JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

October 2024

D-V05

 

Signalment (JPC# 1902055): Sprague-Dawley rat

 

HISTORY: Swellings of the anteroventral cervical area were noted in 3 Sprague-Dawley rats in a colony of 20 rats.

 

HISTOPATHOLOGY DESCRIPTION: Salivary glands, submandibular and parotid: Within the submandibular salivary gland, approximately 80 percent of the salivary adenomeres exhibit one of the following changes: shrunken acini with loss of central acinar lumina (atrophy); acini lined by swollen epithelial cells with vacuolated, lightly basophilic cytoplasm that are occasionally distended up to 20µm by a large clear vacuole (degeneration); acinar cells with condensed, hypereosinophilic cytoplasm with pyknotic nuclei (single cell death); or acini are lost and replaced with fibrin, edema, mild hemorrhage and moderate numbers of neutrophils, fewer lymphocytes, plasma cells, and macrophages. Ducts are often either lined by flattened epithelial cells (squamous metaplasia), lined by hyperplastic cells piled up to 5 cells thick with increased mitotic figures (ductular regeneration), or are occasionally lined by necrotic epithelial cells which slough into duct lumina that multifocally contain eosinophilic and karyorrhectic cellular debris (necrosis). Diffusely, the interstitium, interlobular septa, and periglandular tissue are expanded up to three times normal by edema, fibrin, and hemorrhage admixed with previously described inflammatory cells, and blood vessels are often lined by reactive endothelium. The parotid (serous) salivary gland is similarly but less severely affected.

 

Lymph node, mandibular: There are multiple large, coalescing lymphoid follicles with prominent germinal centers that contain many tingible body macrophages. The paracortex and medulla are mildly expanded by increased lymphocytes and low to moderate numbers of macrophages. Blood vessels are mildly congested. There is moderate acute draining hemorrhage within the medullary sinuses, and minimal hemorrhage, fibrin, and edema in the perinodal interstitium.

 

MORPHOLOGIC DIAGNOSIS:

1. Salivary glands, submandibular and parotid: Sialoadenitis, necrotizing, subacute, diffuse, moderate, with ductular squamous metaplasia and regeneration, Sprague-Dawley rat, rodent.

2. Lymph node, mandibular: Lymphoid hyperplasia, diffuse, mild, with acute draining hemorrhage.

 

ETIOLOGIC DIAGNOSIS: Coronaviral sialoadenitis 

 

CAUSE: Rat coronavirus (Rat sialodacryoadenitis virus - SDAV)

 

GENERAL DISCUSSION:

• Coronaviruses are enveloped viruses approximately 80-220 nm in diameter with single-strand, positive-sense RNA genome ranging from 26-32kB in size; have widely spaced, club-shaped, radial, 20 nm long surface projections that resemble a solar corona
• Four genera: Alphacoronavirus, Betacoronavirus, Deltacoronavirus, and Gammacoronavirus
  1. Alpha- and betacoronaviruses infect mammals
  2. Gamma- and deltacoronaviruses infect birds with some mammalian spillover
• SDAV (Betacoronavirus) causes necrosis of salivary and lacrimal glands; virulence varies between strains
• SDAV causes transient necrotizing lesions affecting the parotid, submaxillary salivary glands, Harderian gland, exorbital glands and other lacrimal glands, lacrimal duct, nasal cavity; may produce respiratory disease in young rats (rhinitis, tracheitis, pneumonia); mucous salivary glands (i.e. sublingual) are not affected
• High morbidity, minimal mortality
• Athymic nude rats are particularly susceptible and develop chronic persistent infections and wasting disease
• Significant additive effects in rats previously exposed to Mycoplasma pulmonis and Filobacterium rodentium

 

PATHOGENESIS:

• Transmitted by infected nasal secretions and saliva > infects and replicates in respiratory epithelial cells > spreads to salivary and lacrimal glands resulting in secondary lesions of the nasopharynx, respiratory tract, and eyes
• Rapid spread in susceptible populations; high morbidity, low mortality
• Often subclinical
• Two stages:

• Acute stage: Virus infects epithelial cells, causing necrosis of ductular structures spreading to adjacent acini and effacement of normal architecture
• Reparative stage: Nonkeratinizing squamous metaplasia of ductal and acinar structures of salivary and lacrimal glands takes place with reactive hyperplasia of cervical lymph nodes 

• Decreases salivary gland production of epidermal growth factor (EGF), affecting carcinogenicity studies and possibly reproduction (damage to olfactory epithelium and epithelium within the vomeronasal organ may affect pheromone detection and therefore reproduction)

 

TYPICAL CLINICAL FINDINGS:

·  Cervical or intermandibular swelling, sniffling, blepharospasm, keratoconjunctivitis (lack of tear production), epiphora, and nasal and lacrimal discharges

• Chromodacryorrhea: Porphyrin-containing red encrustations around eyes    and nares (pink fluorescence under ultraviolet light); NOT specific for rat coronavirus
• Occasional permanent eye damage

 

TYPICAL GROSS FINDINGS:

• Enlarged, blanched submaxillary and parotid salivary glands and the Harderian, extraorbital, and infraorbital lacrimal glands with interlobular    and periglandular edema
• Regional lymph node enlargement
• Unilateral or bilateral glaucoma/megaloglobus, hyphema, and corneal ulceration
• Chromodacryorrhea 
• Rhinitis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Acute stage: 

• Coagulative necrosis of salivary and lacrimal ductal structures with disrupted architecture 
• Edema admixed with mixed inflammatory cell infiltrate and fibrin 
• Respiratory epithelium: Loss of cilia and mucosal necrosis; edema, inflammation, goblet cell loss, fibrinocellular exudates; epithelial hyperplasia (tracheitis, focal bronchitis and bronchiolitis)

• Necrotizing rhinitis with mixed inflammatory infiltrate

• Ophthalmic lesions: Keratitis, keratoconjunctivitis; occasionally anterior uveitis and glaucoma with multifocal retinal degeneration

Reparative stage:

 

ULTRASTRUCTURE:

• Virions are spherical, 80-220 nm diameter, enveloped, with widely spaced, club-shaped, radial, 20 nm long surface glycoprotein projections (peplomers) resembling a solar corona
• Found in cytolysosomes of epithelial cells, in dilated tubules in the smooth ER, and free in the lumen

 

ADDITIONAL DIAGNOSTIC TESTS:

• Serologic testing with IFA and ELISA
• PCR

 

DIFFERENTIAL DIAGNOSIS:

• Parker’s rat coronavirus (PRC): Both SDAV and PRC are considered strains of rat coronaviruses; PRC primarily infects the lungs- interstitial pneumonia, rhinitis, and tracheitis with more mild salivary and lacrimal gland lesions, especially in young rats
• Viral infections of salivary glands

• Cytomegalovirus (betaherpesvirus): Infects salivary and lacrimal glands; ductal cytomegaly with intranuclear and intracytoplasmic inclusions; nonsuppurative inflammation; common in wild mice, not laboratory mice
• Papovavirus (Polyomavirus): Pneumonia and parotid sialoadenitis; intranuclear inclusions in the ductal epithelial cells, occasionally in acini

• Nasal and ocular discharge 

• Sendai virus (Paramyxovirus): More often affects the lower respiratory tract than does SDAV; suppurative to necrotizing bronchitis, alveolitis
• Pneumonia virus of mice (Paramyxovirus): Multifocal, nonsuppurative vasculitis and interstitial pneumonia; also affects hamsters, rats, less often guinea pigs and gerbils
• Mycoplasma pulmonis: Suppurative rhinitis with polymorphonuclear and lymphocytic infiltration and hyperplasia of submucosal glands

• Ocular and nasal irritation in rats: Elevated ammonia levels; stress
• Edema of tissues associated with the head: Pseudomonas aeruginosa 
• Squamous metaplasia: Vitamin A deficiency; lacks inflammation and necrosis

 

COMPARATIVE PATHOLOGY:

Table of common coronaviruses and their associated lesions (excerpted from Kenney, et al. 2021 with additional lagomorph and mustelid coronaviruses):

 

Alphacoronaviruses
Feline CoV	Feline	Gastroenteritis and diarrhea
Feline infectious peritonitis virus (FIP)	Feline	Peritonitis, pneumonia, meningoencephalitis, panophthalmitis; granulomatous phlebitis
Canine CoV	Canine	Gastroenteritis and diarrhea; uncommonly severe enteritis and leukopenia
Transmissible gastroenteritis virus (TGEV)	Porcine	Gastroenteritis; watery diarrhea, vomiting, dehydration
Porcine respiratory CoV	Porcine	Subclinical to mild respiratory disease
Porcine epidemic diarrhea virus (PEDV)	Porcine	Gastroenteritis; watery diarrhea, vomiting, dehydration (western Europe; similar to TGE)
Swine acute diarrhea syndrome (SADS)-CoV	Porcine	Gastroenteritis; watery diarrhea, vomiting, dehydration
Epizootic catarrhal enteritis (ECE)	Ferrets	Profuse, green mucoid diarrhea in adults; thought to be a coronavirus
Systemic Coronavirus-Associated Disease	Ferrets	Pyogranulomatous inflammation similar to FIP in cats within numerous organs
Betacoronaviruses
Porcine hemagglutinating encephalomyelitis virus (PHEV)	Porcine	Vomiting, wasting, encephalomyelitis; anorexia, hyperesthesia, muscle tremors, emaciation (usually no diarrhea)
Mouse hepatitis virus (MHV)	Mouse	Hepatic necrosis, enteritis, demyelinating encephalomyelitis; syncytia formation
Rat CoV/sialodacryoadenitis virus	Rat	Sialodacryoadenitis, porphyrin released from damaged harderian gland, squamous metaplasia of ducts; rhinitis, pneumonia
Bovine CoV (winter dysentery)	Bovine	Gastroenteritis with profuse or bloody diarrhea, dehydration, decreased milk production; respiratory disease
Equine CoV	Equine	Gastroenteritis
Canine respiratory CoV	Canine	Typically mild respiratory disease
Severe acute respiratory syndrome (SARS) CoV	Humans	Respiratory disease (bats and civet cats - natural reservoir; civets may also serve as an amplification host)
Middle East respiratory syndrome (MERS) CoV	Humans	Respiratory disease (bats and dromedary - camels natural reservoir)
COVID-19 SARS-CoV-2	Humans, hamsters, others	Respiratory disease (bats/unknown – natural reservoir)
Rabbit enteric coronavirus	Rabbits	Enteritis, dehydration and emaciation
Gammacoronaviruses
Avian infectious bronchitis virus	Chickens	Tracheobronchitis, nephritis, decreased egg production
Bluecomb virus (Turkey CoV)	Turkeys	Enteritis, diarrhea, depression, cyanotic comb
Deltacoronaviruses
Porcine deltacoronavirus (PDCoV)	Porcine	Gastroenteritis in sows and nursing pigs; low mortality in nursing pigs; clinically indistinguishable from TGEV and PEDV
Pleural effusion disease virus	Rabbits	Multifocal myocardial degeneration and necrosis (no evidence of naturally occurring pathogenesis)

 

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016:27, 125-127.
2. Delaney MA, Treuting PM, Rothenburger JL. Rodentia. In: Terio KA, McAloose D, St. Leger J eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier Inc. 2018:509. 
3. Kenney SP, Wang Q, Vlasova A, et al. Naturally occurring animal coronaviruses as models for studying highly pathogenic human coronaviral disease. Vet Pathol. 2021; 58(3):438-52.

 

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