White paper on pandemic preparedness in the blood supply.

BACKGROUND AND OBJECTIVES: In March 2020, the WHO declared the SARS-CoV-2 corona virus a pandemic which caused a great disruption to global society and had a pronounced effect on the worldwide supply of blood. MATERIALS AND METHODS: In 2022 an on-line meeting was organised with experts from Austria, Canada, Germany, Greece, Netherlands and United States to explore the opportunities for increasing preparedness within blood systems for a potential future pandemic with similar, or more devastating, consequences. The main themes included the value of preparedness, current risks to the blood supply, supply chain vulnerabilities, and the role of innovation in increasing resiliency and safety. RESULTS: Seven key recommendations were formulated and including required actions at different levels. CONCLUSION: Although SARS-CoV-2 might be seen as a unique event, global health risks are expected to increase and will affect blood transfusion medicine if no preparedness plans are developed.

External quality assessment providers' services appear to more impact the immunohaematology performance of laboratories than national regulatory and economic conditions.

OBJECTIVES: Medical laboratories may, at their own discretion, exceed but not undercut regulatory quality requirements. Available economic resources, however, may drive or hinder eagerness to exceed minimum requirements. Depending on the respective scopes of regulatory and economic framework conditions, differing levels of quality efforts to safeguard laboratory performance can be anticipated. However, this has not yet been investigated. METHODS: Immunohaematology external quality assessment (EQA) results collected by 26 EQA providers from their participant laboratories in 73 countries from 2004 to 2019 were evaluated. Error rates were aggregated in groups according to the respective national regulatory and economic framework conditions, to whether or not expert advice was provided in case of incorrect results, and the frequency of EQA samples. RESULTS: These representative data indicate no association between national regulatory (mandatory participation in EQA, monitoring of performance of individual laboratories by authorities, financial consequences of incorrect results) and economic (level of national income, share of national health expenditure) conditions to the quality performance of medical laboratories in immunohaematology. However, EQA providers' support for laboratories in the event of incorrect results appear to be associated with lower error rates, but a high EQA sample frequency with higher error rates. CONCLUSIONS: Further research into the impact of introducing or changing services of EQA providers is needed to confirm the results found in this first of its kind study.

Complications of blood donation reported to haemovigilance systems: analysis of eleven years of international surveillance.

BACKGROUND AND OBJECTIVES: The International Haemovigilance Network collects aggregate data on complications of blood donation from member haemovigilance systems (HVS). We analysed the data collected in 2006-2016 in order to learn from it and consider future improvements. MATERIALS AND METHODS: National HVS entered annual data on donation complications and on annual whole blood and apheresis donations in the 'ISTARE' (International Surveillance of Transfusion Adverse Reactions and Events) online database. We calculated national and aggregate donation complication rates. RESULTS: Twenty-four HVS provided data for 138 country years (CY; median 7 CY, IQR 2-8), covering 155 M donations. The overall complication rate was 6·3/1000 donations and the median country rate 3·2/1000 (IQR 1·1-10·1). Overall and severe complication rates varied considerably between HVS. Vasovagal reactions (VVR) were most commonly reported: 4·6/1000 donations, median country rate 3·1/1000 donations (IQR 0·6-7·7). Rare complications included generalized allergic reaction (0·10/100 000) and major blood vessel injury (category available since 2015; 0·12/100 000). Eighteen HVS reported complications of whole blood donation (WBD) and apheresis separately (89 CY, 101·6 M WBD and 26·3 M apheresis donations). The median country VVR rate was 3·4/1000 WBD (IQR 1·0-9·1) and 1·5/1000 apheresis donations (1·0-4·2). Rates of venepuncture-related complications tended to be higher for apheresis: the median country rate of reported haematomas was 0·39/1000 WBD (IQR 0·31-1·2) vs. 4·2/1000 apheresis donations (0·69-5·6). CONCLUSION: International reporting allows HVS to study rates of blood donation complications and capture information about very rare events. The present variability of reporting and severity assessment hampers comparisons between HVS and requires further work.

Medical student education in transfusion medicine, part II: Moving forward to building up a "Know How" education program in transfusion medicine for under-graduate medical students.

There is a general trend in changing paradigm in teaching medicine; the emerging concept relies on a competence-based approach. Transfusion is either a discipline or a subsidiary of others depending on the countries and systems; this variability can be explained because transfusion is a medical care that is transdisciplinary. As a collective of professionals in both transfusion medicine practice and education, authors aim to propose a revision of the way education in transfusion medicine is delivered in this era of the 'global competency approach'. They advocate in favor of a Know How on 5 key issues: Diagnosing the patient condition in line with the Patient Blood Management principles; Facing acute blood loss; Addressing compatibility and avoiding immunization; Seeking for maximized benefits and dampening complications; and Inlaying competence within global health care issues, also comprising od economy. The methods used would be those developed for medical education at large, such as assessment tools. The global objective is to deliver the necessary competence to manage patients by an intern/resident. At the end of the curriculum, students should be able to self-evaluate the following items: 1) Do I know why my patient is anemic, thrombocytopenic, bleeding….? 2) Do I know the best approach to treat anemia, thrombocytopenia, bleeding (including the "no treatment" option)? 3) Do I know whether a transfusion approach is appropriate for my patients? 4) Do I know how to evaluate and anticipate benefits from blood transfusion and to avoid side-effects in the patient? 5) Do I know how to avoid unnecessary use of the products?

West Nile virus in humans, Greece, 2018: the largest seasonal number of cases, 9 years after its emergence in the country.

BackgroundHuman cases of West Nile virus (WNV) infection are recorded since 2010 in Greece, with seasonal outbreaks occurring almost annually. Enhanced surveillance has been implemented since 2010, to promptly characterise cases' temporal and geographical distribution and inform authorities for implementation of appropriate measures (mosquito control, health education, blood safety).AimWe describe the epidemiology of WNV human infections in Greece focusing on the 2018 season.MethodsThe National Public Health Organization advised physicians to test all suspect WNV infection cases and refer samples to reference laboratories. Laboratories notified diagnosed cases on a daily basis. Treating physicians, patients, and infected blood donors were interviewed within 48 hours after diagnosis and the probable infection location was identified. Hospitalised cases were followed up until discharge.ResultsA total of 317 autochthonous WNV infection cases were diagnosed in 2018. Among them, 243 cases had neuroinvasive disease (WNND), representing a 23% increase of WNND cases compared with 2010, the previous most intense season. There were 51 deaths. Cases started occurring from week 22, earlier than usual. Both rural and urban areas were affected, with 86 (26% of the total) municipalities belonging to seven (54% of the total) regions recording cases. Two major epicentres were identified in Attica and Central Macedonia regions.ConclusionsThe largest number of human cases of WNV infection ever recorded in Greece occurred in 2018, with a wide geographical distribution, suggesting intense virus circulation. Enhanced surveillance is vital for the early detection of human cases and the prompt implementation of response measures.

West Nile and Usutu Virus Infections and Challenges to Blood Safety in the European Union.

West Nile virus (WNV) and Usutu virus (USUV) circulate in several European Union (EU) countries. The risk of transfusion-transmitted West Nile virus (TT-WNV) has been recognized, and preventive blood safety measures have been implemented. We summarized the applied interventions in the EU countries and assessed the safety of the blood supply by compiling data on WNV positivity among blood donors and on reported TT-WNV cases. The paucity of reported TT-WNV infections and the screening results suggest that blood safety interventions are effective. However, limited circulation of WNV in the EU and presumed underrecognition or underreporting of TT-WNV cases contribute to the present situation. Because of cross-reactivity between genetically related flaviviruses in the automated nucleic acid test systems, USUV-positive blood donations are found during routine WNV screening. The clinical relevance of USUV infection in humans and the risk of USUV to blood safety are unknown.

Comparing transfusion reaction risks for various plasma products - an analysis of 7 years of ISTARE haemovigilance data.

Plasma transfusions may result in transfusion reactions. We used the International Surveillance of Transfusion-Associated Reactions and Events (ISTARE) database, containing yearly reported national annual aggregate data on transfusion reactions from participating countries, to investigate risks of plasma transfusion reactions and compare transfusion reaction risks for different plasma types. We calculated risks for plasma transfusion reactions and compared transfusion reaction risks between plasma types using random effects regression on repeated measures. The ISTARE database contains data from 23 countries, reporting units issued and/or transfused and transfusion reactions observed for some portion of 7 years (2006-2012). Interquartile ranges (IQRs) of plasma transfusion reaction risks were: allergic reactions (5·6-72·2 reactions/105 units transfused); febrile non-haemolytic transfusion reactions (0-9·1); transfusion-associated circulatory overload (0-1·9); transfusion related acute lung injury (TRALI) (0-1·2); and hypotensive reactions (0-0·6). Apheresis plasma was associated with more allergic reactions [odds ratio (OR) = 1·29 (95% confidence interval: 1·19-1·40)] and hypotensive reactions [OR = 2·17 (1·38-3·41)] than whole blood-derived plasma. Pathogen-inactivated plasma was associated with fewer transfusion reactions than untreated plasma.

