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Low Cord Blood Pneumococcal Antibody Concentrations Predict More Episodes of Otitis Media
Eric T. Becken, MD;
Kathleen A. Daly, PhD;
Bruce R. Lindgren, MS;
Mary H. Meland, MD;
G. Scott Giebink, MD
Arch Otolaryngol Head Neck Surg. 2001;127:517-522.
ABSTRACT
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Objective To determine if cord blood anticapsular polysaccharide pneumococcal
IgG antibody concentration was related to the number of otitis media (OM)
and acute OM episodes during the first year of life.
Design Prospective study following infants from birth to 24 months.
Setting Health maintenance organization.
Patients The study population consisted of 415 infants whose mothers volunteered
for the study during pregnancy. Cord blood samples were collected and infants
were followed up for OM in the health maintenance organization. Ninety-seven
percent of the infants were white, 49% male, 3% from households with annual
incomes of less than $20 000, and 30% from households with annual incomes
of more than $60 000.
Main Outcome Measure Number of physician-diagnosed OM episodes, including both OM with effusion
and acute OM, and acute OM episodes from birth to 12 months.
Results With univariate analysis, low cord blood antibody concentrations against
serotypes 3 and 19F predicted more acute OM episodes (P = .04 and P = .05, respectively), and low
antibody concentrations against serotypes 19F and 23F predicted more OM episodes
(P = .04 and P = .05, respectively)
over the first year of life. With Poisson regression, which adjusted for variables
related to the recurrence of OM and having low cord blood antibody concentrations,
serotype 19F remained significantly related to the number of OM episodes (relative
risk for lowest quartiles vs upper 3 quartiles 1.23; 95% confidence interval,
1.02-1.50; P = .03).
Conclusions Low cord blood antibody concentrations to serotype 19F predicted more
OM episodes over the first 12 months of life. These results suggest the potential
benefit of maternal immunization to raise neonatal antipolysaccharide pneumococcal
antibody concentration and delay the onset and reduce the number of OM episodes.
INTRODUCTION
OTITIS MEDIA (OM) is the most frequent diagnosis in infants and children
who visit physicians owing to illness and is responsible for more than 30%
of all pediatric health care visits in the United States.1
It is estimated that $3 to $4 billion is spent annually in the United States
on the medical and surgical treatment of OM.2
Among the many factors contributing to the genesis of OM, infants with
OM during the first 6 months of life are at a greater risk for recurrent OM
and chronic OM with effusion (OME) than children of the same age with later
onset of OM.3, 4, 5
This high-risk period for OM correlates with a period of relative immunodeficiency.
The infant's immature immune system responds poorly to certain antigenic challenges
and must rely on a declining concentration of maternally derived antibodies.
A previous study has shown that children with recurrent episodes of
OM do not exhibit total IgG, IgM, or IgA deficiencies compared with healthy
children.6 Other studies have demonstrated
that low concentrations of pneumococcal antipolyscharide (anti-PS) IgG antibodies
correlate with increased susceptibility to recurrent OM.7, 8, 9, 10, 11
Further, infants with low cord blood antibody concentrations against Streptococcus pneumoniae serotypes 14 and 19F have significantly
earlier onset of OM than those with higher levels.12
A study of 10 Swedish children with 6 or more episodes of acute OM (AOM) during
a 12-month period demonstrated that they had lower cord blood antibody concentrations
against S pneumoniae serotypes 6A and 19F than a
cohort of healthy children.11 Streptococcus pneumoniae was the dominant isolate in children with
exceedingly low cord blood pneumococcal antibody concentrations and recurrent
AOM, whereas children with recurrent AOM and high cord blood pneumococcal
antibody concentrations had no isolates of S pneumoniae.11
Without considering the causative agent, children with recurrent OM
or chronic OM with effusion often have tympanostomy tubes placed. In a 1-year
period, 30% of children younger than 24 months, followed up in a Cincinnati,
Ohio, managed health care organization, had tubes placed.13
Another study demonstrated that an increased rate of tube placement mirrored
the increase in recurrent OM. In US children younger than 5 years, recurrent
OM increased from 19% to 26% between 1981 and 1988, and tube placement increased
from 1.3% to 2.4% during the same period.14
An intervention that would decrease recurrent OM episodes could decrease the
rate of tympanostomy tube placement and its associated costs.
A previous report demonstrated that low serotype-specific cord blood
pneumococcal antibody concentration predicted earlier onset of OM.12 This study extended the period of observation of
this cohort to determine the relationship between cord blood pneumococcal
anti-PS IgG antibody concentrations and number of OM and AOM episodes during
the first 12 months of life.
