization of current reagents and testing protocols, can significantly decrease the sensitivity and specificity of this test. PCR is most useful in patients with suspected regressive infection, as this is the only method that will confirm the presence of DNA without the presence of antigen. cycline is warranted. While erythropoietin concentrations are often elevated in cats with FeLV-related anemia, treatment with human recombinant erythropoietin has anecdotally been helpful in some cases. Cats with lymphoma and FeLV should be treated with chemotherapy; however, FeLV infection is a negative prognostic indicator. Prevention The AAFP now recommends vaccinating all kittens against FeLV, regardless of risk for infection. Most veterinarians administer FeLV vaccines on an annual basis, which aligns with the administration recommendations for the leading vaccine on the market. Of the commercially available vaccines, the Fel-O-Vax (bi-vetmedica.com) and Fevaxyn FeLV (merck-animal-health.com) demonstrated up to 100% preventable fractions.7 One recent paper showed the risk for FeLV in unvaccinated cats to be greater than 8 times higher than in vaccinated cats, lending clinical support for vaccination.8 Vaccination against FeLV does not interfere with testing, as the available diagnostic tests are for antigen. REFERENCES Based on AAFP guidelines, any sick cats should be tested for FeLV, regardless of previous test results, age, or vaccine status. All cats should be tested prior to adoption, especially those entering households with uninfected cats, as should be currently owned cats prior to admission of a new, uninfected cat. Any cat recently exposed to an infected cat, or cats with exposure to the outdoors, should be tested. All cats with unknown FeLV status and those that will be blood or tissue donors should be tested. Management It is important to treat secondary diseases in cats with FeLV, as these patients are often immunosuppressed. Blood transfusions are an important part of therapy for those with anemia. If the anemia is regenerative and there is evidence of immunemediated destruction, immunosuppression is indicated. If mycoplasma infection is suspected, antibiotic therapy with doxy- 1. Seroprevalence of feline leukemia virus and feline immunodeficiency virus infection among cats in North America and risk factors for seropositivity. Levy JK, Scot HM, Lachtara JL, Crawford PC. JAVMA 228:371-376, 2006. 2. Seroprevalence of Bartonella henselae, Toxoplasma gondii, FIV and FeLV infections in domestic cats in Japan. Maruyama S, Kabeya H, Nakao R, et al. Microbiol Immunol 47:147-53, 2003. 3. Seroprevalence of feline leukemia virus and feline immunodeficiency virus infection among cats in Canada. Little S, Sears W, Lachtara J, Bienzle D. Can Vet J 50:644-648, 2009. 4. Prevalence of feline immunodeficiency virus and feline leukaemia virus among client-owned cats and risk factors for infection in Germany. Gleich SE, Krieger S, Hartmann K. J Feline Med Surg 11:985-992, 2009. 5. Efficacy of a canarypox virus-vectored vaccine against feline leukaemia. Poulet H, Brunet S, Boularand C, et al. Vet Rec 153:141-145, 2003. 6. Management of healthy feline leukemia virus-positive cats. Cotter SM. JAVMA 199:1470-1473, 1991. 7. Feline leukemia virus immunity induced by whole inactivated virus vaccination. Torres AN, O’Halloran KP, Larson LJ, et al. Vet Immunol Immunopathol 134: 122-131, 2010. 8. Seroprevalence of feline leukemia virus and feline immunodeficiency virus in cats with abscesses or bite wounds and rate of veterinarian compliance with current guidelines for retrovirus testing. Goldcamp CE, Levy JK, Edinboro CH, Lachtara JL. JAVMA 232:1152-1158, 2008. Based on AAFP guidelines, any sick cat should be tested for FeLV, regardless of previous test results, age, or vaccine status. It is important to treat secondary diseases in cats with FeLV, as these patients are often immunosuppressed. clinician’s update™ • 5 FELINE IMMUNODEFICIENCY VIRUS Prevalence & Pathogenesis Feline immunodeficiency virus (FIV) prevalence varies significantly worldwide, with rates reported at 4.3%, 28.9%, 47%, and 2.5% in Canada, Japan, the UK, and the United States, respectively.1-4 The prevalence of FIV is significantly higher in male cats than in females, and it most commonly affects adults. As with FeLV, cats presenting to a veterinary clinic with a wound or abscess are also more likely to test positive for FIV.4 