Human Adenovirus Infections

Definition, Etiology, PathogenesisTop

1. Etiologic agent: Human adenoviruses belong to the family Adenoviridae and include >50 serotypes varying in tissue tropism, divided into 7 subgroups (species) designated A through G. They are nonenveloped and their genome is composed of a linear medium-sized (90-100 nm) nucleocapsid containing double-stranded DNA. Hemagglutinin spikes protruding from the icosahedral capsid bind to host cell receptors. Human adenoviruses efficiently replicate in epithelial cells and are insensitive to environmental factors and surfactants, but they can be destroyed by heat, formalin, and oxidizing agents (hypochlorites). Certain serotypes (eg, 12, 18, and 31) have oncogenic potential. In individuals with immunodeficiency, particularly those after allogeneic hematopoietic stem cell transplant (HSCT), adenoviruses can cause severe, diffuse infections including conjunctivitis as well a respiratory tract, intestinal, and urinary tract infections. The mortality rate for adenovirus pneumonia in such patients may exceed 50%.

Animal adenoviruses, which are typically unable to replicate in human cells, are used as DNA vectors for gene therapy and vaccines (eg, against coronavirus disease 2019 [COVID-19] and Ebola virus infection).

2. Reservoir and transmission: The only reservoir is humans. Sources of infection include symptomatic individuals and asymptomatic individuals with chronic infection. Human adenoviruses spread through direct contact, droplets, fecal–oral route, and indirect contact with contaminated objects (eg, clothing, toiletries, washbasins). Mucous membranes serve as the portal of entry for infection.

3. Risk factors for infection: Staying in crowded areas and in close-contact environments (nurseries, schools, large companies, military barracks). Adenovirus types 3 and 7, which cause the so-called swimming pool conjunctivitis, are highly contagious and likely spread through water. Conjunctivitis caused by human adenovirus type 8—called shipyard eye because of numerous cases reported among shipyard workers—has been partly due to the use of nonsterile ophthalmic equipment.

4. Incubation and contagious period: The incubation period ranges from 5 to 12 days. Shedding duration is 1 to 3 days in common cold in adults, 3 to 5 days in pharyngoconjunctival fever, 2 weeks in conjunctivitis with keratitis, 3 to 6 weeks in respiratory tract infections in children, and 2 to 12 months in persons with immunodeficiency. In the case of acute diarrhea, the contagious period typically persists for 6 to 16 days.

EpidemiologyTop

The epidemiology of human adenovirus infections varies geographically. The most frequently isolated human adenoviruses in immunocompetent individuals include those causing respiratory tract infections (types 1, 2, 3, 5, and 7) or gastrointestinal (GI) infections (types 40 and 41). Infections caused by types 1, 2, 5, and 6 occur mainly in the first years of life, and those due to types 3 and 7, at school age. Types 3, 4, and 7 are also responsible for epidemics among military recruits. Other types (eg, 4, 8, and 19) cause infections in adults. Human adenovirus type 11 may lead to severe respiratory tract infections, eg, in young adults under stress (Table 1).

Clinical Features and Natural HistoryTop

Clinical features of human adenovirus infection vary by individual. The infection may be accompanied by enlargement of regional lymph nodes. Severe infection can be caused by adenovirus types 5, 7, 14, and 21. A single serotype may trigger various clinical syndromes, and several types may cause the same manifestations (Table 2).

1. Respiratory tract infections:

1) Acute influenza-like illness mimicking respiratory tract infections caused by other viruses: Fever, rhinitis, sore throat, headache; often abdominal pain, conjunctivitis, laryngitis, and tracheitis; sometimes myalgia, bronchitis, and pneumonia. Infants and children are most frequently affected. The disease typically lasts 5 to 7 days, up to 2 weeks, and may also resemble croup or pertussis (human adenovirus 5). Bronchiolitis may occur occasionally. The infection may sporadically present as an afebrile common cold. Infections caused by human adenovirus types 3, 4, and 7 are observed in adolescents and adults.

