Margarethe Heiden

The German Haemovigilance System–reports of serious adverse transfusion reactions between 1997 and 2007

Data of the German Haemovigilance System were collected from 1997 to 2007 and assessed on the basis of pre‐defined safety standards. Suspected cases of serious adverse reactions following transfusions reported to the Paul‐Ehrlich‐Institut were evaluated on the basis of national criteria, and the definitions of International Society of Blood Transfusion (ISBT) in compliance with defined causality criteria. The suspected cases were rated as confirmed and unconfirmed transfusion reactions. Assessment of causality took into consideration the clinical course of the adverse reaction and, if necessary, information about donation and manufacturing. Of the 5128 suspected serious adverse reactions, 1603 could be confirmed. Referring to the absolute figures, acute transfusion reactions (e.g. allergic reactions, hypotension and dyspnoea) were recorded most frequently, followed by transfusion‐related acute lung injury (TRALI), haemolytic reactions, transfusion‐related bacterial infections and virus infections. The majority of the 52 transfusion‐related fatalities (14 each) were due to TRALI and acute transfusion reactions (mostly severe allergic reactions). Referred to the blood products administered, immune TRALI cases and TRALI‐related fatal courses were most frequently reported after administration of fresh frozen plasma (FFP) (15/106 and 3.5/106 units, respectively), transfusion‐related bacterial infections after administration of platelet concentrates (7/106 units), acute haemolytic transfusion reactions after administration of red blood cell concentrates (2.3/106units) and acute transfusion reactions after administration of red blood cell or platelet concentrates (7.8/106 and 13/106 units, respectively). Despite the high safety standard required for blood products in Germany, there is still room for reducing the frequency of isolated cases of transfusion reactions by targeted action.

Experience of mandatory nucleic acid test (NAT) screening across all blood organizations in Germany: NAT yield versus breakthrough transmissions.

BACKGROUND: Mandatory nucleic acid test (NAT) blood screening was introduced in Germany in 1999 for hepatitis C virus (HCV) RNA and in 2004 for human immunodeficiency virus Type 1 (HIV‐1) RNA. Minimal sensitivity limits of 5000 IU HCV RNA/mL and 10,000 IU HIV‐1 RNA/mL were defined for the individual donation facilitating testing of minipools (MPs). The NAT yield obtained from all blood organizations is summarized. Transfusion‐associated virus transmissions despite NAT screening (“breakthrough transmissions”) are analyzed.

Benefit of transfusion‐related acute lung injury risk‐minimization measures – German haemovigilance data (2006–2010)

Objective  Based on the frequency of immune‐mediated and non‐immune‐mediated transfusion‐related acute lung injury (TRALI), the effect of risk‐minimization measures was evaluated during a period of 5 years (2006–2010). Risk‐minimization measures were implemented in 2008/2009, consisting of exclusion of female donors with a history of pregnancy or exclusion of female donors with human leucocyte antigen (HLA)/human neutrophil alloantigen (HNA) antibodies.

Transfusion-Transmitted Bacterial Infections - Haemovigilance Data of German Blood Establishments (1997-2010).

Methods: In order to evaluate the benefit of risk minimisation measures, reporting rates of transfusion-transmitted bacterial infections (TTBI) were calculated on the basis of annual reports and distributed blood components. Following the implementation of risk minimisation measures in 2003 and 2008, a comparison of pre- and post-implementation periods was performed. Results: During a period of 14 years, 90 cases of TTBI were confirmed, 34 were caused by red blood cell (RBC) concentrates, 5 by fresh frozen plasma, and 51 by platelet concentrates (PCs). The overall reporting frequency was 1 TTBI in 1.91 million RBC units; 1 TTBI in 0.094 million PC units, and 1 TTBI-associated fatality in 0.57 million PC units. From 2001–2004 the reporting rate was 13.7 per million PC units; 2005–2008, after the implementation of pre-donation sampling; it was 10.8 per million PC units (p > 0.5). After limitation of the shelf life (2008), the reporting rate decreased to 4.49 per million PC units (p = 0.12), and one case of related fatality was reported. Agents with low pathogenicity were reported in 14 of 41 immunosuppressed patients (34%) but only in 1 of 13 patients with non-haematological/oncological diseases. Conclusion: TTBI and associated fatalities could be gradually reduced by the risk minimisation measures, but further strategies such as implementation of sensitive screening tests or pathogen-reducing approaches should be discussed.

