Download Seroconversion status of Hepatitis B vaccination in children with

Dissertation Synopsis.
Name: Dr. Harini R Rao
Address:1st year PG
MD Paediatrics
St. John’s Medical College Hospital.
Bangalore.
Name of the institution: St.John’s National Academy of Health
Sciences
Course of study and subject: MD Paediatrics.
Date of admission: 01.06.2013
Title of dissertation:
Seroconversion status of Hepatitis B vaccination in children with primary
nephrotic syndrome
Aims and objectives of the study:
Primary objective:
To assess the Hepatitis B surface antibody
(anti-HBs) titres in children with primary nephrotic syndrome.
Secondary objective:
To compare the seroconversion response to hepatitis B vaccine among steroid
responders and non-responders in primary nephrotic syndrome.
INTRODUCTION:
Nephrotic syndrome is a clinical syndrome of massive proteinuria defined by
ISKDC as (1)
1.
2.
3.
Urine protein excretion greater than 40 mg/m2/hour on a timed urine
collection or an early morning urine protein creatinine index of >200
mg/mmol
Hypoalbuminaemia of <25 g/l
Oedema
Estimates on the annual incidence of nephrotic syndrome range from 2-7 per
100,000 children, and prevalence from 12-16 per 100,000(2)and approximately
90% of children with nephrotic syndrome have idiopathic nephrotic syndrome.
This most commonly appears between 2-6 years of age and manifests clinically as
generalized odema. The initial episode and subsequent relapses generally follow
infections.[3]
The initial event in the pathophysiology of nephrotic syndrome is a derangement
in the glomerular capillary walls resulting in increased permeability to plasma
proteins resulting in massive proteinuria. This heavy proteinuria leads to the
depletion of albumin mainly, but also lipoproteins and globulins. The loss of
immunoglobulins and low IgG levels make the child vulnerable to infections. [4]
Additionally ,T lymphocyte dysfunction, impaired synthesis and urinary loss of
factor B (co-factor of C3b of alternative pathway of complement) result in
immune dysregulation which again predisposes the child to recurrent infections.
Yet another factor contributing to immunosuppression in children with nephrotic
syndrome is prolonged immunosuppressive therapy.
Hence preventing these infections with adequate immunization is a priority in
children with nephrotic syndrome. It becomes vital to ensure that these children
are adequately protected against preventable infections through appropriate
immunization schedules.
However, immune dysregulation not only result in infections but also leads to
lower seroconversion rates to various vaccines, both live and killed, including
hepatitis B vaccine,. [5,6,7]
Evidence from the western world reveals suboptimal seroconversion of most
vaccines in nephrotic syndrome(6,7,12)
Hence optimal monitoring of seroconversion status of the vaccines is imperative
in the management of nephrotic syndrome.
NEED FOR THE STUDY:
Hepatitis B infection is a public health problem in India. The prevalence of HBsAg
positivity is between 2 to 7% of the population studied, lying in the intermediate
endemicity range.[8] Vaccination against the same has been proven to significantly
reduce the disease load of Hepatitis B all over the globe. Children with nephrotic
syndrome are at increased risk of acquiring hepatitis B infection due to repeated
admissions and prolonged immunosuppressive therapy. The prevalence of
hepatitis B infection in children with nephrotic syndrome in India is found to be
3.1% [9] Adequate seroconversion to hepatitis B vaccination is important to
protect children with nephrotic syndrome against the infection. Poor response to
the hepatitis B vaccine is a matter of concern in children with nephrotic
syndrome.
In general, India faces limitations in the availability of appropriate monitoring
techniques for seroconversion of vaccines. However, mearsurement of hepatitis
B surface antibody (anti-HBs) titres is a feasible option that can be adopted to
study the immunogenicity of vaccines in nephrotic syndrome. There is limited
Indian data on seroconversion status to hepatitis B vaccination in children with
nephrotic syndrome.
We therefore aim to study the seroconversion status of Hepatitis B vaccination in
children with primary nephrotic syndrome and to correlate the extent of the same
with the level of immunosuppression.
REVIEW OF LITERATURE:
Hepatitis B virus is a DNA virus in which spread may occur perinatally (vertical
transmission), during early childhood (horizontal spread), through sexual contact
or nosocomially. It should be noted that, in our country, vertical route (mother to
child ) and horizontal route are the major routes of transmission of Hepatitis B.(10)
The prevalence of HBsAg positivity in India is between 2-7% and approximately
1-4% are chronic carriers of the infection.
Younger the age of acquisition of HBV infection, higher the chances of becoming a
chronic carrier. Infection with HBV is one of the most important causes of chronic
hepatitis, cirrhosis of liver and hepatocellular carcinoma. These outcomes are all
preventable by early childhood immunization. It is for this reason that the World
Health Organization has recommended universal Hepatitis B vaccination.
The vaccine is safe and well tolerated. The classical schedule is 0, 1 and 6 months.
The vaccine is highly immunogenic and seroconversion rates are greater than 95%
after a three dose schedule in healthy infants, children and adolescents .
