JPC SYSTEMIC PATHOLOGY

Respiratory System

October 2023

P-V05

 

Signalment (GV-5): Mouse; age, gender, and strain unknown

 

HISTORY: Dyspnea of unknown duration 

 

HISTOPATHOLOGIC DESCRIPTION: Lung, multiple sections: Affecting up to 95% of each section, alveolar septa are expanded up to 10x by an inflammatory infiltrate composed of macrophages, lymphocytes, plasma cells, fewer neutrophils, and abundant fibrin and edema. Multifocally, alveolar septa are discontinuous and replaced with cellular and karyorrhectic debris (alveolar septal necrosis). Multifocally, alveoli contain eosinophilic fluid (edema), and in severely affected areas, alveolar lumina contain an exudate composed of the previously described inflammatory cells. Multifocally, alveoli are lined by hyperplastic cuboidal to columnar epithelial cells with large, euchromatic, open-faced nuclei with 1-3 distinct nucleoli, and frequent mitotic figures, and often form dense clusters or papillary projections (atypical type II pneumocyte hyperplasia), and there are occasional multinucleate syncytial cells with up to 20 nuclei. Bronchiolar epithelium is similarly hyperplastic with tightly packed tall columnar cells piled up to 5 cell layers deep. Rarely, hyperplastic epithelia contain 1-3 µm eosinophilic intracytoplasmic viral inclusions. Occasionally, bronchiolar epithelium is lost (ulcerated) or attenuated and there is intraluminal exudate composed of low to moderate numbers of foamy macrophages and neutrophils, necrotic debris, fibrin, and edema. Multifocally, peribronchiolar lymphoid tissue is mildly hyperplastic (BALT hyperplasia), there is infiltration of lymphocytes in the perivascular interstitium, and there are dilated lymphatics.

  

MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, bronchointerstitial, lymphoplasmacytic and histiocytic, subacute, multifocal, moderate, with atypical type II pneumocyte hyperplasia, respiratory epithelial hyperplasia and syncytia, and rare eosinophilic intracytoplasmic viral inclusion bodies, strain unspecified, mouse, rodent.

 

ETIOLOGIC DIAGNOSIS: Sendai viral pneumonia

 

CAUSE: Sendai virus 

 

SYNONYMS: Murine parainfluenza virus-1

 

GENERAL DISCUSSION:

• Single-stranded, enveloped RNA virus, genus Respirovirus, family Paramyxoviridae
  • Closely related antigenically to human parainfluenza 1 virus; debate as to human or mouse origin and whether anthropozoonosis occurs 
• Labile, highly contagious virus primarily seen in mice (wild and pet mice, but rare in laboratory populations) 
• 129, DBA/2 and CH3 highly susceptible; B6, AKR, SJL, and Swiss mice resistant
• Infected animals are predisposed to Mycoplasma pulmonis or other bacterial pneumonias, otitis media, and otitis interna; outbreaks of vestibular disease and bacterial pneumonia can often be associated with recent Sendai virus infection

 

PATHOGENESIS

• Unique among murine viruses in that it can cause significant clinical illness in immunocompetent adult mice
• Transmission via aerosol, direct contact, in utero exposure > descending infection of respiratory epithelium (nose, trachea, bronchi, bronchioles, middle ears), including type I and type II pneumocytes > infection cleared by cell-mediated response that also generates disease 
  • Virus by itself is only mildly cytopathic; mice are only mildly ill in “pre-immune” phase; acute disease and mortality are associated with cytotoxic (CD8+) T-cell mediated necrotizing bronchitis and alveolitis 
• The level to which the infection descends the respiratory tree depends on host mucociliary clearance, virus burden, and immune response kinetics
  • DBA/2 are exquisitely sensitive to severe disease due to effective but delayed immune response, allowing infection to extend deep into respiratory tree followed by a zealous inflammatory response
  • B6 often have subclinical infection due to rapid immune response that precludes viral proliferation deep within the respiratory tree
  • T-cell immunodeficient mice lacking effective cell-mediated response have lesions solely due to mild but progressive viral cytopathic effect
• Although there are viral receptors in many tissues, the virus has respiratory tropism because it is dependent on apical budding from respiratory epithelium and is dependent on respiratory proteases to cleave its fusion glycoprotein into a biologically active form; without proteases, the virus is restricted to a single cell cycle

 

