Impact of an electronic medical record reminder on hepatitis B vaccine initiation and completion rates among insured adults with diabetes mellitus.

OBJECTIVE: The Advisory Committee on Immunization Practices recommends Hepatitis B (HepB) vaccine for previously unvaccinated adults <60 years with diabetes mellitus. This observational retrospective cohort study assessed the impact of implementing electronic provider reminders on HepB vaccine initiation and 3-dose series completion rates among insured adults with diabetes aged 19-59 years old. RESEARCH DESIGN AND METHODS: Difference-in-difference (DID) analyses compared changes in vaccine initiation and completion rates (ratio of the rate ratio [RRR] and 95% confidence interval [CI]) during 12 months pre- and post-implementation between intervention and control sites. We examined trends in vaccine initiation and completion rates by plotting monthly rates during the study period. We also calculated the overall HepB vaccine coverage rates with 95% CI among all adults with diabetes aged 19-59 years old at the start and end date of the study period. RESULTS: Baseline HepB vaccine initiation and completion rates were similar at both the intervention and control sites. Gender, age, and race/ethnicity distributions within both sites were similar during the 12 months pre- and post-implementation. DID analyses demonstrated statistically significant differences in the changes of the annual vaccine initiation rates (RRR: 70.7, 95% CI: 62.8-79.6) and the third dose completion rates (RRR = 18.7, 95% CI: 14.2-24.8) between the two sites. The coverage increased significantly at the intervention site while it remained low at the control site. CONCLUSIONS: Use of provider reminders is highly effective in increasing both HepB vaccine initiation and series completion rates among adults with diabetes.

Kaiser Permanente Northern California pregnancy database: Description and proof of concept study.

BACKGROUND/OBJECTIVE: We describe the establishment of a dynamic database linking mothers to newborns with the goal of studying vaccine safety in both pregnant women and their children and provide results of a study utilizing this database as a proof of concept. METHODS: All Kaiser Permanente Northern California (KPNC) live births and their mothers were eligible for inclusion in the pregnancy database. We used the medical record number (MRN), a unique identifier, to retrieve information about events that occurred during the pregnancy and at delivery and linked this same MRN to newborns for post-partum follow up. We conducted a retrospective cohort study to evaluate the association between receipt of tetanus, diphtheria and acellular pertussis (Tdap) vaccine during pregnancy and fever 0-3days after the first dose of diphtheria tetanus and acellular pertussis (DTaP) vaccine in the infant. The study included infants who were born at ⩾37weeks gestation from January 1, 2009 - October 1, 2015 and who received their first DTaP vaccine between 6 and 10weeks of age. We utilized diagnostic codes from inpatient, emergency department, outpatient clinics, and telephone calls. We identified fever using ICD 9 code 780.6, recorded temperature ⩾101 degree Fahrenheit, or parental report. RESULTS: The database contained the starting and ending date of each pregnancy and basic demographic characteristics of mothers and infants. There were 859,699 women and 873,753 children in the database as of January 2016. The proof of concept study included 148,699 infants. In a multivariable logistic regression analysis, Tdap vaccination during pregnancy was not associated with infant fever 0-3daysafter first dose of DTaP (adjusted odds ratio=0.92, 95% CI 0.82-1.04). CONCLUSION: The KPNC pregnancy database can be used for studies investigating exposure during pregnancy and outcomes in mothers and/or infants, particularly monitoring vaccine safety and effectiveness.

Prevalence of HPV types in cervical specimens from an integrated healthcare delivery system: baseline assessment to measure HPV vaccine impact.

PURPOSE: Two human papillomavirus (HPV) vaccines are available to prevent cervical cancer. One early measure of HPV vaccine impact would be a reduction in vaccine-related HPV types (HPV 6, 11, 16, or 18, or HPV 16, 18) in cervical samples from young women. We aimed to assess feasibility of specimen collection and baseline HPV prevalence in an integrated healthcare delivery system. METHODS: Residual cervical specimens collected during routine cervical cancer screening (2006-2008) were retained consecutively from eligible females aged 11-29 years, stratified by age group. Specimens were evaluated for 37 HPV genotypes using the Roche Linear Array assay. RESULTS: Of 10,124 specimens submitted, 10,103 (99 %) were adequate for HPV testing. Prevalence of HPV 6, 11, 16, or 18 genotype was 11.4 % overall and was the highest in the youngest age group (18.1 % in the 11-19-year-olds, 12.5 % in the 20-24-year-olds, and 7.0 % in the 25-29-year-olds). CONCLUSIONS: HPV types 6, 11, 16, or 18 prevalence could be measured over time to assess early HPV vaccine impact using residual specimens from an integrated healthcare delivery system, particularly if sampling focused on young women.

Clinical assessment of serious adverse events in children receiving 2009 H1N1 vaccination.

BACKGROUND: Monovalent 2009 H1N1 influenza vaccines were licensed and administered in the United States during the H1N1 influenza pandemic between 2009 and 2013. METHODS: Vaccine Adverse Event Reporting System received reports of adverse events following immunization (AEFI) after H1N1 vaccination. Selected reports were referred to the Centers for Disease Control and Prevention's Clinical Immunization Safety Assessment network for additional review. We assessed causality using modified World Health Organization criteria. RESULTS: There were 3,928 reports of AEFI in children younger than age 18 years after 2009 H1N1 vaccination received by January 31, 2010. Of these, 214 (5.4%) were classified as serious nonfatal and 109 were referred to Clinical Immunization Safety Assessment for further evaluation. Ninety-nine (91%) had sufficient initial information to begin investigation and are described here. The mean age was 8 years (range, 6 months-17 years) and 38% were female. Median number of days between vaccination and symptom onset was 2 (range, -11 days to +41 days). Receipt of inactivated, live attenuated, or unknown type of 2009 H1N1 vaccines was reported by 68, 26 and 5 cases, respectively. Serious AEFI were categorized as neurologic events in 47 cases, as hypersensitivity in 15 cases and as respiratory events in 10 cases. At the time of evaluation, recovery was described as complete (61), partial (16), no improvement (1), or unknown (21). Causality assessment yielded the following likelihood of association with 2009 H1N1 vaccination: 8 definitely; 8 probably; 21 possibly; 43 unlikely; 17 unrelated; and 2 unclassifiable. CONCLUSIONS: Most AEFI in children evaluated were not causally related to vaccine and resolved without sequelae. Detailed clinical assessment of individual serious AEFI can provide reassurance of vaccine safety.

Vaccination site and risk of local reactions in children 1 through 6 years of age.

OBJECTIVE: Our objective was to assess whether the occurrence of medically attended local reactions to intramuscularly administered vaccines varies by injection site (arm versus thigh) in children 1 to 6 years of age. METHODS: This is a retrospective cohort study of children in the Vaccine Safety Datalink population from 2002 to 2009. Site of injection and the outcome of medically attended local reactions were identified from administrative data. RESULTS: The study cohort of 1.4 million children received 6.0 million intramuscular (IM) vaccines during the study period. The primary analyses evaluated the IM vaccines most commonly administered alone, which included inactivated influenza, hepatitis A, and diphtheria-tetanus-acellular pertussis (DTaP) vaccines. For inactivated influenza and hepatitis A vaccines, local reactions were relatively uncommon, and there was no difference in risk of these events with arm versus thigh injections. The rate of local reactions after DTaP vaccines was higher, and vaccination in the arm was associated with a significantly greater risk of this outcome compared with vaccination in the thigh, both for children 12 to 35 months (relative risk: 1.88 [95% confidence interval: 1.34-2.65]) and 3 to 6 years of age (relative risk: 1.41 [95% confidence interval: 0.84-2.34]), although this difference was not statistically significant in the older age group. CONCLUSIONS: Injection in the thigh is associated with a significantly lower risk of a medically attended local reaction to a DTaP vaccination among children 12 to 35 months of age, supporting current recommendations to administer IM vaccinations in the thigh for children younger than 3 years of age.

Causality assessment of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS).

UNLABELLED: Adverse events following immunization (AEFI) reported to the national Vaccine Adverse Event Reporting System (VAERS) represent true causally related events, as well as events that are temporally, but not necessarily causally related to vaccine. OBJECTIVE: We sought to determine if the causal relationships between the vaccine and the AEFI reported to VAERS could be assessed through expert review. DESIGN: A stratified random sample of 100 VAERS reports received in 2004 contained 13 fatal cases, 19 cases with non-fatal disabilities, 39 other serious non-fatal cases and 29 non-serious cases. Experts knowledgeable about vaccines and clinical outcomes, reviewed each VAERS report and available medical records. MAIN OUTCOME MEASURES: Modified World Health Organization criteria were used to classify the causal relationship between vaccines and AEFI as definite, probable, possible, unlikely or unrelated. Five independent reviewers evaluated each report. If they did not reach a majority agreement on causality after initial review, the report was discussed on a telephone conference to achieve agreement. RESULTS: 108 AEFIs were identified in the selected 100 VAERS reports. After initial review majority agreement was achieved for 83% of the AEFI and 17% required further discussion. In the end, only 3 (3%) of the AEFI were classified as definitely causally related to vaccine received. Of the remaining AEFI 22 (20%) were classified as probably and 22 (20%) were classified as possibly related to vaccine received; a majority (53%) were classified as either unlikely or unrelated to a vaccine received. CONCLUSIONS: Using VAERS reports and additional documentation, causality could be assessed by expert review in the majority of VAERS reports. Assessment of VAERS reports identified that causality was thought to be probable or definite in less than one quarter of reports, and these were dominated by local reactions, allergic reactions, or symptoms known to be associated with the vaccine administered.

Safety of Zostavax™--a cohort study in a managed care organization.

BACKGROUND: Zostavax™ is a live, attenuated varicella-zoster virus vaccine indicated for the prevention of herpes zoster (shingles). An observational post-licensure (Phase IV) study was conducted at Kaiser Permanente Northern California (KPNC), a US managed care organization, to assess the safety of zoster vaccine in people 60 years of age or older, vaccinated in routine medical care. METHODS: We performed a cohort study, comparing rates of clinical events resulting in hospitalizations or emergency department visits in a 42-day risk time period immediately following vaccination with rates in the same cohort in a subsequent comparison time period. The study data were reviewed and interpreted by an external safety review committee of 3 independent experts. RESULTS: Approximately 29,000 people ≥ 60 years of age were vaccinated with zoster vaccine from July 2006 to November 2007. Of the 386 comparisons performed for the main analysis, 4 had an increased relative risk with a nominal p-value ≤ 0.05. After medical records review, the timing of these conditions and procedures was found to be often prior to vaccination, and no clear increase in health events was observed in the risk period following vaccination compared to later. Persons receiving zoster vaccine appeared to be in their optimal health at the time of vaccination, which led to an apparent protective effect of the vaccine for some health outcomes, due to the study design. CONCLUSIONS: There was no evidence of a safety concern for zoster vaccine.

Patterns in influenza antiviral medication use before and during the 2009 H1N1 pandemic, Vaccine Safety Datalink Project, 2000-2010.

BACKGROUND: U.S. recommendations for using influenza antiviral medications changed in response to viral resistance (to reduce adamantane use) and during the 2009 H1N1 pandemic (to focus on protecting high-risk patients). Little information is available on clinician adherence to these recommendations. We characterized population-based outpatient antiviral medication usage, including diagnosis and testing practices, before and during the pandemic. METHODS: Eight medical care organizations in the Vaccine Safety Datalink Project provided data on influenza antiviral medication dispensings from January 2000 through June 2010. Dispensing rates were explored in relation to changes in recommendations and influenza diagnosis and laboratory testing frequencies. Factors associated with oseltamivir dispensings in pandemic versus pre-pandemic periods were identified using multivariable logistic regression. RESULTS: Antiviral use changed coincident with recommendations to avoid adamantanes in 2006, to use alternatives to oseltamivir in 2008, and to use oseltamivir during the pandemic. Of 38,019 oseltamivir dispensings during the pandemic, 31% were to patients not assigned an influenza diagnosis, and 97% were to patients not tested for influenza. Oseltamivir was more likely to be dispensed in pandemic versus pre-pandemic periods to patients <25 years old and to those with underlying conditions, including chronic pulmonary disease or pregnancy (P<0.0001 for each factor in multivariable analysis). CONCLUSIONS: Antiviral medication usage patterns suggest that clinicians followed recommendations to change antiviral prescribing based on resistance and to focus on high-risk patients during the pandemic. Medications were commonly dispensed to patients without influenza diagnoses and tests, suggesting that antiviral dispensings may offer useful supplemental data for monitoring influenza incidence.

Trends and characteristics of culture-confirmed Staphylococcus aureus infections in a large U.S. integrated health care organization.

Infections due to Staphylococcus aureus present a significant health problem in the United States. Between 1990 and 2005, there was a dramatic increase in community-associated methicillin-resistant S. aureus (MRSA), but recent reports suggest that MRSA may be declining. We retrospectively identified S. aureus isolates (n = 133,450) that were obtained from patients in a large integrated health plan between 1 January 1998 and 31 December 2009. Trends over time in MRSA were analyzed, and demographic risk factors for MRSA versus methicillin-susceptible S. aureus (MSSA) were identified. The percentage of S. aureus isolates that were MRSA increased from 9% to 20% between 1998 and 2001 and from 25% to 49% between 2002 and 2005 and decreased from 49% to 43% between 2006 and 2009. The increase in MRSA was seen in blood and in other bacteriological specimens and occurred in all age and race/ethnicity groups, though it was most pronounced in persons aged 18 to <50 years and African-Americans. Hospital onset infections were the most likely to be MRSA (odds ratio [OR], 1.58; confidence interval [CI], 1.46 to 1.70, compared to community-associated cases), but the largest increase in MRSA was in community-associated infections. Isolates from African-Americans (OR, 1.73; CI, 1.64 to 1.82) and Hispanics (OR, 1.11; CI, 1.06 to 1.16) were more likely to be MRSA than those from whites. After substantial increases between 1998 and 2005 in the proportion of S. aureus isolates that were MRSA, the proportion decreased between 2006 and 2009. Hospital onset S. aureus infections are disproportionately MRSA, as are those among African-Americans.

Causality assessment of serious neurologic adverse events following 2009 H1N1 vaccination.

BACKGROUND: Adverse events occurring after vaccination are routinely reported to the Vaccine Adverse Event Reporting System (VAERS). We studied serious adverse events (SAEs) of a neurologic nature reported after receipt of influenza A (H1N1) 2009 monovalent vaccine during the 2009-2010 influenza season. Investigators in the Clinical Immunization Safety Assessment (CISA) network sought to characterize these SAEs and to assess their possible causal relationship to vaccination. METHODS: Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) physicians reviewed all SAE reports (as defined by the Code of Federal Regulations, 21CFR§314.80) after receipt of H1N1 vaccine reported to VAERS between October 1, 2009 and March 31, 2010. Non-fatal SAE reports with neurologic presentation were referred to CISA investigators, who requested and reviewed additional medical records and clinical information as available. CISA investigators assessed the causal relationship between vaccination and the event using modified WHO criteria as defined. RESULTS: 212 VAERS reports of non-fatal serious neurological events were referred for CISA review. Case reports were equally distributed by gender (50.9% female) with an age range of 6 months to 83 years (median 38 years). The most frequent diagnoses reviewed were: Guillain-Barré Syndrome (37.3%), seizures (10.8%), cranial neuropathy (5.7%), and acute disseminated encephalomyelitis (3.8%). Causality assessment resulted in classification of 72 events as "possibly" related (33%), 108 as "unlikely" related (51%), and 20 as "unrelated" (9%) to H1N1 vaccination; none were classified as "probable" or "definite" and 12 were unclassifiable (6%). CONCLUSION: The absence of a specific test to indicate whether a vaccine component contributes to the pathogenesis of an event occurring within a biologically plausible time period makes assessing causality difficult. The development of standardized protocols for providers to use in evaluation of adverse events following immunization, and rapid identification and follow-up of VAERS reports could improve causality assessment.

Overview of the Clinical Consult Case Review of adverse events following immunization: Clinical Immunization Safety Assessment (CISA) network 2004-2009.

BACKGROUND: In 2004 the Clinical Consult Case Review (CCCR) working group was formed within the CDC-funded Clinical Immunization Safety Assessment (CISA) Network to review individual cases of adverse events following immunizations (AEFI). METHODS: Cases were referred by practitioners, health departments, or CDC employees. Vaccine Adverse Event Reporting System (VAERS) searches and literature reviews for similar cases were performed prior to review. After CCCR discussion, AEFI were assessed for a causal relationship with vaccination and recommendations regarding future immunizations were relayed back to the referring physicians. In 2010, surveys were sent to referring physicians to determine the utility and effectiveness of the CCCR service. RESULTS: CISA investigators reviewed 76 cases during 68 conference calls between April 2004 and December 2009. Almost half of the cases (35/76) were neurological in nature. Similar AEFI for the specific vaccines received were discovered for 63 cases through VAERS searches and for 38 cases through PubMed searches. Causality assessment using the modified WHO criteria resulted in classifying 3 cases as definitely related to vaccine administration, 12 as probably related, 16 as possibly related, 18 as unlikely related, 10 as unrelated, and 17 had insufficient information to assign causality. The physician satisfaction survey was returned by 30 (57.7%) of those surveyed and a majority of respondents (93.3%) felt that the CCCR service was useful. CONCLUSIONS: The CCCR provides advice about AEFI to practitioners, assigns potential causality, and contributes to an improved understanding of adverse health events following immunizations.

Understanding the role of human variation in vaccine adverse events: the Clinical Immunization Safety Assessment Network.

The Clinical Immunization Safety Assessment (CISA) Network is a collaboration between the Centers for Disease Control and Prevention (CDC) and 6 academic medical centers to provide support for immunization safety assessment and research. The CISA Network was established by the CDC in 2001 with 4 primary goals: (1) develop research protocols for clinical evaluation, diagnosis, and management of adverse events following immunization (AEFI); (2) improve the understanding of AEFI at the individual level, including determining possible genetic and other risk factors for predisposed people and subpopulations at high risk; (3) develop evidence-based algorithms for vaccination of people at risk of serious AEFI; and (4) serve as subject-matter experts for clinical vaccine-safety inquiries. CISA Network investigators bring in-depth clinical, pathophysiologic, and epidemiologic expertise to assessing causal relationships between vaccines and adverse events and to understanding the pathogenesis of AEFI. CISA Network researchers conduct expert reviews of clinically significant adverse events and determine the validity of the recorded diagnoses on the basis of clinical and laboratory criteria. They also conduct special studies to investigate the possible pathogenesis of adverse events, assess relationships between vaccines and adverse events, and maintain a centralized repository for clinical specimens. The CISA Network provides specific clinical guidance to both health care providers who administer vaccines and those who evaluate and treat patients with possible AEFI. The CISA Network plays an important role in providing critical immunization-safety data and expertise to inform vaccine policy-makers. The CISA Network serves as a unique resource for vaccine-safety monitoring efforts conducted at the CDC.

Surveillance lessons from first-wave pandemic (H1N1) 2009, Northern California, USA.

After the appearance of pandemic (H1N1) 2009 in April 2009, influenza activity was monitored within the Kaiser Permanente Northern California division by using laboratory, pharmacy, telephone calls, and utilization (services patients received) data. A combination of testing and utilization data showed a pattern of disease activity, but this pattern may have been affected by public perception of the epidemic.

Rates of autoimmune diseases in Kaiser Permanente for use in vaccine adverse event safety studies.

Safety monitoring following new vaccine introduction includes assessment of potential new onset autoimmune diseases (AID). As knowledge regarding AID background rates is limited, we evaluated the incidence of 11 AID in Northern California Kaiser Permanente. AID cases were identified using electronic records of members aged 10-62 years from 1998 to 2004, excluding those with AID diagnoses from 1996 to 1997. Using prespecified criteria, all identified cases of rare diseases were verified by medical record review, while a sample of cases was reviewed for common diseases; incidence rates were calculated based on the proportion of confirmed cases. Overall, the incidence of AID varied from 0.8/100,000 person-years (PY) for autoimmune hemolytic anemia (AIHA) to 54.1/100,000 PY for thyroiditis. Incidence rates in increasing order were AIHA, juvenile rheumatoid arthritis, Guillain-Barre Syndrome, idiopathic thromobocytopenia purpura, transverse myelitis, systemic lupus erythematosus, uveitis, multiple sclerosis, rheumatoid arthritis, Type 1 diabetes mellitus and thyroiditis; incidence rates also varied according to age and gender. These background incidence rates should prove useful for future observational vaccine safety studies and will help guide evaluation of potential vaccine AID events following introduction of new vaccines.

Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente.

OBJECTIVE: To assess the direct and indirect effects of the introduction of routine use of pneumococcal conjugate vaccine in infants and toddlers at risk for invasive disease caused by vaccine serotypes and nonvaccine serotypes in vaccinated children and unvaccinated children of the same age. Secondary objectives included determination of the risk of pneumococcal infections in unvaccinated older children and adults in the same population and the impact of vaccine introduction on patterns of antimicrobial resistance. METHODS: Northern California Kaiser Permanente provides integrated comprehensive care to 3.1 million people and has an annual birth cohort of 38,000 infants. Microbiology services use a regional laboratory. Automated laboratory results, immunization records as well as diagnoses for inpatient and outpatient utilization are available from clinical data bases. Beginning in April 2000, the heptavalent pneumococcal conjugate (PNCV7) vaccine was introduced into routine use in the Northern California Kaiser Permanente population. Cases of invasive pneumococcal disease were identified from the automated hospital diagnosis as well as laboratory databases for all individuals, vaccinees and nonvaccinees, inpatient and outpatient. For the purpose of these analyses, pneumococcal invasive disease was defined as a positive culture from a normally sterile site. RESULTS: As of March 2003, 157,471 children had received 1 dose or more of PNCV7, but only 24% of those <2 years of age received all 4 doses as a result of shortages of vaccine. During the last year of observation, no cases of vaccine serotype disease were seen in children <1 year of age compared with an incidence ranging between 51.5 and 98.2 cases per 100,000 person-years (16-34 cases per year) in the years before vaccine introduction. Similar reductions were seen in children <5 years of age. There was no evidence of any concomitant increase in pneumococcal disease caused by nonvaccine serotypes. High level resistance of pneumococci to penicillin fell from a peak of 15% in 2000 to 5% in the first half of 2003. Similar trends were seen for other antibiotics. CONCLUSION: The PNCV7 vaccine is highly effective in reducing the burden of pneumococcal disease in children <5 years of age, and there is evidence of a herd effect as well as a decrease in the antibiotic resistant in strains causing disease. For invasive disease, there is no current evidence of serotype replacement.