Histologic and In Situ Viral Findings in the Myocardium in Cases of Sudden, Unexpected Death

Cioc, Adina; Nuovo, Gerard J.

doi:10.1097/01.mp.0000024291.37651.cd

Cited by 91 publications

(57 citation statements)

References 25 publications

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“…The presence of replicating rotavirus in lung macrophages and the correlation of detecting rotavirus in both the lungs and hearts of RRVinoculated rat pups (P Ͻ 0.001; r ϭ 0.801 [Pearson's correlation coefficient]) are of interest. In cases of fatal pneumonitis, myocarditis, or sudden, unexpected death in adults and children, rotavirus antigen or RNA was detected in infiltrating macrophages, endothelial cells, and pneumocytes (11,35,41). Altogether, our data indicate that detection of rotavirus in the heart and lungs appears to be a rare event, but further studies are warranted to assess the involvement of rotavirus with pulmonary complications and myocarditis.…”

Section: Discussionmentioning

confidence: 82%

“…Rotavirus antigen and RNA were detected in serum samples from approximately 65% of children with rotavirus diarrhea, indicating that antigenemia and possibly viremia occur during rotavirus infection (4, 7, 16). In other reports, rotavirus antigen and/or RNA was detected in the central nervous systems, spleens, hearts, kidneys, testes, and bladders of children who died during rotavirus infections (23, 29-32, 35, 42); in liver biopsies from infants with cholestatic disease (47); and in respiratory secretions, lung cells, or the microvasculature of hearts from children and adults with respiratory infections or cardiorespiratory failure (11,41,48,56) and rotavirus gastroenteritis. These case reports support the concept that rotavirus can escape the intestine and possibly infect cells in a variety of organs, but the sites and prevalence of extraintestinal infection and whether rotavirus can be the etiologic agent of extraintestinal disease have not been established.…”

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confidence: 99%

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Rotavirus Viremia and Extraintestinal Viral Infection in the Neonatal Rat Model

Crawford¹,

Patel

Cheng³

et al. 2006

J Virol

135

133

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Rotaviruses infect mature, differentiated enterocytes of the small intestine and, by an unknown mechanism, escape the gastrointestinal tract and cause viremia. The neonatal rat model of rotavirus infection was used to determine the kinetics of viremia, spread, and pathology of rotavirus in extraintestinal organs. Five-day-old rat pups were inoculated intragastrically with an animal (RRV) or human (HAL1166) rotavirus or phosphatebuffered saline. Blood was collected from a subset of rat pups, and following perfusion to remove residual blood, organs were removed and homogenized to analyze rotavirus-specific antigen by enzyme-linked immunosorbent assay and infectious rotavirus by fluorescent focus assay or fixed in formalin for histology and immunohistochemistry. Viremia was detected following rotavirus infection with RRV and HAL1166. The RRV 50% antigenemia dose was 1.8 ؋ 10 3 PFU, and the 50% diarrhea dose was 7.7 ؋ 10 5 PFU, indicating that infection and viremia occurred in the absence of diarrhea and that detecting rotavirus antigen in the blood was a more sensitive measure of infection than diarrhea. Rotavirus antigens and infectious virus were detected in multiple organs (stomach, intestines, liver, lungs, spleen, kidneys, pancreas, thymus, and bladder). Histopathological changes due to rotavirus infection included acute inflammation of the portal tract and bile duct, microsteatosis, necrosis, and inflammatory cell infiltrates in the parenchymas of the liver and lungs. Colocalization of structural and nonstructural proteins with histopathology in the liver and lungs indicated that the histological changes observed were due to rotavirus infection and replication. Replicating rotavirus was also detected in macrophages in the lungs and blood vessels, indicating a possible mechanism of rotavirus dissemination. Extraintestinal infectious rotavirus, but not diarrhea, was observed in the presence of passively or actively acquired rotavirus-specific antibody. These findings alter the previously accepted concept of rotavirus pathogenesis to include not only gastroenteritis but also viremia, and they indicate that rotavirus could cause a broad array of systemic diseases in a number of different organs.Rotaviruses, responsible for most cases of gastroenteritis in children under the age of five worldwide, have been thought to cause mucosal infections restricted to the mature, differentiated enterocytes of the small intestine. However, an increasing number of reports indicate that rotavirus escapes the gastrointestinal tract. Rotavirus antigen and RNA were detected in serum samples from approximately 65% of children with rotavirus diarrhea, indicating that antigenemia and possibly viremia occur during rotavirus infection (4, 7, 16). In other reports, rotavirus antigen and/or RNA was detected in the central nervous systems, spleens, hearts, kidneys, testes, and bladders of children who died during rotavirus infections (23, 29-32, 35, 42); in liver biopsies from infants with cholestatic disease (47); and in respiratory secre...

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

Rotavirus Viremia and Extraintestinal Viral Infection in the Neonatal Rat Model

Crawford¹,

Patel

Cheng³

et al. 2006

J Virol

135

133

View full text Add to dashboard Cite

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“…Whether putative central nervous system (CNS) infection results from contamination is not known, but one study strongly suggested infection of the CNS (48). In recent studies, rotavirus antigens were detected in myocardium from patients who died unexpectedly (11), and in vitro studies demonstrated the ability of rotavirus to replicate in primary islet cells, an observation that correlates with the temporal association of infection with development of pancreatic islet autoantibodies (14). These case reports strongly indicate that rotavirus infection may have rare systemic sequellae, although one must bear in mind that infectious viruses were not isolated and replication was shown only once (26).…”

Section: Systemic Infection With Rotavirusmentioning

confidence: 93%

Pathogenesis of Intestinal and Systemic Rotavirus Infection

Ramig

2004

J Virol

314

230

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Rotaviruses are responsible for significant gastrointestinal disease, primarily in children Ͻ5 years of age and the young of other mammalian species. Each year rotaviruses cause approximately 111 million episodes of gastroenteritis in children, which result in 25 million visits to clinics, 2 million hospitalizations, and 352,000 to 592,000 deaths. On a worldwide basis, nearly every child experiences rotavirus gastroenteritis by age 5, 1 in 5 visits a clinic, 1 in 65 is hospitalized, and 1 in 293 dies. Children in the poorest countries account for 82% of rotavirus deaths (60). This disease burden underscores a need for interventions such as vaccines. A vaccine was developed and approved, but recommendation for its use was withdrawn because of vaccination-associated adverse events (57). Additional information about the molecular biology, immunology, and pathogenesis of rotavirus infection will inform ongoing vaccine development efforts.Our understanding of rotavirus-induced diarrheal disease is incomplete compared to that of several other pathogens (e.g., cholera). Rotavirus diarrhea has been attributed to several different mechanisms, including malabsorption secondary to enterocyte destruction, a virus-encoded toxin, stimulation of the enteric nervous system (ENS), and villus ischemia (13,45). Over the past several years, numerous studies have addressed mechanisms of diarrhea induction at the cellular and tissue levels, and a new understanding of the mechanisms is beginning to emerge. Here I will briefly outline the new data and present our current understanding of how rotaviruses induce diarrhea in the infected host.Recent studies confirm sporadic case reports that rotavirus infection is not confined to the intestine as was generally assumed. Although systemic sequellae to rotavirus infection are apparently rare, reports have continually appeared in the literature, and recent work with animal models has begun to shed light on how the virus spreads to extraintestinal sites. Our current understanding of extraintestinal spread and infection will also be considered below. GENERAL CHARACTERISTICS OF ROTAVIRUS INFECTION AND DISEASE IN HUMANS AND ANIMALSRotavirus. Rotaviruses comprise a genus within the family Reoviridae. The rotavirion has a nonenveloped, complex, triple-layered capsid structure that surrounds a genome composed of 11 segments of double-stranded RNA. There are six structural proteins and six nonstructural proteins, each encoded in a unique genome segment except for nonstructural proteins 5 and 6 (NSP5 and NSP6), which are encoded in overlapping reading frames of a single segment. The rotavirus genus is divided into serological groups (A to E). Groups A to C infect humans, and all groups infect animals. All the information presented here is in regard to group A virus infections.Pathophysiology of rotavirus diarrhea. The enterocytes lining the small intestine are generally divided into two types: enterocytes and crypt cells (Fig. 1). Villus enterocytes are mature, nonproliferating cells covering the vill...

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“…With regard to the time-dependent course of viral myocarditis, as studied in a mouse model, early virus-induced myocardial damage already takes place before histologic and immunohistochemical signs of myocarditis defined by the Dallas criteria can be observed (23,24). These early-phase-dependent viral lesions can be detected only via electron microscopy; they also occur before immunohistochemical signs of myocarditis (19).…”

Section: Discussionmentioning

confidence: 99%

Role of Virus-Induced Myocardial Affections in Sudden Infant Death Syndrome: A Prospective Postmortem Study

et al. 2004

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The cause of sudden infant death syndrome (SIDS) is an unresolved problem of high relevance. Previous studies indicate a role of infections. In our prospective study, we investigated the frequency of virus-induced myocardial affections in SIDS. Postmortem samples from SIDS victims and control subjects were investigated prospectively. Pediatric cases of unnatural death served as controls. Samples were studied for enteroviruses, adenoviruses, parvovirus B19, and Epstein-Barr virus applying PCR. Immunohistochemical investigations for inflammatory cells, the necrosis marker C5b-9 (m) complement complex, and the enteroviral capsid protein VP1 were performed. Overall, 62 SIDS victims were studied. As controls, 11 infants were enrolled. Enteroviruses were detected in 14 (22.5%), adenoviruses in 2 (3.2%), Epstein-Barr viruses in 3 (4.8%), and parvovirus B19 in 7 (11.2%) cases of SIDS. Control group samples were completely virus negative. Compared with controls, immunohistochemical investigations partially revealed a significant increase in the number of T lymphocytes in SIDS myocardial samples (p Ͻ 0.05). Furthermore, cases with elevated numbers of leukocytes and macrophages, microfocal C5b-9 (m) ϩ necroses, and enteroviral VP1 capsid protein within the myocardium were detected. Applying a comprehensive combination of molecular and immunohistochemical techniques, our results demonstrate a clearly higher prevalence of viral myocardial affections in SIDS. Our results emphasize the importance of PCR-based diagnosis of viral myocardial affections. We suggest preliminary criteria for cellular immunohistochemical diagnosis of viral myocardial affections derived from our findings. The diagnosis of sudden infant death syndrome (SIDS) is established by comprehensive exclusion of all other possible causes of death in the age group. Myocarditis is a widely known explanation for sudden death in cases of suspected SIDS as well as in older children (1). Recent clinical studies and anecdotal communications reported on different viruses in such cases applying molecular techniques to detect the genome sequences of enteroviruses (EV) (2), adenoviruses (AV) (3), Epstein-Barr virus (EBV) (4), and parvovirus B19 (PVB19) (5) in clinical and autopsy samples, respectively. Until recently, a maximum percentage of up to 17% of cases of sudden unexpected death in infancy showing-if at all-histologic hints of viral myocardial affections was assumed (6). The aim of our study was to determine the incidence of virus-induced myocardial affections in cases of SIDS with modern immunohistochemical and molecular pathologic methods. METHODS

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Histologic and In Situ Viral Findings in the Myocardium in Cases of Sudden, Unexpected Death

Cited by 91 publications

References 25 publications

Rotavirus Viremia and Extraintestinal Viral Infection in the Neonatal Rat Model

Rotavirus Viremia and Extraintestinal Viral Infection in the Neonatal Rat Model

Pathogenesis of Intestinal and Systemic Rotavirus Infection

Role of Virus-Induced Myocardial Affections in Sudden Infant Death Syndrome: A Prospective Postmortem Study

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