---

Lung Transplant Rejection — Complete MD Exam Review

---

Overview

---

Classification of Rejection

---

1. Hyperacute Rejection

Pathophysiology

• Caused by preformed donor-specific antibodies (DSA) against HLA or ABO antigens
• Antibodies bind donor endothelium → activate complement → neutrophil influx → microvascular thrombosis and hemorrhagic infarction

Clinical Features

• Occurs within minutes to hours of reperfusion
• Severe hypoxemia, white-out on CXR, rapid graft failure
• Rare due to pre-transplant crossmatch testing

Treatment

• Largely preventable by prospective crossmatch and ABO compatibility
• Once established: plasmapheresis, IVIG, retransplantation (prognosis very poor)

---

2. Acute Cellular Rejection (ACR)

Pathophysiology

• T-lymphocyte mediated (CD4+ and CD8+)
• Donor MHC molecules recognized by recipient T-cells (direct or indirect allorecognition)
• Lymphocytic infiltration of perivascular and peribronchial spaces

Timing & Risk Factors

• Most common in the first post-transplant year, but can occur anytime
• Triggered/augmented by: CMV infection, other viral infections, tapering immunosuppression
• ACR is a major risk factor for CLAD (Harrison's, p. 8150)

ISHLT Grading (A-grade: Vascular; B-grade: Airway)

Clinical Features

• Fever, malaise, dyspnea, decreased exercise tolerance
• Decline in FEV1 / FVC (≥10–15% drop from baseline)
• Hypoxemia, new infiltrates on CXR/CT
• May be asymptomatic (detected on surveillance bronchoscopy)

Diagnosis

• Transbronchial biopsy (TBBx) via bronchoscopy — gold standard
• BAL to exclude infection (always rule out before treating rejection)
• PFTs: obstructive pattern
• CT: ground-glass opacities, septal thickening

Treatment of ACR

• IV methylprednisolone 500–1000 mg/day × 3 days (pulse corticosteroids)
• Response rate ~80–90%

• Optimize baseline immunosuppression (ensure therapeutic tacrolimus levels)
• Add/increase mycophenolate mofetil (MMF)

• Antithymocyte globulin (ATG) — polyclonal T-cell depleting agent
• Total lymphoid irradiation (TLI)
• Photopheresis (extracorporeal photochemotherapy)

---

3. Antibody-Mediated Rejection (AMR)

Pathophysiology

• Mediated by donor-specific antibodies (DSA) against HLA Class I and II
• DSA bind endothelium → complement activation → C4d deposition → neutrophilic capillaritis
• Can be acute (early) or chronic

Histological Hallmarks (ISHLT 2016 Criteria)

• Neutrophilic capillaritis
• C4d deposition in alveolar capillaries (by immunofluorescence or immunohistochemistry)
• Circulating DSA (detected by Luminex single-antigen bead assay)

Clinical Features

• Acute: rapidly progressive respiratory failure, diffuse alveolar damage
• Chronic: contributes to CLAD

Treatment of AMR

---

4. Chronic Lung Allograft Dysfunction (CLAD)

Phenotypes

A. Bronchiolitis Obliterans Syndrome (BOS) — Most Common (~70%)

• Obstructive phenotype
• Fibro-inflammatory obliteration of small airways (bronchioles)
• FEV1 decline, air trapping on CT

B. Restrictive Allograft Syndrome (RAS) — ~30%

• Restrictive phenotype
• TLC and FVC decline
• Peripheral/upper lobe fibrosis on CT
• Worse prognosis than BOS

Pathophysiology of CLAD

• Repeated immunological injury → epithelial damage → aberrant repair
• Transforming growth factor-β (TGF-β) drives fibrogenesis
• Lymphocytic bronchiolitis (B2R ACR) and AMR are key precursors
• Non-immunological triggers: GERD, infections (CMV, Pseudomonas), primary graft dysfunction

---

BOS Staging (ISHLT)

CT Findings in CLAD/BOS

Treatment of CLAD/BOS

---

Maintenance Immunosuppression — The Triple Regimen

---

Surveillance & Monitoring

---

High-Yield Summary for MD Exam

---

• ACR graded on ISHLT A (vascular) and B (airway) scales — A2 and above requires treatment
• BOS is the most common form of chronic rejection; diagnosed by FEV1 <80% of baseline on two occasions ≥3 weeks apart with no reversible cause
• Always rule out infection before treating rejection (bronchoscopy + BAL)
• Azithromycin is unique — it has immunomodulatory properties and can stabilize or partially reverse BOS
• Lung transplant rejection rates are higher than other solid organs due to constant alloantigen exposure from the environment
• Retransplantation is the only definitive treatment for end-stage CLAD but remains controversial

---

Lung Transplant Rejection — Complete MD Exam Guide

---

Why Lungs Are Uniquely Prone to Rejection

• Continuous exposure to inhaled environmental antigens and pathogens
• Rich resident lymphocyte population and dendritic cell network
• Direct airway communication with the outside world
• High MHC expression on bronchial epithelium and vascular endothelium

~50% of recipients have at least one acute rejection episode in year 1; ~50% develop chronic rejection by 5 years (Harrison's 21st ed., p. 8150). Greater immunosuppression is required compared to other solid organs, which significantly increases drug toxicity risk (Bailey & Love's, p. 1666).

---

Classification of Rejection

---

1. Hyperacute Rejection

Mechanism

• Preformed anti-HLA or anti-ABO antibodies in recipient bind donor endothelium
• Immediate complement activation → neutrophil influx → microvascular thrombosis → hemorrhagic infarction
• Essentially massive antibody-mediated destruction

Clinical Features

• Occurs within minutes to hours of reperfusion
• Catastrophic hypoxemia, bilateral white-out on CXR, graft failure on the table
• Essentially irreversible once established

Treatment & Prevention

---

2. Acute Cellular Rejection (ACR)

Pathophysiology

• CD4+ and CD8+ T-lymphocytes recognize donor MHC via:
  • Direct pathway: recipient T-cells recognize intact donor MHC on donor APCs
  • Indirect pathway: recipient T-cells recognize processed donor peptides on self-APCs
• Activated T-cells release IL-2, IFN-γ → lymphocytic infiltration of perivascular and peribronchial tissue
• CMV infection is the strongest trigger — upregulates MHC expression and co-stimulatory molecules (Harrison's, p. 8150)
• ACR is a major independent risk factor for CLAD

Clinical Features

• Fever, malaise, dyspnea, decreased exercise tolerance
• Decline in FEV1 (≥10–15% from personal best)
• Hypoxemia, new bilateral infiltrates on CXR/CT
• Often asymptomatic — detected only on surveillance bronchoscopy

---

ISHLT Histological Grading of ACR

A-Grade: Perivascular Rejection

A2 and above requires treatment. A1 may be treated depending on clinical context.

B-Grade: Lymphocytic Bronchiolitis (Airway Rejection)

---

Diagnosis of ACR

Treatment of ACR

First-Line

• IV methylprednisolone 500–1000 mg/day × 3 days — response rate ~80–90%
• Followed by oral prednisone taper

After Pulse Steroids

• Optimize baseline immunosuppression:
  • Check/increase tacrolimus trough levels (target 10–15 ng/mL early)
  • Maximize mycophenolate mofetil (MMF) dose

Steroid-Refractory ACR

---

3. Antibody-Mediated Rejection (AMR)

Pathophysiology

• Donor-specific antibodies (DSA) against HLA Class I and II (detected by Luminex single-antigen bead assay)
• DSA bind endothelium → activate complement cascade → C4d deposition in alveolar capillaries → neutrophilic capillaritis → microvascular injury (Harrison's, p. 8150)
• Can be de novo (post-transplant sensitization) or from pre-formed antibodies

ISHLT 2016 Diagnostic Criteria for AMR (all required):

1. Allograft dysfunction (PGD, declining FEV1, or new infiltrates)
2. DSA positivity (circulating anti-HLA antibodies)
3. Histology: neutrophilic capillaritis ± diffuse alveolar damage
4. C4d deposition in alveolar capillaries (immunofluorescence or IHC)

Treatment of AMR — Multimodal Strategy

---

4. Chronic Lung Allograft Dysfunction (CLAD)

Two Major Phenotypes

---

BOS Staging (ISHLT)

---

CT Findings in BOS / CLAD

---

Pathogenesis of CLAD

Alloimmune injury (ACR, AMR)
     ↓
Epithelial and endothelial damage
     ↓
Aberrant repair → TGF-β↑, fibroblast activation
     ↓
Submucosal fibrosis → luminal obliteration (BOS)
OR
Pleuroparenchymal fibrosis (RAS)

• GERD with microaspiration (very important)
• CMV, Pseudomonas, Aspergillus infections
• Primary graft dysfunction (PGD)
• Air pollution exposure

---

Treatment of CLAD/BOS

---

Maintenance Immunosuppression — Triple Therapy

• Basiliximab (anti-IL-2Rα/CD25) — most common; IL-2 receptor blockade
• ATG (antithymocyte globulin) — T-cell depletion; used in higher-risk patients
• Not universally applied; significant infection/malignancy risk limits use despite survival benefit (Bailey & Love's, p. 1666)

• Block mTOR → ↓T-cell and B-cell proliferation
• Used as CNI-sparing agents (nephroprotective)
• Some evidence for reducing CLAD progression
• Contraindicated early post-operatively — impairs bronchial anastomotic healing

---

Surveillance Protocol Post-Transplant

---

High-Yield Comparison Table

---

Key Exam Points to Remember

1. Always exclude infection before treating rejection — BAL at bronchoscopy is mandatory; infection and rejection can coexist and mimic each other
2. ACR grade A2 and above always requires treatment; grade A1 may be observed or treated based on clinical context
3. BOS is the most common chronic rejection form (~70% of CLAD); diagnosed by FEV1 <80% of best post-transplant value on two occasions ≥3 weeks apart
4. Azithromycin is the cornerstone of BOS treatment due to its immunomodulatory (not just antimicrobial) properties
5. Lungs require more aggressive immunosuppression than other solid organs, increasing risks of infection, nephrotoxicity, diabetes, hypertension, and malignancy
6. CMV infection is the single most important trigger for ACR
7. GERD/microaspiration is a key modifiable non-immunological risk factor for CLAD — fundoplication may slow progression
8. mTOR inhibitors must be avoided immediately post-transplant (impair anastomotic healing) but have a role later as CNI-sparing/anti-fibrotic agents
9. RAS phenotype carries a worse prognosis than BOS and does not respond as well to standard BOS therapies
10. Retransplantation is the only definitive treatment for end-stage CLAD but outcomes are inferior to primary transplant