What Else Can Adenovirus Cause Besides Acute Hepatitis of Unknown Aetiology?

According to overseas news, Japan’s Ministry of Health, Labour and Welfare reported the first case of acute hepatitis of unknown aetiology in children on 26 April, which is also the first case of infection reported in Asia. WHO and the European Centre for Disease Prevention and Control (ECDC) also reported that 14 countries and territories worldwide have seen children infected with acute hepatitis of unknown aetiology, and about 190 cases have been reported worldwide. The UK Health and Safety Executive (UKHSA) and the US Centers for Disease Control and Prevention say that an adenovirus known as type 41 currently appears to be the most likely cause of acute hepatitis in children. Apart from hepatitis of unknown aetiology, what other diseases are associated with adenovirus infection?

Human adenoviruses (HAdVs) belong to the family Adenoviridae, a genus of mammalian adenoviruses, and are envelope-free, double-stranded DNA viruses. They usually cause minor infections, including upper or lower respiratory tract, gastrointestinal tract or conjunctiva. Rare manifestations of adenovirus infections include haemorrhagic cystitis, hepatitis, haemorrhagic colitis, pancreatitis, nephritis or meningoencephalitis. HAdVs have been classified into seven groups (groups A-G) based on their serum neutralisation response, erythrocyte agglutination antigenic epitopes, gene sequence and function, as well as their oncogenicity in neonatal hamsters and pathological manifestations in humans.

 

I. Clinical Diseases Associated With Adenovirus

 

1. Respiratory Tract Infections

1) HAdVs Associated With Respiratory Diseases

HAdV-B (HAdV-3, 7, 11, 14, 16, 21, 50, 55)

HAdV-C (HAdV-1, 2, 5, 6)

HAdV-E (HAdV-4)

Adenovirus infections account for at least 5-10% of respiratory infections in children; 1-7% of respiratory infections in adults.

Main symptoms: fever, pharyngitis, tonsillitis, cough, sore throat, etc.

 

2. Eye Infections

1) Epidemic Keratoconjunctivitis (EKC)

Common serotypes: HAdV-8, 19, 37, 49

Other serologies: HAdV-53, 54, 56

HAdV-D (HAdV-9, 10, 13, 15, 17, 19, 20, 22-30, 32, 33, 36-39, 42-49)

2) Pharyngeal Conjunctival Fever

Other serology: HAdV-3, 4, 7, 11, 14

3) Non-specific Conjunctivitis

 

3. Gastrointestinal Infections

Common serotypes: HAdV-40, 41

Main symptoms: gastroenteritis or diarrhoeal symptoms

Rare complications: haemorrhagic colitis, hepatitis, cholecystitis, pancreatitis.

 

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4. Urinary Tract Infections

1) Infected People

Haematopoietic stem cell transplant (HSCT) recipients

Solid organ transplant (SOT) recipients

2) Typical Symptoms

Difficulty in urination, haematuria, haemorrhagic cystitis (HC), transplanted kidney dysfunction, renal failure, necrotizing tubulointerstitial nephritis, urinary tract obstruction, urethritis, etc.

3) Serotypes Associated With Haemorrhagic Cystitis (HC)

HAdV-11, 34, 35, 3, 7, 21

Diagnosis: urine culture, PCR, serological tests

 

5. Disseminated disease

Adenovirus is rare in immunocompetent patients, but transmission can be 10%-30% in HSCT recipients, with a mortality rate of 12%-70%.

The morbidity and mortality rate of adenovirus pneumonia is over 50%.

Diagnosis: PCR blood testing

 

6. Rare Diseases

Encephalitis

Meningitis

Myocarditis

Cardiomyopathy

Mononucleosis-like syndrome

Pulmonary dysplasia

Intussusception in children

Sudden infant death

 

Ⅱ. Risk Groups for Adenovirus Infection

1. Healthy People

1) Healthy Children (Especially <4 Years)

2) Adults in Closed Environments (Especially in Military)

The vast majority of infections in healthy populations are limited, with less disseminated and fatal diseases.

2. Recruits

Adenovirus infection accounts for more than 50% of cases of respiratory illness and pneumonia in unvaccinated recruits.

3. Haematopoietic Stem Cell Transplantation (HSCT) Recipients

1) The incidence of adenovirus infection among HSCT recipients varies widely: 3%-47%.

2) The prevalence in children (>20%) is 2-2.5 times higher than in adults.

3) Adenovirus in HSCT recipients is usually detected within 100 days of transplantation.

4) Mortality is high with a risk ratio of up to 3.15 for adenovirus infection.

4. Solid Organ Transplant (SOT) Recipients

1) Prevalence of adenovirus infection in SOT recipients: 5%-22%.  

2) Usually detected within the first 6 months after transplantation.

5. HIV Patients

Prevalence of adenovirus infection in HIV patients: 12-28%.

6. Congenital Immunodeficiency Syndrome

Adenovirus infection often leads to severe pulmonary infection, disseminated disease and even death.

