Acute Hepatitis of Unknown Origin in Pediatric Age Group: Recent Outbreaks and Approach to Management

Abstract

Acute hepatitis has always been a public health concern, but the recent clustering of cases in various parts of the world has drawn some special attention. The sudden rise in cases has mainly been among the pediatric population of around 35 countries around the world, including developed countries such as the United States, the United Kingdom, and European countries. The outbreaks have had a devastating impact, with around 10% of the affected patients developing liver failure. The clinical presentation of patients resembles any other case of acute hepatitis, with the major symptoms being: jaundice (68.8%), vomiting (57.6%), and gastrointestinal symptoms such as abdominal pain (36.1%) and nausea (25.7%). Interestingly, the cases have tested negative for hepatotropic viruses Hep A, B, C, and E, thus giving rise to the terms Hepatitis of Unknown Origin or non-HepA–E hepatitis. Many causes have been attributed to the disease, with major evidence seen for adenovirus and SARS-CoV-2. International agencies have stressed on establishing diagnostic and management protocols to limit these outbreaks. As the understanding has evolved over time, diagnostic and management faculties have found more shape. The current review was designed to comprehensively compile all existing data and whittle it down to evidence-based conclusions to help clinicians.

Genetic characterization of human adenoviruses in patients using metagenomic next-generation sequencing in Hubei, China, from 2018 to 2019

“…Acute hepatitis of unknown etiology among children has recently attracted special attention worldwide. Although the causes of the disease are unclear, adenoviruses and SARS-CoV-2 have become the major focuses of investigations ( Patel et al, 2022 ). In the European region, 53.1% of cases were reported positive for adenovirus and 64.7% positive rate in England, of which, the main suspect is adenovirus subtype 41 ( UK Health Security Agency, 2022 ; World Health Organization, 2022 ).…”

Molecular Understanding of ACE-2 and HLA-Conferred Differential Susceptibility to COVID-19: Host-Directed Insights Opening New Windows in COVID-19 Therapeutics

“…Genetic variation in the three MHC class I genes (human leukocyte antigen A (HLA-A), -B, and -C genes) may influence susceptibility to, and intensity of, the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [ 24 ]. Several classical transmembrane proteins are encoded by HLA genes, such as HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, and HLA-DP and are predominantly associated with the presentation of antigens on the surface of cells that further trigger antiviral responses [ 26 ]. For instance, HLA-B*01 and/or HLA-B*44 are usually found in healthy people, while individuals with HLA-B*08 and HLA-A*25 are at higher risk of COVID-19 infections, as they lack the immune-dominant virus-derived epitope peptides and cannot trigger sufficient immune responses [ 63 ].…”

“…Every individual who has an ACE-2 receptor is susceptible to COVID-19. However, host susceptibility is also influenced by genetic variations in the HLA genes, which encode hundreds of protein-coding genes that regulate fundamental molecular and cellular processes, including immune responses [ 26 ]. The HLA genes are part of the major histocompatibility complex (MHC) located on the short arm of chromosome 6, which is one of the most complex genetic systems.…”

“…In addition to age, gender, and health status, genetic variants of HLA have been found to influence susceptibility to various viral diseases, including SARS-CoV, MERS-CoV, influenza, dengue, and hepatitis B. Susceptibility to and severity of COVID-19 are also considerably associated with genetic variation in HLA, which plays a significant role in identifying populations at higher risk of COVID-19 disease [ 26 ]. HLA molecules of classes I/II play a significant role in human immunity and determine individual susceptibility to COVID-19 infection.…”

“…However, some studies have shown that certain HLA alleles are associated with the protection or susceptibility to other viral infections. For example, HLA-B57:01 has been associated with slower HIV disease progression, while HLA-B15:05 has been associated with susceptibility to hepatitis B virus infection [ 26 ]. These findings suggest that HLA variants may be shaped by viral selection pressures.…”