Family Characteristics Associated with Likelihood of Varicella Vaccination.

CONTEXT: The introduction of the varicella vaccine as a routine pediatric immunization in the US, in 1995, provided an opportunity to assess factors associated with uptake of new vaccines in the member population of the Kaiser Permanente Northwest (KPNW) Health Plan. OBJECTIVE: Identify factors associated with varicella vaccination in the KPNW population in the first five years after varicella vaccine was introduced. DESIGN: A retrospective cohort of children under age 13 years between June 1995 and December 1999, without a history of varicella disease was identified using KPNW automated data. Membership records were linked to vaccine databases. Cox regression was used to estimate likelihood of varicella vaccination during the study period in relation to age, sex, primary clinician's specialty, and Medicaid eligibility. For a subset whose parents answered a behavioral health survey, additional demographic and behavioral characteristics were evaluated. MAIN OUTCOME MEASURE: Varicella vaccination. RESULTS: We identified 88,646 children under age 13 years without a history of varicella; 22% were vaccinated during the study period. Varicella vaccination was more likely among children who were born after 1995, were not Medicaid recipients, or had pediatricians as primary clinicians. In the survey-linked cohort, positively associated family characteristics included smaller family size; higher socioeconomic status; and parents who were older, were college graduates, reported excellent health, and received influenza vaccination. CONCLUSION: Understanding predictors of early varicella vaccine-era vaccine acceptance may help in planning for introduction of new vaccines to routine schedules.

A Ten-Year Case-Control Study of Passive Smoke Exposure as a Risk Factor for Pertussis in Children.

The authors conducted a matched case-control study of laboratory-confirmed pertussis cases, occurring from 1/1/1996 to 12/31/2005, in children up to 12 years of age who were members of a large managed care organization. Sixty-five laboratoryconfirmed cases of pertussis were identified. Using multivariable conditional logistic regression analysis, the authors did not detect a statistically significant association between pertussis and household passive exposure to cigarette smoking.

Passive cigarette smoke exposure and other risk factors for invasive pneumococcal disease in children: a case-control study.

OBJECTIVE: To investigate whether passive cigarette smoke exposure increases the risk of invasive pneumococcal disease in children. METHODS: In a population-based case-control study, 171 children aged 0 to 12 years with culture-confirmed invasive pneumococcal disease during the years 1994 to 2004 were identified. Two controls were matched to each case on age and patterns of Health Plan membership. We reviewed medical records of subjects and family members for information on household cigarette smoke exposure within 2 years of the diagnosis of invasive pneumococcal disease. We collected information on sex, race, pneumococcal vaccination, selected medical conditions, and medications in the 3 months before the diagnosis. RESULTS: Similar proportions of cases (25%) and controls (30%) had definite or probable passive smoke exposure (odds ratio [OR] = 0.76, 95% confidence interval [CI] = 0.47-1.2). Cases of invasive pneumococcal disease were more likely to be nonwhite than controls (OR = 4.4, 95% CI = 2.3-8.2). Elevated risk of invasive pneumococcal disease was found in subjects with recent pulmonary diagnoses (OR = 2.2, 95% CI = 1.2-4.0) and recent antibiotic use (OR = 1.6, 95% CI = 1.1-2.3). CONCLUSIONS: Passive cigarette smoke exposure was not associated with invasive pneumococcal disease in this pediatric population. Invasive pneumococcal disease was associated with recent pulmonary diagnoses and recent antibiotic use.

Wheezing lower respiratory disease and vaccination of premature infants.

PURPOSE: Premature infants are at increased risk of wheezing in association with respiratory syncytial virus (RSV) and rhinovirus infections. We assess possible associations between wheezing and routine vaccinations of premature infants. METHODS: We conducted a self-controlled case series (SCCS) study of premature infants born at five health maintenance organizations (HMO's) from 1997 to 2002 (N=18,628). Episodes of medically attended wheezing lower respiratory diseases (WLRD) were ascertained from ICD-9 coded database records. Relative risks of WLRD during post-vaccination exposure windows were estimated by Cox proportional hazard regression with time-dependent vaccine exposure variables, adjusted for age, season, and frequency of well-baby visits. RESULTS: WLRD hazard ratios (HR) were not significantly elevated for any vaccine type among non-fragile or fragile premature infants. Among non-fragile infants the 8-14 days HR was significantly reduced for live attenuated MMR (0.68, 0.52-0.88) and Varicella (0.71, 0.53-0.94) vaccines, and similarly but insignificantly reduced for infrequently used live attenuated OPV vaccine (0.70, 0.46-1.06). There was a smaller significant reduction (0.83, 0.69-0.998) in the 15-30 days HR for MMR and a similar but not significant reduction (0.86, 0.71-1.05) in the 31-44 days HR for MMR. Hepatitis B vaccine (HBV), which is not a live vaccine, had significantly reduced 8-14 days (0.84, 0.72-0.98) and 31-44 days (0.88, 0.78-0.98) HRs among non-fragile infants. The apparent protective effect of HBV may be confounded by live vaccines administered simultaneously with the third dose of HBV. Among fragile infants there was a large significant reduction in the 8-14 days HR for live attenuated OPV vaccine (0.40, 0.23-0.70) and smaller significant reductions in the 8-14 days HR for inactivated DTaP (0.82, 0.71-0.95), Hib (0.83, 0.73-0.96), and PCV7 (0.84, 0.70-0.997) vaccines. Delays in vaccinating fragile infants may have made simultaneous administration of live vaccines and third doses of these inactivated vaccines more likely. CONCLUSIONS: We found no evidence of increased WLRD risk following routine vaccinations of premature infants. WLRD risk among non-fragile premature infants appears to be reduced for a few weeks after live attenuated vaccinations.

Laboratory characteristics of suspected herpes zoster in vaccinated children.

Varicella vaccination of children has decreased varicella disease incidence, but introduced the occurrence of herpes zoster (HZ) from vaccine-type virus. We identified 14 vaccinated children with suspected HZ and confirmed varicella virus by polymerase chain reaction in 6 cases. Two cases were due to vaccine-type virus. Serum varicella IgM and IgG were not useful for diagnosis of HZ among vaccinated children.

Frequency of medically attended events following rapid revaccination with trivalent inactivated influenza vaccine.

In 2008, potential temperature compromise of one lot of trivalent inactivated influenza vaccine (TIV) led to the revaccination of 13,210 Kaiser Permanente Northwest members within 28 days of receipt of their initial TIV dose. We conducted a retrospective cohort study to determine if these individuals experienced a higher rate of medically attended events (MAE) than those receiving only one TIV dose. We found no increase in MAE among those rapidly revaccinated (odds ratio 1.08; 95% confidence interval 0.80, 1.45), which may reassure individuals of the safety of revaccination with TIV should it be necessary, thereby leading to increased compliance with influenza vaccination recommendations.

Henoch-Schölein purpura and polysaccharide meningococcal vaccine.

BACKGROUND: We describe here a case of Henoch-Schönlein purpura (HSP) that occurred 10 days after administration of the meningococcal polysaccharide vaccine and came to the attention of a Vaccine Safety Datalink (VSD) investigator (but did not occur in the VSD cohort). Periodic case reports have linked vaccines to HSP. OBJECTIVE: To better understand the potential risk for HSP after immunization with the meningococcal polysaccharide vaccine. PATIENTS AND METHODS: We studied the VSD cohort to estimate the 42-day postvaccination incidence rate of HSP in the VSD population 16 to 20 years of age. Electronic data from all 8 VSD sites were gathered. All subjects aged 16 to 20 years who received a meningococcal polysaccharide vaccine were followed for 42 days after that vaccination for evidence of HSP. Background rates were determined by examining all the nonexposed time of the same cohort. RESULTS: No cases of HSP were seen in the 42 days after 49,027 doses of meningococcal polysaccharide vaccine among the entire VSD adolescent and young adult population. The background incidence rate was 4.2 per 100,000 person-years. CONCLUSION: These data provide the strongest evidence so far that HSP is not associated with receipt of meningococcal polysaccharide vaccine in the 16- to 20-year age group.

Multiple vaccinations and the risk of medically attended fever.

Recent increases in the number of vaccinations recommended for infants have triggered concerns about the safety of multiple vaccinations. This study evaluated rates of medically attended fever after infant vaccination using computerized data from 1991 to 2000 from two large U.S. provider groups. The rate of medically attended fever within 7 days after vaccination was low (6.4 per 1000 vaccination visits) and did not increase during the decade. Higher rates of fever occurred during periods when a third dose of oral polio vaccine was used (1994-1995) and when a now-discontinued oral rotavirus vaccine was used (1998-1999). These findings offer reassurance that the multiple vaccinations introduced during the decade studied were not associated with increases in medically attended fever.

Influenza vaccination coverage among adult solid organ transplant recipients at three health maintenance organizations, 1995-2005.

Annual immunization against influenza is recommended for solid organ transplant (SOT) recipients. We used Vaccine Safety Datalink data from 1995 to 2005 to assess influenza vaccination during the first full vaccination season (September-February) following transplant among 1800 kidney, liver, and heart transplant recipients at three health maintenance organizations. Overall, 52% of recipients were vaccinated. Older age at transplant (age 50-64 years, OR 1.81, 95% CI 1.43-2.30; age > or =65 years, OR 1.94, 95% CI 1.39-2.69), receiving vaccination in the full season pre-transplant (OR 4.54, 95% CI 3.67-5.60), and year of transplantation were significant predictors of post-transplant vaccination. Although vaccine coverage increased during study years, SOT recipients are under-immunized against influenza. Efforts to understand barriers to vaccination and increase education of physicians managing patients while awaiting and after receipt of transplant are needed.

Identification and characteristics of vaccine refusers.

BACKGROUND: This study evaluated the utility of immunization registries in identifying vaccine refusals among children. Among refusers, we studied their socioeconomic characteristics and health care utilization patterns. METHODS: Medical records were reviewed to validate refusal status in the immunization registries of two health plans. Racial, education, and income characteristics of children claiming refusal were collected based on the census tract of each child. Health care utilization was identified using both electronic medical record and insurance claims. Within the immunization registries of two HMOs in the study, some providers use refusal and medical contraindication interchangeably, and some providers tend to always use "ever refusal." Therefore, we combined medical contraindication and refusal together and treated them all as "refusal" in this study. RESULTS: The immunization registry, compared to chart review, had negative predictive values of 85-92% and 90-97% for 2- and 6-year olds, and positive predictive values of only 52-74% and 59-62% to identify vaccine refusals. Refusers were more likely to reside in well-educated, higher income areas than non-refusers. Refusers had not opted out of health care system and continued, although less frequently for the age 2 and under group, to use services. CONCLUSION: Without enhancements to immunization registries, identifying children with immunization refusal would be time consuming. Since communities where refusers live are well educated, interventions should target these communities to communicate vaccine adverse events and consequences of vaccine preventable diseases.

Laboratory diagnosis and characteristics of breakthrough varicella in children.

The atypical features of varicella in vaccinated persons (breakthrough varicella [BTV]) present diagnostic challenges. We examined varicella-zoster virus (VZV) polymerase chain reaction (PCR) and immunoglobulin (Ig) M and IgG serologic test results for confirming BTV cases. Among 33 vaccinated children with varicella-like rash, we identified wild-type VZV in 58% overall and in 76% of those with adequate tissue specimens; no vaccine-type virus was found. Of the 12 subjects with PCR-confirmed BTV and acute-phase serum samples, 9 had detectable IgM, and all had highly elevated acute-phase IgG titers. Six subjects with negative PCR results had lower IgG titers and negative IgM results. Although PCR is the preferred method for laboratory confirmation of BTV, a positive serum varicella IgM test result should also be considered to be diagnostic in a suspected BTV case; however, a negative IgM test result cannot be used to rule out the diagnosis. The value of highly elevated IgG titers needs further evaluation. Larger studies are needed to confirm these results.

Comparison of epidemiologic methods for active surveillance of vaccine safety.

OBJECTIVE: We performed a simulation study to compare four study designs [(matched-cohort, vaccinated-only (risk-interval) cohort, case-control, and self-controlled case-series (SCCS)] in the context of vaccine safety active surveillance. METHODS: For each combination of various incidence levels (3, 30, 300 per 10(5) person-years) and relative risks (RR 1.5-18), 100 case sets were infused into the cohort, matching 10(5) vaccinated to 10(5) unvaccinated on age and gender. The matched-cohort was converted into weekly accumulated data intervals with the other three study design samples drawn from each. Analyses were with appropriate regression models. The signal detection time was the first week where the log likelihood ratio (LLR) exceeded the upper boundary from the MaxSPRT sequential analysis method. Empirical type I (false positive) and type II (power) error rates and risk estimate bias were also calculated. RESULTS: The matched-cohort design exhibited the shortest detection time, lowest false positive rate and highest empirical power followed by the risk-interval cohort, SCCS, and case-control. In most monitoring weeks, the risk estimate bias was smallest for the cohort, followed by the risk-interval, SCCS and case-control designs. CONCLUSIONS: The cohort study design performed the best in the sequential analysis of active surveillance for vaccine safety. The risk-interval cohort and SCCS designs offer reasonable and efficient alternatives, especially if selection bias is a concern. Future research should address seasonality or age effects.

Risk of immune thrombocytopenic purpura after measles-mumps-rubella immunization in children.

BACKGROUND: The measles-mumps-rubella vaccine has been associated with immune thrombocytopenia purpura in 2 small studies. METHODS: By using the Vaccine Safety Datalink, we identified measles-mumps-rubella-vaccinated children aged 1 to 18. A case of immune thrombocytopenia purpura was defined as a patient with a platelet count of < or = 50,000/microL with clinical bleeding and normal red and white blood cell indices. The immune thrombocytopenia purpura incidence rates during exposed (42 days after vaccination) and unexposed time periods were determined. A retrospective cohort of vaccinated children was used to determine incident rate ratios for children aged 1 to 18 years, 12 to 23 months, and 12 to 15 months. RESULTS: A total of 1,036,689 children received 1,107,814 measles-mumps-rubella vaccinations; there were 259 confirmed patients with immune thrombocytopenia purpura. Because only 5 exposed cases occurred after age 2, analyses were limited to children aged 12 to 23 months. Exposed patients aged 12 to 23 months had lower median platelet counts than those who were unexposed and had similar median duration of illness (11 vs 10 days). The incident rate ratio was highest for children aged 12 to 15 months at 7.10. The incident rate ratio for boys aged 12 to 15 months was 14.59, and the incident rate ratio for girls in the same age group was 3.22. Seventy-six percent of immune thrombocytopenia purpura cases in children aged 12 to 23 months were attributable to measles-mumps-rubella vaccination. This vaccine causes 1 case of immune thrombocytopenia purpura per every 40,000 doses. CONCLUSION: Measles-mumps-rubella vaccine that is given in the second year of life is associated with an increased risk of immune thrombocytopenia purpura.

Effectiveness of influenza vaccine in the community-dwelling elderly.

BACKGROUND: Reliable estimates of the effectiveness of influenza vaccine among persons 65 years of age and older are important for informed vaccination policies and programs. Short-term studies may provide misleading pictures of long-term benefits, and residual confounding may have biased past results. This study examined the effectiveness of influenza vaccine in seniors over the long term while addressing potential bias and residual confounding in the results. METHODS: Data were pooled from 18 cohorts of community-dwelling elderly members of one U.S. health maintenance organization (HMO) for 1990-1991 through 1999-2000 and of two other HMOs for 1996-1997 through 1999-2000. Logistic regression was used to estimate the effectiveness of the vaccine for the prevention of hospitalization for pneumonia or influenza and death after adjustment for important covariates. Additional analyses explored for evidence of bias and the potential effect of residual confounding. RESULTS: There were 713,872 person-seasons of observation. Most high-risk medical conditions that were measured were more prevalent among vaccinated than among unvaccinated persons. Vaccination was associated with a 27% reduction in the risk of hospitalization for pneumonia or influenza (adjusted odds ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.77) and a 48% reduction in the risk of death (adjusted odds ratio, 0.52; 95% CI, 0.50 to 0.55). Estimates were generally stable across age and risk subgroups. In the sensitivity analyses, we modeled the effect of a hypothetical unmeasured confounder that would have caused overestimation of vaccine effectiveness in the main analysis; vaccination was still associated with statistically significant--though lower--reductions in the risks of both hospitalization and death. CONCLUSIONS: During 10 seasons, influenza vaccination was associated with significant reductions in the risk of hospitalization for pneumonia or influenza and in the risk of death among community-dwelling elderly persons. Vaccine delivery to this high-priority group should be improved.

Vaccines, antibiotics, and atopy.

PURPOSE: Early exposure to vaccines and antibiotics may increase the risk of developing atopy by protecting against infectious agents and reducing duration and severity of infections (the hygiene hypothesis). It may also shift the developing immune system towards a more allergic response. We assess possible associations in young allergy clinic patients. METHODS: We conducted a case-control study of 6- to 16-year-old new allergy clinic patients who were skin tested for inhalant allergens during 1987-2001 and enrolled in KPNW since birth (n = 1074). Atopic cases had positive tests for at least one inhalant allergen. Non-atopic controls had negative tests for all inhalant allergens. Using logistic regression analysis, we estimated atopy odds ratios for vaccine and antibiotic exposure variables and associations between vaccine and antibiotic exposures during the first 2 years of life and subsequent new allergy diagnoses. RESULTS: Atopy was not significantly associated with numbers of vaccine and antigen doses, or number of different antigens during the first 2 years of life. Number of antibiotic prescriptions was negatively associated with atopy risk. Neither exposure was significantly associated with risk of new allergy diagnoses in atopic children. CONCLUSIONS: Atopy development appears to be unrelated to early vaccine exposure. Frequency of antibiotic prescriptions during early life, a proxy for infection frequency, appears to protect against allergic sensitization. Neither vaccines nor antibiotics appear to induce subsequent allergic reactions in atopic children.

Influenza- and RSV-associated hospitalizations among adults.

We estimated influenza- and respiratory syncytial virus (RSV)-associated hospitalizations by age, high-risk status and outcome, during the 1996/1997-1999/2000 respiratory seasons among adults who did not receive influenza vaccine. Using three health maintenance organization (HMO) databases and local viral surveillance data, we identified weeks when influenza and RSV were circulating and estimated influenza- and RSV-associated hospitalizations. Persons aged > or = 65 years with and without high-risk conditions had significantly increased rates of influenza-associated hospitalizations for pneumonia and influenza, and circulatory and respiratory diseases. Persons aged > or = 65 years with high-risk conditions also had significantly increased rates of influenza-associated hospitalizations for cardiac conditions (16.9 per 10,000 person periods). Relative to the influenza estimates for high-risk persons > or = 65 years, we found lower rates of RSV-associated hospitalizations for pneumonia and influenza diseases (23.4 per 10,000 person periods), cardiac diseases (4.3 per 10,000 person periods) and circulatory and respiratory diseases (44.0 per 10,000 person periods). Among low-risk persons aged 50-64 years, we did not identify significantly elevated rates of influenza- or RSV-associated hospitalizations. Excess hospitalization estimates among adults aged > or = 65 years and high-risk 50-64 year olds during the influenza season suggest that these groups should have priority for influenza vaccine during vaccine shortages.

Impact of maternal influenza vaccination during pregnancy on the incidence of acute respiratory illness visits among infants.

OBJECTIVE: To determine whether influenza vaccination of pregnant women prevents visits for respiratory illness in their infants born during the influenza season. DESIGN: Retrospective matched cohort study. SETTING: Four managed care organizations in the United States. Patients A total of 41 129 infants (3160 and 37 969 born to vaccinated and unvaccinated mothers, respectively) born between 1995 and 2001. Main Exposure Maternal influenza vaccination. Infants were considered exposed if their gestational age at birth was at least 30 weeks, if the time from maternal vaccination to birth was at least 28 days, and if they were exposed to at least 14 days of the influenza season. MAIN OUTCOME MEASURES: Incidence of acute respiratory illnesses (outpatient, emergency department, and inpatient settings combined) and incident rate ratios (IRRs) for infants exposed and unexposed to maternal vaccination during the following 4 periods: peak influenza, respiratory syncytial virus predominant, periseasonal, and summer weeks. The time to the first acute respiratory illness during peak influenza weeks was also assessed. RESULTS: During the peak influenza weeks, infant visit rates were 15.4 and 17.1 per 100 person-months for exposed and unexposed infants, respectively (IRR, 0.90; 95% confidence interval, 0.80-1.02). Adjusted IRRs for the 4 periods found a protective effect of infant female sex, whereas Medicaid status and maternal high-risk status increased infant visit rates. Maternal influenza vaccination did not reduce visit rates during any of the 4 time periods (IRR for peak influenza season, 0.96; 95% confidence interval, 0.86-1.07) and did not delay the onset of first respiratory illness. CONCLUSION: We were unable to demonstrate that maternal influenza vaccination reduces respiratory illness visit rates among their infants.

Variation in hepatitis B immunization coverage rates associated with provider practices after the temporary suspension of the birth dose.

BACKGROUND: In 1999, the American Academy of Pediatrics and U.S. Public Health Service recommended suspending the birth dose of hepatitis B vaccine due to concerns about potential mercury exposure. A previous report found that overall national hepatitis B vaccination coverage rates decreased in association with the suspension. It is unknown whether this underimmunization occurred uniformly or was associated with how providers changed their practices for the timing of hepatitis B vaccine doses. We evaluate the impact of the birth dose suspension on underimmunization for the hepatitis B vaccine series among 24-month-olds in five large provider groups and describe provider practices potentially associated with underimmunization following the suspension. METHODS: Retrospective cohort study of children enrolled in five large provider groups in the United States (A-E). Logistic regression was used to evaluate the association between the birth dose suspension and a child's probability of being underimmunized at 24 months for the hepatitis B vaccine series. RESULTS: Prior to July 1999, the percent of children who received a hepatitis B vaccination at birth varied widely (3% to 90%) across the five provider groups. After the national recommendation to suspend the hepatitis B birth dose, the percent of children who received a hepatitis B vaccination at birth decreased in all provider groups, and this trend persisted after the policy was reversed. The most substantial decreases were observed in the two provider groups that shifted the first hepatitis B dose from birth to 5-6 months of age. Accounting for temporal trend, children in these two provider groups were significantly more likely to be underimmunized for the hepatitis B series at 24 months of age if they were in the birth dose suspension cohort compared with baseline (Group D OR 2.7, 95% CI 1.7-4.4; Group E OR 3.1, 95% CI 2.3-4.2). This represented 6% more children in Group D and 9% more children in Group E who were underimmunized in the suspension cohort compared with baseline. Children in the reversal cohort in these groups remained significantly more likely to be underimmunized compared with baseline. In contrast, in a third provider group where the typical timing of the third dose was unchanged and in two other provider groups whose hepatitis B vaccination schedules were unaffected by the birth dose suspension, hepatitis B vaccination coverage either was maintained or improved. CONCLUSION: When the hepatitis B birth dose was suspended, provider groups that moved the first dose of vaccination to 5-6 months of age or later had decreases in hepatitis B vaccine coverage at 24 months. These findings suggest that as vaccine policy changes occur, providers could attempt to minimize underimmunization by adopting vaccination schedules that minimize delays in the recommended timing of vaccine doses.

Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old.

CONTEXT: Beginning with the winter season of 2004-2005, influenza vaccination has been recommended for all children 6 to 23 months old in the United States. However, its safety in young children has not been adequately studied in large populations. OBJECTIVE: To screen for medically attended events in the clinic, emergency department, or hospital after administration of trivalent inactivated influenza vaccine in children 6 to 23 months old. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort using self-control analysis, with chart review of significant medically attended events at 8 managed care organizations in the United States that comprise the Vaccine Safety Datalink. Participants were all children in the Vaccine Safety Datalink cohort 6 to 23 months old who received trivalent inactivated influenza vaccine between January 1, 1991, and May 31, 2003 (45,356 children with 69,359 vaccinations). MAIN OUTCOME MEASURE: Any medically attended event significantly associated with trivalent inactivated influenza vaccine in risk windows 0 to 3 days, 1 to 14 days (primary analysis), 1 to 42 days, or 15 to 42 days after vaccination, compared with 2 control periods, one before vaccination and the second after the risk window. All individual ICD-9 codes as well as predefined aggregate codes were examined. RESULTS: Before chart review, only 1 diagnosis, gastritis/duodenitis, was more likely to occur in the 14 days after trivalent inactivated influenza vaccine (matched odds ratio [OR], 5.50; 95% confidence interval [CI], 1.22-24.81 for control period 1, and matched OR, 4.33; 95% CI, 1.23-15.21 for control period 2). Thirteen medically attended events were less likely to occur after trivalent inactivated influenza vaccine, including acute upper respiratory tract infection, asthma, bronchiolitis, and otitis media. After chart review, gastritis/duodenitis was not significantly associated with trivalent inactivated influenza vaccine (matched OR, 4.00; 95% CI, 0.85-18.84 for control period 1; matched OR, 3.34; 95% CI, 0.92-12.11 for control period 2). CONCLUSIONS: In the largest population-based study to date of the safety of trivalent inactivated influenza vaccine in young children, there were very few medically attended events, none of which were serious, significantly associated with the vaccine. This study provides additional evidence supporting the safety of universally immunizing all children 6 to 23 months old with influenza vaccine.

Four different study designs to evaluate vaccine safety were equally validated with contrasting limitations.

OBJECTIVE: We conducted a simulation study to empirically compare four study designs [cohort, case-control, risk-interval, self-controlled case series (SCCS)] used to assess vaccine safety. STUDY DESIGN AND METHODS: Using Vaccine Safety Datalink data (a Centers for Disease Control and Prevention-funded project), we simulated 250 case sets of an acute illness within a cohort of vaccinated and unvaccinated children. We constructed the other three study designs from the cohort at three different incident rate ratios (IRRs, 2.00, 3.00, and 4.00), 15 levels of decreasing disease incidence, and two confounding levels (20%, 40%) for both fixed and seasonal confounding. Each of the design-specific study samples was analyzed with a regression model. The design-specific beta; estimates were compared. RESULTS: The beta; estimates of the case-control, risk-interval, and SCCS designs were within 5% of the true risk parameters or cohort estimates. However, the case-control's estimates were less precise, less powerful, and biased by fixed confounding. The estimates of SCCS and risk-interval designs were biased by unadjusted seasonal confounding. CONCLUSIONS: All the methods were valid designs, with contrasting strengths and weaknesses. In particular, the SCCS method proved to be an efficient and valid alternative to the cohort method.