2) Pharyngotonsillitis is usually accompanied by fever. Human adenoviruses are the most common cause of inflammation of the palatine tonsils in young children. The infection may manifest with white coating on the tonsils and cervical lymphadenopathy and should be differentiated from streptococcal pharyngitis.

3) Otitis media: Frequently seen in infants.

4) Pneumonia: Human adenoviruses account for 10% to 20% of cases of pneumonia in children. Pneumonia in newborns and infants may follow a severe course with pulmonary (bronchial necrosis, hyaline membrane disease) and extrapulmonary (neutropenia, sporadically cerebrospinal meningitis, hepatitis, myocarditis, nephritis, disseminated intravascular coagulation [DIC]) complications, and often leads to death.

5) Acute respiratory disease in military recruits: Human adenoviruses frequently cause acute respiratory diseases in young adults. Typical manifestations include fever, sore throat, nasal congestion, cough, and malaise. Pneumonia may sometimes develop. The disease most frequently affects young military recruits experiencing stress and fatigue, typically shortly after having been drafted into military service.

2. Eye infections: Human adenoviruses are the most frequent cause of viral conjunctivitis, mainly in those aged >12 years. The conjunctiva of a single eye or both eyes may be involved, and the disease may be accompanied by lymphadenopathy. Mild ocular involvement may occur in respiratory tract infection and in pharyngotonsillitis.

1) Epidemic adenoviral keratoconjunctivitis: The most severe, highly contagious type of adenoviral conjunctivitis; unilateral in two-thirds of cases. The disease occurs more often in the autumn and winter. Human adenoviruses can spread through washbasins and towels. The incubation period lasts 8 days. The disease manifests with conjunctivitis followed by keratitis, which usually resolves within 2 to 3 weeks but may be complicated by subepithelial infiltration, corneal opacity, and dry eye syndrome. Typical manifestations include eye redness, photophobia, epiphora, burning sensation in eyelid area and blepharospasm, and enlarged and tender preauricular lymph nodes.

2) Follicular conjunctivitis: Nonspecific, mild conjunctivitis, without corneal involvement, which resolves within 7 to 10 days.

3) Pharyngoconjunctival fever (fever accompanied by pharyngitis and conjunctivitis) most frequently occurs in children, typically in disease clusters (eg, swimming pool conjunctivitis during summer camps). Pharyngitis is accompanied by conjunctival folliculosis and cervical lymphadenopathy. Fever persists for ~10 days. Bilateral follicular conjunctivitis lasts 1 to 2 weeks and resolves without permanent sequelae.

4) Chronic conjunctivitis is characterized by periodic epiphora, photophobia, and eye redness; it typically follows acute conjunctivitis. The symptoms persist for up to 18 months.

3. GI diseases: Acute diarrhea. Human adenoviruses types 40 and 41, rarely 52, account for 5% to 15% of cases of acute viral GI infections in young children. The remaining types are often identified in feces but do not cause acute diarrhea.

4. Urogenital infections:

1) Acute hemorrhagic cystitis may be caused by human adenovirus types 11 and 21 in children, particularly boys as well as adults with immunodeficiency. The disease most often presents without fever and with normal arterial pressure, which distinguishes it from glomerulonephritis, and resolves spontaneously.

2) Acute urethritis in adults is sporadically caused by human adenovirus types 19 and 37.

3) Tubulointerstitial nephritis occurs in immunocompromised individuals.

5. Central nervous system (CNS) infections: Human adenoviruses (mainly types 3 and 7) sporadically cause meningitis or encephalitis. CNS involvement may be primary or accompany severe respiratory disease.

6. Infections in individuals with immunodeficiency: Human adenoviruses can cause various clinical syndromes ranging from asymptomatic viral transmission to severe, diffuse infections. In many transplant cases endogenous reinfection develops within the first months post transplant.

1) Individuals after organ transplant: Human adenoviruses usually attack the transplanted organ (eg, hemorrhagic cystitis and interstitial nephritis after renal transplant). Infection may result in dysfunction and rejection of the transplanted organ, most often the liver, kidney, and heart. Pneumonia, intestinal infection, or meningoencephalitis, as well as diffuse infection (defined as involving ≥2 organs) may also develop.

