Steven A. Anderson

Transfusion-associated circulatory overload (TACO) and potential risk factors among the inpatient US elderly as recorded in Medicare administrative databases during 2011

Transfusion‐associated circulatory overload (TACO) is a serious transfusion complication resulting in respiratory distress. The studys objective was to assess TACO occurrence and potential risk factors among elderly Medicare beneficiaries (ages 65 and older) in the inpatient setting during 2011.

Transfusion-related acute lung injury and potential risk factors among the inpatient US elderly as recorded in Medicare claims data, during 2007 through 2011.

Transfusion‐related acute lung injury (TRALI) is a serious complication leading to pulmonary edema and respiratory failure. This studys objective was to assess TRALI occurrence and potential risk factors among inpatient US elderly Medicare beneficiaries, ages 65 and older, during 2007 through 2011.

Posttransfusion purpura occurrence and potential risk factors among the inpatient US elderly, as recorded in large Medicare databases during 2011 through 2012

Posttransfusion purpura (PTP) is a serious transfusion complication resulting in sudden thrombocytopenia with bleeding. The studys objective was to assess PTP occurrence and potential risk factors among the inpatient US elderly, ages 65 and older, during 2011 through 2012.

Risk assessment for transmission of variant Creutzfeldt-Jakob disease by transfusion of red blood cells in the United States

Variant Creutzfeldt‐Jakob disease (vCJD) is transmitted by blood transfusion. To mitigate the risk of transfusion‐transmitted vCJD (TTvCJD), the US Food and Drug Administration has recommended deferral of potential at‐risk blood donors, but some risk remains. We describe a quantitative risk assessment to estimate residual, postdeferral TTvCJD risk in the United States.

Febrile non-haemolytic transfusion reaction occurrence and potential risk factors among the U.S. elderly transfused in the inpatient setting, as recorded in Medicare databases during 2011–2012

Febrile non‐haemolytic transfusion reaction (FNHTR) is an acute transfusion complication resulting in fever, chills and/or rigours. Studys objective was to assess FNHTR occurrence and potential risk factors among inpatient U.S. elderly Medicare beneficiaries, ages 65 and older, during 2011–2012.

Babesiosis Occurrence among the Elderly in the United States, as Recorded in Large Medicare Databases during 2006–2013

Background Human babesiosis, caused by intraerythrocytic protozoan parasites, can be an asymptomatic or mild-to-severe disease that may be fatal. The study objective was to assess babesiosis occurrence among the U.S. elderly Medicare beneficiaries, ages 65 and older, during 2006–2013. Methods Our retrospective claims-based study utilized large Medicare administrative databases. Babesiosis occurrence was ascertained by recorded ICD-9-CM diagnosis code. The study assessed babesiosis occurrence rates (per 100,000 elderly Medicare beneficiaries) overall and by year, age, gender, race, state of residence, and diagnosis months. Results A total of 10,305 elderly Medicare beneficiaries had a recorded babesiosis diagnosis during the eight-year study period, for an overall rate of about 5 per 100,000 persons. Study results showed a significant increase in babesiosis occurrence over time (p<0.05), with the largest number of cases recorded in 2013 (N = 1,848) and the highest rates (per 100,000) in five Northeastern states: Connecticut (46), Massachusetts (45), Rhode Island (42), New York (27), and New Jersey (14). About 75% of all cases were diagnosed from May through October. Babesiosis occurrence was significantly higher among males vs. females and whites vs. non-whites. Conclusion Our study reveals increasing babesiosis occurrence among the U.S. elderly during 2006–2013, with highest rates in the babesiosis-endemic states. The study also shows variation in babesiosis occurrence by age, gender, race, state of residence, and diagnosis months. Overall, our study highlights the importance of large administrative databases in assessing the occurrence of emerging infections in the United States.

Geographic exposure risk of variant Creutzfeldt‐Jakob disease in US blood donors: a risk‐ranking model to evaluate alternative donor‐deferral policies

Variant Creutzfeldt‐Jakob disease (vCJD) has been transmitted by blood transfusion (TTvCJD). The US Food and Drug Administration (FDA) recommends deferring blood donors who resided in or traveled to 30 European countries where they may have been exposed to bovine spongiform encephalopathy (BSE) through beef consumption. Those recommendations warrant re‐evaluation, because new cases of BSE and vCJD have markedly abated.

Association of Immune Globulin Intravenous (IGIV) and Thromboembolic Adverse Events (TEEs)

The recent article by Ammann et al. is a meta-analysis of randomized controlled trials (RCTs) performed to determine whether thromboembolic events (TEEs) are more frequent in patients receiving immune globulin intravenous (IGIV). The conclusion of the study is that TEEs are not more frequent after IGIV compared with placebo or no treatment. The authors caution that their results should not be generalized “to older and otherwise higher risk patients” and that “patients with immune deficiencies were under-represented.” However, physicians and healthcare providers should not read the paper and conclude that the risk of TEEs following IGIV treatment is so small or non-existent that careful monitoring of patients for thrombosis is not necessary. Based on earlier published studies and analyses conducted by the Food and Drug Administration (FDA), FDA considers the risk of TEEs following IGIV treatment is small but not zero and the benefits for indicated therapeutic uses outweigh the risks. IGIV is regulated by the FDA Center for Biologics Evaluation and Research, Office of Tissues and Advanced Therapies. In 2010, FDA became aware of a cluster of TEEs associated with certain lots of Octagam, an IGIV product. An FDA investigation showed high levels of coagulation factor XIa (FXIa), a procoagulant impurity, in the TEEsassociated lots of Octagam, and other IG products. The procoagulant FXIa-contaminated Octagam lots were promptly withdrawn from the U.S. market, and multiple regulatory and corrective actions were taken. Specifically, FDA informed manufacturers of the potential issue with FXIa in IG products. FDA, working with the World Health Organization, National Institute for Biological Standards and Control (UK), and European Medicines Agency implemented corrective actions, including developing assays and standards for measuring FXIa, transferring knowledge of these assays to manufacturers, encouraging manufacturers to test their products at lot release, and to consider introduction of dedicated steps to remove FXIa. In addition, FDA required all manufacturers to introduce class labeling changes with a Boxed Warning to highlight the risk of thrombosis and advice to increase monitoring for TEE in treatment of patients with underlying risks factors. FDA webpostings informed users of IG products of the risk. Additionally, the FDA Office of Biostatistics and Epidemiology performed large healthcare database retrospective studies that provided evidence that certain IG products were associated with higher thrombosis risk on the first day of infusion. The findings were consistent with laboratory analyses of products which showed an association of high TEE risk with high levels of FXIa impurity. In addition to the elevated TEE risks with specific products, these studies identified underlying recipient risk factors. What accounts for the discrepancy between Ammann et al.’s conclusion that there is no increased risk of thrombosis, and FDA’s and manufacturers’ laboratory investigations and healthcare database analyses showing an increased risk? The recent study pooled data from multiple study centers involving multiple IGIV products. Since thrombosis is relatively rare and is typically observed in certain lots from a few products, it is likely that pooled RCT data would not detect the risk, as the RCTs were based on smaller sample sizes (enrollment from 40 to 624 participants) and not tailored to detect rare adverse events. In contrast, an earlier study by Amman et al. with a larger number of patients (8035 non-users and 2724 users of IG) involving chronic lymphocytic and multiple myeloma patients, showed a threefold higher rate of arterial TEEs in the first day of IG infusion. Both of FDA’s epidemiological studies were based on substantially greater numbers of exposed persons (11 000 and 101 000 exposures, respectively), and thus could detect rare adverse events. FDA studies, unlike the study by Ammann et al. also represent the use of products in clinical practice, as all IG users were included regardless of age, indications, and underlying risk factors. In summary, FDA acknowledges that the analyses conducted by Ammann et al. are an appropriate scientific investigation of an important issue. However, the data from the Ammann et al. paper should not be considered in isolation from previous studies. FDA continues to evaluate and better quantify TEE risks for IG products for different patient populations and indications as part of a large chart confirmed Sentinel BloodSCAN study. The FDA conclusion from the available data is that the risk of thrombosis from IG products is small but not zero. Accordingly, continued vigilance on the part of the agency, the manufacturers, the healthcare providers, and the patients is warranted.

Overall conceptual framework for studying the genetics of autoimmune diseases following vaccination: a regulatory perspective

The US Vaccine Adverse Event Reporting System contains case reports of autoimmune diseases (ADs) occurring following vaccinations. ADs are rare and occur in unvaccinated people, making the potential association between vaccines and ADs challenging to evaluate. Developing mechanistic pathways that link genes, immune mediators, vaccine components and ADs would be helpful for hypothesis generation, enhancing theories of biologic plausibility and grouping rare autoimmune adverse events to increase the ability to detect and evaluate safety signals. Here, we propose a conceptual framework for investigating the genetics of ADs as safety signals following vaccination, potentially contributing to the identification of relevant biomarkers. We also discuss a study design that incorporates genetic information into postmarket clinical evaluation of autoimmune adverse events following vaccination.

Development of Dose-Response Models of Creutzfeldt-Jakob Disease Infection in Nonhuman Primates for Assessing the Risk of Transfusion-Transmitted Variant Creutzfeldt-Jakob Disease

ABSTRACT Estimates for the risk of transmitting variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion have relied largely on data from rodent experiments, but the relationship between dose (amount of infected blood) and response (vCJD infection) has never been well quantified. The goal of this study was to develop a dose-response model based on nonhuman primate data to better estimate the likelihood of transfusion-transmitted vCJD (TTvCJD) in humans. Our model used dose-response data from nonhuman primates inoculated intracerebrally (i.c.) with brain tissues of patients with sporadic and familial CJD. We analyzed the data statistically by using a beta-Poisson dose-response model. We further adjusted model parameters to account for the differences in infectivity between blood and brain tissue and in transmission efficiency between intravenous (i.v.) and i.c. routes to estimate dose-dependent TTvCJD infection. The model estimates a mean infection rate of 76% among recipients who receive one unit of whole blood collected from an infected donor near the end of the incubation period. The nonhuman primate model provides estimates that are more consistent with those derived from a risk analysis of transfused nonleukoreduced red blood cells in the United Kingdom than prior estimates based on rodent models. IMPORTANCE TTvCJD was recently identified as one of three emerging infectious diseases posing the greatest immediate threat to the safety of the blood supply. Cases of TTvCJD were reported in recipients of nonleukoreduced red blood cells and coagulation factor VIII manufactured from blood of United Kingdom donors. As the quantity of abnormal prions (the causative agent of TTvCJD) varies significantly in different blood components and products, it is necessary to quantify the dose-response relationship for a wide range of doses for the vCJD agent in transfused blood and plasma derivatives. In this paper, we suggest the first mechanistic dose-response model for TTvCJD infection based on data from experiments with nonhuman primates. This new model may improve estimates of the possible risk to humans.