JPC SYSTEMIC PATHOLOGY
RESPIRATORY SYSTEM
SEPTEMBER 2023
P-P01
Signalment (JPC #1374690): Cat, age and breed unspecified
HISTORY: Unknown
HISTOPATHOLOGIC DESCRIPTION: Lung: Diffusely, alveolar septa and, to a lesser extent, peribronchial and peribronchiolar interstitium are thickened up to 10 times normal by numerous macrophages, fewer neutrophils and lymphocytes, fibrin, increased clear space (edema), and moderate vascular congestion. Multifocally, alveolar septa are discontinuous with replacement by eosinophilic and karyorrhectic debris, fibrin, edema, and similar inflammatory cells (alveolar septal necrosis). There is moderate type II pneumocyte hyperplasia. Alveolar lumina, and to a lesser extent the bronchial and bronchiolar lumina, frequently contain moderate numbers of degenerate and nondegenerate neutrophils, macrophages, fewer lymphocytes, erythrocytes (hemorrhage), rare multinucleate giant cell macrophages, eosinophilic cellular and karyorrhectic debris (necrosis), eosinophilic fibrillar beaded material (fibrin), and edema. Occasionally, alveolar macrophages and type II pneumocytes are distended up to 3 times normal by an intracytoplasmic parasitophorous vacuole containing numerous 2-4 um, round to fusiform, basophilic tachyzoites. Tachyzoites are rarely free within alveolar lumina adjacent to ruptured alveolar macrophages. Multifocally, there are perivascular and peribronchial/bronchiolar aggregates of lymphocytes and plasma cells (mild BALT hyperplasia), as well as perivascular edema, and multifocal mesothelial cell hypertrophy (reactive mesothelium).
MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, interstitial, necrotizing, subacute, diffuse, severe, with type II pneumocyte hyperplasia, edema, and intracellular (intrahistiocytic and intraepithelial) and rare extracellular tachyzoites, breed unspecified, feline.
ETIOLOGIC DIAGNOSIS: Pulmonary toxoplasmosis
CAUSE: Toxoplasma gondii
GENERAL DISCUSSION
- Ubiquitous apicomplexan obligate intracellular coccidian parasite that causes disseminated disease, especially enteritis, myositis, pneumonia, hepatitis, encephalitis, ophthalmitis, and abortions in a wide range of intermediate hosts
- Felids are the only definitive hosts (typical coccidian intraintestinal life cycle); whereas many animals (mammals, fish, amphibians, reptiles, birds) can serve as intermediate hosts (extraintestinal life cycle)
- Felids are unique in that they can serve as both definitive and intermediate host
- Clinical disease most common in young and immunocompromised animals
- 3 infectious stages: Tachyzoites (IH/DH), tissue cysts (IH/DH), and oocysts (DH)
- Cannot definitively ID histologically: Need IHC or PCR
LIFE CYCLE
- Definitive host (felids), intestinal “enteroepithelial” cycle:
- Ingestion of infected prey tissue (tachyzoites or tissue cysts containing bradyzoites), or ingesting sporulated oocysts in contaminated food or water
- Sporozoites released from oocysts or bradyzoites released from tissue cysts transition to tachyzoites and infiltrate intestinal epithelial cells, undergoing five asexual stages of reproduction (schizogony) and eventually form merozoites
- In the sexual phase (gametogony), merozoites transform into a male microgamont or female macrogamont; microgamonts are released and fertilize a macrogamont to form an oocyst
- Oocysts (unsporulated, noninfective) are shed in feces 3-10 days after ingesting bradyzoites, 13 days after ingesting tachyzoites, and 18 days after ingesting oocysts
- Sporulation (development of infective sporozoites inside the oocyst) takes 1 to 5 days
- Intermediate hosts, extraintestinal cycle (many mammals and birds, including felids):
- Transmission: Ingestion of sporulated oocysts in contaminated food or water, ingestion of infected prey tissue (tachyzoites, or cysts containing bradyzoites), transplacental tachyzoites (common in sheep and goats) or injected biologic material with tachyzoites or bradyzoites
- Sporozoites released from oocyst or bradyzoites released from tissue cyst within the lumen of the small intestine transition to tachyzoites and invade enterocytes and divide asexually (endodyogeny) within a parasitophorous vacuole to form duplicate tachyzoites
- Tachyzoites lyse the enterocyte and spread locally to adjacent enterocytes, the lamina propria, &tissue leukocytes
- Tachyzoites spread systemically via leukocyte trafficking (lymphocytes, macrophages, and granulocytes) or free in plasma via blood and lymphatics, 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 à cell-to-cell transmission à focal necrosis
- With chronicity and the development of host antibody response, tachyzoites transform into slow-growing bradyzoites within tissue cysts (also in a parasitophorous vacuole)
- Transplacental (vertical) infection can occur when naïve hosts are exposed and infected during pregnancy; tachyzoites multiply in the placental cotyledons and spread to fetal tissues (mechanism of spread is unknown)
PATHOGENESIS
- Intermediate host: Tachyzoites ingested in sporulated oocysts or bradyzoites in tissue cyst → tachyzoite excystation → asexual replication in enterocytes → tachyzoite release → trafficking via lymphatics/blood vessels free or in lymphocytes, macrophages, or granulocytes → replication in somatic cells (some form chronic tissue cysts) → cell lysis → inflammation → protozoal-mediated focal necrosis
- Direct host: Ingestion of bradyzoites in tissue cyst or tachyzoites → zoites infect enterocytes → undergo asexual multiplication (schizogony) → zoites released from enterocytes → infect new enterocytes → undergo sexual multiplication (gametogony) → macrogamont and microgamont fuse → oocyst formed and ruptures enterocyte → unsporulated oocyst shed in felid feces → oocyst sporulates in environment (infectious)
- Encystation allows immune evasion: Driven by increasing host antibody response, immune suppression can allow excystation/active infection
- Coinfection common: Immune suppressors: Canine Morbilivirus (CDV), Feline Leukemia Virus (FeLV), Cetacean Morbilivirus. Others: Chlamydophila (small ruminant abortions), Ehrlichia (canine), Sarcocystis (seals)
Virulence Factors:
- Crosses immunologic barrier systems using motility: Linear myosin, F-actin filaments, and gliding-associated proteins
- Use adhesins to facilitate transfer of the organism through mucosa
- In parasitophorous vacuoles made of host-cell membrane (which modulate target cell functions in support of parasite replication and infection), tachyzoites avoid immune detection and release anti-inflammatory IL-10 and TGF-β
- Rhoptries assist with cellular invasion, as with other apicomplexans
- Tachyzoites express glycosylphosphatidylinositol-linked surface proteins (SAGs, e.g. SAG1 and SAG3) for enterocyte attachment and immune modulation
TYPICAL CLINICAL FINDINGS
- Most common: Fever, lethargy, anorexia, ocular and nasal discharges, and respiratory distress
- Enteroepithelial cycle (cat): Self-limiting diarrhea or asymptomatic
- Extraintestinal cycle: Widespread seropositivity but disease is sporadic and rare unless immunocompromised (exception: an important cause of abortion in sheep and goats)
- Abortion: Common in sheep and goats; early gestation = resorption, mid-gestation = mummies and live weak fetuses, late infection results in healthy fetus (adaptive immune response) with vertical transmission
- CNS infection: Incoordination, circling, tremors, opisthotonos, convulsions,
and paresis.
- Radiculitis and myositis: Paresis
- Clin path: Selective granulocytic bone marrow hypoplasia, increased CK activity
- Rare cause of cutaneous nodules in cats, dogs, humans
- History of feeding raw meats or exposure to cats/cat feces
TYPICAL GROSS FINDINGS
- Systemic Toxoplasmosis Hallmarks: Interstitial pneumonia, focal hepatic necrosis, lymphadenitis, myocarditis, and nonsuppurative meningoencephalitis
- Multiorgan multifocal necrosis from rapid tachyzoite replication
- Lung:
- Irregular gray foci of necrosis on the pleural surface to hemorrhagic pneumonia with confluent involvement of ventral lung fields.
- Pinpoint white foci scattered throughout the lung or diffuse interstitial
Pneumonia (especially in kittens)
- Splenomegaly and lymphadenomegaly
- Eye: Granulomatous chorioretinitis
- Placenta: T. gondii produces pathognomonic gross lesions in the placenta of small ruminants: multifocal necrosis and mineralization of cotyledonary villi; 1-2 mm yellow to white foci of necrosis throughout the villus; intercotyledonary chorioallantois edematous to unaffected
- Adrenal cortex: Focal cortical necrosis
TYPICAL LIGHT MICROSCOPIC FINDINGS
- 3-6 μm crescentic zoites and/or cysts in areas of coagulative necrosis in one or more organs
- Tachyzoites rare in blood neutrophils and monocytes, common in macrophages of infected tissues (lung, intestine)
- Lung:
- Tachyzoites in alveolar macrophages, and may be in bronchiolar epithelium and vessel walls, infect type I pneumocytes
- Interstitial pneumonia: Severe, multifocal necrotizing interstitial
pneumonia with type II pneumocyte proliferation “epithelialization of alveoli”; alveoli filled with macrophages and fibrinonecrotic exudate; scattered septal and bronchiolar necrosis.
