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CASE I – 15680 (AFIP 2746099)
Signalment: 8-month-old, female, spayed, Cavalier King Charles spaniel.
History: This dog had a long history of tachypnea and a 3-week history of exercise intolerance. A cardiac murmur was auscultated by the veterinarian, who then referred the dog to The Royal Veterinary College, University of London. On physical examination, there were signs of left and right heart failure with cardiac dysrhythmia. The dog died spontaneously shortly after the physical examination.
Gross Pathology: There is extensive subcutaneous edema, particularly of the ventral abdomen and hindlegs. Mucous membranes are pale. The lungs have a variegated red and pink pattern and are firm to meaty. Ventral regions of all lung lobes are most severely consolidated. Sections of lung tissue float poorly in 10% neutral buffered formalin. The heart is globoid with a dilated right ventricle and atrium. The right atrium and the adjacent section of pulmonary artery contain numerous tangled, filamentous nematodes. The nematodes are approximately 2-3 cm in length and less than 1 mm in diameter, and are pale tan with a deep red to brown, longitudinal, internal, tubular structure (digestive tract). The nematodes are entrapped in the loose intra-atrial and intra-arterial blood clots. Smaller numbers of worms are observed within the right ventricle.
Ratio of interventricular septum to right ventricle is 2.5:1 (normal is about 3 to 3.5:1). The ratio 2.5 to 1 implies hypertrophy of the right ventricle.
Left AV / Right AV = 45/78 = 0.57 (<0.6 indicates right atrioventricular dilation).
Approximately 470 ml of clear yellow fluid is observed in the peritoneal cavity. The liver is congested and enlarged with rounded edges (weight 380 g).
Gross diagnoses: 1. Right ventricular hypertrophy and right atrial dilatation, moderate, with intraluminal nematodes
2. Pulmonary arterial nematodiasis, severe
3. Pulmonary congestion, diffuse, subacute to chronic, marked
4. Hepatic congestion, diffuse, subacute to chronic, marked
5. Ascites, marked
6. Subcutaneous edema, extensive, marked
Laboratory Results: Parasitology: Parasites from the right side of the heart were identified as Angiostrongylus vasorum.
Contributor’s Diagnosis and Comment: Lung: Pneumonia, interstitial, fibrotic, granulomatous, and necrotizing, chronic, multifocal to coalescing, severe, with arterial thrombosis and intralesional nematodes (Angiostrongylus vasorum), lung.
Lung: The normal architecture of large regions of the pulmonary parenchyma are obliterated by clusters of different stages of nematode parasites, which are surrounded by variably thick, concentrically arranged, plump fibroblasts and epithelioid macrophages, with smaller numbers of foreign body-type, multinucleate, histiocytic giant cells. The parasites are elongate to fusiform, measure 10-30 microns in diameter, and have a thin, eosinophilic cuticle (Angiostrongylus vasorum larvae). Many alveolar spaces are collapsed and contain numerous macrophages, small numbers of larvae, and occasional histiocytic giant cells, plasma cells, and lymphocytes, with multifocal hemorrhage. Extensive regions of the parenchyma that contain parasites are necrotic, with loss of cellular detail, moderate amounts of scattered nuclear debris, and moderate hemorrhage. Occasional sections through 300 micron diameter mature nematodes show a thin, eosinophilic, ridged cuticle, polymyarian-coelomyarian musculature, a body cavity, and a wide digestive tract lined by few uninucleate columnar cells (consistent with metastrongyles).
Two large pulmonary arteries are markedly distended by large thrombi comprised of finely fibrillar eosinophilic material with entrapped degenerate neutrophils, nematode larvae, and erythrocytes. Macrophages infiltrate peripheral regions of the thrombi that have central foci of basophilic, granular material (mineralization). Larvae and inflammatory cells extend through the wall of one of the arteries into the parenchyma. Small numbers of larvae are within medium-sized pulmonary arteries. The subpleural stroma is moderately thickened by collagenous fibrovascular tissue, which contains occasional scattered nematode larvae.
Smaller numbers of Angiostrongylus larvae are also observed in the kidney, myocardium and tracheobronchial lymph node (sections not included). The inflammatory reaction in these tissues is mild to non-existent.
