Viral Infections of
the Gastrointestinal
Tract
Salivary Gland Infection: Mumps Virus
“to mump” means to grimace or grin.
The virion is 120 – 200 nm in diameter
Contains in addition to the six major proteins; V (viral)
protein and S (soluble) protein.
One serotype.
Pathogenesis and Pathology
Mumps is a systemic viral infection commonly
regarded as epidemic parotitis.
Transient viremia disseminates the virus to target
organs.
Virus is actively shed in saliva for as long as 15 days.
The presence of virus in saliva is not dependent upon
the development of clinical parotitis.
Viral involvement of the parotids is neither primary nor
an obligate step in infection.
Viral replication in the parotids is attended by
periductal interstitial edema and local
inflammation.
Virus is also frequently disseminated to CNS,
pancreas, the kidneys, ovaries and testes.
The CNS is a common target for mumps virus
dissemination.
Pancreatic involvement may be mild or severe
and hemorrhagic
Clinical Features
The incubation period is 2-3 weeks.
There may be a prodromal phase.
The clinical features of mumps reflect the
pathogenesis of the infection.
Approximately one third of all mumps virus
infections occur without recognized symptoms.
The feature most characteristics of mumps is
salivary gland swelling which is maximal within
48 hours .
Parotid tenderness and pain on salivation
precede swelling by 2-4 day.
After increasing for about 3 days, the
inflammation subsides over 7-10 days.
Fever is moderate.
Diagnosis
Virus isolation
- Specimens: Saliva, CSF, and Urine
- Cell Cultures: PMK or HEK.
Serology.
Molecular (PCR)
Epidemiology
Mumps has a worldwide distribution but
incidence has dropped dramatically in the
developed countries due to vaccination.
Epidemics occur in unvaccinated communities
at 3 yearly intervals with peak incidence during
winter and spring.
The maximum incidence is in children aged 5-9
years.
Immunity following natural infection is life long.
Mumps virus requires a population of about
200.000 people to sustain its circulation.
Prevention is achieved by live attenuated
vaccine with > 95% efficiency after a single
dose.
A sustained coverage of 85% or greater is
required to prevent transmission of mumps and
eliminate disease.
a vaccine program with low coverage may have
a negative effect despite a decline in the total
number of cases.
Viral Gastroenteritis
It is thought that viruses are responsible for up to
3/4 of all infective diarrhoeas.
Viral gastroenteritis is the second most common
viral illness after upper respiratory tract infection.
In developing countries, viral gastroenteritis is a
major killer of infants who are undernourished.
Many different types of viruses are found in the gut
but only some are associated with gastroenteritis.
Viruses Associated with gastroenteritis
Rotaviruses
Adenoviruses 40, 41
Caliciviruses
Norwalk like viruses or SRSV (Small Round
Structured Viruses)
Astroviruses
SRV (Small Round Viruses)
Coronaviruses
Toroviruses
Viruses Found in the gut, not normally
associated with gastroenteritis
Polioviruses
Coxsackie A
Coxsackie B
Echo
Enteroviruses 68-71
Hepatitis A
Hepatitis E
Adenoviruses 1-39
Reoviruses
Found in the gut as opportunistic
infection
CMV
HSV
VZV
HIV
Gastrointestinal Viruses
Infants:
- Rotavirus A
- Adenovirus 40,41
- Coxsackie A24 virus
Infants, children, and adults:
- Norwalk virus
- Calicivirus
- Astrovirus
- Rotavirus B
Groups of Rotaviruses
Group A subtypes 1, 2, 3, 4 (main human pathogens)
(Further 7 subtypes) also infect animals (monkey, calf,
mouse)
Group B Infects pigs and rats
Found to cause extensive outbreaks in China in past
decade
Group C Infects Pigs (Occasionally Man)
Group D Infects birds
Group E Infects pigs
Human Pathogens
Group A: Main pathogen of infantile
diarrhea
Group B : Cause epidemic adult diarrhea
Group C: Cause human or animal
sporadic diarrhea
Human Rotavirus
70 nm round,
double shelled,
enclosing a
genome of 11
segments of
double stranded
RNA.
Rotavirus
First identified as cause of diarrhea in 1973
Most common cause of severe diarrhea in infants and
young children
Nearly universal infection by 5 years of age
Responsible for up to 500,000 diarrheal deaths each
year worldwide
Very stable and may remain viable for weeks or
months if not disinfected
Rotaviruses are found in many different mammals and
birds.
