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Caprine Arthritis and Encephalitis KATIE SIMPSON, DVM, MS, DACVIM CROSS TIMBERS LARGE ANIMAL CLINIC APRIL 30, 2016 Outline Etiology Transmission Pathogenesis Clinical Signs Diagnosis Prevention Other Lentiviruses Introduction 1st recognized1974 in USA Switzerland 1969 Worldwide Economically important ↑ Cull rates 5-10% arthritis ↑ Incidence ↓ Productivity Etiology Family Retroviridae Oncogenic Non-oncogenic Genus Lentivirus “Slow Viruses” Chronic degenerative disease Long incubation Life-long persistence! Once they are infected, they are infected for life Etiology… Lentiviruses… Caprine Arthritis-Encephalitis Virus (CAEV): Goats Maedi-Visna Virus (MVV): Sheep Bovine Immunodeficiency Virus (BIV) Equine Infectious Anemia (EIA) Feline Immunodeficiency Virus (FIV) Human Immunodeficiency virus (HIV) Etiology… Closely related to MVV Genetically distinct Morphologically/physically the same Comparable syndromes Cross-species transmission Experimental Etiology… Serum antibodies = infection Different strains No tissue tropism Transmission Lactogenic (milk, colostrum) Target organ Mammary gland Macrophages Epithelial cells Transmission… Lactogenic… Nursing dam Even subclinical Pooled colostrum Adams et. al. 1983 Cell free and cell-associated virus Survived concentration and freezing Transmission… Transplacental Occurs, unknown rate 5-10% Lamara et. al. 2001 In vitro infection of oviduct epithelial cells No reports of in vivo occurrence Transmission… Horizontal transmission (one juvenile/adult to another) Intense management High stocking density Also poor management, poor hygiene Possibly through saliva, nasal secretions, urine, feces, blood Older animals Possible delayed latent neonatal infection Transmission… Other means Shared milking facilities Milking infected w/non-infected Iatrogenic Venereal Not proven Transmission… Factors… Breed ↓ Prevalence in Saanen, Golden Guernsey Genetic factors Saanens tend to have lower risk of arthritis Stress Immunosupression 2° infections Pathogenesis Mechanisms unclear Subclinical infections common Prepatent period varies Host cell Monocyte/macrophage (type of white blood cell) Restricted replication Transcription monocytes → macrophages Undetected in monocytes Pathogenesis… Viral load ↓ in asymptomatic Cell mediated immunity Synovial fluid/tissues CD8+ cytotoxic T-cells ↑ [IgG] ↓ level immune stimulation Genetic predisposition Similar to Rheumatoid Arthritis (RA) Pathogenesis… Infected macrophages in all tissues Alter cytokine production Stimulate immune response Released in RA Nitric oxide synthase ↑ In joints Role unknown Pathogenesis… Antibody detection May take weeks → months Suggested that Abs Don’t protect… Enhance infection Immune complexes taken up by macrophages Seen w/ HIV and FIV Pathogenesis… Arthritis: Similar to RA Infiltration of synovial membranes Disease related changes of articular (joint) surface ↓ IL-2 expression Cytokine pattern altered Clinical Signs Chronic inflammatory lesions Most subclinical (NOT apparent) Seroprevalence 0-81% 25-30% develop disease Clinical Signs… 4 (5) clinical manifestations: Arthritis Encephalitis Interstitial pneumonia Indurative mastitis +/- Chronic weight loss Clinical Signs… Arthritis “Big Knee” Adults >1 year Predominant form Course varies Clinical Signs… Carpal joints > tarsal, stifle, fetlock joints, atlantooccipital bursa > coxofemoral joint All synovial membranes Tendons, bursa, periarticular tissues Clinical Signs… Arthritis… Early signs subtle Periarticular swelling of carpus (knee) Fluctuant, cool, not painful to palpation Painful & debilitating Collapse of joint, ankylosis Severe flexion of carpus “Knee walkers” Hindlimb swelling less obvious Gait may resemble incoordination Clinical Signs… Arthritis… Synovial (joint or tendon) fluid