JPC SYSTEMIC PATHOLOGY
SIGNALMENT: Tissue from a 12-day-old beagle
HISTORY: This beagle died suddenly.
HISTOPATHOLOGICAL DESCRIPTION: Kidney: Affecting approximately 50% of the renal parenchyma are multiple foci of coagulative necrosis, with loss of differential staining, accumulation of eosinophilic cellular and karryorrhectic debris and retention of cellular architecture, admixed with hemorrhage, fibrin and edema, radiating through the cortex and into the medulla. Multifocally, tubular epithelium is degenerate, with swollen, pale with vacuolated cytoplasm or necrotic, shrunken and hypereosinophilic with nuclear pyknosis, karyorrhexis, or karyolysis and occasional sloughing into the tubular lumen. Rarely, tubular epithelial cells contain a round to polygonal, 2-4 um diameter, intranuclear, eosinophilic viral inclusion body surrounded by a clear halo that peripheralize chromatin. Multifocally, few glomeruli exhibit one or more of the following changes: segmental to global necrosis, with loss of cellular detail and presence of karyorrhectic debris (necrosis); hypertrophy of the parietal and visceral epithelium, and/or synechiae. Multifocally, blood vessel walls are edematous with small amounts of necrotic cellular debris that extends into the surrounding interstitium and is admixed with hemorrhage and fibrin (vascular necrosis). There is multifocal interstitial and glomerular congestion. Diffusely, the capsule is moderately expanded by edema and hemorrhage.
Liver: Multifocally, there are random foci of coagulative necrosis with loss of differential staining with retention of cellular architecture rimmed by lytic necrosis with loss of normal hepatic cord architecture with replacement by and abundant cellular and karyorrhectic debris. In areas of hepatocellular necrosis there are aggregates of hemosiderin laden macrophages and neutrophils. Occasionally, adjacent to necrotic areas and within less affected hepatocytes are round to polygonal, 2-4 um, eosinophilic, intranuclear viral inclusion bodies, which peripheralize the chromatin. Multifocally, blood vessel walls are expanded and surrounded by necrotic cellular debris with hemorrhage and fibrin (vascular necrosis). Periportal connective tissue is moderately expanded by edema, ectatic lymphatics, and few lymphocytes, plasma cells, macrophages and neutrophils.
Lung: Alveolar septae are multifocally discontinuous or lost and replaced by necrotic cellular debris and fibrin (necrosis) or expanded up to 3 times normal by fibrin, necrotic debris, numerous foamy macrophages, and fewer neutrophils and erythrocytes. Similar inflammatory cells, fibrin and edema multifocally fill alveoli. Multifocally, bronchiolar epithelial cells are necrotic/sloughed and lumina contain low numbers of macrophages, neutrophils and sloughed epithelial cells. Rarely, bronchiolar epithelial cells contain 2-4 um polygonal, eosinophilic intranuclear viral inclusion bodies that peripheralize the chromatin. Multifocally, blood vessel walls are thickened and surrounded by small amounts of necrotic cellular debris with hemorrhage, fibrin and edema extending into the adjacent interstitium (vascular necrosis). Multifocally, peribronchial, peribronchiolar, and perivascular connective tissue is moderately expanded by edema and ectatic lymphatics. There is multifocal alveolar emphysema.
MORPHOLOGIC DIAGNOSIS: 1. Kidney, tubules and glomeruli: Nephritis, necrotizing, acute, multifocal, severe, with vascular necrosis, hemorrhage, edema, and rare epithelial intranuclear viral inclusions, beagle, canine.
- Liver: Hepatitis, necrotizing, random, acute, multifocal, moderate with hepatocellular intranuclear viral inclusion bodies.
- Lung: Pneumonia, bronchointerstitial, necrotizing, acute, multifocal, moderate, with rare bronchiolar epithelial intranuclear inclusion bodies.
