Brigitte Keller-Stanislawski

Specificities of leucocyte alloantibodies in transfusion-related acute lung injury and results of leucocyte antibody screening of blood donors

Background  Antibody‐mediated transfusion‐related acute lung injury (TRALI) is an important cause of transfusion‐associated morbidity and death. Preventive strategies are currently a matter of debate.

Safety of immunization during pregnancy: A review of the evidence of selected inactivated and live attenuated vaccines

Vaccine-preventable infectious diseases are responsible for significant maternal, neonatal, and young infant morbidity and mortality. While there is emerging scientific evidence, as well as theoretical considerations, indicating that certain vaccines are safe for pregnant women and fetuses, policy formulation is challenging because of perceived potential risks to the fetus. This report presents an overview of available evidence on pregnant women vaccination safety monitoring in pregnant women, from both published literature and ongoing surveillance programs. Safety data were reviewed for vaccines against diseases which increase morbidity in pregnant women, their fetus or infant as well as vaccines which are used in mass vaccination campaigns against diseases. They include inactivated seasonal and pandemic influenza, mono- and combined meningococcal polysaccharide and conjugated vaccines, tetanus toxoid and acellular pertussis combination vaccines, as well as monovalent or combined rubella, oral poliomyelitis virus and yellow fever vaccines. No evidence of adverse pregnancy outcomes has been identified from immunization of pregnant women with these vaccines.

Frequency and severity of transfusion-related acute lung injury - German haemovigilance data (2006-2007)

Objective  In an observational cohort study (2006–2007) the Paul‐Ehrlich‐Institut collected epidemiological data to investigate the frequency and causes of TRALI.

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.

A(H1N1)v2009: a controlled observational prospective cohort study on vaccine safety in pregnancy.

BACKGROUND A(H1N1)v2009 influenza vaccination of pregnant women was a challenge for health care providers, as little safety data were available. METHODS We prospectively followed the pregnancies of women who were vaccinated at any time during pregnancy or ≤ 4 weeks prior to conception and compared these outcomes to a control cohort matched by the estimated date of birth. Primary endpoints: rate of spontaneous abortion and major malformations. Secondary endpoints: preeclampsia, gestational age at birth, and birth weight. RESULTS Pregnancy outcome of 323 women immunized with adjuvanted or non-adjuvanted A(H1N1)v2009 influenza vaccines from 2009-09-28 to 2010-03-31 were compared to 1329 control subjects. The risk for spontaneous abortions (HR 0.89; 95% CI 0.36-2.19) and the rate of major malformations (all trimesters: OR 0.87; 95% CI 0.38-1.77; preconception and first trimester exposure: OR 0.79; 95% CI 0.13-2.64) did not vary between the two cohorts. Furthermore, there was no increase in preeclampsia, prematurity, and intrauterine growth retardation in the vaccinated cohort. CONCLUSION The results of our study do not indicate a risk for the pregnant woman and the developing embryo/fetus after H1N1 vaccination. We provide and apply methods novel in observational studies on pregnancy outcome, especially if a single dose exposure is investigated.

Neubewertung des Risikos von Test- und Therapieallergenen Eine Analyse der UAW-Meldungen von 1991 bis 2000