Angiostrongylus vasorum is a metastrongylid nematode parasite of the cardiac right ventricle and pulmonary artery of dogs and foxes. The adult worms cause a proliferative endarteritis, however, the most severe damage is caused by eggs and larvae. The eggs lodge in arterioles and capillaries, with emerging larvae breaking into alveolar spaces. The larvae stimulate a marked fibrotic response, as observed in this case. Large areas of necrosis represent infarcts. Clinical disease is not usually noted until the chronic stage, which occurs months to years after the initial infection. Fibrotic changes in the lung can lead to right-sided cardiac failure. It is rare for acute disease to lead to death of the dog.
Angiostrongylus vasorum has an indirect life cycle. First-stage larvae (L1) are coughed into the pharynx and excreted in the feces. Certain species of slugs and snails, attracted to canine fecal material, ingest the larvae that develop to the third stage (L3). Dogs ingest the intermediate hosts, releasing L3 that penetrate the alimentary tract and develop to L5 within abdominal lymph nodes. Larvae migrate to the cardiac right ventricle and pulmonary artery via the hepatic portal vein, liver, and caudal vena cava, and mature 33-35 days after infection. The disease can be diagnosed by detection of characteristic L1 in the feces.
Endemic foci of this parasite exist in France, Ireland, Denmark, and some southern regions of the United Kingdom (Cornwall and South Wales). Sporadic cases such as this one have been reported in southeast England, and it has been suggested that endemic foci may also establish near Hertfordshire if mild winter weather continues.
AFIP Diagnosis: Lung: Pneumonia and pleuritis, granulomatous, fibrosing, diffuse, severe, with arteritis, thrombosis, infarction, hemorrhage, and numerous metastrongyle larvae and eggs, and few intravascular adults, Cavalier King Charles spaniel, canine, etiology consistent with Angiostrongylus vasorum.
Conference Comment: The pathogenesis of the verminous pneumonia caused by Angiostrongylus vasorum is not completely understood. Presumably the immature parasites produce antigenic factors that cause thrombosing arteritis with subsequent extension of the inflammation into the surrounding lung tissue. Secondary anaphylactic reactions can result from massive numbers of A. vasorum larvae living within the vascular system or from the treatment of infected dogs with anthelmintics, inducing a massive killing of worms. Intravascular (consumptive) coagulopathy can also lead to a hemorrhagic diathesis manifested by anemia, hemoptysis, melena, and subcutaneous hematomas.
Pulmonary fibrosis and induration, hydrothorax, hydropericardium, and hepatic stasis with ascites are possible sequelae to the presence of adult worms and migrating larvae within the heart and vessels. Occasionally, embolic larvae are found in distant organs such as the brain and kidney. Ocular angiostrongylosis with adult worms in the anterior chamber can induce an anterior uveitis. Granulomatous inflammation, hemorrhage and infarcts can result from occlusion of capillaries. Immune complex deposition within glomeruli may be seen with chronic angiostrongylosis.
Contributor: Royal Veterinary College, Department of Pathology and Infectious Diseases, Hawkshead Lane, Hatfield, Hertfordshire AL9 7TA, United Kingdom
References: 1. Bolt G, Monrad J, Koch J, Jensen AL: Canine angiostrongylosis: a review. Vet Rec 135:447-452, 1994
2. Cobb MA, Fisher MA: Angiostrongylus vasorum: transmission in southeast England. Vet Rec 126:529, 1990
3. Patteson MW, Gibbs C, Wotton PR, Day MJ: Angiostrongylus vasorum infection in seven dogs. Vet Rec 133:565-570, 1993
CASE II – Fac. Med. Vet. Da USP (AFIP 2742514)
Signalment: Juvenile, male, common marmoset, Callithrix jacchus
History: This marmoset was captured by the Center for Zoonoses Control (CCZ) of So Paulo city after it had been turned loose and invaded a house. It was placed in an individual, indoor, brick-walled cage at the CCZ for 4 days. The enclosure was located next to dog and cat cages in the section for rabies suspect animals. The monkey received a commercial adult dog biscuit diet and water ad libitum. The animal was not submitted to a physical or laboratory examination at the CCZ. During this period, it was noted to be anorectic and lethargic, and was transferred to the Technical Veterinary Medicine and Fauna Biology Division of the Parks and Green Areas Department of the So Paulo City (DEPAVE) for medical care. Upon arrival at DEPAVE, the monkey weighed 145 g, was hypothermic, dehydrated, bradycardic (88 bpm) and dyspneic. Despite emergency clinical intervention, the animal died a few minutes later.
Gross Pathology: Gross examination revealed a young, thin animal with few deposits of body fat, and empty gastrointestinal tract. There were few nematodes (classified as members of the superfamily Ascaridoidea) in the large intestine. The liver and kidney was a yellow to pale-tan. There were congested lungs, a contracted spleen and enlarged mesenteric lymph nodes. Thin slices of liver floated when placed in 10% buffered formalin. The adrenals, pancreas, thyroids, heart and brain were normal.
Laboratory Results: Heart blood culture: negative.
Contributor’s Diagnosis and Comment: Liver, lipidic intracytoplasmic vacuolation, diffuse, severe, hepatic lipidosis, Callithrix jacchus, New World primate, non-human primate.
In this case, the most remarkable microscopic finding was severe and diffuse fatty change in the liver, characterized by severe intracytoplasmic vacuolation of hepatocytes. Additionally, mild to moderate microvesicular fatty change was observed in the proximal renal tubular epithelium. In both organs, the lipidic nature of the vacuolar contents was confirmed by positive Sudan Black B stain. Gram and PAS stains were negative for microorganisms in both organs.
Additional microscopic findings included mild, acute interstitial pneumonia without observable etiologic agent. There was moderate splenic lymphoid depletion of T-cell areas in primary follicles, moderate bone marrow pancellular hypoplasia, and a single cerebral microglial nodule. A mild to moderate acute gastritis was present with multifocal angioinvasion by mucoraceous hyphae in gastric submucosal vessels.
Fatty change, or steatosis, is a condition characterized by an abnormal accumulation of triglycerides within the cellular cytoplasm that usually occurs in the liver and, sporadically, in the heart, muscle and kidneys. Severe, diffuse hepatic lipidosis requires some time to develop and implies mild cellular injury as a result of nutritional and metabolic imbalance, rather than toxic or anoxic primary injury. In general, the liver is enlarged and floats when placed in formalin. However, the hepatic function is not necessarily abnormal, and the liver can return to normal structure if the metabolic alteration is corrected in time.
Triglyceride accumulation in hepatocytes can occur due to nutritional, metabolic, hormonal, toxic or anoxic/hypoxic disturbances of lipid metabolism. The common factor for each of these possible etiologies is a negative balance between the rates of deposition and dispersal of fat from the liver, resulting in an accumulation of triglycerides in target organs, such as liver and kidneys. Although the pathogenesis of this disturbance is not completely understood, some believe that any deficit in energy intake can lead to an intense mobilization of free fatty acids from fat deposits to make up for general energy demands by important organs in affected animals. Several physiologic and pathologic circumstances in different animal species can cause the development of severe fatty change in the liver, with or without clinical disease. This condition is seen with intense lactation, pregnancy toxemia in cattle, guinea pigs and sheep, hyperlipemia in ponies, hepatic lipidosis syndrome in cats, starvation, diabetes mellitus, anemia, intoxication, choline deficiency, alcoholism in humans, and fatal fasting syndrome in Old World primates.
Fatal fasting syndrome (FFS), also known as fatty liver syndrome, fat macaque syndrome, or hepatic lipidosis, is an acute metabolic syndrome of high mortality, which has been described in macaque species and African green monkeys (Cercopithecus aethiops). In Old World monkeys, FFS is characterized by sudden death in adult, female, overweight macaques that exhibit a short period of anorexia, lethargy and rapid weight loss or no prior signs of illness. Laboratory examination of affected animals usually reveals elevated blood urea nitrogen, creatinine, serum triglycerides, and alkaline phosphatase accompanied by non-regenerative, microcytic, hypochromic anemia, neutrophilic leukocytosis and bilirubinuria. Although the presumptive diagnosis is based on history, clinical signs and laboratory data, the definitive diagnosis is made by microscopic evaluation of a liver biopsy or during necropsy examination. Grossly, animals usually have abundant body fat, an enlarged, friable and pale liver, pale and soft kidneys and necrosis of most body fat stores. Microscopically, diffuse and severe fatty change in hepatocytes and renal proximal tubular epithelium are the most remarkable findings. Among the differential diagnosis, FFS should be distinguished from hepatic steatosis as a result of hypothyroidism, diabetes mellitus or toxemias associated with toxic or infectious agents.