Acute Serous Dark-yellow or blood tinged Fibrin, lymphocytes/macrophages Chronic Normal Clinical Signs… Viral Leukoencephalomyelitis (brain/spine involvement) 2-6 months old Develop slowly Afebrile progressive paralysis Lameness, ataxia, hindlimb CP deficits Asymmetric Hypertonia, hyperreflexia Clinical Signs… Viral Leukoencephalomyelitis… Initially BAR Continue to eat and drink Progresses to paralysis, usually Can also see CNS signs Depression, blindness, abnormal PLRs, nystagmus, opisthotonos (stargazing), head tremor, head tilt, circling, facial nerve deficits, dysphagia, paddling Rarely recover Clinical Signs… Interstitial pneumonia Not reproducible Secondary to other processes Viral, bacterial agents Parasitic Chronic, non-suppurative Progressive dyspnea (difficulty breathing) Usually after stress Weeks to months Clinical Signs… Interstitial pneumonia… Exercise intolerance, wasting, cough Arthritis Similar to pulmonary CL Clinical Signs… Indurative mastitis “Hard udder” or “Hard bag” Non-suppurative Agalactia/hypogalactia Milk appears normal Come into milk over weeks Symmetrical enlargement of udder Enlarged supramammary lymph nodes Clinical Signs… Indurative mastitis… Smith and Cutlip 1988 Associated w/ poor production Milk production, butter fat content, solids nonfat content, somatic cell count Predisposed to nonhemolytic staph. mastitis Clinical Signs… Indurative mastitis… Greenwood 1995 ↑ reproductive failure, ↓ kid birth weights ↓ Growth rate, ↓ milk yields, ↓ days in milk Diagnosis Presumptive History Clinical signs R/O other causes No “Gold Standard” Diagnosis Virus isolation Most definitive diagnosis Viral load low Usually negative Indicator cell lines Goat synovial membrane Milk epithelial cells Fetal membrane cells Diagnosis… Serology (detecting antibodies) Most convenient Ab fluctuations Agar Gel Immuodiffusion (AGID) Enzyme-linked Immunosorbent Assay (ELISA) Radioimmunoprecipitation (RIPA) Radioimmunoassay (RIA) Western Blot (WB) Diagnosis… AGID Most common Detects Abs p28 core antigen gp135 envelope antigen Sensitivity 91% Specificity 100% No false positives Diagnosis… ELISA Many different types Whole virus Recombinant Competitive Sensitivity and specificity vary Diagnosis… Competitive ELISA Most common ELISA used Sensitivity 93-100% Specificity 96.4-100% Diagnosis… ELISA vs. AGID ELISA > proportion of Abs detected ELISA detects seroconversion earlier AGID ↓ Sensitivity AGID less $$$ Diagnosis… PCR (finding viral DNA) Less sensitive than ELISA Detect infection before seroconversion Not fully developed Combination w/ELISA Optimal detection Prevention Based on Minimize doe → kid transmission ID infected animals Minimize contact between (-) and (+) Eliminate infected animals Prevention… Adams et. al. 1983 5 steps to prevent transmission to kids Immediate removal from dam +/- wash kids Isolate kids 2 meters btw kids & infected animals Prevention Steps to prevent transmission Use CAEV-free or heat treated colostrum 56˚ C for 1 hour Use CAEV-free milk, pasteurized milk Test at 6 month intervals Separate (+) and (-) Prevention… Test and Cull Not an option if No virus free replacements High seroprevalence Not economically feasible Lose genetic potential Prevention… Test and Segregate Keep 2 herds Regular testing To be effective must Eliminate shared feeders/waters Walls, double fences Record escapees/exposures Avoid commingling Prevention… Current recommendations Multifaceted Realize seronegative ≠ negative infection Prevent perinatal/lactogenic transmission Serologic surveillance Segregate/cull (+) Milk seronegative 1st Avoid Iatrogenic transmission Potential venereal Prevention… Vaccination Not effective McGuire et. al. 1986 Vaccinated w/inactivated CAEV Increased severity, onset of arthritis Immune response plays a role in CAE arthritis QUESTIONS?