ISARIC CCP activation for acute hepatitis of unknown cause

A number of young children in the UK, and across the world, are developing severe acute hepatitis. The cause is unknown.

We are a group of doctors and scientists who do research in outbreaks in close partnership with public health agencies. Because our study, ISARIC4C, is already set up across the whole country, we can recruit patients everywhere, collate data and samples and gain consent for research and development.

The ISARIC4C approach brings the scalable capacity and cutting-edge capabilities of the academic sector to help the nation respond to public health challenges in time to make a difference to outcome. We have already shown the strongest evidence for the underlying cause of this disease - a combination of common viruses - by reading the DNA sequence of viruses in samples of blood and liver from children with the disease.

We have put together a rapid research plan to tackle the key questions identified by UK public health agencies. To do this, the first thing we need to do is recruit patients and their families into research studies to look for the cause of the disease, understand the role of the immune system, find genetic factors that may explain the disease processes, and suggest new treatments.

A series of cases of severe hepatitis in young children of unknow cause were recognised in Central Scotland in March 2022. By 18 May 2022, there had been 198 such cases across the UK, predominantly in children under 5 years old. The aetiology is unknown but an infection or co-infection is a strong possibility and preliminary data from our work suggests that co-infection with adenovirus 41F and an adeno-associated virus 2 (AAV2) may be responsible.

The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) Clinical Characterisation Protocol (CCP) is a global sleeping protocol to facilitate immediate academic research to characterise new infections and other syndromes. We seek urgent support to enable ongoing recruitment to the ISARIC CCP-UK study of cases of unexplained hepatitis in young children.

We will obtain consent and biological samples, in partnership with public health agencies, in order to characterise the clinical features of this new outbreak, focusing initially on three core questions:

1. What are the clinical features of acute disease?
2. What is the causative agent?
3. What is the role of prior immunity, immune compromise or systemic inflammation in acute disease?

Building on our extensive body of work during the Covid-19 outbreak, we will investigate clinical features of disease using structure case report forms for all consenting cases in the UK. We will perform metagenomic sequencing on samples from cases in order to determine the underlying cause of disease, and characterise the histopathological, immunological and host genetic features mediating the pathophysiology.