Acute hepatitis of unknown origin in children: Behind the statistics

Abstract

Since April 2022, the world has been witnessing a rapidly spreading outbreak of acute hepatitis of unknown origin in children < 16 years old that has affected several countries around the world. Most of the cases have presented with the clinical picture of severe hepatitis that has led to resorting to liver transplantation in several cases. Despite the numerous theories that have been suggested on the possible underlying etiologies of the outbreak, an association with hepatitis A–E viruses and a link to COVID‐19 vaccines have been excluded. Adenovirus serotype 41 has been detected in numerous cases, which makes it the most likely underlying cause of the disease. Nevertheless, other hypotheses are being investigated to justify the severity of the clinical picture, which is not typical of this type of virus. This review aims to summarize the current knowledge about the outbreak, highlight the suggested working hypotheses, and report the public health measures undertaken to tackle the outbreak.

Adeno-associated virus type 2 in US children with acute severe hepatitis

“…As of August 2022, clusters of acute severe hepatitis of unknown etiology in children have been reported from 35 countries, including the United States 1,2 . Previous studies have found human adenoviruses (HAdVs) in the blood from cases in Europe and the United States [3][4][5][6][7] , although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment based sequencing, and agnostic metagenomic sequencing to analyze samples from 16 HAdV-positive cases from October 1, 2021 to May 22, 2022, in parallel with 113 controls.…”

Adeno-associated virus type 2 in children from the United States with acute severe hepatitis

“…Although the 100% detection rate of HAdV may not be surprising as 10 (76.9%) of the 13 cases were known to be adenovirus positive by clinical testing a priori, the detection of HAdV in the 3 remaining cases and in 0 of 45 controls is still significant (p<0.001); further, adenovirus is detected in 45-90% of the overall PUI population 6,[8][9][10][11] . Other co-infecting viruses, including EBV and HHV-6, were detected by PCR in many cases but rarely in controls (P<.001); EV-A71 was also detected by metagenomic sequencing in one case but not in any control.…”

“…Initial epidemiological investigation and molecular testing have found adenovirus in 45-90% of severe acute hepatitis cases 6,[8][9][10][11] . In the UK, 116 of 179 (64.8%) reported cases as of May 2022 have tested positive for adenovirus 1 .…”

“…Affected children were admitted to tertiary care hospitals in 6 states (Alabama, California, Florida, Illinois, North Carolina, and South Dakota) from October 1, 2021 to May 22, 2022 (Extended Data Table 1). Because many patients (12 of 16, 75%) were selected from those PUIs who tested positive for adenovirus and had samples submitted for adenovirus typing, PUIs with adenovirus infection may have been over-represented compared to the overall PUI population, of which adenovirus is detected in 45-90% 6,[8][9][10][11] . The median age of affected children was 3 years.…”

“…Although previously reported as a severe and potentially fatal disease in immunocompromised patients 4,6 , hepatitis from adenovirus infection had been thought to be rare in immunocompetent children without underlying comorbidities 7 . In previous reports, adenoviruses, particularly adenovirus type 41 (HAdV-41), have been found in the blood from a majority of outbreak-associated cases of acute severe hepatitis from Scotland, the United Kingdom (UK), and the US 6,[8][9][10][11] , although it is unclear whether this virus is causative. AAVs have also been reported in children with severe acute hepatitis in a study of 9 patients from the United Kingdom (UK) 18 , often in association with adenovirus or human herpesvirus 6 (HHV-6 infection) 12 .…”