Context Acute otitis media (AOM) frequently complicates influenza infection.
Previous studies have found influenza vaccine effective in reducing the occurrence
of AOM in children mainly older than 2 years.
Objective To evaluate the effectiveness of inactivated influenza vaccine in preventing
AOM in children aged 6 to 24 months.
Design, Setting, and Patients Randomized, double-blind, placebo-controlled trial of 786 children aged
6 to 24 months enrolled at Children's Hospital of Pittsburgh before the 1999-2000
(411 children) and 2000-2001 (375 children) respiratory seasons (defined as
December 1 through March 31 of the respective following year). Children received
influenza vaccine or placebo in a 2:1 ratio. The first cohort was observed
for 1 year and the second cohort until the end of the ensuing respiratory
Intervention Two doses (0.25 mL each) of inactivated trivalent subvirion influenza
vaccine or placebo were administered intramuscularly approximately 4 weeks
Main Outcome Measures Proportion of children who developed AOM, monthly occurrence rate of
AOM, estimated proportion of time with middle ear effusion, and utilization
of selected health care and related resources.
Results Of the 66 children in the vaccine group from whom serum samples were
collected, seroconversion against strains in the vaccine formulations developed
in 88.6% to 96.8%, depending on the specific strain. The efficacy of the vaccine
against culture-confirmed influenza was 66% (95% confidence interval [CI],
34%-82%) in 1999-2000 and −7% (95% CI, −247% to 67%) in 2000-2001;
however, influenza attack rates differed between these 2 periods (in the placebo
group, 15.9% and 3.3%, respectively). Compared with placebo, influenza vaccine
did not reduce the proportion of children who had at least 1 episode of AOM
during the respiratory season (in the first cohort: vaccine, 49.2% vs placebo,
52.2%; P = .56 ]; in the second cohort: vaccine,
55.8% vs placebo, 48.3%; P = .17). The vaccine also
did not reduce the monthly rate of AOM; the estimated proportion of time with
middle ear effusion; or the utilization of selected health care and related
resources. There were also no differences between the vaccine and placebo
groups regarding any of these outcomes during peak influenza periods. The
vaccines administered to both cohorts of children were well tolerated.
Conclusion Administration of inactivated trivalent influenza vaccine to children
aged 6 to 24 months did not reduce their burden of AOM or their utilization
of selected health care and related resources.
Viruses that cause respiratory tract infections are often present in
the middle ear exudate of children with acute otitis media (AOM).1 These viruses may play an important role in the pathogenesis
of AOM and may slow the response to antimicrobial therapy.2,3 Accordingly,
it seems reasonable to expect that the administration of vaccines effective
against viral infections might also serve to lessen morbidity from AOM.
Influenza vaccines (inactivated trivalent administered intramuscularly
or intranasally or live attenuated trivalent administered intranasally) have
been found effective in preventing AOM in 4 previous studies involving children
mainly older than 2 years; reductions of 30% to 44% in the occurrence of AOM
episodes were reported.4-7 However,
certain important limitations of those studies may preclude generalizability
of their results, particularly to children aged 6 to 24 months. These limitations
include small sample size, enrollment only of otitis-prone children or day-care
attendees, nonrandomized allocation of participants, single or incomplete
blinding, dependence on parental reporting of episodes rather than active
surveillance, and lack of standardized criteria for the diagnosis of AOM.
