1. Acute adverse reactions to transfusion: a symptoms- based approach Kathryn E. Webert, MD, MSc, FRCPC Assistant Professor, Departments of Medicine and Molecular Medicine and Pathology McMaster University, Hamilton, Ontario Associate Medical Director, Canadian Blood Services, Hamilton Centre

2. Summary of presentation What is a transfusion reaction ? Classification of transfusion reactions Approach to acute transfusion reactions based on common presenting symptom: Fever Dyspnea Rash/allergic symptoms **Detailed pathophysiology, management, and prevention was covered for most of these reactions in recent presentation**

3. What is a transfusion reaction? Any untoward event that occurs as a result of infusion of a blood component (immediate or delayed) When any unexpected or untoward sign or symptom occurs during or shortly after the transfusion of a blood component, a transfusion reaction must be considered as the precipitating event until proven otherwise Only a high index of suspicion will allow a transfusion reaction to be diagnosed

4. Immediate Adverse Effects Associated with Transfusion Acute hemolytic transfusion reaction Febrile non-hemolytic transfusion reaction Allergic reactions Urticarial Anaphylactic Transfusion-associated circulatory overload (TACO) Transfusion-associated dyspnea (TAD) Transfusion-related acute lung injury (TRALI) Septic transfusion reaction (bacterial contamination) Hypotensive reactions ACE Inhibitors Non-immune red cell hemolysis Metabolic disturbances Hypothermia Hyperkalemia Acidosis

5. Immediate Adverse Effects Associated with Transfusion: risks Complication Risk Acute hemolytic transfusion reaction 1:25,000 Febrile non-hemolytic transfusion reaction 1:10 (plts) Allergic reaction: Anaphylactic 1:40,000 Allergic reaction: Minor 1:100 TRALI 1:5,000 Transfusion-associated circulatory overload (TACO) 1:700

6. Delayed Adverse Effects Associated with Transfusion Delayed hemolytic transfusion reaction Alloimmunization Red Cell Antigens HLA Leukocytes Platelets Graft versus host disease (TA-GVHD) Post-transfusion purpura (PTP) Hemosiderosis Viral and parasitic infections Transfusion-related immunomodulation (TRIM)

7. Signs and Symptoms of TR Fever/chills/rigors Pain Dyspnea/respiratory distress Bleeding Hypotension Hypertension Headache Nausea and vomiting Rash/Hives Angioedema Anaphylaxis Cyanosis Bronchospasm Tachycardia Abdominal cramps Diarrhea Cough Red eye Anxiety Jaundice

8. Classification of reaction by predominant symptom/sign This presentation will focus on 3 common presenting symptoms and signs: 1. Fever 2. Dyspnea 3. Rash and other allergic reaction

9. Disclaimer: This is not easy… Sometimes the patient has not read the text book… More than one predominant presenting symptom More than one reaction going on Atypical presentation Underlying comorbidities unrelated to transfusion

10. Approach to Patients with Transfusion Reactions

11. Approach to Patient with a Transfusion Reaction 65 year old man develops shortness of breath and hypoxia while receiving unit of PRBC. What is the differential diagnosis?

12. Approach to acute transfusion reactions commonly presenting with shortness of breath

13. Differential Diagnosis of TR with SOB Transfusion-related acute lung injury (TRALI) Circulatory overload (TACO) Transfusion associated dyspnea (TAD) Anaphylaxis Acute hemolytic transfusion reaction Bacterial contamination Other etiology unrelated to transfusion SOB is usually the predominant symptom

14. Differential Diagnosis of TR with SOB: Background Transfusion-related acute lung injury (TRALI) Circulatory overload (TACO) Transfusion associated dyspnea (TAD) Anaphylaxis Acute hemolytic transfusion reaction Bacterial contamination Other etiology unrelated to transfusion

15. Canadian Consensus Conference Definition of TRALI During or within 6 hrs of transfusion Acute lung injury Acute onset Hypoxemia PaO 2 /FIO 2  300 SpO 2 < 90% on room air Bilateral infiltrates on CXR No evidence of circulatory overload (PCWP  18) No preexisting ALI or other RF for ALI Kleinman et al. Transfusion 2004;44:1774-89 Toy et al. Crit Care Med 2005;33:721-6

16. TRALI: symptoms and signs Virtually all patients have: Shortness of breath Hypoxia Bilateral lung infitrates on CXR May also have: Hypotension Fever Transient leukopenia Other: Chest findings on auscultation tend to be minimal No evidence of circulatory overload Bux and Sachs. Transfusion Medicine and Hemotherapy. 2008

17. TRALI: Epidemiology 0.4 to 1.6 cases per 1,000 patients transfused Likely under-reported and under-recognized Described with all blood products Usually contain > 60 mL plasma US FDA observed TRALI to be the leading cause of transfusion related deaths 2003-2008. Responsible for 16 to 65% of transfusion-related mortalities In Canadian TTISS Report (2004-2005): 2 nd highest cause of transfusion-related morbidity and mortality Fatalities reported to FDA following blood collection and transfusion. Annual Summary for Fiscal Year 2008. Transfusion Transmitted Injuries Surveillance System, Program Report 2004-2005, Public Health Agency of Canada, March 2008

18. TRALI: Pathophysiology Immune Passive transfer of donor alloantibodies in plasma of transfused product Anti-HLA (Class I) Anti-HLA (Class II) Human neutrophil antigens (HNA) Antibody binding to circulating WBC (and perhaps also pulmonary endothelium) causes cellular activation Recipient WBC

19. TRALI: Pathophysiology Non-immune TRALI is also caused by the infusion of “biologic response modifiers” within the blood component Cytokines (IL-6, IL-8, IL-1, TNF-  Lipids with neutrophil-priming activity CD40 ligand These substances accumulate in cellular blood products with prolonged storage Silliman CC et al., Transfusion 1997 Silliman CC et al., Blood 2003

20. TRALI: Diagnosis No test with which to diagnose TRALI. TRALI should be suspected if a patient has appropriate clinical findings within six hours of a transfusion Exclude of other causes of pulmonary edema Cardiac causes Volume overload Clinical diagnosis

21. TRALI: Treatment and Prognosis Ventilatory support as required Maintenance of hemodynamic status Inotropes, vasopressors 80% of patients show clinical improvement within 48-96 hours In most patients, there are no long-term complications Fatal in 5-10% of cases

22. Differential Diagnosis of TR with SOB: Background Transfusion-related acute lung injury (TRALI) Circulatory overload (TACO) Transfusion associated dyspnea (TAD) Anaphylaxis Acute hemolytic transfusion reaction Bacterial contamination Other etiology unrelated to transfusion

23. TACO Acute pulmonary edema secondary to congestive heart failure precipitated by transfusion of a volume of blood greater than what the recipient’s circulatory system can tolerate Respiratory distress and/or cyanosis associated with pulmonary edema within 6 hours of transfusion Associated with hypertension, tachycardia, positive fluid balance Many patients also complain of a dry cough, headache, chest tightness Bux J, Transfus Med Hemother 2008

24. TACO: Epidemiology Likely the most under-recognized and potentially serious transfusion complication Studies have demonstrated incidence in orthopedic surgery patients (hip or knee arthroplasty) to be 1-8% Bux J, Transfus Med Hemother 2008 Popovsky MA, Transfusion and Apheresis Science, 2006

25. TACO: Risk Factors Too much blood transfused too rapidly Can be precipitated by even a single RBC unit Age 60 years Diminished cardiac reserve Chronic anemia Bux J, Transfus Med Hemother 2008

26. TACO: Treatment and Prevention Prevention Transfuse only when indicated Recognize patients at risk If at risk, transfuse slowly Consider diuretics (before and/or after) Watch fluid balance, monitor patient closely Treatment Stop transfusion Position patient in upright position Supplementary oxygen Diuretics Cardiac and respiratory support as required

27. Bux J, Transfus Med Hemother 2008

28. Differential Diagnosis of TR with SOB: Background Transfusion-related acute lung injury (TRALI) Circulatory overload (TACO) Transfusion associated dyspnea (TAD) Anaphylaxis Acute hemolytic transfusion reaction Bacterial contamination Other etiology unrelated to transfusion

29. Transfusion associated dyspnea (TAD) European Haemovigilience Network (EHN) introduced term to allow for classification of respiratory distress temporally associated with transfusion which could not be assigned to known pulmonary reactions www.ihn-org.net

30. Differential Diagnosis of TR with SOB Transfusion-related acute lung injury (TRALI) Circulatory overload (TACO) Transfusion associated dyspnea (TAD) Anaphylaxis Acute hemolytic transfusion reaction Bacterial contamination Other etiology unrelated to transfusion Can you narrow the diagnosis down?

31. Differential Diagnosis—TR with SOB Other SymptomsTiming of Symptoms TACOElevated JVP, hypertension, pulmonary edema (crackles, rales, S3 gallop) Within several hours of transfusion TRALISOB, hypoxemia, hypotension, pulmonary edema (crackles, relatively quiet chest), fever Within 6 hours of transfusion (usually during) TADAll other pulmonary reactions ruled out Within 6 hours of transfusion AnaphylaxisGeneralized rash, flushing, wheezing, angioedema Usually early in transfusion AHTRFlank pain, DIC, hypotension, fever Usually within first 15 minutes Bacterial sepsis Fever, hypotensionUsually within first 15 minutes

32. Immediate Management: TR with SOB Stop transfusion immediately Notify hospital blood bank of transfusion reaction Sample sent: screen for hemolysis, DAT Maintain IV access (0.9% saline) Monitor patient’s vital signs Recheck identification of patient (wrist band) and label of blood product for discrepancy CXR

33. Serious Reaction What symptoms/signs would suggest a serious reaction? Hypotension/shock Shortness of breath Hypoxemia Hemoglobinuria Nausea and vomiting Bleeding from IV sites Back pain Chest pain Temperature >39 o C

34. Initial management of a serious reaction with SOB Suspect TRALI, TACO Do not restart transfusion Notify blood bank and hematologist on call Maintain IV access CXR Assess patient  JVP, pulmonary edema: suspect TACO Diuresis, supportive therapy Normal JVP, fever, CXR suspicious for ALI: suspect TRALI Supportive therapy

35. Approach to Patient with a Transfusion Reaction 65 year old man develops fever (temp 38 o C) with rigors and chills while receiving unit of PRBC. What is the differential diagnosis?

36. Approach to acute transfusion reactions commonly presenting with fever

37. Differential diagnosis: TR with Fever Acute hemolytic transfusion reactions (AHTR) Febrile non-hemolytic transfusion reactions (FNHTR) Bacterial sepsis or contamination Transfusion-related acute lung injury Etiology unrelated to transfusion Fever is usually the predominant symptom

38. Differential diagnosis: TR with Fever Acute hemolytic transfusion reactions (AHTR) Febrile non-hemolytic transfusion reactions (FNHTR) Bacterial sepsis or contamination Transfusion-related acute lung injury Etiology unrelated to transfusion

39. AHTR Lysis or accelerated clearance of red cells in a transfusion recipient due to immunologic incompatibility between the blood donor and the recipient Antigen-positive red cells are transfused to a recipient who has incompatible alloantibodies Results in intravascular hemolysis Epidemiology Generally within the top 3 causes of transfusion-related mortality 10.8% of all fatalities reported to the US FDA in 2005-2008

40. AHTR—Etiology Often due to the administration of ABO incompatible blood Cross-match error wrong identification of blood specimen blood administered to wrong patient May rarely be due to recipient allo-antibodies to other red cell antigens Other causes of hemolysis include: Overheating of RBC Freezing of RBC Outdated RBC Transfusion under pressure with small bore needle Transfusion with hypotonic solution Causes unrelated to transfusion

41. AHTR-- Pathophysiology Red cell alloantibody (IgM) in recipient binds to antigen on transfused red cell membrane Development of immune complexes and activation of complement Results in formation of membrane attack complex (C5b-9) on the red cell surface which leads to lysis of cells Release of C3a and C5a Hypotension Production of IL-1 from macrophages Fever Activation of coagulation cascade Disseminated intravascular coagulation (DIC)

42. AHTR--Clinical Presentation Acute onset, often within first 15 minutes of starting transfusion Transfusion of as little as 20-30 mL of red cells may result in an acute hemolytic transfusion reaction Initial clinical presentation: Fever and/or chills, anxiety, nausea or vomiting, pain (flank, back, abdomen, chest, head, infusion site), dyspnea, hypotension, brown urine, bleeding Complications: Renal failure, disseminated intravascular coagulation (DIC), death

43. AHTR—Treatment STOP the transfusion immediately Begin infusion with normal saline Alert the blood bank, check for clerical error, send entire transfusion set-up to blood bank for testing Supportive care Monitor vital signs closely Maintain blood pressure and urine output Monitor for hyperkalemia Administer FFP, cryoprecipitate and platelets as required for coagulopathy

44. AHTR—Investigation Clerical check (labels, records in blood bank, review of blood typing results, antibody tests) Repeat ABO type Post-reaction blood specimen Visual check for free hemoglobin DAT ABO type Antibody screen Evidence of hemolysis free serum hemoglobin, haptoglobin, LDH, urine free hemoglobin

45. Transfusion Reactions with Fever: Background Acute hemolytic transfusion reactions (AHTR) Febrile non-hemolytic transfusion reactions (FNHTR) Bacterial sepsis or contamination Transfusion-related acute lung injury Etiology unrelated to transfusion

46. FNHTR—Epidemiology Common adverse event 1 in 10 transfusions of pooled random donor platelets 1 in 3000 units of RBC Frequency varies with: Type of blood product Age of blood product WBC content of blood product Recipient characteristics Use of pre-medications Variability in recording of symptoms Callum J, Pinkerton P. Bloody Easy, 2 nd edition, 2005

47. FNHTR—Etiology Reactions mediated by antibodies Recipient alloantibody reactive to antigens expressed on WBCs in component Antigen-antibody interaction causes the release of endotoxins 1 o mechanism causing FNHTR after transfusion of RBC Reactions mediated by biologic response molecules Accumulation of leukocyte and/or platelet-derived cytokines in the bag during storage IL-1 , IL-6, IL-8, TNF-  Accounts for >90% of reactions to platelet transfusions Heddle et al., 1994; Brittingham and Chaplin, 1957; deRie et al., 1985; Perkins et al., 1966; Heddle et al., 1994; Muylle and Peeterman, 1994; Stack and Snyder, 1994; Aye et al.,1995; Kluter et al., 1995; Flegel et al., 1995.

48. Slide 48 FNHTR—Clinical Presentation Fever (>1 o C rise) during or soon after transfusion Usually associated with chills and rigors May be associated with nausea and vomiting Symptoms typically appear toward the end of the transfusion 5-10% of reactions present 1-2 hours after the transfusion AABB Technical Manual, 14 th Edition, 2002; Heddle et al., 2002; Heddle et al., 1993.

49. FNHTR—Treatment Stop the transfusion while assessing patient Determine that an acute hemolytic transfusion reaction or reaction secondary to bacterial contamination is not occurring Acetaminophen +/- merperidine may help patients with severe chills and rigors Continue transfusion cautiously

50. Transfusion Reactions with Fever: Background Acute hemolytic transfusion reactions (AHTR) Febrile non-hemolytic transfusion reactions (FNHTR) Bacterial sepsis or contamination Transfusion-related acute lung injury Etiology unrelated to transfusion

51. Bacterial Contamination—Epidemiology Most frequent infectious risk associated with transfusion Accounts for ~11% of deaths due to blood components Occurs most frequently with platelets Stored at 20-24 o C Excellent growth medium for bacteria Component Bacterial Contamination Symptomatic Septic Reactions Fatal Bacterial Sepsis Platelet pool1 in 1,0001 in 10,0001 in 40,000 RBC (1 unit) 1 in 50,0001 in 100,0001 in 500,000 Callum and Pinkerton, Bloody Easy 2, 2005 Slide 51

52. Bacterial Contamination: Etiology Blood components may be contaminated by Unrecognized bacteremia in the donor e.g., Yersinia enterocolitica Skin organisms from the donor Difficult to totally decontaminate surface of human skin Small core of skin may enter phlebotomy needle at time of donation (~65% of donations) Bacterial present in deep layers of skin e.g., Staphylococcus epidermidis Contamination from the environment or handling of the product Leaky seals, damaged tubing, etc. e.g., Serratia marcescens

53. Bacterial Contamination—Commonly implicated bacteria Gram-negative Klebsiella pneumoniae Serratia marcescens Pseudomonas species Yersinia enterocolitica Gram-positive Staphylococcus aureus Staphylococcus epidermidis Bacillus cereus

54. Clinical Presentation Depends on bacterial load of product, species of implicated bacteria Rigours, fever, chills Hypotension Tachycardia Nausea and vomiting Dyspnea Disseminated intravascular coagulation Usually occurs during transfusion of implicated product

55. Management and Investigation Stop the transfusion immediately Notify the hospital blood bank Return residual product and tubing to blood bank Collect peripheral blood samples for culture Aggressive supportive therapy Broad-spectrum antibiotic therapy

56. Differential Diagnosis: TR with fever Febrile non-hemolytic transfusion reaction Bacterial contamination Acute hemolytic transfusion reaction TRALI Can you narrow down the diagnoses further?

57. Differential Diagnosis: TR with Fever Other Symptoms Timing of Symptoms Febrile non-hemolytic transfusion reaction Usually temp < 39 o C During transfusion; usually towards the end Bacterial contamination Hypotension, shock, DIC Usually within first 15 minutes Acute hemolytic transfusion reaction Flank pain, DIC, hypotension Usually within first 15 minutes TRALISOB, hypoxemia, hypotension Within 6 hours of transfusion (usually during) 57

58. Immediate Management Stop transfusion immediately Notify hospital blood bank of transfusion reaction Maintain IV access (0.9% saline) Monitor patient’s vital signs Recheck identification of patient (wrist band) and label of blood product for discrepancy

59. Serious Reaction What symptoms/signs would suggest a serious reaction? Hypotension/shock Shortness of breath with hypoxemia Hemoglobinuria Nausea and vomiting Bleeding from IV sites Back pain Chest pain Temperature >39 o C

60. Initial management of non-serious reaction with fever No serious symptoms Possible FNHTR Treat with acetaminophen (+/- Demerol) Restart transfusion with caution Observe patient closely Stop transfusion immediately if patient develops any serious signs or symptoms

61. Initial management of serious reaction with fever Suspect: hemolytic transfusion reaction or bacterial sepsis Do not restart transfusion Notify blood bank and hematologist on call Continue IV fluids Send blood product and set-up (IV tubing) to blood bank Arrange for unit to be cultured and a gram stain performed

62. Initial management of serious reaction with fever Order “transfusion reaction” investigations, post- transfusion sample for Group and screen Direct antiglobulin test (DAT) Antibody screen Blood culture of product Check for hemolysis: free hemoglobin, decreased haptoglobin, hyperbilirubinemia Blood culture of patient Urinalysis (free hemoglobin) +/- CXR

63. Approach to Patient with a Transfusion Reaction 65 year old man develops diffuse, pruretic body rash with throat tightness and wheezing while receiving unit of plasma. What is the differential diagnosis?

64. Approach to transfusion reactions commonly presenting with rash

65. Differential diagnosis: rash Mild allergic reactions Serious allergic reactions Anaphylaxis Anaphylactoid reactions Reactions unrelated to transfusion

66. Allergic Transfusion Reactions

67. Allergic Reactions Usually due to soluble allergenic substances in the plasma of donated blood React with pre-existing IgE antibodies in the recipient Causes release of histamine from mast cells and basophils Possible mechanisms Pre-existing anti-IgA in IgA-deficient patient Pre-existing antibodies to other serum protein that patient is lacking (IgG, Albumin, haptoglobin, a1-antitrypsin, transferrin, C3, C4, etc.) Passive transfer of IgE antibodies Transfusion of allergen to which patient is sensitized (e.g. drugs, chemicals) Vamvakas and Pineda, Transfusion Reactions, AABB Press 2001

68. Allergic reactions Incidence: Mild: 1:33-100 (1% - 3%) Severe: 1:20,000-47,000 Timing During transfusion; up to 3 hours from the start of transfusion Vamvakas and Pineda, Transfusion Reactions, AABB Press 2001

69. Allergic Reactions—Clinical Presentation Signs and Symptoms Skin lesions (hives) May also have Pruritis angioedema Cough and wheezing Nausea and vomiting Abdominal pain Diarrhea Hypotension Cyanosis Tachycardia

70. Allergic reactions: Serious What symptoms/signs would suggest a serious reaction? Hypotension/shock Shortness of breath, hypoxemia Cough Tachycardia Nausea and vomiting Generalized flushing or anxiety Widespread rash (covering more than 2/3 of body) Callum and Pinkerton, Bloody Easy 2, 2005

71. Management of non-serious reaction with rash Antihistamine Diphenhydramine 25-50 mg IV/PO Continue transfusion with caution Stop transfusion if any “serious” symptoms

72. Management of serious reaction with rash Stop the transfusion and do not restart Notify hospital transfusion service Epinephrine Antihistamine Corticosteroids Supportive therapy as required

74. Summary Initial management of transfusion reaction Stop transfusion immediately Notify blood bank Maintain IV access Monitor patient’s vital signs Recheck identification of patient Assess for symptoms of “serious” reaction

75. Summary May be able to classify reaction by predominant presenting symptom Shortness of breath TRALI, TACO, TAD AHTR, allergic reaction, bacterial contamination Fever FNHTR, bacterial contamination, AHTR, TRALI Rash Mild allergic reaction, anaphylaxis

76. The End!!!