Epidemiology

• Incidence: occurs in approximately 4% of lung transplants (although exact diagnostic criteria have not been firmly established)
  • Transplant recipients with acute antibody-mediated lung transplant rejection are not distinguished by age, pre-transplant diagnosis, type of transplant (single, bilateral, heart-lung), or CMV seropositivity
  • Patients may have concomitant acute cellular rejection

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Physiology

• Reaction of Preformed Recipient Donor-Specific Antibodies Against Foreign Donor Human Leukocyte Antigens (HLA)
  • Believed to be due to antibodies that were present at a low titer prior to transplantation or developed after transplantation -> clinical disease develops in the transplanted lung weeks-months after transplant

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Diagnosis

Assay for Donor-Specific HLA Antibodies

• May be Diagnostic

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

• Decreased FEV1
• Decreased FVC

High-Resolution Chest Computed Tomography (HRCT) (see High-Resolution Chest Computed Tomography, [[High-Resolution Chest Computed Tomography]])

• Findings
  • Septal Thickening with Areas of Ground-Glass Opacities within Apices and Bases

Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]])

• Bronchoalveolar Lavage (BAL)/Trans-Bronchial Biopsy (TBB): usually performed to obtain microbiological samples

Open Lung Biopsy

• Capillaritis is Often Present: however, capillaritis is not specific for acute antibody-mediated-mediated lung transplant rejection
• Non-Specific Acute Lung Injury/Diffuse Alveolar Damage: common

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Proposed Clinical Diagnostic Criteria

• Presence of Clinical Lung Allograft Dysfunction
• Donor-Specific Antibodies Present in Recipient Serum
• Presence of Pathology of Acute Lung Injury with/without Capillaritis
• Presence of Sub-Endothelial C4d Deposition in Alveolar Capillaries

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Clinical Manifestations

General Comments

• Onset: weeks-months
  • Median: 258 days post-transplant
  • Range: 1 week to >1 year (the majority of cases are diagnosed between 1-12 mo, although some cases have been reported years after transplant)
• Severity of Clinical Symptoms: acute onset of respiratory symptoms (usually severe enough to require hospitalization)

Pulmonary Manifestations

• Cough (see Cough, [[Cough]])
• Dyspnea (see Dyspnea, [[Dyspnea]]): 100% of cases
• Fever (see Fever, [[Fever]])
• Hemoptysis/Diffuse Alveolar Hemorrhage (DAH) (see Hemoptysis, [[Hemoptysis]] and Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]]): hemoptysis is present in 25% of cases
• Hypoxemia (see Hypoxemia, [[Hypoxemia]])
• Respiratory Failure (see Respiratory Failure, [[Respiratory Failure]]): 18% of cases

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Treatment

• Anti-Thymocyte Globulin (ATG) (see Anti-Thymocyte Globulin, [[Anti-Thymocyte Globulin]])
• Bortezomib (Velcade) (see Bortezomib, [[Bortezomib]]): proteasome inhibitor, which has pro-apoptotic effects on plasma cells -> decreases antibody synthesis
• Corticosteroids (see Corticosteroids, [[Corticosteroids]]): usually not effective
• Cyclophosphamide (Cytoxan) (see Cyclophosphamide, [[Cyclophosphamide]])
• Eculizumab (Soliris) (see Eculizumab, [[Eculizumab]]): anti-complement C5 antibody
• Intravenous Immunoglobulin (IVIG) (see Intravenous Immunoglobulin, [[Intravenous Immunoglobulin]]): causes B-lymphocyte apoptosis, blocks binding of donor-reactive antibodies, and inhibits complement activation
• Plasmapheresis (see Plasmapheresis, [[Plasmapheresis]]): rapidly removes anti-donor antibodies from peripheral blood to prevent further allograft damage
• Rituximab (Rituxan) (see Anti-CD20 Therapy, [[Anti-CD20 Therapy]]): B-lymphocyte depleting monoclonal antibody

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Prognosis

• Median Survival After Diagnosis: 593 days
  • May be fulminant (sometimes fatal)
  • Survivors have increased risk of developing chronic lung allograft dysfunction

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References

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