Case Studies: Fatal Piperacillin-Induced Immune Hemolytic Anemia

Case Studies: Fatal Piperacillin-Induced Immune Hemolytic Anemia
Lauren Eversmeyer PGY1 UCSF Pathology/Lab Medicine

Disclosures I have no relevant financial relationships to disclose

Drug-Induced Immune Hemolytic Anemia (DIIHA) Learning Objective
Review mechanisms of drug induced immune hemolytic anemia

Drug-Induced Immune Hemolytic Anemia (DIIHA) Outline
A patient’s clinical course Mechanisms Serologic findings Management Clinical lessons learned

The Patient 47 year-old man, homeless and paraplegic due to gunshot wound Presented to the ED with infected sacral decubitus ulcers Poor historian Had left AMA from another hospital’s ED a few hours earlier Other history: Almost died due to a transfusion reaction “my red and white cells fought” Recent renal failure due to reaction to an antibiotic, started on hemodialysis

Clinical Findings Vitals ↑ BP=143/92 mmHg ↑ Pulse=125/min Temp 36.8°C
Respirations 16/min ↑ WBC 21.9 x10E9/L (Neutrophils 17.9 x10E9/L) ↓Hemoglobin 8.5 g/dL ↓Hematocrit 24.4% Impression: Sepsis (infected ulcer, UTI, ?Endocarditis, C. difficile colitis)

Patient started on IV Vancomycin and Zosyn (Piperacillin + Tazobactam)
Ab Screen Patient started on IV Vancomycin and Zosyn (Piperacillin + Tazobactam) 7 AM 9 PM 9 AM I II I 3+ II I 1+ II W+ I II Vancomycin + Zosyn 8 RBC + 5 FFP PEA Arrest Hematocrit (%) He was started on IV Vancomycin + Zosyn for suspected sepsis. Antibody screen at time of admission was negative. 01:20 4:15 6:05 7:30 08:19 11:35 16:05 18:50 1:00 3:45 14:00 18:45 5/29 5/30 5/31

Photos courtesy of Dr. Dianna Ng
Spherocytes Profound anemia Erythrophagocytosis PEA Arrest Vancomycin + Zosyn Hematocrit (%) 1:30 AM Ab Screen 7 AM 9 PM 9 AM I II I 3+ II I 1+ II W+ I II 8 RBC + 5 FFP Over the next 24 hours he received 4 doses of Vancomycin and Zosyn He was found to be unresponsive with Pulseless arrest. He was resuscitated and transferred to the ICU but was non-responsive state. Blood samples drawn at that time showed gross hemolysis. His Hct was at 4.4 and then 3.5% at time of arrest. 01:20 4:15 6:05 7:30 08:19 11:35 16:05 18:50 1:00 3:45 14:00 18:45 5/29 5/30 5/31

Hematocrit (%) PEA Arrest Vancomycin + Zosyn 8 RBC + 5 FFP Ab Screen
1:30 AM Ab Screen 7 AM 9 PM 9 AM I II I 3+ II I 1+ II W+ I II Emergency release RBCs were requested. He was transfused a total of 8 red cell units over the next 12 hours. He also was transfused 5 units of plasma. After the RBC transfusions, his Hct remained stable around 31%. The differential for hemolysis included: secondary to sepsis-induced DIC, or possibly, autoimmune. 01:20 4:15 6:05 7:30 08:19 11:35 16:05 18:50 1:00 3:45 14:00 18:45 5/29 5/30 5/31

Drug-dependent antibody test (Vancomycin and Piperacillin)
1:30 AM Ab Screen/IAT: DAT: Vancomycin + Zosyn Eluate: Drug-dependent antibody test (Vancomycin and Piperacillin) 5/29 5/30 5/31 6/1 6/2 6/3 6/4 6/5 7 AM I II 3+ Poly 3+ IgG C3 W+ As part of the work up for his severe hemolysis and arrest, IAT and DAT were ordered. I II 5/29 5/30 5/31 6/1 6/2 6/3 6/4 6/5

Ab Screen/IAT: DAT: Vancomycin + Zosyn Eluate: Drug-dependent antibody test (Vancomycin and Piperacillin) Panel was pan-reactive (2+ to 3+) 5/29 5/30 5/31 6/1 6/2 6/3 6/4 6/5 1:30 AM 7 AM I II 3+ Poly 3+ IgG C3 W+ Both were positive. Antibody screen changed significantly from negative to 3+ positive. Panel was pan-reactive (2+ to 3+). I II 5/29 5/30 5/31 6/1 6/2 6/3 6/4 6/5

