Features of specific etiologies and virology

Rotaviruses

Reovirus-like particles were first identified in 1973 by electron microscopy in duodenal biopsies from children with acute diarrhea.40 This led to a cascade of clinical and laboratory studies that have established the rotavirus as the single most common agent causing diarrhea in childhood.

Table 9.6 Etiological diagnosis of viral infections of the gastrointestinal tract

Viruses Antigen detection EM

PCR

Preferred test method

Rotavirus EIA, latex agglutination ++++ RT-PCR

EIA

Calicivirus EIA +

RT-PCR

RT-PCR

Astrovirus EIA +

RT-PCR

EIA

RT-PCR

Adenovirus EIA +++

RT-PCR

EIA

Cytomegalovirus

PCR

histology,

immunohistochemistry

Picornavirus EIA

RT-PCR

EIA

Epstein-Barr virus

PCR

histology,

immunohistochemistry

EM, electron microscopy; PCR, polymerase chain reaction; EIA, enzyme immunoassay; RT, reverse transcriptase; +, detectable with low sensitivity by a skilled microscopist; +++, visible; ++++, easily visible

The global illness and deaths caused by rotavirus in children were recently estimated by reviewing studies between 1985 and 2000. Rotavirus caused 111 million episodes of gastroenteritis requiring home treatment, 25 million clinic visits, 2 million hospitalizations and 350-600 000 deaths in children less than 5 years of age, worldwide. All children were expected to be infected with rotavirus within 5 years of age, one in five children were expected to need a clinic visit and one in 65 to be hospitalized. Finally, one out of 293 children would die because of rotavirus infection, 84% in the poorest countries.41

Also, in countries with high economic standards, rotaviruses are a major problem. In industrialized countries, the estimates were: a total of 7122 000 episodes of rotavirus gastroenteritis requiring only home care in children less than 5 years of age, a total of approximately 1 781 000 clinic visits and a total of 223 000 rotavirus-associated hospitaliza-tions.41 There are an estimated 3.5 million cases annually among children less than 5 years of age in the USA, leading to 500 000 office visits, 50 000 hospitalizations, and approximately 20 deaths.42 These numbers translate into costs, resulting in US$ 1 billion/ year.43

Infection is widespread throughout the world. Rotavirus infection may occur repeatedly in humans from birth to old age. The first infection is predominant among children aged 6-24 months, although cases may occur in older children. Neonatal infections appear to be nosocomial in origin, because they are rarely seen in babies born at home or at village health centers. Approximately 90% of children in both developed and developing countries experience rotavirus infection by 3 years of age. The cumulative incidence of rotavirus illness by the age of 5 years approaches 0.8 episodes/child per year.

Several factors are responsible for the high spreading of rotavirus. Rotavirus shedding averages 6 days per episode, but may be persistent. Asymptomatic carriers contribute to infection spreading. Infected children develop a protective immunity and, although repeated infections generally occur in growing children, their clinical severity decreases.44 Despite differences among studies in geographical areas, years and age groups, an increase in rotavirus cases is consistently reported in the winter months, with a peak in February to April. In tropical areas, rotaviruses are identified throughout the year.

Transmission occurs through the fecal-oral route. However, droplet transmission has been suggested to explain the rapidity with which the rotavirus can spread through a community.45

Virology

Rotavirus is a double-stranded RNA virus belonging to the Reoviridae family. The virion, 70-75 nm, is composed of a three-layered protein capsid that encloses 11 distinct segments of genomic RNA, each coding for a different capsid or non-structural protein. The internal core contains viral proteins (VP) 1, 2 and 3; the inner capsid contains VP4; the two outer capsid proteins encoded by genes 4 and 7, namely VP4 and VP7, represent the only established neutralization antigens of the virus. The protective role of antibodies directed at these proteins has been confirmed both in experimental animal models and in humans. A possible role has been suggested for antibodies directed at the inner capsid protein VP6, which is not associated with in vitro neutralization. The non-structural proteins NSP1, NSP2 and NSP4 are virulence factors in mice.

