JPC SYSTEMIC PATHOLOGY
CARDIOVASCULAR SYSTEM
March 2022
M-B02 (NP)

Signalment (JPC #2064900):  Young chicken

 

HISTORY:  This chicken was experimentally injected with Staphylococcus aureus.

 

HISTOPATHOLOGIC DESCRIPTION:  Tibia:  Multifocally, metaphyseal vessels extending into the physeal hypertrophic zone are dilated and contain moderate numbers of viable and degenerate heterophils admixed with eosinophilic cellular and karyorrhectic debris (necrosis) and fibrin; similar inflammatory cells and necrotic debris multifocally extend into and disrupt the adjacent physeal cartilage, with loss of matrix and chondrocytes. In the metaphysis, spaces between primary spongiosa are multifocally filled with heterophils, fibrin, and hemorrhage, which occasionally extends into the matrix of individual trabeculae in areas of osteoclastic and chondroclastic resorption.  There is a 2x3 mm area within the hypertrophic cartilage zone where the cartilage matrix has lost basophilic staining and is pale, and chondrocytes in lacunae are brightly eosinophilic and shrunken (necrosis)(focally extensive infarct). Diffusely the synovial membrane is expanded by few heterophils, macrophages, and fewer lymphocytes admixed with fibrin, edema, cellular debris, and congested vessels.  The joint space and adjacent adipose tissue contain abundant heterophils and fewer macrophages admixed with sloughed synoviocytes.

 

MORPHOLOGIC DIAGNOSIS:  1. Tibia, metaphysis:  Osteomyelitis, heterophilic, acute, multifocal, moderate, with arthritis, chicken, avian.

2. Synovial membrane: Synovitis, heterophilic and lymphohistocytic, subacute, diffuse, mild.

 

ETIOLOGIC DIAGNOSIS:  Bacterial osteomyelitis and synovitis

 

CAUSE:  Staphylococcus aureus

 

GENERAL DISCUSSION:

• Definitions: osteitis is inflammation of bone; periostitis is appropriate if the periosteum is involved; osteomyelitis is appropriate if the medullary cavity (and bone marrow) are involved
• Osteomyelitis is most frequently caused by bacteria, but may also be caused by fungi, protozoa, parasites, viruses or trauma
• Osteomyelitis is more common in young animals, especially foals; underdiagnosed as the affected animals often die of septicemia before bone lesions develop (bone lesions may take several months to cause clinical signs or gross lesions)
• Bacterial osteomyelitis targets the capillaries of the metaphysis; however, the entire bone may affected because of the extensive vascular anastomoses between the periosteum, cortex and medulla
• Staphylococcus aureus infections are common in poultry and most frequently occur in epiphyses of long bones, vertebral bodies, and associated joints

 

PATHOGENESIS:

• Three routes of bacterial infection: hematogenous, local extension, and implantation; hematogenous very common in animals, especially poultry, foals and ruminants
• A combination of bone injury and concurrent bacteremia/septicemia may be involved in the pathogenesis of hematogenous osteomyelitis
  • Bacteremia or septicemia > bacterial localize to sites of active endochondral ossification within metaphyses and epiphyses of long bones and vertebral bodies > thrombosis > infarction > osteomyelitis
  • Trauma enhances infection establishment by altering metaphyseal environment
  • Bacterial infection of bone > inflammatory response with edema and suppuration > TNF-a, IL-1, IL-6, PGE2 > osteoclast activation -> bone resorption
• A recent study of chronic osteomyelitis associated bone loss showed that in swine, a strong inflammatory response likely induced proteolytic enzymes leading to lysis rather than osteoclast activity; in addition, contrary to in-vitro models, RANKL-induced osteoclastogenesis was downregulated and IL-26 genes were significantly upregulated (Luthje, J Comp Pathol. 2020)
• Bacteria localize within growing physes of long bones and vertebral bodies; some bacteria (e.g. aureus, Salmonella) have a predilection for bone
  • Capillaries invading mineralizing cartilage (primary spongiosa) make sharp loops, then open into fenestrated, sluggish sinusoidal vessels that communicate with medullary veins
    • Easy access to bone marrow through fenestrations
    • Blood flow slows down in sinusoidal vessels
    • Inefficient phagocytosis within sinusoids
  • aureus can also invade osteoblasts (protective mechanism)
  • Staphylococcus and other bacteria produce mucopolysaccharide glycocalyx layer (biofilm), protecting from phagocytosis, antibodies, and some antibiotics > allows recurrent infection after clinical resolution due to proliferation of bacteria that survived within the biofilm or in necrotic bone
• With vertebral osteomyelitis, the most common sequela is pathologic fracture and collapse of affected vertebrae with dorsal displacement of pus and necrotic bone into the spinal canal > sudden onset of neurologic signs
  • Trueperella pyogenes is most common cause in large animals; others include coli, Salmonella enterica, Staphylococcus sp., Streptococcus sp., Rhodococcus equi (foals); Fusobacterium necrophorum (calves); Mannheimia haemolytica, F. necrophorum and Staphylococcus sp.(sheep); Erysipelothrix rhusiopathiae, Staphylococcus sp., Streptococcus sp.(pigs); migration of plant material (dogs); bite wounds (cats)

 

TYPICAL CLINICAL FINDINGS:

• Lameness; pyrexia; lethargy; anorexia and weight loss; swollen joints, especially tarsal/metatarsal
• Fistulous tract with purulent exudate in chronic cases
• Pathologic fracture
• Paresis if pressure applied to the spinal cord

 

TYPICAL GROSS FINDINGS:

• Abscesses, especially in proximal epiphysis of femur, tibiotarsus, tarsometatarsus, and fifth to seventh vertebrae
• Discrete focal areas of pallor/yellow caseous exudate distinct from bone marrow
• Sequestra: Isolated foci of pale and chalky necrotic bone; an involucrum (sheath of reactive bone or granulation tissue) may form around the sequestrum
• Metaphyseal or epiphyseal abscesses may form (Brodie’s abscesses)
• Septic arthritis, synovitis with inflammatory exudates, or periosteal abscess if infection spreads through the epiphysis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Acute osteomyelitis: Fibrin, neutrophils (or heterophils), necrotic cells in the primary spongiosa, excessive osteoclastic resorption of trabeculae; must be differentiated from active myelopoiesis in young animals
  • The presence of fibrin and many heterophils and necrotic cells within primary spongiosa = osteomyelitis (normally no hematopoietic cells here)
• Chronic osteomyelitis: Necrotic debris in marrow spaces, fibrous connective tissue, mixed inflammatory population, thick granulation tissue surrounding large areas of necrotic bone with prominent osteoclastic activity at the margins
  • Neutrophils and plasma cells within reactive bone and connective tissue supports diagnosis of chronic osteomyelitis

 

ADDITIONAL DIAGNOSTIC TESTS:

• Radiograph: Osteolysis, often with new bone formation and sequestration
• Blood cultures and culture of necrotic debris
• Cytology – lytic bone exfoliates more readily; osteomyelitis usually consists of suppurative to pyogranulomatous inflammation depending on the cause +/- reactive osteoblasts; intracellular bacteria or fungal organisms may be visible

 

DIFFERENTIAL DIAGNOSIS:

• Enterococcus cecorum – an emerging avian pathogen associated with spondylitis, femoral head necrosis, and osteomyelitis in broiler chicken and broiler breeder flocks; more prevalent in males; 2-7% mortality; clinical signs (lameness, reluctance to walk, sitting on their hocks/tails) begin as early as 7-14 days old; pathogenesis not well understood (normal gastrointestinal flora)
• Other bacterial infections - in poultry, aureus and E. coli are most commonly isolated in osteomyelitis secondary to bacteremia; less commonly Salmonella, Yersinia, Streptococcus, Pasturella, and Arizonae Ornithobacterium rhinotracheale uncommonly causes osteomyelitis of the skull, joints, and vertebrae secondary to severe upper respiratory disease
• Mycobacterial infections – predominate in the bone marrow
• Fungal infections – Aspergillus spp, Candida spp, Cryptococcus , Histoplasma capsulatum
• Neoplasia

