JPC SYSTEMIC PATHOLOGY
Signalment (JPC # 2127420): 2‑year‑old ewe
HISTORY: This ewe had sustained severe weight loss over the winter while receiving a ration adequate for maintenance.
HISTOPATHOLOGIC DESCRIPTION: Lung: Diffusely, alveolar septa are expanded up to eight times normal by a cellular infiltrate composed of lymphocytes, macrophages and neutrophils admixed with minimal fibrous connective tissue (fibrosis) and small amounts of fibrin and edema. Multifocally, there is an increased amount of bronchiolar and alveolar smooth muscle (smooth muscle hypertrophy). Multifocally, the peribronchiolar and perivascular connective tissue is expanded by a similar inflammatory infiltrate, increased clear space and dilated lymphatics (edema) and numerous variably-sized aggregates of lymphocytes forming lymphoid follicles with germinal centers. Multifocally, bronchi and bronchioles occasionally contain amphophilic fibrillar to flocculent material (mucin) that is admixed with sloughed epithelial cells, cellular and karyorhectic (necrotic) debris and/or pale eosinophilic homogenous (seroproteinaceous) fluid, fibrin and small amounts of hemorrhage.
MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, interstitial, lymphohistiocytic, chronic, diffuse, marked, with peribronchiolar and perivascular lymphofollicular proliferation (BALT hyperplasia) and bronchiolar smooth muscle hypertrophy, breed unspecified, ovine.
ETIOLOGIC DIAGNOSIS: Ovine lentiviral pneumonia
CONDITION: Ovine progressive pneumonia (OPP)
CAUSE: Small ruminant lentivirus
Signalment (JPC #2127420): 2-year-old LaMancha goat
HISTORY: This LaMancha goat had severe weight loss and clinical signs of respiratory disease.
HISTOPATHOLOGIC DESCRIPTION: Lung: Lung: Multifocally, 70% of bronchioles and blood vessels are surrounded by large aggregates of inflammatory cells that form follicles with prominent germinal cells and are composed predominantly of lymphocytes and macrophages with fewer plasma cells (lymphoid hyperplasia). Diffusely alveolar septa are expanded to up to 50 um by lymphocytes, alveolar macrophages, fewer plasma cells, and fibrosis, and they are often lined by plump cuboidal pneumocytes (type II pneumocyte hyperplasia). Alveolar lumina are filled with abundant eosinophilic proteinaceous fluid (surfactant and edema), mucin, macrophages with foamy cytoplasm, few neutrophils, cellular debris, and occasional small areas of hemorrhage and mineral. Bronchi and broncioles multifocally contain edema and mucin admixed with degenerate and viable neutrophils and sloughed epithelium. Multifocally, the interlobular septa and pleura are expanded up to two times normal by ectatic lymphatics (edema), moderate amounts of fibrin, low numbers of lymphocytes, macrophages, rare eosinophils, occasional mineral and a focally extensive area of mild hemorrhage.
MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, interstitial, lymphohistiocytic, chronic, diffuse, severe with lymphoid (BALT) hyperplasia, type II pneumocyte hyperplasia and abundant pulmonary edema, LaMancha, caprine.