We undertook our study to determine whether inactivated trivalent influenza
vaccine administered intramuscularly is effective in reducing the occurrence
of AOM and other forms of otitis media in the children most vulnerable to
the disease, namely, those aged 6 to 24 months. The study was designed to
evaluate the effect of the vaccine during the influenza season, the broader
respiratory season, and the 1-year period following vaccination. Although
the vaccine does not protect against infections other than influenza, we hypothesized
that preventing episodes of AOM associated with influenza might, by preserving
normal middle ear status, reduce the occurrence of subsequent episodes of
AOM associated with other respiratory viral infections. Secondary objectives
of the study were to evaluate the vaccine's safety, immunogenicity, and efficacy
against culture-proven influenza in these young children, as well as the effects
of vaccination on the children's utilization of selected health care and related
The study was approved by the Children's Hospital of Pittsburgh Human
Rights Committee. We recruited healthy children aged 6 to 24 months from the
hospital's primary care center and from the community at large. Research personnel
informed parents in the primary care center about the study, and advertisements
were placed on the radio and in the regional newspaper. Written informed consent
was obtained from the parent(s) of each enrolled child. We excluded children
who had been born prematurely or had a craniofacial abnormality; or who had
or were living with persons who had any medical condition placing them at
high risk of complications of influenza8; or
who had a neurologic disorder, a history of tympanostomy tube insertion, hypersensitivity
to egg protein or thimerosal, or a febrile illness or severe respiratory illness
within the preceding 48 hours.
We enrolled 2 cohorts of children: during the periods October 4, 1999,
to November 30, 1999, and September 5, 2000, to December 8, 2000. We stratified
the children according to whether they were prone to otitis (ie, had a history
of at least 3 episodes of AOM in the preceding 6 months or 4 episodes in the
preceding 12 months) and whether they were attending day care (defined as
exposed to 3 or more nonfamily children for at least 10 hours per week). We
also stratified children in the second cohort according to whether they had
received at least 1 dose of the then newly available pneumococcal conjugate
vaccine. Within each stratum, we randomly assigned the children in blocks
of 9, using a computer-generated list, to either the vaccine group or the
placebo group in a 2:1 ratio. To each child we administered 2 doses, approximately
4 weeks apart, of either vaccine or placebo (0.25 mL each) intramuscularly.
Administration was performed by nonblinded research nurses who were not involved
in subsequent clinical follow-up of the children. Assignments to treatment
groups were not revealed to parents, investigators, research personnel conducting
clinical follow-up, or nonstudy health care providers, all of whom remained
blinded throughout the study. Randomization lists were kept in locked files
not accessible to blinded personnel.
Inactivated trivalent subvirion influenza vaccine (Fluzone) was supplied
by Aventis Pasteur (Swiftwater, Pa). Strains in the 1999-2000 formulation
were A/Beijing/262/95 (H1N1), A/Sydney/15/97 (H3N2), and B/Yamanashi/166/98;
and in the 2000–2001 formulation, A/New Caledonia/20/99 (H1N1), A/Panama/2007/99
(H3N2), and B/Yamanashi/166/98. The placebo, also supplied by Aventis Pasteur,
consisted only of a standard diluent.
Surveillance for Otitis Media
Surveillance for the occurrence of otitis media following administration
of the second dose of vaccine or placebo was maintained in the first cohort
of children through biweekly visits until the end of the ensuing respiratory
season, ie, March 31, 2000, and through monthly visits thereafter until November
15, 2000. Surveillance in the second cohort was maintained through biweekly
visits until March 31, 2001. Parents were instructed to contact study staff
if any sign or symptom of either an upper respiratory tract infection or AOM
developed so that an interim visit could be arranged. Acute care visits were
defined as those that resulted from the presence of fever (at least 38°C)
within 72 hours or the occurrence of otalgia or that substituted for an illness-related
visit to the children's primary care clinicians. All examinations were conducted
by study clinicians using pneumatic otoscopy, supplemented by tympanometry
and spectral gradient acoustic reflectometry. The diagnosis of middle ear
effusion was based on the presence of 2 of 4 elements: decreased or absent
tympanic membrane mobility, yellow or white discoloration of the tympanic
membrane, opacification of the tympanic membrane not due to scarring, and
visible bubbles or air-fluid levels. The diagnosis of AOM was based on the
presence of purulent otorrhea of recent onset not due to otitis externa or
of middle ear effusion accompanied by 1 or more of the following: ear pain,
marked redness of the tympanic membrane, and substantial bulging of the tympanic
membrane. We prescribed treatment for AOM according to published guidelines.9 Decisions regarding myringotomy and tympanostomy tube
insertion were not part of the study protocol and were made by the children's
primary care clinicians.
