32-07: Adenovirus Infections

General Considerations

At least 60 serotypes of adenovirus are currently described, and these are members of 7 species classified A–G. About half of these subgroups produce a variety of clinical syndromes. Adenoviruses show a worldwide distribution and occur throughout the year. These infections are usually self-limited or clinically inapparent and occur most commonly among infants, young children, and military recruits and appear to be responsible for about 2–7% of childhood viral respiratory infections and 5–11% of viral pneumonia and bronchiolitis. These infections cause particular morbidity and mortality in immunocompromised persons, such as people living with HIV infection and COPD, as well as in patients who have undergone solid organ and hematopoietic stem cell transplantation or cardiac surgery or in those who have received cancer chemotherapy. A few cases of donor-transmitted adenoviral infection have been reported in past years.

Adenoviruses, although a common cause of human disease, also receive particular recognition through their role as vectors in gene therapy and vaccine development.

Clinical Findings

A. Symptoms and Signs

The incubation period is 4–9 days. Clinical syndromes of adenovirus infection, often overlapping, include the following. The common cold (see Chapter 8) is characterized by rhinitis, pharyngitis, and mild malaise without fever. Conjunctivitis is often present. Nonstreptococcal exudative pharyngitis is characterized by fever lasting 2–12 days and accompanied by malaise and myalgia. Lower respiratory tract infection may occur, including bronchiolitis, suggested by cough and rales, or pneumonia. Types 1, 2, 3, 4, 7, and 55 commonly cause acute respiratory disease and atypical pneumonia; coinfections or serial infections are documented to occur. Infections are especially severe in Native American children. Adenovirus type 14 is a cause of severe and sometimes fatal pneumonia in those with chronic lung disease but is also seen in healthy young adults and military recruit outbreaks. Viral or bacterial coinfections occur with adenovirus in 15–20% of cases. Pharyngoconjunctival fever is manifested by fever and malaise, conjunctivitis (often unilateral), mild pharyngitis, and cervical adenitis. Epidemic keratoconjunctivitis (transmissible person-to-person, most often types 8, 19, and 37) occurs in adults and is manifested by bilateral conjunctival redness, pain, tearing, and an enlarged preauricular lymph node (multiple types may be involved in a single outbreak). Keratitis may lead to subepithelial opacities (especially with the above types). Acute hemorrhagic cystitis is a disorder of children often associated with adenovirus type 11 and 21.

Sexually transmitted genitourinary ulcers and urethritis may be caused by types 2, 8, and 37. Adenoviruses also cause acute gastroenteritis (types 40 and 41), mesenteric adenitis, acute appendicitis, rhabdomyolysis, and intussusception. Rarely, they are associated with encephalitis, meningitis, cerebellitis, ARDS, acute flaccid myelitis, and pericarditis. Adenovirus is commonly identified in endomyocardial tissue of patients with myocarditis and dilated cardiomyopathy. Risk factors associated with severity of infection include youth, chronic underlying infections, recent transplantation, and serotypes 5 or 21. Obesity in children is reportedly associated with higher seroprevalence of adenovirus 36 infection, although the seropositive tended in one study to lose weight more readily.

Hepatitis (type 5 adenovirus), pneumonia, and hemorrhagic cystitis (types 11 and 34) tend to develop in infected liver, lung, or kidney transplant recipients, respectively. Disease states that may develop in hematopoietic stem cell transplant patients include hepatitis, pneumonia, diarrhea, hemorrhagic cystitis, tubulointerstitial nephritis, colitis, and encephalitis.

B. Laboratory Findings and Imaging

Antigen detection assays including direct fluorescence assay or enzyme immunoassay are rapid and show sensitivity of 40–60% compared with viral culture (considered the standard). Samples with negative rapid assays require PCR assays or viral cultures for diagnosis. Quantitative real-time rapid-cycle PCR is useful in distinguishing disease from colonization, especially in hematopoietic stem cell transplant patients. Multiplex nucleic acid amplification assays can test for multiple respiratory viruses simultaneously with increased sensitivity. Adenovirus differs from other viral and bacterial respiratory infections seen on chest CT imaging, appearing as a multifocal consolidation or ground-glass opacity without airway inflammatory findings.

Treatment & Prognosis

Treatment is symptomatic. Ribavirin or cidofovir is used in immunocompromised individuals with occasional success, although cidofovir is attendant with significant renal toxicity. Brincidofovir, the lipid-conjugated prodrug of cidofovir, has better oral bioavailability, is better tolerated, and achieves higher intracellular concentrations of active drug than cidofovir but currently is only available through compassionate use policies since its primary indicated use remains for Ebola virus infections. IVIG is used in immunocompromised patients and can be used in combination with other therapies, but data are still limited. Reduced immunosuppression is often required. Adoptive immunotherapy with transfusion of adenovirus-specific T cells is being investigated and has been associated with improved mortality. Typing of isolates is useful epidemiologically and in distinguishing transmission from endogenous reactivation. Topical steroids or tacrolimus may be used to treat adenoviral keratoconjunctivitis. The commercially available synthetic corticosteroid mifepristone shows some in vitro activity against adenoviruses. Complications of adenovirus pneumonia in children include bronchiolitis obliterans. Deaths are reported on occasion.

The control of epidemic adenoviral conjunctivitis is often difficult and requires meticulous attention to hand hygiene, use of disposable gloves, sterilization of equipment (isopropyl alcohol is insufficient, recommendations of manufacturers are preferred), cohorting of cases, and furloughing of employees. Treatment with a combination of povidone-iodine 1.0% eyedrops and dexamethasone 0.1% eyedrops four times a day can reduce symptoms and expedite recovery. Prolonged shedding of adenovirus type 55 is reported.

Vaccines are not available for general use. Use of live oral vaccines containing attenuated type 4 and type 7 was reinstated in military personnel in 2013 and has been associated with significant decrease in adenoviral disease.