JPC SYSTEMIC PATHOLOGY
Signalment (JPC# 1713947): Bovine neonate
HISTORY: Tissue from a bovine neonate that was born premature between 220 to 235 days of gestation; it was weak and experienced respiratory difficulty and died shortly after birth. Its lungs failed to collapse and were uniformly firmer than normal. All lymph nodes examined were 2‑2.5x normal size.
HISTOPATHOLOGIC DESCRIPTION: Lung: Multifocally obscuring 30% of the pulmonary architecture, expanding and occasionally obliterating alveolar lumina and septa are numerous macrophages, moderate numbers of lymphocytes and plasma cells, few neutrophils, and multinucleate macrophages (Langhans and foreign body type) admixed with areas of eosinophilic cellular and karyorrhectic debris (necrosis), hemorrhage, fibrin, and edema. Multifocally, bronchioles contain necrotic cellular exudate. Diffusely the less affected alveolar septa are expanded up to 5 times normal by macrophages, lymphocytes, plasma cells, fibrin, and edema. Perivascular and peribronchiolar adventitia, interlobular septa, and pleura are mildly expanded by similar inflammatory cells, ectatic lymphatics (edema), fibrin, and hemorrhage.
Liver: Essentially normal tissue.
MORPHOLOGIC DIAGNOSIS: Lung: Bronchopneumonia, granulomatous and necrotizing, multifocal to coalescing, moderate, breed unspecified, bovine.
ETIOLOGIC DIAGNOSIS: Pulmonary brucellosis
CAUSE: Brucella abortus
SYNONYMS: Bang’s disease
- Major zoonotic disease worldwide, a leading cause of abortion and sterility
- Gram negative, small (0.4-1.5um long), unencapsulated, facultatively intracellular coccobacillus that is the archetype bacterial cause of placentitis
- Secreted in colostrum and intermittently in milk
- Eradicated from livestock in the U.S. but endemic in bison and elk of the Greater Yellowstone Area with occasional spread to cattle in the area
- Smooth strains ( abortus, B. melitensis) express O side chain on its LPS, rough strains (B. ovis, B. suis, B. canis) do not
- RB51 vaccine strain can cause disease outbreaks when given to pregnant cows
- Transmission by ingestion (inhalation less common) of agent from aborted fetus, placenta, uterine discharge à entry through mucosal epithelium via phagocytosis by macrophages/dendritic cells or endocytosis/transcytosis/exocytosis à leukocyte trafficking or cell-free transit to regional lymph nodes à replication in regional lymph nodes (lymphadenitis) à leukocyte trafficking/hematogenous spread to the spleen, liver, mammary glands and gravid uterus and placenta (female), testes and accessory sex glands (male) à indefinite infection (adults) or clearance (calves)
- Placental trophoblasts produce erythritol, which is theorized to contribute to tropism for the pregnant uterus/placenta due to an unknown effect
- Chorioallantoic ulceration and necrosis à placental disruption, trophoblast infection, replication within rough ER of trophoblasts (unique mechanism of intracellular parasitism) à hematogenous spread to the fetus likely via leukocytic trafficking in fetal macrophage-like cells
- Placentitis à decreased oxygen exchange between fetal and maternal tissue àfetal hypoxia à fetus stimulated to “breathe” à aspiration of infected amniotic fluid containing Brucella organisms
- Smooth strains (more pathogenic, capable of intracellular replication): Cellular entry through interaction with lipid rafts in the plasma membrane via the Brucella LPS O-polysaccharide (O side chain)
- Opsonization aids entry via IgG and complement (C3b and 4b)
- After entry, trafficked to phagosome termed “Brucellosome” via endoplasmic reticulum (ER) and requires low pH (<4.5) for intracellular replication in phagosome/brucellosome
- VirB operon controls genes for type IV secretion system/T4SS and interacts with ER to neutralized pH of phagosome and prevents phago-lysosomal fusion (cyclic glucan synthase also plays a role)
- Brucella expresses 2 superoxide dismutases to neutralize oxidative killing and have a requirement for heme as an iron source in the phagosome; smooth strains inhibit macrophage apoptosis
- Rough strains: Different mechanism of cellular entry (don’t interact with lipid rafts, rather are phagocytized following TLR4 or mannose receptor interactions), more readily invade, are LPS deficient; are defective at intracellular replication
- Evasion of immune response:
- Minimizes stimulation of pattern recognition receptors (PRR) resulting in a reduced immune response
- Induces reduced inflammatory response compared to other Gram-negative bacteria due to its specific LPS structure
- O side chain interferes with MHCII antigen presentation
- Inhibition of apoptosis of infected monocytes/macrophages
- Prevents dendritic cell maturation, antigen presentation, and T cell activation
- Subversion of unfolded protein response (UPR) and IRE1α signaling cascade important for intracellular survival
- Osteolysis due to IL-17 induced osteoclastogenesis
TYPICAL CLINICAL FINDINGS:
- Chronic infections with persistent or recurrent bacteremia
