Download Chapter 2 - Wolters Kluwer Health

Chapter 2
Viral Hepatitis and Hepatitis
Vaccines
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Viral Hepatitis – Overview
• Major HCP occupational concern
• At least 7 distinct viruses identified
– Short & long incubation intervals
– Acute & chronic disease
• Variable & subclinical symptomatology
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
RNA Viruses Involved in Human Hepatitis
• Picornaviruses (enteroviruses)
– HAV, HDV, Coxsackie & Echo viruses
• Flaviviruses – HCV
• Calciviruses – HEV
• Togaviruses
– Yellow fever & rubella viruses
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
RNA Viruses Involved in Human Hepatitis
(cont’d)
• Arenavirus
– Junin virus
– Machup virus
– Lassa virus
– Rift Valley Fever virus
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
RNA Viruses Involved in Human Hepatitis
(cont’d)
• Rhabdoviruses
– Marburg virus
– Ebola virus
• Paramyxovirus
– Measles virus
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
DNA Viruses Involved in Human Hepatitis
• Hepadnavirus – HBV
• Herpesviruses
– Cytomegalovirus
– Epstein-Barr
– Herpes simplex
• Varicella-Zoster virus
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Unclassified Viruses Involved in Human
Hepatitis
• Hepatitis F virus
• Hepatitis G virus
• Transfusion-Transmitted virus (TTV)
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Comparison of Major Microbiological and
Clinical Features of Viral Hepatitis
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Classical Division of Hepatitis Conditions
• Prodromal phase
• Icteric phase
– Marked by jaundice
• Convalescent phase
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Prodromal Phase
• Non-specific respiratory and/or GI symptoms
– Malaise, loss of appetite, headache & nausea
• Any fever usually low-grade
• HBV produces symptoms before seroconversion
– Arthritis & maculopapular skin rashes
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Icteric Phase
• Jaundice – yellowing
– Skin, sclera, mucosa, nail beds & gingiva
– By bilirubin & other bile pigments
– Hallmark hepatitis manifestation
• Dark & foamy urine
• Grayish-white stool color
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Icteric Phase (cont’d)
• Most infections may not cause jaundice
• Elevated liver enzymes before/at clinical onset
– Aminotransferase & transaminases
• Hepatitic tenderness, hepatomegaly & splenomegaly
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Convalescent (Recovery) Phase
• Icteric manifestations disappear
• Malaise & fatigue may persist for months
• Possible long-term, chronic sequelae
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Question 1
Persons with hepatitis A are most infectious
A) During the incubation period.
B) Early in the prodromal phase.
C) In the last 2 weeks of the prodromal phase.
D) Immediately after the onset of jaundice.
E) During the convalescent phase.
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Answer
Persons with hepatitis A are most infectious
C) In the last 2 weeks of the prodromal phase.
The greatest infectivity potential occurs during the 2-week
period immediately before the onset of jaundice. Onset of
symptoms is rapidly followed by a decrease in both
viremia and infectiousness.
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis A
• Picornavirus family
• Small, single-stranded 27nm RNA agent
• Humans are only natural host
• More temperature & pH stable than enteroviruses
– Remains infectious at moderate temp & low pH
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis A (cont’d)
• Survives in feces & exudates
• Stable in environment for months
– Inanimate surfaces
• Inactivated by high temperature, formalin & chlorine
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis A (cont’d)
• First described in 1973
• Common in many developing countries
• Decreasing incidence in U.S.
– 42,000 new infections in 2005 (CDC estimate)
– Still >30% of reported acute hepatitis cases
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis A Transmission
• Person-to-person contact
• Fecal-oral contamination
• Indirect via contaminated water or food
– Raw or inadequately cooked shellfish
• 45% of U.S. cases have no known risk factors
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Risk Factors for Hepatitis A Transmission
• Day care center contact
• International travel
• Intravenous drug use
• Men who have sex with men
• Persons with chronic liver disease
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis A Transmission and
Epidemiology
• Serial human-human propagation
– No carrier state or chronic hepatitis
• Incubation period of 15 - 40 days (average 28 – 30)
• Highest infectivity in late incubation to early prodromal
– Viremia decreases rapidly after symptom onset
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis A Serology
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis A Serology (cont’d)
• IgM-class anti-HAV during/soon after acute phase
• IgG antibodies replace anti-HAV
– High concentration in 4 – 6 weeks
– Remain detectable thereafter
– Confer lifelong protection against HAV
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis A Vaccines
• Inactivated hepatitis A virus
• VAQTA, Havrix (1995) & Twinrix (2001)
• For children in high-incidence areas (CDC, 1999)
• Recommended for all children (2006)
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis B
• Seroprevalence varies greatly worldwide
• Most transmissions perinatal where endemic
• Causes 80% of primary liver cancers
• U.S. incidence decreasing
– Vaccine & infection control precautions
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Prevalence of Hepatitis B in U.S.
