Current Diagnosis & Treatment in Infectious Diseases

Section IV - Viral Infections

32. Adenoviruses

Lawrence W. Drew MD, PhD

Essentials of Diagnosis

  • Respiratory symptoms (plus conjunctivitis).
  • Disseminated infection in immunocompromised patients.
  • Intranuclear inclusions in infected epithelial cells;
  • Growth in tissue culture, especially in human embryonic epithelial cells (eg, kidney, lung).
  • Antigen detection in clinical samples (eg, respiratory by immunofluorescence).
  • Detection of antibody to the adenovirus group antigen by several different assays (eg, complement fixation, hemagglutination inhibition).

General Considerations

Adenoviruses were first isolated in 1953 in human adenoid cell culture. Since then approximately 100 serotypes, at least 47 of which infect humans, have been recognized. All human serotypes are included in a single genus within the family Adenoviridae. Based on homology studies and hemagglutination patterns, each of the 47 serotypes belongs to one of six subgroups. Disorders caused by the adenoviruses include respiratory tract infection, conjunctivitis, hemorrhagic cystitis, and gastroenteritis.

  1. Epidemiology

From 5% to 10% of pediatric respiratory disease can be attributed to adenoviruses. Adenoviruses spread by either respiratory or fecal-oral contact but have been cultured from semen and may also be spread by sexual transmission. Adenoviruses may be shed intermittently from the pharynx and especially in the feces. Most infections are asymptomatic, which greatly facilitates their spread in the community.

Infections with serotypes 1, 2, and 5 are very common in children under 2 years of age and may occur as outbreaks especially in older children. Adenoviruses serotypes 4 and 7 seem especially able to spread and cause outbreaks among military recruits owing to very close, crowded living conditions. Outbreaks of swimming pool conjunctivitis have resulted from inadequate chlorination and the low antibody prevalence to these serotypes in children and young adults.

  1. Microbiology

Adenoviruses are double-stranded DNA viruses with a genome molecular weight of 20 × 106 to 25 × 106 daltons. The core complex within the capsid includes viral DNA and at least two major proteins. In addition there are nine structural proteins.

The virions are nonenveloped icosahedrons with a diameter of 70–90 nm. Projections, or fibers, originate from each of the 12 vertices of the protein capsid. The capsid is composed of 240 capsomeres, which consist of hexons and pentons.

Replication of adenoviruses has been studied extensively in HeLa cell culture. One virus cycle takes ~32–36 h and produces 10,000 virions. The replicative cycle is divided into several stages: attachment, penetration, uncoating, and early and late events. Attachment is probably mediated by the viral fiber protein and a receptor on the host cell membrane. There are approximately 100,000 fiber receptors per cell. The virus enters the cell by endocytosis and is uncoated in the cytoplasm, with subsequent replication in the nucleus. This entire process requires 2 h. Early transcriptional events, after shutdown of host cell macromolecular synthesis, lead to gene products involved in viral DNA replication and cell transformation.

Viral DNA replication in the nucleus signals the beginning of the late phase. In addition, late transcripts encode viral structural proteins at a maximum rate 20 h after infection. Virion capsomeres are produced in the cytoplasm and then transported to the nucleus for viral assembly. DNA possibly enters the capsid through an opening at one of the vertices. The mature particle is stable and infectious. Infected host cells release the virus upon degeneration and cell disruption.

  1. Pathogenesis

Adenoviruses infect epithelial cells lining respiratory and enteric organs. After local replication, viremia may occur with spread to visceral organs. This dissemination is more likely to occur in immunocompromised patients. Variations in target cell specificity among adenovirus serotypes result from differences in viral attachment proteins. The virus has a propensity to become latent in lymphoid tissue, such as adenoids, tonsils, or Peyer's patches, and can be reactivated by immunosuppression.

The histologic hallmark of adenovirus infection is a dense central intranuclear inclusion within an infected epithelial cell. Superficially, this inclusion may resemble those seen in cytomegalovirus infection, but one distinguishing feature is the absence of cellular enlargement (cytomegaly) in adenovirus-infected cells. These inclusions are concentrations of viral DNA and protein. In addition to inclusions, adenovirus infections are characterized by mononuclear cell infiltrates and epithelial cell necrosis. Type-specific neutralizing antibody is associated with protection from reinfection.

