AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

A nonenveloped double-stranded DNA virus, adenovirus was first isolated in the 1950s in adenoid tissue–derived cell cultures, hence the name. These primary cell cultures were often noted to spontaneously degenerate over time, and adenoviruses are now known to be a common cause of asymptomatic respiratory tract infection that produces in vitro cytolysis in these tissues.

An extremely hardy virus, adenovirus is ubiquitous in human and animal populations, survives long periods outside a host, and is endemic throughout the year. Possessing 51 serotypes, adenovirus is recognized as the etiologic agent of a variety of diverse syndromes. It is transmitted via direct inoculation to the conjunctiva, a fecal-oral route, aerosolized droplets, or exposure to infected tissue or blood.

The virus is capable of infecting multiple organ systems; however, most infections do not cause symptoms. Adenovirus is often cultured from the pharynx and stool of asymptomatic children, and most adults have measurable titers of anti-adenovirus antibodies, implying prior infection. Adenovirus is known to be oncogenic in rodents but not in humans.

Adenovirus has been associated with both sporadic and epidemic disease and, with regard to infections among military recruits, is a significant cause of economic cost and morbidity because of the cessation of vaccine production in 1995.

Of most recent interest is the role of adenoviruses as vectors in gene therapy.^{1, 2} Adenoviruses can infect various cells, both proliferating and quiescent, and thus hold the promise of targeting many different tissues and diseased cell lines.

The genome of adenovirus is well known and can be modified with relative ease to induce lysis or cytotoxicity of a specified cell line without affecting others. The greatest challenge in viral gene therapy, as might be expected, is the immune response to the viral vector itself.

The virus itself can be engineered to remove its replicative capacity by removing essential genes. Additionally, specific genes can be inserted into the virus that then can repair defective metabolic, enzymatic, or synthetic pathways in the host. Suicide gene systems that convert nontoxic systemically delivered prodrugs to active chemotherapeutic agents have been delivered via adenoviral vectors directly into cancer cells. The complex mechanisms by which viral vectors may be incorporated into gene therapy and the rapid growth in this field put further discussion beyond the scope of this text.

Pathophysiology

Accounting for its many manifestations, adenovirus produces cytolysis in many types of tissues and induces host inflammatory responses and cytokine production. When human cells are infected by adenovirus, 1 of 3 different interactions with the cells may occur.

The first is lytic infection, which occurs when an adenovirus enters human epithelial cells and continues through an entire replication cycle, which results in host cell death. The second is chronic or latent infection, the exact mechanism of which is unknown, which frequently involves asymptomatic infection of lymphoid tissue. Lastly, oncogenic transformation may occur in rats. During oncogenesis, the replication cycle is truncated, and adenoviral DNA is then integrated into host cell’s DNA. Thereafter, adenovirus produces potent E1A proteins that immortalize primary rodent cells by altering cellular transcription, ultimately leading to deregulation of apoptosis and malignant transformation. A clear role for adenovirus in human oncogenesis has not been established.

Frequency

United States

Adenovirus is isolated most commonly in infants and children. An increased incidence of infection was found in military recruits until the introduction of an effective vaccine against serotype 4 (Ad4) and serotype 7 (Ad7) in 1971. The economy-driven cessation of vaccine production by its sole producer in 1996 resulted in re-emergence of outbreaks, with Ad4 predominating in 98% of cases. The reservoirs exist within the training environment itself, and Ad4 has been detected on lockers, rifles, and bedding. Ad4 seropositivity of new recruits has been demonstrated to rise from 30% to almost 100%. Prolonged pharyngeal shedding and communal quarters contribute to outbreaks, with illness most commonly arising in weeks 3 to 5.

Lost productivity and interrupted military training have prompted reinvestigation of vaccine production. The military has recently awarded a contract for development of a new adenovirus vaccine. Vaccine availability for use in military trainees has been pushed back to 2008. Notably, co-infection with non-vaccine strains (B1 and E) have developed following vaccination,³ and surveillance for emerging non-vaccine strains is still needed.

