What is a common cause of febrile transfusion reactions?

September 25, 2025 •

4 min read

Febrile non-hemolytic transfusion reactions are the most frequent type of transfusion reaction. Understanding what is a common cause of febrile transfusion reactions is key to managing patient safety, as they are typically a benign but manageable consequence of cytokine accumulation in stored blood products.

Quick Summary

A common cause of febrile transfusion reactions is the accumulation of cytokines and other inflammatory mediators released from donor white blood cells (leukocytes) in stored blood products, especially platelets.

Key Points

Cytokine Accumulation: The most common cause is the passive transfer of cytokines, which are inflammatory proteins released by donor white blood cells (leukocytes) that break down in the stored blood product.
Storage Time: The longer a blood product, particularly a platelet concentrate, is stored, the more cytokines accumulate, increasing the likelihood of a febrile reaction.
Leukocyte Antibodies: A less common but important cause involves the recipient's antibodies reacting with donor leukocytes, stimulating a fever response.
Leukoreduction is Key: Universal leukoreduction, the filtering of white blood cells from blood products, has dramatically reduced the incidence of febrile non-hemolytic transfusion reactions.
Diagnosis of Exclusion: Febrile transfusion reactions are diagnosed only after more severe reactions, such as hemolytic or septic reactions, have been ruled out.
Management is Symptomatic: Treatment for a confirmed febrile non-hemolytic reaction involves managing symptoms with appropriate medication.

Understanding Febrile Transfusion Reactions

Febrile transfusion reactions, more accurately called febrile non-hemolytic transfusion reactions (FNHTRs), are among the most common adverse events associated with blood transfusions. While the symptoms can be alarming, FNHTRs are typically not life-threatening. The main culprits behind this phenomenon are the biological components that accumulate within blood products during storage. The reaction is called "non-hemolytic" because it does not involve the destruction of red blood cells, which is a much more severe type of transfusion reaction.

The Role of Cytokines

The most prominent cause of FNHTRs is the passive transfer of cytokines that have accumulated in the blood product during storage. Cytokines are small proteins that are crucial for cell signaling and orchestrating the body's immune response. In the context of a blood transfusion, these cytokines can act as pyrogens, substances that induce fever.

Leukocyte breakdown: Over time, as donated blood is stored, the white blood cells (leukocytes) within the blood product naturally break down.
Cytokine release: This breakdown process releases pro-inflammatory cytokines into the plasma portion of the blood product.
Platelets and storage: Platelet concentrates, which are stored at room temperature, are particularly prone to this process, leading to a higher incidence of febrile reactions compared to refrigerated red blood cells. The longer the storage time, the more cytokines can accumulate.

The Impact of Leukocyte Antibodies

In some cases, the FNHTR is not caused by cytokines in the transfused product but by an immune response from the recipient's body. This is a secondary, less common cause, but still a known mechanism.

Recipient sensitization: Patients who have received multiple blood transfusions or multiparous women (women who have had multiple pregnancies) may develop antibodies to human leukocyte antigens (HLA).
Antibody-antigen reaction: These antibodies in the recipient's blood can react with donor leukocytes present in the transfused product.
Triggering fever: This antigen-antibody reaction activates the recipient's immune system, leading to the release of their own pyrogenic substances, which results in fever.

Prevention through Leukoreduction

Recognizing the role of leukocytes and their cytokines in causing FNHTRs has led to significant advances in prevention. The widespread practice of leukoreduction has dramatically decreased the incidence of these reactions.

What is leukoreduction? Leukoreduction is the process of filtering out white blood cells from blood products before they are stored or transfused.
Effectiveness: This step effectively removes the source of the cytokines and the white cells that could trigger an immune response from the recipient's antibodies, thereby preventing the reaction.
Standard practice: Most blood banks now perform prestorage leukoreduction on blood products, making FNHTRs a much rarer occurrence today.

Differentiating Febrile Reactions from Other Transfusion Issues

Fever and chills can also signal more serious, acute transfusion reactions, so it is crucial for healthcare providers to properly diagnose the cause. FNHTR is a diagnosis of exclusion, meaning more severe reactions must first be ruled out.


Feature	Febrile Non-Hemolytic Reaction (FNHTR)	Acute Hemolytic Transfusion Reaction (AHTR)	Septic Transfusion Reaction	Transfusion-Related Acute Lung Injury (TRALI)
Timing	Within 4 hours of transfusion	Usually within minutes	Any time, often early	Within 6 hours of transfusion
Cause	Donor cytokines or recipient antibodies vs donor leukocytes	Recipient antibodies vs donor red blood cells (ABO incompatibility)	Bacterial contamination of blood product	Donor antibodies vs recipient leukocytes
Key Symptoms	Fever, chills, headache	Fever, chills, back pain, hypotension	High fever, severe chills, profound hypotension	Hypoxemia, respiratory distress
Severity	Generally mild	Severe, potentially fatal	Severe, potentially fatal	Severe, requires supportive care

Management and Future Steps

Management of FNHTR is primarily supportive, focusing on symptom relief. Healthcare providers will stop the transfusion to evaluate the reaction and rule out more serious complications. After confirming the diagnosis, the patient may be given medication to reduce the fever. For patients with a history of recurrent FNHTRs, preventive measures such as leukoreduced blood products are typically implemented for future transfusions.

The ongoing advancement of blood processing and screening technologies, coupled with the routine use of leukoreduction, continues to improve patient safety and reduce the incidence of FNHTRs, ensuring a safer transfusion experience for those who need it. More information on blood transfusion safety can be found on the Centers for Disease Control and Prevention website.

Conclusion

In conclusion, the most common cause of febrile transfusion reactions is the presence of cytokines that build up from the breakdown of white blood cells within stored blood products. This is especially true for platelet products, which are stored at warmer temperatures. An alternative, immunologically-mediated cause involves the reaction between recipient antibodies and donor leukocytes. Thanks to widespread leukoreduction practices, the incidence of these reactions has been significantly reduced, but it remains a key consideration in transfusion medicine. Accurate diagnosis is essential to differentiate FNHTRs from more serious reactions, and management is focused on relieving symptoms and ensuring patient well-being.

Frequently Asked Questions

A febrile non-hemolytic transfusion reaction (FNHTR) causes a fever but does not involve the destruction of red blood cells. An acute hemolytic transfusion reaction (AHTR) is a more severe, and potentially fatal, immune reaction that specifically targets and destroys the transfused red blood cells, often due to ABO incompatibility.

Platelet concentrates are stored at room temperature, which is a more favorable environment for the activation of leukocytes and the accumulation of cytokines over time. Red blood cells, in contrast, are stored at cooler temperatures which slows this process down.

Yes, they can be largely prevented. The most effective method is prestorage leukoreduction, which filters out the white blood cells from the blood product before it is stored. This removes the source of the cytokines that typically cause the reaction.

The transfusion must be stopped immediately. Healthcare providers will then evaluate the patient and follow hospital protocols to rule out more serious reactions like a hemolytic reaction or sepsis. The patient's vital signs are carefully monitored.

Symptoms can include a fever (a temperature increase of at least 1°C or 1.8°F), chills, a headache, and general discomfort. These typically occur during or within four hours of the transfusion.

While the symptoms can be distressing, FNHTRs are generally considered a mild to moderate, benign occurrence. However, because fever can also indicate more serious conditions, all febrile reactions must be thoroughly investigated to rule out more severe issues.

Treatment is symptomatic and primarily focuses on patient comfort after more serious conditions are ruled out. This can include administering an appropriate antipyretic medication to reduce the fever.