Kittens up to 12 weeks of age may test positive due to presence of maternal antibodies. In the acute phases of infection the virus exists in salivary epithelium, lymphocytes, plasma, and serum. Experimentally, FIV is easily transmitted by all parenteral routes. However, in natural settings, FIV transmission occurs primarily by bite or fight wounds. Vertical transmission is also possible, and some kittens will acquire infection in utero or via nursing. Pathogenesis of FIV is influenced by a number of factors, including age at time of infection (young animals develop clinical signs faster), properties of the FIV isolate, amount of virus involved with infection, and route of infection. The hallmark of FIV pathogenesis is progressive disruption of normal immune function. Diagnosis of FIV Diagnostic Test Sample Detects Interpretation Serum FIV-specific antibodies (p24) Very sensitive and specific; vaccine interferes; false negative in acute phase, in end-stage disease Serum, plasma Antibodies Confirmatory test; vaccine interferes IFA Serum, plasma Antibodies Confirmatory test; vaccine interferes PCR Tissue Viral DNA Very sensitive and specific; variable results between labs; genomic variability of virus problematic ELISA Western blot 6 • clinician’s update™ Clinical Signs Clinical signs of FIV infection are nonspecific. In the acute phase, cats may show fever, lethargy, acute gastrointestinal signs, stomatitis, dermatitis, conjunctivitis, or respiratory signs. In experimentally infected cats, enlarged lymph nodes are present in the acute phase. This phase may last from several days to a few weeks, after which cats will appear clinically healthy. The duration of this asymptomatic phase is variable; FIV production continues in cells and tissues and cats are still prone to complications, thus it is not a true latent period. In later stages of disease, clinical signs often reflect opportunistic infections, neoplasia, myelosuppression, and neurologic disease. Ocular abnormalities, including uveitis, glaucoma, and retinal hemorrhages, may be observed. Chronic renal insufficiency has been reported in FIV-positive patients, potentially due to immune complex deposition. Neoplasia has been associated with FIV infection, and FIV-positive cats are more likely to develop lymphoma or leukemia compared to noninfected cats.5 Stomatitis is a common finding during any stage of infection. The cause is unknown; however, histopathology suggests either an immune response to chronic antigenic stimulation or immune dysregulation. Diagnosis Clinical screening is performed by detecting circulating antibodies against the virus, most commonly using the ELISA test, which detects FIV-specific antibodies and is very sensitive. Kittens up to 12 weeks of age may test positive due to the presence of maternal antibodies. For this reason it is advised to retest cats at 6 months of age, at which time they should test negative unless truly infected. Additionally, cats in the acute phase of infection may test negative; thus, cats with a recent history of exposure should be retested in 8 weeks. Confirmatory tests for FIV include western blot, IFA, and PCR. The ELISA, western blot, and IFA tests can all yield false positive Diagnosis of FIV A positive retroviral test should always be confirmed—preferably using a different method than was used for the initial screening test. – Cat is likely not infected Retest in 60 days if recently exposed ELISA <6 months + Consider age of cat Western blot or PCR Likely maternal antibody Retest when >6 months >6 months + Likely infected – Likely not infected; retest in 6 months to confirm clinician’s update™ • 7 results in FIV vaccinated cats. PCR detects viral DNA; therefore, vaccinated cats should not test positive. An ELISA test that detects antibodies against formalin-treated FIV whole virus and untreated transmembrane peptide exists, which can differentiate uninfected from infected cats, regardless of vaccination status. Developed in Japan, this test is not currently available in the US. One study demonstrated this discriminant ELISA was very effective at detecting positively infected cats, regardless of vaccination status, with very high sensitivity (97.1%) and specificity (100%) rates.6 While PCR is very sensitive and specific, false positive and negative results are possible. Additionally, the marked variability of the viral genome raises concerns about the ability of PCR to