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Adenoviruses infect and replicate in epithelial cells of the respiratory tract, eye, gastrointestinal tract, and urinary tract. They usually do not spread beyond the regional lymph nodes. Group C viruses persist as latent infections for years in adenoids and tonsils and are shed in the feces for many months after the initial infection. In fact, the name “adenovirus” reflects the recovery of the initial isolate from explants of human adenoids.
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Most human adenoviruses replicate in intestinal epithelium after ingestion but usually produce subclinical infections rather than overt symptoms. The exceptions are serotypes 40 and 41, which can cause gastrointestinal disease.
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About one-third of the known human serotypes are commonly associated with human illness. It should be noted that a single serotype may cause different clinical diseases and, conversely, that more than one type may cause the same clinical illness. Adenoviruses 1–7 are the most common types worldwide and account for most instances of adenovirus-associated illness.
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Adenoviruses are responsible for about 5% of acute respiratory disease in young children, but they account for much less in adults. Most infections are mild and self-limited. The viruses occasionally cause disease in other organs, particularly the eye and the gastrointestinal tract.
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A. Respiratory Diseases
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Typical symptoms include cough, nasal congestion, fever, and sore throat. This syndrome is most commonly manifested in infants and children and usually involves group C viruses, especially types 1, 2, and 5. Infections with types 3, 4, and 7 occur more often in adolescents and adults. These cases are difficult to distinguish from other mild viral respiratory infections that may exhibit similar symptoms.
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Adenoviruses—particularly types 3, 7, and 21—are thought to be responsible for about 10–20% of pneumonias in childhood. Adenoviral pneumonia has been reported to have a mortality rate up to 10% in the very young.
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An outbreak of severe respiratory disease, sometimes fatal, occurred in 2007 that was caused by a new variant of adenovirus 14. Patients of all ages were affected, including healthy young adults.
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Adenoviruses are the cause of an acute respiratory disease syndrome among military recruits. This syndrome is characterized by fever, sore throat, nasal congestion, cough, and malaise, sometimes leading to pneumonia. It occurs in epidemic form among young military recruits under conditions of fatigue, stress, and crowding soon after induction. This disease is caused by types 4 and 7 and occasionally by type 3. Because of vaccine unavailability, the United States military stopped vaccinating against adenoviruses (types 4 and 7) in the 1990s; this was followed by large epidemics affecting thousands of trainees.
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Mild ocular involvement may be part of the respiratory–pharyngeal syndromes caused by adenoviruses. Pharyngoconjunctival fever tends to occur in outbreaks, such as at children’s summer camps (“swimming pool conjunctivitis”), and is associated with types 3 and 7. The duration of conjunctivitis is 1–2 weeks, and complete recovery with no lasting sequelae is the common outcome.
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A more serious disease is epidemic keratoconjunctivitis. It is caused by types 8, 19, and 37. This disease occurs mainly in adults and is highly contagious. Adenoviruses can remain viable for several weeks on sinks and hand towels, and these may be sources of transmission. The disease is characterized by acute conjunctivitis followed by keratitis that usually resolves in 2 weeks but may leave subepithelial opacities in the cornea for up to 2 years. Adenovirus infection of the cornea induces inflammation through interaction of viral capsids with host cells.
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A study in Japan (1990–2001), where type 37 is the major cause of epidemic keratoconjunctivitis, showed that mutations in the viral genome occurred chronologically and that certain mutations were correlated with epidemics of disease.
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C. Gastrointestinal Disease
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Many adenoviruses replicate in intestinal cells and are present in stools, but the presence of most serotypes is not associated with gastrointestinal disease. However, two serotypes (types 40 and 41) have been etiologically associated with infantile gastroenteritis and may account for 5–15% of cases of viral gastroenteritis in young children. Adenovirus types 40 and 41 are abundantly present in diarrheal stools. These enteropathogenic adenoviruses are very difficult to cultivate.
