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Transfusion-Related Acute Lung Injury (TRALI)

Overview

Transfusion-related acute lung injury (TRALI) represents one of the most serious complications of blood transfusion, characterized by acute respiratory distress occurring within 6 hours of transfusion. As the leading cause of transfusion-related mortality in many countries, TRALI demands immediate recognition and management. This immune-mediated syndrome results in non-cardiogenic pulmonary edema through complex interactions between donor antibodies, recipient neutrophils, and pulmonary endothelium. Despite significant advances in understanding its pathophysiology and implementing preventive strategies, TRALI remains a challenging diagnosis requiring high clinical suspicion and careful differentiation from other causes of post-transfusion respiratory distress.

Definition and Diagnostic Criteria

Current Definition

The International Society of Blood Transfusion (ISBT) working party established consensus criteria for TRALI diagnosis:

TRALI Type I (Without ARDS Risk Factors): - Acute onset within 6 hours of transfusion completion - Hypoxemia: PaO2/FiO2 ≀ 300 mmHg or SpO2 < 90% on room air - Bilateral pulmonary infiltrates on imaging - No evidence of left atrial hypertension or circulatory overload - No temporal relationship to alternative risk factors for acute lung injury

TRALI Type II (With ARDS Risk Factors): - Same clinical and temporal criteria - Presence of mild-moderate ARDS risk factors - Clinical judgment that transfusion contributed to lung injury

Differential Terminology

Possible TRALI (Historical term): - Meets clinical criteria but with concurrent ARDS risk factors - Now incorporated into TRALI Type II

Delayed TRALI: - Onset 6-72 hours post-transfusion - Emerging entity requiring further characterization

Transfusion-associated circulatory overload (TACO): - Key differential diagnosis - Cardiogenic pulmonary edema - Elevated central venous pressure and B-type natriuretic peptide

Epidemiology and Risk Factors

Incidence

TRALI incidence varies by blood product and surveillance methods: - Overall: 0.08-15% of transfusions - Plasma transfusion: Highest risk (1:2000-1:5000) - Platelet transfusion: Moderate risk (1:5000-1:10000) - Red blood cell transfusion: Lower risk (1:10000-1:50000) - Mortality: 5-25% of cases

Blood Product Risk Factors

High-Risk Components: - High-plasma volume products: Fresh frozen plasma, platelets - Multiparous female donors: Increased HLA antibodies - Whole blood-derived platelets: Higher plasma content - Non-leukoreduced products: Contain more microparticles

Lower-Risk Components: - Packed red blood cells: Less plasma volume - Male-donor plasma: Reduced antibody prevalence - Solvent-detergent plasma: Pooling dilutes antibodies

Recipient Risk Factors

Clinical Conditions: - Critical illness: Particularly 04 Vault/Amboss Library/On-call survival guide/Sepsis and 04 Vault/Amboss Library/On-call survival guide/Shock - Hematologic malignancy: Especially with chemotherapy - Cardiac surgery: Inflammatory priming - Massive transfusion: Multiple donor exposures - End-stage liver disease: Altered immunity

Patient Factors: - Alcohol abuse: Impaired neutrophil function - Positive fluid balance: Pre-existing endothelial stress - Mechanical ventilation: Lung injury susceptibility - Higher IL-8 levels: Neutrophil activation marker

Pathophysiology

Two-Hit Hypothesis

TRALI typically requires two events:

First Hit (Priming): - Underlying patient condition causing neutrophil priming - Endothelial activation in pulmonary microvasculature - Examples: Surgery, sepsis, trauma - Creates susceptible lung environment

Second Hit (Activation): - Transfusion of activating substances - Triggers primed neutrophils - Results in capillary leak syndrome - Leads to acute lung injury

Immunologic Mechanisms

Antibody-Mediated TRALI: The classic mechanism involves donor antibodies:

  1. Anti-HLA antibodies:
  2. Class I (HLA-A, -B): On all nucleated cells
  3. Class II (HLA-DR, -DQ): On monocytes, B cells

  4. From pregnancy, transfusion, transplantation

  5. Anti-HNA antibodies (Human Neutrophil Antigens):

  6. HNA-1a, -1b, -2a most commonly implicated
  7. Direct neutrophil activation

  8. Often cause severe TRALI

  9. Pathogenic sequence:

  10. Antibody binds cognate antigen
  11. Neutrophil activation and aggregation
  12. Complement activation (C5a generation)
  13. Release of reactive oxygen species
  14. Endothelial damage and increased permeability

Non-Antibody TRALI: Alternative mechanisms without detectable antibodies:

  1. Biological response modifiers:
  2. Lipid mediators from stored cells
  3. Lysophosphatidylcholines

  4. CD40 ligand from platelets

  5. Microparticles:

  6. From platelets, RBCs, leukocytes
  7. Pro-inflammatory and procoagulant

  8. Accumulate during storage

  9. Neutrophil extracellular traps (NETs):

  10. Released by activated neutrophils
  11. Damage alveolar-capillary membrane
  12. Perpetuate inflammation

Cellular and Molecular Events

Neutrophil-Endothelial Interaction: 1. Neutrophil sequestration in pulmonary capillaries 2. Endothelial activation with adhesion molecule expression 3. Tight junction disruption between endothelial cells 4. Albumin extravasation into alveoli 5. Surfactant dysfunction from protein influx

Inflammatory Cascade: - Cytokine release: TNF-Ξ±, IL-1Ξ², IL-6, IL-8 - Complement activation: C3a, C5a anaphylatoxins - Eicosanoid production: Leukotrienes, prostaglandins - Oxidative stress: Superoxide, hydrogen peroxide

Clinical Presentation

Temporal Relationship

Classic presentation timeline: - Onset: Usually within 1-2 hours (always <6 hours) - Peak symptoms: 2-4 hours - Resolution: Typically 48-96 hours with support

Signs and Symptoms

Respiratory Manifestations: - Acute dyspnea: Universal finding - Tachypnea: Respiratory rate >20 - Hypoxemia: Refractory to oxygen - Cyanosis: In severe cases - Frothy pink sputum: Pulmonary edema

Cardiovascular Signs: - Hypotension: From capillary leak - Tachycardia: Compensatory response - Normal central venous pressure: Unlike TACO - Normal pulmonary capillary wedge pressure

Systemic Features: - Fever: Common (1-2Β°C elevation) - Hypothermia: In severe cases - Leukopenia: From pulmonary sequestration

Laboratory Findings

Blood Gas Analysis: - Hypoxemia: PaO2/FiO2 ratio <300 - Respiratory alkalosis: Initially - Metabolic acidosis: With progression

Complete Blood Count: - Transient leukopenia: Within 30-60 minutes - Recovery with leukocytosis - 03 Spaces/Medical Hub/πŸ“ Exam Prep/Medicine Notebook/Thrombocytopenia: Mild, from consumption

Biomarkers (Research/Supportive): - Elevated neutrophil elastase - Increased myeloperoxidase - Normal/low BNP: Helps exclude TACO

Diagnostic Approach

Clinical Diagnosis

TRALI remains primarily a clinical diagnosis:

  1. Establish temporal relationship to transfusion
  2. Document hypoxemia and bilateral infiltrates
  3. Exclude cardiogenic causes
  4. Consider alternative etiologies

Imaging Studies

Chest Radiography: - Bilateral alveolar infiltrates: Classic finding - Interstitial pattern: May precede alveolar changes - Normal cardiac silhouette: Unlike cardiogenic edema - No Kerley B lines typically

CT Chest: - Ground-glass opacities: Bilateral distribution - Consolidation: In dependent areas - Normal pulmonary vasculature: No congestion

Echocardiography

Used to exclude cardiac causes: - Normal left ventricular function - Normal left atrial pressure - No significant valvular disease - May show right heart strain

Laboratory Investigations

Donor Screening: - HLA antibody testing: Luminex assays - HNA antibody testing: Specialized laboratories - Crossmatching: Donor serum + recipient cells

Recipient Testing: - HLA typing: If antibodies found - Neutrophil antigen typing: When indicated - Pre-transfusion sample: For comparison

Differential Diagnosis

Key conditions to exclude:

Transfusion-associated circulatory overload (TACO): - Elevated CVP and PCWP - Responds to diuretics - Elevated BNP/NT-proBNP - Evidence of fluid overload

Anaphylactic transfusion reaction: - Immediate onset (minutes) - 03 Spaces/Medical Hub/πŸ“ Exam Prep/Medicine Notebook/Urticaria, 03 Spaces/Medical Hub/πŸ₯ Clinical Rotations/Clinical Consult/Angioedema - Bronchospasm prominent - IgA deficiency with anti-IgA

Bacterial contamination: - High fever, rigors - Septic shock - Positive blood cultures - DIC may develop

Other considerations: - Acute respiratory distress syndrome (ARDS) - Transfusion-related immunomodulation (TRIM) - Drug reactions - 04 Vault/Amboss Library/Clinical knowledge/Surgery/Vascular surgery/Pulmonary embolism

Management

Immediate Interventions

Stop Transfusion: - Discontinue immediately upon suspicion - Maintain IV access - Return blood unit to blood bank

Respiratory Support: - High-flow oxygen: Initial therapy - Non-invasive ventilation: CPAP/BiPAP - Mechanical ventilation: 70-80% require - Lung-protective ventilation: Low tidal volumes

Hemodynamic Management: - Fluid restriction: Avoid volume overload - Vasopressors: For hypotension - Inotropic support: If needed - Conservative fluid strategy

Specific Treatments

No proven specific therapy, but considerations include:

Corticosteroids: - Theoretical benefit: Anti-inflammatory - No RCT evidence: Use controversial - Consider methylprednisolone: 1-2 mg/kg

Other Interventions (Anecdotal): - Diuretics: Only if concurrent overload - Extracorporeal membrane oxygenation (ECMO): Severe cases - Plasmapheresis: Remove causative antibodies - Avoid additional transfusions unless critical

Supportive Care

Ventilation Strategy: - Low tidal volume: 6-8 mL/kg ideal body weight - PEEP optimization: Prevent atelectasis - Prone positioning: For severe hypoxemia - Recruitment maneuvers: Cautious use

Monitoring: - Continuous pulse oximetry - Arterial blood gases: Serial monitoring - Central venous pressure: If unclear diagnosis - Daily chest X-rays: Track progression

Prevention Strategies

Blood Product Modifications

Plasma Risk Reduction: - Male-only plasma: For FFP and platelets - Never-pregnant female donors: Alternative strategy - Pooled solvent-detergent plasma: Dilutes antibodies

Component Preparation: - Platelet additive solution: Reduces plasma content - Washed cellular products: For high-risk recipients - Leukoreduction: May reduce bioactive substances

Donor Screening and Management

HLA/HNA Antibody Screening: - Female donors: Especially multiparous - Previously transfused donors - Cost-effectiveness debated

Donor Deferral Strategies: - Positive antibody screen: Permanent plasma deferral - Allow RBC donation: Lower risk - Look-back programs: Identify implicated donors

Clinical Risk Mitigation

Transfusion Practices: - Restrictive transfusion strategies - Avoid unnecessary plasma transfusion - Use blood alternatives when appropriate - Single-donor products: When possible

High-Risk Situations: - Extra vigilance: Critical care, surgery - Washed products: Consider for history of TRALI - Male-donor products: When available

Outcomes and Prognosis

Short-Term Outcomes

Clinical Course: - Resolution: Usually within 72-96 hours - Ventilator days: Mean 2-4 days - ICU stay: Typically 3-7 days - Mortality: 5-25% (improving with recognition)

Predictors of Poor Outcome: - Severity of hypoxemia - Multi-organ failure - High APACHE score - Need for vasopressors

Long-Term Sequelae

Pulmonary Function: - Usually complete recovery - No chronic fibrosis typically - Rare persistent symptoms - Normal spirometry at follow-up

Recurrence Risk: - Can receive future transfusions - Avoid implicated donor if identified - Consider washed products - Careful monitoring required

Reporting and Surveillance

Mandatory Reporting

TRALI cases should be reported to: - Hospital transfusion service - Blood supplier/collection facility - Hemovigilance systems: National programs - FDA (in US): Fatalities within 24 hours

Investigation Protocol

Standard workup includes: 1. Clinical data collection 2. Donor antibody testing 3. Recipient HLA/HNA typing 4. Crossmatch studies 5. Result interpretation 6. Preventive action

Future Directions

Research Priorities

Pathophysiology: - Role of recipient antibodies - Genetic susceptibility markers - Biomarker development - Animal models refinement

Prevention Strategies: - Pathogen reduction technology - Ex vivo lung perfusion models - Antibody removal techniques - Donor screening optimization

Treatment Approaches: - Targeted immunomodulation - Neutrophil inhibitors - Endothelial protectants - Precision medicine applications

Emerging Concepts

Reverse TRALI: - Recipient antibodies against donor antigens - Less common but documented - Implications for cellular therapy

TRALI in New Therapies: - CAR-T cell therapy - Convalescent plasma - Monoclonal antibody therapy - Different risk profiles

Clinical Pearls

  • TRALI can occur with as little as 10-15 mL of plasma (one platelet unit contains ~50-70 mL)
  • Multiparous women have HLA antibodies in 20-30% of cases after 3+ pregnancies
  • TRALI typically causes transient leukopenia followed by leukocytosis
  • BNP levels <100 pg/mL strongly favor TRALI over TACO
  • Fever is common in TRALI but rare in TACO
  • TRALI patients typically improve within 48-96 hours, faster than typical ARDS
  • Male-only plasma policies have reduced TRALI incidence by 50-80%
  • TRALI can occur with autologous transfusion due to biological response modifiers
  • The presence of HLA antibodies doesn't always cause TRALI - cognate antigen required
  • Consider TRALI in any post-transfusion respiratory distress, even with other risk factors

References