III. Common Serological Epidemiology and Characteristics

1. HAdV-1 and HAdV-2

HAdV-1 and HAdV-2 are common causes of acute respiratory infections worldwide and are less virulent than HAdV-3 and HAdV-7.

In USA (2004-2006), HAdV-1 and HAdV-2 accounted for 17.6% and 24.3% of clinical respiratory tracts in children or adults, respectively, and only 0.4% in recruits.

Toronto, Canada (2007-2008): HAdV-1 (18%) and HAdV-2 (26%).

United Kingdom (1984-1988): HAdV-1 (12.1%) and HAdV-2 (18.6%).

Seoul, Korea (1990-1998): HAdV-1 (9.2%) and HAdV-2 (11.2%).

2. HAdV-3

HAdV-3 is one of the most common serotypes for adenovirus infections in children and adults worldwide, which can cause fatal pneumonia.

WHO (1967-1976) reported that HAdV-3 accounted for 13% of respiratory isolates.

In USA (2004-2006), HAdV-3 accounted for 34.6% of respiratory infections caused by adenovirus.

Toronto, Canada (2007-2008): 46%.

United Kingdom (1982-1996): 14.9%.

Seoul, Korea (1990-1998): 15%.

Seoul, South Korea (1991-2007): 37%.

Taiwan, China (1981-1989): 68%. Taiwan, China (1990-1998): 44%.

Taiwan, China (2004-2005): 87.5%. 

3. HAdV-4

HAdV-4 is the cause of sporadic infection.

In the United States (2004-2006), HAdV-4 accounted for 4.8% of respiratory infections caused by adenovirus.

Toronto, Canada (2007-2008): 1%.

Seoul, South Korea (1991-1997): 3.97%.

Taiwan, China (1981-2001): 29% and became the predominant serotype in 2001.  

4. HAdV-7

Clinical symptoms: ocular conjunctivitis, bronchitis, necrotizing fine bronchitis or pneumonia. Studies have reported that HAdV-7 is more virulent than other serotypes and can be fatal in children and adults with pneumonia.

The prevalence of HAdV-7 varies according to geographical region and time.

In South America (1980-1990), HAdV-7 was the leading cause of death from adenovirus pneumonia, causing 62.2% of adenovirus pneumonia and resulting in 94.4% of deaths in studies of adenovirus pneumonia in children in Argentina and Uruguay.

Seoul, Korea (1990-1998): 41%, with HAdV-3 and HAdV-2 each accounting for 15%.

Seoul, Korea (1991-2007): 23.3%, second only to HAdV-3 (37%).

Taiwan, China (1999-2000): 45% as the predominant serotype, but was replaced by HAdV-4 in 2001. 

Beijing, China (1958-1990): 45%, with HAdV-3 and HAdV-7 being the most common serotypes causing pneumonia.

5. HAdV-8

HAdV-8 accounts for less than 1% of adenovirus infections, but is a common cause of EKC. Studies in Asia and the Middle East, HAdV-8 accounted for 64%-79% of EKC.

6. HAdV-11

HAdV-11 is relatively uncommon and can cause haemorrhagic conjunctivitis and pneumonia. It can cause HC in immunocompromised patients. its infections have been reported in South America, the USA, Asia and the Middle East.

7. HAdV-14

HAdV-14 was first isolated in 1955 during an outbreak of acute respiratory disease in Dutch recruits. It was subsequently reported in Uzbekistan in 1962 and Czechoslovakia in 1963.

Outbreaks were caused at several military bases in the USA in 2006 and in at least 15 states in 2007, with fatal pneumonia reported, though the severity varied. In 2007, HAdV-14 replaced HAdV-4 as the predominant serotype on US military bases.

Studies have shown that there is recombination between HAdV-14 and HAdV-11 and that the genomic type HAdV-14p1 is expressed, with HAdV-14p1 having caused severe pneumonia in the USA and Ireland, which has a higher incidence and transmission.

8. HAdV-21

HAdV-21 was endemic among recruits in the Netherlands in the 1960s, followed by only sporadic cases over the next 20 years. In 1984-1985, HAdV-21 caused infection in children in the Netherlands and Germany, which was associated with pharyngitis, conjunctivitis and respiratory tract infections.

In the USA (2004-2006), HAdV-21 accounted for 2%-2.4% of respiratory infections caused by adenovirus.

9. HAdV-31

HAdV-31 causes gastroenteritis in children and is associated with severe fatal infections in HSCT recipients.

10.  HAdV-37

HAdV-37 accounts for less than 1% of adenovirus infections and may cause EKC.

11. HAdV-40, HAdV-41

HAdV-40, HAdV-41 usually causes gastroenteritis and diarrhoeal disease in children, causes dehydration leading to death in infants, and can cause fatal transmission in immunocompromised patients. HAdV-41 is by far the probable cause of unexplained hepatitis.

12. HAdV-55

Infections caused by HAdV-55 are less common and have been related to outbreaks of severe pneumonia and acute respiratory distress syndrome in China since 2006.

References:

[1] Adenovirus: Epidemiology, Global Spread of Novel Types, and Approach to Treatment.

[2] Advances in the epidemiology of human adenovirus.