- Late-term/third trimester abortion; retained placenta; abortion may be the only sign observed
- Orchitis/epididymitis, sterility (orchitis is generally rare; other than abortus orchitis in bulls, the vast majority of cases are actually epididymitis)
- Osteoarticular disease (arthritis, spondylitis)
TYPICAL GROSS FINDINGS:
- Placenta: characteristic but not pathognomonic: Yellow flocculent exudate in the intercotyledonary area between the chorion and endometrium, with “Moroccan leather” surface appearance; variable nonuniform yellow/gray necrotic cotyledons covered by thick brown “caramel” exudate; hematomas at the ends of maternal septa; edematous fetal membranes and umbilical cord
- Fetus: The important fetal lesion is pneumonia characterized by firm, enlarged, reddened lungs with fibrin strands on pleura (if severely affected), bronchitis and bronchopneumonia (may not be grossly apparent); autolysis; edema; subcutaneous, pleural, peritoneal, and retroperitoneal blood-tinged fluid; turbid yellow, flaky abomasal content; the most commonly infected fetal organ is the spleen
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Catarrhal to fibrinous bronchopneumonia with predominantly mononuclear cellular infiltrate and foci of bronchitis, edematous interlobular septa
- Necrotizing arteritis especially of pulmonary vessels
- Edema of the subcutis and skeletal muscles
- Necrosis and granulomatous inflammation in various organs (liver, spleen, kidney, lymph nodes)
- Hyperplasia of adrenal cortex and lymph nodes
- Thymic cortical lymphoid depletion
- Bacteria in macrophages and neutrophils in the lung and also free in vascular lumina
- Placenta: Extensive necrosis, edema, and leukocytic infiltrate in intervillous areas; abundant bacteria “stuffed” in chorionic epithelial cells that often desquamate into the intercotyledonary space; abundant bacteria within trophoblasts predominantly in intercotyledonary areas; necrotic syncytial trophoblasts; vasculitis of maternal and fetal tissues; maternal portions much less affected
- Testicular atrophy and/or infarction; necrotizing orchitis is characteristic but not pathognomonic for brucellosis
ADDITIONAL DIAGNOSTIC TESTS
- PCR, culture, immunofluorescence, immunohistochemistry
- Serum agglutination and complement fixation to detect antibodies; false positives in vaccinated cattle
- Trueperella pyogenes: Also produces suppurative placentitis and fetal lung lesions; forms large bacterial colonies within airways and alveolar spaces
- Campylobacter fetus ssp. venerealis: Abortion usually between the 4th and 6th month of gestation; placenta not retained; diffuse purulent pneumonia
- Aspergillus fumigatus: Mycotic hyphae in necrotic tissue, especially around necrotic and thrombosed vessels
- Man: Susceptible to all species (primarily abortus, B. melitensis, and B. suis)
- Transmission by infected milk products or direct contact with infected tissues
- Symptoms include prolonged or recurrent fever, weakness, impotence
- Swine: B. suis (also B. abortus and B. melitensis) chiefly transmitted via coitus; incites granuloma formation, sterility, abortion, arthritis, and vertebral osteomyelitis; uterine lesion of pale yellow miliary foci is NOT dependent on pregnancy; orchitis is characterized by multiple abscesses rather than confluent necrosis
- Sheep & goats: melitensis is the principal cause of brucellosis in sheep and goats; in goats disease is similar to B. abortus in cattle, but disease is generally less severe in sheep
- Sheep: B. ovis causes epididymitis with resultant periorchitis and rarely placentitis and abortion; primarily coital transmission; epididymitis predisposes sheep to spermiostasis and extravasation with characteristic spermatic granulomas; nonpregnant uterus is not affected; fetus: calcified plaques on hooves (nonspecific)
- Dogs: B. canis causes epididymitis, periorchitis, prostatitis, scrotal dermatitis (licking due to pain), testicular atrophy, late-term abortion (usually after 50 days gestation), discospondylitis, may cause chronic lymphocytic endophthalmitis (immune mediated); B. suis may cause spontaneous granulomatous epididymitis and prostatitis; infected fetuses: pneumonia, endocarditis, hepatitis
- Horse: B. abortus or B. suis causes bursitis (fistulous withers, poll-evil), or other suppurative skeletal or synovial lesions, commonly present with Actinomyces bovis
- Wild ungulates: B. abortus infections are described in a wide variety of mammals, including bison, elk, and reindeer; B. suis reported in a muskox
- Wood rats: neotomae
- Cats: Naturally resistant
- Camelids: susceptible to abortus and B. melitensis, develop orchitis and epididymitis
- Marine mammals: B. ceti and B. pinnipedialis: placentitis, abortions, orchitis, and blubber abscesses, hepatic/splenic/lymph node necrosis, osteoarthritis, mastitis, endometritis, pneumonia; nonsuppurative meningoencephalitis and endocarditis in young striped dolphins
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