JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

October 2023

P-V08

 

Signalment (JPC #1492980): 3-month-old cat

 

HISTORY: This cat was euthanized two days after aerosol infection with an experimental agent.

 

HISTOPATHOLOGIC DESCRIPTION: Lung: There is consolidation and atelectasis affecting approximately 70% of the lung. Within areas of consolidation, alveolar septa are either fragmented, discontinuous, and replaced by fibrin and eosinophilic cellular and karyorrhectic debris (septal necrosis), frequently lined by hyperplastic cuboidal epithelium (type II pneumocyte hyperplasia), or expanded up to 8 times normal by fibrin, edema, neutrophils, and macrophages. Alveolar lumina, and to a lesser extent bronchiolar and bronchial lumina, are filled with an exudate composed of variable amounts of fibrin, edema, hemorrhage, eosinophilic cellular and karyorrhectic debris (necrosis), neutrophils, and alveolar macrophages. There is diffuse, mild bronchial and bronchiolar epithelial hyperplasia. Multifocally, blood vessels are lined by hypertrophic endothelial cells (reactive endothelium). There is mild perivascular and pleural edema, hemorrhage, and fibrin.

 

MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, interstitial, necrotizing, focally extensive, marked, with hemorrhage and type II pneumocyte hyperplasia, breed unspecified, feline.

 

ETIOLOGIC DIAGNOSIS: Caliciviral pneumonia

 

CAUSE: Feline calicivirus (FCV)

 

GENERAL DISCUSSION: 

• Small (35 to 40 nm), non-enveloped, single-stranded RNA virus in the family Caliciviridae, genus Vesivirus 
• Common cause of feline upper respiratory tract disease that can also cause oral ulcers, chronic stomatitis, pneumonia, systemic disease, or lameness
• Caliciviral pneumonia is an uncommon occurrence, although viral pneumonia is the second most common cause of fatal pneumonia in cats (behind bacterial) with FCV as the most common cause (Slaviero, J Comp Path 2021)
• Virulent Systemic Feline Calicivirus (VS-FCV) is a rare manifestation; a febrile systemic hemorrhagic syndrome due to viral recombination (occurring in an individual cat that can emerge as a localized epizootic) highly contagious and rapidly fatal, affecting both kittens and adult cats (including vaccinated) with a mortality of 30-60%
• Potentially linked to feline ulcerative stomatitis and glossitis or lymphocytic-plasmacytic stomatitis
• Novel feline caliciviruses have been isolated from cases of feline lower urinary tract disease (FLUTD)

 

PATHOGENESIS:

• Transmission is by direct contact with infected oronasal secretions, and fomites
• Inhalation or ingestion of virus -> Replication in mucosal epithelium (and likely mucosal macrophages (including within tonsillar crypts)) -> Lysis of epithelium -> Viral shedding -> Ulcerative sinusitis/rhinitis/tracheitis
• Inhalation (especially aerosol) -> Infection of mucosal epithelium and alveolar macrophages and/or leukocyte trafficking -> Pneumonia
• Viral infection causes lysis of type I pneumocytes -> Interstitial pneumonia
• Incubation varies from 2-14 days; many infected cats recover in 7-14 days
• Viral infection persists despite resolution of clinical signs; 25% of infected cats continue to shed virus (oronasal secretions and feces) for months to years (important infective source)
• Antigenic variability of the capsid protein (target of the immune response) allows for viral persistence
• Secondary bacterial infections (e.g., Bordetella bronchiseptica, Pasteurella multocida, or Escherichia coli) are a common complication
• VS-FCV due to recombination of viral capsid genes (antigenic shift) -> Marked increase in viral pathogenicity -> Endotheliotropism -> Vascular injury -> Necrosis, edema, fibrin exudation, and thrombosis

 

TYPICAL CLINICAL FINDINGS:

• Upper respiratory/oral:
  1. Serous or mucopurulent nasal and ocular discharge, oral ulcers, conjunctivitis with ocular and nasal discharge, sneezing and coughing, anorexia, and fever as well as
  2. Ulceration of the oral cavity (tongue, gingiva), tonsil, and oropharyngeal mucosa
• Occasional reports indicate that calicivirus infections can result in pustular and ulcerative skin lesions at various body sites
• After vaccination, or occasionally after infection, some kittens develop transient lameness and acute synovitis due to acute, self-limiting arthritis (“limping kitten syndrome”)
• VS-FCV: Edema and ulcers, mainly on the head, limbs, footpads, and inguinal region; also fever, anorexia, icterus, conjunctivitis

 

TYPICAL GROSS FINDINGS:  

• Mucosal vesicles (5-10 mm) and ulceration that affect the tongue, hard palate, nasal philtrum, lip or periodontal gingival
• Irregularly distributed pneumonia, often include margins of the cranioventral lung
• VS-FCV: Hepatic necrosis, pancreatic necrosis, subcutaneous edema, foci of fat necrosis, DIC, and bronchointerstitial to interstitial pneumonia

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Upper respiratory/oral:
  1. Earliest lesions: Foci of pyknotic cells in stratum corneum and superficial stratum spinosum
  2. Progress to foci of necrosis with vesicle formation; subsequent erosion and ulceration
  3. Regeneration of the ulcerated mucosa occurs within 10-12 days with a single layer of squamous epithelial cells extending from the margins
  4. Viral inclusions have NOT been observed in oral epithelial cells
• Pneumonia
  1. Interstitial pneumonia, thickening of alveolar walls, hyaline membranes, serofibrinous exudate and neutrophils within alveoli
  2. Necrotizing bronchiolitis may be present
  3. Later there is cuboidal type II pneumonocyte hyperplasia, macrophages in alveolar lumens, and alveolar septa thickened by lymphocytes, plasma cells, and fibrous tissue
• VS-FCV
  1. Epithelial necrosis and ulceration, bronchointerstitial pneumonia, hepatic changes ranging from disruption of the parenchyma to extensive disruption of hepatocellular plates, intestinal crypt necrosis and pancreatic necrosis
  2. Microthrombi, interstitial edema, and fibrin accumulation

 

ULTRASTRUCTURAL FINDINGS:  

• 35-40 nm virions with characteristic cuplike depressions in their surface
• Intracytoplasmic virions are either scattered single particles in characteristic linear arrays along microfibrils, small clusters slightly larger than free ribosomes, or paracrystalline arrays within membranous structures
• Degenerative changes in infected cells include dilatation and invagination of the rough endoplasmic reticulum and dense cytoplasmic masses of nucleoprotein-like material

 

ADDITIONAL DIAGNOSTIC TESTS: 

• Oral ulcers are suggestive of calicivirus infection
• PCR and virus isolation from oropharyngeal fluids, oral swabbing of the tonsils, urine, feces, blood, and visceral tissues; also direct fluorescent antibody testing or serology; definitive diagnosis of FCV requires lab support
• Cytology
  1. Upper respiratory/oral: Nonspecific, Variable numbers/types of inflammatory cells
  2. Polyarthritis: Minimal synovial fluid changes, mild increase in macrophages with some leukophagocytosis
  3. VS-FCV: Pancreas: Cytologic evidence of pancreatic necrosis and pancreatic degeneration

 

DIFFERENTIAL DIAGNOSIS:

• Feline rhinotracheitis virus (P-V09, feline herpesvirus type I): Usually a more severe necrotizing disease; may have intranuclear inclusion bodies; definitive diagnosis by viral isolation on conjunctival swabs; In contrast to the bronchointerstitial pneumonia caused by FeHV-1, airway lesions are usually not present in FCV infection
• Chlamydia felis (Chlamydia psittaci var felis): Conjunctivitis and upper respiratory tract disease; definitive diagnosis by cell culture or ELISA
• Bordetella bronchiseptica: Believed to be a secondary infection in respiratory infections; definitive diagnosis by culture
• Toxoplasmosis, sepsis, and aspiration of gastric acid are additional causes of interstitial pneumonia in cats

