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The Etiology of Viral Diarrhea in Children

CHAPTER · JULY 2013

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The Etiology of Viral Diarrhea in
Children
Hamsa T Tayeb*
Department of Genetics, King Faisal Specialist Hospital & Research
Center, P.O.Box 3354, Riyadh 11211, Saudi Arabia
*Corresponding author: Dr. Hamsa T. Tayeb, Department of
Genetics, King Faisal Specialist Hospital & Research Center, P.O.Box
3354, Riyadh 11211, Saudi Arabia, Tel:+966-1-5577607; E-mail:
Hamsa3000@hotmail.com

Introduction
Acute viral gastroenteritis is among the most common causes of mortality and morbidity worldwide [1]. In developing
countries mortality associated with diarrhea is estimated as 2.4-2.8 million deaths every year [2,3]. About half these cases are
believed to be viral in origin and mortality is largely restricted to children below 5y in the developing world. It is also a significant
cause of morbidity in the same age group in developed countries [4] although deaths are fewer. The association of these viral agents
with gastroenteritis has prompted the studies of their classification, epidemiology, and immunity, as well as the development of
diagnostic tests. Methods of management and, most importantly, disease prevention (such as vaccine development for rotavirus)
have been reported [5,6]. The viruses exhibit similarities in their clinical, epidemiological and pathological effects but differ in
relation to the preferred host in which they induce disease.
Epidemiological studies have shown that rotaviruses astroviruses, enteric adenoviruses (serotypes 40 and 41), and caliciviruses
family mostly in developed cuntreas are the principal cause of acute gastroenteritis in infants and young children (six years of age
or less) [7-9]. The principal source of epidemic viral gastroenteritis is person to person and contaminated water or food [10,11].
Infections are commonly characterized by severe watery diarrhea leading to isotonic dehydration in infants and young children
and accompanied in some cases with nausea, vomiting, abdominal cramps, headache and fever [11]. Across the world it has been
found that the same viruses induce diarrhea, although the frequency of each and the outcomes of infection may vary. The main
viruses concerned are the human rotaviruses (HRV); enteric adenoviruses (EAdV); human astroviruses (HAstV) and the human
caliciviruses (Norovirus and Sapovirus, NoV and SaV respectively). The basic properties of each virus and the type of illness induced
are given in the table below (Table 1). Each agent is considered in more detail below.

Virus Family Size EM shape Nucleic acid Characterization

ds segmented Groups A,B,C has 2 subgroups multiple serotypes Classified
Rotavirus Reovirida 70 nm Wheel-shaped
RNA on the basisof two outer capsidproteins (P &G)
Adenovirus Adenovirida 80 nm Icosahedrial dsDNA Enteric serotypes 40, 41, 31, and types 42-48
Astrovirus Astrovirida 28-30 nm Star-shaped morphology ss(+)RNA 8 serotypes
Small round Structured
Calicivirus Calicivirida 28-35 nm ss(+)RNA Two genogroups:Norwalk-lik viruses and, Sapporo-like viruses
viruses with calices
Table 1: The main gastroenteritis viruses concerned are the human rotaviruses (HRV); enteric adenoviruses (EAdV); human astroviruses(HAstV) and the
human caliciviruses (Norovirus and Sapovirus, NoV and SaV respectively) [1,65,118-119].

Human rotavirus (HRV)

Rotaviruses are members of the Reoviridae, whose members possess a double layer of icosahedral shells, approximately 70
nm in diameter. The rotavirus is a non-enveloped particle double stranded RNA genome consists of 11 gene segments, which can
be separated by polyacrylamide gel electrophoresis [7]. Two major types, termed the long and short RNA electrophoretypes, are
currently recognized based on differences in the relative migration patterns of segments 10 and 11 in polyacrylamide gels.
The genome is enclosed by a triple layered protein capsid, consisting of outer capsid proteins VP4 and VP7 and inner capsid
proteins VP6 and the core protein VP1, VP2 and VP3 [12] (Figure 1). HRV is resistant to chloroform, ether, other fluorocarbons,
CsCl, non-ionic detergents, and pH 3-9, but are inactivated by by ethanol, phenol, bleach and formaldehyde [13]. Based on group
specificity, which is conferred predominantly by VP6, rotaviruses are divided into 7 groups, A-G. HVR-associated infections are
predominantly caused by group A, and less commonly by group B or C.
Among diarrhea viruses, rotavirus remains by far the most important cause of infantile gastroenteritis and mortality worldwide
and has been the focus of intensive investigation. It is estimated that in developing countries ,severe dehydrating diarrhea, caused
by human rotavirus (HRV) resultes in an estimated 500,000 to 870,000 childhood deaths annually [5,6]. Group A rotaviruses are the
most common, accounting for 20% to 70% of all hospitalized patients for diarrhea worldwide [4,14,15]. Group B rotaviruses, also
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known as adult diarrhea rotaviruses (ADRV), have been associated with epidemic outbreaks of waterborne diarrheal disease among
adults and were first reported in China [16] and more recently in India [17]. Group C rotaviruses have been detected worldwide and
are primarily associated with sporadic cases of diarrhea among both children and adults.
RV genotypes, serotypes and variants
The outer layer of the rotavirus capsid is formed of two proteins; the glycoprotein VP7 and the protease-sensitive Vp4. These
are the main antigens responsible for inducing neutralizing immune responses [18]. Each of the surface proteins exist in a limited 002
 Knob Domain

Fiber
Penton Base

Hexon Linear Genomic DNA

Core Protein
Terminal Protein

Figure 1: Adenoviruses are non-enveloped, regular icosahedral particles displaying 20 triangular faces and 12 vertices. A fiber projects from
each of the vertex and differs with serotype The capsid encloses the virus genome which is double-stranded, linear DNA with a size of 30-38kbp.

number of antigenic variants, thus we can recognise distinct “types” of both VP4 and 7. These are termed G types (for glycoprotein)
relating to VP7 and P types (protease sensitive) relating to VP4. To date, 14 G serotypes (G1-14) and 11 P (P1-11) serotypes have
been described for group A viruses and most are found in viruses infecting both humans and animals [19]. Ten G serotypes and 7 P
serotypes have been identified in human strains of virus each specified by a distinct RNA segment. The genes encoding VP7 (G) and
VP4 (P) proteins are highly polymorphic and the segmented nature of the genome permits easy reassortment from a mixed infection.
Thus each protein may be inherited independently permitting a great number of different combinations and generating a spectrum of
antigenic possibilities for reassortant viruses. Genotypes of rotavirus have been identified and found to correlate with the corresponding
serotypes [20,21]. Eighty different strains of rotavirus could result from various combination of the known 10 G and 8 P serotypes
of HRV and the most prevalent type varies considerably from one geographic area to another. Types G1-G4 are the most common
serotypes globaly [22] but unusual strains are predominate in some developing countries, such as the [P6] strains found in India, and
Saudi Arabia (G1[P6], G2[P6], G3[P6], G4[P6]), and the extremely atypical G9[P6] [Ramachandran et al., 1996; Tayeb et al 2008].
Epidemiology of HRV infection
The epidemiologic studies emerging from both the developed and developing countries show that rotaviruses are the major
etiologic agents of serious diarrheal illness in infants and young children under 2 years of age. Generally, two patterns of disease are
noted, endemic and epidemic diarrhea. Typically, children suffer serial bouts of infection by strains inducing endemic diarrhea in their
communities,. Greater than 90% of children have developed antibody to group A rotavirus by age 3. Superimposed on this pattern are
the epidemic strains which typically include rotavirus groups B and C. These outbreaks often result from a contaminated food or water
source [11,23]. In temperate countries, rotavirus is the main cause of winter gastroenteritis, while in tropical and developing countries
diarrhea occurs all year round, with a peak in summer. Outbreaks of HRV infection in adults are unusual because of the level of
rotavirus immunity that most adults have acquired from previous infections although subclinical infections may occur throughout life
providing another means for maintaining the virus as an endemic infection within the community. Occasionally these infections can
cause illness in parents of children with rotavirus diarrhea, exhibiting gastrointestinal symptoms such as diarrhea or abdominal cramps.
The less usual viruses, to which adults may not have been exposed as children can still cause adult infections and several large outbreaks
amongst adults have been reported caused by group B rotaviruses in various parts of the world [24,25]. In China, reports described
12,000 to 20,000 adult individuals who developed cholera-like, watery diarrhea with a few deaths of elderly [26-28]. Prevalence studies
have shown that serotypes G1-G4 are the most common globally and account for almost all rotavirus gastroenteritis in humans [22,29].
These four common serotypes were, therefore, incorporated into Rotashield, the tetravalent rhesus monkey rotavirus-HRV reassortant
vaccine. Analysis of strains collected worldwide showed that the most common combination of rotavirus genotypes are [P8]G1, [P4]
G2, [P8]G3, and [P8]G4 [22,29]. However, other G serotypes have now been found to be common in several other regions of the world,
serotypes G5, G8 and G10 in Brazil [30], G8 in Malawi [31], and G9 in India, and Saudi Arabia [29,32].
Rotavirus infection in animals
Rotaviruses have a wide host range as indicated by their recovery from the newborn of many animal species [33]. They have also
been associated with diarrhea and respiratory illness in various animal species [34]. HRV strains induce diarrheal illness in newborn
animals such as gnotobiotic calves, conventional piglets, rhesus monkeys, gnotobiotic lambs, puppy dogs [35-37]. In China, a human
rotavirus was shown to induce a severe diarrhea illness in a non-human primate [38]. Rotaviruses are widely distributed in animals
and have been identified in almost every species. Animal strains do not always infect human or may cause few symptoms if they do so:
bovine rotaviruses have been suggested as possible immunogens ina Jennerian approach to vaccination for these viruses. However the
existence of strains that may infect both humans and animals generates an animal reservoir for viruses within which reassortants may
be generated in much the same way os for influenza. However the outcomes are less serious and global epidemics (pandemics) such as
those seen for influenza do not occur.
Control of Rotavirus Infection
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Attempts to develop vaccines have concentrated on endemic strains. Analysis of strains collected worldwide showed that the
most common combination of rotavirus genotypes are G1[P8], G2[P4], G3[P8], and G4[P8] [22]. Since serotypes G1-G4 are the most
common globally, accounting for almost all endemic rotavirus gastroenteritis [22,39]. These four serotypes were, incorporated into
Rotashield, the tetravalent rhesus monkey rotavirus-HRV reassortant vaccine [40,41]. Tetravalent rotavirus vaccine (RRV-TV)had
been developed to protect against the four epidemiological rotavirus serotypes. It was estimated that 1.5 million doses had been given.
Because of a number of intusssception cases were reported that prompted further investigation, Therefore, the Centers for Disease 003
Control and Prevention (CDC) in 1999 withdrew its recommendation for RRV-TV [42,43].
 However, other G serotypes have now been found to be common in several other regions of the world, serotypes G5, G8 and G10 in
Brazil [30], G8 in Malawi [31], G9 in India [32] and, G12 in Brazil [44] and this implies that modifications to the strains used in vaccine
preparation will be necessary for each region.
Since rotaviruses are the most common cause of severe diarrhea in infants and children worldwide. The vaccines development
program continues to receive attention. There are a variety of vaccines currently in and, some are available in the market (Table 2).

