Hepatitis B in children and adolescent , virology,clinical scenario, serology, diagnosis and management.

1. Presented by
Dr. Kaniz Fathema
Resident, Phase- B (year 4)
Paediatric Gastroenterology & Nutrition
B S M M U
Hepatitis B virus infection
in children and adolescents

2. Discussion
 Virus
 Acute HBV infevion
 Chronic HBV infevion
 Immunization
 Management

3. Hepatitis B Virus

6. Pathogenesis
 HBV is a predominantly noncytopathogenic virus that
 causes injury mostly by immune-mediated processes.
 most complete immune response being associated with the
greatest likelihood of viral clearance but also the most severe
injury to hepatocytes.
 infection of hepatocytes by HBV, resulting in expression of viral
antigens (nucleocapsid antigens—HBcAg and HBeAg) on the
cell surface.
 These antigens, in combination with class I major
histocompatibility proteins, make the cell a target for cytotoxic
T-cell lysis.
 Circulating immune complexes containing HBsAg can result in
extrahepatic manifestation
 Fulminant HBV due to hyper-vigorous immune response

7. Routes of transmission
 Hepatitis B virus can be transmitted via body fluids, either through mother-to-
infant transmission (70 – 80%) or horizontally through blood transfusion,
injection, sexual exposure, or close contact in the family or with caretakers.
 Intrauterine HBV infection occurs rarely, in <5% of the infants of HBeAg- and
HBsAg-positive mothers.
 most perinatal HBV transmission occurs at or near the time of birth, 90 percent of
these infants will acquire acute HBV infection if no preventive measures are
taken.
 High infectivity : 0.0002 ml of infected blood is sufficient
 Stable in environment for 7 days

8. High Intermediate Low
Carrier rate ≥8% 2 to 7% ≤1%
Predominant age
at infection
Perinatal and
early childhood
Early childhood Adult
Predominant
mode of infection
Mother to child;
percutaneous
Percutaneous;
sexual
Percutaneous;
sexual
Epidemiology and modes of transmission of

9. Age of infection Rate of persistent infection
Perinatal period
Mother HBeAg(+), HBsAg(+) >90%
Mother HBeAg(-),
HBsAg(+)
<5%, but with risk of acute or
fulminant hepatitis
Preschool age 23%
Young adults 2.7~10%

10. Risk of chronic hepatitis B virus carriage by age of infection

11. Why perinatal infection become chonic
 The relatively high maternal viral load transmitted to the
neonate with a physiologically immature immune system
during perinatal period .
 The e antigen is a small viral secretory protein that can cross
the placenta barrier. As both HBeAg and HBcAg are highly
cross-reactive in terms of helper T-cell recognition,
transplacental HBeAg may induce a specific unresponsiveness
of helper T-cells to HBeAg and HBcAg in the neonates born to
HBeAg-positive, HBsAg positive mothers .
 the coreprotein or major histocompatibility class I protein
might not be recognized, the cytotoxic lymphocytes might not
be activated.

12. Spectrum of clinical illness
Acute :
1. Sub clinical or an-icteric hepatitis
2. Icteric hepatitis
3. Fulminant hepatitis
Chronic :
1. Asypmtomatic HBsAg carrier state
2. Chronic hepatitis
3. Cirrhosis
4. Hepatocellular carcinoma

13. Extrahepatic Manifestations
 Serum sickness–like syndrome
 Glomerulonephritis:
 Polyarthritis:
 Polyarteritis nodosa:
 Dermatologic condition: Bullous pemphigoid,
lichen planus, Gianotti-Crosti syndrome
 Cryoglobulinemia :
 Neurologic/psychological condition : GBS, altered
mental status, depression/psychosis

15. Serologic responses to HBV infection

16. Interpretation of the hepatitis B serologic panel
HBsAg anti-HBc anti-HBs Interpretation
N N N Susceptible
N Positive Positive Immune due to
natural infection
Negative Negative Positive Immune due to
hepatitis B
vaccination
Positive Positive
anti-HBc
IgM
Negative Acutely infected
Positive anti-HBc
Positive
Positive Chronically infected
IgM anti-
HBc
Negative
Negative Positive Negative Four interpretations
possible

17. Four interpretations:
1. Might be recovering from acute HBV infection.
2. Might be distantly immune and test not sensitive enough to
detect very low level of anti-HBs in serum.
3. Might be susceptible with a false positive anti-HBc.
4. Might be undetectable level of HBsAg present in the
serum, and the person is actually chronically infected.

