What differentiates Febrile Non-Hemolytic Transfusion Reaction (FNHTR) from Delayed Hemolytic Transfusion Reaction (DHTR)?

Differentiating Febrile Non-Hemolytic Transfusion Reaction (FNHTR) from Delayed Hemolytic Transfusion Reaction (DHTR)

FNHTR is a benign reaction occurring during or within 4-24 hours of transfusion characterized by isolated fever (≥38°C or ≥1°C rise) and chills without hemolysis, whereas DHTR is a serious immune-mediated destruction of transfused red cells occurring 1-21 days post-transfusion with significant hemoglobin drop, hemoglobinuria, and laboratory evidence of hemolysis. 1, 2, 3

Timing of Onset

• FNHTR occurs acutely: Symptoms develop during transfusion or within 4-24 hours after completion 1, 3
• DHTR occurs in a delayed fashion: Presents 1-21 days post-transfusion, typically 5-14 days after exposure 2, 4

Clinical Presentation

FNHTR Symptoms

• Isolated fever (temperature ≥38°C or rise of ≥1°C from baseline) 1, 3
• Chills, rigors, or shaking 1, 3
• Headache and nausea may occur 3
• Critically, no signs of hemolysis are present 1, 5
• Patients remain hemodynamically stable without hypotension or tachycardia beyond what fever alone would cause 1

DHTR Symptoms

• Significant hemoglobin drop within 21 days post-transfusion (often below pre-transfusion levels in hyperhemolysis syndrome) 2, 4
• Hemoglobinuria (dark or red-colored urine) 2, 4
• Jaundice from elevated bilirubin 4, 6
• Fever and bone pain that can mimic vaso-occlusive crisis in sickle cell patients 4, 6
• Hypotension and tachycardia may develop 1, 7

Laboratory Findings

FNHTR Laboratory Profile

• No evidence of hemolysis: Normal LDH, haptoglobin, and bilirubin 5, 3
• Negative direct antiglobulin test (DAT) 3
• No new red cell alloantibodies detected 3
• Hemoglobin remains stable or increases appropriately from transfusion 5

DHTR Laboratory Profile

• Positive DAT in most cases (though can be negative in hyperhemolysis) 2, 7
• New red cell alloantibody detected on repeat antibody screen 2, 8
• Elevated LDH (significant rise from baseline) 2, 4
• Low or undetectable haptoglobin 7
• Elevated indirect bilirubin 4, 6
• In sickle cell patients: accelerated HbS% increase with concomitant fall in HbA 2, 4
• Relative reticulocytopenia or paradoxical reticulocytosis 2, 4

Pathophysiology

FNHTR Mechanism

• Immune pathway: Anti-HLA antibodies in the recipient react against residual donor leukocytes (more common in women with pregnancy history or multiply-transfused patients) 3
• Non-immune pathway: Inflammatory cytokines (particularly IL-6) accumulate in stored blood products and are infused with transfusion 3, 9
• Does not involve red cell destruction 5, 3

DHTR Mechanism

• Anamnestic antibody response: Pre-existing alloantibodies (from prior transfusion or pregnancy) that were undetectable at time of transfusion undergo rapid increase upon re-exposure to the antigen 2, 8
• Antibody-mediated extravascular hemolysis destroys transfused red cells 2, 4
• In severe cases (hyperhemolysis syndrome), both transfused and patient's own red cells are destroyed 4, 6

Management Approach

FNHTR Management

• Stop the transfusion temporarily and assess the patient 1
• Administer intravenous paracetamol for fever (do not use steroids or antihistamines indiscriminately) 1
• Rule out more serious reactions (TACO, TRALI, bacterial contamination, hemolytic reactions) by checking vital signs, respiratory status, and urine color 1
• Once FNHTR is confirmed, transfusion may be resumed slowly after fever resolves 1
• No further diagnostic workup is typically required beyond initial assessment 5

DHTR Management

• Immediately stop all transfusions unless life-threatening anemia is present 2, 7
• Send blood for repeat type and crossmatch, DAT, hemolysis markers (LDH, haptoglobin, bilirubin, free hemoglobin), and reticulocyte count 7
• Initiate first-line immunosuppression promptly for ongoing hyperhemolysis: IVIg 0.4-1 g/kg/day for 3-5 days (total dose up to 2 g/kg) plus high-dose steroids (methylprednisolone or prednisone 1-4 mg/kg/day) 2, 7
• Consider eculizumab as second-line therapy for complement inhibition 2
• Provide supportive care with erythropoietin with or without IV iron 2, 7
• Critical pitfall to avoid: Do not transfuse additional blood in hyperhemolysis without immunosuppressive therapy, as this exacerbates hemolysis and can cause death 7, 6

Severity and Prognosis

• FNHTR is generally benign with no long-term sequelae, though it causes significant patient distress and healthcare resource utilization (79% undergo blood cultures, 25% have chest imaging, 15% of outpatients require hospital admission) 5
• DHTR can be life-threatening, particularly in hyperhemolysis syndrome where it may lead to multiorgan failure and death if not recognized and treated promptly 2, 7, 6

Prevention Strategies

FNHTR Prevention

• Prestorage leukoreduction of blood products significantly reduces FNHTR incidence 3
• Prophylactic antipyretics before transfusion remain controversial and are not routinely recommended 1, 3

DHTR Prevention

• Extended antigen matching (C/c, E/e, K, Jka/Jkb, Fya/Fyb, S/s) for high-risk patients reduces alloimmunization 2, 7
• For patients with history of multiple or life-threatening DHTRs, consider prophylactic immunosuppression (IVIg, steroids, and/or rituximab) before transfusion 2, 7