Vaccine Serotype Concept Status Company/Inventor

Pentavalent vaccine, modified WC3-QV to
Merck/HF Clark [Clark et al., 2003; Orellana et
RotaTeq G1, 2, 3, 4 P1A[8], 5 also contain VP7 gene from human serotype Phase III
al., 2003]
G4
Quadrivalent vaccine, human-bovine re-
WC3-QV G1, 2, 3 P1A[8], 5 assortants; bovine parent strain (WC3) with 3 Phase III Merck/HF Clark
VP7 and 1 VP4 genes from human strains
Monovalent vaccine, symptomatic human GSK/RL Ward and DI Berstein [Vesikari et al.,
Rotarix G1 P1A[8] Phase III
rotavirus strain 89-12 2004; Clemens et al., 2004]

Lanshou Institute of Biological Products,

LLR G10 P[12] Monovalent vaccine, lamb rotavirus Licenced, China, 2000
China/Z-S Bai [Kirkwood et al., 2003]

RV3 G3 P2[6] Monovalent vaccine, human neonatal strain Phase II Biofarm Indonesia/RF Bishop and GL Barnes
116E G9 P[11] Monovalent vaccine, human neonatal strain Phase I Bharat Biotech India/BK Das and RI Glass
Monovalent vaccine natural human/bovine
I321 G10 P[11] Phase I Bharat Biotech India/BK Das and RI Glass
reassortant
Table 2: Over view of rotavirus vaccines [120].