Recently, media attention following outbreaks in the United States has focused on serotype 14. The CDC's Morbidity and Mortality Weekly Review recently published an article entitled "Acute Respiratory Disease Associated with Adenovirus Serotype 14—Four States, 2006-2007."

Mortality/Morbidity

• Severe morbidity and mortality are rare in an immunocompetent host. Uncommon complications include meningoencephalitis and pneumonitis.
• Severe infection is associated with host immune deficiency, as in the setting of transplantation or inherited and acquired immunodeficiency states. Mortality rates among recipients of hematopoietic stem cell transplants are close to 26%.
• Morbidity and deaths have occurred in past gene vector trials due to pronounced host inflammatory responses.
• As with polio vaccines, live adenovirus vaccines in the 1950s became contaminated with simian virus 40 (SV40), with resulting concern that this virus caused various cancers. After subsequent long-term follow-up, some studies have found a moderate association between SV40 and human cancers as a transforming virus, while some other studies have reported no such findings.^{4, 5}

Race

• No race predilection has been described.

Sex

• Males have a higher prevalence of urinary tract disease than females. The prevalence of other syndromes does not appear to be affected by the sex of the individual.

Age

• Adenovirus infection typically affects children from infancy to school age, but children of any age may be affected, including neonates. Young adults in any setting of close quarters and stress may be affected, as with military trainees.

CLINICAL

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History

Because the manifestations of adenovirus infections are protean, the major syndromes are discussed separately. The major syndromes covered in this article are (1) acute respiratory disease (ARD), (2) pharyngoconjunctival fever, (3) epidemic keratoconjunctivitis, (4) acute hemorrhagic cystitis, (5) gastroenteritis, and (5) adenoviral infections in immunocompromised hosts.

Given the range of manifestations, the varying levels and effects of immunosuppressive therapies, and rapid advances in molecular methods of detection, a comprehensive review of adenovirus infection in the immunosuppressed host is beyond the scope of this article; however, the author plans to report the most salient features and general updates here. The reader is encouraged to review the literature for more detail regarding infection in specific settings.

• Acute respiratory disease (predominantly serotypes 4 and 7)
• • As with many other viral syndromes, ARD is more common in spring and winter months. Approximately half of adenovirus respiratory infections do not cause symptoms. Adenoviruses account for 10% of all childhood lower respiratory tract infections.
  • The contagiousness of adenovirus is facilitated by very high levels of viral particles (100,000-1,000,000/mL) in the sputum or oral secretions of infected adults. Additionally, adults who lack antibody may be infected by the inhalation of as few as 5 virions in droplet nuclei.
  • In the prevaccine era from the 1950s to 1971, adenoviruses accounted for significant acute disease in 70% of military recruits. As many as 20% of affected recruits were hospitalized with a febrile respiratory illness characterized by sore throat, headache, and cough. Adenovirus serotypes 4 and 7 are primarily involved. A live enteric-coated oral vaccine against these serotypes was introduced in 1971. This vaccine reduced adenovirus-related respiratory illness by more than 95% in recruits and thus attenuated outbreaks. Vaccine production ceased in 1995 for economic reasons, and vaccination administration was limited to high-risk time periods until supplies ran out in 1999. In 1997, a large epidemic of more than 500 cases associated with serotypes 3 and 7 occurred in US Navy recruits. Most recent analyses suggest that serotype 4 has caused most military outbreaks since 1999, with the exception of the newly emerging virulence in serotype 14 (Ad14).^{6, 7}
  • Adenovirus serotype 14
  • • Ad14, referred to as the "super cold" in the media, has caused rare outbreaks of ARD since 1955.
    • Recent epidemiologic tracking suggests that a new and more virulent variant of this strain is emerging in the United States. Between May 2006 and June 2007, 141 cases of Ad14 infection were reported in clusters in New York, Oregon, Texas, and Washington. Almost 40% of affected persons were hospitalized, almost half in intensive care, with a 5% overall mortality rate. The cases in Texas involved military trainees at Lackland Air Force Base, and subsequent cases have been reported in declining numbers at Lackland, 3 other Texas military bases, and 1 eye culture in a civilian unassociated with the military.
    • More investigation is needed to determine risk factors and preventive measures, and testing is underway to determine whether the new Ad4/Ad7 military vaccine will be effective against Ad14. The CDC recommends a heightened awareness on the part of clinicians and public of the possibility of an emerging pathogen; however, management currently remains supportive. Clinicians with questions related to testing are directed to their state health departments.⁸
  • Adenovirus may be isolated from children with whooping cough syndrome in the presence or absence of Bordetella pertussis infection; however, whether adenovirus is an etiologic cause of the syndrome remains unclear.^{9, 10}
  • Lower respiratory tract infections, including tracheobronchitis, bronchiolitis, and pneumonia, may mimic respiratory syncytial virus infection or influenza. Notably, conjunctivitis in the presence of bronchitis suggests adenoviral infection.
  • Fatal pneumonia is uncommon but is more likely in neonates.
  • Encephalitis is uncommon.
  • Fever, rhinorrhea, cough, and sore throat usually lasting 3-5 days are typical symptoms of adenoviral ARD.
• Pharyngoconjunctival fever (predominantly serotypes 3, 4, and 7)
• • This syndrome most often affects school-aged children. Contagious in nature, sporadic outbreaks of adenovirus infection occur in small groups, especially summer camps in the setting of an inadequately chlorinated water source such as a pool or lake. Interestingly, water sample cultures are often not confirmatory. Spread occurs via the respiratory route and contact with ocular secretions during the acute illness.
  • Acute conjunctivitis may occur both as a separate entity, with or without pharyngitis, or a respiratory syndrome. Encephalitis may occur but is rare.
  • The classic presentation is characterized by fever, sore throat, coryza, and red eyes. Upper respiratory tract symptoms may precede ocular findings or may be absent.
  • Conjunctivitis usually begins with one eye then spreads to the other, although both eyes may be affected simultaneously. Severe pain is atypical, but mild pain or discomfort, tearing, pruritus, and morning crusting are common.
  • It usually is self-limited to 5 days (incubation period is 5 d).
  • Uncommonly, an exanthem or diarrhea may occur.
• Epidemic keratoconjunctivitis (predominantly serotypes 8, 19, and 37)
• • This is highly contagious, with approximately 10% transmission in household contacts via hands and fomites. Transmission has also been associated with instrumentation, industrial trauma (shipyard workers [ie, shipyard eye], welders, airborne particles), contaminated ophthalmic solutions, and the hands of health care workers. Corneal trauma facilitates infection.
  • After an 8-day incubation period, an insidious onset of unilateral red eye occurs, which spreads to involve both eyes. Patients have photophobia, tearing, and pain (indicating corneal involvement). Children may have fever and lymphadenopathy.
  • Malaise and headache are reported.
  • Inflammation may persist for weeks, and residual scarring and visual impairment may occur.
• Acute hemorrhagic cystitis (serotypes 11 and 21)/nephritis
• • Acute hemorrhagic cystitis usually affects children aged 5-15 years but may also affect immunosuppressed adults (eg, from kidney or bone marrow transplantation, AIDS). Boys are affected more often than girls.
  • Dysuria, frequency, and grossly bloody urine are reported. Hematuria is self-limited to 3 days, and other symptoms resolve later. Symptoms may be more prolonged in recipients of hematopoietic stem cell transplants.
  • Nephritis has occurred in recipients of hematopoietic stem cell transplants and is associated with fever, hematuria, and flank pain.¹¹
• Gastroenteritis (most commonly associated with serotypes 40 and 41, but others may be involved)
• • Enteric adenovirus infection is a common cause of infantile diarrhea in the daycare setting, but it is a less common cause than rotavirus infection and, in some settings, less common than infection with astroviruses. It can also affect adults; in addition, a nosocomial outbreak in a hematology unit has been reported.¹² Adenoviruses replicate readily in the human intestine and may be cultured from asymptomatic individuals; thus, their presence in the setting of a diarrheal syndrome may be incidental.
  • Many serotypes are fastidious in culture. Serotypes 40 and 41 had been termed "noncultivatable." However, they have been cultured in the setting of diarrheal syndromes using newer cell lines. Monoclonal antibody assays, enzyme-linked immunosorbent assay, and electron microscopy also support the association of these strains with enteric disease. However, one cannot assume that enteric disease is limited to these strains. In fact, various serotypes of adenovirus have been associated with infectious diarrheal syndromes in recipients of hematopoietic stem cell transplants.
  • Nonenteric adenovirus serotypes (ie, 1, 2, 3, 5, 6) has been associated with intussusception. Approximately 40% of infants with intussusception have positive findings from cultures of stool or mesenteric lymph nodes for nonenteric serotypes, and most have no evidence of infection with enteric strains (ie, 40, 41). The role of adenovirus in this setting is unclear. Mesenteric lymphadenitis or hyperirritable small bowel associated with nonenteric adenoviral infection has been postulated to lead to intussusception. However, most patients with intussusception have no evidence of adenoviral infection (based on culture, serology, or histopathologic viral inclusion findings); thus, intussusception may be related to multiple etiologies.
  • Fever and watery diarrhea are usually limited to 1-2 weeks.
• Adenoviral infections in immunocompromised hosts (multiple serotypes)
• • Adenovirus is increasingly known to cause disease during the posttransplantation period in patients who have received hematopoietic stem cell transplants. Risk factors for adenovirus disease include allogeneic stem cell transplantation, T-cell depletion and nonmyeloablative conditioning regimens such as high-dose alemtuzumab (Campath) antibody therapy, lymphopenia, young age, and graft versus host disease. Prolonged neutropenia or immunosuppression also enhances the risk of developing adenoviral infections. Manifestations may vary but include hemorrhagic cystitis/nephritis, pneumonitis, hepatitis/liver failure, and gastroenteritis, particularly during the acute posttransplantation period prior to engraftment. In one series, nephritis was associated with acute renal failure in more than 90% of patients. Adenovirus should be considered in patients with a fever, hematuria, flank pain, and worsening renal function.
  • Uncommonly, T-cell immunodeficiency related to HIV infection has been associated with adenoviral infections, particularly in infants and children infected with HIV. Pneumonitis and hemorrhagic cystitis are cited most often. Cholecystitis, severe hepatitis, and liver failure have been reported.^{13, 14}
  • Immunosuppression in recipients of solid organ transplants has also been associated with the above syndromes, as has diffuse adenoviral infection of the allograft itself. Both allograft loss and recovery have been reported.¹⁴
  • Importantly, note that a prior history of adenoviral infection in a patient with recovered immunocompetence may herald recurrence when the patient again becomes immunosuppressed. A high level of suspicion for adenovirus is warranted in these cases.
• General considerations
• • Pulmonary infiltrates are often diffuse and reticulonodular, but they may be lobar.
  • Hematuria may occur in the setting of nephritis or hemorrhagic cystitis.
  • Abnormal transaminase levels, which may be dramatic, may indicate adenoviral hepatitis.
  • Diarrhea may indicate adenoviral gastroenteritis.

