Delay in diphtheria, pertussis, tetanus vaccination is associated with

Delay in diphtheria, pertussis, tetanus vaccination is associated with

Delay in diphtheria, pertussis, tetanus vaccination is
associated with a reduced risk of childhood asthma
Kara L. McDonald, MSc, a Shamima I. Huq, B S c , b d e Lisa M. Lix, PhD, a d Allan B. Becker, MD, FRCPC,0
and Anita L. Kozyrskyj, phD a , b ' c ' d e
Winnipeg, Manitoba, Canada
Background: Early childhood immunizations have been
viewed as promoters of asthma development by stimulating a
T H 2-type immune response or decreasing microbial
pressure, which shifts the balance between T H 1 and T H 2
immunity.
Objective: Differing time schedules for childhood
immunizations may explain the discrepant findings of an
association with asthma reported in observational studies. This
research was undertaken to determine whether timing of
diphtheria, pertussis, tetanus (DPT) immunization has an effect
on the development of childhood asthma by age 7 years.
Methods: This was a retrospective longitudinal study of a cohort
of children born in Manitoba in 1995. The complete
immunization and health care records of cohort children from
birth until age 7 years were available for analysis. The adjusted
odds ratio for asthma at age 7 years according to timing of DPT
immunization was computed from multivariable logistic
regression.
Results: Among 11, 531 children who received at least 4 doses of
DPT, the risk of asthma was reduced to Vi in children whose first
dose of DPT was delayed by more than 2 months. The likelihood
of asthma in children with delays in all 3 doses was 0.39 (95%
CI, 0.18-0.86).
Conclusion: We found a negative association between delay in
administration of the first dose of whole-cell DPT immunization
in childhood and the development of asthma; the association
was greater with delays in all of the first 3 doses. The
mechanism for this phenomenon requires further research.
(J Allergy Clin Immunol 2008;121:626-31.)
Key words: DPT combination vaccine, childhood asthma, retrospective birth cohort, administrative health data
F r o m J the Faculty of Medicine, D e p a r t m e n t of C o m m u n i t y Health Sciences, b the Faculty
of Pharmacy, and " the Faculty of M e d i c i n e , D e p a r t m e n t of Pediatrics and Child Health,
Section of Allergy and Clinical I m m u n o l o g y , University of M a n i t o b a ; and "'Manitoba
Centre for Health Policy and e M a n i t o b a Institute f o r Child Health.
Supported by the C a n a d i a n Institutes of H e a l t h R e s e a r c h . K . L . M . received studentships
f r o m the Western Regional Training C e n t e r f o r H e a l t h Services R e s e a r c h and the
National Training Program in Allergy and A s t h m a . A . L . K . and L . M . L . are C a n a d i a n
Institutes of Health Research New Investigators.
Disclosure of potential conflict of interest: K. L. M c D o n a l d has received research support
f r o m Western Regional Training C e n t e r and the National Training P r o g r a m for Allergy
and Asthma. A. B. B e c k e r has received research support f r o m the C a n a d i a n Institutes
of Health Research, Allergen, and Novartis. T h e rest of the authors have declared that
they have n o conflict of interest.
