Read-Only Case Details Reviewed: Sep 2008

JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

AUGUST 2023

P-B10

Slide A: Signalment (JPC #4117518): Three-year-old, male cynomolgus macaque (Macaca fascicularis) from China.

HISTORY: This animal was found dead on day 109 of a 6-month routine general toxicity study. There were no reported clinical signs. Three consecutive tuberculosis skin tests as well as routine infectious agent screens were all negative, with the exception of measles which was positive due to vaccination with live vaccine. On gross examination there were moderate, focal to multifocal, tan foci on the liver and lung with moderate swelling of the mediastinum. Skin discolorations with abrasions and scabs were present on the ventral abdomen and right forelimb.

HISTOPATHOLOGIC DESCRIPTION: Lung: Approximately 60% of the parenchyma is effaced and replaced by multifocal to coalescing poorly formed granulomas. Granulomas range up to 4mm in diameter and are composed of necrotic centers containing large numbers of viable and degenerate neutrophils and moderate numbers of macrophages mixed with eosinophilic cellular and karyorrhectic debris, basophilic mucin, and scattered mineralization. These areas of necrosis are surrounded by numerous epithelioid macrophages, few multinucleated giant cells (Langhans and foreign body type), and more peripherally by lymphocytes and plasma cells. Less mature granulomas lack a necrotic center. Some granulomas are circumscribed by a thin fibrous connective tissue capsule. Intervening alveolar lumina are filled by varying combinations and concentrations of edema fluid, small amounts of hemorrhage and fibrin, foamy alveolar macrophages, and neutrophils. Alveolar septa are occasionally lined by hyperplastic type II pneumocytes and expanded by congestion, hyperplastic interstitial and intravascular macrophages, and circulating neutrophils, and occasionally small amounts of collagen. Airways are filled and expanded by an exudate composed of abundant basophilic mucus and large numbers of viable and degenerate neutrophils and macrophages admixed with cellular debris. Multifocally, aggregates of lymphocytes and plasma cells surround blood vessels.

Spleen: There is diffuse severe follicular hyperplasia of the white pulp, and normal red pulp architecture is effaced by large numbers of macrophages filling sinusoids. At one edge is a cluster of granulomas similar to those previously described, but with abundant fragmented crystalline mineral within the necrotic center.

Liver: Essentially normal tissue.

SLIDE B: Acid-fast stain: There are rare, intrahistiocytic, 0.5x2µm, acid-fast bacilli.

MORPHOLOGIC DIAGNOSIS: 1. Lung: Granulomas, chronic, multifocal to coalescing, severe, with rare intrahistiocytic acid-fast bacilli, cynomolgus macaque (Macaca fascicularis), nonhuman primate.

2. Spleen: Granulomas, chronic, multifocal to coalescing, severe, with mineralization.

ETIOLOGIC DIAGNOSIS: Mycobacterial pneumonia and splenitis

CAUSE: Mycobacterium tuberculosis

CONDITION: Tuberculosis

Slide C: Signalment JPC #3133951): 11-month-old, male Sannen goat (Capra aegagrus hircus)

HISTORY: This animal was part of a herd that had previously tested positive for bovine tuberculosis. It presented with fever, dyspnea, and claudication and tested positive for tuberculin cervical skin test.

SLIDE C: Lung: Affecting approximately 40% of this section, there are multifocal to coalescing granulomas that efface the pulmonary parenchyma, compress adjacent alveoli, and elevate the pleural surface. Granulomas are centered on large areas of lytic necrosis composed of abundant eosinophilic karyorrhectic and cellular debris with aggregates of mineral, surrounded by a layer of viable and degenerate neutrophils, surrounded by epithelioid macrophages with occasional multi-nucleated giant cells (Langhan’s and foreign-body type), further surrounded by lymphocytes and plasma cells with a rim of fibrous connective tissue. Adjacent alveolar septa are congested and thickened by macrophages, neutrophils, lymphocytes, and plasma cells. Alveoli occasionally contain pale eosinophilic fluid (edema) with increased numbers of alveolar macrophages. Blood vessels are occasionally surrounded by aggregates of lymphocytes and plasma cells. There is perivascular edema surrounding larger vessels. The pleural surface is moderately thickened by edema and increased fibrous connective tissue with scattered macrophages.

MORPHOLOGIC DIAGNOSIS: Lung: Granulomas, chronic, multifocal to coalescing, severe, Sannen goat (Capra aegagrus hircus), caprine.

ETIOLOGIC DIAGNOSIS: Mycobacterial pneumonia

CAUSE: Mycobacterium bovis

CONDITION: Tuberculosis

GENERAL DISCUSSION:

Mycobacterium spp. are facultative intracellular, aerobic, gram positive (but poorly staining), non-motile, non-spore-forming bacilli
Mycobacteria are acid-fast because of the mycolic acid and high lipid content of their cell walls; also very resistant to heat, pH changes and many disinfectants
Mycobacteria are generally divided into three large groups
1. Tuberculosis group (referred to as M. tuberculosis complex or MTBC): M. tuberculosis, M. bovis, M. microti, M. mungi, M. caprae, and others
2. Leprosy group: M. lepraemurium, M. leprae, M. visibilis
3. Opportunistic group:
  - Rapid-growing: e.g. M. fortuitum, M. chelonae, M. abscessus
  - Slow-growing: e.g. M. ulcerans, M. avium-intracellulare complex (MAIC) including M. avium spp. paratuberculosis
Of the MTBC, M. tuberculosis and M. bovis are most common
1. “Tuberculosis” refers to disease caused by either M. tuberculosis or M. bovis, “mycobacteriosis” is used to refer to other nontuberculous mycobacteria
Humans serve as reservoir for M. tuberculosis which most commonly infects non-human primates (and contact with humans is the primary route of exposure)

PATHOGENESIS:

Bacteria are inhaled, then enter terminal bronchioles and alveolar spaces
Cell wall glycolipids and waxes of bacteria help trigger initial macrophage response
Bacteria are phagocytized by macrophages through interaction with pathogen pattern recognition receptors (PRRs) including complement receptors 1, 3, and 4, mannose, surfactant proteins, LAM, and CD14
Bacteria are either killed or survive by inhibiting phagosome-lysosome fusion and antimicrobial mechanisms of macrophages
Bacterial PAMPs activate macrophage PRRs -> more monocyte, macrophage, neutrophil recruitment -> more granulomatous inflammation
γδ T-cells increased in early M. tuberculosis infection; may help bridge gap between innate and adaptive immune response(Pereira et. al J Comp Pathol 2021)
Macrophages cause a delayed type IV hypersensitivity reaction by acting as antigen-presenting cells and secreting IL-12 which causes CD4+ TH1 lymphocytes to secrete IFN-gamma (which activates additional macrophages) and IL-2 (which induces proliferation and survival of T lymphocytes) leading to a cell-mediated immunityàtuberculoid granuloma
Heavily infected macrophages die off forming the necrotic center
1. Combination of hypoxia and free radical-mediated injury
Large numbers of organisms lead to extensive cell necrosis and tissue destruction; bacilli may become dormant within caseous center replicate extracellularly in the liquefied material
In humans and non-human primates, infection can be maintained in a controlled state by the host immune system, spontaneously reactivate, or become reactivated if the host immune system is suppressed by another cause.
1. T-cell response critical for controlling disease
Natural resistance-associated macrophage protein (Nramp 1 & 2) is a membrane protein involved in innate immunity to M. bovis (in humans and mice) that is primarily expressed in macrophages and tissues of the reticuloendothelial system
Bacilli are released when tubercles rupture and enter the airways, spreading to other parts of the lung or may be coughed up and swallowed, entering the GI tract
1. Hematogenous spread can occur when a granuloma erodes a vessel wall
2. Leukocyte trafficking is another method of dissemination suggested in some host/species interactions
Mycobacterial virulence factors (including proteins and cell wall components):
1. Early secreted antigenic target (ESAT)-6: Helps induce macrophage recruitment, phagosome lysis, induction of apoptosis, induction of TNF-alpha secretion by T lymphocytes -> granuloma formation/expansion
  - Used for interferon gamma release assay (IGRA) diagnostic test used in humans (Pereira et. al J Comp Pathol 2021)
2. TB10.4 protein: Structural and functional homolog of ESAT-6; contains CD8+ T-cell epitopes, also important for granuloma formation/maintenance
3. Hydrophobic layer of mycolic acids: Bestows hydrophobicity to cell wallàenvironmental and antimicrobial resistance
4. Cord factor (trehalose dimycolyl): Surface glycolipid that inhibits chemotaxis, acts as adjuvant and is leukotoxic; also main component of complete Freund’s adjuvant (CFA)
5. Mycosides form a barrier against lysosomal digestion and allow organism to survive within macrophage
6. Tuberculoproteins and purified protein derivatives (PPD) are necessary for development of humoral and cell-mediated immune responses (used for intradermal skin testing)
7. Sulfatides: Surface glycolipid containing sulfur which prevents fusion of phagosome with lysosome and interferes with reactive oxygen species
8. Lipoarabinomannan (LAM): Heteropolysaccharide, cell wall component; inhibits macrophage activation by IFN-gamma, induces macrophages to secrete TNF-alpha (causes fever, tissue damage) and IL-10 (suppresses T cell proliferation), and can scavenge oxygen radicals
9. Phthiocerol dimycocerosate (PDIM): Present on outermost surface of cell wall; influences TLR binding and activation of macrophages
10. Urease: Secreted enzyme that inhibits acidification of phagosomes
11. Cell wall lipid lipomannan: Induces fusion of epitheliod macrophages

TYPICAL CLINICAL FINDINGS:

Anorexia with listlessness, weakness, depression
Reduced milk production
Progressive emaciation
Cutaneous abscesses and peripheral lymphadenopathy
Hepatomegaly, splenomegaly
Coughing, exercise intolerance, progressive dyspnea
Blood smear – In rare systemic infections, bacilli may appear as clear rods within neutrophils or macrophages (do not stain with Wright stain)

TYPICAL GROSS FINDINGS:

Classic gross lesion: Tubercles that are circumscribed, often encapsulated, tan to yellow foci of granulomatous inflammation with a central core of caseous necrosis and/or mineralization
1. Larger lesions may have a liquid or suppurative core
Other lesions depend on the Mycobacterial species, affected species and immune response, route of exposure, and stage of disease and include regional lymph nodes, spleen, liver, kidney, intestine, mesenteric lymph nodes, vertebra, spinal cord, eyes, bone, skin

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Tubercles are the classic lesion: Central core of necrosis with nuclear debris +/- mineral, surrounded by epithelioid macrophages and multi-nucleated giant Langhans cells (fused, activated macrophages), encapsulated by collagenous connective tissue with lymphocytes, plasma cells, +/- neutrophils; acid-fast bacilli variably seen within macrophages or extracellularly
In elk and deer with M. bovis, suppurative inflammation may be prominent with less fibrosis and giant cells

ULTRASTRUCTURAL FINDINGS:

Fibrillar, electron-opaque nuclear area
Periphery is densely filled with ribosomes
Capsule in close contact with cell wall

ADDITIONAL DIAGNOSTIC TESTS:

Intradermal tuberculin skin test (eyelid or abdominal skin, I-M01)
PCR, ELISA
Special stains: Acid-fast (Fite-Faraco, Ziehl-Nielson) and more recently developed technique: Auramine O and Rhodamine B fluorescent stains
Culture: Lowenstein-Jensen media, takes 4-8 weeks to culture
1. M. tuberculosis prefers glycerol and is niacin-positive; M. bovis is inhibited by glycerol and is niacin-negative
TiKa – novel decontamination and culture technique to improve growth

DIFFERENTIAL DIAGNOSIS:

Foreign body granuloma or foreign body pneumonia (granulomatous pneumonia in pigs)
Cestode cysts
Pneumonyssus simicola (lung mite): Important differential in macaques
Bacterial diseases: Nocardiosis, actinomycosis, actinobacillosis, Fusobacterium necrophorum, Mycoplasma bovis, Rhodococcus equi in horses
Fungal diseases: Cryptococcosis, blastomycosis, aspergillosis, histoplasmosis, coccidiodomycosis

COMPARATIVE PATHOLOGY:

Mycobacterium spp. in other animals:

MTBC affects old and new world primates
1. M. tuberculosis usually spread from humans; infection with M. bovis also possible
2. NW primates more resistant; may not always form pulmonary granulomas, especially in the early course of the disease
3. OW primates: disease spreads rapidly in captive populations, high morbidity and mortality
  - Cynomolgus monkeys may develop clinically silent disease
4. Non-human primates are also susceptible to M. avium-intracellulare complex (MAIC) and many atypical mycobacteria (M. marinum, M. kansasii, M. lepraemurium)
  - Atypical mycobacteria usually don’t cause clinical disease, but may cause positive intradermal TB tests
Apes: All ape species susceptible to MTBC pathogens
1. Transmission usually from humans to apes; oral infection from unpasteurized milk fed to infant apes possible as well
2. Clinical course and lesions similar to OW primates
Cattle: Respiratory and enteric syndromes

M. bovis - Pneumonia; extensive caseation and calcification of tubercles; May spread to pleura (hard, white nodules= “pearl disease”)
M. avium ss. paratuberculosis - Johne’s disease

Horse: Usually enteric with lesions in retropharyngeal and mesenteric lymph nodes and intestine; most commonly MAIC, M. tuberculosis, or M. bovis
1. Hematogenous dissemination to lungs possible -> granulomas not caseous or calcified (often resemble sarcomatous nodules)
Sheep and Goats: Usually respiratory syndrome (granulomatous pneumonia), similar to cattle; M. caprae is most common but M. bovis and MAIC also occur
Swine: M. bovis, M. tuberculosis and MAIC

M. bovis, similar lesions as in cattle
- Wild boar are considered spillover/dead-end host
  - Boar with higher Porcine circovirus 2 prevalence also have higher M. bovis prevalence and more severe disease
MAIC - usually enteric with lesions in retropharyngeal and mesenteric lymph nodes and spreads hematogenously to lungs

Guinea pigs: Highly susceptible to M. tuberculosis and M. bovis but natural disease is rare
Mice: Relatively resistant; MAIC most reported
1. B6 and BALB/c carry Bcg^s susceptibility allele
2. DBA/2 and C3H/He carry Bcg^r resistance allele
Hamsters: Documented but rare infection with M. tuberculosis and M. chelonai
Rabbits: Susceptible to M. bovis and M. tuberculosis but natural infection is rare
1. Prone to develop cavitary pulmonary lesions with dissemination to other organs -> valued as models for human tuberculosis
Cat/dog: Uncommon; enteric disease in cats, respiratory disease in dogs
1. Cats: Usually M. bovis, M. microti also reported; M. tuberculosis infection is rare
  - Feline ocular mycobacteriosis reported species include M. bovis, M. microti, MTBC, MAIC
  - Feline leprosy – M. lepraemurium, and M. tuberculosis can both cause dermal lesions in cats
2. Tuberculosis in dogs and cats often appears as granulation tissue; discrete tubercles are uncommon
Fish: M. marinum, M. fortuitum, M. chelonae, and others
1. Most common chronic disease of aquarium fish (also affects wild fish); infects kidney, spleen, other viscera, skin, bones; not specific to respiratory system (gills)
  - Mycobacterium persistent in biofilms in artificial aquatic systems
African clawed frogs: M. marinum; sarcoma-like inflammatory response
Australian marsupials – Highly susceptible, MTBC and MAIC infections reported
1. Brushtail possums in New Zealand are M. bovis reservoir
2. Fibrous encapsulation not a prominent feature of granulomas in marsupials, may allow bacteria to be transmitted more easily
Elephants: Most commonly M. tuberculosis with rare cases of M. bovis and other MTBC species
1. Both zoonotic and anthropozoonotic infections can occur
2. Infection most often result in pulmonary disease with spread to thoracic lymph nodes; typically chronic sub-clinical disease
Free ranging rhinos: M. bovis and M. tuberculosis have been reported to cause granulomas in lungs and lymph nodes
1. M. orygis reported in free-ranging Indian rhinoceros
Hyrax: Specific variant of MTBC called “dassie bacillis” and M. microti-like bacteria reported in some cases
1. Weight loss, lameness, pneumonia, and reproductive failure have been associated with infections; granulomas are found in the lungs, liver, spleen, and kidney
Mustelids: M. bovis and MAIC
1. Ferrets - Affects spleen, liver, intestines (hepatic lesions most common)
  - Feral ferrets in New Zeland are reservoir host; can amplify and transmit to cattle
2. Badgers – Pulmonary granulomas most common lesion
Giraffes and non-domestic bovids: Sporadic infection with M. tuberbulosis reported; may be indistinguishable from M. bovis
M. bovis reservoir hosts in wildlife species include African buffalo, lechwe (antelope), wood bison, white-tailed deer, waipiti, fallow deer, and red deer (cervids may be infected with M. caprae as well)
1. Kudu may act as maintenance host or spillover host
  - Kudu usually get swelling in parotid and submandibular areas with draining fistulae
2. Roe deer may be spillover host
3. Cervids may be infected for years without showing clinical sings, and shed bacteria during that time
  - Red deer identified as supershedders (susceptible and resistant breed lines)
4. Cervids: Tuberculous lesions in lungs, tonsils, several lymph nodes, ileocecal junction
Camelids: Disease reported more frequently in Old World camelids New World camelids; M. tuberculosis, M. bovis, or other members of tuberculosis complex
1. Giant cells rarely seen in OW camelids but may be seen in M. microti infections in NW camelids
Carnivores: Red foxes, gray foxes, wolves, coyotes, fennec foxes (captive), black bears, sloth bears (captive)
1. Infection with M. bovis – Transmission may occur by eating infected prey
2. Gross lesions often not seen (need histo or other testing)
3. Wild and captive felids mainly infected with M. bovis
  - Factors related to susceptibility to disease and recrudescence include inbreeding in lion populations and stress or concurrent disease
  - External lesions: Decubital ulcers, alopecia, corneal opacity, elbow and hock hygromas
  - Internal lesions: Systemic or granulomatous inflammation in the lung, lymph nodes, spleen, kidneys, adrenal glands, eye, arthritis, osteomyelitis (plus sequelae - pneumothorax, hydrothorax, pleural adhesions)
    - Typical granulomas are uncommon
Meerkats - M. suricatta and M. microti
- Spread by grooming (inhalation)
Mongoose - Nasal lesions from M. mungi
- Other lesions develop from hematogenous spread
  - Fibrosis is minimal, casesous necrosis in granulomas is variable in lung and lymph node lesions
- M. bovis lesions in mongoose are typical granulomas
Prosimians (ring-tailed, ruffed, black, and mongoose lemurs): M. tuberculosis
1. Sub-clinical or disease; clinical disease includes typical granulomatous inflammation or granulomas
2. M. xenopi described in a captive black and white-ruffed lemur with similar extra-pulmonary lesions
Cetaceans: Diverse species of bacteria, large spectrum of lesions (atypical mycobacteriosis)
1. M. chelonae in a bottle-nosed dolphin
  - Panniculitis with blubber pyogranulomas, necrosuppurative pneumonia and lymphadenitis
2. M. abscessus in a bottle-nosed dolphin
  - Pyogranulomatous pneumonia
3. M. marinum in a beluga whale
  - Ulcerative dermatitis, panniculitis, and chronic proliferative pleuritis
4. Untyped mycobacterium in pygmy sperm whale
  - Pyogranulomatous lymphadenitis
Pinnipeds -M. pinnepedii (member of MTBC)
1. Clinical disease - poor body condition, 2 main gross presentations:
  - 1 - Granulomatous to pyogranulomatous pleuropneumonia, thoracic lymphadenitis and mediastinitis with pronounced fibrinous or serosanguinous effusion
  - 2 - Multifocal caseating granulomas within the lungs and thoracic lymph nodes
Captive Sirenia (manatees) - M. marinum, M. fortuitum, M. kansaii, and M. chelonei
1. Typical tuberculoid granulomas in lungs and lymph nodes
  - Lesions in pleura, testicles, skin also possible
Reptiles and amphibians: Mostly non-tuberculous infections reported in captive reptiles and amphibians, less frequently in free-ranging animals
1. Pulmonary mycobacteriosis common in boids (typical reptilian granulomatous inflammation)

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