Syncytial Giant Cells Research Articles

Nipah Virus Infection: Pathology and Pathogenesis of an Emerging Paramyxoviral Zoonosis

In 1998, an outbreak of acute encephalitis with high mortality rates among pig handlers in Malaysia led to the discovery of a novel paramyxovirus named Nipah virus. A multidisciplinary investigation that included epidemiology, microbiology, molecular biology, and pathology was pivotal in the discovery of this new human infection. Clinical and autopsy findings were derived from a series of 32 fatal human cases of Nipah virus infection. Diagnosis was established in all cases by a combination of immunohistochemistry (IHC) and serology. Routine histological stains, IHC, and electron microscopy were used to examine autopsy tissues. The main histopathological findings included a systemic vasculitis with extensive thrombosis and parenchymal necrosis, particularly in the central nervous system. Endothelial cell damage, necrosis, and syncytial giant cell formation were seen in affected vessels. Characteristic viral inclusions were seen by light and electron microscopy. IHC analysis showed widespread presence of Nipah virus antigens in endothelial and smooth muscle cells of blood vessels. Abundant viral antigens were also seen in various parenchymal cells, particularly in neurons. Infection of endothelial cells and neurons as well as vasculitis and thrombosis seem to be critical to the pathogenesis of this new human disease.

Biliary atresia.

Biliary atresia.

Neonatal Syncytial Giant Cell Hepatitis with Paramyxoviral-like Inclusions

Syncytial giant cell hepatitis in the neonatal period has been associated with many different etiologic agents and may present initially as cholestasis. Infectious causes are most common and include: (1) generalized bacterial sepsis, (2) viral agents, (3) toxoplasmosis, (4) syphilis, (5) listeriosis, and (6) tuberculosis. Viral hepatitis may be due to cytomegalovirus, rubella virus, herpes simplex, HHV-6, varicella, coxsackievirus, echovirus, reovirus 3, parvovirus B19, HIV, enteroviruses, paramyxovirus, and hepatitis A, B, or C (rare). Giant cell hepatitis may result in fulminant liver failure with massive hepatocyte necrosis and severe liver dysfunction leading to death, resolution with severely compromised liver function, or liver transplantation. The authors report a 6-week-old male who had an unremarkable perinatal period, became jaundiced after developing diarrhea, and subsequently developed liver dysfunction with massively increased liver enzymes and a coagulopathy. Open wedge and core liver biopsies were performed to determine if the patient should be listed for liver transplantation. Giant cell hepatitis with a significant mixed lymphocytic and neutrophilic infiltrate was present on both the wedge and core biopsies. The residual 60% of hepatocytes had ballooning degeneration and many possessed pyknotic nuclei. The hepatocytes were arranged in a pseudoacinar pattern. Electron microscopy showed paramyxoviral-like inclusions in the giant cells, characterized as large inclusions with fine filamentous, beaded substructures (18-20 nm). Paramyxoviridae are nonsegmented, negative-sense, single-stranded RNA viruses. This family is divided into the Paramyxovirinae subfamily containing respirovirus (Sendai virus, parainfluenza virus type 3), rubula virus (mumps, parainfluenza virus type 2), and morbillivirus genera (measles); and Pneumovirinae subfamily (pneumovirus genus [respiratory syncytial virus]). Supportive care to determine if hepatic function resolves following the viral episode, liver transplantation with fulminant liver failure, and ongoing evaluation in those who recover to assess chronic liver disease are necessary. Ultrastructural evaluation may unmask the etiologic agent for hepatitis and direct therapy.

A retrospective search for bovine respiratory syncytial virus (BRSV) antigens in histological specimens by immunofluorescence and immunohistochemistry

Bovine respiratory syncytial virus (BRSV) has been only sporadically identified as a causative agent of respiratory disease in Brazil. This contrasts with frequent reports of clinical and histopathological findings suggestive of BRSV-associated disease. In order to examine a possible involvement of BRSV in cases of calf pneumonia, a retrospective search was performed for BRSV antigens in histological specimens submitted to veterinary diagnostic services from the states of Rio Grande do Sul and Minas Gerais. Ten out of 41 cases examined (24.4%) were positive for BRSV antigens by immunohistochemistry (IPX). Eight of these cases (19.5%) were also positive by indirect immunofluorescence (IFA), and 31 cases (75.6%) were negative in both assays. In the lungs, BRSV antigens were predominantly observed in epithelial cells of bronchioles and less frequently found in alveoli. In one case, antigens were detected only in the epithelium of the alveolar septae. The presence of antigen-positive cells was largely restricted to epithelial cells of these airways. In two cases, positive staining was also observed in cells and cellular debris in the exudate within the pulmonary airways. The clinical cases positive for BRSV antigens were observed mainly in young animals (2 to 12 month-old) from dairy herds. The main microscopic changes included bronchointerstitial pneumonia characterized by thickening of alveolar septae adjacent to airways by mononuclear cell infiltrates, and the presence of alveolar syncytial giant cells. In summary, the results demonstrate the suitability of the immunodetection of viral antigens in routinely fixed tissue specimens as a diagnostic tool for BRSV infection. Moreover, the findings provide further evidence of the importance of BRSV as a respiratory pathogen of young cattle in southeastern and southern Brazil.

Retrospective study of porcine circovirus 2 infection in Japan: seven cases in 1989.

Retrospectively, we demonstrated that seven pigs necropsied in 1989 had characteristic porcine circovirus 2 (PCV-2) lymphoid tissue lesions of severe lymphoid depletion, syncytial giant cell formation, and intracytoplasmic inclusion bodies in macrophages. Immunohistochemically, PCV-2 antigen was detected in these tissues and the distribution of positive staining corresponded to the distribution of inclusion bodies. Electron microscopy demonstrated viral particles compatible with porcine PCV-2. Therefore, the disease occurred in Japan as early as 1989.

Adult syncytial giant cell chronic hepatitis due to herbal remedy

Syncytial giant cell hepatitis is an uncommon form of chronic hepatitis in adults, although it has been reported in association with viral infection (including HCV and HIV infection), drug reactions and autoimmune disorders. We here report a very unusual case of giant cell chronic hepatitis in a 26-old-woman, who had been taking a herbal remedy (ISABGOL) for chronic constipation. The presence of viral and metabolic diseases has been excluded; an autoimmune etiology was very unlikely as the autoimmunity test remained negative during the year of follow-up and the total disease score normalized (from 13 to 8) without corticosteroid treatment. The causative role of the herbal remedy was further supported by the spontaneous and dramatic clinical, biochemical and histologic improvement observed following its withdrawal, despite the absence of any treatment.

A case of syncytial giant cell hepatitis with features of a paramyxoviral infection

Adult syncytial giant cell hepatitis (GCH) is an uncommon and often fulminant form of hepatitis that may be caused by infection with a novel paramyxo-like virus. We present the case of a 69-yr-old man who presented with acute, community-acquired hepatitis and chronic lymphocytic leukemia. A liver biopsy showed the typical findings of panlobular syncytial giant cell hepatitis. Electron microscopic examination demonstrated abundant nucleocapsid-like protein material in the cytoplasm and nuclei of affected hepatocytes. These structures were similar to, but distinct from, those of known paramyxoviridae, suggesting infection with a novel, related virus. In situ hybridization studies with a probe directed against the measles fusion protein gene gave a positive signal with a hepatocyte distribution. No signal was obtained with the measles nucleocapsid protein probe, suggesting that the disease agent was genetically distinct from, but related to, the measles virus. Subsequent liver biopsies were characterized by the gradual disappearance of the giant cell changes and by the concomitant development of cirrhosis. This is a case of adult GCH that resolved spontaneously and led to cirrhosis, thus implicating GCH as a potential cause of “cryptogenic” liver disease. Our findings provide further support for the existence of a distinct, as yet unidentified viral species as a cause of this disease.

Asthma and respiratory syncytial virus infection in infancy: is there a link?

Asthma and respiratory syncytial virus infection in infancy: is there a link?

Extracardiac myxoma: An unusual right ventricular epicardial location

(J Thorac Cardiovasc Surg 1997;114:672-4)

Subfulminant syncytial giant cell hepatitis: recurrence after liver transplantation treated with ribavirin

We report the case of an adult patient affected by acute syncytial giant cell hepatitis which had a subfulminant course leading to liver transplantation. Syncytial giant cell hepatitis recurred after transplantation and was efficiently treated with ribavirin. In this patient, the recurrence of the disease, the presence of filamentous strands on electron microscopy during both bouts of hepatitis and the efficacy of ribavirin on post-transplantation hepatitis suggest that the disease was caused by an original virus. This observation also suggests that early administration of ribavirin in patients affected by acute syncytial giant cell hepatitis of unknown origin could avoid liver transplantation.

Infectivity of basal epithelial cells in herpetic dendritic epithelial keratitis.

In patients with herpes virus dendritic epithelial keratitis, the pathologic morphogenesis of the dendritic lesion was investigated by means of impression cytology. Impression specimens were taken from the lesions of 24 consecutive patients assessed with a slit lamp biomicroscope. After a Millipore membrane impression was stained with hematoxylin-eosin and examined by light microscope, cellular patterns were analyzed. The results of these examinations showed that most cells were epithelial cells; there were also occasional multinucleated syncytial giant cells, inclusion bodies and inflammatory cells. Basal epithelial cells were most prominent at the actively infected lesion, whereas superficial epithelial cells were shown at the margin of the active lesion and terminal bulb. These findings suggest that in dendritic keratitis, viral spread and replication in the dendritic keratitis may progress through basal epithelial cells along the nerve within the basal epithelium-stromal interface.

Antibodies to cytokeratins bind to epitopes in human uterine smooth muscle cells in normal and pathological pregnancies.

Cytokeratin antibodies have been widely used for the identification of trophoblast cells in the placental bed, following their invasion from the developing conceptus. Their identification centres upon the expression of cytokeratin in epithelial cells, from which trophoblast cells are derived. Our recent observations indicate that this strict relationship may be more complex than was thought. Cryostat and paraffin sections of human decidua and myometrium, taken from the placental bed and the uterotomy cut, were examined immunocytochemically for cytokeratins using ten antibody clones selected to identify different cytokeratin proteins and antigenic epitopes. Biopsy specimens were obtained from normal and pathological pregnancies (pre-eclampsia, fetal retardation, amnioninfection, hysterorrhexis, placenta praevia) at the time of caesarean section (26-41 weeks of pregnancy). Antibodies against nine clones, CAM 5.2, MNF 116, AE1/AE3, CK5, KS-B17.2, CY-90, M20, E3, and 34 beta E12 identified, as expected, syncytial giant cells and mononuclear trophoblasts within the placental bed and glandular epithelial cells throughout the uterus. In addition, they stained numerous fusiform cells that were classified by established criteria to represent smooth muscle cells, both within blood vessels and myometrium. No staining differences were observed between normal and pathological disorders. These results indicate that cytokeratin antibodies CAM 5.2, MNF 116 and AE1/AE3, and other antibodies targeting proteins 8 and 18, cross-react with epitopes expressed in cells other than giant trophoblastic cells and mononuclear trophoblasts in the uterus and, thus, caution has to be used when such antibodies are used for the diagnostic characterization of tissues related to the placental bed.

Characterization of a reovirus isolate from a rattle snake, Crotalus viridis, with neurological dysfunction.

A virus isolate from the brain of a rattle snake with central nervous system (CNS) symptoms was identified as a reovirus. The isolate did not agglutinate pig erythrocytes and was not neutralized by antisera against avian reovirus S1133 and mammalian reovirus type 3. The cytopathic effect in Vero cells was characterized by formation of syncytial giant cells. Electrophoretic analysis of the genome revealed 10 segments of dsRNA. The isolate displayed characteristics distinct from avian and mammalian reoviruses.

Human neural xenografts: Progress in developing an in-vivo model to study human immunodeficiency virus (HIV) and human cytomegalovirus (HCMV) infection

Human immunodeficiency virus type 1 (HIV-1) infection is highly specific for its human host. In order to study HIV-1 infection of the human nervous system, we have established a small animal model in which second-trimester (11-17.5 weeks) human fetal brain or neural retina is transplanted into the anterior chamber of the eye of immunosuppressed adult rats (Epstein et al., 1992; Cvetkovich et al., 1992), and more recently in immunodeficient (SCID) mice. The human xenografts survive for many months, vascularize and form a blood-brain barrier. Immunohistochemistry with PGP 9.5 identified neuronal cell bodies and neuritic processes. Electron microscopy revealed axonal growth cones and synaptic junctions. Infection of these xenografts with cell-free HIV-1 proved difficult, however co-engraftment with HIV-1-infected human monocytes resulted in characteristic pathological changes, including the formation of syncytial giant cells, neuronal loss, and astroglial proliferation, supporting the hypothesis that these cells can mediate neurotoxicity. In other studies, xenografts of human fetal retinal tissue were readily infected with cell-free human cytomegalovirus (HCMV) strain AD169. These grafts contained cells with intracytoplasmic and intranuclear inclusions typical of HCMV infection. Productive infection within these grafts was demonstrated by the presence of immediate early, and late (capsid) HCMV antigens, by recovery of HCMV on human fibroblast cultures, and by serial passage of virus to additional retinal xenografts (DiLoreto et al., 1994).(ABSTRACT TRUNCATED AT 250 WORDS)

Humoral Hypercalcemia Associated With a Dysgerminoma

A 16-year-old girl sought medical attention at the Mayo Clinic because of a 4.5-kg weight loss, hypercalcemia, and a pelvic mass. Preoperatively, the level of the beta-subunit of human chorionic gonadotropin was 147 IU/liter. After a brief period for observation and hydration, abdominal exploration revealed a stage III dysgerminoma; total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. Within the dysgerminoma, syncytial giant cells expressed human chorionic gonadotropin-positive immunostaining in the cytoplasm. Postoperatively, the value of the beta-subunit of human chorionic gonadotropin decreased rapidly. The patient received whole-abdomen irradiation 4 weeks postoperatively, after which the level of calcium returned to normal. The patient has been free of disease for more than 7 years.

Syncytial giant-cell hepatitis — a specific disease entity?

Syncytial giant-cell hepatitis was recently reported to be related to a paramyxovirus and carried a poor prognosis. Twelve patients with syncytial giant-cell hepatitis seen in an 8 1 2 -year period in our institute were reviewed. Seven patients had an identifiable aetiological cause: two had autoimmune chronic active hepatitis, one had primary sclerosing cholangitis and autoimmune chronic active hepatitis, two presented with prolonged jaundice after acute hepatitis A and B, one had chronic Epstein-Barr virus infection and the remaining patient was seropositive for antibody to hepatitis C virus. One patient with autoimmune chronic active hepatitis who had frequent syncytial giant cells in the liver responded promptly to corticosteroid treatment and a repeated biopsy 3 years later showed histological improvement with a marked decrease in the number of syncytial giant cells. Of the remaining five patients, three ran a clinical course of fulminant hepatic failure and two had severe chronic active hepatitis. These data indicate that syncytial giant-cell hepatitis is unlikely to be related to only one single aetiological agent and that syncytial giant-cell hepatitis does not always carry an ominous prognosis.

90-Day toxicity study of dichloroacetate in dogs

Male and female juvenile beagle dogs were dosed daily for 90 days with dichloroacetate (DCA). The compound was administered orally via gelatin capsules at doses of 0, 12.5, 39.5, and 72 mg/kg/day. Each dose group consisted of five males and five females. The dogs were observed clinically and blood samples were taken at 15-day intervals for hematologic and serum chemistry values. Decreased total erythrocyte count and hemoglobin levels were observed in mid- and high-dose dogs beginning at Day 30. Serum concentrations of LDH were elevated at Days 30 and 45 in females and at Day 75 in males treated with DCA at 72 mg/kg/day. One female of the high-dose group died at Day 50 and two high-dose males died at Days 51 and 74. Hindlimb partial paralysis was observed in many high-dose dogs. Vacuolization of myelinated white tracts of cerebrum, cerebellum, and/or spinal cord was observed in many high-dose dogs as well as some mid- and low-dose subjects. Degeneration of testicular germinal epithelium and syncytial giant cell formation was noted in males of all dose groups. Hepatic vacuolar change and chronic hepatitis appeared only in DCA-treated dogs. In addition, suppurative bronchopneumonia and chronic pancreatitis were noted in many high-dose and some middose subjects. A “no-adverse-effect level” was not determined in this study.

In vitro cytopathogenicity and in vivo virulence of two strains of canine parainfluenza virus.

In vivo and in vitro properties of two strains of canine parainfluenza virus (CPIV) were investigated. One strain, designated CPIV(+), induced syncytial giant cell formation and cytolysis in vitro, whereas the second strain, CPIV(-), caused only a mild strand-forming cytopathic effect with few, small syncytial giant cells. Vero cells infected with CPIV(+) or CPIV(-) were 100% positive for CPIV antigen as determined by immunofluorescent staining; however, 100% of CPIV(+) and less than 10% of CPIV(-) infected cells were hemadsorption positive. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis revealed no differences in electrophoretic mobility of viral polypeptides between both strains; however, in CPIV(-), reduced or absent synthesis of the putative HN and F1 proteins was observed. Isopycnic separation of CPIV(+) progeny virions showed a high proportion of viral particles with a buoyant density of 1.18 g/cm3. In contrast, CPIV(-) progeny virions had a heterogeneous density profile ranging from 1.08 to 1.18 g/cm3. Intracerebral infection of six ferrets with CPIV(+) resulted in moderate lymphocytic and histiocytic choroiditis, meningitis, and ependymitis, whereas CPIV(-) infection caused only mild to moderate inflammation. Immunohistologically, CPIV antigen was prominent in ependymal lining cells of the ventricles in CPIV(+)-infected ferrets and was reduced or lacking in CPIV(-)-infected ferrets (n = 6). Sham-injected ferrets (n = 6) did not have histologic lesions and no viral antigen was identified. The present findings suggest that certain changes in the activities of CPIV glycoproteins may lead to alterations of CPIV virulence in vivo.

Syncytial Giant-Cell Hepatitis

We describe a new form of hepatitis, occurring in 10 patients over a period of six years, characterized clinically by manifestations of severe hepatitis, histologically by large syncytial giant hepatocytes, and ultrastructurally by intracytoplasmic structures consistent with paramyxoviral nucleocapsids. The patients ranged in age from 5 months to 41 years. The tentative clinical diagnosis before biopsy was non-A, non-B hepatitis in five patients and autoimmune chronic active hepatitis in the others. Five patients underwent liver transplantation; the others died. The diagnosis of syncytial giant-cell hepatitis was established pathologically. The liver cords were replaced in all 10 patients by syncytial giant cells with up to 30 nuclei. In 8 of the 10 the cytoplasm contained pleomorphic particles of 150 to 250 microns, filamentous strands, and particles of 14 to 17 nm with peripherally disposed spikes resembling paramyxoviral nucleocapsids. Structures resembling degenerated forms were found in the other two patients. One of two chimpanzees injected with a liver homogenate from the index patient had an increase in the titer of paramyxoviral antibodies, probably an anamnestic reaction to previous paramyxoviral infection, suggesting that a paramyxoviral antigen but not viable virus was present in the liver homogenate. Although further virologic studies will be required for precise classification, we believe that paramyxoviruses should be considered in patients with severe sporadic hepatitis.

90-Day Toxicity Study of Dichloroacetate in Dogs

90-Day Toxicity Study of Dichloroacetate in Dogs. CICMANEC, J. L., CONDIE, L W., OLSON, G. R., AND WANG, S. R. (1991). Fundam. Appl. Toxrcol. 17,376–389. Male and female juvenile beagle dogs were dosed daily for 90 days with dichloroacetate (DCA). The compound was administered orally was gelatin capsules at doses of 0, 12.5, 39.5, and 72 mg/kg/day. Each dose group consisted of five males and five females. The dogs were observed clinically and blood samples were taken at 15-day intervals for hematologic and serum chemistry values. Decreased total erythrocyte count and hemoglobin levels were observed in mid- and high-dose beginning at Day 30. Serum concentrations of LDH were elevated at Days 30 and 45 in females and at Day 75 in males treated with DCA at 72 mg/kg/day. One female of the high-dose group died at Day 50 and two high-dose males died at Days 51 and 74. Hindlimb partial paralysis was observed in many high-dose dogs Vacuolization of myelinated white tracts of cerebrum, cerebellum, and/or spinal cord was observed in many high-dose dogs as well as some mid- and low-dose subjects Degeneration of testicular germinal epithelium and syncytial giant cell formation was noted in males of all dose groups. Hepatic vacuolar change and chronic hepatitis appeared only in DCA-treated dogs. In ddition, suppurative bronchopneumonia and chronic pancreatitis were noted in many high-dose and some middose subjacts. A “no-adverse-effect level” was not determined In this study.