Lung Transplantation

Introduction

Historical Background

• First human lung transplant attempted by James Hardy in 1963 at the University of Mississippi - the recipient survived only 18 days.
• The modern era began in 1983 when Joel Cooper (Toronto) performed the first successful single-lung transplant in a patient with pulmonary fibrosis.
• The first successful double-lung transplant followed in 1986.
• Heart-lung transplantation was initially used for isolated pulmonary disease, but with improvement in isolated lung transplant outcomes, this is now reserved for combined cardiopulmonary failure.

Indications

• Untreatable end-stage pulmonary parenchymal or vascular disease
• Substantial limitation of daily activities (NYHA class III or IV)
• Projected life expectancy <50% over 2-3 years without transplantation
• Disease-specific mortality exceeding transplant-specific mortality over 1-2 years
• Satisfactory psychosocial profile and emotional support system
• Rehabilitation potential
• Acceptable nutritional status

Contraindications

• Malignancy within the past 2-5 years (except non-melanoma skin cancer)
• Untreatable dysfunction of another major organ (heart, liver, kidneys) - unless combined transplant planned
• Active or refractory sepsis
• Non-curable chronic extrapulmonary infection (e.g., active TB, chronic active hepatitis B)
• Significant chest wall or spinal deformity
• Documented non-adherence or inability to comply with medical management

• Age >70 years
• Critical or unstable clinical condition (shock, mechanical ventilation, ECMO) - though ECMO as bridge to transplant is increasingly used
• Severely limited functional status with poor rehabilitation potential
• Colonization with highly resistant or virulent organisms (Burkholderia cenocepacia, pan-resistant Pseudomonas/Aspergillus)
• BMI >30 kg/m² (severe obesity)
• Severe or symptomatic osteoporosis
• Active smoking, alcoholism, or substance abuse

Types of Lung Transplantation

1. Single-lung transplant (SLT): Used for IPF and COPD in older patients; simpler procedure; results in higher ventilation/perfusion mismatch risk
2. Bilateral sequential (double) lung transplant (BLT): Now 75% of all lung transplants; preferred for CF, bronchiectasis, pulmonary hypertension, and younger patients; better long-term survival except in elderly fibrotic patients
3. Heart-lung transplant (HLT): Reserved for end-stage pulmonary disease with irreversible left or biventricular cardiac failure; used in Eisenmenger syndrome, complex congenital heart disease
4. Living-donor lobar transplant: Two donors each donate a lower lobe; used in Japan; now rare in Western countries

Donor Selection

• Age <55 years
• Smoking history <20 pack-years
• Clear chest X-ray
• No purulent secretions on bronchoscopy
• No significant chest trauma
• PaO2:FiO2 ratio >300 on FiO2 1.0 and PEEP 5 cmH2O

• DCD donors (Donation after Cardiac Death): growing in use in Europe and Australia (4.8% of US lung donors in 2018)
• Extended criteria donors: do not meet all ideal criteria but can give good outcomes
• HCV-infected donors: now acceptable with direct-acting antivirals (DAA) therapy post-transplant
• Ex vivo lung perfusion (EVLP): allows assessment and reconditioning of marginal donor lungs before implantation - major advance in expanding donor pool

Surgical Technique

• Incision: Bilateral sequential transplant can be performed through clamshell (bilateral thoracosternotomy), median sternotomy, or bilateral anterior thoracotomies
• Airway management: Double-lumen endotracheal tube for one-lung ventilation and direct bronchial access
• Anastomoses (bronchial first, then pulmonary artery, then pulmonary veins/left atrium): Bronchial anastomosis using a "telescoping" technique reduces the incidence of bronchial dehiscence
• Cardiopulmonary bypass (CPB): Used when hemodynamics deteriorate or in pulmonary hypertension; ECMO is increasingly preferred over traditional CPB
• Monitoring: Invasive arterial line, PA catheter, TEE

Immunosuppression

1. Calcineurin inhibitor: Tacrolimus (preferred) or cyclosporine
2. Antimetabolite: Mycophenolate mofetil or azathioprine
3. Corticosteroids: Prednisolone (chronic low-dose)

