Background Despite widely available safety information for the COVID-19 vaccines, vaccine hesitancy remains a challenge. In some cases, vaccine hesitancy may be related to concerns about the number of reports of death to the Vaccine Adverse Event Reporting System (VAERS). Objective To provide information and context about reports of death to VAERS following COVID-19 vaccination. Design Descriptive study; reporting rates for VAERS death reports. Setting United States; December 14, 2020, to November 17, 2021. Participants COVID-19 vaccine recipients. Measurements Reporting rates for death events per million persons vaccinated; adverse event counts; data mining signals of disproportionate reporting. Results 9,201 death events were reported for COVID-19 vaccine recipients aged five years and older (or age unknown). Reporting rates for death events increased with increasing age, and males generally had higher reporting rates than females. For death events within seven days and 42 days of vaccination, respectively, observed reporting rates were lower than the expected all-cause death rates. Reporting rates for Ad26.COV2.S vaccine were generally higher than for mRNA COVID-19 vaccines, but still lower than the expected all-cause death rates. Reported adverse events were non-specific or reflected the known leading causes of death. Limitations VAERS data are subject to several limitations such as reporting bias (underreporting and stimulated reporting), missing or inaccurate information, and lack of a control group. Reported diagnoses, including deaths, are not causally verified diagnoses. Conclusion Reporting rates for death events were lower than the expected all-cause mortality rates. Trends in reporting rates reflected known trends in background mortality rates. These findings do not suggest an association between vaccination and overall increased mortality. Funding Source No external sources of funding were used.

Importance As part of postauthorization safety surveillance, the US Food and Drug Administration (FDA) has identified a potential safety concern for Guillain-Barré syndrome (GBS) following receipt of the Ad26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccine. Objective To assess reports of GBS received in the Vaccine Adverse Event Reporting System (VAERS) following Ad26.COV2.S vaccination. Design, Setting, and Participants Reports of presumptive GBS were identified in a US passive reporting system (VAERS) February-July 2021 and characterized, including demographics, clinical characteristics, and relevant medical history. Exposures Receipt of the Ad26.COV2.S vaccine; the comparator was the background rate of GBS in the general (unvaccinated) population that had been estimated and published based on a standardized case definition. Main Outcomes and Measures Presumptive GBS; the reporting rate was analyzed, including calculation of the observed to expected ratio based on background rates and vaccine administration data. Because of limited availability of medical records, cases were not assessed according to the Brighton Collaboration criteria for GBS. Results As of July 24, 2021, 130 reports of presumptive GBS were identified in VAERS following Ad26.COV2.S vaccination (median age, 56 years; IQR, 45-62 years; 111 individuals [86.0%] were < 65 years; 77 men [59.7%]). The median time to onset of GBS following vaccination was 13 days (IQR, 10-18 days), with 105 cases (81.4%) beginning within 21 days and 123 (95.3%) within 42 days. One hundred twenty-one reports (93.1%) were serious, including 1 death. With approximately 13 209 858 doses of vaccine administered to adults in the US, the estimated crude reporting rate was 1 case of GBS per 100 000 doses administered. The overall estimated observed to expected rate ratio was 4.18 (95% CI, 3.47-4.98) for the 42-day window, and in the worst-case scenario analysis for adults 18 years or older, corresponded to an estimated absolute rate increase of 6.36 per 100 000 person-years (based on a rate of approximately 8.36 cases per 100 000 person-years [123 cases per 1 472 162 person-years] compared with a background rate of approximately 2 cases per 100 000 person-years). For both risk windows, the observed to expected rate ratio was elevated in all age groups except individuals aged 18 through 29 years. Conclusions and Relevance These findings suggest a potential small but statistically significant safety concern for Guillain-Barré syndrome following receipt of the Ad26.COV2.S vaccine. However, the findings are subject to the limitations of passive reporting systems and presumptive case definition, and they must be considered preliminary pending analysis of medical records to establish a definitive diagnosis.

