JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

September 2023

P-V02

 

Signalment (JPC #1506681): Monkey

 

HISTORY: One of 16 monkeys that had a skin rash 

 

HISTOPATHOLOGIC DESCRIPTION: Lung: Diffusely expanding the alveolar septa and filling alveolar lumina is abundant fibrin, edema, and small amounts of necrotic debris admixed with moderate numbers of degenerate neutrophils and macrophages and fewer lymphocytes and plasma cells. There is multifocal necrosis and loss of type I pneumocytes and alveolar septa are often lined by hyperplastic II pneumocytes. Multifocally within alveolar septa and lumina, alveolar pneumocytes and macrophages form syncytial cells that contain numerous vesiculate nuclei with multiple 7-10 µm eosinophilic intranuclear and intracytoplasmic viral inclusion bodies. Bronchial epithelium exhibits one of the following changes: attenuation, necrosis, loss, or hyperplasia. There is perivascular edema. The pleura is covered by a 50 µm thick plaque composed of fibrin, degenerate neutrophils, and mild hemorrhage and edema.

 

MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, bronchointerstitial, fibrinonecrotic, subacute, diffuse, severe, with fibrinosuppurative pleuritis, type II pneumocyte hyperplasia, and viral syncytial cells with intranuclear and intracytoplasmic eosinophilic viral inclusions, species unspecified, nonhuman primate

 

ETIOLOGIC DIAGNOSIS: Morbilliviral pneumonia  

 

CAUSE: Measles (Rubeola) virus 

 

GENERAL DISCUSSION:

• Highly contagious, aerosolized virus of captive nonhuman primates that does not occur in their natural habitat; zooanthroponotic disease - animals contract the virus after contact with humans (humans are the only natural host)
• Genus Morbillivirus in the family Paramyxoviridae; single-stranded RNA virus
• Species variation in susceptibility; fatalities common in young and New World species (marmosets, aotus)
• In marmosets, lesions are often localized in the gastrointestinal tract and disease lacks the characteristic features of human measles

 

PATHOGENESIS:   

• Direct contact/aerosol/fomite transfer of virus > invasion of respiratory/conjunctival mucosa and/or tonsil; virus binds to: 
  • SLAM [signal lymphocyte activation molecule (CD150+)] – regulates production of TH2 cytokines by CD4+ T cells receptors, or 
  • CD46 receptor (viral hemagglutinin in the viral envelope binds) > inactivation of C3 convertase > disruption of classical and alternative complement pathways 
  • In non-immune cells (e.g. polarized epithelia, CNS), the receptor is nectin-4 (cell adhesion molecule) 
• Initial viral replication in regional lymph nodes > spread to lymphoreticular system and upper respiratory epithelium > multiplies in upper respiratory tract epithelial cells, B (CD150+) and T (CD4+ and CD8+) lymphocytes, and macrophages > eventual systemic dissemination by lymphoid cells > immune complex-induced endothelial damage > epithelial necrosis > maculopapular rash, respiratory, and gastrointestinal lesions > immunosuppression due to decreased IL-12, thymic destruction, and viral inhibition of IFN-gamma upregulation of MHC class II > secondary bacterial infection > cytolytic complement-dependent antibodies eliminate the virus and persist for life
• Resolution of infection correlates with the appearance of cytotoxic CD8+ T lymphocytes

 

CLINICAL FINDINGS:  

Old World primates:

• Disease is usually mild unless animals are stressed or immunocompromised
• Fever, leukopenia, conjunctivitis, occasionally coughing, dyspnea, and diarrhea  
• May become more susceptible to enteric bacterial infections, e.g. Shigella flexneri, and may present with primary gastrointestinal signs; concurrent infection may adversely impact morbidity and mortality
• CNS signs are rare and may occur in the absence of other signs 
• Colony-maintained animals frequently have a 100% seroconversion rate

New World primates:

• Disease is more severe with a rapidly progressive course and predominance of gastrointestinal signs; mortality may approach 100%
• May not develop conjunctivitis or cutaneous lesions
• Death occurs due to viral-induced immunosuppression (and subsequent secondary bacterial infections or reactivation of latent viruses) and enterocolitis

 

TYPICAL GROSS FINDINGS:

Old World primates:

• Lungs: Heavy, firm, moist, mottled grey to red; fibrinous exudate adherent to the visceral pleura; laryngeal air sacs may be involved
• Gingiva and tongue: Multiple, 1 mm diameter, raised white spots (Koplik’s spots, exanthema of the oral cavity), rimmed in red with bluish centers; pathognomonic but are inconsistent findings; these precede the skin rash
• Skin: Erythematous maculopapular rash on face, ventral abdomen and inner thighs [Arthus-type (Type III Ag/Ab complex) reaction] 
• Lymphoid organs: Hilar lymph nodes and mesenteric lymph nodes enlarged, splenomegaly
• GI tract: Gastric, colonic and cecal hemorrhage, 

New World primates:

• Necrotizing enterocolitis

• Edema of the periorbital region may be pronounced

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Lung: 
  • Fibrinous or proliferative and necrotizing bronchointerstitial pneumonia centered on small bronchioles and alveolar ducts
  • Desquamation of bronchiolar epithelium and alveolar lining cells
  • Alveolar epithelial necrosis
  • Characteristic multinucleated syncytial cells 
  • Intranuclear and cytoplasmic eosinophilic viral inclusions (type II pneumocytes and macrophages)
  • Increased numbers of bronchoalveolar macrophages
  • Interstitial infiltrates of moderate numbers of mononuclear cells; 
  • +/- Type II pneumocyte hyperplasia may occur
  • +/- Secondary bacterial bronchopneumonia may be superimposed due to lymphopenia/immunosuppression (see below)

