JPC SYSTEMIC PATHOLOGY
Signalment (AFIP# 2237950): Ten-year-old female rhesus monkey
HISTORY: Tissue from a rhesus monkey that was inoculated intramuscularly with an infectious agent as a part of a research project. Multifocally the lungs were wet and tan to red. Lymphoid tissue and thymus were markedly reduced in size.
HISTOPATHOLOGIC DESCRIPTION: Lung: There is mild to moderate patchy to diffuse consolidation throughout the section with multifocal alveolar emphysema and perivascular edema. Alveolar septa are diffusely and mildly to moderately expanded by macrophages, fewer lymphocytes and plasma cells, eosinophilic beaded fibrillar material (fibrin), homogenous eosinophilic fluid (edema), and there is multifocal necrosis and loss of type I pneumocytes with replacement by cuboidal epithelial cells (type II pneumocytes hyperplasia). Many alveolar lumina contain 1-2 multinucleated giant syncytial cells that are up to 90 um in diameter, with abundant granular, eosinophilic cytoplasm and multiple nuclei (up to 25 nuclei). Syncytial cells are admixed with low numbers of alveolar macrophages, lymphocytes, plasma cells and fewer neutrophils, fibrin and edema. Alveolar lumina also less frequently and multifocally contain eosinophilic flocculent aggregates of fungal trophic forms, within macrophages as well as extracellular, characterized by: round shape, 1-2 um in diameter, thin eosinophilic cell wall and clear interior. Bronchiolar epithelium is mildly, multifocally lost or attenuated, with mild goblet cell hyperplasia. Bronchiolar lumina contain small amounts of mucin, sloughed epithelial cells, fibrin and edema. The tunica adventitia and surrounding vascular interstitium is mildly expanded by edema with ectatic lymphatics, and contains a few multifocal aggregates of lymphocytes and plasma cells.
MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, interstitial, lymphohistiocytic, chronic, diffuse, moderate, with viral syncytial cells, perivascular edema, and fungal trophic forms consistent with Pneumocystis spp., rhesus monkey (Macaca mulatta), nonhuman primate.
ETIOLOGIC DIAGNOSIS: Simian lentiviral pneumonia
CAUSE: Simian Immunodeficiency virus (SIV)
SYNONYMS: Giant cell pneumonia
- Simian immunodeficiency viruses (SIV) are enveloped RNA virus (family Retroviridae; subfamily Lentiviridae) indigenous to African nonhuman primates.
- There are seven major lineages of related viruses that occur naturally and are indigenous in several species of Old World primates; these animals are persistently infected, but do not develop clinical illness or gross lesions; disease is caused when an ‘unnatural host’ is infected with a particular subset of the virus.
- Natural disease in New World nonhuman primates has not been identified.
- SIV serves as a model for study of pathogenesis and strategies for vaccination and therapy for AIDS in humans
- Lentiviruses are associated with chronic disease and a variety of syndromes, including immunodeficiency, encephalitis, pneumonia, arthritis, and lymphoid hyperplasia (subacute)/depletion (chronic)
- Common opportunistic infectious agents include: Pneumocystis spp, Mycobacterium spp, Cryptosporidium, cytomegalovirus (CMV), adenovirus, papovavirus, Cryptococcus neoformans, Candida albicans and Plasmodium sp.
