Haemovigilance Annual report 2013 Summer 2014

Transcription

1 Summer 2014 Haemovigilance Annual report 2013

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3 1 Haemovigilance Annual report 2013 The annual report was written by: Dr. Markus Jutzi and Dr. Lorenz Amsler Clinical Reviewers Haemovigilance / Swissmedic markus.jutzi@swissmedic.ch lorenz.amsler@swissmedic.ch Additional information is available in the Haemovigilance section of the Swissmedic website -> market surveillance -> Blood components

4 2 Table of contents Abbreviations 1. General information on haemovigilance 1.1 Introduction 1.2 Origin, effects and clarification of haemovigilance events 2. Reports received 2.1 Summary 2.2 Distribution of the reports 2.3 Transfusion reactions (TRs) Frequency Imputability (relationship to the transfusion) Severity Transfusion reactions by blood components 2.4 Number of transfused blood components and risks in Switzerland Numbers of transfusions Reporting rates Transfusion risks Risks of life-threatening and fatal transfusion reactions 2.5 IBCT (transfusion errors / incorrect transfusions) and near miss events IBCT Near miss events 2.6 Donor reactions 3. Preventive measures and conclusions 3.2 Pathogen inactivation of platelet concentrates (PC) using the Intercept procedure Refractory condition following platelet transfusion / reduced efficacy TRALI 3.3 Measures to prevent transfusion-transmitted infections 4. Sample case reports 4.1 Deaths 4.2 Transfusion reactions of grade 3 severity 4.3 Other case examples of transfusion reactions 4.4 IBCT cases 5. Bibliography

5 3 Abbreviations C degrees centigrade AB antibodies AML acute myeloid leukaemia ARDS acute respiratory distress syndrome ASAT aspartate aminotransferase BP blood pressure BG blood group BNP brain natriuretic peptide SRC Swiss Red Cross C3d fragment of the complement system CK creatine kinase CK-MB creatine kinase of sub-unit M (muscle type) and B (brain type), isoform 2 CO 2 carbon dioxide CPAP continuous positive airway pressure (apparatus-based respiration therapy) CRP c-reactive protein (inflammation marker) CT computed tomography DAT direct antiglobulin test, also known as direct Coombs test DNA desoxy-ribonuclein acid prbc packed red blood cells FGP fresh frozen plasma FGP (SD) fresh frozen plasma, (solvent-detergent) virus-inactivated FGP q fresh frozen plasma, quarantine-stored FNHTR febrile non-haemolytic transfusion reaction G/l giga (10 9 ) per litre g/l grams per litre GOT glutamate-oxalacetate transferase Hb haemoglobin HBV hepatitis B virus Anti- antibodies to hepatitis B virus core antigen HBc-AB HBs-Ag hepatitis B virus surface antigen HCV hepatitis C virus HI-TR high imputability transfusion reactions HIV human immunodeficiency virus HLA human leucocyte antigen HNA human neutrophil antigen HPA human platelet antigen HTR haemolytic transfusion reaction IBCT incorrect blood component transfused ID identification IgA class A immunoglobulins IgE class E immunoglobulins IgG class G immunoglobulins IgM class M immunoglobulins IH immunohaematology i.v. intravenous cpc conventional platelet concentrate LDH lactate dehydrogenase MELD model for end-stage liver disease ml millilitre mm Hg millimetre mercury column, measuring unit for (blood) pressure neg negative ng/l nanograms per litre NM near miss O 2 oxygen Peni/ resistant to penicillin and ampicillin Ampi R PI-PC pathogen-inactivated platelet concentrate Pos. positive, (e.g. BG O-pos = Blood group O, rhesus factor positive) RFID radio frequency identification Rh rhesus (factor) SIRS systemic inflammatory response syndrome TACO transfusion-associated circulatory overload TAD transfusion-associated dyspnoea PC platelet concentrate (PCa: apheresis-derived platelet concentrate) TR transfusion reaction TRALI transfusion-related acute lung injury TTI transfusion-transmitted infection T&S type and screen (to define blood group and detect irregular antibodies) U/l unit(s) per litre umol/l micromole per litre

6 4 1. General information on haemovigilance 1.1 Introduction In this Annual Haemovigilance Report we present the evaluation of the reports received in 2013 on suspected transfusion reactions (TRs), near misses (NMs) and cases of incorrect blood component transfused (IBCT). Differences compared to the previous year are shown, and where possible and useful their cause and significance is explained. Based on the current figures, we show the risks related to transfusion. In the section Preventive measures and conclusions, we analyse the effects of the measures taken and assess the individual potential risks. Additional information can be obtained from the works cited and on the Swissmedic website, as shown on page 1 of this report. 1.2 Origin, consequences and clarification of haemovigilance events The diagram of the transfusion chain illustrates which occupational groups play a role in the chain, and what actions must be performed, in what order, to carry out a transfusion. Every step carried out or omitted can trigger an adverse event. Near misses can in general be discovered at any time, whereas transfusion errors and transfusion reactions are only noticed at the end of the actions, i.e. during or following the transfusion. The analysis of the errors and reactions is therefore retrospective, and measures taken as a result should confirm the diagnosis of the affected patient, contribute towards reducing harm, and within the framework of the national haemovigilance system, permit findings with regard to current risks and potential optimisation. For that reason, it continues to be of central importance that health care professionals reliably report suspected adverse transfusion events. Figure 1 Transfusion chain - Decision to transfuse - Prescription - Evaluation of effect - Follow-up patient - Donor recruitment - Blood donation - Donor screening - Production of blood product (BP) - Storage - Issue of components - Blood sampling for T&S - Pretransfusion test - Issue of BP for individual patient - Reception, handling of BP - Check product/patient ID - Transfusion of product - Observation of patient Blood transfusion service IH-Laboratory Nursing Doctor