Blood screening nucleic acid amplification tests for human immunodeficiency virus Type 1 may require two different amplification targets.

BACKGROUND: Five cases of human immunodeficiency virus Type 1 (HIV‐1) RNA–positive blood donations are described that escaped detection by three different CE‐marked nucleic acid amplification technique (NAT) screening assays. These events were associated with two HIV‐1 transmissions to recipients of blood components. The implicated NAT assays are monotarget assays and amplify in different viral genome regions (group‐specific antigen or long terminal repeat). Investigations into the cause of the false‐negative test results were initiated.

Management of blood supplies during an influenza pandemic.

BACKGROUND: Blood supplies are delicate resources, particularly vulnerable to incidents affecting the health of donors. The critical impact of a pandemic on the availability of red blood cells (RBCs) has been demonstrated in previous research; however, a detailed estimate of the expected deficit is missing. This has become a priority issue in the face of the current influenza pandemic.

The harmonization of the regulation of blood products: a European perspective

The development of blood products as medicines initially took place on the national level in various countries, which resulted in considerable diversity of mechanisms and stringency of regulatory oversight. The scenario changed dramatically with the catastrophic experience that severe virus infections had been transmitted by blood products world‐wide. Blood products, which had been regulated differently in the member states, became subject to the European pharmaceutical legislation in 1989. A specialized directive regulating the blood transfusion sector and the collection of plasma for fractionation was enacted in 2002. The European Community, particularly the Commission and the European Medicines Agency, is continuously refining the requirements, providing detailed technical and scientific guidance. In addition, institutions of the Council of Europe play an important role in the transfusion sector, the elaboration of the European Pharmacopoeia prescriptions, and the co‐ordination of Official Medicines Control Laboratory or Laboratories batch release. However, further and sustained efforts towards international harmonization are needed. There are already important mechanisms in place, such as the International Conference on Harmonization initiative, which is producing internationally recognized guidelines on central issues. Another important achievement is the common technical document format, which enables the use of uniform applications for marketing authorization. However, there is still room for progress, for example, questions regarding regulatory requirements for licensing of in vitro diagnostic devices, or mutual recognition of inspections. The World Health Organization continues to play an important role in harmonization, both substantially by the production of high‐level guidance documents or the establishment of physical international standard preparations, and in a more general sense by providing a platform for international collaboration. A very important aspect is the transparency of the creation and refinement of regulatory requirements. It is currently the rule that draft legal texts, monographs and guidelines are published for a consultation period before adoption. Effort and attention are required to keep track of the developments. However, in the era of modern electronic communication tools, the necessary information can be found on websites and comments can easily be submitted. Networking and exchange of information will continue to be crucial for development and maintenance of sound and balanced regulatory requirements.

Quality of therapeutic plasma-requirements for marketing authorization.

