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.

The BLOODSAFE program: Building the future of access to safe blood in Sub-Saharan Africa.

BACKGROUND: The supply of blood in many low- and middle-income nations in Sub-Saharan Africa (SSA) does not meet the patient care needs. Lack and delay of blood transfusion cause harm to patients and slow the rate of progress in other parts of the health system. Recognizing the power of implementation science, the BLOODSAFE Program was initiated which supports three SSA research study teams and one data coordinating center (DCC) with the goal to improve access to safe blood transfusion in SSA. STUDY DESIGN AND METHODS: The study team in Ghana is focusing on studying and decreasing iron deficiency in blood donors and evaluating social engagement of blood donors through different approaches. The study team in Kenya is building a "vein to vein" workflow model to elucidate and devise strategies to overcome barriers to blood donation and improve infrastructural components of blood product production and use. The Malawi team is studying the infectious disease ramifications of blood donation as well as blood donor retention strategies aimed at blood donors who commence their donation career in secondary schools. RESULTS AND DISCUSSION: Together the project teams and the DCC work as a consortium to support each other through a shared study protocol that will study donor motivations, outcomes, and adverse events across all three countries. The BLOODSAFE Program has the potential to lead to generalizable improvement approaches for increasing access to safe blood in SSA as well as mentoring and building the research capacity and careers of many investigators.

NIH Workshop on HIV-Associated Comorbidities, Coinfections, and Complications: Summary and Recommendation for Future Research.

BACKGROUND: With potent antiretroviral therapy and simplified regimens, people living with HIV (PWH) are achieving near-normal lifespans but not necessarily a normal health span or healthy aging. PWH have a higher than expected risk of developing a number of non-AIDS comorbidities, coinfections, and complications (CCC), often against a background of stigma, poverty, and isolation. SETTING: To gain a better understanding of research needs for HIV-associated CCC, the NIH convened a 2-day workshop (HIV-associated CCC, or HIV ACTION). METHODS: A cross-institute NIH planning committee identified 6 key research areas: epidemiology and population research, pathogenesis and basic science research, clinical research, implementation science research, syndemics research and international research in low and middle income countries. Investigators were selected to lead working groups (WGs) to assess the state-of-the-art and identify 3-5 priority areas in each field before the workshop. A 2-day program at the NIH was developed which included presentations by invited experts and WG members. RESULTS: Over 400 participants attended the workshop. After general and individual WG discussions, the most pressing gaps, questions, or proposed action items were identified. Priority lists of pressing research issues were presented by cochairs of each WG. A detailed report is posted at the NHLBI website. This article reports the streamlined priority list and a summary of WG discussions to inform investigators of current priorities in the field. CONCLUSION: Collaborative efforts of many disciplines are needed to improve the health and wellbeing of PWH. Several common themes emerged across WG representing potential priorities for investigators and recommendations for the NIH.

HIV prevalence and incidence estimates among blood donors in five regions in China.

BACKGROUND: Previous data, although scant, indicated that the incidence of HIV in China has increased over the past decade. There is a growing concern about the impact of the HIV epidemic on blood safety. METHODS AND MATERIALS: We used donation data from five geographically-disperse blood centers in 2013-2016 participating in the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) China program to estimate HIV prevalence and incidence among blood donors. Multivariable logistic regression model was used to examine factors associated with HIV infection in Chinese blood donors. RESULTS: The overall HIV prevalence among first-time donors from 2013 through 2016 was 68.04 per 100,000 donors (95% CI 61.68-74.40). The HIV incidence rate was estimated to be 37.93 per 100,000 person-years (95% CI 30.62-46.97) among first-time donors and 20.55 per 100,000 person-years (95% CI 16.95-24.91) among repeat donors. There was substantial variation in HIV prevalence and incidence rates across blood centers. Multivariable logistic regression results showed that among first-time donors, being male, older than 25 years, minority ethnicity, less than college education, and certain occupations (commercial services, factory workers, retired, unemployed, or self-employed) were associated with positive HIV confirmatory testing results. CONCLUSION: HIV prevalence and incidence among blood donors remain low in the selected five regions in China; however, an increasing trend is observed at some blood centers. It is important to monitor HIV epidemiology in Chinese blood donors on a continuous basis, especially among populations and regions of higher risk.

Addressing gaps in international blood availability and transfusion safety in low- and middle-income countries: a NHLBI workshop.

In April 2017, a workshop sponsored by the National Heart, Lung, and Blood Institute, Division of Blood Diseases and Resources, and the Center for Translation Research and Implementation Science was held to discuss blood availability and transfusion safety in low- and middle-income countries (LMICs). The purpose of the workshop was to identify research opportunities for implementation science (IS) to improve the availability of safe blood and blood components and transfusion practices in LMICs. IS describes the late stages of the translational research spectrum and studies optimal and sustainable strategies to deliver proven-effective interventions. Regional working groups were formed to focus on opportunities and challenges in East Africa, Central/West Africa, Middle East and North Africa, Latin America and the Caribbean, Southeast Asia, Western Pacific Asia, Eastern Europe, and Central Asia. The need for an "adequate supply of safe blood" emerged as the major overriding theme. Among the regional working groups, common cross-cutting themes were evident. The majority of research questions, priorities, and strategies fell into the categories of blood availability, blood transfusion safety, appropriate use of blood, quality systems, health economics and budgeting, and training and education in IS. The workshop also brought into focus inadequate country-level data that can be used as the basis for IS initiatives. A mixed approach of needs assessment and targeted interventions with sufficient evidence base to move toward sustainment is an appropriate next step for blood availability and transfusion safety research in LMICs.

Refining Current Scientific Priorities and Identifying New Scientific Gaps in HIV-Related Heart, Lung, Blood, and Sleep Research.

The National Heart, Lung, and Blood Institute (NHLBI) AIDS Program's goal is to provide direction and support for research and training programs in areas of HIV-related heart, lung, blood, and sleep (HLBS) diseases. To better define NHLBI current HIV-related scientific priorities and with the goal of identifying new scientific priorities and gaps in HIV-related HLBS research, a wide group of investigators gathered for a scientific NHLBI HIV Working Group on December 14-15, 2015, in Bethesda, MD. The core objectives of the Working Group included discussions on: (1) HIV-related HLBS comorbidities in the antiretroviral era; (2) HIV cure; (3) HIV prevention; and (4) mechanisms to implement new scientific discoveries in an efficient and timely manner so as to have the most impact on people living with HIV. The 2015 Working Group represented an opportunity for the NHLBI to obtain expert advice on HIV/AIDS scientific priorities and approaches over the next decade.

Perspectives from NHLBI Global Health Think Tank Meeting for Late Stage (T4) Translation Research.

Almost three-quarters (74%) of all the noncommunicable disease burden is found within low- and middle-income countries. In September 2014, the National Heart, Lung, and Blood Institute held a Global Health Think Tank meeting to obtain expert advice and recommendations for addressing compelling scientific questions for late stage (T4) research-research that studies implementation strategies for proven effective interventions-to inform and guide the National Heart, Lung, and Blood Institute's global health research and training efforts. Major themes emerged in two broad categories: 1) developing research capacity; and 2) efficiently defining compelling scientific questions within the local context. Compelling scientific questions included how to deliver inexpensive, scalable, and sustainable interventions using alternative health delivery models that leverage existing human capital, technologies and therapeutics, and entrepreneurial strategies. These broad themes provide perspectives that inform an overarching strategy needed to reduce the heart, lung, blood, and sleep disorders disease burden and global health disparities.

Reducing Health Inequities in the U.S.: Recommendations From the NHLBI's Health Inequities Think Tank Meeting.

The National, Heart, Lung, and Blood Institute convened a Think Tank meeting to obtain insight and recommendations regarding the objectives and design of the next generation of research aimed at reducing health inequities in the United States. The panel recommended several specific actions, including: 1) embrace broad and inclusive research themes; 2) develop research platforms that optimize the ability to conduct informative and innovative research, and promote systems science approaches; 3) develop networks of collaborators and stakeholders, and launch transformative studies that can serve as benchmarks; 4) optimize the use of new data sources, platforms, and natural experiments; and 5) develop unique transdisciplinary training programs to build research capacity. Confronting health inequities will require engaging multiple disciplines and sectors (including communities), using systems science, and intervening through combinations of individual, family, provider, health system, and community-targeted approaches. Details of the panel's remarks and recommendations are provided in this report.

Research on the human virome: where are we and what is next.

The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened a Working Group on the Microbiome in Cardiovascular, Pulmonary and Hematologic Health and Diseases from June 25, 2014, to June 26, 2014. The Working Group's central goal was to define what major microbiome research areas warranted additional study in the context of heart, lung, and blood (HLB) diseases. The Working Group identified studies of the human virome a key priority.

2015 proceedings of the National Heart, Lung, and Blood Institute's State of the Science in Transfusion Medicine symposium.

On March 25 and 26, 2015, the National Heart, Lung, and Blood Institute sponsored a meeting on the State of the Science in Transfusion Medicine on the National Institutes of Health (NIH) campus in Bethesda, Maryland, which was attended by a diverse group of 330 registrants. The meeting's goal was to identify important research questions that could be answered in the next 5 to 10 years and which would have the potential to transform the clinical practice of transfusion medicine. These questions could be addressed by basic, translational, and/or clinical research studies and were focused on four areas: the three "classical" transfusion products (i.e., red blood cells, platelets, and plasma) and blood donor issues. Before the meeting, four working groups, one for each area, prepared five major questions for discussion along with a list of five to 10 additional questions for consideration. At the meeting itself, all of these questions, and others, were discussed in keynote lectures, small-group breakout sessions, and large-group sessions with open discourse involving all meeting attendees. In addition to the final lists of questions, provided herein, the meeting attendees identified multiple overarching, cross-cutting themes that addressed issues common to all four areas; the latter are also provided. It is anticipated that addressing these scientific priorities, with careful attention to the overarching themes, will inform funding priorities developed by the NIH and provide a solid research platform for transforming the future practice of transfusion medicine.

Hematopoietic cell transplantation and HIV cure: where we are and what next?

The report of the so-called Berlin patient cured of HIV with hematopoietic stem cell transplantation and a few other studies raised tremendous hope, excitement, and curiosity in the field. The National Heart, Lung and Blood Institute of the National Institutes of Health convened a Working Group to address emerging heart, lung, and blood research priorities related to HIV infection. Hematopoietic cells could contribute to HIV cure through allogeneic or autologous transplantation of naturally occurring or engineered cells with anti-HIV moieties. Protection of central memory T cells from HIV infection could be a critical determinant of achieving a functional cure. HIV cure can only be achieved if the virus is eradicated from reservoirs in resting T cells and possibly other hematopoietic cells. The Working Group recommended multidisciplinary efforts leveraging HIV and cell therapy expertise to answer the critical need to support research toward an HIV cure.

Dengue viremia in blood donors identified by RNA and detection of dengue transfusion transmission during the 2007 dengue outbreak in Puerto Rico.

BACKGROUND: In 2007, a total of 10,508 suspected dengue cases were reported in Puerto Rico. Blood donations were tested for dengue virus (DENV) RNA and recipients of RNA-positive donations traced to assess transfusion transmission. STUDY DESIGN AND METHODS: Blood donation samples from 2007 were maintained in a repository and tested individually for DENV RNA by transcription-mediated amplification (TMA); a subset was further tested by an enhanced TMA (eTMA) assay. TMA-reactive samples were considered confirmed if TMA (including eTMA) was repeat reactive (RR). All TMA-RR samples were tested by quantitative, DENV type-specific reverse transcriptase-polymerase chain reaction (RT-PCR) and for anti-DENV immunoglobulin (Ig)M by enzyme-linked immunosorbent assay. Samples positive by RT-PCR were further tested for infectivity in mosquito cell culture. Patients receiving components from TMA-RR donations were followed. RESULTS: Of 15,350 donation samples tested, 29 were TMA-RR for a prevalence of 1 per 529 (0.19%). DENV Types 1, 2, and 3 with viral titers of 10(5) to 10(9) copies/mL were detected by RT-PCR in 12 samples of which all were infectious in mosquito culture. Six TMA-RR samples were IgM positive. Three of the 29 recipients receiving TMA-RR donations were tested. One recipient in Puerto Rico transfused with red blood cells containing 10(8) copies/mL DENV-2 became febrile 3 days posttransfusion and developed dengue hemorrhagic fever. The recipient was DENV-2 RNA positive by RT-PCR; both the donor and the recipient viruses had identical envelope sequences. CONCLUSIONS: High rates of viremia were detected in blood donors in Puerto Rico coupled with the first documented transfusion transmission of severe dengue disease, suggesting that further research on interventions is needed.

Surveillance of transfusion-transmissible infections comparison of systems in five developed countries.

Most industrialized countries maintain surveillance programs for monitoring transmissible infection in blood donations, revising approaches to methodology and risk assessment as new threats emerge. A comparison of programs in the United States, Canada, France, the UK, and Australia indicates that they have similar function, although the structure of blood programs vary as does the extent and nature of formal ties with public health. The emergence of HIV in the late 1970s and early 1980s was key in recognizing that surveillance systems specific to blood transfusion were essential. Hence, most industrialized countries monitor transfusion-transmissible infections in donors and evaluate the impact of new testing and of predonation screening strategies. Emerging infections since HIV have had different transmission pathways and challenged blood programs to draw upon resources for a rapid and effective response, with recognition that the original focus on sexual/drug-related risk of HIV and hepatitis was inadequate. The focus of surveillance programs on new and emerging pathogens fulfills a key role in risk assessment and policy formulation. The precise nature of such activities varies by country because of the structure of the blood programs and surveillance systems, the strategic focus of the blood programs, and the epidemiology of disease in each country.

Xenotropic murine leukemia virus-related virus does not pose a risk to blood recipient safety.

BACKGROUND: When xenotropic murine leukemia virus-related virus (XMRV) was first reported in association with chronic fatigue syndrome, it was suggested that it might offer a risk to blood safety. Thus, the prevalence of the virus among blood donors and, if present, its transmissibility by transfusion need to be defined. STUDY DESIGN AND METHODS: Two populations of routine blood donor samples (1435 and 13,399) were obtained for prevalence evaluations; samples from a linked donor-recipient repository were also evaluated. Samples were tested for the presence of antibodies to XMRV-related recombinant antigens and/or for XMRV RNA, using validated, high-throughput systems. RESULTS: The presence of antibodies to XMRV could not be confirmed among a total of 17,249 blood donors or recipients (0%; 95% confidence interval [CI], 0%-0.017%); 1763 tested samples were nonreactive for XMRV RNA (0%; 95% CI, 0%-0.17%). Evidence of infection was absent from 109 recipients and 830 evaluable blood samples tested after transfusion of a total of 3741 blood components. CONCLUSIONS: XMRV and related murine leukemia virus (MLV) markers are not present among a large population of blood donors and evidence of transfusion transmission could not be detected. Thus, these viruses do not currently pose a threat to blood recipient safety and further actions relating to XMRV and MLV are not justified.

Donor testing and risk: current prevalence, incidence, and residual risk of transfusion-transmissible agents in US allogeneic donations.

Over the past 20 years, there has been a major increase in the safety of the blood supply, as demonstrated by declining rates of posttransfusion infection and reductions in estimated residual risk for such infections. Reliable estimates of residual risk have been possible within the American Red Cross system because of the availability of a large amount of reliable and consistent data on donations and infectious disease testing results. Among allogeneic blood donations, the prevalence rates of infection markers for hepatitis C virus (HCV) and hepatitis B virus have decreased over time, although rates for markers of human immunodeficiency virus (HIV) and human T-cell lymphotropic virus did not. The incidence (/100 000 person-years) of HIV and HCV among repeat donors showed apparent increases from 1.55 and 1.89 in 2000 through 2001 to 2.16 and 2.98 in 2007 through 2008. These observed fluctuations confirm the need for continuous monitoring and evaluation. The residual risk of HIV, HCV, and human T-cell lymphotropic virus among all allogeneic donations is currently below 1 per 1 million donations, and that of hepatitis B surface antigen is close to 1 per 300 000 donations.

Blood donation screening for hepatitis B virus markers in the era of nucleic acid testing: are all tests of value?

BACKGROUND: The American Red Cross implemented hepatitis B virus (HBV) minipool (MP)-nucleic acid testing (NAT) in June 2009, in addition to existing tests for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B core antigen (anti-HBc). The value of all three tests was evaluated. STUDY DESIGN AND METHODS: HBsAg, anti-HBc, and HBV DNA (Ultrio MP-NAT, Gen-Probe/Novartis) donation results were analyzed during a 12-month period (July 1, 2009-June 30, 2010). Additional testing by individual-donation (ID) polymerase chain reaction (PCR) to confirm donor infection was performed when any HBV screening test was reactive or positive, except in the case of HBsAg neutralization-positive, anti-HBc-reactive samples. Numbers of blood donations identified as reactive or positive versus nonreactive or negative were compared. RESULTS: Of about 6.5 million donations, 699 were defined as from HBV-infected donors, of which 64% (444) were reactive for all three markers. More than 99% (697) had reactivity to one or both serologic tests with 68% (477) showing reactivity by MP-NAT. Only two donations were DNA-positive, seronegative NAT-yield donations (1 per 3.23 million), fewer than expected (p = 0.0075). Among MP-NAT-reactive donors, only small numbers represented early infection (2 or 0.4% with negative serology and 10 or 2.1% who were HBsAg confirmed positive, anti-HBc nonreactive). Of the 142 occult HBV-infected donors, 85% were MP-NAT nonreactive requiring ID-PCR for detection (121 or 54.5% of all MP-NAT nonreactives vs. 21 or 4.4% of all MP-NAT reactives). CONCLUSIONS: The HBV DNA-positive yield rate from MP-NAT was lower than expected, likely representing the rarity of such findings even in very large studies. With the implementation of HBV MP-NAT, the value of maintaining anti-HBc for the detection of low-level HBV DNA-positive donors was confirmed; however, HBsAg screening showed no blood safety value.

Human T-lymphotropic virus antibody screening of blood donors: rates of false-positive results and evaluation of a potential donor reentry algorithm.

BACKGROUND: Blood donor screening with enzyme immunoassays (EIAs) for antibodies to human T-lymphotropic virus (HTLV)-I, and later to HTLV-I/II, has led to the unnecessary deferral of tens of thousands of individuals. The licensure of the Abbott PRISM HTLV-I/HTLV-II chemiluminescent immunoassay (ChLIA) may permit the reinstatement of historically deferred donors. STUDY DESIGN AND METHODS: The efficacy of a reentry algorithm involving a follow-up sample from EIA-deferred donors testing HTLV-I/II ChLIA nonreactive was evaluated using 386 serologic confirmed-positive samples archived since the inception of anti-HTLV donor screening. Reactivity of the 386 samples by the ChLIA, when coupled with the package insert sensitivity data, may be used to demonstrate efficacy of the reentry algorithm. Donor incidence was also examined from 2008 through 2009 to evaluate changes to the existing HTLV screening policy. RESULTS: From January 1, 1995, to April 28, 2008, a total of 64,052 donors to the American Red Cross were deferred solely because of HTLV EIA false positivity, representing more than 130,000 US donors. HTLV ChLIA identified 386 confirmed-positive donations from 386 randomly selected donors representing reactivity to both the bioMérieux and the Abbott HTLV-I/II EIAs (95% confidence interval [CI], 99.2%-100%); both EIAs have since been discontinued. This is comparable to the detection of 843 of 843 confirmed-positive samples during the ChLIA clinical trials (95% CI, 99.48%-100%). Incident HTLV infections occurred primarily among female repeat donors during 2008 throughout 2009. CONCLUSIONS: Donors testing falsely positive by historic EIAs since 1988 should be considered for reinstatement if a contemporary sample tests ChLIA nonreactive. Changes to the existing screening algorithm seem unlikely since new HTLV infections were detected among repeat donors.

West Nile fever characteristics among viremic persons identified through blood donor screening.

Nucleic acid testing (NAT) of blood donors provides opportunities for identifying West Nile virus (WNV)-infected persons before symptoms develop and for characterizing subsequent illness. From June 2003 through 2008, the American Red Cross performed follow­up interviews with and additional laboratory testing for 1436 donors whose donations had initial test results that were reactive for WNV RNA; 821 of the donors were subsequently confirmed to have WNV infection, and the remainder were unconfirmed or determined to have false­positive results. Symptoms attributed to WNV infection were determined by comparing symptom frequency among 576 donors identified with early WNV infection (immunoglobulin M antibody negative) and those with unconfirmed infection. We estimate that 26% of WNV­infected persons become symptomatic, defined by the presence of at least 3 of 8 indicator symptoms. Nearly one­half of symptomatic persons sought medical care; only 5% received a diagnosis of WNV infection. Female subjects and persons with higher viral loads detected in the index donation were more likely than other subjects to develop symptoms.

Prevalence, incidence, and residual risk of human immunodeficiency virus and hepatitis C virus infections among United States blood donors since the introduction of nucleic acid testing.

BACKGROUND: Nucleic acid testing (NAT) for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) was introduced for blood donation screening in the United States in 1999. This study analyzes temporal trends of these two infections since NAT introduction. STUDY DESIGN AND METHODS: Donation data from 1999 to 2008 were analyzed; each donation was tested for antibodies and viral RNA for HIV and HCV. Incidence for first-time (FT) donors was derived by multiplying that among repeat (RP) donors by the ratio of NAT yield rates between FT and RP donors. Incidence for all donors was the weighted mean based on percentage of FT and RP donors. Residual risk (RR) was determined using the window-period model. RESULTS: During the 10-year period approximately 66 million donations were screened with 32 HIV (1:2 million) and 244 HCV (1:270,000) NAT yield donations identified. HCV prevalence among FT donors decreased by 53% for 2008 compared to 1999. HIV and HCV incidence among RP donors increased in 2007 through 2008 compared to 2005 through 2006. During 2007 through 2008, HIV incidence was 3.1 per 10(5) person-years (py), with an RR estimate of 0.68 per 10(6) (1:1,467,000) donations; HCV incidence was 5.1 per 10(5) py, with an RR estimate of 0.87 per 10(6) (1:1,149,000). The increase in HIV incidence was primarily among 16- to 19-year-old, male African American donors and that in HCV was primarily among Caucasian donors of 50 or more years. Donors from the Southern United States had higher incidence rates. CONCLUSION: HCV prevalence decreased significantly since NAT introduction. The increase in HIV and HCV incidence in 2007 through 2008 warrants continued monitoring and investigation.