Adenovirus

Authors: Gregory C. Gray, MD, MPH, FIDSA, Margaret L. Chorazy, MPH

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VIROLOGY

Human adenoviruses are double-stranded, non-enveloped DNA viruses, having an icosahedral structure and diameter of approximately 70-100nm. They belong to the genus Mastadenovirus and have a genome of about 36kbp of linear DNA. The icosahedral protein structure is comprised of 252 capsomeres, 240 of which are made of hexon proteins and 12 of which are comprised chiefly of fiber proteins. The fiber proteins vary in length by adenovirus type and project out like antennae from the icosahedron. Each fiber protein has a penton protein base. The hexon, fiber, and penton proteins are important in classifying the 52 recognized unique human adenovirus types. The 52 unique types are distinguished through studies with type-specific antisera and grouped into species A-G (14) by their hemagglutination by various types of erythrocytes. Hexons proteins are important in both type-specific and species-specific recognition, fiber proteins are important in type-specific distinction, and penton proteins are important in hemagglutination.

Adenoviruses are very stable with respect to physical and chemical exposures. Among viruses prevalent in water, adenovirus inviability is being considered one marker for successful waste water treatment. Adenoviruses are thought to be very host-specific. However, some studies suggest cross-species infections may occasionally occur. Some adenovirus serotypes have been determined to be oncogenic in animals and to transform cell lines, but adenoviruses are not thought to be oncogenic in humans.

The 52 types have different tissue tropisms and different associations with clinical signs and symptoms. Various genotype variants within a single type have often been associated with epidemics. Novel genotypes may be generated through mutation or recombination. Recombination within a species seems much more common than recombination across adenovirus species.

Because much has recently been learned about adenovirus entry and replication within cells and how to manipulate them, both human and animal adenoviruses are being widely developed as vaccine constructs and vectors for gene therapy.

EPIDEMIOLOGY

Adenoviruses, first recognized in the 1950s, were the subject of extensive epidemiologic study more than 35 years ago. Cohorts of US families living in Ohio, Kansas, Louisiana, New York, and Washington, were prospectively followed for viral respiratory illness and adenovirus isolates were carefully characterized. Reports from the 1950s through 1970s revealed that adenovirus infections occurred early in childhood, approximately 50% were asymptomatic, and in general symptomatic infections were mild without sequelae. However, the situation was quite different for US military populations concomitantly studied during this period. New military trainees often suffered explosive adenovirus outbreaks, with many ill trainees requiring hospitalizations for pneumonia. These military outbreaks were often due to adenovirus types 4, 7, and 21 (Ad4, Ad7, Ad21) which became the targets of vaccine development (9). Hence, with the exception of morbidity among military trainees, adenovirus infections were largely considered innocuous viruses causing mild upper respiratory tract infections in children.

However, much has changed since these early US epidemiological studies were conducted. In contrast to the modest number of adenovirus types detected 35 years ago, 52 unique types and many more genotypes are now recognized. It has now been noted that specific viruses have different and dynamic geographical distributions (11), they differ in their potential for epidemics (5), and may differ in their associated virulence. Due to advances in molecular diagnostics, adenoviruses have also been associated with a number of acute and chronic diseases including: sudden infant perinatal death, chronic airway disease, myocarditis, cardiomyopathy, mononucleosis-like syndromes, intussusception, and most recently, the development of obesity. Further, it has been noted that adenovirus infections among the immunocompromised can be severe, especially for bone marrow transplant patients.

Recently numerous adenovirus outbreaks have been documented among pediatric and adult long-term care facility patients (13) with high attack rates, severe disease and deaths. Emergent, possibly more virulent, strains of Ad3, Ad7, and Ad14 (1) have emerged, sometimes causing severe disease, in multiple regions of the United States.

Adenoviruses are known to be transmitted by direct contact, aerosolization, fecal-oral transmission, and via water. Adenoviruses are often transmitted in the home, in day care centers, in long-term care facilities, in swimming pools, and in hospital settings. The incubation period likely varies with the viral load and clinical syndrome, ranging from 2 days to 2 weeks.

CLINICAL MANIFESTATIONS

Adenoviruses cause diverse clinical syndromes with some adenovirus type specificity.

Upper Respiratory Tract Infection: Adenoviruses, especially Ad1, Ad2, Ad3, Ad5, and Ad6, frequently cause asymptomatic or mild upper respiratory tract disease in children. Common syndromes include pharyngitis, bronchitis, bronchiolitis, and croup. The incidence of infection is higher in late winter, spring, and early summer. Day care facilities, neonatal intensive care units, chronic care facilities, and orphanages may suffer epidemics.