 

COMPARATIVE PATHOLOGY:

• Avian: Various aerobic and anaerobic bacteria; Mycoplasma meleagridis in turkey poults may cause osteomyelitis secondary to cervical airsacculitis in adjacent vertebrae; “Green liver-osteomyelitis complex” in turkeys is caused by aureus (and E. coli to a lesser extent) consisting of a green discolored liver and associated arthritis/synovitis, soft tissue abscesses and osteomyelitis of the proximal tibia
• Foals: Younger than 4 months; typically epiphyseal (rather than metaphyseal); most infections are beneath the thickest part of the articular cartilage especially in the caudal aspect of the femoral condyles dorsal to the weight-bearing surface; other sites include distal intermediate ridge of the tibia, medial styloid process of the radius, and proximal humerus; 70% have septic arthritis concurrently; common sequel to septicemia; Eschericha coli, Salmonella, Klebsiella spp., and Rhodococcus equi
  • A recent study in foals with septic arthritis/osteomyelitis showed that bacteria, neutrophils, and/or granulation tissue present within cartilage canals was associated with ischemic chondronecrosis and delayed ossification, which establishes sepsis as a cause of some osteochondral lesions in horses (Wormstrand 2018, Vet Pathol)
• Cattle: Not confined to young animals (2wk to 5yrs); hematogenous osteomyelitis 5x more common than posttraumatic osteomyelitis;
  • Metaphyseal osteomyelitis (type 1) in long bones, particularly distal metacarpus, metatarsus, radius and tibia (associated with Trueperella pyogenes, usually >6 months old)
  • Epiphyseal osteomyelitis in distal femoral condyle, distal radius and patella (associated with Salmonella, usually < 3 months old); usually have bacterial arthritis concurrently
  • Mandibular osteomyelitis (“lumpy jaw”) from Actinomyces bovis following a penetrating injury of the oral mucosa or periodontitis, affected mandible has a “honeycomb” appearance, “bone sand” (purulent exudate) with light yellow “sulfur” granules, Splendore-Hoeppli material on H&E
  • Local osteomyelitis secondary to trauma, dehorning, foot rot (Fusobacterium necrophorum), etc. is also common in cattle
• Dogs: Rare; may occur in bacteremic puppies due to neutropenia or neutrophil adhesion defects (e.g. parvovirus survivor, LAD); more often from local extension (severe bacterial periodontitis into the maxilla or mandible in older dogs) or implantation (open fractures [long bones of appendicular skeleton more common], contaminated surgical repair, bite wounds, gunshot injury, implants); Staphylococcus (especially pseudintermedius) and Streptococcus the most common organism;
• Cats: Rare; reported with Bartonella vinsonii bacteremia; more often from local extension (infected/loose maxillary canine teeth causing surrounding alveolar bone to form a smooth nodular proliferation, even after tooth removal – alveolar osteitis or feline buccal bone expansion) or implantation (see discussion in dogs above)
• Swine: “Atrophic rhinitis” osteomyelitis due to co-infection of toxigenic multocida type D and Bordetella bronchiseptica inhibiting osteoblast differentiation and stimulating osteoclast activity, resulting in bone loss; tail biting and tail docking in piglets may provide a route of entry for vertebral osteomyelitis
• Lambs, goats, and deer: Hematogenous osteomyelitis and arthritis frequently occur together (like in foals and cattle); in lambs, tail docking may provide a portal of entry for vertebral osteomyelitis; Rhodococcus equi (with VapN plasmid) reported to uncommonly cause vertebral and humeral osteomyelitis in goats as part of a systemic pyogranulomatous disease process
• Non-human primates: rare (or under-reported); local osteomyelitis more common and often secondary to fractures or fight wounds; single case of hematogenous osteomyelitis affecting both knees in an immunosuppressed rhesus macaque 42 days after the onset of salmonella enteritis; tuberculosis involving the bone has been infrequently described
• Snakes: A recent study reclassified bony alterations in 24 post-cranial skeletons as osteomyelitis rather than neoplasia; osteomyelitis was most common in Viperidae snakes (Rothschild, J Comp Pathol. 2021)
• Ring tailed lemur: A recent case report of osteomyelitis caused by systemic infection with Yersinia pseudotuberculosis with lesions in the musculature, periosteum, and bone marrow of the hip, ribs, and cervicothoracic junction vertebra (Walker, J Comp Pathol. 2018)
• Painted reed frogs: Case series of granulomatous spinal osteomyelitis associated with Mycobacterium chelonae complex in 20 animals (Barrows, J Comp Pathol. 2017)