Medical student education in transfusion medicine: Proposal from the "European and Mediterranean initiative in transfusion medicine".

A large body of observations indicate that there is an inconsistent knowledge of Transfusion Medicine among health care professionals as well as inconsistent knowledge in all aspects of the transfusion process, from blood donation to transfusion on the ward. It is obvious to consider that appropriate education in Transfusion Medicine should be achieved in the education of specialists who will prescribe transfusion on a regular basis (hematologists, critical care specialists, anaethesiologists and others.) However,we also believe that education in Transfusion Medicine should also be delivered to almost all other medical specialists who may prescribe blood components. The variability in education of undergraduates in medical schools is universal most likely due to an absence of a predefined common platform. This paper, therefore, focuses on education at the undergraduate level and advocates coverage of the essential physiology and pathophysiology of blood as applied to blood transfusion as well as the medical and societal aspects of issues related to blood donation. It proposes incremental levels of training in Transfusion Medicine, with what is being therefore referred to as 'A', 'B', 'C' etc. curricula in ascending order of complexity; for example, 'A' and 'B' levels would involve medical, midwifery and nursing students, covering a broad base of the subject: they will be detailed in the present essay; ongoing further curricula will focus on physicians and other professionals working within the area or with responsibility for different aspects of the transfusion chain. It is intended that these courses include aspects of donor care, patient care and the appropriate use, safety and effectiveness of blood products. Next, it is advocated that curricula are addressed not only for high-income countries but also for middle- and low-income ones.

Associations of ABO, D, and Lewis blood groups and HLA Class I and Class II alleles with West Nile virus Lineage 2 disease outcome in Greece, 2010 to 2013.

BACKGROUND: West Nile virus (WNV) infection, commonly asymptomatic, may cause mild West Nile fever (WNF) or potentially fatal neuroinvasive disease (WNND). An outbreak of 262 cases of the new Lineage 2 strain in Greece in 2010 continued with high mortality (17%) in WNND. The objective was to investigate ABO, D, and Lewis blood groups, as well as HLA Class I and Class II alleles, in relation to WNV Lineage 2 disease morbidity. STUDY DESIGN AND METHODS: A cohort of 132 Greek WNV cases in 2010 to 2013 (65% male; mean age 64 years; 41% WNF, 59% WNND) was compared to 51,339 healthy WNV-negative blood donors and 246 healthy subjects. RESULTS: Blood group A was more common in WNV cases (51%) than blood donors (39%) and group O less common (32% vs. 42%). D negativity within group A was higher in WNV than in blood donors (18% vs. 10%, p = 0.044). The frequency of secretors (Lewis(a-b+)) was 60% in WNV and 68% in donors (p = 0.16). HLA alleles C*08, DRB1*O4:O5, and DQB1*O2 occurred significantly less frequently in WNV than controls (p < 0.05 unadjusted for multiple testing) and DRB1*10:O1 more frequently (p = 0.039). CONCLUSION: This first study of symptomatic WNV Lineage 2 suggests A/D negativity as a new risk factor associated with WNV infection and level of morbidity. Further studies are required of the possibility that HLA C*08, DRB1*O4:O5, and DQB1*O2 are protective alleles and DRB1*10:O1 a "susceptible" allele to WNV infection and the role of secretor status in relation to WNV infection.

The role and importance of epidemiology in transfusion medicine.

Transfusion therapy is an indispensable form of treatment, and an important element of the public health system. Due to its origin, blood's clinical use is associated with various risks that may cause adverse reactions and events. Progress in quality and safety of blood components has eliminated numerous risks, especially those of infectious origin. However, some risks cannot be predicted, while others cannot always be prevented. Globalisation and climate change constantly favour the spread of infectious agents. Against this, epidemiology plays a central role in ensuring the safety of transfusion treatment, by continuous surveillance and timely identification of risks, and in the development of routine and additional tests as measures for risk mitigation. As a quantitative discipline based on research methods, epidemiology is a method of reasoning; it relies on the generation and testing of hypotheses; it utilises other scientific resources, particularly in the field of blood donation and blood transfusion, thus having many applications. The main focus falls on transfusion-transmissible infections, and on environmental or occupational diseases, injuries, disabilities and death causes at large. The practice of epidemiology relies on a systematic approach and measurement of disease frequencies. Surveillance is a key element, involving continuously gathering, analysing, and evaluating data regarding diseases, morbidity and mortality, and disseminating the conclusions of the analyses to relevant competent authorities; in this way, action is taken for disease prevention and control. Surveillance systems also provide an important tool for risk assessment, a method to assess and characterise the critical parameters in the functionality of equipment, systems or processes of using scientific data in order to estimate the magnitude of any health effect that derives from decisions of policy makers. Epidemiological surveillance, particularly for the incidence of adverse reactions and adverse events associated with blood transfusion at the national and international levels, has demonstrated the importance of multidisciplinary cooperation between blood and public health services.

