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Adverse Reactions to Transfusion:

TRALI and TACO

Objectives

Review the historical perspective and background of TRALI and TACO including definition of both

Identify mechanisms of action, management, outcomes and prevention of both TRALI and TACO

2015-APL-02503 1

Transfusion Related Fatalities by Complication, FY2009 through FY2013

2015-APL-02503 2

Transfusion Related Acute Lung Injury

(TRALI)

2015-APL-02503 3

TRALI: Historical Perspective

1950’s Description Acute hypoxemia and noncardiogenic pulmonary

edema

1950 and 1960 Literature Document transfusion associated pulmonary

edema without evidence of volume overload

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TRALI: Historical Perspective

1980’s Marked the emergence of a basic understanding of

TRALI1992 1st fatality reported to CBER

2000 to 2015 2000 TRALI represented 13% of all transfusions #1 cause of transfusion related fatalities

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TRALI: ReportsFatalities Majority of deaths associated with FFP

Less frequent with RBCs, cryo, platelets and rare with IvIg

Investigation Donor antibody screens implicated multiparous females

Non-Fatal Events Reports by licensed blood establishments are on the

increase Because of misdiagnosis and/or reporting the full scope of

TRALI not known

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TRALI

MechanismMay be attributable to the presence of Anti-HLA or Anti-granulocyte antibodies

Once transfused antibodies may cause complement activation

TRALI recipients have no specific demographics

Clinical results may be subtleor significant

Does not always occur through donor transfusions

In either case, there is marked hypoxemia, hypotension, fever, severe bilateral pulmonary edema

Antibodies implicated are usually of DONOR origin

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TRALI: Immunologic Mechanism

Activation of complement cascade and/or mobilization of cytotoxic agents lead to acute lung injury in

approximately 85% of cases

Donor plasma contains Anti-HLA or Anti-Neutrophil antibodies that react with HLA or Neutrophil antigens on

recipient leukocytes

Antibody-antigen complexes collect in the pulmonary microvasculature

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TRALI Non Immune Mechanism

Pre-existing condition activates neutrophils

Stored blood accumulates lipids and/or cytokines and upon transfusion activate the primed neutrophils

Activated primed neutrophils secrete toxic substances – may explain the 15% of cases where antibodies are

not detected

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TRALI RatesEstimated incidence of TRALI is 0.014 – 0.08 %

• 1 in 1271 Units TRALI• 1 in 534 units possible

TRALI

Rana et al Transfusion

2006;46:1478

• 0.02% per unit of blood transfused

• 0.16% per transfused patient

Popovsky et al Am Rev Respir Dis

1983;128:185

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TRALI: Definition

Hypoxemia (PaO2/FiO2

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TRALI

Common Signs and Symptoms Dyspnea Cyanosis Hypoxemia Fever (low grade) Chills Hypotension Bilateral pulmonary edema (new onset)

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TRALI: Diagnosis

This is a clinical diagnosis plus supporting labs/images

Diagnosis of exclusion: rule out other causes of transfusion associated respiratory distress

Differential diagnosis TACO (increased BP, I & O’s, BNP, diuresis helps) Anaphylaxis (rash, wheezing) Bacterial contamination (gram stain/culture) Hemolytic transfusion reaction (type/screen/cross, DAT)

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TRALI – Management

Respiratory Support

Dictated by clinical picture

Nasal cannula 2L to intubation

Diuretics

Play no role in TRALI

Pathology involves microvascular injury no fluid

overload

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TRALI Prevention: Donor Selection

AABB Standard 5.4.1.2 Plasma and whole blood for allogeneic transfusion

shall be from males, females who have not been pregnant or females who have been tested since their most recent pregnancy and results interpreted as negative for HLA antibodies

AABB – Donor CentersAABB – Donor Centers

Plasma containing products frequently

implicated

Donors with antibodies should

be deferredUse of male plasma has reduced rates

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TRALI – Risk ReductionTransfusion Centers

