JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

October 2023

P-V15

 

Signalment (JPC # 3167330): 7-month-old spayed female domestic shorthair cat

 

HISTORY: Chronic lethargy, anemia, icterus; presented with low body temperature. Serum total protein was 10g/dL with a globulin of 7.5g/dL.

 

HISTOPATHOLOGIC DESCRIPTION: Lung: Approximately 90% of the alveoli are filled with a homogenous, eosinophilic, proteinaceous fluid (edema) with a moderate increase of foamy alveolar macrophages. Multifocally affecting approximately 20% of the section, vessel walls of medium and small caliber veins are expanded up to 5x normal by a transmural inflammatory infiltrate composed primarily of lymphocytes and macrophages with fewer plasma cells admixed with cellular and karyorrhectic debris (necrotizing vasculitis) and beaded eosinophilic fibrillar material (fibrin; fibrinoid necrosis). The vascular inflammatory infiltrate often extends into the surrounding parenchyma. Rarely, veins are occluded by organized fibrillar material adherent to the vessel wall with entrapped red blood cells and inflammatory cells (fibrin thrombus), and the vascular wall in these veins is often transmurally necrotic. 

 

MORPHOLOGIC DIAGNOSIS: Lung: Phlebitis, fibrinonecrotizing, lymphocytic and histiocytic, multifocal, acute, severe, with rare fibrin thrombi, and severe alveolar edema, domestic shorthair, feline. 

 

ETIOLOGIC DIAGNOSIS: Coronaviral phlebitis

 

CAUSE: Mutated feline coronavirus (FCoV) (Feline Infectious Peritonitis Virus (FIPV))

 

CONDITION: Feline Infectious Peritonitis

 

GENERAL DISCUSSION:

• Caused by a mutated form of FCoV with the ability to replicate within macrophages as well as alterations in inflammatory response; some cats can have systemic FCoV infection without disease (Malbon, J Comp Pathol. 2019)
• Worldwide fatal disease, affects all ages but primarily young (<2 years) intact male cats
• Oronasal transmission; most commonly from viral infected feces (shared litter boxes)  
• More frequent in catteries and multiple cat households with persistent infections

due to chronic asymptomatic carriers/shedders

• Widely spread throughout domestic and occasionally wild Felidae
• Two serotypes; both serotypes may cause FIP but most commonly Type I

• Type I: Cytopathic
• Type II: Non-cytopathic
• Both serotypes utilize DC-SIGN to infect monocytes; Type II additionally uses APN

• Coronavirus is a single stranded RNA virus, about 100nm in diameter with 15nm petal‑shaped envelope projections (peplomers)

• FCoVs are in group 1a (Alphacoronaviruses) of Coronaviridae 

 

PATHOGENESIS:

• Fecal-oral transmission and possibly by inhalation of FCoV > replication in enterocytes / lymphoid system > spontaneous viral genetic mutation during replication in infected host (FIPV), virus able to replicate in macrophages > secondary macrophage associated viremia and macrophages are activated> dissemination to multiple organs and vessels (systemic infection) > host immune response > granulomatous inflammation with vasculitis (phlebitis)
• The progression of disease depends on the cat’s immune response:

• Strong cell-mediated immune response: Results in activation of macrophages, FIP virus replication is terminated, and cleared  
• Weak or ineffective cell-mediated response: Delayed (Type IV) hypersensitivity response; noneffusive (dry form) syndrome ensues, with a less florid macrophage response in tissue and reduced virus production; this form has a more prolonged clinical course (1-6 months) 
• No/ineffective cell-mediated immunity: Antibody is produced, but there is a failure to generate a cell-mediated response and cats develop effusive disease (wet form); vasculitis results from both Type III hypersensitivity response [primary immune complex] and activation of virus infected macrophages; this syndrome has a rapid clinical course, progressing to death in 1-12 weeks 
• The wet and dry forms in general are considered extremes of a continuum of syndromes that may result from infection

• Granulomatous inflammation and granulomatous vasculitis (due to enhanced adhesion of virally infected monocytes/macrophages to endothelial cells) 
• Antibody-mediated lysis of infected macrophages in or around vessels (predominantly veins) may enhance the inflammatory reaction
• Serum levels of VEGF, produced by infected activated macrophages, correlate with quantity of body effusions
• Monocytes/macrophages strongly express cytokines TNF alpha and IL-1, adhesion molecule CD18, and matrix metalloproteinase-9; effusions contain high levels of IFN gamma
• Response to infection may be associated with levels of TNF-α and interferon-γ; high TNF- α and low interferon-γ favors disease
• Increased expression of TLR 2, 4, and 8 in mesenteric lymph nodes is associated with FIP in FCoV infected cats and may play a role in development of FIP (Malbon et al, J Vet Diagn Invest 2019.

