JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
February 2022
E-P01 (NP)

Signalment (JPC #1410389):  Cat

HISTORY:  This cat presented with a generalized disease.

HISTOPATHOLOLOGIC DESCRIPTION:  Adrenal gland:  Randomly within all layers of the cortex and occasionally extending into the medulla are multifocal areas of lytic necrosis characterized by loss of tissue architecture and replacement by eosinophilic cellular and karyorrhectic debris.  Adjacent to the necrotic foci, occasional cells have pyknotic or karyolytic nuclei and loss of cellular detail (single cell death), and are surrounded by mild hemorrhage, fibrin, and edema.  Within and at the periphery of necrotic areas are few aggregates of intracytoplasmic and extracellular, 2-3 um, round to crescent-shaped, basophilic, apicomplexan tachyzoites.  Foci of necrosis in the medulla contain many neutrophils and few macrophages.  Occasionally, there are few intracellular tachyzoites within these macrophages and neutrophils.

Lung:  Over 75% of the alveolar lumina and to a lesser extent bronchiolar lumina are multifocally filled with high numbers of macrophages, active and necrotic neutrophils, and fewer lymphocytes admixed with variable amounts of edema, hemorrhage, eosinophilic fibrillar material (fibrin), and sloughed necrotic epithelial cells.  Alveolar macrophages are occasionally multinucleated and frequently contain aggregated, and less often individualized, 2-3 um, round to crescent-shaped, basophilic, intracytoplasmic tachyzoites.  In the most severely affected areas, alveolar septa are discontinuous or lost and replaced by eosinophilic cellular and karyorrhectic debris (septal necrosis).  Remaining alveolar septa are expanded up to 5x normal by congestion, fibrin, and edema, and are occasionally lined by few hyperplastic type II pneumocytes.

MORPHOLOGIC DIAGNOSIS:  1.  Adrenal gland:  Adrenalitis, necrotizing, acute, multifocal, moderate, with extracellular and intracytoplasmic apicomplexan tachyzoites, breed unspecified, feline.

2. Lung: Pneumonia, interstitial, necrotizing, subacute, multifocal to coalescing, severe, with edema and extracellular and intracytoplasmic apicomplexan tachyzoites.

ETIOLOGY:  Toxoplasma gondii

ETIOLOGIC DIAGNOSIS:  Adrenal and pulmonary toxoplasmosis

GENERAL DISCUSSION:

• Cyst-forming, obligate intracellular coccidian in the phylum Apicomplexa; causes disseminated disease, central nervous system infections, and abortions in many species (except cattle are resistant to abortion)
• Entire life cycle is completed only in the felid (definitive host); over 200 species of mammals and birds can serve as intermediate hosts
• Sporozoites and tachyzoites are readily destroyed; tissue cysts (bradyzoites) are resistant and perpetuate the disease
  • Tachyzoites (trophozoites) are rapidly dividing forms and occur in free groups
  • Bradyzoites multiply slowly and are found in tissue cysts
  • Oocysts contain infective sporozoites after being shed in the cat feces; oocysts are only shed for 1-2 weeks

LIFE CYCLE:

Definitive host, intestinal/enteroepithelial/coccidian cycle (felids):

• Ingestion of infected prey tissue (tachyzoites or cysts containing bradyzoites), or ingesting sporulated oocysts in contaminated food or water à sporozoites released (excyst) from oocyst or bradyzoites infiltrate intestinal epithelial cells (especially the ileum) and undergo five recognized asexual stages (schizont cycle) and eventually form a male microgamont or female macrogamont à in the sexual phase (gamont cycle), microgamonts are released and fertilize a macrogamont to form an oocyst à oocysts (unsporulated, noninfective) are shed in feces 3-10 days after ingesting bradyzoites, 13 days after ingesting tachyzoites, and 18 days after ingesting oocysts à sporulation (development of infective sporozoites inside the oocyst) takes 1 to 5 days, depending on environmental conditions

Intermediate hosts, extraintestinal cycle (many mammals and birds, including felids):

• Ingestion of infected prey tissue (tachyzoites, or cysts containing bradyzoites), ingestion of sporulated oocysts in contaminated food or water, or transplacental (common in sheep and goats) à sporozoites released from oocyst or bradyzoites released from tissue cyst within the lumen of the small intestine à invade enterocytes and divide asexually (endodyogeny) within a parasitophorous vacuole to form tachyzoites (rapidly dividing; form associated with acute disease) à tachyzoites lyse the enterocyte and spread locally to adjacent enterocytes, the lamina propria, and monocytes-macrophages, and to local and regional lymphoid tissues (e.g. Peyer’s patches, mesenteric lymph nodes) à tachyzoites spread systemically and can multiply and survive intracellularly in almost any tissue in the body (e.g. lungs, lymphoid system, liver, heart, skeletal muscle, pancreas, intestine, eyes, nervous system) within a parasitophorous vacuole, destroying the host cell with cell-to-cell transmission à focal necrosis
• With chronicity and the development of an antibody response, tachyzoites transform into slow-growing/replicating bradyzoites within tissues; these bradyzoites may proliferate for an indefinite number of generations
• Transplacental infection can occur when previously uninfected hosts are exposed and infected during pregnancy; the organism multiplies in the placenta and spreads to fetal tissues (mechanism of spread is unknown)

PATHOGENESIS:

• Transmission efficacy varies based on life stage ingested: cats can become infected after ingestion of one bradyzoite, but it takes up to 1,000 oocysts
• gondii may localize in the adrenal cortex (similar to other infectious agents) due to the high local concentration of steroids, which suppress the cell mediated immune response
• gondii tachyzoites express glycosylphosphatidylinositol-linked surface proteins (SAGs, e.g. SAG1 and SAG3) that function in target cell attachment and immune modulation, and may also cause direct injury to enterocytes; SAG1 binds to enterocyte laminin, lectin, and SAG receptor proteins
• gondii is able to infect all types of cells because it binds laminin (an extracellular matrix protein) and then binds to laminin receptors on the target cell
• Rhoptries in apex of tachyzoites produce lytic substances that facilitate cell invasion and form a parasitophorous vacuole
• Parasitophorous vacuole: A “hybrid” membrane within the host cell that helps the organism avoid detection by the immune system, avoids fusion with macrophage lysosomes, and promotes the production of anti-inflammatory cytokines IL-10 and TGF-β (which inhibit production of IL-12, IFN-γ, and TNF-α)
• Low levels of IFN-γ à decreased macrophage activation à predisposition to systemic toxoplasmosis and other diseases (e.g. canine distemper, ehrlichiosis, and lymphoma in dogs)
• Bradyzoites revert to tachyzoites in the absence of IFN-γ
• Necrosis due to direct cell damage from organism multiplication and inflammatory cytokine-mediated destruction
• gondii can cross barrier systems (intestinal mucosa, blood-brain barrier, blood-retinal barrier, and placenta) using parasite motility (linear myosin, F-actin filaments, and gliding-associated proteins) and infect endothelial cells > vasculitis > ischemic necrosis
• Humoral and cell mediated immunity cause formation of tissue cysts within the CNS, skeletal and cardiac muscle
• Type III hypersensitivity may be involved in vascular injury and type IV hypersensitivity may be involved in tissue necrosis
• Immunosuppression of latently infected hosts allows cysts to rupture with reactivation of acute disease
• CNS infection occurs hematogenously; neurons and astrocytes are the eventual targets

TYPICAL CLINICAL FINDINGS:

• Infects wild and captive felids; rarely associated with disease, except captive Pallas’ cats uniquely susceptible
  • High neonatal mortality: pneumonia, necrotizing encephalitis, +/- hepatitis, necrotizing to granulomatous inflammation in kidney, adipose, and spleen
  • Aged Pallas’ cats: encephalomyelitis
• Enteroepithelial cycle (other cats): Self-limiting diarrhea or asymptomatic
• Extraintestinal cycle: Infection is widespread (determined by serologic studies), but disease is sporadic and rare unless immunocompromised (exception: an important cause of abortion in sheep and goats); clinical signs depend on organs affected:
  • CNS infection (N-P02): Neurologic signs vary with age, species, and lesion localization; may include seizures, paresis, weakness, tremors, depression, circling, blindness, and ataxia
  • Radiculoneuritis: Affects puppies less than 3 months old; acute paraparesis with rigid extension of hind limbs, loss of patellar and withdrawal reflexes, pain, and muscle wasting
  • Disseminated disease: Fever, lethargy, anorexia, ocular and nasal discharges, and respiratory distress
  • Abortion (R-P01): common in sheep and goats; outcome depends on maternal and fetal immune response and stage of gestation:
    • Early or mid-gestation infection: fetal death with resorption or mummification
    • Mid-gestation infection: Occasionally lambs survive to term but are stillborn or are weak and die shortly after birth
    • Late pregnancy: Fetus develops an immune response and is born live, infected, and immune
    • Few fetuses may develop cerebral leukoencephalomalacia secondary to the anoxia from placentitis or fetal inflammatory syndrome (Gutierrez-Exposito et al., Vet Pathol. 2020)

TYPICAL GROSS FINDINGS:

• Hallmarks: Interstitial pneumonia, focal hepatic necrosis, lymphadenitis, myocarditis, and nonsuppurative meningoencephalitis
• Multifocal necrosis is present in multiple organs (lung, liver, kidneys, intestine, pancreas, placenta, skeletal muscle, heart) and thought to be related to the rapid replication of tachyzoites
• Lung (P-P01): Most commonly identified in kittens; pinpoint white foci scattered throughout the lung or diffuse interstitial pneumonia
• Splenomegaly and lymphadenomegaly
• Eye: Granulomatous chorioretinitis
• Aborted fetus: gondii produces pathognomonic lesions in the placenta of sheep and goats, consisting of multifocal necrosis and mineralization of cotyledonary villi; individual cotyledons contain 1-2 mm yellow to white foci of necrosis or flecks of mineral anywhere on the villus from the tip to the base; bright to dark red cotyledons (purple color is normal); intercotyledonary chorioallantois may be edematous or unaffected

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• The finding of tachyzoites and/or cysts in association with areas of coagulative or lytic necrosis in one or more organs is highly suggestive of toxoplasmosis; inflammatory response often minimal
• Lung:
  • Tachyzoites are usually evident in alveolar macrophages and may be in bronchiolar epithelium and vessel walls
  • Diffuse interstitial pneumonia: Alveolar septa thickened by predominantly mononuclear inflammatory cells (fewer neutrophils, eosinophils); alveoli filled with macrophages and fibrinous to fibrinonecrotic exudate +/- occasional hyaline membranes; scattered foci of necrosis of alveolar septa, bronchiolar epithelium, and blood vessels
  • Subacute: Abundant type II pneumocyte hyperplasia, or “epithelialization of alveoli”; may be sufficiently abundant to appear adenomatous
• Other tissues (liver, lymph nodes, spleen, pancreas, heart, skeletal muscle): Intracellular tachyzoites, variably sized necrotic foci with variable presence of inflammation (predominantly mononuclear)
• CNS: Nonsuppurative meningoencephalitis of gray and white matter (especially perivascular), vasculitis, hemorrhage, necrosis, tissue cysts, leptomeningitis; gliosis and tissue cysts in chronic cases
• Radiculoneuritis: Lymphoplasmacytic and histiocytic inflammation most severe in the roots of the lumbosacral spinal cord
• Eye: Granulomatous chorioretinitis
• Placenta: Multifocal cotyledonary necrosis +/- mineralization with rare organisms within trophoblasts; fetal brain - multifocal necrosis and gliosis (Meixner N. et al., J Vet Diagn Invest. 2020)
• Aborted fetus:
  • Brain: 95% of infected fetuses have mild nonsuppurative encephalitis with few scattered foci of necrosis and glial and mononuclear infiltrates; protozoa are more likely to be found in parts of the brain rostral to the pons and in the optic tracts; focal areas of leukoencephalomalacia without cellular infiltration and toxoplasma cysts at the periphery of lesions

ULTRASTRUCTURAL FINDINGS:

• Tachyzoites within a parasitophorous vacuole, 4-6 um diameter
• Pellicle (outer membrane) consists of 3 membranes: A plasmalemma and two closely applied membranes that form an inner membrane complex
• At the anterior surface is a cylindrical cone (conoid) consisting of microtubules wound like a spring and is used to probe host cell surface prior to entry
• Rhoptries are club-shaped excretory organelles between the anterior tip and nucleus that secrete a proteolytic enzyme used in host cell penetration
• Micronemes are rod-shaped structures found at the anterior end
• Also contain a nucleus, amylopectin granules, microtubules, and dense bodies

ADDITIONAL DIAGNOSTIC TESTS:

• Cytology: +/- tachyzoites in the acute phase especially with Geimsa stain
• Immunohistochemistry: cross reactivity with Neospora antibodies possible
  • ISH and IHC combined with rtPCR may be useful detection methods to improve histologic evaluation of gondii and N. caninum (Meixner et al., J Vet Diagn Invest 2020)
• Serology (antibody tests) is of limited value

DIFFERENTIAL DIAGNOSIS:

• Neospora caninum: Requires EM or IHC to differentiate from Toxoplasma; cysts are only found in the CNS
• Leishmania and Trypanosoma: Amastigotes have a kinetoplast and a distinct nucleus (two basophilic dots); (Toxoplasma only has a nucleus – one basophilic dot)
• Histoplasma: Organisms are about the same size but have a PAS-positive and GMS-positive cell wall (Toxoplasma is PAS-positive only)
• Pneumocystis carinii: Much smaller, almost always found in alveoli; size of the cyst similar but cyst walls GMS positive, poorly staining on H&E (Toxoplasma is GMS negative)
• Encephalitozoon and Nosema: May resemble Toxoplasma bradyzoites especially in the brain; cyst walls Gram positive (Toxoplasma is Gram negative)
• Sarcocystis: Both can be PAS-positive; Sarcocystis zoites are not in a parasitophorous vacuole; merozoites lack rhoptries
• Hammondia hammondi: Enteroepithelial cycle in cats, not found in the lamina propria and does not cause extraepithelial infection in cats

COMPARATIVE PATHOLOGY:

1. gondii in other species:

• Dogs (N-P02): Most frequently seen in puppies; characterized by neurologic signs, gastrointestinal disease with diarrhea, or pneumonia; disease is triggered by immunosuppression, such as with canine distemper virus infection; in a recent case report, diagnosis was made via cytologic examination of cerebrospinal fluid, the first to be reported in dogs (Borges-Silva et al. J Vet Diagn Invest. 2021)
• Pigs: Sporadic outbreaks; embryonic death; sows with fever and mild illness; hepatitis and lymphadenitis in congenitally infected piglets; abortion in swine with fetal lesions reported, but rarely occur
• Bovids:
• Cattle: resistant; rarely abort or show signs of disease; usual cause of abortion is due to Neospora caninum with no useful identifying gross lesions
• Other bovids: Those that are susceptible develop placentitis, abortion, early neonatal death, pneumonia, or disseminated, fatal disease; species include:
• Bazelles (dama, Cuvier’s, slender-horned), gerenuk, dik, saiga
• Pronghorn: highly susceptible to experimental disease
• Muskoxen and nilgai: Abortion and neonatal death have been reported
• Sheep and Goats (R-P01): Important cause of abortion
• Horses: Single case report resulting in granulomatous and necrotizing lymphadenitis, splenitis, pneumonia, hepatitis, and typhlitis (Kimble et al., J Comp Pathol. 2021)
• Mice: Wild mice are frequent intermediate hosts for gondii
• Guinea pigs: Usually subclinical clinical infections; active infections may result in multifocal hepatitis and pneumonitis; subclinical chronic infections may produce cysts in the myocardium and CNS
• Rabbits:
• Report of an outbreak - lesions included multiple foci of necrosis and granulomatous inflammation in the lung, liver, and spleen; no lesions were found in the brain
• Another report identified a clinically ill rabbit with lesions (cysts) in the brain only
• Wild and domestic meat rabbits are considered a major source for human infection with gondii
• Patagonian maras: Recent report in two captive animals resulting in fatal systemic toxoplasmosis to include coagulative necrosis and lymphohistiocytic inflammatory infiltrates in the myocardium, adrenal glands, liver, and urinary bladder (Ostevik et al. J Vet Diagn Invest. 2019)
• Birds: Infection in poultry and wild birds common; infection in cage birds rare; rarely causes disease; heart (nonsuppurative myocarditis), brain (necrotizing meningoencephalitis), and lung (heterophilic interstitial pneumonia and pulmonary necrosis) are common targets; significant cause of liver disease (multifocal, random necrosis and lymphoplasmacytic, histiocytic, or heterophilic inflammation); may also see intestinal lesions, mild lymphoplasmacytic interstitial nephritis, muscle cysts, nonsuppurative chorioretinitis and ocular atrophy, serous and fibrinous serositis (canaries and other small passerine cage birds), and splenitis
• Camelids: Frequent cause of reproductive infections in llamas and alpacas; case report of toxoplasmosis-associated abortion in one alpaca (Dubey et al., J Zoo Wildl Med 2014)
• Mustelidae: Less commonly causes placentitis and abortion
• European Moles: Single case report resulting in severe pneumonitis and hepatitis (Simpson et al., J Comp Pathol. 2019)
• Prosimians: Results in placentitis, abortion or stillbirth, disseminated fetal infection, or neonatal death
• Lemur: Single case report of localized infection causing placentitis, stillbirth, and disseminated fetal infection (Juan-Salles et al., J Vet Diagn Invest. 2011)
• Nonhuman primates: Causes abortion in NWM and OWM
• Hyraxes: Fatal toxoplasmosis reported in pregnant, young rock/cape and tree hyraxes; causes abortion and stillbirth in pregnant hyrax
• Cetaceans: Causes necrotizing placentitis and abortion; disseminated toxoplasmosis a comorbidity of cetacean morbillivirus in a recent report in Guiana dolphins (Groch et al., Vet Pathol. 2020)
• Pinnipeds: In California sea lions, vertical infection verified by identification of toxoplasmosis in aborted pups; Single case report of co-infection of gondii and cetacean morbillivirus in a Mediterranean monk seal pup resulting in necrotizing myocarditis, interstitial pneumonia, necrotizing arteritis, and non-suppurative meningoencephalitis (Mazzariol et al., J Comp Pathol. 2021)
• Macropods: Single case report of co-infection of gondii and amoebiasis resulting in necrotizing and ulcerative gastritis and typhlitis (Ilha and Coarsey, J Comp Pathol. 2019); single case report of co-infection of T. gondii and Trypanosoma cruzi in a Red-Necked Wallaby resulting in lymphohistiocytic and necrotizing pancarditis, necrotizing splenitis, acute renal tubular degeneration with proteinosis and pigmented casts, and pulmonary edema with fibrin histiocytosis and rare fibrin microthombi (Diaz-Delgado J et al., J Comp Pathol. 2020); recent report of systemic toxoplasmosis in a mob of red kangaroos resulting in widespread necrotizing lesions in multiple organs and/or sudden death (Carossino et al. J Vet Diagn Invest. 2021)

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