key: cord-0036373-mnnz7m1a authors: Tomasella, Federica; Mascaretti, Luca G. title: Adverse Transfusion Reactions in Critically Ill Patients date: 2014-09-16 journal: Hematologic Problems in the Critically Ill DOI: 10.1007/978-88-470-5301-4_7 sha: b9156980f38238d7a4beccb6bd5857abdf566580 doc_id: 36373 cord_uid: mnnz7m1a Although transfusion therapy in the past 30 years has achieved high levels of safety, severe adverse reactions can still complicate a red blood cell, plasma, or platelet transfusion. Adverse events can be either of infectious nature (Infectious Adverse Reactions to Transfusion–IARTs) or noninfectious (NIARTs). The former are due to viruses, bacteria, or protozoa present in the transfused component. Medical doctors faced with an infectious disease in a hospitalized patient should always collect an accurate clinical history that must include transfusion of blood components and take into consideration that the viral/bacterial/protozoan infection could be related to a transfusion event. If a transfusion-transmitted infection is suspected, the clinician must contact the transfusion center that will provide a look-back of the blood products and a follow-up of the involved donors. NIARTs may be of immunological and nonimmunological nature. This chapter provides an overview of pathogenesis, presentation, therapy, and prevention of the main NIARTs. Finally, organizational measures for the management of NIARTs are presented, in order to ensure the highest possible level of safety for the patients. As transfusion entered routine clinical practice in the mid-twentieth century, it was apparent that the benefits were counterbalanced by unwanted reactions both of infectious and noninfectious nature [ 1 , 2 ] . Whereas the former received wide attention also by the general population [ 3 ] , the latter mainly remained of restricted interest to transfusion scientists (and naturally to the patients). It is a well-known fact that in the past 25 years, blood testing and donor selection have had a notable impact on reducing infectious complications [ 4 , 5 ] and today, noninfectious adverse reactions to transfusion (NIART) are prevalent. If we look at the UK's Serious Hazards of Blood Transfusion hemovigilance data for 2012 [ 6 ] , of the 538 cases analyzed only 3 were transfusion-transmitted infections; 372 acute transfusion reactions, 42 hemolytic transfusion reactions, 11 transfusion-related acute lung injuries, and 82 transfusionassociated circulatory overload. Hemovigilance data for our region, Friuli Venezia Giulia (North East Italy), are presented in Table 7 .1 [ 7 ] . The critically ill patient can be affected by both infectious and noninfectious adverse reactions after a transfusion therapy and the importance of diagnosis is remarkable for the severity of clinical conditions usually treated in an intensive care unit. Transfusion reactions, in fact, can be masked by the severity of the main illness and the lack of active collaboration of the patient [ 8 ] . The aim of this chapter is to give an overview of the most common adverse transfusion reactions. IARTs can be caused by viruses, bacteria, and protozoa. Potentially, an undefined number of infective agents are liable to transmit a disease after a transfusion, but we shall consider the most frequent and pathogenic. In this field, it is important to know that not all infectious reactions have the same incidence in different countries, and for this reason the policy of detecting tests varies from USA [ 9 ] and Europe, and at the same time among European countries (EU). In this paper, we will focus on Italian policy, which is harmonized with EU regulations. The transmission of viruses after a transfusion therapy is usually due to the presence of the infective agent in the circulation of the donor. In the past 30 years, the risk of transmitting a virus infection with transfusion has greatly decreased because of the development of microbiological research and new detection techniques (serological and nucleic acid testing (NAT)). At the same time, more restrictive donor selection criteria and pathogen reduction or inactivation technologies are usually employed to further reduce the risk of infection [ 10 ] . Residual risk is due to asymptomatic donors who donate in the "window period." Table 7 .2 summarizes information related to the principal virus infections potentially transmitted by transfusion. It is useful for ICU specialists to know the main transfusionrelated viral infections. In fact, differently from the main immunological adverse reactions, the symptoms of IARTs can appear some days after transfusion and can be confused with the main disease. Particularly, it is necessary to pay attention to patients with a compromised immunological system who need immediate therapy to stop virus replication. Bacteria infections following transfusion (Table 7. 3 ) are often derived from microbial flora present on donor skin which contaminate blood products. They can also be due to systemic bacterial infections, though this is a rare event. From 2008, the Italian National Blood Center recommends using the first 40 ml of collected blood for testing, diverting it in tubes during withdrawal. Regarding the kind of blood components, platelet concentrates are more frequently involved in IARTs, because their storage is at room temperature (22 ± 2 °C). However, medical and nursing staff must inspect the blood component before administration to check for integrity of bags, hemolysis, change in color, gas formation, and clots. Any of these findings must be communicated to the transfusion center to which the product must be returned. Several bacteria are involved in IARTs, but symptoms of infection are usually the same like high fever (an increase >2 °C), chills, malaise, and diffuse pain. If the symptoms appear during transfusion, therapy must be stopped and the residual blood component sent to the transfusion center. It is mandatory to perform a blood culture for identification of microbial agent and begin immediately an antibiotic and antipyretic therapy. Following the laboratory result, pharmacological therapy can be modified to become more effective. The transmission of protozoa after transfusion is unequivocally due to the presence of the agent in the circulating blood of the donor. Sometimes it is not easy to identify infective donors, because some of these protozoa give no symptoms for years. In Italy, donor selection criteria specify a period of deferral for individuals who were born or visited endemic areas. The main problem with protozoan infections is the globalization in tourism and immigration from countries in which infection is endemic (Table 7 .4 ). A protozoan infection can be detected with a peripheral blood smear which may be followed by a serological assay. The precision of diagnosis is very important for a timely treatment, because often the acute phase is severe and involves different body systems. Chemotherapy is targeted for each different agent and in all cases the diagnosis must be notified to the transfusion center. In the past years, numerous emerging infections have been described in different areas of the world. Because of globalization of travel and immigration, it is a challenge for transfusion centers in the prevention of emerging IARTs [ 18 ] . The variant of Creutzfeldt-Jakob Disease (vCJD) is transmissible spongiform encephalopathy. Like the primitive CJD, it results from the changing of a prion protein into a proteaseresistant form (PrP Sc). Originally, bovine spongiform encephalopathy affected cattle. The use of animal protein in bovine feed diffused the disease in cows. Successively, meat consumption by humans was responsible for the variant of Creutzfeldt-Jakob Disease, which has an earlier onset with neurological manifestations, dementia, and death in 7-38 months. At present, there are no invasive tests available for donors or patients and diagnosis is mainly confirmed postmortem. The policy for blood collection consists in deferring donors who lived in the UK (the area of first onset of the disease) from 1980 to 1992 and donors who present neurological diseases [ 19 ] . Severe Acute Respiratory Syndrome (SARS) is a recent disease emerged explosively in Asia in 2004. The coronavirus agent can cause pneumonia with rapid onset and is often fatal. The transmission by transfusion is not clearly detected, but it can be possible in the asymptomatic viral phase. Quarantine and traveler surveillance is employed in airports during the endemic period. Middle East Respiratory Syndrome (MERS) is due to another coronavirus identified in Saudi Arabia in 2012. The virus can affect many types of animals, but recently dromedaries seem to be the most important source of infection for humans. Actually interhuman transmission is not demonstrated. Most infected patients report a severe respiratory disease with acute renal failure and high fatal rates [ 20 ] . As during SARS pandemia, travelers' surveillance in airports is important in the endemic periods. Xenotropic murine leukemia virus-related virus (XMRV) is a recent discovery and reported in uncertain association with chronic fatigue syndrome (CFS). This disease can potentially be transmitted by transfusion, but more extensive studies are needed to define the pathology [ 21 ] . Medical doctors when faced with an infectious disease in a hospitalized patient should always collect an accurate clinical history that must include transfusion of blood components and take into consideration that the viral/bacterial/protozoan infection could be related to a transfusion event. If a transfusiontransmitted infection is suspected, the clinician must contact the transfusion center that will provide a look-back of the blood products and a follow-up of the involved donors. There are many excellent reviews on noninfectious transfusion complications published in journals or as chapters in textbooks [ 22 -24 ] , and this paper does not intend duplicating them. Our aims are to illustrate different criteria with which NIARTs have been classified, mention the most important pathogenetic mechanisms involved, suggest organizational measures that hospitals may adopt to manage NIARTs, and discuss the laboratory's support for NIART diagnosis. Although NIARTs have different grades of severity, it must be underlined that most adverse reactions can occur in critically ill patients. There are different ways in which NIARTS can be classified: according to time of presentation (acute, within 24 h or delayed, after 24 h from the transfusion event) or according to pathogenesis (immunologic vs. nonimmunologic). Whereas the former is a more practical classification oriented to clinicians, the latter is of greater interest for the transfusion scientist. Classification of NIARTs according to pathogenesis (with the exception of transfusion errors, see following paragraph) is presented in Table 7 .5 . It may be incorrect to include transfusion errors in Table 7 .5 , mainly because part of transfusion