Jason M. Glanz

The Vaccine Safety Datalink: A Model for Monitoring Immunization Safety

The Vaccine Safety Datalink (VSD) project is a collaborative project between the Centers for Disease Control and Prevention and 8 managed care organizations (MCOs) in the United States. Established in 1990 to conduct postmarketing evaluations of vaccine safety, the project has created an infrastructure that allows for high-quality research and surveillance. The 8 participating MCOs comprise a large population of 8.8 million members annually (3% of the US population), which enables researchers to conduct studies that assess adverse events after immunization. Each MCO prepares computerized data files by using a standardized data dictionary containing demographic and medical information on its members, such as age and gender, health plan enrollment, vaccinations, hospitalizations, outpatient clinic visits, emergency department visits, urgent care visits, and mortality data, as well as additional birth information (eg, birth weight) when available. Other information sources, such as medical chart review, member surveys, and pharmacy, laboratory, and radiology data, are often used in VSD studies to validate outcomes and vaccination data. Since 2000, the VSD has undergone significant changes including an increase in the number of participating MCOs and enrolled population, changes in data-collection procedures, the creation of near real-time data files, and the development of near real-time postmarketing surveillance for newly licensed vaccines or changes in vaccine recommendations. Recognized as an important resource in vaccine safety, the VSD is working toward increasing transparency through data-sharing and external input. With its recent enhancements, the VSD provides scientific expertise, continues to develop innovative approaches for vaccine-safety research, and may serve as a model for other patient safety collaborative research projects.

National trends in pharmaceutical opioid related overdose deaths compared to other substance related overdose deaths: 1999–2009☆

BACKGROUND Pharmaceutical opioid related deaths have increased. This study aimed to place pharmaceutical opioid overdose deaths within the context of heroin, cocaine, psychostimulants, and pharmaceutical sedative hypnotics examine demographic trends, and describe common combinations of substances involved in opioid related deaths. METHODS We reviewed deaths among 15-64 year olds in the US from 1999-2009 using death certificate data available through the CDC Wide-Ranging Online Data for Epidemiologic Research (WONDER) Database. We identified International Classification of Disease-10 codes describing accidental overdose deaths, including poisonings related to stimulants, pharmaceutical drugs, and heroin. We used crude and age adjusted death rates (deaths/100,000 person years [p-y] and 95% confidence interval [CI] and multivariable Poisson regression models, yielding incident rate ratios; IRRs), for analysis. RESULTS The age adjusted death rate related to pharmaceutical opioids increased almost 4-fold from 1999 to 2009 (1.54/100,000 p-y [95% CI 1.49-1.60] to 6.05/100,000 p-y [95% CI 5.95-6.16; p<0.001). From 1999 to 2009, pharmaceutical opioids were responsible for the highest relative increase in overdose death rates (IRR 4.22, 95% CI 3.03-5.87) followed by sedative hypnotics (IRR 3.53, 95% CI 2.11-5.90). Heroin related overdose death rates increased from 2007 to 2009 (1.05/100,000 persons [95% CI 1.00-1.09] to 1.43/100,000 persons [95% CI 1.38-1.48; p<0.001). From 2005-2009 the combination of pharmaceutical opioids and benzodiazepines was the most common cause of polysubstance overdose deaths (1.27/100,000 p-y (95% CI 1.25-1.30). CONCLUSION Strategies, such as wider implementation of naloxone, expanded access to treatment, and development of new interventions are needed to curb the pharmaceutical opioid overdose epidemic.

A systematic review of interventions for reducing parental vaccine refusal and vaccine hesitancy.

Unvaccinated individuals pose a public health threat to communities. Research has identified many factors associated with parental vaccine refusal and hesitancy toward childhood and adolescent immunizations. However, data on the effectiveness of interventions to address parental refusal are limited. We conducted a systematic review of four online databases to identify interventional studies. We used criteria recommended by the WHOs Strategic Advisory Group of Experts on immunization (SAGE) for the quality assessment of studies. Intervention categories and outcomes were evaluated for each body of evidence and confidence in overall estimates of effect was determined. There is limited evidence to guide implementation of effective strategies to deal with the emerging threat of parental vaccine refusal. There is a need for appropriately designed, executed and evaluated intervention studies to address this gap in knowledge.

Parental Refusal of Pertussis Vaccination Is Associated With an Increased Risk of Pertussis Infection in Children

OBJECTIVE. The objective of this study was to determine if children who contracted pertussis infection were more likely to have parents who refused pertussis vaccinations than a similar group of children who did not develop pertussis infection. METHODS. We conducted a case-control study of children enrolled in the Kaiser Permanente of Colorado health plan between 1996 and 2007. Each pertussis case was matched to 4 randomly selected controls. Pertussis case status and vaccination status were ascertained by medical chart review. RESULTS. We identified 156 laboratory-confirmed pertussis cases and 595 matched controls. There were 18 (12%) pertussis vaccine refusers among the cases and 3 (0.5%) pertussis vaccine refusers among the controls. Children of parents who refused pertussis immunizations were at an increased risk for pertussis compared with children of parents who accepted vaccinations. In a secondary case-control analysis of children continuously enrolled in Kaiser Permanente of Colorado from 2 to 20 months of age, vaccine refusal was associated with a similarly increased risk of pertussis. In the entire Kaiser Permanente of Colorado pediatric population, 11% of all pertussis cases were attributed to parental vaccine refusal. CONCLUSIONS. Children of parents who refuse pertussis immunizations are at high risk for pertussis infection relative to vaccinated children. Herd immunity does not seem to completely protect unvaccinated children from pertussis. These findings stress the need to further understand why parents refuse immunizations and to develop strategies for conveying the risks and benefits of immunizations to parents more effectively.

Risk of Intussusception after Monovalent Rotavirus Vaccination

BACKGROUND Although current rotavirus vaccines were not associated with an increased risk of intussusception in large trials before licensure, recent postlicensure data from international settings suggest the possibility of a small increase in risk of intussusception after monovalent rotavirus vaccination. We examined this risk in a population in the United States. METHODS Participants were infants between the ages of 4 and 34 weeks who were enrolled in six integrated health care organizations in the Vaccine Safety Datalink (VSD) project. We reviewed medical records and visits for intussusception within 7 days after monovalent rotavirus vaccination from April 2008 through March 2013. Using sequential analyses, we then compared the risk of intussusception among children receiving monovalent rotavirus vaccine with historical background rates. We further compared the risk after monovalent rotavirus vaccination with the risk in a concurrent cohort of infants who received the pentavalent rotavirus vaccine. RESULTS During the study period, 207,955 doses of monovalent rotavirus vaccine (including 115,908 first doses and 92,047 second doses) were administered in the VSD population. We identified 6 cases of intussusception within 7 days after the administration of either dose of vaccine. For the two doses combined, the expected number of intussusception cases was 0.72, resulting in a significant relative risk of 8.4. For the pentavalent rotavirus vaccine, 1,301,810 doses were administered during the study period, with 8 observed intussusception cases (7.11 expected), for a nonsignificant relative risk of 1.1. The relative risk of chart-confirmed intussusception within 7 days after monovalent rotavirus vaccination, as compared with the risk after pentavalent rotavirus vaccination, was 9.4 (95% confidence interval, 1.4 to 103.8). The attributable risk of intussusception after the administration of two doses of monovalent rotavirus vaccine was estimated to be 5.3 per 100,000 infants vaccinated. CONCLUSIONS In this prospective postlicensure study of more than 200,000 doses of monovalent rotavirus vaccine, we observed a significant increase in the rate of intussusception after vaccination, a risk that must be weighed against the benefits of preventing rotavirus-associated illness. (Funded by the Centers for Disease Control and Prevention.).

Risk of Intussusception Following Administration of a Pentavalent Rotavirus Vaccine in US Infants

CONTEXT Current rotavirus vaccines were not associated with intussusception in large prelicensure trials. However, recent postlicensure data from international settings suggest the possibility of a low-level elevated risk, primarily in the first week after the first vaccine dose. OBJECTIVE To examine the risk of intussusception following pentavalent rotavirus vaccine (RV5) in US infants. DESIGN, SETTING, AND PATIENTS This cohort study included infants 4 to 34 weeks of age, enrolled in the Vaccine Safety Datalink (VSD) who received RV5 from May 2006-February 2010. We calculated standardized incidence ratios (SIRs), relative risks (RRs), and 95% confidence intervals for the association between intussusception and RV5 by comparing the rates of intussusception in infants who had received RV5 with the rates of intussusception in infants who received other recommended vaccines without concomitant RV5 during the concurrent period and with the expected number of intussusception visits based on background rates assessed prior to US licensure of the RV5 (2001-2005). MAIN OUTCOME MEASURE Intussusception occurring in the 1- to 7-day and 1- to 30-day risk windows following RV5 vaccination. RESULTS During the study period, 786,725 total RV5 doses, which included 309,844 first doses, were administered. We did not observe a statistically significant increased risk of intussusception with RV5 for either comparison group following any dose in either the 1- to 7-day or 1- to 30-day risk window. For the 1- to 30-day window following all RV5 doses, we observed 21 cases of intussusception compared with 20.9 expected cases (SIR, 1.01; 95% CI, 0.62-1.54); following dose 1, we observed 7 cases compared with 5.7 expected cases (SIR, 1.23; 95% CI, 0.5-2.54). For the 1- to 7-day window following all RV5 doses, we observed 4 cases compared with 4.3 expected cases (SIR, 0.92; 95% CI, 0.25-2.36); for dose 1, we observed 1 case compared with 0.8 expected case (SIR, 1.21; 95% CI, 0.03-6.75). The upper 95% CI limit of the SIR (6.75) from the historical comparison translates to an upper limit for the attributable risk of 1 intussusception case per 65,287 RV5 dose-1 recipients. CONCLUSION Among US infants aged 4 to 34 weeks who received RV5, the risk of intussusception was not increased compared with infants who did not receive the rotavirus vaccine.

Drug Sharing Among Heroin Networks: Implications for HIV and Hepatitis B and C Prevention

Qualitative and quantitative findings from the baseline survey of a longitudinal, socially-focused blood-borne disease intervention study among 611 heroin IDU in Denver indicate that high risk injection practices—the sharing of contaminated drug solution in particular—often occur as a consequence of how heroin is obtained, the quantity obtained and the setting where it is injected. Contamination occurs if a contaminated syringe is used to liquefy and apportion the shared drug. In our cohort of 304 heroin injecting networks there was at least one member who, when asked to describe their last injection, reported dividing the drug as a liquid (82%), using a reservoir of water that syringes had been rinsed in to mix drugs (67%), using a common cooker (86%)—a proxy for drug sharing—and beating a shared cotton filter (58%). In contrast, only 22% reported syringe sharing. Variables associated with various injection practices included location of the last injection episode, quantity of drug injected, dope sickness, and years injecting. When compared to those who injected in a safe setting, those in an unsafe location had almost three times the odds (OR = 2.9; 95% CI: 1.9, 4.6) of being part of an injection episode where there was cooker sharing; and the smaller the quantity of heroin (≤1/4 gram v. > 1/4 gram) present at the episode, the greater the odds that cooker sharing occurred (OR = 1.8; 95% CI: 1.2, 2.6). Use of a used, unbleached syringe to prepare shared drugs had twice the odds of occurring in “unsafe” v. safe settings (OR = 2.2; 95% CI: 1.3, 4.0) and in episodes in which a participant was dopesick (OR = 2.1; 95% CI: 1.2, 3.6). In summary, risky injection practices occur within an injection process that is, in part, a response to a structurally imposed risk environment. Lessening the blood-borne disease risks embedded within this process requires interventions designed to mitigate the environmental factors that influence it, including syringe accessibility, law enforcement strategies and the settings where IDU inject drugs.

Near Real-Time Surveillance for Influenza Vaccine Safety: Proof-of-Concept in the Vaccine Safety Datalink Project

The emergence of pandemic H1N1 influenza in 2009 has prompted public health responses, including production and licensure of new influenza A (H1N1) 2009 monovalent vaccines. Safety monitoring is a critical component of vaccination programs. As proof-of-concept, the authors mimicked near real-time prospective surveillance for prespecified neurologic and allergic adverse events among enrollees in 8 medical care organizations (the Vaccine Safety Datalink Project) who received seasonal trivalent inactivated influenza vaccine during the 2005/06-2007/08 influenza seasons. In self-controlled case series analysis, the risk of adverse events in a prespecified exposure period following vaccination was compared with the risk in 1 control period for the same individual either before or after vaccination. In difference-in-difference analysis, the relative risk in exposed versus control periods each season was compared with the relative risk in previous seasons since 2000/01. The authors used Poisson-based analysis to compare the risk of Guillain-Barré syndrome following vaccination in each season with that in previous seasons. Maximized sequential probability ratio tests were used to adjust for repeated analyses on weekly data. With administration of 1,195,552 doses to children under age 18 years and 4,773,956 doses to adults, no elevated risk of adverse events was identified. Near real-time surveillance for selected adverse events can be implemented prospectively to rapidly assess seasonal and pandemic influenza vaccine safety.

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 ≤50000/μL 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 1036689 children received 1107814 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 40000 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.

The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety

The Vaccine Safety Datalink (VSD) is a collaborative project between the Centers for Disease Control and Prevention (CDC) and 9 health care organizations. Established in 1990, VSD is a vital resource informing policy makers and the public about the safety of vaccines used in the United States. Large linked databases are used to identify and evaluate adverse events in over 9 million individuals annually. VSD generates rapid, important safety assessments for both routine vaccinations and emergency vaccination campaigns. VSD monitors safety of seasonal influenza vaccines in near-real time, and provided essential information on the safety of influenza A (H1N1) 2009 monovalent vaccine during the recent pandemic. VSD investigators have published important studies demonstrating that childhood vaccines are not associated with autism or other developmental disabilities. VSD prioritizes evaluation of new vaccines; searches for possible unusual health events after vaccination; monitors vaccine safety in pregnant women; and has pioneered development of biostatistical research methods.