Diagnosis and analysis of unexplained cases of childhood encephalitis in Australia using metatranscriptomic
Ci-Xiu Li1,2, Rebecca Burrell2,3, Russell C Dale4
1School of Life and Environmental Sciences and School of Medical Sciences, The University of Sydney, NSW, Australia.
Abstract:
Encephalitis is most often caused by a variety of infectious agents identified through diagnostic tests utilizing cerebrospinal fluid. We investigated the clinical characteristics and potential aetiological agents of unexplained encephalitis through metagenomic sequencing of residual clinical samples from multiple tissue types and independent clinical review. Forty-three specimens were collected from 18 encephalitis cases with no cause identified by the Australian Childhood Encephalitis study. Samples were subjected to total RNA sequencing ('metatranscriptomics') to determine the presence and abundance of potential pathogens, and to describe the possible aetiologies of unexplained encephalitis. Using this protocol, we identified five RNA and two DNA viruses associated with human infection from both non-sterile and sterile sites, which were confirmed by PCR. These comprised two human rhinoviruses, two human seasonal coronaviruses, two polyomaviruses and one picobirnavirus. Human rhinovirus and seasonal coronaviruses may be responsible for five of the encephalitis cases. Immune-mediated encephalitis was considered likely in six cases and metatranscriptomics did not identify a possible pathogen in these cases. The aetiology remained unknown in nine cases. Our study emphasizes the importance of respiratory viruses in the aetiology of unexplained child encephalitis and suggests that non-central-nervous-system sampling in encephalitis clinical guidelines and protocols could improve the diagnostic yield.
Insights
Unexplained childhood encephalitis cases were investigated using metagenomic sequencing. Respiratory viruses like human rhinovirus and seasonal coronaviruses were identified as potential causes in some cases.
Area of Science:
- Virology
- Neurology
- Genomics
Background:
- Encephalitis is often caused by infectious agents, typically identified via cerebrospinal fluid analysis.
- Unexplained encephalitis cases pose diagnostic challenges, necessitating advanced molecular techniques.
- The Australian Childhood Encephalitis study identified numerous cases lacking a definitive etiological diagnosis.
Purpose of the Study:
- To investigate the clinical characteristics and potential etiological agents of unexplained encephalitis.
- To utilize metagenomic sequencing on residual clinical samples to identify causative pathogens.
- To improve diagnostic yield for encephalitis by exploring non-central nervous system sample types.
Main Methods:
- Metagenomic sequencing (metatranscriptomics) of total RNA from 43 clinical specimens across 18 encephalitis cases.
- Independent clinical review of case data.
- Polymerase Chain Reaction (PCR) for confirmation of identified viral agents.
Main Results:
- Identified seven viruses (five RNA, two DNA) associated with human infection: two human rhinoviruses, two human seasonal coronaviruses, two polyomaviruses, and one picobirnavirus.
- Human rhinovirus and seasonal coronaviruses were implicated in five encephalitis cases.
- Immune-mediated encephalitis was suspected in six cases; metatranscriptomics did not identify a pathogen in these or in the nine cases where etiology remained unknown.
Conclusions:
- Respiratory viruses, including human rhinovirus and seasonal coronaviruses, play a significant role in unexplained childhood encephalitis.
- Metatranscriptomics is a valuable tool for identifying viral pathogens in encephalitis cases.
- Expanding clinical sampling protocols to include non-central nervous system sites could enhance diagnostic capabilities for encephalitis.