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Immunocompromised patients may suffer from a variety of casual and severe adenovirus infections. The most common problem caused by adenovirus infection in transplant patients is respiratory disease that may progress to severe pneumonia or disseminated infection and may be fatal (usually types 1–7). Children receiving liver transplants may develop adenovirus hepatitis in the allograft. In addition, children with heart transplants who develop myocardial adenovirus infections are at increased risk of graft loss. Pediatric recipients of hematopoietic stem cell transplants may develop infections with a wide variety of adenovirus types. Patients with acquired immunodeficiency syndrome (AIDS) may experience adenovirus infections, especially in the gastrointestinal tract.
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Types 11 and 21 may cause acute hemorrhagic cystitis in children, especially boys. Virus commonly occurs in the urine of such patients.
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Adenoviruses induce effective and long-lasting immunity against reinfection. This may reflect the fact that adenoviruses also infect the regional lymph nodes and lymphoid cells in the gastrointestinal tract. Resistance to clinical disease appears to be directly related to the presence of circulating neutralizing antibodies, which probably persist for life. Although type-specific neutralizing antibodies may protect against disease symptoms, they may not always prevent reinfection. (Infections with adenoviruses frequently occur without the production of overt illness.)
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Maternal antibodies usually protect infants against severe adenovirus respiratory infections. Neutralizing antibodies against one or more types have been detected in more than 50% of infants 6–11 months old. Normal, healthy adults generally have antibodies to several types.
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A group-reactive antibody response, different from the type-specific neutralizing antibody, may be measured by complement-fixation, immunofluorescence, or enzyme-linked immunosorbent assay. Group-specific antibodies are not protective, decline with time, and do not reveal the serotypes of previous viral infections.
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A. Detection, Isolation, and Identification of Virus
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Samples should be collected from affected sites early in the illness to optimize virus detection. Depending on the clinical disease, virus may be found in respiratory samples, conjunctiva, throat, blood, stool, or urine. Duration of adenovirus excretion varies among different illnesses: 1–7 days, respiratory samples of adults with common cold; 3–14 days, throat, stool, and eye, for pharyngoconjunctival fever; 2 weeks, eye, for keratoconjunctivitis; 3–6 weeks, respiratory samples, throat and stool of children with respiratory illnesses; 2–12 months, blood, urine, throat, and stool of immunocompromised patients.
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Virus isolation in a cell culture requires human cells. Primary human embryonic kidney cells are most susceptible but usually unavailable. Established human epithelial cell lines, such as HEp-2, HeLa, and KB, are sensitive but are difficult to maintain without degeneration for the length of time (28 days) required to detect some slow-growing natural isolates. Isolates can be identified as adenoviruses by immunofluorescence tests using an antihexon antibody on infected cells. Hemagglutination-inhibition and neutralization tests measure type-specific antigens and can be used to identify specific serotypes.
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Infectious adenovirus detection may be made rapidly using the shell vial technique. Viral specimens are centrifuged directly onto tissue culture cells; cultures are incubated for 1–2 days and are then tested with monoclonal antibodies directed against a group-reactive epitope on the hexon antigen. Also, nasal epithelial cells from a patient may be stained directly to detect viral antigens.
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Polymerase chain reaction (PCR) assays are routinely used for diagnosis of adenovirus infections in respiratory samples, blood, tissues, or body fluids, usually by using primers from a conserved viral sequence (eg, hexon, VA I) that can detect all serotypes. PCR assays have been described that use single primer pairs that target conserved segments that bracket a hypervariable region in the hexon gene. The assays can detect all known serotypes of human adenoviruses, and sequencing of the amplicon allows serotype identification. This method is rapid compared with the weeks required for virus isolation followed by neutralization assays. Adenovirus PCR is commonly included in respiratory viral detection panels. However, the sensitivity of the PCR assay may result in detection of latent adenoviruses in some patients.
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Characterization of viral DNA by hybridization or by restriction endonuclease digestion patterns can identify an isolate as an adenovirus and group it. These approaches are especially useful for types that are difficult to cultivate.
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The fastidious enteropathogenic adenoviruses can be detected by direct examination of fecal extracts by electron microscopy, by enzyme-linked immunosorbent assay, or by latex agglutination test. With difficulty, they can be isolated in a line of human embryonic kidney cells transformed with a fragment of adenovirus 5 DNA (293 cells).
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Because adenoviruses can persist in the gut and in lymphoid tissue for long periods and because recrudescent viral shedding can be precipitated by other infections, the significance of a viral detection must be interpreted with caution. Viral recovery from the eye, lung, or genital tract is diagnostic of current infection. Isolation of virus from nasopharyngeal or throat secretions of a patient with respiratory illness can be considered relevant to the clinical disease. Viral detection from stool of patients with gastroenteritis is inconclusive unless shown to be one of the enteropathogenic types; enzyme immunoassays are available to specifically detect these serotypes 40 and 41.
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Infection of humans with any adenovirus type stimulates a rise in complement-fixing antibodies to adenovirus group antigens shared by all types. The complement-fixation test is an easily applied method for detecting infection by any member of the adenovirus group, although the test has low sensitivity. A fourfold or greater rise in complement-fixing antibody titer between acute-phase and convalescent-phase sera indicates recent infection with an adenovirus, but it gives no clue about the specific type involved.
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If specific identification of a patient’s serologic response is required, antibody neutralization or hemagglutination-inhibition tests can be used. The neutralization test is the most sensitive. In most cases, the neutralizing antibody titer of infected persons shows a fourfold or greater rise against the adenovirus type recovered from the patient.
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Adenoviruses exist in all parts of the world. They are present year round and usually do not cause community outbreaks of disease. The most common serotypes in clinical samples are the low-numbered respiratory types (1, 2, 3, 5, and 7) and the gastroenteritis types (40 and 41). Adenoviruses are spread by direct contact, by the fecal–oral route, by respiratory droplets, or by contaminated fomites. Most adenovirus-related diseases are not clinically pathognomonic, and many infections are subclinical.
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Infections with types 1, 2, 5, and 6 occur chiefly during the first years of life; types 3 and 7 are contracted during school years; and other types (such as 4, 8, and 19) may not be encountered until adulthood.
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Although adenoviruses cause only 2–5% of all respiratory illness in the general population, respiratory disease caused by types 3, 4, and 7 is common among military recruits and young adults in group or institutional settings.
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Eye infections can be transmitted in several ways, but hand-to-eye transfer is particularly important. Outbreaks of swimming pool conjunctivitis are presumably waterborne, usually occur in the summer, and are commonly caused by types 3 and 7. Epidemic keratoconjunctivitis is a highly contagious and serious disease. The disease, caused by type 8, spread in 1941 from Australia via the Hawaiian Islands to the Pacific Coast. It spread rapidly through the shipyards (hence the name “shipyard eye”) and across the United States. In the United States, the incidence of neutralizing antibody to type 8 in the general population is very low (~1%), but in Japan it is more than 30%. More recently, adenovirus types 19 and 37 have caused epidemics of typical epidemic keratoconjunctivitis. Outbreaks of conjunctivitis traced to ophthalmologists’ offices were presumably caused by contaminated ophthalmic solutions or diagnostic equipment.
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The incidence of adenovirus infection in patients undergoing bone marrow transplantation has been estimated to be from about 5% to as high as 30%. The reported incidence is higher in pediatric patients than in adults. Patients may develop fatal disseminated infections. Types 34 and 35 are found most often in bone marrow and renal transplant recipients. The most likely source of infection in transplant patients is endogenous viral reactivation, although primary infections may be a factor in the pediatric population.
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There is no specific treatment for adenovirus infections.
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Prevention and Control
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Careful hand washing is the easiest way to prevent infections. Environmental surfaces can be disinfected with sodium hypochlorite. In group settings, paper towels may be advisable because dirty towels can be a source of infection in outbreaks. The risk of waterborne outbreaks of conjunctivitis can be minimized by chlorination of swimming pools and waste water. Strict asepsis during eye examinations, coupled with adequate sterilization of equipment, is essential for the control of epidemic keratoconjunctivitis.
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Attempts to control adenovirus infections in the military have focused on vaccines. Live adenovirus vaccine containing types 4 and 7, encased in gelatin-coated capsules and given orally, was introduced in 1971. In this way virus bypasses the respiratory tract, where it could cause disease, and is released in the intestine, where it replicates and induces neutralizing antibody. The vaccine proved highly effective but was discontinued in 1999, and was re-approved in 2011 for U.S. military personnel only.