CLINICAL SYNDROMES

Adenoviruses cause primary infection in children and, less commonly, adults. Reactivation of virus occurs in immunocompromised children and adults. Several distinct clinical syndromes are associated with adenovirus infection (Box 32-1).

ACUTE RESPIRATORY DISEASE

  1. Signs and Symptoms.Acute pharyngitis is usually nonexudative but is associated with fever. Acute respiratory disease is a syndrome of fever, cough, pharyngitis, and cervical adenitis seen primarily in outbreaks among military recruits usually with serotypes 4 and 7. Adenoviruses are definite but infrequent causes of true viral pneumonia in both children and adults including military recruits. Laryngitis, croup, and bronchiolitis may also occur. Pertussis-like illness with a prolonged clinical course has been associated with adenoviruses. Adenovirus conjunctivitis may occur concurrently with acute respiratory disease and may be the clue to an adenovirus etiology.
  2. Laboratory Findings.The blood leukocyte count is normal as is the rest of the complete blood count and blood chemistry assays.
  3. Imaging

In patients with clinical evidence of pneumonia, chest x-ray may reveal scattered interstitial infiltrates, usually in the lower lung fields.

  1. Differential Diagnosis.Influenzal and other viral pneumonias, as well as nonbacterial pneumonias, eg, mycoplasma and chlamydial, are the major components of the differential diagnosis. Influenzal pneumonia has a pronounced seasonal epidemiology, but adenovirus does not.

BOX 32-1 Adenovirus Infection

 

Children

Adults

More common

· Upper respiratory infection

· Pharyngitis

· Conjunctivitis

· Acute respiratory disease

· Conjunctivitis

Less common

· Hemorrhagic cystitis

· Pneumonia

· Diarrhea

· Pertussislike illness

· Systemic infection in immunocompromised patients

· Pneumonia

CONJUNCTIVITIS

  1. Signs and Symptoms.Adenoviruses cause a follicular conjunctivitis in which the mucosa of the palpebral conjunctiva becomes pebbled or nodular, while both conjunctivae (palpebral and bulbar) become inflamed. Conjunctivitis may occur sporadically or in outbreaks that can be traced to a common source, eg, swimming pools. Corneal involvement may occur with mechanical irritation of the eye and is most striking when it spreads in epidemic form, eg, shipyard conjunctivitis, also described as epidemic keratoconjunctivitis.
  2. Differential Diagnosis.Adenovirus conjunctivitis is frequently bilateral and has a granular or follicular appearance. C trachomatisconjunctivitis is similar but is more severe in the bulbar conjunctiva than is adenovirus. Coexisting acute respiratory disease suggests adenovirus, as does preauricular adenopathy.
  3. Complications

Keratitis may develop as the conjunctivitis subsides and may persist for months.

ACUTE GASTROENTERITIS

  1. Signs and Symptoms.Adenovirus serotypes 40 and 41, which are very difficult to isolate in tissue culture, appear to be responsible for episodes of diarrhea in infants.
  2. Laboratory Findings.Adenovirus does not cause an acute inflammatory response. Polymorphonuclear leukocytes are not present in stool smears and are not increased in peripheral blood counts.
  3. Complications

Although mesenteric adenitis and intussusception may be complications of adenovirus infections, these associations remain unproven.

Table 32-1. Clinical syndromes associated with adenoviruses.1

Clinical Syndrome

Virus Serotypes

Patient Group

Acute febrile pharyngitis

1, 2, 3, 4, 5, 7a

Young children

Pharyngo conjuntival fever

5a

Older children

Acute respiratory disease including fever, cough pharyngitis, cervical adenitis, and skin rash

2, 3, 4, 5, 7, 8, 11, 14, 21

Military recruits

Conjunctivitis

3, 7, 8, 9, 19

Children and adults

Acute gastroenteritis

40, 41

Infants

Acute hemorrhagic cystitis

11, 21

Young children

Systemic infection in immunocompromised patients

1, 2, 4, 5, 6, 7, 7a, 11, 31, 32, 34, 35

Children and adults

1Highlighted serotypes are especially associated with disease states.