- SIV is a zoonotic agent
- The natural route of transmission is thought to occur horizontally and vertically; experimentally, SIV is transmissible via infected blood or serum and through the mucous membranes
- SIV targets lymphoid tissues, specifically cells expressing CD4 (helper T lymphocytes, monocytes, macrophages, and dendritic cells)
- The viral protein gp120 binds two host cell proteins to gain entry: CD4 and CCR5
- The viral envelope glycoprotein gp120 interacts with CD4 on host cells à conformational change in gp120 à gp120 binds CCR5 (a host cell chemokine receptor) à virus protein gp41 penetrates cell membrane à enter cytoplasm à viral RNA transcribed in DNA and integrated in to host genome à transcription of viral RNA à synthesis of proteins and assembly of virion à budding and release from cells à severe depletion of CD4+ lymphocytes (cytopathic effects of virus plays large role) à severe immune dysfunction and death due to opportunistic infection or lymphoma
- Infected cells (expressing gp120 viral envelope glycoprotein on surface) fuse with noninfected CD4+ cells > syncytia formation and cell death
- Formation of syncytia not well defined but presumed to be multifactorial
- Macrophages are more resistant to lysis, serve as reservoirs for virus replication and aid in virus dissemination throughout the body
TYPICAL CLINICAL FINDINGS:
- Severe weight loss, depression, diarrhea, dry cough, weakness and tremors
- Maculopapular skin rash on sparsely haired portions of the body
- Various opportunistic infections
TYPICAL GROSS FINDINGS:
- Rarely, fibrous adhesions develop between the visceral and parietal pleurae
- Lungs fail to collapse with dark red-gray to tan or yellow areas at the surface and within the parenchyma of the lung; spongy to firm on palpation
- Lymphadenopathy and splenomegaly due to lymphoid hyperplasia in early stages of disease with lymphoid atrophy (depletion) in later stages
- Maculopapular viral exanthema
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Lung: Interstitial pneumonia with histiocytic and numerous multinucleated giant cell (CD4+ cells, viral syncytial cells) infiltration of the alveolar septa and lumina; syncytial cells may also be present in the lymph nodes, spleen, kidney, gastrointestinal tract, and brain
- Cardiovascular: Arteriopathy in pulmomary arteries with thrombosis and infarction of pulmonary parenchyma; arterial lesions reported in other organs including kidney, liver, pancreas, heart, lymphoid tissue and testis
- Urinary: Nephropathy characterized by glomerulosclerosis with variable interstitial nephritis
- Brain and spinal cord: Meningoencephalomyelitis (histiocytes and multinucleated giant cells), perivascular cuffs of mononuclear cells and occasional multinucleated giant cells
- Heart: Lymphohistiocytic inflammation, myocyte necrosis, reparative fibrosis
- Small intestine: Nonspecific enteropathy, blunting and atrophy of villi
- Retroperitoneal fibromatosis (also possible with Simian retrovirus type D): Despite name can involve intestine, regional nodes, mesentery; retroperitoneal fibromatosis-associated herpesvirus a co-factor.
- Skin: Congestion of superficial dermal capillaries with lymphocytic perivascular infiltrates
- Synovitis: Synovial lining cell proliferation and nodular infiltrates of lymphocytes and macrophages
- Lentiviruses have a dense conical core
ADDITIONAL DIAGNOSTIC TESTS: Immunohistochemistry, polymerase chain reaction, in situ hybridization, transmission electron microscopy
Pneumonia in macaques:
- Human measles virus (Paramyxoviridae: Morbillivirus) – Interstitial pneumonia with syncytial giant cells that have inclusion bodies, and orientation of inflammation around small bronchioles; multinucleated giant cells in skin, lymph nodes, lung; eosinophilic intranuclear and intracytoplasmic inclusion bodies
- Cytomegalovirus / Beta herpesvirus (Macacine herpesvirus 3: May occur secondary to SIV infection; cytomegaly, very large intranuclear inclusions (INIB) and occasional intracytoplasmic inclusions (ICIB)
- Non-human primate herpesviruses:
- Macacine herpes-1 (Alphaherpesvirus): Pneumonia with INIBs, syncytial cells
- Simian varicella virus-neurotropic (Alphaherpesvirus): Papulovesicular rash at mucosa with Cowdry type A INIBs in perivesicular cells
- Herpes simplex (Alphaherpesvirus): Syncytial cells with INIBs
- Poxvirus: Fibrinonecrotic pneumonia with ICIBs (Guarnieri bodies)
- Adenovirus: Large, deeply basophilic, and “smudgy” intranuclear inclusions that are not surrounded by a clear halo (often in pancreas)
- Simian virus 40 (Polyomavirus): Type II pneumocyte hyperplasia; pneumocytes with prominent basophilic INIBs; bronchial and bronchiolar epithelium not affected
Examples of lentiviruses of family Retroviridae:
- Domestic cats and cheetahs - Feline immunodeficiency virus
- Cattle - Bovine immunodeficiency (or immunodeficiency-like) virus
- Horses - Equine infectious anemia virus
- Goats - Small ruminant lentivirus
- Sheep - Maedi-visna virus (ovine progressive pneumonia)
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