Washed Cellular

Products

Pre-storage Leukoreduction Plasma

Expensive, time consuming Small amounts

of plasma can cause TRALI

Not effective in inhibiting BRM mediated TRALI in-vivo

In Norway – no TRALI reported in the use of solvent-detergent plasma

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Transfusion Related Acute Lung Injury (TRALI)

Preventive Measures: American Red Cross TRALI Mitigation:

Defer donors implicated in a TRALI reaction All Transfusable plasma

from male donors Women who report a history of no pregnancy Females who have been tested and found to have an

acceptably low level of HLS antibodies

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Transfusion Related Acute Lung Injury (TRALI)

Preventive Measures: American Red Cross TRALI Mitigation

Reduce the Risk of TRALI in single donor platelets Defer donors implicated in TRALI Prevent the manufacture of high volume products from donors

known to harbor HLA antibodies Leukoreducing all apheresis platelet products to prevent

interaction with recipient HLA antibodies Increasing the proportion of donations from male donors Testing female apheresis donors Ruling out testing of all ever-pregnant females donors

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Transfusion Related Acute Lung Injury (TRALI)

Preventive Measures: Hospital:

Minimize the inappropriate transfusion of blood products Minimize AB plasma utilization; group specific plasma should

be given when time permits.

Note: Avoidance of discard is not an indication for use.

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TRALI Outcomes

• Mortality varies• Reported

between 5% & 25%

Mortality

• 80% recover quickly

• Between 24 to 72 hours

Recovery

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Immediate steps to take when an adverse reaction to transfusion is suspected

1. Recognize2. Stop3. Assess4. Notify5. Treat6. Report7. Document

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TRALI – Recommendations

Be alert to respiratory

distress

Immediately discontinue transfusion

Begin oxygen and supportive

therapy

Follow your routine

notification sops

Transfusion Service will

notify the Blood Center

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Possible Clinical Interventions

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Fever, Chills/ Rigors

Shock Respiratory Distress Urticaria

Febrile Non-

HemolyticHemolytic Septic TRALI TACO Anaphy-lactic

Mild Allergic

•Antipyretics•Analgesics

•Antipyretics•Analgesics•Fluids•Pressors•Diuretics

•Antipyretics•Analgesics•Broad spectrum antibiotics

•Blood Cultures

•Oxygen•Antipyretics•Intubation•Blood pressure support

•Chest x-ray

•Oxygen•Upright position

•Diuretics

•Oxygen•Feet up•Fluids•Epinephrine•Intubation•Anti-histamines

•Cortico-steroids

•Beta 2 agonists

•Anti-histamines

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TRALI: Common Question

Question: Can a patient be transfused after a TRALI reaction?

Answer: yes The reaction is an issue with the donor, not the

patient Once the transfusion reaction workup has been done

and hemolysis is ruled out, the patient may be transfused again

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TRALI: Reporting

Method DetailsE-mail: http://www.fda.gov/medwatchTelephone/voice mail: 1-800-FDA-1088Fax: 1-800-FDA-0178Express Mail: MedWatch

HF-25600 Fishers LaneRockville, MD 20852

• Fatalities from TRALI should be reported to CBER in accordance with 21CFR606.170(b)

• FDA encourages voluntary reporting of TRALI as a serious adverse reaction to transfusions

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Transfusion Related Fatalities by Complication, FY2009 through FY2013

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Transfusion Associated

Circulatory Overload (TACO)

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TACO History

Historical InformationPhysicians have known transfusion is a risk factor for circulatory overloadTACO not taken seriouslyRediscovered now that TRALI is a major focusClinical impact recognized to be more that giving supplemental oxygen and a dose of diuretics

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TACO Reports

Massachusetts Medicare Study Popovsky demonstrated TACO patients required

more intensive care and longer length of care

FDA Data Demonstrate TACO is the second most common cause of death

from transfusion

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TACO Reports

Fiscal 2005-2006 Fatal case reports increased from 2-13% of all

fatalities

French Hemovigilance 6 year period 742 cases identified resulting in 27

deathsUS Biovigilance Program Undoubtedly more fatalities identified

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TACO Mechanism

Inability of circulatory system to tolerate volume or rate of transfusion

“Cardiogenic pulmonary edema”

