Download Non-hepatotropic Viruses

Milad Haddad, MD
Head of Gastroenterology Department, Ibn Alnafis Hospital
Liver Functions
• Metabolic
• Synthetic & storage
• Excretory &
detoxification
• Immune & Filtering
Metabolic
Synthetic
&
Storage
Excretory
&
Detoxification
Immune
&
Filtering
 Glucose, protein & fat
 Hormones & vitamins
 Proteins (clotting factors & acute
phase proteins)
 Hormones & vitamins
 Store: glycogen, fat, vitamins,
iron, & copper
 Bilirubin, bile acids, cholesterol, &
phospholipids
 Detoxification of drugs & toxins
 Poisons, nutrients, & damaged
cells
 Excretion of IgA
 Kupffer cells (macrophages)
Hepatitis Viruses
A
Hepatotropic
Viruses
A-E hepatitis viruses:
HAV, HBV, HCV, HDV, & HEV
Non-A-E hepatitis viruses:
• Flaviviridae: GBV-C/HGV, Yellow
fever virus (YFV)
• Circoviridae: Torque teno virus
(TTV), Sanban, Yonban, SEN viruses,
TTV-like mini virus (TTMV), TTV-like
midi virus (TTMDV)
B
Non-hepatotropic
Viruses
• Herpesviridae : EBV, CMV, HSV, VZV, &
HHV – 6
• Severe acute respiratory syndrome/
coronavirus (SARS/CoV)
• Parvovirus B19
• Measles virus
• HIV
• Lassa, Marburg, Ebola
Hepatitis Viruses
Natural History of HBV infection
HCC
5-10%
Acute
infection
Chronic
infection
 90% of children
 < 5% of adults
Cirrhosis
30%
Liver
Transplantation
23%/5 yr
Decompensation
Torreti J. Gastroneterology, 2000;118:S83-103
Fattovich G.Hepatology, 1995;21;77-92.
Moyer LA. AmJ Prov Med. 1994:10:45-55
Death
Natural History of HCV infection
HCC
Cirrhosis
Chronic
hepatitis
HCV infection
1%/yr
(1-3%/yr)
15%
(10-30%)
25 years
80%
(60-95%)
100%
Predicted outcome of HAV infection
Parameter
Predicted Outcome
Children (<5 years)
Adults
Inapparent disease
80-95%
10-25%
Anicteric or icteric disease
5-20%
75-90%
Complete recovery
99+%
98+%
Chronic disease
Mortality rate
• ≤ 14 years
• 15-39 years
• ≥ 40 years
None
• 0.1%
• 0.3%
• 2.1%
Hollinger FB and Ticehurst JR. Hepatitis A virus. In: Fields Virology, 3rd ed.
Philadelphia, Lippincott - Raven, 1996:735-782
Epidemiology
 From 11% to 22% of patients with acute hepatitis A
require hospitalization.
 An average length of stay of 4.6 days, costing on
average $7926 per patient.
 On average, 27 workdays are lost per adult case of
hepatitis A.
• Hepatitis A is the most common form of acute viral
hepatitis worldwide. It is a self-limited infection
Worldwide Endemicity of HAV Infection
HAV
ENDEMICITY
Very high
High
Intermediate
Low
Very low
REGIONS BY
EPIDEMIOLOGICAL
PATTERN
Africa, parts of South
America, the Middle East
and of south-east Asia
AVERAGE AGE
OF PATIENTS
(YEARS)
Under 5
MOST LIKELY MODE
OF
TRANSMISSION
•
•
Person-to-person
Contaminated food
and water
Brazil’s Amazon basin,
China and Latin America
5-14
•
•
Person-to-person
Outbreaks/contamin
ated food or water
Southern and Eastern
Europe, some regions of the
Middle East
5-24
•
•
Person-to-person
Outbreaks/contamin
ated food or water
Australia, USA, Western
Europe
5-40
•
Common source
outbreaks
•
Exposure during
travel to high
endemicity areas,
uncommon Source
Northern Europe and Japan
Over 20
Virology of HAV
• Nonenveloped Icosahedral
spherical shape.
• 27-32 nm in diameter.
• HAV genome consists of a
positive single-stranded
RNA that is 7.48 kb long and
linear.