Seroconversion rates are lower in the elderly, the immunocompromised and
those with chronic renal failure. Four doses at 0, 1, 2 and12 months of double
dose may be given in these patients.[10]Efficacy of hepatitis B vaccination is
estimated by measuring anti HBs titer and titer of >10mIU/ml is considered to be
seroprotective. Children with nephrotic syndrome are considered to be
immunocompromised due to immune dysregulation, immunosuppressive therapy
and loss of protective immunoglobulins in urine. It is therefore feasible to
anticipate lower seroconversion rates to vaccinations in these children. [4]
In a study done in Poland to compare efficacy of standard dose of vaccine versus
double dose, in both groups the seroprotection rate was similar (standard dose
group-96%, double dose group-93%), however the anti-HBs antibody level was
significantly higher in the double dose group during a 3 month observation
period. Also the best results were obtained in the group of patients in remission
of nephrotic syndrome.[11]
A study done in Naples, Italy in 1992, comparing the response to Hepatitis B
vaccination in boys with steroid sensitive nephrotic syndrome showed that the
percentage of patients who responded to vaccination was significantly lower than
the control group. [12]
Another study done in Istanbul in 2013 showed that patients with nephrotic
syndrome on steroids were found to seroconvert less than patients with
nephrotic syndrome not on steroids. [13]
A recent study in a tertiary care hospital in India showed that children with
nephrotic syndrome were less likely to seroconvert following HBV vaccination.
The study showed 52% children in the group studied were unprotected (having
values <10 mIU/ml antibody titres).63.6% of children with SSNS and 35.7% of
children with SRNS were found to have protective levels of titres in the study.[5]
MATERIALS AND METHODS:
Design: Cross sectional study
Source of data: Children with Primary Nephrotic Syndrome from Out patient
clinics and In-patient wards of Departments of Pediatrics and Pediatric
Nephrology, SJMCH .
Inclusion criteria:
1. Children with Primary nephrotic syndrome
2. Age: 1 year to 18 years of age.
3. Children with a negative test for Hepatitis B surface Antigen
4. Children with a clearly documented and completed course of HBV
vaccination
Exclusion criteria:
1. Child with CKD(Stage 2-5)
2. Children known to have other chronic diseases/ other immunosuppressive
states ( Chronic liver/ heart disease/retro infection)
3. Children who have received hepatitis B vaccine after the onset of nephrotic
syndrome
Study duration:
2 years
Sample size:
50 children with primary nephrotic syndrome included.
For seropositivity rates of 65-70%,with 95% confidence interval and precision of
10%, we would need a sample size of 50 children .
DEFINITIONS
1. NEPHROTIC SYNDROME:
A clinical syndrome of massive proteinuria defined by:
1. Urine protein excretion greater than 40 mg/m2/hour on a timed urine
collection or an early morning urine protein creatinine index of >200
mg/mmol;
2. Hypoalbuminaemia of <25 g/l,
3. Oedema.
2. REMISSION:
Urinary protein excretion < 4 mg/m2/hour or urine dipstix nil/trace for 3
consecutive days.
3. RELAPSE:
Urinary protein excretion > 40 mg/m2/hour or urine dipstix ++ or more for 3
consecutive days.
4. FREQUENT RELAPSES:
Two or more relapses within 6 months of initial response or four or more relapses
within any 12 month period.
5. STEROID DEPENDENCE:
Two consecutive relapses occurring during the period of steroid taper or within 14
days of its cessation.
6. STEROID RESISTANCE:
Failure to achieve remission in spite of 4 weeks of standard prednisolone therapy
Method of collection of data:
Sociodemographic factors such as name, age, gender, residential address, and
others will be noted.
Clinical history will be noted including
1. Age of onset of nephrotic syndrome
2. Type of nephrotic syndrome ie. Primary or secondary
3. If primary whether-infrequent relapser, frequent relapser, steroid
dependant or steroid resistant.
4. Type of immunosuppressant and duration
5. Schedule and dose of HBV vaccination received
6. Timing of HB vaccination
A thorough clinical examination will be performed.
Laboratory Investigations
After the patient/parents had provided informed
consent, 3 ml of venous blood sample will be collected
from each patient.
This sample will be used to determine HBsAg positivity
 if positive, the child will be excluded from the study
 if negative, anti HBs antibody titres will be measured in the same sample
after storing under appropriate conditions-sera will be separated
and stored at( −20 °C ) until further testing.
The anti-HBs titers of all patients will be quantitatively determined
by immunoenzymometric assay using a commercially
available kit (ErbaLisa SEN HBsAg ) as per the
manufacturer’s instructions. The anti-HBs titers will be estimated
quantitatively from 0–1,000 mIU/mL. The validation
criteria provided by the manufacturer will be fulfilled for all samples.
Interpretation of titres: (10)
Antibody titers greater than 10 mIU/ml signify a response and are considered
seroprotective
Outcome measures:
 Antibody titres in primary nephrotic syndrome
 Antibody titres in steroid responsive and steroid resistant states of
nephrotic syndrome
Statistical analysis:
 All data will be compiled in an Excel spreadsheet and analyzed using
descriptive statistics.
 The mean and standard deviation (SD) will be calculated for the baseline
characteristics and antibody titers.
 The chi2-test will be used to compare groups with categorical data, and the
Student t test or one-way analysis of variance was used to compare the
association between groups with continuous data.
 For all comparisons the 5 % probability level (P<0.05) will be considered
significant
Ethical clearance:
Application for ethical clearance shall be submitted to the Institutional Ethical
Review Board at St. John’s Medical College Hospital
REFERENCES
1. Report of APN. Cyclophosphamide treatment of steroid dependent
nephrotic syndrome: comparison of l8 weeks with twelve weeks. Arch Dis
Child 1987; 62:1102-06
2. Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet 2003; 362:
629-39
3. Nelsons textbook of pediatrics- 19th edition -Nephrotic syndrome page
1801-07
4. Robbins and Cotran Pathologic basis of disease, 7th edition Pg 978
5. MuktaMantan, Nagaraj Pandharikar, Sangeeta Yadav, Anita Chakravarti,
Gulshan Rai Sethi.Seroprotection for hepatitis B in children with nephrotic
syndrome. PediatrNephrolDOI 10.1007/s00467-013-2538-0
6. Kemper MJ, Altrogge H, Gansehow R, Wiefel DE (2002) Serum levels of
immunoglobulins and IgG subclasses in steroid sensitive nephrotic
syndrome. PediatrNephrol 17:413–417
7. Han JW, Lee KY, Hwang JY, Koh DK, Lee J (2010) Antibody status in children
with steroid-sensitive nephrotic syndrome. Yonsei Med J 51:239–243
8. Batham A, Narula D, Toteja T, Sreenivas V, Puliyel J (2007) Systematic
review and meta-analysis of prevalence of hepatitis B in India. Indian
Pediatrics 44:663–674
9. Ahmad B, Grover R, Ratho RK, Mahajan RC (2001) Prevalence of hepatitis B
virus infection in Chandigarh over a six year period. Trop Gastroenterol
22:18–19
10.IAP guidebook on immunization page 74-78
11.Grzesiowski P, Tańska A, Sieniawska M (1995) The influence of hepatitis B
vaccine dose on direct results of hepatitis B vaccination in children with
nephrotic syndrome. Pediatr Pol 70:25–28
12.LaManna A, Polito C, Foglia AC, Di Toro A, CafaroMR, Del Gado R (1992)
Reduced response to hepatitis B virus vaccination in boys with steroidsensitive nephrotic syndrome. PediatrNephrol 6:251–253
.
PROFORMA:
NAME:
OP/IP No:
ADDRESS:
DOA:
AGE:
SEX:
DOD:
CONSENT:I have been explained, in a language well understood by me, the risks
and benefits involved in the study. I, in my full sense, having understood the
same, give my consent to take part in the study.
Signature of legal guardian:
Date:
PRESENTING COMPLAINTS:
1.
2.
3.
4.
5.
6.
7.
8.
9.
Age of onset of nephrotic syndrome
First episode
If second episode- when was first episode?
Treatment of earlier episodes
Dose and duration of steroids
If any other immunosuppressant used
If yes- type and duration
Schedule and dose of HBV vaccination received
Timing of HB vaccination
GENERAL PHYSICAL EXAMINATION:
Weight:
Height :
Vitals:
Pulse rate:
RR:
Temperature:
BP:
Pallor:
Icterus:
Cyanosis:
Clubbing:
Lymphadenopathy:
Edema:
SYSTEMIC EXAMINATION:
CVS
RS
CNS
P/A
Signature of the candidate:
Name and designation of the guide:
Dr. Indumathi C.K
Associate Professor,
Department of Paediatrics,
St.Johns Medical College Hospital, Bangalore.
Signature of the guide:
Remarks of the guide:
Nephrotic syndrome being an immunocompromised state is associated with
recurrent infections. Preventing these infections with adequate immunization is a
priority. However immune dysregulation not only results in infections but also
leads to low seroconversion rates to various vaccines including Hepatitis B.
Prevalence of Hepatitis B infection is around 3.1% in children with nephrotic
syndrome. Adequate sero conversion to Hepatitis B vaccination is important to
protect children against disease. Seroconversion is measured by anti-HBs
antibody titres after vaccination. There is paucity of data on seroconversion
status in children with nephrotic syndrome. We aim to study the seroconversion
status of Hepatitis B vaccine in children with nephrotic syndrome which would
help to take a decision on the need to revaccinate these children if titres found to
be non seroprotective. Being a tertiary care centre with a Pediatric nephrology
department, it is feasible to conduct the study in our hospital.
Name and designation of Co-guide:
Dr. Arpana Iyengar
Additional Professor
Department of Pediatrics/Pediatric Nephrology
St.Johns Medical College & Hospital, Bangalore.
Signature of Co-guide:
Signature of the Head of Department:
Dr Sylvan John Rego
Professor and Head
Department of Paediatrics,
St.Johns Medical College Hospital, Bangalore
Remarks of the chairman and principal:
Signature: