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Lung transplantation 

Lung transplantation
Chapter:
Lung transplantation
Author(s):

Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

DOI:
10.1093/med/9780198703860.003.0032
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date: 26 October 2021

Patient selection

Lung transplantation was first performed successfully in the 1980s. Since then, the number of candidates for transplantation has increased significantly. However, there is a significant shortage of donor organs, and so an increasing number of patients (up to 10–15%) die on the waiting list. There are five UK transplant centres: Harefield, Papworth, Birmingham, Manchester, and Newcastle. ~175 lung transplants and five heart–lung transplants were carried out in the UK in 2011 (source: NHS Blood and Transplant). Worldwide, 3, 000 lung transplants were carried out in 2009, from International Society of Heart and Lung Transplantation Registry data. Average waiting times in the UK are around 12 months for lung transplantation and 16 months for heart–lung transplantation. Matching is carried out according to patient size and major blood groups; HLA matching is not carried out.

Underlying conditions

Most common diagnoses, in order:

  • COPD

  • IPF

  • CF

  • α‎1-AT deficiency

  • IPAH

  • Pulmonary fibrosis (other)

  • Bronchiectasis

  • PHT 2° to congenital cardiac disease (Eisenmenger’s syndrome)

  • Others, including sarcoidosis, LAM, LCH, collagen vascular disease-related lung disease, bronchoalveolar cell carcinoma (successful transplantation has been carried out, although tumour recurrence in the donor lung is common).

Indications

Referral for transplant assessment should be considered in patients with progressive, chronic end-stage lung disease, despite maximal medical therapy, whose life expectancy is 2–3y or less (so that transplantation would be expected to prolong their survival). Candidates should be functionally disabled but still able to walk, with no significant untreatable cardiac, renal, or hepatic impairment. Suggested age limits are 55y for heart–lung, 60y for bilateral lung, and 65y for single-lung transplant.

General referral criteria for lung transplantation

  • Normal renal function, with creatinine clearance >50mL/min

  • Normal LV function and normal coronary arteries/coronary artery disease not amenable to intervention

  • Preserved liver synthetic function

  • No osteoporosis

  • No systemic sepsis

  • BMI >17 or <30

  • No untreatable psychiatric disorder

  • No history of malignancy within 5y

  • Reliable social support.

Contraindications

Absolute (although occasional exceptions may occur)

  • Severe, untreatable extrapulmonary organ dysfunction (including renal, hepatic, and cardiac disease)

  • Active cancer or recent history (within 2y) of cancer with substantial likelihood of recurrence; a 5y disease-free interval is recommended (excluding cutaneous squamous or basal cell carcinomas)

  • Severe untreatable psychiatric illness or non-compliance with treatment/follow-up

  • Incurable chronic extrapulmonary infection (including HIV, active hepatitis B and C)

  • Active or recent (6 months) substance addiction (cigarette smoking, alcohol, narcotics)

  • Significant chest wall/spinal deformity.

Relative

  • Age >65y

  • Chronic medical conditions that are poorly controlled or associated with target-organ damage (hypertension, diabetes, coronary artery disease)

  • Severe or symptomatic osteoporosis (risk of post-transplant fractures and poor QoL; start treatment prior to transplant)

  • Severe obesity (BMI >30) or malnutrition (BMI <17)

  • Poor rehabilitation potential

  • Mechanical ventilation (excluding NIV) or acute critical illness

  • Extensive pleural thickening (from infection or prior surgery, e.g. pleurodesis)—procedure is technically more difficult

  • Active collagen vascular disease

  • Preoperative colonization of the airway with pan-resistant bacteria, fungi, or Mycobacterium in CF; there are no clear data to support exclusion of pan-resistant Pseudomonas, although it remains a relative contraindication in some centres. B. cepacia colonization (particularly with genomovar III), however, is high risk and an absolute contraindication in many centres.

Contentious

  • NTM, especially M. chelonae

  • Aspergilloma (ABPA is not generally a contraindication, though patients would not be transplanted during an exacerbation and would be treated with prophylactic voriconazole)

  • Portal hypertension (prophylactic variceal sclerotherapy may be offered).