detect all FIV variants. Methods for this test are not yet standardized; results from different laboratories have shown widely variable results, with misdiagnosis of both uninfected and infected cats.7 FIV prevention includes minimizing risk of transmission and vaccination. Management It is important to keep cats with FIV indoors. These patients should visit the veterinarian at least twice yearly, for a physical examination, basic blood analysis, and a urinalysis. When underlying infections are present, cultures should be considered to determine the most appropriate antibiotic therapy. It is recommended that intact animals be spayed or neutered. While the immune deficiency often associated with this disease can affect response to vaccines, it is important to protect these patients against diseases for which vaccines exist. It is generally recommended that killed vaccines be used to eliminate the potential of cats developing illness from modified live vaccines. Prevention FIV prevention includes minimizing risk of transmission and vaccination. Vaccination can cause false positive results using the ELISA test for at least 1 year.8 8 • clinician’s update™ The risk versus benefit of vaccination for each individual cat should be strongly considered. The difficulty in yielding false positive results in vaccinated cats may be mitigated by microchip implantation at the time of vaccination, as well as future improvements in diagnostic testing for FIV. REFERENCES 1. Seroprevalence of feline leukemia virus and feline immunodeficiency virus infection among cats in Canada. Little S, Sears W, Lachtara J, Bienzle D. Can Vet J 50:644-648, 2009. 2. Feline immunodeficiency virus in cats of Japan. Ishida T, Washizu T, Toriyabe K, et al. JAVMA 194:221225, 1989. 3. Phylogeographic patterns of feline immunodeficiency virus genetic diversity in the domestic cat. Carpenter MA, Brown EW, MacDonald DW, O’Brien SJ. Virology 251:234-243, 1998. 4. Seroprevalence of feline leukemia virus and feline immunodeficiency virus infection among cats in North America and risk factors for seropositivity. Levy JK, Scot HM, Lachtara JL, Crawford PC. JAVMA 228:371-376, 2006. 5. Feline immunodeficiency virus and feline leukemia virus infections and their relationships to lymphoid malignancies in cats: A retrospective study (1968-1988). Shelton GH, Grant CK, Cotter SM, et al. J Acquir Immune Defic Syndr 3:623-630, 1990. 6. Differentiation of feline immunodeficiency virus vaccination, infection, or vaccination and infection in cats. Levy JK, Crawford PC, Kusuhara H, et al. J Vet Intern Med 22:330-334, 2008. 7. Accuracy of polymerase chain reaction assays for diagnosis of feline immunodeficiency virus infection in cats. Crawford PC, Slater MR, Levy JK. JAVMA 226:1503-1509, 2005. 8. Effect of vaccination against feline immunodeficiency virus on results of serologic testing in cats JAVMA 225:1558-1561, 2004. Developing a Feline Vaccine Protocol: Core and Noncore Gary D. Norsworthy, DVM, DABVP (Feline) Alamo Feline Health Center San Antonio, Texas Dozens of small animal vaccine protocols are in use in the United States. Some are used based on expert recommendations, others after personal research. This document details the results of the investigative process that I undertook in developing a vaccine protocol for my feline practice. RISK ASSESSMENT Prior to 1985, cats were vaccinated against feline panleukopenia virus, feline herpesvirus-1 (FHV-1), feline calicivirus (FCV), and rabies. Every cat presented for vaccination received all 4 antigens, 3 of which were combined into a single vaccine known as FVRCP. The concept of risk assessment began in 1985 with the introduction of the feline leukemia virus (FeLV) vaccine. Some veterinarians administered it to every cat; others, like me, limited it to cats with risk of exposure. The concept of risk exposure was popularized when the American Association of Feline Practitioners (AAFP) made its first vaccine recommendations. It is an idea that should be embraced by all veterinarians who vaccinate cats. Giving every available vaccine to every cat should be unthinkable. CORE VACCINES There is little debate among veterinarians regarding what constitutes a feline core vaccine; FVRCP and rabies vaccines are as universally accepted now as they were 30 years ago. With 60% of practitioners still not adopting the AAFP recommended intervals,1 debate remains regarding the frequency of administering