 

REFERENCES:

1. Barger AM. Musculoskeletal System. In: Raskin RE, Meyer DJ, eds. Canine and Feline Cytology: A Color Atlas and Interpretation Guide. 3^rd St. Louis, MO: Elsevier; 2016:363-364.
2. Barrows M, Koeppel K, Michel A, Mitchell E. Mycobacterial arthritis and synovitis in painted reed frogs (Hyperolius marmoratus). J Comp Pathol. 2017;56(2-3):275-280.
3. Borst LB, Suyemoto MM, Sarsour AH, et al. Pathogenesis of Enterococcal Spondylitis Caused by Enterococcus cecorum in Broiler Chickens. Vet Pathol. 2017;54(1):61-73.
4. Craig LE, Dittmer KE, Thompson K. Bones and joints: In: Maxie MG, ed. Jubb Kennedy and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:97-103.
5. Fulton RL. Bacterial diseases. In: Boulianne M, et al, eds. Avian Disease Manual. 8^th Jacksonville, FL: AAAP, Inc.; 2019:81-82, 94, 109-110, 114.
6. Levi M, Dittmer KE, Gentile A, et al. Growth plate lesions of fattening bulls. Vet Pathol. 2017;54(3):437-444.
7. Luthje FL, Skovgaard K, Jensen HE, et al. Receptor activator of nuclear factor kappa-B ligand is not regulated during chronic osteomyelitis in pigs. J Comp Pathol. 2020;179:7-24.
8. Olson EJ and Carlson CS. Bones, Joints, Tendons, and Ligaments. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6^th St. Louis, MO: Elsevier, 2017:983-986.
9. Pritzker KPH and Kessler MJ. Arthritis, Muscle, Adipose Tissue, and Bone Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, et al, eds. Nonhuman Primates in Biomedical Research, Vol 2. 2^nd San Diego, CA: Academic Press; 2012:664.
10. Rothschild B. Survey of post-cranial skeletal pathology in snakes. J Comp Pathol. 2021;183:39-44.
11. Schmidt RE, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2^nd Ames, IA: John Wiley and Sons, Inc; 2015:212-213.
12. Shivaprasad HL. Miscellaneous diseases. In: Boulianne M, et al, eds. Avian Disease Manual. 8^th Jacksonville, FL: AAAP, Inc.; 2019:170.
13. Stranahan LW, Plumlee QD, Lawhon SD, et al. Rhodococcus equi infections in goats: characterization of virulence plasmids. Vet Pathol. 2018;55(2):273-276.
14. Walker D, Gibbons J, Harris JD, et al. Systemic Yersinia pseudotuberculosis as a cause of osteomyelitis in a captive ring-tailed lemur (Lemur catta). J Comp Pathol. 2018;164:27-31.
15. Wormstrand B, Ostevik L, Ekman S, et al. Septic arthritis/osteomyelitis may lead to osteochondrosis-like lesions in foals. Vet Pathol. 2018;55(5):693-702.

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