ESPID Reports and Reviews

CONTENTS
Viruses in Human Gastroenteritis

EDITORIAL BOARD
Co-Editors: Delane Shingadia and Nicole Ritz
Board Members
David Burgner (Melbourne, Cristiana Nascimento-Carvalho George Syrogiannopoulos
Australia) (Bahia, Brazil) (Larissa, Greece)
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) The Netherlands)

Newly Identified Viruses in Human Gastroenteritis

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
I nfectious diarrheal diseases remain a com-
mon cause of morbidity and mortality
especially in children younger than 5 years in
clinical expression of infection remain.
Sequence-independent amplification of
and the healthy and disease causing microor-
ganisms that inhabit the human body. This is
nucleic acids combined with next-generation particularly the case for the gut microbiome
low-income and middle-income countries.1 sequencing technology and bioinformatics and virome, which not only consists of human-
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.
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-
nover, Germany; Artemis One Health, Utrecht,
acterization of the entire virome in a clinical 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
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.
This work was partially funded by the European Com- sequences that may be of viral origin. Since the outcome of virus infection.6 Viruses may only
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
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
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-
text and are provided in the HTML and PDF rus, astrovirus, circovirus and polyomavirus
versions of this article on the journals 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?
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

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.

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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 unveiling its clinical significance as is different species11 and were originally (MWPyV), HPyV10, MX polyomavirus, STL
highlighted below by conveying what is cur- identified in 2008 in the feces of South polyomavirus and HPyV12. A case-control
rently known of a subset of the most studied Asian children with non-polio acute flac- study to explore the prevalence of 10 human
viruses, focusing on virus families known to cid paralysis17 and shown to be present at polyomaviruses (BKPyV, JCPyV, KIPyV,
infect vertebrates and for which case-control high prevalence in feces of both healthy WUPyV, MCPyV, HPyV6, HPyV7, trichod-
studies were conducted (see Table, Supple- (44% and 25.4%) and paralyzed (49% ysplasia spinulosa-associated polyomavirus,
mental Digital Content 1, http://links.lww. and 42.8%) children from Pakistan and HPyV9 and MWPyV) was conducted in
com/INF/C297). Tunisia, respectively.17,18 In China, cosavi- China by testing fecal specimens from 211
rus was detected in children with (3.2%) hospitalized children with diarrhea and from
Picornaviridae and without (1.6%) diarrhea.19 Cosavirus 208 asymptomatic control subjects collected
Many new viruses belonging to the prevalence was also reported in the feces between April 2011 and January 2012.25
family Picornaviridae have been identified of healthy Brazilian children from a com- Only KIPyV (0.5 and 0%), WUPyV (4.3%
in recent years in stool samples. The Picor- munity child-care center (49% in 2008 and and 1.9%), MCPyV (30.3% and 27.9%) and
naviridae family contains human and animal 6.5% in 2011) and with gastroenteritis in MWPyV (1.4% and 2.9%) were detected in
viruses of considerable clinical and socioeco- a pediatrics department (3.6%).20 Strong healthy controls and children with diarrhea,
nomic importance, such as enterovirus, pare- associations of cosavirus infection with respectively.25 STL polyomavirus was present
chovirus and hepatitis A virus. In addition, 4 gastroenteritis were not obtained. in 2.2% of hospitalized Chinese children with
new genera are recognized: cardiovirus (saf- gastroenteritis and 3.0% of healthy children.26
fold virus), cosavirus, kobuvirus (Aichivirus) Despite the relatively frequent detection of
and salivirus (klassevirus), viruses which Kobuvirus (some of the) human polyomaviruses in fecal
were identified in human stool but for which The Kobuvirus genus contains 3 spe- samples, a causative role of polyomaviruses in
the clinical significance in gastroenteritis or cies, Aichivirus AC, of which only Aichi- gastroenteritis was not supported.25
other disease syndromes remains unclear.10,11 virus 1 from species A infects humans.21
Seroprevalence studies performed in Asia, Parvoviridae
Europe and North Africa demonstrated high New human bocaviruses (HBoVs)
Cardiovirus levels of Aichivirus 1 antibodies (8099%) and bufaviruses were identified in the family
Phylogenetic analysis suggests the in adults, suggesting a worldwide distribu- Parvoviridae. HBoV subtypes 14 have been
existence of 8 distinct genetic saffold virus tion of the virus.21 In contrast, much lower detected in respiratory and gastrointestinal
lineages. Screening for cardiovirus infec- reverse-transcriptionPCR prevalence data infections worldwide.27 In contrast to HBoV1,
tions has occurred in many countries, includ- were obtained, with Aichivirus 1 being HBoV2, HBoV3 and HBoV4 occur mainly in
ing Afghanistan, Canada, China, Germany, detected in 0.5%3% of human gastroen- stool.28 HBoV2 is the most common with PCR
Pakistan and the US, showing that this virus teritis cases in Asia, Europe, South-Amer- prevalence up to 26%, followed by HBoV3
has spread worldwide with polymerase chain ica and Africa, similar to observations with (5%) and HBoV4 (2%). The detection rates in
reaction (PCR) prevalence rates in enteric saffold viruses.10,11,20,21 The epidemiological adults may be lower than in children.28 Case-
specimens ranging from 0.5% to 12%.1015 data suggest that the virus might circulate control studies to investigate a link between
Cardioviruses are mostly found in infants without causing any symptoms or with bocavirus 1 and gastroenteritis in China
and children <6 years of age.1015 Seropreva- mild symptoms that do not require medical between 2006 and 2008 showed no statisti-
lence studies of saffold viruses 2 and 3 using attention. cally significant differences in the prevalence