18. Acute HBV infection
 The incubation period lasts one to four months.
 A serum sickness-like syndrome may develop during the
prodromal period, followed by mostly mild constitutional
symptoms, anorexia, nausea, jaundice, and right upper
quadrant discomfort.
 The symptoms and jaundice generally disappear after one to
three months, but some patients have prolonged fatigue even
after normalization of serum aminotransferase concentrations.

19. HBs
Ag
HBe
Ag
IgM
anti-
HBc
Total
anti-
HBc*
Anti-
HBs
Anti-
HBe
HBV
DNA ALT Interpreta
tion
+ + + +++ Elevated Early
phase
+ + Elevated Window
phase
+ + + ± Normal Recovery
phase
Diagnostic tests to determine phase of acute or
chronic hepatitis B virus infection.

20. Acute hepatitis
HBsAg +ve
AntiHBc
IgM +ve
Acute Hep B
No Rx
>90% will recover.
and clear HBsAg
5-10% will
progress to CHB
Anti HBcIgM -ve
Chronic Hepatitis B
Follow up child , if
HBsAg positive after
6 months - Chronic

21. HBV Sequelae

22. MANAGEMENT OF ACUTE HBV
 supportive management alone.
 severe acute hepatitis, treatment with a nucleoside/tide
analog might be considered.
 fulminant hepatitis caused by HBV, liver transplant may
be necessary.

23. Chronic HBV infection
 Asymptomatic and grow and develop normal
 vague right upper quadrant discomfort and fatigue.
 Extrahepatic manifestations.
 chronic HBV infection is characterized by persistently
positive HBsAg > 6 month.
 In contrast with acute HBV, total anti-HBc is usually
positive (because of the immunoglobulin G [IgG]
component), while IgM anti-HBc is negative (unless during
a flare of chronic HBV).

24.  Rates of spontaneous seroconversion (loss of HBeAg) are
less than 2 percent per year in children younger than three
years of age, and increase to about 8 percent per year during
puberty and young adulthood.

25. History
risk factors for coinfection with HCV and/or HIV, use
of alcohol, and family history of HBV infection, liver
disease, and liver cancer.
physical examination
assess for growth parameters and for signs of chronic
liver disease

26. Laboratory testing
Initial evaluation:
 Complete blood count with platelets, albumin, and prothrombin time-----
normal in children with chronic HBV.
 Liver biochemical tests (ALT,AST, total bilirubin,ALP)
 tests for HBV replication HBeAg, HBeAb, and HBV DNA.
 Testing for coinfectio--- HCV, HAV, HDV, HIV
Additional evaluation :
 other causes of liver disease in children with signs and symptoms that are
atypical for HBV
 Screening for HCC
 Liver biopsy for patients who are being considered for treatment of
chronic HBV infection
Testing for HBV genotype is not necessary at the time of diagnosis

27. Chronic HBV infection (HBsAg-positive for >6 months with positive (total) anti-HBc, and negative IgM anti-HBc.)
+ + + - - +++
(Serum HBV typically >1
million international
units/mL) (HBV DNA
>20,000 international
units/mL or 105 copies/mL)
Normal or mildly
elevated(ALT <2
times the upper
limit of normal)
Immune-tolerant phaseΔ
+ + + - - +++
(Serum HBV >20,000
international units/mLor
105 copies/mL) )
Persistently
elevated(ALT >1.5
to 2 times the
upper limit of
normal)
Immune-active HBeAg-
positive / immune
clearance (HBeAg-
positive chronic hepatitis)
+ - + - + ++
(Serum HBV >2000
international units/mL)
Elevatednormal or Immune-active, HBeAg-
negative OR reactivation
OR HBeAg-negative
chronic HBV or HBeAg-
negative replicative phase
HBeAg-negative chronic
hepatitis
+ - + + - to ++
(Serum HBV ≤2000
international units/mL)
Normal or mildly
elevated
Inactive chronic HBV OR
latent, nonreplicative or
inactive carrier
- - ±(ge
neral
± ± + in liver; - to + in serum Normal Occult HBV
H
Bs
A
g
H
Be
Ag
Ig
M
anti
-Bc
Total
anti-
HBc*
Ant
i-
HB
s
Anti
-
HBe
HBV DNA ALT¶ Interpretation

30. SCREENING

31. screened for HBV regardless of their vaccination
history
 Individuals born in areas with high (≥8%) or
intermediate (≥2%) prevalence rates for HBV.
 Pregnant women
 Those requiring immunosuppressive therapy
 Donors of blood, plasma, organs, tissues, or semen
 Infants born to HBV-infected mothers

32. screened if they were not vaccinated or were
vaccinated but did not have screening prior to
vaccination
 infants whose parents were born in regions with high HBV
endemicity (≥8%)
 Household and sexual contacts of HBsAg-positive persons
 Persons who have ever injected drugs
 Persons with multiple sexual partners and/or history of
sexually transmitted diseases
 Men who have sex with men
 Inmates of correctional facilities
 Individuals with chronic liver disease
 Individuals with HIV infection
 Individuals infected with HCV
 Patients with end-stage renal disease.

33. IMMUNIZATION

34. VACCINE FORMULATIONS
TYPE: Single antigen vaccines , Combination vaccines
Storage : between 36 and 46°F (2 and 8°C) .
Efficacy : >90% in preventing HBV infection
Vaccine-induced immunity : long lasting .
Routine booster doses are not necessary for children and
adolescents with normal immune status.
Route : intramuscularly (IM)
Site: anterolateral thigh (for children <3 years) or deltoid (for
children ≥3 years).

35. Inappropriate administration
 Intervals that were too short (eg, <4 weeks between the first
and second dose; <8 weeks between the second and third
dose; or <16 weeks between the first and third dose); doses
administered four or fewer days less than these intervals are
considered valid
 Receipt of the final dose of the primary infant series at <24
weeks of age;
 Administration by a route other than intramuscular
 Administration at a site other than the anterolateral thigh or
deltoid

36. Catch-up hepatitis B (HepB) vaccine
●unvaccinated or incompletely vaccinated against HBV
●unknown or uncertain vaccination status
●received doses of HepB vaccine that were administered
inappropriately, unless serologic testing (if performed)
indicates that they responded adequately.
HepB vaccine series does not need to be restarted if it
was interrupted

37. POSTEXPOSURE IMMUNIZATION
with or without adjunctive hepatitis B immune globulin
is recommended for unvaccinated or incompletely
vaccinated children and adolescents with exposure to
blood or infectious secretions (eg, bite, needlestick,
sexual assault).

38. prevaccination serology
 not routinely necessary.
 The risk of adverse effects is not increased in
persons who are immune to HBV because of past
infection or immunization .

39. Single antigen
vaccines Age group Volume
(mL)
Dose
HBsAg
(mcg)
Recombivax HB
Pediatric/adolesce
nt formulation
Birth through
17 years
0.5 5
Adult formulation 11 through 15
years
1 10
Engerix B¶ Birth through
17 years
0.5 10
Recommended doses of formulations of hepatitis B

40. Maternal
HBsAg
status
Single antigen* plus
combination vaccine
Dose Age
Positive 1 Birth (≤12 hours)*
HBIG Birth (≤12 hours)
2 2 months
3 4 months
4 6 months
Unknown 1 Birth (≤12 hours)*
2 2 months
3 4 months
4 6 months
Negative 1 Birth (≤24 hours)*
2 2 months
3 4 months
4 6 months
hepatitis B immunoprophylaxis for term and preterm infants
with birth weight ≥2 kg
If mother find as HBsAg-positive or status remains unknown HBIG 0.5 mL should be given by one
week of age.

41. Maternal
HBsAg status
Single antigen plus combination
vaccine*
Dose Age
Positive¶ 1 Birth (≤12 hours)
HBIG Birth (≤12 hours)
2 2 months
3 4 months
4 6 months
Unknown 1 Birth (≤12 hours)
HBIG Birth (≤12 hours)
2 2 months
3 4 months
4 6 months
Negative 1 Hospital discharge or
age 1 month
2 2 months
3 4 months
4 6 months
hepatitis B immuno-prophylaxis for preterm infants
with birth weight <2 kg

42.  Single-antigen vaccines should be used for the birth dose.
 Combination vaccines (eg, Pediarix) cannot be administered at
birth or before age 6 weeks.
 Infants born to HBsAg-positive mothers should receive
immunoprophylaxis as recommended whether or not their mother
received antiviral therapy during the third trimester.
 The final dose in the vaccine series should not be administered
before age 24 weeks (164 days).
Some Consideration…..

43. POSTVACCINATION SEROLOGY
usually is not necessary for immunocompetent children and
adolescents Except
●Women who are HBsAg-positive
●Women whose prenatal HBsAg results were not available at
the time of delivery but who have other evidence suggestive of
chronic hepatitis B infection
●Women whose HBsAg-status cannot be determined
Test : both HBsAg and anti-HBs]should be obtained after
receiving ≥3 doses of HepB vaccine, usually at 9 to 12 months of
age or one to two months after the last dose of HepB vaccine

44. Hemodialysis patients and Immune-
compromised patients
 anti-HBs one to two months after administration of
the last dose of the primary HepB vaccine series
 annual anti-HBs testing for hemodialysis patients
and administer a booster dose of HepB vaccine
when the anti-HBs concentration is <10 mIU/mL,

45. Contraindications and precautions for hepatitis B vaccines
ADVERSE REACTIONS :
• ususlly safe. Pain, erythema at the injection and fever
>37.7°C (99°F)
Contraindications
 Severe allergic reaction (eg, anaphylaxis) after a previous
dose or to a vaccine component (eg, yeast)
Precautions
 Infant weighing <2 kg (4.4 pounds)
 Moderate or severe illness with or without fever (ie, illness
more severe than upper respiratory infection, otitis media,
gastroenteritis)

46. incorrectly perceived as contraindications or precautions to hepatitis B
vaccine
 Pregnancy
 Autoimmune disease (eg, systemic lupus erythematosus, rheumatoid arthritis)
 Mild acute illness with or without fever (eg, upper respiratory infection,
otitis media, gastroenteritis)
 Mild-to-moderate local reaction (eg, swelling, redness, soreness) after
previous dose
 Low-grade or moderate fever after previous dose
 Current antibacterial therapy (except for oral typhoid vaccine)
 Convalescent phase of illness
 Recent exposure to infectious disease
 History of penicillin allergy, other nonvaccine allergies, relatives with
allergies, or receiving allergen extract immunotherapy
 History of Guillain-Barré syndrome

47. Management

48. COUNSELING
 Household members of children with chronic HBV should be
screnned and vaccinated
 risk of transmission to others, including perinatal transmission
and risk of environmental exposure from blood
 Household members should not share toothbrushes or razors
 no special measures in sharing of eating utensils
 to participate in all regular activities (school and sports)
 universal precautions in daycare centers, schools, sports
clubs, and camps

49. MONITORING
ALT HBeAg HBeAb USG For
HCC
Immune
tolerant
phase
every 6 to
12 months
every 12
months
every 12
months
2 to 3
yearly
Immune
active, HB
eAg-
positive
phase
ALT becomes elevated (>40
international units/L), biochemical
tests and serologies should be
measured more frequently (eg,
every three to six months).
6 monthly
Inactive
chronic
HBV
every 6 to
12 months
every 12
months
every 12
months
needed

50. SELECTION OF PATIENTS FOR ANTIVIRAL
TREATMENT
goal of treatment
reduce the risks of progression to cirrhosis and of
hepatocellular carcinoma (HCC).
efficacy of treatment measured through intermediate
outcomes such as changes in short-term virologic,
biochemical, and histologic parameters.

