Astroviruses-Emerging Neurotropic Pathogens.

Viral encephalitis has a complex origin, with >100 viruses implicated in its etiology. Furthermore, a significant fraction of suspected cases of viral encephalitis defy conventional efforts at microbial diagnosis and have no attributable etiology. For example, the California Encephalitis Project [1] analyzed encephalitis cases in the United States by using a combination of nucleic acid–based, serological, and culturebased assays against a broad panel of potential etiologic agents. Despite these extensive efforts, >60% of the cases were negative in all the assays. In recent years, new developments in technology have facilitated the emergence of novel approaches to microbial diagnosis that vary from the traditional “1 agent, 1 assay” paradigm. In particular, high-throughput sequencing (HTS)–based detection of microbial nucleic acids is, in principle, unbiased and can systematically detect all microbes present in a specimen. Such methods rely on (1) the availability of suitably collected and preserved clinical specimens, (2) sequencing of nucleic acids in the specimens to sufficient depth, and (3) bioinformatic analysis to identify sequences of microbial origin. Although still used primarily in research settings, nascent efforts to apply these methods to challenging diagnostic cases are emerging. In this issue of the Journal of Pediatric Infectious Diseases, Fremond et al [2] used HTS for the diagnostic evaluation of a 14-year-old patient with X-linked agammaglobulinemia suffering from encephalitis. From RNA extracted from a brain biopsy specimen, the authors sequenced the genome of a virus very closely related to the astrovirus VA1/HMO-C. Viruses in the family Astroviridae are generally considered to be diarrheacausing pathogens limited to the gastrointestinal tract. In humans, the first astrovirus was discovered in 1975, and subsequently, 8 closely related serotypes have been identified. More recently, astrovirus VA1/HMO-C, which is highly divergent from the classic human astroviruses and is the prototype of a distinct evolutionary clade of astroviruses, was found in 2009 in fecal samples from an unexplained outbreak of gastroenteritis in the United States [3] and also in stool from children in Nepal [4]. Subsequent serological analysis revealed that infection with astrovirus VA1/HMO-C is common; 65% of adults are antibody positive [5]. This case represents the fourth example wherein the application of HTS has identified a virus closely related to astrovirus VA1/HMO-C in brain tissue of immunocompromised patients with encephalitis. The first case described in 2010 was of a 15-year-old patient who also had X-linked agammaglobulinemia [6]. HTS identified multiple astrovirus reads, and these results were further confirmed by immunohistochemical staining, which detected astrovirus capsid protein in astrocytes in the brain. Earlier this year, 2 additional fatal encephalitis cases in which astrovirus VA1/HMOC was found were reported; both patients, an adult [7] and a child [8], were transplant recipients. A common feature to all 4 cases was the detection of the virus in brain biopsy specimens. As in the previous case, the sequencing results were confirmed by immunohistochemistry or in situ hybridization. Collectively, these 4 independent case reports show the ability of astrovirus VA1/HMO-C to infect the brain and incriminate this virus as an etiologic agent of encephalitis, at least in the context of immunosuppression. In addition to astrovirus VA1/HMOC, classic human astrovirus was also implicated recently in neurological disease. Astrovirus serotype 4 was detected in brain tissue, as well as in blood, stool, and multiple additional organs, in a 3-month-old patient with severe combined immunodeficiency and meningoencephalitis who had undergone a bone marrow transplant Editorial Commentary