Thirty years of hemovigilance - Achievements and future perspectives.

Since its emergence in the early 1990s, hemovigilance has gradually evolved from a blood safety concept focused on surveillance of adverse reactions and events in patients, to a well-defined system that monitors the entire transfusion chain and improves its safety. The importance of hemovigilance has been recognized globally in a relatively short time, but the level of its implementation varies significantly between countries. The cooperation of international organizations has significantly contributed to the promotion, implementation, and education in this field. Thanks to initiatives taken, the safety of transfusion practice has been improved in many segments, primarily related to the risks of adverse events in recipients of blood components. In parallel with changing transfusion practice, the hemovigilance process has also matured. In addition to the reduction of existing risks and the early detection of emerging risks, hemovigilance has also embraced the principles of patient blood management. Research in hemovigilance is more increasingly focused on specific categories of patients, specific blood components and methods of their preparation, rare reactions, and transfusion efficacy and efficiency. A proactive approach and use of big data can play an important role in achieving these goals. Additional and sustained efforts should be made to prevent underreporting of events and to improve data comparability through clear definitions and grading systems. This review provides a historical overview of hemovigilance and its achievements, current challenges, and future plans.

Education in transfusion medicine, Part III - The importance of haemovigilance education.

According to the literature, there are significant differences in the availability of education and training in transfusion medicine worldwide, with significant heterogeneity in the existing curricula. Recognising the need for education with the aim of achieving globally standardised competencies in transfusion medicine, a group of experts collaborating in the European and Mediterranean Initiative in Transfusion medicine (EMITm) proposed a process of incremental training and education. Subsequent to two previous papers published by this group on general education in transfusion medicine, this paper specifically refers to the field of education in haemovigilance. This topic is of particular importance when one considers the role of haemovigilance in improving the safety of transfusion practice, and the fact that this role can only be realised through the cooperation of all participants in the transfusion chain. In addition to promoting the importance of education in haemovigilance, this paper provides an overview of the available literature on this topic and proposes an education programme on haemovigilance for medical students and residents.

Ethics in transfusion medicine: Are the intricate layers of ethics all universal? A global view.

Ethical principles have been considered, and in several respects regulated, along the entire blood procurement chain from donor motivation to transfusion to the patient. Consent of donors and voluntary non-remunerated donation are fields which have been addressed by codes of ethics and legislation. Caring for donor health is an area of further development of ethical standards. In part, blood products have also become a market, where commercial principles may synergize, but also creating issues in equality and maintaining human dignity that challenge societal solutions. At the bedside, the main global challenge remains to procure enough blood products for each patient in medical need. Allocation of rare blood, ethical evaluation of transfusion triggers, attitudes towards refusing blood transfusion and provision of blood products to remote settings are areas which should receive consideration.

The 2022 West Nile Virus Season in Greece; A Quite Intense Season.

Since 2010, the West Nile virus (WNV) has been established in Greece. We describe the epidemiology of diagnosed human WNV infections in Greece with a focus on the 2022 season. During the transmission period, clinicians were sending samples from suspected cases for testing. Active laboratory-based surveillance was performed with immediate notification of diagnosed cases. We collected clinical information and interviewed patients on a timely basis to identify their place of exposure. Besides serological and molecular diagnostic methods, next-generation sequencing was also performed. In 2022, 286 cases of WNV infection were diagnosed, including 278 symptomatic cases and 184 (64%) cases with neuroinvasive disease (WNND); 33 patients died. This was the third most intense season concerning the number of WNND cases, following 2018 and 2010. Most (96%) cases were recorded in two regions, in northern and central Greece. The virus strain was a variant of previous years, clustering into the Central European subclade of WNV lineage 2. The 2022 WNV season was quite intense in Greece. The prompt diagnosis and investigation of cases are considered pivotal for the timely response, while the availability of whole genome sequences enables studies on the molecular epidemiology of the disease.

Post-donation information management.

