Adenovirus 41 could be at the basis of mysterious cases of childhood hepatitis


Nine young children from Alabama affected by a mysterious hepatitis (inflammation of the liver) all tested positive for a common pathogen called adenovirus 41, a study by the US health agency said Friday.

The children, who ranged in age from about one to six years old and were all previously healthy, are among around 170 cases across 11 countries in recent weeks, according to the World Health Organization. Another state, Wisconsin, is investigating a death.

The Centers for Disease Control and Prevention’s new paper is specifically about the cluster in Alabama, even as investigations continue nationwide.

“At this time, we believe adenovirus may be the cause for these reported cases, but other potential environmental and situational factors are still being investigated,” the CDC said in a statement that accompanied the study.

Adenovirus 41 is known to cause gastroenteritis in children, but “it is not usually known as a cause of hepatitis in otherwise healthy children,” the agency said.

Adenoviruses (AdVs) are pathogens that can be engineered to become therapeutic tools (12). More than 100 types of human AdVs (HAdVs) have been described so far ( and grouped in seven species (HAdV-A to HAdV-G). HAdVs cause acute infections in the respiratory and gastrointestinal tracts, as well as conjunctivitis.

Most AdV infections are subclinical, but they can cause significant morbidity and even mortality in immunocompromised patients (3). There are currently no vaccines for use in the general population (although some are available for U.S. military personnel) or approved antiviral therapies for AdV infections.

FIG. 1 The cryo-EM structure of HAdV-F41 at 4.0 Å.
(A) Radially colored surface rendering of the HAdV-F41 map viewed down the twofold icosahedral axis. One facet is identified by a white triangle. Icosahedral symmetry axes are indicated with white symbols: fivefold (pentagon), threefold (triangle), and twofold (oval). A Gaussian filter has been applied to the map to accentuate the main features. (B) The molecular models of the major and minor coat proteins traced in the icosahedral HAdV-F41 facet. Top: view from outside the capsid. Bottom: view inside the capsid. Protein colors as indicated by the legend at the left hand side. The four hexon trimers in the asymmetric unit (AU) are numbered H1 to H4. (C) Cartoon depicting the icosahedral AU and surrounding hexons, as seen from outside the capsid. The icosahedral symmetry axes are indicated with red filled symbols. A hollow red triangle indicates the L3 axis between hexons 2, 3, and 4.

However, an investigation had ruled out other common exposures, including COVID; hepatitis viruses A, B, and C (the most common causes of hepatitis in the US); autoimmune hepatitis and Wilson disease.

The nine Alabama cases occurred between October 2021 and February 2022. Three experienced acute liver failure, two of whom required liver transplants.

“All patients have recovered or are recovering, including the two transplant recipients,” the paper said.

Six tested positive for Epstein-Barr Virus but did not have antibodies, which implies an earlier infection, not active.

Before hospitalization, most of the children experienced vomiting and diarrhea, while some experienced upper respiratory symptoms. During hospitalization, most had yellowing eyes and yellowing skin (jaundice), and enlarged livers.

Last week, the CDC issued a health alert to notify doctors and public health authorities to be on the lookout for similar cases.

Wisconsin is investigating four cases, including two children who had severe outcomes, one who needed a liver transplant and one fatality. Cases have also been reported in Illinois and elsewhere.

CDC recommends children stay up to date on their vaccinations and that parents and caregivers practice preventive actions such as hand hygiene, avoiding people who are sick, covering coughs and sneezes, and avoiding touching the eyes, nose or mouth.

Adenoviruses are commonly spread by close personal contact, respiratory droplets and surfaces. There are more than 50 types of adenoviruses, which most commonly cause the cold, but also many other diseases.

Since 1990, mortality rate of children with diarrhea has been significantly decreased because of the improvements in water, sanitation, and hygiene (1, 2).

However, diarrhea is still the world’s second leading infectious cause of death in children under 5 years old. According to a previous report, approximately 530,000 children under the age of 5 died from diarrheal diseases in 2017 (1).

Therefore, monitoring diarrheal diseases is still a priority. Watery diarrhea and vomiting can cause dehydration. Delays of admission to a hospital, incorrect or imprompt treatment may increase disease severity, which may subsequently result in death. A diarrheal episode could cause serious damages to the bodies of young children, which would take a long time to restore normal nutrition.

Thus, the growth and development of children would be affected (3). Acute diarrhea could be caused by many factors, among which viral infection is the most common one (4). Previous studies have identified that rotavirus (RV), norovirus (NoV), human adenovirus (HAdV), sapovirus (SaV), and human astrovirus (HAstV), are major viral etiologies of diarrheal illness (2). RV remains the leading cause of severe gastroenteritis worldwide.

However, the introduction of RV vaccine could provide effective protection for children (5). Therefore, other diarrheal viruses, such as HAdV, HAstV, and SaV have attracted more attention (6). Currently, routine diagnostics are performed for RV and NoV using enzyme immunoassays (EIAs), but surveillance for HAdV, HAstV, and SaV in China is still limited.

Therefore, additional molecular screening for these viruses was implemented at a children’s hospital outpatient department for three years in this study, which would be benefit in understanding of epidemiology in SaV, HAstV, and HAdV.

Human adenovirus is a non-enveloped linear double-stranded DNA virus detected in various glands, such as the tonsils and mesenteric lymph nodes. HAdV has been divided into over 100 serotypes (HAdV Working Group, updated April, 20211), which can be further grouped into seven genotypes (A–G).

Different genotypes may cause different symptoms. In addition to gastroenteritis, HAdV also causes acute respiratory illness, conjunctiva, hemorrhagic cystitis, hepatitis, hemorrhagic colitis, pancreatitis, nephritis, and meningoencephalitis (7).

It has been proposed that both HAdV41 and HAdV40 belong to the subgroup of F, which are known as enteric adenoviruses (EAds) (8, 9).

HAstV was first identified in 1975 by Appleton and Higgins during electron microscopic examination of fecal specimens, obtained from children with acute gastroenteritis. HAstV are non-enveloped single-stranded RNA (ssRNA) viruses with genome size of 6.2–7.7 kb, which contains three open reading frames (ORFs, that are, ORF1a, ORF1b, and ORF2). ORF1a and ORF1b encode some non-structural proteins, such as RNA-dependent RNA polymerase whilst ORF2 encodes the capsid protein precursor (10).

Currently, HAstV strains are categorized into eight classic genotypes (HAstV-1–HAstV-8), and two novel genotypes (HAstV-MLB and HAstV-VA/HMO). The majority of childhood diarrhea is caused by the classic HAstV genotypes and there is still uncertainty about the role of HAstV-MLB and HAstV-VA/HMO in diarrheal disease (11).

Sapovirus, a genus in the Caliciviridae family alongside NoV, is increasingly recognized as an important cause of childhood diarrhea. Overall, 19 genogroups (GI–GXIX) have been described in SaV, with genogroups GI, GII, GIV, and GV limited to humans (including GI.1–7; GII.1–8; GIV.1; and GV.1–2) (12). SaV was rarely studied compared to NoV in the past. Recently, it has been shown that SaV infection is widely distributed. SaV is responsible for both sporadic cases and outbreaks of acute diarrhea.

As a city located on the intersection of two rivers (Yangtze River and Jialing River), Chongqing has extreme seasonal variations displayed in temperature (“hot summer and cold winter”) compared to other cities. In the present study, three diarrheal viruses in pediatric patients in Chongqing were monitored throughout the year for the early detection of new variants in the population. Therefore, the improved surveillance could provide better guidance for diarrhea prevention.

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