errors (those which are AB0 incompatible) would be registered under acute hemolytic reactions. However, since transfusion errors are an important source of adverse reactions we believe that it is useful to keep a focus on this type of unwanted event. Klein and Anstee [ 24 ] use a more specific "pathogenetic" classification criterion in that they divide NIARTs into those due to red cell incompatibility, leukocyte antibodies, platelet antibodies, reactions to transfused proteins, and nonimmunological reactions. The aim of this section is to give an overview of the main NIARTs, irrespective of their severity. Tables 7.6 and 7.7 summarize the main mechanisms responsible for immunological and nonimmunological NIARTs, respectively, as well as the incidences as reported in literature. As far as the latter are concerned, it should be kept in mind that correct estimates are very difficult to obtain and vary according to clinical setting, accuracy of reporting, type of blood component transfused, and whether a transfusion event or number of units are considered in the denominator. A specific reference is included for all NIARTS. Transfusion of a RBC unit to the "wrong patient" is a very significant problem in transfusion medicine although it is only part of a wider problem of hospital adverse events due to misidentification [ 35 ] . It is estimated that a transfusion error occurs about 1:16,000 transfused units, and in the majority of cases it is due to misidentification of the patient. An AB0incompatible transfusion error will occur 1:33,000 units; 50 % of these will give rise to hemolysis but the mortality incidence due to an incompatible transfusion is calculated as being 1:800,000 [ 4 ] . These figures are surely underestimated due to the legal implications of reporting a transfusion-associated mistake. It is interesting to note that the Joint Commission International accreditation system [ 36 ] quite rightly consider transfusion errors as "sentinel events," which implies that a thorough root-cause analysis must be performed in the health facility where the event occurs. Today, technology for the prevention of transfusion errors is available [ 37 ] and hospitals should consider its implementation. Every health facility practicing transfusion therapy should have a system in place to ensure the highest possible level of safety for the patients. Figure 7 .1 depicts the main critical points for a safe transfusion. Transfusion requests originate in the ward and clinicians first of all should ask themselves whether their patient does in fact need the transfusion. This means that clinicians should rely on guidelines for which there is a wide consensus on the appropriate use of blood. An important role in this regard is played by the Hospital Transfusion Committee, which is the ideal forum in which these documents are prepared and shared by the hospital medical staff. Clinicians should always bear in mind that the safest transfusion is the one which is not performed. A written request form must be made specifying correct patient data (name, surname, place, and date of birth), condition requiring transfusion, ward, type and number of blood components required, urgency of transfusion, blood group and red blood cell antibody status if previously determined, history of sensitization episodes, previous NIARTs, signature of medical doctor. Fulfilling the request form correctly is the first step toward a safe transfusion. The second step relates to withdrawing blood samples; patient must be identified at the bedside; when possible the patient should be asked his/her name and surname and date of birth, otherwise the patient record must be used. Here again it must be pointed out that many transfusion errors are made at this truly critical point. Traceability (an important ingredient of safety) is enhanced by bar codes on the request form and sample labels. Moreover, as far as AB0 and Rh testing is concerned, it should be performed previous to the request form on a separate blood sample. This is to reduce the risk of mistakes due to swapping of patients. The nurse or medical doctor who withdraws blood should sign the label on blood sample tube to testify that patient identity has been checked. The request form and sample is then sent to the transfusion center; the date and time of arrival must be registered and the coherence of data reported on the request form and on the sample label checked. Each center should have a policy that clearly states when samples should be rejected. Transfusion centers should have computer software (with adequate backups) on which to store patient data (as already mentioned, barcodes are very useful and should be used whenever possible). The best softwares are those that allow a complete traceability "from vein to vein" (donor to recipient) thus permitting to perform lookback studies should it be necessary. The transfusion technician should check that the patient for whom blood components are being requested has been tested for AB0 and Rh and has undergone red cell antibody screening (if red blood cells are needed). The transfusion center should have a Standard Operating Procedure (SOP) in place specifying what type of compatibility testing is performed for which type of patient (e.g., type and screen for nonimmunized recipients, cross-matching for immunized patients). The SOP should also specify what tests should be performed in case of very urgent cases. Once the request form is registered, pretransfusion testing can be performed. If we consider safety at 360° as it ought to be, we must also mention that quality of testing plays a major role in transfusion safety. This means that a quality management system should be in place in the immunohematology laboratory foreseeing SOPs for all activities (testing, blood component preparation, and storage), internal quality control on reagents and blood components (including sterility), external proficiency testing (for blood groups, antibody screening, and identification), maintenance program for instruments, a training program for the staff, and a quality improvement scheme. Once testing is completed (an AB0 direct test should be performed on all samples accompanying the request form), compatible units are chosen according to an SOP; this document should also state in which conditions nonideally compatible units can be issued (e.g., group 0 Rh positive red blood cell units for 0 Rh negative recipients). The issuing of blood components should be registered on the software, which also prints a form that accompanies the units on which patient data number and blood group of unit are reported. This "transfusion form" ideally should be divided in two with one section that must be returned to the transfusion center testifying that the patient has been transfused; should adverse reactions be observed, these should be registered on this form. Units are then sent to the ward (in appropriate containers at controlled temperature). Before transfusion, personnel (in Italy a nurse and medical doctor) should check, with the aid of a checklist, the patient's identity (possibly asking name, surname, and date of birth), blood group on patient record, blood unit label, and transfusion form. This check is pivotal for the safety of transfusion since it is the last chance for a transfusion error to be stopped. In fact, it has been published many times that a superficial pretransfusion check at the patient's bedside is the single most frequent cause of transfusion mistakes. Transfusion then starts and must be monitored for the appearance of adverse reactions. It is of fundamental importance for clinicians and nurses who are directly involved in transfusing patients to be aware of the different NIARTs in order to recognize them promptly and give appropriate treatment. It is a good measure to register in the patient's record the blood pressure, heart rate, and temperature before and after the end of transfusion. One of the difficulties concerns differential diagnosis of NIARTs in that many signs and symptoms are common to more than one reaction; Table 7 .8 reports some signs and symptoms of NIARTs (for a more thorough description see specific references). A second difficulty concerns the fact that fortunately, the majority of NIARTs are rare events and therefore personnel may have little experience in dealing with them. Third, in some cases (patients in intensive care units for example) symptoms may be heavily modified by the patient's clinical condition (hemoglobinuria may be the only sign of an acute hemolytic transfusion reaction in patients under anesthesia). Finally, for reactions occurring at considerable time period from transfusion (posttransfusion purpura, delayed hemolytic transfusion reaction, transfusion-associated graft vs. host disease), establishing a link between symptoms and the transfusion event may not be so obvious. Once an acute NIART is suspected or diagnosed (during transfusion), TRANSFUSION MUST BE STOPPED IMMEDIATELY, but a line must be kept for infusion if necessary. The transfusion center must be promptly informed and a blood sample together with the remains of the transfusion unit must be sent to the transfusion center together with a description of signs and symptoms (on transfusion form). Treatment must be started immediately and specialized opinion may be sought from an intensive care unit specialist or from a nephrologists or other specialist. A synthesis of the most important therapeutic and preventive strategies for immunologic NIARTs is shown in Table 7 .9 . Data regarding any NIART should be registered on the patient's medical record for future preventive measures. Blood transfusion is a complex procedure and guaranteeing a safe transfusion requires a joint effort from the clinician and transfusion specialist. As we all know, a "zero risk" transfusion does not exist and thus risk management systems must be implemented since knowing the extent of risk is the first step for controlling it. This means that statistics must be prepared on all types of NIARTs and discussed at the Transfusion Committee. One of the obstacles that prevent NIARTs from being successfully managed is underreporting; this is due to underrecognition in the ward but also due to a reticence from clinicians who may be worried that, for example, a transfusion error may lead to legal problems. An anonymous form for adverse event reporting must be available in the wards. Clinicians must feel adequately supported by the transfusion laboratory which must perform all necessary tests in a timely manner. The final word goes to training; continuous updating and "refresher" courses should be given to both nurses and doctors working at the patient's bedside as well as to personnel working in transfusion centers to allow prompt recognition, laboratory diagnosis, effective treatment, and implementation of prevention strategies in order to guarantee an as-safe-as-possible transfusion for our patients. 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