Spontaneous reports of primary ovarian insufficiency after vaccination: A review of the vaccine adverse event reporting system (VAERS)

BackgroundSince 2012, reports of primary ovarian insufficiency (POI) temporally associated with receipt of human papillomavirus (HPV) vaccine have been published leading to questions about a potential causal association. A Vaccine Safety Datalink study did not find an increased risk for POI after vaccination. We reviewed the Vaccine Adverse Event Reporting System (VAERS) to describe POI reports.MethodsWe searched VAERS, a U.S. passive surveillance system, for domestic POI reports received from 01/01/1990 to 12/31/2017 after any vaccination. The search used both Medical Dictionary for Regulatory Activity Preferred Terms and a text-based search for POI and its symptoms. All reports were reviewed, and the American College of Obstetricians and Gynecologists (ACOG) guidelines for POI diagnosis were applied. Data mining for disproportionate reporting was conducted.ResultsSix hundred fifty-two reports met the search criteria and clinical review identified 19 POI reports. Most reports (n = 16) were received between 2013 and 2017. The median age at vaccination was 14.5 years (range 10–25 years) and the median interval between first dose of vaccination and reporting the event to VAERS was 43 months (range 4–132 months; mean 59.6 months). Four reports met ACOG diagnostic criteria; one with an underlying cause (47XXX chromosomal abnormality) reported. Eleven reports documented menstrual irregularity ≥ 3 months; 5 had ≥ 1 laboratory test result used to diagnose POI. Eighteen of 19 reports described receipt of HPV vaccine with or without other vaccines. Other vaccines reported were meningococcal conjugate vaccine, hepatitis A, varicella and tetanus toxoid, reduced diphtheria toxoid and acellular pertussis. Disproportionate reporting was found for three relevant coding terms after HPV vaccination.ConclusionsPOI is rarely reported to VAERS. Most reports contained limited diagnostic information and were submitted after published cases of POI following HPV vaccination. Results of our review do not suggest a safety concern.     

医疗不良事件报告体系研究

医疗不良事件是指因诊疗活动而非疾病本身造成的损害。建立医疗不良事件报告制度是医院医疗安全体系建设的重要措施之一。医疗不良事件报告应实行非惩罚性报告和奖励措施,要做到“早发现、早报告、早处置、早控制”,目的是及时发现医院安全系统存在的不足,分析整个医疗服务系统中存在的不安全因素,防范医疗事故,保护患者利益。     

Reliability of adverse symptom event reporting by clinicians

Purpose

Adverse symptom event reporting is vital as part of clinical trials and drug labeling to ensure patient safety and inform risk?Cbenefit decision making. The purpose of this study was to assess the reliability of adverse event reporting of different clinicians for the same patient for the same visit.

Methods

A retrospective reliability analysis was completed for a sample of 393 cancer patients (42.8% men; age 26?C91, M?=?62.39) from lung (n?=?134), prostate (n?=?113), and Ob/Gyn (n?=?146) clinics. These patients were each seen by two clinicians who independently rated seven Common Terminology Criteria for Adverse Events (CTCAE) symptoms. Twenty-three percent of patients were enrolled in therapeutic clinical trials.

Results

The average time between rater evaluations was 68?min. Intraclass correlation coefficients were moderate for constipation (0.50), diarrhea (0.58), dyspnea (0.69), fatigue (0.50), nausea (0.52), neuropathy (0.71), and vomiting (0.46). These values demonstrated stability over follow-up visits. Two-point differences, which would likely affect treatment decisions, were most frequently seen among symptomatic patients for constipation (18%), vomiting (15%), and nausea (8%).

Conclusion

Agreement between different clinicians when reporting adverse symptom events is moderate at best. Modification of approaches to adverse symptom reporting, such as patient self-reporting, should be considered.     

近10年药物流行病学研究国内外选题的辨析与启示

  目的  探讨神经外科手术患者抗菌药物应用的药物流行病学特征,并进行合理性评价。  方法  以真实世界研究的方法,采集沈阳市某三级甲等医院2015年1月 — 2020年1月神经外科1446例手术患者病历信息,以《抗菌药物应用时间调查表》分析抗菌药物的应用时机。  结果   1446例神经外科手术患者中,Ⅰ类切口852例,Ⅱ类切口 594 例,抗菌药物使用率为100 %,合计使用5152 例次;抗菌药物应用的适应证合理性为 83.20 %（1203/1446）,手术前使用的合理性为 92.19 %（1333/1446）,手术中追加使用的合理性为 92.95 %（1344/1446）,手术后使用的合理性为 90.25 %（1305/1446）;合计382 例次（7.41 %,382/5152）患者用药时间不合理。  结论   抗菌药物合理使用是需要持续关注的最重要的公共卫生问题之一,把控预防性使用抗菌药物的用药时机有助于提高抗菌药物的合理用药水平。     

Generation of an annotated reference standard for vaccine adverse event reports

As part of a collaborative project between the US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention for the development of a web-based natural language processing (NLP) workbench, we created a corpus of 1000 Vaccine Adverse Event Reporting System (VAERS) reports annotated for 36,726 clinical features, 13,365 temporal features, and 22,395 clinical-temporal links. This paper describes the final corpus, as well as the methodology used to create it, so that clinical NLP researchers outside FDA can evaluate the utility of the corpus to aid their own work. The creation of this standard went through four phases: pre-training, pre-production, production-clinical feature annotation, and production-temporal annotation. The pre-production phase used a double annotation followed by adjudication strategy to refine and finalize the annotation model while the production phases followed a single annotation strategy to maximize the number of reports in the corpus. An analysis of 30 reports randomly selected as part of a quality control assessment yielded accuracies of 0.97, 0.96, and 0.83 for clinical features, temporal features, and clinical-temporal associations, respectively and speaks to the quality of the corpus.     