Reassortment of gene segments can occur and thus
create hybrid viruses.
Rotaviruses resemble enveloped viruses but they are
stable at room temperature and to treatment with
detergents, pH extremes of 3.5 to 10 or even repeated
freezing and thawing.
Infectivity is enhanced by proteolytic enzymes such as
trypsin.
Proteolytic cleavage of the outer capsid activates the
virus and produces an intermediate/infectious subviral
particle (ISVP).
Pathogenesis
Viral replication occurs after adsorption to columnar
epithelial cells covering the villi of the small intestine.
Shortening and blunting of the microvilli and
mononuclear cell infiltration into the lamina propria is
observed.
Infection prevents the absorption of water causing a
net secretion of water and loss of ions which together
result in a watery diarrhea.
The attendant loss of fluids and electrolytes can lead
to severe dehydration and even death.
Rotavirus Clinical Features
Incubation period 1-3 days
Clinical manifestations depend on whether it is
the first infection or reinfection
First infection after age 3 months generally
most severe
May be asymptomatic or result in severe
dehydrating diarrhea with fever and vomiting
Gastrointestinal symptoms generally resolve in
3 to 7 days
Rotavirus Complications
Severe diarrhea
Dehydration
Electrolyte imbalance
Metabolic acidosis
Immunodeficient children may have more
severe or persistent disease
Rotavirus Immunity
Antibody against VP7 and VP4 probably
important for protection
First infection usually does not lead to
permanent immunity
Reinfection can occur at any age
Subsequent infections generally less severe
Rotavirus Epidemiology
Reservoir
Human-GI tract
Transmission
Fecal-oral, fomites
Temporal
pattern
Fall and winter
(temperate areas)
Communicability
2 days before to 10
days after onset
Epidemiology
Infection with rotaviruses has a worldwide
distribution.
Transmission is by the oral fecal route.
Outbreaks are common in preschool children,
among day care centers and hospitalized
infants.
Most children are infected by the age of 4 years
during the cooler months of the year.
Risk Groups for Rotavirus Diarrhea
Groups with increased exposure to virus




Children in child care centers
Children in hospital wards (nosocomial rotavirus)
Caretakers, parents of these children
Children, adults with immunodeficiency related diseases
(e.g. SCID, HIV, bone marrow transplant)
Prevention
Vaccines are available since the late 1990’s.
Animal; rhesus monkey and bovine rotaviruses
were utilized.
Live tetravalent vaccine was tried from August
1998 to October 1999 and was stopped
because of association with intussusception
(15 cases in 1.5 million doses).
®
Rotavirus Vaccine (RotaTeq )
Approved by FDA in February 2006
Contains five reassortant rotaviruses developed
from human and bovine parent rotavirus strains
Vaccine viruses suspended in a solution of
buffer (sodium citrate and phosphate) and
stabilizer
Contains no preservatives or thimerosal
®
Rotarix Rotavirus Vaccine
Approved by FDA in April 2008
Contains one strain of live attenuated human
rotavirus
Two oral doses at 2 and 4 months of age
(minimum interval 4 weeks)
Minimum age 6 weeks
Maximum age 24 weeks
RotaTeq Vaccine Efficacy
Phase III trials included more than 70,000
infants in 11 countries
Efficacy

All rotavirus disease - 74%

Severe rotavirus disease - 98%

Physician visits for diarrhea-86% reduction

Rotavirus-related hospitalization-96% reduction
Efficacy of fewer than 3 doses is not known
N Eng J Med 2006;354:23-33
Rotavirus Vaccine
Recommendations
Routine immunization of all infants without
contraindications
Administered at 2, 4, and 6 months of age*
Minimum age of first doses is 6 weeks
First dose should be administered between 6 and 12
weeks of age (until age 13 weeks)
Do not initiate series after 12 weeks of age
Rotavirus Vaccine and
Intussusception*
Within 42 days
of vaccination
Within 1 year
of vaccination
Vaccine
Placebo
Recipients Recipients
6 cases
5 cases
13 cases
15 cases
Rotavirus Vaccine
Adverse Reactions
Vomiting
15%
Diarrhea
24%
Nasopharyngitis
7%
Fever
43%
No serious adverse reactions reported
*data shown are for RotaTeq
MMWR 2006;55:(RR-12):1-13.