Human adenoviruses (HAdV)

Adenoviruses belong to family Adenoviridae, which is divided into two genera, Mastadenovirus and Avidenovirus [45].
Mastadenovirus genus includes human, simian, bovine, equine, porcine, ovine, canine, and opossum viruses. There are some 51 types
of human adenovirus have been dividedinto six roups, A through F, based on various biologicaland morphological criteria [46]. The
enteric viruses together comprise group F. Although types 42 and above have only been reported in AIDS patients. Most of these types
have a propensity to replicate in the gut and can often be recovered from faeces even if the major site of symptomatic infection in the
body lies elsewhere (eg respiratory or ocular). These viruses are usually shed in small numbers from the gut and can be readily cultured
in cell lines. However seroypes 40 and 41 are true enteric virusesfor whom the gut is the target tissue. Symptoms when they occurr are
those of gastroenteritis. These viruses are shed from the gut in large numbers but cannot be grown in normal cell cultures. These two
classes of virus have been termed the fastidious (types 40/41) and the non-fastidious (all other types) of adenoviruses [47,48].
Virological characteristics of HAdV
Adenoviruses are non-enveloped, regular icosahedral particles displaying 20 triangular faces and 12 vertices. A fiber projects from
each of the vertex and differs with serotype [45,49] (Figure 1). The virus capsid is composed of 252 morphological units (each of which
is a multimer of virus coat proteins) 240 of these are multimers of a protein termed hexon protein. The resuting nonamer is termed
a hexon because they are distributed across the virus coat in groups of 6. Twelve capsomers are constructed from a different protein
termed penton. These multimers occur in groups 5 and are located at each vertex of the icosahedron [50]. The capsid encloses the virus
genome which is double-stranded, linear DNA with a size of 30-38kbp. The virus has no membrane or lipids and is, therefore, stable in
solvents such as ether and ethanol.

Enteric HAdV (EAdV)

The enteric adenoviruses together comprise group F adenoviruses. Prior to their serological and genomic characterization, these
viruses were described as fastidious adenoviruses that were cultivable only in human embryonic kidney (HEK) cell line [47]. Later these
were found to consist of two distinct viruses differing serologically and in sequence or restriction endonuclease digestion products and
designated Ad40 and Ad41 [51,52], nucleic acid hybridization [53], and detection by the polymerase chain reaction (PCR) [54].
The total length of the DNA was estimated to be 34.0 kb for Ad40 and 34.7 kb for Ad41. DNA homology studies have shown that,
the Ad40 and Ad41 genomes have 62-69% identity [55,56]. Eleven Ad40 DNA variants (D1-D11) and 28 Ad41 DNA variants (D1-D28)
have been described, [55,57].
Epidemiology of EAdV infection
EAdV types 40 and 41 appear to be endemic in most countries [51,58-62]. EAdV cause 5-17% of cases of gastroenteritis in infants
and preschool children [63,64]. Peak incidence is among children under 2 years of age and shows very little variation in shedding
rates [29,60,62]. Infections occur throughout the year with no clear peaks. Adult contacts were infrequently affected with or without
symptoms although some cases have been observed in the elderly [65].

Human astroviruses (HAstV)

Human astroviruses (HAstV) are non-enveloped virusesthat were first detected by electron microscopy (EM) in 1975 in stool
specimens from infants with diarrhea [66,67]. HAstV are a common cause of sporadic cases and outbreaks of viral diarrhea among
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young children [68]. HAstV is also a common agent in persistent diarrhea, which is a significant public health problem in developing
countries [69].
Virological characteristics of HAstV
Astroviruses are small, non-enveloped, viruses and are 28-30 nm in diameter. Initially characterised as having a smooth margin it is
now clear that they actually have surface projections which are sometimes ill defined. The viruses exhibit a 5 or 6 pointed star-like motif 004
on their surfaces although this is also often not clear (Figures 2 and 3).
 Rotavirus
Rotaviru
r s
ru Adenoviru
r s
ru
Adenovirus

Caliclvirus
Caliclviru
r s
ru Astroviru
r s
ru
Astrovirus
Figure 2: Electron microscopy image for viral agent of gastroenteritis.

Figure 3: EM image of astroviruses exhibit a 5 or 6 pointed star-like motif on their surfaces although this is also often not clear.