Physical

• Acute respiratory disease
• • Pharyngitis, which may be exudative, is a finding. Conjunctivitis may occur in this setting.
  • Patients have pulmonary rhonchi and rales.
• Pharyngoconjunctival fever
• • Fever; coryza; pharyngitis, which may be exudative; follicular, bulbar, and palpebral conjunctivitis (typically mild granular appearance); and headache are reported.
  • Cervical lymphadenopathy is a finding.
  • The hallmark is preauricular lymphadenopathy (ie, Parinaud syndrome), with small lymph nodes palpable just anterior to the ear. This finding is not common; however, its presence in the setting of a viral conjunctivitis is very suggestive of adenovirus infection.
• Epidemic keratoconjunctivitis
• • Severe follicular keratoconjunctivitis is reported. Palpebral conjunctiva may be granular.
  • Palpebral edema is a finding.
  • Preauricular lymphadenopathy is not common but is a pathognomonic finding with adenovirus infection.
  • Hemorrhagic conjunctivitis may develop.
  • Visual haziness or impairment resulting from keratitis develops and may persist for months to years.
• Acute hemorrhagic cystitis/nephritis
• • No significant features are described in the setting of hemorrhagic cystitis, other than evidence of blood in the urine.
  • Nephritis is characterized by flank pain.
  • Patients with hemorrhagic cystitis are afebrile. Nephritis is characterized by fever.
• Gastroenteritis: If severe, the patient has signs of dehydration.
• Adenoviral infections in immunocompromised hosts: Features include dyspnea, dry cough, pulmonary rhonchi and rales, grossly bloody urine, and diarrhea.

DIFFERENTIALS

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Other Problems to be Considered

Allergic conjunctivitis
Bronchiolitis
Glaucoma
Measles
Respiratory Syncytial Virus Infection
Scleritis
Tracheobronchitis
Uveitis
Whooping cough

WORKUP

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Lab Studies

• Adenovirus is stable in routine viral transport medium, including specimens of nasopharyngeal, rectal, and corneal secretions; urine; and unfixed biopsy tissue. Detection is enhanced if specimens are taken as early in the clinical course as possible and promptly shipped cold or frozen to the appropriate laboratory.
• Many adenovirus serotypes can be isolated in cell culture lines commonly used in diagnostic virology laboratories; however, others fail to grow. Primary human embryonic kidney cells support growth of many fastidious adenovirus serotypes, but their additional cost may be prohibitive in some settings. Adeno-associated virus has also been known to contaminate this cell line. Other cell lines may not support the growth of ocular strains well, may be less sensitive, or may not be maintainable to support slower-growing strains.
• Seroreactivity to adenovirus is common. By age 4 years, approximately half of all children have positive adenovirus titers. As a result, serology is less useful in the acute clinical setting. If a serologic diagnosis is pursued, serum should be obtained as early as possible in the clinical course, followed by a second titer 2-4 weeks later. A 4-fold rise in acute titers to convalescent titers is diagnostic.
• Indirect immunofluorescence assays may be used for direct examination of tissue specimens.
• Polymerase chain reaction and other rapid molecular diagnostic assays in the management of infection in immunosuppressed persons are in the process of investigation,^{15, 16} and a standard approach has not yet been validated. Serial quantitative polymerase chain reaction seems promising, particularly in pediatric transplantation patients, in whom a rise in viremia has been documented in cases of fatal adenoviral sepsis.¹⁷
• Serotyping is generally in the domain of epidemiology and research and is not typically used in clinical practice. However, as specific syndromes are associated with specific serotypes and as molecular methods advance to allow rapid detection and typing, these assays may become clinically useful.
• Certain serotypes of enteric adenovirus have been seen in stool specimens using electron microscopy, but they have been difficult to isolate in routine tissue culture. These types have been referred to as noncultivatable enteric adenoviruses. Adenovirus has been identified using electron microscopy and immunohistochemistry techniques. The isolation of enteric adenovirus infection in recipients of small bowel transplants in whom allograft damage is a risk may warrant stool cultures or biopsy.
• The following laboratory studies are suggested in the given syndromes, both to diagnose adenoviral infections and to evaluate for other diagnoses in the differential of each syndrome.
• • Acute respiratory disease
  • • Nasopharyngeal swab for culture of respiratory viruses (eg, influenza virus, adenovirus) is suggested.
    • Consider Monospot assay or respiratory syncytial virus culture for Epstein-Barr virus and respiratory syncytial virus.
    • Consider rapid group A Streptococcus throat swab and culture.
  • Pharyngoconjunctival fever
  • • Nasopharyngeal swab for culture of respiratory viruses (eg, influenza virus, adenovirus) is suggested.
    • Consider Monospot assay or respiratory syncytial virus culture for Epstein-Barr virus and respiratory syncytial virus.
    • Consider rapid group A Streptococcus throat swab and culture.
  • Epidemic keratoconjunctivitis: Viral and bacterial swab cultures of conjunctival secretions and scrapings are suggested.
  • Acute hemorrhagic cystitis or nephritis: Urinalysis and cultures for bacterial and viral pathogens are suggested.
  • Gastroenteritis: Consider stool Wright stain, ova and parasites examination, culture for bacterial enteric pathogens, rotavirus assay, and Clostridium difficile toxin assay.

Imaging Studies

• Pneumonia: Plain radiography or CT scanning demonstrates typically diffuse and reticulonodular infiltrates; however, findings may be lobar.
• Hepatitis: Liver ultrasonography may be helpful to exclude obstructive causes of transaminitis or hyperbilirubinemia.
• Nephritis: Renal ultrasonography is helpful to exclude obstructive causes of renal insufficiency or renal swelling that may indicate infection.

Other Tests

• Urine cytology should be considered to exclude other causes hemorrhagic cystitis does not resolve within 5 days.

Procedures

• Biopsy may be considered in the setting of pneumonia, hepatitis, nephritis, enteritis, or other suspected end-organ involvement in immunocompromised patients, particularly in transplant recipients. Histology, molecular detection, and immunohistochemical staining may be the only means of definitive diagnosis.

Histologic Findings

• Pneumonia: Obliterative bronchiolitis is seen; viral intranuclear and intracytoplasmic inclusions with positive immunohistochemical staining specific for adenovirus are noted.
• Enteritis: Denudation of the gastrointestinal mucosa with edema may be seen. Also, acute and chronic inflammatory infiltrate involving the full thickness of the bowel wall may be noted. Viral intranuclear and intracytoplasmic inclusions with positive immunohistochemical staining specific for adenovirus are noted within infected cells.
• Hepatitis: Viral intranuclear and intracytoplasmic inclusions with positive immunohistochemical staining specific for adenovirus are noted within infected cells.
• Nephritis: Viral intranuclear and intracytoplasmic inclusions with positive immunohistochemical staining specific for adenovirus are noted within infected cells. Tubular epithelium is typically involved until late; extension may occur thereafter to the Bowman capsule and the glomerulus.

TREATMENT

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Medical Care

Currently, specific therapy for adenovirus infection, other than supportive and symptomatic treatment, remains a matter of debate.

• Several case reports of successes with ribavirin therapy have been cited for serious adenoviral disease in immunocompromised patients; however, the number of failed treatments that have not been reported remains uncertain.
• • Attempts to shed light on this issue have included retrospective reviews of adenoviral disease in recipients of bone marrow transplants.¹⁸ 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.^{19, 20, 21} Cidofovir treatment resulted in complete clinical resolution in 56 of 57 pediatric recipients of hematopoietic stem cell transplants in whom the virus became undetectable, without dose-limited nephrotoxicity.²²
  • Engraftment or recovery of T-cell–specific immunity has been suggested as vital to recovery from pulmonary or disseminated infection, regardless of antiviral therapy.²³ In one study involving children who underwent hematopoietic stem cell transplantation, all patients who died from adenoviral infection lacked specific T cells against adenovirus.²³
  • Clinical trials are warranted to determine the role and possible sequencing of ribavirin and cidofovir, as well as to document the adverse events that may be unique to specific transplantation populations.
• No available studies adequately address issues such as which syndromes are most likely to respond to treatment, which patients develop limiting hematologic toxicity from ribavirin or nephrotoxicity from cidofovir, or which patients, if any, may benefit from adjunctive therapy with leukocyte transfusions.
• • Certainly, given the increasing recognition of the impact of adenovirus infection in immunosuppressed persons, the increasing use of immune modulators and transplantation for various illnesses, and the attendant likely rise in the incidence of adenovirus infection, more attention will be paid to effective treatment.
  • Prospective controlled trials and the development of new antiviral agents must address the critical issue of treating adenoviral infections in immunocompromised patients.
  • Because successful outcomes and evidence of viremic control with antiviral therapy has been described, the benefits of treating individual patients should be carefully considered. The risks of serious morbidity and mortality related to adenoviral disease must also be weighed carefully against those related to its treatment.
  • No evidence-based guidelines for or against specific antiviral therapies in this setting are available, and treatment decisions should be individualized; current evidence somewhat favors treatment.
• Fortunately, most infections are self-limited in the setting of a normal immune response and do not warrant specific therapy.