ETIOLOGIC DIAGNOSIS: Lentiviral pneumonia
CAUSE: Small ruminant lentivirus; caprine arthritis encephalitis virus (CAEV)
SYNONYMS: Lymphoid interstitial pneumonia, maedi-visna (MVV), Graaff-Reinet (South Africa), Zwoegerziekte (Netherlands) and La bouhite (France)
- “Small Ruminant Lentivirus” is preferred over “Maedi-Visna” or “Caprine arthritis encephalitis virus” due to cross species infection of some strains of the virus
- Lifelong, persistent viral disease of sheep and goats characterized by a slowly progressive interstitial pneumonia, encephalitis, arthritis (in adult goats) and mastitis; the various syndromes may occur independently or concurrently; presentations are variable and influenced by breed, genetics, and tissue microenvironments, among other factors
- Sheep: Respiratory form most common; encepahlitis, arthritis and mastitis are uncommon presentations in sheep
- First reported in Iceland; “maedi” (respiratory form) occurs in sheep older than three years old; “visna” (neurologic form) in 2-4 month old kids
- Goats: Two major clinicopathologic forms:
- Kids and young goats (<4 months): nonsuppurative leukoencephalomyelitis
- Adults: chronic nonsuppurative arthritis and synovitis (most common presentation)
- Mastitis and interstitial pneumonia may occur concurrently are independently of the two major forms at any age (i.e. a single animal can have multiple forms of infection)
- Small Ruminant lentivirus is a single-stranded, enveloped, RNA virus in the family Retroviridae composed of viral genes: (1) gag encodes group-specific nucleocapsid and matrix protein, (2) pol encodes reverse transcriptase and other enzymes and (3) env encodes surface glycoproteins which mediate receptor binding and entry into the cell; regulatory proteins encoded by vif, rev and vpr-like
- Lentiviral diseases in sheep and goats are marked by their variability
- Pulmonary, mammary, and nervous forms most common in sheep; nervous and articular forms more common in goats
- Dysregulation of monocyte macrophage system and ineffective immune response
- Cells harbor virus in the latent state in which viral antigens are not produced in sufficient quantities for detection and destruction by the immune system
- Co-infections include Pasteurella multocida, Trueperella pyogenes, Dictyocaulus sp. or Protostrongylus sp. and retroviral pulmonary adenomatosis (sheep)
- Immunosuppression is not a feature of small ruminant lentiviral infection
- Endemic in sheep population in Wyoming with seropositive for anti-SRLV antibodies and OPP-infected flocks in Wyoming of OPP 0% and 47.5%, respectively
- Experimentally infected lambs with strain 697 (nervous tissue origin) SRLV extracts showed mostly lung lesions; lambs infected with strain 496 (articular origin) showed mostly carpal arthritis and interstitial pneumonia.
- Transmission through colostrum or milk is the major route of disease spread; inhalation of nasal secretions following prolonged close contact, as occurs in winter months, is an important mode of horizontal transmission
- Viral infection occurs in many cell types (endothelium, choroid plexus and mammary epithelium) and viral antigen and nucleic acid is widespread, but complete viral replication and assembly only occurs in mature macrophages
- Virus infected macrophages release virus and/or die à release of virus into mucus and mucosae à virus infected alveolar macrophages migrate to local lymphoid tissue (BALT) and regional lymph nodes
- In bone marrow, virus may infect a small number of immature monocyte precursors (monoblasts and promonocytes); the ability of the virus to replicate in a cell is directly related to the maturity of the permanently affected cell; when infected monocytes mature and differentiate into macrophages in tissue, virus is able to replicate in these cells and express viral proteins and pro-inflammatory cytokines resulting in inflammation; macrophages can infect and activate other susceptible and differentiated tissue macrophages, (e.g. alveolar macrophages) resulting in chronic-active granulomatous inflammation
- In persistently infected sheep, OPP viral antigen is found in CD163- (anti-inflammatory) and CD172a- (downregulatory) positive alveolar macrophages of the lung and mammary gland and synovial membrane intercellular areas (they are NOT in synoviocytes; some of which are phagocytic)
- Interstitial pneumonia results from virus-infected alveolar macrophages expressing high concentrations of IL-8, which results in inflammatory cell recruitment
- In addition to the cellular infiltrate, alveolar septa are thickened by hypertrophy of smooth muscle and mild interstitial fibrosis as a result of the activation of macrophages and lymphocytes which release growth factor (TGF-beta; proliferation of fibroblasts), endothelial cells and fibrogenic cells and cytokines (IL-13; increased collagen synthesis)