ANY patient may get TACO – especially if transfused rapidly

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TACO Rates

1. Gajic et al Crit Care Med 2006; 34:S1092. Popovsky et al Immunohematol 1996; 12:873. Rana et al Transfusion 2006; 46:1478

• 0.03%-8% of transfusions depending on criteria

Rate Ranges

• TACO occurred in 1 of 356 transfusions

ICU Patient Study

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TACO

Patients with the following are most at risk:Diminished cardiac reserve

Renal failure or dysfunction

Older (85% occur in patients greater than age 60)

Younger (smaller total blood volume)

Chronic anemias (e.g. sickle cell, thallasemias)Those receiving large amounts of blood products in a short time frame OR receiving double red cell transfusions

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Transfusion Associated Circulatory Overload (TACO)

Definition: Infusion volume that cannot be effectively processed

by the recipient either due to high rate and/or volume of infusion or an underlying cardiac or pulmonary pathology.

Can occur after only a few ml up to 6 hrs after Fairly Common → occur in ~1-8% of transfusions

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TACO: Diagnosis

Physical exam: lung crackles, rales, elevated JVP, S3 gallop

Chest XR: Alveolar and interstitial edema, Kerley B lines, pleural effusions, cardiomegaly

Elevated BNP Non-immune mediated, so no antibodies

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TACO: Signs/Symptoms

Shortness of breath, cough, chest tightness (from fluid accumulation in the lungs)

Headache (from the increased systolic pressure) Most typically towards the end of transfusion or

shortly afterwards when the maximum amount of fluid was transfused

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Transfusion Associated Circulatory Overload (TACO)

Common Signs and Symptoms Dyspnea Cough Pulmonary edema Hypertension Tachycardia Elevated brain natriuetic peptide (BNP) Orthopnea Elevated central venous pressure (CVP) Cyanosis Evidence of left heart failure Headache Distended neck veins Chest tightness Pedal edema

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TACO: Management

Stop the transfusion Follow your facilities routine procedures for adverse

reactions Evaluate the patient (you may want to sit the patient

upright to minimize fluid accumulation in the lungs) Give supplemental oxygen Diuretics to decrease the blood volume Severe cases may require therapeutic phlebotomy

though typically patients respond to supportive therapy

2015-APL-02503 39

Possible Clinical Interventions

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Fever, Chills/ Rigors

Shock Respiratory Distress Urticaria

Febrile Non-

HemolyticHemolytic Septic TRALI TACO Anaphy-lactic

Mild Allergic

•Antipyretics•Analgesics

•Antipyretics•Analgesics•Fluids•Pressors•Diuretics

•Antipyretics•Analgesics•Broad spectrum antibiotics

•Blood Cultures

•Oxygen•Antipyretics•Intubation•Blood pressure support

•Chest x-ray

•Oxygen•Upright position

•Diuretics

•Oxygen•Feet up•Fluids•Epinephrine•Intubation•Anti-histamines

•Cortico-steroids

•Beta 2 agonists

•Anti-histamines

2015-APL-02503 40

TACO

PreventionControl rate of infusion (suggest: 1 mL/Kg/hour

Split units in half or use aliquots

Consider lower volume units, or reduced volume units

Some suggest simultaneous administration of furosemide

“critical care level” nursing supervision in high-risk patients

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TACO OutcomesOne study showed the following:

18% (n=98) of pts required transfer to

ICU

8% suffered a major

complication2% died

Early recognition

better clinical outcomes

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TACO: Outcomes

Andrzejewski and colleagues found at 15 minutes after transfusion, systolic blood pressure, pulse pressure, and mean arterial pressure were significantly higher in fluid-challenged patients than those not overloaded

These patients could benefit from bedside monitoring

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TACO: Reporting

Report to blood bank as a possible transfusion reaction so the proper investigation may begin

Contemplate differential diagnosis and encourage appropriate patient care, laboratory analysis, or other diagnostic measures

Document all details for the EMR and blood bank

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TACO: Follow-Up

Ask patients if they have any history of previous transfusion reactions and if so, to please describe

Clinical follow-up—the outcome varies with overall clinical status of the patient so clinical correlation is recommended to decide upon what time frame to follow up with the clinician

Ensure all elements are documented

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TRALI or TACO: Fatality

When the death of a patient is a result of a transfusion reaction or a complication related to a transfusion current good manufacturing practice (cGMP) regulations require reporting of the fatality to the FDA by the facility that performed the compatibility testing.