Astroviruses have a five or six-pointed star shape of
28-30 nm in diameter with an icosahedral symmetry.
They typically cause outbreaks of gastroenteritis
as a result of common source contamination
(water, shellfish, food service).
Spread is by the fecal-oral route.
Outbreaks occur year around in schools, resorts,
hospitals, nursing homes, restaurants and cruise
ships.
They are similar clinically to rotavirus disease.
Caliciviruses and Related Agents
Caliciviruses are 27-38
nm, non enveloped,
icosahedral viruses with a
(+) ss RNA genome (7500
bases).
Norwalk agent (now called
Norovirus) was discovered
by EM in stool from adults
during an epidemic of an
acute gastroenteritis in
1968 in Norwalk, Ohio.
Noroviruses
Noroviruses (genus Norovirus, family Caliciviridae)
are a group of related, single-stranded RNA,
nonenveloped viruses that cause acute gastroenteritis
in humans.
Norovirus was recently approved as the official genus
name for the group of viruses provisionally described
as “Norwalk-like viruses” (NLV).
Currently, there are at least five norovirus genogroups
(GI, GII, GIII, GIV and GV), which in turn are divided
into at least 31 genetic clusters.
Virus Transmission
Noroviruses are transmitted primarily through the
fecal-oral route, either by consumption of fecally
contaminated food or water or by direct person-toperson spread.
Environmental and fomite contamination may also act
as a source of infection.
Good evidence exists for transmission due to
aerosolization of vomitus that presumably results in
droplets contaminating surfaces or entering the oral
mucosa and being swallowed.
No evidence suggests that infection occurs
through the respiratory system.
Noroviruses are highly contagious and as few
as 10 viral particles may be sufficient to infect
an individual.
During outbreaks of norovirus gastroenteritis,
several modes of transmission have been
documented; for example, initial foodborne
transmission in a restaurant, followed by
secondary person-to-person transmission to
household contacts.
Although presymptomatic viral shedding may
occur, shedding usually begins with onset of
symptoms and may continue for 2 weeks after
recovery.
It is unclear to what extent viral shedding over
72 hours after recovery signifies continued
infectivity
Clinical Presentation
The incubation period for norovirus - associated
gastroenteritis in humans is usually between 24
and 48 hours (median in outbreaks 33 to 36
hours), but cases can occur within 12 hours of
exposure.
Norovirus infection usually presents as acuteonset vomiting, watery non-bloody diarrhea with
abdominal cramps, and nausea. Low-grade
fever also occasionally occurs
Dehydration is the most common complication,
especially among the young and elderly, and may
require medical attention.
Symptoms usually last 24 to 60 hours. Recovery is
usually complete and there is no evidence of any
serious long-term sequalae.
Studies with volunteers given stool filtrates have
shown that asymptomatic infection may occur in as
many as 30% of infections, although the role of
asymptomatic infection in norovirus transmission is not
well understood.
Immunity to Norovirus
Mechanisms of immunity to norovirus are unclear. It
appears that immunity may be strain-specific and lasts
only a few months; therefore, given the genetic
variability of noroviruses, individuals are likely to be
repeatedly infected throughout their lifetimes.
This may explain the high attack rates in all age
groups reported in outbreaks.
Recent evidence also suggests that susceptibility to
infection may be genetically determined, with people
of blood group O being at greatest risk for severe
infection.
Disease burden of Norovirus Gastroenteritis
CDC estimates that 23 million cases of acute
gastroenteritis in USA are due to norovirus infection,
and it is now thought that at least 50% of all foodborne
outbreaks of gastroenteritis can be attributed to
noroviruses.
Among the 232 outbreaks of norovirus illness reported
to CDC from July 1997 to June 2000, 57% were
foodborne, 16% were due to person-to-person spread,
and 3% were waterborne; in 23% of outbreaks, the
cause of transmission was not determined.
Most food borne outbreaks of norovirus illness are
likely to arise through direct contamination of food
by a food handler immediately before its
consumption.
Outbreaks have frequently been associated with
consumption of cold foods, including various
salads, sandwiches, and bakery products.
Liquid items (e.g., salad dressing or cake icing)
that allow virus to mix evenly are often implicated
as a cause of outbreaks.
Food can also be contaminated at its source, and
oysters from contaminated waters have been
associated with widespread outbreaks of
gastroenteritis.
Other foods, including raspberries and salads, have
been contaminated before widespread distribution and
subsequently caused extensive outbreaks.
Waterborne outbreaks of norovirus disease in
community settings have often been caused by
sewage contamination of wells and recreational water.
Diagnosis of Norovirus
Real time (RT-PCR) detects the norovirus RNA and
can be used to test stool and emesis samples, as
well as environmental swabs in special studies.
Identification of the virus can be best made from
stool specimens taken within 48 to 72 hours after
onset of symptoms, although good results can be
obtained by using RT-PCR on samples taken as
long as 5 days after symptom onset.
Virus can sometimes be found in stool samples
taken as late as 2 weeks after recovery.
Older methods for diagnosis include direct and
immune electron microscopy of fecal
specimens, and detection of a fourfold increase
of specific antibodies in acute and convalescent
phase blood samples.
Several commercially available enzyme-linked
immunosorbent assays for detection of virus in
stools have been developed but await further
evaluation regarding sensitivity and specificity.
Sequencing of norovirus strains found in clinical
and environmental samples has greatly helped
in conducting epidemiologic investigations by
linking cases to each other and to a common
source and by differentiating outbreaks that
were mistakenly connected.
In addition to microbiological techniques,
several epidemiologic criteria have been
proposed for use in determining whether an
outbreak of gastroenteritis is of viral origin.
Kaplan's criteria
Viral etiology is suspected if:
1) a mean (or median) illness duration of 12 to
60 hours,
2) a mean (or median) incubation period of 24 to 48
hours,
3) more than 50% of people with vomiting, and
4) no bacterial agent previously found.
Although quite specific, these criteria are not very
sensitive, and therefore the possibility of a viral
etiology should not be discarded if the criteria are not
met.
Management of Norovirus Infection
No specific therapy exists for norovirus
gastroenteritis.
Symptomatic therapy consists of replacing
fluid losses and correcting electrolyte
disturbances through oral and intravenous
fluid administration.
Prevention
Relatively simple measures, such as correct handling
of cold foods, strict hand washing after using the
bathroom and before handling food items, and paid
sick leave, may substantially reduce foodborne
transmission of noroviruses.
Prevention of norovirus disease spread via droplets
from vomitus (person to person transmission) should
focus on methods to limit transmission including
isolation precautions (e.g., cohort sick patients in a
healthcare facility) and environmental disinfection.
Adenovirus Gastrointestinal Disease
Diarrhea
Types 40 and 41
Intussusception
Mesenteric adenitis. Types 1, 2, 5 and 6.
Celiac Disease
Type 12. Structural homology between E1B
protein and α-gliadin
Enteric Adenoviruses
Fastidious enteric adenovirus types 40 and 41 are
associated with endemic gastroenteritis, usually in
young children and neonates.
Can cause occasional outbreaks.
Possibly the second most common viral cause of
gastroenteritis (7-15% of all endemic cases).
Similar disease to rotaviruses.
Most people have antibodies against enteric
adenoviruses by the age of three years.
Diagnosed by electron microscopy or by the
detection of adenovirus antigens in faeces by
ELISA or other assays.
Other Possible Diarrhoeal Viruses
Coronaviruses
RNA viruses with a crown-like appearance
No convincing evidence to be associated with
gastroenteritis at present
Small Round Viruses
Small virus-like particles with a smooth surface, 2228nm in diameter
May possibly be parvoviruses, enteroviruses, or cubic
bacteriophages
Occasionally seen in the faeces of endemic or
epidemic cases of gastroenteritis
Gastrointestinal Viruses
Virus
Genome
Typical disease
incubation
Duration
Rotaviruses:
Group A, B, C
ds-segmented
RNA
Major cause of diarrhea
in children
1-3 days
24-56 h
5-8 days
3-7 days
Caliciviruses
Norwalk agents
ssRNA
Infects adults and
children
Epidemic viral
gastroenteritis
1-3 days
18-24 h
1-3 days
12-48 h
EAd 40,41
Linear dsRNA
diarrhea in children
7-8 days
8-12 d
Astrovirus
+ssRNA
Infects mainly children
and elderly
1-4 days
1-4 d