Lung transplantation
What it offers
- Definitive therapy for end-stage lung disease when medical therapy is exhausted
- Trades a fatal lung disease for a chronic, immunosuppressed, allograft disease - it prolongs and improves life, it does not cure
Procedure types
| Used for | |
|---|---|
| Bilateral sequential | CF, bronchiectasis (mandatory - suppurative), PAH, most COPD and ILD now |
| Single | Selected ILD, COPD in older recipients; donor-sparing |
| Heart-lung | Eisenmenger with uncorrectable defect, PAH with irreversible RV failure |
| Lobar / living donor | Size mismatch, paediatric |
- *Any suppurative lung disease requires bilateral transplant* - a retained native lung seeds the graft
- Median survival ~6.7 yr overall; ~8-9 yr for bilateral, ~5 yr for single; better for CF, worse for IPF and older recipients
Activity in Australia
- ~200 lung transplants/yr in Australia (Alfred, St Vincent's Sydney, Prince Charles Brisbane, Fiona Stanley Perth)
- Commonest indications: COPD/emphysema, IPF and other fibrotic ILD, CF, PAH
- CF referrals have fallen sharply since CFTR modulators; fibrotic ILD now the largest group
- ~1-year survival 85-90%; the steepest attrition is in the first year (primary graft dysfunction, infection) and after year 3 (CLAD)
Why the lung is the hardest organ to transplant
- Continuously exposed to the environment - inhaled pathogens and antigens
- Large mucosal lymphoid burden, high immunogenicity
- Denervated below the anastomosis -> absent cough reflex below the suture line -> aspiration and retention
- Impaired mucociliary clearance
- Bronchial circulation not routinely re-anastomosed -> ischaemic airway anastomosis -> stenosis, dehiscence, malacia
- -> highest rate of chronic rejection and lowest survival of any solid organ transplant
Rejection mechanisms
- Primary graft dysfunction (PGD) - ischaemia-reperfusion injury; ARDS-like in the first 72 h; the strongest risk factor for later CLAD
- Acute cellular rejection - perivascular lymphocytic infiltrate (graded A0-A4); peaks in the first year
- Antibody-mediated rejection - donor-specific antibodies (DSA), C4d deposition
- CLAD - chronic; the final common pathway
- BOS (obstructive) - obliterative bronchiolitis; fibrous obliteration of small airways; ~70%
- RAS (restrictive) - pleuroparenchymal fibroelastosis pattern; worse prognosis
Who to refer, and when
*Refer early - waitlist mortality is the main cause of death in IPF and PAH.*
- General referral criteria: severe end-stage lung disease, exhausted medical therapy, estimated survival <2-3 yr without transplant, ambulatory with rehabilitation potential, no other failing major organ, adequate psychosocial support and adherence
| Disease | Refer when |
|---|---|
| COPD | BODE 5-7, FEV1 <25%, PaCO2 >50 mmHg or PaO2 <60 mmHg, progressive despite maximal therapy, not LVRS-eligible, frequent exacerbations |
| IPF / fibrotic ILD | *Refer at diagnosis. DLCO <40% or falling, FVC <80% or dec >=10% in 6 months*, any O2 requirement, PH |
| CF / bronchiectasis | FEV1 <30% and falling, rapid decline, hypercapnia, PH, frequent exacerbations or ICU admissions, massive haemoptysis, pneumothorax |
| PAH | High-risk on REVEAL/ESC risk score despite maximal therapy incl. parenteral prostacyclin, RV failure, syncope, haemoptysis |
- In IPF, DLCO is a more sensitive trigger than FVC - a rapidly falling DLCO is the classic listing indication
Contraindications - ISHLT 2021
Contraindications - ISHLT 2021 substantially narrowed these
Absolute
- Malignancy with high recurrence risk (intervals are tumour-specific, not a blanket 5 years)
- Untreatable dysfunction of another major organ not amenable to combined transplant
- Uncontrolled or untreatable systemic infection
- Significant unrevascularisable CAD or LVEF <40%
- Severe cerebrovascular disease
- Documented non-adherence or refusal of treatment; untreatable severe psychiatric illness
- Absent social support
- Substance use (tobacco, alcohol, other drugs) within ~6 months
- Severe chest wall/spinal deformity, severe obesity
- *Age is NOT an absolute contraindication. ISHLT 2021 lists age >70 as a relative contraindication/risk factor, superseding the older 55/60/65 cut-offs for heart-lung/bilateral/single transplant - physiological age and comorbidity burden decide*
Relative
- Age >70, frailty, BMI >30 or <16, osteoporosis, poor rehabilitation potential
- *Colonisation with resistant organisms - Burkholderia cenocepacia, M. abscessus, Lomentospora/Scedosporium** (markedly worse outcomes; some centres regard B. cenocepacia as absolute*)
- Prior thoracic surgery/pleurodesis, mechanical ventilation or ECMO (bridging is now done in selected centres)
- HIV, hepatitis B/C - now transplantable with controlled viraemia
Post-transplant monitoring
- Home spirometry daily - a sustained fall in FEV1 or FVC >10-15% triggers investigation
- Lung function plateaus by ~3 months - that value becomes the personal baseline for CLAD definitions
- Surveillance bronchoscopy with transbronchial biopsy and BAL - frequent in year 1
- CXR/CT, immunosuppressant trough levels, FBC, UEC, CRP, CMV PCR, donor-specific antibody screening
- Skin surveillance, cancer screening, bone density, metabolic screening
Interpreting a deteriorating graft
| Pattern | Think |
|---|---|
| Early (<72 h), diffuse infiltrates, hypoxaemia | Primary graft dysfunction |
