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CASE I – N00-112 (AFIP 2738756)
Signalment: 5-year-old, male, Newfoundland, canine, Canis familiaris
History: The dog was euthanized by barbiturate overdose after a four-month clinical history of weight loss, poor appetite, generalized lymphadenomegaly and moderate splenomegaly.
Gross Pathology: Diffuse lymphadenomegaly, with most lymph nodes being 2–3 times larger than expected for the size of the animal, but with retention of normal architecture. Diffusely, subcutaneous tissues were intensely icteric, but elastic tissues were not. There was a 10 x 3 x 2 cm hematoma along the right dorsal aspect of the rectum. The spleen was moderately enlarged, but no more than expected for barbiturate euthanasia.
Laboratory Results: Shortly prior to euthanasia, a complete blood count revealed a non-regenerative anemia (PCV=21%; normal range 38–57%), lymphopenia (0.6 x103/ul; normal range 1.5–5.2 x103/ul), monocytopenia (0.2 x103/ul; normal range 0.3–2.2 x103/ul) and thrombocytopenia (135 x103/ul; normal range 179–510 x103/ul).
A biochemical profile revealed mild hyponatremia (140 mEq/l; normal range 141–156 mEq/ul); hypokalemia (3.1 mEq/l; normal range 3.8–5.5 mEq/l); hyperphosphatemia (7.5 mg/dl; normal range 2.3–6.5 mg/dl); azotemia (creatinine 4.7 mg/dl, normal range 0.5–1.4 mg/dl; BUN 99 mg/dl, normal range 8–30 mg/dl); hyperglobulinemia (9.6 g/dl; normal range 1.8–4.2 g/dl); and hypoalbuminemia (2.3 g/dl; normal range 3.0–4.5 g/dl).
Decreased iron (43 ug/dl; normal range 46–241 ug/dl), decreased total iron binding capacity (206 ug/dl; normal range 235–495 ug/dl) and increased amylase (2275 U/L; normal range 286–1124 U/L) were also noted.
Urine specific gravity was 1.018, while dipstick and sediment examination was unremarkable. Urine protein : creatinine ratio was 5.4, compatible with proteinuria, while fractional excretion of sodium (1.27%), chloride (1.45%) and potassium (54.0%) were all increased, compatible with renal insufficiency and kaliuresis. A proximal tubular acidosis was suspected on the basis of aciduria and known renal disease. An endogenous creatinine clearance test confirmed renal insufficiency, with an estimated GFR of 0.39 ml/min/kg (normal range 2–5 ml/min/kg). Decreased antithrombin III (59%; normal range 75–120%) prompted consideration of thromboembolic complications of proteinuria.
Mixed venous blood gas analysis revealed borderline acidemia (pH 7.31; normal range 7.31-7.50), with a primary metabolic acidosis (bicarbonate 14 mEq/l; normal range 25-35 mEq/l) characterized by a low inorganic strong ion difference (30 mEq/l) and appropriate respiratory compensation.
Thoracic radiographs were unremarkable, while abdominal films revealed mild splenomegaly and questionable prostatomegaly. Abdominal ultrasonography was within normal limits.
An ANA titer was low-positive (1:40), compatible with a non-specific, positive result in the face of visceral leishmaniasis. All outstanding titers were negative, other than that for Babesia canis (low positive 1:32); Leishmania sp. titer pending.
Contributor’s Diagnosis and Comment: Spleen – There is diffuse lymphoid hyperplasia, plasmacytosis with numerous Mott cells, and histiocytosis with intracellular, 0.5-1.0 m m, spherical organisms. There is also hemosiderosis and extramedullary hematopoiesis.
Morphologic Diagnosis: Diffuse plasmacytic and histiocytic splenitis with intralesional amastigote organisms.
Etiologic diagnosis: Visceral leishmaniasis.
Lesions with intrahistiocytic organisms were also present in lymph nodes, bone marrow, liver and epididymis. In the latter instance, the reaction appeared confined to the interstitium and no organisms were seen within the spermatic tubule. No organisms were detected in skin samples. In the kidney there were changes interpreted as membranoproliferative glomerulonephritis.
