JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2024

U-V02 

 

Signalment (JPC Accession #2236078): Steer

 

HISTORY: Tissue from a steer that developed fever, mucopurulent nasal discharge, corneal opacities, and oronasal erosions prior to death.

 

HISTOPATHOLOGIC DESCRIPTION: 

Kidney: Multifocally affecting vessels, predominantly small and medium-sized arteries, within the cortex and medulla, there is marked fibrinonecrotizing vasculitis. The tunica intima is frequently discontinuous and replaced by necrotic debris. The tunica media and adventitia are markedly expanded by eosinophilic beaded fibrillar material (fibrin), increased clear space (edema), rare hemorrhage, cellular and karyorrhectic debris (necrosis). Transmigrating the tunica media and tunica adventitia and expanding into adjacent interstitium are many lymphocytes, macrophages, plasma cells, neutrophils. Leiomyocytes of the tunica media are frequently swollen and microvacuolated (degeneration). In less affected vessels, there is endothelial hypertrophy. Remaining tubular epithelial cells display one of the following changes: pale, swollen, and vacuolated (degeneration), or rare shrunken, hypereosinophilic cells with pyknotic nuclei (necrosis). Separating and surrounding adjacent glomeruli and tubules, the interstitium contains multifocal to coalescing aggregates of lymphocytes, plasma cells, and macrophages.

 

Haired skin: Multifocally affecting vessels within the dermis, the tunica intima is effaced; and the tunica media and adventitia are markedly expanded by fibrin, rare hemorrhage, edema, cellular and karyorrhectic debris (necrotizing vasculitis).  Multifocally, vessel lumina are partially to completely occluded by a pale eosinophilic, fibrillar material (fibrin) containing inflammatory cells (fibrin thrombi). Multifocally, there is a perivascular, periadnexal and dermal infiltrate composed of lymphocytes, plasma cells, fewer macrophages and neutrophils which surrounds and separates skeletal muscle, adnexal glands and nerves (myositis, adenitis, and perineuritis). Individual rhabdomyocytes are either atrophied with a shrunken, rounded sarcoplasm or contain a hypereosinophilic, fragmented sarcoplasm, with loss of cross striations and nuclear pyknosis, karyolysis or karyorrhexis (myocyte necrosis). Within the epidermis, there is increased clear space (spongiosis), acanthosis with rete ridges, multifocal erosions and ulcerations, frequent intracorneal pustules containing sloughed keratinocytes, necrotic debris, viable and degenerate neutrophils, fewer lymphocytes and macrophages (intraepidermal pustule). Multifocally within the ulcerated epidermis and superficial dermis there are colonies of 1-2 µm basophilic coccobacilli. 

 

MORPHOLOGIC DIAGNOSIS:  

1. Kidney: Vasculitis, necrotizing, lymphoplasmacytic, subacute, multifocal, severe, with lymphoplasmacytic interstitial nephritis and tubular degeneration, breed unspecified, bovine.

2. Haired skin: Vasculitis, necrotizing, lymphocytic, subacute, multifocal, moderate, with fibrin thrombi, ulcerative epidermitis, intraepidermal pustules, and lymphocytic myositis, adenitis, and perineuritis, breed unspecified, bovine.

 

ETIOLOGIC DIAGNOSIS: Cutaneous and renal gammaherpesviral vasculitis.

 

CAUSE: Alcelaphine herpesvirus-1 (AlHV-1), Ovine herpesvirus-2 (OvHV-2)

 

CONDITION:  Malignant catarrhal fever (MCF)   

 

GENERAL DISCUSSION:  

• Malignant catarrhal fever is a sporadic, fatal, multisystemic disease of cattle, small domestic ruminants and wild ruminants (deer, buffalo, antelope), with worldwide distribution
• Notable for spread from asymptomatic carriers of reservoir species to susceptible species in which it causes severe disease with high morbidity and mortality
• Primary target tissues are lymphoid organs (specifically T lymphocytes), epithelial tissues (primarily respiratory and gastrointestinal) and vasculature
• Characterized by lymphoproliferation, vasculitis and erosive to ulcerative mucosal and cutaneous lesions
• Mortality approaches 100% in susceptible species
• Causative agents are Gammaherpesviruses in the genus Macavirus, family Herpesviridae; see also S-V01 and D-V15