- Other tissues (liver, lymph nodes, spleen, pancreas, heart, skeletal muscle): Intracellular tachyzoites, random necrotic foci, with variable presence of inflammation (predominantly mononuclear)
- CNS (N-P02): Nonsuppurative meningoencephalitis of gray and white matter (especially perivascular), necrotic vasculitis, hemorrhage, tissue cysts, microglial nodules in chronic cases
- Radiculoneuritis and Myositis: Lymphoplasmacytic and histiocytic inflammation,
myofiber necrosis and atrophy (especially in puppies/kittens)
- Eye: Chorioretinitis, lesion in retina, uvea, or extraocular muscles, varies from focal, acute coagulative necrosis to granulomatous/lymphocytic inflammation. Feline lymphoplasmacytic anterior uveitis with positive T. gondii serology is more common
- Placenta (R-P01): Multifocal cotyledonary necrosis +/- mineralization with rare organisms within trophoblasts
- Aborted fetus: 95% of fetuses will have a mild, nonsuppurative encephalitis or necrosis of cerebral white matter (due to placentitis and hypoxemia)
ULTRASTRUCTURAL FINDINGS
- Tachyzoites present within a parasitophorous vacuole, 4-6 µm diameter, contain an anterior apical complex with conoid, micronemes, and rhoptries
- Also contain a nucleus, amylopectin granules, microtubules, and dense bodies
ADDITIONAL DIAGNOSTIC TESTS
- Cytology: Tachyzoites may be detected in the acute phase in blood/CSF/pulmonary
- Electron microscopy
- Immunohistochemistry: Cross reactivity with Neospora antibodies possible
- PCR
- Serology not specific, but paired IgM-IgG serology is helpful in determining acute vs. chronic
- Modified acid-fast stain on impression smears of placenta
DIFFERENTIAL DIAGNOSIS
- Neospora caninum: Requires immunohistochemical techniques or electron microscopy to differentiate from Toxoplasma organisms; may or may not have a parasitophorous vacuole; slightly thicker cyst wall than T. gondii or Sarcocystis, N. caninum cysts are found only in the CNS. N. caninum is commonly associated with bovine abortion
- Sarcocystis sp.: Requires Immunohistochemical techniques or electron microscopy to differentiate from Toxoplasma organisms; ultrastructurally, zoites of Sarcocystis are not within a parasitophorous vacuole, and merozoites lack rhoptries; associated with limited tissue necrosis
- Encephalitozoon cuniculi: Pseudocyst is larger (up to 120µm, Toxoplasma is 60um), spores are acid fast (Toxoplasma is not), gram positive (Toxoplasma is gram negative), necrosis is not a common finding
- Hammondia hammondi: Has an entero-epithelial cycle in cats, but is not found in the lamina propria and does not cause extraepithelial infection in cats
- Neospora hughesi: Specific to horses; T. gondii is usually not clinical in horses
- Leishmania and Trypanosoma spp.: Tachyzoites with a kinetoplast and a distinct nucleus, often seen together as two basophilic dots
- Histoplasma sp.: Organisms are about the same size as Toxoplasma but have a PAS-positive and GMS-positive cell wall, and found only within macrophages/histiocytes; Toxoplasma is PAS-positive only
- Pneumocystis carinii: Much smaller and almost always found in pulmonary alveoli
COMPARATIVE PATHOLOGY
- Toxoplasma gondii can infect a wide variety of animals as intermediate hosts (extraintestinal life cycle) including fish, amphibians, reptiles, birds, human beings and many other mammals
- Dogs: 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
- Sheep and Goats: Important cause of abortion
- Swine: Pneumonia, encephalitis, abortion (rare)
- Cattle: Not a significant abortifacient (unlike ddx Neospora caninum)
- Cetaceans: Nonsuppurative meningoencephalitis, necrotizing placentitis, and abortion in dolphins, associated with morbillivirus coinfection
- New World monkeys, Pallas’ cats, sea otters, black-footed ferrets, and Australian marsupials are highly susceptible and acute disease can be fatal
- Avians: Potentially severe serofibrinous serositis in canaries; brain, eye, lung, liver, and heart predilection, rare in cage birds, poultry, and wild birds
- Rabbit: Wild/domestic meat rabbits are major source of human infection; E. cuniculi zoites are gram+, T. gondii is gram-
- Lab animal: Infection is rare due to current housing practices, but may be introduced by injection of contaminated biological materials
- Old World monkeys, rats, cattle and horses seem highly resistant
- Wildlife: Infection has been described in many wildlife species including hyrax, meerkats, raccoons with CDV, pinnipeds, marsupials, bovids, foxes, bears
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