Leishmania donovani is currently regarded as a species complex of viscerotropic, flagellate protozoans transmitted naturally by the bite of an infected female phlebotomine sand fly. Once transmitted, the organism assumes an aflagellate amastigote form associated with the disease known as visceral leishmaniasis. Around the world, the human disease goes by a number of names including kala-azar, dumdum fever, infantile splenic fever, and febrile tropical splenomegaly. Endemic areas are extensive around the Mediterranean, Northeastern Africa, Indian sub-continent, and Central and South America.
The disease is also common in domestic dogs in endemic areas, and generally occurs in both human and canine species simultaneously. Dogs and wild canids are frequently the major reservoir and it is likely that organisms within skin lesions are important in transmission to vectors. The issue of transmission is not entirely clear in dogs. Experimental dog-tick-dog transmission has been reported. Direct dog-to-dog transmission is suspected to have occurred in Europe.
Recently, canine visceral leishmaniasis has been diagnosed in an outbreak in foxhounds in the northeastern US. At the time of our submission, the mode of transmission or the extent of infection in these dogs is unknown. Although sand fly species that are potentially capable of transmitting Leishmania sp. occur in the southern US, no definitive vector is known to be present in the northeast.
The dog in this case originated from a breeding establishment in Pennsylvania and had never been out of the US; however, a puppy whose mother was diagnosed with leishmaniasis was imported into the establishment from Italy. The puppy subsequently died with a presumptive, not definitive, diagnosis of leishmaniasis. Subsequent to the diagnosis, several other dogs from the establishment were euthanized after being found to be seropositive.
AFIP Diagnosis: 1. Spleen: Splenitis, histiocytic, diffuse, moderate, with plasmacytosis, lymphoid hyperplasia and numerous intrahistiocytic amastigotes, Newfoundland, canine, etiology consistent with Leishmania sp.
2. Spleen: Hemosiderosis, diffuse, mild.
Conference Comment: Canine leishmaniasis, with an incubation period of 3-7 months, most frequently manifests as cutaneous lesions with areas of alopecia and pruritus, mainly over joints and in skin folds. As the disease becomes chronic, animals become anorexic, febrile, anemic and emaciated. Splenomegaly, hepatomegaly, lymphadenopathy and intestinal ulceration are frequently seen postmortem. Highly parasitized dogs can have mild clinical signs and serve as a significant reservoir for human infection in areas where the sand fly vector is found.
One of the most sensitive procedures for diagnosing leishmaniasis is cytological examination of fine needle aspirates of infected spleen. Because cells tend to swell in cytological preparations, the morphology of the amastigote, with a nucleus perpendicular to its kinetoplast, is more easily recognized within the parasitized macrophages using this method. For this reason, differentiation of leishmaniasis from histoplasmosis and sporotrichosis may also be easier by cytology.
This case came with a wealth of useful clinical pathological data. The cause of the anemia was the subject of some discussion by conference participants. Most believed that anemia of chronic disease was the major cause of the low hematocrit; however, at 21%, the hematocrit was considered to be lower than expected by this mechanism. Anemia of chronic disease is often mild with hematocrits usually not less than 30%. Bone marrow replacement was also discussed, but was considered a less likely cause of the anemia because of the tremendous reserve capacity of canine bone marrow. Bone marrow suppression and blood loss are possible contributing factors.
Contributor: Cornell University, Section of Pathology, Department of Biomedical Sciences, College of Veterinary Medicine, Ithaca, NY 14853
References: 1. Acha PN, Szyfres B: Visceral leishmaniasis. In: Zoonoses and Communicable Diseases Common to Man and Animals, 2nd ed., pp. 640-648, Pan American Health Organization Scientific Publication No. 503, Washington, DC, 1991
2. Monti DJ: Hunters hounded as leishmaniasis is diagnosed in foxhounds. J Am Vet Med Assoc 216(12):1887, 2000
3. Trees A, Shaw S: Imported diseases in small animals. In Practice 21:482-491, 1999
CASE II – OL8259-21 (AFIP 2741628)
Signalment: 5-month-old ApoE-deficient mice (Mus musculus)
History: The mice were part of a control group from a study to test the efficacy of an experimental cholesterol-lowering agent. They were fed a high-fat, high-cholesterol, Western-type diet for 12 weeks.
Gross Pathology: There were atherosclerotic plaques in the aorta (especially at the root). There was widespread cutaneous xanthomatosis.
Laboratory Results: Total serum cholesterol: 1,300-2,200 mg/dl
Contributor’s Diagnosis and Comment: Skin (various locations): Xanthoma with chronic active inflammation and epidermal hyperplasia (acanthosis and hypergranulosis) and ulceration.
Etiology: Hypercholesterolemia due to disruption of the apolipoprotein E gene and lipid-rich diet.
The dermis and upper subcutis are markedly, diffusely thickened by coalescing accumulations of large, foamy, frequently multinucleated macrophages with vacuolated cytoplasm (foam cells) admixed with varying numbers of cholesterol clefts. There are scattered small aggregates of lymphocytes, neutrophils and proliferating fibroblasts (especially in the deeper dermis). The overlying epidermis is mildly to moderately thickened due to acanthosis and hypergranulosis. There is locally extensive epidermal ulceration with serocellular crusting and underlying fibrosis and inflammation (mostly neutrophils). There are also scattered small areas of necrosis with cellular debris and few neutrophils.
ApoE-deficient (“knock-out”) mice are frequently used to test the efficacy of various therapeutic modalities aimed at lowering serum cholesterol. Disruption of the apolipoprotein E gene results in very high plasma concentrations of very low density lipoprotein (VLDL)- and low density lipoprotein (LDL)-cholesterol and accelerated atherogenesis. In addition, these mice are very prone to oxidative stress, which may also explain the accelerated atherogenesis.
By 12-weeks-of-age, fatty-streaks are visible in the aorta (mainly at the root). By 20-weeks, lesions may progress beyond the fatty-streak stage and develop into fibro-proliferative intermediate lesions. Atherosclerotic plaques upon aging are grossly visible and can be quantified using a variety of techniques.
Few other lesions have been reported in ApoE-deficient mice. However, on a high-fat, high-cholesterol, western-type diet, these mice develop other lesions due to their hypercholesterolemia, including the cutaneous xanthomas. The extent of cutaneous foam cell formation correlates directly with the degree of atherosclerosis in the aorta.
In humans, ApoE deficiency leads to familial dysbetalipoproteinemia characterized by increased serum cholesterol and triglyceride levels due to increased quantities of chylomicron and VLDL remnants. These alterations in lipid metabolism are associated with an increased risk of not only atherosclerosis, but also cutaneous xanthoma.
AFIP Diagnosis: Haired skin: Dermatitis, xanthogranulomatous, diffuse, severe, with acanthosis, hyperkeratosis and ulceration, apolipoprotein E-deficient mouse (Mus musculus), rodent.
Conference Comment: A popular theory of atherogenesis is that atherosclerosis is due to an excessive fibroproliferative response to an insult to the arterial wall. A similar mechanism proposed for xanthoma formation in skin states that lesions develop due to damage of the basal lamina with a deposition of lipids and resultant foreign-body type inflammation.
Xanthomas are seldom reported in animals other than birds. When they occur in dogs and cats, they present grossly as yellow to white plaques or nodules within the dermis, with erythematous borders which may extend into the subcutaneous tissue. Watanabe heritable hyperlipidemic rabbits develop xanthomatosis secondary to hypercholesterolemia due to a single genetic defect for low density lipoprotein receptors. The same defective gene is found in some human patients with familial hypercholesterolemia.
Contributor: Pharmacia/Searle, 4901 Searle Parkway, Skokie, IL 60077
References: 1. Accad M, Smith SJ, Newland DL, Sanan DA, King, LE, Linton MF, Fazio S, Farese RV: Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1. J Clin Inv 105:711-719, 2000
2. Feingold KR, Elias PM, Man MQ, Fartasch M, Zhang SH, Maeda N: Apolipoprotein E deficiency leads to cutaneous foam cell formation in mice. J Inv Derm 104:246-250, 1995
3. Moghadasian MH, Nguyen LB, Shefer S, McManus BM, Frohlich JJ: Histologic, hematologic, and biochemical characteristics of ApoE-deficient mice: effects of dietary cholesterol and phytosterols. Lab Inves, 79:355-364, 1999
4. Smith JD: Mouse models of atherosclerosis. Lab Anim Sci 48:573-579, 1998
CASE III – 00-0132 (AFIP 2741050)
Signalment: 14-week-old, male, New Zealand white rabbit, Oryctolagus cuniculus
History: This rabbit died suddenly with no observed clinical symptoms.