• Alcelaphine herpesvirus-1 (AlHV-1; wildebeest-associated form (WA-MCF)), carried by wildebeest; occurs in Africa; wildebeest are infected for life and transmit AHV-1 to their calves without showing clinical signs; subclinical infection in Topi and Hartebeest; clinical infection in Barbary red deer, domestic cattle
• Ovine herpesvirus-2 (OvHV-2; sheep-associated form (SA-MCF)), carried by asymptomatic domestic sheep; can be transmitted to other susceptible species (wild and domestic)
• Caprine herpesvirus-2 (CpHV-2), endemic in domestic goats; infects sika deer, roe deer, moose, white-tailed deer
• Caprine herpesvirus-3 (CpHV-3), aka MCF-white-tailed deer; goat reservoir
• Alcelaphine herpesvirus-2 (AlHV-2), carried by hartebeest and topi bison; infects Barbary red deer and bison
• Ibex MCF virus (Ibex-MCF), carried by Nubian ibex; infects bongo and anoa
• Other related gammaherpes viruses identified in bovids not yet associated with MCF

• Disease is not contagious among affected cattle, which are thought to be dead end hosts
• Viral behavior mimics other lymphotropic herpesviruses such as Epstein-Barr virus, Herpesvirus saimiri, and Marek’s disease virus
• In affected cattle the virus does not induce herpetic necrosis; there are no inclusion bodies or syncytial giant cell formation 

 

PATHOGENESIS:  

• Exposure via direct contact or aerosolized secretions (nasal, ocular, reproductive fluids)  > virus enters through oral cavity or tonsillar mucosa > viremia > transformation of lymphoid cells > systemic lymphoproliferative disease > disruption of secondary lymphoid tissues, perivascular accumulation, and proliferation of transformed lymphoid cells > vasculitis, lymphoid invasion into mucosal and/or cutaneous tissues > cytotoxicity likely responsible for tissue damage (CD8+ T-cells, NK cells)
• Wildebeest have lifetime infection > transmit AHV-1 to offspring > infected calves shed infective cell-free virus in nasal and ocular secretions, semen and feces > transmitted to cattle via aerosolization (mucosa of the upper respiratory tract and/or tonsil are the primary route of entry) or food/forage contaminated with virus laden secretions > transmission to cattle with or without direct contact > viral replication occurs in lymphocytes > dysfunction of cytotoxic T lymphocytes > T cell lymphoproliferation (CD3+, CD8+, CD4- T cells) > cytotoxic activity resulting in epithelial and vascular lesions
• Sheep-associated MCF: OvHV-2 infected T cells, monocytes, and locally proliferating macrophages contribute to vasculitis (Saura-Martinez, Vet Pathol. 2020)

• Trigger for leukocyte recruitment unknown; infected endothelial cells may play a role, inducing activated macrophages to release pro-inflammatory mediators which cause vascular changes

 

TYPICAL CLINICAL FINDINGS:

• Variable, but may include fever, severe mucopurulent nasal discharge, corneal opacity, diarrhea, lymphadenopathy, neurologic disease
• Clinical MCF divided into four variable and overlapping categories: 

1. Peracute form: Severe oral and nasal mucosal inflammation, hemorrhagic gastroenteritis
2. Intestinal form: Pyrexia, diarrhea, hyperemic oral and nasal mucosa with profuse catarrhal and mucopurulent discharge, generalized lymphadenopathy; most commonly seen in deer
3. Head-and-eye form (most common): Pyrexia, copious serous to mucopurulent ocular and nasal secretions, encrusted muzzle with occluded nostrils, dyspnea and open-mouthed breathing, oral mucosal hyperemia with erosions, sloughed buccal mucosal tips

• Ocular lesions: Ophthalmia, photophobia with copious lacrimation, palpebral conjunctival hyperemia and edema, corneal opacity, +/- hypopyon 
• Less pronounced in cervids

1. Mild form: Mild oral and nasal mucosal erosions

• Clinical signs in bison can be subtle; high percentage of animals will die without clinical signs or very soon after the onset of clinical disease
• Neurologic signs also possible (hyperesthesia, head pressing, nystagmus, etc)

 

TYPICAL GROSS FINDINGS: 

• Gross changes are the consequence of widespread arteritis-phlebitis of medium caliber vessels, lymphoid proliferation and production of atypical lymphoblastoid cells, and mucosal ulceration in digestive, urinary and respiratory tracts
• Urinary tract lesions:

• Kidney: Multiple raised 2-4mm white lymphoproliferative lesions, ecchymotic hemorrhages, infarcts, renomegaly
• Urinary bladder: Mucosal hyperemia, edema, inflammation, hemorrhage, erosion, ulceration

