JPC SYSTEMIC PATHOLOGY
Signalment (JPC #1788178): Yearling heifer
HISTORY: This heifer had protracted bloody diarrhea. Gross lesions were noted in the oral cavity, the esophagus, rumen, and small and large intestines.
HISTOPATHOLOGIC DESCRIPTION: Slide D-V09a: Colon: Diffusely, the mucosa is thin and there is marked erosion and necrosis/loss of up to 50% of the glands and expansion of the lamina propria by hemorrhage, fibrin, edema, moderate numbers of degenerate and viable neutrophils, macrophages, fewer lymphocytes, and plasma cells. The remaining glands are ectatic (up to 250 um) with attenuated cuboidal to flat epithelium, and contain low to moderate numbers of degenerate and viable neutrophils, macrophages, sloughed epithelial cells, cellular and karyorrhectic debris, and fibrin (crypt abscesses). Multifocally ectatic glands extend into or thru the muscularis mucosa and into the submucosa (crypt herniation). Necrotic debris and previously mentioned inflammatory cells are also present within the lumen of the colon. Less affected glands exhibit loss of mucous cells and there is multifocal erosion and ulceration of the superficial mucosal epithelium. The submucosa contains previously described inflammatory cells in low to moderate numbers and mild hemorrhage, and there is an absence of lymphoid tissue. Expanding the submucosa and dissecting into the muscularis are ectatic lymphatics and increased clear space (edema) and fibrin. There is multifocal mesothelial cell hypertrophy.
Slide D-V09b: Esophagus: Affecting approximately 40% of the mucosal surface with variable extension to the submucosa, there are multifocal well demarcated areas of mucosal erosion and necrosis affecting the stratum corneum and granulosum, and extending into the stratum spinosum; changes are characterized by loss of epithelium with replacement by necrotic debris, many degenerate neutrophils which occasionally form microabscesses, fibrin, and fewer eosinophils and lymphocytes, and mild hemorrhage and edema. Adjacent to areas of erosion, epithelial cells have pale swollen, vacuolated cytoplasm and/or demonstrate hydropic degeneration (degeneration) or lack differential staining with pyknosis and karyolysis (necrosis) with few transmigrating neutrophils. There is mild submucosal edema underlying the basil epithelium, and low numbers of neutrophils, lymphocytes and plasma cells are present within the superficial submucosa.
Slide D-V09b: Lymph node: Subcapsular and medullary sinuses are expanded by moderately increased clear space (edema) with increased numbers of draining macrophages, neutrophils, fewer eosinophils, and fibrin. In the hilus, a medium-sized artery contains an organized thrombus.
- 1. Colon: Colitis, erosive, subacute, diffuse, severe, with crypt abscesses and marked transmural edema, breed unspecified, bovine.
- Esophagus: Esophagitis, necrotizing, subacute, multifocal, moderate.
- Lymph node, site unspecified: Edema, diffuse, moderate, with sinus histiocytosis.
ETIOLOGIC DIAGNOSIS: Pestiviral colitis and esophagitis
CAUSE: Bovine pestivirus
CONDITION(S): Bovine viral diarrhea; mucosal disease
- Bovine viral diarrhea virus (BVDV), is of the genus Pestivirus, family Flaviviridae, and is a small, enveloped RNA virus
- Susceptible species to BVDV infection include cattle, pigs, sheep, goats, bison, captive and wild cervids, and Old World and New World camelids, with recent accounts of BVDV infections in alpacas and wild cervids in North America
- The majority of BVDV infections, regardless of infecting strain type, result in asymptomatic infections that largely go undetected
- BVDV is taxonomically divided into BVDV1 and BVDV2 genotypes, both of which contain cytopathic (CP) and noncytopathic (NCP) biotypes
- A new pestivirus-‘BVDV3’ or HoBi-like virus from South America, genetically and antigenically similar to BVDV, causes similar disease, but is not detected by commercial tests nor protected against with current BVDV vaccines
- A 3rd biotype of BVDV, the lymphocytopathic biotype, consists of a subpopulation of NCP strains that are capable of causing CP effect in lymphocytes cultured in vitro; NCP strains that are lymphocytopathic have been associated with severe clinical disease
