Lung Transplant Rejection — Full Details

Overview

1. Hyperacute Rejection

Pathophysiology

• Caused by pre-formed recipient antibodies against donor HLA antigens or ABO blood group antigens.
• Antibodies bind to donor endothelium → complement activation → neutrophil recruitment → endothelial injury → vascular occlusion → ischemic necrosis within minutes to hours.
• Rare due to pre-transplant crossmatching and ABO matching.

Clinical Features

• Sudden onset graft failure immediately post-reperfusion.
• Severe hypoxemia, pulmonary edema, hemodynamic instability.
• Often indistinguishable clinically from severe primary graft dysfunction (PGD).

Management

• Largely preventable (crossmatch/ABO compatibility).
• Treatment: plasmapheresis, IVIG, anti-CD20 (rituximab), eculizumab.

2. Acute Cellular Rejection (ACR)

Epidemiology

• Most common in the first post-transplant year, though can occur at any time (Harrison's, p. 8150).
• Frequency decreases after year one but never disappears.
• Infections (especially CMV) can stimulate and precipitate ACR.

Pathophysiology

• T-lymphocyte mediated response to donor MHC antigens.
• Direct pathway: recipient T cells recognize intact donor MHC molecules on donor APCs.
• Indirect pathway: recipient APCs present processed donor peptides to host T cells.
• Leads to lymphocytic infiltration around blood vessels (perivascular) and airways.

Histopathology (ISHLT Grading — A and B grades)

Clinical Features

• May be asymptomatic (detected on surveillance bronchoscopy).
• Symptoms when present: dyspnea, dry cough, low-grade fever, hypoxemia, reduced exercise tolerance.
• Decline in FEV₁/FVC on spirometry.
• CXR/CT: may be normal or show subtle infiltrates, interstitial thickening.

Diagnosis

• Transbronchial biopsy (TBB) via bronchoscopy — gold standard.
• BAL to exclude infection concurrently.
• Routine surveillance bronchoscopy programs are widely used at 1, 3, 6, 12 months post-transplant.

Treatment

• High-dose IV methylprednisolone (500–1000 mg/day × 3 days) — first-line.
• Refractory cases: antithymocyte globulin (ATG), alemtuzumab.
• Optimization of baseline immunosuppression (tacrolimus levels, MMF dosing).
• ACR is a major risk factor for CLAD (Harrison's, p. 8150).

3. Antibody-Mediated Rejection (AMR)

Pathophysiology

• Caused by donor-specific antibodies (DSA) — usually anti-HLA class I or II antibodies.
• DSA bind to donor vascular endothelium → complement activation (C1q → C4d deposition) → neutrophilic vasculitis → capillary injury.
• Increasingly recognized as a distinct and important form of rejection (Harrison's, p. 8150).

Histopathology

• Neutrophilic capillaritis involving small vessels and capillaries.
• C4d deposition on immunofluorescence (marker of complement activation).
• May be acute or chronic.

Clinical Features

• Often presents as acute deterioration in lung function.
• May mimic ACR or infectious pneumonia.
• Associated with circulating DSA on laboratory testing.

Diagnosis

• Triad:
  1. Clinical/functional decline
  2. Circulating DSA (Luminex bead assay)
  3. Histological evidence (neutrophilic capillaritis + C4d positivity)

Treatment

• Plasmapheresis (remove circulating antibodies)
• IVIG (immune modulation)
• Rituximab (anti-CD20, deplete B cells)
• Bortezomib (proteasome inhibitor — targets plasma cells)
• Eculizumab (anti-C5, blocks complement) in refractory cases
• Optimize calcineurin inhibitor levels

4. Chronic Lung Allograft Dysfunction (CLAD)

Overview

• The most important long-term complication of lung transplantation.
• Defined as a sustained (≥3 weeks) decline in FEV₁ to <80% of best post-transplant value.
• Affects ~50% of recipients by 5 years; the primary cause of death beyond year 1.
• Has two main phenotypes: BOS and RAS.

4a. Bronchiolitis Obliterans Syndrome (BOS)

• Obliterative bronchiolitis (OB): fibroproliferative process affecting small airways.
• Subepithelial fibrosis → luminal obliteration of bronchioles → obstructive ventilatory defect.
• Triggered by repeated alloimmune injury (ACR episodes, AMR) and non-alloimmune injury (infection, GERD, aspiration).

• Insidious progressive dyspnea and cough.
• Obstructive pattern on PFTs.
• CT: mosaic attenuation, air trapping on expiration, bronchiectasis.
• TBB often non-diagnostic (patchy lesions missed); diagnosis is clinical/functional.

• No proven disease-modifying therapy.
• Azithromycin — anti-inflammatory properties; shown to improve FEV₁ in some patients.
• Inhaled cyclosporine — some benefit in selected patients.
• Augmented systemic immunosuppression (tacrolimus, MMF adjustment).
• Extracorporeal photopheresis (ECP) — in refractory BOS.
• Manage treatable triggers: anti-reflux surgery (Nissen fundoplication) for GERD/aspiration, treat infections.
• Re-transplantation in selected patients with end-stage BOS.

4b. Restrictive Allograft Syndrome (RAS)

• Pleuroparenchymal fibroelastosis + peripheral fibrosis.
• Restrictive ventilatory defect (reduced TLC).
• Upper-lobe predominant fibrosis on HRCT.

• Rapid progressive dyspnea.
• Restrictive PFT pattern.
• CT: upper-lobe pleural and subpleural fibrosis.

• Median survival after RAS diagnosis: ~6–18 months (much worse than BOS).
• Poor response to current therapies.

Summary Comparison Table

Risk Factors for Rejection

• HLA mismatch (especially HLA-DR)
• Prior episodes of ACR
• CMV infection/mismatch (donor+/recipient−)
• Non-adherence to immunosuppression
• GERD and chronic aspiration
• Community-acquired respiratory infections
• De novo DSA development
• Prolonged ischemic time

Immunosuppression Maintenance (Standard Triple Therapy)

1. Calcineurin inhibitor: Tacrolimus (preferred) or cyclosporine
2. Antiproliferative agent: Mycophenolate mofetil (MMF) or azathioprine
3. Corticosteroid: Prednisone (tapering dose)

Imaging in Lung Transplant Rejection

Prognosis

• 5-year survival post-lung transplant: ~55% (ISHLT Registry).
• CLAD develops in ~50% by year 5 and accounts for ~30–40% of all post-transplant deaths.
• RAS carries a median post-diagnosis survival of <2 years.
• Re-transplantation is the only definitive treatment for end-stage CLAD but outcomes are inferior to primary transplant.