AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

Hemolymphatic System

April 2018

H-P05

 

Signalment (JPC Accession # 1913179): Bull, age and breed unspecified

 

HISTORY: This bull was inoculated with an infectious agent. On day 8 post-inoculation, there was a slight febrile reaction. By day 18, the peripheral lymph nodes were enlarged. The animal became progressively anorectic and emaciated and was euthanized and necropsied on day 25.

 

HISTOPATHOLOGIC DESCRIPTION: Slide A: Lymph node: Diffusely, the cortical and medullary architecture is expanded and obscured by sheets of large, monomorphic “lymphoblastic cells” that multifocally infiltrate the capsule. Lymphoblasts have variably distinct cell borders, scant amphophilic cytoplasm, round to oval vesiculate nuclei, and 1-2 prominent nucleoli. Mitotic figures average 4 per 40X HPF. Rarely lymphoblasts contain 1-2 um diameter, round, basophilic, intracytoplasmic protozoal schizonts (Koch’s bodies). There is multifocal lymphocytolysis in both the cortex and paracortical areas. Cortical germinal centers are often replaced by small foci of fibrin and eosinophilic and karryorhectic debris (necrosis). Small numbers of tingible body macrophages are randomly scattered within the cortex and medulla. Multifocally, cortical and medullary sinuses contain mild, draining hemorrhage admixed with low numbers of hemosiderin laden macrophages. The lymph node capsule is thickened up to 2x normal and expanded by low numbers of lymphocytes, plasma cells, fewer macrophages and hemorrhage.

 

MORPHOLOGIC DIAGNOSIS: Lymph node: Hyperplasia, lymphoblastic, diffuse, severe, with multifocal necrosis and intralymphoblastic protozoal schizonts, breed not specified, bovine.

 

HISTOPATHOLOGIC DESCRIPTION: Slide B: Cerebrum: There are multifocal to coalescing areas of necrosis within the cortex and extending into the medulla. Affected areas are often well demarcated and characterized byloss of grey and white matter and replacement by necrotic debris containing many gitter cells mixed with fewer lymphocytes and plasma cells, and moderate amounts of hemorrhage, fibrin, and proteinaceous fluid (infarct). Adjacent cortical and meningeal vessels are often partially occluded by fibrin thrombi and/or distended by manylymphoblastic cells. Lymphoblasts have distinct cell borders, scant amphophilic cytoplasm, and large, irregularly round, vesiculate nuclei with 1-2 prominent nucleoli. Mitotic figures among lymphoblasts average 1 per 40X HPF; and occasionally, lymphoblasts contain 1-2 um diameter, round, intracytoplasmic protozoal schizonts (Koch’s bodies). Diffusely, blood vessels within the neuropil and meninges are lined by hypertrophied, reactive endothelium; and rarely, vessel walls are disrupted by low numbers of neutrophils, macrophages, fibrin, edema and necrotic debris (vasculitis). Multifocally, Virchow-Robin space and the meninges are expanded up to 3x normal by moderate numbers of lymphocytes, plasma cells, and fewer macrophages and lymphoblasts. Diffusely, there is vacuolation of the gray matter (spongiosis), mild gliosis consisting of low to moderate numbers of astrocytes, fewer gemistocytic astroctytes, and rod-shaped microglia. Multifocally within the white matter there are dilated myelin sheaths and swollen, eosinophilic axons (spheroids).

 

MORPHOLOGIC DIAGNOSIS: Cerebrum: Encephalomalacia, acute, multifocal to coalescing, marked with multifocal thrombosis (infarct), moderate nonsuppurative meningoencephalitis, many intra and perivascular lymphoblasts, and intralymphoblastic protozoal schizonts, breed not specified, bovine.

ETIOLOGIC DIAGNOSIS: Lymph nodal and cerebral theileriosis

CAUSE: Theileria parva parva

 

SYNONYMS: East Coast Fever; turning sickness

GENERAL DISCUSSION:

·      East Coast Fever (ECF) is a tick-transmitted protozoal disease of cattle characterized by high fever and lymphadenopathy

·      The disease is confined to areas of eastern, central, and southern Africa where the principle vector, Rhipicephalus appendiculatus, occurs

·      Within endemic areas, mortality in susceptible cattle may approach 90-100%, especially in non-indigenous or naïve indigenous species

·      The severity of clinical signs is dose-dependent and also depends on the virulence of the infecting strain