The genome consists of positive sense, single-stranded RNA approximately 6,800 nucleotides in length. The genome is composed
of three open reading frames which encode both a full genomic and a sub genomic RNA (ORF 1a,ORF 1b, and ORF 2) [70,71].
Eight serotypes of HAstV have been identified, according to the reactivity of the capsid proteins with polyclonal sera and monoclonal
antibodies, but type 7 is extremely rare. Human faecal astrovirus can be grown in a continuous colonic carcinoma (CaCO-2) cell line
[72,73]. The full details of the replication cycle are not known, but it is suspected that replication occurs primarily in the cytoplasm in a
manner analogous to that of the picornaviruses although there is a possible nucelear involvement [71].
Epidemiology of HAst infection
HAstV cause infectious diarrhea worldwide and account for 2-8% of cases of diarrhea in infants and young children. Symptomatic
virus shedding has been noted in the newborn, although asymptomatic infections have been noted. Symptomatic illness occurs rarely in
adults [74,75]. Astroviruses are not only responsible for causing gastrointestinal disorders in humans, but also in cats, dogs, lambs, deer,
mice, and cows. The development of more advanced methods of detection such as enzyme-linked immunosorbent assays (ELISA) and
reverse transcription-polymerase chain reaction (RT-PCR) have revealed that astroviruses are a common cause of viral gastroenteritis
in children worldwide [76]. Studies have shown a prevalence of 8.6% in Thailand [77], 4.2% in Melbourne [78], and 61% in Chiapas,
Mexico [74]. Most of children are infected in the first 2 years of life and producing early immunity to astroviruses. Astrovirus infections
are detected in winter [76].
Prevalence of HAstV Serotypes
Numerous studies indicate that HAstV serotype 1 is the most predominant serotype worldwide. An enzyme immunoassay typing
(TYPE-EIA) method showed that among 64 astrovirus-positive specimens collected from seven different countries, 52% were astrovirus
serotype 1, 11% were astrovirus serotype 2, 16% were astrovirus serotype 3, 10% were astrovirus serotype 4, 2% were astrovirus serotype
5, 2% were astrovirus serotype 6, and 0% were astrovirus serotype 7 [72,79] confirmed the earlier work of Oxford and found that type
1 is the prevalent strain in the UK, accounting for some 86% of cases. However, this situation may be changing with the emergence of
more cases of astrovirus type 4 [80]. In contrast, type 2 was the most prevalent in Mexico City (35%) and type 1 was relatively rare (4%)
[81]. Foodborne transmission is not usually reproted; although an outbreak of food borne astrovirus infection was reported in Japan in
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1991 and associated with astrovirus type 6 [75,82]. In 2010 astrovirus type 8 been reported in Saudi Arabia as the most common type
detected out of 1.9% gastro infection caused by astrovirus [83]. This pattern of occurrence suggests that there may be a requirement for
a vaccine for these viruses although progress in this is not likely until HRV the more serious threat has been controlled [84].

Human Caliciviruses (HuCV)

Caliciviruses are single-stranded RNA viruses belong to family Caliciviride which are divided into 4 genera (Vesivirus,Lagovirus,
Norovirus and Sapovirus) [85]. Within the Caliciviride the Human strains, comprise two agents each found in a separate genus within
005
the family. The noroviruses (formerly the small round structured viruses and Norwalk-like viruses), and the sapoviruses, (formerly the
Human caliciviruses and Sapporo-like viruses). This family includes the most common cause of non-bacterial gastroenteritis amongst
adults [86,87].

Norovirus and Sapovirus

In 1968 an outbreak of acute gastroenteritis occurred amongst students and teachers in a school in Norwalk, Ohio [88]. The
infection was characterized by vomiting and diarrhea and showed a high attack rate and short incubation period. Attempts to propagate
the agent in cell, and organ culture failed [89]. In 1972, Kapikian used immune electron microscopy (IEM) to identify viral particles,
which became known as the Norwalk agent [90]. Initially these were reported as 27nm but this was later revised upwards to 34nm. The
particles were fuzzy and indistinct in outline but showed indications of surface structure reminiscent of the caliciviruses then known
in animals. The characteristic cup-like depressions were however almost always unclear. Similar studies later demonstrated that other
caliciviruses (now termed sapoviruses) were associated with a gastroenteritis outbreak in infants in Sapporo, Japan in 1977 [91]. These
particles resembled animal strains much more closely and did display the cup-like depression on the surface. These were termed human
caliciviruses and for some while it was not clear whether the noroviruses and sapoviruses were actually distinct types of virus. This
situation has now been resolved using molecular data to resolve these viruses into distinct genera by sequence comparison analysis.
More details regarding the differentiation between NoV and SaV genome are placed in the calicivirus genome structure section.
However, progress in the characterization of the human caliciviruses has been severely hampered by the lack of a cell culture system,
the low number of viruses often shed in stool during the infection and the absence of a reliable animal model. Recent developments
using molecular biology especially RT-PCR and sequencing have increased our knowledge and understanding of this group of viruses,
and the first successful culture in cells has now been reported [92].