Abbreviations
DaPT:
DPT:
ICD-9:
MIMS:
MHSIP:
OR:
used
Diphtheria, acellular pertussis, tetanus
Diphtheria, pertussis, tetanus
International Classification of Diseases, Ninth Revision
Manitoba Immunization Monitoring System
Manitoba Health Services Insurance Program
O d d s ratio
Childhood asthma is one of the most common childhood
diseases in the developed world. The rising prevalence of asthma
in many industrialized countries over the last quarter century has
occurred alongside improvements in hygienic standards. The
hygiene hypothesis postulates that growing up in a more hygienic
environment with less microbial exposure may enhance atopic
(T h 2) immune responses, whereas microbial exposure would
drive the response of the immune system—which is skewed in
the atopic T H 2 direction during fetal life—toward a balanced
T h I and T H 2 immunity. In this context, many early childhood
vaccinations have been viewed as promoters of asthma development, directly by stimulating a T H 2-type immune response, or indirectly by decreasing the microbial pressure; both effects would
shift the cytokine balance away from T H 1 and T H 2 immunity. 1-2
What is the evidence that early childhood immunizations promote
the development of asthma? An IgE response to vaccine antigens
is commonly detectable in the sera of children vaccinated with
diphtheria/tetanus, and the IgE response to vaccine antigens is
more pronounced among atopic individuals. 3,4
The epidemiologic evidence linking diphtheria, pertussis,
tetanus (DPT) immunizations to childhood asthma or atopy is
mixed, with studies showing an increased 4 " 9 or decreased r i s k 1 0 1 2
of developing asthma, or no association. 13 " 19 These studies have
primarily addressed the question of whether asthma is more likely
to develop in vaccinated versus unvaccinated children. As most
children are vaccinated, it is difficult to obtain numbers adequate
to examine the vaccination-asthma relationship, and unvaccinated
children are usually a highly selected and atypical group. 20 ' 21
Recent evidence indicates that the association with childhood
asthma is dependent on the timing of exposure to microbes. 22
Different schedules for immunization may explain the discrepant
findings of an association with asthma reported in observational
studies of vaccinated children. This research was undertaken to
determine whether timing of DPT vaccination has an influence
on the development of childhood asthma by age 7 years.
Received for publication S e p t e m b e r 22, 2 0 0 6 ; revised N o v e m b e r 11, 2007; accepted for
publication N o v e m b e r 13, 2007.
Available online January 21, 2008.
Reprint requests: Anita L. Kozyrskyj, P h D , R m 2 1 0 P h a r m a c y Building, W i n n i p e g , M B ,
METHODS
This w a s a retrospective longitudinal study of a cohort of chi ldren w h o w e r e
C a n a d a , R 3 T 2N2. E-mail: k o z y r s k @ c c . u m a n i t o b a . c a .
0091-6749/$34,00
b o r n in M a n i t o b a in 1 9 9 5 a n d r e m a i n e d in M a n i t o b a until at least a g e 7 y e a r s
© 2008 American A c a d e m y of Allergy, A s t h m a & I m m u n o l o g y
(13,980
doi; 10.1016/j.jaci.2007.11.034
of
626
children).
cohort
children
The
from
complete
birth
immunization
until
age
7
and
were
health
available
care
for
records
analysis.
J ALLERGY CLIN I M M U N O L
M C D O N A L D ET AL 627
V O L U M E 121, N U M B E R 3
Immunization data were obtained from the Manitoba Immunization Monitoring System (MIMS).
Manitoba Immunization Monitoring System data are collected from (1)
physician billing claims, (2) the manual entry of immunization record forms
completed by public health nurses, and (3) hospital departments for immunizations that are not billed by physicians. Immunization tariff codes from the
billing claims are entered into the children's records. MIMS monitors each
record at set intervals (1 year, 2 year, and 6 years of age) to identify which
children are behind in their immunization schedules. When this is detected, a
letter reminding the child's health care provider of their missed immunizations
is mailed out. When children turn 5'/2 years of age, their parents or legal
guardians receive a notification letter of all the immunizations the child should
have received and then states the ones that were either missed or MIMS has no
record of the child receiving. 2 3
Health care records included physician visits, hospitalizations, and prescription drugs collected by the Manitoba Health Services Insurance Program
(MHSIP) in the provision of universal health insurance to Manitoba residents.
Records of physician reimbursement for medical care provided are submitted
under a fee-for-service arrangement and contain information on patient diagnosis at the 3-digit level of the International Classification of Diseases, Ninth
Revision, Clinical Modification (ICD-9) classification system. Discharge
abstracts for hospital services include information on as many as 16 ICD-9CM diagnostic codes, of which the first diagnosis is the primary diagnosis that is
most responsible for the hospital stay. Prescription records submitted by retail
pharmacies contain data on the date of prescription dispensing, drug name and
identification number, dosage form, and quantity dispensed. The MHSIP
databases are reliable and valid data sources for describing health care contact
for specific conditions and prescriptions d i s p e n s e d . L i n k a g e among databases is achieved by the use of anonymized personal identifiers. A family registration number present in the MHSIP registry permits linkage of health care data
of children with the data of parents and siblings.