7 5 2. Reports received 2.1 Summary In total, 2,031 haemovigilance reports were received by Swissmedic in 2013, of which 16 were identified as duplicates following checks on their reception. The remaining reports to be analysed were classified as follows: 1,175 transfusion reactions (TRs), 26 transfusion errors / Incorrect Blood Component Transfused (IBCT), 799 near misses (NMs) and 15 donor reactions. Table 1: Number of haemovigilance reports in 2013 Category Number Number of reports of adverse transfusion 1,175 events Number of IBCT reports 26 Number of near miss reports 799 Number of reports of averse donation 15 events Total number of reports 2, Distribution of the reports After a slight decrease in the previous year, the number of TRs reported in 2013 increased again, with 1,175 reports received. Over several years, the number of reports (with the exception of 2012) increased constantly. Analysis of the present reports revealed that 8 cases did not meet the criteria for transfusion reactions. The distribution of the 1,167 reports included in the analysis of the transfusion reaction categories is shown in Figure Frequency Figure 3: TRs reported in % TR 2013 by classification and frequency 3.2% 14.0% 0.5% 0.3% 0.3% 0.3% 1.7% 0.2% 46.2% 31.0% FNHTR Allo-immunisation Allergic TR TACO Other Hypotensive TR Infection TRALI HTR TAD Platelet refractoryness Figure 2: Events reported in Number of events by type NM IBCT TR Once again, alloimmunisations, febrile non-haemolytic transfusion reactions (FNHTRs) and allergic TRs together account for approximately 90% of the transfusion reactions reported. The greatest increase is seen in alloimmunisations, for which the number of reports has increased by 259, from 280 to 539 (from 28% last year to 46% of all TR reports at present): this is mainly due to one centre that began to report these events in The proportions of the various categories of transfusion reaction have therefore shifted compared with the previous year. Correspondingly, the proportion of FNHTRs has decreased from 43.2% to 31.0% (439 and 361 reports respectively) compared to the previous year, and that of allergic reactions has decreased from 18.1% to 14.0% (182 and 163 reports respectively). The increase in the total number of reports received in 2013 is due to a 16% increase in the number of TRs and a 29% increase in NMs. The number of IBCT reports decreased by 54% (Figure 2). 2.3 Transfusion reactions (TRs) As in previous years, reports of transfusion-associated circulatory overload (TACO) and hypotensive transfusion reactions are still in fourth and fifth place in terms of frequency. The proportion of reports on transfusion associated circulatory overload (TACO) has again decreased compared with previous years (from 3.9% to 3.2%), with the absolute figure virtually unchanged (39 vs. 37 reports). The distribution of the other suspected transfusion reactions has not changed in comparison with the previous year, with the exception of haemolytic transfusion reactions

8 6 (HTRs), where there is a decrease from 1.0% to 0.3% (10 vs. 4 reports). The significance of these frequencies in the light of the risk of adverse transfusion reactions is assessed taking imputability into account in Section 2.4.3, Transfusion risks Imputability (relationship to the transfusion) In 2013, high imputability was attributed to 815 events (70% of reported TRs). This means that the likelihood of their causal relationship with the transfusion was considered to be probable or certain. The increased percentage of these reactions in comparison with the previous year (from 59% to 70%) is the result of a larger number of cases with alloantibodies reported and which were identified in the laboratory, and thus virtually always showed high imputability. Table 2: Number of events in 2013 by category and imputability Imputability all low possible high Allergic TR (78%) FNHTR (29%) Allo-immunisation (99%) HTR: acute delayed 1 1 Hypotensive TR Infection, viral 2 2 bacterial TACO (68%) TAD TRALI Platelet 2 2 refractoryness Other Number events of 1, (4.5%) 297 (26%) 815 (70%) Table 2 shows that following assessment, the imputability for 96% of the reported transfusion reactions was considered to be high or possible. Final assessment allowed to establish a causal relationship in 4 out of 5 allergic reactions. This is at least partially due to immediate type reactions being reliably identified based on clinical grounds. The fact that other potential triggers, such as medication administered for the first time during the relevant time period can be excluded in most cases, may also substantially contribute to the above mentioned observation. It also appears plausible that high imputability is assigned to FNHTR in only 29% of the reports, since for non-specific symptoms, there are numerous other possible causes such as the underlying condition (for example in the case of pre-existing infections), complications of the treatment independently of the transfusion (e.g. febrile neutropenia) or newly occurring infections (urinary tract infection, pneumonia, catheter-related bacteraemia). These occur relatively frequently in patients requiring transfusions, and confirming or excluding one or more of the various possible causes conclusively is not usually possible. For that reason, following assessment, the transfusion is one among several possible causes in 60% of reported cases of FNHTR, so the imputability assigned as possible. In the following, only cases with high imputability are presented in order to provide the most specific possible illustration of haemovigilance data in Switzerland. Low imputability: causal relationship with the transfusion excluded or unlikely High imputability: causal relationship with the transfusion probable or certain

9 Severity Table 3 High imputability events for 2013 by category and severity Severity all Grade 1 Grade 2 Grade 3 Allergic TR mild anaphylactoid anaphylactic FNHTR Alloimmunisation HTR: acute 1 1 HTR: delayed 1 1 Hypotensive TR Bacterial 1 1 infection TACO TAD 3 3 TRALI Platelet refractoryness 2 2 Other 2 2 Number of events Percentage of all events Grade 4 100% 31% 67% 2.1% 0% The proportions of events with the various grades of severity differ from those of the previous year. Table 3 shows the distribution of the grades of severity by type of reaction. In 2013, 31% of the transfusion reactions reported were assessed as non-severe (Grade 1) compared with 47% the previous year, and 67% were assessed as severe or having caused permanent damage (Grade 2) compared with 50% the previous year. This increase in Grade 2 reactions compared with the previous year is mainly due to reports of alloimunisation, which are by definition categorised as Grade 2. We consider these reactions to constitute permanent damage or a permanent risk, since for patients with alloantibodies relevant to transfusion medicine, compatible products must be selected for future transfusions in order to avoid alloantibodymediated haemolytic transfusion reactions. Depending on the number and specificity of the antibodies, the proportion of appropriate blood components can lie in single-digit percentages, making their availability within routine clinical practice difficult. The proportion of life-threatening (Grade 3) or fatal (Grade 4) transfusion reactions in 2013 was, at 2.1% (17 out of 815 TRs), again lower than for the previous year (2.8%, 17 events out of 599). In absolute figures, however, there have been no changes here and considering the decreasing number of blood products transfused, the risk of transfusion reactions with severity grades 3 or 4 has not reduced compared with the previous year. The development of the absolute figures from is shown in Figure 4. Of the 17 cases of life-threatening transfusion reactions in 2013, 6 were in connection with packed red blood cell (prbc) transfusions, 3 with plasma, 7 with platelet concentrate (PC) and one with a combination of products (prbc and quarantine-stored freshfrozen plasma (FFPq). In 2013, no fatal events with high imputability to transfusions were reported. Four reports on deaths in temporal association to a transfusion were received. These are addressed in Section 4. Figure 4: Distribution of the life-threatening or fatal events Grade 3&4 TRs Other Hyperkalaemia Delayed HTR TAD Hypotensive TR Bacterial infection TRALI Acute HTR TACO Allergic TR In 2013, allergic transfusion reactions, cases of transfusion-associated circulatory overload (TACO) and cases of transfusion-related acute lung injury (TRALI) were reported as life-threatening reactions.

10 Transfusion reactions by blood components The percentage distribution of the 815 high-imputability TRs by blood component shows that the proportion of reports with packed red bloods cells (prbc) has increased slightly compared with the previous year (from 75% to 84%). This is due to the higher number of alloimmunisation cases reported. A decrease of the apheresis-derived platelet concentrate (PCa) is observed, from 16% to 9% (Table 4). Table 4 prbc (packed red blood cells) 84% (681) Fresh frozen plasma (FFP)* 3% (23) PCa (apheresis-derived) 9% (76) PCb (whole blood-derived, buffy-coat) 2% (15) Multiple blood components 2% (20) *Fresh Frozen Plasma, quarantine-stored (FFPq) or solvent-detergent virus-inactivated (FFP-SD) When considering absolute figures, relevant changes have only been observed in the numbers of alloimmunisations reported following prbc transfusions. (529 reports in 2013 and 267 the previous year). Together with FNHTR (91 reports in 2013, 103 the previous year), they again accounted for the majority (77%) of the prbc-related TRs reported. This is followed by reports of allergic reactions (27 reports, previous year 44) and TACO (21 reports, previous year 23). Except for one FNHTR, all reports related to plasma transfusions described allergic reactions (22 in 2013, 30 reports the previous year). International data on FFPq and FFP-SD show no major differences in their specific risk profiles [1]. Allergic reactions were also the most commonly reported reaction after PC transfusion, with 69 reports (65 the previous year), followed by FNHTR (10 in 2013 and 22 in the previous year), TACO and TRALI (3 of each in 2013 and 1 of each the previous year) as well as alloimmunisations (3 in 2013, 8 in the previous year). Since the Intercept procedure for pathogen inactivation had been implemented, no more transfusion reactions due to bacterially contaminated PC were reported. Following the transfusion of multiple different blood components, allergic reactions (9) and FNHTR (4) were most frequently reported. 2.4 Number of transfused blood components and risks in Switzerland Numbers of transfusions The annual statistics of the Blood Transfusion Service of the Swiss Red Cross (BTS SRC) show the number of blood components issued in Switzerland over the last 6 years (Table 5). Table 5: Numbers of transfusions Blood components prbc 313, , , , , ,510 FFP (therapeutic units) 65,800 70,300 61,500 50,063 49,832 44,083 PC (products) 27,600 29,600 29,900 33,068 34,265 34,750 Total blood components 407, , , , , ,343 The total number of blood components issued was again lower than in the previous year. Approximately 6% fewer prbc and approximately 9% fewer FFP products were issued than in The use of PC increased by 1.5% in comparison with the previous year and the proportion of whole blood derived PC was 35%, which is in line with that for the previous year (34%) Reporting rates The overall reporting rate rose again in 2013 and is currently 5.6 reports (including NM) per 1,000 transfusions (see Figure 5). Figure 5 Reports per 1,000 transfusions Progression of the reporting rate

11 Transfusion risks The presentation of transfusion risks provides the treating doctor with a basis for the risk-benefit analysis when considering transfusion and for providing advice to the patient about possible adverse effects. We display unavoidable transfusion risks as well as those that can in principle be avoided. For potentially avoidable transfusion reactions, the frequency of the events shows where risk minimisation measures are indicated and documents the effect of measures already taken. Based on the number of transfusion reactions with high imputability and on the number of blood components issued, we express the reporting rates in 2013 for prbc, plasma and PC in the format of one event per XXX products issued (Figure 6), and have limited this to TRs for which there were more than 10 reports. Events occurring more rarely cannot be reliably expressed as risks on an annual basis because of the small absolute number of cases. The reporting rates shown provide information on the type and extent of transfusion risks in Switzerland at present. A precise quantification of the risks with the help of the reporting rates is nevertheless not possible, since despite good reporting behaviour from many hospitals, it cannot be considered that 100% of all TRs will be reported. It is known, however, that severe reactions are reported more reliably than mild ones, and it can be assumed that this is the case in Switzerland for all 3 labile blood products. Therefore, the risks for the individual products can be compared with one another (relative risk). Figure 6 shows that the risk of experiencing any TR is 5 times lower for plasma than for prbc and PC. The risk of an allergic reaction to prbc, however, is 5 times lower than for plasma and approximately 20 times lower than for PC. Figure Risks of life-threatening and fatal transfusion reactions Figure 7 shows the Grade 3 and 4 TRs for all blood components by category and number for the last 6 years. Once again, only cases with high imputability are shown. The numbers of cases are small, but they have not decreased further in 2013 (total 17, i.e. the same as in 2012). The risks cannot be quantified precisely for an individual year, so we estimate them from the cumulative data Figure 7 Total Rate PC Allergic TR PC Total Rate RBC Allo-immunisation RBC Allergic TR RBC Total Rate FFP Allergic TR FFP Total risik all TR FNHTR RBC TACO RBC Allergic TR TACO TRALI Acute HTR Hypotensive TR Bacterial infection TAD Hyperkalaemia Delayed HTR Reporting rate by product 2013 ~ 1:3000 ~ 1:10'000 ~ 1:13'000 8 / ~ 1:300'000 7 / ~ 1:350'000 6 / ~ 1:400'000 6 / ~ 1:400'000 5 / ~ 1:500'000 1 / ~ 1:2.5 Mio 1 / ~ 1:2.5 Mio ~ 1:2'000 ~ 1:2' / ~ 1:80' / ~ 1:30'000 ~ 1:500 ~ 1:500 TR Grade 3 & , all blood components ~ 1:380 ~ 1: / ~ 1:15'000 Total During this period, four transfusion-associated deaths occurred (in 2008, one TACO after FFP and one TRALI after PC, in 2009, one acute HTR following AB0-incompatible prbc transfusion and in 2012, one TACO after prbc).

12 IBCT (transfusion errors / incorrect transfusions) and near miss events The number of reported IBCT cases has decreased from 57 in 2012 to 26 in 2013, and accounts for 1.3% of all reports in 2013 (3.4% the previous year). In contrast, the number of near miss events reported increased again: the 799 events reported represent 39% of all reports received (previous year 37%, i.e. 619 reports) IBCT The deviation leading to the transfusion of a blood component that was intended for another patient or was not optimally suited to the patient to whom it was administered occurred during the prescription or ordering stage in 5 cases and during administration of the blood products in 12 cases. Two events were due to errors when testing the patient samples at the laboratory. For 7 patients, pre-existing but no longer detectable alloantibodies were not taken into consideration because the laboratory concerned was not aware of the situation. With the exception of these 7 cases, all of the events reported could have been avoided by carrying out the steps throughout the transfusion chain correctly (Table 6). Table 7: Transfusion errors in the strict sense Transfusion error Number Description AB0-system, incompatible AB0-system, fortuitously compatible (Table 7). The important aspect when analysing these cases is not whether, or how severely, the patient was harmed but realising which incorrect action was behind the event and how it is possible to prevent it from recurring. Allo-Antibodyincompatible Administration of untested prbc 2 Blood group A prbc transfused to patient of blood group 0, blood group 0 FFP transfused to blood group A- patient 6 PC instead of FFP, 2x PC transfused to wrong patient, 3x patient mix-up, blood groups identical 5 3x direct compatibility test not performed, 2x Phenotype not known 3 Even though tested prbc were readily available Table 6: IBCTs, by localisation of deviations Stage of transfusion Number chain Laboratory 9 Preparation 5 Prescription/ordering Administration Total 26 Issue (7) Testing (2) Examples 12 Transfusion Patient mix-up Wrong product prescribed, product ordered for the wrong patient Failure to take account of pre-existing allo-antibodies that were no longer detectable Mix-up of samples resulting in the transfusion of prbcs of blood group A neg to a patient with blood group 0 pos For further analysis, we only consider the 16 reported cases of transfusion errors in the strict sense, i.e. the transfusion of a product for which compatibility in terms of ABO-, Rh- or other blood group antigens is not ensured (except in emergency situations). This also includes transfusions of products intended for another patient but which were fortuitously compatible

13 11 Analysis of the sequence of events leading to the 8 transfusion errors related to the ABO system revealed the following basic deviations: In the 4 prbc transfusions: Patient mix-up, incompatible blood group: The mixing up of patient blood samples in the laboratory led to the issue and transfusion of 4 units of prbc of blood group (BG) A-neg to an O-pos patient, with a drop in haemoglobin (Hb) from 9.7 g/l initially to 6.0 g/l, but without clinical symptoms of acute haemolysis (see Case 12, IBCT in Section 4). Patient mix-up, compatible BG: associated with the administration of 2 transfusions to patients with similar names, in the same rooms, coincidentally with the same BG; after a cross-check of the product and patients BG card adhering to the four-eyes principle, but that was not carried out at the bedside when an incorrect product was taken from the refrigerator (mixing up the product number) (same BG, Type&Screen (T&S) neg) and failure of the pretransfusion check In the 4 PC and FFP transfusions: Incorrectly taking BG 0 FFP from the self-service freezer located in a peripheral area and transfusing it to a patient with BG A Following an incorrect order, administration of PC instead of FFP Following an order with incorrect print labels, administration of PC to the wrong patient Following a laboratory error, delivery of PC to the wrong patient, administration without checking the prescription In two other cases, prbcs were issued without extended phenotype (phenotyping that includes blood group systems other than ABO and the rhesus system). In one case, non-phenotyped prbcs were issued for an emergency transfusion for obstetric haemorrhage, for a female patient with known anti-kell antibodies, because no phenotyped products were available. One unit of prbc was ultimately identified as K-positive. In a further case, prbc with unknown Jkb phenotype was transfused following inadequate increase in Hb after the transfusion of a Jkb-negative prbc the previous day. An adequate increase in Hb was observed as a result of the transfusion of the prbc with unknown Jkb status. In the case described, the formal criteria for a transfusion error are met, without direct clinical consequences being observed. Although fewer cases of IBCT were reported in comparison with the previous year, those presented nevertheless show that considerable attention must still be paid to efficient, well-targeted processes and that practical quality assurance measures for avoiding and preventing errors continue to be extremely important Near miss events Definition: an error or a deviation from standard operating procedures or directives that is discovered before initiating a transfusion and that could have resulted in a transfusion error or a transfusion reaction if it had not been detected. In 3 of the 5 reported cases of antibody-incompatible transfusions, no cross-matching was carried out: In the case of previously known but currently undetectable antibodies (which nevertheless were taken into consideration) In the case of a slightly positive direct antiglobulin test (DAT) In the case of a known cold anti-i autoantibody, negative T&S; adequate increase in haemoglobin (Hb), no signs of haemolysis

14 12 Table 8 Classification of events by site of deviation in the transfusion chain Stage Number Comments, examples of most common deviations Preparation 510 Deviation from predefined operating procedure 111 Laboratory 88 including 363 cases in which laboratory analyses had to be repeated and 100 cases where the blood components involved had to be destroyed These are not Near Miss events in the strict sense of the definition, but rather additional safety measures that have not been performed as specified (usually related to preparation) including 24 associated with issue, 12 associated with storage, 6 associated with testing, 28 associated with delivering Admini stration 16 Other 74 Total 799 For example prbc reached ambient temperature, was not transfused and had to be destroyed The number of NM events reported was again higher in comparison to the previous year: 799 reports were received from 30 institutions (compared with 619 from 14 hospitals in 2012). As displayed in Table 8, deviations can be located at all sites along the transfusion chain, even though most of the errors reported occur during preparation. In the majority of the cases, these errors during preparation were discovered only slightly later, during the sample reception checks in the laboratory. It can also be seen from Table 8 that the number of NM events reported decreases towards the end of the transfusion chain. The earlier an error occurs, the greater the likelihood that it will be discovered in time and can be corrected. According to haemovigilance data, the probability of an error occurring is therefore in principle inversely proportional to the likelihood of damage. For that reason, maintaining or improving quality assurance systems at all points along the transfusion chain is very important, and not only in the preparation stage where the large majority of the reports originate. behaviour certainly is a possible cause. If this development should, however, become a stable trend over a number of years, it could be interpreted as an indication that visible improvements in transfusion safety have been achieved by existing or newly implemented quality assurance measures. Near miss events in the strict sense (506 cases, 63% of the NM reports) We use the term near miss in the strict sense to describe deviations that, if undetected, could have led to a transfusion error. They are categorised by type of deviation in Table 9. The NM reports that occurred during administration of the blood products (16 cases, 2% of the NM reports) have decreased in comparison with the previous year (45 cases, 7%). It is noteworthy that in parallel, there was a decrease in the number of IBCTs and haemolytic transfusion reactions. This observation is based on small numbers and its significance is therefore not clear at present. A fluctuation in reporting

15 13 Table 9 Type of deviation Patient ID problems of administrative origin Mix-up of patients or samples when obtaining blood for pre-transfusion testing Number (%) Comments 8 (2%) E.g. Name variants, incorrect recording of patient on admission, identity fraud, more than one set of medical records in the name of the same patient 69 (14%) Similar names, missing or incorrect verification of ID. Often detected only on the basis of a blood group discrepancy from an earlier value, in which case sequence of events often not reconstructable. Sampling error 7 (1%) Sample diluted, wrong type of tube used Labelling/inscription errors of all kinds 307 (61%) Labelling of samples and/or order absent, incorrect, discrepant, or with details of another patient Ordering errors 19 (4%) Wrong product ordered or product ordered for wrong patient, specification not observed/stated Issue 7 (1%) Wrong product, product for wrong patient or product with incorrect patient details Laboratory error 23 (5%) Samples mixed up in laboratory, errors in transmission of results, result misinterpreted Communication 11 (2%) Information (about known antibodies, transfusion/ stem cell transplantation history) not passed on; misunderstanding (expiration T&S / Product) Other 55 (11%) Delivery of patient samples to laboratory delayed (including 38 reports of cases due to recently installed pneumatic delivery system) Total 506 The proportion of the NM events in the strict sense in the overall total of NM reports has remained stable compared with the previous year (383 reports, 62%). The incorrect labelling of patient samples or laboratory orders as the most frequent deviation type 61% for 2013 has not changed significantly from the previous year (66%). It will be interesting to observe whether this type of deviation will become less frequent as a result of the increasing introduction of computer-assisted systems for patient identification and for the attribution of blood samples and laboratory orders (bar code- or RFID-based systems). Together with the actual data from these systems that document the number of cases where incorrect attribution could be prevented, this would permit a quantitative assessment of the effectiveness and use of such systems. The appropriate functionalities and evaluation possibilities should be taken into consideration when planning and implementing such systems. Process deviations (111 cases, 22% of the NM reports) With the exception of one, these reports all originated from a single hospital which had implemented an additional control system for patient identification. Incorrect intermediate storage of blood components (182 cases, 36% of the NM reports) The number of reports relating to the handling and intermediate storage of blood components after issue was again substantially higher than in the previous year. The proportion rose from 22% in 2012 to 36% in Ninety-eight of these reports concerned blood products that had been ordered or issued but were then not transfused: In most cases, this led to the destruction of the blood products. 2.6 Donor reactions In 2013, 15 individual case reports on donor reactions were received. Eight of them, were related to whole blood donations, and 7 occurred during or following apheresis (of which 6 were platelet donations). Three donors experienced two events each, therefore the number of events reported was 18. The severity was classified as mild in one report, moderate in 10 and severe in 4.

16 14 Out of 18 events, 6 were vascular reactions, including the two following cases that were classified as severe. One case concerned thrombophlebitis occurring after a whole blood donation and requiring treatment with antibiotics, and the other report described a large haematoma (40 x 15 cm) following a plasma apheresis. Eight events were vasovagal reactions, 2 of them were classified as severe: a severe vagal reaction with loss of consciousness, urine incontinence, convulsions and temporary loss of sight in the right eye affected a 31-year old, first-time female donor 80 minutes after a whole blood donation. The second case concerned a 20-year old second-time male donor, who remained supine for 10 minutes after a whole blood donation but collapsed afterwards and fell heavily. He was hospitalised for 2 days for observation due to suspected concussion, but recovered completely. The other 4 events concerned 3 citrate reactions and 1 anaphylactoid reaction with eyelid oedema and bronchospasm during and after apheresis. Reports on donor reactions were received from 3 centres in accumulated form. Of the 268 events, 228 occurred in connection with whole blood donations and 40 with apheresis. Of the 228 events with whole blood donations, 191 (84%) were vasovagal reactions (thereof 5 classified as severe), 23 (10%) were local reactions (thereof 1 severe), and 14 (6%) were other reactions (mainly hypotension). Of the 40 events associated with apheresis, 19 (48%) were local reactions (thereof 1 severe). Of the other cases associated with apheresis, 7 (18%) were classified as vasovagal reactions, 13 (33%) as citrate reactions (thereof 1 severe), and 1 as other. 3. Preventive measures and conclusions In addition to overall risk assessment, initiating and assessing preventive measures is among the core tasks of the haemovigilance system. Below, we present the assessment of three preventive measures that have already been implemented in Switzerland or that currently are in operation. Our descriptions briefly summarise the key points and reference is made to more in-depth reports. demonstrated in a statistically robust way after several years. Two fundamental mechanisms are discussed for the pathophysiology of TRALI: immune TRALI (leukocyte-specific HNA or HLA antibodies react with recipient leukocytes) non-immune TRALI (activation of neutrophil granulocytes by biologically active substances, e.g. lipids in the blood product) The objective of the strategy of having principally male donors is to reduce the possibility of HLA or HNA antibodies being present in the plasma to be transfused. These antibodies can occur, among other causes, as a result of pregnancy or giving birth. For that reason, only donations from men or from women who have never been knowingly pregnant or whose test results for HLA and HNA antibodies are negative have been used to manufacture plasma for transfusion in Switzerland since For the assessment of this measure, the frequency of TRALI reports during the period prior to the implementation of the measure ( ) was compared with the period following the implementation ( ); The reports were classified in accordance with the definitions by the TRALI consensus panel held in Canada, 2004 [2]. Figure 8 shows the absolute numbers of TRALI cases reported during the two periods. In addition, Figure 9 shows a disproportionality analysis in which the proportion of TRALI cases among all reports of TR related to FFP transfusion are compared for the two periods. The number of plasma transfusions administered is comparable for both periods (435,000 from ; 342,000 from ). Therefore, the considerable decrease of cases is also reflected in a clear decrease in the reporting rate, from 1/21,000 to 1/86,000 plasma transfusions. 3.1 Male donor strategy for plasma This measure was already implemented in 2007; Transfusion-associated acute lung injury (TRALI), which was the reaction to be prevented, is rare. For that reason, the effect of the measure can only be

17 15 Figure 8 Number of cases Figure 9 100% 98% 96% 94% 92% 90% 88% TRALI cases related to FFP Disproportionality analysis 21 (6.9%) 4 (1.4%) TRALI, possible TRALI, certain or probable TRALI associated with FFP All other TR associated with FFP Relative Risk=0.21 (95% VI ) p= (Fisher exact - test) The number of TRALI reports decreased significantly with the introduction of this preventive measure. Various other comparisons (TRALI with other products, cases of circulatory overload) between the two periods revealed no indication of reporting bias or other bias that could have only simulated the difference in the risk. The figures presented confirm the effectiveness of the strategy of having principally male donors of plasma for transfusion: the TRALI risk for plasma has clearly been reduced by the measure. This data is in line with publications from other countries. The full report (as a poster.pdf) can be ordered from vigilance@swissmedic.ch. 3.2 Pathogen inactivation of platelet concentrates (PC) using the Intercept procedure After pathogen inactivation for PC was introduced in 2011, the data for the last 5 years permit a comparison of the transfusion risks of conventional PC (cpc) with that of pathogen-inactivated PC (PI-PC). A background report on the subject was published in the Swiss Medical Forum in March 2013 [3]. Table 10 compares the risks of transfusion between pathogen-inactivated PC and conventional PC. Since the introduction of the pathogen inactivation procedure for all PC in Switzerland, no more cases of sepsis due to PC have been reported. The main intended benefit, i.e. the reliable prevention of clinically relevant bacterial contamination of platelet concentrates, was clearly achieved by the countrywide implementation of the Intercept procedure for all PC in Switzerland. The number of transfusion-transmitted bacterial infections that were avoided by the consistent use of the Intercept procedure can be estimated based on the reports received prior to the introduction of the measure as well as taking into account recently published international data. From , 16 septic transfusion reactions caused by bacterially contaminated PC were reported, including 3 deaths. During the corresponding period, 191,700 conventional PC (i.e. not pathogen inactivated) were transfused. Based on the Swiss figures, the risk of transfusion-mediated sepsis is 1:12,000, and that for death caused by bacterially contaminated PC is 1:65,000. In Canada, these risks for the period , despite the bacterial screening of all PC, were quantified as 1:86,000 (sepsis) and 1:600,000 (deaths). In France, where neither bacterial screening nor pathogen inactivation is routinely performed for PC, sepsis and deaths for the period are stated as 1:43,000 and 1:250,000 respectively. In a monitoring programme one transfusion centre in the USA, quantified the risk of transfusion-transmitted sepsis at 1:1,600 PC. [4] Correspondingly we can conclude from these figures that the use of the Intercept procedure for all PC in Switzerland avoids septic transfusion reactions, which without this measure would occur at a ratio of between 1:1,600 and 1:86,000 PC transfusions. Regarding deaths, the ratio would be between 1:65,000 and 1:600,000 PC transfusions without pathogen inactivation.

18 16 Table 10 Transfusion reactions reported with conventional and pathogen-inactivated PC Transfusion reactions Units transfused Risk = 1 reaction per x PC All high imputability reports High imputability reports Grade 3 & ktk PI-TK 66,000 95,515 Reports Risk Reports Risk 223 ~ 1: ~ 1:400 23* ~ 1:3,000 13* ~ 1:7,000 *p=0.04 (Fisher exact test) Table 10 shows that in addition to reliably preventing septic transfusion reactions, the introduction of the Intercept procedure for all platelet concentrates has led to a reduction in the number and severity of noninfectious TRs after PC transfusion. Platelet refractoriness / reduced efficacy and respiratory reactions (including TRALI) are being discussed as possible reactions related to the pathogen reduction procedure. Indications for both potential risks have been published in scientific literature. Evidence confirming or excluding their clinical relevance is absent to date. Below, we discuss the two potential adverse events in the light of Swiss data Platelet refractoriness / reduced efficacy Possible effects of the pathogen inactivation procedure on platelet stability and functionality have long been the subject of research. Overall, the efficacy and safety of pathogen-inactivated platelet concentrates were demonstrated in clinical trials [5-10]. Haemovigilance data indicated a positive safety profile of PI-PC in general and compared with conventional PC in particular [3, 11, 12]. In response to the question of whether clinically relevant limitations to the efficacy of pathogen inactivated PC could occur in isolated cases, it is necessary to consult other data sources in addition to the clinical studies. Swiss haemovigilance data can also provide an important contribution here. Although the reported cases usually involve transfusion reactions and near miss events, haemovigilance officers and doctors are also required to report suspected cases where blood products are not effective if product-specific factors are suspected or if the lack of efficacy cannot be explained. In Switzerland, two cases of platelet refractoriness were reported for the first time in Both events concerned the same patient after two different platelet transfusions on two consecutive days. On the first day, the patient, suffering from multiple myeloma, was transfused with platelets from whole blood donations, and on the second day he was transfused with apheresis-derived platelets. After both transfusions, the patient developed fever and chills but remained stable on a haemodynamic level. The platelet count dropped from 7 G/l prior to the first transfusion to 5 G/l 24 hours later, and from 5 G/l prior to the second transfusion to 4 G/l one hour later. Anti-HLA A and B antibodies had been identified in the patient, and in particular a marked anti-hla A2 (with negative anti-hpa antibody test). Prior to the transfusions, the patient had undergone a third autologous stem cell transplant. Both of these cases of platelet refractoriness following platelet transfusions were probably caused by the confirmed presence of HLA-antibodies. To date, no further reports of reduced efficacy have been received by Swissmedic. There are no indications from the haemovigilance system that pathogen inactivation of platelets would lead to functional limitations. Further investigations of this topic are in progress, including in Switzerland TRALI In a clinical trial from 2001, 5 cases of acute respiratory distress syndrome (ARDS) occurred in the group receiving pathogen inactivated PC (N=318), whereas in the control group of the same size, in which the

19 17 participants received conventional PC, no cases of ARDS were observed [6]. Subsequent detailed analysis of the same trial revealed a trend in the same direction, but less pronounced and statistically no longer significant [13]. It was later demonstrated, in lipopolysaccharide-treated mice, that UVB-irradiated PC contributed towards the development of lung injury, whereas this was not observed following the transfusions of non UV-irradiated PC [14]. Since then, there has been controversial discussion on whether platelet concentrates that are treated with the Intercept procedure and are thus UVA-irradiated constitute a higher risk of TRALI than conventional platelet concentrates. Against this background, the TRALI haemovigilance data from Switzerland is of particular interest. Since it became mandatory for adverse transfusion reactions to be reported, Swissmedic has received reports on 12 cases of at least possible TRALI following transfusions of platelet concentrates PC alone or in combination with other blood components. During 2011, pathogen inactivation of platelet concentrates was gradually introduced by all regional blood transfusion centres. Correspondingly, the reported cases of TRALI following PC transfusion in 2003 and 2008 were observed in connection with conventional products. The two reports from 2011 also related to conventional PC, whereas all cases of TRALI following PC transfusions since 2012 concerned Intercept-treated products. Figure 10 shows the cases of TRALI reported in Switzerland in connection with platelet transfusions TRALI cases associated with PC in Switzerland Year 2003 (2 cases) 2008 (4 cases) 2011 (2 cases) 2012 (1 case) 2013 (3 cases) Imputability Certain Possible Probable Probable Probable Immune versus Non- Immune TRALI Product(s) transfused Severity 3 3 Immune Non-Immune PC FFP + PC Possible/unlikely Possible Probable Possible Unknown Unknown Immune Immune PC (Apheresis) + RBC PC (Apheresis)+FFP+RBC PC (Apheresis) PC (Apheresis) Immune Immune PC + RBC PC (Apheresis) 3 3 Immune PC (Apheresis) Probable Probable Probable Nom-immune Immune Immune PC (buffy coat) PC (buffy coat) PC (Apheresis) Blue = conventional PC, green = pathogen-inactivated PC. Severity grade 2 = severe, 3= life-threatening, 4= fatal. The cases are listed by year, and the order within the individual fields is the same. Reading example: for the second case of TRALI in 2003, the imputability was probable ; this was a non-immune TRALI in which the patient received FFP and PC, and the severity grade was 3 (life-threatening).

20 18 Between 2002 and 2011, 247,700 units of conventional PC were transfused and 8 cases of TRALI (5 cases of immune TRALI, 2 cases of TRALI with unknown aetiology and 1 case of non-immune TRALI) were reported, whereas from 2011 to 2013, with 95,450 units of pathogen-inactivated PC transfused, 4 TRALI reports were received (3 cases of immune TRALI and 1 case of non-immune TRALI). This corresponds to a TRALI frequency of approximately 1:30,000 for conventional and 1:24,000 for pathogen-inactivated PC respectively. A potentially increased risk would be expected to result in an increase of cases of non-immune TRALI, since immune TRALI is caused by antibodies originating from the donor and the Intercept procedure has no influence on their incidence. Based on one case of non-immune TRALI each following transfusion of cpc and PI-PC respectively, the complete Swiss haemovigilance data available today do neither allow to prove nor to exclude a slight increase of the risk for TRALI related to the Intercept procedure being applied to platelet concentrates. Further assessment of this potential risk, incorporating new findings and vigilance data, is therefore extremely valuable. It is equally important that in the future, all those involved in the transfusion process are aware of the possibility of severe transfusion reactions with respiratory symptoms and that in case of suspicion, they initiate investigations and forward the reports to Swissmedic. 3.3 Measures to prevent transfusion-transmitted infections Measures taken at various points along the transfusion chain (such as donor screening, strict adherence to donor eligibility criteria and look backs) are the corner stones of preventing transfusion-transmitted infections (TTI). Leukocyte depletion and donor exclusion criteria for recipients of transfusions were introduced many years ago, and also protect against emerging or previously unknown infectious diseases. The measures taken and potential needs for additional steps to prevent transfusion-transmitted infections are constantly reviewed and adapted to current realities and requirements. Since 2013, Chagas screening is mandatory in donors at risk. In addition, a preparedness plan has been developed for the case of autochthonous West Nile virus infections occurring in Switzerland; the first version was completed in In addition to these adjustments to donor eligibility and screening procedures, various product-related measures have contributed to the high level of safety of blood products in Switzerland. For example, pathogen inactivation of platelet concentrates, described earlier in this section, was also introduced for plasma in some regional centres in The blood transfusion centres are responsible for introducing and implementing these measures to ensure the safety of the products. This is carried out in collaboration with the reference centre for infections transmissible by blood and blood components, which is also mandated by the Federal Office of Public Health. Supervising blood transfusion services, Swissmedic assesses, whether measures taken are in accordance with the current state of science and technology. Furthermore, Swissmedic analyses whether market surveillance data indicate the necessity of additional measures to protect patients. Table 11 contains the TTI cases reported in 2013 and the currently estimated risk. Table 11: Cases of TTI in 2013 and estimated risks Cases reported Infection ) Imputability Estimated risks Bacterial Infection HBV HIV HCV 4 1 probable 1 possible 1 unlikely 1 excluded 1 pending (s. case 2 chapter 4) 1 excluded 1:600,000 2) 1:400,000 donations 3) 1:4,100,000 donations 3) 1:6,700,000 donations 3) Syphilis Theoretical Risk 4) Chagas West- Nile-Virus Theoretical risk in CH 5) Theoretical risk in CH 6) 1) The table shows all cases received as haemovigilance reports. In addition to the two suspected viral transmissions in the table, two further viral cases so far unreported to the haemovigilance system are investigated by look back procedures: In one of these cases, another HCV transmission was suspected, but a causal relationship with the transfusion was excluded. The other case involves a further suspected HBV transmission and the investigations are ongoing.