2) Individuals after HSCT: Most frequently severe respiratory tract infections, colitis, hepatitis, hemorrhagic cystitis, interstitial nephritis, and diffuse infections are observed.

3) Acquired immunodeficiency syndrome (AIDS): Human adenovirus infections are rare, usually involve the GI tract, and result in chronic diarrhea; they sporadically cause death due to encephalitis, pneumonia, or hepatitis.

DiagnosisTop

Diagnostic Tests

1. Identification of the etiologic agent:

1) Molecular studies to identify virus types based on DNA analysis.

2) Adenovirus culture.

3) Immunofluorescence or immunochromatographic test to detect virus antigens; high sensitivity within the first 5 days of infection, higher in children than in adults.

4) Serologic studies:

a) Complement fixation test to detect adenovirus antigens; low sensitivity.

b) Neutralization test or hemagglutination inhibition test to detect specific neutralizing antibodies against the virus.

c) Immunoenzymatic test or latex agglutination test to detect adenovirus antigens in feces.

The diagnostic modality of choice is molecular (polymerase chain reaction [PCR]); other methods include viral culture or antigen detection, which is less sensitive. Serologic diagnosis requires paired acute and convalescent sera and the demonstration of a 4-fold rise in antibodies. Specimens should be collected from infection sites at a possibly early disease stage. Depending on clinical manifestations, the virus can be isolated from pharyngeal, conjunctival, or anal swabs, feces, and urine. Virus isolation from specimens obtained from the eye, lungs, or birth canal are diagnostic for local infection at those sites. As human adenoviruses can persist in the intestines or lymphatic tissue for weeks, isolation from pharyngeal swab and feces should be interpreted with caution (except types 40 and 41 during acute diarrhea).

Diagnostic Criteria

Diagnosis is usually established based on clinical features and confirmed with laboratory workup. Pneumonia with conjunctivitis raises a suspicion of adenovirus infection, particularly in immunosuppressed individuals.

Differential Diagnosis

1) Respiratory tract infections, including influenza, COVID-19, pertussis.

2) Pharyngotonsillitis: Streptococcal pharyngitis.

3) Hemorrhagic cystitis: Acute interstitial nephritis, nephrolithiasis, bleeding from the urinary tract.

4) Eye infections: Purulent conjunctivitis, allergic conjunctivitis, Kawasaki disease, pediatric inflammatory multisystem syndrome (PIMS) associated with COVID-19.

5) Infections among recipients of solid organs: Transplant rejection.

6) Infections among recipients of allogeneic HSCT: Sepsis, cytomegaly, neutropenic fever.

7) Systemic infection: Sepsis.

TreatmentTop

Antiviral Treatment

No antiviral treatment is available. Cidofovir and brincidofovir are rescue drugs for severe pneumonia or life-threatening disease in HSCT recipients.

Symptomatic Treatment

Antipyretics and analgesics are used as needed. Topical treatments are applied in eye infections.

ComplicationsTop

1) Respiratory tract infections, particularly in small children, may be complicated by bronchial necrosis, hyaloid membrane disease, and extrapulmonary complications: neutropenia, sporadically cerebrospinal meningitis, hepatitis, myocarditis, nephritis, and DIC.

2) Conjunctivitis may progress to chronic disease; keratitis may lead to corneal opacity and dry eye syndrome.

3) Complications of acute diarrhea: Dehydration and electrolyte balance disorders.

4) Infections among solid organ recipients may lead to failure of the transplanted organ.

PrognosisTop

Prognosis in immunocompetent individuals is good. Complications and death prevail among young children and individuals with immunodeficiency, especially after HSCT.

PreventionTop

Specific Prevention

Vaccination: None available.

Nonspecific Prevention

Personal protective measures: Careful hand hygiene is the easiest way to prevent infection. Paper towels should be used in public toilets. Sodium hypochlorite or other disinfectants effective against adenoviruses can be used to clean surfaces. Using chlorine for swimming pool sanitation and sewage treatment decreases the risk of a conjunctivitis epidemic. Ophthalmic examination should be performed under sterile conditions, and medical equipment should be sterilized.

TablesTop