ARTICLE
Vaccine Effectiveness Against Medically Attended,
Laboratory-Confirmed Influenza Among Children
Aged 6 to 59 Months, 2003–2004
Carrie M. Shuler, DVM, MPHa,b, Martha Iwamoto, MD, MPHa, Carolyn Buxton Bridges, MDc, Mona Marin, MDa, Ruth Neeman, RN, BSNb, Paul Gargiullo, PhDc, Terrace A. Yoder, MDd, Harry L. Keyserling, MDe, Pauline D. Terebuh, MD, MPHb
aEpidemic Intelligence Service,cCenters for Disease Control and Prevention, Atlanta, Georgia;bNotifiable Diseases Section, Division of Public Health, Georgia Department
of Human Resources, Atlanta, Georgia;dChildren’s Medical Group, Atlanta, Georgia;eSchool of Medicine, Emory University, Atlanta, Georgia
The authors have indicated they have no financial relationships relevant to this article to disclose.
ABSTRACT
OBJECTIVES.Influenza is a leading cause of illness among children. Studies rarely have measured influenza vaccine effectiveness among young children, particularly when antigenic match between vaccine and circulating viruses is suboptimal. We assessed vaccine effectiveness against medically attended, laboratory-confirmed influenza for children who were aged 6 to 59 months during the 2003–2004 influenza season.
METHODS.In a case-control study that was conducted in a single pediatric practice, case patients who were aged 6 to 59 months and had laboratory-confirmed influenza were age matched 1:2 to eligible control subjects. Vaccination status was ascertained as of the date of the case patient’s symptom onset. Conditional logistic regression was used to calculate vaccine effectiveness, adjusting for underlying medical conditions and health care usage.
RESULTS.We identified 290 influenza case patients who were seen for medical care from November 1, 2003, to January 31, 2004. Vaccine effectiveness among fully vaccinated children, compared with unvaccinated children, was 49%. Partially vaccinated children who were aged 6 to 23 months had no significant reduction in
influenza (vaccine effectiveness: ⫺70%), but partially vaccinated children who
were aged 24 to 59 months had a significant (65%) reduction in influenza, compared with unvaccinated children.
CONCLUSIONS.Full vaccination provided measurable protection against laboratory-confirmed influenza among children who were aged 6 to 59 months during a season with suboptimal vaccine match. No vaccine effectiveness was identified with partial vaccination among children who were aged 6 to 23 months, affirming that children need to be fully vaccinated to obtain protective effects. These results strengthen the evidence of the vaccine’s ability to reduce substantially the burden of disease in this age group.
www.pediatrics.org/cgi/doi/10.1542/ peds.2006-1878
doi:10.1542/peds.2006-1878 This work was presented in part at the Infectious Diseases Society of America Conference; October 6 –9, 2005; San Francisco, CA.
The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
Key Words
influenza, children, vaccine effectiveness
Abbreviations
ACIP—Advisory Committee on Immunization Practices VE—vaccine effectiveness ILI—influenza-like illness RAD—reactive airway disease OR— odds ratio
aOR—adjusted odds ratio CI— confidence interval P&I—pneumonia and influenza
Accepted for publication Sep 26, 2006
Address correspondence to Carrie M. Shuler, DVM, MPH, Georgia Division of Public Health, 2 Peachtree St, Suite 14-232, Atlanta, GA 30303. E-mail: cmshuler@dhr.state.ga.us
I
NFLUENZA IS ONEof a limited number of viral respira-tory diseases that are preventable by vaccination. It is common among young children, resulting in an esti-mated annual average of 50 to 95 outpatient visits and 6 to 27 emergency department visits per 1000 children, 9 hospitalizations per 10 000 children, and an annualav-erage of ⬃92 deaths among US children aged ⬍5
years.1–4 Compared with older children, children who
are aged ⬍24 months have higher rates of acute otitis
media, pneumonia and other lower respiratory tract dis-ease, and hospitalization related to the influenza infec-tion.1,5–8
For maximization of the immune response and pro-tection against influenza, previously unvaccinated
chil-dren who are aged ⬍9 years and for whom vaccine is
recommended should receive 2 doses of influenza
vac-cine at least 1 month apart.9The short period between
vaccine availability and the start of the influenza season, however, can make receipt of 2 doses before influenza exposure difficult and requires extra health care pro-vider visits.10–12
Limited data have been published on the effectiveness of influenza vaccine among young children overall and
particularly on the effectiveness of 1 vs 2 doses.13–17Such
data are especially important during years of influenza vaccine shortage or when the influenza season occurs early, because children might not have received their second dose of vaccine before being exposed.
For the 2003–2004 influenza season, the Advisory Committee on Immunization Practices (ACIP) encour-aged vaccinating all children who are encour-aged 6 to 23
months and household contacts of children aged ⬍2
years and continued to strongly recommend the
vac-cination of children who are aged ⱖ6 months with
medical conditions that place them at increased risk for
influenza-related complications.18In 2004, ACIP
recom-mended annual vaccination for all children who are
aged 6 to 23 months.19
Nationally, during the 2003–2004 influenza season, influenza viruses began circulating unusually early and
influenza A (H3N2) viruses predominated.20In Georgia,
the first reported laboratory-confirmed patient had ill-ness onset in October, and overall influenza activity
peaked in late December.21Only 25% of the circulating
influenza viruses nationally and in Georgia were similar antigenically to the vaccine strain, and severe
complica-tions, including pediatric deaths, were reported.20,22
Be-cause clinical illness that is Be-caused by influenza virus is not distinguishable from other causes of respiratory ill-ness, laboratory confirmation of influenza is essential to increase the accuracy of vaccine effectiveness (VE) esti-mates. Use of nonspecific outcomes for influenza
diag-noses may lower VE estimates substantially.23We
eval-uated the effectiveness of the trivalent inactivated influenza vaccine against medically attended, laborato-ry-confirmed influenza among children who were aged
6 to 59 months in Georgia during a season with a sub-optimal antigenic match between the vaccine and circu-lating strains.
METHODS
Study Population and Location
Children who were examined for 1 or more outpatient visits (either well-child or sick visits) at a private metro-politan Atlanta pediatric practice during February 1, 2003, to January 31, 2004, and who were born during October 1, 1998, to April 1, 2003 (ie, aged 6 –59 months during the 2003–2004 influenza season), were eligible for the study. We identified 7139 children who met the inclusion criteria (study children). The study practice has
16 health care providers and serves⬃400 patients a day.
The physicians offered influenza vaccine to patients con-sistent with the 2003–2004 ACIP guidelines (children
aged ⱖ6 months at high-risk, all children aged 6 –23
months, and household contacts of children aged ⬍2
years) and routinely performed in-house rapid influenza antigen testing on children with influenza-like illness (ILI). This assessment of influenza VE was initiated as a public health response; therefore, the Centers for Dis-ease Control and Prevention and the Georgia Division of Public Health determined these activities as nonresearch and did not require review by an institutional review board. However, personal identifiers were removed and confidentiality was preserved in data collection and analysis.
Laboratory-Confirmed Influenza Outcome
The practice providers used the QuickVue Influenza test (Quidel Corp, San Diego, CA) to screen nasopharyngeal swab samples for influenza antigen. This rapid antigen
test has a sensitivity of⬃73% and specificity of⬃96%.24
Because of a test kit shortage in the community, addi-tional kits were provided to the practice on January 5, 2004, to allow for influenza testing at the practice with-out interruption. To determine the feasibility of conduct-ing the retrospective observational study at the pediatric practice, a survey of the providers was conducted to evaluate potential diagnostic testing biases. The provid-ers were asked how their patients’ vaccination status, age, underlying medical conditions, clinical symptoms, and insurance reimbursement affected their decision to test for influenza (more likely to test, less likely to test, or would not affect decision to test).
Case Patient Identification
the patient’s case status. Information was collected on illness symptoms, treatment with influenza antiviral medication, influenza complications, influenza vaccina-tion, gender, chronic medical conditions, and child care or school participation.
Control Subject Selection
Two age-matched study children were randomly se-lected as control subjects for each case patient. The eli-gible control subjects for each case patient included study children who were born during the same month and year and had not become a case before the influenza illness onset date of the case patient. We excluded from the study non-Georgia residents and children with no vaccination history indicated in the medical chart. Case patients were eligible to serve as control subjects until the date of chart-documented, laboratory-confirmed
in-fluenza.25,26Although limited in-and-out migration from
the study population probably occurred, any child with a visit to the practice during the previous year was con-sidered at risk during the influenza season and became unavailable for control section only on the date of
be-coming a case patient and thereafter.27We did not
ex-clude children who were examined at the practice with ILI, who were not tested for influenza. Selecting a child as a control subject more than once for case patients with different symptom onset dates did not necessarily lead to repeat exposure information, because vaccina-tion status varied with time. The vaccinavaccina-tion status of each set of case patients and control subjects was com-pared on the date of illness onset of the case patient.
Vaccination Status
By using the date of symptom onset as the anchor date, vaccination status and other covariates for case patients and their age-matched control subjects were categorized. We considered children who had received 2 doses of
influenza vaccine at least 1 month apart and ⱖ14 days
before the anchor date as fully vaccinated. Children who were vaccinated during a previous season needed only 1
dose of vaccine during the 2003–2004 seasonⱖ14 days
before the anchor date to be fully vaccinated. We cate-gorized children with the following 2 situations as par-tially vaccinated: (1) children who were not vaccinated in a previous season and had received 2 doses of influ-enza vaccine since September 2003 with an anchor date
⬍14 days after the second dose and (2) children who
were not vaccinated in a previous season and received
only 1 dose of vaccine since September 2003ⱖ14 days
before the anchor date. We considered children who had received no doses of influenza vaccine during the 2003– 2004 season on or before the anchor date and children
who had received 1 dose since September 2003 ⬍14
days before the anchor date as unvaccinated, even if they had received vaccine during a previous season.
Presence of Underlying Medical Conditions
ACIP recommendations for multiple years have targeted children with certain medical conditions to be at in-creased risk for complications related to influenza virus
infection.5,9We sought documentation of high-risk
con-ditions in the medical chart and included concon-ditions that were designated by the ACIP during the 2003– 2004 season: reactive airway disease (RAD) or asthma (listed explicitly on at least 2 occasions), chronic lung disease, chronic metabolic disease, cardiovascular dis-ease, renal disdis-ease, hemoglobinopathy, cancer, other im-munosuppressive conditions, long-term aspirin therapy,
or residence in a long-term care facility.18
Child Care or School Status
We ascertained child care or school participation to ad-just for the possible increase in influenza virus exposure; priming from previous influenza infections has been reported to be associated with higher immune response
after vaccination.12,16,28–30 The practice physicians
col-lected on a standardized form information on child care or school attendance during health care visits. When no notation had been made in the medical chart during our study period or the section on the medical chart had been left blank, we recorded the child’s out-of-home care status as unknown.
Health Care Usage
We used the number of office visits billed for each child during the year before the beginning of the 2003–2004 influenza season (November 1, 2002, to November 1, 2003) as an indicator of health care usage. When the number of visits was more than the median value for the child’s corresponding age category, the child was classi-fied as a high health care user.
Statistical Analysis
We modeled the association between influenza vaccina-tion and medically attended, laboratory-confirmed in-fluenza with conditional logistic regression. A matched analysis was used to estimate an odds ratio (OR) for disease in which each matched set (1 case patient and 2 control subjects) was treated as a unique stratum. We included high-risk status and health care usage in the
final models.31We analyzed vaccination status as a
cat-egorical exposure measure with unvaccinated as refer-ent. Fully vaccinated children were compared with un-vaccinated children. Partially un-vaccinated children were compared with unvaccinated children who might have become partially vaccinated during the 2003–2004 in-fluenza season (ie, children who were categorized as unvaccinated and were not vaccinated during a previous season). We also calculated separate VE estimates for children who were aged 6 to 23 months and 24 to 59 months. The adjusted OR (aOR) was used to estimate VE
RESULTS
Provider Testing Practices
Of the 16 providers, 8 completed the survey. One pro-vider reported that patients’ vaccination status affected the decision to test for influenza (more likely to test unvaccinated patients and less likely to test vaccinated patients). The other respondents reported that patients’ vaccination status did not affect their decision to test. Many of the 8 practitioner-respondents identified other clinical factors that would make them more likely to test
a patient for influenza: patient high-risk condition (n⫽
7), household contact at increased risk for an
influenza-related complication (n ⫽ 8), fever ⬎104°F (n ⫽ 6),
illness duration ⬍2 days (n ⫽4), and decision to
pre-scribe antiviral medications (n⫽8). A fever⬍101°F was
identified by 5 respondents as a patient factor that would make them less likely to test.
Description of Case Patients
A total of 293 children who were aged 6 to 59 months and had laboratory-confirmed influenza during Novem-ber 1 to January 31, 2004, were identified from the practice’s records. Three children did not have complete vaccination records and were excluded from the analysis
(N⫽290; Fig 1). The majority of case patients who were
identified early in the season were unvaccinated. The epidemiologic curve of case patients who were identified in the practice was similar to the curve that was identi-fied through Georgia’s influenza surveillance.
The case patients’ clinical course and treatment are described in Table 1 by age category (6 –23 months and 24 –59 months). Fever, cough, and rhinorrhea were listed as symptoms for 97%, 89%, and 83% of all case patients, respectively. The physicians prescribed oselta-mivir for 133 (46%) of the influenza case patients, and 1 patient was prescribed amantadine. Influenza-related
complications were identified within 3 weeks of their influenza illness onset among 32% of children who were aged 6 to 23 months and 22% of children who were aged 24 to 59 months (Table 1). Only 2 chil-dren were hospitalized as a result of their influenza infection: a child who was aged 16 months and had a history of RAD/asthma and a child who was aged 9 months and was not at high risk. Both children were fully vaccinated for influenza at the time of illness onset. A comparison of influenza case patient symptoms before and after the receipt of supplemental test kits to the practice found that children who were aged 6 to 23 months and tested positive for influenza were less likely to present with a cough, and children who were aged 24
FIGURE 1
Laboratory-confirmed influenza cases (n⫽290) accord-ing to date of influenza onset and vaccination status in the Georgia pediatric practice, 2003–2004.
TABLE 1 Symptoms, Treatment, and Complications of Influenza Case Patients (Nⴝ290) According to Age Category
Parameter Aged 6–23 mo (n⫽111)
Aged 24–59 mo (n⫽179)
Symptoms,n(%)
Fevera 107 (96.4) 175 (97.8)
Cough 93 (83.8)b 165 (92.2)b
Rhinorrhea 98 (88.3)b 142 (79.3)b
Decreased appetite 59 (53.1) 102 (56.9)
Vomiting 24 (21.6) 47 (26.3)
Diarrhea 17 (15.3) 18 (10.1)
Treatment,n(%)
Oseltamivir 51 (46.4) 82 (45.6)
Amantadine 0 (0.0) 1 (0.6)
Complications,n(%)
Otitis media 21 (19.1) 26 (14.4)
RAD/asthma exacerbation 9 (8.2) 10 (5.6)
Pneumonia 2 (1.8) 5 (2.7)
Sinusitis 2 (1.8) 3 (1.7)
Hospitalization 2 (1.8) 0 (0.0)
to 59 months were less likely to present with vomiting after the test kits were provided compared with be-fore. Otherwise, there was no difference in the pre-senting symptoms of influenza-positive patients be-fore and after the test kits were provided to the practice.
Characteristics of Case Patients and Age-Matched Control Subjects
Table 2 describes the vaccination status, gender, medical conditions, child care participation, and health care us-age of the case patients and their us-age-matched control subjects. A higher proportion of children who were aged 6 to 23 months (42.7% of the case patients and 56.8% of control subjects) compared with older children were considered fully vaccinated at the time of their respective anchor dates. Among children who were aged 24 to 59 months, 22.3% of case patients and 30.5% of control subjects were fully vaccinated. Gender was evenly dis-tributed between the age categories and between the case patients and control subjects.
RAD/asthma was the most prevalent underlying medical condition, with 19.8% of case patients and 14.9% of control patients who were aged 6 to 23 months having documentation in the medical chart during the study period; among children who were aged 24 to 59 months, 18.4% of case patients and 17.9% of control subjects had RAD or asthma. A total of 52.5% of case patients and 39.2% of control subjects who were aged 6 to 23 months participated in child care or school, com-pared with 77.7% of case patients and 74.9% of control subjects who were aged 24 to 59 months. Younger dren had higher health care usage rates than older chil-dren, with a median of 11 office visits for case patients and 9 visits for control subjects during the year before the 2003–2004 influenza season. The overall 6- to 23-month age category median number of office visits was 10. Case patients who were aged 24 to 59 months had a median of 5 office visits, and control subjects had a median of 4 visits, with an overall age category median number of 4 office visits.
TABLE 2 Characteristics of Influenza Case Patients and Age-Matched Control Subjects According to Age Category (Nⴝ870)
Characteristics,n(%) Aged 6–23 mo Aged 24–59 mo
Case Patients (n⫽111)
Control Subjects (n⫽222)
Case Patients (n⫽179)
Control Subjects (n⫽358)
Vaccination status
Fully vaccinated 47 (42.7) 126 (56.8) 40 (22.3) 109 (30.4)
2 doses 25 (22.5) 66 (29.7) 9 (5.0) 18 (5.0)
1 dose and vaccinated in previous season 22 (19.8) 60 (27.0) 31 (17.3) 91 (25.4)
Partially vaccinated 25 (22.5) 27 (12.2) 11 (6.1) 40 (11.2)
2 dosesa,b 4 (3.6) 5 (2.3) 0 (0.0) 8 (2.3)
1 dosea,c 21 (18.9) 22 (9.9) 11 (6.1) 32 (9.0)
Unvaccinated 39 (35.1) 69 (31.0) 128 (71.5) 209 (58.3)
Vaccinated in previous season 9 (8.1) 14 (6.3) 22 (12.3) 61 (17.0)
Not vaccinated in previous season 30 (27.1) 55 (24.8) 106 (59.2) 148 (41.3)
Vaccinated in previous season 31 (27.9) 78 (35.1) 53 (29.6) 152 (42.5)
Male gender 55 (49.5) 119 (53.9 92 (51.4) 188 (52.5)
High-risk conditionsd
Cancer 0 (0) 0 (0) 0 (0) 1 (0.3)
Cardiovascular disease 1 (0.9) 5 (2.3) 0 (0) 4 (1.1)
RAD/asthma 22 (19.8) 33 (14.9) 33 (18.4) 64 (17.9)
Renal disease 1 (0.9) 1 (0.5) 1 (0.6) 1 (0.5)
Chronic lung disease 0 (0) 1 (0.5) 0 (0) 0 (0)
Immunosuppression 0 (0) 1 (0.5) 0 (0) 0 (0)
Metabolic disease 0 (0) 1 (0.5) 0 (0) 1 (0.3)
Other 0 (0) 2 (0.9) 0 (0) 8 (2.2)
Any 24 (21.6) 44 (19.8) 34 (19.0) 79 (22.1)
Child care/school
Yes 58 (52.5) 87 (39.2) 139 (77.7) 268 (74.9)
No 53 (47.8) 134 (60.4) 33 (18.4) 80 (22.3)
Unknown 0 (0) 1 (0.4) 7 (3.9) 10 (2.8)
No. of office visits
Median visits 11 9 5 4
High health care usagee 71 (64.0) 110 (49.6) 111 (62.0) 221 (61.7)
aNot vaccinated in a previous season. bSecond dose⬍14 days before symptom onset. cFirst doseⱖ14 days before symptom onset.
dCase patients and control subjects might have had⬎1 medical condition.
VE Estimates
Vaccination status, health care usage, and child care participation were associated significantly with influenza in the univariate model. However, in the multivariate model, only vaccination status and health care usage were associated independently with laboratory-con-firmed influenza. VE estimates were adjusted for health care usage, an important confounder, and high-risk sta-tus for comparability with previously reported VE esti-mates (Table 3). In the multivariate model, child care status did not affect the relationship between vac-cination and having influenza and was not included in the final model. For children who were aged 6 to 59 months, fully vaccinated children had a significant re-duction in influenza when compared with unvaccinated children, with a VE estimate of 49% (95% confidence interval [CI]: 30%– 60%). Partially vaccinated children who were aged 6 to 59 months did not have a significant reduction in influenza (aOR: 0.76; 95% CI: 0.5–1.2).
Fully vaccinated children who were aged 6 to 23 months had a significant (52%) reduction in influenza, compared with unvaccinated children (95% CI: 20%– 70%). Children who were aged 6 to 23 months and were partially vaccinated did not have a significant reduction in influenza, compared with unvaccinated children who were not vaccinated in a previous season (aOR: 1.70; 95% CI: 0.9 –3.8). A significant (45%) reduction in in-fluenza for children who were aged 24 to 59 months was identified when fully vaccinated children were com-pared with unvaccinated children (95% CI: 10%–70%). Partially vaccinated children who were aged 24 to 59 months had a significant (65%) reduction in influenza when compared with unvaccinated children who had not been vaccinated during a previous season (95% CI: 30%– 80%).
DISCUSSION
Fully vaccinated children who were aged 6 to 59 months and partially vaccinated children who were aged 24 to 59 months had significant reductions in medically at-tended, laboratory-confirmed influenza, compared with respective unvaccinated children, even during a year with a suboptimal match between the vaccine and
cir-culating strains. However, we identified no VE with par-tial vaccination among children who were aged 6 to 23 months. These results support recommendations for an-nual influenza vaccination of children and highlight the importance of achieving full vaccination before the start of the influenza season.
Comparison With Other Studies
Our results are consistent with other studies that have evaluated either the efficacy or the effectiveness of the influenza vaccine among children through randomized, controlled trials (efficacy) and observational studies
(ef-fectiveness).12–15,17 VE estimates can vary widely,
de-pending on the study population (age, immune health, previous exposure to influenza, and access to vaccine), specificity of the outcome (laboratory-confirmed influ-enza through serology, culture, or rapid antigen tests or such symptoms as ILI), and the influenza season (how the vaccine strains relate to the circulating strains and relative contribution of influenza to the burden of ILI).
In a study by Ritzwoller et al13during the 2003–2004
influenza season, VE against ILI (not laboratory con-firmed) for fully vaccinated children who were aged 6 months to 8 years was 23% and 51% for pneumonia and influenza (P&I). For fully vaccinated children who were aged 6 to 23 months, VE was 25% against ILI and
49% against P&I.13VE against P&I yielded a similar VE
to the laboratory-confirmed influenza outcome in our study. Unlike the study by Ritzwoller et al, our study identified a protective effect for partial vaccination among children who were aged 24 to 59 months. This difference might be caused by our population’s having had more previous exposures to influenza, or the more specific outcome of laboratory-confirmed influenza al-lowed for the detection of this benefit. Similar to Ritz-woller et al, our study provides reassurance that vacci-nation of young children provides benefit, even in a year with a suboptimal match.
A limited number of studies have been published on the effectiveness or efficacy of the influenza vaccine
among children aged who are ⬍5 years.13–15,17,28,32 In a
Cochrane review of studies that were conducted among healthy children, published in early 2005, only 1 study
TABLE 3 Multivariate Conditional Logistic Regression Analysis of Laboratory-Confirmed Influenza by Vaccination Status, Adjusting for High-Risk Status and Health Care Usage According to Age Category (Nⴝ870)
Parameter Aged 6–59 mo Aged 6–23 mo Aged 24–59 mo
aOR (95% CI) VE, % aOR (95% CI) VE, % aOR (95% CI) VE, %
Vaccination status
Fully vaccinated versus unvaccinated 0.51 (0.4–0.7)a 49 0.48 (0.3–0.8)a 52 0.55 (0.3–0.9)b 45
Partially vaccinated versus unvaccinatedc 0.76 (0.5–1.2) 1.7 (0.9–3.8) 0.35 (0.2–0.7)b 65
High health care usaged 1.6 (1.1–2.1)a 2.5 (1.4–4.2)a 1.2 (0.8–1.8)
High-risk conditions 0.9 (0.7–1.3) 1.0 (0.6–1.8) 0.9 (0.6–1.3)
aP⬍.01;bP⬍.05; otherwise not significant.
cUnvaccinated children not vaccinated during a previous season.
of children who were agedⱕ2 years by Hoberman et al14 was included. In that 2-year randomized, placebo-con-trolled study, vaccine efficacy against culture-confirmed influenza was 66% during a year when the attack rate
was 16% among unvaccinated children and⫺7% during
a second year, when only 3% of children had influenza. A limited number of children during the second-year study cohort were influenza culture positive, substantially re-ducing the ability to detect a difference between the vac-cine groups. The decreased sensitivity and specificity of the rapid antigen test that was used in our study com-pared with culture and the less optimal antigenic match between the vaccine and circulating strains might ex-plain the lower VE that was identified during our study.
Our study was unique in that the study population was highly vaccinated: 77% of study participants who
were aged 6 to 23 months had ⱖ1 dose of influenza
vaccine by the end of the season. In Georgia overall, only 19.5% (95% CI: 12.9 –28.4) of children who were aged 6 to 23 months during the 2003–2004 influenza season
had hadⱖ1 dose of influenza vaccine.33Providers at the
pediatric practice routinely tested patients with suspect illness for influenza. For young children who might experience numerous medically attended respiratory ill-nesses during the first years of life, our main outcome measure of medically attended, laboratory-confirmed influenza rather than ILI is a substantial advantage in providing an influenza-specific VE estimate. In addition, chart and billing record review of all case patients and control subjects permitted precise ascertainment of in-fluenza vaccination dates, underlying medical conditions, health care usage, and child care or school attendance. These factors can influence a patient’s vaccination status (opportunity or health indication for vaccination) and also are related to diagnosis of laboratory-confirmed influenza. Adjusting for these variables allowed us to control for their potentially confounding effect in our assessment of influenza VE.31,34
Partially Vaccinated Children
We found a significant reduction in laboratory-con-firmed influenza among partially vaccinated children who were aged 24 to 59 months. The VE estimate for partially vaccinated children who were aged 24 to 59 months was higher than that for fully vaccinated chil-dren, but the sample sizes were small and the CIs for the 2 estimates overlapped. Older children are less likely to be immunologically naı¨ve and therefore can produce a protective response with a single dose of influenza
vac-cine.28 However, given the yearly variability in the
cir-culation of influenza viruses from community to com-munity, many children who are aged 24 months to 8 years are likely not to have been exposed to circulating
influenza viruses.28,35 Therefore, previously
unvacci-nated children who are aged⬍9 years should continue
to be provided 2 doses to offer maximum protection from circulating types and subtypes of influenza.
Limitations
Observational VE studies similar to our study have intrin-sic limitations.23Bias in selection of patients for vaccination or in the diagnosis of influenza cannot be excluded be-cause of variability in patient health care–seeking behav-iors. Providers were aware of the vaccination status of the children when deciding which patients to test for influ-enza. Preferentially vaccinating patients with an increased risk for exposure to influenza (eg, children who were en-rolled in child care) might decrease the VE estimate, whereas preferentially testing unvaccinated patients might increase the VE estimate. We attempted to minimize these potentially confounding effects by evaluating the contribu-tion of high-risk status and child care participacontribu-tion, by controlling for health care usage, and by choosing a pedi-atric practice study site that strongly supported the ACIP vaccination recommendations and routinely tested pa-tients who had ILI for influenza. The provider survey in-dicated that most of the practitioners were not influenced by vaccination status when deciding to test for influenza; however, a standardized protocol for influenza testing did not exist, and testing was at the discretion of individual providers.
Although using influenza rapid testing for laboratory confirmation of medically attended influenza enhanced the precision of the influenza outcome measure, mis-classification of case patients and control subjects still was possible. Patients with mild or atypical influenza symptoms might not have been tested for influenza, although we have no reason to believe that symptoms differed among vaccinated compared with unvaccinated children with influenza. Virus shedding is greatest dur-ing the first days of influenza infection; therefore, pa-tients who were tested during the early phase of the illness were more likely to test positive. Because the
influenza rapid test is⬃73% sensitive, certain medically
CONCLUSIONS
Influenza vaccination provided protection against med-ically attended, laboratory-confirmed influenza among children who were aged 6 to 23 months and 24 to 59 months during a season with a suboptimal match be-tween vaccine and circulating strains. The benefit of the vaccine was measurable among children who were fully vaccinated in comparison with those who were unvac-cinated and resulted in an estimated decreased risk for medically attended influenza of 52% and 45%, respec-tively. Older children, those who were aged 24 to 59
months, benefited from partial vaccination (ⱖ14 days
since receipt of 1 of 2 recommended doses), but we determined no VE with partial vaccination among younger children. These results support
recommenda-tions for influenza vaccination of children and
strengthen the evidence of the vaccine’s ability to reduce substantially the burden of disease among this age group.
ACKNOWLEDGMENTS
We thank Jim Alexander, Sharon Bloom, and Jane Seward for guidance with study design and data inter-pretation; Connie Knight for administrative support; and Erin Murray and Mona Heaven for assistance with sta-tistical and data management.
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DOI: 10.1542/peds.2006-1878
2007;119;e587
Pediatrics
Terebuh
Neeman, Paul Gargiullo, Terrace A. Yoder, Harry L. Keyserling and Pauline D.
Carrie M. Shuler, Martha Iwamoto, Carolyn Buxton Bridges, Mona Marin, Ruth
2004
−
Influenza Among Children Aged 6 to 59 Months, 2003
Vaccine Effectiveness Against Medically Attended, Laboratory-Confirmed
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DOI: 10.1542/peds.2006-1878
2007;119;e587
Pediatrics
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Neeman, Paul Gargiullo, Terrace A. Yoder, Harry L. Keyserling and Pauline D.
Carrie M. Shuler, Martha Iwamoto, Carolyn Buxton Bridges, Mona Marin, Ruth
2004
−
Influenza Among Children Aged 6 to 59 Months, 2003
Vaccine Effectiveness Against Medically Attended, Laboratory-Confirmed
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