Paediatrica Indonesiana

VOLUME 48 November  NUMBER 6

Original Article

Association between immunization coverage and

atopy in children with or without family history of
atopic disease
Isabella Riandani, Budi Setiabudiawan, Cissy B. Kartasasmita

Abstract
Background Atopic diseases are determined by the interaction
between genetic and environmental factors. The possible effects
RILPPXQL]DWLRQDVRQHRIHQYLURQPHQWDOIDFWRUVRQDWRS\UHPDLQ
a matter of controversy.
Objective :HFRQGXFWHGDQREVHUYDWLRQDOFOLQLFDOHSLGHPLRORJ\
to find out the protective effect of high vaccination coverage to
atopy in children.
Methods'XULQJ-DQXDU\WKURXJK0DUFKRIFKLOGUHQ
DW*DUXGD3DGDVXNDDQG%DEDNDQ6DUL3ULPDU\+HDOWK&DUHLQ
Bandung were randomized from group with and without family
history of atopic disease. Atopy derived from skin prick test and
total serum IgE was evaluated. Atopy was defined as a positive
skin test to any of the eight allergens tested. The immunizations
T
he atopic diseases like allergic rhino
FRQMXQFWLYLWLVDVWKPDDQGDWRSLFGHUPDWLWLV
are the most common chronic diseases of
childhood and the prevalence is still
increasing.3 ,Q GHYHORSLQJ FRXQWULHV DVWKPD ZDV
considered to be low but recent studies have shown
that the prevalence is increasing especially in urban
compared to rural areas.4 Asthma and other atopic
diseases were determined by the interaction between
genetic and environmental factors. Family history is
an important risk factor for atopy.4-6 Many other risk
factors for the development of atopic disease have
were recorded from Kartu Menuju Sehat .066WDWLVWLFDODQDO\VHV
LQFOXGHG&KLVTXDUHWRFRPSDUHSUHYDOHQFHLQGHSHQGHQW7WHVW
DQG0DQQ:KLWQH\WRFRPSDUHPHDQ
Results$WRS\ZDVIRXQGLQRIVXEMHFWVRIZKLFK
ZLWKDQGZLWKRXWDIDPLO\KLVWRU\RIDWRSLFGLVHDVH7KH
median of total serum IgE level was higher in children with family
history of atopic disease and in atopy children. Children were
JURXSHGDFFRUGLQJWRWRWDOGRVHRIEDVLFLPPXQL]DWLRQVDQG
EHHQLGHQWLILHG such as infection. Bacterial and viral
LQIHFWLRQVLQGXFHD7KSDWWHUQRIF\WRNLQHUHOHDVH
SRWHQWLDOO\ VXSSUHVVLQJ WKH 7K LPPXQH UHVSRQVH
involved in IgE mediated allergy and inhibited the
development of atopy.
,QWKHILUVW\HDURI OLIHWKHFKLOGUHQVLPPXQH
EDVHGRQProgram Pengembangan Imunisasi 33,7KHUHZDV system is relatively immature. This immaturity creates
nonsignificant association between total doses of immunization
DQGDWRS\(YHQWKRXJKQRVWDWLVWLFDOO\VLJQLILFDQWWKHFXPXODWLYH
immunization doses were inversely related to the median of total
serum IgE level.
Conclusions The immunization coverage has not decreased atopy
risk.[Paediatr Indones. 2008;48:358-63]. )URP 'HSDUWPHQW RI &KLOG +HDOWK 0HGLFDO 6FKRRO 3DGMDGMDUDQ
8QLYHUVLW\+DVDQ6DGLNLQ*HQHUDO+RVSLWDO%DQGXQJ,QGRQHVLD

Keywords: atopy, immunization, total serum IgE, Request reprint to ,VDEHOOD 5LDQGDQL 0' 'HSDUWPHQW RI &KLOG
family history of atopic disease +HDOWK0HGLFDO6FKRRO3DGMDGMDUDQ8QLYHUVLW\+DVDQ6DGLNLQ*HQHUDO
+RVSLWDO-O3DVWHXU1R%DQGXQJ,QGRQHVLD7HO
)D[

358Paediatr Indones, Vol. 48, No. 6, November 2008

 Isabella Riandani et al: Association between immunization coverage and atopy
D ZLQGRZ SHULRG EHWZHHQ ELUWK DQG  PRQWKV
of age during which is an enhanced risk of allergic
sensitization and subsequent atopic disease. An issue
RISDUWLFXODULQWHUHVWZKLFKLVEHFRPLQJLQFUHDVLQJO\
FRQWURYHUVLDO FRQFHUQV LQWHUDFWLRQV EHWZHHQ WKH
developing immune system in children genetically
susceptible to atopy and microbial stimulation through
normal environment contact or through deliberate
exposure by vaccination. This hypothesis known
as hygiene hypothesis argues that early childhood
infections inhibit the tendency to develop allergic
disease.
Immunization as one of the factors that effect
WKHLPPXQHV\VWHPLQHDUO\OLIHFRXOGKDYHSRVLWLYHRU
negative effect on allergic disease. This issue become
an interest of the researchers but the possible effects of
immunization on atopy remains a matter of controversy.
A number of studies have found no association
between immunization and atopy.Some studies
found the association between immunization and
DWRS\ HLWKHU D SURWHFWLYH HIIHFW DJDLQVW DWRS\ or
increased the risk for atopy. 1HYHUWKHOHVV WKH
)URPFKLOGUHQMRLQLQJWKHILUVWSKDVHRQO\
 ZHUH HOLJLEOH IRU WKH QH[W SKDVH RI ZKLFK 
children had family history of atopic disease. The
subjects for this study were randomized from two
groups with and without history of atopic disease. Each
JURXSFRQVLVWHGRIFKLOGUHQ6XEMHFWVZKRIXOILOOHG
the inclusion criteria were brought to Hasan Sadikin
KRVSLWDO %DQGXQJ IRU FOLQLFDO HYDOXDWLRQ ZKLFK
LQFOXGHGDPHGLFDOKLVWRU\SK\VLFDOH[DPLQDWLRQVNLQ
SULFNWHVWDQGEORRGGUDZIRUWRWDOVHUXP,J(
The skin prick test used the allergens Dermato-
phagoides pteronyssinus, Blomia tropicalis, FDWKDLUFRZV
PLONHJJVZKLWHVR\EHDQVFRFNURDFKDQGSHDQXWV
Both positive (histamine) and negative controls
(saline solution) were also used. Skin prick test was
considered positive if the product of perpendicular
ZKHDOGLDPHWHUVZDVPPWRDQ\RIWKHDOOHUJHQV
tested when there was no reaction to saline solution.
Atopy was defined as a positive skin test to any of the
eight allergens tested.
Total serum IgE was analysed in Hasan Sadikin
hospital laboratory using electrochemiluminescence
question of an association between immunization and
atopy remains. The aim of this study was to find out
the protective effect of high vaccination coverage to
atopy in children.
LPPXQRDVVD\(&/,$PHWKRGZLWK,8P/DVD
normal value from reagent package insert for children
\HDUVRIDJH
Immunizations records were obtained from
.06 RU RWKHU OHJDO OHWWHUV $FFRUGLQJ WR Program
Methods
:HFRQGXFWHGDQREVHUYDWLRQDOFOLQLFDOHSLGHPLRORJ\
on groups with and without family history of atopic
Pengembangan Imunisasi 33, LPPXQL]DWLRQ IRU
FKLOGUHQWKURXJKPRQWKVFRQVLVWVRI%&*3ROLR
KHSDWLWLV%'37DQGPHDVOHV
6WDWLVWLFDO DQDO\VLV SHUIRUPHG E\ XVLQJ 6366
VRIWZDUHYHUVLRQIRUZLQGRZVDQG(SL,QIRYHUVLRQ
GLVHDVH DV D SDUW RI 3UHYDOHQFH RI DOOHUJLF DQG
identification of risk factors in the first two years of life
VWXG\DW*DUXGD3DGDVXNDDQG%DEDNDQ6DUL3ULPDU\
Health Care in Bandung. The first phase study was
a community survey that was done on May through
$XJXVW  7KH VHFRQG SKDVH ZDV RQ -DQXDU\
WKURXJK0DUFK,IWKHSDUHQWVDJUHHGDZULWWHQ
informed consent was obtained. Inclusion criteria
LQFOXGHGWKDWWKHFKLOGPXVWKDGMRLQHGWKHILUVWSKDVH
ZDVSK\VLFDOO\KHDOWK\DQGKDGKartu Menuju Sehat
 &KLVTXDUH C WHVW ZDV DSSOLHG WR FRPSDUH
SUHYDOHQFH .ROPRJRURY6PLUQRY WHVW IRU QRPLQDO
GDWD LQGHSHQGHQW 7WHVW IRU PHDQV DQG 0DQQ
:KLWQH\IRUPHGLDQVEHWZHHQJURXSV
This study was approved by the Health Study
(WKLFV &RPPLWWHH DW 0HGLFDO 6FKRRO 3DGMDGMDUDQ
8QLYHUVLW\+DVDQ 6DGLNLQ *HQHUDO +RVSLWDO
Bandung.
.06RURWKHUOHJDOOHWWHUV7KHH[FOXVLRQFULWHULD
included that the child had change the address or
was in the therapy of first generation antihistamine
IRU WKUHH GD\V QRQVHGDWHG DQWLKLVWDPLQH IRU VHYHQ
GD\VDQGV\VWHPLFRUWRSLFDOFRUWLFRVWHURLGIRUWKUHH
months before skin prick test.
Results
)URPVXEMHFWVQLQHFKLOGUHQKDGDOUHDG\PRYHG
from the address and the parents of seven children
UHIXVHG WKH VWXG\ WKHUHIRUH WKHUH ZHUH RQO\ 
VXEMHFWVLQWKLVVWXG\ZLWKFKLOGUHQLQHDFKJURXS
Paediatr Indones, Vol. 48, No. 6, November 2008359
 Isabella Riandani et al: Association between immunization coverage and atopy

The subject characteristics based on family history greater on atopy children and significantly different
of atopic disease was seen in Table 1. There were no 3H[FHSWIRUJURXSZLWKIDPLO\KLVWRU\RIDWRSLF
statistical differences between groups with or without GLVHDVH3 
KLVWRU\RIDWRSLFGLVHDVH7KHUHIRUHWKHVXEMHFWVZHUH
homogen. Table 3. The association between total serum ige level and
atopy
Table 1. Characteristic of children based on family history of P
atopic disease Total serum IgE on Atopy Nonatopy
value
History of atopic disease (+)
Family history of atopic disease
Characteristic P value N 44 92
0.317
(+)
 Median 162.8 125.8
Sex Range 18.28-1,517 12.12->2,500
Boys 64 (45.1%) 66 (46.5%) 0.812 *KUVQT[QHCVQRKEFKUGCUG

Girls 78 (54.9%) 76 (53.5%) N 34 101
0.015*
Age (mo) Median 196.8 94.3
X (SB) 36.4 (1.8) 36.2 (1.8) 0.233 Range 16.08->2,500 5.22-1,459
All of Subjects
Range 32.1 40.5 32.5 40.2
N 78 193
Nutritional status 0.011*
Median 181.8 106.5
underweight 32 (22.5%) 39 (27.5%)
0.995 Range 16.08->2,500 5.22->2,500
well nourished 107 (75.4%) 101 (71.1%)
overweight 3 (2.1%) 2 (1.4%) Note: *P<0.05

$WRS\ZDVIRXQGLQFKLOGUHQ3UHYD- )URP LPPXQL]DWLRQ UHFRUGV ZH IRXQG RQO\

lence of atopy on group with history of atopic disease   FKLOGUHQ KDG DOUHDG\ FRPSOHWHG EDVLF
ZDVJUHDWHUWKDQWKHRWKHUJURXSEXWWKHGLIIHUHQFH immunization according to Program Pengembangan
ZDVQRWVWDWLVWLFDOO\VLJQLILFDQW25&,WR Imunisasi 33, 6HYHQ FKLOGUHQ  KDG QRW DQ\
3 7KHDWRS\SUHYDOHQFHEDVHGRQIDPLO\ vaccination at all and the rest had not completely
history of atopic disease was described in Table 2. immunized. The subjects than were divided into two
groups based on total dose of basic immunization. The
Table 2. Prevalence of atopy based on family history of atopic children who did not immunize and not fully immunized
disease ZHUHRQWKHILUVWJURXSDQGWKHFKLOGUHQZKR
Family history of Atopy Nonatopy Total KDGDOOWKHEDVLFLPPXQL]DWLRQDQGPRUHRQ
atopic disease n % n % n % the other group. Based on family history of atopic
(+) 46 32.4 96 67.6 142 100 GLVHDVHWKHUHZDVQRVLJQLILFDQWGLIIHUHQFH3 

 34 23.9 108 76.1 142 100 in number of children between the two groups.
Total 80 28.2 204 71.8 284 100 The association between atopy and immunization
Note: C2: 2.506; P= 0.113; OR : 1.52 (95%CI 0.87 to 2.65) coverage was seen on Table 4. There was no
association found between immunization coverage
)URP  VXEMHFWV ZH KDG RQO\ EHHQ DEOH WR DQGDWRS\LQFKLOGUHQZKHWKHULQJHQHUDORUEDVHG
FROOHFWVHUDIRUWRWDOVHUXP,J(DQDO\VLV RQIDPLO\KLVWRU\RIDWRSLFGLVHDVH3!
,Q WKLV VWXG\ WKH PHGLDQ RI WRWDO VHUXP ,J( ZDV The median differences of total serum IgE based
,8P/!,8P/7KHPHGLDQRI on groups of immunization coverage was seen on
WRWDOVHUXP,J(ZDV,8P/!,8 Table 5.
P/IRUJURXSZLWKIDPLO\KLVWRU\RIDWRSLFGLVHDVH
DVFRPSDUHGWR,8P/!,8P/ Table 4. The association between immunization coverage and
IRUWKHRWKHUJURXS+RZHYHUWKHUHZDVQRVWDWLVWLFDO atopy
GLIIHUHQFHEHWZHHQWKHJURXSV3  Family history of atopic disease
Immunization
The association between total serum IgE and (+)
 Total Statistic
Coverage
Atopy Nonatopy Atopy Nonatopy
the prevalence of atopy was indicated in Table 3.
0-17 14 30 8 29 81 C2: 0.996
Generally for all subjects that had skin prick test and  32 66 26 79 203 P= 0.802
WRWDOVHUXP,J(DQDO\VLVWKHPHGLDQRI,J(OHYHOZDV Total 46 96 34 108 284 df = 3

360Paediatr Indones, Vol. 48, No. 6, November 2008

 Isabella Riandani et al: Association between immunization coverage and atopy

Table 5. Total serum ige level on immunization coverage that even often appear before any clinical symptoms
Immunization Coverage P have developed.
Total serum IgE on
0-17  value The median of IgE level was also higher on
History of atopic disease (+)
atopy than nonatopy children and the difference was
N 42 94
Median 150.35 123.30
0.320 statistically significance except on group with family
Range 15.83->2,500 12.12-2,482 history of atopic disease. A child with atopy indicates
D7KSUHGRPLQDQFHWKDWSURGXFHV,J(DQWLERGLHVLQ
,Q WKLV VWXG\ ZH IRXQG WKDW WKH KLJKHU WKH response to ordinary exposures to allergens and
FXPXODWLYH GRVHV RI LPPXQL]DWLRQ WKH ORZHU WKH the term atopy can not be used until IgE sensitization
PHGLDQ RI WRWDO VHUXP ,J( EXW VWDWLVWLFDOO\ QR has been documented by a positive skin prick test.
VLJQLILFDQW3!
Discussion
Family history is an important risk factor for atopic
disease. Subjects with a family history of atopic disease
have a two- to threefold higher risk to develop atopic
The different kinetic in the development of IgE
antibodies in atopic and nonatopic children is well
known because excessive IgE antibody formation is a
hallmark of the atopic individual.
7KHLPPXQL]DWLRQUHFRUGVVKRZHGRQO\
children had completed basic immunization. There
was no difference of atopy between groups that had
completed and uncompleted basic immunization (OR:
disease than those with no such history.4-6  &,  3  $QGHUVRQ ZKR
,QWKLVVWXG\WKHSUHYDOHQFHRIDWRS\RQJURXS used ecologic analysis to find the relation between the
ZLWK IDPLO\ KLVWRU\ RI DWRSLF GLVHDVH ZDV  prevalence of symptoms of atopic diseases in children
FRPSDUHGWRRQJURXSZLWKRXW%M|UNVWpQFLWHG and immunization records at the national and local
E\ .RQLQJ found that if a child has one atopic
SDUHQWWKHULVNWREHFRPHDOOHUJLFLVDSSUR[LPDWHO\
 LQFUHDVLQJ WR  ZLWK WZR DWRSLF SDUHQWV
whereas without atopic parents the risk is around
 Alford6 IRXQG  DWRS\ FKLOGUHQ LI WKH\
KDG DQ DWRSLF PRWKHU DQG  DWRS\ FKLOGUHQ LI
WKHLUIDWKHUKDGDWRSLFGLVHDVHZKHUHDVZLWKRXWDWRSLF
SDUHQWV WKH SUHYDOHQFH RI DWRS\ ZDV 6 In this
VWXG\WKHIDPLO\KLVWRU\RIDWRSLFGLVHDVHEDVHGRQO\
on anamnesis without other examinations such as skin
SULFNWHVWRUVHUXPDOOHUJHQVSHFLILF,J(PLJKWFDXVH
a nonsignificant different of atopy between children
with or without family history of atopic disease.
The median of total serum IgE was higher than
QRUPDO YDOXH IURP SDFNDJH LQVHUW UHDJHQW 
,6$$& FHQWUH OHYHOV IRU '37 %&* DQG PHDVOHV
found no association with national immunization
rates to atopic disease in children. On the other
VLGH*UXEHUZKRDQDO\VHGWKHSUHYDOHQFHRIDWRSLF
GLVHDVHLQUHODWLRQWRLPPXQL]DWLRQFRYHUDJHIRXQG
the cumulative vaccine dose was inversely related to
atopic dermatitis and asthma prevalences.18
Our study showed no association between
immunization and atopy as atopy could be caused
by multifactor and immunization is only one of the
environmental factors. The limited information
regarding life style factors could lead to confounding
bias. A conscious choice of parents not to have their
child immunized might go with other lifestyle factors
that effect the development of atopy.
,8P/,8P/,QDGGLWLRQWRDJHDQGJHQHWLF
IDFWRUVWKHWRWDOVHUXP,J(ZDVLQIOXHQFHGE\UDFLDO
IDFWRU2UJDOZKRVWXGLHG)LOLSLQRDQGZKLWH
children born and raised in the United States found
that in Filipino children the mean IgE level were
significantly higher than in white children. The
IgE level was higher on group with as compared to
group without family history of atopic disease but the
difference was not statistically significant. It was likely
because children with family history of atopic disease
had a familial tendency to produce IgE antibodies
The mechanism contributing to microbial
SURWHFWLRQ DJDLQVW DWRS\ UHODWHV WR GHQGULWLF FHOOV
DQ HIILFLHQW $3& WKDW FDQ VWLPXODWH QDLYH 7 FHOOV
DQG GULYH WKHP WR 7K RU 7K :KHQ VWLPXODWHG
dendritic cells can produce cytokines that may down-
regulated allergic responses. The limited induction of
Th1 responses after immunization early in life appears
WRUHVXOWIURPVXERSWLPDOLQWHUDFWLRQVEHWZHHQ$3&
and T cells in infancy. The induction of adult-like Th1
responses early in life requires optimal activation of
neonatal dendritic cells.
Paediatr Indones, Vol. 48, No. 6, November 2008361
 Isabella Riandani et al: Association between immunization coverage and atopy
Since modern subunit vaccines were mostly
ODFN RI PLFURELDO DQWLJHQV WKH\ PD\ QRW DFWLYDWH
GHQGULWLF FHOOV HIILFLHQWO\ $V D UHVXOW WKH DEVHQFH
of microbial antigens from vaccines may impair
regulation of the adaptive immune response. Recent
advances in understanding how cell-mediated
immunity is regulated have indicated substantial
differences between responses after natural infection
and immunization that may contribute to the limited
induction of Th1 responses after immunization.
An interesting issue we found in this study was
WKHKLJKHUWKHLPPXQL]DWLRQFRYHUDJHWKHORZHUWKH
WRWDOVHUXP,J(EXWWKHGLIIHUHQFHZDVQRWVWDWLVWLFDOO\
significant. Gruber found the similar result that the
median of total serum IgE was inversely related to
immunization coverage.18 IgE was produced as a
response to certain antigen like allergen and parasite.
/RZ GRVHDQWLJHQZLOOLQGXFH7KFHOOVWRSURGXFH
 :DKQ8YRQ0XWLXV(&KLOGKRRGULVNIDFWRUVIRUDWRS\DQG
WKHLPSRUWDQFHRIHDUO\LQWHUYHQWLRQ-$OOHUJ\&OLQ,PPXQRO

 6DYHONRXO +)- 1HLMHQV +- ,PPXQH UHVSRQVHV GXULQJ
allergic sensitization and the development of atopy. Allergy.

 +ROW3*5XGLQ$0DFDXEDV&+ROW%-5RZH-/RK5et al.
Development of immunologic memory against tetanus toxoid
and pertactin antigens from the diphtheria-tetanus-pertussis
YDFFLQHLQDWRSLFYHUVXVQRQDWRSLFFKLOGUHQ-$OOHUJ\&OLQ
,PPXQRO
 :LOOV.DUS06DQWHOL]-.DUS&/7KHJHUPOHVVWKHRU\RI
allergic disease: revisiting the hygiene hypothesis. Nature
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%M|UNVWpQ%$VKHU0,,PPXQL]DWLRQDQGV\PSWRPVRIDWRSLF
disease in children: results from the International Study of
$VWKPDDQG$OOHUJLHVLQ&KLOGKRRG$P-3XEOLF+HDOWK
IL-4 and IL-13 that stimulates the production of IgE.1
Immunization could directly stimulate Th1 immunity.
Th1 cells response was down modulating the effects of
7KFHOOVWKDWZRXOGLQIOXHQFH,J(SURGXFWLRQ31
:H FRQFOXGH WKDW WKH LPPXQL]DWLRQ FRYHUDJH
has not decreased atopy risk in children. The higher
WKHLPPXQL]DWLRQFRYHUDJHWKHORZHUWKHWRWDOVHUXP
IgE.
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trial of the effect of pertussis vaccines on atopic disease. Arch
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 1LOVVRQ/.MHOOPDQ0%M|UNVWpQ%$OOHUJLFGLVHDVHDWWKH
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3HGLDWU$GROHVF0HG
 0DLWUD $ 6KUULII $ *ULIILWKV 0 +HQGHUVRQ - 3HUWXVVLV
vaccination in infancy and asthma or allergy in later
FKLOGKRRGELUWKFRKRUWVWXG\%0-
 0F.HHYHU7/HZLV6$6PLWK&+XEEDUG59DFFLQDWLRQ
DQGDOOHUJLFGLVHDVHDELUWKFRKRUWVWXG\$P-3XEOLF+HDOWK

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 %0-
 ,6$$&:RUOGZLGHYDULDWLRQVLQWKHSUHYDOHQFHRIDVWKPD  *UEHU&,OOL6/DX61LFNHO5)RUVWHU-.DPLQ:et al.
symptoms: the International Study of Asthma and Allergies Transient suppression of atopy in early childhood is associated
LQ&KLOGKRRG,6$$&(XU5HVSLU-
 :HLQEHUJ(*8UEDQL]DWLRQDQGFKLOGKRRGDVWKPDLQ6RXWK
$IULFD$&,,QWHUQDWLRQDO6
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,Q+DPVWHQ09+:LFNPDQ0HGLWRUV\HDUVZLWK,J(
&RSHQKDJHQ0XQNVJDDUGS
 $OIRUG +6 =RUDWWL ( 3HWHUVRQ (/ 0DOLDULN 0 2ZQE\
'5-RKQVRQ&&3DUHQWDOKLVWRU\RIDWRSLFGLVHDVHGLVHDVH
ZLWKKLJKYDFFLQDWLRQFRYHUDJH3HGLDWULFV
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risk of atopic disorders in whole cell pertussis-vaccinated
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SRVVLEOHLPSOLFDWLRQVRIHWKQLFLW\-$OOHUJ\&OLQ,PPXQRO

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SDWWHUQDQGULVNRISHGLDWULFDWRS\LQRIIVSULQJ-$OOHUJ\&OLQ DVWKPDLVWKHUHDOLQN"-$0$
,PPXQRO  +HQGHUVRQ - 1RUWK . *ULIILWKV 0 +DUYH\ , *ROGLQJ -
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362Paediatr Indones, Vol. 48, No. 6, November 2008

 Isabella Riandani et al: Association between immunization coverage and atopy

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%4/RFNH\5)et al. Revised nomenclature for allergy for
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Allergy: principles and practice. 3th ed. Toronto: CV Mosby
&RPSDQ\S
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Paediatr Indones, Vol. 48, No. 6, November 2008363