Changes in transfusion-transmissible infection prevalence and demographics among US blood donors during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic impacted the US blood supply. We compared blood donor demography and infectious disease prevalence before and during the pandemic using a large multicenter database. METHODS: Data were categorized as "Before COVID-19" (March 2018-February 2020) or "During COVID-19" (March 2020-February 2022). Donor demographics, donation frequency, and infectious marker prevalence of HIV, HBV, and HCV were compared for the two time periods. The odds of a donor testing positive for these infections among the two time periods were calculated using multivariable logistic regression. RESULTS: Our study assessed a total of 26,672,213 donations including 13,430,380 before and 13,241,833 during COVID-19. There were significantly more donations from donors who were female, aged 40 and older, white, and repeat, during COVID-19. Donation frequency comparison quantified the increase in donations from donors who were white, female, older, and repeat during the pandemic. The prevalence of HIV and HCV decreased significantly during COVID-19 compared to before, but not for HBV. For HIV, the adjusted odds of infection during the pandemic did not differ but for HBV, the odds were significantly more likely during the pandemic and were significantly lower for HCV. DISCUSSION: Demographics and infectious disease marker prevalence changed during the COVID-19 pandemic in the United States. Prevalence of each infection in the donor population will continue to be monitored to determine if changes were specific to the pandemic period.

How we forecast tomorrow's haemovigilance.

The field of haemovigilance continues to develop, building on more than forty years of international experience. This review considers the current scope and activities of haemovigilance around the world and explores aspects of preparation for the advent of new blood products and alternative therapies to transfusion; new tools for data acquisition (including patient- and donor-reported outcomes, and data from 'wearables') and the analysis and communication of haemovigilance results.

Haemovigilance resources available for everyone: A report from the International Haemovigilance Tools Collaborative Project.

BACKGROUND AND OBJECTIVES: Haemovigilance systems are intended to collect and analyse data, and report findings relating to transfusion complications, such as blood product safety, procedural incidents, and adverse reactions in donors and patients. A common problem among developing haemovigilance programs is the lack of resources and tools available to countries striving to establish or enhance their haemovigilance system. MATERIALS AND METHODS: World Health Organization, in collaboration with International Society for Blood Transfusion (ISBT), International Haemovigilance Network and other haemovigilance experts embarked on a Haemovigilance Tools Project to collect and provide materials and resources to assist with the stepwise implementation of haemovigilance. RESULTS AND CONCLUSIONS: Resources are housed as a virtual compendium on the ISBT website under the Haemovigilance Working Party. These are managed by a subcommittee of the Working Party and are freely available and downloadable to all without requiring ISBT membership.

HIV risk behavior profiles among men who have sex with men interested in donating blood: Findings from the Assessing Donor Variability and New Concepts in Eligibility study.

BACKGROUND: Individual risk assessment allows donors to be evaluated based on their own behaviors. Study objectives were to assess human immunodeficiency virus (HIV) risk behaviors in men who have sex with men (MSM) and estimate the proportion of the study population who would not be deferred for higher risk HIV sexual behaviors. STUDY DESIGN AND METHODS: Cross-sectional survey and biomarker assessment were conducted in eight U.S. cities. Participants were sexually active MSM interested in blood donation aged 18-39 years, assigned male sex at birth. Participants completed surveys during two study visits to define eligibility, and self-reported sexual and HIV prevention behaviors. Blood was drawn at study visit 1 and tested for HIV and the presence of tenofovir, one of the drugs in oral HIV pre-exposure prophylaxis (PrEP). Associations were assessed between HIV infection status or HIV PrEP use and behaviors, including sex partners, new partners, and anal sex. RESULTS: A total of 1566 MSM completed the visit 1 questionnaire and blood draw and 1197 completed the visit 2 questionnaire. Among 1562 persons without HIV, 789 (50.4%) were not taking PrEP. Of those not taking PrEP, 66.2% reported one sexual partner or no anal sex and 69% reported no new sexual partners or no anal sex with a new partner in the past 3 months. CONCLUSION: The study found that questions were able to identify sexually active, HIV-negative MSM who report lower risk sexual behaviors. About a quarter of enrolled study participants would be potentially eligible blood donors using individual risk assessment questions.