| Weeks-months, dec FEV1, infiltrates, responds to steroid | Acute cellular rejection |
| Fever, infiltrates, dec FEV1 | Infection - the great mimic; bronchoscopy before escalating immunosuppression |
| New obstructive defect, dec FEV1 not reversible | BOS / CLAD |
| Restrictive defect + upper zone fibrosis | RAS phenotype of CLAD |
| Focal, at the anastomosis | Airway stenosis or malacia |
1. Immunosuppression
- Induction: basiliximab (IL-2R antagonist) or ATG in most centres
- Maintenance - triple therapy, higher intensity than any other organ
- Calcineurin inhibitor - tacrolimus (preferred) or ciclosporin
- Antiproliferative - mycophenolate or azathioprine
- Prednisolone - usually continued long-term (unlike kidney)
- mTOR inhibitors (sirolimus, everolimus) are avoided early - impair bronchial anastomotic healing
- CF-specific: malabsorption makes calcineurin inhibitor absorption erratic - higher doses, frequent levels; CFTR modulators and azole antifungals both interact with CYP3A4
2. Infection prophylaxis
2. Infection prophylaxis - a defining part of care
- Co-trimoxazole - lifelong PJP prophylaxis (also covers Toxoplasma, Nocardia)
- Valganciclovir - CMV prophylaxis, especially D+/R- (highest risk)
- Antifungal (itraconazole/voriconazole or nebulised amphotericin) for Aspergillus, particularly with airway colonisation
- Vaccination before transplant; no live vaccines afterwards
- Sun protection from day one
3. Acute rejection
- Pulse methylprednisolone; augment maintenance
- AMR: plasma exchange, IVIg, rituximab, bortezomib
- *Always exclude infection with bronchoscopy before treating a deterioration as rejection*
4. CLAD
- Azithromycin trial - the neutrophilic reversible allograft dysfunction (NRAD) subgroup responds
- Optimise immunosuppression, treat GORD (fundoplication reduces CLAD), extracorporeal photopheresis, montelukast
- No therapy reliably reverses established CLAD - re-transplantation is the only definitive option, with poorer outcomes
5. Lifelong complication surveillance
- Malignancy - skin cancer (very high; SCC dominates), PTLD (EBV-driven, highest in D+/R-, first year), lung cancer in the native lung after single transplant
- Renal impairment - calcineurin inhibitor nephrotoxicity; ~25% develop CKD
- Diabetes, hypertension, dyslipidaemia, obesity - steroids and CNI
- Osteoporosis - already present pre-transplant in most
- GORD and aspiration, gastroparesis, DIOS in CF
- Anastomotic stenosis -> balloon dilatation or stent
6. What transplantation does not fix
- *In CF: sinus disease, CFRD, liver disease, osteoporosis, DIOS and infertility all persist or worsen*
- Steroids worsen CFRD and bone disease; malabsorption complicates drug levels
- In alpha-1 antitrypsin deficiency: liver disease continues
- In systemic sclerosis or sarcoid: the systemic disease continues and may recur in the graft
- Sarcoidosis, LAM and PLCH can recur in the allograft
7. Practical points for the physician seeing a transplant recipient
- Any fever or fall in spirometry = urgent transplant-centre contact
- Never adjust immunosuppression without the transplant unit
- Check interactions before every new prescription - azoles, macrolides, rifampicin, statins, diltiazem, CFTR modulators all alter CNI levels
- Avoid nephrotoxins; use caution with NSAIDs
- A transplant recipient with pneumonia needs a broader differential: CMV, PJP, Aspergillus, Nocardia, NTM, as well as rejection
Complications
- CLAD/BOS - the dominant long-term problem
- CMV disease - pneumonitis, colitis, retinitis; independently increases CLAD risk
- Invasive aspergillosis and airway colonisation
- PJP, Nocardia, NTM, community respiratory viruses (RSV, influenza - trigger CLAD)
- PTLD and other EBV-driven lymphoproliferation
- Skin malignancy - ~50-100x risk; annual dermatology review
- CKD from calcineurin inhibitors
- Post-transplant diabetes, hypertension, dyslipidaemia
- Osteoporosis and fragility fracture
- GORD and aspiration - both cause and consequence
- Anxiety, depression, adherence difficulty
- Donor-derived infection or malignancy (rare)
Survival
- Median survival ~6.7 yr (bilateral ~8-9 yr, single ~5 yr); conditional survival improves markedly for those surviving the first year
- 1-year survival ~85-90%; best outcomes in CF and younger recipients, worst in IPF and older recipients
Causes of death by era
| Timing | Cause |
|---|---|
| <30 days | Primary graft dysfunction, technical/surgical, haemorrhage |
| 1-12 months | Infection (bacterial, CMV, fungal), acute rejection |
| >1 year | CLAD/BOS, infection, malignancy, renal failure |
- CLAD affects ~50% by 5 years and is the leading cause of late death
- Quality of life and exercise capacity typically improve dramatically in the first year
Risk factors for CLAD
- Primary graft dysfunction, recurrent or severe acute cellular rejection, lymphocytic bronchiolitis
- Donor-specific antibodies, CMV pneumonitis, community respiratory viral infection
- GORD and aspiration, Pseudomonas or Aspergillus colonisation
- Non-adherence with immunosuppression
Monitor lifelong
- Home spirometry, renal function, drug levels, glucose, lipids, bone density
- Skin checks, age-appropriate cancer screening, EBV/CMV where indicated
- A single unexplained sustained fall in FEV1 is the most important sign the patient can detect themselves
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