Gross Pathology: The rabbit is in normal body condition. There is severe fibrinopurulent pleuritis and pyothorax. Lungs have anterioventral consolidation and suppurative exudate can be observed on cut surface. No other gross lesions are present.
Laboratory Results: Culture of pulmonary tissue yielded 4+ growth of Pasteurella multocida.
Contributor’s Diagnoses and Comment: 1. Fibrinopurulent and necrotizing broncho-alveolar pneumonia with vascular thrombosis
2. Fibrinopurulent pleuritis with bacterial colonies
Pasteurella multocida is a major pathogen of laboratory rabbits which causes severe respiratory tract disease as well as septicemia, abcessation and reproductive abnormalities. Features typical of P. multocida infection observed in lung sections from this rabbit include fibrinopurulent exudate in airways and alveoli, multifocal areas of parenchymal necrosis, fibrin thrombi, and fibrinopurulent pleuritis. Although these findings are typical for P. multocida pneumonia and pleuritis, we have also observed a sudden death syndrome in affected rabbits that have much less severe pulmonary lesions and positive culture results.
Pasteurellosis is endemic in many rabbit colonies. The organism is frequently present in the nasal cavity of apparently healthy animals with asymptomatic chronic infections. In research colonies with pasteurellosis, serologic surveys have also shown that as many as 59% of rabbits, that were not specific pathogen free, had serum antibodies to P. multocida. There are five capsular serogroups and 16 somatic serotypes of P. multocida and these bacterial differences may, in part, determine progression to clinical disease. Pneumonic and septicemic pasteurellosis in laboratory rabbits is caused mainly by serogroup A isolates and, less often, by serogroup D isolates. However, the same serotypes may be isolated from asymptomatic carrier animals indicating that host and environmental factors also play a significant role in disease development.
AFIP Diagnosis: Lung: Bronchopneumonia, necrotizing, fibrinosuppurative, multifocal, severe, with diffuse pleuritis and numerous bacilli, New Zealand white rabbit (Oryctolagus cuniculus), lagomorph.
Conference Comment: Pneumonic pasteurellosis may vary from localized cranioventral bronchopneumonia to more extensive fibrinosuppurative pneumonia. As in this case, there is often fibrinopurulent pleuritis. In acute infections, airway epithelium is necrotic and there is a fibrinous, neutrophilic exudate that extends into adjacent parenchyma and fills alveoli.
Bacterial strain virulence is the main determinant of the clinical manifestation of disease. The mucoid strains are better able to colonize the nasal passages than nonmucoid strains, possibly due to production of exotoxins, endotoxin, antiphagocytic substances, or adhesins. Various isolates of P. multocida also elicit antibody responses of differing intensities.
Contributor: Department of Comparative Medicine, Stanford University School of Medicine, RAF-1, Quad 7, Bldg. 330, Stanford, CA 94305-5410
References: 1. Dabo SM, Confer AW, Montelongo M, Lu Y-S: Characterization of rabbit Pasteurella multocida isolates by use of whole-cell, outer-membrane, and polymerase chain reaction typing. Lab Anim Sci 49:551-559, 1999
2. DeLong D, Manning PJ. In: The Biology of the Laboratory Rabbit, ed. Manning PJ, 2nd ed., pp. 131-140. Academic Press, San Diego, CA, 1994
3. DeLong D, Manning PJ, Gunther R, Swanson DL: Colonization of rabbits by Pasteurella multocida: serum IgG responses following intranasal challenge with serologically distinct isolates. Lab Anim Sci 42:13-18, 1991
4. Percy DH, Barthold SW. In: Pathology of Laboratory Rodents and Rabbits, pp. 188-191. Iowa State University Press, Ames, IA, 1993
5. Zaoutis TE, Reinhard GR, Cioffe CJ, Moore PB, Stark DM: Screening rabbit colonies for antibodies to Pasteurella multocida by an ELISA. Lab Anim Sci 41: 419-422, 1991
CASE IV – S214/99 (AFIP 2742244)
Signalment: 21-week-old, male, pathogen-free white leghorn (VALO) chicken
History: This chicken was infected, as control in a vaccination study, with 3 x 103 PFU of a virulent, wild-type infectious laryngotracheitis virus (ILTV) by intratracheal and eye drop routes. Two days after infection, the animal showed heavy, gasping respiration and coughing and was euthanized on day 4 p.i.
