Amy Warner, MPH - The ABCs of Pediatric Viral Hepatitis

The ABC
S
of Pediatric Viral
Hepatitis
Amy E. Warner, MPH
Colorado Department of Public Health
and Environment
Viral Hepatitis Program ph: 303-692-2780
http://www.hepatitiscolorado.info fax: 303-759-5257
Hepatitis A
Hepatitis A
Picornavirus(RNA)
Incubation: 15-50 days (mean 28)
Transmission:
Oral-fecal (household, intimate, institutions)
Common Source (water, food, shellfish)
Parenteral (rare)
Clinical Hepatitis A
Symptoms by Age
<6 years of age =30%
>6 years of age =70% or more
Flu like symptoms: fever, malaise, anorexia,
nausea, abdominal pain, jaundice
Children less likely to be jaundiced
Peak period of being infectious
2 weeks before symptoms
Complications:
Fulminant hepatic failure (1:10,000)
Relapsing hepatitis
Risk of Acquiring Hepatitis A
U.S.
Risk groups:
International travel,
Men who have sex with
men
Users of Injection and
Noninjectiondrugs
Person with
Occupational Risk
Persons with Clotting-
Factor Disorders
Persons with chronic
liver disease
Less Likely Risk
Groups
Food handlers
Child care centers
Health-care workers
Persons with
developmental
disabilities
Schools
Workers exposed to
sewage
MMWR: May 19, 2006/Vol.55/No.RR-7
Hepatitis A Risks
Higher Risk
Transmission
High Risk of Severe
Outcomes
Public Health
Implications
International Travel Persons with chronic liver
disease
Food workers
Men who have sex with
men
Persons with clotting
factor disorders
Healthcare workers
Users of illicit injectable
and non-injectable drugs
Childcare centers
Viral Hepatitis Program
http://www.hepatitiscolorado.info
Hepatitis A Worldwide
In developing countries, infection in the first
decade of life is common
In developed countries, infection occurs at an older
age
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USA
Sweden
0.0
5.0
10.0
15.0
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25.0
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1983 85 87 89 91 93 95 97 99 01 03 05 07 09
R
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Report Year
880 cases
Hepatitis A Rates in Colorado, 1983-2009
Hepatitis A
vaccine available
27 cases
The hepatitis A vaccine is safe and effective. Since Colorado
introduced it in 1996, hepatitis A has declined dramatically.
Hepatitis A: Colorado Cases
Hepatitis A Prevention
The best way to prevent hepatitis A
infection is to get the hepatitis A vaccine
Vaccine is recommended
Before international travel
For all children at age one
Others in high risk groups
Hepatitis A Vaccine
Inactivated vaccine.
Very effective immunogenicity
97-100% seroconversionat one month after vaccination
Approved for children 1 year and older
Duration of protection estimated 12-25 years
Contraindications
a history of severe allergic reaction to a previous dose or to a
vaccine component (alum, phenoxyethanol)
Specific dosing guidelines are available in the Redbook
and on the CDC guidelines
Who to Vaccinate??
Occupational
Risk
Travelers to
endemic
regions
Children 1
year of age
or older
Chronic
liver
disease
High risk
behaviors
Transplant
recipients
Preventing Transmission U.S.
Vaccination (preferred)
All those at risk
All children 1 year of age or older
Immunoglobulin
Short-term protection through passive
transfer of anti-HAV
85% effective if given 2 wks of exposure
protection conferred for up to 5 months
Given post-exposure to individuals < 1
year of age or >40 years of age
Hepatitis B
Hepatitis B
DNA virus from the heptadnavirus
Incubation: 60-15 days (mean 90 days)
Results in an acute or chronic infection
CDC Pink Book 12
th
Edition
Hepatitis B:Transmission
Vertical transmission
Immigration from endemic areas
Infection by HBsAg+ household contacts
Chronic HBV infection develops in
90% of infants infected as neonates
25-50% of children aged 1-5 years of age
5-10% of adults
Hepatitis B: Epidemiology
Universal vaccination
of infants
Clinical Hepatitis B
At least 50% of infections are asymptomatic even
more if you are <5 years of age
The risk of chronic HBV infection decreases with
age
An estimated 3,000 4,000 persons die of
hepatitis B related cirrhosis each year in U.S.
