Correspondence n engl j med 375;5 nejm.org August 4, 2016 Human Coronavirus OC43 Associated with Fatal EncephalitisTo the Editor: Encephalitis is a serious neurologic syndrome characterized by brain inflammation that may be fatal. Although the majority of cases are caused by viruses, the identification of a causal organism can be difficult. Encephalopathy that affects patients with immunodeficiency is particularly challenging to diagnose, since the clinical presentation may be atypical and the differential diagnosis may include unusual pathogens or a noninfective cause. Deep sequencing of clinical samples has the potential to identify the pathogens associated with encephalitis, particularly in cases in which traditional techniques have not identified the candidate causative pathogen. 1Here we report the use of deep sequencing of a brain biopsy sample obtained from an 11-monthold boy with severe combined immunodeficiency who had symptoms of viral encephalitis with negative results on conventional diagnostic polymerase-chain-reaction (PCR) assay. The boy's family provided written informed consent.The boy underwent unconditioned cord-blood transplantation, which resulted in T-cell engraftment. Nonetheless, his condition continued to deteriorate, and he died 1.5 months after receiving the transplant. RNA sequencing of a brain biopsy sample obtained 2 months after the onset of symptoms showed the presence of human coronavirus OC43 (HCoV-OC43), which was sub- sequently confirmed on real-time PCR (threshold cycle, 24) and brain immunohistochemical analysis (Fig. 1). Full details on the case history, library preparation, bioinformatics analysis, species identification as reported by the profiling method metaMix, 2 PCR confirmation, immunohistochemical analysis, and phylogenetic and variant analyses are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.The human betacoronaviruses, including HCoV-OC43, are predominantly associated with respiratory tract infections. The group includes viruses that cause the severe acute respiratory syndrome and the Middle East respiratory syndrome. HCoV-OC43 is generally associated with mild upper respiratory tract infections, although it has been shown to have neuroinvasive properties. In vivo studies in mice have shown that HCoV-OC43 can infect neurons and cause encephalitis.3 The virus has also been shown to cause persistent infections in human neural-cell lines. 4 A single report identified HCoV-OC43 RNA in the cerebrospinal fluid of a child with acute disseminated encephalomyelitis. 5 In the case we describe here, three independent methods were used to identify HCoV-OC43 in brain tissue of a child with acute encephalomyelitis.Deep sequencing of biopsy material provides an important tool for the diagnosis of unexplained encephalomyelitis, particularly in patients with immunodeficiency who have undergone stem-cell transplantation, when the differential diagnosis may include immune-mediated inflammation or drug toxicity. The identificatio...
Type I interferon (IFN-α/β) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis following inoculation of the live-attenuated measles, mumps and rubella (MMR) vaccine. By targeted resequencing we identified a homozygous mutation in the high-affinity * Correspondence to: christopher.duncan@ncl.ac.uk or sophie.hambleton@ncl.ac.uk.
There is increasing evidence of a role for NGS in the work-up of undiagnosed encephalitis. Lower costs and increasing accessibility of these technologies will facilitate larger studies of these patients. We recommend NGS should be considered as a front-line diagnostic test in chronic and recurring presentations and, given current sample-to-result turn-around times, as second-line in acute cases of encephalitis.
Brain biopsy from a child with unknown cause of encephalopathy was deep-sequenced. Astrovirus VA1/HMO-C was identified, highly divergent from human astroviruses and 95% identical to astrovirus previously associated with encephalitis. Findings suggest astrovirus VA1/HMO-C is an under-recognized cause of viral encephalitis.
Noroviruses are a leading cause of human gastroenteritis worldwide. The norovirus genotype GII.4 is the most prevalent genotype in the human population and has caused six pandemics since 1995. A novel norovirus lineage containing the GII.P16 polymerase and pandemic GII.4 Sydney 2012 capsid was recently detected in Asia and Germany. We demonstrate that this lineage is also circulating within the UK and USA and has been circulating since October 2014 or earlier. While the lineage does not contain unique substitutions in the capsid, it does contain polymerase substitutions close to positions known to influence polymerase function and virus transmission. These polymerase substitutions are shared with a GII.P16-GII.2 virus that dominated outbreaks in Germany in Winter 2016. We suggest that the substitutions in the polymerase may have resulted in a more transmissible virus and the combination of this polymerase and the pandemic GII.4 capsid may result in a highly transmissible virus. Further surveillance efforts will be required to determine whether the GII.P16-GII.4 Sydney 2012 lineage increases in frequency over the coming months.
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