Particle Structure
A Classification scheme described by Caul and Appleton in 1982, drew a morphological distinction between NoV and SaV, The
NoV have an amorphous structure with a ragged outer edge and SaV display the true cup-shaped structures from which the calicivirus
family derives its name. Both particles were approximately 30-35nm in diameter.
Both NoV and SaV have been subdivided by Cluster analysis into genogroups, these in turn have been divided into genotypes
(Figure 4). NoV with genogroups I and II, have been genotyped so far into 15 genotypes and SaV have been divided into 2 genogroups
with 4 genotypes [93,94]. For NoV genogroups I (GGI), includes Norwalk, Southampton, Desert shield, Queens arms, and Winchester
viruses. NoV genogroups II (GGII) includes Hawaii, Mexico, Lordsdale, Melksham, Hillingdon, Grimsby and others [95]. From
the epidemiological studies, the outbreak with GGII strains is relatively more common than GGI strains. Strains circulating in the
community vary with time [96,97]. For example in winter season of 1995/1996 in Netherland a large epidemic scale was observed due
to a Lordsale-like virus, in 1994, a small epidemic was associated with a Mexico-like virus, and from September through December
of 1996 outbreaks were caused by the Leeds genotype were observed [98]. Since 2002 there has been a global emergence of a new
type of norovirus commonly associated with outbreaks in nursing home, termed genogroup 2, genotype 4 (GII4) viruses. These show
increased severity of infection and have displaced strains that were circulating previously to become the dominant strains worldwide;
UK, United States, France, Japan and Thailand, [99-102]. In addition recombination between caliciviruses appears frequent and takes
place primarily at the ORF1 and ORF2 boundary. However, for sapovirus GGI (Saporo (Houston/86), Houston/90, Stockholm) genus
Saporo were the most common strain detected in SaV cases in Netherland from 1996-1998 [103]. London strains which belong to
GGII, were the most commonly detected strains of sapoviruses infection in Sweden and UK [104]. As well as, in recent study of genetic
characterization of calicivirus among children with acute gastroenteritis in the United States at 2005, half of the positive samples of
sapovirus grouped with London strain [99]. In Hungary at 2002, all the positive samples for sapovirus in infant and children was belong
to London strain [105].

Saporoviruses Noroviruses

Genogroups II Genogroups I Genogroups II Genogroups I

(GGII) (GGI) (GGII) (GGI)

London strain Saporo

Hawaii Norwalk
(Houston/86)

Houston/90 Mexico Southampton

Stockholm Melksham Desertshield

Hillingdon Queens arms

Grimsby Winchester
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Others

Figure 4: Norovirus, and sapovirus genus. Both NoV and SaV have been subdivided by Cluster analysis into genogroups, these in turn have been
divided into genotypes. NoV with genogroups I and II, have been genotyped so far into 15 genotypes and SaV have been divided into 2 genogroups with
4 genotypes. Accession numbers of calicivirus are as follows: Houston SLV (U95643), Houston 90 SLV (U95644), Stockholm (AF194182), London/92
SLV (U95645), Southampton NLV (L07418), Norwalk virus (M87661), Desert Shield NLV (U04464), Lordsdale NLV (X86557), Hawaii NLV (U07611),
Mexico/89 NLV (U22498), Melksham/89/UK NLV ( X81879), Hillingdon/90/UK, NLV (AJ277607), Grimsby/95/UK, NLV( AJ004864), Winchester/94/UK,
NLV(AJ277609).
006
Genome Structure HuCV
Caliciviruses possess a single-stranded, positive-sense RNA genome approximately 7400-7800 nucleotides length not including the
poly A tail. The genome has a characteristic arrangement of ORFs that distinguishes them from the Picornaviridae [85].
The genome of NoVs is organized in three ORFs. The first ORF at the 5’ end encodes a large polyprotein of 1738 amino acids with
molecular weight of 193.5K. The 5’ end codes for precursor of the nonstructural proteins. ORF2 encodes 530 amino acids capsid protein
of molecular weight of 56.6K. The ORF3 at the 3’ end of the genome encodes a small basic protein of 212 amino acids with molecular
weight of 22.5K [106]. In Feline calicivirus this forms a minor component of the virion and is known as VP2 [107]. It is assumed that
the ORF3 protein from NoV performs a similar function.
The genome of SaV is slightly different. The major difference between the genome of SaV and the NoV genome, is that the capsid
structural protein gene is in the same frame as ORF1 [108,109]. The second ORF then encodes the small basic and presumed minor
capsid protein which shows no sequence homology to other viral proteins in the database [108].

