Approach Considerations
Fortunately, most infections are self-limited in the setting of a normal immune response and do not warrant specific therapy. Therapy for most adenovirus infections is supportive and symptomatic, except in the case of immunocompromised individuals who are at risk fo increased morbidity and mortality. Treatment guidelines for high risk individuals are limited but evolving. [32, 33]
Medical Care
Specific therapy for adenovirus infection, other than supportive and symptomatic treatment, remains a matter of debate. Fortunately, most infections are self-limited in the setting of a normal immune response and do not warrant specific therapy.
In immunocompromised patients, several drugs, such as cidofovir, ribavirin, ganciclovir, and vidarabine, have been used to treat adenovirus infections. Most of these agents are virostatic, may induce drug resistance, and have significant risks of toxicities, as well as risks to healthcare staff, depending on mode of delivery (eg, aerosolized ribavirin).
Adenovirus viremia is not uncommon among solid organ transplant recipients, and most cases appear to be self-limited and without sequelae. [34] In cases involving severe disease, such as adenoviral pneumonia after lung transplantation, cidofovir has been used successfully. [35]
Pediatric solid organ transplant recipients fare considerably worse, with greater incidence of adenoviral viremia and mortality rates of 50%. Surveillance for viremia is of benefit in determining need for antiviral therapy.
Adenoviral disease in allogeneic (as opposed to autologous) hematologic stem cell transplantation (HSCT) is quite significant, and the management and prevention of severe adenovirus-related disease is complex and continues to evolve. Reduction of immunosuppression is not always feasible during the first 100 days post-transplantation, during which the risk of death is highest. Disease may be fulminant, with mortality as high as 80% for both adults and children with viremia and disseminated disease. Consequently, attention has focused on predictive value of PCR quantitation in blood and stool. Indeed, both nasopharyngeal and stool detection prior to allo-HSCT predicts invesive disease in pediatric reciptients of allo-HSCT. Children status post allo-HSCT experiencing either a rapid rise in quantitative PCR or very high stool burden (PCR over 06 virus copies per gram of stool experienced 70% of disseminated adenoviral infections in children at one center. [32]
The increasing use of unrelated donors and umbilical cord blood often requires increasing use of T-cell–depleted transplants to prevent acute graft-versus-host disease. Risk of mortality due to reactivated viruses is proportional to the degree of HLA-mismatch between donor and recipient and time to T-cell reconstitution. T-cell–depleted grafts, delayed engraftment, and high levels of viremia are major risk factors for adenoviral disease after HSCT. Engraftment or reconstitution of T-cell–specific immunity is vital to recovery from pulmonary or disseminated infection, regardless of antiviral therapy. [36] In one study involving children who underwent hematopoietic stem cell transplantation, all patients who died of adenoviral infection lacked specific T cells against adenovirus. [36] Rapid transfer of donor-derived, virus-specific memory T cells offers substantial promise in controlling severe disease with low adverse effects in those with intolerance or nonresponse to antivirals. Indeed, banking of donor-derived and third-party–derived virus-specific T cells is being explored for use in HSCT and can provide broad defense against multiple endemic viruses. [37, 38, 39, 40]
Some benefit of both ribavirin and cidofovir has been documented in case series, as demonstrated by decreased viremia and concomitant clinical improvement with antiviral therapy. [41, 42, 43, 44] Intravenous cidofovir treatment resulted in complete clinical resolution in 56 of 57 pediatric HSCT recipients, in whom the virus became undetectable without dose-limited nephrotoxicity. [45] Intravenous immunoglobulin (IVIG) has also been used in conjunction with antivirals. [46, 47]
A significant advance in antiviral therapy, brincidofovir is a lipid conjugate of cidofovir that may be given orally and demonstrates potent activity against adenovirus. While diarrhea may be significant, it appears to have significantly reduced bone marrow or renal toxicity in clinical studies with limited numbers of patients in an expanded access program. No significant resistance to brincidofovir has been observed. Preventive treatment and therapy initiated early into viremia after HSCT appears to reduce viral burden, severe disease, and overall mortality. [48, 49, 50] The biopharmaceutical company, Chimerix, Inc, ended its clinical trials of brincidofovir for the treatment of adenovirus infections in May 2019. Remaining drug was made available via expanded access for serious adenoviral and orthopoxvirus infections until the supply exhausted in August 2020. Brincidofovir is not FDA-approved nor available via expanded access at this time. [51]
A rabbit model has demonstrated in vitro and in vivo effectiveness of topical filocidofivir similar to cidofovir against ocular adenovirus infection. [52]
Consultations
Consultation with an ophthalmologist should be sought in the follow-up care of persons with keratoconjunctivitis, preferably early, but particularly if they develop corneal opacities.
If hemorrhagic cystitis does not resolve within 5 days, consider noninfectious etiologies and consultation with a urologist or nephrologist, as appropriate.