江苏地区宫内节育器不良事件报告表质量评价方法研究

目的 对国家人口计生委计划生育药具不良反应监测中心收集到的江苏地区宫内节育器（intrauterine devices,IUD）不良事件报告表进行质量评价。方法 根据二阶段抽样原则,随机抽取2012-2014年间收集的IUD不良事件报告表769份,利用自行设计的质评表进行质量评价。结果 769份报告平均得分为（91.76±5.38）,各年分值差异有统计学意义（χ²=293.87,P<0.001）,报告表中不良事件和IUD情况两部分填写不规范和缺项是失分的主要原因。结论 应继续加强针对本地区不同水平的业务培训,采用量化评价指标有利于监测试点报告质量的进一步提高。     

The vaccine adverse event reporting system and vaccine safety research in the genomics era

Advances in genetics hold promise for integrating genomics into vaccine safety research. Given the rarity of many vaccine adverse effects, and the challenges in finding sufficient numbers of patients to study, consideration should be given to employing the Vaccine Adverse Event Reporting System (VAERS) for genetic studies of vaccine adverse events. VAERS could be used to build a repository of biospecimens allowing for the systematic evaluation of vaccine adverse events. If successful, such research would enable the identification of specific subgroups of people at particularly increased risk for adverse events.     

山东省医疗机构医疗不良事件内部报告制度建立现况调查

[目的]了解山东省医疗机构建立和实施内部不良事件报告制度的情况。[方法]采用分层随机抽样方法,调查山东省6个样本市30家二、三级医院内部不良事件报告制度建立情况。[结果]82.76%的医疗机构建立了医疗不良事件内部报告制度,建立内部报告制度的医院数逐年增加,报告数量也逐年增多。[结论]山东省医疗不良事件内部报告制度建立呈普及趋势,但报告环境有待改善。     

Mixed-effects Poisson regression analysis of adverse event reports: the relationship between antidepressants and suicide

A new statistical methodology is developed for the analysis of spontaneous adverse event (AE) reports from post-marketing drug surveillance data. The method involves both empirical Bayes (EB) and fully Bayes estimation of rate multipliers for each drug within a class of drugs, for a particular AE, based on a mixed-effects Poisson regression model. Both parametric and semiparametric models for the random-effect distribution are examined. The method is applied to data from Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) on the relationship between antidepressants and suicide. We obtain point estimates and 95 per cent confidence (posterior) intervals for the rate multiplier for each drug (e.g. antidepressants), which can be used to determine whether a particular drug has an increased risk of association with a particular AE (e.g. suicide). Confidence (posterior) intervals that do not include 1.0 provide evidence for either significant protective or harmful associations of the drug and the adverse effect. We also examine EB, parametric Bayes, and semiparametric Bayes estimators of the rate multipliers and associated confidence (posterior) intervals. Results of our analysis of the FDA AERS data revealed that newer antidepressants are associated with lower rates of suicide adverse event reports compared with older antidepressants. We recommend improvements to the existing AERS system, which are likely to improve its public health value as an early warning system.     

Vaccination of yeast sensitive individuals: review of safety data in the US vaccine adverse event reporting system (VAERS)

The preparation of recombinant hepatitis B vaccines involves using cellular cultures of Saccharomyces cerevisiae, otherwise known as baker's yeast. Prior to vaccine licensure, clinical trials were performed to address whether residual yeast proteins in the vaccines could induce anaphylaxis, including testing for IgE anti-yeast antibody levels. 1-2% of subjects had anti-yeast IgE antibodies before immunization, but demonstrated no significant rise in IgE after HBV. We searched reports in the Vaccine Adverse Event Reporting System (VAERS) for those that mentioned a history of allergy to yeast and then reviewed the adverse events described in these reports for potential anaphylactic reactions. Probable anaphylaxis was defined as the presence of one or more dermatologic symptoms and one or more respiratory, gastrointestinal, or cardiovascular symptoms with onset within 4 h of Hepatitis B vaccination. Possible anaphylaxis was defined in one of two ways: (1) cases that described dermatologic or respiratory symptoms (but not both) occurring within 4h of vaccination; or (2) cases that described one or more dermatologic and/or respiratory symptoms occurring 4-12 h post vaccination. Among the 107 reports of pre-existing "yeast allergies," 11 reports described probable or possible anaphylaxis after HBV. Four additional cases were described after other vaccines. The majority of vaccinees who met the case definitions and had a history of yeast allergies were female, ages ranged from 10 to 64, and symptom onset ranged from 15 min to 5 h after vaccination. No deaths were reported. The small number of reports to VAERS may be partly due to health care professionals observing current contraindications by not vaccinating yeast sensitive individuals. Nevertheless, yeast associated anaphylaxis after HBV in sensitized patients appears to be a rare event.     

Arthritis and arthralgia as an adverse event following immunization: A systematic literature review

Background

Arthritis and arthralgia are reported as adverse events following immunization with various vaccines.

Nutravigilance: principles and practices to enhance adverse event reporting in the dietary supplement and natural products industry

Nutravigilance is defined as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects related to the use of a food, dietary supplement, or medical food”. The nutravigilance approach is derived from well-defined principles of pharmacovigilance in the drug and biologics industries, which have been developed and refined over a number of years through expert recommendations. While the primary purpose of nutravigilance is to protect customer/patient safety, it also serves to reduce product liability risks for manufacturers and marketing agents of such products. Compliance with the current FDA adverse event reporting requirements is suboptimal, and FDA oversight and enforcement activities have recently increased. In order to better protect customer and product safety, dietary supplement manufacturers must significantly change their current approach, and demonstrate a proactive, systematic, risk-based, scientific approach to product safety, similar to one utilized successfully in the pharmaceutical industry. While this article focuses on FDA regulations, the principles are widely relevant to the supplement industry in the rest of the world.     

Postmarketing safety surveillance of quadrivalent recombinant influenza vaccine: Reports to the vaccine adverse event reporting system

On October 7, 2016, the Food and Drug Administration approved recombinant hemagglutinin quadrivalent influenza vaccine (RIV4) (Spodoptera frugiperda cell line; Flublok Quadrivalent) for active immunization for the prevention of influenza disease in individuals 18 years of age and older. Clinical trials did not reveal any major differences in adverse events or serious adverse events following Flublok Quadrivalent versus standard-dose quadrivalent inactivated influenza vaccine. To improve our understanding of the safety profile of this vaccine, we reviewed and summarized adverse event reports after Flublok Quadrivalent administration to the Vaccine Adverse Event Reporting System (VAERS). Through June 30, 2020, VAERS received 849 reports after RIV4 vaccination. The vast majority (810; 95%) were non-serious. Among serious events, there were 10 cases of Guillain-Barré syndrome, including 5 people who required mechanical ventilation and 2 people who died. Many allergic reactions were reported as non-serious, but required interventions to treat a life-threatening event, e.g., epinephrine, nebulizers, albuterol, glucocorticoids, and supplemental oxygen. Two people experienced a positive rechallenge (i.e., allergic reactions after repeated vaccination with RIV4), including a person who—despite premedication with antihistamines—developed respiratory difficulties, required epinephrine, and was transported to the emergency department. The occurrence of anaphylaxis and other allergic reactions in some individuals may reflect an underlying predisposition to atopy that may manifest itself after an exposure to any drug or vaccine, and does not necessarily suggest that Flublok Quadrivalent is particularly allergenic. Postmarketing safety surveillance will continue to be vital for understanding the benefits and risks of quadrivalent recombinant influenza vaccine.     

Testing the technology acceptance model for evaluating healthcare professionals' intention to use an adverse event reporting system

Background. Many healthcare organizations have implemented adverse eventreporting systems in the hope of learning from experience toprevent adverse events and medical errors. However, a numberof these applications have failed or not been implemented aspredicted. Objective. This study presents an extended technology acceptance modelthat integrates variables connoting trust and management supportinto the model to investigate what determines acceptance ofadverse event reporting systems by healthcare professionals. Method. The proposed model was empirically tested using data collectedfrom a survey in the hospital environment. A confirmatory factoranalysis was performed to examine the reliability and validityof the measurement model, and a structural equation modelingtechnique was used to evaluate the causal model. Results. The results indicated that perceived usefulness, perceived easeof use, subjective norm, and trust had a significant effecton a professional's intention to use an adverse event reportingsystem. Among them, subjective norm had the most contribution(total effect). Perceived ease of use and subjective norm alsohad a direct effect on perceived usefulness and trust, respectively.Management support had a direct effect on perceived usefulness,perceived ease of use, and subjective norm. Conclusion. The proposed model provides a means to understand what factorsdetermine the behavioral intention of healthcare professionalsto use an adverse event reporting system and how this may affectfuture use. In addition, understanding the factors contributingto behavioral intent may potentially be used in advance of systemdevelopment to predict reporting systems acceptance.     

医疗不良事件报告系统的研究进展

医疗不良事件报告系统对于提高医疗质量、保障患者安全的积极作用已经在世界范围内被人们所肯定和接受。从医疗不良事件的定义、分类、发生情况和医疗不良事件报告系统的建立、分类以及国内外的研究进展等方面对医疗不良事件报告系统的研究进展作了简要概述,并就如何加快我国医疗不良事件报告系统地建设与完善,充分保障患者安全提出了分析与思考。