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Newly Identified Viruses in Human Gastroenteritis Mahalakshmi PIDJ ESPID REPORTS AND REVIEWS PIDJ-215-932 CONTENTS Viruses in Human Gastroenteritis ESPID Reports and Reviews EDITORIAL BOARD Co-Editors: Delane Shingadia and Nicole Ritz Smits et al Board Members David Burgner (Melbourne, Cristiana Nascimento-Carvalho George Syrogiannopoulos Australia) (Bahia, Brazil) (Larissa, Greece) XXX Kow-Tong Chen (Tainan,Taiwan) Ville Peltola (Turku, Finland) Tobias Tenenbaum (Mannhein, Germany) Luisa Galli (Florence, Italy) Emmanuel Roilides (Thessaloniki, Marc Tebruegge (Southampton, UK) Steve Graham (Melbourne, Greece) Marceline van Furth (Amsterdam, Australia) Ira Shah (Mumbai, India) Pediatr Infect Dis J The Netherlands) Lippincott Williams & Wilkins Newly Identified Viruses in Human Gastroenteritis Hagerstown, MD Pathogens or Not? Saskia L. Smits, PhD,* Albert D.M.E. Osterhaus, PhD,†‡§ and Marion P. Koopmans, PhD*¶ Key Words: human, gastroenteritis, diarrhea, rotavirus A, norovirus, sapovirus, enteric ade- which information is relevant for patient man- virus, pathogen, age, viral metagenomics, disease, noviruses and astrovirus. In addition to these agement, and for the public health professional picornavirus, polyomavirus, parvovirus, picobirna- well-established etiologies, a large number of focusing on population health decisions. The virus, astrovirus, case-control moderate to severe diarrhea cases go without expanding universe of microbes, discovered etiological diagnosis and many unanswered through virome and microbiome studies, has questions surrounding the burden and etiol- opened an entirely new field of research, seek- ogy of diarrhea, and the factors determining ing to understand the interactions between hosts nfectious diarrheal diseases remain a com- clinical expression of infection remain. and the “healthy” and disease causing microor- Imon cause of morbidity and mortality Sequence-independent amplification of ganisms that inhabit the human body. This is especially in children younger than 5 years in nucleic acids combined with next-generation 1 particularly the case for the gut microbiome low-income and middle-income countries. sequencing technology and bioinformatics and virome, which not only consists of human- 2015 The most common viral pathogens known analyses or viral metagenomics is a relatively associated microbes but also reflect the host to cause acute gastroenteritis in humans are new strategy for rapid identification of viruses environment. Viruses identified in human stool From the *Department of Viroscience, Erasmus Medi- in clinical and public health settings. In contrast samples may originate from a dietary source cal Center, Rotterdam, The Netherlands; †Viroclin- to classical molecular detection techniques, or may replicate in the gut microbiota, such as ics Biosciences BV, Rotterdam, The Netherlands; even those detecting multiple viruses, viral bacteria, parasites, protozoan or nematodes. Copyright © 2015 Wolters Kluwer Health, Inc. All rights ‡Research Center for Emerging Infections and metagenomics theoretically allows the char- Even in the case of viruses with human tropism, Zoonoses, University of Veterinary Medicine, Han- acterization of the entire virome in a clinical reserved. nover, Germany; §Artemis One Health, Utrecht, not only many factors, such as immune status, The Netherlands; and ¶Virology Division, Centre sample, consisting of known pathogens, novel age and nutritional status, but also geographic 104 for Infectious Diseases Research, Diagnostics and pathogens that elude conventional testing, bac- location and even seasonal differences, play an Screening, National Institute for Public Health and teriophages, plant viruses and unannotated important role in the exposure to and clinical the Environment, Bilthoven, The Netherlands. 6 This work was partially funded by the European Com- sequences that may be of viral origin. Since the outcome of virus infection. Viruses may only 107 mission's COMPARE H2020 project under grant first applications of metagenomics to the field become pathogenic in the context of certain agreement No 643476, the Dutch government pro- of gastroenteritis,2,3 it has been increasingly host backgrounds (ie, immunodeficiency, coin- ject number FES0908, by Netherlands Genomics applied for virus discovery purposes resulting fections, genetic factors), exemplified by sim- Initiative (NGI) project number 050-060-452, and 0891-3668 ZonMW TOP project 91213058. in the identification of a plethora of previously ian immunodeficiency virus infections in dif- Address for correspondence: Saskia Smits, Depart- unknown viruses in human and animal enteric ferent primate host species.7 This underlines the ment of Viroscience, Erasmus MC, P.O. Box 2040, specimens.4 Many