To diagnose influenza, we performed throat cultures during visits at
which patients had symptoms or signs of an upper respiratory tract infection
accompanied by fever (at least 38°C), AOM, or both. The culture swabs
were placed into viral transport media and immediately refrigerated. Within
4 hours, monkey kidney cell culture tubes were inoculated with processed throat
specimens. On weekends and after routine hours, throat swabs were stored in
viral transport media at 4°C until the next business day. Cultures were
maintained at between 33°C and 35°C, examined daily for cytopathic
effect, and tested for hemadsorption at 4, 7, and 14 days after inoculation
and anytime cytopathic effect was observed. Typing and subtyping of influenza
strains were performed using standard techniques.10 No
attempt was made to culture other viral pathogens.
At the beginning of the enrollment period each year, research personnel
asked consecutive parents for additional permission to obtain blood samples
from their children. Samples were collected from 53 children in the first
cohort and 40 children in the second cohort immediately before administering
the first dose of vaccine or placebo and again 4 weeks after the second dose.
Serum samples were tested by blinded personnel in a laboratory at East Virginia
Medical School, Norfolk, Va, for the presence of antibody to the 3 influenza
serotypes using a standardized hemagglutination-inhibition assay.11 Seroconversion was defined as a 4-fold increase in
antibody titers and/or a postimmunization antibody titer greater than 1:40.
Monitoring of unexpected adverse events was conducted at each visit
by review of the child's medical record and interview with the parent. The
occurrence of minor adverse reactions (eg, injection site reactions, low-grade
fever, crying) was not systematically recorded.
At each visit, parents were asked about any illnesses their child had
since the preceding visit, visits to primary care clinicians and emergency
departments, hospitalizations, use of antibiotics, and whether the study visit
substituted for a clinician visit. Parents were also asked about illnesses
in other family members, time lost from work, or a need for alternative child-care
arrangements because of the child's illness.
The study's primary outcome measure was the proportion of children who
had at least 1 episode of AOM during the ensuing respiratory season. To detect
a 33% reduction in the proportion of such children (eg, 30% of control children
vs 20% of immunized children), with 2-tailed α level of .05 and β
level of .20, we calculated that 466 evaluable children in the vaccine group
and 232 evaluable children in the placebo group were needed during the 2-year
study period. To determine the efficacy of the vaccine against influenza,
the analysis was conducted for cases that occurred at any time following administration
of the first dose and were based on person-months at risk; confidence intervals
(CIs) for vaccine efficacy were based on an assumption of asymptotic normality
of the log of the ratio of Poisson rates.12 Otitis
media–related outcomes were included in analyses if they occurred at
least 2 weeks following administration of the second dose.
We based results on an intention-to-treat analysis that included all
available data from all participants. The number of episodes of AOM for each
child was calculated by totaling episodes that presented acutely and episodes
defined as new because evidence of AOM persisted for more than 28 days, or
supervened in the course of otitis media with effusion, or recurred after
documented resolution of an episode. We estimated the proportion of days with
middle ear effusion based on the diagnosis at each visit and on interpolations
for intervals between visits, provided that the intervals did not exceed 60
days. If an interval between 2 visits exceeded 60 days, we assumed the status
at the first visit to have continued for 30 additional days and the status
at the second visit to have prevailed for 30 days preceding that visit. Middle
ear status for the remaining days in the interval was considered indeterminate.
We used a logistic regression model that included adjustment for the
stratification variables to compare by treatment groups the proportion of
children who had at least 1 episode of AOM. We assessed differences between
monthly rates of episodes of AOM and of febrile respiratory tract infections
using a Poisson regression model in which the stratification variables were
included as independent variables. We used a weighted regression model to
compare mean proportions of days with middle ear effusion, with weights equal
to the lengths of observed time, after first applying an arcsine transformation
to obtain a distribution that better approximated a normal distribution.
For health care resource utilization outcomes, we compared treatment
groups applying the method of generalized estimated equations.13 Analyses
were performed with SAS version 8.2 (SAS Institute Inc, Cary, NC).