TYPICAL CLINICAL FINDINGS

• Often subclinical, but may see respiratory distress, dyspnea, sneezing, poor coat quality, weight loss, anorexia
• More severe signs are associated with concurrent Mycoplasma infection
• Immunodeficient mice: More protracted clinical course, progressive pneumonia, wasting syndrome
• Pregnant dams: Fetal resorption, prolonged gestation, fetal death (although there is no vertical transmission)

 

TYPICAL GROSS FINDINGS

• Sharply demarcated plum-colored consolidation/atelectasis of the pulmonary hilus, cranioventral lung, or entire lung lobes; these foci may turn grey in surviving mice
• Diffuse pulmonary edema
• Lymphadenopathy, splenomegaly

 

TYPICAL LIGHT MICROSCOPIC FINDINGS

• Pre-immune phase: Hypertrophic/hyperplastic bronchiolar epithelium with virus-induced syncytia, +/- eosinophilic intracytoplasmic viral inclusions, +/- intranuclear viral inclusions (nude mice only); these changes are rapidly obscured by immune-mediated necrosis in immunocompetent mice
• Immune phase: Segmental necrotizing inflammation of nasal and airway epithelium (necrotizing rhinitis, laryngotracheitis, bronchitis, and bronchiolitis), bronchointerstitial pneumonia associated with terminal airways; inflammatory cells vary depending on stage of infection including neutrophils, lymphocytes, macrophages; alveoli may be atelectic or filled with fibrin, leukocytes, and necrotic cells; microscopic features are diagnostic in immunocompetent adult mice
• Resolution: Sloughed airway epithelium is replaced by proliferating hyperplastic epithelium +/- transient marked nonkeratinizing squamous metaplasia; alveoli lined by cuboidal epithelium (type II pneumocyte hyperplasia); lymphoid proliferation within bronchial tree, vascular adventitia, and alveolar septa; severely affected lungs may have foci of fibrosing alveolitis and bronchiolitis obliterans

 

 

ADDITIONAL DIAGNOSTIC TESTS

• Serology
• PCR 

 

DIFFERENTIAL DIAGNOSIS 

• Respiratory disease in mice

  • Pneumonia virus of mice (PVM): Similar to immunodeficient (nude, SCID) presentation of Sendai virus; pneumovirus of the family Paramyxoviridae; natural disease only in immunodeficient mice; mild neutrophilic and histiocytic interstitial pneumonia, without bronchiolar epithelial hyperplasia or syncytia
  • Mouse hepatitis virus (coronavirus): Respiratory strains with tropism for upper respiratory mucosa (viral replication with subsequent dissemination); syncytia of pulmonary vascular endothelium (immunocompromised mice only)
  • Corynebacterium kutscheri: Embolic suppurative pneumonia
  • Mycoplasma pulmonis: Bronchopneumonia, large lymphoid aggregates, bronchiectasis
  • K Virus (Polyomaviridae): Tropic for pulmonary endothelium, can cause neonatal pulmonary endothelial necrosis, edema, and hemorrhage 
  • Filobacterium rodentium (formerly CAR Bacillus): Silver stain reveals organism paralleling cilia of respiratory epithelia  
  • Pneumocystis murina: GMS or PAS stain reveals organism within flocculent debris of alveolar lumina

• Pulmonary epithelial proliferation: Pulmonary adenoma, adenocarcinoma

 

COMPARATIVE PATHOLOGY 

• Sendai virus can cause disease in mice, rats, hamsters, and gerbils, and seroconversion occurs in guinea pigs; can also affect rabbits, ferrets, birds, swine, non‑human primates, and humans; distinct strain variations among all species except rodents
  • Sendai virus alone in rats is of little significance
  • Gerbils can be carriers
• Other viruses of Respirovirus genus, Paramyxoviridae family: Bovine parainfluenza virus 3, human parainfluenza viruses 1, simian virus 10

 

REFERENCES

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016: 13, 27-29, 32-35, 63, 128, 134, 142, 178-179, 200, 220, 267.
2. Delaney MA, Treuting PM, Rothenburger JL. Rodentia. In: Terio KA, McAloose D, St. Leger J ed. Pathology of Wildlife and Zoo Animals.  Cambridge, MA: Elsevier Inc. 2018:507-508.
3. Wachtman L, Mansfield K. Viral diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, eds. Nonhuman Primates in Biomedical Research. Vol 2. 2^nd Ed. San Diego, CA: Academic Press;2012:42-43. 

 

Click the slide to view.

---