previously unknown viruses importance of studying both host and pathogen 10.1097/INF.0000000000000950 3000 Rotterdam, Netherlands, E-mail: s.smits@ have been characterized in human stool alone erasmusmc.nl. parameters in an integrated way in pathogenic- Supplemental digital content is available for this arti- in recent years, such as salivirus, cosavirus, ity studies. cle. Direct URL citations appear in the printed bufavirus, picobirnavirus, recovirus, anellovi- The Pediatric Infectious Disease Journal text and are provided in the HTML and PDF rus, astrovirus, circovirus and polyomavirus versions of this article on the journal’s website (see Table, Supplemental Digital Content 1, NEWLY IDENTIFIED VIRUSES (www.pidj.com). http://links.lww.com/INF/C297).5 IN HUMAN GASTROENTERITIS: Copyright © 2015 Wolters Kluwer Health, Inc. All PATHOGENS OR NOT? 35 rights reserved. The increasing application of such ISSN: 0891-3668/16/3501-0104 “unbiased” or catch all detection methods raises Establishing disease causation in the DOI: 10.1097/INF.0000000000000950 questions for the clinician, trying to understand molecular era has been debated since the start 1 The ESPID Reports and Reviews of Pediatric Infectious Diseases series topics, authors and contents are chosen and approved independently by the Editorial Board of ESPID. January 104 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 35, Number 1, January 2016 2016 Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. The Pediatric Infectious Disease Journal • Volume 35, Number 1, January 2016 ESPID Reports and Reviews of the use of molecular detection techniques virus neutralization assays in Africa, Asia Salivirus in biomedical research laboratories.8 Fulfill- and Europe revealed that generally 75% of Since the identification of saliviruses, ing Koch postulates for all newly identified children <24 months are seropositive versus they have been detected in stool samples viruses remains unlikely. Comparing viral >90% in older children and adults.13,15 This of children with gastroenteritis worldwide, incidence or prevalence in diseased versus epidemiologic pattern suggests that cardiovi- with prevalence rates ranging from 2.1% to matched controls, seroconversion and/or rus infection is acquired early in life, similar 8.6%.10,11,22 A possible association was reported detection of antigen/nucleic acid in affected to other viruses in the family Picornaviridae. between salivirus detection and gastroenteritis tissue may aid in studying viral pathogenic- So far, epidemiological studies and 2 case- in case-control studies.10,23,24 However, the virus ity. As nicely reviewed previously,9 major control studies in young children have failed has also been detected in healthy children and hurdles exist in performing these types of to provide a clear picture of the relationship in association with other known enteric patho- studies. The comparison of virus preva- between cardiovirus infection and actual dis- genic viruses, such as norovirus and adenovi- lence in disease cases with healthy controls ease in humans.10,12 Rather, available data rus, and thus, indicating that the potential asso- requires careful subject matching to preclude suggest that saffold viruses rarely cause dis- ciation of salivirus with enteric disease needs misleading results explained by host differ- ease and most likely go unnoticed in a high to be studied in more detail, similar to other ences instead of viral pathogenicity. Healthy proportion of infections.11,16 However, this is members of the family Picornaviridae.22,23 control samples are often a limiting factor, as also the case for other picornaviruses, that these are not ordinarily collected in medical nonetheless cause serious disease: for polio, Polyomaviridae settings. Measurement of antibody responses an estimated 1:100 to 1:1000 infected indi- Virus discovery programs using clini- requires (often difficult) cell culture systems viduals develop neurological illness. Such cal samples from a range of conditions have and/or proper antigen synthesis and positive disease associations, however, cannot be yielded multiple newly identified viruses control sera, and biopsy results of patients for detected through the studies that have been in the family Polyomaviridae, including KI antigen detection are often not available.9 In conducted so far. polyomavirus (KIPyV), WU polyomavi- addition, the extent of viral genetic and phe- rus (WUPyV), Merkel cell polyomavirus notypic diversity is complicating develop- (MCPyV), human polyomavirus 6 (HPyV6), ment of specific and sensitive assays. Thus, Cosavirus HPyV7, trichodysplasia spinulosa-associated finding a new virus does not automatically Cosaviruses are classified into 5 polyomavirus, HPyV9, MW polyomavirus mean
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