- Host defense mechanisms are ineffective in terminating viral infection due to the viral genome becoming part of the host genome
- Chronic inflammation caused by abundant anti-viral non-neutralizing antibody forms immune complexes
- Bone marrow stromal cells represent a viral reservoir in asymptomatic animals
- Ineffective host defense mechanisms and persistent infection:
- Chromosomal genome insertion: Viral genome is inserted into DNA of host cell; selectivity and specificity of tissues (lung, brain, mammary gland, and synovia) is determined by locations where macrophages are permissive to genome
- Immunosuppression is not a feature of small ruminant lentiviral infection
- Infection and shedding of the virus is lifelong
TYPICAL CLINICAL FINDINGS:
- Slowly progressive disease with emaciation and death
- Pneumonia: increased respiratory rate and dyspnea (especially during exertion)
- Arthritis and synovitis: lameness with swollen joints “big knee”, mostly in adults (especially carpal and tarsal joints)
- Mastitis: hard, indurated udder and reduced milk production (agalactia)
TYPICAL GROSS FINDINGS:
- Sheep: Remarkably heavy, pale gray or tan and have a diffusely firm or rubbery texture with rib imprints; failure to collapse when the chest is opened; cut surfaces bulge but are not edematous or exudative
- Goat: Diffuse or multifocal pale firm lesions throughout lung; firm, dense rubbery and enlarged lungs, stippled with small, white foci, bulge on cut surface, airway may contain mucus; caudal lung lobes most severely affected
- Concurrent bronchopneumonia or lungworms may be superimposed
- Caudal lung lobes most severely affected
- Lymph nodes: Mediastinal and tracheobronchial lymph nodes are enlarged, white and edematous
- Joints: Polyarthritis; swollen (hygroma) with thickened capsule mostly affecting carpal joints, less commonly tarsal, fetlock, stifle, atlanto-occipital joints
- Encephalomyelitis: Asymmetric, brownish-pink areas that may compress adjacent tissue within the brain and spinal cord (malacia)
- Mammary gland: Reduced milk yield; progressive atrophy and induration of glands; mastitis (“hardbag”);
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Sheep: Interstitial pneumonia with prominent perivascular and peribronchial/peribronchiolar lymphoid nodules with germinal centers are a characteristic feature of Maedi; marked smooth muscle hypertrophy of terminal bronchioles and alveoli and mild interstitial fibrosis; type II pneumocyte hyperplasia is NOT a feature in OPP (in contrast with CAEV)
- Goats: Chronic interstitial pneumonia with expansion of alveolar septa by lymphocytes, macrophages, and plasma cells; formation of cuffs of lymphoid cells around blood vessels and airways; type II pneumocyte hyperplasia; and alveoli filled with abundant dense eosinophilic proteinaceous material (surfactant)
- Lymph node: Extensive hyperplasia of cortical (B-cell) lymphoid elements
- Joint: Villous hyperplasia of synovial membrane with infiltration of lymphocytes and plasma cells
- Mammary gland: Massive infiltration of lymphocytes and plasma cells into ductal and acinar interstitia; degeneration, necrosis and loss of acini and ducts; mastitis is often a subclinical lesion, but not a presenting complaint
- Artery: Non-suppurative arteritis of small muscular arteries and arterioles in carpal joint capsules, kidney, meninges, brain, lung and trachea
- CNS: Affects brain and spinal cord; lymphocytic leukoencephalomyelitis; zones of demyelination surrounded by gliosis and lymphocytic infiltration; necrosis of white matter in cerebrum and cerebellum, mainly periventricular and may form lymphoid follicles in the choroid plexus; meningitis
- The proteinaceous material filling alveoli has structural features of pulmonary surfactant
- AGID (agar gel immunodiffusion) or ELISA (serology for screening flocks; false negative and false positive may occur); Quantitative PCR assays; Immunohistochemistry (p27, gp130 viral protein)
- For respiratory lesions:
- Ovine pulmonary carcinomatosis (adenomatosis, type B/D retrovirus, closely associated with OPP): Prominent proliferative foci of cuboidal to columnar cells line alveoli and form papillary projections
- Mycoplasmal pneumonia ( ovipneumoniae): Interstitial lymphoid cuffs; bronchiolitis; absence of smooth muscle hypertrophy
- Contagious caprine pleuropnemonia (Mycoplasma capricolum capripneumoniae) - acute fibrinous pleuropneumonia
- Mannheimia haemolytica - sporadic cases of acute bronchopneumonia and pleuritis in kids
- Pasteurella multocida - less fulminating fibrinopurulent bronchopneumonia
- Parasitic pneumonia: Muelleris capillaris- lymphocytic interstitial pneumonia
Equine infectious anemia virus (EIAV)
Human immunodeficiency virus (HIV)
Bovine immunodeficiency virus (BIV)
Jembrana disease (JD)
Feline immunodeficiency virus (FIV)
Simian immunodeficiency virus (SIV)
- Campbell RSF, Robinson WF. The comparative pathology of the lentiviruses. J Comp Pathol. 1998;119(4):333-395.