Further information

Orens JB et al. International guidelines for the selection of lung transplant candidates: 2006 update. J Heart Lung Transplant 2006;25:745–55.Find this resource:

Glanville AR, Estenne M. Indications, patient selection and timing of referral for lung transplantation. Eur Resp J 2003;22:845–52.Find this resource:

Specific conditions

Timing of referral

This can be difficult; life expectancy should be <2–3y, but patients must be fit for the procedure during a waiting time of up to 16 months. The decision should not be based on a single factor; instead, a combination of clinical, laboratory, and functional assessments should be considered. Patients with CF and IPF have particularly high waiting list mortalities, suggesting inappropriately late referral for these conditions. Disease-specific guidelines for referral are described next:

COPD

  • BODE index >5 (incorporating BMI, FEV1, degree of dyspnoea, and 6min walk; see Lung transplantation p. [link])

  • History of hospitalization for exacerbation associated with acute hypercapnia (PaCO2 >6.7kPa; 49% 2y survival)

  • PHT or cor pulmonale despite O2 therapy

  • FEV1 <20% predicted and either TLCO <20% or homogeneous distribution of emphysema (median survival 3y with medical therapy)

  • Patients should be on maximal medical therapy, have completed pulmonary rehabilitation, have stopped smoking for at least 6 months (if in doubt, check urinary cotinine levels), and ideally <60y old.

IPF

  • Given the poor prognosis and high waiting list mortality associated with IPF, guidelines recommend referral of all suitable patients with histological or radiographic evidence of UIP, irrespective of VC and without delaying for trials of treatment; these are not widely applied in the UK

  • TLCO <40% predicted, fall in FVC ≥10% over 6 months, O2 desaturation <88% on 6min walk, honeycombing on HRCT (each associated with high mortality).

CF

  • Defining referral criteria is especially difficult for patients with CF, due to considerable inter-individual variation in course and prognosis

  • FEV1 ≤30% predicted or FEV1 >30%, with rapid progressive deterioration, e.g. increasing frequency of exacerbations, rapid fall in FEV1

  • History of ITU admission for pulmonary exacerbation

  • O2-dependent respiratory failure, hypercapnia, or PHT

  • Severe recurrent haemoptysis despite embolization

  • Refractory and/or recurrent pneumothorax

  • Young (<20y) ♀ patients with rapid deterioration have a poor prognosis and should be considered for early referral

  • Invasive ventilation is a contraindication in most centres.

IPAH

  • New York Heart Association (NYHA) functional class III or IV, rapidly progressive disease/failing medical therapy, low (<350m) or declining 6MWT, mean right atrial pressure >15mmHg, cardiac index <2L/min/m2.

Investigations and surgical approaches

Investigations prior to referral

Consult transplant referral centre for details, and avoid repetition of investigations. Important investigations include full PFTs, tests of exercise performance (e.g. 6min walk), sputum microbiology, ECG, echo, HRCT chest, LFTs, viral serology (e.g. HIV, CMV, hepatitis B and C), 24h creatinine clearance, stress echo, and/or coronary angiography. If on waiting list, inform transplant centre of changes in clinical condition. Remember that the referring physician remains responsible for continuing regular medical care of the patient to ensure they remain optimally treated during the waiting period, with particular attention to:

  • Maintenance of nutrition (may require PEG feeding)

  • Avoidance of obesity

  • Maintenance of mobility, continuing exercise, and rehabilitation

  • Monitoring comorbid disease: heart, kidney, liver, bones. Optimize treatment of diabetes, systemic hypertension, osteoporosis, peptic ulcer disease, gastro-oesophageal reflux and sinus disease

  • Early NIV, if indicated

  • Avoiding intubation, if possible.

Surgical approaches for transplant

Single lung

  • Technically easier, allows two recipients from one donor

  • Generally now only used in ILD

  • Overdistension of the compliant native lung in emphysema is uncommon but may be problematic.

Bilateral sequential

  • Worldwide, 80% of lung transplants are now double

  • Sequential right and left single-lung transplants at one time

  • Selective lung ventilation may render cardiopulmonary bypass unnecessary.

Heart–lung

  • Indicated in Eisenmenger’s syndrome, or advanced lung disease with concurrent LV dysfunction or coronary disease

  • Cor pulmonale is not in itself an indication, as RVH resolves rapidly following lung transplantation alone

  • Certain patients without cardiac disease may undergo a ‘domino’ procedure where they receive a combined heart–lung transplant, because this is technically easier and their healthy heart is then used for a patient needing a heart transplant.

Living lobar transplantation

  • Bilateral grafting of lower lobes from two living adult donors to replace lungs of child or small adult

  • Appears to be safe for the donor, with lung volume reductions of about 15%, but potential for 300% overall mortality (two donors and one recipient)

  • Not widely performed in the UK.

Follow-up

Patients are usually discharged about 1 month after transplant, following post-transplant bronchoscopy with BAL and biopsy. They will be followed up closely by their transplant centre but may also attend general respiratory clinics intermittently between transplant centre visits. Be alert to possible complications (see Lung transplantation pp. [link][link]). Spirometric values are generally very stable from 3 months after transplantation, and sustained falls ≥10–15% warrant further investigation. Remember drug interactions (particularly ciclosporin and tacrolimus) if new medications are added. Check immunosuppressant drug blood levels, and perform routine blood tests, according to the local transplant centre policy.

