Acute severe hepatitis outbreak in children: A perfect storm. What do we know, and what questions remain?

Abstract

During the first half of 2022, the World Health Organization reported an outbreak of acute severe hepatitis of unknown aetiology (AS-Hep-UA) in children, following initial alerts from the United Kingdom (UK) where a cluster of cases was first observed in previously well children aged <6 years. Sporadic cases were then reported across Europe and worldwide, although in most countries incidence did not increase above the expected baseline. There were no consistent epidemiological links between cases, and microbiological investigations ruled out known infectious causes of hepatitis. In this review, we explore the evidence for the role of viral infection, superimposed on a specific host genetic background, as a trigger for liver pathology. This hypothesis is based on a high prevalence of Human Adenovirus (HAdV) 41F in affected children, together with metagenomic evidence of adeno-associated virus (Adeno-associated viruses)-2, which is a putative trigger for an immune-mediated liver injury. Roles for superantigen-mediated pathology have also been explored, with a focus on the potential contribution of SARS-CoV-2 infection. Affected children also had a high frequency of the MHC allele HLA-DRB1*04:01, supporting an immunological predisposition, and may have been vulnerable to viral coinfections due to disruption in normal patterns of exposure and immunity as a result of population lockdowns during the COVID-19 pandemic. We discuss areas of ongoing uncertainty, and highlight the need for ongoing scrutiny to inform clinical and public health interventions for this outbreak and for others that may evolve in future.

Liver Transaminases in Pediatric Adenovirus Infection—A Five-Year Study in Two Major Reference Centers from Romania

“…Overall globally, 46.7% of samples tested for HAdV were positive, and of these, adenovirus type 41 was the most common [ 20 ]. However, there is no clear evidence to confirm that HAdV is the etiological agent responsible for the AS-Hep-UA outbreak [ 21 , 22 ]. As mentioned in the introduction, a number of pediatric cases of adenovirus-associated hepatitis, including adenovirus type 41, have been published over time, but these have been reported in immunocompromised children [ 14 , 23 , 24 , 25 ].…”

“…Therefore, the main aim of our study was to evaluate the dynamics of clinical manifestations and laboratory changes of transaminases in hospitalized children with confirmed HAdV infection, across the entire spectrum of illness severity, over 5 years in two tertiary hospitals in the Romanian capital. We retrospectively collected clinical data, taking into account the case definition for AS-Hep-UA [ 21 ] so as to provide as clear a picture as possible of HAdV infection that can be used for further analysis.…”

Respiratory viruses: new challenges for old enemies

“…[69] To date, it is considered unlikely a direct virus-induced liver damage, as demonstrated by histological findings, but rather it is speculated that viral and immune factors and perhaps either COVID infection or COVID period immunity changes related together with Adenovirus infection may represent the cause of this new hepatitis. [69]…”

Looking back on the outbreak of acute severe hepatitis with unknown etiology in children in 2022: What do we know now and where do we go from here?

“…Two major prerequisites are likely needed for this wave of acute severe hepatitis with unknown etiology in children: first, the certain increase of prevalence of AAV‐2 and the “helper virus” coinfection following the lift of social‐distancing restrictions, due to the general susceptibility of children to infection resulted from disruption in normal patterns of exposure and immunity under COVID mitigation measures; second, perhaps more importantly, the genetic susceptibility of the infected children to cause disease, which is likely associated with, if not determined by, the MHC allele HLA‐DRB1*04:01 18 . Despite the vague role of SARS‐CoV‐2 infection in the pathogenesis of pediatric hepatitis, SARS‐CoV‐2 pandemic does influence lives in countless ways.…”

“…As a matter of fact, hepatotoxicity and thrombotic microangiopathy represent the most frequent adverse events in patients treated with AAV vector-based gene therapy,17 which seemingly coincides with the detected AAV-2 RNA in hepatocytes and endothelial cells recently 7. From another perspective, prolonged monitor of extrahepatic tissue inflammation and damage is needed considering the diverse organ tropism of different AAV serotypes.Nevertheless, whether the long reported adverse effects of AAV are directly related to its immunogenicity and/or patients' HLA variations (i.e., HLA-DRB1*04:01) still awaits investigation.Two major prerequisites are likely needed for this wave of acute severe hepatitis with unknown etiology in children: first, the certain increase of prevalence of AAV-2 and the "helper virus" coinfection following the lift of social-distancing restrictions, due to the general susceptibility of children to infection resulted from disruption in normal patterns of exposure and immunity under COVID mitigation measures; second, perhaps more importantly, the genetic susceptibility of the infected children to cause disease, which is likely associated with, if not determined by, the MHC allele HLA-DRB1*04:01 18. Despite the vague role of SARS-CoV-2 infection in the pathogenesis of pediatric hepatitis, SARS-CoV-2 pandemic does influence lives in countless ways.…”