• HAV has only 1 known
serotype in humans and no
antigenic crossreactivity
with HBV, HCV, HDV, HEV, or
GBV-C.
• No cytopathic effect is
observed.
• HAV infection provides a
lifelong protection.
HAV Genomic Organization
Millward-Sadler GH, Wright R, Arther MJP, editors. Wright’s liver and biliary disease. 3rd
ed.London: WB Saunders; 1992. p 679
Modes of Transmisiion
Modes of
Transmission
HAV Stability
HAV is extremely resistant to degradation by environmental conditions
HAV is resistant to:





•
•
•
Thermal denaturation (survives at 70°C
for up to 10 min)
Acid treatment (pH 1 for 2 h at room
temperature), 20% ether, chloroform,
dichlorodifluoromethane, and
trichlorotrifluoroethane
Perchloracetic acid (300 mg/l for 15
min at 20°C)
Detergent inactivation (survives at 37°C
for 30 min in 1% SDS)
Storage at –20°C for years
HAV is capable of surviving in sea water
(4%survival rate),
dried feces at room temperature for 4
weeks
live oysters for 5 days
WHO/CDS/CSR/EDC/2000.7: hepatitis A
HAV is inactivated by:










Heating to 85°C for 1 min
Autoclaving (121°C for 20 min)
Ultraviolet radiation (1.1 W at a depth of
0.9 cm for 1 min)
Formalin (8% for 1 min at 25°C)
â-propriolactone (0.03% for 72 h at 4°C)
Potassium permanganate (30 mg/l for 5
min)
Iodine (3 mg/l for 5 min)
Chlorine (free residual chlorine
concentration of 2.0 to 2.5 mg/l for 15 min)
Chlorine-containing compounds (3 to 10
mg/l sodium hypochlorite at 20°C for 5 to
15 min)
Shellfish from contaminated areas should
be heated to 90°C for 4 min or steamed for
90 sec
Pathogenesis
•
•
•
•
•
•
•
•
After HAV is ingested and survives gastric acid, it traverses the small
intestinal mucosa, reaches the liver via the portal vein, and is taken
up by hepatocytes.
In hepatocytes, virus particles replicate, assemble, and are secreted
into the biliary canaliculus, from which they pass into the bile duct
and back to the small intestine, with eventual excretion in the feces.
The enterohepatic cycles of the virus life cycle continue until
neutralizing antibodies and other immune mechanisms interrupt the
cycle.
The lack of injury to cells in cell culture systems suggests that HAV is
not cytopathic.
Immunologically mediated cell damage is more likely. The emergence
of anti-HAV could result in hepatic necrosis during immunologically
mediated elimination of HAV.
Death appears to be inevitable when necrosis involves more than 65
- 80% of the total hepatocyte fraction.
In patients who survive an episode of acute fulminant hepatic failure,
neither functional nor pathologic sequelae are common, despite the
widespread necrosis.
The damaged hepatic tissue is usually restored within 8 to 12 weeks.
Detection of HAV and Infectivity of Human
Secretions or Excretions
Secretion/Excretion
Comment
Stool
The main source of infection. HAV is detectable during the incubation
period and for several weeks after the onset of disease. After the
onset of symptoms, HAV is detectable in 45% and 11% of fecal
specimens collected during the first and second weeks of illness,
respectively, whereas HAV RNA (by PCR assay) is detectable for 4 to 5
months.
Blood
Viremia is present during the incubation period. Blood collected 3 and
11 days before the onset of symptoms has caused post-transfusion
infection in recipients. Chronic viremia does not occur.
Bile
HAV has been detected in the bile of chimpanzees infected with HAV.
Urine
HAV is detected in low titer during the viremic phase. A urine sample
was reported to be infectious after oral inoculation. Urine
contaminated with blood was also infectious.
Nasopharyngeal
Unknown in humans. HAV has been identified in the oropharynx of
experimentally infected chimpanzees.
Semen, vaginal fluid
Uncertain. HAV may be detectable during the viremic phase.
