Chapter 254 Adenoviruses
Adenoviruses (AdVs) are a common cause of human disease. Conjunctivitis is a familiar illness associated with AdVs, but these viruses also cause upper and lower respiratory disease, pharyngitis, gastroenteritis, and hemorrhagic cystitis. AdVs can cause severe disease in immunocompromised hosts. Outbreaks of AdV occur in communities and close populations, notably the military. No specific antivirals that are highly effective against AdVs are available. Vaccines are available for serotypes 4 and 7 but are used only for military populations.
Adenoviruses were first isolated from human adenoidal surgical specimens in 1953. They 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 defines >50 serotypes grouped into seven species. Species differ in their tissue tropism and target organs, causing distinct clinical infections (Table 254-1). AdV can be shed from the gastrointestinal tract for prolonged periods and can establish chronic low-level infection of the tonsils and adenoids.
Table 254-1 ADENOVIRUS SEROTYPES WITH ASSOCIATED INFECTIONS
| SPECIES | SEROTYPE | PREFERRED SITE OF INFECTION |
|---|---|---|
| A | 12, 18, 31 | Gastrointestinal |
| B1 | 3, 7, 16, 21, 50 | Respiratory |
| B2 | 11, 14, 34, 35 | Renal/urinary tract epithelium |
| C | 1, 2, 5, 6 | Respiratory |
| D | 8, 9, 10, 13, 15, 17, 19a, 19p, 20, 22-30, 32, 33, 36, 37, 38, 39, 42-48, 49, 51 | Ocular |
| E | 4 | Respiratory |
| F | 40, 41 | Gastrointestinal |
AdVs circulate worldwide and cause endemic infections year-round in immunocompetent hosts. Asymptomatic infections are also common. Only about one third of all known human AdV serotypes are associated with clinically apparent disease. The most prevalent types in recent surveillance studies are AdVs 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 AdV 4 and AdV 7 are a major source of morbidity in military barracks, with attack rates ranging from 25% to >90%. Spread of AdV occurs by respiratory and fecal-oral routes. An important factor in AdV transmission, especially in epidemics, is the ability of the nonenveloped particle to survive on inanimate objects in the environment. Nosocomial outbreaks have been reported.
AdVs 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. AdVs recruit neutrophils, macrophages, and natural killer cells to the site of infection and induce these cells to elaborate a number of cytokines and chemokines. Host immune response thus contributes to the symptoms of AdV infection, but specific mechanisms of pathogenesis are poorly understood.
AdVs 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 (RSV), human metapneumovirus (HMPV), human rhinovirus (HRV), rotavirus, group A streptococcus, and other common viral and bacterial pathogens.
Respiratory tract infections are common manifestations of AdV infections in children and adults. AdV cause an estimated 5-10% of all childhood respiratory disease. Primary infections in infants may manifest as bronchiolitis or pneumonia. AdV pneumonia may manifest as features more typical of bacterial disease (lobar infiltrates, high fever, parapneumonic effusions). Pharyngitis due to AdV 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.
Common follicular conjunctivitis due to AdV 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.
AdVs can be detected in the stools of 5-10% of children with acute diarrhea. Most cases of acute diarrhea are self-limiting, though severe disease can occur. Enteric infection with AdV is often asymptomatic, so the causative role in these episodes is frequently uncertain. AdV 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; the illness resolves on its own in 1-2 wk.
Rarely, AdVs are associated with myocarditis, hepatitis, or meningoencephalitis in immunocompetent individuals.
Immunocompromised persons are at high risk for severe disease due to AdVs, particularly recipients of hematopoietic stem cell transplants (HSCTs) and solid organ transplants. Organ failure due to pneumonia, hepatitis, gastroenteritis, and disseminated infection occurs primarily in these patients. AdV infection in HSCT recipients commonly manifests as pulmonary or disseminated disease and is most likely to occur in the first 100 days after transplantation. Infections due to AdV in solid organ transplant recipients usually involve the transplanted organ. Immunocompromised children are at greater risk than immunocompromised adults for complicated AdV infection, presumably because of a lack of pre-existing immunity. Additional risk factors are T cell–depleted grafts, high-level immunosuppression, and presence of graft versus host disease. Some experts advocate a preemptive screening approach to detect and treat AdV infection early in immunocompromised patients, with the intent to prevent dissemination and severe illness in this vulnerable population.
AdV may be suspected as the etiology of an illness on the basis of epidemiologic or clinical features; neither of these categories is specific enough to firmly establish the diagnosis. Rapid tests for AdV are not commercially available. Most AdV serotypes grow well in culture, although this method requires 2-7 days and thus is not helpful for early identification. Molecular techniques such as polymerase chain reaction (PCR) offer rapid, sensitive, and specific diagnosis of AdV infections and are most useful clinically for the management of suspected AdV infections in immunocompromised hosts. The frequency of asymptomatic shedding of AdV makes assigning causality to this pathogen difficult at times. Serology is generally useful only in epidemiologic investigations.
AdV pneumonia can lead to respiratory failure requiring mechanical ventilation, especially in the immunocompromised patient. Secondary bacterial pneumonias do not appear to be as common following AdV infection as they are after influenza infection, but data for this issue are limited. Severe AdV pneumonia has been linked to chronic lung disease and bronchiolitis obliterans in a minority of cases. Epidemic keratoconjunctivitis is a sight-threatening form of AdV infection. Nearly any form of AdV 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 AdV or AdV pneumonia.
Supportive care is the mainstay of AdV treatment in most cases. Patients with severe AdV conjunctivitis should be referred for ophthalmologic consultation. No specific antiviral therapy has been shown to produce a definite clinical benefit against AdV infection. The nucleoside analogue cidofovir has in vitro activity against most AdV serotypes. Cidofovir is used topically to treat epidemic keratoconjunctivitis, although topical steroids are often prescribed later in the disease course to limit the inflammatory component. Cidofovir may be used intravenously for AdV infections in immunocompromised patients. Cidofovir is highly nephrotoxic; however, prehydration, concomitant administration of probenecid, and weekly dosing may alleviate renal toxicity. Clinical studies suggest benefit from cidofovir, but there are no prospective, randomized controlled trials of cidofovir for AdV. In addition, no formal guidelines or recommendations for treatment exist. Anecdotal descriptions of benefit from intravenous immunoglobulin (IVIG) and donor lymphocyte infusion have also been reported.
Environmental and fomite transmission of AdVs occurs readily; therefore, simple measures such as handwashing and cleaning reduce spread. Live attenuated AdV 4 and AdV 7 vaccines were used effectively in the USA military from the 1970s until 1999. Cessation of their use led to widespread outbreaks in barracks, and these vaccines have been re-introduced into military use. AdVs are highly immunogenic and have been used as gene therapy vectors and vaccine vectors for other pathogens, including malaria and HIV, but no AdV-specific vaccines are commercially available.
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