Immunosuppressed patients may present with various adenoviral syndromes, ranging from afebrile hemorrhagic cystitis to fulminant disseminated disease (followed by shock and death). Consultation with an infectious disease specialist is helpful in this setting.
Prevention
After a 12-year hiatus, the FDA approved a live oral vaccine against adenovirus types 4 and 7 in 2011. It is indicated for use only by the US Department of Defense for military recruits entering basic training. No commercial vaccine is currently approved for public use.
Vaccination has been limited to military use because of the increased risk of clinically significant disease and potential for hospitalization. In 1971, the administration of live enteric-coated adenovirus vaccine (serotypes 4 and 7) was begun, with notable effectiveness. When given orally, these serotypes induce effective humoral immunity without producing disease. Because of economic factors, vaccine production was ceased in 1996, and rates of ARD in the military rose significantly. A large outbreak of ARD (serotype 4; >1000 cases) between May and December 1997 reinforced the need for immunization. [53] A live oral enteric-coated vaccine against adenovirus types 4 and 7 was approved by the FDA in 2011 for use only by the US Department of Defense in new military recruits entering basic training.
Approximately 80% of current isolates remain serotypes 4 and 7. However, serotypes 3 and 21 also appear to cause significant disease and may be appropriate targets of future immunization. [54] Further, breakthrough infection may occur with nonvaccine strains in persons who have been immunized, and vaccination programs may promote emergence of new epidemic strains. Surveillance and modification of vaccine strains may become necessary over time.
Genotyping of serotype 4 strains during outbreaks has demonstrated stable populations that vary geographically by training site. This suggests that epidemics arise from an endemic environmental source rather than from new recruits, and prevention programs may further require effective environmental control. [14, 55]
Isolation procedures, handwashing, and sterilization of instruments
Effective isolation procedures, handwashing, and sterilization of instruments can prevent nosocomial infection. [56]
Hospitalized patients with adenoviral conjunctivitis require contact precautions. Adenoviral pneumonia requires both droplet and contact precautions.
Health care workers with any adenoviral syndrome should be relieved of patient care duties and sent home until symptoms resolve. Health care workers should be educated to report to the employee health office if they develop symptoms that suggest conjunctivitis.
Strict hand hygiene should be emphasized, particularly in ophthalmologic care settings. Hand-sanitizing solutions containing 70% ethanol are effective against adenovirus. Careful attention to labeling is necessary to ensure coverage of adenovirus.
Elimination of environmental reservoirs and fomites includes proper disinfection of tonometry and ophthalmologic instruments according to local infection control and manufacturer guidelines. Proper use and monitoring of open, multiple-use ophthalmic solutions (and timely discarding of these) according to local infection control and manufacturer guidelines is essential.
Chlorination of swimming pools
Adequate chlorination of swimming pools may prevent waterborne outbreaks. Adenovirus is relatively hardy and survives long periods on surfaces and in fresh water. Like norovirus and rotavirus, adenovirus is resistant to many common disinfectants, but killed by properly maintained disinfection of recreational aquatic venues. Residential and public pools should be maintained at a continuous free chlorine range within 1-3 ppm and pH 7.2-7.8, which close attention during heavy use periods. Residential and public hot tubs should be maintained at a free chlorine of 3-10 ppm and pH 7.2-7.8. Regularly updated recommendations and evidence-based Model Aquatic Health Code are found at Healthy Water | CDC.
Long-Term Monitoring
Most disease is self-limited, and reassurance suffices; however, patients with keratoconjunctivitis or significant respiratory disease may need a follow-up evaluation within 2 weeks to monitor resolution. Immunosuppression often warrants hospitalization.
Consultation with an ophthalmologist may be indicated in the setting of corneal opacities. In addition, if hemorrhagic cystitis does not resolve within 5 days, consider noninfectious etiologies as the cause and refer the patient to a urologist or nephrologist, as appropriate.
Further Inpatient Care
Patients with meningoencephalitis or severe respiratory disease, including pneumonia, or those who are immunosuppressed require hospitalization.
Patients with severe keratitis who are suggested to have bacterial superinfection may require hospitalization.
Transfer
Hospitalized patients who are immunosuppressed and have suspected adenoviral disease may benefit from early transfer to centers experienced in the treatment of critically ill immunosuppressed patients because rapid decompensation may occur.
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A virus image from the International Committee on Taxonomy of Viruses, in The Big Picture Book of Viruses, available at http://www.virology.net/Big_Virology/BVDNAadeno.html.
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Transmission electron micrograph of adenovirus. Image courtesy of the US Centers for Disease Control and Prevention.
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Pseudomembranes and conjunctival inflammation due to adenovirus epidemic keratoconjunctivitis. Courtesy of Steve Tuft, Moorfields Eye Hospital, and Community Eye Health Journal.
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Subepithelial infiltrates characteristic of adenoviral keratoconjunctivitis. Courtesy of Wikimedia Commons (author Imrankabirhossain).
