Adenovirus

Background

Adenovirus, a DNA virus, 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.

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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_Vi....

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 52 serotypes, adenovirus is recognized as the etiologic agent of various 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 are asymptomatic. 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, who were routinely immunized against types 4 and 7 from 1971 until the cessation of vaccine production in 1996. Adenovirus became a significant cause of economic cost and morbidity in this setting. A live oral vaccine against adenovirus types 4 and 7 was approved for use in this population by the US Food and Drug Administration (FDA) in 2011, and subsequent incidence of acute respiratory disease declined.

Of interest is the role of adenoviruses as vectors in vaccination and in gene therapy.^{[1, 2, 3]} 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 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. However, the greatest challenge in viral gene therapy, as might be expected, is the immune response to the viral vector itself.

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.

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Pathophysiology

Adenovirus is a double-stranded DNA virus that measures 70-90 nm and that has an icosahedral capsid.

The site of entry generally determines the site of infection; respiratory tract infection infections result from droplet inhalation, while gastrointestinal tract involvement results from fecal-oral transmission. Upon infection with adenovirus, one of three 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 cytolysis, cytokine production, and induction of host inflammatory response.

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 has been observed in rats. During oncogenesis, the replication cycle is truncated, and adenoviral DNA is then integrated into the 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.

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Epidemiology

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 crowded 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 prompted reinvestigation of vaccine production. Live oral adenovirus types 4 and 7 vaccine was approved by the FDA in 2011, significantly decreasing and the incidence of febrile respiratory illness. Notably, co-infection with non-vaccine strains (B1 and E) have developed following vaccination,^[4] and surveillance for emerging non-vaccine strains is still needed.

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

Mortality/Morbidity

Severe morbidity and mortality associated with adenovirus infections are rare in immunocompetent hosts. Uncommon complications that increase the risk of mortality include meningoencephalitis and pneumonitis.

Severe adenovirus infections have been reported in immunocompromised patients, such as transplant patients and those with inherited and acquired immunodeficiency states. Mortality rates associated with adenovirus infections among pediatric and adult transplant recipients have varied from 6%-70%.^[5]

Morbidity and deaths due to pronounced host inflammatory responses have occurred in past gene vector trials.

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.^{[6, 7]}

Race

No racial predilection has been described.

Sex

Adenovirus urinary tract infections are more common in males. 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 in the case of military trainees.

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Prognosis

The prognosis of adenovirus infection is generally good in immunocompetent hosts, but mortality rates may be as high as 70% in immunocompromised individuals.

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Patient Education

Frequent hand hygiene with soap and water or sanitizers that specify coverage of adenoviruses 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.

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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 include (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. The reader is encouraged to review the literature for more detail regarding infection in specific settings.

Acute respiratory disease (predominantly adenovirus types 1, 2, 4, 5, and 6; occasionally, 3 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.

Fever, rhinorrhea, cough, and sore throat, usually lasting 3-5 days, are typical symptoms of adenoviral ARD. Causes of sore throat may include pharyngitis, adenoiditis, or tonsillitis. Tonsillitis and otitis media were reported in up to 60% and 30%, respectively in a series of young children with serotype 4 predominance. Prolonged fevers, leukocytosis, and elevations in C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were also noted in over half of cases, suggesting potential for confusion of this viral syndrome with bacterial infections.^[8]

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 and has been associated with serotypes 3, 7, 14, 21, and 30.^[9]

Encephalitis, hepatitis, and myocarditis are uncommon.

From the 1950s to 1971 (prevaccine era), adenoviruses accounted for significant acute disease in 70% of military recruits. Adenovirus serotypes 4 and 7 were primarily involved. A live enteric-coated oral vaccine against these serotypes was introduced in 1971 and reduced adenovirus-related respiratory illness by more than 95% in recruits and thus attenuated outbreaks. Vaccine production ceased in 1996 for economic reasons, and vaccination administration was limited to high-risk 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 Ad14. Outbreaks in basic trainees declined with the reintroduction of live oral enteric-coated adenovirus vaccine against types 4 and 7.^{[10, 11]}

Adenovirus serotype 14

Ad14, referred to as the "super cold" in the media, has caused rare outbreaks of ARD since 1955.

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 were reported at Lackland, three other Texas military bases, and one eye culture in a civilian unassociated with the military. 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.^{[12, 13]}

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.

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.

Acute conjunctivitis may occur with or without pharyngitis or a respiratory syndrome. Encephalitis may occur but is rare.

Conjunctivitis usually begins in one eye and 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 days).

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.^[14] Corneal trauma facilitates infection.

After an 8-day incubation period, an insidious onset of unilateral red eye occurs, spreading 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) or 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 hematopoietic stem cell recipients.

Nephritis has occurred in recipients of hematopoietic stem cell transplants and is associated with fever, hematuria, and flank pain.^{[15, 16]}

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 less common 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.^[17] 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 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.

Fever and watery diarrhea are usually limited to 1-2 weeks.

Mesenteric adenitis and intussusception have been associated with nonenteric adenovirus serotypes (ie, types 1, 2, 3, 5, 6). 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.

Adenoviral infections in immunocompromised hosts (multiple serotypes)

Adenovirus is 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 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.^{[18, 5]}

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.^[19]

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.^[18] Adenoviral infection following pediatric lung transplantation has been reported.^[20]

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.

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Physical

Acute respiratory disease

Exudative pharyngitis and conjunctivitis may be seen.