 

COMPARATIVE PATHOLOGY:  

Other Caliciviruses:

• Several different caliciviruses (family Caliciviridae, genus Norovirus; formerly Norwalk-like viruses, and genus Nebovirus) are linked or potentially linked to enteritis (especially neonatal diarrhea) in several species, including cattle (calves), pigs (a calici-like virus causes villus atrophy in gnotobiotic pigs), dogs, cats, mink kits
• Caliciviruses have been isolated in the stool of several nonhuman primates 

• Swine: Vesicular Exanthema of Swine (VES, genus Vesivirus) causes fever, vesicles on the snout, oral cavity, and feet and abortion; it is indistinguishable from San Miguel sea lion virus (see below)
• Lagomorphs: Caliciviruses are highly significant pathogens of lagomorphs 
  1. Rabbit Viral Hemorrhagic Disease (RVHD) (D-V31) 
     • Affects European rabbits (Oryctolagus cuniculus) (Sylvilagus rabbits and hares are resistant to RHD virus infection), reportable disease in United States
     • Highly resistant virus spread by multiple means; characterized by hemorrhage from the nares and hemorrhagic lesions especially in the serosa, peritoneum, lung, and liver (acute necrotizing hepatitis), disseminated intravascular coagulation, and death; there is a related virus RVHD2 which is similar, but rabbits tend to survive longer
  2. European Brown Hare Syndrome (EBHS) affects European brown hares (Lepus europaeus); characterized by necrotizing hepatitis, nephrosis, congestion and hemorrhages of the tracheal mucosa and lungs, and splenic vascular congestion
  3. Rabbit Vesivirus Infection: Causes severe diarrhea and enteritis; may be related to marine caliciviruses and a nonhuman primate calicivirus
• Pinnipeds: Calicivirus is ubiquitous in marine environment; there are 40 serotypes, San Miguel Sea Lion Virus (I-V14) and Walrus Calicivirus are notable: Cause severe vesicular stomatitis and dermatitis especially of unhaired skin, abortion; opal-eyed fish may be natural host; indistinguishable from vesicular stomatitis of swine

 

References:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016: 264-266. 
2. Bell RRW, Latouche JS, Borjesson DL. The Pancreas. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:324. 
3. Brady AG and Carville AAL. Digestive System Diseases of Nonhuman. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2^nd ed. San Diego, CA: Elsevier; 2012: 589-628.
4. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG, ed. Jubb, Kennedy, Palmer's Pathology of Domestic Animals. Vol. 2. 6th ed. Philadelphia, PA: Elsevier; 2016:475, 510, 588, 589.
5. Cheville NF. Cytopathology of viral diseases. In: Cheville NF, ed. Ultrastructural Pathology: The Comparative Cellular Basis of Disease. 2nd ed.   Ames, IA: Wiley-Blackwell; 2009: 399-401.
6. Cianciolo RE, Mohr FC. Urinary System. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:456, 460. 
7. Colegrove KM, Burek-Huntington KA, Roe W, Siebert U. Pinnipediae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:423. 
8. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:490-491. 
9. Fernandes PJ. Synovial Fluid Analysis. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:199, 200-201. 
10. Slaviero M, Ehlers LP, et al. Causes and Lesions of Fatal Pneumonia in Domestic Cats. J Comp Pathol. 2021;189:59-71.
11. Terio KA, McAloose D, Mitchell E. Felidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:273. 
12. Uzal FA, Plattner BL, Hostetter JM. Alimentary System. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:15, 16, 20, 31, 112, 113, 121. 
13. Wellman ML, Radin MJ. Nasal Exudates and Masses. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:124. 
14. Williams BH, Burek-Huntington KA, Miller M. Mustelids. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:296. 

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