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.

Keywords: adeno-associated virus; adenovirus; aetiology; epidemiology; hepatitis; liver; outbreak; paediatric.

FIGURE 1

Schematic showing possible factors contributing to the aetiology of AS-Hep-UA in children. (A) Possible aetiological agents that have been explored. (B) Likely pathogenic pathway underlying paediatric hepatitis outbreak in 2022. AAV - adeno-associated virus; HHV-6 - human herpes virus 6. Figure created using BioRender with a licence to publish.

FIGURE 2

Epidemiology of AS-Hep-UA in Europe. (A) Number of cumulative AS-Hep-UA cases reported in European countries by the European Centre for Disease Prevention and Control (ECDC) as of 25 August 2022. Cumulative case numbers are presented for countries for which data was available from the ECDC, and labelled as ‘missing’ for those for which no data were reported. (B) Number of weekly probable AS-Hep-UA cases of unknown origin in European children reported between the 39th week of 2021 and the 36th week of 2022. Underlying data for both figure panels sourced from European Centre for Disease Prevention and Control (ECDC) (ECDC, 2022d).

FIGURE 3

Region of origin of AS-Hep-UA cases and outcomes. Data collected by TESSy for 513 cases of AS-Hep-UA from 21 different countries (Joint ECDC-WHO Regional Office for Europe Hepatitis of Unknown Origin in Children Surveillance Bulletin).

FIGURE 4

Histopathology of the liver of a child in the United Kingdom with AS-Hep-UA in which AAV-2 was detected. Severe hepatitis is present, with cytoplasmic vacuolation of hepatocytes (arraws) as well as a prominent proliferation of the bile ductules (*) and infiltration with neutrophils, lymphocytes, plasma cells, and macrophafes. HE staining, scale bar 50 μm.

FIGURE 5

Rate of positivity for viruses among tested samples by ECDC and in UKHSA. (A) ECDC/WHO data for 513 samples indicating number tested and number positive (ECDC, 2022d). Panels B, C, D, E show UKHSA data reported in Technical Briefing 4 (UKHSA Investigation into acute hepatitis, 2022). Proportion of samples testing positive for HAdV in all AS-Hep-UA cases (B) and children undergoing transplant (C). Proportion of HAdV typing as 41F in all AS-Hep-UA cases (D) and explant tissue (E). HAdV - human adenovirus. HHV-7–human herpes virus 7, HHV-6c–human herpes virus 6, EBV—Epstein-Barr virus, CMV–cytomegalovirus, VZV—varicella-zoster virus, HSV-1–herpes simplex virus 1, RSV–respiratory syncytial virus, SARS-CoV-2–severe acute respiratory syndrome coronavirus 2.

FIGURE 6

Rate of positivity for AAV among samples tested in the United Kingdom to represent AS-Hep-UA cases and a set of paediatric control samples. In each case, purple represents samples testing AAV-positive by PCR, with grey showing AAV-negative cases, demonstrating a significant excess of AAV-positives in AS-Hep-UA cases (A,B) compared to samples collected from children in control groups (C–E). Data are collated from the report by Morfopoulou et al. (2022).