ETIOLOGIC DIAGNOSIS: Herpesviral nephritis, hepatitis, and pneumonia
CAUSE: Canine herpesvirus type 1 (CaHV-1); canid alphaherpesvirus I
- Subfamily Alphaherpesvirinae (genus Varicellovirus); dsDNA genome
- A highly fatal, systemic disease of neonatal puppies (less than 4-6 weeks) characterized by foci of necrosis (including vascular necrosis) and hemorrhage in numerous organs; has also been associated with renal dysplasia
- In older pups (> 12-16 weeks), herpesviral infections fail to produce renal lesions
- In adult dogs, produces mild upper respiratory, genital, and ocular disease; systemic infection in adults is rare (typically in immune suppressed animals)
- Recent reports of fatal CaHV-1 induced necrohemorhagic rhinotracheitis, bronchointerstitial pneumonia, hepatitis and gastroenteritis in several healthy adult dogs
- The virus is extremely temperature sensitive; viral replication occurs readily in cell cultures at 37degrees C (99 degrees F), but is greatly diminished at 39 degrees C (102 degrees F); therefore, it replicates more readily in the cooler respiratory and genital epithelial tissues; the relatively low and poorly regulated body temperature of neonates contributes to their susceptibility to systemic dissemination
- Susceptible to common disinfectants and unstable outside the host cell
- Pups are infected in utero (transplacentally), at birth via contact with infectious vaginal or nasal secretions, or through direct contact with infected littermates
- Transplacental infection during mid to late gestation may result in abortion, stillborn, or weak puppies that die within a few days
- Venereal transmission produces a serous vaginal or preputial discharge and mild nodular inflammation of the genital epithelium
- Pups <1 week old: Oronasal infection > viral replication in epithelial cells of the nasal mucosa, pharynx, and tonsils > hematogenous dissemination via leukocytes (probably macrophages) > localization in mononuclear phagocytic cells of the lymph nodes and spleen > multifocal hemorrhagic necrosis, in adrenal glands, kidneys, lungs, spleen, and liver (less frequently intestinal lamina propria, meninges, and brain)
- In naturally acquired CHV infection, the cerebellar granule neurons are an important site of viral replication
- If the pup survives initial infection> lifelong latency in in both the lymphoreticular system and the neurons of the lumbosacral, vestibular and trigeminal ganglia> can be reactivated and shed during periods of immunosuppression
- Reactivation of latent CaHV-1 infection in adult dogs associated with immunosuppression
TYPICAL CLINICAL FINDINGS:
- Pups: Signs occur by seven to ten days of age and include depression, crying, anorexia, dyspnea, mucopurulent nasal discharge, widespread petechial hemorrhages and mild vesicular vulvovaginitis; animals are not febrile (often low rectal temperature), and death occurs within 24 hours, often without clinical signs
- Older animals: Clinically inapparent; usually non-fatal necrotizing rhinotracheitis; implicated in canine infectious respiratory disease complex “kennel cough”
TYPICAL GROSS FINDINGS:
- Diffuse petechial and ecchymotic hemorrhages (particularly in the kidneys, adrenal glands, liver, lungs, and GI tract)
- Wedge shaped hemorrhages radiating outward from the renal pelvis
- Edematous lungs, sanguineous pleural and peritoneal effusion, splenomegaly, enlarged and hyperemic lymph nodes
- Nonsuppurative meningoencephalitis; CNS signs rarely noted because of early death of animals
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Multifocal perivascular necrosis and hemorrhage (most extensive in the kidneys and lungs); usually very little inflammatory response
- Infrequent 2-4 um eosinophilic intranuclear viral inclusion bodies (more apparent in renal tubular and nasal epithelium; also infects endothelial cells)
- Nonsuppurative meningoencephalomyelitis and ganglioneuritis, cerebellar dysplasia and keratitis, retinal dysplasia, necrosis and detachment, and peripheral anterior synechiae
- Mature dogs:
- Necrotizing pharyngitis or catarrhal tracheobronchitis with intranuclear viral inclusion bodies
- Cutaneous or mucosal lesions
- Vaginitis or multifocal necrotizing placentitis, with intranuclear viral inclusion bodies in trophoblasts
- Enveloped virions, 150 nm, (innermost to outermost): DNA containing core; 100 nm diameter icosahedral nucleocapsid; lipid bilayered envelope
- Enveloped nucleocapsid is the infectious particle
- Nuclear swelling characterized by lysis of nuclear matrix and peripheralization of chromatin, giving the karyoplasm a finely granular homogenous appearance (“ground glass” nuclei)
ADDITIONAL DIAGNOSTIC TESTS:
- Diagnosis is based on rapidity of neonatal death, necrosis and hemorrhage in multiple organs, and presence of intranuclear inclusion bodies
- Cell culture of mucosal surfaces (refrigerated tissue): kidneys, spleen, liver
- PCR, in situ hybridization (ISH)
- Glial nodules in CHV cases typically contain large number of IBA positive cells
DIFFERENTIAL DIAGNOSIS: (diseases in young dogs which cause renal lesions)
- Infectious Canine Hepatitis (Canine adenovirus type 1):
- Dogs less than one year of age (but typically older than those with herpesvirus)
- Large, amphophilic intranuclear viral inclusion bodies in renal glomeruli and renal tubular vascular endothelium, Kupffer cells, hepatic parenchymal cells
- Hepatomegaly (fibrinous exudate on surface) and thickened, edematous gallbladder; corneal edema (blue eye); petechial and ecchymotic hemorrhages on serosal surfaces; peritoneal effusion and hemorrhage
- Centrilobular to panlobular hepatic necrosis and interstitial fibrosis
- Canine Distemper Virus (Morbillivirus):
- Puppies 12-16 weeks of age
- 1-5 um, eosinophilic, intracytoplasmic or intranuclear viral inclusion bodies most commonly in renal epithelium, transitional epithelium of the bladder, and type II pneumocytes
- Weak puppies with focal to diffuse interstitial pneumonia, thymic atrophy, and lymphoid depletion; defects in enamel of teeth; acute fatal encephalitis with neuronal and myelin degeneration; “hard pad” (hyperkeratosis)
- Demyelination; viral inclusion bodies in astrocytes
- Toxoplasmosis (Toxoplasma gondii):
- Generalized toxoplasmosis occurs mostly in dogs less than one year of age
- Often secondary to canine distemper virus immunosuppression or canine adenovirus type 2 (lesions of both may be present)
- Granulomatous and nonsuppurative inflammation in kidney and brain; extensive hepatic necrosis
- Other causes of non-suppurative interstitial nephritis in dogs:
- Lymes disease
- Hepatozoon canis infection
- Canine adenovirus 1
- Pigs: Suid herpesvirus 1 (pseudorabies, Aujeszky’s Disease)
- Abortions; multifocal inflammation and necrosis in liver, lung, adrenal, and lymphoid tissues; inclusion bodies in chorionic epithelium
- Adults: Dermatitis, encephalitis
- Goats: Caprine herpesvirus 1
- Abortions; multifocal inflammation and necrosis in various organs
- Equine herpesvirus 1
- Abortions; multifocal inflammation and necrosis in liver, lung, adrenal glands, and lymphoid tissues with intranuclear inclusion bodies
- Adults: Encephalomyelitis, rhinopneumonitis
- Equine herpesvirus 3: Coital exanthema
- Equine herpesvirus 4: Rhinopneumonitis
- Bovine herpesvirus 1 (infectious bovine rhinotracheitis): Pneumonia, rhinotracheitis, and vulvovaginitis
- Bovine herpesvirus 2: Bovine mammillitis, pseudo-lumpy skin disease
- Bovine herpesvirus 5: Encephalitis
- Cats: Feline herpesvirus 1
- Rhinitis, sinusitis, and conjunctivitis with intranuclear viral inclusions
- Cheetahs: Eosinophilic facial dermatitis
- Non-Human Primates: Macacine herpesvirus 1 (B virus)
- Characteristic vesicular and ulcerative lesions on oral and genital mucosae with multinucleated, syncytial cells and intranuclear viral inclusions
- Gallid herpesvirus 1: Infectious Laryngotracheitis of chickens
- Gallid herpesvirus 2: Marek’s disease of chickens
- Anatid herpesvirus type 1: Duck Plague
- Psittacid herpesvirus: Pacheco’s disease
- Breshears MA, Confer AW. The urinary system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:677.
- Caswell JL, Williams KJ. Respiratory system In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016: 577.
- Cianciolo RE, Mohr FC. Urinary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016: 432.
- Gadsden BJ, Maes RK, Wise AG, et al. Fatal Canid herpesvirus 1 infection in an adult dog. J Vet Diagn Invest. 2012;24(4):604-607.
- Giaretta PR, Rissi DR. Pathology in practice. CHV-1 infection. J Am Vet Med Assoc. 2014; 245(6):639-641.
- Jager MC, Sloma EA, Shelton M, et al. Naturally acquired canine herpesvirus-associated meningoencephalitis. Vet Pathol. 2017; 54(5):820-827.
- Kapil S. Canid herpesvirus 1 (CHV-1)-related disease in older puppies and CHV-1 shedding in the vagina of adult pregnant dogs. J Vet Diagn Invest. 2015; 27(6):758-761.
- Kumar S, Driskell EA, Cooley AJ, et al. Fatal canid herpesvirus 1 respiratory infections in 4 clinically healthy adult dogs. Vet Pathol. 2015;52(4):681-687.
- Lopez A, Martinson SA. Respiratory system, mediastinum, and pleurae. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:546.
- MacLachlan NJ, Dubovi EJ, eds. Fenner’s Veterinary Virology. 5th ed. London, UK; 2017:70, 202.
- Muro SM, Jugan MC, Ruoff C, et al. What is your diagnosis? Canine herpesvirus-1 infection. J Am Vet Med Assoc. 2015; 247(7):747-749.
- Pesavento PA, Murphy BG. Common and emerging infectious diseases in the animal shelter. Vet Pathol. 2014;51(2):478-491.
- Schlafer DH, Foster RA. Female genital System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016: 431-433.
- Zachary JF. Mechanisms of microbial infection. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: