Rejection in Lung Transplantation - Complete MD Exam Answer

Introduction

1. HYPERACUTE REJECTION

• Caused by pre-formed recipient antibodies against donor HLA (Class I/II) or ABO antigens.
• Antibody-antigen binding activates complement cascade → endothelial injury → platelet aggregation → microvascular thrombosis → ischemic necrosis of the allograft.

2. ACCELERATED ACUTE REJECTION

3. ACUTE REJECTION

3a. Acute Cellular Rejection (ACR)

• T-cell mediated. Alloreactive CD4+ and CD8+ T cells recognize donor HLA antigens via:
  • Direct pathway: T cells recognize intact donor MHC on donor APCs (early post-transplant)
  • Indirect pathway: T cells recognize processed donor peptides on self-APCs (later)
• T-cell activation requires:
  1. Signal 1: TCR-MHC interaction
  2. Signal 2: Costimulatory signals (CD28-B7)
  3. Signal 3: Cytokine signals (IL-2, IL-15)
• Activated T cells proliferate and differentiate into cytotoxic effectors that destroy donor cells.

• Often asymptomatic (especially A1)
• Fever, dyspnoea, non-productive cough
• Decline in FEV1/FVC (>10% decline is clinically significant)
• Chest X-ray: may show perihilar infiltrates, interstitial edema, pleural effusions - or be normal
• Crackles, ronchi on auscultation; exertional desaturation

• Fiberoptic bronchoscopy with transbronchial biopsy (TBB) and bronchoalveolar lavage (BAL) - gold standard
• Clinical impression alone is accurate in only ~50% of cases (must be distinguished from infection, as symptoms overlap completely)
• BAL: lymphocytosis may suggest rejection; neutrophilia - infection
• Spirometry: >10% fall in FEV1 or FVC is significant
• Pulmonary function testing (PFT) regularly monitors graft function

• First-line: IV methylprednisolone 500-1000 mg/day for 3 days ("pulse steroids")
• After pulse therapy: oral prednisolone taper
• Steroid-resistant ACR:
  • Antithymocyte globulin (ATG/thymoglobulin) - polyclonal antibody depleting T cells
  • Muromonab-CD3 (OKT3) - historically used, now discontinued
  • Optimize baseline immunosuppression (switch cyclosporine to tacrolimus; add/increase mycophenolate mofetil)
  • Photopheresis (extracorporeal photochemotherapy)
  • Total lymphoid irradiation
• Surveillance: Repeat TBB at 3-4 weeks to confirm resolution

3b. Antibody-Mediated Rejection (AMR)

• Donor-specific antibodies (DSA) against HLA or non-HLA antigens bind donor endothelium → complement activation (C4d deposition) → endothelial injury, neutrophil recruitment, microvascular injury.
• Distinct from cell-mediated rejection; requires humoral targeting.

1. Graft dysfunction (clinical)
2. DSA present in serum
3. Histopathology: capillaritis, neutrophilic infiltration
4. C4d deposition in capillaries on immunofluorescence/immunohistochemistry

• Plasmapheresis (removes circulating DSA)
• Intravenous immunoglobulin (IVIG) - modulates Fc receptor function, anti-idiotype antibodies
• Rituximab (anti-CD20) - depletes B cells producing DSA
• Proteasome inhibitors (bortezomib) - target plasma cells
• Complement inhibition: eculizumab (anti-C5)
• Optimize maintenance immunosuppression
• Carfilzomib (newer proteasome inhibitor) in refractory cases

4. CHRONIC REJECTION - Bronchiolitis Obliterans Syndrome (BOS) / CLAD

Pathobiology

• BOS is a manifestation of chronic lung allograft dysfunction (CLAD).
• Risk factors:
  • Multiple episodes of acute rejection (strongest risk factor)
  • Prior symptomatic CMV infection
  • Gastroesophageal reflux (aspiration-mediated injury)
  • HLA mismatching; DSA
  • Chronic infection (Pseudomonas colonization)
  • Primary graft dysfunction
• Pathology:
  • Early: inflammation and disruption of bronchiolar epithelium
  • Granulation tissue grows into small airway lumen
  • Granulation tissue organizes and fibroses → complete or partial obliteration of bronchiole lumen ("constrictive bronchiolitis obliterans")
  • End-stage: scarring with dense fibrosis completely obliterating bronchiolar lumen

CLAD Phenotypes (modern classification):

BOS Staging (based on FEV1% of best post-transplant value):

Clinical Manifestations:

• Progressive exertional breathlessness
• Dry cough
• PFTs: progressive obstructive pattern (FEV1/FVC ratio falls, air trapping on body plethysmography)
• HRCT: mosaic attenuation, air trapping on expiratory images, bronchiectasis
• Often there are no radiographic abnormalities early
• Predisposition to recurrent Pseudomonas infections

Diagnosis:

• Clinical diagnosis (FEV1 decline + exclusion of other causes) - biopsy not required for BOS staging
• TBB has low sensitivity for obliterative bronchiolitis (patchy disease) - may miss lesions
• HRCT chest: expiratory air trapping is suggestive
• BAL to exclude infection

Management of Chronic Rejection / BOS:

• Optimize/augment maintenance immunosuppression:
  • Tacrolimus preferred over cyclosporine (tacrolimus shown in prospective trials to reduce BOS risk)
  • Increase mycophenolate mofetil (MMF) dose
  • Convert azathioprine to MMF
• Azithromycin (250-500 mg 3x/week) - anti-inflammatory, macrolide immunomodulatory effects; improves FEV1 in some patients (particularly those with BAL neutrophilia)
• mTOR inhibitors (sirolimus/everolimus) - may slow progression, particularly in early BOS
• Extracorporeal photopheresis (ECP) - photochemotherapy with 8-methoxypsoralen and UVA irradiation of lymphocytes; shown to stabilize lung function in refractory BOS
• Total lymphoid irradiation (TLI)
• Antithymocyte globulin (ATG) for acute exacerbations
• Proton pump inhibitors / fundoplication for GERD (reflux aspiration as trigger)
• Inhaled cyclosporine - nebulized delivery to allograft; reduces acute rejection and BOS in some trials
• Inhaled corticosteroids
• Pirfenidone/nintedanib - antifibrotic agents (role under investigation for RAS phenotype)

• Bronchoscopic intervention for obstructive secretions
• Re-transplantation - only definitive treatment; limited by donor organ availability and ethically complex given resources; 5-year survival post-re-transplantation ~50%

5. MAINTENANCE IMMUNOSUPPRESSION (Prevention of All Rejection)

1. Calcineurin inhibitor (CNI): Tacrolimus (preferred) or cyclosporine - blocks NFAT-mediated IL-2 transcription
2. Antiproliferative agent: Mycophenolate mofetil (MMF) or azathioprine - inhibits purine synthesis, prevents lymphocyte proliferation
3. Corticosteroids: Prednisolone - broad anti-inflammatory

• Basiliximab (anti-CD25/IL-2R) - preferred; safer profile
• ATG/thymoglobulin - stronger, used in high-rejection-risk patients

6. KEY DISTINGUISHING FEATURES: Rejection vs. Infection

7. PROGNOSIS

• Median survival after lung transplantation: 6.2 years (range 4.8-7.8 years depending on indication and procedure)
• Annual mortality rate: 7-10%/year largely attributable to BOS/chronic rejection
• Multiple acute rejection episodes are the strongest predictor of BOS development
• Re-transplantation for BOS: 5-year survival ~50%

Summary Table

• Goldman-Cecil Medicine, International Edition, Vol. 2 - Lung Transplantation chapter
• Sabiston Textbook of Surgery, 21e - Transplantation Immunology
• Washington Manual of Medical Therapeutics - Acute Rejection, Lung
• Murray & Nadel's Textbook of Respiratory Medicine - Lung Transplantation
• Fishman's Pulmonary Diseases and Disorders

Recent evidence note: A 2024 review (PMID 38305383) emphasizes that CLAD management now recognizes BOS vs. RAS as phenotypically distinct chronic rejection variants, each with different treatment implications - RAS has worse prognosis and may respond differently to therapy.