- NCP isolates account for approximately 90% of BVDV isolates; within the U.S. cattle population, there are 3 major subtypes, BVDV1a, BVDV1b, and BVDV2a, with the BVDV1b subtype predominating from diagnostic laboratory submissions and PI prevalence studies
- BVDV1b reported to cause hemorrhage and/or thrombocytopenia in fetuses
- By recombination of RNA the more common NCP can shift biotype to CP
- Recombination results in splitting of the NS2-3 protein to NS3, a marker for CP BVDV
- Cytopathic/noncytopathic refers to virus activity in vitro, not in vivo
- CP- causes cellular vacuolation and apoptosis in tissue culture
- NCP- causes inapparent persistent infection in cultured cells
- Outcome of infection depends on viral strain and virulence, whether or not the host is immunotolerant or immunocompetent to BVDV, whether or not the animal is pregnant, and if so, the stage of pregnancy, and concurrent level of stress at the time of infection
- The two most clinically severe forms of BVD are mucosal disease in persistently infected animals and severe acute BVD caused by very virulent virus strains
- Virus is shed in fluids: saliva, blood, oculonasal discharge, urine, feces, semen, uterine secretions, amniotic fluid, fetal tissue, and blood
- Virus outer membrane proteins E1 and E2 may act as attachment proteins
- Receptor mediated endocytosis to target cells possibly through: clathrin, lysosomal-associated membrane protein-2, mannose receptors
- Transmission is via ingestion or inhalation with primary replication occurs in tonsils and oropharyngeal lymphoid tissue (Waldeyer’s ring)
- Lymphoid cells initially proliferate but undergo massive lysis once viral replication occurs
- BVDV targets lymphocytes and macrophages; enters circulating monocytes and is transported to lymphoid tissues and the subepithelial connective tissue of the dermis and GI tract, where it spreads locally to overlying epithelial cells
- Possible outcomes of infection include: fetal infection (depends on stage of gestation at time of infection but can result in early embryonic death, abortion, persistent infection (PI), congenital abnormalities), classical BVD, severe acute BVD, mucosal disease
- Transplacental infections – How BVDV affects the fetus:
- Infection during 50-100 days gestation: Fetal death, abortion, mummification
- Infection during 100-150 days gestation: Congenital defects such as microencephaly, hypomyelinogenesis, cerebellar hypoplasia and dysgenesis, hydranencephaly, hydrocephalus, defective myelination of the spinal cord; other lesions include microphthalmia, cataracts, retinal degeneration, atrophy and dysplasia, optic neuritis, thymic aplasia, hypotrichosis, alopecia, brachygnathia and other skeletal abnormalities, growth restriction, and pulmonary hypoplasia
- Osteopetrosis due to decreased osteoclasts and impaired bone formation
- Mechanism for cerebellar hypoplasia: BVDV infects the developing germinal cells of the cerebellum and kills Purkinje’s cells in the granular layer, resulting in necrosis and inflammation
- If the calf survives an in utero NCP infection prior to 125 days of gestation, it may develop immunotolerance and persistent infection (PI)
- Bovine fetuses become immunocompetent at 150-200 days of gestation
Persistent infection (PI)
- PI calves may be normal, weak, or undersized at birth and most succumb to mucosal disease
- Survivors are viremic and shed virus constantly thus are the most important source of infection for other cattle
- Characterized by low morbidity but high mortality
- Occurs in PI animals that become infected with a CP strain or after RNA recombination of the NCP persistent virus
- Results in overwhelming infection with little/no immune response > death usually within two weeks
- Acute and chronic mucosal disease can occur; if the animal survives the acute form, and does not die in the expected time frame, they develop chronic symptoms; these cattle are unthrifty with intermittent diarrhea, chronic bloat, decreased appetite, weight loss, interdigital erosions, or nonhealing erosive skin lesions; persistent ocular and nasal discharges are common; alopecia and hyperkeratinization of the skin, typically in the neck area; chronic lameness due to coronitis, or even laminitis can develop; these chronically affected animals usually die within 18 months due to severe debilitation
- Pathogenesis: In utero infection (prior to day 125) with NCP strain > immune tolerance and PI > infection with CP strain > mucosal disease