Complications

1. Primary Graft Dysfunction (PGD)

• Commonest cause of early morbidity and mortality
• An acute lung injury syndrome occurring within the first 72 hours post-transplant
• Characterized by diffuse allograft infiltrates + hypoxemia (PaO2/FiO2 <300) in the absence of other identifiable cause
• Graded 0-3 by ISHLT criteria based on P/F ratio
• Risk factors: recipient pulmonary hypertension, obesity, use of CPB; donor smoking history, high BMI, cause of death
• Treatment: lung-protective ventilation, inhaled NO, ECMO if severe
• Long-term consequence: strong risk factor for bronchiolitis obliterans syndrome

2. Airway Complications

• Bronchial anastomotic dehiscence: Reduced dramatically with telescoping technique; incidence now <3%
• Bronchial stenosis: More common; managed with balloon dilation or stenting
• Bronchomalacia

3. Acute Cellular Rejection (ACR)

• Occurs in approximately 30% of recipients
• Most common in the first year
• Clinical features: dyspnea, fever, hypoxia, perihilar infiltrates, declining spirometry
• Diagnosis: transbronchial biopsy - perivascular mononuclear infiltrates (graded A0-A4 by ISHLT)
• Treatment: high-dose IV methylprednisolone (1 g/day x 3 days)

4. Chronic Lung Allograft Dysfunction (CLAD)

• Leading cause of late morbidity and mortality after lung transplantation (affects ~50% by 5 years)
• Two main phenotypes:
  • Bronchiolitis Obliterans Syndrome (BOS): Obstructive pattern; progressive irreversible decline in FEV1; fibrous obliteration of small airways; diagnosed clinically by sustained fall in FEV1 to <80% of baseline; BOS grades 0-3
  • Restrictive Allograft Syndrome (RAS): Restrictive pattern with upper lobe fibrosis; diffuse alveolar damage; worse prognosis than BOS
• Risk factors: acute rejection episodes, lymphocytic bronchiolitis, PGD, CMV infection, GERD
• Treatment: augmented immunosuppression (azithromycin, extracorporeal photopheresis), re-transplantation in selected cases

5. Infectious Complications

• Bacterial infections (most common early): gram-negative organisms, Pseudomonas
• Fungal infections: Aspergillus (prophylaxis with voriconazole/itraconazole)
• Viral infections: CMV (most important - prophylaxis with valganciclovir), EBV
• PCP pneumonia: Prophylaxis with TMP-SMX

6. Post-transplant Lymphoproliferative Disorder (PTLD)

• Incidence 5% at 1 year, 20% at 5 years for any malignancy
• PTLD = 18% of malignancies at 1 year
• Usually EBV-driven B-cell proliferation under therapeutic immunosuppression
• Risk: EBV-negative recipient receiving seropositive donor lung
• Treatment: reduction of immunosuppression, rituximab, chemotherapy

7. Other malignancies

• Skin cancers (squamous cell carcinoma, basal cell carcinoma) = 35% of malignancies
• Significantly increased risk with prolonged voriconazole use

Outcomes and Survival

• Median survival: Approximately 6-7 years (ISHLT Registry)
• 5-year survival: 50-60%; better with bilateral vs. single lung transplants (except elderly IPF patients where no difference exists)
• Causes of death by time period:
  • Early (<30 days): PGD, surgical complications
  • 30 days to 1 year: Infection (bacterial, fungal, viral)

  • 1 year: CLAD/BOS, malignancy, infections

Scoring and Allocation

• In the USA, the Lung Allocation Score (LAS) introduced in 2005 replaced time-on-waitlist with a medical urgency/benefit-based score; this reduced waiting list mortality but increased sicker candidates being transplanted
• Median wait time has decreased to approximately 2.5 months with modern allocation

Key Points for Exam

• CF patients must receive bilateral transplantation (infected contralateral lung would seed the allograft)
• IPF is now the #1 indication in the United States since 2007
• BOS is the #1 cause of late death and the major obstacle to better long-term outcomes
• PGD in the first 72 hours is distinct from hyperacute rejection (antibody-mediated) and ACR
• Ischemic time must be kept <4-6 hours; EVLP is used to recondition marginal donor lungs
• Bronchial anastomosis heals by collateral circulation from pulmonary vessels (bronchial artery supply is interrupted); this makes it the "Achilles heel" of the operation