Transfusion medicine

Transfusion reactions & complications

Febrile nonhemolytic

Editorial Board Member: Patricia Tsang, M.D., M.B.A.
Hanqiao (Ciao) Zheng, M.D., Ph.D.
Reggie Thomasson, M.S., M.D.

Last author update: 27 August 2020
Last staff update: 1 February 2022

Copyright: 2002-2023,, Inc.

PubMed Search: Febrile nonhemolytic transfusion reaction pathology

Hanqiao (Ciao) Zheng, M.D., Ph.D.
Reggie Thomasson, M.S., M.D.
Page views in 2022: 1,484
Page views in 2023 to date: 498
Cite this page: Zheng H, Thomasson R. Febrile nonhemolytic. website. Accessed June 8th, 2023.
Definition / general
  • Acute reaction that occurs during or within 4 hours of cessation of blood product transfusion
  • Otherwise unexplained fever ≥ 38 °C (100.4 °F) and a change of at least 1 °C (1.8 °F) from pretransfusion value or chills / rigors
Essential features
  • Common acute transfusion reaction, roughly 0.62% of transfusions (Transfusion 2016;56:2587)
  • Important to treat as possible serious transfusion reaction (hemolytic, TRALI, etc.) until workup is complete, as these symptoms are identical (fever, chills / rigors, vital signs changes)
  • Most common complication of platelet transfusion (115.3 FNHTRs per 100,000 components transfused)
  • Incidence depends on
    • Extent of reporting (active versus passive)
    • Type of product transfused (platelet, red blood cell)
    • Blood product modifications (leukocyte reduced, platelet additive solution, washed)
    • Patient risk factors (higher risk in patients with hematologic disease and HLA alloimmunization from prior transfusions or pregnancy)
    • Pretreatment of recipients with antipyretics
  • Signs and symptoms must occur within 4 hours of transfusion
  • Reaction due to cytokine release most commonly by activated donor leukocytes
  • Diagnosis of exclusion
    • Unrelated to underlying medical conditions
    • Other transfusion reactions (hemolysis, sepsis, transfusion related acute lung injury, etc.) ruled out
  • Direct antiglobulin test (DAT) / Coombs test
  • Febrile type reaction
  • Febrile nonhemolytic transfusion reaction (FNHTR)
  • Human leukocyte antigen (HLA)
  • Human platelet antigen (HPA)
  • Leukocyte reduced / leukoreduction (LR)
  • Platelet additive solution (PAS)
  • Platelet (PLT)
  • Red blood cell (RBC)
  • Transfusion related acute lung injury (TRALI)
  • Pyrogenic / inflammatory cytokines (e.g. IL1β, IL6, TNFα) released from activated leukocytes, commonly from donor during product storage
  • Cytokines lead to production of prostaglandin E2, causing the hypothalamus to increase the body temperature
    • Nonimmune mediated usually associated with platelet transfusions
      • Passive transfusion of accumulated inflammatory cytokines in the plasma of the transfused unit
    • Immune mediated usually associated with red blood cell transfusions
      • 2 general mechanisms:
        • Recipient antibodies (mainly anti-HLA) activates donor leukocytes to release cytokines
        • Recipient leukocytes are activated to release cytokines by immune complexes formed from recipient antibodies and donor leukocytes
      • Other non-HLA antibodies have been implicated, including those directed against human platelet antigens (Clin Chim Acta 2017;474:120)
Clinical features
  • Not a life threatening condition
  • See symptoms below
  • No specific tests available
  • Reaction workup negative (clerical check, direct antiglobulin test, visual hemolysis inspection, ABO confirmation)
  • Hemolysis laboratory markers unremarkable
  • Bacterial contamination ruled out
Case reports
  • 19 year old woman with thalassemia and asymptomatic malaria has an unusual manifestation of delayed febrile posttransfusion reaction mimicking FNHTR (Transfusion 2011;51:469)
  • 64 year old man with history of allogeneic hematopoietic stem cell transplantation with complication after receiving 1 red blood cell unit (Transfus Med Hemother 2019;46:384)
  • Stop transfusion immediately
  • Notify blood bank / transfusion medicine service for reaction workup (direct antiglobulin test, visual inspection for hemolysis, etc.)
  • Close observation with frequent vital signs
  • Fever usually self limiting
  • Antipyretics (e.g. acetaminophen) for symptom relief
  • Meperidine for severe reactions with rigors
  • Reference: Lancet 2016;388:2825
Sample assessment & plan
  • Assessment: Jane Doe is a 26 year old female¬†with a history of menorrhagia, anemia and mild fatigue. She received 1 unit of red blood cells that was well tolerated with stable vital signs throughout. 30 minutes after completion, she spiked a temperature of 101.3 °F with no other complaints. She was given acetaminophen and blood bank was notified for a transfusion reaction workup. The clerical check revealed no incompatibility. Direct antiglobulin test and antibody screening were both negative with an unremarkable visual inspection for hemolysis. Her temperature returned to baseline (98.9 °F) within 1 hour. The reaction is most appropriately classified as a febrile nonhemolytic reaction with no clinical sequelae.
  • Plan: Ms. Doe is cleared for additional blood product transfusions if clinically indicated. May consider pretreatment with acetaminophen prior to future transfusions. Please continue to report any suspected transfusion reactions to the blood bank.
Differential diagnosis
  • Hemolytic transfusion:
    • Hemoglobinemia, hemoglobinuria, hypotension, flank pain, pain at needle site, unexpected bleeding
    • Lab tests consistent with hemolysis
  • Septic transfusion reaction:
    • High and persistent temperature (temperature increase ≥ 2 °C)
    • Signs of bacterial infection
    • Unit culture positive
  • Transfusion related acute lung injury:
    • Hypoxemia
    • Radiographic evidence of bilateral lung infiltration
Board review style question #1
A 61 year man with end stage renal failure who received kidney transplantation 1 year ago was transfused 1 unit of red blood cells. About 1 hour into the transfusion, he complained of chills. The transfusion was stopped immediately. Upon examination, he appears uncomfortable. His vital signs are as follows: heart rate 78 beats/min, blood pressure 140/80 mmHg, respiratory rate 17/min, temperature 100.9 °F, SaO2 98%. His pretransfusion vital signs are heart rate 76 beats/min, blood pressure 145/80 mmHg, respiratory rate 18/min, temperature 98.9 °F, SaO2 99%. Transfusion workup confirms that he was transfused an ABO identical RBC unit, serum was pale yellow, DAT negative. Which of the following is the most likely cause of his symptoms?

  1. Febrile nonhemolytic transfusion reaction
  2. Hemolytic transfusion reaction
  3. Septic transfusion reaction
  4. Transfusion related acute lung injury
Board review style answer #1
A. Febrile nonhemolytic transfusion reaction

Comment Here

Reference: Febrile nonhemolytic transfusion reaction (FNHTR)
Board review style question #2
The previous patient was given a blanket to keep warm. His symptoms resolved an hour later. Which of the following blood product modifications would be the most effective way to decrease the possibility of the same type of transfusion reaction in the future?

  1. Leukocyte reduction before storage
  2. Leukocyte reduction before the transfusion
  3. Radiating the product
  4. Washed product
Board review style answer #2
A. Leukocyte reduction before storage

Comment Here

Reference: Febrile nonhemolytic transfusion reaction (FNHTR)
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