1,000-1,500 people die of HBV-related liver
cancer annually in the U.S.
Consequences of HBV infection
Incident Hepatitis
Recovery
Asymptomatic Carrier
Chronic infection FHF
Death
90-95%
Chronic Hepatitis
Hepatocellular Carcinoma
Cirrhosis
<1%
80%
20%
5% adults
30%- 50% for children 1-5 years
90% for children <1 year
30-70%
25%
25%
Pediatric Infections in the U.S.
International adoptees
Children born in endemic countries even if
records indicate HBV vaccination.
Children born to HBsAg+ mothers who did
not receive prophylaxis
Clinical Hepatitis B
Prodrome: serum sickness, rash, arthritis
Symptomatic phase: fatigue, fever, myalgia,
nausea, vomiting, abdominal pain, jaundice,
icterus(often anictericin children)
Convalescence
Complications: FHF, membranous
nephropathy, vasculitis, papular
acrodermatitis
Children to Screen for HCV:
Children born to HCV-infected mothers (IOM, CDC, NIH)
Children born in HBV endemic countries even if they
received hepatitis B vaccine
Children born in the US to immigrant parents from endemic
areas
Children living with an HBsAg+individual
Children using illicit injection drugs even once in the
distant past - especially if drugs, equipment, paraphernalia
or rinse water were shared (IOM,CDC, NIH) IV (IOM,
CDC)
Persons with HIV (IOM, CDC)
Approach to patient
HBsAgtest
If high suspicion and HBsAgnegative, anti
HBcIgM or retest HBsAg2-3 weeks
Post exposure prophylaxis: HBIG, Hepatitis
B vaccine
Phase Labs and Histology Note
Immune
Tolerant
DNA>20,000 IU/ml
ALT normal
HBsAg and HBeAg detectable
Minimal liver inflammation and fibrosis
Antiviral therapies are generally
ineffective
Risk of drug resistance if treated
Immune
Active
DNA levels decline
ALT elevated
HBsAg and HBeAg remain detectable
Liver inflammation and fibrosis can develop
Most children still show no signs
or symptoms of disease
Inactive
HBsAg
Carrier
DNA<2,000 IU/ml or undetectable
ALT normalizes
HBeAg undetectable, anti-HBe present
No liver inflammation, fibrosis may regress
Age at serocoversion appears to
be influenced by HBV genotype
Risk of developing cirrhosis and
HCC declines
Reactivation
DNA levels increase
ALT normal or elevated
HBeAg remains undetectable
Occurs in 20-30 % of patients
e-antigen-negative disease
Usually due to a mutant virus
Phases of Chronic Hepatitis B I nfection
Haber BA, et al., Pediatrics 2009;124:e1007-13
Hepatitis B Foundation www.hepb.org
Recommended approach
to monitoring children
with chronic hepatitis B
infection
ALT and WBC/Pit are
generally part of a hepatitis
function panel and CBC
Greater than the testing
laboratory ULN, or >40
IU/L, whichever is lower
ALT and AFP q6-12 mos;
HBeAg/Anti-Hbeand HBV
DNA q12 mos; Also
consider ultrasound q1-2yr,
particularly with elevated
ALT or AFP or family
history of HCC
Hepatitis B: Treatment
The primary means of treatment of hepatitis
B is prevention of acquisition.
Second goal is the treatment of HBV if the
first goal is not achieved.
Mast EE, et al, MMWR RecommRep. 2005;54(RR-16):131 [corrections in MMWR 2006;55(6):158 159; MMWR 2007;56(48):1267]
HBV Childhood Vaccination
Recommendations
All infants at birth
Newborns of mothers with detected
HBsAg+ or mothers with unknown HBsAg
status. Vaccinate within 12 hours of birth,
plus 1 dose of HBIG at separate sites
All children <19 years old who were not
previously vaccinated
Goals of treatment
Eliminate HBV (unlikely)
Decrease risk of chronic liver disease/HCC
Decrease social stigma/isolation
Decrease transmission
Decrease HBV DNA to <2000 IU/ml or less
Most children will not require treatment,
however routine monitoring for progression
of disease is essential
Chronic HBV infection
selection of patients who may benefit
appropriate timing of treatment
choice of antiviral therapy
Limited therapeutic options for children and
significant potential for development of
viral resistance to nucleos(t)ideanalogs
J onas, MM, et al. Hepatology. Published online ahead of print Oct 1, 2010
Pediatric Treatment Challenges
Hepatitis B Foundation
www.hepb.org
a
ALT ULN is the local testing lab ULN, or 40
IU/L, whichever is lower. For treatment
consideration, ALT should be 1.5 x the lab ULN,
or 60 IU/L (1.5 x 40 IU/L), whichever is lower, at
least twice in 6 months for HBeAg-positive
disease, and at least 3 times in 12 months for
HBeAg-negative disease.
