In a patient who develops a fever of ≥38 °C (or a rise of ≥1 °C) during or within four hours after a blood component transfusion without any signs of hemolysis, what is the most likely diagnosis and what immediate and future management steps should be taken?

Febrile Non-Hemolytic Transfusion Reaction (FNHTR)

In a patient developing isolated fever (≥38°C or rise ≥1°C) during or within 4 hours of transfusion without hemolysis signs, the most likely diagnosis is febrile non-hemolytic transfusion reaction (FNHTR), but you must immediately stop the transfusion and systematically exclude life-threatening causes—particularly bacterial contamination and acute hemolytic reaction—before attributing fever to benign FNHTR. 1

Immediate Management Algorithm

Step 1: Stop Transfusion and Stabilize

• Stop the blood transfusion immediately and maintain IV access with normal saline 1
• Assess vital signs including heart rate, blood pressure, respiratory rate, oxygen saturation, and repeat temperature 1
• Check patient identification and blood component compatibility labels for clerical errors 1
• Notify the transfusion laboratory/blood bank immediately 1

Step 2: Risk Stratification Based on Clinical Presentation

High-Risk Features (Serious Reaction—NOT Simple FNHTR):

• Fever + hypotension or tachycardia suggests hemolytic reaction or bacterial contamination 1
• Fever + respiratory symptoms within 1-6 hours indicates possible TRALI 1
• Fever within 6 hours after platelet transfusion may indicate bacterial contamination—a leading cause of transfusion-related death 1, 2
• Fever + oliguria/dark urine suggests hemolytic reaction with renal involvement 1
• Back pain, chest pain, or feeling "odd" are critical warning signs of acute hemolytic reaction 3

Low-Risk Features (Possible FNHTR):

• Isolated fever without hemodynamic instability
• No respiratory distress
• No signs of hemolysis (no dark urine, back pain, or chest pain)
• Occurs with red blood cell transfusion (more commonly associated with FNHTR than platelets) 4

Step 3: Mandatory Diagnostic Workup

Even if FNHTR seems likely, you must exclude serious reactions:

• Send the blood component bag with administration set back to transfusion laboratory 1
• Collect post-reaction blood samples for:
  • Complete blood count 1
  • Direct antiglobulin test (Coombs test) 1
  • Repeat crossmatch 1
  • Visual inspection of plasma for hemolysis 1
  • Urine analysis for hemoglobinuria 1
• Obtain blood cultures if bacterial contamination suspected (especially with platelet transfusions) 1

Step 4: Treatment Based on Final Diagnosis

If FNHTR is confirmed (after excluding serious causes):

• Administer acetaminophen 650-1000 mg orally or IV for fever control 1
• Provide supportive care
• Do NOT restart the transfusion before laboratory clearance, even if symptoms improve 1

If serious reaction identified:

• Bacterial contamination: Initiate broad-spectrum antibiotics immediately after blood cultures 1
• Hemolytic reaction: Aggressive fluid resuscitation to maintain urine output >100 mL/hour 1
• TRALI: Provide oxygen therapy and critical care supportive measures; avoid diuretics 3

Future Transfusion Management

Prevention Strategies

• Prestorage leukoreduction significantly reduces FNHTR incidence from 0.33% to 0.19% for RBCs and from 0.45% to 0.11% for platelets 5
• Avoid routine premedication with antipyretics or antihistamines—current recommendations advise against indiscriminate use; instead use a personalized approach based on previous reaction symptoms 4
• For patients with prior FNHTR, consider intravenous paracetamol specifically for febrile reactions 4

Risk Factors for Recurrent FNHTR

• Women with reproductive history (due to anti-HLA antibodies from pregnancy) 6
• Patients with multiple prior transfusions 6
• Primary hematologic disease or malignant disease 6
• Transfusion with >6 units of leukocyte-depleted packed red blood cells 6

Critical Pitfalls to Avoid

Never assume isolated fever is "just FNHTR" without proper workup:

• General anesthesia and critical illness can mask early signs of serious reactions 1
• Bacterial contamination from platelets can present with isolated fever within 6 hours and is potentially fatal 1
• In neutropenic patients, fever may be masked by scheduled NSAIDs/acetaminophen, so maintain high suspicion even with subtle signs 1

Never restart the transfusion before laboratory clearance:

• Even if symptoms improve, the reaction may worsen with continued exposure 1
• Laboratory investigation is mandatory to exclude hemolysis and bacterial contamination

Never continue transfusion "just to finish the unit":

• Stopping immediately is the single most critical intervention that can prevent progression to severe morbidity or mortality 1

Understanding FNHTR Epidemiology

• FNHTR is the most common transfusion reaction, occurring in approximately 1.1% of transfusions with prestorage leukoreduction 3, 6
• Despite being labeled "non-serious," FNHTR carries substantial burden: 25% undergo chest imaging, 79% have blood cultures, and 15% of outpatients require hospital admission to exclude other causes 7
• The overall per-product rate is 0.24%, with RBCs at 0.17% and platelets at 0.25% 7

Pathophysiology

FNHTR occurs through two mechanisms:

• Immune pathway: Anti-HLA antibodies in transfused patients (especially multiparous women) react against residual donor leukocytes 6
• Non-immune pathway: Inflammatory cytokines (particularly IL-6) released from blood products during storage 6, 8