1:30 AM Ab Screen/IAT: 7 AM DAT: Vancomycin + Zosyn Eluate: Drug-dependent antibody test (Vancomycin and Piperacillin) Panel was pan-reactive (2+ to 3+) 5/29 5/30 5/31 6/1 6/2 6/3 6/4 6/5 I II 3+ Poly 3+ IgG C3 W+ The eluate was negative. Due to the severity of hemolysis, the rapid change in the antibody screen over 24 hours, and a negative eluate….drug-induced hemolytic anemia, rather than a new warm autoantibody was suspected. Sample was submitted to the reference lab in order to test for drug-dependent antibodies to vancomycin and piperacillin. I II 5/29 5/30 5/31 6/1 6/2 6/3 6/4 6/5

Review of the patient’s outside hospital records revealed some interesting findings….

Zosyn Hospital #1 #2 Zosyn Zosyn DAT: IgG (2+) and C3 (micro)
Hemoglobin (g/dL) RBC Hospital #1 #2 Zosyn Zosyn 5/5 5/7 5/12 5/16 5/19 5/23 5/26 5/29 RBC I 3+ II III 3+ I 3+ II III DAT: Negative Gel Screen: Gel Screen: They showed that earlier in the month he had been admitted to hospital #1 for infection. He received a few doses of Zosyn and then was switched to a different antibiotic for a few days due to no clinical improvement. His hemoglobin dropped from 10 to 5.6 over a few days. Type and screen and RBC units were ordered. Pan-reactive LISS panel Positive Auto-control Reference Lab #2 Reference Lab #1 DAT: IgG (2+) and C3 (micro) Elution NOT DONE (hx of warm autoAb) Warm AutoAb with anti-e specificity (patient is e-positive) No underlying alloAbs DAT positive for IgG and C3 Elution NOT DONE (no txn in prior 3 mo.) Warm AutoAb with no underlying AlloAbs

. Due to drop and RBC transfusions had been ordered.
Zosyn Gel Screen: Pan-reactive LISS panel Positive Auto-control RBC Hospital #1 . Due to drop and RBC transfusions had been ordered. . Due to drop in TYSC and RBC transfusions had been ordered. #2 Zosyn Zosyn 5/5 5/7 5/12 5/16 5/19 5/23 5/26 5/29 RBC Hemoglobin (g/dL) I 3+ II III 3+ I 3+ II III DAT: Negative Gel Screen: His antibody screen was 3+ with all 3 cells, and the panel was pan-reactive with a positive auto-control. So the sample was sent to Reference lab #1 for further work-up. Reference Lab #2 Reference Lab #1 DAT: IgG (2+) and C3 (micro) Elution NOT DONE (hx of warm autoAb) Warm AutoAb with anti-e specificity (patient is e-positive) No underlying alloAbs DAT positive for IgG and C3 Elution NOT DONE (no txn in prior 3 mo.) Warm AutoAb with no underlying AlloAbs

Reference Lab #1 DAT positive for IgG and C3 Elution NOT DONE (no txn in prior 3 mo.) Warm AutoAb with no underlying AlloAbs Hospital #1 . Due to drop and RBC transfusions had been ordered. . Due to drop in TYSC and RBC transfusions had been ordered. #2 Zosyn Zosyn Zosyn 5/5 5/7 5/12 5/16 5/19 5/23 5/26 5/29 RBC RBC Hemoglobin (g/dL) I 3+ II III 3+ I 3+ II III DAT: Negative Gel Screen: Gel Screen: Reference lab #1: DAT was positive for both IgG and C3. Elution was not performed since the patient had not been transfused in the prior 3 months. The pan-reactive panel was interpreted as a warm autoantibody, with no underlying alloantibodies detected after PEG autoadsorption. Pan-reactive LISS panel Positive Auto-control Reference Lab #2 DAT: IgG (2+) and C3 (micro) Elution NOT DONE (hx of warm autoAb) Warm AutoAb with anti-e specificity (patient is e-positive) No underlying alloAbs

Reference Lab #1 DAT positive for IgG and C3 Elution NOT DONE (no txn in prior 3 mo.) Warm AutoAb with no underlying AlloAbs Hospital #1 . Due to drop and RBC transfusions had been ordered. . Due to drop in TYSC and RBC transfusions had been ordered. #2 Zosyn Zosyn Zosyn 5/5 5/7 5/12 5/16 5/19 5/23 5/26 5/29 RBC RBC Hemoglobin (g/dL) I 3+ II III 3+ I 3+ II III DAT: Negative Gel Screen: Gel Screen: Zosyn was restarted 5 days after the last dose and he had an acute drop in Hgb from 8.3 to 3.5. Drug-induced hemolysis was suspected, so Zosyn was added to his list of medication allergies. Pan-reactive LISS panel Positive Auto-control Reference Lab #2 DAT: IgG (2+) and C3 (micro) Elution NOT DONE (hx of warm autoAb) Warm AutoAb with anti-e specificity (patient is e-positive) No underlying alloAbs

. Due to drop in TYSC and RBC transfusions had been ordered. #2
Reference Lab #1 DAT positive for IgG and C3 Elution NOT DONE (no txn in prior 3 mo.) Warm AutoAb with no underlying AlloAbs DAT: Negative Hospital #1 . Due to drop in TYSC and RBC transfusions had been ordered. #2 Zosyn Zosyn Zosyn . Due to drop and RBC transfusions had been ordered. 5/5 5/7 5/12 5/16 5/19 5/23 5/26 5/29 RBC RBC Hemoglobin (g/dL) I 3+ II III 3+ I 3+ II III Gel Screen: Gel Screen: 4 days later, his antibody screen was negative A few days after that, his DAT was also negative. Pan-reactive LISS panel Positive Auto-control Reference Lab #2 DAT: IgG (2+) and C3 (micro) Elution NOT DONE (hx of warm autoAb) Warm AutoAb with anti-e specificity (patient is e-positive) No underlying alloAbs

. Due to drop in TYSC and RBC transfusions had been ordered.
Reference Lab #1 DAT positive for IgG and C3 Elution NOT DONE (no txn in prior 3 mo.) Warm AutoAb with no underlying AlloAbs DAT: Negative Hospital #1 #2 . Due to drop in TYSC and RBC transfusions had been ordered. Zosyn Zosyn Zosyn . 5/5 5/7 5/12 5/16 5/19 5/23 5/26 5/29 RBC RBC Hemoglobin (g/dL) I 3+ II III 3+ I 3+ II III Gel Screen: Gel Screen: He left hospital #1 AMA, interrupting his course of IV antibiotics. A few days later, he presented to the emergency room of hospital #2 to get treatment for his wound infection. Pan-reactive LISS panel Positive Auto-control Reference Lab #2 DAT: IgG (2+) and C3 (micro) Elution NOT DONE (hx of warm autoAb) Warm AutoAb with anti-e specificity (patient is e-positive) No underlying alloAbs

Hospital #1 #2 Zosyn Zosyn Zosyn DAT: IgG (2+) and C3 (micro)
Reference Lab #1 DAT positive for IgG and C3 Elution NOT DONE (no txn in prior 3 mo.) Warm AutoAb with no underlying AlloAbs Hospital #1 #2 Zosyn Zosyn Zosyn 5/5 5/7 5/12 5/16 5/19 5/23 5/26 5/29 RBC RBC Hemoglobin (g/dL) I 3+ II III 3+ I 3+ II III DAT: Negative Gel Screen: Gel Screen: At hospital #2, Zosyn was given and his Hgb acutely dropped from 10 to 5.7. Type and screen and RBC units were ordered. Pan-reactive LISS panel Positive Auto-control Reference Lab #2 DAT: IgG (2+) and C3 (micro) Elution NOT DONE (hx of warm autoAb) Warm AutoAb with anti-e specificity (patient is e-positive) No underlying alloAbs

Reference Lab #1 DAT positive for IgG and C3 Elution NOT DONE (no txn in prior 3 mo.) Warm AutoAb with no underlying AlloAbs Hospital #1 #2 Gel Screen: Reference Lab #2 Zosyn Zosyn Zosyn 5/5 5/7 5/12 5/16 5/19 5/23 5/26 5/29 RBC RBC Hemoglobin (g/dL) I 3+ II III 3+ I 3+ II III DAT: Negative Gel Screen: The antibody screen showed all 3 cells were positive so the sample was sent to reference lab #2 for work up (different from the first ref lab). Pan-reactive LISS panel Positive Auto-control DAT: IgG (2+) and C3 (micro) Elution NOT DONE (hx of warm autoAb) Warm AutoAb with anti-e specificity (patient is e-positive) No underlying alloAbs

5/5 5/7 5/12 5/16 5/19 5/23 5/26 5/29 RBC RBC Hemoglobin (g/dL) Reference Lab #1 DAT positive for IgG and C3 Elution NOT DONE (no txn in prior 3 mo.) Warm AutoAb with no underlying AlloAbs Gel Screen: Reference Lab #2 DAT: IgG (2+) and C3 (micro) Elution NOT DONE (hx of warm autoAb) Warm AutoAb with anti-e specificity (patient is e-positive) No underlying alloAbs I 3+ II III 3+ I 3+ II III DAT: Negative Gel Screen: Reference lab #2 = DAT was 2+ and complement microscopically positive. Elution was not done. Since he HAD received multiple units of RBCs in the last month, the reason for not doing an eluate was due to his history of a warm autoantibody per Ref Lab#1’s recent work up. The panel was negative in LISS, but showed anti-e pattern with PEG. Since the patient was e-positive, this was interpreted as a warm autoantibody with anti-e specificity. Pan-reactive LISS panel Positive Auto-control