Recommended approach to selection of children
for treatment
Treatment of Chronic HBV
Infection
7 drugs are currently
approved for use in
adults (2 IFNs, 5
nucleos(t)ide analogs)
4 of these are labeled
for use in children (<18
years old) (IFN, 3
analogs)
2 are available for young
children under 3 years
old (IFN, 1 analog)
IFN response:
30-40% response in older children and
adults.
60-80% response in younger children
Predictors of response to therapy
<5 years
ALT >>normal
Low HBV DNA
Compensated liver disease
HBV genotype A and B
Low drug resistant mutant
rates
HBeAg+hepatitis
Low HBsAglevels
>5 years
Normal ALT
High HBV DNA
Liver failure
HBV genotype C and D
High drug resistance mutant
rates
HBeAgnegative hepatitis
HDV
High HBsAglevels
Higher response rates Lower response rates
Special Populations That Should Also Be
Considered for HBV Treatment
Regardless of HBV DNA & ALT Levels
Patients with rapid deterioration of liver function
Patients with compensated cirrhosis
If DNA >2,000 IU/mL, regardless of ALT
Patients with decompensatedcirrhosis (IFN
contraindicated)
Recurrent HBV infection post liver transplantation
HBV carriers undergoing immunosuppressive or cytotoxic
chemotherapy
Lok A, et al. Hepatology. 2007;45:507-539. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
EASL HBV Guidelines. Journal of Hepatology. 2009;50:227242. Sorrell MF, et al. Ann Intern Med.
2009;150:104-110.
Screen:
Conduct HBsAgand anti-HBctests on children at
high risk for HBV, especially those born in endemic
countries even if they received HBV vaccine in their
country of origin
Monitor
Children with chronic HBV infections and routinely
consult with a pediatric liver specialist.
Refer to a pediatric liver specialist
Any child with an elevated ALT and/or AFP level,
and/or a positive family history for liver disease,
especially liver cancer.
Summary: Screen, Monitor, and Refer
Hepatitis C
PUB MED:24,641 articles, 1645 in children
Hepatitis C- Epidemiology
* HCV affects >170 million people worldwide
2.7 million
HCV+
Hepatitis C: Epidemiology
CDC Website
Features of Hepatitis C Virus
Infection
Single stranded RNA flavivirus
Incubation 6-7 weeks ( range 2-26 weeks)
Chronic infection up to 85%
Case fatality rate is low
Cirrhosis
17
Chronic
85
Risk of Fatal Outcome in Persons Who
Develop HCV
Courtesy of Seeff, LB and Alter, HJ .
Time
100
Resolve
15
Stable
68
Stable
13
Mortality
4
80%
20%
75%
25%
15%
85%
Reported Risk Factors for Acute
Hepatitis C, United States, 2001-2004
Injection drug use (39%)
Transfusions (2%)
Occupation (4%)
Sex with known anti-HCV (+)
partner (10%)
No Identified Risk (33%)
Aggregate Risk Factor (4%)*
Sex with >2 partners
in past 6 mos (6%)
Source: Sentinel Counties Study of Acute Viral Hepatitis, CDC
Household (3%)
Recent Trends Children: CDC
Most infections in children are due to
passage at birth, or risk taking behaviors
in adolescents
The risk for perinatal HCV transmission
is about 5%
If coinfected with HIV the risk for
perinatal infection is about 19%
Risk of vertical transmission of
HCV?