51. Treatment of Phase of chronic HBV
Immune
tolerant
NOT as chance
development
of drug
resistance,
Exception : cirrhosis or other signs of severe liver
disease even if the ALT levels are normal
Immune
active, HBsAg-
positive
(clearance)
phase –
markedly elevated ALT values (>10 times the ULN), observation for
several months then Testing at least every three months
There are three possible outcomes :
Spontaneous seroconversion to inactive chronic HBV ("carrier" state)
: no treatment
Persistent immune active phase : treatment is indicated.
Spontaneous resolution of the HBV infection: monitored for
reactivation of infection and for HCC
Inactive
chronic HBV
should not be
treated
HBV DNA should be measured if ALT becomes
elevated
Immune
active, HBeAg-
negative
(reactivation)
close monitoring and Antiviral therapy is indicated to minimize liver
damage
Adults with this condition are typically treated indefinitely.

52. Algorithm for selection of children for antiviral
treatment of chronic HBV

53.  Immune active, HBsAg-positive (clearance) phase treatment
for patients who have persistently abnormal ALT (>2 times
the ULN or >60 units/L, whichever is lower) and HBV DNA
>20,000 international units/mL or 105 copies/mL for at least
four to six months either HBeAg-positive or HBeAg is
negative treatment should be given.
 If there is evidence of hepatic decompensation, treatment
should be initiated earlier

54. who will be undergoing immunosuppression –
 Treatment is appropriate in all phases
 a nucleos(t)ide is often used in an effort to prevent reactivation;
 drugs may be discontinued after the immunosuppressive therapy
is complete and if HBV DNA remains <20,000 units/mL and ALT is
normal.

55. DRUGS

56. Pegylated
IFNα
Entecavir* Tenofovir
Duration of
treatment
1 year >1 year¶ >1 year¶
Age group
(FDA approval)
≥3 years ≥2 years ≥2 years
Route Subcutaneous Oral Oral
Side effects Many Negligible
Potential
nephrotoxicity, reduced
bone mineral density (
Drug
resistanceΔ
None
∼1% up to year
6
None, up to year 8

57. Entecavir, Tenofovir:
 without cirrhosis treatment should continue for
at least 12 months after seroconversion from
HBeAg to anti-Hbe or treatment indefinitely
unless the patient clears HBsAg.
 with cirrhosis continued indefinitely unless they
clear HBsAg.
 patients are at risk for exacerbations of
hepatitis B after discontinuation ofall
nucleos(t)ide .

58. New biomarkers of HBV infection
Hepatitis B core-related antigen (HBcrAg)
 composite bio- marker comprising several antigens expressed from the
precore/- core gene: HBcAg, HBeAg, and prec22 precursor protein.
 concerning the translational activity of the HBV infection beyond HBsAg
quantification.
 partly reflect the amount of intrahepatic DNA and cccDNA in
hepatocytes especially in HBeAg-positive patients.
 defining the phase of chronic HBV infection, especially in HBe- negative
patients,
 predicting the long-term HCC risk.
 to monitor NA or PegIFNa based treatments and pre- dicting therapeutic
efficacy including the risk of relapse after stopping NAs.

59. Circulating HBV RNA
 HBV RNA can be released into the serum in the form of
enveloped pregenomic RNA containing virions .
 interesting marker to study cccDNA transcrip- tional activity.
 correlation between quantitative serum HBV RNA dynamics
and HBeAg loss in both NA and PegIFNa treated patients
demonstrated by using a new rapid amplification of cDNA-
ends with polymerase chain reaction (RACE-PCR)
 new marker for monitoring NA therapy.
 in predicting viral rebound after discontinuation of NAs.

60. Take home messages….
 Management is difficult
 Treatment is costly
 Treatment outcome guarded
 Prevention is better than cure
 Health education and vaccination at birth
are the logical and practical approach.