In this case, the young marmoset had a history of stressful housing, inappropriate diet, a known short period of anorexia, apathy, and weight loss that led to systemic collapse and death after relocation. The main pathological findings were the severe and diffuse hepatic lipidosis accompanied by anemia and gastric mucormycosis. Despite the lack of laboratory data and detailed clinical description in this case, it is possible to compare the pathological findings to those found in reported FFS cases. We preliminarily designated this hepatic lipidosis process as a fatal fasting syndrome-like disease in this common marmoset. Since the first description of fatal fasting syndrome (FFS) in macaques, a small number of cases involving Old World primates has been reported in the literature, but none-to-date in New World primates.
AFIP Diagnosis: Liver, hepatocytes: Vacuolar change, lipid-type, diffuse, severe, common marmoset (Callithrix jacchus), nonhuman primate.
Conference Comment: Currently, the pathogenesis of fatal fasting syndrome in obese macaques is poorly understood and no single event seems to predispose a monkey to the disease. It is seen most commonly in obese, older female macaques that have been exposed to some stress or other cause of sudden fasting. It is not known to be associated with liver dysfunction or any other disease. Weight loss and fatty change in organs such as the liver are commonly seen in animals with a negative energy balance. Normal animals should be able to tolerate such a condition until starvation level is reached. The fact that these macaques usually have abundant fat stores implies an inappropriate handling of free fatty acid mobilization.
Other lesions occasionally seen are pancreatic ectasia with small areas of necrosis, focal degeneration of cardiac myofibers, and saponification of fat. In many ways, this syndrome is similar to diseases seen in cats, guinea pigs, ponies, sheep, and cattle that also result in hepatic lipidosis.
Contributor: Universidade de So Paulo, Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Av. Prof. Dr. Orlando Marques de Paiva 87, Cid. Universitária, So Paulo, SP, 05508-000, Brazil
References: 1. Brady AG, Morton DG: Digestive system. In: Nonhuman Primates In Biomedical Research: Diseases, ed. Bennett BT, Abee CR, Henrickson R, pp. 405-406. Academic Press, Inc., New York, NY, 1998
2. Bronson RT, O’Connell M, Klepper-Kilgore N, Chalifoux LV, Sehgal P: Fatal fasting syndrome of obese macaques. Lab Anim Sci 32(2):187-191, 1982
3. Christie KL, Valverde CR: The use of a percutaneous endoscopic gastrotomy (PEG) tube to reverse fatal fasting syndrome in a cynomolgus macaque (Macaca fascicularis). Contemp Topics 38(4):12-15, 1999
4. Cotran RS, Kumar V, Collins T: Cellular pathology II: adaptations, intracellular accumulations, and cell aging. In: Robbins’ Pathologic Basis of Disease, 6th ed., pp. 38-40. WB Saunders, Co., Philadelphia, PA, 1999
5. Gliatto M, Bronson RT: Fatal fasting syndrome of obese macaques. In: Nonhuman Primates I, ed. Jones TC, Mohr U, Hunt RD, pp. 198-202. Springer-Verlag, New York, NY, 1993
6. Kelly WR: The liver and biliary system. In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy PC, Palmer N, 4th ed., vol. 2, pp. 331-336. Academic Press, Inc., New York, NY, 1993
7. Laber-Laird KE, Jokinen MP, Lehner NDM: Fatal fasting liver-kidney syndrome in obese monkeys. Lab Anim Sci 37(2):205-209, 1987
CASE III – D00-817 (AFIP 2739154)
Signalment: 4-week-old, breed and sex not specified, bovine
History: This calf was a veal feeder and had been suffering from “respiratory symptoms”. Approximately 60% of its pen mates were similarly affected. This calf was treated with Micotil, Trivetrin and Nuflor with little response and was subsequently euthanized.
Gross Pathology: Portions of heart and lung were submitted. The lung had multifocal, 2-3 cm, red to purple areas.
Laboratory Results: Immunohistochemistry for bovine respiratory syncytial virus (BRSV) antigen was performed. There is diffuse positive staining in the respiratory epithelium. No bacteria were isolated from the lung.