Rotavirus groups A-F have been described, but only groups A, B and C have been identified in humans. Most human infections are caused by group A rotaviruses that are classified into serotypes by a dual classification system based on neutralizing antigens on two outer capsid proteins, VP7 (G serotype) and VP4 (P serotype). To date, 10 G types and almost as many P types have been identified in infected humans. There is great genetic diversity within each G and P type, as shown by gel electrophoretic analysis of gene patterns (electropherotypes). Epidemiological and molecular studies in many countries show complex changes from year to year in the serotypes and electropherotypes that cause diarrhea in children from the same geographical areas.46,47 The majority of severe diseases have been caused by serotypes G1 to G4, P1A and P1B, worldwide.48 Epidemiological studies in Bangladesh,49 Brazil,50 India,51 Kenya48 and the USA52 show that other G and P types (G5 to G10, P2A and P8) can be common and may be of emerging importance in communities.53 Specific strains may express stronger virulence factors, which could be related to the severity of symptoms. More severe diseases may also be related to the reintroduction of strains in areas where they have been previously absent.54

Astroviruses

Human astroviruses (HAstVs) were first identified in 1975 in an outbreak of diarrhea in infants, and were named astrovirus because of the distinctive five- or six-pointed stars seen at electron microscopy.55

Recent studies have established that astrovirus is the third most frequent cause of diarrhea in children and the second in selected settings. The reported infection rates depend on detection methods. These include electron microscopy (EM), enzyme immunoassay (EIA) or reverse transcriptase-polymerase chain reaction (RT-PCR).56 Incidence rates also depend on the population under study. The reported incidence of HAstV diarrhea ranges from 2% of children seeking medical care in Baltimore, to 17% of children with persistent diarrhea in Bangladesh.57 Younger infants are at greater risk of developing diarrhea than older children. In a child-care center, attack rates among infants and toddlers ranged between 11 and 89%.58

HAstV may be an important agent of diarrhea in immunocompromised hosts such as those infected with HIV59 and bone marrow transplanted patients.60,61 Current evidence supports food-borne, water-borne and person-to-person transmission. The incidence peaks in winter months in temperate climates.

Virology

HAsVs are non-enveloped, single-stranded RNA viruses with a distinctive star appearance and a smooth particle edge. The genomic organization is unique among positive stranded RNA and warrants classification of astroviruses as a separate family, the Astroviridae.62 Eight antigenic types have been identified. The complete genomic sequence of types 1 and 2 and the sequence of the capsid gene of types 3, 4, 5, 6, 7 and 8 have been obtained.63

HAstV-1 is the dominant genotype followed by HAstV-2. It is not known whether infection with one serotype confers protection against subsequent infection with other serotypes.

Caliciviruses

In 1972, the 'Norwalk agent' was discovered in fecal specimens during a gastroenteritis outbreak in an elementary school in Norwalk, Ohio.64,65 This was the first discovered viral agent of gastroenteritis in humans using EM. Subsequently, a large number of other small round structured viruses (SRSVs) were detected. These agents appeared morphologically indistinguishable from the Norwalk virus by EM, but they were antigeni-cally distinct by immune EM. SRSVs were discovered during investigations of gastroenteritis outbreaks and were named for the investigation site (e.g. Bristol, Hawaii, Snow Mountains, etc.). In addition, a morphologically distinct SRSV, defined as 'classic human calicivirus', was first described in the UK,66 and the prototype strain - the Sapporo agent - was subsequently identified in Japan.67

This rather confusing classification system of these viruses has been recently revised and is now based on genetic sequences of the viruses and of their genomic organization. All viruses belong to the family Caliciviridae, and fall into two provisionally named genera: 'Norwalk-like viruses' (NLV) and 'Sapporo-like viruses' (SLV).

Molecular epidemiological studies showed that caliciviruses are the main cause of non-bacterial gastroenteritis outbreaks causing over 90% of outbreaks of acute, non-bacterial gastroenteritis in the USA.68 They are spread by the fecal-oral route, but outbreaks are often caused by contaminated food or water.69 Contaminated surfaces carry calicivirus in detectable amounts, thereby providing another important substrate for explosive outbreaks.70 Droplets or person-to-person transmission explain outbreaks in which other spreading routes cannot be identified.71 Infections rates increase in cold seasons,72 almost disappearing in the warm summer months. NLVs have been found in 5-20% of stool specimens from sporadic cases of diarrhea using RT-PCR.73 SLVs cause predominantly diarrheal diseases, while NLVs cause 'winter vomiting disease' in young children.74

Virology

Caliciviruses are single-stranded, positive sense RNA viruses closely related to picornaviruses.

