The number of pediatric hepatitis cases has remained steady since 2017, new research from the Centers for Disease Control and Prevention (CDC) suggests, despite the recent investigation into children with hepatitis of unknown cause. The study also found there was no indication of elevated rates of adenovirus type 40/41 infection in children.

But Rohit Kohli, MBBS, MS, chief of the Division of Gastroenterology, Hepatology and Nutrition at the Children’s Hospital of Los Angeles, California, says that although the study is “well-designed and robust,” that does not mean that these hepatitis cases of unknown origin are no longer a concern, he told Medscape Medical News. He was not involved with the CDC research. “As a clinician, I’m still worried,” he said. “Why I feel like this is not conclusive is that there are other data from entities like the United Kingdom Health Security Agency that are incongruent with [these findings],” he said.

The research was published June 14, 2022, in the CDC’s Morbidity and Mortality Weekly Report (MMWR).

In November 2021, the Alabama Department of Public Health began an investigation with the CDC after a cluster of children were admitted to a children’s hospital in the state with severe hepatitis who all tested positive for adenovirus. When the United Kingdom’s Health Security Agency announced an investigation into similar cases in early April 2022, the CDC decided to expand their search nationally.

Now, as of June 15, the agency is investigating 290 cases in 41 states and US territories. Worldwide, 650 cases in 33 countries have been reported, according to the most recent update by the World Health Organization on May 27, 2022. At least 38 patients have needed liver transplants, and nine deaths have been reported to WHO.

In its most recent press call on the topic the CDC announced that it’s aware of six deaths in the United States through May 20, 2022. The COVID-19 vaccine has been ruled out as a potential cause because the majority of affected children are unvaccinated or are too young to receive the vaccine. Adenovirus infection remains a leading suspect in these sick children because the virus has been detected in 60.8% of tested cases, WHO reports.

Investigators have detected an increase in reported pediatric hepatitis cases compared with prior years in the United Kingdom, but it was not clear whether that same pattern would be found in the United States. Neither pediatric hepatitis nor adenovirus type 40/41 are reportable conditions in the US. In the May 20 CDC press call, Umesh Parashar, MD, chief of the CDC’s Viral Gastroenteritis Branch, said that an estimated 1500-2000 children aged younger than 10 are hospitalized in the US for hepatitis every year. “That’s a fairly large number,” he said, and it might make it difficult to detect a small increase in cases.

To better estimate trends in pediatric hepatitis and adenovirus infection in the US, investigators collected available data on emergency department (ED) visits, hospitalizations, and liver transplants associated with hepatitis in children as well as adenovirus stool testing results. Researchers used four large databases: the National Syndromic Surveillance Program; the Premier Healthcare Database Special Release; the Organ Procurement and Transplant Network; and Labcorp, which is a large commercial lab network.

To account for changes in healthcare utilization in the first year of the COVID-19 pandemic, the team compared hepatitis-associated ED visits, hospitalizations, and liver transplants from October 2021 to March 2022 vs the same months (January to March and October to December) in 2017, 2018, and 2019. For adenovirus stool testing, results from October 2021 to March 2022 were compared with the same calendar months (October to March) from 2017-2018, 2018-2019, and 2019-2020, to help control for seasonality.

Investigators found no statistically significant increases in the outcomes during October 2021 to March 2022 vs pre-pandemic years:

• Weekly ED visits with hepatitis-associated discharge codes

• Hepatitis-associated monthly hospitalizations in children aged 0-4 years (22 vs 19.5; P = .26)

• Hepatitis-associated monthly hospitalization in children aged 5-11 years (12 vs 10.5; P = .42)

• Monthly liver transplants (5 vs 4; P = .19)

• Percentage of stool specimens positive for adenovirus types 40/41, though the number of specimens tested was highest in March 2022

The authors acknowledged that pediatric hepatitis is rare, so it may be difficult tease out small changes in the number of cases. Also, data on hospitalizations and liver transplants have a 2- to 3-month reporting delay, so the case counts for March 2022 “might be underreported,” they wrote. Kohli noted that because hepatitis and adenovirus are not reportable conditions, the analysis relied on retrospective data from insurance companies and electronic medical records. Retrospective data are inherently limited compared with prospective analyses, he said, and it’s possible that certain cases could be included in more than one database and thus be double-counted, whereas other cases could be missed entirely.

These findings also conflict with data from the UK, which in May reported that the average number of hepatitis cases had increased compared with previous years, he said. More data are needed, he said, and he is involved with a study with the North American Society for Pediatric Gastroenterology and the American Association for the Study of Liver Diseases that is also collecting data to try to understand whether there has been an uptick in pediatric hepatitis cases. The study will collect patient data directly from hospitals as well as include additional pathology data, such as biopsy results.

“We should not be inhibited to look further academically — and public health–wise — while we take into cognizance this very good, robust attempt from the CDC,” he said.

Morb Mortal Wkly Rep (MMWR). June 14, 2022. Full text

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