Back to his current admission at Hospital #3…

+ Zosyn 5/29 5/30 5/31 6/1 6/2 6/3 6/4 6/5 Ab Screen/IAT: 1:30 AM 7 AM 9 PM 9 AM 9 PM 9 AM I II 3+ 1+ W+ 4:30 AM Poly 3+ IgG C3 W+ 3+ 2+ 1+ 2+ 1+ 2+ W+ W+ DAT: Eluate: His antibody screen became non-reactive about 24 hrs after his last dose of Zosyn. The DAT was negative 6 days later, and was presumably negative earlier but had not been checked. I II 5/29 5/30 5/31 6/1 6/2 6/3 6/4 6/5 DAT: 4+ IgG, 1+ C3, microscopic IgM, no IgA Drug-dependent antibody test (Vancomycin and Piperacillin) POSITIVE for Piperacillin antibodies in serum and eluate

+ Zosyn 5/29 5/30 5/31 6/1 6/2 6/3 6/4 6/5 Ab Screen/IAT: 1:30 AM Drug-dependent antibody test (Vancomycin and Piperacillin) 7 AM 9 PM 9 AM 9 PM 9 AM I II 3+ 1+ W+ 4:30 AM Poly 3+ IgG C3 W+ 3+ 2+ 1+ 2+ 1+ 2+ W+ W+ DAT: Eluate: The work up from Ref lab #3 showed: Drug-dependent antibody testing positive for piperacillin antibodies in both the serum and the eluate. The DAT was strongly positive: 4+ with IgG, 1+ with C3, and microscopically positive for IgM. I II 5/29 5/30 5/31 6/1 6/2 6/3 6/4 6/5 DAT: 4+ IgG, 1+ C3, microscopic IgM, no IgA POSITIVE for Piperacillin antibodies in serum and eluate

Clinical Outcome Anoxic brain injury, poor prognosis
Discharged to a rehab facility at request of family Died 3 months after discharge

How often do we see Drug-Induced Immune Hemolytic Anemia (DIIHA)?
It is very rare. Autoimmune hemolytic anemia (AIHA) occurs in about 1 in 100,000 of the population Drug-induced immune hemolytic anemia (DIIHA) occurs in about 1 in 1,000,000 of the population Most reports are of severe hemolytic anemia It is possible there are a number of less severe cases that are not identified Blood Reviews ;

Drugs Commonly Involved
Anti-microbials (40%) Anti-inflammatory (13%) Anti-neoplastic (13%) Diuretic/Anti-hypertensive (6%) Most common seen in one lab over 30 years = piperacillin, cefotetan, ceftriaxone Most commonly associated with fatal HA = cefotetan and ceftriaxone Blood Reviews ; Immunohematology ;2

Drug-Independent antibodies (DIABs) Drug-Dependent antibodies (DDABs)
DIIHA Mechanisms Drug-Independent antibodies (DIABs) Drug-Dependent antibodies (DDABs) Immunohematology ;2

Drug-Independent Antibodies (DIABs)
Drug does NOT need to be present for in vitro detection The drug stimulates the immune system to make AUTO-antibodies against red blood cells Possibly by molecular mimicry, drug adsorption causing altered RBC membrane protein antigens, and immune dysregulation. Serologically indistinguishable from Warm autoimmune hemolytic anemia (WAIHA) Clinically, resolves after stopping the drug, and returns if drug taken again. Positive antibody screen Positive ID panel Positive autocontrol Positive DAT Positive Eluate Immunohematology ;2

Drug-Independent Antibodies (DIABs)
Historically, methyldopa was the most common cause. Fludarabine is currently the most common drug to lead to drug-induced WAIHA. Used as treatment in some chronic lymphocytic leukemia (CLL/SLL) patients Note that many patients with hematologic malignancy can have a positive DAT and/or hemolytic anemia prior to treatment. Webmd.com Am J Clin Pathol 2011;136:7

Drug-Dependent Antibodies (DDABs)
Drug binds to surface of RBCs and stimulates immune system to make antibodies against either: An epitope on the drug alone OR an epitope created from drug and RBC membrane. Blood Reviews ;