Person-to-person contact
- Households
- Sexual contact: men who have sex with men
- Child day care centers
Food & water contamination
- Infected food handlers
- Raw shellfish
Blood & blood products exposure (rare)
- Transfusion
- IV drug abusers
Modes of Transmission
Transmission
route
Hepatitis
A
Hepatitis
B
Hepatitis
C
Hepatitis
D
Hepatitis
E
Food-Borne
•
Ø
Ø
Ø
•
Fecal-Oral
•
Ø
Ø
Ø
•
Water-Borne
•
Ø
Ø
Ø
•
Raw-Shellfish
•
Ø
Ø
Ø
Suspected
IntraInstitutional
•
•
•
•
•
IV drug use
∆
•
•
•
Ø
Transfusion
∆
•
•
•
∆
Hemodialysis
∆
•
•
•
Ø
Sexual
∆
•
∆
•
∆
Oral-Oral
•
∆
Ø
Ø
•
Household
•
∆
∆
∆
•
Perinatal
∆
•
∆
•
∆
• Common
∆ Infrequent
Ø Never
Role of non-human primates in the
transmission of HAV
 Various monkey species such as chimpanzees, owl,
cynomolgus, rhesus, stump-tailed, & African green monkeys,
tamarins, marmosets and squirrel monkeys are susceptible to
HAV.
 HAV-induced disease in non-human primates resembles
human disease, but is usually milder, or subclinical, followed
by complete recovery.
 Simian HAV strains, closely related antigenically to human
HAV strains despite major divergence at the nucleotide level
(>10%).
 Well documented is the natural transmission of human HAV
from experimentally infected animals to humans.
High Risk Groups for HAV Infection
 People in household/sexual
contact with infected persons
 Medical and paramedical
personnel in hospitals
 International travellers from
developed countries to regions of
the world where HAV is endemic
(3/1000 to 20/1000 people per
month’s stay abroad)
 Persons living in regions with
endemic hepatitis A
 Persons residing in areas where
extended community outbreaks
exist
 Preschool children attending daycare centres, their parents and
siblings
 Day-care centre employees
 Residents and staff of closed
communities (institutions)
 Refugees residing in temporary
camps following catastrophes
 Homosexually active men
 Injecting drug users using
unsterilized injection needles
 Persons with clotting factor
disorders
 Persons with chronic liver disease
 Food-service establishments/food
handlers
 Persons working with non-human
primates
Reported risk factors among persons with hepatitis A
United States, 1990–2000
CHARACTERISTICS OF FOODBORNE
TRANSMISSION
Transmission due to contamination of food at the
point of sale or service
 The source of most reported foodborne hepatitis A outbreaks has
been HAV-infected food handlers present at the point of sale (such as in
a restaurant) or who prepare food for social events (such as a wedding).
 A single HAV-infected food handler can transmit HAV to dozens or
even hundreds of persons and cause a substantial economic burden to
public health [18, 19].
The societal cost of a single foodborne outbreak of hepatitis A in
Denver involving 43 cases was estimated to be more than $800,000,
with 190% of these costs borne by the public health department and
attributed to immunoglobulin administration [18].
CHARACTERISTICS OF FOODBORNE
TRANSMISSION
Transmission due to contamination of food during
growing, harvesting, processing, or distribution
Hepatitis A outbreaks have been also associated
with consumption of fresh produce contaminated
with HAV during cultivation, harvesting,
processing, or distribution
 Outbreaks involving a food item that was
contaminated before distribution are particularly
challenging to identify and might be widely
distributed geographically.
Transmission due to exposure to
contaminated water.
• Water treatment processes and dilution within
municipal water systems are apparently sufficient to
render HAV noninfectious, although no studies have
demonstrated which specific treatment processes are
the most effective.
• Outbreaks of hepatitis A among persons who use small
private or community wells or swimming pools have
been reported, and contamination by adjacent septic
systems has been implicated as the source of
contamination [49–53].
• hepatitis A outbreaks after flooding-related sewage
contamination of potable water sources is recognized.
Guidelines for Epidemic Measures
 Determination of mode of transmission, whether personto-person or by common vector (vehicle).
 Identification of the population exposed to increased risk of
infection. Elimination of common sources of infection.
 Improvement of sanitary and hygienic practices to
eliminate faecal contamination of food and water.
 Hepatitis A vaccination has been shown to be effective in
controlling outbreaks of infection in communities that have
high or intermediate rates of infection, provided a sufficient
percent of the target population is reached.
 Passive immunization provides temporary protection, but it
is not effective in controlling HAV on a community level.
WHO/CDS/CSR/EDC/2000.7
Thank You