Signalment:  

3 year-old, female, Rasa Aragonesa sheep (Ovis aries)


Gross Description:  

Prior to post-mortem examination, educational computed tomography (CT) scans were performed of the thorax and evinced a diffuse bronchointerstitial pattern and increased thickness of the bronchiolar walls. At necropsy, the sheep showed cachexia (1/5). The lungs were diffusely enlarged, grey, and had a rubbery-like firmness. Lung weight was also increased. Over the pulmonary surface there were multifocal 1-2 mm grey dots. Mediastinal and tracheobronchial lymph nodes were enlarged.


Histopathologic Description:

Lung: There is a diffuse inflammatory process that expands the alveolar septa of around the 100% of the section and there is multifocal prominent hyperplasia of bronchial/bronchiolar associated lymphoid tissue (BALT). Diffusely, alveolar septa are thickened up to 5 times by lymphocytes, histiocytes, plasma cells and rare neutrophils. BALT follicles show an enlarged diameter by increased numbers of centrocytes/centroblast (BALT hyperplasia). These follicles tend to coalesce and multifocally bulge towards the pleura. Multifocally, interstitial and bronchial/bronchiolar smooth muscle is enlarged and there is an increased number of myocytes/myofibroblasts (smooth muscle hypertrophy-hyperplasia).


Morphologic Diagnosis:  

Lung: Pneumonia, interstitial, diffuse, severe, chronic with prominent BALT hyperplasia and smooth muscle hypertrophy-hyperplasia.

Condition: Maedi. Ovine Progressive pneumonia
Cause: Small ruminant lentivirus (Visna/maedi virus)


Lab Results:  

The blood count showed moderate normochromic, normocytic anemia. Quantitative PCR, considered positive when quantitation cycle (Cq value) was lower than 38, was performed in a lung sample. It was positive for Visna-Maedi/Caprine Arthritis Encephalitis virus (Cq value: 27,7) and for Mycoplasma ovipneumoniae (Cq value: 35,5) and negative for Pasteurella multocida and Mannheimia haemolytica.


Condition:  

Ovine progressive pneumonia


Contributor Comment:  

This is the respiratory form of small ruminant lentiviruses. This respiratory disease is caused by a group of non-oncogenic exogenous retroviruses of the genus lentivirus that target immune cells, mainly macrophages.

The Small Ruminant Lentiviruses are a group of highly related single stranded RNA viruses with high mutational potential that affect mainly sheep but also goats.1 These viruses induce chronic inflammation that usually remains subclinical. When it becomes clinical, the disease can express mainly in four different locations: lung, joints (mainly carpus), central nervous system and mammary gland.3 The expression of each form as well as the gravity of the lesion depends on host immune response and the viral factors.

The respiratory form, termed maedi or ovine progressive pneumonia, is the most common presentation of the disease in sheep.1 The process consists of an afebrile chronic progressive pneumonia that leads to weight loss and marked dyspnea. Grossly, the lungs show a rubbery firm appearance and do not collapse when the thoracic cavity is opened. Microscopically, is characterized by an inflammatory interstitial pattern and formation of lymphoid nodules with germinal centers around bronchioles and vessels. Mild interstitial fibrosis and smooth muscle hypertrophy are usually present. Unlike goats, type II pneumocytes hyperplasia is rarely seen in sheep.

Neurologic form is characterized by leuokencephalomyelitis and demyelination that leads to ataxia and profound weight loss.6 This form progresses faster than the respiratory one and usually occurs in adult sheep and goat kids (2-4 months). Articular form curse with arthritis affecting mainly the carpal joints.4 The mammary form implies interstitial mastitis and is associated with agalactia.

The main route of transmission is aerosol, particularly under intensive housing. Colostrum transmission plays also an important role.3 The virus infects a variety of cell types (mammary epithelium, fibroblast, endothelial cells, monocytes, choroid plexus) but its replication just occur in mature macrophages.1 Lentiviral-infected macrophages produce cytokines that recruit and activate other leukocytes but also hence lentiviral replication. Indeed, clinical signs and histopathological lesions are the result of the inflammatory process instead of the direct viral damage to the organ. There is neither treatment nor commercial vaccines for the disease, which is what makes immunization of the ovine population against the virus challenging.8

The main differential diagnosis of maedi is the classical form of ovine pulmonary adenocarcinoma (OPA). This disease is also presented as chronic progressive respiratory problems. However, there is abundant fluid production that leads to nasal exudate and the gross appearance of the lung shows consolidation of the apical lobes and ventral areas of the organ. The contribution of Mycoplasma ovipneumoniae should be taken into consideration in our case either as possible enhancer of the lentiviral infection or as secondary opportunistic pathogen.


JPC Diagnosis:  

Lung: Pneumonia, interstitial, lymphohistiocytic, diffuse, moderate with peribronchiolar and perivascular lymphoid hyperplasia, and smooth muscle hypertrophy.


Conference Comment:  

The contributor provides a concise review of one of the most important respiratory diseases of small ruminants. The disease was first reported in South Africa in the eastern town of Graff-Rinet (hence the name Graff-Rinet disease). In 1923, it was identified in the United States by Dr. H.W. W Marsh (with various appellations such as ovine progressive pneumonia (OPP), Montana progressive pneumonia, and Marsh’s progressive pneumonia), and an errant combined paper by Dr. Marsh and Dr. E.V. Cowdry, determined that morphologically, the diseases of jaagsiekte (or ovine pulmonary carcinoma, OPA) and Montana progressive pneumonia were one and the same.2

The introduction of 20 infected Karakul sheep into Iceland in the early 1930’s from Uzbehkistan introduced both OPA and ovine progressive pneumonia (OPP) to Iceland. 10 In 1935, cases of both were identified in Iceland, and cases of OPP (named maedi for shortness of breath in Icelandic) were identified in farms across the country and were traced back to the imported sheep. Maedi was not fully recognized as a disease different from OPA (jaagsiekte) until 1939 by Dr. G. Gislason, who further epidemiologically delineated the disease as a chronic progressive disease with a 2-3 year incubation period. He discovered that close housing of sheep spread the agent, and faced with a 20-30% mortality annually of older sheep, the Icelandic government slaughtered and replaced all sheep in affected areas and within 10 years, became the first country to eradicate OPP.10 The disease still remains in all major sheep producing countries of the world, except for Australia and New Zealand, where it has never been seen.

Research in Iceland continued on maedi and a related virus, visna with numerous transmission tests, and the viruses were finally isolated in 1957 (visna) and 1958 (maedi). Following the discovery of reverse transcriptase in these viruses, they became the prototype for the non-oncogenic retroviruses the lentiviruses (lenti=slow), of which additional viruses, were have isolated, including the disease agents of equine infectious anemia (EIAV - 1976) and caprine arthritis-encephalitis (CAEV-1980.) After experimental cross infection of sheep by CAEV and goats by MVV, the three viruses were grouped together under the name small ruminant lentiviruses (SRLV).10 The grouping is further reinforced by the ability of SRLVs to cause disease syndromes in sheep that have been previously identified in only in goats, such as viral arthritis.5

One of the other peculiarities of the SRLVs, like other lentiviruses, is its predilection for mutation, which may not only help it cross between small ruminant species, but also generate new quasi species, further confounding vaccinologists. Reproduction via reverse transcriptase is not a precise science, as insertional and deletion mutations occur with some frequency. While core genes of gag and pol are largely conserved, mutations are occasionally found in certain parts of env which result in variability, particularly in antibody-binding regions. 1

As mentioned above, small ruminant lentiviruses may infected a range of cells, but like other lentivirus, they show a particular tropism for cells of macrophage/monocyte lineages to include dendritic cells, mammary gland epithelium (helpful for transmission in colostrum to neonates) and the endothelia and microglia of the CNS (which may help in causation of visna in young lambs and kids. ) The maedi-visna virus (MVV) is also unique among lentiviruses as it is the only one in which respiratory transmission is significant (although whether free viruses or exhaled infected cells is the culprit remains to be seen.)1

This entity has made a number of appearances in the WSC over the years (see WSC 1995-96, Conference 21, Case 3; WSC 2005-2006, Conference 23, Case 1; WSC 2009, Conference 10, Case 1).

In the conference, the participants reviewed and compared the different manifestation of small ruminant lentiviruses. One of the points of discussion was the difference in pneumonia seen in the goat versus the lamb; the pneumonia in goats is characterized by less prominent lymphoid follicles formation and marked type II pneumocyte hyperplasia and filling of alveoli with surfactant.


References:

1. Blacklaws BA. Small ruminant lentiviruses: Immunopathogenesis of visna-maedi and caprine arthritis and encephalitis virus. Comp Immunol Microbiol Infect Dis. 2012;35(3):259–269.
2. Cowdry EV and Marsh HW. Comparative pathology of South African Jagziekte and Montana progressive pneumonia of sheep. J Exper Med,1927:571-585.
3. Gayo E, Polledo L, Balseiro A, et al. Inflammatory Lesion Patterns in Target Organs of Visna/Maedi in Sheep and their Significance in the Pathogenesis and Diagnosis of the Infection. J Comp Pathol. 2018;159:49–56.
4. Minguijón E, Reina R, Pérez M, et al. Small ruminant lentivirus infections and diseases. Vet Microbiol. 2015;181(1–2):75–89.
5. Pérez M, Biescas E, Reina R, et al. Small Ruminant Lentivirus–Induced Arthritis. Vet Pathol. 2015;52(1):132–139.
6. Pinczowski P, Sanjosé L, Gimeno M, et al. Small Ruminant Lentiviruses in Sheep. Vet Pathol. 2017;54:413–424.
7. Polledo L, González J, Benavides J, et al. Patterns of Lesion and Local Host Cellular Immune Response in Natural Cases of Ovine Maedi-Visna. J Comp Pathol. 2012;147(1):1–10.
8. Pritchard GC, McConnel I. Maedi-Visna. In: Aitken ID, editor. Diseases of sheep. Fourth Edition. Oxford (UK): Blackwell Publishing; 2007. 217–223.
9. Reina R, de Andrés D, Amorena B. Immunization against small ruminant lentiviruses. Viruses. 2013;5:1948–1963.
10. Thormar H. The origin of lentivirus research: maedi-visna virus. Curr HIV Res 2013; 11:2-9.


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04-1. Lung, sheep.


04-2. Lung, sheep.


04-3. Lung, sheep.


04-4. Lung, sheep.


04-5. Lung, sheep.



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