• Oral cavity: Focal necrosis, neutrophil exudate, and neovascularization near the opening of Stensen ducts (Koplik’s spots)
• Skin: Follicular necrosis; parakeratosis; occasional epithelial syncytia and fewer epidermal intranuclear and cytoplasmic viral inclusions 
• Lymphoid organs (lymph nodes, spleen and thymus): Initial hypertrophy and hyperplasia of germinal follicles; formation of large syncytial cells derived from lymphocytes (Warthin-Finkeldey cells); eventual marked depletion of lymphoid tissue
• GI tract: Epithelial necrosis in stomach, cecum, and colon with syncytia and viral inclusions in all epithelial tissues and GALT; lymphoid hyperplasia and germinal center necrosis in GALT
• CNS: Rare; nonsuppurative encephalitis with diffuse gliosis, perivascular mononuclear cuffing, and intranuclear and cytoplasmic viral inclusion bodies in astrocytes and neurons
• Other: Large epithelial syncytia can form in salivary gland, pancreatic duct, thyroid gland, and liver 

 

ULTRASTRUCTURAL FINDINGS:

 

DIAGNOSTICS:

• Serology
• Virus isolation (from lymphocytes)
• Viral RNA detection / PCR
• Immunostaining of cytology and/or conjunctival smears

 

DIFFERENTIAL DIAGNOSIS:

Nonhuman primates with bronchointerstitial pneumonia:  

• Cytomegalovirus: Beta-Herpesvirus; cytomegalic cells contain characteristic large, eosinophilic to basophilic, intranuclear inclusions surrounded by a clear halo
• Simian immunodeficiency virus: Lentivirus; no necrotizing bronchiolitis or viral inclusions; giant cell pneumonia
• Macacine herpesvirus 1 (Cercopithicine herpesvirus 1/Herpes B virus): Eosinophilic to basophilic intranuclear viral inclusions and syncytial cells are associated with necrotizing lesions
• Cercopithicine herpesvirus 2/SA8: Eosinophilic to basophilic intranuclear viral inclusions
• Paramyxovirus 1 (Sendai virus): Intranuclear and cytoplasmic eosinophilic viral inclusions with syncytial cells
• Simian adenovirus (SV-20): Large, deeply basophilic, and "smudgy" intranuclear viral inclusions; not surrounded by a clear halo; necrotizing alveolitis and bronchiolitis; pneumonia
• Influenza viruses (orthomyxoviruses): Alveolitis, hyaline membranes, and microvascular thrombi
• SV-40 (polyomavirus): Pneumocytes with prominent basophilic intranuclear viral inclusions; interstitial pneumonia; type II pneumocyte hyperplasia; bronchial and bronchiolar epithelium not affected

 

COMPARATIVE PATHOLOGY:   

Selected other paramyxoviruses:

• Dogs, many terrestrial carnivores, pinnipeds: Canine distemper virus (morbillivirus) (N-V11)
• Marine mammals: Phocine distemper virus, dolphin morbillivirus (N-V12, P-V03)
• Cattle and other ungulates: Rinderpest (morbillivirus) (D-V28)
• Rats, Hamsters, Mice: Neurotropic variants can be produced by injections of the virus into the brains of these animals
• Goats and sheep: Peste des petits ruminants (morbillivirus) with similar pulmonary changes; similar to Rinderpest
• Horses: Hendra virus (henipavirus) (P-V26); pulmonary vasculopathy with endothelial syncytia

 

References:

1. Bailey C, Mansfield K.  Emerging and reemerging infectious disease of nonhuman primates in laboratory setting. Vet Pathol. 2010; 47(3):462-481.  
2. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed., Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol. 2. 6^th ed. Philadelphia, PA:Elsevier Saunders; 2016:574-576.
3. Lowenstine LJ. Measles virus infection, nonhuman primates. In: Jones TC, Mohr U, Hunt RD, eds., Monographs On Pathology of Laboratory Animals, Nonhuman Primates. Vol 1. Washington, DC:Springer-Verlag, International Life Sciences Institute; 1993:108-116.
4. Lowenstine LJ, Osborn KG. Respiratory system diseases. In: Abee CR, Mansfield K, Tardif S, Morris T, eds., Nonhuman Primates in Biomedical Research, Diseases. San Diego, CA:Academic Press; 2012:445-446.
5. Kramer JA, Bielitzki J. Integumentary system diseases. In: Abee CR, Mansfield K, Tardif S, Morris T, eds., Nonhuman Primates in Biomedical Research, Diseases. San Diego, CA:Academic Press; 2012:570-571.
6. Matz-Rensing K, Lowenstine LJ. New World and Old World Monkeys. In: Terio KA, McAloose D, St. Leger J. Pathology of Wildlife and Zoo Animals. London: Elsevier/Academic Press; 2018: 388.
7. Wachtman L, Mansfield K. Viral diseases. In: Abee CR, Mansfield K, Tardif S, Morris T, eds., Nonhuman Primates in Biomedical Research, Diseases. San Diego, CA:Academic Press; 2012:43-46.
8. Yanagi Y, Takeda M, Ohno S. Measles virus: cellular receptors, tropism and pathogenesis. Jour Gen Virol. 2006; 87(10):2767-79.
9. Zachary JF. Mechanisms of microbial infections. In: Zachary JF, ed., Pathologic Basis of Veterinary Disease. 7^th ed. St. Louis, MO:Mosby Elsevier, 2022:272-273.

 

 

Click the slide to view.

---