Epidemiology of HuCV Infection

Caliciviruses are among the most common cause of acute non bacterial gastroenteritis outbreaks in all age groups in industrial
countries [100]. Their significance as a cause of gastroenteritis outbreaks in developing countries is not clear [99]. Transmission of these
viruses is associated with food and waterborne contamination and also person to person spread [10,103]. Several studies have found
human caliciviruses second only to rotaviruses as a cause of gastroenteritis in young children [110].
Epidemiological studies were conducted in various locations worldwide; for example a molecular epidemiological study in Spain
reported that NoVs are the most common cause of gastroenteritis outbreaks. They were detected in 25 cases out of 44 (56%) cases
positive for caliciviruses [111]. A similar study was conducted in France between December 1998 to February 2004 and it was reported
that 172 cases of caliciviruses have been detected (93% NoV and 7% for SaV), most of the positive cases (91%) were detected in winter
[112].
The incidence of NoV in an epidemiological study of infectious intestinal disease (IID) in Netherlands from 1996-1999, was 5.1%
and it was significantly higher in young children, but remained at around 3-5% for all ages [113]. In England 1% of children 1 year of
age and less were infected with NoV [114].
In Netherland, NoVs were associated with more than 80% of reported outbreaks of gastroenteritis from 1994-1999. NoV and SaV
were detected from community in 16.5%, 6.3% respectively by using RT-PCR and 5.1%, 2.4% from patients visiting their physician with
acute gastroenteritis [103].
In Sweden at 2005 Johansson et al have first reported the nosocomial outbreaks with sapovirus infection among adults and as a
result, it was recommended to include the diagnostic test for sapoviruses in investigation of gastroenteritis in adults. Sapovirus infection
of adults was also recognized in the UK in 1985 when HuCV infection (the older term for SaV) was noted in this host [115]. Moreover
studies of calicivirus prevalence in the USA [116] have concluded that gastroenteritis was frequently caused by these viruses in children;
leading to hospitalization in 7.1% for NoV and 1.4% for SaV infections. Incidence of SaV has also been estimated. In the Netherlands
SaV was found in 2.4% of samples, almost exclusively from children [113], a similar incidence was found in England [114].

Symptoms, Transmission, Prevention, and Management of Viral Diarrhea

Most episodes of serious, acute diarrhea in infants and young children are caused by the above-described three viruses, HRV, EAdV
HAStV and calicivirus (NLV& SLV). Illnesses from these viruses usually start with fever, an upset stomach and vomiting, followed by
diarrhea. The diarrhea can be mild to severe and generally will last 3 to 9 days. Contaminated hands food, water, or other surfaces often
transmit viruses from one infected child to another. Careful and frequent hand washing, chlorination of swimming pools and drinking
water, disinfection of household areas, and proper disposal of sewage and diapers can prevent the spread of the infection to other
people. Dehydration is the biggest threat from diarrheal diseases in children. Illnesses that cause diarrhea can lead to dehydration if the
child loses body fluids and salts, as the child may require special rehydration fluids, such as Oralyte, which will correct acute sodium
loss [11].

Laboratory Diagnosis of Viruses Causing Viral Diarrheal Disease

Laboratory diagnosis of viruses causing viral diarrheal disease is becoming possible using either antibody-based or molecular
methods. Demonstration of the viruses (HRV, EAdV, HastV) by electron microscopy is being superceded as antibody tests are becoming
available e.g. commercial ELISA or latex agglutination kits. Stool extracts of positive samples may contain sufficient virus nucleic acid
for direct demonstration by PAGE or to differentiate between EadV subtypes [117]. PCR techniques for detecting and typing diarrhea
viruses have been developed in research laboratories but are not yet available for widespread routine use [1].

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