these vaccines; however, there is little debate on whether or not to use them. Still, many of my clients with indoor-only cats no longer vaccinate their cats with FVRCP, claiming they never leave the house. The lifestyle of an indoor-only cat may reduce potential exposure; however, it does not remove it. When clients tell me this, I remind them that their cats do leave the house when they take them to a veterinary hospital. Few have given thought to the potential exposure that occurs when sitting in a veterinary waiting room or being hospitalized with other cats. This is an important talking point that we, as veterinarians, need to convey to clients. Rabies vaccination is also debated. Most states, including mine (Texas), have mandated cats be vaccinated against rabies. I wholeheartedly endorse that mandate for public health reasons and comply with it for both my personal cats and my hospital cats. However, this recommendation is more difficult to explain for resistant owners of indoor-only cats. While it is unlikely indooronly cats will be exposed to rabies, the law must be enforced, and we need to be agents of education on this point. Giving every vaccine to every cat should be unthinkable. NONCORE VACCINES Noncore vaccinations include those against feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV). Each is used only when real risk for exposure exists. When starting a kitten vaccine series, we ask clients if the cat will be going outdoors unsupervised. If not, we limit our recommendations to core vaccines. However, we The lifestyle of an indoor-only cat may reduce potential exposure; however, it does not remove it. clinician’s update™ • 9 advise clients that if the cat’s lifestyle changes, other vaccines will be needed. This approach works well for very motivated clients. Answers from casual cat clients may not be as reliable so we tend to be more aggressive in recommending our noncore vaccines. In general, exposure risk for FeLV and FIV is the same. Both are found in saliva and can be transmitted by bite wounds. Social contact (sharing food and water bowls, cogrooming) can readily transmit FeLV and, to a lesser degree, FIV.2 Therefore, the 2 main at-risk groups are: 1) cats that go outdoors unsupervised, and 2) cats living in direct contact with infected cats. FeLV PREVENTION It is my very strong opinion that no cat at risk for FeLV exposure should be denied FeLV vaccine. FeLV vaccine has been used in the US since 1985. At that time, FeLV-infected cats might be seen on a weekly, if not daily, basis. While virus testing was available as of 1973, we remained frustrated at the infection rate within our patient populations. The introduction of Leukocell by Norden Laboratories was The efficacy and safety of the FeLV vaccine were very good, and allowed veterinarians to quickly reduce the incidence of this deadly infection. one of the greatest events in the history of feline medicine. Its efficacy and safety were very good, allowing veterinarians to quickly reduce the incidence of this deadly infection. Veterinary graduates of the past 15 years have a difficult time understanding the positive change this vaccine has made in feline health. In the early 1990s, recognition of feline injection-site sarcomas (FISS), at the time incompletely referred to as vaccine-associated sarcomas, dampened enthusiasm of some toward FeLV vaccination. However, as time and research have progressed, informed practitioners realize it is not the agent (vaccine or other injectable products) that is the cause of these tumors. Rather, it is a genetic predisposition of the individual cat that permits them to occur. Hopefully, as this concept becomes better accepted, reluctance to give FeLV vaccine will dissipate. It is my very strong opinion that no cat at risk for FeLV exposure should be denied FeLV vaccine. FIV PREVENTION Figure 1: An 8-year-old cat was diagnosed with lymphoplasmacytic stomatitis gingivitis and treated medically for several months. When response to medical therapy failed, all of the premolars and molars were extracted. However, the expected response did not occur. Many FIV-infected cats do not respond to treatment as well as uninfected cats. The cat was euthanized for humane reasons. 