• 260,000 infected in the 1980’s
• 78,000 infected in 2001
• 51,000 infected in 2005
• 1 million carriers
– 20% - 40% will develop life-threatening conditions
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
HBV and Antigens
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis B Virus Morphology
• 42nm, double-shelled DNA virus
• Complete virion is called the Dane particle
• Several well-defined antigen-antibody systems
– Hepatitis B surface antigen (HBsAg)
– Core antigen (HBc)
– Hepatitis B e antigen (HBeAg)
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Serologic Pattern of Acute Hepatitis B
Infection
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis Terminology
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Interpretation of the Hepatitis B Serologic
Profiles
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Outcomes of Hepatitis B Infection
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Serologic Profile of HBV Carrier State
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis B Clinical Course
• Incubation period of 50 – 180 days (average 60 – 120)
• Variety of ultimate outcomes
• Chronic infection in ~ 5-10% of adolescents & adults
• Most cases anicteric (no jaundice)
• As many as 80% of infections undiagnosed
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Clinical Signs And Symptoms of Acute
Hepatitis B Infection
• Anorexia
• Jaundice
• Malaise
• Skin rashes
• Nausea
• Arthralgia
• Vomiting
• Arthritis
• Abdominal pain
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Symptoms of Chronic HBV Infection
• Disease-specific
• Nausea
– Cirrhosis
• Anorexia
– Hepatocellular
carcinoma
• Upper right quadrant
tenderness
• Severe fatigue
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
HBV Transmission Modes
• Parenteral
– Percutaneous – efficient, 7+ day incubation
– Non-percutaneous – inefficient, ~54 d incubation
• Longer period to transmit disease
• Sexual
• Vertical (perinatal & parent-child contact)
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Prevalence of Hepatitis B Serologic
Markers Among DHCP (1979-81)
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Prevalence of HBV Infection in Dentistry
• 13.6% of general practitioners positive in 1976
• 8.5% of dentists & 6.8% of hygienists positive in 2005
• Greater exposure risk than general population
– General dentists: 3x risk
– Oral surgeons: 6x risk
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
HBV Transmission from Carrier Dentists to
Patients
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Active Immunity
• Antigens stimulate immune response
• Long-term protection after a latent period
• Conferred by
– Host recovery from infection
– Vaccination
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Passive Immunity
• Antibodies from actively immunized host
– Ig (ISG) – against HAV primarily, inexpensive
– HBIG – against HBV for 2 months, expensive
• Protection immediate & transitory
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Plasma-Derived HBV Vaccine (1982)
• Serum from carriers, high HBsAg concentration
– Boiled 1 minute (Krugman, et al.)
– Lost infectivity & retained antigenicity
• Viral coat protein extraction & purification
• No HIV transmission risk
• Heptavax-B discontinued in 1989
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Antibody Responses to Hepatitis B ThreeInjection Vaccine Series
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Recombinant DNA HBV Vaccines (1986)
• Gene for HBsAg inserted into yeast plasmid
• HBsAg harvested from lysed yeast cells
• Final product has 10 μg HBsAg protein/mL
• Recombivax-HB & Engerix-B
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Pre-Testing (HBV Vaccination)
• Cost-effective when prevalence high
– Anti-HBs-positive persons don’t need vaccine
• Not cost-effective in average dental office
– Only 6.7% of DHCP are positive
• May be offered per 1991 OSHA BBP Standard
• Significant number of false-positives
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Post-Testing (HBV Vaccination)
• Preferably 1-2 months after 3rd inoculation
• Second 3-dose course for non-responders
• After years, anti-HBs-negative recipient may be
– Primary non-responder, susceptible
– Antibody level undetectably low, immune
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Question 2
After administration of hepatitis B vaccine, blood should be
tested for
A) HBsAg within 1-2 months.
B) Anti-HBs within 6 months.
C) HBsAg every 10 years.
D) Anti-HBs every year.
E) Both A and D
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Answer
After administration of hepatitis B vaccine, blood should be
tested for
B) Anti-HBs within 6 months.
HBsAg (surface antigen) indicates infection, not immunity.
Post-testing should be scheduled soon after the last
inoculation, preferably within 1-2 months, because
antibody levels may become undetectably low over time.
Annual testing is not required because the protective
anamnestic response is very long-term, even if anti-HBs
is no longer detectable.
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Acute HCV Infection
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis C
• RNA virus related to genera Flavivirus & Pestivirus
• Strains exhibit high genetic diversity
– Mutation within host during replication
– Very high (85%) rate of chronic infection
– No vaccine or PEP available
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis C – Transmission
• Illegal intravenous drug use – 60%
• Other routes have low transmission rates
• Transmitted inefficiently by occupational exposures
– 1.8% of percutaneous exposures
• Low risk from environmental contamination
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis C – Acute Infection
• Incubation period 30 – 150 days
• 60%-70% have no or nonspecific symptoms
• Less hepatic inflammatory response vs. HAV & HBV
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
HCV Infection in Dentistry
• Prevalence among HCP has declined
• Similar incidence as general population (1%-2%)
• Risk of surgeon to patient transmission (0.17%)
• Limited risk of DHCP to patient transmission
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Schematic Morphology of HDV
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Delta Hepatitis
• Requires HBV as helper virus
– Outer protein coat (HBsAg) & replication
– Active HBV immunity protects against HDV
• Endemic in Mediterranean, parts of Africa & S. America
– Transmitted by intimate contact & transmucosally
• Transmitted percutaneously where not endemic
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
HDV Infection Modes
• Simultaneous infection with HBV and HDV
– Often resolves with limited clinical course
• Acute delta superinfection in HBV carriers
– Already have high titer of circulating HBsAg
– More serious, fulminating & chronic infections
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Hepatitis E Virus
• Single-stranded RNA calcivirus
• Transmitted enterically via fecal-oral route
• No outbreaks in U.S., Europe or Australia
• Very low transmission risk in occupational exposures
• Incubation period 15 – 70 days
• Generally self-limiting, except during pregnancy
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Question 3
Which of the following requires an additional etiologic agent
for clinical expression?
A) Hepatitis A virus
B) Hepatitis B virus
C) Hepatitis C virus
D) Hepatitis D virus
E) Hepatitis E virus
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Answer
Which of the following requires an additional etiologic agent
for clinical expression?
D) Hepatitis D virus
Although HDV is unique and distinct from HBV, it requires
HBV as a helper virus for an outer protein coat (HBsAg),
and thus for replication.
Copyright © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins