Active influenza vaccine safety surveillance: potential within a healthcare claims environment.

BACKGROUND: Rapid safety assessment of novel vaccines, especially those targeted against pandemic influenza, is a public health priority. OBJECTIVES: Assess the feasibility of using healthcare claims data to rapidly detect influenza vaccine adverse events using sequential analytic methods. RESEARCH DESIGN: Retrospective pilot study simulating prospective surveillance using 6 cumulative monthly administrative claims data extracts. The first included encounters occurring in October; each subsequent extract included an additional month of encounters. Ten adverse events were evaluated, comparing postvaccination rates during the 2006-2007 influenza season to those expected based on rates observed in the prior season. SUBJECTS: Members of a large, multistate health insurer who had a claim for influenza vaccination during the 2005-2006 or 2006-2007 influenza seasons. MEASURES: The completeness of monthly claims extracts. RESULTS: Most vaccinations and outcomes were identified early in the 2006-2007 season; about 50% of vaccinations and short latency events were identified in the second monthly data extract, which would typically become available by mid-December, and 80% of vaccinations and events were identified in the third extract. With respect to overall claims lag, approximately 90% of vaccinations and events were identified within 1 to 2 months after vaccination, regardless of vaccination month. CONCLUSIONS: This study suggests that administrative claims data might contribute to same season influenza vaccine safety surveillance in large, defined populations, especially during a threat of pandemic influenza. Based on our previous work, we believe this method could be applied to multiple health plans' data to monitor a large portion of the US population.

What should an ideal vaccine postlicensure safety system be?

In 2007 the National Vaccine Program, along with the Centers for Disease Control and Prevention, the Food and Drug Administration, the National Institutes of Health, and the Health Resources and Services Administration, sponsored a public conference titled "Vaccine Safety Evaluation: Post Marketing Surveillance." The objective was to discuss enhanced approaches to postlicensure evaluation of vaccine safety, including active and passive surveillance systems and special studies. The conference participants reviewed the evolution of the assessment of vaccine safety, detailed current national approaches to postmarketing safety, and offered new approaches to evaluating vaccine safety. A number of the participants recommended that information systems be expanded to include reliable information on vaccination and health outcomes in large populations. We summarize the major meeting presentations and discussions.

Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine.

CONTEXT: In June 2006, the Food and Drug Administration licensed the quadrivalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine (qHPV) in the United States for use in females aged 9 to 26 years; the Advisory Committee on Immunization Practices then recommended qHPV for routine vaccination of girls aged 11 to 12 years. OBJECTIVE: To summarize reports to the Vaccine Adverse Event Reporting System (VAERS) following receipt of qHPV. DESIGN, SETTING, AND PARTICIPANTS: Review and describe adverse events following immunization (AEFIs) reported to VAERS, a national, voluntary, passive surveillance system, from June 1, 2006, through December 31, 2008. Additional analyses were performed for some AEFIs in prelicensure trials, those of unusual severity, or those that had received public attention. Statistical data mining, including proportional reporting ratios (PRRs) and empirical Bayesian geometric mean methods, were used to detect disproportionality in reporting. MAIN OUTCOME MEASURES: Numbers of reported AEFIs, reporting rates (reports per 100,000 doses of distributed vaccine or per person-years at risk), and comparisons with expected background rates. RESULTS: VAERS received 12 424 reports of AEFIs following qHPV distribution, a rate of 53.9 reports per 100,000 doses distributed. A total of 772 reports (6.2% of all reports) described serious AEFIs, including 32 reports of death. The reporting rates per 100,000 qHPV doses distributed were 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders, and Guillain-Barré syndrome; 0.1 for anaphylaxis and death; 0.04 for transverse myelitis and pancreatitis; and 0.009 for motor neuron disease. Disproportional reporting of syncope and venous thromboembolic events was noted with data mining methods. CONCLUSIONS: Most of the AEFI rates were not greater than the background rates compared with other vaccines, but there was disproportional reporting of syncope and venous thromboembolic events. The significance of these findings must be tempered with the limitations (possible underreporting) of a passive reporting system.

Effects of stratification on data mining in the US Vaccine Adverse Event Reporting System (VAERS).

BACKGROUND: Vaccines are administered differentially according to age and sex, and disease patterns also vary among people of different age and sex groups. Estimates of disproportionality should be calculated based on comparisons of groups that have a similar likelihood of receiving similar vaccines and experiencing similar adverse events, to prevent false disproportionality from occurring. Stratified empirical Bayesian (EB) methods have been compared with crude, but not stratified, proportional reporting ratios (PRRs) in their performance on adverse event data. OBJECTIVES: (i) to implement stratification of PRR; (ii) to quantify and compare vaccine-event pairs that are highlighted by PRR and EB05 (the lower bound of the 90% CI of the EB geometric mean), for both crude and stratified; and (iii) to evaluate the effects of stratification by age and sex, in identifying adverse events that are accepted to be caused by vaccines. METHODS: We applied EB and PRR data mining methods to data from the US Vaccine Adverse Event Reporting System (VAERS). We stratified PRR and EB05 by age and sex. To study the effects of stratification, we compared the crude PRR and stratified PRR. We also assessed the crude EB05 and stratified EB05, and then compared the effects of stratification on EB05 and PRR. RESULTS: Stratification not only changed the number of vaccine-event pairs that were highlighted, but also changed which pairs were highlighted. There were 283 vaccine-event pairs that were highlighted by the crude EB05, but not the stratified; 12 that were highlighted by the stratified EB05, but not the crude; and 162 that were highlighted by both. Similarly, there were 701 vaccine-event pairs that were highlighted by the crude PRR, but not the stratified; 139 that were highlighted by the stratified PRR, but not the crude; and 895 that were highlighted by both. There were 1466 vaccine-event pairs in which the effect of stratification was different for EB05 and PRR. CONCLUSION: To our knowledge, this is the first published analysis using stratified PRRs. In this analysis of passive surveillance data, stratification revealed and reduced confounding in EB and PRR, and also unmasked some vaccine-event pairs that the crude values did not highlight. Stratification should be applied if confounding is suspected. By decreasing the total number of highlighted vaccine-event pairs, stratification is likely to increase efficiency and therefore might reduce workload.

Preventable mix-ups of tuberculin and vaccines: reports to the US Vaccine and Drug Safety Reporting Systems.

BACKGROUND: Errors involving the mix-up of tuberculin purified protein derivative (PPD) and vaccines leading to adverse reactions and unnecessary medical management have been reported previously. OBJECTIVES: To determine the frequency of PPD-vaccine mix-ups reported to the US Vaccine Adverse Event Reporting System (VAERS) and the Adverse Event Reporting System (AERS), characterize adverse events and clusters involving mix-ups and describe reported contributory factors. METHODS: We reviewed AERS reports from 1969 to 2005 and VAERS reports from 1990 to 2005. We defined a mix-up error event as an incident in which a single patient or a cluster of patients inadvertently received vaccine instead of a PPD product or received a PPD product instead of vaccine. We defined a cluster as inadvertent administration of PPD or vaccine products to more than one patient in the same facility within 1 month. RESULTS: Of 115 mix-up events identified, 101 involved inadvertent administration of vaccines instead of PPD. Product confusion involved PPD and multiple vaccines. The annual number of reported mix-ups increased from an average of one event per year in the early 1990s to an average of ten events per year in the early part of this decade. More than 240 adults and children were affected and the majority reported local injection site reactions. Four individuals were hospitalized (all recovered) after receiving the wrong products. Several patients were inappropriately started on tuberculosis prophylaxis as a result of a vaccine local reaction being interpreted as a positive tuberculin skin test. Reported potential contributory factors involved both system factors (e.g. similar packaging) and human errors (e.g. failure to read label before product administration). CONCLUSIONS: To prevent PPD-vaccine mix-ups, proper storage, handling and administration of vaccine and PPD products is necessary.