Drug-Dependent Antibodies Reactive with Drug-Treated RBCs
Drugs like penicillin, ampicillin and some cephalosporins can covalently bind to red cells This makes it possible to coat the red cells with the drug in the lab and Eluate Add eluate Blood Reviews ;

Drug-Dependent Antibodies Reactive with Untreated RBCS in the Presence of Drug
(Or enzyme-treated) and Eluate Testing for drugs such as piperacillin and ceftriaxone Drug or metabolite must be present in vitro for the antibody in the patient’s serum to be detected Immunohematology ;2

Drug-Dependent Antibodies Reactive with Untreated RBCS in the Presence of Drug Initial Serologic Findings If there is NOT sufficient circulating drug If sufficient drug is circulating in patient’s plasma Then it is POSSIBLE to have Negative antibody screen Negative ID panel Whether the antibody screen is positive or not depends on there being enough circulating drug, the properties of the drug and how it interacts with red blood cell membranes. Positive antibody screen Positive ID panel Am J Clin Pathol 2011;136:7

Blood Group Specificities of Drug Antibodies
A rare finding First report was in 1977 with a streptomycin antibody having Rh specificity Described since 1984 for piperacillin antibodies Immunohematology ;2

Blood Group Specificities of Drug Antibodies
A rare finding First report was in 1977 with a streptomycin antibody having Rh specificity Described since 1984 for piperacillin antibodies **Our patient: Reference Lab#2 work up indicated a Warm autoantibody with anti-e specificity. Immunohematology ;2

Drug-Independent DIIHA
Serologic Findings Hemolytic anemia & Positive DAT Eluate positive Eluate negative Suspicious for: Warm autoimmune HA Drug-Independent DIIHA Suspicious for: Drug-Dependent DIIHA Send to Reference Lab Am J Clin Pathol 2011;136:7

Serologic Findings Our Patient
Sufficient piperacillin was circulating in plasma Positive antibody screen Positive ID panel Hemolytic anemia & Positive DAT Our Patient Eluate positive Eluate negative Add anti-e specificity Make the eluate pos part transparent Suspicious for: Warm autoimmune HA Drug-Independent DIIHA Suspicious for: Drug-Dependent DIIHA Send to Ref Lab Am J Clin Pathol 2011;136:7

Management of DIIHA Primary treatment: Secondary treatment:
Stop the Drug! Hematologic recovery should occur within 2 weeks Transfuse if patient is sufficiently anemic Secondary treatment: Steroids (minimal evidence for efficacy) Plasma exchange – if acute intravascular hemolysis has occurred and the drug has been previously associated with fatalities. (ASFA Category III for severe WAIHA) Preventative: This drug becomes a “severe allergy” for the patient and they are warned to NEVER receive the offending agent. Journal of Clinical Apheresis 31:149–338 [p ] (2016) Am J Clin Pathol 2011;136:7

Lessons Learned A precipitous drop in Hgb/Hct should at least raise suspicion for drug-induced antibodies. Some drug antibodies may present like warm autoantibodies with pan-reactive panels and positive autocontrol/DAT. Warm autoantibodies usually have positive pan-reactive eluates. In contrast, drug antibodies often have a negative eluate.

Changes Made to Transfusion Service
All provider-ordered DATs will have an elution performed. If a provider orders a DAT and the reaction 2+ or stronger with a negative eluate, the Transfusion Service MD is notified to review chart for drug-induced hemolysis potential. When a patient has a pan-reactive plasma panel with positive autocontrol and DAT, it is NOT reported as a warm autoantibody unless the eluate is also pan-reactive. ~ If eluate is negative, case is reviewed by Transfusion Service MD.

This case highlights the need for…
Better integration of electronic medical records across multiple institutions. A better way of being sure the patient knows and understands the importance of having a severe drug allergy. Some means of allergy identification carried by the patient, such as the wallet cards given for alloantibodies

Thank you Dr. Morvarid Moayeri, UCSF Transfusion Medicine
Dr. Dianna Ng, UCSF Pathology Dr. Ashok Nambiar and Dr. Sara Bakhtary, UCSF Transfusion Medicine Dr. Elizabeth St. Lezin, SFVAMC Transfusion Medicine

Journal of Clinical Apheresis 31:149–338 (2016)
Guidelines on the Use of Therapeutic Apheresis in Clinical Practice—Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Seventh Special Issue. Joseph Schwartz et al. Journal of Clinical Apheresis 31:149–338 (2016)

Case Studies: Fatal Piperacillin-Induced Immune Hemolytic Anemia

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Case Studies: Fatal Piperacillin-Induced Immune Hemolytic Anemia

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