- Cantile C, Youssef S. Maxie MG, Youssef S. Nervous system. In: Maxie MG, ed. Jubb, Kennedy, Palmer"s Pathology of Domestic Animals. Vol.1. 6th ed. Philadelphia, PA: Elsevier; 2016:378-379.
- Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy, Palmer"s Pathology of Domestic Animals. Vol. 2. 6th ed. Philadelphia, PA: Elsevier; 2016:558-559.
- Dabareiner RM: Diseases of bones, joints, and connective tissue. In: Smith BP, ed. Large Animal Internal Medicine, 4th ed. St. Louis, MO: Mosby Elsevier; 2009:1206-1207.
- Gerstner S, Adamovicz JJ, Duncan JV, Laegreid WW, et al. Prevalence of and Risk Associated with Ovine Progressive Pneumonia in Wyoming Sheep Flocks. J Am Vet Med Assoc. 2015 Oct 15;247(8):932-7.
- Hermann-Hoesing LM, Noh SM, Snekvik KR, et al. Ovine progressive pneumonia virus capsid antigen as found in CD163- and CD172a-positive alveolar macrophages of persistently infected sheep. Vet Pathol. 2010;47(3):518-528.
- Highland MA. Small Animal Lentiviruses: Strain Variation, Viral Tropism, and Genetics Influence Pathogenesis. Vet Pathol. 2017 May; 54(3): 353-354.
- Hudachek SF, Kraft SL, Thamm DH, et al. Lung tumor development and spontaneous regression in lambs coinfected with jaagsiekte sheep retrovirus and ovine lentivirus. Vet Pathol. 2010;47(1):148-162.
- Jones TC, Hunt RD, King NW. Diseases caused by viruses. In: Jones TC, Hunt RD, King NW, eds. Veterinary Pathology. 6th ed. Baltimore, MD: Williams & Wilkins; 1997:331-334.
- Lechner F, Machado J, Bertoni G, et al. Caprine arthritis encephalitis virus dysregulates the expression of cytokines in macrophages. J Virol. 1997 Oct;71(10):7488-97.
- Lujan L, Begara I, Collie DDS, Watt NJ. Ovine lentivirus (maedi-visna virus) protein expression in sheep alveolar macrophages. Vet Pathol. 1994;31(6):695-703.
- Perez M, Biescas E, Reina R, et al. Small ruminant lentivirus-induced arthritis: clinicopathologic findings in sheep infected by a highly replicative SRLV B2 genotype. Vet Pathol. 2015 Jan 52(1):132-9.
- Pinczowski P, Sanjose L, Gimeon M, Crespo H, et al. Small Ruminant Lentiviruses in Sheep: Pathology and Tropism of 2 Strains Using the Bone Marrow route. Vet Pathol. 2017 May:54(3):413-424.
- Summers BA, Cummings JF, de Lahunta A. Inflammatory diseases of the central nervous system. In: Summers BA, Cummings JF, de Lahunta A, eds. Veterinary Neuropathology. St. Louis, MO: Mosby-Year Book, Inc.; 1995:128-132.
- Varea R, Monleon, E, Pacheco C, et al. Early detection of maedi-visna (ovine progressive pneumonia) virus seroconversion in field sheep samples. J Vet Diagn Invest. 2001;13(4):301-307.
- Woodall CJ, MacLaren LJ, Watt NJ. Differential levels of mRNAs for cytokines, the interleukin-2 receptor and class II DR/DQ genes in ovine interstitial pneumonia induced by maedi visna infection. Vet Pathol. 1997;34(3):204-211.
- Zachary JF. Mechanisms of microbial infection. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease, 6th ed. St. Louis, MO: Elsevier; 2016:209-210; 537.