Lower Respiratory Tract Disease: Occasionally young children suffer tracheobronchitis and pneumonia due to adenovirus infection but these more serious manifestations are more common among closed communities such as boarding schools and military recruit camps. In these closed settings, attack rates and hospitalizations can be quite high. Research has documented adenovirus pneumonia rates among military trainees as high as 6-8/100 men per week. Ad3, Ad4, Ad7, Ad14, and Ad21 have been the most frequent causes of lower respiratory tract disease and epidemics. Often lower respiratory tract disease is preceded by sore throat, fever, cough, coryza, rhinorrhea, and headache. Adenovirus pneumonia is often remarkable for little consolidation and patchy interstitial infiltrates, primarily in the lower lung fields, upon chest radiograph. Pneumonia among healthy young adults is normally self-limited. However, occasionally it can lead to more severe systemic disease and death (12).

Ocular Disease: Epidemics of adenovirus-associated ocular disease are fairly common. Patients may suffer conjunctivitis, edema of the eye, pain, photophobia and increased lacrimation. These manifestations have been associated with Ad8, Ad19, and Ad37. Sometimes these outbreaks have been associated with contaminated ophthalmic solutions or instruments.

Pharyngoconjunctival Fever: Adenovirus may also cause combinations of the above mentioned conditions. Pharyngoconjunctival fever was first described in the 1920s, and characterized by pharyngitis, conjunctivitis, and fever. The usually self-limiting syndrome has been associated with lakes or poor chlorination of swimming pools. One or both eyes may be affected. Patients may also suffer diarrhea and coryza. Tonsilar exudates and lymphadenopathy may be observed. Ad3, Ad4, Ad7, and Ad14 have most often been associated with pharyngoconjunctival fever.

Hemorrhagic Cystitis: Adenoviruses are known to cause hemorrhagic cystitis, especially in children. The specific route of transmission is not known. Ad11 and Ad21 are common culprits. Boys are more often affected than girls. Patients may suffer from gross or microscopic hematuria, dysuria, and urinary frequency. Often no viremia is detected. Bone marrow and renal transplant patients may suffer these infections.

Gastroenteritis: Enteric adenoviruses (Ad40, Ad41, and Ad52) are recognized as causes of gastroenteritis, watery diarrhea, and fever. These adenoviruses are difficult to culture and thought to be defective. Generally, such adenovirus illnesses are self-limiting.

Rare Manifestations: Adenoviruses have occasionally been found to cause encephalitis, meningoencephalitis, cardiomyopathy, mononucleosis-like syndromes, orchitis, urethritis, parotitis, and toxic shock-like syndrome. Adenoviruses have also been associated with cases of sudden infant death syndrome, acute flaccid paralysis, airway obstruction, pulmonary dysplasia, and obesity. Among the immunocompromised, especially transplant patients, adenovirus infections may have systemic disease manifestations that lead to death.

LABORATORY DIAGNOSIS

Laboratory diagnostic tools for adenoviruses are plentiful. Swab and tissue specimens should be transported in viral transport media containing antibiotics. Clinical specimens and tissue may be frozen at -80°C until adenovirus testing is available. Urine, stool and cerebrospinal fluid should be transported in clean containers and not in transport media. Stool suspensions yield virus more often than rectal swabs.

When present in high titers adenoviruses can be detected with DHA or rapid monoclonal antibody lateral flow tests. When viral particles are more sparse, adenoviruses can be amplified through PCR, real-time PCR, or culture (HEK, A549, HeLa, Hep-2, KB, and MRC-5 cell lines). Various diagnostic kits are available for molecular detection and species determination (multiplex PCR). Serotyping with animal sera or whole genome digests with restriction enzymes have been the classical methods to characterize strains. These methods are being supplanted by sequence-based typing strategies which focus upon hypervariable regions of the hexon and fiber genes. These sequence typing methods can generate a typing result in 1-2 days in contrast to the classical methods which could take weeks. Thus, sequence typing is now useful in studying acute adenovirus outbreaks, ascertaining source of adenovirus infections among hospitalized patients, in determining options for chemotherapy (some adenoviruses appear resistant to certain antivirals), and in governing chemotherapy. New technologies which amplify adenovirus genome segments and measure molecular weight, measure other physical properties, or search for patterns of specific DNA sequences (microarrays) are also being evaluated to further shorten adenovirus typing time. Adenovirus infection may retrospectively be detected through paired sera evaluations. Generally a rise in titer can be recognized 2-4 weeks after infection.

PATHOGENESIS

Pathology due to adenovirus infection is due to a number of factors: route of inoculation, viral load, adenovirus type, adenovirus tissue tropism and the immune status of the host. Adenovirus infections may similarly have diverse clinical presentations. They may be asymptomatic, cause mild, or cause severe clinical disease. They may be acute with or without sequelae or chronic. Adenoviruses can be transmitted through direct contact, aerosol, blood, water-borne, or through fecal-oral contamination. Adenoviruses are thought to be preserved in tonsilar and lymphatic tissues and reactivation of latent adenovirus is possible. Persistent adenovirus infections have been alleged to cause obstructive airway disease.