Potential population-based electronic data sources for rapid pandemic influenza vaccine adverse event detection: a survey of health plans.

PURPOSE: A vaccine against pandemic influenza may be rapidly and widely distributed, and could be used in populations with little prior exposure to influenza vaccines. Under such conditions, it will be important to gain timely information about the rates of vaccine adverse events, ideally by using electronic data from large populations. Many public and private health plans and payers have such information. METHODS: Between May and September 2007, we conducted a decision maker interview and technical assessment with several health plans in the United States. The interview and survey evaluated technical capability, organizational capacity, and willingness to participate in a coordinated program of rapid safety research targeting pandemic and other influenza vaccines. RESULTS: Eleven health plans (eight private, three public) participated in the decision maker interview. Most interviewees were medical directors or held similar positions within their organizations. Participating plans provided coverage and/or care for approximately 150 million members in the U.S. Nine health plans completed a technical assessment survey. Most decision makers indicated interest and willingness to participate in a coordinated rapid safety surveillance program, and all reported the necessary claims data analysis experience. Respondents noted legal, procedural, budgetary, and technical barriers to participation. CONCLUSIONS: Senior decision makers representing private and public health plans were willing and asserted the ability of their organizations to participate in pandemic influenza vaccine safety monitoring. Developing working relationships, negotiating contracts, and obtaining necessary regulatory and legal approvals were identified as key barriers. These findings may be generalizable to other vaccines and pharmaceutical products.

Perinatal hepatitis B transmission and vaccination timing in a managed care cohort: assessment of the temporary delay in newborn hepatitis B vaccination due to thimerosal content.

BACKGROUND: From July to September 1999, due to a concern of toxicity from exposure to thimerosal-containing vaccines, the American Academy of Pediatrics and U.S. Public Health Service temporarily recommended delaying the administration of first dose of hepatitis B vaccine until the age of 2-6 months for infants born to hepatitis B surface antigen negative mothers. Our objectives were to determine whether the recommendation affected the rate of perinatal hepatitis B infection in a multistate managed care population; to describe neonatal and early childhood cases of hepatitis B infection and to evaluate a possible role of the recommendation; and to assess the timeliness, with respect to the U.S. childhood immunization schedule, of vaccinations during the first 2 years of life. METHODS: We identified 3 cohorts of infants born before (July 1998 to June 1999), during (July 1999 to September 1999) and after (October 1999 to September 2000) the recommendation period. We used automated claims data to identify possible neonatal and early childhood hepatitis B cases using specific ICD-9 diagnosis and CPT procedure codes and validated cases through medical record review. Using Health Plan Employer Data and Information Set (HEDIS) data, we calculated vaccination coverage for the first dose of hepatitis B vaccine at 3-month intervals from January 1999 to September 2000. RESULTS: The eligible populations in the "before," "during" and "after" cohorts were 29,347, 7791 and 29,215 infants, respectively. Of 41 possible hepatitis B cases identified in the 3 cohorts, we confirmed 1 case in the after cohort with medical record review. Despite receiving the first dose of hepatitis B vaccine and hepatitis B immunoglobulin within 12-24 hours of birth, the infant was diagnosed with laboratory-confirmed chronic hepatitis B at age of 9 months. An analysis of HEDIS data showed that vaccination coverage for the first dose of hepatitis B vaccine was 98% (January to March 1999) and 96% (April to June 1999) for the "before" cohort and 66% for the "during" cohort. For the "after" cohort the coverage was 72% (October to December 1999), 83% (January to March 2000), 91% (April to June 2000) and 95% (July to September 2000). CONCLUSIONS: This study did not identify any perinatal hepatitis B transmission among health plan enrollees associated with the 1999 recommendation. The recommendation did result in a delay of hepatitis B birth dose in the "during" cohort as intended for infants born to hepatitis B surface antigen negative mothers. Six months after the recommendation was rescinded there was still a delay in the timing of first dose of hepatitis B vaccine, but the timing had returned to the prerecommendation level after 9-12 months.