The level of significance for all outcomes was .05.
The first cohort of the study included 411 children and the second cohort
included 375 children. Of these, 373 (91%) and 346 (92%) completed the study,
defined as having a final visit after August 2000 for the first cohort and
during March 2001 for the second cohort (Figure 1). Selected demographic and clinical characteristics of
the children are summarized in Table 1.
Approximately half were aged 6 to 12 months at enrollment. There were no significant
differences in characteristics between the vaccine and placebo groups in either
of the 2 cohorts.
Immunogenicity of Vaccine
Of the 66 children in the vaccine group from whom serum samples were
collected, seroconversion (defined as a hemagglutination-inhibition titer
of ≥1:40, a 4-fold or greater increase in antibody titer, or both) against
strains in the vaccine formulations developed in 88.6% to 96.8%, depending
on the strain (Table 2).
Influenza. Throat cultures for influenza virus
were obtained in 1113 (88%) of 1260 episodes of illness in which fever, AOM,
or both were present. During the first year of the study, influenza was epidemic
in the community. The influenza season was defined as the 6-week period (January
3 to February 15, 2000) during which 25 (67%) of the 37 culture-proven cases
of influenza occurred; the other 12 cases occurred during the remaining 25
weeks of surveillance. During the second year, influenza occurred infrequently
and there was no clustering of cases. The influenza season was defined as
the 13-week period (January 4 to March 30, 2001) during which 11 (85%) of
the 13 culture-proven cases occurred; the other 2 cases occurred during the
remaining 16 weeks of surveillance. In the first cohort, culture-proven influenza
was identified in 15 (5.5%) of 273 children in the vaccine group and 22 (15.9%)
of 138 children in the placebo group. In the second cohort, corresponding
values were 9 (3.6%) of 252 children in the vaccine group and 4 (3.3%) of
123 children in the placebo group. Accordingly, efficacy rates against influenza
were 66% (95% confidence interval [CI], 34%-82%) in the first cohort and −7%
(95% CI, −247% to 67%) in the second cohort. In the first cohort, efficacy
rates against influenza in children aged 6 to 12 months, 13 to 18 months,
and 19 to 24 months were 63%, 66%, and 69%, respectively. Of the 37 cases
that occurred in the first cohort, 14 were caused by A/Beijing, 18 by A/Sydney,
and 5 were not typed. Of the 13 cases that occurred in the second cohort,
5 were caused by A/New Caledonia, 5 by B/Yamanashi, 1 by A/Panama, and 2 were
not typed. Circulating influenza strains were well matched with vaccine strains
in the 2 respiratory seasons during which the study was conducted. All of
the 24 cases in the vaccine group and 24 of the 26 cases in the placebo group
occurred 2 weeks or longer after the second dose of vaccine or placebo.
Respiratory Tract Infections. In the first
cohort, no differences in rates of febrile respiratory tract infections were
noted between the influenza vaccine and placebo groups during the influenza
season (0.23 vs 0.25 episodes per person-month, respectively, P = .71) or during the respiratory season (0.21 vs 0.22 episodes per
person-month, respectively, P = .66). However, in
the second cohort, rates were actually higher in the vaccine group than in
the placebo group during the influenza season (0.23 vs 0.17 episodes per person-month,
respectively, P = .03) and during the respiratory
season (0.22 vs 0.17 episodes per person-month, respectively, P = .10).
Episodes of AOM. Table 3 shows that in the first cohort, there were no differences
overall between the vaccine group and the placebo group in the proportions
of children who had at least 1 episode of AOM during the ensuing influenza
season (30.5% vs 29.9%, P = .89), during the respiratory
season (49.2% vs 52.2%, P = .56), or during the entire
1-year follow-up period (57.3% vs 61.9%, P = .35).
