Feline Infectious Diseases

Feline Infectious Diseases THANK YOU! Thanks to sponsorship from Merial, the makers of PUREVAX vaccines! Introduction Garret Pachtinger, VMD, DACVECC COO, VETgirl Introduction Justine A. Lee, DVM, DACVECC, DABT CEO, VETgirl VETgirl on the run! The tech-savvy way to get RACE-approved, online veterinary CE! A subscription-based service offering veterinary RACE-approved CE VETgirl ELITE! 50-60 podcasts/year plus 30+ hours of webinars! $199/year 40+ hours of RACE-CE 1

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Introduction Alice M. Wolf, DVM, DACVIM, DABVP Feline Infectious Diseases General vaccine immunology Vaccine Protocols Panleukopenia Parvovirus URI Agents: Herpesvirus, Calicivirus Influenza? Coronavirus (FIP) FeLV FIV General Immunology Should I/Can I use antibody titer testing to determine the immune status of my patient? General Immunology Serologic Protective Immunity Relevant for pediatric patients without active immunity Only Cornell has challenge studies Mostly irrelevant for actively immunized animals General Immunology Ab titers don t always correlate with protection in actively immunized animals: If titer is high: Usually supports protection But Ab makes some diseases worse: Coronavirus (FIP) Calicivirus? General Immunology Ab testing ignores: Memory cells that regenerate protection within hours CMI CMI most important for some diseases: Retrovirus (FeLV) Lentivirus (FIV) 3

General Immunology I vaccinated my patient why did it Still develop clinical signs of disease? Become a chronic carrier of the disease? Sterilizing vs Non- Sterilizing immunity General Immunology Sterilizing Immunity General Immunology Feline Vaccination Guidelines American Association of Feline Practitioners (AAFP) Non-sterilizing Vaccine First guidelines 1998 Last revision - 2013 Non-Sterilizing Immunity Feline Vaccination Guidelines World Small Animal VMA Second revision 2016 European Advisory Board on Cat Diseases (ABCD) Vaccines 2009 ISS Prevention/Mgmt - 2015 Vaccine-associated Sarcoma 8 yo, SF Persian Photo credit: Dr. Jeff Chalkey 4

Feline Vaccination Guidelines NON-Core Vaccines: FeLV adult cats Intranasal URI (Herpes/Calici) Chlamydia (Chlamydophila) Bordetella FIP Feline Vaccination Schedule Kittens Core: 8-12-16 wks or 6-9-12-16 wks Repeat FVRCP Year 1 No more often than q3years thereafter RV as labeled FeLV Year 1 then? VAS What is it? Connective tissue tumor at an injection site Thought to be caused by chronic injection site inflammation What is a Vaccine Adjuvant? Chemical additive used to enhance the immunologic response to killed antigens One of the ways that they work is by creating chronic injection-site inflammation Role of Inflammation in Oncogenesis PubMed search: Inflammation Induction Cancer 2800+ entries Other veterinary examples: Post-traumatic Ocular Sarcoma Cats Spirocerca dog Bone plates TPLO surgery (implants) VAS But isn t it just the genetics of the cat? Doesn t explain the appearance of this problem worldwide at the same time May be some genetic susceptibility to inflammation-induced cancer in cats BUT we can t control the genetics of the cat!! 5

VAS We can control how much inflammation we create! Use less inflammatory products: AAFP (2006) Vaccination should be performed as necessary but as infrequently as possible VAS WSAVA (2016) Non-adjuvanted vaccines should be administered to cats wherever possible. ABCD European Advisory Board on Cat Diseases (2015) Non-adjuvanted, modified live or recombinant vaccines should be selected in preference to adjuvanted vaccines. Risk Management Wilcock et al: Can Vet J: 2012 The only proven cause for injection site sarcomas in cats is prior administration of a killed, adjuvanted vaccine. Rabies and leukemia vaccines are the only ones with solid causal associations. Claims implicating other agents such as lufenuron or microchips are unsubstantiated because previous vaccination in that same location could not be ruled out. Risk Management Wilcock et al: Can Vet J: 2012 the interval between vaccine administration and detection of a sarcoma may be as short as 4 months or as long as 13 to 15 years. Risk Management Srivastav: JAVMA Sep 1, 2012, 595-602 Results consistently showed that case (VAS) cats were significantly LESS likely to have received recombinant vaccines than inactivated vaccines; ORs from regression analyses equaled 0.1, with 95% confidence intervals ranging from 0 to 0.4 and 0 to 0.7 depending on control group and time period of exposure used. Feline Parvovirus (Panleukopenia) Do cats become infected or ill from Canine Parvovirus? If Yes What are the implications for my patients? For my practice? 6

Feline Parvovirus (Panleukopenia) CPV- can infect cats: Clinical disease - rare Asymptomatic shedding PCR feces 2a or 2b (2011) 32% of healthy cats in Feline-only shelter 40% of healthy cats in Mixed shelter NO FPV isolated NO CPV from dogs NO CPV in environment May shed for 4-6 weeks Feline Parvovirus (Panleukopenia) Practical implications: FPV vaccine protects cats from clinical CPV disease Don t house CPV-dogs in the cat ward? Don t house cats with susceptible puppies? URI Agents, Feline Calicivirus Why do my URI-vaccinated patients still show clinical URI signs? How can I prevent early age URI infection in my patients? Would more frequent vaccination provide better protection? URI Agents, Feline Calicivirus URI Vaccines only establish Non-sterilizing immunity Clinical signs reduced, not eliminated Don t prevent chronic carriage Don t prevent shedding URI Agents, Feline Calicivirus Protection does wane over time however: Number of clinically affected cats and severity of signs in challenged cats not significantly different weeks to years (3 to 7.5) post-vaccination Shedding post-challenge is less in more recently vaccinated cats URI Agents, Feline Calicivirus Early age infection IN vaccines may be helpful in high density environments Maternal Ab persistence: Blocking of active immune response to parenteral vaccines beyond 12 weeks of age 7

URI Agents, Feline Calicivirus High asymptomatic carriage rates in the population (in spite of vaccination): HHP: ~20-30% Cattery cats/multiple cat environments: Up to 80% + for either or both Recrudescence of clinical signs Stress, etc. Especially Herpes: Eye, etc. URI Agents Feline Calicivirus Calicivirus most problematic for protection: Plethora of antigenic variants Plasticity of virus Emergence of new variants Arthrotropic, Hypervirulent variants Feline Calicivirus Feline Calicivirus Classical URI disease: Fever Oral ulcers Oculo/nasal discharge Rarely lower URI signs Feline Calicivirus Common chronic manifestations: Gingivitis/stomatitis Feline Calicivirus Common chronic manifestations: Super eruption of teeth 8

Calicivirus Uncommon: Skin Lesions Calicivirus Feline Calicivirus What about virulent systemic calicivirus? aka: Killer Calicivirus Virulent Calicivirus It is NOT a new disease It is NOT a disease of household pets It IS a very RARE disease of group-housed cats with less than ideal husbandry Shelters Catteries Rescues Hoarders, etc. Virulent Calicivirus Each isolate genetically unique: Spontaneous mutation from circulating calicivirus in the population No common mutation to explain virulence Single virus strain in vaccine will not protect against other mutants Virulent Calicivirus High fever (105 106 F) URI signs Edema of face, feet, trunk Necrosis of tissue in edematous areas Can be associated with severe pneumonia, hepatitis, pancreatitis, enteritis, DIC, death 9

Virulent Calicivirus Tissue necrosis Virulent Calicivirus Virulent Calicivirus Photo: Dr. Thompson - VIN Virulent Calicivirus Bottom line: Not a concern for average household pets Use excellent isolation techniques for ALL hospitalized URI cats Especially if from high density environments Or treat all URI cats as outpatients 10

Chronic Ocular Complications Chronic complications: Ocular lesions Recurring conjunctivitis, ulcers Eosinophilic keratitis Corneal sequestrum Less common: SKIN LESIONS Ulcerated areas in the haired skin of: Nasal planum Head, face, or ears Feet Ventrum Often in areas in contact with lacrimal or salivary secretions Major clinical DDX: Mosquito Hypersensitivity Eosinophilic granuloma complex Squamous cell carcinoma Allergy Microscopic: Ulceration and necrosis Inflammatory infiltrate contains many eosinophils Intranuclear herpesvirus inclusions only on histopathology Special diagnostic tools: Immunohistochemistry PCR on tissue biopsy Serology or PCR of oral swabs are not diagnostic Many cats carry FHV-1 11

Herpesvirus dermatitis Mosquito Hypersensitivity Herpesvirus SCC Cryptococcus Herpesvirus or EGC? Photo credit - Dr. Abramo - VIN FHV-1 Dr. McElroy - VIN Dr. Gotthelf - VIN Dr. Lindquist - VIN 12

Confirmed Herpes by BX DDX from Dirty Faced Persian Dr. Ortunez - VIN Dr. Povar - VIN Dr. Zimmerman - VIN Dr. Wilkie - VIN Diagnosis: Immunohistochemistry PCR on tissue Confirmed DX is important because steroids will worsen the condition Treatment: L-lysine Not harmful but questionably useful IFNα? 30 30,000 U PO q24h 250-500K U SQ 3X/week for 6 weeks Treatment: Acyclovir Not effective against FHV-1 Famciclovir 90 mg/kg PO q8-12h (125 mg tabs) Not approved for cats Active metabolite penciclovir in tears Imiquimod (Aldara ) 5% Cream Topical immunomodulatory - Herpes Apply topically to lesions q48-72h Do Cats get Influenza? Not Canine (H3N2, H3N8) Not Equine 13

Do Cats get Influenza? Outbreak of Avian Influenza H7N2 Shelter in NYC Dec 2016 Jan 2017 One human infected Do Cats get Influenza? Source of the outbreak/infection unknown No further cases reported since this outbreak Feline Coronavirus Why do I see FIP in an isolated household cat? Why don t we have an effective FIP vaccine? What s new in FIP treatment? Feline Coronavirus Ubiquity of FECV carriage: ~30% of HHP 80-90% of Cattery, Shelter cats Spontaneous pathogenic mutations in carrier cats Replication and emergence of pathogenic mutants is enhanced by high carriage rates, stress, crowding, poor husbandry, poor nutrition, etc. Feline Coronavirus Other influences: Genetic predisposition Macrophage receptors for coronavirus Concurrent diseases FeLV FIV Age Feline Coronavirus 14

Feline Coronavirus High Ab, little CMI Effusive disease Ab, Partial CMI Non-effusive disease Ab?, Strong CMI No disease? Feline Coronavirus No common mutation accounts for virulence No FIP-specific test At this time, no target has been identified that can specifically ID FIP coronavirus Feline Coronavirus FIP Vaccine Conventional vaccine strategies are ineffective Current FIP vaccine not effective Shelter study in Germany May sensitize to infection (Cornell studies Fred Scott) Not recommended Feline Coronavirus Best preventative strategies Prevent intestinal colonization by coronavirus Vaccine that stimulates strong CMI with little to no humoral response Recombinants and other genetically engineered vaccines? Feline Coronavirus New frontiers in treatment: PPI Polyprenyl immunostimulant 3CL protease inhibitor GC376 Feline Coronavirus PPI Commercially available Approved to treat FVR NOT a cure May > survival time and QOL 15

Feline Coronavirus 3CL protease inhibitor GC376 Drs. Pedersen, Kim, and Chang Inhibits protease enzyme Blocks virus from infecting more cells and replicating Feline Coronavirus 3CL protease inhibitor GC376 Experimental studies Clinical trials Not commercially available Looking for manufacturer Feline Leukemia Virus FeLV (FeLV) Type C oncornavirus in the retrovirus group. Horizontal and vertical transmisison. A disease of friendly cats, close, intimate contact needed for transmission. (FeLV) Testing conundrums: Which cats should be tested and when? Which test should be used for screening? Which test should be used for confirmation? (FeLV) Which cats to test? AAFP: The retrovirus status of all cats should be known. Pre-vaccination of kittens/cats Sick cats Routine health screening? 16