Contributor’s Diagnosis and Comment: Lung, fibrinopurulent bronchopneumonia and pleuritis, subacute, severe, multifocal, necrotizing and hemorrhagic.
There is a lobular pattern of hypercellularity and partial alveolar collapse in approximately 60% of the tissue sections received. Neutrophils occupy a significant portion of the bronchiolar lumen and alveoli. Associated with this inflammation is a deep eosinophilic, fibrillar (fibrin) and homogeneous (hyaline membrane) material, mild hemorrhage and, occasionally, nuclear and cellular debris. Bronchiolar cells are disrupted and are hypertrophied along with pneumocytes. Multinucleated cells with eosinophilic, intracytoplasmic inclusion bodies (syncytial cells) typical of BRSV are frequent. Tunica media cells of the arterioles are hypertrophied. The pleura is frequently thickened due to fibrin and mild neutrophilic infiltrate. There are multiple, deeply basophilic, striated globules, that could be nuclear lymphocytic accumulations, randomly scattered throughout the affected sections.
BRSV is a common cause of pneumonia in cattle worldwide. Respiratory diseases associated with BRSV often occur as sporadic outbreaks, with high morbidity and variable mortality (1-30%). Calves between 1-3 months of age are primarily affected, but adult cattle can be involved in some outbreaks. This disease is virtually absent in calves less than 2 weeks old.
BRSV is suspected to be transmitted via aerosols. The incubation period ranges from 2-7 days. Following exposure, BRSV replicates in cells of the nasal mucosa, pharynx, trachea and lung. Clinical signs of this disease in calves include anorexia, depression, nasal discharge, salivation, lacrimation, fever, tachypnea, dyspnea and coughing. A presumptive diagnosis of BRSV can be made with histological examination of lung tissue as typical lesions include bronchiolar epithelial syncytial cells, often with eosinophilic inclusion bodies. Diffuse interstitial pneumonitis, hyaline membranes and alveolar epithelialization are other common histopathologic findings. Definitive diagnosis in this case was made by immunohistochemistry on formalin-fixed tissue.
AFIP Diagnosis: Lung: Pneumonia, bronchointerstitial, subacute, multifocal, moderate, with interlobular edema, epithelial syncytia and eosinophilic, intracytoplasmic inclusion bodies, breed not specified, bovine.
Conference Comment: The pathogenesis and immunopathogenesis of BRSV infection is not entirely understood. Circulating BRSV antibody is not protective against reinfection; however, subsequent illness is mild or subclinical. Lesions in the cranioventral lung lobes are due to direct viral cytopathologic effect on respiratory epithelium, causing necrosis and often leading to bronchiolitis obliterans and obstructive atelectasis. Hypersensitivity reactions may also be involved in disease progression. BRSV-infected cells can activate complement, producing the anaphylotoxins C3a and C5a that circulate systemically and induce bronchoconstriction, neutrophil chemotaxis, and activation of mast cells. Mast cell degranulation releases other inflammatory mediators, including histamine, platelet activating factor, and leukotrienes. C5a activates the lipoxygenase pathway of arachidonic acid metabolism in neutrophils and monocytes. The subsequent severe bronchoconstriction and increased vascular permeability results in edema and emphysema throughout all portions of the lung. Cell-mediated immunity is important in recovery from infection.
Parainfluenza virus 3 (another paramyxovirus) causes similar histologic lesions with syncytia and eosinophilic intracytoplasmic inclusion bodies. The prominence of syncytial cells in bronchioles in this case is more typical of BRSV pneumonia.
Contributor: University of Saskatchewan, Department of Veterinary Pathology, WCVM, 53 Campus Drive, Saskatoon, SK S7N 5B4
References: 1. Baker JC, Ellis JA, Clark EG: Bovine respiratory syncytial virus. In: Veterinary Clinics of North America: Food Animal Practice 133(3):425-454, 1997
2. Dungworth DL: The respiratory system. In: Pathology of Domestic Animals, ed. Jubb KVF, Kennedy PC, Palmer N, 4th ed., vol 2, pp. 615-617. Academic Press Inc., New York, NY, 1993
3. Sharma R, Woldehiwet Z: Bovine respiratory syncytial virus: a review. Vet Bull 61(11):1117-1131, 1991
CASE IV – 377-99 (AFIP 2741020)
Signalment: 35-year-old, female, Chilean flamingo (Phoenicopterus chilensis)
History: One of several flamingos to present weak and ataxic. Cases of malaria had been diagnosed in an adjacent cage of penguins.
