JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2024

U-V07 (NP)

 

Signalment (JPC # 2019293): Two-year-old, female Yorkshire terrier.

 

HISTORY: This dog was debilitated with labored respiration and a low-grade, persistent fever.  

 

HISTOPATHOLOGIC DESCRIPTION: Urinary bladder: Diffusely, urothelial cells are swollen with abundant vacuolated cytoplasm and vesiculate nuclei (degeneration) and frequently contain one or more 2-6 µm round, eosinophilic intranuclear and/or intracytoplasmic viral inclusion bodies. Rarely, individual epithelial cells are shrunken with hypereosinophilic cytoplasm and nuclear pyknosis (necrotic). Multifocally, lymphatic vessels are ectatic (edema).

 

Lung: Affecting approximately 60% of the lung, there is loss of differential staining with retention of alveolar architecture (coagulative necrosis) and areas with loss of architecture and replacement with eosinophilic cellular and karyorrhectic debris (lytic necrosis). Remaining alveolar lumens are variably expanded by fibrin, foamy macrophages, lymphocytes, plasma cells, fewer neutrophils, sloughed necrotic epithelial cells, and/or cellular debris. Less affected alveolar septa are expanded up to 5 times normal by fibrin, increased clear space (edema), moderate numbers of macrophages, and fewer neutrophils and lymphocytes, and are occasionally lined by cuboidal pneumocytes (type II pneumocyte hyperplasia). Multifocally, there is necrosis of bronchiolar epithelium and attenuation of remaining intact epithelium, and bronchiolar epithelial cells, alveolar macrophages, and/or type II pneumocytes occasionally contain 2-6 µm, round, brightly eosinophilic intranuclear and/or intracytoplasmic viral inclusion bodies. Respiratory epithelial cells occasionally coalesce and form viral syncytia with up to 6 nuclei. Occasionally, alveolar and interstitial macrophages are distended up to 3 times normal by an intracytoplasmic parasitophorous vacuole containing numerous 2-4 um, round to fusiform, basophilic tachyzoites. Peribronchiolar and perivascular connective tissue is multifocally mildly expanded by fibrin, edema, macrophages, and fewer neutrophils, lymphocytes, and plasma cells.  

 

MORPHOLOGIC DIAGNOSIS:  

1. Urinary bladder, transitional epithelium: Degeneration and necrosis, diffuse, with intracytoplasmic and intranuclear viral inclusion bodies, Yorkshire terrier, canine

 

2. Lung: Pneumonia, bronchointerstitial, necrotizing, subacute, diffuse, severe, with viral syncytia, and intracytoplasmic and intranuclear viral inclusions, and few intrahistiocytic tachyzoites.

 

ETIOLOGIC DIAGNOSIS: 

1. Morbilliviral transitional epithelial necrosis

2. Morbilliviral pneumonia and pulmonary toxoplasmosis 

 

ETIOLOGY: Canine Morbillivirus; Toxoplasma gondii 

 

SYNONYMS: Canine distemper; Canine Distemper Virus (CDV)

 

GENERAL DISCUSSION:  

• Genus Morbillivirus, family Paramyxoviridae; closely related to rinderpest, peste de petit ruminants, measles, and phocine distemper virus (PDV)
• Negative-sense, single-stranded, enveloped RNA virus 
• Canine distemper is an important, ubiquitous infectious disease of a wide range of terrestrial carnivores including canids, mustelids, and procyonids, as well as pinnipeds
• Systemic disease affecting respiratory (P-V01), gastrointestinal, nervous (N-V12), and integumentary (I-V12) systems
• Causes immunosuppression with common secondary infections including Bartonella, Pneumocystis, Toxoplasma, Clostridium piliforme, Sarcocystis, Encephalitozoon, Cryptosporidium, and E. coli 
• Toxoplasma gondii (P-P01): Apicomplexan obligate intracellular coccidian parasite that causes disseminated disease, central nervous system infections, and abortions in a wide range of intermediate hosts; clinical disease is seen most commonly in young, immunologically immature animals and in immunocompromised animals

 

PATHOGENESIS:

