Adenoviruses

James D. Cherry

Adenoviruses cause a diverse array of diseases in children, most commonly respiratory and gastrointestinal illnesses. Certain clinical manifestations of adenovirus infections are distinctive, although most illnesses are difficult to differentiate from those caused by other viral and bacterial pathogens.

ETIOLOGY

Adenoviruses are DNA viruses; 49 types are known to infect humans. Six subgroups are defined based on biochemical and biophysical criteria. Adenoviruses can be grown in tissue culture cell preparations of human epithelial origin. Exceptions are enteric adenovirus types 40 and 41, which were identified by electron microscopy and grow in Graham 293 cells and the PLC/PRF/5 cell line. Infected tissue cultures have a characteristic cytopathic effect in 1 day to 4 weeks.

EPIDEMIOLOGY

Adenoviral infections occur throughout the world. In temperate climates, sporadic disease occurs year round; epidemic disease commonly occurs in winter, spring, and early summer. Seasonal variation with adenoviral gastroenteritis has not been described.

Transplacental antibody appears to be protective in early infancy. However, when adenoviral infection occurs in the neonate, severe and rarely fatal pulmonary or multiorgan system diseases may occur. Adenoviral infections in children commonly are caused by types 1, 2, 3, and 5. Types 6 and 7 occur slightly less frequently. The incidence of adenoviral infection peaks in children between ages 6 months and 5 years. An increased susceptibility to adenoviruses is reported in neonates and small infants, in immunocompromised patients, and occasionally in male subjects.

The transmission of adenoviruses occurs through small droplets or the fecal-oral route and is facilitated by closed environments. Contaminated swimming pool water has been implicated in the spread of pharyngoconjunctival fever. The incubation period of adenoviruses is between 3 and 7 days. Viruses may be shed from the respiratory tract up to 2 days before and 5 days after clinical symptoms develop. Viruses may be found in the stool for several months. Adenoviruses commonly are isolated from the throat, conjunctiva, and stool.

PATHOGENESIS

The characteristics of adenoviral infections vary with the infecting serotype and the immune status of the host. Infection usually involves the upper respiratory tract and the conjunctivae. Spread to the lower respiratory tract may occur by progression or viremia. Rashes and multiorgan infections also may result from viremia. Swallowed virus is thought to cause gastrointestinal infection. Pathologic changes that occur in self-limited respiratory infections are not well studied. Autopsy material from lethal infections has revealed necrotizing bronchitis, bronchiolitis and pneumonia, focal hepatic necrosis, and cerebral edema with perivascular lymphocytic infiltrates. Characteristic small eosinophilic and larger basophilic intranuclear inclusions are seen in all infected tissues. Severe illnesses with manifestations of septic shock are associated with elevated serum levels of tumor necrosis factor–alpha, interleukin-6, and interleukin-8.

In humans, adenoviruses can cause lytic and latent infections. Oncogenic cell transformation is reported in animals but not in humans.

CLINICAL MANIFESTATIONS AND COMPLICATIONS

Respiratory Infections

Serologic surveys indicate that 10% of respiratory infections in children are caused by adenoviruses (Table 187.1). Rarely, adenoviruses cause common colds. Usually, respiratory infections with adenoviruses are characterized by fever and pharyngitis. Symptoms that occur with acute adenoviral pharyngitis include malaise, headache, sore throat, cough, cervical adenopathy, abdominal pain, and coryza, especially in the young. Pharyngeal exudates may be thin and spotty or thick and membranous. Laryngotracheitis, bronchitis, pneumonia, and rarely, bronchiolitis may occur concomitantly with pharyngeal disease. Illness of 5 to 7 days’ duration occurs commonly, although symptoms may persist for 2 weeks.

TABLE 187.1. CLINICAL MANIFESTATIONS OF ADENOVIRAL INFECTIONS BY SEROTYPE AND FREQUENCY

System/Organ	Illness Category	Frequency	Adenoviral Types
Respiratory	Common cold	Rare	1, 2, 3, 5, 7
	Nasopharyngitis, pharyngitis, and tonsillitis*	Common	1^‡, 2^‡, 3^‡, 4, 5^‡, 7^‡, 7a, 14, 15 (21/H21 + 35)^‡
	Acute respiratory disease*	Very common	2, 3, 4^‡, 5, 7^‡, 8, 11, 14, 21
	Acute laryngotracheitis	Occasional	1, 2, 3, 5, 6, 7
	Acute bronchiolitis	Occasional	3, 7, 21
	Pneumonia (civilian population)*	Common	1, 2, 3^‡, 4, 5, 7^‡, 7a^‡, 8, 11, 21^‡, (21/H21 + 35)^‡, 35
	Atypical pneumonia in military recruits*	Common	4^‡, 7^‡, 21
	Pertussis-like syndrome	Rare	1, 2, 3, 5, 12, 19
	Bronchiolitis obliterans	Rare	7, 21
	Unilateral hyperlucent lung	Rare	7, 21
Eye	Acute follicular conjunctivitis*	Common	1, 2, 3, 4, 6, 7, 9, 10, 11, 15, 16, 17, 19, 20, 22, 34, 37
	Pharyngoconjunctival fever*	Common	1, 2^‡, 3^‡, 4^‡, 5, 6, 7^‡, 7a^‡, 8, 14^‡, 37
	Epidemic keratoconjunctivitis*	Occasional	2, 3, 4, 5, 7, 8^‡, 10, 11, 13, 14, 15, 16, 17, 19, 23, 29, 37
Skin	Morbilliform and rubelliform exanthem	Occasional	3, 4, 7, 7a
	Roseola-like	Occasional	1, 2
	Stevens-Johnson syndrome	Rare	7
	Petechial exanthem	Rare	7
Genitourinary	Acute hemorrhagic cystitis	Rare	7, 11, 21
	Nephritis	Rare	3, 4, 7a
	Orchitis	Rare	Unknown
	Oculogenital syndrome*	Rare	19, 37
Gastrointestinal	Gastroenteritis*	Common	1, 2, 3^‡, 5, 7^‡, 11, 12, 15, 17, 31^‡, 32, 33, 40^‡, 41^‡
	Mesenteric lymphadenitis	Rare	1, 2, 3, 5, 7
	Intussusception	Rare	1, 2, 3, 5, 6, 7
	Appendicitis	Rare	1, 2, 7
	Hepatitis	Rare	1, 2, 3, 5^‡, 7 (11 + 35/H11 + 35)^‡
Heart	Myocarditis	Rare	7, 7a, 21
Heart	Pericarditis	Rare	7
Neurologic	Encephalitis and meningitis	Rare	1, 2, 3, 5, 6, 7, 11, 12, 32
Joint	Arthritis	Rare	7
Auditory	Deafness	Rare	3
Endocrine	Thyroiditis	Rare	Unknown
* Occurs in outbreaks. ^† Most common. ^‡ Intermediate strain.