Developmental regression and autism reported to the Vaccine Adverse Event Reporting System.

We report demographic and clinical characteristics of children reported to the US Vaccine Adverse Event Reporting System (VAERS) as having autism or another developmental disorder after vaccination. We completed 124 interviews with parents and reviewed medical records for 31 children whose records contained sufficient information to evaluate the child's developmental history. Medical record review indicated that 27 of 31 (87%) children had autism/ASD and 19 (61.3%) had evidence of developmental regression (loss of social, language, or motor skills). The proportion of VAERS cases of autism with regression was greater than that reported in population-based studies, based on the subset of VAERS cases with medical record confirmation. This difference may reflect preferential reporting to VAERS of autism with regression. In other respects, the children in this study appear to be similar to other children with autism. Further research might determine whether the pathogenesis of autism with developmental regression differs from that of autism without regression.

Autologous cultured chondrocytes: adverse events reported to the United States Food and Drug Administration.

BACKGROUND: Carticel is an autologous cultured chondrocyte product that has been approved by the United States Food and Drug Administration for the repair of symptomatic cartilaginous defects of the femoral condyle that are caused by acute or repetitive trauma in patients who have been previously managed with arthroscopy or other surgical procedures. The present report describes the adverse events following Carticel implantation as reported to the Food and Drug Administration from 1996 to 2003. METHODS: We reviewed adverse event reports that had been submitted to the Food and Drug Administration's MedWatch system for information on demographic characteristics, adverse events, and surgical revisions. Adverse events were categorized into sixteen non-mutually exclusive groups. Five categories were used to classify reoperations. Food and Drug Administration regulations require manufacturers to report adverse events; however, reporting by clinicians and others is voluntary. Therefore, adverse event reporting is likely to underestimate the number of event occurrences. Adverse events may be either causally or coincidentally related to the product. RESULTS: A total of 497 adverse events among 294 patients receiving Carticel were reported. The median interval from Carticel implantation to the diagnosis of an adverse event was 240 days (range, one to 2105 days). The median age of the patients was thirty-eight years, and 63% of the patients were male. Of the 270 events for which the anatomic site was noted, 258 (96%) involved the femoral condyles. More than one adverse event was reported for 135 patients (46%). The most commonly reported events were graft failure (seventy-three patients; 25%), delamination (sixty-five patients; 22%), and tissue hypertrophy (fifty-two patients; 18%). In addition, eighteen surgical site infections were reported, including eleven joint and seven soft-tissue infections. Surgical revision subsequent to Carticel implantation was mentioned in the records for 273 patients (93%). The reasons for the 389 revision procedures included graft-related problems (187 procedures; 48.1%), periarticular soft-tissue problems (ninety-seven procedures; 24.9%), and intra-articular problems (sixty-three procedures; 16.2%). Eight patients had a total knee replacement. Based on the manufacturer's reported distribution of 7500 Carticel lots between 1995 and 2002, 285 patients (3.8%) had an adverse event that was reported to the Food and Drug Administration. CONCLUSIONS: The most common adverse events reported in association with the Carticel technique involved graft failure, delamination, and tissue hypertrophy.

Thromboembolic adverse events after use of recombinant human coagulation factor VIIa.

CONTEXT: The US Food and Drug Administration (FDA) licensed recombinant human coagulation factor VIIa (rFVIIa) on March 25, 1999, for bleeding in patients with hemophilia A or B and inhibitors to factors VIII or IX. Use in patients without hemophilia has been increasing since licensure. OBJECTIVE: To review serious thromboembolic adverse events (AEs) reported to the FDA's Adverse Event Reporting System (AERS). DESIGN, SETTING, AND PATIENTS: The AERS database was reviewed from March 25, 1999, through December 31, 2004, for thromboembolic AE reports with rFVIIa. The AERS database includes US and non-US spontaneous AE reports from both approved (specific indications for patients with hemophilia) and unlabeled uses. It also includes serious AEs in patients enrolled in postlicensure clinical trials who received rFVIIa. Manufacturer reporting to FDA is mandatory, but primary notification from clinicians and others to FDA or manufacturers is voluntary for spontaneous reports; therefore, AERS underrepresents actual event occurrences. MAIN OUTCOME MEASURE: Reported thromboembolic events occurring in patients administered rFVIIa. RESULTS: A total of 431 AE reports for rFVIIa were found, of which 168 reports described 185 thromboembolic events. Seventeen events occurred in patients with hemophilia and 59 occurred in patients enrolled in postlicensure trials. Unlabeled indications accounted for 151 of the reports, most with active bleeding (n = 115). Reported AEs were thromboembolic cerebrovascular accident (n = 39), acute myocardial infarction (n = 34), other arterial thromboses (n = 26), pulmonary embolism (n = 32), other venous thromboses (including deep vein thrombosis) (n = 42), and clotted devices (n = 10). In 36 (72%) of 50 reported deaths, the probable cause of death was the thromboembolic event. In 144 patients with timing information, 73 events (52%) occurred in the first 24 hours after the last dose (30 events within 2 hours). Sixty-four reports (38%) noted concomitant use of hemostatic agents. Most reports lacked sufficient information to evaluate potential dosage associations. CONCLUSIONS: Most reported thromboembolic AEs followed the use of rFVIIa for unlabeled indications and occurred in arterial and venous systems, often resulting in serious morbidity and mortality. Analysis of the relationship between AEs and rFVIIa is hindered by concomitant medications, preexisting medical conditions, confounding by indication, and inherent limitations of passive surveillance. Randomized controlled trials are needed to establish the safety and efficacy of rFVIIa in patients without hemophilia.

Botulinum toxin type A injections: adverse events reported to the US Food and Drug Administration in therapeutic and cosmetic cases.

BACKGROUND: Botulinum toxin type A (BTA) (Botox) received Food and Drug Administration (FDA) approval for therapeutic treatment of strabismus and blepharospasm in 1989, cervical dystonia in 2000, and cosmetic treatment of glabellar wrinkles (Botox Cosmetic) in 2002. In 2002 alone there were approximately 1.1 to 1.6 million patients using cosmetic BTA. Our objective was to review adverse event (AE) reporting to the FDA after BTA administration. METHODS: We reviewed all (therapeutic and cosmetic use) serious (per FDA regulations) AEs reported to the FDA for the 13.5 years since licensure of the product (December 1989-May 2003) and nonserious AEs reported from December 2001 to November 2002. AEs are reported to the FDA through the MedWatch system. RESULTS: We reviewed 1437 AE reports; 406 followed therapeutic use of BTA (217 serious and 189 nonserious) and 1031 followed cosmetic use (36 serious and 995 nonserious). Reported AEs occurred predominantly in female patients, with a median age of 50 years. In the year December 2001 to November 2002, when both serious and nonserious reports were evaluated, the proportion of reports classified as serious was 33-fold higher for therapeutic than for cosmetic cases. The 217 serious AEs reported in therapeutic cases involved a wide spectrum of events and included all 28 reported deaths. Among cosmetic users, no deaths were reported and, of the 36 serious AEs, 30 were included as possible complications in the FDA-approved label. The remaining 6 serious AEs did not display a pattern suggesting a common causal relationship to BTA. Among the 995 cosmetic cases reported to have nonserious AEs, most commonly noted were lack of effect (623, 63%), injection site reaction (190, 19%), and ptosis (111, 11%). CONCLUSIONS: Serious AEs were more likely to be reported for therapeutic than for cosmetic use, which may be related to higher doses, complicated underlying diseases, or both. Among cosmetic cases, few serious AEs were reported, and these were predominantly events that were previously recognized in clinical trials of BTA for the labeled use. This study is limited primarily by the incomplete nature of AE reporting by clinicians. Numerous departures from FDA-approved recommendations for drug dose, dilution, handling, site of injection, and storage were noted in these AE reports.

Case reports of heart failure after therapy with a tumor necrosis factor antagonist.

BACKGROUND: Etanercept and infliximab are U.S. Food and Drug Administration-approved tumor necrosis factor (TNF) antagonists. OBJECTIVE: To describe adverse event reports of heart failure after TNF antagonist therapy. DESIGN: Case series. SETTING: The U.S. Food and Drug Administration's MedWatch program. PATIENTS: 47 patients who developed new or worsening heart failure during TNF antagonist therapy. MEASUREMENTS: Clinical and laboratory reports. RESULTS: After TNF antagonist therapy, 38 patients developed new-onset heart failure and 9 patients experienced heart failure exacerbation. Of the 38 patients with new-onset heart failure, 19 (50%) had no identifiable risk factors. Ten patients younger than 50 years of age developed new-onset heart failure after receiving TNF antagonists. After TNF antagonist therapy was discontinued and heart failure therapy was started in these 10 patients, 3 had complete resolution of heart failure, 6 improved, and 1 died. CONCLUSION: In a fraction of patients, TNF antagonists might induce new-onset heart failure or exacerbate existing disease.

Adverse events reported following live, cold-adapted, intranasal influenza vaccine.

CONTEXT: In June 2003, the US Food and Drug Administration licensed a trivalent live, attenuated influenza vaccine (LAIV-T) for intranasal administration to healthy persons 5 to 49 years of age. Although prelicensure testing involved 20 228 vaccinees, clinical trials were not of sufficient size to detect rare adverse events reliably. OBJECTIVE: To identify adverse events reported following LAIV-T administration after licensure. DESIGN, SETTING, AND PARTICIPANTS: All adverse events reported to the US Vaccine Adverse Event Reporting System (VAERS) during the 2003-2004 and the 2004-2005 influenza seasons. MAIN OUTCOME MEASURES: Numbers and proportions of reported adverse events and reporting rates of adverse events per 100,000 vaccinees. RESULTS: Approximately 2,500,000 persons received LAIV-T during the first 2 postlicensure seasons. As of August 16, 2005, VAERS received 460 adverse event reports for vaccinations received from August 2003 through July 2005. No fatalities were reported. There were 7 reports of possible anaphylaxis, 2 reports of Guillain-Barré syndrome, 1 report of Bell palsy, and 8 reports of asthma exacerbation among individuals with a prior asthma history. Events in individuals for whom the vaccine was not indicated accounted for 73 reports (16%). CONCLUSIONS: Reports to VAERS in the first 2 seasons of LAIV-T use did not identify any unexpected serious risks with this vaccine when used according to approved indications. Like many vaccines and other medical products, LAIV-T may rarely cause anaphylaxis. Secondary transmission of the vaccine virus merits further investigation. Reports of asthma exacerbations in vaccinees with prior asthma history highlight the risks of vaccine use inconsistent with approved labeling.

Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS)--United States, 1991-2001.

PROBLEM/CONDITION: Vaccines are usually administered to healthy persons who have substantial expectations for the safety of the vaccines. Adverse events after vaccinations occur but are generally rare. Some adverse events are unlikely to be detected in prelicensure clinical trials because of their low frequency, the limited numbers of enrolled subjects, and other study limitations. Therefore, postmarketing monitoring of adverse events after vaccinations is essential. The cornerstone of monitoring safety is review and analysis of spontaneously reported adverse events. REPORTING PERIOD COVERED: This report summarizes the adverse events reported to the Vaccine Adverse Event Reporting System (VAERS) from January 1, 1991, through December 31, 2001. DESCRIPTION OF SYSTEMS: VAERS was established in 1990 under the joint administration of CDC and the Food and Drug Administration (FDA) to accept reports of suspected adverse events after administration of any vaccine licensed in the United States. VAERS is a passive surveillance system: reports of events are voluntarily submitted by those who experience them, their caregivers, or others. Passive surveillance systems (e.g., VAERS) are subject to multiple limitations, including underreporting, reporting of temporal associations or unconfirmed diagnoses, and lack of denominator data and unbiased comparison groups. Because of these limitations, determining causal associations between vaccines and adverse events from VAERS reports is usually not possible. Vaccine safety concerns identified through adverse event monitoring nearly always require confirmation using an epidemiologic or other (e.g., laboratory) study. Reports may be submitted by anyone suspecting that an adverse event might have been caused by vaccination and are usually submitted by mail or fax. A web-based electronic reporting system has recently become available. Information from the reports is entered into the VAERS database, and new reports are analyzed weekly. VAERS data stripped of personal identifiers can be reviewed by the public by accessing http://www.vaers.org. The objectives of VAERS are to 1) detect new, unusual, or rare vaccine adverse events; 2) monitor increases in known adverse events; 3) determine patient risk factors for particular types of adverse events; 4) identify vaccine lots with increased numbers or types of reported adverse events; and 5) assess the safety of newly licensed vaccines. RESULTS: During 1991-2001, VAERS received 128,717 reports, whereas >1.9 billion net doses of human vaccines were distributed. The overall dose-based reporting rate for the 27 frequently reported vaccine types was 11.4 reports per 100,000 net doses distributed. The proportions of reports in the age groups <1 year, 1-6 years, 7-17 years, 18-64 years, and >/= years were 18.1%, 26.7%, 8.0%, 32.6%, and 4.9%, respectively. In all of the adult age groups, a predominance among the number of women reporting was observed, but the difference in sex was minimal among children. Overall, the most commonly reported adverse event was fever, which appeared in 25.8% of all reports, followed by injection-site hypersensitivity (15.8%), rash (unspecified) (11.0%), injection-site edema (10.8%), and vasodilatation (10.8%). A total of 14.2% of all reports described serious adverse events, which by regulatory definition include death, life-threatening illness, hospitalization or prolongation of hospitalization, or permanent disability. Examples of the uses of VAERS data for vaccine safety surveillance are included in this report. INTERPRETATION: As a national public health surveillance system, VAERS is a key component in ensuring the safety of vaccines. VAERS data are used by CDC, FDA, and other organizations to monitor and study vaccine safety. CDC and FDA use VAERS data to respond to public inquiries regarding vaccine safety, and both organizations have published and presented vaccine safety studies based on VAERS data. VAERS data are also used by the Advisory Committee on Immunization Practices and the Vaccine and Related Biological Products Advisory Committee to evaluate possible adverse events after vaccinations and to develop recommendations for precautions and contraindications to vaccinations. Reviews of VAERS reports and the studies based on VAERS reports during 1991-2001 have demonstrated that vaccines are usually safe and that serious adverse events occur but are rare. PUBLIC HEALTH ACTIONS: Through continued reporting of adverse events after vaccination to VAERS by health-care providers, public health professionals, and the public and monitoring of reported events by the VAERS working group, the public health system will continue to be able to detect rare but potentially serious consequences of vaccination. This knowledge facilitates improvement in the safety of vaccines and the vaccination process.

Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor.

Infliximab, a tumor necrosis factor (TNF) antagonist, is associated with tuberculosis (TB), but it is unknown whether this phenomenon is true of all TNF antagonists. We reviewed 25 cases of TB due to another TNF antagonist, etanercept, that were reported to the US Food and Drug Administration (FDA) between November 1998 and March 2002. Such cases are sometimes incomplete and are subject to underreporting. Fifteen patients received other immunosuppressive medications. The median interval between the receipt of the first dose of etanercept and the diagnosis of TB was 11.5 months. Thirteen patients had extrapulmonary TB at the time of diagnosis. Diagnosis was made on the basis of culture results for 12 patients, biopsy findings for 9, and sputum staining for 4. There were 2 deaths, 1 of which was directly attributed to TB. The estimated number of TB cases reported to the FDA for each person-year of treatment with etanercept (i.e., the "reporting rate") among patients with rheumatoid arthritis (RA) was ~10 cases/100,000 patient-years of exposure. Clinicians considering etanercept for patients with RA should be alert to the possibility of the occurrence of TB, sometimes with an unusual extrapulmonary presentation. It is unclear whether etanercept therapy increases the risk of TB beyond the elevated TB rates already documented for patients with RA.

Development of case definitions for acute encephalopathy, encephalitis, and multiple sclerosis reports to the vaccine: Adverse Event Reporting System.

The Vaccine Adverse Event Reporting System (VAERS), administered by the FDA and CDC, is the U.S. system for surveillance of vaccine adverse events (AE). Acute encephalopathy age <18 months (EO < 18), age > or =18 months (EO > or = 18), encephalitis (EI), and multiple sclerosis (MS) after vaccination have been reported to VAERS, but reports often contain insufficient information to validate diagnoses. Standardized case definitions would enhance the utility of VAERS reports for AE surveillance. We developed practical case definitions for classification of VAERS reports, and three neurologists independently applied the definitions to reports submitted in 1993. Inter-observer agreement was assessed, and non-concordant classifications were reviewed in a follow-up conference call. Reports of EO < 18 (n = 8), EO > or = 18 (n = 20), EI (n = 15), and MS (n = 16) were classified as "definite" in 7% to 30% of the cases, while 26% to 51% of reports were thought to have insufficient information to make a classification. Agreement among reviewers was good to excellent, (kappa: 0.65 to 0.85) except for EO < 18 m for which it was marginal (kappa: 0.37). It is possible to develop reproducible case definitions for acute encephalopathy, encephalitis, and multiple sclerosis using a standardized approach. Application of standardized case definitions to VAERS reports documents the limited information in many reports, specifies data for supplemental collection, and indicates that VAERS reports should be cautiously interpreted. Development and application of case definitions for other adverse events reported after vaccination should enhance the value of vaccine safety databases. Published by Elsevier Science Inc.

Understanding vaccine safety information from the Vaccine Adverse Event Reporting System.

The Vaccine Adverse Event Reporting System (VAERS) is administered by the Food and Drug Administration and CDC and is a key component of postlicensure vaccine safety surveillance. Its primary function is to detect early warning signals and generate hypotheses about possible new vaccine adverse events or changes in frequency of known ones. VAERS is a passive surveillance system that relies on physicians and others to voluntarily submit reports of illness after vaccination. Manufacturers are required to report all adverse events of which they become aware. There are a number of well-described limitations of such reporting systems. These include, for example, variability in report quality, biased reporting, underreporting and the inability to determine whether a vaccine caused the adverse event in any individual report. Strengths of VAERS are that it is national in scope and timely. The information in VAERS reports is not necessarily complete nor is it verified systematically. Reports are classified as serious or nonserious based on regulatory criteria. Reports are coded by VAERS in a uniform way with a limited number of terms using a terminology called COSTART. Coding is useful for search purposes but is necessarily imprecise. VAERS is useful in detecting adverse events related to vaccines and most recently was used for enhanced reporting of adverse events in the national smallpox immunization campaign. VAERS data have always been publicly available. However, it is essential for users of VAERS data to be fully aware of the strengths and weaknesses of the system. VAERS data contain strong biases. Incidence rates and relative risks of specific adverse events cannot be calculated. Statistical significance tests and confidence intervals should be used with great caution and not routinely. Signals detected in VAERS should be subjected to further clinical and descriptive epidemiologic analysis. Confirmation in a controlled study is usually required. An understanding of the system's defined objectives and inherent drawbacks is vital to the effective use of VAERS data in vaccine safety investigations.