NHLBI Workshop on Implementation Research to Address Gaps in International Blood Availability and Transfusion Safety in Low and Middle Income Countries (LMICs)
Blood supplies in high income countries (HICs) are usually sufficient and have low risks of transfusion-associated adverse events due to well-organized and coordinated blood systems; the use of (relatively) effective donor education, recruitment and interviewing; sensitive laboratory testing strategies; process automation and the application of good manufacturing and laboratory practices. However, such measures have not been adequately implemented in low and middle income countries (LMICs), especially in low resource settings. Some of the measures may also not be appropriate, practical, or validated for LMIC settings. The potential adverse events for recipients include transfusion-transmitted infections (TTI) including but not limited to human immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV) as well as transfusion-associated injuries due to errors, bacterial contamination, fluid overload, and transfusion reactions. The potential adverse events for donors can include incomplete or inaccurate testing leading to incorrect donor notification and an inability to follow up on donors with positive screening tests.
There are significant gaps between demand and blood supply in LMICs. National reports to the World Health Organization (WHO) Global Database for Blood Safety (GDBS) as well as published data further suggest that poor quality or lack of blood donation screening could be the most important gap in blood safety internationally. In most LMIC countries, the blood supplies rely on volunteer non-remunerated as well as family/replacement donors in ratios ranging between 0 and 100%. While the number of paid blood donations has been reduced in some settings, with successful conversion to voluntary donation, paid donation of labile blood and components may still account for a significant proportion of transfusion-transmissible infections globally due to the higher risk of infections associated with such donations. Inadequate or inconsistent supplies and acute shortages of blood for transfusion in low resources settings, often coupled with the questionable quality of the available blood supply, pose real risks to the health of patients who need blood transfusion. Such patients include those in need of transfusion secondary to malaria, sickle cell disease, thalassemia, obstetric hemorrhage, and trauma.
At the National Institutes of Health (NIH), research on blood availability and transfusion safety is supported by the National Heart, Lung, and Blood Institute (NHLBI). To identify key research priorities for improving global blood availability and transfusion safety, NHLBI convened a workshop on April 18-19, 2017 in Bethesda, MD, which was jointly organized by the Division of Blood Diseases and Resources (DBDR) and the Center for Translation Research and Implementation Science (CTRIS) of NHLBI. DBDR has a major responsibility for research to assure the adequacy and safety of the blood supply and transfusion safety while CTRIS plans, fosters, and supports integrated and coordinated programs of research to understand optimal and sustainable implementation strategies for evidence-based interventions. The focus of the workshop was to identify strategies and research opportunities to foster implementation research to improve the safety and availability of blood and blood components in LMICs.
Experts from LMICs of various regions (Africa, Middle East and North Africa, Southeast Asia, Latin America and the Caribbean, Asia and the Pacific, Eastern Europe and Central Asia) and experts from HICs were invited to participate in the workshop. Representatives from WHO, the Centers for Disease Control and Prevention (CDC), the International Society for Blood Transfusion (ISBT), AABB (formerly American Association for Blood Banks) and the America’s Blood Centers (ABC) as well as other agencies within and outside of NIH were also invited to participate in the workshop.
Three conference calls were held prior to the workshop to discuss challenges and opportunities in international blood availability and transfusion safety, and to identify gaps as well as potential key scientific priorities and research strategies to be further discussed at the in-person meeting. In addition, seven regional working groups were formed, each including at least one expert from the local region and other experts in transfusion medicine and implementation research. The seven working groups held multiple calls and were asked to identify key scientific priorities and research strategies for their region. The findings from these working groups were presented and discussed by all participants at the workshop on April 18-19, 2017. Invited experts who were not able to attend the in-person meeting in Bethesda, MD also provided input through their active participation by teleconference, both prior to and during the worshop.
2. Opportunities in LMICs
Essential aspects of blood transfusion services have been or are being established to various degrees in many LMICs. These include improved government engagement, oversight and regulation, with efforts such as establishment of national blood policies, nationally coordinated transfusion services and advancing capability within hospital blood banks. Blood availability and transfusion safety is now included as government priorities in many LMICs. There has been an increase in trained personnel working on blood availability and transfusion safety, including laboratory and clinical personnel. There have been training programs for transfusion medicine at institutional, national and regional levels with local and international partnerships. The transition from more externally supported blood program operations to a system of domestically-supported operations will provide additional opportunities for implementation research on blood availability and transfusion safety.
International, regional and national professional organizations as well as transfusion research networks have been developed. For example, key baseline data have been collected during the last two decades from several research studies in Africa to provide initial knowledge on the determinants of blood availability and transfusion safety. Professional organizations and networks could now be leveraged to facilitate research. Other health networks, such as those for infectious diseases like HIV, Malaria and tuberculosis as well as those for non-communicable diseases, could also now be leveraged to facilitate research in blood availability and transfusion safety.
Various international, regional and national initiatives on blood availability and transfusion safety have been implemented in some LMICs, such as T-REC (an international consortium of academics and health practitioners working to strengthen the capacity of African researchers to do research on blood transfusion) and the Francophone Africa Research Network. These initiatives have in various ways laid the foundation for future research efforts. The experience and lessons learned from these initiatives can also inform the design and execution of future implementation research.
New technologies such as electronic health information management systems have been deployed and mobile devices such as telephones and tablets are available and adaptable to resource-limited settings, including areas with limited or no power sources. Furthermore, the rapid growth of point of care and rapid diagnostic tests could help facilitate research on blood availability and transfusion safety in many LMICs. Different TTI testing algorithms could be explored for different settings.
The diverse situations in different LMICs also provide unique opportunities. For example, countries that are in different stages of development need to implement strategies that are feasible and sustainable locally. The experience gained from countries that have gone from low to middle income status could be of value to other LMICs. Furthermore, populations in many LMICs have different genetic and environmental factors that influence health and disease, providing unique opportunities for research on blood availability and transfusion safety. This includes populations with inherited bleeding disorders such as hemophilia, sickle cell disease, and thalassemia as well as acquired disorders such as HIV patients with chronic blood transfusion needs. Finally, the diversity in transfusion resources and infrastructure within LMICs, such as urban vs rural settings, low vs. high socio-economic levels, or the use of private vs public health facilities, needs to be taken into account for designing feasible and sustainable strategies.
3. Challenges in LMICs
Unmet needs for transfusion in LMICs were identified. These needs could be due to: a disproportionately low percentage of the population donating blood; a rapidly increasing demand due to improved access to healthcare; inappropriate clinical use; deferral of a relatively large proportion of donors because of high infection rates for TTIs or false positive screening results; or wastage and discard due to a lack of appropriate storage, delivery, inventory, quality, and management capacities. In many countries, blood transfusion services are highly fragmented with significant variation in quality and performance based on geography, urban vs. rural settings or differences in infrastructure development. For example, in certain countries, large amounts of plasma recovered from whole-blood donations are discarded because of quality concerns or logistical, contractual, and budgetary requirements that prevent the use of this plasma in fractionation.
Participants emphasized that donor recruitment and donation practices that work well in HICs cannot simply be “transferred to” or ‘adopted by’ LMICs. Motivations and deterrents to optimal blood donation behaviors include social and cultural factors that may be different from those in HICs. These factors are often poorly understood in LMICs or by experts in HICs, leading to sub-optimal recruitment and retention strategies and inadequate design of the necessary research. There have been limited human capital and financial resources dedicated to donor education, sensitization/motivation, recruitment and retention programs. Additionally, donor health concerns, such as donation-induced iron deficiency and anemia, have not been assessed in many LMICs.
Challenges to transfusion safety include insufficient regulatory and professional oversight; lack of legislation, regulations and policies or their effective implementation; lack of quality systems and safety programs such as those for donor screening and donation testing; and lack of monitoring systems (hemovigilance) to track patient and donor outcomes, including both infectious and non-infectious adverse events. In some LMICs, the high rates for transmission of TTIs pose substantial challenges, and there is a high probability that these rates are currently underestimated. In some LMICs, emerging infections could also pose unique challenges.
The lack of compliance and/or the ability to comply with TTI testing requirements, an irregular or absent supply of high-performing blood donation testing kits, as well as the lack of stringent proceses were highlighted as major issues facing some LMICs. Also highlighted was the need for the routine implementation of immunohematology tests using sensitive techniques to detect antibodies and to prevent or reduce transfusion reactions.
The relationship between an insufficient supply of blood for transfusion and unnecessary transfusion is not well-defined for LMICs. Inappropriate transfusion of blood products exists in many LMICs, which could be due to limited training in transfusion medicine and either a lack of clinical transfusion guidelines or their effective implementation. Social and cultural factors could also play a role in adherence to suboptimal clinical transfusion practices. Chronic blood shortage has a major influence on blood product prescription setting, for instance in the use of hemoglobin levels of 4-6 g/dl instead of 7-8 g/dl to prompt transfusion, and in the limitation of transfusion requests to 1 or 2 blood units.
In many LMICs, knowledge and financial contributions from HICs and international organizations have played a key role in developing the infrastructure and capacities for an adequate supply of safe blood for clinical transfusion. These resources are subject to the vagaries of the global economy and political shifts. Without continuing external support, how to sustain the blood supply system and services with limited resources poses a major challenge. This represents an area with tremendous risk to the sustainability of the supply, but also an opportunity for implementation research.
4. Key Questions, Priorities and Strategies Identified
The key questions, priorities and strategies identified by each of the seven regions can be grouped into the following categories:
Six of the seven regions identified blood availability as a priority. The questions requiring investigation include identification of factors that influence blood donation, including both motivations and deterrents; effective donor recruitment strategies for increasing blood collections in resource limited settings; more sensitive and specific donor health questionnaire (DHQ) for use in local settings; knowledge, attitude, practice (KAP) surveys and implementation strategies to achieve a volunteer non-remunerated blood donor base; the most effective interventions to increase and sustain repeat voluntary donation; development of systems to encourage young donors including recruitment of future donors by interventions with high school teachers and by introducing chapters in course curriculum for students; and major enabling factors for the successful transformation from family/replacement donors that represent 0-100% of the current blood supply to repeat voluntary non-remunerated blood donors. Finally, blood donor safety was also seen as not only important for blood availability but also a responsibility of governments as well as blood establishments. Anemia is often the major reason of deferral for many donors who are then not followed up or treated appropriately. Critical questions in this regard relate to the rate and clinical consequences of iron depletion among blood donors, as well as the best interventions to avoid iron deficiency among repeat blood donors. Particularly, the safety of blood donation is critically important when young donors (16-18 years) are targeted for recruitment.
Blood and transfusion safety
Questions and priorities identified by the regional working groups related to blood and transfusion safety were common to all regions, but the priority topics were variable. These included the development of locally-appropriate donor history questionnaire based upon locally-validated TTI risk factors; the use of “leap-frog technologies” such as a shared laboratory information system (LIS) located “in the cloud”; low-cost methods for pre-transfusion identity verification of recipients; hemovigilance systems for transfusion-transmitted infections and noninfectious serious transfusion hazards (e.g. immediate and delayed hemolysis); prevention of alloimmunization to RBCs antigens in congenital anemia patients; and assessment of the efficacy, safety, affordability and sustainability of implementing whole blood or component pathogen reduction technology. Several regions also highlighted the need for research on the risk of emerging and re-emerging pathogens. The neglected topic of transfusion-transmitted malaria needs to be addressed in the context of molecular testing, new preemptive anti-malarial drugs, and whole blood pathogen reduction methods.
Appropriate use of blood
Five of the seven regions also identified appropriate use of blood as a priority. For example, studies are needed to define appropriate clinical indications for blood transfusion that are relevant to LMIC clinical illnesses, to assess how blood transfusions are being used, and to understand whether actual use conforms to relevant best clinical practice. There is insufficient information on the extent to which blood centers and hospitals have established guidelines for transfusion indications and on the best way to implement guidelines for blood transfusions to avoid either under-transfusion or unnecessary blood transfusion. Research is needed into the role of hospital transfusion committees as well as effective implementation and sustainable uptake of clinical transfusion guidelines and hemovigilance systems. Patient blood management was also discussed. Transfusion of fresh whole blood has a prominent place in some LMICs but needs to be specifically examined with respect to definition, quality assurance and clinical indications.
The implementation of quality systems was identified as essential for blood and transfusion safety. Examples of questions that were deemed relevant for LMICs included: the status of temperature monitored and controlled transportation of blood and components in local settings and planning of intervention whenever applicable; interventions needed to improve, strengthen, correct or implement quality systems for blood safety; regulatory bodies sufficiently developed to promote/require quality systems; improvement of blood quality with appropriate tools including external quality assessment scheme (EQAS) for TTI testing and quality control (QC) in LMICs; and contribution of establishing regional centralized proficiency testing reference laboratories to assessing and improving the quality of blood donor screening. The cost of these proposals is paramount to their implementation and needs to be carefully assessed.
Health economics and budgeting
The need for incorporating health economics into implementation research for blood availability and transfusion safety was highlighted by two regions and elements of health economics were also included among the priorities identified by other regions. Relevant questions to address included: the success factors and strategies adopted by successful blood systems in ensuring blood availability and transfusion safety, including the allocation of resources and effective governance; sustainable models for financing blood safety in LMICs of different profiles with a focus on low income countries. Challenging questions without clear answers were also raised, such as the cost-effectiveness of blood transfusion strategies in patient blood management of sickle cell disease (SCD). Equally important is to collect comparative data on the production costs of blood products and channels and levels of reimbursement by governments, public or private insurance or patients themselves.
Training and education
The need for better training and education of blood center professionals in laboratory, clinical and implementation science research was reflected in many of the priorities stated above. This would establish local capacity to develop scientific evidence toward improving blood and transfusion safety as well as the recipient and donor experience. There was a specific suggestion to develop a training program for implementation research, similar in scope to an earlier fellowship program NHLBI supported for transfusion medicine.
For a complete list of questions, priorities and strategies identified by all seven regions, the reader is asked to please refer to the linked workshop booklet that includes the agenda, the roster of participants, the scientific priorities and the research strategies identified by the seven regional working groups.
5. Major Research Priorities Discussed at the Workshop
The need for an “adequate supply of safe blood” emerged as a major overriding theme from the discussions following the presentations of scientific priorities and research strategies by all regions at the in-person workshop on April 18-19, 2017. Significant gaps remain in safe blood availability especially in low resource settings, and in implementing appropriate clinical transfusion guidelines. Common challenges include lack of financial support or a sustainable financial model, lacking or low government/regulatory oversight, lack of quality systems, lack of adequately trained personnel, and lack of suitable donation screening algorithms and tests. To address these issues and improve blood availability and transfusion safety, there is a compelling need for the systematic collection and compilation of data, and a need for epidemiological and implementation research. Implementation research addresses the acceptability, affordability, appropriateness, feasibility, fidelity, penetration and sustainability of interventions as well as their effectiveness. The need for training personnel devoted to laboratory medicine, transfusion medicine, and implementation research were also emphasized.
At the strategic level, a coordinated multi-tiered approach to provision of blood within a country or region could be developed and assessed; for example, a centralized blood supply system(s) supplemented with various hospital- or organization-based supplies tailoring out to different settings in rural or austere parts of a country or region. Research needs to be conducted to identify the motivators and inhibitors or deterrents to blood donation in local settings, including the impact of socio-psychological and behavioral factors. Once motivators and deterrents are known and potential recruitment and retention strategies identified, implementation research to evaluate which strategies may best improve sustained recruitment and retention of safe blood donors in specific settings is warranted. While voluntary non-remunerated blood donation remains the goal, research into other feasible and sustainable approaches should be conducted, such as conversion of family and replacement donors to voluntary non-remunerated blood donors for repeat blood donations. Inducing young people to become blood donors could be explored, providing donor health is safe-guarded. Donor safety in general, including research to evaluate the consequences of and how to mitigate iron depletion, as well as cost-effectiveness assessments of interventions to protect donor health, is under-studied and an area in which research needs to be strengthened. Research on blood needs, including the best method for estimating such needs, and blood utilization as well as implementation research to evaluate patient blood management strategies are needed. Further related to blood availability are the issues of appropriate balance between whole blood and blood component production and effective strategies to minimize plasma and blood wastage. Research on feasible and sustainable means, including improved inventory management and use of recovered plasma for fractionation, could not only enhance blood availability for clinical transfusion but may also provide opportunities for improving the supply of fractionated blood products which are often in short supply in LMICs.
Blood and Transfusion Safety
Both innovation and implementation research are needed to develop and evaluate low-cost patient identification mechanisms (to decrease ABO incompatibility errors), laboratory information systems (to keep track of donor and donation information), rapid tests and point of care testing with high predictive values, small pool plasma fractionation methods, transportation and delivery systems, and pathogen reduction techniques appropriate for low resource settings. Furthermore, research is required to identify and implement effective yet locally feasible and sustainable quality systems (including external quality assessment systems) and procedures to ensure the quality of donor selection, donation screening, processing and delivery, and transfusion to recipients. While many challenges exist in low resource settings, the availability of new technologies, such as mobile communication, offer unique opportunities throughout the transfusion chain. In view of the lack of reliable data on prevalence and incidence of major TTIs including HIV, HBV and HCV, as well as associated risk factors in many low-resource settings, epidemiologic research is also required to generate baseline data to inform local policy formulation and decision making. Solid data on transfusion-transmitted malaria and policies to prevent such transmission, particularly in vulnerable patients such as children and pregnant women, need to be generated.
Health Economics Research
Health economics research for sustainability, including models of blood system financing such as cost recovery, was recognized as a major gap area. Such research may help identify potential options for country-specific blood supply system(s). Additionally, research that incorporates cost-effectiveness within local feasibility and sustainability assessments, by clearly demonstrating the public health benefits of such efforts, could enhance government commitment to an adequate supply of safe blood for patients.
Training and Education on Implementation Research
There is a need for training and education in implementation research to sustain blood availability and transfusion safety in LMICs. There has been very limited implementation research conducted by investigators in transfusion medicine and, vice versa, even fewer researchers in implementation science have considered conducting studies in transfusion medicine. Various venues for such training and education could be evaluated: for example, “special training symposia and on the job training” as performed within programs like the NHLBI Recipient Epidemiology and Donor Evaluation Study – III (REDS-III) program, training programs supported by the NIH Fogarty International Center in collaboration with relevant NIH institutes or centers, special fellowship programs for physicians to pursue implementation research careers, and training programs provided by T-REC -- an international consortium of academics and health practitioners working to strengthen the capacity of African researchers to do research on blood transfusion.
In summary, the workshop identified key research opportunities and priorities which countries and regions can refer to when they develop their research strategies. In addition, the workshop delineated what strategies, if implemented, have the greatest potential to advance blood availability and transfusion safety in LMICs.