• Shed in all excretions (especially respiratory) during the systemic infection
• Inhalation > infection of macrophages or lymphocytes of upper respiratory tract or lungs > replication in tonsils and bronchial lymph nodes > cell-associated and cell-free viremia 2 days post-infection (PI) > spread to all lymphoreticular tissues and blood lymphocytes one week PI > lymphocytolysis and leukopenia > immunosuppression > leukocyte trafficking and viremic-spread to respiratory, GI, urinary, central nervous systems; skin, endocrine, and exocrine glands also affected 
• Viral induced immunosuppression
• In lungs, primary target cells are ciliated and non-ciliated mucosal epithelial cells > cells lyse > inhibit mucociliary clearance > predisposes to secondary infections
• Disease severity depends on host immunity, envelope glycoprotein antibody titers, age, and virus strain:

• Adequate humoral and cellular immunity à Clear infection by 14 days
• Intermediate immunity à Infection of mucosal epithelium and brain
• Poor immunity à Systemic infection of epithelial tissues

• Pantropic virus: 
  1. Entry receptor on immune cells is CD 150 (SLAM)
  2. Epithelial receptor is PVRL4 (nectin-4)
• Fusion glycoproteins (F protein) facilitate penetration into cell, cell-to-cell spreading, and formation of syncytia 
• Viral attachment is mediated by hemagglutinin glycoproteins (H protein)

 

TYPICAL CLINICAL FINDINGS:

• Biphasic fever, depression, anorexia, oculonasal discharge, pharyngitis, coughing, vomiting, diarrhea (targets intestinal cryptal epithelium), hyperkeratosis of foot pads and nose, enamel hypoplasia, abortion
• Neurologic signs: Seizures, myoclonus, ataxia, paraparesis or paraplegia
• Thrombocytopenia (due to virus-antibody complexes on platelet membranes and direct viral infection of megakaryocytes)

 

TYPICAL GROSS FINDINGS:  

• Urinary tract: Gross lesions not observed

• Respiratory: Serous, catarrhal, or mucopurulent exudate in nasopharynx; pulmonary edema; bronchointerstitial pneumonia (patchy to generalized, red to tan, rubbery)
• Lymphoid: Inapparent, atrophied, or swollen lymphoid organs
• Integument (I-V12): Hyperkeratosis of the nose, footpad (“hardpad disease”), pustular dermatitis
• Digestive: Small intestine; enamel hypoplasia
• Ocular: Mucopurulent conjunctivitis
• Cardiovascular: Pale streaks in heart

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Eosinophilic intracytoplasmic and intranuclear inclusion bodies: most obvious in brain (astrocytes, neurons) and epithelial tissues (particularly urinary bladder and renal pelvis in acute disease) and less obvious in lymphoid tissues; nervous tissue typically contains intranuclear inclusions; all other tissues often contain intracytoplasmic inclusions
• Lung (P-V01): Bronchointerstitial pneumonia with inclusions in bronchial and bronchiolar epithelial cells most prominent 10-14 days PI; alveolar epithelial viral syncytia; type II pneumocyte hyperplasia

• Lymphoid depletion; thymic atrophy common in puppies

• CNS (N-V11): Demyelination in white matter tracts; astrocytes contain nuclear inclusions and rarely form syncytia; less commonly there may be neural degeneration/necrosis with nuclear or cytoplasmic inclusions and mild nonsuppurative meningitis; old dog encephalitis is a rare variant characterized by chronic progressive neurologic disease with perivascular lymphoplasmacytic inflammation 
• Digestive: Ameloblast degeneration/necrosis  à enamel hypoplasia
• Eye: Optic neuritis, conjunctivitis, keratitis, and retinitis; intranuclear inclusions in ganglion cells and glia; with chronicity, progression to neuronal loss, retinal scarring, proliferative retinal pigmented epithelium 
• Skin: Typically footpad and nose, and less often haired-skin; INIBs and ICIBs with syncytial cells in the epidermis
• Heart: Myocardial necrosis and mineralization 

 

ULTRASTRUCTURAL FINDINGS:

 

ADDITIONAL DIAGNOSTIC TESTS:

• Erythrocyte, neutrophil, and lymphocyte inclusions are rarely seen on blood smear; occur in early stages before clinical signs; pink or blue variably sized/shaped amorphous inclusions better visualized on quick-dip stains; inclusions are considered pathognomonic in leukocytes
• IHC, immunofluorescence, in situ hybridization, PCR

 

DIFFERENTIAL DIAGNOSIS:   

 

COMPARATIVE PATHOLOGY: 

Other morbilliviruses in domestic and lab animal species:

• Feline morbillivirus: Emerging morbillivirus associated with changes similar to chronic kidney disease in cats; pathogenesis poorly understood
• Rinderpest virus (D-V28):  Erosions, ulcerations, and hemorrhagic lesions affecting oral cavity, and rarely the rumen and reticulum, in domestic cattle, buffalo, and yaks
• Peste des petits ruminants virus (goat plague, ovine rinderpest, stomatitis-pneumoenteritis complex)(P-V04): Pseudomembranous oral lesions, necrotizing tonsillitis, fibrinonecrotic tracheitis, bronchointerstitial pneumonia, fibrinohemorrhagic enteritis; intracytoplasmic and intranuclear eosinophilic viral inclusions, viral syncytia
• Measles virus (Rubeola) (P-V02): Highly contagious disease in captive NHPs
  • Old World primates: Bronchointerstitial pneumonia, Koplik’s spots (small, white foci rimmed by a raised red border within oral mucosa near opening of Stensen ducts) are considered pathognomonic but are inconsistent, lymphoid depletion
  • New World primates: Necrotizing enterocolitis, periorbital edema

Other paramyxoviruses (non-morbilliviruses) in domestic and lab animal species:

• Equine paramyxovirus (Hendra virus; genus Henipavirus)(P-V26): Sporadic cause of acute interstitial pneumonia
• Porcine paramyxovirus (Nipah virus; genus Henipavirus): Closely related to equine paramyxovirus; necrotizing vasculitis affecting arterioles, venules, and capillaries of lung, brain, renal glomeruli, and lymphoid organs; also moderate lymphoplasmcytic bronchointerstitial pneumonia and mild necrotizing bronchiolitis; occasionally eosinophilic intracytoplasmic and intranuclear inclusions in neurons and syncytial endothelial cells

CDV in zoo and exotic species:

• Collared peccaries: Encephalitis; lesions restricted to brain, with intracytoplasmic eosinophilic inclusions in neurons
• Canidae, ursidae, and aliuridae
  • Acute lesions in non-domestic canids, as well as the few reports in free ranging ursids, are similar to those seen in domestic dogs
  • Red pandas: Reports of vaccine-induced CDV infections, with lesions similar to those seen with natural infection

• Foxes: Gray foxes have mortality near 100%; 
  1. Fennec fox: Case report of vaccine induced CDV and canine adenovirus-2 coinfection following vaccination with a multivalent modified live virus vaccine containing CDV and canine adenovirus-2 (Tamukai et al., J Vet Diagn Invest 2020)
     • Gray wolf: Case report of severe systemic CDV infection, with evidence of canine parvovirus-2 infection in the spleen, following vaccination with a multivalent vaccine that included CDV, and canine parvovirus (Stilwell, J Vet Diagn Invest 2019)

• Felidae: CDV a significant concern; lesions similar to other carnivores; infection of wild felids associated with unvaccinated wild dogs 
• Mustelids: Infection with CDV and another morbillivirus similar to phocine distemper virus reported; black-footed ferrets have increased sensitivity; striped skunks are relatively resistant
• Procyonidae, viverridae, hyenidae, herpestidae, eypleridae, and prionodontidae: CDV reported in most listed groups; most common microscopic findings are bronchointerstitial pneumonia and generalized lymphoid depletion
• Xenartha, erinacoemorpha, some afrotheria, and phloidota: reported in a single family group of giant anteaters
  • Sloths: Natural CDV reported in 5 adult Linnaeus’s 2-toed sloths; lesions included widespread and random hepatic necrosis, lymphoid depletion, and bronchointerstitial pneumonia; absence of gross or microscopic lesions in the brain, though CDV antigen was present (Watson et al., Vet Pathol 2020)

Other morbilliviruses in zoo and exotic species:

• Pinnipeds (fur seal, sea lion, true seal, walrus): PDV common, with similar findings to CDV in carnivores, including immunosuppression and concurrent infections
• Cetaceans (whales, dolphins, porpoises): Cetacean morbilliviruses (CeMV; P-V03) include at least 6 strains (porpoise morbillivirus, dolphin morbillivirus, pilot whale morbillivirus, beaked whale morbillivirus); most cause pneumonia and encephalitis, with secondary infections
  • Recent report describes pathology of cetacean morbillivirus infection in Guiana dolphin mortality event; primary lesions were bronchointerstitial pneumonia and lymphoid depletion; however, morbilliviral antigen was identified for the first time in the kidney (glomerular epithelium, tubules, pelvic urothelium, mononuclear inflammatory cells), and other organs (salivary gland, optic nerve, heart, diaphragm, vulva, thyroid)

 

REFERENCES:  

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