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Overview
First discovered in the 1950s among US patients with respiratory disease, adenoviruses are now recognized to be of worldwide medical importance. Adenoviruses have been recovered from virtually every human organ system and have been associated with a wide spectrum of clinical disease. Common clinical manifestations of adenoviral infection include: rhinorrhea, nasal congestion, cough, sneezing, pharyngitis, keratoconjunctivitis, pneumonia, meningitis, gastroenteritis, and cystitis. Less often adenoviral infections cause encephalitis. Often clinical manifestations are associated with specific serotypes.
Structure
Human adenovirus is a non-enveloped, DNA virus with icosahedral symmetry and a size of 60-90nm. The DNA is linear, double-stranded and non-segmented. The outer structure of the virus is comprised of 240 hexons, and 12 pentons at vertices of the icosahedron (Fig. 1). Adenovirus fibers of species-specific lengths extend from the penton and are associated with hemagglutination properties. Adenovirus serotype is determined by neutralizing serotype-specific antibodies directed against the hypervariable regions of the hexon.
Adenoviruses are often transmitted by person-to-person contact, particularly among young children where fecal-oral spread is common. Aerosol transmission is possible and likely common among crowded populations. Swimming pool related outbreaks, particularly of strains causing keratoconjunctivitis or pharyngitis, are not uncommon. The incubation period from infection to clinical symptoms is thought to be 2 to 9 days and may be dose-dependent.
Different subgroups of adenovirus have different affinity for different human tissues. 10 Respiratory adenoviruses have been shown to target both airway and gas exchange epithelial cells (primarily type II cells) in the lung. Experimentally, respiratory adenovirus transmitted by small particle aerosol (0.3-2.5 u in diameter) has been shown to cause lower respiratory tract infections. 7 Adenoviral DNA may be found in tonsillar tissue, peripheral blood lymphocytes, and lung epithelial cells long after clinical disease has abated.
Most adenoviral infections occur in childhood where symptoms vary in severity. Some children may be asymptomatic. However, outbreaks can be explosive, especially among crowded closed populations. A 1965 adenoviral outbreak among 47 children in a chronic care facility had an estimated attack rate of 84% over a several-month period. In 1997 an outbreak investigation among 240 high school students documented a 61% attack rate over a 20-day period with 29% of the ill having lower respiratory track infection. The upper respiratory track manifestations included high fever and pharyngitis.
Crowded and stressful conditions increase the probability of adenoviral respiratory epidemics. A 1998 US serological study demonstrated that today's young adults are still very likely to suffer from adenovirus infection. Among 303 US young adults studied, 66% and 73% were susceptible to adenovirus types 4 and 7 infections, respectively.
Adenoviruses may cause severe disease and death among healthy individuals. Among the immunocompromised, especially bone-marrow and solid organ transplant patients, they are a critically important cause of morbidity and mortality. When infections occur there is no effective treatment and patients often expire.
Nosocomial transmission likely increases morbidity among closed medical populations. In a 1982 report, a physician with conjunctivitis likely served as the index case for an outbreak in a pediatric chronic care facility that resulted in 40 infections and two deaths among facility patients and staff.
Military trainees are particularly affected by adenovirus infections. In 1958, adenoviral infections were reported to have caused hospitalization of an estimated 10% of military recruits. 20 Adenoviral disease is often highest during winter months, and recent data show that adenoviral infections may account for more than 90% of all recruits who seek medical attention with febrile respiratory disease.
Respiratory adenovirus infections were a major cause of morbidity among US military populations until the 1970s when adenoviral vaccines were developed and first used. However, due to economic pressures the last stores of these vaccines were depleted in 1999 and subsequently, thousands of preventable infections have occurred among military trainees, many of whom have been hospitalized. At least two otherwise healthy trainees have recently died due to adenovirus-associated disease.
There is considerable evidence that the strains of adenovirus affecting military trainees today differ from the endemic strains studied 30 years ago. Epidemiological studies among civilian populations might provide the foundation for clinical trials of these vaccines among high-risk civilian populations.
While sparse data are available regarding the recent epidemiology of adenoviral infections among US civilian populations, seemingly more frequent and severe epidemics of adenoviral disease have occurred. The limited US surveillance data indicate that possibly more virulent adenovirus genotypes, responsible for epidemics of severe disease in foreign countries, have now entered the United States. We seek to better understand these observations.