Gross Pathology: The flamingo is slightly thin and in good post mortem condition. A subdural hematoma is present over the cerebellum. The heart has an irregular contour. Numerous areas of pallor extend from the surface into the myocardium. The aorta and renal arteries have multifocal areas of atherosclerosis.
Laboratory Results: Abnormal blood results were limited to a decreased Na+, K+, and Cl-. The hematocrit was slightly decreased. The globulins were elevated. West Nile Virus was isolated from tissues submitted for viral isolation. By immunohistochemistry, sections of the heart were positive for West Nile Virus antigen. In situ hybridization for West Nile Virus on the heart was positive.
Contributor’s Diagnosis and Comment: Myocarditis, multifocal to coalescing, chronic with hemorrhage, myocyte necrosis, and macrophages ingesting myofibers.
This flamingo was part of an outbreak of West Nile virus in the late summer and early fall of 1999 that occurred in and around New York City. The outbreak resulted in fatal, neurologic disease in humans, as well as a variety of native and exotic birds and some horses. A complete description of the pathology observed in the avian cases and the diagnostic techniques can be found in Veterinary Pathology 37(3):208-224, May, 2000.
AFIP Diagnosis: Heart: Pancarditis, necrotizing, lymphoplasmacytic and histiocytic, multifocal to coalescing, moderate, Chilean flamingo (Phoenicopterus chilensis), avian.
Conference Comment: West Nile virus is an arbovirus of the family Flaviviridae, genus Flavivirus, in the Japanese encephalitis virus antigenic complex. Birds are the reservoir for sylvatic transmission, with humans and horses becoming infected during the urban transmission cycle. Culex pipiens is considered the primary vector, although other mosquito species and ticks are capable of harboring the virus.
With the 1999 outbreak, the most prominent gross lesions in birds infected by West Nile virus were hemorrhage of the brain, splenomegaly, myocarditis, and meningoencephalitis. During the investigative workup, the differential diagnosis of exotic Newcastle’s disease (END), highly pathogenic avian influenza (HPAI) and eastern equine encephalitis (EEE) were considered, pursued and systemically ruled out. END and HPAI cause mortality in chickens and turkeys; however, these birds were not affected. Of the arboviruses known to be pathogenic for birds, EEE was a possibility, but emus are highly sensitive to EEE, and they were not affected.
The molecular layer of the cerebellum, to include the Purkinje cells, had the greatest amount of viral antigen and was the most common area of the brain affected. Cerebral neurons were not commonly affected. Transmission electron microscopy performed on infected tissue showed virions that measured 35-45 nm in diameter, characterized by a dense core surrounded by a diffuse outer layer. Virions were localized to cytoplasmic vacuoles in perikaryon and neuritic processes, and less frequently in rough endoplasmic reticulum. 100 nm smooth membrane vesicles (SMV), characteristic of flaviviruses, were present in dilated rough endoplasmic reticulum and vacuoles. Marked vesiculation and vacuolation of the cytoplasm, with disorganization of the rough endoplasmic reticulum and Golgi apparatus were also present.
Contributor: Wildlife Conservation Society, Wildlife Health Center, 2300 Southern Boulevard, Bronx, NY, 10460
Reference: 1. Steele KE, Linn MJ, Schoepp RJ, Komar N, Geisbert TW, Manduca RM, Calle PP, Raphael BL, Clippinger TL, Larsen T, Smith J, Lanciotti RS, Panella NA, McNamara TS: Pathology of fatal West Nile virus infections in native and exotic birds during the 1999 outbreak in New York City. Vet Pathol 37(3):208-224, 2000
2. Sampson BA, Ambrosi C, Charlot A, Reiber K, Veress J, Armbrustmacher
V: The pathology of human West Nile virus infection. Human Pathol
31(5):527-531, 2000
*Sponsored by the American Veterinary Medical Association, the American College of Veterinary Pathologists and the C. L. Davis Foundation.
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