Reoviruses

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.

Reovirus is now used as a therapeutic agent in the treatment of various types of malignancy. Reolysin, a strain of reovirus, has been studied extensively as an anticancer agent in the treatment of head and neck cancers, metastatic melanoma, and other solid-organ tumors.[1, 2, 3]

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.[4] 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.[4]

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.

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.[5] Because of their widespread prevalence in nature and the ease of infection in laboratory animals, reoviruses have been used widely in pathogenicity studies.[6, 7, 8]

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.[9] 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.

Coloradotick 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.[10] 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.[11] 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.[11]

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.

Coloradotick 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. In a 2015 study of 75 cases of CTF from 2002 to 2012, Wyoming had the highest annual incidence, followed by Montana and Utah.[12] 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.[13]

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.

Coloradotick fever

CTF virus can infect and replicate within both the KG-1a human progenitor cell line and human bone marrow progenitor cells.[14] 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.

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.[15] 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.[16] 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.[17] 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.[18] 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.[1, 19, 20] 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.[19, 21]

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.[22]

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.[23]

Colorado tick fever

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.

Rotavirus

Infants 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).[24]

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.[25]

An association of rotavirus with aseptic meningitis and Kawasaki syndrome has been reported.[26] 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.[27] 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.[28] Nevertheless, the questions of how common viremia is in immunocompetent children and whether it is associated with extraintestinal manifestations remain unsolved.

Reovirus

Reoviruses usually cause mild physical illness. In rare cases when complications (eg, pneumonia, encephalitis, meningitis) occur, associated physical findings may be observed.

Coloradotick 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 meningitis[29] , 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.

See Epidemiology and Pathophysiology.

Routine laboratory tests, such as CBC count, electrolytes, and liver profile, may be needed.

Reovirus

Reoviruses have been shown to replicate in various cell culture types used by laboratories for general viral culture, but these agents are only rarely isolated from clinical samples.

Paired acute- and convalescent-phase serum samples can be used to detect seroconversion via hemagglutination inhibition, complement fixation, or virus neutralization.

Colorado tick fever

Diagnosis of CTF in humans has been established most reliably by isolation of the virus from the erythrocyte fraction of whole blood or by demonstrating the presence of viral antigen in the erythrocytes via the direct fluorescent-antibody technique. The CTF virus has been shown to persist in erythrocytes of patients for as long as 120 days. The virus has been found in cerebrospinal fluid in people with no apparent encephalitis or meningitic involvement. Whole blood specimens shipped unrefrigerated to the laboratory by surface mail are satisfactory for virus isolation. However, virus isolation and identification takes 1-2 weeks from the time of receipt of the specimen. The fluorescent-antibody technique requires special equipment that some laboratories do not possess, and interpretation of the results is subjective.

Detection of antibody is also an adequate tool for diagnosing infection with this virus, but dependence on this method has several drawbacks. Various serologic procedures, such as neutralization tests in suckling and weanling mice, tissue culture neutralization, plaque-reduction methods, complement fixation, and direct immunofluorescence, have been used. Complement fixation antibody titers are low usually, and about 25% of infected individuals do not develop a complement fixation antibody response.

To demonstrate a diagnostically significant change in antibody titer, sera must be obtained at least 1 week after onset and again 3-4 weeks later. The specific neutralizing and complement fixing antibodies appear in the blood between the eighth and 14th days of the illness; neutralizing antibodies have been demonstrated to be present for many years. Blood from acute- or convalescent-phase samples can be inoculated into suckling mice or susceptible cell cultures (eg, baby hamster kidney [BHK] or Vero cells).

PCR techniques have been developed that allow the diagnosis to be established from the first day of symptoms.

Rotavirus

Rotaviruses are fastidious agents to culture and cannot be detected via routine viral isolation techniques. Most HRVs can be cultivated if pretreated with the proteolytic enzyme trypsin and if low levels of trypsin are included in the tissue culture medium. This cleaves an outer capsid protein and facilitates uncoating.

Direct electron microscopy, although the least sensitive technique, affords by far the most rapid method for detecting fecal viruses and has proven to be an especially useful diagnostic and teaching tool when used to test the first available stool sample from acutely ill patients with diarrhea during periods of rotavirus activity.

Direct EIA and on-grid immunoelectron microscopy (IEM) techniques are approximately equivalent in sensitivity and reliability. Compared with the conventional electron microscopy method, both techniques are about 9 times more sensitive in detecting purified SA-11 (simian rotavirus) and 3 times more sensitive in detecting HRV in crude stool samples. The IEM technique is presently the best method for detecting all of the known gastroenteritis viruses, especially in rectal swab specimens, but, with most stool specimens, IEM takes hours longer than direct electron microscopy to provide the same diagnostic result.

The Rotazyme test is a useful tool in the diagnosis of HRV gastroenteritis. Testing should be performed early in the course of the illness. The maximum number of viral particles is found in the stool of infants in the first few days of illness, especially between the second and fifth days. Excretion generally continues for as long as 8 days, with some reports of excretion as late as 23 days and even later in the immunosuppressed population. Because of the decreasing concentrations of viral particles excreted as the patient improves, testing after 23 days may fail to detect viral antigen. Because rotavirus infects the epithelial cells of small intestinal villi, mucosal gut antibodies are the most reliable indicators of immune response following natural rotavirus infection or rotavirus vaccination. In one study, saliva was used as a marker of intestinal immune response following natural rotavirus diarrhea in infants, the reasoning being that primed immunocompetent cells from the gut migrate to distant mucosal sites where they produce antibodies.[30] ​

Quantitative real-time PCR can also be used in the diagnosis of rotavirus, along with other bacteria and viruses in a multiplex platform.[31]

Usually, no abnormalities of peripheral white blood cell count or significantly elevated numbers of polymorphonuclear leukocytes or immature forms are found. These cells may have higher alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.

Hypophosphatemia may be present in as many as 50% of cases of rotavirus gastroenteritis. Uric acid levels above 10 mg/dL also can be present. Most patients have mild compensated metabolic acidosis with decreased plasma bicarbonate levels.

Reovirus

No specific treatment or prevention measures have been recommended for reovirus infections in humans because of the lack of definitive association with disease.

Colorado tick fever

Ribavirin may merit consideration in the appropriate clinical setting. Bed rest, fluids, and antipyretics are recommended as symptomatic therapy.

Rotavirus

Treatment of rotavirus gastroenteritis consists of restoring the fluid loss in dehydrated patients. Emphasis has shifted from intravenous to oral rehydration using glucose electrolyte solutions. The solution recommended by the World Health Organization (WHO) contains 30 mEq/L of sodium, 30 mEq/L of potassium, and 30 mEq of bicarbonate. In cases of severe dehydration, intravenous solutions can be used. Antimotility drugs are rarely indicated in children with gastroenteritis because the potential risks outweigh the benefits.

Start feeding within 24 hours of rotavirus gastroenteritis. This includes breast milk or diluted formula or milk in infants and lactose-free, carbohydrate-rich foods in older children. Fruit juice and soft drinks are not recommended because of their low sodium and high glucose concentrations.

No specific medications are used for treatment of diseases caused by Reoviridae family.

Reovirus

No specific treatment or prevention measures are recommended for reovirus infections in humans because of the lack of definitive association with disease. Vaccine preparations are available for veterinary use.

Colorado tick fever

CTF is best prevented by avoiding contact with the wood tick. This may be achieved by wearing suitable clothing to decrease the possibility of an infected tick becoming attached to the body. Instruct patients and family members to inspect the scalp and neck and the sleeve, belt, trouser, and sock line areas carefully for ticks several times each day and to remove any ticks that may be found to prevent them from becoming imbedded in the skin.

Repellent can be sprayed on clothing or applied to exposed skin in adults. Remind patients and family members to tuck long pants into socks, to wear shirts tucked in, and to inspect clothing and skin frequently for attached ticks. Identifying ticks on light-colored clothing is easier. Persons with documented CTF should be prohibited from blood donation until the viremia, which often is prolonged, has cleared.

Education is the best means by far of preventing the disease. Periodically remind the public of the clinical features of CTF and the ticks that transmit the causative agents. Because of the generally benign nature of the disease, attempts at active immunization do not appear to be indicated, and extensive specific measures to rid any large area of the United States of the wood tick do not appear to be warranted.

Rotavirus

Rotavirus typically infects children in the first 3 years of life during epidemics that occur in the winter in temperate climates. In developed countries with ready access to medical care and careful attention to oral and intravenous rehydration, fatalities are relatively rare, but rotavirus illness is still an important cause of morbidity. In developing countries, the impact of the disease is much more striking, with estimates that rotavirus may be the leading cause of childhood mortality in many countries.

In view of the fecal-oral route of transmission, wastewater treatment and sanitation are significant control measures.

Responses to the vaccine are generally assessed by evaluating the rise in serum antibody levels. However, several rotavirus vaccine trials indicate that clinical efficacy rates are higher than seroconversion rates, suggesting that serum antibodies are not sensitive enough indicators of immune responses and that assessment of local immunity may prove more reliable.

Studies addressing the role of serum antibody as a predictor of susceptibility to infection and illness have yielded conflicting results because monitoring of serum antibody responses may underestimate mucosal antibody by as much as 200%.

Precedents for using animal rotavirus strains as vaccine candidates include (1) the antigenic relatedness between human and animal rotaviruses and (2) evidence for the stimulation of heterologous protective immunity using one strain of rotavirus as an immunogen. For example, calves infected in utero with calf rotavirus developed resistance to challenge with HRV.

A rhesus rotavirus-tetravalent vaccine (RRV-TV, Rotashield) was licensed for use in the United States in August 1998. The vaccine consists of a quadrivalent formulation incorporating the VP7 neutralization specificity of each of the 4 clinically important serotypes with the attenuation phenotype of rhesus rotavirus.

The rhesus rotavirus–based quadrivalent vaccine was very successful in preventing severe rotavirus diarrhea in 2 trials in the United States and in one in Finland, with protection rates of 80-91%. In developing countries, its efficacy has been less impressive.

In Peru and Brazil, the efficacy of RRV-TV afforded only 20% and 35% protection respectively for any rotavirus gastroenteritis and 50-60% protection for severe rotavirus gastroenteritis. A febrile reaction occurred in about 30% of those vaccinated in Finland. Although most reactions were mild and clinically insignificant, the finding is an important part of the total clinical profile of the vaccine. In a United States multicenter trial, only 7% of vaccine recipients and 4% of placebo recipients had fever during the 5 days after the first vaccination. On July 16, 1999, the Centers for Disease Control and Prevention recommended that health care providers suspend use of the licensed RRV-TV (RotaShield, Wyeth Laboratories, Inc, Marietta, Pennsylvania) in response to 15 cases of intussusception.[32]

The risk of intussusception following RotaShield immunization is estimated to be 1 in 10,000-32,000.[33] The risk is highest during the 3-14 days following receipt of the first dose of vaccine. Infants older than 3 months at the time of the first dose of vaccine are at increased risk of intussusception. Although debate continues surrounding the exact quantitation of risk of intussusception, it is accepted as a rare adverse event.

Several rotavirus vaccines are now marketed in the United States. The orally administered live-virus vaccines exhibit similar safety characteristics. RotaTeq is a pentavalent vaccine that contains 5 live reassortant rotaviruses and is administered as a 3-dose regimen against G1, G2, G3, and G4 serotypes, the 4 most common rotavirus group A serotypes. RotaTeq also contains attachment protein P1A (genotype P[8]). Rotarix protects against rotavirus gastroenteritis caused by G1, G3, G4, and G9 strains and is administered as a 2-dose series in infants aged 6-24 weeks.

Reovirus

Rare cases of reovirus-induced neurologic disease in humans, including encephalitis and meningitis, have been reported. A 10-month-old infant with encephalitis, pneumonitis, myocarditis, and hepatitis was reported in whom reovirus serotype 1 was isolated from stool specimens and postmortem brain tissue. Tillotson and Lerner (1967) reported a 5-year-old girl who had extensive pneumonia and died after 15 days of illness.[16]

Joske and associates (1964) noted a 10-month-old girl who died after a respiratory illness of 4 days' duration.[17] Reovirus type 1 was recovered from the stool and brain of this child, and postmortem study revealed interstitial pneumonia, myocarditis, hepatitis, and encephalitis.

Colorado tick fever

In a few cases, complications such as encephalitis, aseptic meningitis, and hemorrhage have been reported. Other associated syndromes include pericarditis, epididymoorchitis, rheumatic fever syndrome, and atypical pneumonitis. The association of hepatitis with CTF also has been described.

Rotavirus

Rotavirus infections are associated with aseptic meningitis, necrotizing enterocolitis, acute myositis, hepatic abscess, pneumonia, Kawasaki disease[26] , SIDS[34] , and Crohn disease.

Reovirus and CTF infections

Reovirus and CTF infections are usually benign diseases with excellent prognosis.

Rotavirus

In developed countries with ready access to medical care and careful attention to oral and intravenous rehydration, fatalities are relatively rare, but rotavirus illness is still an important cause of morbidity.

In developing countries, the impact of the disease is much more striking, with estimates that it may be the leading cause of childhood mortality in many countries.

Because reovirus and rotavirus infections occur by fecal-oral transmission, wastewater treatment and sanitation are significant control measures.

Colorado tick fever: Education is by far the best means of preventing the disease. The public should be periodically reminded of the clinical features of CTF and the ticks that transmit the causative agents. Repellents can be sprayed on clothing or applied to exposed skin. Remind patients and family members to tuck long pants into socks, to wear shirts tucked in, and to inspect clothing and skin frequently for attached ticks. Identifying ticks on light-colored clothing is easier.

For excellent patient education resources, visit eMedicineHealth's Children's Health Center. Also, see eMedicineHealth's patient education articles Ticks and Sudden Infant Death Syndrome (SIDS).