Introduction
Background
The family Reoviridae is divided into 9 genera, 4 of which—Orthoreovirus, Coltivirus, Rotavirus, and Orbivirus —can infect humans and animals. Four other genera infect only plants and insects, and one infects fish. Although almost 100 orbivirus serotypes are known, only 3 serotypes of orthoreovirus and 2 of coltivirus have been identified. The genus Rotavirus contains 3 groups, A, B, and C, with group A causing most outbreaks of disease. Both orthoreoviruses and orbiviruses contain 10 segments of double-stranded RNA. Rotaviruses contain 11 genome segments, and coltiviruses have 12 segments.
Structure and Composition
The virions of Reoviridae family viruses measure 60-80 nm in diameter and possess 2 concentric capsid shells, each of which is icosahedral. No envelope is present. The inner capsids of all genera display sharply defined subunits; the outer capsids of rotaviruses and orbiviruses lack well-defined subunit structures. The genome consists of double-stranded RNA in 10-12 discrete segments, with a total genome size of 16-27 kilobase pair (kbp), depending on the genus. The double-shelled particle is the complete infectious form of the virus. The individual RNA segments vary in size from 680 base pair (bp), ie, rotavirus, to 3900 bp, ie, orthoreovirus. The virion core contains several enzymes needed for transcription and capping of viral RNA.
Reoviruses are unusually stable to heat, to a pH range of 3.0-9.0, and to lipid solvents, but they are inactivated by 95% ethanol, phenol, and chlorine.
The first human orthoreovirus was isolated in 1953 from a rectal swab collected from a healthy child and was originally the prototype for echovirus type 10 of the Picornaviridae family. Subsequently, 3 serotypes were identified, and these agents, designated as reovirus, were placed into the Reoviridae family. In 1959, Sabin proposed the name reovirus to reflect the fact that viruses of this group had been isolated from the respiratory and enteric tracts and were orphan (reo) viruses without known associated disease. From these early isolation studies, the respiratory and enteric tracts are assumed to represent the natural portals of entry for reoviruses into the host.
The 3 serotypes share a common group antigen as detected with complement fixation.
Reoviruses are ubiquitous in nature, but their role in human disease is vague. Numerous early reports noted their association with human disease; however, during the last 2 decades, few cases of human disease have been reported. These viruses also have been evaluated extensively in studies involving laboratory animals.
Characteristics of the Pathogen
Reoviruses (which also are called orthoreoviruses to avoid confusion with the family Reoviridae) are nonenveloped viruses. Reovirus particles are composed of an inner protein shell (ie, core) of a diameter of 60 nm, which is surrounded by an outer protein shell (ie, outer capsid) that measures 81 nm in diameter. The core is composed of 3 major (ie, lambda-1, lambda-2, sigma-2) and several minor proteins that surround 10 segments of double-stranded RNA. The virions also contain 3 nonstructural proteins. Reoviruses are moderately heat-stable, stable through a wide pH range, and stable in aerosols, particularly when the relative humidity is high.
Reoviruses replicate with a cytopathic effect in a large number of tissue culture systems of both primate and other animal origin. For recovery from clinical material, monkey kidney tissue cultures are satisfactory. Because of their widespread prevalence in nature and the ease of infection in laboratory animals, reoviruses have been used widely in pathogenicity studies.
Orbivirus
Orbiviruses commonly infect insects, and many can be transmitted by insects to vertebrates. More than 100 serotypes have been identified. Serious animal pathogens include bluetongue virus of sheep and African horse sickness virus. Antibodies are found in many vertebrates, including humans. The genome consists of 10 segments of double-stranded RNA. The replicative cycle is similar to that of reoviruses. In contrast with the general stability of other reoviruses, orbiviruses are inactivated by low pH.
Orungo virus, isolated in Africa, has been implicated in an acute illness with myalgias and headache. Lebombo virus is another orbivirus isolated from humans in Africa. Kemerovo virus has been implicated in neurologic infections in central Europe and Russia. Serologic evidence of infection with Lipovnik or Tribec virus has been demonstrated in patients with polyradiculitis in the former Czechoslovakia. Changuinola virus has been isolated from humans in Panama.
Coltivirus
Coltiviruses resemble the orbiviruses in size and in having 2 capsids. These viruses contain 12 RNA segments. Colorado tick fever (CTF), Salmon River virus (in Idaho), Eyach virus (in Germany and France), isolate S6-14-03 (in California), Banna virus, Beijing virus, and Gansu virus (in China) either are proved or suspected of causing human disease.
Colorado tick fever
During early investigations of Rocky Mountain spotted fever (RMSF), sporadic cases of an illness that followed a tick bite were recognized. This illness differed from RMSF in that the characteristic skin rash was absent. Because this new illness was thought to occur predominantly in Colorado, it was named CTF to distinguish it from the more severe RMSF. Mountain fever and mountain tick fever are other names for this disease. The etiologic agent was recognized as a virus in 1946. CTF virus is the prototype species for the genus Coltivirus of the family Reoviridae. CTF virus has a genome that consists of 12 segments of double-stranded RNA. The virus is transmitted to mammals, including humans, principally by the adult Rocky Mountain wood tick (ie, Dermacentor andersoni), and exposure to the virus is therefore restricted to the vector habitat. Clinical cases peak between May and July.
Historically, CTF has been the most frequently reported arboviral disease in the United States. Nevertheless, it is considered an underdiagnosed condition. Viral maintenance is achieved via larval and nymphal stages of D andersoni and various rodent species.
In most cases, a history of tick bite can be obtained, but, occasionally, only body contact with a tick is remembered. In certain instances, the bite has been unnoticed, and only a history of having been in a tick-infested area can be elicited. Occasionally, the tick may be found imbedded in the skin only after very careful examination with particularly close observation of body folds, skin creases, and areas with hair. The illness occurs primarily in spring and summer, with most cases occurring in April and May at lower altitudes and in June and July at higher elevations. The disease may affect persons of any age.
Rotavirus
Infection with human rotavirus (HRV) appears to cause a substantial portion of cases of gastroenteritis in children aged 6 months to 2 years. The rotavirus particle consists of an 11 double-stranded RNA genome enclosed in a double-shelled capsid. The outer shell is composed of a major glycoprotein with a molecular weight of 34,000 (ie, viral protein [VP]7) and a minor, trypsin-sensitive protein with a molecular weight of 84,000 (ie, VP4, previously designated VP3). Four proteins (ie, VP1, VP2, VP3, VP6) make up the virus core. Six nonstructural (NS) proteins (ie, NS53, NS34, NS35, NS28, NS26, NS12) are also produced during rotavirus infection.
Trypsin cleavage of VP4, which yields 2 polypeptides, VP8 and VP5, with molecular weights of 27,000 and 58,000, respectively, is required for the activation of infectivity. Originally, serotyping was based solely on differences in the VP7 protein because animals hyperimmunized with rotaviruses develop most neutralizing antibody to this protein. Cross-neutralization studies conducted with these hyperimmune sera readily separated the strains into VP7 serotypes. Later, a dual serotyping scheme was developed when VP4 was discovered to be the dominant neutralization protein in some cases. Rotavirus serotypes include a description of both the VP4 (protease-sensitive protein, P) and the VP7 (glycoprotein, G) types.
HRVs belonging to 11 G serotypes have been isolated, but the vast majority have been identified as G1, G2, G3, or G4, and strains belonging to these G types have commonly been designated as serotype 1, 2, 3, or 4, respectively. The severity of illness caused by viruses that belong to these 4 serotypes varies little, if at all. At least 6 different HRV P types have been identified. P type 1a, the most common, is usually associated with G types 1, 3, or 4; whereas, P type 1b is usually associated with G type 2.
Rotaviruses are closely related to reoviruses in terms of morphology and strategy of replication.
Epidemiology
Reovirus
Reoviruses cause many inapparent infections because most people have serum antibodies by early adulthood. Antibodies are also present in other species. All 3 types have been recovered from healthy children, from young children during outbreaks of minor febrile illness, and from children with diarrhea or enteritis. Human volunteer studies have failed to demonstrate a clear cause-and-effect relationship between reoviruses and human illness. The method of transmission of reoviruses is unknown. However, because these viruses are recovered most frequently from the feces, primary spread seems most likely to be by the fecal-oral route. Because the reoviruses are stable in aerosols and because respiratory illness has been associated with reovirus infections, this route is an additional possibility.
Colorado tick fever
CTF is the most common arboviral disease among humans in the United States. It has been reported from at least 11 Western states in the United States and from Alberta and British Columbia in Canada. CTF is transmitted to people by the adult hard-shelled wood tick D andersoni. The virus has been found in as many as 14% of these ticks harvested in endemic areas and is maintained in rather complex cycles between the tick vector and the host animals.
Both male and female adult ticks can transmit infection to humans, and the period of attachment required for transmission of the virus may be very brief. In rare cases, CTF has developed in persons who did not travel to areas of known risk; for example, in persons exposed to ticks brought home on clothing of family members and by transfusion. Most cases occur in May and June, when adult ticks are most active, but infections occurring from March to November have been reported. CTF affects young and old persons who, through occupational or recreational activities, come into contact with D andersoni. Because the disease is relatively benign, the true incidence cannot be assessed. Many cases are never recognized by a physician, or, if cases are recognized, the illness may not be recognized as CTF.
A 1974 ecologic study in Rocky Mountain National Park in north central Colorado identified the primary vertebrate host species for the CTF virus as the least chipmunk (ie, Tamias minimus) and the golden-mantled ground squirrel (ie, Spermophilus lateralis). Secondary hosts were the Uinta chipmunk (ie, Tamias umbrinus), Richardson ground squirrels (ie, Spermophilus richardsonii), and the deer mouse (Peromyscus maniculatus). Larval and nymphal stages of D andersoni ticks were responsible for transmission of CTF virus among rodents, and overwintering of the virus occurred in nymphal and adult D andersoni. Only adult ticks transmit CTF virus to humans.
Rotavirus
The disease has been found on all continents and in all races, but its worldwide prevalence is not known. Since its discovery in 1973, rotavirus has been well documented as an important cause of diarrheal disease in infants and young children. Estimates of the global disease burden of rotavirus diarrhea have been refined and suggest that mortality rates have not declined and that, among hospitalized patients with diarrhea, the fraction of cases associated with rotavirus has increased in many countries. In the United States, the estimated number of hospitalizations attributed to rotavirus has increased.
Although rotaviruses are found in high concentrations in the stools of children with diarrhea and are found less often in children without diarrhea, the presence of rotavirus in the feces is not always associated with symptomatic disease. While asymptomatic endemic rotavirus infections have been observed in newborns, isolation rates of rotavirus infection in asymptomatic infants and children have been reported to be very low.
Morbidity and mortality data from selected studies conducted in the last 3 decades in Africa, Latin America, and Asia show that morbidity rates are highest in infants aged 6-11 months, while the mortality rates are highest in infants and children aged 1 year. In children younger than 5 years, the median incidence of diarrhea is 2.2 episodes per child per year for all studies.
Asymptomatic infections are common in infants younger than 6 months, the time during which protective maternal antibody acquired passively by newborns should be present. Such neonatal infection does not prevent reinfection, but it may protect against the development of severe disease during reinfection.
In temperate climates, rotaviruses are responsible for a large number of cases of diarrheal disease in the winter. The seasonality of rotavirus disease is less apparent in tropical climates but is still more prevalent in the drier, cooler months.
The transmission of rotavirus infections is believed to be fecal-oral, with little evidence of airborne transmission. Adult contacts may be infected, as evidenced by seroconversion, but they rarely exhibit symptoms, and the virus is detected infrequently in their stools. A common source of infection is contact with children who are infected. However, epidemics of severe disease have occurred in adults, especially in closed populations, as in a geriatric ward.
In one study, cases of asymptomatic infection and cases with mild symptoms were characteristic of rotavirus infections among pediatric nurses, indicating that poor handwashing practices by the nursing staff may contribute to the spread of rotavirus gastroenteritis in pediatric wards.1
Pathophysiology
Reovirus
Human volunteer studies have failed to demonstrate a clear cause-and-effect relationship between reoviruses and human illness. Reoviruses have been associated with upper respiratory infections, fever, enteritis, and febrile exanthema in childhood.
Colorado tick fever
CTF virus can infect and replicate within both the KG-1a human progenitor cell line and human bone marrow progenitor cells.2 The finding of viral replication 16-48 hours after infection both with plaque assay and with electron microscopy followed by pronounced cytopathic effects at 72-96 hours suggests that the virus is taken up by progenitor cells and diminishes both the numbers and the functions of these cells. While progenitor cells may provide a hospitable environment for viral replication, the in vitro data do not suggest that the cells serve as a long-term reservoir of virus. The CTF virus infects the bone marrow in the initial phases of infection but does not persist. Viral replication occurs in the bone marrow, lymph nodes, spleen, heart, and liver of rhesus monkeys but without histological abnormalities.
Human erythrocytes are known to carry the virus, and the virus has been shown to replicate in erythroblasts and reticulocytes of infected mice. The viral presence in mature erythrocytes is postulated to be a result of replication of the virus in hematopoietic erythrocyte precursor cells and simultaneous maturation of the infected immature cells rather than a result of direct entry and replication of CTF virus in mature erythrocytes.
Rotavirus
After fecal-oral transmission of rotavirus, infection is initiated in the upper intestine and typically leads to a series of histologic and physiologic changes. The incubation period is brief. Rotaviruses infect cells in the villi of the small intestine (gastric and colonic mucosa are spared). They multiply in the cytoplasm of enterocytes and damage their transport mechanism.
One of the rotavirus-encoded proteins, NSP4, is a viral enterotoxin that induces secretion by triggering a signal transduction pathway. Damaged cells may slough into the lumen of the intestine and release large quantities of viruses, which appear in stool. Viral excretion usually lasts 2-12 days in healthy patients but may be prolonged in those with poor nutrition. Diarrhea caused by rotaviruses may be due to impaired sodium and glucose absorption as damaged cells on villi are replaced by nonabsorbing immature crypt cells. Three to 8 weeks may be necessary for normal function to be restored. Antibodies present in the intestinal lumen have been shown to play a role in the passive protection of young animals.
Frequency
United States
Reoviruses cause many inapparent infections; thus, estimating the true frequency of the infection is difficult. CTF is the most common arboviral disease among people in the United States. It has been reported in at least 11 Western states in the United States. Rotavirus infections account for 3.5 million cases of diarrhea each year and for 20 deaths that occur among children younger than 5 years.
International
CTF has been reported from Alberta and British Colombia in Canada. In developing countries, 3-5 billion cases of gastroenteritis occur each year. A significant proportion is believed to be caused by rotaviruses.
Mortality/Morbidity
- Reovirus infection usually has a benign course. Little mortality is associated with reovirus infection.
- CTF has a benign course, with an excellent prognosis. Rarely, CTF results in death, usually from hemorrhagic complications.
- In developing countries, rotavirus accounts for 10-20% of gastroenteritis-associated deaths (ie, 5-10 million deaths each year).
Race
No clear racial predilection exists for reovirus, CTF virus, or rotavirus infection.
Sex
No clear sexual predilection exists for rotavirus, CTF virus, or rotavirus infection.
Age
A lower rate of acute or symptomatic infections is observed with reoviruses and rotaviruses with increasing age, which is a consequence of the development of antibodies to these viruses. A single attack of CTF produces lifelong immunity.
Clinical
History
Reovirus
Reoviruses have been associated with upper respiratory infections, enteritis, fever, and febrile exanthema in childhood. In one study in which volunteers were inoculated intranasally with each of the 3 reovirus serotypes, most infections were asymptomatic, but illness associated with serotypes 1 and 2 included symptoms of the common cold. A few reports have been made of isolation from the cerebrospinal fluid or brain of infants who have central nervous system disease. Some studies suggest a relationship between reoviruses and neonatal biliary atresia or congenital hepatitis.
- Neurologic disease
- Reovirus infection in rodents, especially mice, has been used extensively as an experimental model system for studying the pathogenesis of viral disease of the central nervous system.
- Rare cases of reovirus-induced neurologic disease in humans, including encephalitis and meningitis, have been reported. Reoviruses have been associated with neurologic illnesses in nonhumans, including hydrocephalus in monkeys, encephalitis in dogs, and ataxia in cats.
- For reoviruses to infect and injure the CNS, they must (1) enter the host, (2) spread from the site of entry to the CNS, (3) infect cells within nervous tissue, (4) cause death of infected neuronal cells, and (5) successfully avoid the host's immune defenses.
- A few isolated reports associating reoviruses with human disease of the CNS have been presented. In one report, reovirus serotype 1 was isolated from stool specimens and postmortem brain tissue from a 10-month-old infant with encephalitis, pneumonitis, myocarditis, and hepatitis.
- A virus immunologically related to reovirus type 3 was isolated from the CSF and from postmortem samples of the brain and spinal cord of a woman who died of encephalitis. In another case report, a previously healthy 3-month-old girl presented with symptoms of meningitis, diarrhea, vomiting, and fever. Green monkey kidney cells inoculated with CSF revealed reoviruslike particles on electron microscopy. RNA-gel electrophoresis, immunofluorescence, and virus neutralization have been used to identify the pathogen isolated from CSF as reovirus serotype 1. The CSF isolate was also neutralized by reovirus serotype 1 antibodies.
- Reovirus serotypes 1 and 3 produce unique and essentially nonoverlapping patterns of CNS injury in mice, and reovirus serotype 2 produces encephalitis in suckling mice. Serotype 3 produces a neuronal infection that results in lethal encephalitis. Serotype 1 appears not to infect neurons but instead causes ependymitis and hydrocephalus.
- Upper respiratory illness
- In the winter of 1957, Rosen and colleagues noted an outbreak of infection with reovirus serotype 1 in children in nursery school in a welfare institution.3 Illness was characterized by low-grade fever, rhinorrhea, and pharyngitis. The average duration of fever was 2.2 days. In another study at the same institution during the winter of 1955-1956, 4 children with reovirus serotype 3 infection and illness were noted. One child had a temperature of 38.9°C, coryza, and tonsillitis; another child had fever (ie, temperature 38.2°C), cough, and diarrhea; and 2 children only had coryza. During another reovirus serotype 3 outbreak in the fall of 1957, all 6 infected infants had symptoms. Five children had mild fever, 5 had coryza, and 4 had diarrhea.
- Other sporadic instances of similar mild upper respiratory illnesses have been described. In one study of volunteer trials in young adults, reovirus serotype 1 infection was associated with malaise, rhinorrhea, cough, sneezing, pharyngitis, and headache in some subjects, and a coldlike illness was observed in 37% of subjects in another trial. In both volunteer studies and in natural infection, mild diarrhea occurred with the upper respiratory illness.
- Pneumonia
- Tillotson and Lerner (1967) reported on a 5-year-old girl who had extensive pneumonia and died after 15 days of illness.4 This child initially had fever, cough, rhinorrhea, and a generalized maculopapular rash. When admitted to the hospital on the 10th day of illness, the child was cyanotic and in marked respiratory distress. A chest radiograph revealed a diffuse confluent pneumonia, and reovirus type 3 was recovered from the lungs, adrenals, liver, spleen, kidney, (one) lymph node, heart, brain, and blood. Joske and Keall (1964) noted a 10-month-old girl who died after a respiratory illness of 4 days' duration.5 Reovirus type 1 was recovered from the stool and brain of this child, and postmortem study revealed interstitial pneumonia, myocarditis, hepatitis, and encephalitis.
- El-Rai and Evans (1963) reported the case of an 18-year-old boy who had fever, nausea, vomiting, cough, and patchy pneumonia.6 He had serologic evidence of infection with reovirus type 1. Pneumonia has been noted in another child with reovirus type 3 infection. Reovirus is a good pathogen in which to study mucosal immunity initiated in the respiratory tract.
- Experiments using reovirus as a model pathogen in adult, newborn, and immunodeficient animals have been useful in determining factors that mediate susceptibility and resistance to viral diseases, generation of specific immunity, and identification of determinants that can regulate generation of specific mucosal immunity.
- Because reovirus elicits immune responses after either enteric or respiratory infections, it can be used in studies concerning the relationship between mucosal immune responses at these sites. In addition, reovirus infection provides an opportunity to study molecular and cellular events that regulate the induction and expression of mucosal immune responses.
- Reovirus might prove to be an effective vehicle for delivery of mucosal vaccines. In conclusion, much of the advancement in current knowledge of mucosal immune responses has been facilitated by studies of respiratory and enteric reovirus infection, and reovirus likely will continue to be used as a probe to understand the function and regulation of one of the most important defenses, mucosal immunity.
- Bronchiolitis obliterans-organizing pneumonia
- Bronchiolitis obliterans-organizing pneumonia (BOOP) is a term that was first applied in 1985 to describe a long-observed but unclassified pattern of acute lung injury. BOOP lesions are characterized by fibrous extensions into the alveolar spaces in association with a peribronchiolar organizing pneumonia. Although BOOP can be associated with numerous documented pulmonary insults, many cases are not associated with known causes and thus are classified as idiopathic. In one study, CBA/J mice infected with reovirus serotype 1 developed BOOP lesions. These lesions closely resembled lesions observed in humans and developed in a well-defined temporal sequence that proceeded from initial peribronchiolar inflammatory lesions to characteristic fibrotic cellular BOOP lesions over a 3-week period.7
- Gastrointestinal manifestations
- Mild diarrhea has been noted both in association with upper respiratory illness and as an isolated event. Because reovirus type 3 consistently produces steatorrhea in mice, this clinical manifestation has been sought and noted in illnesses of children. Patients have been reported with hepatitis and encephalitis.
- Extrahepatic biliary atresia (EHBA) and choledochal cysts (CDCs) are important causes of obstructive jaundice in pediatric patients. Viruses in general, and reoviruses in particular, have long been considered as possible etiologic agents responsible for inciting the inflammatory process that leads to these infantile obstructive cholangiopathies.
- In one study, hepatic and biliary tissues were obtained at the time of liver biopsy or surgical procedure from 23 patients with EHBA, 9 patients with CDC, 33 patients with other hepatobiliary diseases, and at autopsy from 17 patients who died without known liver or biliary disease. Reovirus RNA was detected in hepatic and/or biliary tissue from 55% of patients with EHBA and 78% of patients with CDC. Reovirus RNA was also found in extracts of hepatic and/or biliary tissue from 21% of patients with other hepatobiliary diseases and in 12% of autopsy cases. The prevalence of reovirus RNA in tissues from patients with EHBA and CDC was significantly greater than that in patients with other hepatobiliary diseases. A sensitive and specific reverse transcriptase–polymerase chain reaction (RT-PCR) technique was used to amplify a portion of the reovirus 1 gene segment from extracts of liver and/or biliary tissues.8
- Diabetes mellitus: Reovirus may be involved in the pathogenesis of type 1 diabetes mellitus by inducing beta cell–specific autoimmunity, with or without infection of the beta cells.9
The incubation period is 3-6 days. The clinical picture is characterized by the sudden onset of chilliness, variable fever, and headache with retro-orbital pain, generalized aches (especially of the back and extremities), malaise, nausea, and, occasionally, vomiting. In most cases, the severity of symptoms reaches the maximum intensity within a few hours. The fever is variable, and temperature may be as high as 104°F within the first 24 hours of symptoms. A rash is generally absent but may be noted on occasion and can be macular, maculopapular, or petechial. No characteristic distribution is observed.
The single most important laboratory finding that confirms diagnosis is a moderate-to-marked leukopenia, which is invariably present. On the first day of illness, the white blood cell count may be within the reference range, but, usually by the third day, the white cell count has decreased to 4000 cells/μL or lower, with a relative lymphocytosis. The leukopenia is generally most profound during the second bout of fever. In CTF, mononuclear cell production of granulocyte colony-stimulating factor is decreased, and an increase in circulating granulopoietic inhibitory factors is found in the serum of such patients.
CTF usually has a biphasic course with 2 bouts of fever, each of which lasts 2-3 days, separated by a remission of approximately equal duration. This produces the so-called saddle-backed temperature curve. On occasion, the patient may remain febrile during the entire course of the disease, while, in other instances, a third or even fourth exacerbation of fever may occur. The usual duration of the febrile period is approximately 1 week but may be longer. In most cases, the febrile period is followed by several days of moderate-to-marked weakness and malaise. Convalescence may be prolonged. Mild and subclinical infections occur, and one infection usually produces lifelong immunity.
Although CTF usually has a benign course and carries an excellent prognosis, in a few cases, complications such as encephalitis, aseptic meningitis, and hemorrhage have been reported. Other associated syndromes include pericarditis, epididymoorchitis, a rheumatic fever–like syndrome, and atypical pneumonitis. The association of hepatitis with CTF also has been described. Saddle-backed fever is absent in as many as 52-58% of patients.
Circulating immune complexes may be the cause of the second phase of illness that many patients experience, as well as some of the unusual manifestations of the disease such as hepatitis, epididymoorchitis, rheumatic fever–like illness, and atypical pneumonitis. The virus is easily isolated from the erythrocytes of most affected patients and from the cerebrospinal fluid of those with central nervous system involvement. Viral replication occurs in the bone marrow, lymph nodes, spleen, heart, and liver of rhesus monkeys but without histological abnormalities. Human erythrocytes are shown to carry the virus, and the virus has been shown to replicate in erythroblasts and reticulocytes of infected mice. Viral presence in mature erythrocytes is postulated to be the result of replication of the virus in hematopoietic erythrocyte precursor cells followed by maturation of the infected cells rather than the result of direct entry and replication of CTF virus in mature erythrocytes.
The early course of RMSF and CTF share many features: a history of tick bite, abrupt onset, fever, chills, headache, myalgia, and photophobia. However, later in the course, the distinctive features of these illnesses emerge. The disappearance of symptoms after 2-3 days strongly favors CTF, as does the appearance of marked leukopenia. Rash can occur in both diseases, although it is infrequent in CTF and is usually present in RMSF. The rash of RMSF may be distinguished by its centrifugal distribution, involvement of the palms and soles, and progression from a petechial stage to a purpuric stage.
Edema, pneumonitis, and involvement of other organs are observed only in RMSF and reflect the diffuse vasculitis of this disease. Bleeding secondary to thrombocytopenia can be a serious complication of CTF. The acute phase of CTF typically lasts 5-10 days and is followed by convalescence, which may be protracted, especially in adults. Although the incubation time from tick exposure to the onset of symptoms is about 4 days, the range is from less than 1 day to 14 days.
RotavirusInfants and young children most commonly have fever, vomiting, diarrhea, and (occasionally) dehydration. Vomiting, usually short-lived, can occur before or after the onset of diarrhea. Symptoms of an apparent respiratory infection may be present. The patient's stools can be watery, green or yellow, and not obviously bloody. Stools rarely contain mucus and number as many as 10 per day. In most cases, diarrhea lessens soon after admission and, in only a few cases, persists longer than 3-4 days.
The association of HRV, gastroenteritis, and upper respiratory tract symptoms has been noted frequently. Santosham et al (1983) detected HRV in the respiratory secretions of 4 infants with enzyme-linked immunoassay (ELISA).10
The low rate of severe gastroenteritis observed in newborns infected with rotavirus possibly is a function of relatively low intestinal concentration of trypsin and other proteolytic enzymes required for the development of diarrheal disease. In one study, rotavirus was detected in the stools of 5 children who, over a 3-week period, developed sudden infant death syndrome (SIDS). While none of the children had acute gastroenteritis, 4 of the 5 had acute upper respiratory infections.
Rotavirus was identified in tracheal aspirates from 2 of the infants. Extensive investigations failed to reveal the presence of any other virus or toxins in specimens obtained from the 5 children with SIDS. Rotavirus was not found in the stool specimens obtained from a control group of 36 infants, including 6 who died of causes other than SIDS.11
An association of rotavirus with aseptic meningitis and Kawasaki syndrome has been reported.12 In adults, symptoms are generally mild and are associated with a low density of viral shedding compared with that of pediatric diarrhea, in which the density of viral shedding in stool generally is 10-fold higher. Preexisting partial immunity of adults might mask overt symptoms of diarrhea. Asymptomatic shedders of rotavirus might serve as a reservoir for disease transmission, particularly to susceptible children.
Rotavirus can also cause gastroenteritis in adults not in contact with sick children. The main difficulty in studying rotavirus gastroenteritis in adults is that symptoms are often minimal and the individual does not seek medical advice. Asymptomatic rotaviral infection is uncommon, and the association between rotavirus and diarrhea is not necessarily an etiologic one. Consequently, recovery of rotavirus from feces is of little diagnostic significance because it does not differentiate between rotavirus-induced and rotavirus-associated diarrhea.
Rotavirus also has been reported as an agent of travelers' diarrhea in adults.13 The coexistence of respiratory symptoms in several patients suggests that the virus might infect the respiratory epithelium as well, but no proof exists for HRV infection outside of the gut.
Rotavirus infection in immunocompromised adults can have a variable course, from no symptoms to severe and sustained infection.
The extraintestinal spread of the virus may occur through blood because viremia has been documented occasionally in animals and humans.14 Nevertheless, the questions of how common viremia is in immunocompetent children and whether it is associated with extraintestinal manifestations remain unsolved.
Physical
Reovirus
Reoviruses usually cause mild physical illness. In rare cases when complications (eg, pneumonia, encephalitis, meningitis) occur, associated physical findings may be observed.
Colorado tick fever
The triad of high fever, severe myalgia, and headache is typical but not specific. Tachycardia, flushed facies, and variable degrees of conjunctival and pharyngeal injection may be present. Occasionally, the spleen is palpable. In some cases, evidence of central nervous system involvement, with clouding of the sensorium, neck stiffness, and vomiting, may be present. Rarely, encephalitis, aseptic meningitis15 , and hemorrhage have been reported. Other associated syndromes include pericarditis, epididymo-orchitis, rheumatic fever syndrome, and atypical pneumonitis. The association of hepatitis with CTF also has been described. In these cases, the related physical findings can be present.
Rotavirus
Physical findings in rotavirus gastroenteritis depend on the severity of dehydration. Findings characteristic of shock (eg, tachycardia, hypotension, clammy skin, weak pulse) can be present in severe disease.
Causes
See Epidemiology and Pathophysiology.
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 Overview: Reoviruses |
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References
Hjelt K, Grauballe PC, Henriksen L, Krasilnikoff PA. Rotavirus infections among the staff of a general paediatric department. Acta Paediatr Scand. Jul 1985;74(4):617-8. [Medline].
Philipp CS, Callaway C, Chu MC, Huang GH, Monath TP, Trent D, et al. Replication of Colorado tick fever virus within human hematopoietic progenitor cells. J Virol. Apr 1993;67(4):2389-95. [Medline].
Rosen L, Hovis JF, Mastrota FM. An outbreak of infection with type 1 reovirus among children in an institution. Am J Hyg. 1960;71:266-74.
Tillotson JR, Lerner AM. Reovirus type 3 associated with fatal pneumonia. N Engl J Med. May 11 1967;276(19):1060-3. [Medline].
Joske RA, Keall DD, Leak PJ, Stanley NF, Walters MN. Hepatitis-encephalitis in humans with reovirus infection. Arch Intern Med. Jun 1964;113:811-6. [Medline].
El-Rai FM, Evans AS. Reovirus infections in children and young adults. Arch Environ Health. Dec 1963;7:700-4. [Medline].
Bellum SC, Dove D, Harley RA, Greene WB, Judson MA, London L, et al. Respiratory reovirus 1/L induction of intraluminal fibrosis. A model for the study of bronchiolitis obliterans organizing pneumonia. Am J Pathol. Jun 1997;150(6):2243-54. [Medline].
Joensuu J, Koskenniemi E, Pang XL, Vesikari T. Randomised placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis. Lancet. Oct 25 1997;350(9086):1205-9. [Medline].
Jun HS, Yoon JW. A new look at viruses in type 1 diabetes [reprint]. ILAR J. 2004;45(3):349-74.
Santosham M, Yolken RH, Quiroz E, Dillman L, Oro G, Reeves WC, et al. Detection of rotavirus in respiratory secretions of children with pneumonia. J Pediatr. Oct 1983;103(4):583-5. [Medline].
Yolken R, Murphy M. Sudden infant death syndrome associated with rotavirus infection. J Med Virol. 1982;10(4):291-6. [Medline].
Matsuno S, Utagawa E, Sugiura A. Association of rotavirus infection with Kawasaki syndrome. J Infect Dis. Jul 1983;148(1):177. [Medline].
Vollet JJ, Ericsson CD, Gibson G, Pickering LK, DuPont HL, Kohl S, et al. Human rotavirus in an adult population with travelers' diarrhea and its relationship to the location of food consumption. J Med Virol. 1979;4(2):81-7. [Medline].
Chiappini E, Azzari C, Moriondo M, Galli L, de Martino M. Viraemia is a common finding in immunocompetent children with rotavirus infection. J Med Virol. Jun 2005;76(2):265-7. [Medline].
Wong CJ, Price Z, Bruckner DA. Aseptic meningitis in an infant with rotavirus gastroenteritis. Pediatr Infect Dis. May-Jun 1984;3(3):244-6. [Medline].
Aiyar J, Bhan MK, Bhandari N, Kumar R, Raj P, Sazawal S. Rotavirus-specific antibody response in saliva of infants with rotavirus diarrhea. J Infect Dis. Dec 1990;162(6):1383-4. [Medline].
Centers for Disease Control and Prevention (CDC. Suspension of rotavirus vaccine after reports of intussusception--United States, 1999. MMWR Morb Mortal Wkly Rep. Sep 3 2004;53(34):786-9. [Medline].
Bines JE. Rotavirus vaccines and intussusception risk. Curr Opin Gastroenterol. Jan 2005;21(1):20-5. [Medline].
Yang WQ, Senger DL, Lun XQ, Muzik H, Shi ZQ, Dyck RH, et al. Reovirus as an experimental therapeutic for brain and leptomeningeal metastases from breast cancer. Gene Ther. Nov 2004;11(21):1579-89. [Medline].
Norman KL, Lee PW. Reovirus as a novel oncolytic agent. J Clin Invest. Apr 2000;105(8):1035-8. [Medline].
Clarke P, Debiasi RL, Goody R, Hoyt CC, Richardson-Burns S, Tyler KL. Mechanisms of reovirus-induced cell death and tissue injury: role of apoptosis and virus-induced perturbation of host-cell signaling and transcription factor activation. Viral Immunol. 2005;18(1):89-115. [Medline].
Kim M, Chung YH, Johnson RN. Reovirus and tumor oncolysis. J Microbiol. 06/2007;45(3):187-92. [Medline].
Coulson BS, Grimwood K, Hudson IL, Barnes GL, Bishop RF. Role of coproantibody in clinical protection of children during reinfection with rotavirus. J Clin Microbiol. Jul 1992;30(7):1678-84. [Medline].
Adelberg EA, Brooks GF, Jawetz E, et al. Medical Microbiology. 19th ed. Norwalk, Conn: Appleton & Lange; 1991:460-468.
Andersen RD, Entringer MA, Robinson WA. Virus-induced leukopenia: Colorado tick fever as a human model. J Infect Dis. Mar 1985;151(3):449-53. [Medline].
Anderson EJ, Weber SG. Rotavirus infection in adults. Lancet Infect Dis. Feb 2004;4(2):91-9. [Medline].
Armstrong D, Cohen J. Infectious Diseases. Vol 2. St. Louis, Mo: Mosby Inc; 1999.
Bishop RF, Barnes GL, Cipriani E, Lund JS. Clinical immunity after neonatal rotavirus infection. A prospective longitudinal study in young children. N Engl J Med. Jul 14 1983;309(2):72-6. [Medline].
Brandt CD, Kim HW, Rodriguez WJ, Thomas L, Yolken RH, Arrobio JO, et al. Comparison of direct electron microscopy, immune electron microscopy, and rotavirus enzyme-linked immunosorbent assay for detection of gastroenteritis viruses in children. J Clin Microbiol. May 1981;13(5):976-81. [Medline].
Burgdorfer W. Tick-borne diseases in the United States: Rocky Mountain spotted fever and Colorado tick fever. A review. Acta Trop. Jun 1977;34(2):103-26. [Medline].
Carr ME, McKendrick GD, Spyridakis T. The clinical features of infantile gastroenteritis due to rotavirus. Scand J Infect Dis. 1976;8(4):241-3. [Medline].
Champsaur H, Questiaux E, Prevot J, Henry-Amar M, Goldszmidt D, Bourjouane M, et al. Rotavirus carriage, asymptomatic infection, and disease in the first two years of life. I. Virus shedding. J Infect Dis. May 1984;149(5):667-74. [Medline].
Christy C, Madore HP, Pichichero ME, Gala C, Pincus P, Vosefski D, et al. Field trial of rhesus rotavirus vaccine in infants. Pediatr Infect Dis J. Sep 1988;7(9):645-50. [Medline].
Clark HF, Offit PA. Vaccines for rotavirus gastroenteritis universally needed for infants. Pediatr Ann. Aug 2004;33(8):536-43. [Medline].
Davidson GP, Hogg RJ, Kirubakaran CP. Serum and intestinal immune response to rotavirus enteritis in children. Infect Immun. May 1983;40(2):447-52. [Medline].
Elliott EJ, Dalby-Payne JR. 2. Acute infectious diarrhoea and dehydration in children. Med J Aust. Nov 15 2004;181(10):565-70. [Medline].
Emmons RW, Lennette EH. Immunofluorescent staining in the laboratory diagnosis of Colorado tick fever. J Lab Clin Med. Dec 1966;68(6):923-9. [Medline].
Feigin RD, Cherry JD. In: Textbook of Pediatric Infectious Diseases. Vol 2. Philadelphia, Pa: WB Saunders Co; 1998:1897-1922.
Fraser CH, Schiff DW. Colorado Tick Fever Encephalitis. Pediatrics. 1962;29:187-190.
Gorbach SL, Bartlett JG, Neil RB. Infectious Diseases. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1998:2193-9.
Gothefors L, Wadell G, Juto P, Taniguchi K, Kapikian AZ, Glass RI. Prolonged efficacy of rhesus rotavirus vaccine in Swedish children. J Infect Dis. Apr 1989;159(4):753-7. [Medline].
Gouvea V, Glass RI, Woods P, Taniguchi K, Clark HF, Forrester B, et al. Polymerase chain reaction amplification and typing of rotavirus nucleic acid from stool specimens. J Clin Microbiol. Feb 1990;28(2):276-82. [Medline].
Grimwood K, Lund JC, Coulson BS, Hudson IL, Bishop RF, Barnes GL. Comparison of serum and mucosal antibody responses following severe acute rotavirus gastroenteritis in young children. J Clin Microbiol. Apr 1988;26(4):732-8. [Medline].
Johnson AJ, Karabatsos N, Lanciotti RS. Detection of Colorado tick fever virus by using reverse transcriptase PCR and application of the technique in laboratory diagnosis. J Clin Microbiol. May 1997;35(5):1203-8. [Medline].
Kapikian AZ, Kim HW, Wyatt RG, Cline WL, Arrobio JO, Brandt CD, et al. Human reovirus-like agent as the major pathogen associated with "winter" gastroenteritis in hospitalized infants and young children. N Engl J Med. Apr 29 1976;294(18):965-72. [Medline].
Klasco R. Colorado tick fever. Med Clin North Am. Mar 2002;86(2):435-40, ix. [Medline].
Kovacs A, Chan L, Hotrakitya C, Overturf G, Portnoy B. Rotavirus gastroenteritis. Clinical and laboratory features and use of the Rotazyme test. Am J Dis Child. Feb 1987;141(2):161-6. [Medline].
Lane RS, Emmons RW, Devlin V, Dondero DV, Nelson BC. Survey for evidence of Colorado tick fever virus outside of the known endemic area in California. Am J Trop Med Hyg. Jul 1982;31(4):837-43. [Medline].
Lerner AM, Cherry JD, Klein JO, Finland M. Infections with reoviruses. N Engl J Med. Nov 8 1962;267:947-52. [Medline].
Madore HP, Christy C, Pichichero M, Long C, Pincus P, Vosefsky D, et al. Field trial of rhesus rotavirus or human-rhesus rotavirus reassortant vaccine of VP7 serotype 3 or 1 specificity in infants. The Elmwood, Panorama, and Westfall Pediatric Groups. J Infect Dis. Aug 1992;166(2):235-43. [Medline].
Major AS, Rubin DH, Cuff CF. Mucosal immunity to reovirus infection. Curr Top Microbiol Immunol. 1998;233 Reovir.ii:163-77. [Medline].
Mandell GL, Bennett JE, Dolin R. Principles and Practice of Infectious Diseases. Vol 2. St. Louis, Mo:. Mosby;2000:1693-1703.
Matson DO, O'Ryan ML, Herrera I, Pickering LK, Estes MK. Fecal antibody responses to symptomatic and asymptomatic rotavirus infections. J Infect Dis. Mar 1993;167(3):577-83. [Medline].
McLean RG, Shriner RB, Pokorny KS, Bowen GS. The ecology of Colorado tick fever in Rocky Mountain National Park in 1974. III. Habitats supporting the virus. Am J Trop Med Hyg. Jan 1989;40(1):86-93. [Medline].
Meurman OH, Laine MJ. Rotavirus epidemic in adults. N Engl J Med. Jun 2 1977;296(22):1298-9. [Medline].
Perez-Schael I, Garcia D, Gonzalez M, Gonzalez R, Daoud N, Perez M, et al. Prospective study of diarrheal diseases in Venezuelan children to evaluate the efficacy of rhesus rotavirus vaccine. J Med Virol. Mar 1990;30(3):219-29. [Medline].
Perez-Schael I, Guntinas MJ, Perez M, Pagone V, Rojas AM, Gonzalez R, et al. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela. N Engl J Med. Oct 23 1997;337(17):1181-7. [Medline].
Riepenhoff-Talty M, Bogger-Goren S, Li P, Carmody PJ, Barrett HJ, Ogra PL. Development of serum and intestinal antibody response to rotavirus after naturally acquired rotavirus infection in man. J Med Virol. 1981;8(3):215-22. [Medline].
Rubenstein AS, Miller MF. Comparison of an enzyme immunoassay with electron microscopic procedures for detecting rotavirus. J Clin Microbiol. May 1982;15(5):938-44. [Medline].
Salmi TT, Arstila P, Koivikko A. Central nervous system involvement in patients with rotavirus gastroenteritis. Scand J Infect Dis. 1978;10(1):29-31. [Medline].
Silver HK, Meiklejohn G, Kempe CH. Colorado Tick Fever. Am J Dis Child. 1961;101:56-62.
Snyder JD, Merson MH. The magnitude of the global problem of acute diarrhoeal disease: a review of active surveillance data. Bull World Health Organ. 1982;60(4):605-13. [Medline].
Spruance SL, Bailey A. Colorado Tick Fever. A review of 115 laboratory confirmed cases. Arch Intern Med. Feb 1973;131(2):288-93. [Medline].
Tallett S, MacKenzie C, Middleton P, Kerzner B, Hamilton R. Clinical, laboratory, and epidemiologic features of a viral gastroenteritis in infants and children. Pediatrics. Aug 1977;60(2):217-22. [Medline].
Tyler KL. Pathogenesis of reovirus infections of the central nervous system. Curr Top Microbiol Immunol. 1998;233 Reovir.ii:93-124. [Medline].
Tyler KL, Sokol RJ, Oberhaus SM, Le M, Karrer FM, Narkewicz MR, et al. Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology. Jun 1998;27(6):1475-82. [Medline].
Virgin HW, Dermody TS, Tyler KL. Cellular and humoral immunity to reovirus infection. Curr Top Microbiol Immunol. 1998;233(Pt 2):147-61. [Medline].
Walsh JA, Warren KS. Selective primary health care: an interim strategy for disease control in developing countries. N Engl J Med. Nov 1 1979;301(18):967-74. [Medline].
Walther FJ, Bruggeman C, Daniels-Bosman MS, Pourier S, Grauls G, Stals F, et al. Symptomatic and asymptomatic rotavirus infections in hospitalized children. Acta Paediatr Scand. Sep 1983;72(5):659-63. [Medline].
Widdowson MA, Bresee JS, Gentsch JR, Glass RI. Rotavirus disease and its prevention. Curr Opin Gastroenterol. Jan 2005;21(1):26-31. [Medline].
Wright PF, Tajima T, Thompson J, Kokubun K, Kapikian A, Karzon DT. Candidate rotavirus vaccine (rhesus rotavirus strain) in children: an evaluation. Pediatrics. Oct 1987;80(4):473-80. [Medline].
[Best Evidence] Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, Abate H, Breuer T, Clemens SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. Jan 5 2006;354(1):11-22. [Medline].
Further Reading
Keywords
reoviruses, Reoviridae, orthoreovirus, Coltivirus, rotavirus, Rota virus, human rotavirus, HRV, orbivirus, arbovirus, Colorado tick fever virus, Colorado tick fever, CTF, Dermacentor andersoni, D andersoni, Orungo virus, Lebombo virus, Kemerovo virus, Lipovnik virus, Tribec virus, Changuinola virus, Salmon River virus, Eyach virus, isolate S6-14-03, Banna virus, Beijing virus, Gansu virus, bluetongue virus, African horse sickness virus, Rocky Mountain spotted fever, RMSF, mountain fever, mountain tick fever, Rocky Mountain wood tick, least chipmunk, Tamias minimus, T minimus, golden-mantled ground squirrel, Spermophilus lateralis, S lateralis, Uinta chipmunk, Tamias umbrinus, T umbrinus, Richardson ground squirrel, Spermophilus richardsonii, S richardsonii, deer mouse, Peromyscus maniculatus, P maniculatus, NSP4, bronchiolitis obliterans-organizing pneumonia, BOOP, diabetes mellitus