The patient’s underlying illness may make determination of the cause of death difficult.

If there is any clinical suspicion that the transfusion may have contributed to the patient’s death, an investigation into that possibility should be performed

2015-APL-02503 46

TRALI or TACO: Reporting

Method DetailsE-mail: http://www.fda.gov/medwatchTelephone/voice mail: 1-800-FDA-1088Fax: 1-800-FDA-0178Express Mail: MedWatch

HF-25600 Fishers LaneRockville, MD 20852

• Fatalities from any transfusion should be reported to CBER in accordance with 21CFR606.170(b)

• FDA encourages voluntary reporting of TRALI as a serious adverse reaction to transfusions

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TRALI vs. TACOFeature TRALI TACO

Body Temperature Fever can be present Unchanged

Blood Pressure Hypotension Hypertension

Respiratory Symptoms Acute dyspnea Acute dyspnea

Neck Veins Unchanged Can be distended

Auscultation Rales Rales, S3 may be present

Chest radiograph Diffuse bilateral infiltrates Diffuse bilateral infiltrates

Ejection fraction Normal, decreased Decreased

PA auscultation pressure 18 mmHg or less Greater than 18 mmHg

Pulmonary edema fluid Exudate Transudate

Fluid balance Positive, even, negative Positive

Response to diuretic Minimal Significant

White count Transient leukopenia Unchanged

BNP 1200 pg/ml

Leukocyte antibodies

Donor leukocyte antibodies present, crossmatch incompatibility between donor and recipient

Donor leukocyte antibodies may or may not be present, positive results can suggest TRALI even with true TACO cases

Skeate and Eastlund Curr Opin Hematol 2007; 14:6822015-APL-02503 48

Conditions That Mimic Transfusion-Related Acute Lung Injury With Symptoms and Circumstances That Help Distinguish Them

Condition Hints

Congestive heart failure,† acute left ventricular failure

History of congestive heart failure

Recent bypass surgery

Poor ejection fraction

Peripheral edema

Pleural effusions on chest x-ray or physical examination

Jugular venous distension on physical examination

Dilated superior vena cava on ultrasound

B-natriuretic peptide (BNP) > about 500 pg/mL

Pulmonary capillary wedge pressure > 18 mmHg

Distended pulmonary artery on chest x-ray

Cardiomegaly on chest x-ray

Response to diuresis

†Congestive heart failure is a chronic volume overload state, because heart failure induces fluid retention as a compensatory mechanism. The overlap in findings and symptoms with acute volume overload unrelated to heart failure is therefore not unexpected.

Table adapted from: Eder and Chambers Arch Pathol Lab Med 2007; 131:708

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Conditions That Mimic Transfusion-Related Acute Lung Injury With Symptoms and Circumstances That Help Distinguish Them

Condition Hints*

Acute circulatory (volume) overload

High-volume fluid infusion or transfusion over a short period

Elderly or very young patient

Increase in systolic blood pressure

Pre-existing chronic volume overload state (e.g.: renal failure, congestive heart failure)

Severe chronic anemia

Cardiomegaly on chest x-ray

Rales on pulmonary auscultation

Distended pulmonary artery on chest x-ray

Response to diuresis

Pulmonary embolism

Hypercoagulable state (e.g.: pregnancy, known thrombophiliasyndrome)

Immobility

Disseminated malignancy

No or little pulmonary edema on chest x-rayTable adapted from: Eder and Chambers Arch Pathol Lab Med 2007; 131:7082015-APL-02503 50