SUBJECTS, MATERIALS, AND METHODS
POPULATION
The study population consisted of 592 infants born to women from separate
but similar cohorts followed up by the same Minneapolis–St Paul health
maintenance organization. Detailed recruitment and data collection methods
are reported elsewhere.12 Briefly, one cohort
of women, between the ages of 18 and 35 years, was enrolled during the third
trimester of pregnancy. Women were excluded for conditions known to interfere
with gestation or infant birth weight, a terminated pregnancy within 1 year,
or a history of infertility. The second cohort of women was recruited from
those 18 years or older who received obstetric care at the same health maintenance
organization as those in the first cohort. The study population was limited
to women from both cohorts whose children were born during the enrollment
period and received care at the health maintenance organization clinics.
DATA COLLECTION
Women completed forms during the third trimester of pregnancy and monthly
for 6 months after birth. The questionnaires were designed to measure demographic
and environmental variables, such as maternal and paternal age, household
income, ethnicity, maternal educational level, passive smoking exposure, day
care attendance, and infant feeding methods. The questionnaires also addressed
family history of OM ( 3 episodes of OM in a 12-month period, tympanostomy
tubes, chronic otorrhea, or persistent middle ear effusion). Birth weight
and gestational age were abstracted from the medical record.
Infants' ears were examined by pneumatic otoscopy and tympanometry at
scheduled 2-, 4-, and 6-month well-child visits, and with pneumatic otoscopy
at 2 weeks and at 9- to 12-, 15-, and 24-month well-child visits and all illness
visits through 24 months. At each visit an ear examination form was completed
detailing symptoms, tympanic membrane position, color, mobility, appearance,
and middle ear diagnosis. The examiners, who included pediatricians, pediatric
nurse practitioners, and family practitioners, had no knowledge of pneumococcal
antibody levels. Owing to the sample size and geographic variability, the
use of validated otoscopists for each examination was infeasible. However,
a validated otoscopist and an investigator (G.S.G.) performed interobserver
testing with a sample of the examiners. Diagnostic consistency was also evaluated
by comparing recorded signs and symptoms with a middle ear algorithm. Acute
OM was defined as a middle ear effusion with a red or yellow tympanic membrane,
an effusion with fever, irritability, otalgia, or by the presence of a tympanic
membrane perforation and otorrhea. Otitis media with effusion was defined
as an opaque, red or yellow, full to bulging tympanic membrane with abnormal
mobility. Otitis media included both AOM and OME.
LABORATORY METHODS
A cord blood sample was collected at the time of birth from 415 infants.
Samples were analyzed by enzyme-linked immunosorbent assay for pneumococcal
anti-PS IgG antibody serotypes 3, 4, 6B, 14, 18C, 19F, and 23F; levels were
adjusted to Food and Drug Administration lot 89-SF reference values as previously
described.12 Assays were performed after all
infants were 6 months old.
STATISTICAL ANALYSIS
The number of physician-diagnosed OM and AOM episodes from 0 to 12 months
were the outcome variables. In the following data analyses, the term OM encompasses
episodes of both AOM and OME, whereas AOM refers to acute episodes only. A
new OM episode was defined as either AOM or OME in either ear after a normal
middle ear examination, or a new episode of AOM 21 days or more after a previous
diagnosis of AOM or OME.
Infants were stratified into 2 groups on the basis of antibody concentration,
as in the earlier article.12 The low antibody
group included those with concentrations in the lowest quartile, and the high
antibody group included those with concentrations in the upper 3 quartiles.
Early onset was defined as the occurrence of an OM episode before the age
of 6 months, and later onset was the occurrence of the first OM episode between
the age of 6 and 12 months. To explore the influence of both OM onset and
antibody concentration on number of OM episodes, 4 subsets were created separately
for serotypes 14 and 19F: low antibody concentration and early onset, low
antibody concentration and later onset, high antibody concentration and early
onset, and high antibody concentration and later onset. These analyses included
only serotypes 14 and 19F because they were both significantly associated
with early OM onset, whereas other tested serotypes were not.12
The relationship between number of OM episodes and each subset was determined
from 0 to 12 months for the early-onset groups, and from 6 to 18 months for
later-onset groups. Further analyses combined both early- and both late-onset
groups to determine the relationship between antibody concentration alone
and number of OM episodes. Only those with OM onset by the age of 12 months
were included in these analyses.
