The Pathology of Rotavirus-Associated Deaths, Using New Molecular Diagnostics

Lynch, Maureen; Shieh, Wun‐Ju; Tatti, Kathleen M.; Gentsch, Jon R.; Harris, Tara Ferebee; Jiang, Baoming; Guarner, Jeannette; Bresee, J. S.; Greenwald, Margaret; Cullen, Steve; Davies, H. Dele; Trevenen, Cynthia; Zaki, Sherif R.; Glass, Roger I.

doi:10.1086/379322

Cited by 64 publications

(50 citation statements)

References 28 publications

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“…Two of the three children had rotavirus RNA in extraintestinal tissues (spleen, heart, lung, kidney, testes, bladder, adrenal gland, and pancreas), as determined by reverse transcription-PCR. Confirmation of positive PCR products by hybridization with serotype-specific probes indicated that the two children with extraintestinal rotavirus were infected with different G serotypes (47). These findings show that viral antigen and/or virus particles enter the circulation.…”

Section: Systemic Infection With Rotavirusmentioning

confidence: 72%

Pathogenesis of Intestinal and Systemic Rotavirus Infection

Ramig

2004

J Virol

316

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 A vaccine was developed and approved, but recommendation for its use was withdrawn because of vaccination-associated adverse events (57).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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Section: Systemic Infection With Rotavirusmentioning

confidence: 72%

Pathogenesis of Intestinal and Systemic Rotavirus Infection

Ramig

2004

J Virol

316

230

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“…The role of rotavirus in upper respiratory tract infections of children requires additional study, as does the presence of rotavirus viremia in children and its possible consequence related to detection of HRV in the cerebrospinal fluid of children with central nervous system disease (16,38). The diarrhea associated with rotavirus typically lasts from 2 to 8 days, but immunodeficiency, immunosuppression, and malnutrition are risk factors for severe and prolonged symptoms and chronic infection (9,16). The incidence of rotavirus infection is similar in both developed and developing countries, but the morbidity and mortality of the disease are much greater in developing countries.…”

Section: Discussionmentioning

confidence: 99%

Viremia and Nasal and Rectal Shedding of Rotavirus in Gnotobiotic Pigs Inoculated with Wa Human Rotavirus

Azevedo

Yuan

Jeong

et al. 2005

J Virol

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Group A rotaviruses are the most common cause of dehydrating diarrhea in infants and young children worldwide, with more than 2 million hospitalizations yearly and approximately 440,000 deaths. It is estimated that 82% of rotavirus deaths occur in children in the poorest countries (23). Rotavirus transmission occurs mainly by the fecal-oral route, although respiratory transmission has been suggested to occur (7).Rotavirus infection was thought to be limited to the gastrointestinal tract. However, respiratory symptoms and rotavirus shedding in nasopharyngeal secretions have been reported in children with and without gastrointestinal symptoms (19,26,42). Rotavirus antigen was detected in the lung of 1 of 13 experimentally infected 3-week-old conventional pigs at postinoculation day 2 (30) and in liver and kidney specimens from immunodeficient children (9). Rotavirus RNA has also been detected in cerebrospinal fluid and blood of children with central nervous system disease (20,34). Recently, Blutt and colleagues (2) detected rotavirus antigenemia in the serum of children, mice, rabbits, and calves. They further demonstrated that serum from infected mice induced rectal rotavirus antigen shedding after oral inoculation of rotavirus-negative adult mice with the serum. Previously, another enteric virus, the porcine enteric calicivirus (PEC), has also been associated with transient viremia (infectious virus in serum) after oral inoculation of gnotobiotic pigs (11).We choose gnotobiotic pigs because they constitute an animal model of HRV-induced disease. Their gastrointestinal tract physiology and their development of mucosal immunity resemble that of humans. These similarities with HRV infections of infants allow us to establish correlations which could be applied for rotavirus vaccine development (14,25) The question addressed in our study was whether an attenuated human rotavirus and virulent HRV causes upper respiratory tract infections or viremia in naïve neonatal gnotobiotic pigs after various routes of inoculation. In this study we evaluated nasal and rectal virus shedding and viremia after oral, intranasal, feeding tube (gavage), and intravenous inoculation of neonatal gnotobiotic pigs with the Wa strain of attenuated HRV or virulent HRV. The presence of infectious virus in serum of gnotobiotic pigs after oral inoculation with Wa HRV was also investigated by oral and intravenous reinoculation of gnotobiotic pigs with a pool of the HRV-positive sera. MATERIALS AND METHODSVirus. The attenuated cell culture-adapted Wa strain HRV (P1A [8]G1), derived from the 27th HRV passage in African Green monkey kidney cells (MA104) and the virulent Wa HRV from pooled intestinal contents of gnotobiotic pigs were used for inoculation of the gnotobiotic pigs at doses of 5 ϫ 10 7

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“…Reye's-like syndrome sometimes mimics Reye's syndrome in children with genetic defects of fatty acid oxidation. There are three reports of systemic rotavirus infection involving the central nervous system, all of which included elevated transaminase levels and lipid droplets in the liver (5,6,9). In these cases, analysis of amino acids and/or organic acids was normal.…”

Section: Case Reportmentioning

confidence: 99%

“…In these cases, analysis of amino acids and/or organic acids was normal. In two of the three cases, the patients had a history of chickenpox 2 weeks before admission (6,9). Mitochondrial functional analysis was undertaken in another two cases and was normal (5,6).…”

Section: Case Reportmentioning

confidence: 99%

Sudden Death from Systemic Rotavirus Infection and Detection of Nonstructural Rotavirus Proteins

Nakano¹,

Taniguchi

Ishibashi‐Ueda

et al. 2011

J Clin Microbiol

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A 2.5-year-old girl died suddenly during the course of rotavirus gastroenteritis. The autopsy showed encephalopathy with rotavirus systemic infection. Here, we provide evidence of rotavirus replication in multiple organs. Our findings clarify that rotavirus infection in children can extend beyond the intestinal tract through viremia. CASE REPORTA previously healthy 2.5-year-old girl presented to our hospital following two febrile seizures. She had a 2-day history of diarrhea due to rotavirus gastroenteritis, which had been diagnosed before admission by a positive rotavirus antigen test of her stool. The seizures were generalized tonic-clonic seizures lasting 1 to 5 min each and occurred within 5 h of each other.On examination, she was alert with a temperature of 39.3°C. Examination showed normal pupillary light reflexes, normal muscle tone, and normal patellar and Achilles tendon reflexes. The heart and lung sounds were also normal.Laboratory analysis of blood obtained while in the emergency room showed the following: white blood cell count, 23,800/l (97% neutrophils); hemoglobin, 11.9 g/dl; platelet count, 366,000/l; erythrocyte sedimentation rate, 11 mm/h; C-reactive protein, 0.79 mg/dl; blood sugar, 121 mg/dl; serum ammonia, 22 mg/dl; sodium, 131 meq/liter; potassium, 4.1 meq/ liter; chloride, 99 meq/liter; aspartate aminotransferase (AST), 50 IU/liter; alanine aminotransferase (ALT), 32 IU/liter; lactate dehydrogenase, 317 IU/liter; and creatinine phosphokinase, 420 IU/liter. Immune function testing revealed a low IgG level, at 384 mg/dl (normal range for age 2 years, 649 to 1,306 mg/dl) but normal IgG subclass analysis. the IgA level was 31 mg/dl, and the IgM level was 74 mg/dl. Coagulation tests were not performed. A blood culture yielded no bacterial growth.An hour after arrival at the hospital, the patient experienced two more seizures. The fourth and final seizure developed into status epilepticus and was treated with intravenous diazepam. As the seizure gradually ended, the electrocardiogram monitor showed a brief period of ventricular fibrillation followed by asystole. Immediate resuscitation attempts were unsuccessful.An autopsy was undertaken 12 h after the patient died. Cardiac tissues were submitted to the National Cardiovascular Center (Japan) for pathological analysis.Analysis of the cerebrospinal fluid (CSF) obtained at autopsy revealed a leukocyte level of 240/mm 3 and a protein level of 288 mg/dl. Rotavirus RNA was detected in the CSF by reverse transcription-PCR (RT-PCR). Serum diluted 1:16 showed a positive enzyme-linked immunosorbent assay (ELISA) reaction using an anti-VP6 mouse monoclonal antibody (YO-156) to detect antigenemia (12). The optical density at 492 nm obtained with the patient's serum was 0.932, compared with 0.035 for the negative control.The autopsy revealed brain edema but no cerebral herniation. Although there was focal inflammatory cell infiltration in parts of the subarachnoid space, this was not indicative of encephalitis or meningitis. There was concentric cardiac hyp...

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The Pathology of Rotavirus-Associated Deaths, Using New Molecular Diagnostics

Cited by 64 publications

References 28 publications

Pathogenesis of Intestinal and Systemic Rotavirus Infection

Pathogenesis of Intestinal and Systemic Rotavirus Infection

Viremia and Nasal and Rectal Shedding of Rotavirus in Gnotobiotic Pigs Inoculated with Wa Human Rotavirus

Sudden Death from Systemic Rotavirus Infection and Detection of Nonstructural Rotavirus Proteins

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