10 • clinician’s update™ FIV was first isolated in 1986. The virus is primarily transmitted by bite wounds. There is a long latency period before the onset of immune suppression and disease. As cats may have no signs of disease for 5 to 10 years, some practitioners maintain a more casual attitude regarding its pathogenicity. However, once immunosuppression occurs, mild infections, especially upper respiratory infections and otitis externa, can be very difficult to resolve or may even become lifethreatening. Cats with lymphoplasmacytic stomatitis gingivitis complex (Figure 1) that are infected with FIV are much more resistant to treatment and are often euthanized. The incidence of FIV is consistently shown to be greater than that of FeLV for 2 reasons. It is more common in adult cats, and the prolonged latency period makes infected cats a source of infection for scores of other cats. The in-house ELISA test for FIV detects antibodies to the virus as well as those produced in response to FIV vaccination. This is most easily solved by microchipping. When a cat is first introduced to a shelter or a stray is first presented to a veterinary practice, responsible employees of either institution will scan the cat for a microchip. If present, the cat’s owner can be contacted. This should be done prior to FIV testing. In addition, a PCR test offered by IDEXX Laboratories reacts positively to only an FIV infection and can be used when there is a question regarding the meaning of a positive ELISA test. SUMMARY Vaccine protocols have been controversial for over 15 years and are likely to remain so for many years to come. It is incumbent The prolonged latency period makes infected cats a source of infection for scores of other cats. on each practitioner to study the literature objectively when deciding on what protocol is most appropriate for his or her patient population (see Additional Reading). Although high-profile speakers and other experts influence the thoughts of many practitioners on this subject, personal research of the peerreviewed literature should be part of the decision-making process. You are the one who must answer to the cat owner when an infection occurs in a cat whose vaccination protocol is suboptimal. REFERENCES 1. Vets slowly move to 3-year vaccine protocols. Ford R. Vet Pract News 25:24-25, 2013. 2. Long-term impact on a closed household of pet cats of natural infection with feline coronavirus, feline leukaemia virus and feline immunodeficiency virus. Addie DD, Dennis JM, Toth S, et al. Vet Rec 146:419-424, 2000. It is incumbent on each practitioner to study the literature objectively when deciding on what protocol is most appropriate for his or her patient population. ADDITIONAL READING • Resistance to tumors.Tizard I. Veterinary Immunology, 9th ed—St Louis: Elsevier Saunders 2013, pp 395-398. • HIV-1 p24 vaccine protects cats against feline immunodeficiency virus infection. Coleman JK, Pu R, Martin M, et al. AIDS 19:1457-1466, 2005. • Dual-subtype vaccine (Fel-O-Vax FIV®) protects cats against contact challenge with heterologous subtype B FIV infected cats. Kusuhara H, Hohdatsu T, Okumura M, et al. Vet Microbiol 108:155-165, 2005. • Immunogenicity of an anti-clade B feline immunodeficiency fixed-cell virus vaccine in field cats. Matteucci D, Poli A, Mazzetti P, et. al. J Virol 74:10911-10919, 2000. • Dual-subtype FIV vaccine protects cats against in vivo swarms of both homologous and heterologous subtype FIV isolates. Pu R, Coleman J, Omori M, et al. AIDS 15:1225-1237, 2001. • Dual-subtype FIV vaccine (Fel-O-Vax FIV®) protection against a heterologous subtype B FIV isolate. Pu R, Coleman J, Coisman J, et al. J Feline Med Surg 7:65-70, 2005. • HIV-1 p24 vaccine protects cats against feline immunodeficiency virus infection. Coleman JK, Pu R, Martin M, et al. AIDS 19:1457-1466, 2005. clinician’s update™ • 11 Current Thinking on Feline Injection-Site Sarcomas Andrew Sparkes, BVetMed, PhD, DECVIM, MRCVS Veterinary Director, International Cat Care & International Society of Feline Medicine A direct link between administration of vaccines that caused greater local inflammatory reactions and an increased risk for subsequent sarcoma formation was never demonstrated. Feline injection-site sarcomas (FISS) are a rare occurrence, but can have devastating consequences for the individual cat when they do occur. Understandably, FISS cause considerable concern among veterinarians and owners alike; addressing the issue properly requires careful consideration of the known facts. This article briefly reviews historical and contemporary data on FISS to enable rational conclusions to be drawn in regard to managing the issue. HISTORICAL ASPECTS Awareness that injectables may sometimes have the ability to trigger sarcoma formation in cats first came to light in the early 1990s when US studies appeared potentially linking the development of fibrosarcomas to injection sites.1 At around the same time, reports also emerged of very severe local reactions (necrotizing panniculitis) in some dogs and cats inoculated with rabies vaccines.2 Aggressive, recurrent fibrosarcoma affecting the hindlimb of a cat—recurrence despite limb amputation. 12 • clinician’s update™ Early reports of what was initially termed vaccine-associated sarcomas (VAS), suggested these occurred more commonly with the use of adjuvanted vaccines—particularly rabies and FeLV vaccines.3,4 An apparent rise in the prevalence of this type of fibrosarcoma also appeared to occur coincidentally with changes in legislation that mandated rabies vaccination, adding further speculation to the role of rabies vaccine in tumorigenesis.3 Early (though somewhat limited) epidemiologic studies appeared to confirm the link between rabies and FeLV vaccination and an increased risk for sarcoma formation. The studies also identified an increased risk with the injection of multiple vaccines at the same site.4 By the mid to late 1990s, several studies and publications on VAS had appeared. A number of these attempted to quantify the risk of sarcoma formation; estimates varied between approximately 2 and 36 cases of sarcoma for each 10,000 doses of vaccine administered.5-11 Some, but not all, reports still suggested a link between rabies and/or FeLV vaccination, but it became apparent that other vaccine antigens (eg, feline herpesvirus-1, calicivirus, and feline parvovirus [FVRCP]) might also be linked to VAS.10 A common assumption was that sarcoma formation was linked to inflammation induced by the vaccine at the site of injections. This was based partly on the knowledge that VAS were commonly associated with a marked inflammatory response3, 12-14 and partly with the knowledge that some vaccines produced greater inflammation than others at the site of inoculation.15-17 Nevertheless, a direct link between admin- istration of vaccines that caused greater local inflammatory reactions and an increased risk for subsequent sarcoma formation was never demonstrated. MORE RECENT STUDIES In 2002 and 2003, 2 larger epidemiologic studies from North America were published. One study followed more than 30,000 vaccinated cats for a period of 1 to 3 years, the second was a multicenter casecontrol study evaluating nearly 1,500 cats.18, 19 These were much more substantial studies than had been published previously and suggested that the risk for VAS may be much lower than previous estimates (in the order of 1 per 30,000 doses of vaccine) and, further, that VAS were not associated with any particular manufacturer or brand. In fact, no increased risk was found even with the use of killed, adjuvanted, or multidose vaccines in the case-control study. However, the possibility of injectable products other than vaccines also being associated with the formation of some sarcomas was noted. The 2003 case-control study concluded that the results did not support the superiority of any single vaccine brand for preventing VAS. Further, results were consistent with the concept that a vaccine alone was insufficient to cause a sarcoma but might, in some cases, be a contributory factor along with other factors such as underlying genetics. Results of a 2003 case-control study were consistent with the concept that a vaccine alone was insufficient to cause a sarcoma. The traditional site for vaccination may no longer be appropriate. A Rational Approach to Feline Injection-Site Sarcoma • Recognize and communicate with clients that FISS is a rare problem, although serious when it occurs. Sarcomas are seen as a spontaneous disease, but there is evidence that many (if not all) injectable products may have a role in increasing the risk in some cats. It is likely that vaccines carry a higher risk than other injectables, but the association with vaccines is not unique. • Searching for a “perfect” vaccine that is safe, efficacious, and has no ability to be involved in triggering a sarcoma formation is likely to be futile. All vaccines appear to carry a risk and FISS are not, as previously thought, particularly associated with rabies or FeLV vaccines—or even with adjuvanted vaccines. • At present, we have no way of identifying which population of cats might be more at risk for developing FISS nor any knowledge of other factors involved that may enable preventive measures to be taken. • Reducing the frequency of vaccination and avoiding unnecessary vaccination while maintaining vaccines’ protective benefits is a sensible and logical approach to helping reduce the prevalence of vaccine-associated adverse events. Both the AAFP and World Small Animal Veterinary Association (as well as other veterinary organizations) have recommended a reduced frequency of vaccination in many situations for at least some vaccine components.30, 31 Altering the site of vaccination according to AAFP and Vaccine-Associated Feline Sarcoma Task Force guidelines may also help in managing the problem.30, 32, 33 • As the risk for FISS cannot be prevented (other than by avoiding injecting cats entirely, which would cause vastly more health and welfare problems) and as the risk is actually very low, a more important priority is to monitor cats carefully after vaccination. Although not subjected to critical scientific appraisal, the so-called “3-2-1 rule” would seem highly appropriate to emphasize34: any local swelling at the site of vaccination that persists for 3 months after vaccination, and/or is greater than 2 cm in diameter, and/or is getting larger 1 month after vaccination, should be biopsied and dealt with according to the histopathologic diagnosis. It would also seem prudent to apply this rule to the use of all injectable products and not just to single out vaccines. Client communication and vigilance are vital in this regard. clinician’s update™ • 13 A further study published in 2007 evaluated adverse vaccine reactions recorded in cats vaccinated at Banfield Pet Hospitals in North America.20 The study looked at adverse reactions that occurred within 30 days of vaccination, then followed the cats for a further 1 to 2 years. The reported adverse reaction rate was approximately 0.5% (2,560 cases out of over 469,000 vaccines administered), with the most common being lethargy and/or fever (54%), local reactions (25%), vomiting (10%), facial edema (6%), and pruritus (2%). None of the cats that developed localized reactions developed a sarcoma at the injection site during the 1- to 2-year period and no VAS were identified among the nearly 470,000 cats vaccinated again, in contrast to the earlier much higher estimates of prevalence. Along with these data, case reports have emerged linking the occasional development of subcutaneous sarcomas in cats with the use of other injectable products, including glucocorticoids, NSAIDs, cisplatin, lufenuron, nonabsorbable suture material, and microchips.19, 21-23 Based on these data and the knowledge from epidemiologic studies, the syndrome was Fine needle aspirate appearance of fibrosarcoma (stained with Diff-Quik®). 14 • clinician’s update™ subsequently renamed feline injection-site sarcoma (FISS) rather than VAS to more accurately reflect the current state of knowledge and apparent risk associated with a variety of injectable products. While studies examining the severity of postvaccination inflammation at the injection site failed to show a clear direct link with the risk for sarcoma formation, other investigators evaluated potential genetic traits that may increase the risk. Although no breed-associated risk has been identified, 1 study from the US did suggest that polymorphism in the p53 tumor suppressor gene was significantly associated with an increased risk for FISS.24 However, another more recent study from Germany was unable to substantiate this finding.25 Further work is clearly needed in this area. Most information about FISS has come from studies and publications in the US. However, FISS is seen worldwide.26,27 A recent study reviewed cases seen in the UK in 2007.28 This study estimated the frequency of FISS to be around 1 per 17,000 to 50,000 cats registered at practices, or 1 per 5,000 to 12,500 vaccination visits. The authors concluded that the frequency of FISS was very low (and similar to estimates from the US), that evidence of a causal relationship between FISS and vaccination remains weak, and that many other diseases have a much greater impact on feline health and remain more important targets for improving feline welfare. A further US case-control study compared control cats with those