The prevalence of asthma in the cohort was identified from health care
administrative records. More specifically, a child was defined as an asthma
patient if he or she had 1 or more physician visits with an asthma diagnosis
code (ICD-9-CM 493), 1 or more hospitalizations with an asthma diagnosis
code (ICD-9-CM 493), or at least 1 prescription for any asthma drug (inhaled/
oral (3-agonists, inhaled corticosteroids or cromones or leukotriene receptor
antagonists) in the year preceding his or her seventh birthday. This asthma
definition was chosen on the basis of a validation study conducted in a subset
of children recruited for clinical assessment by an allergist as part of a nested
case-control study. 2 ''"' Several health care database definitions of asthma
were compared to the gold standard of allergist diagnosis of asthma based
on symptoms and history. The positive predictive value of this definition
was 88% (95% CI, 77% to 95%), and the specificity was 81% (95% CI,
64% to 92%).
The exposure measure was time of administration of DPT immunizations.
It was categorized by months from birth for each dose according to the
Manitoba childhood immunization schedule (within 2 days after the
recommended period) as follows: first dose (2 months [62 days] or less,
between 2 and 3 months [63 to 93 days], between 3 and 4 months [94 to 124
days], and greater than 4 months [125 days or more]); second dose (4 months
[124 days] or less, between 4 and 5 months [125 to 155 days], between 5 and 6
months [156 to 186 days], and greater than 6 months [187 days or more]); third
dose (6 months [186 days] or less, between 6 and 7 months [187 to 217 days],
between 7 and 8 months [218 to 248 days], and greater than 8 months [249 and
more]); and fourth dose (18 months [558 days] or less, between 18 and 24
months [559 to 744 days], and greater than 24 months [745 days and over]).
Measures of risk or protective factors for asthma were also derived from
health care administrative records. 2 ' These included sex, number of siblings,
urban or rural residence, neighborhood income group, number of antibiotic
prescriptions (0, 1-2, 3-4, and 5 or more courses), total number of physician
visits during the first year of life, and maternal history of asthma (at least 1 physician visit or hospitalization for asthma [ICD-9-CM 493] or 1 prescription for
an asthma drug during the birth year). A neighborhood income measure was
derived from Statistics Canada Census 1996 public use files. Children were
placed into income quintiles and according to the postal code of residence
at birth. These quintiles were derived separately for urban and rural residents.
Multivariable logistic regression models were used to compute the adjusted
odds ratio (OR) for asthma at age 7 years according to timing of DPT
immunization. Separate models were defined for each DPT dose, with the
following periods defined as the reference categories to denote on time
administration of dose (within 2 days of the Manitoba childhood immunization schedule): 2 months for the first dose, 4 months for the second dose, 6
months for the third dose, and 18 months for the fourth dose. A sensitivity
analysis was conducted by rerunning models after the recategorization of the
DPT administration time variable by adding 7 days instead of 2 days to the
intervals. All of the models were adjusted for sex, urban/rural location, income
quintile, number of siblings, number of antibiotic prescriptions, the number of
health care visits during the first year, and maternal history of asthma.
Variables were retained in the models at P < .05. All of the variables in the
model were also tested for collinearity. SAS software (SAS Institute, Cary,
NC) was used for all analysis.
This study received approval from both the University of Manitoba Human
Research Ethics Committee and Manitoba Health's Health Information
Privacy Committee.