• Gastrointestinal tract: Mucosal necrosis, edema, hemorrhage (cranial esophagus, forestomachs); especially prominent in bison
• Lymph nodes: Lymphadenopathy - enlarged, edematous, +/- hemorrhagic; minimal in bison
• Respiratory: Serous to mucopurulent nasal discharge, crusted muzzle, edematous lungs, gray-yellow pseudomembranes that cover laryngeal and pharyngeal erosions
• Ocular: Corneal opacity, ocular mucopurulent discharge, +/- hypopyon 
• Liver: Hepatomegaly, hemorrhagic and erosive gallbladder mucosa
• Oral cavity: Mucosal erosions first observed at mucocutaneous junction (oral lesions observed in most cases)
• Skin: Cutaneous ulceration and necrosis, exudative dermatitis with matted hair, hyperemia

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Lymphocyte proliferation in tissues and paracortex (T-cells), with large granular lymphocytes, variable mitotic activity
• Widespread mucosal necrosis 
• Systemic necrotizing vasculitis with perivascular and intramural infiltration of large lymphocytes 
• Vessels: Fibrinoid necrotizing vasculitis; intramural and perivascular accumulation of mononuclear cells, endothelial swelling, +/- fibrinoid necrosis
• Kidney: Infarcts, 2-4 mm foci of nonsuppurative interstitial nephritis, vasculitis of smaller arterioles and afferent arterioles, pelvic and ureteral mucosal petechial and ecchymotic hemorrhages
• Urinary bladder: Hemorrhagic cystitis may be the dominant lesion in cattle and deer
• Lymph nodes: Severe edema, ectatic lymphatics, lymphocytic hyperplasia, and reticuloendothelial cell proliferation
• CNS: Nonsuppurative meningoencephalomyelitis, lymphocytic perivascular cuffing, perivascular and meningeal edema
  • Variable Neuropathological Phenotype (Hierweger, Vet Pathol. 2020): Necrotizing arteritis, plasma exudation into the meninges or Virchow-Robin space, and the predominantly adventitial lymphocytic response are, in the brain of cattle, unique to MCF
• Gastrointestinal tract: Edema, congestion, mucosal erosions, abomasal ulcers and submucosal eosinophilic inflammation; severity correlates with amount of lymphoid tissue in subjacent areas
• Oral and pharyngeal mucosa: Epithelial necrosis, lymphocytic inflammation
• Ocular: Ophthalmitis, corneal edema, retinal vasculitis, optic neuritis
• Skin: Exudative lymphocytic lichenoid dermatitis, edema, epithelial necrosis
• Liver: Perivascular accumulation of mononuclear cells in the portal triads +/- fibrinoid necrosis

 

ULTRASTRUCTURAL FINDINGS:  

• Icosahedral enveloped virions 140-220 nm in diameter, with an 85-100 nm central capsid 
• Lymphoblasts have eccentric, round to irregular nuclei, and euchromatic chromatin

 

ADDITIONAL DIAGNOSTICS:

• PCR (multiplex PCR useful to distinguish viral species; qPCR recommended for diagnosis of OvHV-2)
• In-situ hybridization technique allows for localization of OvHV-2 nucleic acids in lymphocytes of experimentally and naturally infected animals (Pesavento, Vet Pathol. 2019)
• Immunohistochemistry: Positive immunoreactivity to monoclonal antibody 15A (Mab-15A) recently demonstrated in the cytoplasm of epithelial cells and leukocytes in OHV-2 infected cattle (Headley, J Comp Pathol. 2020) 
• MCF antibody detection with complement fixation, ELISA
• Virus isolation

 

DIFFERENTIAL DIAGNOSIS:

• Lymphoproliferative Diseases:

• Enzootic bovine lymphosarcoma (Bovine leukemia virus)
• Jembrana disease (lentivirus): Perivascular accumulations of lymphoblastic cells; perifollicular T-lymphocyte proliferation with atrophy of B-cell follicles (similar to MCF)
• East Coast Fever caused by the protozoan Theileria parva 

• Diseases causing vasculitis in cattle and wild ruminants:

• Viral: Bovine viral diarrhea (Bovine pestivirus), Bluetongue (Ovine orbivirus), adenoviral hemorrhagic disease 
• Bacterial: Salmonellosis;Histophilus somni (thrombotic meningoencephalitis; TME) 
• Mycotic: Phycomycosis, aspergillosis
• Parasitic: Elaeophora schneideri
• Immune-mediated: Polyarteritis nodosa, drug-induced hypersensitivity

• Diseases causing inflammation, erosion, and ulcerations of the nasal and alimentary tracts: 

• Bovine virus diarrhea/mucosal disease (Bovine pestivirus): Oral lesions are discrete, rounded or have sharply defined depressions; lymphoid tissue is expected to be atrophic; arteritis is mainly limited to the submucosa in the lower alimentary tract
  1. MCF usually affects one or more organ systems or tissues not involved in mucosal disease (liver, kidney, bladder, eye, brain, tracheobronchial tree)
• Bluetongue (Ovine orbivirus): Commonly lame, corneal opacity and ophthalmia are rare
• Epizootic hemorrhagic disease (Cervid orbivirus): Deer, similar to bluetongue
• Rinderpest (Bovine morbillivirus): Similar to BVD/mucosal disease; syncytia and both intranuclear and intracytoplasmic viral inclusions

• Vesicular diseases in ruminants:  

• Foot-and-mouth disease (FMD) 
• Vesicular stomatitis (VS)
• Bovine Papular Stomatitis
• Infectious Bovine Rhinitis (IBR)

• Ingestion of caustic agents
• Photosensitization
• Mycotoxins
• Diseases causing ocular lesions: Bovine infectious keratoconjunctivitis (Moraxella bovis/Mycoplasma bovoculi)

            

COMPARATIVE PATHOLOGY:

• Duiker Deer: Lymphocytic arteritis, lymphadenomegaly, pleural effusion (Carvallo, Vet Pathol. 2020)
• Hamsters, rats, and guinea pigs develop MCF-like lesions when exposed to AlHV-1
• American bison: Infected with OvHV-2; predominant form is acute clinical disease; characteristic gross lesions include oculonasal discharge, hemorrhagic cystitis, necrohemorrhagic typhlocolitis, erosive-ulcerative rhinitis, stomatitis, pharyngitis, laryngitis and esophagitis
• Water buffalo: Infected with OvHV-2; clinical signs and lesions are similar to cattle
• Cervids: Susceptibility varies among species; Pere David’s deer and white-tailed deer highly susceptible, fallow deer relatively resistant (numerous species reported to be susceptible)

• Most often infected with OvHV-2, which can cause death in 1-3 days
• Other viral agents: AlHV-1, AlHV-2, caprine HV-2, MCF virus-white-tailed deer

• Domestic pigs: Similar to cattle presenting with a head and eye form of MCF
• Domestic goats: Infected with CpHV-2; present with weight loss and alopecia with serocellular crusting of head, neck, thorax, abdomen and limbs

• Malignant catarrhal fever viruses uncommonly cause granulomatous mural folliculitis (Westermann, Vet Pathol. 2023)

 

References:

1. Carvallo FR, Uzal FA, Moore JD, et al. Ibex-Associated Malignant Catarrhal Fever in Duikers (Cephalophus Spp). Vet Pathol. 2020; 57(4):577-581. 
2. Cianciolo RE, Mohr FC.  Urinary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:459-460.
3. Headley SA, Oliveira TES, Li S, et al.  Immunohistochemical detection of intralesional antigens of ovine gammaherpesvirus-2 in cattle with sheep-associated malignant catarrhal fever. J Comp Pathol. 2020; (174):86-98. 
4. Hierweger MM, Boujon CL, Kauer RV, et al. Cerebral Ovine Herpesvirus 2 Infection of Cattle is Associated with a Variable Neuropathological Phenotype. Vet Pathol. 2021;58(2):384-395.
5. Howerth EW, Nemeth NM, Ryser-Degiorgis MP. Cervidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:156-157. 
6. Jones MEB, Gasper DJ, Mitchell E. Bovidae, Antilocapridae, Giraffidae,Tragulidae, Hippopotamidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:124-126, 129.
7. Miller AD, Porter, BF. Nervous System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:968-969.
8. Milliron, SM, Stranahan LW, Rivera-Valdez AG, et al. Systemic proliferative arteriopathy and hypophysitis in a cow with chonic ovine herpesvirus 2-induced malignant catarrhal fever. J Vet Diagn Invest. 2022; 34(5):905-908.
9. Pesavento PA, Dange RB, Carmen Ferreras M, et al. Systemic Necrotizing Vasculitis in Sheep Is Associated With Ovine Herpesvirus 2. Vet Pathol. 2019;56(1):87-92.
10. Saura-Martinez H, Al-Saadi M, Stewart JP, Kipar A. Sheep-associated malignant catarrhal fever: Role of latent virus and macrophages in vasculitis. Vet Pathol. 2021;58(2):332-345.
11. 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. Philadelphia, PA: Elsevier Saunders; 2016:131-136.
12. Westermann T, Demeter EA, Diel DG, et al. Granulomatous mural folliculitis in 16 domestic goats: Infection with malignant catarrhal fever viruses and colocalization with ovine herpesvirus-2 using in situ hybridization. Vet Pathol. 2023;60(6)876-887.

 

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