Jason B. Weinberg, John V. Williams
Human adenoviruses (HAdVs) are a common cause of human disease. Conjunctivitis is a familiar illness associated with the HAdVs, but these viruses also cause upper and lower respiratory disease, pharyngitis, gastroenteritis, and hemorrhagic cystitis. HAdVs can cause severe disease in immunocompromised hosts. Outbreaks of HAdV infection occur in communities and closed populations, notably the military. No currently approved antiviral drugs are highly effective against HAdVs. Vaccines are available for HAdV types 4 and 7 but are used only for military populations.
Adenoviruses are nonenveloped viruses with an icosahedral protein capsid. The double-stranded DNA genome is contained within the particle complexed with several viral proteins. Antigenic variability in surface proteins of the virion and genomic sequencing define at least 70 serotypes grouped into seven species. Species differ in their tissue tropism and target organs, causing distinct clinical infections (Table 289.1 ). HAdVs can be shed from the gastrointestinal tract for prolonged periods and can establish persistent infection of the tonsils and adenoids.
Table 289.1
HAdVs circulate worldwide and cause endemic infections year-round in immunocompetent hosts. Asymptomatic infections are also common. Only about one third of all known HAdV types are associated with clinically apparent disease. The most prevalent types in recent surveillance studies are HAdV types 3, 2, 1, and 5. Epidemics of conjunctivitis (often severe), pharyngitis, and respiratory disease occur, especially in schools and military settings. Outbreaks of febrile respiratory illness caused by HAdV-4 and HAdV-7 are a major source of morbidity in military barracks, with attack rates ranging from 25% to > 90%. The spread of HAdV occurs by respiratory and fecal-oral routes. An important factor in HAdV transmission, especially in epidemics, is the ability of the nonenveloped particle to survive on inanimate objects in the environment. Nosocomial outbreaks have been reported.
HAdVs bind to cell surface receptors and trigger internalization by endocytosis. Acidification of the endosome induces conformational changes in the capsid, leading to eventual translocation of the genome to the cell nucleus. Viral messenger RNA transcription and genomic replication occur in the nucleus. Progeny virion particles assemble in the nucleus. Lysis of the cell releases new infectious particles and causes damage to epithelial mucosa, sloughing of cell debris, and inflammation. Host responses to HAdV infection include the recruitment of neutrophils, macrophages, and natural killer cells to the site of infection and the elaboration by those cells of a number of cytokines and chemokines. This host immune response is likely to contribute to the symptoms of HAdV infection, but specific mechanisms of pathogenesis are poorly understood. The strict species specificity of the adenoviruses has precluded the development of an animal model for HAdVs, although recent work with HAdV in a humanized mouse model shows promise. Mouse adenovirus has also been used to study adenovirus pathogenesis using a murine model.
HAdVs cause a variety of common clinical syndromes in both immunocompetent and immunocompromised hosts. These syndromes are difficult to distinguish reliably from similar illnesses caused by other pathogens, such as respiratory syncytial virus, human metapneumovirus, human rhinovirus, rotavirus, group A streptococcus, and other common viral and bacterial pathogens.
Respiratory tract infections are common manifestations of HAdV infections in children and adults. HAdVs cause an estimated 5–10% of all childhood respiratory diseases. Primary infections in infants may manifest as bronchiolitis or pneumonia. HAdV pneumonia may present with features more typical of bacterial disease (lobar infiltrates, high fever, parapneumonic effusions). HAdV-14 has emerged as a significant cause of severe acute respiratory disease in military and civilian populations, in some cases leading to hospitalization and death. Pharyngitis caused by HAdV typically includes symptoms of coryza, sore throat, and fever. The virus can be identified in 15–20% of children with isolated pharyngitis, mostly in preschool children and infants.
The common follicular conjunctivitis caused by HAdV is self-limiting and requires no specific treatment. A more severe form called epidemic keratoconjunctivitis involves the cornea and conjunctiva. Pharyngoconjunctival fever is a distinct syndrome that includes a high temperature, pharyngitis, nonpurulent conjunctivitis, and preauricular and cervical lymphadenopathy.
HAdV can be detected in the stools of 5–10% of children with acute diarrhea. Most cases of acute diarrhea are self-limiting, although severe disease can occur. Enteric infection with HAdV is often asymptomatic, and shedding of virus after acute infection can be prolonged, so the causative role in these episodes is frequently uncertain. HAdV may also cause mesenteric adenitis.
Hemorrhage cystitis consists of a sudden onset of hematuria, dysuria, frequency, and urgency with negative urine bacterial culture results. Urinalysis may show sterile pyuria in addition to red blood cells. This illness occurs more frequently in young males and typically resolves on its own in 1-2 wk.
Less frequently, HAdVs are associated with myocarditis, hepatitis, or meningoencephalitis in immunocompetent individuals.
Immunocompromised persons, particularly recipients of hematopoietic stem cell transplants (HSCTs) and solid-organ transplants, are at high risk for severe and fatal disease caused by HAdV. These patients may experience primary HAdV infection. Reactivation of persistent virus in a transplant recipient and transmission of virus from a donor organ may also occur. Organ failure as a consequence of pneumonia, hepatitis, gastroenteritis, and disseminated infection occurs primarily in these patients. HAdV infection in HSCT recipients commonly manifests as pulmonary or disseminated disease and is most likely to occur in the first 100 days after transplantation. Hemorrhagic cystitis caused by HAdV can be severe in HSCT recipients. Infections caused by HAdV in solid-organ transplant recipients usually involve the transplanted organ. Immunocompromised children are at greater risk than immunocompromised adults for complicated HAdV infection, presumably because of a lack of preexisting immunity. Additional risk factors include T-cell–depleted grafts, high-level immunosuppression, and the presence of graft-versus-host disease. Some experts advocate a preemptive screening approach to detect and treat HAdV infection early in immunocompromised patients, with the intent to prevent dissemination and severe illness in this vulnerable population, though no highly effective antiviral therapy exists.
HAdV may be suspected as the etiology of an illness on the basis of epidemiologic or clinical features, but neither of these categories is specific enough to firmly establish the diagnosis. The frequency of asymptomatic shedding of HAdV makes assigning causality to this pathogen difficult at times. Most HAdV serotypes grow well in culture, although this method requires several days and thus is not helpful for early identification. Cells from respiratory or ocular specimens can be tested using immunofluorescent staining with antibodies to detect HAdV protein. Commercially available enzyme-linked immunoassays can be used to rapidly detect HAdV in patient specimens, usually in stool. Molecular techniques, such as polymerase chain reaction, offer a rapid, sensitive, and specific diagnosis of HAdV infections and are most useful clinically for the management of suspected HAdV infections in immunocompromised hosts. In these patients, measurement of the HAdV genome copy number using a quantitative real-time polymerase chain reaction can facilitate the diagnosis, and repeated measurements can aid in assessing a patient's response to treatment. Multiplex molecular assays capable of identifying HAdV in addition to other pathogens are increasingly available and useful for rapid diagnosis. Serology is generally useful only in epidemiologic investigations.
HAdV pneumonia can lead to respiratory failure requiring mechanical ventilation, especially in immunocompromised patients. Secondary bacterial pneumonia does not appear to be as common following HAdV infection as it is after influenza infection, but data that address this issue are limited. Severe HAdV pneumonia has been linked to chronic lung disease and bronchiolitis obliterans in a minority of cases. Epidemic keratoconjunctivitis is a vision-threatening form of HAdV infection. Nearly any form of HAdV infection can be fatal in an HSCT or solid-organ transplant recipient. Refractory severe anemia requiring repeated blood transfusions can develop in HSCT recipients with hemorrhagic cystitis. Mortality rates of up to 60–80% have been reported in transplant recipients with disseminated HAdV or HAdV pneumonia.
Supportive care is the mainstay of HAdV treatment in most cases. Patients with severe HAdV conjunctivitis should be referred for ophthalmologic consultation. No specific antiviral therapy produces a definite clinical benefit against HAdV infection. The nucleoside analog cidofovir has in vitro activity against most HAdV serotypes. Cidofovir is used topically to treat epidemic keratoconjunctivitis, often in conjunction with topical steroids or other immunosuppressive agents to limit the inflammatory component. Cidofovir may be used intravenously for HAdV infections in immunocompromised patients. Cidofovir is highly nephrotoxic; however, prehydration, concomitant administration of probenecid, and weekly dosing may reduce renal toxicity. Clinical studies suggest some benefit from cidofovir, but there are no prospective, randomized controlled trials of cidofovir for HAdV infection. In addition, no formal guidelines or recommendations for treatment exist. The cidofovir derivative brincidofovir is better tolerated than cidofovir and shows promise as an approach to the prevention and treatment of HAdV disease in immunocompromised patients, but experience remains limited. There are anecdotal descriptions of benefit from intravenous immunoglobulin. Adoptive immunotherapy involving the infusion of HAdV-specific T cells may also provide some benefit for immunocompromised patients with life-threatening HAdV infections, but this intervention is not yet considered standard therapy.
Environmental and fomite transmission of HAdV occurs readily; therefore, simple measures such as handwashing and cleaning are likely to reduce spread. HAdVs are highly immunogenic and have been used as gene therapy vectors and vaccine vectors for other pathogens, including malaria and HIV, but no HAdV-specific vaccines are available for routine use. Live-attenuated HAdV-4 and HAdV-7 vaccines were used effectively in the United States military from the 1970s until 1999. Cessation of their use led to widespread outbreaks in barracks, and those vaccines were subsequently reintroduced into military use.