Since age at onset was not predictive of the number of OM episodes when
considered jointly with antibody concentration, the following analyses included
all infants irrespective of OM onset. Low and high antibody groups for serotypes
3, 4, 6B, 14, 18C, 19F, and 23F, responsible for 9%, 1%, 10%, 15%, 4%, 15%,
and 13% of AOM episodes, respectively,15 were
analyzed individually for number of OM and AOM episodes during the first 12
months of life. The t tests for independent means
were used to test for significant differences in the number of episodes between
high and low antibody groups of the previously mentioned serotypes. Those
with P .1 for both AOM and OM episodes were further
analyzed using Poisson regression to adjust for previously described variables
related to both the recurrence of OM and low cord blood antibody concentrations.
These variables include conjunctivitis in the first 6 months of life, birth
in the fall, and having more than 1 sibling.16, 17
Several models were explored, using each antibody that met the criteria with
the confounding covariates. Groups of antibodies were also combined with covariates,
and antibodies were removed if their associated P
value was greater than .05. Risk ratios were calculated for each variable
in the final model.
RESULTS
The study cohort was preponderantly white (97%) and 49% were male. Three
percent of the subjects came from households with annual incomes of less than
$20 000, and 30% came from households with annual incomes greater than
$60 000. Birth weight ranged from 1.5 to 5.1 kg (mean birth weight, 3.3
kg). At the ages of 2 weeks and 6 months, 80% and 39%, respectively, were
either fully or partially breastfed. By 6 months of age 48% of the children
attended out-of-home day care. Physicians' diagnoses, which were used for
statistical analyses, agreed well with the previously described middle ear
algorithm ( = 0.92).12 Statistics
comparing an investigator and a validated otoscopist with a sample of the
clinical examiners were 0.54 and 0.65, respectively.12
Cord blood antipneumococcal serotype quartile distributions, geometric mean
titers, and 95% confidence intervals, adjusted to 89-SF standard values, are
given in Table 1. Other characteristics
of the cohort have been described elsewhere.12
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Table 1. Cord Blood Antipneumococcal Antipolysaccharide IgG Serotype
Quartile Distributions, Geometric Mean Titers (GMT), and 95% Confidence Intervals
(CI) Adjusted to 89-SF Standard Values
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Mean OM episodes for the 4 subsets of high-low antibody concentration
and early-late onset did not differ significantly for serotype 14 (P = .31). Serotype 19F demonstrated an overall significant difference
for these same four subsets (P = .02). The trend
was for children in the low antibody group to have more OM episodes than those
in the high antibody group, independent of onset, but no significant pairwise
differences were demonstrated. When considering antibody strata alone, mean
number of OM episodes was significantly higher among those with low 19F concentrations
than those with high 19F concentrations (4.65 vs 3.79, P<.01), but the difference between means was of borderline significance
for serotype 14 (4.35 vs 3.85, P = .07).
Given that early or later OM onset did not significantly influence the
number of episodes, the following analyses focused on the relationship between
antibody concentrations and AOM and OM episodes. Between the age of 0 and
12 months, children with the lowest quartile of antibody against serotype
3 had significantly more AOM episodes than those with antibody concentrations
in the upper 3 quartiles (P = .04) and the relationship
between 19F and number of AOM episodes was of borderline significance (P = .05) (Table 2).
Similarly, between the age of 0 and 12 months infants with the lowest quartile
of antibody against serotype 19F had significantly more OM episodes (P = .04) and the relationship between 23F and number of
OM episodes was of borderline significance (P = .05)
(Table 2).
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Table 2. Mean Number of Acute Otitis Media and Otitis Media Episodes
According to Pneumococcal Cord Blood Antibody Profiles During the First 12
Months of Life
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Serotypes 3, 19F, and 23F, with P.1 for
both AOM and OM episodes, were entered into the Poisson regression model predicting
the number of episodes in first 12 months. This model adjusted for variables
related to both the recurrence of OM and having low cord blood antibody concentrations.
Only low levels of serotype 19F remained significantly related to number of
OM episodes in the first 12 months, with a 23% increase in the average number
of episodes (Table 3).
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Table 3. Poisson Regression Model Adjusting for Variables Related to
Both the Recurrence of Otitis Media and Low Cord Blood Antibody Concentrations
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COMMENT
This study illustrates that low cord blood pneumococcal antibody concentrations
against serotype 19F, independent of age at first OM episode, conjunctivitis
in the first 6 months of life, birth in the fall, and having more than 1 sibling
predicts a greater number of OM episodes during the first 12 months of life.