RESULTS
Thirty children were excluded from the analysis because they
had physician visits for asthma diagnoses before their first
immunization. Of the remaining 13,950 children, 11,531 children
(82.6%) received at least 4 doses of DPT. These children were
primarily immunized with whole-cell pertussis DPT, because the
diphtheria, acellular pertussis, tetanus (DaPT) vaccine was phased
in throughout the province beginning in November 1997. There
were 12,105 children in the 1995 cohort who were immunized
with 1 or more doses of DaPT, although the majority of the cohort
(80.2%) received only 1 dose of DaPT, typically their fifth dose.
The medical, hospital, prescription, and immunization records
of 11,531 children receiving 4 or more doses of DPT were
analyzed. The prevalence of asthma among these children was
11.7%. Children with asthma were predominately male (3:2) and
lived in urban areas (70.3%). Approximately 25% of children
with asthma were from low-income homes. Of the children with
asthma, 10.1% had mothers with a history of asthma, whereas
4.7% of the children without asthma had mothers with a maternal
history of asthma. Children with more siblings were less likely to
develop asthma (children with no siblings had an asthma rate of
15.4%, children with 2 siblings had an asthma rate of 10.4%, and
children with 4 siblings had an asthma rate of 8.0%).
There were 4978 children who were immunized with their first
dose of DPT by 62 days after birth, of whom 685 developed
asthma (13.8%) (Table I). Many of the children were immunized
after 62 days following birth, but before 93 days after birth (n = 5;
965 children), of whom 614 or 10.3% developed asthma. Only
417 and 171 children had their first dose by 124 days and more
than 4 months, respectively. Asthma prevalence rates decreased
successively from 13.8% to 5.9% with each month delay in
DPT administration.
The adjusted ORs for asthma according to timing of DPT dose
are listed in Table II. Children who rcccivcd their first, sccond,
third, and fourth doses of DPT according to schedule (2, 4, 6,
and 18 months after birth) constituted the reference categories
for the other groups. Children who were delayed by as long as
1 month in their first dose of DPT were significantly less likely
to develop asthma compared with children who received their first
dose of DPT by 62 days after birth (OR, 0.84; 95% CI, 0.75-0.95).
The likelihood of asthma at age 7 years was halved in children
who received their first dose of DPT at more than 4 months after
J ALLERGY CLIN IMMUNOL
6 2 8 M C D O N A L D ET AL
MARCH 2008
TABLE I. Number of children by months after birth in which they
received their doses of DPT and the corresponding asthma rates
Total no. of
children
No. with
asthma
Asthma
rate (%)
First DPT dose
685
614
13.8
171
38
10
9.1
5.9
4238
5909
839
545
570
661
79
37
13.5
11.2
9.4
6.8
3799
5383
506
615
13.3
11.4
1162
1187
128
98
II.O
8.3
1785
246
1019
82
1347
13.8
11.4
10.1
11.7
2 Mo after birth
4978
3 Mo after birth
5965
417
4 Mo after birth
More than 4 mo after birth
Second D P T dose
4 M o after birth
5 Mo after birth
6 M o after birth
More than 6 mo after birth
Third D P T dose
6 Mo after birth
7 Mo after birth
8 Mo after birth
More than 8 mo after birth
Fourth D P T dose
18 Mo after birth
24 Mo after birth
More than 24 mo after birth
Total
8935
811
11,531
10.3
birth (OR, 0.50; 95% CI, 0.25-0.97). Forty-three children received their first dose before 6 weeks and 1215 children received
their first dose before 58 days, before the 6-week to 8-week period
recommended by the World Health Organization. 28 There was no
difference in the likelihood of asthma between children receiving
early doses (OR, 1.60; 95% CI, 0.55-4.61 for <45 days; and OR,
1.18; 95% CI, 0.97-1.44 for <58 days) and children receiving
their first dose on schedule between 45 and 62 days, providing justification for grouping them together. On switching the reference
group in Table II from on time to early administration (<8 weeks),
a 2-month or greater delay in the first dose was associated with a
similar reduction of asthma risk (OR, 0.56; 95% CI, 0.28-1.11).
However, this reduced the sample size of the reference group,
and findings were no longer significant.