Based on morphology, typical and atypical caliciviruses have been described. SLVs have the typical calicivirus morphology, with a six-pointed star appearance similar to those of many animal caliciviruses. In contrast, the surface structure of NLVs is rather smooth, leading to the designation 'small round structured viruses'.

The family Caliciviridae encompasses four distinct virus genera. Two, the NLVs and SLVs, contain the human calicivirus (previously referred to as small round structured viruses) and the classic human caliciviruses, respectively. Phylogenetic analyses of sequences in the RNA polymerase and the capsid regions of the genome revealed that currently identified NLVs and SLVs can be divided into genogroups and genetic clusters. The NLV genus includes two genogroups (I and II) and at least 15 genetic clusters.75 The SLV genus has fewer members, with a total of 4-5 genetic clusters.

Enteric adenoviruses

There are six different groups of adenovirus, but only group F, including serotypes 40 and 41, are referred to as enteric adenoviruses. Both cause endemic diarrhea and outbreaks in hospitals, orphanages and day-care centers.

The enteric adenoviruses are non-enveloped particles, containing double-stranded DNA.76

These viruses infect children more than adults; more than 50% of children are seropositive by years 3-4 of life.77 Enteric adenoviruses are detected in 1.5-4% of children with diarrhea and are isolated throughout the year with no specific seasonal distribution.78,79 Transmission is fecal-oral. The incubation lasts from 3 to 10 days. Adenovirus diarrhea lasts for 6-9 days and may be associated with vomiting and fever. Stools are watery, without blood or fecal leukocytes. EM initially was used to detect enteric adenoviruses, but commercial enzyme-linked immunosorbent assays are now widely available.

Toroviruses

Toroviruses include the Breda virus of cattle and Berne virus of horses,80-82 and were first documented in 1984 by EM in humans with gastroenteritis.83 These enveloped RNA viruses contain a tightly coiled tubular nucleocapsid that generally assumes a 'donut' torus shape in the virion.80 Toroviruses were classified on the basis of the Berne virus genome sequence as members of the family Coronaviridae, which together with the family Arteriviridae are now classified in the order Nidovirales.84-86

Study of torovirus infections in calves indicates that Breda viruses infect differentiating crypt cells, expecially in the large intestine.81,82

The incidence of torovirus infection remains relatively constant throughout the year. Early studies indicated that toroviruses infect school-age children, and are responsible for nosocomial infections, more frequently in immunocompromised patients.87

The clinical manifestations of torovirus infection are similar to those of rotavirus or astrovirus, except that children with torovirus infection had less vomiting and bloodier diarrhea.83,87 Symptom duration is similar to that of rotavirus infection, but toroviruses more frequently induce persistent diarrhea.87 Further epidemiological studies are needed to determine its frequency in the community.

Picornaviruses (the Aichi virus)

In 1989, a cytopathic small round virus was isolated from a patient with oyster-associated gastroenteritis.88 Genetic analyses of this virus, named Aichi virus, led to its classification into the Picornavirus family. It is distinct from any other genus such as the enterrhino-, cardio-, aptho-, hepato- and parechovirus group.89 The Aichi virus is presently an unassigned species in the Picornavirus family.90 Recently, it has been proposed to assign the Aichi virus to a new genus named Kobuvirus.91

The Aichi viruses cause acute gastroenteritis outbreaks. The main clinical symptoms are diarrhea (59%), abdominal pain (83%), nausea (92%), vomiting (71%) and fever (58%).92

Coronaviruses

Coronaviruses are large enveloped single-stranded RNA viruses related to toroviruses. These viruses are a well-documented cause of gastroenteritis in animals and of the common cold in humans. Coronaviruses have been identified in the stools of children with diarrhea, but their role as a cause of diarrhea is unknown. They have been detected more commonly in the diarrheal stools of older children and young adults. The prolonged virus excretion makes it difficult to assess their etiologi-cal role. Recently, coronavirus mutants have been implicated in the severe acute respiratory syndrome (SARS).93

Picobirnaviruses

These viruses have icosahedral symmetry with triangulation number (T) equal to 3.94 They have been detected in diarrheic as well as non-diarrheic animals, and occasionally in children and in humans with HIV infection. Their etiological role in immunocompetent children is unknown.

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