eMedicine Specialties > Infectious Diseases > Viral Infections

Adenoviruses

Author: Sandra G Gompf, MD, FACP, FIDSA, Associate Professor of Infectious Diseases and International Medicine, University of South Florida College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley Veterans Hospital
Coauthor(s): Dhanashree Kelkar, MD, Fellow, Department of Infectious Diseases and International Medicine, University of South Florida College of Medicine; Richard L Oehler, MD, FACP, Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases and Tropical Medicine, Univ of South Florida College of Medicine; Assistant Epidemiologist, Division of Infectious Diseases, Tampa VA Medical Center
Contributor Information and Disclosures

Updated: Feb 12, 2010

Introduction

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.

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, is a significant cause of economic cost and morbidity because of the cessation of vaccine production in 1996.

Of most recent 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.

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. 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. 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 with military trainees.

Clinical

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; 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 adenovirus types 1, 2, 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.
  • 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 30.⁸
  • 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.^9,10
  • 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.^11,12
• 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 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.¹³ 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)/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.^14,15
• 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.¹⁶ 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 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 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.^17,5
  • 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.¹⁸
  • 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.¹⁷ Adenoviral infection following pediatric lung transplantation has been reported.¹⁹
  • 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
  • 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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