If Mom is HIV negative, HCV PCR positive
26 studies 1157 infant mother pairs: 6.48%
BMJ 23 studies: 6.2% (95% CI: 4.6-7.8%)
If Mom is HIV negative and HCV PCR negative (HCV
antibody positive)
BMJ : 0% (95% CI: 0-0.4%)
If Mom is HIV positive and HCV antibody positive
BMJ : 15.8% (95% CI: 11.8-19.8%)
BMJ 315:333, 1997
Hepatitis C Perinatal Aquisition
Avoid use of fetal scalp monitors
Scheduled C-sections: ?slight decrease? In
transmission compared to vaginal delivery
HepC in colostrumand breast milk,
however NO increased risk of transmission
unless mastitis
Strategies for child of HCV positive mother
Mom HCV antibody/PCR positive
Negative
NO HCV
Refer to specialist for
follow-up evaluation
Infant anti-HCV/
PCR positive
Infant HCV PCR negative
Long Term Outcome: Perinatal HCV
Generally uncertain
Benign Extreme: (Hepatology39:90, 2005)
35 year f/u of mini transfusions 31 at risk, 18
infected
10% with ALT >1.5 times uln
No or minimal fibrosis in 82%
Severe Extreme: (Am J Gastro 98:660, 2003)
77% of 112 children with HCV had hepatic fibrosis
Higher fibrosis score if >10 years of infection
Rate of fibrosis would predict cirrhosis by ~40
years of age in the majority
Outcome of Pediatric HCV
Most children have
normal LFTs
LFTs do not correlate
with histology
No long term
outcome data from
vertical infection
available
Moderate-
Severe
Hepatitis
Mild
Non Specific
Bortolotti J PGN 18:281, 1994
Treatment in Children
Augment spontaneous clearance
No consensus on
If we should treat children
Who to treat
When to treat
Strategies for HCV Infected Children
No treatment prior to 2 years (high rate of clearance, SE)
Vaccinate for HBV, HAV, Counsel to avoid alcohol, or
risk behaviors
Baseline Genotype, PCR
Twice a year LFTs, CBC, Annual AFP, US ?
Liver biopsy if persistently abnormal LFTs or disease >10
years
Treatment:
Strongly consider: Genotype 2 or 3 or aggressive liver biopsy
Individual option: Genotype 1 with minimal disease
Wait: Individuals with high risk of reexposure, psychiatric
contraindications, thyroid disease, autoimmune disease
Factors that may affect
outcome/response to treatment
Viral load (lower is better)
Duration of disease (shorter is better)
Genotype 2 and 3 more responsive to interferon
>80% response
No apparent genotype dependent response to ribavirin
Abnormal transaminases
Low liver iron
Absence of cirrhosis
IL28b polymorphism (not studied in children)
Children almost always have 3/6
VIRUS
Genotype(1,2,3 or 4), quasispecies,
proteins inhibit t cell activation
ENVIRONMENT
Toxins, alcohol,
iron overload
HOST
IFN production, immuno-
tolerance, fibrosis, genes
Factors for HCV Treatment Response
Hepatitis C: Treatment
Interferon
Class II family of alpha-helical cytokines
Effects: direct antiviral, immunomodulatory, anti-proliferative,
anti-angiogenic, anti-tumor, control of apoptosis
Pegylationof interferon decreases clearance and allows once a
week dosing
PEG and ribavirinis current treatment of choice in adults where the
response rate is ~40-50% genotype 1 and 80-90% for genotype 2 or 3
Ribavirin
Guanosine-like nucleoside analogue
Mechanism: mutation in HCV virus leading to less replication
and easier clearance?
Single agent: reduces ALT, but not viral load
When combined with IFN generally reduces relapse after treatment
(SVR)
Interferon/Ribavirin Side Effects
Flu like symptoms are uniform
GI symptoms: 40%
Neuropsychiatric/Behavioral symptoms: 70%
Neutropeniarequiring dose reduction: 35%
Mean Hemoglobin decline of 2 gm/dl
Mean weight loss of ~10%, regained after
treatment
Severe side effects: suicide attempts,
retinopathy
Shikha S. Sundaram, MD MSCI
The Childrens Hospital
Digestive Health Institute
Alicia Cronquist, RN
Communicable Disease
Colorado Department of Public Health and Environment
Candace Vonderwahl
Colorado Department of Public Health and Environment
THANKS!!!

Amy Warner, MPH - The ABCs of Pediatric Viral Hepatitis

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