(FeLV) ELISA (enzyme-linked immunosorbent assay) Best for screening due to speed, ease of use in-house, and sensitivity. Of the in-house tests, the IDEXX SNAP appears to have the highest sensitivity and specificity (2016) (FeLV) IFA test Looks for viral antigen in cells Cannot be performed in-house Delay in results Substrates submit air dried slides: o Peripheral blood (WBC, platelets) o Bone marrow (FeLV) PCR test Detects minute amounts of viral protein o Excellent correlation with ELISA results Cannot be performed in-house Delay in results Substrates o Peripheral blood o Bone marrow (FeLV) Incidence in the population must be taken into account when interpreting FeLV test results Healthy cats: 1-3% Sick cats: up to 30% SPINS and SNOUTS SPecificity: Positive test rules in DX Specificity of 98% Test 100 positives cats, 98 will test positive SeNsitivity: Neg test rules out DX Sensitivity of 98% Test 100 negative cats, 98 will test negative Test Reliability If the incidence in the population is 1%: You will get 3 positives/100 cats tested o ONE true positive o TWO false positives RELIABILITY: 33% Recheck positive results in low risk animals! 17

(FeLV) False positive tests? Weak positives often false positives o Retest with serum, not whole blood ELISA positives should be confirmed with an IFA or PCR testing Vaccination Which FeLV vaccine is the best? Field efficacy is impossible to determine: Incidence of FeLV in population is low Effect of age-related resistance Difficulty in collecting data (FeLV) Age-related resistance < 6 weeks of age ~ 100% susceptible > 1 year of age <10% susceptible Vaccination Difficulty comparing studies Apples and Oranges Read materials/methods of each publication Age of cats Challenge model Artificial immunosuppression Vaccination Newest comparative FeLV vaccine study (Biologicals: In press: 2017): Recombinant FeLV (non-adjuvanted) Two inactivated, adjuvanted FeLV o Subjects: Kittens 9-10 weeks of age o Identical laboratory conditions and mimicking natural challenge Vaccination Newest comparative FeLV vaccine study (2017): No statistically significant differences among the vaccines ability to protect against persistent viremia. I recommend using the least reactive (non-adjuvanted) vaccine 18

Vaccination Which cats should be vaccinated against FeLV? Kittens are the most susceptible group In nature most are infected from the dam in-utero or during the nursing period Vaccination Because of high kitten susceptibility: All feline vaccination guidelines recommend universal kittenhood vaccination Vaccination of adults after 1 year of age depends on risk assessment. Feline Immunodeficiency Virus Feline Immunodeficiency Virus FIV is a relatively benign disease in most cats Only 3 viral isolates (of all those isolated) consistently cause fatal immunodeficiency disease under experimental conditions Two clade A (one of which is Petaluma), one clade C Feline Immunodeficiency Virus Transmission in stable households is rare FIV is a disease of unfriendly cats Bite wound transmission Feline Immunodeficiency Virus FIV testing Screening test: ELISA Detects antibody against p24 Confirmatory test: Western Blot Positive result requires at least 3 bands of antibody identity to different FIV antigens 19

Feline Immunodeficiency Virus How do I differentiate truly FIV-infected cats from those that may have been FIV vaccinated? Witness FeLV/FIV Anigen Rapid FeLV/FIV Do not detect vaccine-ab positive cats Feline Immunodeficiency Virus FIV vaccine? No longer a question FIV vaccine is no longer manufactured or distributed in North America Ineffective (UK study) Sensitized cats to infection when challenged Feline Immunodeficiency Virus If it was easy to protect against FIV, we would have had an effective HIV vaccine long before now! FIV used as model in HIV studies Billions of $$ in research to date FIV Vaccine Challenges Genetic diversity of FIVs Present and increasing Among/between clades Viral envelope proteins Target for virus neutralization Highly variable and changing Feline Immunodeficiency Virus Questions? 20

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