JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

October 2023

P-V12

 

Signalment (JPC #90-52055): Rhesus macaque (Macaca mulatta).

 

HISTORY: This 1-year-old male rhesus monkey was injected with SIV/δ. Nine weeks post-inoculation, fulminant disease developed with respiratory distress, diarrhea, anorexia, weight loss, elevated BUN and LDH, anemia, and thrombocytopenia. The animal was euthanized eight days after these symptoms appeared. 

 

HISTOPATHOLOGIC DESCRIPTION: Lung: There are multifocal to coalescing areas of consolidation affecting approximately 20% of the lung section. Multifocally and predominantly in areas of consolidation, approximately 40% of the alveolar septa are thickened up to three times normal by moderate numbers of macrophages, lymphocytes, plasma cells, fewer neutrophils, fibrin, and edema. Predominantly in areas of consolidation, there is loss of type I pneumocytes with replacement by cuboidal cells (type II pneumocyte hyperplasia) or by pneumocytes that are enlarged up to two times normal (cytomegaly) and have a nucleus that is enlarged up to 20 µm (karyomegaly) and often contains a 5-15 µm, eosinophilic, ovoid, intranuclear viral inclusion body. Multifocally alveolar lumina contain an exudate composed of variable numbers of necrotic pneumocytes, foamy alveolar macrophages which often contain previously described intranuclear viral inclusion bodies, occasional multinucleate cells with up to 10 nuclei (syncytia), lymphocytes, plasma cells, and mild hemorrhage, fibrin, and edema. Occasionally, bronchial and bronchiolar epithelium is mildly hyperplastic.  Multifocally bronchial-associated lymphoid tissue (BALT) is mildly hyperplastic. Diffusely, perivascular, peribronchial, peribronchiolar, interlobular, and pleural connective tissues are expanded up to eight times normal by edema admixed with moderate numbers of macrophages, fewer lymphocytes, plasma cells, and rare neutrophils. The pleura is multifocally lined by hypertrophic mesothelial cells (reactive).

 

MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, interstitial, lymphohistiocytic, multifocal, moderate, with type II pneumocyte hyperplasia, viral syncytial cells, epithelial karyomegaly and cytomegaly, and epithelial eosinophilic intranuclear viral inclusion bodies, rhesus macaque, Macaca mulatta, primate.

 

ETIOLOGIC DIAGNOSIS: Herpesviral pneumonia and Lentiviral pneumonia

 

CAUSE: Macacine herpesvirus-3 and Simian immunodeficiency virus (SIV)

 

SYNONYMS: Macacine herpesvirus-3; Rhesus cytomegalovirus (RhCMV); Simian cytomegalovirus; Cercopithicine herpesvirus 8 (former name)

 

GENERAL DISCUSSION:  

• Rhesus Cytomegalovirus (aka: Macacine herpesvirus-3) is one of the most common secondary infections in rhesus monkeys with Simian immunodeficiency virus (SIV) [like in this case]; SIV is the cause of the syncytial giant cells
• Betaherpesvirus, enveloped, dsDNA viruses, replicates within the nucleus, resulting in intranuclear inclusion bodies (INIB)

• Viral envelope acquired via budding through the nuclear membrane
• Typically narrowly restricted host range causing latent infections
  • Replicate slowly, highly restricted host range, often produce enlarged cells
  • Found normally in most species (seroprevalence approaches 100% in macaque colonies); usually only causes disease in immunosuppressed
  • Nonhuman primates cytomegalovirus infection recognized in the rhesus, owl, capuchin, woolly, squirrel, marmoset, drill, and African green monkeys, mangabeys, baboons, tamarins, and chimpanzees

 

PATHOGENESIS: 

• CMV is slowly cytolytic; during replication, enveloped virions accumulate in large cytoplasmic vacuoles, resulting in marked cytomegaly
• Rhesus CMV encodes a CXC chemokine within the genomic UL/b’ region which is chemotactic for neutrophils
• Infection is generally latent/subclinical, but clinical disease may occur in immunodeficient animals, neonates, and fetuses   
• Latent infections persist in glandular tissue (salivary glands), lymphoreticular cells, and the kidneys (rather than in sensory ganglia like alphaherpesviruses), and may be shed periodically in secretions
• Immunosuppressed animals may exhibit reactivation of latent virus, dissemination, and clinical signs of disease
• In macaques with SIV, CMV reactivation is associated with suppression of both humoral and cellular immunity
• Transmission via contact with infected cells in saliva, urogenital excretions, or free virus in aerosols
• Transplacental fetal infection documented in humans, but not proven in macaques
• Reactivation of virus in immunosuppressed macaques results in disseminated lesions in brain, lymph nodes, liver, spleen, kidney, small intestine, nervous system, and arteries

 

TYPICAL CLINICAL FINDINGS:

• Immunocompetent animals: Limited to absent clinical signs
• Immunocompromised animal: Can cause meningitis, interstitial pneumonia, arteritis, enterocolitis, orchitis, hepatic and splenic necrosis

 

TYPICAL GROSS FINDINGS:  

• Nonspecific edematous and miliary hemorrhagic to necrotic lesions in the lungs, meninges, skin, heart, eye, gastrointestinal tract, and reproductive organs 

• Pulmonary: Small, miliary (1-3 mm), hemorrhagic foci 
• Meninges: Thickened, edematous, opaque, and yellow-tan 

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Lung is the most frequently affected organ
• Necrotizing/proliferative vasculitis can occur in any tissue
• Characteristic large intranuclear inclusion bodies (often surrounded by a clear halo with margination of chromatin) within cytomegalic cells (in alveolar septal lining cells and macrophages); often also smaller, amphophilic, intracytoplasmic inclusions
• Unlike many viral infections, significant numbers of neutrophils are common
• Typically two patterns of interstitial pneumonia:

• Multifocal pattern: Commonly perihilar, perivascular, and peribronchial with thickened, hypercellular septa and hypertrophic alveolar cells; macrophages, neutrophils, proteinaceous fluid, fibrin, and erythrocytes are present in the airways; type II pneumocyte hyperplasia
• Diffuse pattern: Lesions are more severe, chronic, and have more extensive, organizing, fibrinous exudate

• Associated facial neuritis and neutrophil-rich gastrointestinal masses
• Similar lesions may be found in the CNS (meningoencephalomyelitis), liver, spleen, salivary gland, gastrointestinal tract, lymph node, kidney, and testes

 

ULTRASTRUCTURAL FINDINGS: 

• Inclusions are typical of herpesvirus
• Virion: 120-200 nm diameter; icosahedral capsid: 100-110 nm in diameter
• Though icosahedral, the capsid appears round in images
• Enveloped and unenveloped forms may be seen in infected cells

 

ADDITIONAL DIAGNOSTIC TESTS:  

 

DIFFERENTIAL DIAGNOSIS: 

• CMV (compared to other viruses with intranuclear inclusions) exhibits cytomegaly, very large intranuclear inclusions (INIB) and occasional intracytoplasmic inclusions (ICIB)
• Selected other 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)
• Measles (P-V02, Morbillivirus): Giant cell pneumonia centered on small bronchioles with numerous eosinophilic INIBs & ICIBs; relatively normal-sized nuclei
• Simian virus 40 (Polyomavirus): Type II pneumocyte hyperplasia; pneumocytes with prominent basophilic INIBs; bronchial and bronchiolar epithelium not affected
• Secondary lung infections commonly associated with SIV [like in this case]: 

• Cytomegalovirus, adenovirus, SV-40 (Papovavirus), Mycobacterium avium-intracellulare, Pneumocystis carinii, Cryptosporidium sp., Cryptococcus neoformans, Candida albicans

 

COMPARATIVE PATHOLOGY: 

Key cytomegaloviruses in animal species: 

• Betaherpesvirus: 

• Swine: Porcine cytomegalovirus (P-V13, suid herpesvirus-2, SuHV-2) 

• Large inclusions in the mucus gland of the turbinate mucosa (inclusion body rhinitis), salivary gland, and renal tubular epithelium; 
• Most severely affects piglets less than two weeks old

• Mouse: Mouse cytomegalovirus (murid herpesvirus-1 & 2, MCMV)

• Most commonly diffuse interstitial pneumonia; eosinophilic INIBs and ICIBs mandibular salivary glands 
• Synergistic effect with Pseudomonas aeruginosa

• Rat: Rat cytomegalovirus (murid herpesvirus-8, RCMV): Similar to mouse cytomegalovirus 
• Hamster: Cricetid herpesvirus-1 (CrHV-1): Similar to mouse cytomegalovirus 
• Guinea Pig: Guinea pig cytomegalovirus (D-V12, caviid herpesvirus-2) 

• Infection commonly involves the salivary gland, lung, kidney, and liver
• Model for human CMV infections (single layer of placental trophoblasts) facilitating transplacental transmission studies

• Elephant: (non-cytomegalovirus betaherpesvirus) Endotheliotropic elephant herpesvirus (EEHV1A and EEHV1B)

• Viral replication in vascular endothelium, casues massive hemorrhagic disease; often presents with oral ulcers or vesicles

• Gammaherpesvirus:

• Bovine: Bovine cytomegalovirus (bovine herpesvirus-4, BoHV-4)

• Presents as pneumonia, enteritis, metritis, mammillitis 
• Causes disease syndrome “epivag” which is characterized by vaginitis, salpingitis, and oophoritis, or epididymitis

 

REFERENCES:  

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th  ed. Ames, IA: Iowa State Press; 2016:219,175,15-16,122
2. Caswell JL, et al. The respiratory system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, Vol 2, 6th ed. St. Louis, MO: Elsevier; 2016: 529
3. Cheville NF. Ultrastructural Pathology: The Comparative Cellular Basis of Disease. 2nd ed.  Ames, Iowa: Blackwell Publishing; 2009:335.

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