- Immunocompetent animals over six months may develop classical BVD
- Usually due to NCP BVDV
- Transient high morbidity low mortality
- Fever, mild oculonasal discharge, and mild oral erosions and ulcers
- Affected animals are probably immune for life
Severe Acute Bovine Viral Diarrhea:
- Transplacental infections – How BVDV affects the fetus:
- Severe acute BVD is characterized by high morbidity and high mortality in all age groups of susceptible animals and has a peracute to acute course, with fever, sudden death, diarrhea, or pneumonia
- Usually due to BVDV type 2
- Can be associated with thrombocytopenic syndrome with epistaxis, hyphema, mucosal hemorrhage, bloody diarrhea
TYPICAL CLINICAL FINDINGS:
- Acute BVD: In the mild form, there is transient fever, neutropenia with no left shift, thrombocytopenia, mild depression, inappetence, drop in milk production, oculonasal discharge, and diarrhea
- Severe acute BVD: high morbidity and mortality in all age groups; peracute to acute course: with fever, sudden death, diarrhea, or pneumonia
- MD: Pyrexia, depression, weakness, lameness, anorexia, dehydration, hypersalivation, mucopurulent nasal discharge, lacrimation, corneal edema, profuse watery diarrhea with tenesmus (tenesmus causes the “tiger stripe” colonic lesions)
TYPICAL GROSS FINDINGS:
- Acute BVD: In the mild form, mild erosions or shallow ulcerations of the oral cavity
- Severe acute BVD: lesions closely resemble mucosal disease (below)
- Linear esophageal ulcerations
- Erosions and ulcerations of mouth, tongue, oral and ruminal papillae, abomasum, cecum/colon
- Peyer's patches swollen, necrohemorrhagic, +/- diphtheritic membrane
- Erosive-ulcerative interdigital dermatitis and coronitis
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Peyer’s patches: Severe, acute inflammation in overlying intestinal mucosa with crypt herniation; destruction of underlying glands; collapse of lamina propria; lymphocytolysis
- Hyaline degeneration or fibrinoid necrosis of blood vessels (submucosal and mesenteric arterioles); vasculitis in multiple organs accompanied by a mild-to-moderate mononuclear cell infiltrate in the vessel walls and perivascular tissues
- Mesenteric lymph nodes and spleen: lymphocytolysis and lymphoid depletion
- Erosions in the skin are similar to those seen in the intestinal mucosa
- Virus isolation; Immunofluorescent antibody assays; Viral RNA detection using PCR; Antigen detection using immunohistochemistry; Serum virus neutralization; Antigen capture ELISA
- Rinderpest (Paramyxoviridae, morbillivirus): Distinguish from BVDV by looking for both intranuclear and intracytoplasmic inclusion bodies as well as syncytia
- MCF: Malignant catarrhal fever (Herpesviridae, gammaherpesvirus): Similar gross findings, with additional conjunctivitis and corneal edema; histologically, if fibrinoid necrosis is present, BVD and MCF can be distinguished by looking at lymphoid organs; involution of lymphoid tissue occurs in BVD and lymphoproliferation occurs in MCF
- IBR: Infectious bovine rhinotracheitis (Herpesviridae, alphaherpesvirus): Similar gross findings; also epithelial necrosis and intranuclear inclusions
- Diseases with both oral lesions AND diarrhea: In North American bovids, BVD/MD and MCF are the two most common diseases with both of these symptoms
- Diseases with oral lesions: Foot and mouth disease (Picornaviridae, aphthovirus); vesicular stomatitis (Rhabdoviridae, vesiculovirus); bluetongue (Reoviridae, orbivirus); bovine papular stomatitis (Poxviridae, parapoxvirus); and necrotic stomatitis or oral necrobacillosis (Fusobacterium necrophorum), and malignant catarrhal fever
- Diseases with diarrhea: Salmonellosis, cryptosporidiosis, coccidiosis, coronavirus, rotavirus, paratuberculosis (Mycobacterium avium subsp. paratuberculosis), intestinal parasitism, arsenic poisoning, and copper poisoning
- Other causes of pneumonia: Bovine respiratory syncytial virus, mannheimiosis, pasteurellosis, hemophilosis, or mycoplasmosis
- Diseases that mimic the hemorrhagic syndrome: Septicemia with subsequent DIC, sweet clover poisoning, and bracken fern poisoning
Other pestiviruses of domestic animals:
- Pigs – Classical swine fever
- Sheep – Border disease
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