Proceedings of the 2022 NHLBI and OASH state of the science in transfusion medicine symposium.

BACKGROUND: State of the Science (SoS) meetings are used to define and highlight important unanswered scientific questions. The National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, and the Office of the Assistant Secretary for Health (OASH), Department of Health and Human Services held a virtual SoS in transfusion medicine (TM) symposium. STUDY DESIGN AND METHODS: In advance of the symposium, six multidisciplinary working groups (WG) convened to define research priorities in the areas of: blood donors and the supply, optimizing transfusion outcomes for recipients, emerging infections, mechanistic aspects of components and transfusion, new computational methods in transfusion science, and impact of health disparities on donors and recipients. The overall objective was to identify key basic, translational, and clinical research questions that will help to increase and diversify the volunteer donor pool, ensure safe and effective transfusion strategies for recipients, and identify which blood products from which donors best meet the clinical needs of specific recipient populations. RESULTS: On August 29-30, 2022, over 400 researchers, clinicians, industry experts, government officials, community members, and patient advocates discussed the research priorities presented by each WG. Dialogue focused on the five highest priority research areas identified by each WG and included the rationale, proposed methodological approaches, feasibility, and barriers for success. DISCUSSION: This report summarizes the key ideas and research priorities identified during the NHLBI/OASH SoS in TM symposium. The report highlights major gaps in our current knowledge and provides a road map for TM research.

Early and out-of-hospital use of COVID-19 convalescent plasma: An international assessment of utilization and feasibility.

BACKGROUND AND OBJECTIVES: The use of coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) in the treatment of patients with severe acute respiratory syndrome-2 infection has been controversial. Early administration of CCP before hospital admission offers a potential advantage. This manuscript summarizes current trials of early use of CCP and explores the feasibility of this approach in different countries. MATERIALS AND METHODS: A questionnaire was distributed to the International Society of Blood Transfusion (ISBT) CCP working group. We recorded respondents' input on existing trials on early/outpatient CCP and out-of-hospital (OOH)/home transfusion (HT) practices in their countries and feedback on challenges in initiating home CCP infusion programmes. In addition, details of existing trials registered on clinicaltrials.gov were summarized. RESULTS: A total of 31 country representatives participated. Early/OOH CCP transfusion studies were reported in the United States, the Netherlands, Spain and Brazil. There were a total of six published and five ongoing trials on the prophylactic and therapeutic early use of CCP. HT was practised in Australia, the UK, Belgium, France, Japan, Nigeria, the Netherlands, Spain, Italy, Norway, the United States and some provinces in Canada. Thirty-four representatives indicated a lack of OOH CCP or HT in their institutions and countries. Barriers to implementation of OOH/HT included existing legislation, lack of policies pertaining to outpatient transfusion, and associated logistical challenges, including lack of staffing and resources. CONCLUSION: Early administration of CCP remains a potential option in COVID-19 management in countries with existing OOH/HT programmes. Legislation and regulatory bodies should consider OOH/HT practice for transfusion in future pandemics.

Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study.

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. METHODS AND FINDINGS: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. CONCLUSIONS: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT#: NCT04338360.

Differentiation of SARS-CoV-2 naturally infected and vaccinated individuals in an inner-city emergency department.

BACKGROUND: Emergency Departments (EDs) can serve as surveillance sites for infectious diseases. Our purpose was to determine the burden of SARS-CoV-2 infection and prevalence of vaccination against COVID-19 among patients attending an urban ED in Baltimore City. METHODS: Using 1914 samples of known exposure status, we developed an algorithm to differentiate previously infected, vaccinated, and unexposed individuals using a combination of antibody assays. We applied this testing algorithm to 4360 samples ED patients obtained in the springs of 2020 and 2021. Using multinomial logistic regression, we determined factors associated with infection and vaccination. RESULTS: For the algorithm, sensitivity and specificity for identifying vaccinated individuals was 100% and 99%, respectively, and 84% and 100% for naturally infected individuals. Among the ED subjects, seroprevalence to SARS-CoV-2 increased from 2% to 24% between April 2020 and March 2021. Vaccination prevalence rose to 11% by mid-March 2021. Marked differences in burden of disease and vaccination coverage were seen by sex, race, and ethnicity. Hispanic patients, though 7% of the study population, had the highest relative burden of disease (17% of total infections) but similar vaccination rates. Women and White individuals were more likely to be vaccinated than men or Black individuals (adjusted odds ratios [aOR] 1.35 [95% CI: 1.02, 1.80] and aOR 2.26 [95% CI: 1.67, 3.07], respectively). CONCLUSIONS: Individuals previously infected with SARS-CoV-2 can be differentiated from vaccinated individuals using a serologic testing algorithm. SARS-CoV-2 exposure and vaccination uptake frequencies reflect gender, race and ethnic health disparities in this urban context. SUMMARY: Using an antibody testing algorithm, we distinguished between immune responses from SARS-CoV-2-infected and vaccinated individuals. When applied to blood samples from an emergency department in Baltimore, disparities in disease burden and vaccine uptake by sex, race, and ethnicity were identified.

Risk of transfusion-transmitted Babesia microti in Canada.

BACKGROUND: Babesia microti has gained a foothold in Canada as tick vectors become established in broader geographic areas. B. microti infection is associated with mild or no symptoms in healthy individuals but is transfusion-transmissible and can be fatal in immunocompromised individuals. This is the first estimate of clinically significant transfusion-transmitted babesiosis (TTB) risk in Canada. STUDY DESIGN AND METHODS: The proportion of B. microti-antibody (AB)/nucleic acid amplification test (NAT)-positive whole blood donations was estimated at 5.5% of the proportion of the general population with reported Lyme Disease (also tick-borne) based on US data. Monte Carlo simulation estimated the number and proportion of infectious red cell units for three scenarios: base, localized incidence (risk in Manitoba only), and donor study informed (prevalence from donor data). The model simulated 1,029,800 donations repeated 100,000 times for each. RESULTS: In the base scenario 0.5 (0.01, 1.75), B. microti-NAT-positive donations would be expected per year, with 0.08 (0, 0.38) recipients suffering clinically significant TTB (1 every 12.5 years). In the localized incidence scenario, there were 0.21(0, 0.7) B. microti-NAT-positive donations, with 0.04 (0, 0.14) recipient infections (about 1 every 25 years). In the donor study informed scenario, there were 4.6 (0.3, 15.8) B. microti-NAT-positive donations expected, and 0.81 (0.05, 3.14) clinically significant TTB cases per year. DISCUSSION: The likelihood of clinically relevant TTB is low. Testing would have very little utility in Canada at this time. Ongoing pathogen surveillance in tick vectors is important as B. microti prevalence appears to be slowly increasing in Canada.

Promoting access to COVID-19 convalescent plasma in low- and middle-income countries.

Low- and middle-income countries (LMICs) remain neglected in the Coronavirus 19 (COVID-19) pandemic. COVID-19 convalescent plasma (CCP) (i.e. plasma collected from individuals after their recovery from COVID-19) has emerged as a leading medical treatment for COVID-19. Studies to date support the safety-and increasingly the efficacy-of CCP to treat COVID-19. This has motivated large-scale procurement and transfusion of CCP, notably in the United States (US), where inventories of CCP have been attained, and government-supported stockpiling of CCP is underway. CCP is a therapy that could be implemented in LMICs. However, systemic and transfusion-specific challenges (e.g. capacity for donor mobilization and collections) impede local procurement of this resource in sufficient volumes to meet clinical demand. This raises the question as to whether there are strategies to facilitate sharing of CCP with LMICs and/or bolstering local capacity for collection to contend with the health crisis. While compelling, there are cost-related, logistical and regulatory barriers to both approaches. For one, there is complexity in diverting national interest (e.g. in the US) away from an epidemic that displays few signs of abating. There are also concerns regarding equitable distribution of CCP in LMICs and how that might be overcome. Further, the barriers to blood donation in general apply to collection of CCP; these obstacles are longstanding, accounting for the inability of many LMICs to meet their blood transfusion needs. Nonetheless, CCP affords dual opportunity for humanitarian outreach while tackling a broader challenge of blood transfusion safety and availability.