A Retrospective Review of Center for Biologics Evaluation and Research Advisory Committee Meetings in the Context of the FDA's Benefit-Risk Framework.

The US FDA Center for Biologics Evaluation and Research (CBER) is responsible for the regulation of biologically derived products. FDA has established Advisory Committees (AC) as vehicles to seek external expert advice on scientific and technical matters related to the development and evaluation of products regulated by the agency. We aimed to identify and evaluate common topics discussed in CBER AC meetings during the regulatory decision-making process for biological products and medical devices. We analyzed the content of 119 CBER-led AC meetings between 2009 and 2021 listed on the FDA AC webpage. We reviewed publicly available meeting materials such as briefing documents, summaries, and transcripts. Using a structured review codebook based on FDA benefit-risk guidance, we identified important considerations within the benefit-risk dimensions discussed at the AC meetings: therapeutic context, benefit, risk and risk management, and benefit-risk trade-off, where evidence and uncertainty are critical parts of the FDA benefit-risk framework. Based on a detailed review of 24 topics discussed in 23 selected AC meetings conducted between 2016 and 2021, the two most frequently discussed considerations were "Uncertainty about assessment of the safety profile" and "Uncertainty about assessment of the benefit based on clinical trial data" (16/24 times each) as defined in our codebook. Most of the reviewed meetings discussed Investigational New Drug or Biologics License Applications of products. This review could help sponsors better plan and design studies by contextualizing how the benefit-risk dimensions were embedded in the AC discussions and the considerations that went into the final AC recommendations.

Modeling the Risk of HIV Transfusion Transmission.

BACKGROUND: Blood donations are routinely screened for HIV to prevent an infectious unit from being released to the blood supply. Despite improvements to blood screening assays, donations from infected donors remain undetectable during the window period (WP), when the virus has not yet replicated above the lower limit of detection (LOD) of a screening assay. To aid in the quantitative risk assessments of WP donations, a dose-response model describing the probability of transfusion-transmission of HIV over a range of viral RNA copies was developed. METHODS: An exponential model was chosen based on data fit and parsimony. A data set from a HIV challenge study using a nonhuman primate model and another data set from reported human blood transfusions associated with HIV infected donors were separately fit to the model to generate parameter estimates. A Bayesian framework using No-U-Turn Sampling (NUTS) and Monte Carlo simulations was performed to generate posterior distributions quantifying uncertainty in parameter estimation and model predictions. RESULTS: The parameters of the exponential model for both nonhuman primate and human data were estimated with a mean (95% credible intervals) of 2.70 × 10 -2 (7.74 × 10 -3 , 6.06 × 10 -2 ) and 7.56 × 10 -4 (3.68 × 10 -4 , 1.31 × 10 -3 ), respectively. The predicted ID 50 for the animal and human models was 26 (12, 90) and 918 (529, 1886) RNA copies transfused, respectively. CONCLUSION: This dose-response model can be used in a quantitative framework to estimate the probability of transfusion-transmission of HIV through WP donations. These models can be especially informative when assessing risk from blood components with low viral load.

Regulatory considerations for study of infant protection through maternal immunization.