ZusammenfassungZur Risikobewertung von Test- und Therapieallergenen wurden die dem Paul-Ehrlich-Institut in der Zeit von 1991 bis 2000 aus Deutschland gemeldeten Verdachtsfälle von unerwünschten Arzneimittelnebenwirkungen (UAW) einer Analyse unterzogen. Nur die als “schwerwiegend” eingestuften UAW-Meldungen, die im gesicherten, wahrscheinlichen oder möglichen Kausalzusammenhang mit der Applikation von Test- und Therapieallergenen standen, wurden hinsichtlich möglicher Risikofaktoren ausgewertet. Es wurden zwölf lebensbedrohliche Reaktionen bei der Anwendung von Testallergenen, 555 schwerwiegende UAW nach Injektion sowie drei nach oraler oder sublingualer Applikation von Therapieallergenen registriert. Leider kamen auch drei Todesfälle zur Meldung. Die schwerwiegenden UAW nach subkutaner Injektion von Therapie-Extrakten wurden getrennt in zwei Fünfjahreszeiträumen, 1991–1995, 1996–2000, analysiert. Im Vergleich der beiden Zeitperioden reduzierte sich die Zahl der Meldungen um 25%. Gravierende Unterschiede hinsichtlich der zu eruierenden Risikofaktoren waren, bis auf ein Ansteigen schwerwiegender UAW bei Patienten mit Asthma und einer Zunahme der Reaktionen durch körperliche oder psychische Belastungen, nicht feststellbar. Den Ärzten fällt bei der Risikominimierung eine Schlüsselrolle zu. Durch Einhaltung der entscheidenden Sicherheitsvoraussetzungen bei der spezifischen Immuntherapie wären von den 555 schweren systemischen Reaktionen über 37% möglicherweise vermeidbar gewesen. Neue Risikosignale konnten nicht detektiert werden. Zur Abwägung des Nutzen-Risiko-Verhältnisses wurden die aus der Literatur und den periodischen Sicherheitsberichten der Hersteller bekannten Inzidenzen schwerer, nicht fatal verlaufender Nebenreaktionen herangezogen. Es wird eingeschätzt, dass dem Risiko bei der Anwendung von Test- und Therapieallergenen ein hoher Nutzen dieser Präparate gegenüber steht.AbstractFor the risk assessment, all adverse drug reactions (ADR) to diagnostic and therapeutic allergen extracts in Germany in the time period from 1991 to 2000 were analyzed. Only ADR that were categorized as “serious” according to international definitions and which had at least a possible causal relationship with the usage of diagnostic and therapeutic allergen extracts, were included in the analysis. 12 live-threatening reactions after application of diagnostic allergen extracts, 555 after subcutaneous injection and 3 after oral or sublingual application of therapeutic allergen preparations were reported. Three incidences with fatal outcome were registered. Serious ADR after conventional immunotherapy were analyzed seperately for two time periods, 1991 to 1995 and 1996 to 2000, respectively. The comparison of the two time periods showed a reduction of approximately 25% of registered serious ADRs. Significant differences in regard to evaluated risk factors, with the exception of asthma, were not observed. Approximate 37% of 555 serious systemic reactions were avoidable. Physicians have an important role to minimise the risk of serious ADRs. For the assessment of risk-benefit-ratio of the application of diagnostic and therapeutic allergen extracts, the incidences of serious, but non-fatal ADRs as reported in published studies and periodic safety reports of extract manufacturers, were used. This analysis indicated that the benefits of allergy diagnosis and immunotherapy outweighs the risk of application of diagnostic and therapeutic allergen extracts.

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.

Thromboembolic events associated with immunoglobulin treatment

Due to an increasing number of reported thromboembolic events (TEE) after the administration of one intravenous immunoglobulin (IVIG) and one subcutaneous immunoglobulin (SCIG), pharmacovigilance and laboratory data were collected to analyse the root cause and assess the reporting frequency of TEEs for various IG products.

Case definition for progressive multifocal leukoencephalopathy following treatment with monoclonal antibodies

Background Novel immunosuppressive/modulating therapies with monoclonal antibodies (MABs) have been associated with progressive multifocal leukoencephalopathy (PML), a potentially fatal disease of the brain caused by the JC virus. Taking the complex diagnostic testing and heterogeneous clinical presentation of PML into account, an agreed case definition for PML is a prerequisite for a thorough assessment of PML. Objective/methods A working group was established to develop a standardised case definition for PML which permits data comparability across clinical trials, postauthorisation safety studies and passive postmarketing surveillance. The case definition is designed to define levels of diagnostic certainty of reported PML cases following treatment with MABs. It was subsequently used to categorise retrospectively suspected PML cases from Germany reported to the Paul-Ehrlich-Institute as the responsible national competent authority. Results The algorithm of the case definition is based on clinical symptoms, PCR for JC virus DNA in cerebrospinal fluid, brain MRI, and brain biopsy/autopsy. The case definition was applied to 119 suspected cases of PML following treatment with MABs and is considered to be helpful for case ascertainment of suspected PML cases for various MABs covering a broad spectrum of indications. Even if the available information is not yet complete, the case definition provides a level of diagnostic certainty. Conclusions The proposed case definition permits data comparability among different medicinal products and among active as well as passive surveillance settings. It may form a basis for meaningful risk analysis and communication for regulators and healthcare professionals.