|
|
|
Indian Pediatr 2019;56: 659-662 |
 |
Hepatitis B Seroprotection in Pediatric
Nephrotic Syndrome
|
|
Nischal Neupane 1,
Sriram Krishnamurthy1,
Barath Jagadisan1
and Rahul Dhodapkar2
From Departments of 1Pediatrics and 2Microbiology,
Jawaharlal Institute of Postgraduate Medical Education and Research
(JIPMER), Puducherry, India.
Correspondence to: Dr. Sriram Krishnamurthy,
Additional Professor, Department of Pediatrics, JIPMER,
Puducherry 605 006, India.
Email: [email protected]
Received: October 03, 2018;
Initial review: February 25, 2019;
Accepted: June 04, 2019.
|
|
Objectives: To study the
prevalence of Hepatitis B seroprotection in children (>1 y) with
nephrotic syndrome vaccinated against Hepatitis B vaccine as per the
Universal Immunization Program schedule (0,6,10,14 wk); to compare the
Hepatitis B seroprotection rates and anti-HBs titers among different
phenotypes of nephrotic syndrome; to evaluate the association between
Hepatitis B seroprotection status and the immunosuppressive agents; and
to study the correlation between anti-HBs titres and proteinuria.
Methods: Hepatitis B serology and anti-HBs titers were analyzed in
100 children (age-1-18 y) with different clinical phenotypes of
nephrotic syndrome (cases) and 100 healthy controls. Results: The
proportion of seroprotected children among the cases and controls was
37% (n=37) and 61% (n=61), respectively (P<0.04).
The median (IQR) anti- HBs antibodies titers among the cases
was 75 (62.5, 81) mIU/mL and 112 (56, 367) mIU/mL among the controls (P=0.001). The
proportion of seroprotected children among the steroid sensitive
nephrotic syndrome, steroid-resistant nephrotic syndrome and controls
was 40% (n=28), 30% (n=9) and 61% (n=61),
respectively (P<0.01). No differences in the anti-HBs titers
between children receiving steroids versus steroids along with
other immunosuppressants were found. Weak negative correlation was noted
between proteinuria and protective titers (r = -0.155; P=0.039).
Conclusion: Children with nephrotic syndrome, in general, and
steroid-resistant nephrotic syndrome in particular, show poor
seroprotection with Hepatitis B vaccination.
Keywords: Corticosteroids, Hepatitis B
vaccine, Seroconversion.
|
|
N ephrotic syndrome (NS) in
children is classified into steroid-sensitive nephrotic syndrome (SSNS)
or steroid-resistant nephrotic syndrome (SRNS); the former being
subdivided into infrequently-relapsing (IFRNS), frequently relapsing
(FRNS) and steroid-dependent nephrotic syndrome (SDNS). The proteinuria
in NS causes loss of albumin as well as various protective
immunoglobulins in the body that have been acquired actively or
passively [1,2]. In India, 2-7% of individuals are carriers of hepatitis
B virus (HBV) that places this region in an intermediate endemicity zone
[3]. HBV infection acquired in childhood has higher chance of
progression to chronic hepatitis, cirrhosis and hepatocellular carcinoma
[4]. The World Health Organization (WHO) recommends hepatitis B
vaccination for all children. It has been speculated that children with
NS might have decreased hepatitis B seroprotection rates due to
prolonged immuno-suppressive therapy and proteinuria [5]. However, there
is paucity of information regarding the seroprotection status in
pediatric NS. The primary objective of this study was to evaluate the
prevalence of hepatitis B seroprotection (defined as anti-HBs titers
³ 10 mIU/mL)
in children with NS who had previously been vaccinated against hepatitis
B as per the Universal Immunization Program (UIP). The secondary
objectives were to compare hepatitis B seroprotection rates among
different clinical phenotypes of NS; to evaluate the association between
hepatitis B seroprotection and immuno-suppressive agents received; and
to study the correlation between anti-HBs titers and proteinuria.
Methods
This cross-sectional study was conducted from March
2016 through July 2018 after obtaining approval from the Institute
ethics committee and obtaining written consent from the parents.
Consecutively presenting patients were recruited from the pediatric
nephrology clinic (for cases) and the general pediatric outpatient
department (OPD) (for controls).
Children ( ³1
year) with primary nephrotic syndrome who had received full course of
Hepatitis B vaccination (as verified by the vaccination card) as per the
UIP (at 0, 6 weeks, 10 weeks, 14 weeks) [6,7] were included. Cases of
secondary nephrotic syndrome (e.g. IgA nephropathy, lupus
nephritis), chronic kidney disease with creatinine clearance <60 mL/min/1.73
m2, hepatitis B positivity
and those who had received any blood product/ intravenous immunoglobulin
within 3 months were excluded. Age-matched, healthy, non-proteinuric
controls (age 1-18 y) who had received hepatitis B vaccine as per the
same schedule as cases were recruited from patients visiting general OPD
for minor ailments (e.g., upper respiratory tract infections,
elective surgery).
Nephrotic syndrome was managed as per Indian Society
of Pediatric Nephrology guidelines (8,9). Data were recorded in a
structured proforma. The anti-HBs titres were quantitatively determined
by immuno-enzymometric assay using a commercially available kit (Elecsys
anti-HBs II, Cobas) as per the manufacturer’s instructions. The anti-HBs
titers were estimated quantitatively. Seroprotection was defined as
anti-Hbs titers ³10
mIU/mL [10].
The sample size was calculated to be 87 for
estimating the proportion of hepatitis B seroprotected individuals as
65% [13]; with 95% confidence level and precision of 10%, Accounting for
attrition of 10%, we planned to recruit a minimum of 96 participants.
Statistical analysis: Student’s t-test
was used to compare normally distributed continuous variables and
proportions were compared using Chi-square test or Fisher exact test as
applicable. Median and distribution were compared using Mann Whitney U
test. The outcome variables between more than two subgroups of NS were
analyzed using ANOVA or Kruskal-Wallis test. Pearson’s Correlation
coefficient was used to measure linear correlation between two
continuous variables. Data were analysed using SPSS version 19.
Results
One hundred and thirty two children with NS were
assessed for eligibility. Thirty two cases were excluded from the study.
Reasons for exclusion included: 6 cases of secondary nephrotic syndrome
(Lupus nephritis 2, IgA nephropathy 2, Membranoproliferative glomerulo-nephritis
1, Henoch Schonlein purpura nephritis); 2 children with creatinine
clearance <60 mL/min/1.73 m 2;
16 patients having had no immunization card; and 8 patients who were
partially vaccinated against Hepatitis B. Finally, 100 children with NS
were enrolled.
The characteristics of children with NS are depicted
in Table I. All the recruited children were
on prednisolone and/or alternate immunosuppressive therapy at
recruitment. Among 70 SSNS cases, 15 (22%) received steroids alone and
55 (78%) received atleast one additional immunosuppressant at enrolment.
All SRNS cases were on immunosuppressants at enrolment. Among SRNS
cases, 14 (50%) had received more than one immunosuppressant. Majority
(25 of 30) of SRNS patients were in complete or partial remission. The
histopathological profile among SRNS included minimal change disease
(36.6%), focal segmental glomerulosclerosis (46.7%) and
mesangioproliferative glomerulonephritis (16.7%).
TABLE I Clinical and Biochemical Characteristics of Children (N=100) With Nephrotic Syndrome Enrolled in the Study
|
Characteristic
|
Value
|
|
Age at enrolment (y)* |
7.5 (4.3,9.3) |
|
Male sex |
60 (60%) |
|
Age at onset of NS (y)* |
4.6 (2,6.5) |
|
Duration of NS (y) |
2.4 (1.7,3.4) |
|
Weight-for-age Z score |
-0.66 (0.26) |
|
H eight-for-age Z score |
-1.79 (0.6) |
|
Body surface area (m2) # |
0.89 (0.33) |
|
Clinical type of NS |
|
|
Infrequently relapsing
|
20 (20%)
|
|
Frequently relapsing
|
32 (32%)
|
|
Steroid dependent
|
16 (16%) |
|
Steroid resistant
|
30 (30%) |
|
First episode |
2 (2%) |
|
Immunosuppressants received
|
|
|
Prednisolone
|
22 (20%)
|
|
Levamisole |
24 (24%)
|
|
Mycophenolate mofetil |
20 (20%) |
|
Oral cyclophosphamide |
6 (6%)
|
|
IV cyclophosphamide |
7 (7%) |
|
Cyclosporin |
15 (15%) |
|
Rituximab + Mycophenolate mofetil |
4 (4%) |
|
Tacrolimus |
2 (2%) |
|
Values in n (%) or *median (IQR) or #mean (SD); NS:
nephrotic syndrome. |
The proportion of seroprotected children among the
cases and controls was 37% (n=37) and 61% (n=61),
respectively. Anti-HBs titers were higher among cases than controls (Table
II). Comparison of the SSNS and SRNS cases revealed significant
difference between serum albumin and urine protein:creatinine ratio (Up:Uc)
(Web Table I). The proportion of
seroprotected children among the SSNS, SRNS and controls was 40% (n=28),
30% (n=9) and 61% (n=61), respectively (P=0.002).
The median (IQR) anti-HBsAg titers were 76.5 (64.2, 85.5), 63.5 (55.2,
66.7) and 112 (56, 367) mIU/mL, respectively among these 3 groups (P=0.002).
The proportion of seroprotected children was similar between IFRNS,
FRNS, SDNS and SRNS; as well as among children receiving various
immunosuppressants.
TABLE II Baseline Characteristics and Outcome Variables in the Study Participants
|
Characteristic |
Cases
|
Controls |
P value |
|
(n=100) |
(n=100) |
|
|
Age at enrolment (y)* |
7.4 (4.3,9.3) |
7.6 (4.35,9.6) |
0.93 |
|
Male sex
|
60 (60%) |
55 (55%) |
0.95 |
|
Weight (kg)* |
23.6 (17,28.2) |
22.8 (16, 27.7) |
0.35 |
|
Height (cm) # |
118.99 (29) |
120.5 (35)
|
0.41 |
|
Body surface area (m2) # |
0.88 (0.33) |
0.86 (0.35)
|
0.66 |
|
Serum creatinine (mg/dL)# |
0.65 (0.2)
|
0.6 (0.1) |
0.36 |
|
Serum albumin (g/dL) # |
3 (0.3)
|
3.4 (0.5)
|
0.001 |
|
Serum cholesterol (mg/dL) # |
187 (20) |
149 (25). |
0.001 |
|
Anti-HBs titer (mIU/mL)* |
75 (62.5, 81) |
112 (56, 367) |
0.004 |
|
Seroprotection
|
37 (37%) |
61 (61%) |
0.001 |
|
Values in n(%). *median (IQR) or #mean (SD) |
On comparison of children with seroprotected (n=63)
and non-seroprotected titres (n=37), significant differences were
found between the proportion of children with Up:Uc >2 g/g (22.2% vs.
0%, P=0.01) and serum cholesterol levels (P=0.014). Weak
negative correlation was noted between proteinuria and protective titers
(r = -0.155; P=0.039).
Discussion
In this study, a large proportion of children with
NS, who had received hepatitis vaccine as per UIP, had low anti-HBs
antibody titers in comparison to healthy controls. Children with SSNS
were found to be seroprotected to a greater extent than SRNS. The degree
of proteinuria was higher in the non-seroprotected children, implying
the central role of proteinuria in the etiology of poor seroprotection.
There is paucity of information regarding the degree
of hepatitis B seroprotection in children with NS, particularly SRNS.
Mantan, et al. [11] enrolled 75 children with NS out of whom 56%
had SRNS, and 61.3 % had received hepatitis B vaccination through
pediatric nephrology services (double dose at 0, 1 and 6 months). The
proportion of children with seroprotective titers was higher in SSNS
than in SRNS, as well as in those who received steroids alone as against
in combination other immunosuppressants. In another study, La Manna,
et al. [12] vaccinated 18 boys with SSNS and a control group of 21
healthy boys against hepatitis B. The percentage of patients who
responded to vaccination was significantly lower than the control group.
The differences between the results of these studies [3,10] and our
study could be related to heterogeneity in study designs, different
patient populations, and variable vaccination schedules doses of
vaccine. Repeated and protracted proteinuria in SRNS might have
contributed to the low titers in our study [12,13]. Some studies on
hepatitis B seroprotection in children with NS have used double dose of
the vaccine [11]. Some studies in other immunocompromised states have
shown titers after double dose vaccination of hepatitis B to be better
[13].
We observed relatively low seroprotection status
among controls (61%). An earlier study from Ghana concluded that all
healthy children who received hepatitis B vaccination at 6, 10 and 14
weeks seroconverted initially, but the antibody titers waned with
increasing age [14]. In our study, the median age of the controls was
7.6 years; hence, there is a possibility of titers having waned in this
group.
The limitations of present study is that considering
anti-HBs antibody titer alone as a marker of protection may not be
adequate. It is the immune memory that is crucial [15]. In addition,
this study may not be adequately powered to draw conclusions regarding
the inter-group comparisons.
As the hepatitis B seroprotection status in
vaccinated children with NS was found to be suboptimal, it may be
worthwhile to screen all children with SSNS as well as SRNS for
hepatitis B seroprotection status, and augment it accordingly.
Contributors: NN: collected the data,
reviewed the literature and drafted the first version of the manuscript;
SK: conceptualized the study, designed the study protocol, reviewed the
literature and revised the manuscript; BJ: participated in protocol
preparations and critically reviewed the manuscript; RD: participated in
protocol preparations, supervised the laboratory tests and critically
reviewed the manuscript. All authors approved the final version of the
manuscript, and are willing to be accountable for all aspects of the
study. SK: shall act as guarantor of the paper.
Funding: Intramural funding from JIPMER,
Puducherry.
Competing interest: None stated.
|
What This Study Adds?
• Lesser proportion of children with
nephrotic syndrome have seroprotection against hepatitis B
following 4 doses of vaccine (0,6,10,14 wk) during infancy.
• Children with steroid-resistant nephrotic syndrome have
lower anti-HBs titers than steroid-sensitive nephrotic syndrome.
|
References
1. Bagga A, Mantan M. Nephrotic syndrome in children.
Indian J Med Res. 2005;122:13-28.
2. Grzesiowski P, Tañska A, Sieniawska M. The
influence of hepatitis B vaccine dose on direct results of hepatitis B
vaccination in children with nephrotic syndrome. Pediatr Pol.
1995;70:25-8.
3. Batham A, Narula D, Toteja T, Sreenivas V, Puliyel
JM. Systematic review and meta-analysis of prevalence of hepatitis B in
India. Indian Pediatr. 2007;44:663-74.
4. Mast E, Mahoney FJ, Kane M, Margolis H. Hepatitis
B vaccine. In: Plotkin SA, Orenstein WA (eds) Vaccines,
4th edn. WB Saunders, Philadelphia, 2004. p. 299-337.
5. Kemper MJ, Altrogge H, Gansehow R, Wiefel DE.
Serum levels of immunoglobulins and IgG subclasses in steroid sensitive
nephrotic syndrome. Pediatr Nephrol. 2002;17:413-7.
6. Universal Immunization Program. National Health
portal. 2016. Available from:
http://www.nhp.gov.in/universal-immunization-programme- uip_pg.
Accessed June 5, 2019.
7. Vashishtha VM, Choudhury P, Bansal CP, Yewale V,
Agarwal R. IAP Guidebook on Immunization. 2013-14. Indian Academy of
Pediatrics, National Publication House, Gwalior 2014 p. 129-138.
8. Indian Pediatric Nephrology Group, Indian Academy
of Pediatrics, Bagga A, Ali U, Banerjee S, Kanitkar M, Phadke KD, et
al. Management of steroid sensitive nephrotic syndrome: Revised
guidelines. Indian Pediatr. 2008;45:203-14.
9. Indian Society of Pediatric Nephrology, Gulati A,
Bagga A, Gulati S, Mehta KP, Vijayakumar M. Management of steroid
resistant nephrotic syndrome. Indian Pediatr. 2009;46:35-47.
10. Jack AD, Hall AJ, Maine N, Mendy M, Whittle HC.
What level of hepatitis B antibody is protective? J Infect Dis.
1999;179:489-92.
11. Mantan M, Pandharikar N, Yadav S, Chakravarti A,
Sethi GR. Seroprotection for hepatitis B in children with nephrotic
syndrome. Pediatr Nephrol. 2013;28:2125-30.
12. La Manna A, Polito C, Foglia AC, Di Toro A,
Cafaro MR, Del Gado R. Reduced response to hepatitis B virus vaccination
in boys with steroid-sensitive nephrotic syndrome. Pediatr Nephrol.
1992; 6:251-3.
13. Baytan B, Gunes AM, Gunay U. Efficacy of primary
hepatitis B immunization in children with acute lymphoblastic leukemia.
Indian Pediatr. 2008: 45:265-70.
14. Dassah S, Sakyi SA, Frempong MT, Luuse AT,
Ephraim RK, Anto EO, et al. Seroconversion of hepatitis B vaccine
in young children in the Kassena Nankana District of Ghana: A
cross-sectional study. PLoS One. 2015;10:e0145209.
15. Banatvala J, Van Damme P, Oehen S. Lifelong
protection against hepatitis B: The role of vaccine immunogenicity in
immune memory. Vaccine. 2000;19:877-85.
|
|
|
 |
|