This is consistent with the finding that infants with recurrent AOM had significantly
lower concentrations of antibodies against 19F than healthy children.11
Although having a low antibody concentration against serotype 14 was
associated with early-onset OM,12 it was not
associated with number of OM episodes during the first year of life. Unlike
the first OM episode, which depends on infection with a single organism or
serotype, the number of episodes in the first 12 months of life could be the
result of exposure to and infection with several different pneumococcal serotypes
or organisms. Serotype 14 may be important in early-onset OM, but other organisms
and serotypes may be the causative agents in later episodes, diminishing the
relationship between serotype 14 cord blood antibody concentrations and the
number of OM episodes. Although serotypes 14 and 19F are each responsible
for 15% of pneumococcal OM in children younger than 6 years according to national
data collected by the Centers for Disease Control and Prevention, Atlanta,
Ga,15 it is difficult to know if these serotypes
are responsible for the same proportion of OM in Minnesota children or, more
specifically, in the study cohort.
Infants are poorly equipped to respond to pneumococcal PS. During the
first 6 months of life, maternally acquired antibody declines while infant
immune systems begin producing IgM followed by IgG.18
Serotypes 14 and 19F have been shown to be poor immunogens in infants vaccinated
with pneumococcal polysaccharide vaccine.19
In one study, few infants 12 months or younger had prevaccination and postvaccination
antibody concentrations presumed to be protective (>300 ng/mL) against serotypes
14 and 19F, but a higher proportion had protective levels against 14 than
against 19F.19 This suggests that infants in
the first year of life may be more prone to multiple infections of serotype
19F than of serotype 14 because they make less antibody to 19F.
The number of OM episodes experienced by a child results in part from
having low concentrations of passively acquired and/or actively produced serotype-specific
pneumococcal antibodies. Other important contributing factors include the
exposure to other young children (eg, day care attendance, siblings), prevalence
of serotypes to which the infant has low antibody concentrations (which affects
the likelihood of exposure to those organisms), and other bacterial and host
factors that affect the infectivity, pathogenicity, and immunogenicity of
encountered organisms. Actively produced antibody is in short supply during
the first year of life and passively acquired antibody is a reflection of
maternal supply. Maternal antibody concentrations to specific pneumococcal
serotypes probably result from cross-reactive antigens20
and previous exposures to specific pneumococcal serotypes carried by older
children in day care centers. Carriage rates of specific serotypes have been
shown to vary substantially among day care centers in the same community.21 Thus, given adequate maternal antibody production
and transfer, cord blood antibody concentrations are likely to be elevated
against serotypes to which the mother had been recently exposed. For example,
children of women who were exposed mainly to serotype 19F may have fewer OM
episodes due to 19F because they have high concentrations of passively transferred
19F antibody, whereas repeated exposure to a serotype that the infant's mother
had not encountered may result in more OM episodes due to low antibody concentrations
to those serotypes. Therefore, developing an OM episode depends on low cord
blood antibody concentration to a specific serotype and encountering a sufficient
exposure to that same serotype.
Cord blood antibodies are a consequence of maternal production and placental
transport. Low cord blood antibody concentrations may be a result of low maternal
production due to a genetically compromised immune system, a defect in maternal-fetal
antibody transfer, or lack of recent maternal exposure to S pneumoniae. A previous study documented that individuals with G2m(n),
an allotype antigen of IgG2 heavy chains, had higher preimmunization and postimmunization
antibody titers to PS antigens than individuals lacking G2m(n).22
Infants of G2m(n)-negative mothers would not only receive less maternal antibody
due to poor production, but those inheriting maternal G2m(n)-negative status
would be unable to respond as vigorously as G2m(n)-positive infants. Thus,
their active response would be compromised and they would also have lower
levels of maternally derived antibodies to respond to pneumococcal PS challenges.
Other studies of OM-prone children have documented decreased responsiveness
to pneumococcal vaccines. Pelton et al23 demonstrated
that children with relatively lower preimmunization pneumococcal antibody
concentrations had more episodes of OM during the following 24 months than
other children. Another study has shown that OM-prone children respond more
vigorously to pneumococcal conjugate vaccine than to the pneumococcal PS vaccine.
Conversely, OM-free children respond equally well to both, suggesting a state
of hyporesponsiveness to pneumococcal PS in OM-prone children.24
Maternal-fetal transfer of IgG antibodies begins at 17 weeks of gestation
and increases in proportion to gestational age.25
At term, the concentration of IgG in the infant is usually 10% to 15% higher
than in the mother.25 The exception is children
born to mothers with exceptionally high levels of IgG. In this case the placenta
transfer mechanism acts as a limiting step and the infant will have relatively
less than the mother.25 More specifically,
correlation between maternal and infant serum concentrations of IgG1 against
pneumococcal serotypes 1, 6A, 14, 19F, and 23F is strong,26, 27
thus it is unlikely that selective or defective maternal-fetal transfer is
an adequate explanation.
In addition to providing passive immunity, maternal-fetal antibody transfer
may also prime the immune system.25, 28
Priming the immune system is thought to occur when anti-idiotypic antibodies,
along with protective antibodies, cross the placenta and induce the synthesis
of protective antibodies in the fetus.25 In
an experimental system, maternal immunization with anti-idiotypic antibody
fragments, which mimicked the conformation of the capsular antigen, protected
neonatal mice against group B streptococcus infection.29
This may explain why infants with low concentrations of cord blood antibodies
to specific serotypes have more episodes of OM, that is, infants who receive
low concentrations of specific antibody may also receive low concentrations
of anti-idiotypic antibodies. Thus, they would not only lack passive maternally
derived antibody protection, they would also lack immune priming. Although
anti-idiotypic immune priming has been documented in mice, little is known
about the effects of anti-idiotypic antibodies in humans.25
Many physicians and nurse practitioners examined infants, and OM may
have been both underdiagnosed and overdiagnosed. However, values for
OM diagnosis comparing 20 clinicians, an investigator, and a validated otoscopist
demonstrated moderate to substantial agreement, and comparing physician
diagnoses with the algorithm was 0.92.16 Since
examiners did not have information about antibody concentrations, these findings
could not have influenced their diagnostic decisions. Nondifferential misclassification
of disease status (eg, unbiased misdiagnoses) results in a decreased rather
than an increased estimate of the effect of the association between independent
and dependent variables.30
CONCLUSIONS
Infants with low cord blood antibody concentrations against serotype
19F have a greater number of OM episodes during the first 12 months of life
than those with higher antibody concentrations when controlling for confounding
factors in multivariate analysis. These results suggest the potential benefit
of maternal immunization to delay the onset of OM and to also reduce the number
of subsequent episodes up to the age of 12 months. Since this strategy has
never been tested, it is impossible to estimate the effectiveness of maternal
vaccination alone or in combination with infant pneumococcal vaccination in
reducing OM in the first 6 months of life. Studies by Black et al31 and Eskola and Kilpi32
demonstrate that infant immunization with at least 3 doses of pneumococcal
conjugate vaccine reduced OM by 6% to 7%, and frequent OM by 20% after the
third dose of vaccine. However, no data are available on OM reduction prior
to the age of 6 months.31 Both maternal and
infant immunization against pneumococcal disease are attractive prevention
strategies for infants given the disturbing rise in antibiotic-resistant strains
of S pneumoniae over the past decade. Serotypes included
in the conjugate vaccine match resistant serotypes involved in pediatric invasive
pneumococcal infections.33 Ultimately, both
maternal and infant immunization strategies have the potential to reduce infant
OM in the first year of life, thus decreasing tympanostomy tube placement
and the monetary costs and morbidity associated with recurrent OM.
AUTHOR INFORMATION
Accepted for publication February 6, 2001.
This investigation was supported in part by grants R01-DC01242 (Dr Daly)
and P01-DC00133 (Dr Giebink) from the National Institute on Deafness and Other
Communication Disorders, National Institutes of Health, Bethesda, Md, the
Minnesota Medical Foundation, Minneapolis (Dr Daly), the Deafness Research
Foundation, New York, NY (Dr Daly), and the Lions Multiple District 5M Hearing
Foundation, Minneapolis (Dr Daly).
Presented in part at the 15th Annual Meeting of the American Society
of Pediatric Otolaryngology, Orlando, Fla, May 18, 2000.
From the University of Minnesota Medical School (Dr Becken), the Otitis
Media Research Center (Drs Becken, Daly, and Giebink), the Departments of
Otolaryngology (Drs Daly and Giebink) and Pediatrics (Dr Giebink), and the
Division of Biostatistics (Mr Lindgren), University of Minnesota School of
Public Health, and HealthPartners Inc (Dr Meland), Minneapolis.
Corresponding author and reprints: Kathleen A. Daly, PhD, Otitis
Media Research Center, MMC 396, University of Minnesota, 420 Delaware St SE,
Minneapolis, MN 55455 (e-mail: dalyx002{at}umn.edu).
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