that developed sarcomas in the interscapular region.29 No significant difference was found in the use of inactivated and recombinant rabies vaccines, between the use of inactivated and recombinant FeLV vaccines, or between use of inactivated and live FVRCP vaccines. Comparing the same data for cats that developed sarcomas in the hindlimb regions, there was also no significant difference in the use of inactivated and live FVRCP vaccines, but there was evidence of a significantly higher use of inactivated rather than recombinant rabies vaccines in the sarcoma group. However, the study authors noted that all vaccine types appeared to be associated with some risk for FISS, and there appeared to be a trend for a higher risk with the use of modifiedlive FVRCP compared with inactivated FVRCP. This study also highlighted that, of all the cats that developed sarcomas at potential injection sites, only 56% were reported to have received vaccinations and 13% had received another injectable product. An increased risk for FISS was again noted with the injection of a variety of glucocorticoid products. While unequivocally serious and even devastating when it arises, FISS is fortunately rare. WHERE DO THESE STUDIES LEAVE US NOW? FISS remains an enigmatic problem. While unequivocally serious and even devastating when it arises, it is fortunately rare. Current and most reliable estimates suggest occurrence with a frequency of around 1 for every 10,000 to 30,000 vaccines,18-20,28 and it is clear that vaccines are not the only injections associated with FISS development. The relatively rare nature of these tumors means that studying causal and contributory factors to their development is very difficult. The current belief is that vaccines and a number of other (potentially all) injectable products may have the ability to contribute to sarcoma formation, as might other forms of tissue trauma. It is believed likely that inflammation at the injection site and the genetic makeup of the cat may contribute to the risk of sarcoma development, but these are all putative, rather than proven, risks; the exact relationship between any of these and the development of sarcomas remains elusive. It appears clear that, in contrast to early reports, FISS is not linked primarily with FeLV or rabies vaccination, but in fact all vaccines appear to carry a risk. Whether this is because early studies were based on a limited number of cases or whether it is because of changes in vaccine formulation since the initial reports remains unknown. However, it seems clear that all vaccines carry some risk of being a contributory factor in triggering sarcoma formation in some cats. As clinicians, the question remains as to how we can best approach minimizing the small risk for FISS occurring in our patients. Until our understanding of the etiopathogenesis of these tumors improves, this remains challenging. However, from current evidence and the accumulated data reviewed here, it is possible to develop a rational and pragmatic approach (see A Rational Approach to Feline InjectionSite Sarcoma). Keeping a perspective on the true prevalence of and risks for FISS occurring should help in formulating rational and informed approaches to managing the problem. While the unnecessary use of injectable products should be avoided, the very low risk for FISS formation should not preclude their use, especially when the health benefits (eg, vaccination) clearly vastly outweigh the very small risk for FISS development. Further work is clearly needed, however, to understand how injectable products may contribute to sarcoma development, which cats might be at increased risk, and how, if possible, FISS might ultimately be prevented. In the meantime, vigilance after using injectable products is perhaps the best way of minimizing the impact of sarcoma formation, should it arise. REFERENCES 1. Do injection site reactions induce fibrosarcomas in cats? [letter]. Hendrick MJ, Goldschmidt MH. JAVMA 199:968, 1991. 2. Focal necrotizing granulomatous panniculitis associated with subcutaneous injection of rabies vaccine in cats and dogs: 10 cases (1988-1989). Hendrick MJ, Dunagan CA. JAVMA 198:304-305, 1991. 3. Postvaccinal sarcomas in the cat: Epidemiology and electron probe microanalytical identification of aluminum. Hendrick MJ, Goldschmidt MH, Shofer FS, et al. Cancer Res 52:5391-5394, 1992. 4. 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