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Febrile Nonhemolytic Reactions

Febrile nonhemolytic transfusion reactions (FNHTR) are the most common type of transfusion reaction reported to the blood bank. Because their symptoms of fever and chills also occur with acute hemolytic reactions, it is essential to evaluate all such reactions immediately.

Most febrile reactions that occur during transfusion of red blood cells are caused by the interaction of leukocyte antibodies in the recipient’s plasma with donor leukocytes, stimulating the release of pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF). Patients who have had multiple prior transfusions or pregnancies are more likely to have these antibodies. Two thirds of these antibodies have HLA specificity, while one third are specific for platelet or granulocyte antigens. Antibodies usually reach detectable levels within 1 to 2 weeks after transfusion and are often transient. The transient nature of these antibodies may explain why only 1 in 7 patients experience repeat febrile reactions.

At least 2 mechanisms are responsible for febrile reactions to platelet transfusions. Approximately 95% of reactions are caused by cytokines that accumulate in the platelet concentrate during storage. Most of these cytokines do not reach detectable levels until day 3 of storage and may reach high levels by day 5. Transfusion of high levels of these cytokines produces fever. The second mechanism that is responsible for 5% of platelet associated febrile reaction is the interaction of donor leukocytes with anti-leukocyte antibodies in recipient plasma, similar to febrile reactions induced by red cells.

The National Healthcare Safety Network (NHSN) hemovigilance protocol defines a FNHTR as a fever greater than or equal to 101.4° F (38° C) oral and a change of at least 1.8° F (1° C) from the pretransfusion temperature or chills or rigors that occurs during or within 4 hours of cessation of transfusion.

Fever may persist for 8 to 12 hours. Chills may precede the fever or occur up to 30 minutes after the onset of fever. In some patients, headache, flushing, or tachycardia may accompany fever and chills. Patients, who are febrile at the onset of transfusion or have been febrile in the preceding 24 hours, are more prone to febrile reactions.

It is important to recognize and report febrile reactions because they may be the first indication of a septic or hemolytic transfusion reaction. A febrile reaction, by itself, is not usually serious, although the patient will have discomfort.

A transfusion reaction work-up should be initiated to rule out a hemolytic or septic reaction. A clerical check should be performed to determine whether the patient received the correct unit. A lavender top tube of blood should be sent to the laboratory. The Transfusion Service should rule out a hemolytic transfusion reaction. If no clerical error has occurred, the plasma is not red or pink, and the DAT is negative, an acute hemolytic reaction is unlikely and it can be assumed that a febrile reaction occurred. Patient’s medical record should be carefully reviewed to determine if there are any other underlying medical conditions that might be responsible for the fever and/or chills.

The transfusion should be discontinued, but the IV line kept open. Medication is usually not required for mild febrile reactions. Antipyretics can be given to relieve moderate to severe symptoms. Acetaminophen is preferred over aspirin. Diphenhydramine is not effective in reducing temperature, but can be given to alleviate chills. Meperidine (Demerol) may be helpful in treating rigors.

Only 1 in 7 patients experiencing a febrile nonhemolytic reaction will have another reaction at their next transfusion. The best way to prevent severe febrile reactions is to use prestorage leukocyte reduced red blood cells and apheresis platelets. If a patient continues to have febrile reactions to leukocyte reduced single donor platelets, it may be helpful to remove plasma from the platelet unit immediately prior to transfusion. Alternatively, platelets can be washed. Both plasma reduction and washing may activate platelets and decrease their hemostatic effectiveness.

If a patient continues to experience febrile reactions even after receiving leukocyte reduced blood components, it may be necessary to pre-medicate them with acetaminophen and diphenhydramine. Pre-medication should be used judiciously since it may mask the early signs and symptoms of a hemolytic reaction.

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