Implementation outcomes of policy and programme innovations to prevent obstetric haemorrhage in low- and middle-income countries: a systematic review.

Globally, obstetric haemorrhage (OH) remains the leading cause of maternal mortality. Much of the associated mortality is ascribed to challenges surrounding deployment of innovations rather than lack of availability. In low- and middle-income countries (LMICs), where the burden is highest, there is a growing interest in implementation research as a means to bridge the 'know-do' gap between proven interventions and their reliable implementation at scale. In this systematic review, we identified and synthesized qualitative and quantitative data across the implementation outcomes of OH prevention innovations in LMICs using a taxonomy developed by Proctor et al. We also identified service outcomes for the included innovations, as well as implementation strategies and implementation facilitators and barriers. Eligible studies were empirical, focused on the implementation of OH prevention programmes or policies and occurred in an LMIC. Eight databases were searched. Two authors independently assessed studies for selection and extracted data; the first author resolved discrepancies. Narrative synthesis was used to analyse and interpret the findings. Studies were predominantly focused in Africa and on primary prevention. Interventions included prophylactic use of uterotonics (n = 7), clinical provider skills training (n = 4) and provision of clinical guidelines (n = 1); some (n = 3) were also part of a multi-component quality improvement bundle. Various barriers were reported, including challenges among intervention beneficiaries, providers and within the health system; however, studies reported the development and testing of practical implementation solutions. These included training and monitoring of implementers, community and stakeholder engagement and guidance by external mentors. Some studies linked successful delivery to implementation outcomes, most commonly adoption and acceptability, but also feasibility, penetration and sustainability. Findings suggest that innovations to prevent OH can be acceptable, appropriate and feasible in LMIC settings; however, more research is needed to better evaluate these and other under-reported implementation outcomes.

Financial analysis of large-volume delayed sampling to reduce bacterial contamination of platelets.

BACKGROUND: Effective and financially viable mitigation approaches are needed to reduce bacterial contamination of platelets in the US. Expected costs of large-volume delayed sampling (LVDS), which would be performed by a blood center prior to shipment to a hospital, were compared to those of pathogen reduction (PR), point-of-release testing (PORt), and secondary bacterial culture (SBC). METHODS: Using a Markov-based decision-tree model, the financial and clinical impact of implementing all variants of LVDS, PR, PORt, and SBC described in FDA guidance were evaluated from a hospital perspective. Hospitals were assumed to acquire leukoreduced apheresis platelets, with LVDS adding $30 per unit. Monte Carlo simulations were run to estimate the direct medical costs for platelet acquisition, testing, transfusion, and possible complications associated with each approach. Input parameters, including test sensitivity and specificity, were drawn from existing literature and costs (2018US$) were based on a hospital perspective. A one-way sensitivity analysis varied the assumed additional cost of LVDS. RESULTS: Under an approach of LVDS (7-day), the total cost per transfused unit is $735.78, which falls between estimates for SBC (7-day) and PORt. Assuming 20,000 transfusions each year, LVDS would cost $14.72 million annually. Per-unit LVDS costs would need to be less than $22.32 to be cheaper per transfusion than all other strategies, less than $32.02 to be cheaper than SBC (7-day), and less than $196.19 to be cheaper than PR (5-day). CONCLUSIONS: LVDS is an effective and cost-competitive approach, assuming additional costs to blood centers and associated charges to hospitals are modest.

Sociodemographic and behavioral characteristics associated with blood donation in the United States: a population-based study.

BACKGROUND: Contemporary population-based data on characteristics associated with blood donation in the United States (U.S.) are limited. STUDY DESIGN AND METHODS: A cross-sectional analysis was performed among 28,739 persons aged 18 years and older who participated in the 2016 National Health Interview Survey, a household survey of the noninstitutionalized U.S. civilian population. Analyses were weighted and accounted for the complex survey design. Adjusted prevalence ratios (aPR) were estimated by multivariable log-binomial regression. RESULTS: The percentage of individuals reporting a past-year history of blood donation was 5.7% (95% confidence interval [CI], 5.3%-6.1%) and was highest in the youngest age group (18-24 years, 8.4%). A past-year history of blood donation was more common in males compared to females (6.3% vs. 5.1%; aPR, 1.12 [95% CI, 0.99-1.27]) and those born in the U.S. compared to individuals born outside the U.S. (6.4% vs. 2.4%; aPR, 1.92 [95% CI, 1.49-2.47]). The percentage of individuals with a past-year history of blood donation was significantly lower in blacks (3.9%; aPR, 0.60 [95% CI, 0.47-0.75]) and Hispanics (3.0%; aPR, 0.63 [95% CI, 0.48-0.83]) in comparison to whites (6.9%). Being a college graduate, being employed, being physically active, and never being a cigarette smoker were factors positively associated with blood donation. The percentage of individuals with a past-year history of blood donation varied by geographic census region, with prevalence being higher in the Midwest (7.3%) and South (6.0%) compared to the Northeast (4.7%) and West (4.4%). CONCLUSION: Continued differences in the blood donor population with reference to the U.S. population underscore the need to understand barriers or deterrents to blood donation. Evidence-based donor recruitment and related policies remain imperative to ensure that there is a sustainable blood supply.

Financial impact of alternative approaches to reduce bacterial contamination of platelet transfusions.

BACKGROUND: Bacterial contamination of platelets remains the leading infectious risk from blood transfusion. Pathogen reduction (PR), point-of-release testing (PORt), and secondary bacterial culture (SBC) have been proposed as alternative risk control strategies, but a comprehensive financial comparison has not been conducted. STUDY DESIGN AND METHODS: A Markov-based decision tree was constructed to model the financial and clinical impact of PR, PORt, and SBC, as well as a baseline strategy involving routine testing only. Hospitals were assumed to acquire leukoreduced apheresis platelets on Day 3 after collection, and, in the base case analysis, expiration would occur at the end of Day 5 (PR and SBC) or 7 (PORt). Monte Carlo simulations assessed the direct medical costs for platelet acquisition, testing, transfusion, and possible complications. Input parameters, including test sensitivity and specificity, were drawn from existing literature, and costs (2018 US dollars) were based on a hospital perspective. RESULTS: The total costs per unit acquired by the hospital under the baseline strategy, PR, PORt, and SBC were $651.45, $827.82, $686.33, and $668.50, respectively. All risk-reduction strategies decreased septic transfusion reactions and associated expenses, with the greatest reductions from PR. PR would add $191.09 in per-unit acquisition costs, whereas PORt and SBC would increase per-unit testing costs by $31.79 and $17.26, respectively. Financial outcomes were sensitive to platelet dating; allowing 7-day storage with SBC would lead to a cost savings of $12.41 per transfused unit. Results remained robust in probabilistic sensitivity analyses. CONCLUSIONS: All three strategies are viable approaches to reducing bacterially contaminated platelet transfusions, although SBC is likely to be the cheapest overall.

Zika Virus: Knowledge Assessment of Residents and Health-Care Providers in Roatán, Honduras, following an Outbreak.

Few studies have evaluated the effectiveness of Zika virus (ZIKV) public health educational campaigns. Following a ZIKV educational campaign in Roatán, Honduras (October 2016), a survey was administered (March-May 2017) to residents (N = 348) and health-care professionals ([HCPs]; N = 44) to evaluate ZIKV knowledge, attitudes, and preventive practices, with attention to sexual health. Knowledge scores were calculated and mapped using participants' home locations. The knowledge scores between HCPs and residents were significantly different (mean 17 versus 11; P < 0.001). Only 6% of residents and 14% of HCPs knew that ZIKV was sexually transmissible. Few reported abstinence (2.6% residents; 9.4% HCPs) or condom use (1.6% residents; 12.5% HCPs) to prevent ZIKV infection. Of all subjects, 15.6% were pregnant or had a pregnant partner in the past year; 57.6% expressed concern over ZIKV. Mapping demonstrated spatial heterogeneity in knowledge. The findings suggest a need for improved public health messaging in ZIKV-affected areas.

Funding blood safety in the 21st century.

BACKGROUND: Since 2000, there has been an historic increase in international development assistance, including blood safety projects. The result has been increased blood donations and infectious disease screening in many beneficiary countries. A comprehensive examination of international development assistance for blood safety has yet to be completed. STUDY DESIGN AND METHODS: This report examines publicly available information, including donor agency websites and databases and data from the 2008 and 2012 World Health Organization Global Database on Blood Safety. RESULTS: Between 2000 and 2015, from $602.4 million to $2.1 billion in international development assistance was allocated to blood safety programs worldwide, mostly as part of the global response to the human immunodeficiency virus/acquired immunodeficiency syndrome epidemic. The US President's Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, Tuberculosis, and Malaria were responsible for the majority of blood safety funding, which peaked in 2010 and declined through 2015. CONCLUSION: Between 2000 and 2015, countries with high burdens of human immunodeficiency virus/acquired immunodeficiency syndrome received funding and technical assistance to improve national laboratories, increase blood component production, and strengthen clinical practice. Global trends in international development assistance at large, including aid for blood safety, suggest that funding will not rebound.

Medical and economic implications of strategies to prevent alloimmunization in sickle cell disease.

BACKGROUND: The pathogenesis of alloimmunization is not well understood, and initiatives that aim to reduce the incidence of alloimmunization are generally expensive and either ineffective or unproven. In this review, we summarize the current medical literature regarding alloimmunization in the sickle cell disease (SCD) population, with a special focus on the financial implications of different approaches to prevent alloimmunization. STUDY DESIGN AND METHODS: A review of EMBASE and MEDLINE data from January 2006 through January 2016 was conducted to identify articles relating to complications of SCD. The search was specifically designed to capture articles that evaluated the costs of various strategies to prevent alloimmunization and its sequelae. RESULTS: Currently, there is no proven, inexpensive way to prevent alloimmunization among individuals with SCD. Serologic matching programs are not uniformly successful in preventing alloimmunization, particularly to Rh antigens, because of the high frequency of variant Rh alleles in the SCD population. A genotypic matching program could offer some cost savings compared to a serologic matching program, but the efficacy of gene matching for the prevention of alloimmunization is largely unproven, and large-scale implementation could be expensive. CONCLUSIONS: Future reductions in the costs associated with genotype matching could make a large-scale program economically feasible. Novel techniques to identify patients at highest risk for alloimmunization could improve the cost effectiveness of antigen matching programs. A clinical trial comparing the efficacy of serologic matching to genotype matching would be informative.

Costs, consequences, and cost-effectiveness of strategies for Babesia microti donor screening of the US blood supply.

BACKGROUND: Babesia microti is regarded as the foremost infectious risk to the US blood supply for which a regulatory-approved screening test is unavailable. More than 160 cases of transfusion-transmitted Babesia microti (TTB) have been reported to date, yet there is little consensus regarding a mitigation strategy. STUDY DESIGN AND METHODS: This study sought to assess the cost-utility of donation screening by mode of testing (immunofluorescence assay, enzyme-linked immunosorbent assay [ELISA], polymerase chain reaction [PCR], and combinations thereof) as well as extent of geographic inclusion (4-state, 7-state, 20-state, or national screening). A discrete-time Markov cohort model to simulate the outcomes of B. microti infection and survival of the transfused population was developed. Seroprevalence was estimated by extrapolating babesiosis claims from the Centers for Medicaid and Medicare Services and reports to the Centers for Disease Control and Prevention. Test performance was estimated from clinical diagnostics and limited donor screening studies, while transmissibility was estimated as a weighted average of three studies. Results are reported as the cost per quality-adjusted life-year (QALY) for each strategy compared to no screening. RESULTS: Given model inputs, 4-state and 7-state ELISA in combination with PCR would cost $5.2 million and $6.6 million/QALY, respectively. Cost-effectiveness for 20-state and national screening strategies were less favorable. CONCLUSION: Targeted screening in states with the highest seroprevalence of infection is likely to exceed an implicit threshold of $1 million/QALY often used in blood safety. However, the proportion of donor-seronegative parasitemia, transmissibility, and clinical outcomes resulting from TTB are uncertain.