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. [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.
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 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.
