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While adenovirus remains a prime suspect in the unexplained cases of acute hepatitis in children, the CDC is "keeping an open mind and focusing on hypothesis generation," said Jacqueline Tate, PhD, of the CDC's National Center for Immunization and Respiratory Diseases, during a Clinician Outreach and Community Activity (COCA) this week.

To date, of the mysterious hepatitis in kids are under investigation across 36 U.S. states and territories, according to the CDC. At a press briefing on Friday, agency officials said that over 90% of cases under investigation reported onset prior to May 2022, with most being retrospectively identified.

Adenovirus has been detected in nearly half of the cases and "continues to be a strong lead," according to the agency.

Six children in the U.S. have died, with the latest death reported on Friday. However, the proportion of patients requiring liver transplant has fallen from 15% to 9%, as more cases have been identified, and no deaths have been reported since February.

Globally, more than 232 cases have been reported in children under 16 in the World Health Organization European region, and another 72 cases have been reported in 12 additional countries. Adenovirus viremia was found in "more than two-thirds of patients across many countries," Tate noted during the COCA webinar on Thursday. "Limited data" show higher viral load in children who required transplant.

Of note, the age group affected by these hepatitis cases is the same age group who are typically affected by adenovirus. However, CDC researchers added that an estimated 30% to 50% of all hepatitis cases in children are of unknown cause, and they have so far not been able to pinpoint a "spike" in overall pediatric hepatitis cases.

In the U.S., the unusual cases first surfaced in a cohort from Alabama. Nine kids identified in the state had adenovirus infections (type 41 in the five samples sequenced) along with low levels of other viruses, including evidence of Epstein-Barr virus in six; enterovirus/rhinovirus in four; and metapneumovirus, respiratory syncytial virus, and human coronavirus OC43 in one child each.

Of 163 acute hepatitis cases included in a , 72% tested positive for adenovirus and 18% tested positive for SARS-CoV-2.

"The leading hypothesis in the U.K. is that a co-factor affecting young children is rendering normal adenovirus infections more severe or causing them to trigger immunopathy," Tate said. However, scientists are continuing to study the role of SARS-CoV-2 and attempting to rule out other potential toxins.

The CDC is "also exploring other potential exposures, including medications, other infections, toxins, food, water, etc.," she added. CDC researchers noted that they have not seen the hypothesis about dog exposure, first posited in the U.K., pan out.

Adenovirus type 41 is known to cause pediatric gastritis, Tate pointed out. Diarrhea and emesis are common symptoms in these cases. CDC investigators are trying to discern whether there has been "an unusually large enteric adenovirus season," which might suggest cases were "magnified" following a lack of exposure to adenovirus during the pandemic, leaving a greater number of children susceptible to the illness, she explained.

There is also the theory of "altered susceptibility" to adenovirus (again, due to lack of exposure) co-occurring with another pathogen, such as SARS-CoV-2, or a "toxin, drug, or environmental exposure," Tate said.

However, "adenovirus is not a well-recognized cause of hepatitis in healthy children, and the pathology is not consistent with typical adenovirus hepatitis in immunocompromised children," she noted.

Furthermore, investigators have yet to find evidence of viral infection in the liver, she added.

Elizabeth Moulton, MD, PhD, of Baylor College of Medicine and Texas Children's Hospital in Houston, suggested that an adenovirus infection in the gastrointestinal tract may have triggered a "misdirected immune response against the liver."

However, whether the liver is causing damage to itself or whether an infection in another part of the body is causing an inflammatory response leading to injury is still unclear, she said.

In the U.S. cases recorded to date, fewer than 20% of children had evidence of SARS-CoV-2, but CDC researchers noted on Friday that some people with COVID develop a prolonged infection in the gastrointestinal tract, and that could trigger an immune response that might potentially damage the liver.

The CDC is continuing to urge parents and caregivers to be cognizant of the symptoms of hepatitis, including jaundice, and is also calling on clinicians to report detailed medical charts, as well as to have patients complete a comprehensive questionnaire regarding possible exposures and to complete additional lab tests.

The agency recently issued guidance on adenovirus testing and typing for suspected cases. Experts on the COCA call reiterated that whole blood specimens should be used over plasma, since this testing is more sensitive.

The CDC will soon begin sharing on the patients under investigation.

Deputy Managing Editor Molly Walker contributed to this report.

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