Acute adverse reactions to transfusion: a symptoms-based approach

Acute adverse reactions to transfusion: a symptoms-based approach

Kathryn E. Webert, MD, MSc, FRCPC

Assistant Professor, Departments of Medicine and Molecular Medicine and PathologyMcMaster University, Hamilton, Ontario

Associate Medical Director, Canadian Blood Services, Hamilton Centre

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**

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

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

Immediate Adverse Effects Associated with Transfusion: risks

Complication RiskAcute hemolytic transfusion reaction 1:25,000Febrile non-hemolytic transfusion reaction 1:10 (plts)Allergic reaction: Anaphylactic 1:40,000Allergic reaction: Minor 1:100TRALI 1:5,000Transfusion-associated circulatory overload (TACO) 1:700

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)

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

Classification of reaction by predominant symptom/sign

• This presentation will focus on 3 common presenting symptoms and signs:

1. Fever2. Dyspnea3. Rash and other allergic reaction

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

Approach to Patients Approach to Patients with Transfusion with Transfusion

ReactionsReactions

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?

Approach to acute transfusion

reactions commonly presenting with

shortness of breath

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

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


Canadian Consensus Conference Definition of TRALI• During or within 6 hrs of transfusion

• Acute lung injury• Acute onset• Hypoxemia

• PaO2/FIO2 300• SpO2 < 90% on room air

• Bilateral infiltrates on CXR• No evidence of circulatory

overload (PCWP18)

• No preexisting ALI or other RF for ALI

Kleinman et al. Transfusion 2004;44:1774-89Toy et al. Crit Care Med 2005;33:721-6

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

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):• 2nd 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

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

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 1997Silliman CC et al., Blood 2003

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

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




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

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 2008Popovsky MA, Transfusion and Apheresis Science, 2006

TACO: Risk Factors

• Too much blood transfused too rapidly• Can be precipitated by even a single RBC unit

• Age <3 or >60 years• Diminished cardiac reserve• Chronic anemia


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





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

Differential Diagnosis of TR with SOB

• Transfusion-related acute lung injury (TRALI)• Circulatory overload (TACO)• Transfusion associated dyspnea (TAD)



• Can you narrow the diagnosis down?

Differential Diagnosis—TR with SOBOther Symptoms Timing of Symptoms

TACO Elevated JVP, hypertension, pulmonary edema (crackles, rales, S3 gallop)

Within several hours of transfusion

TRALI SOB, hypoxemia, hypotension, pulmonary edema (crackles, relatively quiet chest), fever

Within 6 hours of transfusion (usually during)

TAD All other pulmonary reactions ruled out

Within 6 hours of transfusion

Anaphylaxis Generalized rash, flushing, wheezing, angioedema

Usually early in transfusion

AHTR Flank pain, DIC, hypotension, fever

Usually within first 15 minutes

Bacterial sepsis

Fever, hypotension Usually within first 15 minutes

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

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 >39oC

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


• 65 year old man develops fever (temp 38oC) with rigors and chills while receiving unit of PRBC.

•What is the differential diagnosis?

Approach to acute transfusion

reactions commonly presenting with

fever

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

Differential diagnosis: TR with Fever






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

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

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)

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

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

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

Transfusion Reactions with Fever: Background






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, 2nd edition, 2005

FNHTR—Etiology

Reactions mediated by antibodies•Recipient alloantibody reactive to antigens expressed on WBCs in component•Antigen-antibody interaction causes the release of endotoxins•1o 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 .

Slide 48

FNHTR—Clinical Presentation

• Fever (>1oC 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, 14th Edition, 2002; Heddle et al., 2002; Heddle et al., 1993.

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

Transfusion Reactions with Fever: Background






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 20-24oC• Excellent growth medium for bacteria

Component Bacterial Contamination

Symptomatic Septic Reactions

Fatal Bacterial Sepsis

Platelet pool 1 in 1,000 1 in 10,000 1 in 40,000

RBC (1 unit)

1 in 50,000 1 in 100,000 1 in 500,000

Callum and Pinkerton, Bloody Easy 2, 2005 Slide 51

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

Bacterial Contamination—Commonly implicated bacteria

Gram-negative

• Klebsiella pneumoniae• Serratia marcescens• Pseudomonas species• Yersinia enterocolitica

Gram-positive

• Staphylococcus aureus• Staphylococcus epidermidis• Bacillus cereus

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

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

Differential Diagnosis: TR with fever

• Febrile non-hemolytic transfusion reaction

• Bacterial contamination

• Acute hemolytic transfusion reaction

• TRALI

• Can you narrow down the diagnoses further?

Differential Diagnosis: TR with Fever

Other Symptoms

Timing of Symptoms

Febrile non-hemolytic transfusion reaction

Usually temp < 39oC

During transfusion; usually towards the end

Bacterial contamination

Hypotension, shock, DIC


Acute hemolytic transfusion reaction

Flank pain, DIC, hypotension


TRALI SOB, hypoxemia, hypotension

Within 6 hours of transfusion (usually during)

57

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

Serious Reaction


• Hypotension/shock• Shortness of breath with hypoxemia• Hemoglobinuria• Nausea and vomiting• Bleeding from IV sites• Back pain• Chest pain• Temperature >39oC

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

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

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


• 65 year old man develops diffuse, pruretic body rash with throat tightness and wheezing while receiving unit of plasma.

•What is the differential diagnosis?

Approach to transfusion

reactions commonly presenting with rash

Differential diagnosis: rash• Mild allergic reactions• Serious allergic reactions

• Anaphylaxis• Anaphylactoid reactions

• Reactions unrelated to transfusion

Allergic Transfusion Allergic Transfusion ReactionsReactions

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

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

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

Allergic reactions: Serious


• 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

Management of non-serious reaction with rash• Antihistamine

• Diphenhydramine 25-50 mg IV/PO

• Continue transfusion with caution

• Stop transfusion if any “serious” symptoms

Management of serious reaction with rash• Stop the transfusion and do not restart

• Notify hospital transfusion service

• Epinephrine

• Antihistamine

• Corticosteroids

• Supportive therapy as required

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

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

The End!!!

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Acute adverse reactions to transfusion: a symptoms-based approach

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