·      Members of the genus Theileria are protozoan parasites belonging to the phylum Apicomplexa, order Piroplasmida, and the family Theileriidae

PATHOGENESIS:

·      Ticks feeding on the host transmit sporozoites within their saliva > sporozoites enter lymphocytes within local lymph nodes and macrophages > macroschizonts are formed during schizogony which transform infected lymphocytes into lymphoblastic cells (leukocytic or tissue phase) > lymphoblastic cells proliferate, dividing synchronously with macroschizonts to infect daughter cells (clonal expansion) > 10 days post-infection, macroschizonts undergo merogony to produce merozoites (microschizonts) > merozoites are released and invade erythrocytes (erythrocytic phase) to form piroplasms which are infective to ticks

·      Lympholysis and progressive anemia also occur during the acute phase when lymphocytes contain schizonts

·      The parasite blocks inhibition of NF-KB; NF-KB becomes persistently activated, protecting the cell from apoptosis; NF-KB also causes upregulation of IL-2 (and its receptor), which is mitogenic for T-cells

·      In infected B-cells, T. parva induces c-Myc and activates anti-apoptotic protein Mcl-1; overexpression of c-Myc is important in certain B-cell lymphomas

·      Transformation of parasitized lymphocytes is reversible; upon drug-induced parasite death, parasitized lymphocytes stop proliferating and revert to a resting state or undergo apoptosis

·      Morbidity and mortality depend on the magnitude of the infected tick challenge, host susceptibility, and virulence of the infecting strain of parasite

TYPICAL CLINICAL FINDINGS:

·      Acute: massive lympholysis and progressive anemia

·      After 2 week incubation period, there is swelling of the parotid lymph node (the ear is the preferred feeding site for ticks), followed by high fever, anorexia and depression; in later stages, there is generalized enlargement of the superficial lymph nodes, nasal and ocular discharge, corneal opacity, and splenomegaly with diarrhea, dyspnea, recumbency, and coma in terminal stages

·      Turning sickness: Fatal condition in which parasitized lymphocytes accumulate and form thrombi within cerebrospinal vessels; characterized by circling in affected cattle

·      Progressive leukopenia and anemia

·      Abortions are common

TYPICAL GROSS FINDINGS:

·      There is enlargement of lymphoid tissues, including Peyer’s patches; on cut section, lymph nodes have a red-brown cortex containing focal hemorrhages, and a dark red-brown medullary area

·      Cerebrum- acute: Multifocal infarcts, meningocerebral congestion, hemorrhage, and thrombosis, yellowish discoloration of brain, intraventricular hemorrhage

·      Cerebrum -chronic: Resorption of necrotic tissue results in intracerebral cystic spaces

·      Splenomegaly in acute cases; shrunken spleen with chronicity

·      Ulcerative abomasitis; erosive or catarrhal enteritis

·      Small gray-white patches (“pseudo-infarcts”) on surface of liver and kidney that bulge slightly (proliferative foci of perivascular lymphocytes)

·      Severe pulmonary edema and congestion; copious froth in airways; hydrothorax and hydropericardium

TYPICAL LIGHT MICROSCOPIC FINDINGS:

·      Lymphoid organs: In early stages, there is diffuse lymphoid hyperplasia (in part due to production of IL-2 by parasitized lymphocytes); with progression, there is a general loss of small lymphocytes which are replaced by numerous parasitized lymphoblasts containing intracytoplasmic schizonts (Koch’s blue bodies); in terminal stages, there is widespread, prominent lymphocytolysis, especially within germinal centers that is accompanied by hemorrhage and fibrinous exudate within the cortex of lymph nodes

·      Lymphocytic infiltrates in liver (periacinar and to a lesser extent, periportal) and kidney (perivascular and periglomerular)

·      Lung: Severe pulmonary edema and lymphoid infiltration of the alveolar septa

·      Bone marrow: In terminal stages, marrow is hypoplastic, and the remaining cells consist of parasitized, blastic lymphocytes and atypical erythroblasts

·      Turning sickness: Hemorrhagic infarcts in brain and spinal cord due to thrombi containing parasitized lymphocytes

ADDITIONAL DIAGNOSTIC TESTS:

·      Peripheral blood or lymph node smears stained with Giemsa may show 2-16 um diameter, macroschizonts (Koch’s blue bodies) which are considered diagnostic to identify Theileria spp.