Childhood Immunization is one of the critical strategies to decrease infant morbidity and mortality due to infectious diseases, but primary immunization schedules for infants in most countries start at 2 months of age. Childhood vaccines therefore begin providing adequate protection later in life, leaving infants vulnerable to infectious diseases and creating an immunity gap that results in higher morbidity and mortality among younger infants. Maternal immunization, the practice of vaccinating individuals during pregnancy, reduces the risk of infant infection primarily through the transfer of protective maternal antibodies to the fetus during late pregnancy. Although much progress has been made in public health policies to support maternal immunization research, inclusion of pregnant individuals and children in clinical trials remains challenging. This has resulted in paucity of evidence regarding safety and effectiveness of vaccines to support licensure of products intended for use during pregnancy and lactation to prevent disease in the infant. In addition, although safeguards for clinical research in pregnancy are supportive, experimental vaccines, e.g., Respiratory Syncytial Virus, are more complicated to study because data on safety, efficacy, and dosing are limited. This requires randomized controlled trials with safety monitoring for the mother, the fetus, and the infant with follow-up for at least 1 year or longer to assess long-term health outcomes that may be associated with peripartum vaccine exposure. The goal of this paper is to discuss the general regulatory considerations for clinical research to evaluate safety and effectiveness of vaccines administered during pregnancy to protect infants from disease. This could be useful to inform future vaccine trials. This discussion is not intended to provide agency guidance nor to articulate agency policy.

Early administration of COVID-19 convalescent plasma with high titer antibody content by live viral neutralization assay is associated with modest clinical efficacy.

The efficacy of COVID-19 convalescent plasma (CCP) as a treatment for hospitalized patients with COVID-19 remains somewhat controversial; however, many studies have not evaluated CCP documented to have high neutralizing antibody titer by a highly accurate assay. To evaluate the correlation of the administration of CCP with titer determined by a live viral neutralization assay with 7- and 28-day death rates during hospitalization, a total of 23 118 patients receiving a single unit of CCP were stratified into two groups: those receiving high titer CCP (>250 50% inhibitory dilution, ID50; n = 13 636) or low titer CCP (≤250 ID50; n = 9482). Multivariable Cox regression was performed to assess risk factors. Non-intubated patients who were transfused with high titer CCP showed 1.1% and 1.7% absolute reductions in overall 7- and 28-day death rates, respectively, compared to those non-intubated patients receiving low titer CCP. No benefit of CCP was observed in intubated patients. The relative benefit of high titer CCP was confirmed in multivariable Cox regression. Administration of CCP with high titer antibody content determined by live viral neutralization assay to non-intubated patients is associated with modest clinical efficacy. Although shown to be only of modest clinical benefit, CCP may play a role in the future should viral variants develop that are not neutralized by other available therapeutics.

Neonatal and pediatric blood bank practice in the United States: Results from the AABB pediatric transfusion medicine subsection survey.

BACKGROUND: There are limited standards guiding the selection and processing of blood components specific for neonatal and pediatric transfusions. Therefore, blood banks (BBs) and transfusion services must create their own policies and procedures. STUDY DESIGN AND METHODS: The American Association of Blood Banks (AABB) Pediatric Transfusion Medicine Subsection Committee developed a 74-question survey to capture neonatal and pediatric BB practices in the United States. RESULTS: Thirty-five centers completed the survey: a response rate 15.8%. Responses indicated that most carry a mixed inventory of red blood cells (RBCs); 94.2% allow more than one type of RBC product for small-volume (SV) and large-volume (LV) transfusions to neonatal and pediatric patients. Many had storage age thresholds for RBCs transfused to neonates (SV = 60%, LV = 67.7%) but not older pediatric patients. The use of Group O for nonurgent RBC transfusion in neonates was common (74.2%). Responses related to special processing of RBCs and platelets indicated that 100% RBC and platelets are leukocyte-reduced (LR) for neonates and 97% for non-neonates. Irradiation of RBCs and platelets was commonly performed for neonatal transfusion (88.6%). Providing cytomegalovirus (CMV) seronegative products, volume reduction, and washing were variable. All centers transfused single-donor apheresis platelets; 20% allowed pathogen reduction (PR). The majority of centers have strategies limiting the amount of incompatible plasma transfused; however, few titrate ABO isoagglutinins in plasma-containing products (20% for platelets and 9.1% for plasma). CONCLUSIONS: Variability exists in BB practice for neonatal and pediatric transfusion. Future studies are needed to understand and define best BB practices in these patient populations.

Babesiosis Occurrence Among United States Medicare Beneficiaries, Ages 65 and Older, During 2006-2017: Overall and by State and County of Residence.

BACKGROUND: Human babesiosis is a mild-to-severe parasitic infection that poses health concerns especially in older and other at-risk populations. The study objective was to assess babesiosis occurrence among US Medicare beneficiaries, ages 65 and older, during 2006-2017. METHODS: Our retrospective claims-based study used Medicare databases. Babesiosis cases were identified using recorded diagnosis codes. The study estimated rates (per 100 000 beneficiary-years) overall, by year, diagnosis month, demographics, and state and county of residence. RESULTS: Nationwide, 19 469 beneficiaries had babesiosis recorded, at a rate of 6 per 100 000 person-years, ranging from 4 in 2006 to 9 in 2017 (P < .05). The highest babesiosis rates by state were in the following: Massachusetts (62), Rhode Island (61), Connecticut (51), New York (30), and New Jersey (19). The highest rates by county were in the following: Nantucket, Massachusetts (1089); Dukes, Massachusetts (236); Barnstable, Massachusetts (213); and Dutchess, New York (205). Increasing rates, from 2006 through 2017 (P < .05), were identified in multiple states, including states previously considered nonendemic. New Hampshire, Maine, Vermont, Pennsylvania, and Delaware saw rates increase by several times. CONCLUSIONS: Our 12-year study shows substantially increasing babesiosis diagnosis trends, with highest rates in well established endemic states. It also suggests expansion of babesiosis infections in other states and highlights the utility of real-world evidence.

The Food and Drug Administration Biologics Effectiveness and Safety Initiative Facilitates Detection of Vaccine Administrations From Unstructured Data in Medical Records Through Natural Language Processing.

Introduction: The Food and Drug Administration Center for Biologics Evaluation and Research conducts post-market surveillance of biologic products to ensure their safety and effectiveness. Studies have found that common vaccine exposures may be missing from structured data elements of electronic health records (EHRs), instead being captured in clinical notes. This impacts monitoring of adverse events following immunizations (AEFIs). For example, COVID-19 vaccines have been regularly administered outside of traditional medical settings. We developed a natural language processing (NLP) algorithm to mine unstructured clinical notes for vaccinations not captured in structured EHR data. Methods: A random sample of 1,000 influenza vaccine administrations, representing 995 unique patients, was extracted from a large U.S. EHR database. NLP techniques were used to detect administrations from the clinical notes in the training dataset [80% (N = 797) of patients]. The algorithm was applied to the validation dataset [20% (N = 198) of patients] to assess performance. Full medical charts for 28 randomly selected administration events in the validation dataset were reviewed by clinicians. The NLP algorithm was then applied across the entire dataset (N = 995) to quantify the number of additional events identified. Results: A total of 3,199 administrations were identified in the structured data and clinical notes combined. Of these, 2,740 (85.7%) were identified in the structured data, while the NLP algorithm identified 1,183 (37.0%) administrations in clinical notes; 459 were not also captured in the structured data. This represents a 16.8% increase in the identification of vaccine administrations compared to using structured data alone. The validation of 28 vaccine administrations confirmed 27 (96.4%) as "definite" vaccine administrations; 18 (64.3%) had evidence of a vaccination event in the structured data, while 10 (35.7%) were found solely in the unstructured notes. Discussion: We demonstrated the utility of an NLP algorithm to identify vaccine administrations not captured in structured EHR data. NLP techniques have the potential to improve detection of vaccine administrations not otherwise reported without increasing the analysis burden on physicians or practitioners. Future applications could include refining estimates of vaccine coverage and detecting other exposures, population characteristics, and outcomes not reliably captured in structured EHR data.

Use of a rapid electronic survey methodology to estimate blood donors' potential exposure to emerging infectious diseases: Application of a statistically representative sampling methodology to assess risk in US blood centers.

Risk assessments of transfusion-transmitted emerging infectious diseases (EIDs) are complicated by the fact that blood donors' demographics and behaviors can be different from the general population. Therefore, when assessing potential blood donor exposure to EIDs, the use of general population characteristics, such as U.S. travel statistics, may invoke uncertainties that result in inaccurate estimates of blood donor exposure. This may, in turn, lead to the creation of donor deferral policies that do not match actual risk. STUDY DESIGN AND METHODS: This article reports on the development of a system to rapidly assess EID risks for a nationally representative portion of the U.S. blood donor population. To assess the effectiveness of this system, a test survey was developed and deployed to a statistically representative sample frame of blood donors from five blood collecting organizations. Donors were directed to an online survey to ascertain their recent travel and potential exposure to Middle East respiratory syndrome coronavirus (MERS-CoV). RESULTS: A total of 7128 responses were received from 54 256 invitations. The age-adjusted estimated total number of blood donors potentially exposed to MERS-CoV was approximately 15 640 blood donors compared to a lower U.S. general population-based estimate of 9610 blood donors. CONCLUSION: The structured donor demographic sample-based data provided an assessment of blood donors' potential exposure to an emerging pathogen that was 63% larger than the U.S. population-based estimate. This illustrates the need for tailored blood donor-based EID risk assessments that provide more specific demographic risk intelligence and can inform appropriate regulatory decision making.

Safety incident reports associated with blood transfusions.

BACKGROUND: Patient safety remains a critical issue in health care. Adverse events related to blood transfusion constitute a threat to patient safety. The aim of this study is to compare and contrast reporting trends of patient safety events that occur during the transfusion of blood components in pediatric and adult hospital care settings. STUDY DESIGN AND METHODS: This is a multicenter analysis of reported patient safety incidents occurring during the administration of blood components for four children's and 21 adult hospitals from January 2010 through September 2017. Denominators were pediatric or adult transfusions per year for a subset of two pediatric and two adult hospitals able to provide denominators for the complete reporting period. Rates were calculated on the subset of four hospitals per 100,000 components transfused with Pearson's chi square for comparison (p < 0.05 as significant). RESULTS: There were 1902 reports for an estimated 1.1 million transfusions: 358 reports from pediatric hospitals and 1544 reports from adult hospitals. From hospitals able to provide denominator data; there were 192 reports for 128,560 pediatric transfusions and 183 reports for 377,563 adult transfusions. The reporting rate per 100,000 components from these four hospitals was 149 for pediatric and 48 for adult reports (p < 0.01). CONCLUSION: This analysis demonstrates the continued need for transfusion safety practices. The type of incident reports differed in the pediatric setting compared to the adult setting. Understanding patient safety event reporting trends related to blood transfusion will help target hemovigilance education and interventions to the appropriate patient populations.

International validation of harmonized definitions for complications of blood donations.

BACKGROUND: In December 2014, a multinational collaboration of hemovigilance experts from the International Society of Blood Transfusion (ISBT), the International Hemovigilance Network, and AABB published harmonized definitions of complications related to blood donation titled "Standard for Surveillance of Complications Related to Blood Donation." Both mandatory and optional terms were included. The definitions are endorsed by the Alliance of Blood Operators and the European Blood Alliance. STUDY DESIGN AND METHODS: The objective of this study was to validate harmonized donor hemovigilance definitions with potential users. In June 2016, 30 real-world cases were sent to potential users around the world along with the definitions, an answer sheet, and instructions on how to complete the validation exercise. RESULTS: Overall, 54 responses from 25 countries were received, including over 400 comments. The results were presented for feedback at both ISBT and AABB meetings. Case diagnoses were consistent across most responders. Exceptions were rare adverse events, nonstandard presentations, or incomplete information. In general, the application of optional definitions, including severity grading and imputability, had the most variability. CONCLUSION: The use of standardized terms in the donor setting serves to increase focus on donor safety, facilitate conversation, foster exchange of information, and frame questions for future research. Overall, the definitions provide adequate coverage of donor reactions; however, some terms require clarification. Severity grading and imputability and other optional terms need clear and objective definitions and instructions on when and how to use them. Additional feedback and final recommendations are summarized in this report.

Impact of changes to donor hemoglobin criteria on the rate of donor deferral.

BACKGROUND: The Food and Drug Administration's requirements for "Blood and Blood Components Intended for Transfusion or Further Manufacturing Use" (Final Rule) effective May 2016 changed eligibility criteria for blood donors. A multivariate analysis was performed to measure its impact on donor deferral rates. STUDY DESIGN AND METHODS: Four blood centers submitted data for similar 6-month periods before and after implementation of the Final Rule. Data included presenting donors, units collected, deferrals, intended products from deferred donors, deferral reasons, presenting donor demographics, donor hemoglobin (Hgb), hematocrit (HCT), pulse, blood pressure (BP), temperature, and other reasons for deferral. Data were aggregated and periods compared. RESULTS: After Final Rule implementation, successful donations decreased by 1.3% (83.1%-81.9%), despite a 0.2% increase in presenting donors. The rate of Hgb/HCT, pulse, and deferrals increased, while deferrals for other reasons decreased. Male Hgb/HCT deferral rates increased 1.2% (4213 total). Black male donors' Hgb/HCT deferral rate increased (2.7%-5.2%) but was counterbalanced by an overall 3.7% decrease in black female Hgb/HCT deferrals. While Hgb/HCT deferrals of black donors remained stable overall (17.0% vs. 16.2%), this trend was not observed by all centers. Deferrals for pulse increased (0.2%), as did BP deferrals (0.2%). CONCLUSION: Although there was a small increase in presenting donors after implementation of the Final Rule, there was a decrease in successful donations. While it appeared that deferral in black donors was unchanged, this trend was not observed across all centers. Pulse and BP deferrals rose dissimilarly among centers, according to individual procedures.

A brief overview of clinical significance of blood group antibodies.

CONCLUSIONS: This review was derived from a presentation made on September 2, 2016 for the first Academy Day presented by the Working Party on Immunohematology at the International Society of Blood Transfusion (ISBT) Congress in Dubai. The focus of this review is to provide a brief overview of the clinical significance of blood group antibodies. Blood group antibodies can be naturally occurring (e.g., anti-A and anti-B through exposure to naturally occurring red blood cell [RBC] antigen-like substances) or can occur via exposure to foreign (donor) RBC antigens through previous transfusions, transplants, or exposure to fetal RBCs during or after pregnancy. However, not all blood group antibodies are clinically significant. Clinically significant blood group antibodies can cause adverse events after blood component transfusion or transplantation and/or can cause hemolytic disease of the fetus and newborn.

Analysis of pediatric adverse reactions to transfusions.

BACKGROUND: Children are known to be physiologically and biochemically different from adults. However, there are no multi-institutional studies examining the differences in the frequency, type, and severity of transfusion reactions in pediatric versus adult patients. This study aims to characterize differences between pediatric and adult patients regarding adverse responses to transfusions. STUDY DESIGN AND METHODS: This is a retrospective data analysis of nine children's hospitals and 35 adult hospitals from January 2009 through December 2015. Included were pediatric and adult patients who had a reported reaction to transfusion of any blood component. Rates are reported as per 100,000 transfusions for comparison between pediatric and adult patients. RESULTS: Pediatric patients had an overall higher reaction rate compared to adults: 538 versus 252 per 100,000 transfusions, notably higher for red blood cell (577 vs. 278 per 100,000; p < 0.001) and platelet (833 vs. 358 per 100,000; p < 0.001) transfusions. Statistically higher rates of allergic reactions, febrile nonhemolytic reactions, and acute hemolytic reactions were observed in pediatric patients. Adults had a higher rate of delayed serologic transfusion reactions, delayed hemolytic transfusion reactions, and transfusion-associated circulatory overload. CONCLUSION: Pediatric patients had double the rate of transfusion reactions compared to adults. The nationally reported data on reaction rates are consistent with this study's findings in adults but much lower than the observed rates for pediatric patients. Future studies are needed to address the differences in reaction rates, particularly in allergic and febrile reactions, and to further address blood transfusion practices in the pediatric patient population.