 

TYPICAL CLINICAL FINDINGS:

• Effusive (wet form): Ascites, pleural and pericardial effusion, weight loss, dyspnea, tachypnea, mild pyrexia, icterus, scrotal enlargement, palpable abdominal masses (from adhesions)  

• Clinicopathological Features: 

• Plasma proteins typically elevated because of hypergammaglobulinemia (may be polyclonal or monoclonal) due to chronic inflammation and antibody production 
• Effusion is a viscous, pale to deep yellow, high protein exudate or modified transudate containing fibrin
• Albumin:globulin ratio less than 0.8 and typically 0.45 or less (albumin level remains normal or falls slightly and globulin levels increase, possibly through stimulation of B cells by IL-6)
• Elevated Alpha1-acid glycoprotein (AGP) >1500 ug/ml 
• Neutrophillia with left shift

• Noneffusive (dry parenchymatous form, often affecting brain and eye): Typically granulomatous inflammation, localized in the lymph nodes, kidneys, uvea, meninges, ependyma, and choroid plexus of the brain and spinal cord

• Often vague signs of dullness, weight loss, and anorexia   
• Ocular lesions: Iritis (manifest in color change in iris), bilateral anterior uveitis, corneal ‘keratic precipitates’, a fibrinous exudate in the anterior chamber, and cuffing of the retinal vasculature and/ or pyogranulomata on the retina  
• CNS signs (ataxia, nystagmus, seizures) in 12.5% of cases
• Clinicopathological Features: 

• Lymphopenia
• Neutrophilia with left shift
• Nonregenerative anemia ([HCT] <30%; anemia of chronic disease)
• Cerebral spinal fluid elevated protein levels (56-348 mg/dl with normal <25 mg/dl) and pleocytosis (100-10,000 nucleated cells/ml)

 

TYPICAL GROSS FINDINGS:  

• Effusive form: Fibrinous pleuritis, peritonitis, pericarditis:

• Body cavities are typically filled with flocculent (fibrin), straw colored, high protein (>3.5 g/dl) fluid and strands of fibrin
• Small (1-2 mm), white plaques on peritoneal and pleural surfaces
• Pulmonary edema

• Noneffusive form:  

• Granulomas in various organs including kidney, eye, and brain 
• Solitary mural intestinal mass (uncommon, but recognized)
• Hydrocephalus occasionally
• May be few recognizable gross lesions

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Generalized vasculitis and perivasculitis; phlebitis (vessels typically surrounded by a zone of necrosis and a mixed inflammatory cell infiltrate)
• Pyogranulomas, large or small, consolidated or numerous, focal tissue necrosis
• Lymphoid tissue: T-cell (CD4+ lymphocytes) and B-cell lymphocyte depletion due to apoptosis 
• In the CNS, three primary patterns are identified – periventricular encephalitis, rhombencephalitis, and diffuse leptomeningitis
• Gliosis in affected retinas (Ziolkowska, Vet Pathol. 2017)

 

ADDITIONAL DIAGNOSTIC TESTS:

• Clinical signs and typical gross and histologic findings are critical diagnostically

• Detection of intracellular FCoV antigen by immunoflourescence or immunohistochemistry (CCV2-2 more sensitive than FIPV3-70)
• There is a lack of specificity of serologic tests for the FIP virus due to cross reaction with other antigenically related coronaviruses
• RT-PCR (Reverse Transcriptase-PCR) in conjunction with IHC can be useful in cats with uveitis (Sangl et al., J Vet Diagn Invest 2020)

• Immunocytochemistry of FNAs is not reliable (Felten et al, J Vet Diagn Invest 2019)

 

DIFFERENTIAL DIAGNOSIS:   

• For mass lesions: Lymphoma; FIP mass lesions often have an angiocentric distribution

• Other differentials for non-effusive form include steatitis and mycotic infections

• For transudative/exudative diseases: Chylothorax, pyothorax, cancers associated with effusion, heart failure or cirrhosis of the liver with abdominal transudate, chronic bacterial peritonitis

• For ocular lesions: Toxoplasmosis, lymphosarcoma, and mycotic infections 

 

COMPARATIVE PATHOLOGY:

CORONAVIRUSES

Bovine coronavirus (winter dysentery)	Bovine	Gastroenteritis, thought to be a coronavirus – still some debate
Canine coronavirus	Canine	Enteritis
Mutated feline enteric coronavirus (FIP)	Feline	Peritonitis, pneumonia, meningoencephalitis, panophthalmitis; granulomatous to lymphohistiocytic vasculitis/phlebitis
Feline enteric coronavirus	Feline	Diarrhea in kittens
Mouse hepatitis virus (MHV)	Mouse	Hepatitis, enteritis, encephalomyelitis; syncytia formation
Porcine transmissible gastroenteritis (TGE)	Porcine	Gastroenteritis
Porcine hemagglutinating encephalomyelitis virus	Porcine	Vomiting, wasting and encephalomyelitis (usually no diarrhea)
Porcine epidemic diarrhea	Porcine	Gastroenteritis (similar to TGE)
Rat coronavirus	Rat	Rhinitis, tracheitis, pneumonitis in young
Rat sialodacryoadenitis virus	Rat	Sialodacryoadenitis, porphyrin released from damaged harderian gland, squamous metaplasia of ducts
Avian infectious bronchitis	Chickens	Tracheobronchitis, nephritis, wrinkled egg
Bluecomb (turkeys)	Turkeys	Enteritis, cyanosis of the comb, “Bluecomb”
Rabbit coronavirus	Rabbits	Enteritis, myocarditis
SARS-CoV-1 virus	Humans; civets	Severe Acute Respiratory Syndrome (humans); mild respiratory signs (civets)
Ferret enteric coronavirus	Ferrets	Enteritis;  Ferret systemic coronavirus infection (Similar to dry form of FIP; no effusion, icterus, or increased bilirubin)
Middle Eastern Respiratory Coronavirus (MERS)	Humans; dromedary camels
SARS-CoV-2 (COVID19)	Humans; dogs; cats; mink	Severe atypical interstitial pneumonia; myocarditis; acute respiratory distress syndrome (ARDS); similar findings in mink (Molenaar, Vet Pathol. 2020)

 

References:   

1. Agnew D. Camelidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier. 2018:197.
2. Barger, AM. Musculoskeletal System. In: Raskin RE, Meyer DM, Boes, KM. Canine and Feline Cytology, 4^th Ed. St. Louis, MO:Elsevier. 2023:374.
3. Church ME, Terio KA, Keel MK. Procyonidae, Viverridae, Hyenidae, Herpestidae, Eupleridae, and Prionodontidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier. 2018:197.
4. Felten S, Hartmann K, Doerfelt S, Sangl L, Hirschberger J, Matiasek K. Immunocytochemistry of mesenteric lymph node fine-needle aspirates in the diagnosis of feline infectious peritonitis. J Vet Diagn Invest. 2019;31(2):210-216. 
5. Malbon AJ, Meli ML, Barker EN, Davidson AD, Tasker S, Kipar A. Inflammatory mediators in the mesenteric lymph nodes, site of a possible intermediate phase in the immune response to feline coronavirus and the pathogenesis of feline infectious peritonitis? J Comp Pathol. 2019;166:69-86.
6. Meyer, DJ. The Liver. In: Raskin RE, Meyer DM, Boes, KM. Canine and Feline Cytology, 4^th Ed. St. Louis, MO:Elsevier. 2023:271 - 272.
7. Miller, AD and Porter, BF. Nervous system. In: Zachary JF, eds. Pathological Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:982.
8. Molenaar RJ, Vreman S, Hakze-van der Honing R, et. Al.  Clinical and pathological findings in SARS-CoV-2 disease outbreaks in farmed mink (Neovison vison).  Vet Pathol. 2020;57(5):653-657.
9. Rissi DR. A retrospective study of the neuropathology and diagnosis in naturally occurring feline infectious peritonitis. J Vet Diagn Invest. 2018; 30(3):392-399.
10. Sangl L, Felten S, Matiasek K, et al. Detection of feline coronavirus RNA, Spike gene mutations, and feline coronavirus antigen in macrophages in aqueous humor of cats in the diagnosis of feline infectious peritonitis. J Vet Diagn Invest. 2020;32(4):527-534. 
11. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Hoboken, NJ: Wiley; 2013: 350, 515, 615, 680.
12. Stranieri A, Paltrinieri S, Giordano A. Diagnosing feline infectious peritonitis using sysmex XT-2000iV based on frozen supernatants from cavitary effusions. J Vet Diagn Invest. 2017; 29(3):321-324.
13. Terio KA, McAloose D, Mitchell E. Felidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier. 2018:273
14. Thompson CA. Body Cavity Fluids. In: Raskin RE, Meyer DM, Boes, KM. Canine and Feline Cytology, 4^th Ed. St. Louis, MO:Elsevier. 2023:199-200.
15. Uzal FA, Plattner BL, Hostetter JM. Alimentary system.  In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol. 2. 6th ed. St. Louis, MO: Elsevier; 2016:253-255.
16. Valenciano, AC and Rizzi, TE. Abdominal, thoracic, and pericardial effusions. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier; 2020:217-218, 239. 
17. Wilcock BP, Njaa BL. Special senses. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol. 1. 6th ed. St. Louis, MO: Elsevier; 2016:453.
18. Williams BH, Burek Huntington KA, Miller M. Mustelids. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier. 2018:296.
19. Wronski JG, de Cecco BS, Raiter J, et al. Ophthalmic and immunopathological characterization of Systemic Infectious Diseases in cats. Vet Pathol. 2023;60(3):352-359. 
20. Ziolkowska N, et. al. Feline infectious peritonitis: immunohistochemical features of ocular inflammation and the distribution of viral antigens in structures of the eye. Vet Pathol. 2017;(54)6:933-944. 

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