Post-donation information (PDI) can be defined as any information provided by the donor or other source following a donation, that, had it been known to the blood establishment during the selection process, would have resulted in the donor's deferral. PDI reflects the shortcomings, limitations and complexity of the donor selection process. Knowledge of the causes of PDI events, their types and frequency, is a prerequisite not only for their effective management, but also for the implementation of measures to improve the selection process and the safety of donated blood. Managing PDI requires a considerable investment of time and close collaboration between the various stakeholders involved in this process. Despite its regular occurrence and the fact that PDI points to a possible problem of blood safety, very few studies have been published so far, mostly by US and Canadian authors. This review article aims at collecting and discussing available information on all aspects of PDI management, with particular reference to European experiences.

Molecular characterization of occult hepatitis B cases in Greek blood donors.

The use of sensitive nucleic acid testing for hepatitis B virus in blood donors revealed a number of HBV DNA(+) cases among HBsAg(-) donors, a status known as occult HBV infection. The purpose of this study was the serological and molecular characterization of occult HBV infection in Greek blood donors. A prospective study was undertaken in order to identify occult HBV infection cases in blood donors. As part of the routine screening of blood donations in Greece, blood units were screened individually by a multiplex HIV-1/HCV/HBV nucleic acid assay. Initially reactive samples were retested with discriminatory assays. HBV DNA(+)/HBsAg(-) samples were tested further for HBV serological markers and HBV DNA was quantified by real-time PCR. Molecular characterization was performed by sequencing the envelope and polymerase genes of HBV. Preliminary screening revealed 21 occult cases with the following patterns: anti-HBc only: 7 donors, anti-HBc/anti-HBs: 7 donors, anti-HBc/anti-HBe: 5 donors, anti-HBc/anti-HBs/anti-HBe: 2 donors. In all cases, the HBV DNA load was <351 IU/ml. Sequencing was successful in 10 donors (classified within genotype D) revealing several amino acid substitutions related to diagnostic escape and antiviral resistance. HBsAg diagnostic failure and low viral replication in occult HBV infection carriers could possibly be attributed to multiple changes in envelope and polymerase regions, respectively.

Pathogen reduction of blood components during outbreaks of infectious diseases in the European Union: an expert opinion from the European Centre for Disease Prevention and Control consultation meeting.

Pathogen reduction (PR) of selected blood components is a technology that has been adopted in practice in various ways. Although they offer great advantages in improving the safety of the blood supply, these technologies have limitations which hinder their broader use, e.g. increased costs. In this context, the European Centre for Disease Prevention and Control (ECDC), in co-operation with the Italian National Blood Centre, organised an expert consultation meeting to discuss the potential role of pathogen reduction technologies (PRT) as a blood safety intervention during outbreaks of infectious diseases for which (in most cases) laboratory screening of blood donations is not available. The meeting brought together 26 experts and representatives of national competent authorities for blood from thirteen European Union and European Economic Area (EU/EEA) Member States (MS), Switzerland, the World Health Organization, the European Directorate for the Quality of Medicines and Health Care of the Council of Europe, the US Food and Drug Administration, and the ECDC. During the meeting, the current use of PRTs in the EU/EEA MS and Switzerland was verified, with particular reference to emerging infectious diseases (see Appendix). In this article, we also present expert discussions and a common view on the potential use of PRT as a part of both preparedness and response to threats posed to blood safety by outbreaks of infectious disease.

Amino acid signatures in the HLA class II peptide-binding region associated with protection/susceptibility to the severe West Nile Virus disease.

The MHC class II region in humans is highly polymorphic. Each MHC molecule is formed by an α and a ß chain, produced by different genes, creating an antigen-binding groove. In the groove there are several pockets into which antigens anchor and fit. The affinity of this fitting determines the recognition specificity of a given peptide. Here, based on our previous results about the association of MHC class II with the WNV disease, we examined the role of the binding pockets of HLA-DPA1, -DQA1 and-DRB1 in the severe form of the disease. In HLA-DQA1, variants in all pockets 1, 6 and 9 were found to be associated with either protection and/or susceptibility to neuroinvasion caused by WNV. Similarly, pockets 7, 9 and 10 in HLA-DRB1 were associated with severe disease. Protein modeling of these molecules revealed structural and functional differences among alleles with opposite roles concerning the development of the disease. Different amino acids in positions α52 and α66 (HLA-DQA1) significantly influenced the peptide binding while DYWLR/EFA combination (HLA-DRB1) was associated with neuronal damage. Further studies could help us understand the selectivity of pocket variants in order to create suitable peptides for an effective response.