Emily Jane Woo

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.

Adverse Events After Recombinant Human BMP2 in Nonspinal Orthopaedic Procedures

BackgroundThe FDA has approved recombinant human bone morphogenetic protein 2 (rhBMP-2) for treating acute, open tibial shaft fractures. However, the nature and frequency of complications after the use of rhBMP-2 in nonspinal orthopaedic surgery have not been well characterized.Questions/purposesTo determine what types of adverse events have been reported after the use of rhBMP-2, whether they were severe enough to require additional surgery, and after what types of operations these adverse events occurred.MethodsAdverse events reported to the FDA’s Manufacturer and User Facility Device Experience database were reviewed and summarized.ResultsThrough December 31, 2011, the FDA has received 62 reports of adverse events involving rhBMP-2 in nonspinal orthopaedic procedures. Surgical site infections and other wound complications, heterotopic bone, pseudarthrosis, and local inflammation were among the most commonly reported adverse events. Almost half of the reports (30 reports; 48%) stated that the patients required secondary interventions to address the reported adverse events. The majority (49 reports; 79%) described adverse events occurring after unapproved uses, such as management of tibial plateau fractures, treatment of congenital pseudarthrosis of the tibia, and humeral reconstruction.ConclusionsSerious adverse events can occur after the use of rhBMP-2 in nonspinal orthopaedic procedures and may necessitate additional surgery. Most events in this analysis occurred after off-label uses. Postmarketing review of adverse event reports remains an important approach for identifying potential safety concerns.

Adverse Events Reported After the Use of Recombinant Human Bone Morphogenetic Protein 2

PURPOSE The US Food and Drug Administration has approved recombinant human bone morphogenetic protein 2 (rhBMP-2) (Infuse Bone Graft; Medtronic Sofamor Danek, Minneapolis, MN) as an alternative to autogenous bone graft for sinus augmentations and for localized alveolar ridge augmentations for defects associated with extraction sockets. The objective of this analysis was to characterize adverse events reported after the use of rhBMP-2 in oral and maxillofacial procedures. MATERIALS AND METHODS The US Food and Drug Administrations Manufacturer and User Facility Device Experience database contains reports of adverse events involving medical devices. The publicly available version of the database was searched for reports for the brand name Infuse Bone Graft. Descriptive statistics were used to summarize the procedures and adverse events. RESULTS As of April 30, 2011, the Manufacturer and User Facility Device Experience database contained 83 reports of adverse events after oral and maxillofacial operations involving rhBMP-2. Of these reports, 55 (66.3%) described off-label uses, such as reconstruction of the mandible after fracture or cancer or alveolar cleft repair. The most commonly reported adverse events included local reactions, graft failure, infections, and other wound complications. Of the reports, 25 (30.1%) stated that the patient required additional surgery to address the reported adverse event. CONCLUSIONS Serious adverse events, some of which may require a second operation, can occur after the use of rhBMP-2 in oral and maxillofacial procedures. In this analysis graft, failure and pseudarthrosis were more commonly reported after off-label uses of rhBMP-2 than approved uses.

Kawasaki disease after vaccination: reports to the vaccine adverse event reporting system 1990-2007.

Background: Kawasaki disease (KD) is a multisystemic vasculitis primarily affecting children <5 years. A review of RotaTeq (rotavirus vaccine live) clinical trial data revealed higher, though not statistically significantly, KD rates among RotaTeq vaccines than placebo recipients. In June 2007, the RotaTeq label was revised accordingly. Objectives: To describe and assess KD reported to Vaccine Adverse Event Reporting System (VAERS) for all US licensed vaccines. Methods: We reviewed all KD reports received by VAERS from 1990 through mid-October 2007. Cases were characterized by age, gender, onset interval, and vaccine type. Proportional reporting ratio (PRR) was used to evaluate KD reporting for each vaccine compared with all others. Reporting rates were calculated using number of doses distributed as denominator. Results: Through October14, 2007, 107 KD reports were received by VAERS: 26 were categorized as classic cases, 19 atypical, 52 possible, and 10 were noncases. Of the 97 cases, 91% were children <5 years. There was no clustering of onset intervals after day 1 postvaccination. Before the RotaTeq label revision, the KD PRR was elevated only for Pediarix (DTaP, hepB, and IPV combined) but the KD reporting rate for Pediarix (0.59/100,000 person-years) was much lower than the background incidence rate (9–19/100,000 person-years) for children <5 years in the United States. After the revision, reporting of KD for RotaTeq was stimulated but the reporting rate for RotaTeq (1.47/100,000 person-years) was still much lower than the background rate. Conclusions: Our review does not suggest an elevated KD risk for RotaTeq or other vaccines. Continued postmarketing monitoring for KD is ongoing.

Vaccine Risk Perception Among Reporters of Autism After Vaccination: Vaccine Adverse Event Reporting System 1990–2001

OBJECTIVES We investigated vaccine risk perception among reporters of autism to the Vaccine Adverse Event Reporting System (VAERS). METHODS We conducted structured interviews with 124 parents who reported autism and related disorders to VAERS from 1990 to 2001 and compared results with those of a published survey of parents in the general population. RESULTS Respondents perceived vaccine-preventable diseases as less serious than did other parents. Only 15% of respondents deemed immunization extremely important for childrens health; two thirds had withheld vaccines from their children. CONCLUSIONS Views of parents who believe vaccines injured their children differ significantly from those of the general population regarding the benefits of immunization. Understanding the factors that shape this perspective can improve communication among vaccine providers, policymakers, and parents/patients.

Thrombocytopenia after vaccination: case reports to the US Vaccine Adverse Event Reporting System, 1990-2008.

We reviewed thrombocytopenia (TP) reports to the US Vaccine Adverse Event Reporting System (VAERS). We examined TP patterns for differences in single versus multiple immunization reports, presence of a live viral vaccine, seriousness, age, and interval to symptom onset. We found 1510 reports of possible TP and after exclusions evaluated 1440 for possible causes. Most (1078; 75%) met the regulatory definition of a serious adverse event. TP was reported after inactivated and live viral vaccines. Platelet counts <10×10(9)/L were reported. Identified vaccines could be prioritized for hypothesis-testing studies.

Letter to the Editor: Fatal varicella due to the vaccine-strain varicella-zoster virus

Leung et al. present a case report of a fatal varicella due to vaccine-strain virus. In an earlier US case, vaccine-strain varicella zoster virus (VZV) may have contributed to death after routine immunization with live varicella vaccine. In 2006, the US Vaccine Adverse Event Reporting System (VAERS) received the following information. Within 4 weeks after vaccination with live varicella vaccine and live measles, mumps, and rubella vaccine, a 13-month-old female was hospitalized with disseminated varicella, septic shock, and multi-organ failure. During her hospitalization, she was diagnosed with severe combined immunodeficiency (SCID) due to adenosine deaminase deficiency (ADA). She had clinical varicella and a progressive severe pulmonary syndrome with isolation of all 4 vaccine viruses from the respiratory tract. In addition, she had a generalized rash that a dermatologist described as consistent with active varicella infection, and viral culture demonstrated varicella (strain not specified). Treatment included acyclovir, foscarnet, cefotaxime, ribavirin, clindamycin, trimethoprim-sulfamethoxazole, and fluconazole. Her hospital course was notable for respiratory failure requiring high-frequency oscillatory ventilation and extracorporeal membrane oxygenation; cardiovascular compromise and shock necessitating hemodynamic and inotropic support; neurological deterioration; and deep venous thrombosis. Sputum culture and polymerase chain reaction identified vaccine-strain varicella, measles, mumps, and rubella. Hypotension and irreversible respiratory failure persisted, despite extensive inotropic support and attempts at mechanical ventilation, and the child died approximately 10 weeks after vaccination. According to the autopsy report, the cause of death was catastrophic left intracerebral hemorrhage with uncal and cerebellar tonsillar herniation complicating SCID related to ADA, with multiple vaccine-derived viral infections and in-hospital development of non-vaccine-related adenovirus pneumonia. Postmortem evaluation revealed the vaccine strains of varicella, measles, mumps, and rubella in the lungs, and multiple healed, scabbed lesions consistent with varicella were noted on the skin. Retrospective medical chart review revealed a long history of recurrent pulmonary infections, persistent oral candidiasis, failure to thrive, and possible pulmonary fibrosis—evidence that might have prompted a work-up for congenital immunodeficiency. Although it is difficult to assess the relative contribution of each of the vaccine viruses, particularly in the context of adenovirus pneumonia, the isolation of vaccine-strain viruses in biologic specimens suggests a causal or contributory role in the death of this severely immunocompromised child. Vaccination has substantially reduced the burden of wild-type disease from varicella as well as measles, but live viral vaccines carry a small risk of serious complications in very rare circumstances. These 2 fatalities emphasize the importance of obtaining a careful history to identify individuals in whom an evaluation for immunodeficiency may be warranted. For those whose medical histories suggest immunodeficiency disorders (e.g., individuals with frequent or persistent infections), evaluation before vaccination should be considered to determine whether these patients are immunocompetent and to determine the risks and benefits of vaccination.

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 childs 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.

Adverse Events After MMR or MMRV Vaccine in Infants Under Nine Months Old.

Background: In the United States, measles is resurging, with more than 700 confirmed cases since January 2014. During measles outbreaks, vaccination as early as at 6 months of age is sometimes recommended for infants who are at risk for exposure. Methods: We searched the Vaccine Adverse Event Reporting System for reports of measles, mumps and rubella vaccine combined or measles, mumps, rubella and varicella vaccine combined vaccination in children less than 9 months of age. We performed a clinical assessment of each report and summarized the frequency, range, onset time and severity of adverse events. Results: After excluding 346 reports because they were duplicates or because they contained insufficient information about the child’s age or vaccine(s), we retained 204 reports in the analysis, including 35 (17%) that were serious. Among the 169 nonserious reports, more than half (88; 52%) described a vaccination error without any adverse event per se. Other nonserious reports described fever, injection reactions and gastrointestinal symptoms. Serious adverse events included developmental disorders, fever and fussiness. There were 44 reports of fever, but only 4 cases began 5–12 days after immunization, the peak risk window. The vast majority of fever reports listed concomitant vaccines, such as diphtheria and tetanus toxoids, acellular or whole-cell pertussis vaccine. Conclusions: This review did not identify any major safety concerns. These findings may facilitate discussions about the risks and benefits of vaccinating infants who are potentially exposed to this life-threatening disease.

Using Probabilistic Record Linkage of Structured and Unstructured Data to Identify Duplicate Cases in Spontaneous Adverse Event Reporting Systems

IntroductionDuplicate case reports in spontaneous adverse event reporting systems pose a challenge for medical reviewers to efficiently perform individual and aggregate safety analyses. Duplicate cases can bias data mining by generating spurious signals of disproportional reporting of product-adverse event pairs.ObjectiveWe have developed a probabilistic record linkage algorithm for identifying duplicate cases in the US Vaccine Adverse Event Reporting System (VAERS) and the US Food and Drug Administration Adverse Event Reporting System (FAERS).MethodsIn addition to using structured field data, the algorithm incorporates the non-structured narrative text of adverse event reports by examining clinical and temporal information extracted by the Event-based Text-mining of Health Electronic Records system, a natural language processing tool. The final component of the algorithm is a novel duplicate confidence value that is calculated by a rule-based empirical approach that looks for similarities in a number of criteria between two case reports.ResultsFor VAERS, the algorithm identified 77% of known duplicate pairs with a precision (or positive predictive value) of 95%. For FAERS, it identified 13% of known duplicate pairs with a precision of 100%. The textual information did not improve the algorithm’s automated classification for VAERS or FAERS. The empirical duplicate confidence value increased performance on both VAERS and FAERS, mainly by reducing the occurrence of false-positives.ConclusionsThe algorithm was shown to be effective at identifying pre-linked duplicate VAERS reports. The narrative text was not shown to be a key component in the automated detection evaluation; however, it is essential for supporting the semi-automated approach that is likely to be deployed at the Food and Drug Administration, where medical reviewers will perform some manual review of the most highly ranked reports identified by the algorithm.