Gross Pathology: The tracheal mucosa was diffusely hemorrhagic and the lumen was obstructed with blood and necrohemorrhagic debris. The lungs were congested and edematous. Cranial and caudal portions of both lungs were consolidated and had a mottled, purplish-red and gray cut surface. The lumens of mesobronchi were filled with caseous exudate.
Laboratory Results: ILTV was recovered by tissue culture from tracheal swabs taken on day 3 p.i.
Contributor’s Diagnoses and Comment: 1. Lung: Bronchitis, necrotizing, desquamative, fibrinosuppurative and hemorrhagic, acute, multifocal, severe, with multinucleate epithelial cells (syncytia) and eosinophilic intranuclear inclusion bodies, etiology consistent with gallid herpesvirus 1 (ILTV).
2. Peribronchitis, lymphocytic and histiocytic, acute, locally extensive.
Further histologic lesions included severe necrohemorrhagic laryngotracheitis with desquamation of hyperplastic epithelial cells, syncytia, and eosinophilic intranuclear inclusion bodies (not submitted).
Avian infectious laryngotracheitis is a worldwide, acute, and highly contagious respiratory disease of chickens caused by infectious laryngotracheitis virus (ILTV). ILTV is currently designated as gallid herpesvirus 1, a member of the Alphaherpesvirinae subfamily of the Herpesviridae. Clinical signs vary considerably with the virulence of different ILTV strains and immunological protection of flocks by vaccination. Marked dyspnea, with expectoration and nasal discharge of blood and mucohemorrhagic exudate, characterizes severe forms of the disease. Progressive obstruction of the trachea and large bronchi with mucus, blood and caseous exudate forces the bird to inhale with an extended neck and widely opened beak and can lead to death by asphyxia in severe cases. Mild, enzootic courses are associated with sinusitis, conjunctivitis, and economic losses due to reduced egg production. In general, most chickens recover in two weeks, but chronic courses up to four weeks and longer have been reported. As preventive measures, attenuated live virus vaccines are available. Most viral strains used in live vaccines are genetically uncharacterized and still moderately pathogenic. There is the risk of spontaneous reversion to a more virulent phenotype that may persist in the flocks. Further losses may occur due to ILT alone or in combination with other pathogens such as Newcastle disease virus, Mycoplasma gallisepticum or infectious bronchitis virus.
As a prerequisite for the development of genetically engineered vaccines, most of the ILTV genome has been characterized over the last few years. In contrast to UL-50 deletion mutants of herpes simplex virus 1 and pseudorabies virus that are significantly attenuated in mice or pigs, the UL-50 gene of ILTV encodes a dUTPase that is not a virulence factor.
AFIP Diagnosis: Lung: Bronchopneumonia, necrotizing, heterophilic and lymphohistiocytic, multifocal, severe, with syncytia and eosinophilic intranuclear inclusion bodies, white leghorn (VALO) chicken, avian, etiology consistent with gallid herpesvirus-1.
Conference Comment: Unlike other herpesviruses, natural transmission of infectious laryngotracheitis is exclusively aerogenic. The virus has affinity for the respiratory epithelium and viremia does not develop. Early microscopic findings in tracheal mucosa include the loss of goblet cells, submucosal edema and loss of cilia. Multinucleate syncytial cells occur and lymphocytes, macrophages and plasma cells migrate into the mucosa and submucosa after 2-3 days. Later, cytolytic destruction and desquamation typical of alphaherpesviruses results in ulceration and hemorrhage.
Contributor: Federal Research Centre for Virus Diseases of Animals (BFAV),
Friedrich-Loeffler Institute, Boddenblick 5A, 17498 Insel Riems, Germany
References: 1. Bagust TJ, Guy JS: Laryngotracheitis. In: Diseases of Poultry, ed. Calnek BW, Barnes HJ, Beard CW, McDougald LR & Saif YM, 10th ed., pp. 527-539. Iowa State University Press, Ames, IA, 1997
2. Fuchs W, Ziemann K, Teifke JP, Werner O, Mettenleiter TC:
The non-essential UL50 gene of avian infectious laryngotracheitis
virus encodes a functional dUTPase which is not a virulence factor.
J Gen Virol 81:627-638, 2000
*Sponsored by the American Veterinary Medical Association, the American College of Veterinary Pathologists and the C. L. Davis Foundation.
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