SUSCEPTIBILITY IN VITRO AND IN VIVO

Susceptibility In Vitro

Methods used to establish the susceptibility of adenoviruses to antivirals are not standardized, and thus, comparison of data across studies is at times complicated. Several studies have established the antiviral activity of cidofovir against adenovirus species A through F in cell culture; reported EC50-values range from 4.6-17 µg/ml. The antiviral activity of ribavirin is limited to group C adenoviruses only and is dependent upon the cell line used; EC50-values reported by a recent study range from 11.7-26.4 µg/ml (16, 19).

Susceptibility In Vivo

Since adenoviruses are highly specific to a particular host species, most human adenoviruses do not replicate productively in non-human animals (15, 16). Species B and C adenoviruses have been reported to infect the lungs of mice and cotton rats, but replication is abortive and limited to the synthesis of early adenovirus proteins. Species C adenoviruses (Ad1, Ad2, Ad5, and Ad6) have been shown to replicate in the eyes of cotton rats and New Zealand white rabbits. The time course for viral shedding and the ocular adenovirus titers in this model are similar to what is observed in human ocular adenoviral infection. Several studies have reported that topical administration of cidofovir to the eye significantly reduces ocular adenovirus titers in both therapeutic and prophylactic schedules. In vivo models for disseminated adenovirus infections necessitate the use of a non-human adenovirus since adenoviruses are species-specific. Recently, a model was developed using mouse adenovirus type I (MAV-1) and BALB/c-derived ‘severe combined immunodeficient’ (SCID) mice to mimic the clinical presentation of adenovirus in immunocompromised humans (17). When cidofovir was evaluated in this model, MAV-1-induced disease was delayed but cidofovir was unable to completely suppress replication.

ANTIVIRAL THERAPY

Currently, there remains no consensus with respect to effective antiviral treatment or prophylactic therapy against adenovirus infections. There have been several therapeutic case series reports, but they are not in agreement regarding specific antiviral therapy benefit. It seems apparent that controlled, multi-center studies of antiviral therapy for severe adenovirus infections are needed. Interventions with mixed success have included gamma globulin, interferon beta, ribavirin, cidofovir, ganciclovir, acyclovir, and vidarabine. Most frequently ribavirin and cidofovir have been used. A recent study has suggested that adenoviruses of the C species are the only species susceptible to ribavirin. All species of adenovirus are thought to be susceptible to cidofovir, but cidofovir-associated nephrotoxicity seems a prevalent problem.

In one retrospective study of 45 bone marrow transplant patients, treated with cidofovir for adenovirus infections, 69% had successful outcomes after cidofovir therapy; however, 18 (40%) of the 45 patients developed cidofovir-associated toxicity (18). In another study of 57 hematopoietic stem cell transplantation patients with adenovirus infections, 98% safely responded to a course of cidofovir therapy (25). More recently, 3 of 4 and 7 of 7 children who suffered severe adenovirus disease after transplantation improved with a carefully monitored 4–week regimen of cidofovir (2, 6).

ADJUNCTIVE THERAPY

Not applicable.

ENDPOINTS FOR MONITORING THERAPY

In limited prospective studies of bone marrow transplant patients, real-time PCR detection of adenovirus in blood, urine, and stool has been used with some success as a marker for modulating chemotherapy (7, 25).

VACCINES

Wyeth manufactured safe and effective live oral enteric coated Ad4 and Ad7 vaccines for US military trainees from 1971 until the mid 1990s (9). When stocks of these vaccines were depleted, US military trainees experienced explosive epidemics in many settings (10). In some camps, infections with prevalent adenovirus strains were nearly 100% among susceptible men and women within weeks of their arrival at the camps (21). Currently, no vaccine for adenoviruses is commercially available. Subsequent to these outbreaks the US Department of Defense contracted with Duramed, Inc. to use the same seed viruses to bring the vaccines into modern production. Initial studies of these vaccines are promising, and the expectation is that Ad4 and Ad7 vaccines will soon be again available to US military trainees. As other populations, especially persons associated with long-term care facilities, have also suffered from Ad7 epidemics, one might see the value of seeking FDA approval to use at least the Ad7 vaccine in these populations.

Adenoviruses are also being used in research as vaccine delivery systems for numerous antigens. Excellent reviews have recently been published discussing the advantages and drawbacks of recombinant adenovirus vaccine strategies (3, 4, 8, 20, 23, 24).

PREVENTION OR INFECTION CONTROL MEASURES

Nonpharmaceutical interventions during adenovirus epidemics have been shown to be beneficial. In one study of military trainees, frequent hand washing resulted in a 45% reduction in outpatient visits for acute respiratory disease (22).

REFERENCES

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