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Copyright 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Smits et al The Pediatric Infectious Disease Journal Volume 35, Number 1, January 2016

(3.5%4.3%), clinical disease presentation Nevertheless, viral metagenomics can be food safety), the type of pathogen (viruses,
and virus loads between children with and used as a potentially cost-saving research bacteria and parasites) and the sample type.
without gastroenteritis.29,30 Human bocavirus tool to study viral incidence, level of viral The primary sequence output and derived
2 was detected at much higher prevalences of coinfections and their correlation to clini- data, such as assemblies and functional
20.4% and 12.3% in children with diarrhea and cal diarrheic disease in well-designed cohort annotation data, in combination with associ-
healthy controls, respectively.30 An association studies in the years to come and to resolve ated clinical, microbiological, and epidemi-
of human bocavirus 2 infection and acute gas- some of the outstanding questions simultane- ological data would lead to a more in depth
troenteritis was shown in a case-control study ously for a wide range of viruses. Provided view of the human virome in correlation to
in Australian children, but not in adults or chil- samples from large enough matched cohorts disease. This does require engagement of
dren in the United Kingdom.31,32 Bufaviruses are analyzed from different human popula- clinicians, bioinformaticians, epidemiolo-
were first detected in West African children tions with and without disease, the obtained gists and laboratory scientists, to fully cap-
with diarrhea33 and have subsequently been data may not only provide basic insight into ture the potential of these novel technologies
shown in diarrhea specimens from all over the the viral burden of diarrhea in general instead for infectious disease research.
world with PCR prevalence rates between 0.8% of focusing on one or a few viral pathogens
and 4% in patients with gastroenteritis.34,35 as is classically done, but it may allow (i) elu-
cidation of viral pathogens or combinations
ACKNOWLEDGMENTS
Astroviridae of pathogens involved in disease burden, This work was partially funded by the
(ii) surveillance for as yet unidentified enteric European Commission COMPARE H2020
The classic human astroviruses sero-
viruses and zoonotic events, (iii) the study of project under grant agreement No 643476,
types 18 have been associated with acute
effects of vaccination on viral incidence lev- the Dutch government project number
gastroenteritis in humans. Many more differ-
els (eg, rotavirus) and whether other viruses FES0908, by Netherlands Genomics Initia-
ent human astroviruses have been identified
fill the niche that vaccination leaves behind tive (NGI) project number 050-060-452 and
in diarrhea specimens in recent years, such
and (iv) an appraisal of host differences in ZonMW TOP project 91213058.
as MLB1-3 and VA1-4, which seem to have a
worldwide distribution.36 A case-control study viral disease burden. Theoretically, it would
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The Pediatric Infectious Disease Journal Volume 35, Number 1, January 2016 ESPID Reports and Reviews

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