Adenoviruses cause 5–8% of acute respiratory disease in infants, plus a wide array of other syndromes including pharyngoconjunctival fever, follicular conjunctivitis, epidemic keratoconjunctivitis, hemorrhagic cystitis, acute diarrhea, intussusception, and encephalomyelitis. Only a third of the 37-plus serotypes have been associated with disease. Although fatalities are rare, they are associated with infections by certain serotypes (particularly type 7) and with infections in severely immunocompromised hosts.
Adenoviruses are DNA viruses of intermediate size, which are classified into subgenera A to G. Types 1–39 are in subgenera A to E, type 40 is subgenus F, and type 41 is subgenus G. The virion has an icosohedral coat made up of several proteins, the most abundant of which is the "hexon," a cross-reacting antigen common to all mammalian adenoviruses. The "penton" confers type specificity, and antibody to it is protective. It is also cytotoxic in tissue culture, and toxic properties have been ascribed to it in vivo as well. Adenoviruses can also be classified by the "fingerprints" their DNA make on gels after being digested with restriction endonucleases, and this classification generally conforms to their antigenic types.
All adenovirus types except types 40 and 41 grow in primary human embryonic kidney cells, and most grow in HEp-2 or HeLa cells, producing a typical destructive cytopathic effect. Types 40 and 41 (and other serotypes as well) grow in 293 cells, a line of human embryonic kidney cells into which certain "early" adenovirus genes have been introduced.
Many adenovirus types, but particularly the common childhood types (1, 2, and 5), are shed for prolonged periods from both the respiratory and gastrointestinal tracts. These types also establish low-level and chronic infection of the tonsils.
Adenoviral infections are distributed worldwide. They occur year-round but are most prevalent in spring or early summer and again in midwinter in temperate climates. Certain types tend to occur in epidemics, notably types 4 and
7 in epidemics of febrile respiratory disease, types 3, 7, and 21 in severe pneumonia, type 3 in pharyngoconjunctival fever, type 11 in cystitis, and types 8, 19, and 37 in epidemic keratoconjunctivitis. For unexplained reasons, adenovirus types 3 and 7 cause frequent severe epidemics of pneumonia in the children of northern , with mortality rates of 5–15%. China
Over 60% of school-age children have antibodies to the common respiratory types. Almost all adults have serum antibody to types 1–7. Infections with types 1 and 2 tend to occur during the 1st yr or 2 of life, and types 3 and 5 occur a little later. Spread occurs by the respiratory and fecal-oral routes, although it is not clear whether spread is by large- or small-particle aerosol. Hospital outbreaks of respiratory disease and keratoconjunctivitis have been described.
PATHOLOGY AND PATHOGENESIS.
Adenoviruses are one of the few "respiratory" viruses that grow well in the epithelium of the small intestine. Although mucosal surfaces are the primary target early in infection, it is likely that viremia is common, accompanying fever. Viremia is, however, of little consequence except in rare instances or in the immunocompromised patient.
Adenoviral pneumonia produces characteristic microscopic changes, with dense lymphocytic infiltrates, destruction of the bronchial and bronchiolar epithelium, focal necrosis of mucous glands, hyaline membrane formation, and several types of nuclear inclusion bodies.
Adenoviruses cause a wide array of syndromes:
Acute Respiratory Disease. This is the most common manifestation of adenovirus infection in children and adults. Acute respiratory infections in infants and children are not clinically distinctive and are usually caused by types 1, 2, 3, 5, or 6. They are usually mild but may be complicated or severe. Primary infections in infants are frequently associated with fever and respiratory symptoms and in some series are complicated by otitis in more than half of the patients. Adenovirus respiratory infections are associated with a significant incidence of diarrhea.
Pharyngitis is a characteristic clinical syndrome, and adenoviruses can be identified in 15–20% of children with isolated pharyngitis, mostly in preschoolers and infants. The pharyngitis may be exudative and is often febrile. Most cases are due to type 1, 2, 3, or 5.
Pneumonia is uncommon but 7–9% of hospitalized children with acute pneumonia have adenovirus infection. Any of the "respiratory" types can cause pneumonia, but severe infections are most likely due to type 3, 7, or 21. Such infections have a mortality as high as 10%, and survivors may have residual airway damage, manifested by bronchiectasis, bronchiolitis obliterans, or, rarely, pulmonary fibrosis.
A pertussis-like syndrome has been described in association with adenovirus infections. In such instances adenoviruses frequently accompany Bordetella pertussis as coinfecting agents, but they may also be causative on their own. In many cases this illness represents activation of latent or low-level chronic respiratory or tonsillar infection by the virus. With improved methods for detecting B. pertussis, doubt has increased that adenovirus (or any respiratory virus) can produce the classic pertussis syndrome on its own.
Pharyngoconjunctival fever is a clinically distinct syndrome that occurs particularly in association with type 3 adenoviral infection. Features include a high fever that lasts 4–5 days, pharyngitis with characteristic involvement of pharyngeal lymphoid tissue, conjunctivitis, preauricular and cervical adenopathy, and rhinitis. Nonpurulent conjunctivitis occurs in 75% of patients and is manifested by inflammation of both the bulbar and palpebral conjunctivae of one or both eyes; it often persists after the fever and other symptoms have resolved. Headache, malaise, and weakness are common, and there is considerable lethargy after the acute stage.
Conjunctivitis and Keratoconjunctivitis. Adenovirus is one of the most common causes of follicular conjunctivitis and keratoconjunctivitis. The former is a relatively mild illness. The latter, which may occur in epidemics, is associated with infection by adenovirus types 8, 19, and 37. The disease may cause corneal opacities that last several years.
Gastrointestinal Infections. Adenoviruses can be found in the stools of 5–9% of children with acute diarrhea. About one half of these are the "enteric" types, 40 or 41. It is also clear that enteric infection with any adenovirus serotype is often asymptomatic, so the causative role in these episodes is frequently uncertain.
The pathogenesis of intussusception is thought by many to include enlarged lymph nodes as an initiating factor. Adenoviruses have been recovered from mesenteric lymph nodes at surgery and also from surface cultures in a higher percentage of children with intussusception than from controls. Adenoviruses have also been found in the appendices of children with appendicitis. Whether these findings represent acute etiologic relationships or are manifestations of a protracted, low-level intestinal infection analogous to that described in the tonsils is not clear.
Hemorrhagic Cystitis. This syndrome has a sudden onset of bacteriologically sterile hematuria, dysuria, frequency, and urgency lasting 1–2 wk. Infection with adenovirus types 11 and 21 has been found in some affected children and young adults.
Reye Syndrome and Reye-like Syndromes. Typical Reye syndrome has followed demonstrated adenovirus infection of several serotypes, particularly in very young children. In addition, several cases of a Reye-like syndrome have been reported, all of which are caused by infection with adenovirus type 7. The latter disease, which is frequently fatal, is characterized by severe bronchopneumonia, hepatitis, seizures, and disseminated intravascular coagulation. Circulating adenovirus penton antigen has been found in several patients and has been implicated in the pathogenesis.
Infections in Immunocompromised Hosts. Adenoviruses are important pathogens in the immunocompromised host. This includes those with either B- or T-cell deficiencies. In B cell–deficient children, a chronic meningoencephalitis very similar to that caused by enteroviruses has been described. In T cell–deficient patients, regardless of whether this deficiency is congenital, acquired, or iatrogenic, fulminant hepatitis and pneumonia, frequently with a fatal outcome, have been described. There is also a close association between adenovirus infection and both hemorrhagic cystitis and tubulointerstitial nephritis in immunosuppressed children.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS.
The laboratory diagnosis of adenovirus infection in children may be made by culture (or other method of identifying the presence of the virus), demonstration of a rise in serum antibody level, or some combination of the two. If virus is found in a "privileged" site, such as blood, urine, or cerebrospinal fluid, or in a biopsy of the lung or liver, the implication of infection with disease and organ damage is strong. Likewise, detection of certain adenovirus types in respiratory secretions (type 7 or 21) probably indicates their etiologic involvement. The presence of untyped virus or the common childhood types in respiratory secretions or stool does not, however, indicate clinical adenovirus infection because these viruses may be excreted chronically and asymptomatically. In these instances, discovery of a coincident rise in antibody by either complement fixation or some more type-specific test is helpful in assigning a specific microorganism to disease. Adenovirus infection may also be considered etiologic if a rise in antibody is found between sera drawn in the acute stage and in convalescence from a patient with an appropriate illness. Adenovirus infection often results in a high erythrocyte sedimentation rate and white cell count.
Differential diagnosis is complex and depends on which syndrome is seen.
PREVENTION AND TREATMENT.
Vaccines that contain either killed or live virus have been developed to prevent types 4 and 7 infections in military recruits. These vaccines have not, however, been used in children. There are at present no recognized antiviral agents that are effective in treating adenovirus infections. Ribavirin can inhibit viral growth of some strains in vitro, but evidence of its clinical efficacy is lacking.
Key words and phrases: viral upper respiratory tract infections, common cold, Croup,
mist tent, humidification, Ribavirine, parainfluenza, adenovirus, RS-virus, rhinovirus.
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