Febrile Non-Hemolytic Transfusion Reaction

Febrile nonhemolytic transfusion reaction is a temperature rise of at least 1 degree Celsius above baseline to 38 degrees Celsius or higher, during or within 4 hours of a transfusion, without hemolysis, infection or another cause. It is the commonest transfusion reaction. It occurs in about 0.1 to 1% of red cell transfusions and 1 to 3% of platelet transfusions, and is more frequent in patients who have been transfused many times or have been pregnant.

Two mechanisms operate

• Recipient anti-leukocyte antibodies (against HLA or granulocyte antigens) react with donor white cells and release pyrogenic cytokines
• Cytokines accumulated in stored components (IL-1 beta, IL-6, IL-8 and TNF alpha), especially in platelets stored for several days at room temperature

Removal of white cells before storage (prestorage leukoreduction) reduces the rate by more than half. The reaction is benign and self-limiting, but it is a diagnosis of exclusion, because fever may be the first sign of a hemolytic reaction or bacterial contamination. Complications: recurrence with later transfusions and unnecessary interruption of treatment.

• Temperature rise, chills and rigors, headache, mild nausea and tachycardia, starting 30 minutes to 4 hours after the start of transfusion and sometimes after it ends
• Blood pressure stable, no hemoglobinuria, no flank or infusion site pain
• Fever usually settles within 2 to 6 hours
• Red flags: temperature of 39 degrees Celsius or higher, a rise of 2 degrees Celsius or more, hypotension, severe rigors, dyspnea, back pain, dark urine, and onset within 15 minutes of starting

1. Stop the transfusion and examine the patient: vital signs, urine color, chest and abdomen.
2. Clerical check of the unit and patient identity.
3. Exclude hemolysis: visual check of the post-transfusion plasma color, direct antiglobulin test and repeat ABO group.
4. Exclude bacterial contamination when fever is 39 degrees Celsius or higher, hypotension is present or the patient is septic: blood cultures from the patient and Gram stain and culture of the bag.
5. Exclude other reactions: oxygen saturation and chest radiograph for lung injury and circulatory overload, tryptase for anaphylaxis if urticaria or wheeze.
6. Review the underlying illness (infection, drug fever, malignancy) as an alternative cause.

Differentials: acute hemolytic reaction, bacterial contamination of the unit, transfusion-related lung injury, anaphylaxis, sepsis, drug fever.

1. Stop the transfusion and keep the line open with 0.9% saline.
2. Antipyretic: paracetamol 1 g orally or IV once, up to 4 g in 24 hours (children 15 mg/kg, maximum 1 g).
3. Severe rigors: pethidine 25 mg IV once (children 0.5 to 1 mg/kg, maximum 25 mg), avoided in patients on monoamine oxidase inhibitors. Warm blankets.
4. Antibiotics only when there is hypotension, fever of 39 degrees Celsius or higher, or suspicion of infection: piperacillin-tazobactam 4.5 g IV every 6 hours (children 100 mg/kg of piperacillin every 8 hours) after cultures, and stop when cultures are negative at 48 hours.
5. Resuming transfusion: only after hemolysis and contamination are excluded and the fever is settled, using a new unit and a slower rate (starting at 1 mL/kg/h for the first 15 minutes).
6. Prevention in patients with recurrent reactions:
   • Prestorage leukoreduced red cells and platelets.
   • Platelets in additive solution or washed platelets.
   • HLA-matched or crossmatch-compatible platelets when HLA antibodies are present.
   • Paracetamol 1 g orally 30 minutes before the next transfusion (routine premedication does not prevent reactions and can mask the first sign of a serious one, so it is reserved for repeated reactions).
   • Slow transfusion rate and close observation during the first 15 minutes.
7. Documentation and reporting to the transfusion laboratory.

No follow-up is needed once recovered. Counsel patients who are transfused regularly that fever may recur and that it should always be reported at once.