The difference between the vaccine and placebo groups in the proportion
of children with AOM during the respiratory season was 3.0% (95% CI, −13.4%
to 7.4%). Within the subgroup of children in the first cohort aged 19 to 24
months, the proportions who had at least 1 episode of AOM during the ensuing
influenza and respiratory seasons were suggestively lower in the vaccine group
than in the placebo group (19.4% vs 34.3%, P = .10;
and 36.8% vs 54.3%, P = .09, respectively), and during
the 1-year follow-up period, significantly lower (44.1% vs 65.7%, P = .04). Nevertheless, tests for interaction between vaccine effectiveness
and age group produced nonsignificant results. In the second cohort there
were no significant differences between the vaccine and placebo groups in
the proportions who had at least 1 episode of AOM.
Table 4 shows data from
both cohorts concerning the distribution of observed episodes of AOM and the
mean monthly rates of occurrence of episodes of AOM during the influenza and
respiratory seasons, and from the first cohort, values for the entire follow-up
year. None of the differences between the vaccine and placebo groups was statistically
The proportions of children who had an episode of AOM within 1 week
of having a positive throat culture for influenza were similar between groups
with 13 (54.2%) of 24 in the vaccine and 12 (48.0%) of 25 in the placebo groups
(P = .88). Acute otitis media was diagnosed at 465
(36.8%) of 1262 acute care visits vs 468 (9.6%) of 4881 routine visits (P<.001). That fact notwithstanding, to test the possibility
that a vaccine-vs-placebo difference might have been obscured by the inclusion,
in the overall analysis, of more or less subclinical cases of AOM diagnosed
at other than acute care visits, we further considered the effectiveness of
the vaccine in an analysis limited to acute care visits during the influenza
and respiratory seasons of each year of the study. Again, there were no differences
between the vaccine group and the placebo group in the proportions of children
who experienced at least 1 episode of AOM during the 2 influenza seasons (35.6%
vs 37.1% and 42.9% vs 31.0%, respectively) or during the 2 respiratory seasons
(45.9% vs 41.8% and 44.8% vs 34.2%, respectively).
Table 5 shows that there
were no significant differences between the vaccine group and the placebo
group in the proportions of days with middle ear effusion during the influenza
and respiratory seasons.
Table 6 shows that in neither
cohort were there any statistically significant differences between the vaccine
group and the placebo group during ensuing respiratory seasons regarding utilization
of selected health care resources. During the second year of the study the
rate of hospitalization was actually higher in the vaccine group than in the
During the 2 years of the study, 39 children in the vaccine group and
12 children in the placebo group underwent insertion of tympanostomy tubes,
and 27 and 12 children, respectively, were hospitalized for other reasons.
Three adverse events occurred that were considered serious and possibly related
to receipt of influenza vaccine: 1 child had 2 brief episodes of unexplained
staring on the day of the first vaccination; 1 child had mild intercostal
retractions and wheezing 1 day after the second vaccination, and 1 child developed
acute gastroenteritis 3 days after the first vaccination.
In our study, influenza vaccination in a group of healthy children aged
6 to 24 months failed to affect the overall occurrence of AOM, although during
an epidemic season the vaccine might have provided a measure of protection
against AOM to children aged 19 to 24 months and provided some measure of
protection against influenza across the age spectrum studied. The results
in our study of whether influenza vaccination affects AOM are thus at variance
with the results of previous studies in which use of the vaccine reportedly
provided an approximate one-third reduction in AOM occurrence.4-6 The
discordant results may be attributable to some of the methodological differences
between studies, the most important of which may involve age. More than 75%
of the children we enrolled were aged 18 months or younger (mean age, 14 months)
compared with mean ages ranging from 20 to 43 months in 3 of the earlier studies.4-6 Two age-related factors
may have been operative. First, the proportion of viral respiratory infections
due to influenza virus may be lower in younger children than in older children,
so that in younger children the consequences of noninfluenza viral infections
may have obscured any effect of influenza vaccination. Evidence that most
episodes of respiratory tract infection in the children in our study were
caused by viruses other than influenza consists of the facts that during the
respiratory seasons, more than 90% of the children with febrile illnesses
whom we tested were culture-negative for influenza virus and that during the
second year of our study, the incidence of influenza never reached epidemic
proportions. Differences between our results and those of a recently reported
study that evaluated the efficacy of an intranasally administered, inactivated,
virosomal influenza vaccine7 may be attributable
to the generally younger age of our participants; the inclusion in that study
only of otitis-prone children who had had an episode of AOM within 2 to 8
weeks; and differences in the manufacture, contents, and route of administration
of the vaccines.
A second age-related factor could be that, although satisfactorily immunogenic
in young children, influenza vaccine may for other reasons be less effective
in preventing influenza—and accordingly, influenza-related otitis media—in
younger children than in older children. In a recent study by Hurwitz et al,14 children aged 24 to 60 months were randomized to
receive either inactivated influenza vaccine or placebo and were observed
during the ensuing winter for influenza infection, using serologic criteria
for the diagnosis. The investigators found no reductions in vaccinated children
in respiratory-related events, including ear infections, physician visits,
antibiotics prescribed, or missed day-care attendance by children or work
attendance by parents. Children with prevaccination titers of 1:5 or lower
were less likely to achieve a 4-fold increase in antibody titer after vaccination
than children with prevaccination titers of 1:10 or more. In addition, children
aged 36 months or older were more likely to respond to vaccination than were
younger children. Overall, efficacy of the inactivated vaccine against serologically
confirmed influenza was only 31% to 45%, and efficacy was greater in children
with prevaccination titers of 1:10 or higher than in those with titers of
1:5 or less. By comparison, in both cohorts in our study, the seroconversion
rate to each vaccine serotype was approximately 90%, and the vaccine was not
more likely to induce significant antibody responses in older than in younger
children. Nonetheless, among the few children in our study whom we tested,
those who had prevaccination hemagglutination-inhibition titers of 1:10 or
higher (36% in the first cohort and 8% in the second cohort) also had the
highest postvaccination titers. It seems possible that lack of previous exposure
to influenza viruses on the part of our study population contributed, in the
second year of the study, to the vaccine's inability to prevent influenza,
and in both years, to its inability to reduce the incidence of AOM. Finally,
it is possible, although not likely, that the vaccines formulated for the
1999-2000 and 2000-2001 seasons were not as effective overall in preventing
influenza as vaccines formulated in previous years.
Given that our study did not find a significant difference between vaccine
and placebo, it is important to consider the magnitude of difference we were
able to detect. The 95% CIs for detecting a difference between the vaccine
and placebo groups in the proportion of children with AOM during the respiratory
season were −13.4% to 7.4% for the first cohort, −3.5% to 18.5%
for the second cohort, and −5.7% to 9.5% for the combined cohorts. Accordingly,
our study cannot statistically eliminate the possibility of a decrease in
the proportion of children with AOM of 13.4% for the first, 3.3% for the second,
and 5.7% for the combined cohorts. An additional consideration is that only
15.9% of children in the placebo group in the first cohort and 3.6% in the
second cohort had influenza, and therefore, only a small reduction of AOM
could be expected in the vaccine group.
Our study had a number of limitations beyond the fact that, during its
second year, the incidence of influenza in the community never reached epidemic
proportions. First, we performed cultures for influenza using throat swabs,
a method chosen as less invasive than using nasopharyngeal swabs, which may
have resulted in underidentification of the virus. Second, because our surveillance,
although relatively intensive, relied to some extent on parents' initiating
visits for illness, episodes of either influenza or AOM might have been missed.
And third, our study was not powered to rule out the possibility of differences
in efficacy within specific age subgroups.
Recently, the Advisory Committee on Immunization Practices of the Centers
for Disease Control and Prevention and the American Academy of Pediatrics
issued statements encouraging the vaccination of children aged 6 to 23 months
against influenza,8 based on reports that hospitalization
rates in such children increase during periods of influenza activity.15-17 Our study was not
designed or powered to detect differences in hospitalization rates. Although
influenza vaccination did not reduce the occurrence of AOM in the children
we studied, the limited protection we found against the occurrence of influenza
itself may be viewed as lending support to immunize healthy infants and young
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