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.

MEDICATION

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Medical therapy is not indicated in healthy hosts. However, adenoviral keratitis has been treated with early topical steroids to avoid loss of sight; refer to the available ophthalmologic literature for details on the management of adenoviral ophthalmologic infections.

Ribavirin and cidofovir therapy have been used with variable success in immunosuppressed hosts. Anecdotal evidence suggests success against adenoviral infection with combined intravenous ribavirin and pooled human intravenous immunoglobulin. Also anecdotally, intravesical cidofovir has been reported to be successful in persons with adenoviral hemorrhagic cystitis; the latter delivery method may obviate the systemic toxicity of this agent and warrants investigation.²⁴

Weighing the severity of illness, the likelihood of response in a given setting, and the possibility of adverse events, decisions regarding treatment should be individualized at this time. Evidence-based standardized treatment guidelines currently are lacking, and consultation with an infectious diseases clinician is recommended.

Drug Category: Antivirals

These agents inhibit viral DNA and protein synthesis.

FOLLOW-UP

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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.

Further Outpatient Care

• 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.

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.

Deterrence/Prevention

• 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. 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. 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.^{25, 6}
• 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.^{6, 26}
• 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. Women traditionally had not been offered vaccination because of the lack of documented epidemics in women-only training programs; this outbreak illustrated the risk of significant ARD in female recruits entering sex-integrated basic combat-training programs. The ranks of women in the military continue to climb, and vaccination strategies will need to incorporate the evolving epidemiology.²⁷
• Effective isolation procedures, handwashing, and sterilization of instruments can prevent nosocomial infection.
• • 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 handwashing protocols should be emphasized, particularly in ophthalmologic care settings.
  • 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.
• Adequate chlorination of swimming pools may prevent waterborne outbreaks.

Complications

• Meningoencephalitis rarely occurs, usually in association with pneumonia. No pathognomonic features distinguish adenovirus aseptic meningitis or meningoencephalitis from other causes.
• Immunosuppression in the host permits more severe manifestations. Pediatric liver transplantation, AIDS, and hematopoietic stem cell transplantation have been associated with protean adenovirus infections.

Prognosis

• Overall, prognosis is good, except in cases of immunosuppressed patients with severe disease.

Patient Education

• Frequent handwashing and avoidance of towel and pillow sharing among household contacts of patients with conjunctivitis is helpful.
• Hygienic measures in children are difficult to enforce, but they should be taught regardless.
• Patients should be advised of the contagiousness and possible long-term ocular sequelae of ophthalmologic disease.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to recognize severe keratitis with bacterial superinfection requiring hospitalization (ie, possible loss of vision or loss of eye)
• Failure to recognize central nervous system or pulmonary disease that requires supportive care in the hospital
• Failure to carefully monitor progression in immunosuppressed patients

MULTIMEDIA

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Media file 1:  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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Media type:  Image

Media file 2:  Transmission electron micrograph of adenovirus. Image courtesy of the US Centers for Disease Control and Prevention.
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REFERENCES

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Article Last Updated: Dec 3, 2007