Outcomes

Survival

  • Survival rates: 85% 1y, 63% 3y, 50% 5y. Median survival is 5.5y from 2011 report of International Society of Heart and Lung Transplantation

  • Bilateral lung transplant recipients have better median survival than single—6.8y vs 4.7y. Reason unclear: may relate to procedure or selection factors

  • Compared with patients on the waiting list, lung transplant conveys a survival benefit to patients with CF and IPF, but not emphysema

  • Rate of death is highest in first year (infection, 1° graft failure)

  • Risk factors for early death are pre-existing PHT, ventilator dependence, recipient age >50, donor age >50

  • No survival difference between single- and double-lung transplant.

Functional

  • Lung function usually normalizes after bilateral transplant and markedly improves following single-lung transplant. In COPD, FEV1 increases to 50–60% of predicted value after single-lung transplant

  • Arterial oxygenation rapidly normalizes

  • 6min walk distance typically doubles; most patients resume active lifestyle, although fewer than 40% of patients return to work

  • Limited data on QoL; initial improvement suggested, but effects after 1y are unclear. ~85% survivors have no functional limitations after 5y.

Routine surgery after lung transplant

Routine surgery >3 months after transplant can be carried out locally, but inform the transplant centre. Routine antibiotic prophylaxis is adequate; there is no increased risk of SBE. The morning dose of calcineurin inhibitor (ciclosporin, tacrolimus) should be omitted, as there is a risk of nephrotoxicity with hypovolaemia.

Future developments

are likely to address both the development of more effective treatments for chronic rejection (new immunosuppressive drugs, induction of immune tolerance) and the shortage of donor organs (e.g. living lobar transplantation, xenotransplantation, and further research in lung preservation. Ex vivo lung perfusion (EVLP) is now undergoing clinical trials to try to increase the number of organs available for transplant. This involves controlled perfusion and ventilation of donor lungs for a number of hours in an attempt to improve the quality of donor organs, to make previously unusable organs suitable for transplantation.

Complications 1

Early graft dysfunction

  • Characterized by pulmonary infiltrates, hypoxaemia, and diffuse alveolar damage or OP on biopsy; not uncommon during first few days after transplant. Clinical severity ranges from very mild acute lung injury to ARDS

  • Presumably related to preservation and ischaemia–reperfusion injury

  • Exclude other causes, e.g. volume overload, pneumonia, rejection, occlusion of venous anastomosis, aspiration

  • Treatment is supportive (mechanical ventilation)

  • High mortality (40–60%).

Airway complications

  • Anastomotic stenosis most common and typically occurs weeks to months after transplant; suggested clinically by localized wheeze, recurrent pneumonia, or suboptimal lung function. Treat with balloon dilatation (sometimes repeated) or stent placement via bronchoscopy

  • Complete dehiscence of bronchial anastomosis now rare and requires immediate surgery or retransplantation

  • Partial dehiscence is managed conservatively; drain pneumothorax; reduce steroid dose.

Infection

Bacteria

  • May occur early (first month after transplant) or late (associated with BOS)

  • Most commonly due to Gram-negative organisms, particularly Pseudomonas aeruginosa

  • Recipients with CF are not at greater risk than other patients; an exception is B. cepacia colonization, which is associated with a high risk of often lethal post-operative infections.

CMV

  • CMV-seronegative recipients from seropositive donors are at particular risk of severe infection, including pneumonitis; this is usually treated successfully with ganciclovir

  • Increases risk of bacterial or fungal superinfection

  • Ganciclovir prophylaxis probably results in later, less severe infection

  • CMV infection may be a risk factor for development of BOS.

Aspergillus

  • Aspergillus frequently colonizes the airways after lung transplant, but clinically apparent infection develops in only a minority of patients

  • Peak disease incidence at 2 months after transplant

  • Sites of disease include airways (may lead to mucosal oedema, ulceration, and pseudomembranes; usually responds to itraconazole, voriconazole, or amphotericin B), fresh bronchial anastomosis, lung parenchyma, and disseminated aspergillosis (associated with high mortality).

Drug-related

Immunosuppressive drugs must be taken lifelong following transplantation. Agents used include ciclosporin or tacrolimus, azathioprine or mycophenolate mofetil (MMF), and prednisolone. They are associated with many drug interactions and side effects, particularly nephrotoxicity and osteoporosis. Ciclosporin and tacrolimus blood levels need to be closely monitored.

Further information

Kotloff A. Medical complications of lung transplantation. Eur Resp J 2004;23:334–42.Find this resource:

Knoop C et al. Immunosuppressive therapy after human lung transplantation. Eur Resp J 2004;23:159–71.Find this resource:

Complications 2

Acute rejection

  • Very common, particularly within 3 months of transplant

  • Affects approximately 60% in the first year. Rare after 12 months

  • Asymptomatic or may be associated with malaise, fever, dyspnoea, cough, hypoxia. May present similarly to pneumonia or COP

  • CXR may be normal or show non-specific infiltrates

  • Common finding is fall in spirometry >10%, although this does not distinguish from other complications, particularly infection

  • Refer back to the transplant centre if these problems develop within 3 months of the transplant

  • Ideally confirm histologically: TBBs are safe and typically show perivascular lymphocytic infiltrates. Routine surveillance TBBs are increasingly used to detect acute rejection prior to falls in lung function

  • Treatment IV methylprednisolone pulses are given within the first 3 months of transplant; after this, high-dose oral corticosteroids are used. The majority of patients respond quickly; consider switching immunosuppressive agent from ciclosporin to tacrolimus if ongoing or recurrent acute rejection

  • Recurrent acute rejection is the main risk factor for the development of chronic rejection

  • Acute rejection is an uncommon cause of breathlessness after 3 months, and other common causes of SOB should be considered.

Chronic rejection

  • A significant problem, accounting for poor long-term prognosis following lung transplant

  • Uncommon in first 6 months, but prevalence subsequently increases steadily, affecting 50–60% of patients at 5y

  • Pathogenesis Incompletely understood, likely involves immune-mediated injury to epithelial and endothelial cells, possibly with an environmental trigger; risk factors for development include previous episodes of recurrent acute rejection, CMV pneumonitis, presence of anti-HLA antibodies pre-transplant, gastro-oesophageal reflux, community respiratory infections, and medical non-compliance

  • Clinically Insidious onset of breathlessness and cough, and progressive airflow obstruction on spirometry

  • Manifest histologically as bronchiolitis obliterans, a fibroproliferative process affecting small airways. Histological confirmation is difficult: TBBs have a low sensitivity, so a clinical diagnosis of ‘BOS’ is defined as an unexplained and sustained (≥3 weeks) fall in FEV1 to <80% of peak value post-transplant. ‘Potential BOS’ is defined as FEV1 81–90% of baseline and/or forced mid-expiratory flow (FEV2575%) to ≤75% of baseline and indicates the need for close monitoring/further investigation

  • CXR unhelpful; HRCT may show expiratory air trapping and peripheral bronchiectasis

  • P. aeruginosa colonization is common, with recurrent purulent tracheobronchitis

  • Treatment is challenging and involves either modified or increased immunosuppression (e.g. switch ciclosporin to tacrolimus; MMF to azathioprine, high-dose steroid pulses, and antilymphocyte antibodies; inhaled ciclosporin may have a role), and, if effective, this acts only to reduce the rate of disease progression. Infection is investigated and treated aggressively, sometimes with reductions in immunosuppression. Azithromycin is often used for deteriorating BOS. Gastro-oesophageal reflux is treated, sometimes with surgery. Total lymphoid irradiation is sometimes recommended when other immunomodulatory treatments have failed

  • Prognosis is poor: mortality is 40% within 2y of diagnosis; the rate of decline is very variable between individuals

  • Retransplantation is the only definitive treatment and is controversial.

Recurrence of primary disease

Documented in sarcoidosis, LAM, giant cell interstitial pneumonitis, diffuse pan-bronchiolitis, and bronchoalveolar cell carcinoma.

Malignancy

Increased risk of certain malignancies, e.g. lymphoma (and other EBV-related post-transplant lymphoproliferative diseases), skin, lip, vulval, and perineal carcinomas, in situ cervical cancer, and Kaposi’s sarcoma.

  • Most lymphomas appear within the first year, and the lung allograft is the most common site of involvement, with pulmonary nodule(s) ± mediastinal lymphadenopathy. Lymphocyte aggregates from acute rejection may mimic the appearance of post-transplant lymphoproliferative disease on small TBB specimens. Lymphomas presenting after the first year are more commonly disseminated or intra-abdominal (e.g. presenting with tonsillar enlargement, peripheral lymphadenopathy, skin nodules, or bowel complications such as intussusception). Patients should be referred back to the transplant centre for treatment, rather than the local haematologist. The usual treatment is a reduction in immunosuppression or rituximab (monoclonal antibody against CD20 on B cells)

  • Lung cancer occurs in patients with COPD and IPF. Unclear if transplantation itself increases the risk of lung cancer. May progress unusually rapidly, mimicking infection.

Differential diagnosis of CXR nodules following lung transplant

  • Post-transplant lymphoproliferative disease

  • Infection (Pseudomonas, Nocardia, aspergilloma, TB)

  • Disease recurrence

  • 1° lung cancer.