1	Transfusion Complications Seeing the Forest Through the Trees Claire E. Meena-Leist, M.D. Chief Medical Officer American Red Cross Blood Services Crossroads of America Division
2	Case # 1 75 year old male received three units of RBCs over two days Due to a post video assisted lung thoracic surgery (VATS) and pleural biopsy procedure Diagnosed with malignant mesothelioma
3	Case #1 Subsequent to the transfusion, he experienced Cyclic fevers Kept meticulous records of his fever cycles Nausea/vomiting Shaking chills
4	Case #3 Initial diagnosis of P. falciparum was made by peripheral blood smear Not often an easy diagnosis…
5	Case #1 Diagnostic Plasmodium falciparum slide Characteristic signet rings and “banana” shaped gametocyte
6	Interesting Case #1 Transferred to a large medical center Slides re-read as….
7	Case #1 Babesiosis!! Polymorphic, ring-like organisms closely resembling P. falciparum Mature forms often have a Maltese cross pattern
8	Case #1
9	Case #1 Babesiosis Babesiosis is the number one reported transfusion transmitted tick-borne pathogen in endemic areas The odds of contracting babesiosis are estimated at 1:100,000 transfused red blood cells
10	Case #1 Babesiosis It is caused by the intra-erythrocytic parasite, Babesia microti Transmitted by Ixodes scapularis, The same tick vector which carries Borrelia burgdorferi (the spirochete which causes Lyme Disease).
11	Case #1 The patient had no other risks for babesiosis infection other than transfusion The three blood donors were investigated Two donors gave no significant history The third donor reported working as the Ecology Director at a scout reservation and hiked several miles daily, often through narrow wooded trails. He recalls being bit by several ticks but he did not experience any symptoms prior to his donation two months following the tick bites.
12	Babesiosis The donors with no significant history tested negative by immunofluorescent assay (IFA) for IgG and IgM antibodies against B. microti A sample of the hiker’s blood indicated past infection positive by IFA for IgG 1:128; reference range <1:16 = antibody not detected and negative by IFA for IgM <1:20;reference range <1:20 = antibody not detected.
13	Babesiosis At present there is no licensed test to screen blood donations for B. microti Only a known risk of babesiosis will defer a donor It’s been suggested that donor-reported tick bites be used as a deferral but implementing such criteria is estimated to defer up to 9% of blood donors Not acceptable
14	Babesiosis Physicians should be aware! The risk of contracting babesiosis through a RBC transfusion is roughly twenty times greater than of contracting HIV Physicians should have a high degree of clinical suspicion in persons having characteristic clinical findings
15	Transfusion Transmitted Babesiosis – Often Misdiagnosed? C Meena-Leist, ARC, Louisville, KY; B. Farrah, OSU, Columbus, OH; P. Para OSU, Columbus, OH, C Kiel, ARC, Ft. Wayne, IN; C. Thomas, ARC Ft. Wayne, IN; P Ball, ARC, Ft. Wayne, IN; T Deibold, ARC, Louisville, KY; WB Lockwood, UofL, Louisville, KY Transfusion, Vol.47, No.3S, September 2007 Supplement, pg 211A
16	Case #2 In a perfect world… 65 year old male with a history of severe liver disease with PT/PTT significantly above normal admitted for an invasive procedure 2 units of FFP ordered 15 minutes into the first unit he developed an increase in temperature, shortness of breath, decrease in BP, increase in pulse
17	Case #2 Respiratory distress worsens and he is eventually intubated CXR reveals bilateral pulmonary edema A trial of Lasix is unsuccessful He eventually recovers
18	Case #2 The case is reported to the ARC The donor is a female with a history of 4 previous pregnancies A sample of her blood reveals HLA Type I antibodies A diagnosis of …………….is made The donor is deferred from future donations There are no special transfusion recommendations for the patient
19	TRALI Transfusion Related Acute Lung Injury
20	TRALI Classic Definition First Recognized as a distinct clinical entity by Popovsky et al in 1983 Initially called non-cardiogenic pulmonary edema Classically characterized by respiratory distress that is difficult to distinguish from ARDS
21	TRALI Census Conference Canada 2004 “A new episode of acute lung injury (ALI) that occurs during or within 6 hours of a completed blood transfusion which is NOT temporally related to a competing etiology of ALI.”
22	TRALI Census Conference Canada 2004 TRALI is a clinical and radiographic diagnosis It is NOT dependent on the results of lab tests TRALI is considered a clinical syndrome
23	TRALI Census Conference Canada 2004 TRALI CRITERIA ALI Acute Onset Hypoxia PaO₂/FIO₂< 300 or SPO2<90% on room air or other clinical evidence of hypoxemia Bilateral infiltrates on frontal CXR No evidence of left atrial HTN (i.e. circulatory overload) No preexisting ALI before transfusion During or w/in 6 hr of transfusion >90% of cases within 1-2 hours* 100% of cases within 6 hours* No temporal relationship to an alternative risk factor for ALI *Popovsky MA & Moore SB. Transfusion 1985;25:573-577
24	TRALI Census Conference Canada 2004 “Possible” TRALI Criteria ALI No preexisting ALI before transfusion During or w/in 6 hr of transfusion A clear temporal relationship to an alternative risk factor for ALI
25	Acute Lung Injury Risk Factors Indirect Lung Injury Severe Sepsis Shock Multiple trauma Burn injury Acute pancreatitis Cardiopulmonary bypass Drug overdose Transfusion 2004:44:1774-1789 Direct Lung Injury Aspiration Pneumonia Toxin inhalation Lung contusion Near drowning
26	TRALI Clinical Presentation Severe Dyspnea Hypoxemia Pulmonary Edema Hypotension Fever Mild Dyspnea Fever
27	TRALI Clinical/Laboratory Features Webert K and Blajchman TMR 2003:17
28	TRALI Clinical Features Continued Hypotension does not respond to IV Fluids Rales and diminished breath sounds No Fluid Overload Normal jugular venous pressure Absent S3 Normal/low pulmonary wedge pressure BNP not elevated
29	TRALI Implicated Blood Products Most Frequent RBC’s FFP Platelets (apheresis and random donor) Infrequent Cryoprecipitate IVIG No other plasma derivatives have been implicated
30	Incidence of TRALI 1982 -1985: 1:5,000 plasma-containing transfusions Mayo Clinic Specially trained nurses administer non-operating room transfusions Current incidence unknown #1 cause of transfusion death Hemolytic transfusion reactions (ABO mismatch) vs. bacterial contamination vs. TRALI Evidence of under-recognition and under-reporting Mark Popovsky, M.D, AABB Audio Conference March 16, 2005
31	FDA-reported Fatalities:
32	TRALI Mortality Rate 5-10% is most commonly quoted Range in literature is from 6-23%
33	Differential Diagnosis of Transfusion Associated Respiratory Distress TRALI Transfusion Associated Circulatory Overload (TACO) Allergic/Anaphylactic transfusion reaction IgA Deficiency Acute hemolytic reaction Bacterial contamination
34	Differential Diagnosis Transfusion-Associated Cardiac Overload (TACO) Rapid administration/excessive volume Signs of CHF Dyspnea Engorged neck veins Increased BP Pulmonary rales Elevated BNP May appear during or up to 24 hours after transfusion
35	TRALI vs TACO
36	Differential Diagnosis Anaphylactic Reaction Severe allergic reactions to transfused plasma components IgA Deficiency Absence of Fever Premedication! Can occur with as little as 5 mL of blood Good nursing is critical!!! Other symptoms Flushing, puritis, wheezing, hypotension, abdominal pain
37	Differential Diagnosis Hemolytic Transfusion Reactions (HTN) Intravascular HTN Complement activation ABO mismatch Fever, chills, shock, DIC, back pain, hemoglobinemia, hemoglobinuria, chest pain, oliguria Transfusion reaction work-up will help rule in/out
38	Differential Diagnosis Bacterial Contamination Most frequent signs/symptoms Fever Chills/Rigors Hypotension Less respiratory distress Gram stain/culture
39	Differential Diagnosis of Transfusion Associated Respiratory Distress TRALI Transfusion Associated Circulatory Overload (TACO) Allergic/Anaphylactic transfusion reaction IgA Deficiency Acute hemolytic reaction Bacterial contamination
40	TRALI Pathogenesis Antibody Hypothesis Donor Ab: Recipient Ag (or reverse) PMN mediated alveolar capillary endothelial damage 2 Event Hypothesis (aka Neutrophil Priming Hypothesis) Recipient: Underlying system illness Donor Unit: Bioactive mediators PMN mediated alveolar capillary endothelial damage Dr. Brian Berry AABB Audio Conference March 16, 2005
41	Pathogenesis Noxious Agents Antibodies HLA I HLA II Anti-granulocyte HNA -3a Anti-Monocyte Biologically Active Mediators Lysophosphatidycholines Neutral Lipids Dr. Brian Berry AABB Audio Conference March 16, 2005
42	Pathogenesis
43	A03-35: Lung 400x
44	TRALI Work-Up TRALI IS A CLINICAL DIAGNOSIS Accurate and timely case reporting Consultation with the blood bank and blood center CXR BNP Blood bank work up Pre/post ABO negative Pre/post DAT negative Post plasma sample no visual hemolysis Stat gram stain negative
45	TRALI Work-Up Recipient Sample Plasma/cellular sample HLA I/II typing Frozen sample stored Consider HLA Granulocyte Ab testing Donor Sample Freeze plasma from spent bags HLA I/II Ab’s Granulocyte Ab’s Female tested first Donors closest to the time of reaction
46	Donor and Patient Management Donor Implicated donors are indefinitely deferred Patient No “special” management for future transfusions No need to wash products
47	Case #2 Actual world… Making dinner when my cell phone rings A minute into the call my son gets “the look,” meaning grab a reduced fat cheese stick and a bag of carrots, this is going to be a while…
48	Case #2 Actual world… 65 year old male with a history of 2 cardiac stents placed 2 years ago. Stable, on no cardiac meds or physical restrictions. Automatic admit to the hospital from doc’s office; not quite sure why. No pre-admit CXR. Going for some sort of procedure; 2 units of FFP and a unit of RBC’s ordered; again, no further history.
49	Case #2 Actual world… Received both units of FFP without incidence About 7 hours later received the unit of RBC’s An hour after the infusion of RBC’s his BP fell, pulse increased, and he developed shortness of breath; he was not febrile His respiratory distressed progressed to having to be admitted to the ICU; we think he was not intubated
50	Case #2 Actual world… Attending reported it directly to the lab with a diagnosis of TRALI Some question of pneumonia on CXR and the attending also though the patient could have sepsis but wanted to report it to the BB as TRALI to ensure the donor was deferred from future donations
51	Case #2 Actual world… Advice to the Pathologist Get a better admitting history Get a copy of the CXR report Did they order a BNP? Higher than normal results suggest the patient is in heart failure (which would NOT be consistent with a diagnosis of TRALI) Did they order Lasix and, if so, what were the results? Verify timing of reactions Did they pre-medicate the patient with Tylenol?
52	Case #2 Actual world… Admitting history made sense (cannot remember the details) CXR report indicated left lower lobe infiltrate consistent with pneumonia BNP was not elevated They did order Lasix and the patient did diurese Unsure of the premedication issue, but the patient could have had steroids in the treatment of the reaction (possibly masking a fever)
53	Case #2 Actual world… My advise NOT TRALI CXR revealed pneumonia and the attending thought it could be sepsis. Needed blood cultures, (quick Gram stain) Report to ARC? No
54	Case #3 79 year old male received approx 40 ml of RBC’s. 32 minutes into the transfusion he developed symptoms of nausea/vomiting, dyspnea and neck pain ARC form marked as follows: “Probably not related to the blood transfusion” “Suspected cause is possible exaggeration of dyspnea in a patient who already had symptoms of CHF”
55	Case #3 Was the transfusion the cause of the reaction? Was it TRALI? Did the case need to be reported to ARC?
56	Case #4 67 year old female undergoing chemotherapy for ovarian carcinoma 2 units FFP and one unit RBC’s ordered 10 minutes into the first unit of FFP the woman experienced SOB, fever, increase pulse, decrease BP Respiratory symptoms worsened, requiring intubation
57	Case #4 CXR 30 minutes into the reaction revealed fluffy bilateral infiltrates She did not respond to Lasix A BNP was not ordered Eventually she recovered She had no history of cardiac or lung disease; previous CXR’s were unremarkable
58	Case #4 The donor was a 24 year old female. She did not report a history of transfusion/transplant or pregnancy Samples were sent for testing There was no evidence of HLA or Granulocyte antibodies
59	Case #4 Diagnosis?? Management of donor and patient?
60	Case #5 48 year old male with a history of carcinoma of the prostate Three hours after infusion of one unit of RBC’s he developed severe respiratory distress, fever, increase in BP, increase in pulse Respiratory distressed worsened He was admitted to ICU and intubated
61	Case #5 CXR revealed bilateral infiltrates Discovered he received approximately 2 liters of fluid in a 12 hour period and responded to a dose of IV Lasix Donor is a 34 year old female first time donor with a history of 2 pregnancies A sample of her serum revealed HLA type II antibodies
62	Case #5 Diagnosis? Management of donor/patient?
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