·      With Romanowsky-type stains (including Giemsa), schizonts and piroplasms have pale blue cytoplasm with red chromatin granules, and in piroplasms only the chromatin occupies a single pole

·      Serology: ELISA, indirect immunofluorescent antibody test (IFAT), complement fixation, indirect hemagglutination

·      PCR required for species differentiation

DIFFERENTIAL DIAGNOSIS:

·      Gross and histological lesions resemble malignant catarrhal fever (MCF) (gammaherpesvirus); presence of Koch’s blue bodies support ECF

§  Hallmark features of MCF include fibrinoid necrotizing vasculitis in addition to lymphocytic and lymphoblastic proliferation (especially T-lymphocytes)

·      Jembrana disease: A lentiviral disease of Bali cattle and buffalo that causes lymphoblastoid and histiocytic infiltration of many organs

·      Heartwater (Ehrlichia ruminantium) – differential for pulmonary edema

·      Trypanosomiasis – differential for anemia, edema, and lymphadenopathy

·      Babesiosis/ anaplasmosis – differentials for anemia and fever

·      Bovine viral diarrhea (pestivirus)/ rinderpest (morbillivirus) – differentials for fever, diarrhea, and lymphoid necrosis

·      Lymphoma

COMPARATIVE PATHOLOGY:

·      T. parva lawrenci causes corridor disease of calves in southern Africa; endemic in buffalo

·      T. parva bovis causes January disease in cattle in east and central Africa; infection is more acute than classical ECF; only occurs from January to March

·      T. mutans causes Tzaneen disease in cattle, which is mild with few clinical signs

·      T. annulata causes Mediterranean or tropical theileriosis across north Africa and central Asia; usually benign

·      T. hirci causes disease similar to ECF in sheep and goats in north Africa, the Middle East, and southern Eurasia

·      T. ovis is the ovine equivalent of T. mutans and is fairly benign; same geographic distribution as T. hirci

·      Cytauxzoon felis affects felids in the United States, reproduces by fission in red cells and by schizogony in macrophages; whereas Theileria sp. are found in red cells and reproduce by schizogony in lymphocytes

·      T. cervi infects white tailed deer in the US; does not cause significant disease

·      T. buffeli; widely distributed in East Asia and is relatively benign; single report of infection in a Missouri beef herd where it caused severe clinical illness and death in only one animal

 

References:

1.    Boes KM, Durham AC. Bone marrow, blood cells, and the lymphoid / lymphatic system. In: Zachary JF, ed. Pathological Basis of Veterinary Disease. 6th ed. Philadelphia, PA: Mosby Elsevier Inc.; 2017:748-749.

2.    Constable PD, Hinchcliff KW, Done SH, Grünberg W. Veterinary Medicine: A Textbook of the Diseases of Cattle, Sheep, Pigs, Goats and Horses. 11th ed. London, England, UK: WB Saunders Company LTD; 2017:2144-2145.

3.    Dessauge F, Lizundia R, Baumgartner M, Chaussepied M, Langsley G. Taking the MThyc is bad for Theileria. Trends Parasitol. 2005;21:377-85.

4.    Forsyth LMG, Minns FC, Kirvar E, et al. Tissue Damage in Cattle Infected with Theileria annulata Accompanied by Metastasis of Cytokine-producing, Schizont-infected Mononuclear Phagocytes. J Comp Path. 1999;120:39-57.

5.    Lawrence JA, de Vos AJ, Irvin AD. East Coast Fever; Turning Sickness. In: Coetzer JAW, Thomson GR, Tustin RC, eds. Infectious Diseases of Livestock with special reference to Southern Africa. 2nd ed. Vol 1. Oxford, UK: Oxford University Press; 1994:309-314,331-333.

6.    Mans BJ, Pienaar R, Latif AA. A review of Theileria diagnostics and epidemiology. Int J Parasitol Parasites Wildl. 2015;4(1):104-118.

7.    Miller LM, Gal A. Cardiovascular system and lymphatic vessels. In: Zachary JF, ed. Pathological Basis of Veterinary Disease. 6th ed. Philadelphia, PA: Mosby Elsevier Inc.; 2017:605.

8.    Stockham SL, Kjemtrup AM, Conrad PA, et al. Theileriosis in a Missouri beef herd caused by Theileria buffeli: Case report, herd investigation, ultrastructure, phylogenetic analysis, and experimental transmission. Vet Pathol. 2000;37:11-21.

9.    Valli VEO, Kiupel M, Bienzle D. Hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:176-178.


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