Background: Guillain-Barre syndrome (GBS) is a serious acute demyelinating disease, an increased risk of which was found after the 1976 swine flu vaccinations. The U.S. Food and Drug Administration, in collaboration with the Centers for Medicare & Medicaid Services, has been conducting active surveillance for GBS after influenza vaccinations of Medicare Fee-For-Service beneficiaries since 2009. Methods: We conducted active surveillance for CBS claims in the 2015-2016 and 2016-2017 influenza seasons using the Updating Sequential Probability Ratio Test (USPRT) to monitor for signals of GBS risk. We performed self-controlled risk interval (SCRI) analyses at the end of both seasons, including chart confirmation in the 2015-2016 season, to estimate the odds ratio of GBS risk. We used 1-42 and 8-21 days post-vaccination as primary and secondary risk windows, respectively, and 43-84 days post-vaccination as the control window. Results: Over 13 million beneficiaries were vaccinated in each season. USPRT found a low magnitude signal for GBS in both seasons. SCRI analyses did not find excess GBS risk following any influenza vaccine for days 1-42 post-vaccination in either season. In the 2015-2016 season, for the 8-21 day window, our chart-confirmation showed an attributable GBS risk of 0.87 (95% CI: 0.16, 1.49) and 1.68 (95% Cl: 0.69, 2.41) cases per million vaccinees after all seasonal and high dose (HD) vaccines, respectively, an elevated GBS risk for beneficiaries aged >= 75 years following all seasonal vaccines (OR: 2.25; 95% CI: 1.15, 4.39) and HD vaccine (OR: 3.67, 95% CI: 1.52, 8.85), and an elevated GBS risk for males who received seasonal vaccines (OR: 2.18; 95% CI: 1.15, 4.15) and HD vaccine (OR: 3.33; 95% CI: 1.35, 8.20). The finding of elevated CBS risk with advancing age and in males is consistent with literature; however, a distinction between HD and SD was a new finding. In the 2016-17 season, for the 8-21 day window, attributed cases showed an attributable GBS risk of 0.87 (95% CI: 0.03, 1.61) and 1.11 (95% CI: 0.00, 2.01) cases per million vaccinees after all seasonal and HD vaccines, respectively. We found no excess GBS risk for standard dose vaccines in the 8-21 day window in either season. Conclusions: Our primary analysis finding of no excess GBS risk during both seasons was reassuring. The slightly elevated GBS risk, although in the expected range, in the 8-21 day window after all seasonal and high dose vaccines, but not after standard dose vaccines is hypothesis-generating because the difference may be due to vaccine factors such as antigen amount or strains in various seasons or due to host factors. (C) 2019 Elsevier Ltd. All rights reserved.

Introduction Duplicate 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. Objective We 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). Methods In 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. Results For 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. Conclusions The 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.

Introduction: The Vaccine Adverse Event Reporting System (VAERS) is the spontaneous (passive) reporting system CDC and FDA use to monitor vaccine safety. We used cognitive testing to evaluate proposed revisions to the current VAERS form.Methods: We conducted in-person cognitive interviews with 22 volunteers to evaluate proposed revisions in a prototype VAERS 2.0 form (new VAERS form). We analyzed data using thematic analysis.Results: Repeating themes included preferences for: brevity, simplicity and clarity; features to minimize time requirements and facilitate ease of completion; logical ordering of questions by topic and importance; and visual cues like color-coded highlighting. Interviews identified instances of discordance between the intended meaning questions (from the perspective of CDC and FDA) and interpretation by volunteers.Conclusions: Cognitive testing yielded useful information to guide further revisions of the VAERS form. Cognitive testing can be an effective tool for public health programs interested in developing surveys and reporting forms. Published by Elsevier Ltd.

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There have been isolated case reports of medication product mix-ups involving insulin unintentionally given to patients when the intent was to administer vaccines. Information on how and why these types of errors occur is limited.

OBJECTIVE To determine the effect of graft choice (allograft, bone-patellar tendon-bone autograft, or hamstring autograft) on deep tissue infections following anterior cruciate ligament (ACL) reconstructions. DESIGN Retrospective cohort study. SETTING AND POPULATION Patients from 6 US health plans who underwent ACL reconstruction from January 1, 2000, through December 31, 2008. METHODS We identified ACL reconstructions and potential postoperative infections using claims data. A hierarchical stratified sampling strategy was used to identify patients for medical record review to confirm ACL reconstructions and to determine allograft vs autograft tissue implanted, clinical characteristics, and infection status. We estimated infection rates overall and by graft type. We used logistic regression to assess the association between infections and patients’ demographic characteristics, comorbidities, and choice of graft. RESULTS On review of 1,452 medical records, we found 55 deep wound infections. With correction for sampling weights, infection rates varied by graft type: 0.5% (95% CI, 0.3%-0.8%) with allografts, 0.6% (0.1%–1.5%) with bone-patellar tendon-bone autografts, and 2.5% (1.9%–3.1%) with hamstring autograft. After adjusting for potential confounders, we found an increased infection risk with hamstring autografts compared with allografts (odds ratio, 5.9; 95% CI, 2.8–12.8). However, there was no difference in infection risk among bone-patellar tendon-bone autografts vs allografts (odds ratio, 1.2; 95% CI, 0.3–4.8). CONCLUSIONS The overall risk for deep wound infections following ACL reconstruction is low but it does vary by graft type. Infection risk was highest in hamstring autograft recipients compared with allograft recipients and bone-patellar tendon-bone autograft recipients. Infect Control Hosp Epidemiol 2016;37:827–833

Objective.To explore the feasibility of identifying anterior cruciate ligament (ACL) allograft implantations and infections using claims.Design.Retrospective cohort study.Methods.We identified ACL reconstructions using procedure codes at 6 health plans from 2000 to 2008. We then identified potential infections using claims-based indicators of infection, including diagnoses, procedures, antibiotic dispensings, specialty consultations, emergency department visits, and hospitalizations. Patients' medical records were reviewed to determine graft type, validate infection status, and calculate sensitivity and positive predictive value (PPV) for indicators of ACL allografts and infections.Results.A total of 11,778 patients with codes for ACL reconstruction were identified. After chart review, PPV for ACL reconstruction was 96% (95% confidence interval [CI], 94%–97%). Of the confirmed ACL reconstructions, 39% (95% CI, 35%–42%) used allograft tissues. The deep infection rate after ACL reconstruction was 1.0% (95% CI, 0.7%–1.4%). The odds ratio of infection for allografts versus autografts was 0.41 (95% CI, 0.19–0.78). Sensitivity of individual claims-based indicators for deep infection after ACL reconstruction ranged from 0% to 75% and PPV from 0% to 100%. Claims-based infection indicators could be combined to enhance sensitivity or PPV but not both.Conclusions.While claims data accurately identify ACL reconstructions, they poorly distinguish between allografts and autografts and identify infections with variable accuracy. Claims data could be useful to monitor infection trends after ACL reconstruction, with different algorithms optimized for different surveillance goals.Infect Control Hosp Epidemiol 2014;35(6):652–659

Objective: To estimate the incidence of infectious endophthalmitis after corneal transplant or cataract surgery, to evaluate the trend of endophthalmitis during the study period, and to assess demographic risk factors for endophthalmitis after surgeries.Design: A retrospective population-based cohort study.Participants and Controls: Study cohorts were derived from the Medicare claims databases, 2006 to 2011. Patients were continuously enrolled in Medicare Part A, Part B, and Part D. Patients undergoing corneal transplant or cataract surgery were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes.Methods: Endophthalmitis was defined in 3 different ways: (1) using ICD-9-CM codes (sensitive definition), (2) combining ICD-9-CM codes with Current Procedural Terminology, Fourth Edition (CPT-4) codes (specific definition), or (3) combining ICD-9-CM codes with antifungal prescriptions for endophthalmitis caused by fungal infection. Demographic risk factors for endophthalmitis were examined using multivariate Cox models.Main Outcome Measures: Incidence rates of endophthalmitis were calculated and compared for each definition of endophthalmitis at 6-week and 6-month intervals after corneal transplant or cataract surgery.Results: The infectious endophthalmitis incidence rates ranged from 0.11% to 1.05% in the corneal transplant cohort, 0.06% to 0.20% in the cataract surgery cohort, and 0.16% to 0.68% in the concurrent surgery cohort, depending on the definition and time interval after surgery. Compared with the cataract surgery cohort, the corneal transplant cohort had a higher adjusted hazard ratio (HR) of endophthalmitis within the 6-week postoperative interval (HR, 2.744; 95% confidence interval [CI], 1.544-4.880 in the sensitive definition and HR, 2.792; 95% CI, 1.146-6.802 in the specific definition) and within the 6-month postoperative interval (HR, 4.607; 95% CI, 3.144-6.752 for the sensitive definition and HR, 4.385; 95% CI, 2.245-8.566 for the specific definition).Conclusions: It is possible to monitor the trend of infectious endophthalmitis after corneal transplant or cataract surgery through examining Medicare claims databases as long as a consistent definition of endophthalmitis is used. The annual incidence of endophthalmitis was stable over time during the study period for both corneal transplant and cataract surgery procedures; however, there was a wider year-to-year variation for the corneal transplant cohort. (C) 2014 by the American Academy of Ophthalmology.

Meghan Baker1, Michael Nguyen2, Jerald Mullersman2, Jillian Lauer3, Craig Zinderman2, Karen Riedlinger4, Cynthia Nakasato5, Elizabeth Chrischilles6, Crystal Garcia3, Carolyn Balsbaugh3 and Madhavi Vajani3 1Harvard Medical School, Brigham and Women’s Hospital 2Food and Drug Administration 3Harvard Medical School 4Kaiser Permanente Northwest 5Kaiser Permanente Hawaii 6University of Iowa

Assess whether Medicare data are useful for monitoring tissue allograft safety and utilization. We used health care claims (billing) data from 2007 for 35 million fee-for-service Medicare beneficiaries, a predominantly elderly population. Using search terms for transplant-related procedures, we generated lists of ICD-9-CM and CPT(®) codes and assessed the frequency of selected allograft procedures. Step 1 used inpatient data and ICD-9-CM procedure codes. Step 2 added non-institutional provider (e.g., physician) claims, outpatient institutional claims, and CPT codes. We assembled preliminary lists of diagnosis codes for infections after selected allograft procedures. Many ICD-9-CM codes were ambiguous as to whether the procedure involved an allograft. Among 1.3 million persons with a procedure ascertained using the list of ICD-9-CM codes, only 1,886 claims clearly involved an allograft. CPT codes enabled better ascertainment of some allograft procedures (over 17,000 persons had corneal transplants and over 2,700 had allograft skin transplants). For spinal fusion procedures, CPT codes improved specificity for allografts; of nearly 100,000 patients with ICD-9-CM codes for spinal fusions, more than 34,000 had CPT codes indicating allograft use. Monitoring infrequent events (infections) after infrequent exposures (tissue allografts) requires large study populations. A strength of the large Medicare databases is the substantial number of certain allograft procedures. Limitations include lack of clinical detail and donor information. Medicare data can potentially augment passive reporting systems and may be useful for monitoring tissue allograft safety and utilization where codes clearly identify allograft use and coding algorithms can effectively screen for infections.

Background/Aims The infectious risk of human tissue allografts is unknown. Healthcare claims data from large populations may be useful for quantifying and monitoring rates of infection after tissue allograft transplantation, but require accurate algorithms to identify allograft implantations and infections. We explored the feasibility of identifying allograft implantations and infections using claims data. Methods We identified all patients with procedure codes for anterior cruciate ligament (ACL) surgery within four HMO Research Network sites during calendar years 2000–2008. Charts were randomly selected for review to determine the frequency of allograft versus autograft use. We then flagged patients with claims-based indicators of possible infection including suggestive ICD9 diagnosis codes, procedures, antibiotic prescriptions, specialty consultations, emergency department visits, and readmissions within the 90 days following surgery. We reviewed charts of patients with and without infection indicators and calculated the sensitivity and positive predictive value of individual indicators as well as combinations of multiple indicators. Results We identified 6,615 patients with codes for ACL surgeries in four HMO Research Network sites. On review of randomly selected charts, allografts were utilized in 128/536 (24%) surgeries and autografts in 392/536 (73%) surgeries. Implant type was inadequately documented in the remaining 16 charts (3%). Possible claims-based infection indicators were present in 1,827/6,615 (28%) surgeries. We reviewed 765 charts with indicators of possible infection and 475 charts without infectious indicators. There were 30 confirmed deep tissue infections, all amongst patients with possible infection indicators. Correcting for sampling weights, we estimated 1.6 versus 1.0 infections per 100 surgeries in allograft versus autograft implants (crude odds ratio 1.7, 95% CI 1.1–2.8). The sensitivity of individual indicators ranged from 0 to 70% and positive predictive value from 0 to 24%. Combining indicators increased sensitivity to >90% but positive predictive values remained poor. Discussion Procedure codes for ACL surgeries are not specific for allograft versus autograft implants. Claims-based indicators of possible infections reliably capture all patients with serious infections but also flag many false positives. We are now validating the sensitivity and positive predictive value of claims-based infection indicators using data from two additional HMO Research Network sites.

Processors distributed about 1.5 million human tissue allografts in the U.S. in 2007. The potential for transmitting infections through allografts concerns clinicians and patients. In 2005, FDA implemented Current Good Tissue Practice (CGTP) rules requiring tissue establishments to report to FDA certain serious infections after allograft transplantations. We describe infection reports following tissue transplants received by FDA from 2005 through June, 2010, and compare reporting before and after implementation of CGTP rules. We identified reports received by FDA from January 2001 through June, 2010, for infections in human tissue recipients, examining the reports by tissue type, organism, time to onset, severity, and reporter characteristics. Among 562 reports, 83 (20.8/year) were received from 2001-2004, before the CGTP rules, 43 in the 2005 transition year, and 436 (96.9/year) from 2006 through June, 2010, after the rules. Tissue processors accounted for 84.2% of reports submitted after the rules, compared to 26.5% previously. Bacterial infections were the most commonly reported organisms before (64.6%) and after (62.2%) the new rules. Afterward, 2.5% (11) of reports described deaths, and 33.7% (147) involved hospitalizations. Before the rules, 13% (11) described deaths, and another 72% involved hospitalizations. Reports received by the FDA quadrupled since 2005, suggesting that CGTP regulations have contributed to increased reporting and improved tissue safety surveillance. However, these data do not confirm that the reported infections were caused by suspect tissues; most reports may represent routine post-surgical infections not actually due to allografts.

Background: Nonstandardized allergen extracts have been used for a century. Until 1972, these products were regulated by the National Institutes of Health, and products were not required to have an individualized showing of effectiveness. Jurisdiction was then transferred to the US Food and Drug Administration (FDA), which established external review panels to make recommendations regarding safety and effectiveness. Two external panels deliberated, the first from 1974-1979 and the second from 1982-1983.Objective: We sought to review external panels' recommendations and assess the safety and effectiveness of nonstandardized allergen extracts, FDA-reviewed available literature, and databases since 1972.Methods: Currently licensed nonstandardized allergen extracts were reviewed according to extract type. Available data were collected from medical and nonscientific search engines. Nomenclature was ascertained by consulting www.itis.gov or www.atcc.org. The FDA's Adverse Event Reporting System was probed for events associated with extract use. Provisional threshold levels of safety and effectiveness were established, and extracts were sorted according to whether they met the thresholds.Results: In the Adverse Event Reporting System, there were 178 adverse event reports, including 13 deaths, associatedwith allergen extract use over 23 years. Nosingle group of extracts predominated. Among 1269 allergen extracts reviewed, there were 480 for which use in the diagnosis and treatment of allergic disease were addressed in the literature, 207 for which only diagnostic use was addressed, 565 for which minimal or no supportive literature was identified, and 17 for which potential safety concerns were found.Conclusions: When used according to professional guidelines, almost all nonstandardized allergen extracts for diagnosis and therapy appear to be safe. Provisional thresholds of effectiveness were met by 54% of extracts reviewed. (J Allergy Clin Immunol 2012;129:1014-9.)

Michael Klompas, MD, MPH1, Michael Murphy, BA1, Aysha Akhtar, MD, MPH2, Cynthia Nakasato, MD3, James Nordin, MD, MPH4, Michael Schum, PhD5, Ann von Worley, RN, BSHS5, Melissa Butler, PharmD, PhD6, Robert Davis, MD, MPH6, Laura Johnson, MD7, Mayur Ramesh, MD7, Craig Zinderman, MD, MPH2, Hector Izurieta, MD, MPH2 and Richard Platt, MD, MSc1 1Harvard Pilgrim Health Care Institute 2Food and Drug Administration 3Kaiser Permanente Hawaii 4Health Partners 5LCF Research 6Kaiser Permanente Georgia 7Henry Ford Health System