Conditions That Mimic Transfusion-Related Acute Lung Injury With Symptoms and Circumstances That Help Distinguish Them

Condition Hints*

Rapidly progressive pneumonia (especiallyviral or fungal)

Fever

High white blood cell count

Progression of infiltrates on chest x-ray

Patchy or lobar pattern of infiltrates on chest x-ray

Pre-existing diagnosis of pneumonia

Patient at risk for infection (e.g.: Neutropenic)

Adult respiratory distress syndrome (ARDS)/acute lung injury (ALI)

Underlying illness classically associated with ARDS/ALI such as:

• Sepsis (especially associated with pneumonia)• Shock• Disseminated intravascular coagulation• Multiple trauma

Progression or lack of resolution for 1-3 days

High mortality

No or little pulmonary edema on chest x-ray

Table adapted from: Eder and Chambers Arch Pathol Lab Med 2007; 131:708

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TRALI vs. TACO

Which of the following is not included in the diagnosis of TACO?A. Elevated JVPB. Increased or new pulmonary edemaC. Antibodies to HLA or neutrophilsD. Increased BNPE. Cardiomegaly

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TRALI vs. TACO

Which of the following is not included in the management of TACO?A. DiureticsB. OxygenC. Hold off on future transfusions for a whileD. Sitting uprightE. Vasopressors

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TRALI vs. TACO

Which of the following is NOT a symptom of TACO?A. DyspneaB. Back painC. CoughD. Chest tightnessE. Hypertension

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TRALI vs. TACO

Which of the following does not support the diagnosis of TRALI?A. Bilateral infiltrates on CXRB. Symptoms typically begin 1-2 hours after

transfusion and are fully manifest within 1-6 hoursC. Transient leukopenia, neutropenia,

monocytopenia, hypocomplementemiaD. Decreased BP in response to diureticsE. Frothy pink secretions from ETT

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TRALI vs. TACO

Which of the following is not included in the investigation or prevention of TRALI?A. Determine if donor has HLA or neutrophil

antibodiesB. Determine if recipient has corresponding antigen

to donor antibodiesC. Remove implicated donor from donor poolD. Universal leukoreduction of donor productsE. Transfuse male donor-only plasma

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TRALI vs. TACO

Which of the following is not included in the definition of TRALI?A. Hypoxemia B. Occurring 24 hours after transfusionC. Bilateral infiltrates on chest XRD. No pre-existing acute lung injury before

transfusionE. No evidence of TACO

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TRALI vs. TACO

Which of the following is not included in the proposed mechanisms for TRALI?A. Gram negative cocciB. Anti-HLA antibodiesC. Anti-neutrophil antibodiesD. Biologically active lipidsE. Cytokines

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Adverse Reaction Case Studies

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Case Study – Patient History

• 67 year old female with a history of multiple myeloma and TTP • Plasma exchange scheduled for next morning

• Transfusion service order received• Type & Screen• 4000 mL plasma

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Transfusion Services Result History

2015-APL-02503

Previous History

B positive

Nonreactive Antibody Screen

History of multiple RBC and plasma transfusions

Current Results

B positive

Nonreactive Antibody Screen

16 units B positive plasma prepared

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Transfusion Event

• The plasma exchange was completed and transportation was called to return the patient to the room, when the patient said she did not feel well. She complained of shortness of breath.

• An adverse reaction to the plasma was suspected• Patient’s Physician was paged• Transfusion Service was called

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Transfusion Event Timeline

• Post-transfusion nursing clerical check OK:

3)Patient armband

2)Product tag

1) Product label Patient first/last name Unique identification

number Blood unit number ABO/Rh

1230

Pre-Pooled Plasma (4000 mL)

10101000 125011001030 11301120 1150 1200 1230

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The nurse sent the following to the lab for investigation…

• all paperwork

• the bags from all 16 units of plasma

• administration set

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• No abnormalities• All accompanying IV solutions compatible

Adverse Reaction- Laboratory Investigation

Inspect product

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Adverse Reaction- Laboratory Investigation

• Post-transfusion laboratory clerical check OK:

3)Patient armband

2)Product tag

1) Product label Patient first/last name Unique identification

number Blood unit number ABO/Rh

Clerical check

Inspect product

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• Patient’s Pre-transfusionspecimen is clear and there is no evidence of hemolysis or icterus

Adverse Reaction- Laboratory Investigation

• Patient’s Post-transfusionspecimen is clear and there is no evidence of hemolysis or icterus

Compare specimens

Clerical check

Inspect product

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Adverse Reaction- Laboratory Investigation

Pre-transfusion Specimen

B positive

Nonreactive Antibody Screen

Polyspecific DAT nonreactive

Post-transfusion specimen

B positive

Nonreactive Antibody Screen

Polyspecific DAT nonreactive

Test specimens

Compare specimens

Clerical check

Inspect product

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Adverse Reaction Signs and Symptoms: REVIEW

Laboratory investigation: Clerical check (lab/nursing) identical No visual hemolyisis—serum or urine Pre- and post- sample testing identical DAT nonreactive

Pre-FFP transfusion

15 min Post-FFP transfusion

Blood Pressure (mmHg) 138/84 139/83 100/68

Pulse (beats/minute) 88 86 115Respirations(breaths/minute) 16 15 25

Temperature (oF/oC) 98.6 98.7 101oF/oCDyspnea and felt unwell

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Chest X-Ray

Anesthesia UK Website

Normal Patient

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Adverse Reaction: Transfusion Event

• After this x-ray was taken: • Patient required Oxygen

• Oxygen saturations 85% on 2L nasal cannula• Patient was subsequently intubated and admitted to

the ICU• Patient condition continued to deteriorate Patient expired on day 4

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Reaction Follow-Up

• TRALI reaction reported to blood supplier• Patient received 16 units of thawed plasma exhibiting

a reaction within 6 hours• Blood Supplier

• Determined 4 of 16 donors were at ‘risk’ for developing HLA antibodies

• All 4 ‘suspect’ donors were tested for HLA antibodies• One donor tested positive for HLA Granulocyte Class I

and II antibodies• This donor was permanently deferred

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Summary

TRALI and TACO have been documented for several decades

In the event of a transfusion reaction, the first thing to do is stop the transfusion

Prevention is best, but also recall that early recognition leads to better clinical outcomes

Understanding the profiles of TRALI versus TACO can not only expedite appropriate patient care but also helps the blood bank and blood provider be aware of transfusion-related complications

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References Andrzejewski CA, Popovsky MA, Stec TC. Measured and derived vital sign changes in transfusion reactions

associated with fluid challenges. Transfusion 2008;48 Suppl:204A Anesthesia UK Website Center for Biologics Evaluation and Research. Fatalities reported to FDA. Following blood collection & transfusion.

Annual summary for fiscal years 2005 and 2006. Rockville: CBER; 2008. Available from http://www.fda.gov/Cber/blood/fatal0506.htm

David B. Haemovigilance: a comparison of three national systems. 27th Congress of the International Society of Blood Transfusion, 24-29 August 2002, Vancouver.

Eder and Chambers Arch Pathol Lab Med 2007; 131:708 Flesland O.IntensiveCareMed.2007.Jun;33Suppl1S17-21 Gajic et al Crit Care Med 2006; 34:S109 Lieberman L et al. TransfusMedRev.2013.Oct27(4) Popovsky MA.Transfusion.1985.Nov25(6):573- 7. Popovsky et al Immunohematol 1996; 12:87 Popovsky MA, Audet A, Andrzejewski C. Transfusion-associated circulatory overload in orthopedic surgery

patients: a multi-institutional study. Immunohematology 1996;12:87-9. Rana et al Transfusion 2006; 46:1478 Rizk A, Gorson K, Kenny L, and Weinstein R: Transfusion-related acute lung injury after the infusion of IVIG.

Transfusion 2001; 41:264-268. Skeate and Eastlund Curr Opin Hematol 2007; 14:682

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