There were 4238 children who received their second dose of
DPT by 124 days (4 months), 5909 children who received their
second dose between 4 and 5 months after birth, 839 children who
received their second dose between 5 and 6 months, and 545
children who received their second dose more than 6 months after
birth (Table I). Children who received their second dose according to schedule had asthma rates of 13.5%, and these rates
declined successively with each delay in DPT administration to
6.8%. Only children with the greatest delay in administration of
the second DPT dose had an adjusted OR that was statistically
significant (Table II). They were 59% as likely to have asthma
in comparison with children who were immunized with their
second dose of DPT by 4 months after birth.
There were 3799 children who received their third dose of DPT
by 6 months after birth, of whom 506 developed asthma (13.3%;
Table I). More children were immunized between 6 to 7 months
after birth (5383), of whom 615 developed asthma (11.4%). There
were also 1162 children who were immunized with their third
dose of DPT between 7 and 8 months after birth and 1187 who
were immunized with their third dose of DPT after this period.
These children had asthma rates of 11.0% and 8.3% respectively.
In comparison with children who were immunized with their third
dose of DPT by 6 months after birth, the likelihood of asthma was
significantly reduced (OR, 0.73; 95% CI, 0.58-0.94) only in children who received their third DPT immunization after 8 months
following birth (Table II).
Finally, there were 1785 children who were immunized with
their fourth dose of DPT by 18 months after birth, of whom 246
developed asthma (13.8%; Table I). The majority of cohort children (n = 8935) were immunized with their fourth dose of DPT
between 18 and 24 months after birth. These children had an
asthma prevalence rate of 11.4%. Among the 811 children who
were immunized with their fourth dose of DPT after 24 months
following birth, 82 of them developed asthma (10.1%). None of
the adjusted ORs were statistically significant (Table II).
The sensitivity analysis, which involved extending the intervals
for DPT administration to 7 days postschedule, yielded similar
findings. More than 2-month delays in the administration of DPT
doses resulted in the following reduced risk for asthma: OR, 0.41,
95% CI, 0.19-0.90 for the first dose; OR, 0.56, 95% CI, 0.37-0.83
for the second dose; and OR, 0.75, 95% CI, 0.59-0.95 for the third
dose. This reduction in asthma risk was of greater magnitude than
for the ORs obtained by using the 2-day postschedule allowance.
Among children with greater than a 2-month delay in receiving
the first dose, 88% experienced the same delay in the second dose,
and 86% had delays in all 3 doses. The percent of children with
asthma in the latter group was 5%, in comparison with 12% in the
remainder of the cohort. The likelihood of asthma among children
with greater than 2-month delays in all 3 doses of DPT was 0.39
(95% CI, 0.18-0.86). Reductions in asthma likelihood subsequent
to greater than 2-month delays in the administration of the second
and third doses were observed in children who had received the
first dose on schedule (Table III). However, these reductions were
not statistically significant.
DISCUSSION
In a complete birth cohort of 11,531 children who were
immunized with at least 4 doses of DPT, we have uncovered an
association between timing of DPT administration and onset of
asthma at age 7 years. Delayed administration of the first dose of
DPT of more than 2 months from the recommended 2-month
period was associated with a reduced risk of childhood asthma
by 50%. Sensitivity analyses that varied the interval for DPT
immunization demonstrated that our findings are robust. Very few
studies have published on the timing of childhood immunizations
and childhood asthma. Bremner et al 29 documented a reduced risk
for hay fever among children with delayed completion of the third
DPT vaccination. On the other hand, McKeever et al 6 did not find
an association between asthma onset and age at first injection of
diptheria, polio, pertussis, and tetanus vaccine in their database
study of 29,000 children. To our knowledge, we are the first to report that delay in administration of the first dose of DPT immunization is significantly associated with a reduced risk of developing
asthma in childhood.
We also found a decreased likelihood of childhood asthma after
delays in the administration of the second and third doses of DPT.