 

ACUTE HEMORRHAGIC CYSTITIS

  1. Signs and Symptoms.Acute hemorrhagic cystitis with dysuria and hematuria is associated with serotypes 11 and 21. This condition occurs predominantly in young boys with blood in urine persisting for an average of 3 days. The associated dysuria and frequency persist for an additional several days.
  2. Laboratory Findings.Gross and, subsequently, microscopic hematuria is present for several days.
  3. Imaging

No renal or bladder abnormalities are present in x-rays.

  1. Differential Diagnosis.Other causes of hematuria include bacterial cystitis, stones, or tumors, but an acute self-limited illness suggestive of urinary tract infection is compatible with adenovirus infection, especially in young boys.

SYSTEMIC INFECTION IN IMMUNOCOMPROMISED PATIENTS

Immunocompromised patients (especially transplant recipients) are at risk of serious adenovirus infections, although not as often as from infections caused by the herpes viruses. Diseases include pneumonia and hepatitis as well as disseminated disease. These illnesses are severe and may be fatal. Infection appears to be from exogenous or endogenous (reactivation) sources. In AIDS patients, adenoviruses appear to be responsible for gastrointestinal disease, as revealed by biopsy. Adenoviruses are also recovered from urine or semen of AIDS patients, but their significance is unknown. There is no known effective treatment for adenovirus infections in patients.

Diagnosis of Adenovirus Infection

Direct detection of adenovirus antigens by fluorescent antibody immunoassays have been used with partial success to rapidly identify adenovirus in clinical samples, such as those from the respiratory tract. Enzyme immunoassay and electron microscopy are used to identify enteric adenovirus serotypes 40 and 41, which do not grow in heteroploid cell cultures but may be responsible for infant diarrhea (Table 32-1). Characteristic intranuclear inclusions can be seen in infected tissue during histologic examination. Inclusions, however, are rare and must be distinguished from those resulting from cytomegalovirus.

Isolation of the virus is best accomplished in cell cultures derived from epithelial cells, for example, primary human embryonic kidney (HEK) cells or continuous (transformed) lines such as HeLa or human epidermal carcinoma (Hep-2) cells. Recovery in cell culture requires an average of 6 days. Isolation of adenovirus in culture has variable significance. If the isolate is from a site not frequently colonized by adenovirus, isolation may be diagnostic of the etiology (eg, recovery from conjunctiva, bloody urine, or viscera such as the lung). However, recovery from stool but not the respiratory tract of a patient with pharyngitis provides little diagnostic help. Adenoviruses may be shed in feces for weeks to months after infection. Isolation of adenovirus from the throat of a patient with pharyngitis is usually diagnostic, if laboratory findings eliminate other common etiologies such as Streptococcus pyogenes.

Complement fixation, hemagglutination inhibition, enzyme immunoassay, and neutralization techniques have been used to detect specific antibodies after adenovirus infection. A seroconversion between acute and convalescent serum specimens is necessary before the result can be considered diagnostic of active infection, although a fourfold or greater rise in titer may also be of diagnostic significance. Serologic diagnosis is rarely used except occasionally to confirm the significance of a fecal or upper respiratory isolate.

BOX 32-2 Control of Adenovirus Infection

Prophylactic measures

· Vaccine (military recruits)

Isolation precautions

· Respiratory, enteric

 

Prevention & Control

Live, oral enteric-coated vaccines have been used to prevent adenovirus 4 and 7 infections in military recruits, but they are not used in the civilian population (Box 32-2). Because the virus may be oncogenic, it is unlikely that live virus vaccines will be widely used. However, genetically engineered subunit vaccines could be prepared and used in the future.

REFERENCES

Fox JP, Hall CE, Cooney M: The Seattle Virus Watch. VII. Observations of adenovirus infections. Am J Epidemiol 1977;105:362. (The definitive study of adenovirus respiratory infection in civilians.).

Hierholzer JC: Adenoviruses in the immunocompromised host. Clin Microbiol Rev 1992;5:262.