Fresh frozen plasma (FFP) contains higher levels of intact coagulation factors and coagulation and fibrinolysis inhibitors than solvent/detergent-treated plasma (SD plasma), and also greater residual cell contamination. SD plasma is a particle-free plasma of uniform quality. SD treatment, however, has the specific result of reducing the activities of some inhibitors. Both plasma types carry a minimal residual risk of transmitting human immunodeficiency virus (HIV)-1/2, hepatitis virus B (HBV), and hepatitis virus C (HCV), but SDP is, in addition, also safe with respect to other lipid-enveloped viruses and perhaps with respect to hepatitis virus A (HAV), also due to its antibody (Ab) content. Future revisions of therapeutic plasma safety and quality standards should consider the following points:For FFP:reduce residual cell count in all FFP units to values below 5 x 10(6) leukocytes/l;screen donors for Parvovirus B19 genome and antibodies in order to establish a sufficiently large collection of genome-negative and antibody-positive donors whose FFP can be used for selected patients;For SDP:introduce pool testing for Parvovirus B19 genome; fix an upper limit for genome and a lower limit for antibody content;in addition to the standard quality control methods for therapeutic plasma, focus on assays to test for functionally intact proteinase inhibitors such as alpha(2)antiplasmin (alpha(2)AP) and alpha(1)proteinase inhibitor (alpha(1)PI) that are important for plasma indications. Commercially available kits may not be sufficient to show changes in inhibition kinetics. For both types:introduce an activation marker such as thrombin-antithrombin complex (TAT) as a random test to monitor activation processes during withdrawal, separation, manufacturing, and storage;abolish inappropriate parameters like Antithrombin III (AT III) and coagulation factor XI that are not relevant for changes in plasma quality;finally, support every effort towards establishing an efficient documentation and reporting system on efficacy and side effects of plasma transfusions. Effective reporting alone might help to reveal deficiencies of specific plasma quality and to overcome them through modifications to manufacturing processes and testing, or by defining its indications more precisely.

Sexual risk behaviour and donor deferral in Europe

One of the most controversial policies in blood transfusion worldwide is the permanent deferral from donating blood of men with sexual contacts to other men (MSM). This policy was implemented for safety reasons as sex between men is known to be a high risk factor for acquiring severe infectious diseases transmissible by blood transfusion. Sexual contacts among heterosexual persons may hold similar risks but a clear‐cut discrimination between different individual risks is impossible. Nevertheless, the current blood donor deferral periods defined by European Union (EU) legislation depend on a distinction of different grades of risk with respect to sexual behaviour. Under the aegis of the Steering Committee on Blood Transfusion (CD‐P‐TS) of the Council of Europe (CoE), an international working group evaluated epidemiological and behavioural data, modelling studies on residual risk and spread of infections, and studies on adherence to donor selection criteria. The aim was to distinguish sexual behaviour of different risk categories. It was concluded, that existing data confirm that MSM and commercial sex workers (CSW) are groups at high risk. Any further grading lacks a scientific data base. Modelling studies indicate that adherence to deferral policies is of major relevance suggesting that good donor adherence may outweigh the small negative effects on blood safety postulated for changing from permanent to temporary deferral periods for high risk sexual behaviours. The fact that a considerable percentage of donors are MSM – despite the permanent deferral policy – demonstrates the need to increase donor understanding and adherence.

Quality and Safety in Blood Supply in 2010

The past two decades saw tremendous achievements in blood safety, which are due to the commitment of blood establishments and industry, progress in technology such as the improvement of serological and NAT screening tests, and stringent regulatory control. Milestones in the legislation were the inclusion of plasma derivatives in the pharmaceutical legislation of the European Community (EC) in the year 1989 and special laws for the blood sector in EC and in member states, such as the Transfusionsgesetz (Transfusion Law) in Germany. The legal frame has to be supplemented by scientific and technical guidance, which is provided on the European level by the European Directorate for the Quality of Medicines and Health Care and by the European Medicines Agency. In the member states, guidelines taking into account the national peculiarities can be elaborated, such as the German hemotherapy guidelines issued by the German Medical Association (BundesÄrztekammer) in agreement with the Paul-Ehrlich-Institut. The regulatory control of screening tests, and the introduction of NAT testing lead to a remarkably high degree of safety concerning the most relevant viruses HIV, HBV and HCV. Issues needing further attention are bacterial contamination and transfusion-associated acute lung injury (TRALI). Measures aiming at minimizing risks have to be balanced against their impact on supply. In order to ensure the assured supply with safe blood products, sustained efforts and research are needed as well as a continuous dialogue among blood services, industry, physicians, patients and regulatory authorities.