Consistent with immunization guidelines, the majority of these
delays were in children with delays in their first dose. Our data
indicate that the reduction in asthma risk for the second and third
doses was primarily a result of the delay in the first dose, because
no statistically significant differences in asthma risk were seen
with delays in the second and third doses in the absence of delays
MCDONALD ET AL 629
J ALLERGY CLIN I M M U N O L
VOLUME 121, NUMBER 3
TABLE II. Adjusted* ORs (OR, 95% CI) for asthma at age 7 years by month of DPT dose administration (n = 11,531)
DPT dose
1
Months after birth
2
3
4
5
6
7
8
9
2
OR
95% CI
Referencef
0.84
0.81
0.50
0.75-0.95
0.56-1.16
0.25-0.97
3
OR
95% CI
Reference!
0.93
0.90
0.59
0.82-1.06
0.69-1.17
0.41-0.85
4
OR
95% CI
Referencef
0.95
1.04
0.74
0.83-1.08
0.83-1.29
0.58-0.94
OR
95% CI
Referencef
0.92
0.91
0.78-1.07
0.69-1.20
10
11
12
18
24
More than 24
* A d j u s t e d for s e x , m a t e r n a l h i s t o r y a s t h m a , u r b a n / r u r a l l o c a t i o n , h o u s e h o l d i n c o m e , n u m b e r of s i b l i n g s , n u m b e r of c o u r s e s of a n t i b i o t i c s , a n d n u m b e r of h e a l t h c a r e visits,
f R e f e r e n c e g r o u p s a r e c h i l d r e n r e c e i v i n g D P T d o s e s a c c o r d i n g to s c h e d u l e .
in the first dose. However, among children with delays in all 3
doses, the likelihood of asthma was further reduced to 60%.
The majority of studies investigating the effect of vaccination on
the development of asthma have compared vaccinated and unvaccinated children. Because unvaccinated children have environmental exposures that may protect against asthma in known and
unknown ways, 30 the strength of our study is that the comparison
group consisted of children vaccinated with at least 4 doses of
DPT. Having said this, children with delayed DPT immunization
may differ from other children in several ways. Some of the previous vaccine-asthma associations have been explained by ascertainment bias, 6 whereby asthma has been reported to be less prevalent
in unvaccinated children with a low frequency of physician visits.
Similarly, even among vaccinated children, it is possible that families who consult their general practitioner less often would be less
likely to attend for routine vaccination on time, and less likely to
present their child with asthma symptoms."1 In addition, children
from larger families are less likely to complete their vaccinations
on time, and having a greater number of older or younger siblings
is strongly protective of asthma. ' 2 Low family socioeconomic status is another risk factor for delayed childhood vaccinations that
has been associated with childhood asthma. 33 To address these 3
potential sources of bias, analyses were adjusted for the frequency
of health care contact, the number of siblings, and income quintile.
These adjustments had no effect on our findings. The association
between delayed administration of vaccination and decreased
onset of asthma was independent of these factors.
One of the main reasons for delayed immunization is the
presence of fever or an infection in the child. 31 ~34 Fever during the
first year of life has been shown to decrease the likelihood of
childhood asthma and atopy. 22 Attendance at day care, especially
during the first 6 months of life, causes more frequent infections,
but protects against asthma at age 6 years. 35 Bremner et al 29 proposed that delay in immunization because of current infection was
the most plausible explanation for their findings of an association
with decreased risk of hay fever. However, their analysis of the
monthly infection rate did not show a graded relation with vaccination delay. In our analysis, the OR was adjusted for the number
of antibiotic prescriptions, which are excellent proxy measures
TABLE III. Adjusted* ORs (OR, 95% CI) for asthma at age 7 years
by month of DPT administration for dose 2 and dose 3 in children
receiving dose 1 on schedule (n = 11,360)
DPT dose
2
Months
after birth
4
5
6
7
8
9
3
OR
95% CI
Reference
0.94
0.90
0.68
0.83-1.06
0.69-1.17
0.45-1.01
OR
95% CI
Reference
0.95
1.06
0.79
0.83-1.08
0.85-1.32
0.62-1.02
* Adjusted for sex, maternal history asthma, urban/rural location, household income,
n u m b e r o f s i b l i n g s , n u m b e r of c o u r s e s of a n t i b i o t i c s , a n d n u m b e r o f h e a l t h c a r e visits.
for respiratory tract infections. 36 Further, we are certain of the integrity of the MIMS database, and we have used a database definition for childhood asthma that has been validated by pediatric
allergist assessment in a subset of children.