Pulmonary rhonchi and rales may be found on auscultation.

Pharyngoconjunctival fever

Fever, coryza, pharyngitis (may be exudative), follicles in bulbar, and/or palpebral conjunctivae (typically mild granular appearance) may be observed.

Cervical lymphadenopathy may be seen.

Preauricular lymphadenopathy (ie, Parinaud syndrome), with small lymph nodes palpable just anterior to the ear is not common; however, its presence in the setting of a viral conjunctivitis is very suggestive of adenovirus infection.

Epidemic keratoconjunctivitis

Severe follicular keratoconjunctivitis has been reported (conjunctiva may be granular). Hemorrhagic conjunctivitis develops in some cases.

Palpebral edema is a finding.

Preauricular lymphadenopathy is not common but is a pathognomonic finding with adenovirus infection.

Visual haziness or impairment resulting from keratitis or corneal involvement may develop 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. Fever is generally absent.

Flank pain and fever are seen in nephritis.

Gastroenteritis

Patients with severe gastroenteritis may have signs of dehydration.

Adenoviral infections in immunocompromised hosts

Features include dyspnea, dry cough, pulmonary rhonchi and rales, grossly bloody urine, and diarrhea.

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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.

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Laboratory Studies

Culture

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 collected early in the clinical course 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; a few, such as types 40 and 41, 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. 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.

Serology

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.

Antigen tests

Indirect immunofluorescence assays may be used for direct examination of tissue specimens.

Polymerase chain reaction

Polymerase chain reaction (PCR) is being used with high specificity on various specimens (eg, respiratory, tissue, urine, blood) to identify adenovirus.^{[5, 21]} ​

Serotyping

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, tests can be performed in a reference laboratory.

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.

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Transmission electron micrograph of adenovirus. Image courtesy of the US Centers for Disease Control and Prevention.

Syndrome-specific testing

The following laboratory studies are suggested in the given syndromes, both to diagnose adenoviral infections and to evaluate for other diagnoses in the differential diagnoses of each syndrome.

Acute respiratory disease

Nasopharyngeal swab for culture of respiratory viruses (eg, influenza virus, adenovirus, respiratory syncytial virus, rhinovirus) is suggested.

Consider Monospot assay for Epstein-Barr 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.

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; assays for norovirus, rotavirus, and Cyclospora; and Clostridium difficile toxin assay.

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Imaging Studies

Pneumonia

Plain radiography or CT scanning demonstrates typically diffuse and reticulonodular infiltrates. High-resolution CT scanning may show "crazy-paving" patterns in immunocompromised patients.^[22] Occasionally, findings are 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.

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Other Tests

Urine cytology

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

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Procedures

Biopsy

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.

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Histologic Findings

Pneumonia

Obliterative bronchiolitis is seen; viral intranuclear and intracytoplasmic inclusions with positive immunohistochemical staining specific for adenovirus are noted. The intranuclear inclusions during late infection are surrounded by a clear halo, which may obstruct visualization of the nuclear membrane, resulting in a smudged appearance. These "smudged" cells are classically seen in adenovirus infection.

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.

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Medical Care

Currently, 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.^[23] In cases involving severe disease, such as adenoviral pneumonia after lung transplantation, cidofovir has been used successfully.^[24]

The management and prevention of severe adenovirus-related disease in hematologic stem cell transplantation (HSCT) is of particular importance and continues to evolve. There are as yet no evidence-based guidelines for or against specific antiviral therapies in this setting. Reduction of immunosuppression is not always feasible during the first 100 days post-transplantation, during which the risk is highest.

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.^[25] In one study involving children who underwent hematopoietic stem cell transplantation, all patients who died of adenoviral infection lacked specific T cells against adenovirus.^[25] 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.^{[26, 27, 28, 29]}

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.^{[30, 31, 32, 33]} 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.^[34] Intravenous immunoglobulin (IVIG) has also been used in conjunction with antivirals.^{[35, 36]}

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.^{[37, 38, 39]}

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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.

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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.^[40] 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.^[41] 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.^{[10, 42]}

Isolation procedures, handwashing, and sterilization of instruments

Effective isolation procedures, handwashing, and sterilization of instruments can prevent nosocomial infection.^[43]

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 chlorine is virucidal at a concentration of 2 parts per million (ppm).

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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.

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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.

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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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Medication Summary

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.^[44]

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.

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Ribavirin (Virazole)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits viral replication by inhibiting DNA and RNA synthesis. Antiviral against RSV, influenza virus, herpes simplex virus, and hepatitis C virus. The latter requires adjunctive treatment with interferons.

The likelihood that most adenovirus infections in immunosuppressed hosts are disseminated warrants intravenous rather than inhalational therapy, including in the setting of adenoviral pneumonia.

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Cidofovir (Vistide)

• Dosing, Interactions, etc.

Clinical Context:  Nucleotide analog that selectively inhibits viral DNA production in CMV and other herpes viruses. Indicated for CMV retinitis.

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Class Summary

These agents inhibit viral DNA and protein synthesis.

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Adenovirus vaccine types 4 and 7 live, oral

Clinical Context:  Live oral vaccine that replicates in intestinal tract and induces immunity in persons with low or no preexisting neutralizing antibodies to adenoviruses types 4 and 7. Indicated for active immunization of military populations aged 17-50 y for prevention of febrile acute respiratory disease caused by adenovirus types 4 and 7.

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Class Summary

Decreases incidence of adenovirus outbreaks in military personnel.

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