An urgent call to identify the probable cause of severe acute hepatitis outbreak in children

While the world continues to battle with Coronavirus, yet another new outbreak has been announced by the WHO due to a sudden increase of unexplained severe acute hepatitis in children. Although alerts of cases were first released by the public health of Scotland on March 31, 2022, it seems that the problem may have begun much earlier in 2021 [1,2]. As of April 21, 2022, at least 169 cases have been reported from 11 countries around Europe and the USA. Interestingly, there have been continuing reports of cases of acute hepatitis of unknown origin among young children, including in Indonesia [3].

Notably, among 22 reported cases in Scotland [1,2], 63.6% of cases were positive for human adenovirus (HAdV), and among HAdV-infected kids, 40.9% of cases were identified as HAdV-41. Despite several reports of acute liver failure due to HadV in immunocompetent children [4], so far, there is no adequate evidence indicating HAdV-41 as the cause of hepatitis [5]. Another interesting point to note is that most of the cases, there exists co-infections with other viral agents such as rhinovirus, enterovirus, norovirus, sapovirus, parainfluenza virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), or human coronavirus NL63/OC43, despite no immunocompromised conditions. Although previously acute liver failure due to type 2 autoimmune hepatitis has been reported in children infected with SARS-CoV-2 [6], only 5 cases have been positively tested for SARS-CoV-2 [2]. Thus, reflecting that other probable non- and infectious agents or causes may be responsible for the occurrence of the disease.

Gastrointestinal symptoms, including diarrhea or vomiting, seems to be associated with the early phase of the disease, followed by jaundice and elevated transaminase levels. However, currently, due to a lack of research focusing on the relationship between HAdV-41 with hepatitis, it is impossible to determine the main cause of the disease. Although viruses are the most common causes of acute hepatitis, bacterial infection should also be considered as one of the possible etiology of this clinical entity [7]. Moreover, it is also possible to speculate that commercially available nucleic acid assays may have inadequate sensitivity in detecting lower viremia levels in patients with acute hepatitis of unknown etiology (HUE) as previously described [8]. Hence, more evidence including viral genotyping using sequence-independent complementary DNA amplification and next-generation sequencing (NGS), liver biopsy, and immunohistochemistry are crucial to elucidate the probable cause of HUE. Additionally, a complete clinical and laboratory assessment, as well as virological/bacteriological and epidemiological data are urgently needed from more available cases to provide a bigger picture of the disease.

Author contribution

ZU conceived, analyzed and wrote the article, GS wrote the article.

Conflict of interest

The authors declare that there are no conflicts of interest.