Whole-cell pertussis DPT is no longer used in many countries,
but our study generates some interesting hypotheses for the
biological mechanisms behind early childhood vaccination and
the development of asthma. The acellular pertussis vaccine was
developed because of high rates of adverse reactions for the
whole-cell vaccine, such as neurological disorders and high
fever. 37 ' 3 * Fevers result from the release of inflammatory cytokines by cells involved in the innate immunity response to infections and have been proposed as markers for the intensity of innate
i m m u n e s y s t e m s t i m u l a t i o n a n d e a r l y s k e w i n g t o w a r d the T H 1
phenotype during infancy. 39 At birth, the newborn immune system has a limited ability to produce T H 1 cytokines, but levels increase over the period of the next 6 months. 40 ' 41 Similar to the
fever-asthma association reported by Williams et al, 22 a high fever
response elicited by the cellular pertussis vaccine in later infancy
potentially has a greater effect in stimulating the innate immune
response than a fever response in early infancy. An alternate interpretation of our findings is that vaccine stimulation of IgE levels at
J ALLERGY CLIN IMMUNOL
6 3 0 M C D O N A L D ET AL
MARCH 2008
a later time during infancy, when the T H 1 immune system gains
more prominence, may have little effect in promoting T H 2 skewing. 42 Our study would need to be repeated in a later birth cohort
to assess the effect of the acellular pertussis vaccine because the
DaPT vaccine has been found to be less reactogenic, with a lower
incidence of adverse events. 34
It is premature to make recommendations until these findings
have been confirmed with the DaPT vaccine, and the benefits of
altering immunization schedules need to be weighed against the
risks. North American childhood immunization schedules, which
normally include 2-month, 4-month, and 6-month intervals, were
introduced in the 1950s to increase overall immunization rates.
The rationale for continuing to use this schedule is to provide
protection in early infancy as quickly as possible to the greatest
number of infants. 28 However, immunization schedules vary by
country subsequent to differences in infectious disease prevalence, public demand, and the level of health care. The childhood
immunization schedule in Japan recommends that children be immunized with 3 doses of DaPT between 6 to 9 months after birth;
first doses can be given no earlier than 3 months. 43 It is interesting
to note that between 1975 and 1988, Japan did not recommend
immunizing children under 2 years of age. 38 In 1982, Japan's
asthma prevalence rate in children was approximately 3.2%,
and by 2002 it was 6.5%. Although these statistics represent a
doubling of asthma over a period of 20 years, these prevalence
rates are well below those seen in North America. 44 However,
the administration of pertussis vaccine in Japan to children after
2 years of age resulted in higher rates of pertussis than in children
given the vaccine at an earlier time. 38 ' 43
Asthma in children is a significant contributor to morbidity and
health care costs.46*48 Our study offers hypotheses regarding the
timing of immunization and the development of this common
childhood disease. Although we believe that antibiotic use is a
sufficient adjustment for existing infection, further analyses are
required to refute the issue of early-life infections as an explanation for the association between delayed immunization and
protection against the development of asthma. For example, children hospitalized for respiratory syncytial virus are more likely to
have delayed pertussis immunization, yet respiratory syncytial
virus is associated with an increased risk of asthma. 49 Moreover,
further study is vital to gain a detailed understanding of the relationship between vaccination and allergic disease, because a perception that vaccination is harmful may have an adverse effect on
the effectiveness of immunization programs.
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Health is intended or should be inferred. We acknowledge the computer
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