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Adenoviruses: 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 1).

Adenoviruses: Clinical Syndromes

ACUTE RESPIRATORY DISEASE

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.

Adenoviruses: Clinical Syndromes

Laboratory Findings

The blood leukocyte count is normal as is the rest of the complete blood count and blood chemistry assays.

Adenoviruses: Clinical Syndromes

Imaging

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

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.

CONJUNCTIVITIS

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.

Differential Diagnosis

Adenovirus conjunctivitis is frequently bilateral and has a granular or follicular appearance. C trachomatis conjunctivitis is similar but is more severe in the bulbar conjunctiva than is adenovirus. Coexisting acute respiratory disease suggests adenovirus, as does preauricular adenopathy.

Complications

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

ACUTE GASTROENTERITIS

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.

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.

Complications

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

ACUTE HEMORRHAGIC CYSTITIS

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.

Laboratory Findings

Gross and, subsequently, microscopic hematuria is present for several days.

Imaging

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

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 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.

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 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.

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