LUNG TRANSPLANTATION

Dr Brendan Madden MD, MSc, FRCPI, FRCP
Consultant Cardiothoracic Physician and Reader in
Cardiothoracic Medicine St George’s Hospital, London

LEARNING OBJECTIVES

The aim of this section is to provide an overview of lung transplantation to familiarise you with the type of patients who may be considered for lung transplantation, the operative techniques available and the postoperative complications and results.

INTRODUCTION

Lung transplantation has an established role in the management of a variety of pulmonary vascular and parenchymal lung diseases leading to end stage respiratory failure. The transplant operations available include single lung transplantation (SLT), bilateral sequential lung transplantation (BSLT), heart and lung transplantation (HLT) and lobar transplantation.

INDICATIONS AND CONTRAINDICATIONS TO LUNG TRANSPLANTATION

The main indications for lung transplantation are:
• Severe respiratory failure despite maximal medical therapy.
• Severely impaired quality of life.
• Patient positively wants a transplant.

Only patients who have deteriorating chronic respiratory failure should be accepted onto the transplant waiting list and in practice the FEV1 is usually less than 30% of the predicted value. Careful psychological assessment is necessary to exclude patients with intractable psychosocial instability that may interfere with their ability to cope with the operation and to comply with the strict postoperative follow up and immunosuppressive regimes. In most centres the upper age limit is 60 years for SLT and 50 years for HLT and BSLT. Contraindications to lung transplantation are listed in Table 1. Patients with cushingoid features are excluded until these changes subside with reduction in steroid therapy. There is concern that long term steroid therapy in excess of Prednisolone 10mg daily may adversely affect tissue healing and in particular healing of the major airway anastomoses after transplantation. A number of risk factors significantly increase early mortality after lung transplantation. Previous pleurodesis or thoracic surgery increases the risk of bleeding and attendant complications, patients on preoperative ventilatory support may have colonisation of their sputum with resistant bacteria and hence may develop postoperative infection and combined BSLT or HLT and liver transplantation in cystic fibrosis patients with respiratory failure and portal hypertension is associated with increased early mortality.

Question 1.
The following are strong contraindications to lung transplantation:

1. Non compliance with treatment
2. Malignant disease successfully treated 7 years prior to assessment
3. Methicillin-resistant staphylococcus aureus in sputum
4. Previous thoracic surgery
5. Active aspergillus or mycobacterial infection

SURGICAL PROCEDURES

Heart lung transplantation: With a reduction in the number of donor organs available worldwide the indications for HLT have been redefined. In practice HLT is reserved for patients with Eisenmengers syndrome who have a surgically incorrectable cardiac defect. It has been applied to patients with pulmonary vascular and parenchymal lung diseases in the past. This transplant operation is performed via a median sternotomy incision with cardiopulmonary bypass and the anastomoses are fashioned at the level of the right atrium, aorta and trachea. The trachea receives an important blood supply from the coronary to bronchial collateral circulation and this is not disturbed with HLT. Therefore airway ischaemic complications, (the major cause of mortality in the early days of lung transplantation) are uncommon.

Another cited advantage of HLT is domino cardiac transplantation. In this procedure the heart from a patient who receives HLT for conditions other than Eisenmengers syndrome can, if healthy, be successfully transplanted into a patient requiring cardiac transplantation alone, so long as there is no severe irreversible elevation in pulmonary vascular resistance. The results of this procedure are very encouraging and in addition it offers advantages of short organ ischaemic time and non exposure of the donor heart to the effects of brain stem death.

Bilateral lung transplantation: This procedure allows the patient to retain his own heart but healing of the airway anastomoses may be jeopardised as a result of ischaemia secondary to interruption of the coronary to bronchial collateral circulation. BSLT is performed more frequently world wide than HLT. The procedure is usually performed via bilateral thoracotomy incisions or via a thoraco-sternotomy (clamshell) incision. The clamshell incision provides excellent exposure to the thoracic cavity allowing the surgeon to deal with pleural adhesions. The lungs are inserted in a sequential fashion and bi-bronchial anastomoses are fashioned in addition to pulmonary arterial and venous anastomoses. The procedure can often be undertaken without cardiopulmonary bypass and thus avoids attendant complications such as bleeding, complement activation and neurological defects. Double lung transplantation (DLT) is performed on cardiopulmonary bypass and a tracheal anastomosis is performed.

Single lung transplantation: SLT is the most commonly performed pulmonary transplant operation worldwide. This is performed through a postero-lateral thoracotomy. Anastomoses are made at the level of the main bronchus, pulmonary artery and pulmonary veins (with a cuff of donor atrium to recipient left atrium).

Choice of operation: The current indications for HLT, DLT, BSLT and SLT are listed in Table 2. The primary indication for SLT is restrictive lung disease e.g. pulmonary fibrosis. The increase in elastic recoil and vascular resistance of the remaining fibrotic lung in these patients ensures a progressive shift of alveolar ventilation and lung perfusion from the native to the transplanted side. Ventilation perfusion mismatching is therefore uncommon. BSLT may be a better alternative for patients with emphysema (Figure 1). Although patients with primary pulmonary hypertension may be treated successfully with SLT the development of pulmonary oedema in the transplanted lung in the early postoperative period is associated with a high mortality. As a consequence of this risk many centres advocate BSLT or HLT for primary pulmonary hypertension. In general patients who have pulmonary hypertension require replacement of both lungs if the mean pulmonary artery pressure exceeds 50mmHg. Pre-existing sepsis e.g. in cystic fibrosis or bronchiectasis usually precludes SLT because there is a high risk of the transplanted lung becoming infected by sputum overspill from the remaining native lung. SLT with pneumonectomy is not considered appropriate for suppurative lung diseases because of the high risk of bronchial stump dehiscence and empyema in an immunocompromised host.

Lobar transplantation: Living related lobar transplantation has been applied successfully to patients with cystic fibrosis. Following bilateral pneumonectomy the recipient received a bilateral sequential transplant of a lower lobe from each of two living donors. Intermediate term results are comparable to cadaveric lung transplantation with respect to survival, function and incidence of complications.

Question 2.
Bilateral sequential lung transplantation is:

1. More frequently performed worldwide than HLT
2. Performed usually using cardiopulmonary bypass
3. Is indicated for patients with Eisenmenger’s syndrome with a surgically incorrectable cardiac defect
4. Is usually performed in patients with pulmonary fibrosis
5. Is frequently performed in patients with suppurative lung disease

DONOR SELECTION

Guidelines to determine organ suitability are listed in Table 3. Good donor cardiac and respiratory function are essential to optimise success of cardiac and pulmonary transplantation. The commonest cause of brain death in donors is trauma with brain injury and cerebral vascular events. It is appreciated that with increasing demand and scarcity of suitable donor organs the criteria listed in Table 3 may change. The organ ischaemic time is the time between placement of the cross clamp on the donor aorta and reperfusion with the recipient's blood after implantation. The best results are achieved when this time is less than five hours.

DONOR AND RECIPIENT MATCHING

Matching criteria are based on ABO blood group compatibility, size of thoracic cage and cytomegalovirus (CMV) antibody status. Potential recipients are also screened for pre-formed antibodies against a panel of HLA antigens. However, unlike renal transplantation, formal tissue type matching for pulmonary transplantation is not practical as it would increase the organ ischaemic time and furthermore the benefit of HLA matching in pulmonary transplantation is unclear. Ideally the donor lung should be slightly smaller than the recipient chest cavity as organs which are too big may predispose to atelectasis and uneven ventilation due to compression. On the other hand lungs which are too small may fail to obliterate the plural space with the potential risk of early plural effusion or empyema formation.

Question 3.
The following are recognised matching criteria for lung transplant recipients:

1. ABO blood group
2. Toxoplasma antibody status
3. Cytomegalovirus antibody status
4. Size of thoracic cage
5. Rhesus factor

PRETRANSPLANT ASSESSMENT:

Patients are admitted to hospital for a period of about one week which enables them to get to know the staff, visit the surgical centre and meet some patients who have already been transplanted. During the assessment the patients receive a full history and physical examination together with assessment of psychosocial suitability. Investigations will include full lung function tests, arterial blood gas analysis on room air, thoracic CT scan, electrocardiography, transthoracic 2D echocardiography, 24 hour Holter monitoring, right and left heart catheterisation in selected patients, routine haematological and biochemical investigations together with serological investigations for CMV, Epstein-Barr virus, hepatitis A, B and C, toxoplasmosis, Human Immunodeficiency Virus I & II and herpes simplex. Microbiological examination of the sputum is undertaken for pathogenic organisms, acid fast bacilli and fungi.

WAITING LIST

It is essential that patients and their family are fully prepared for the events which may ensue following acceptance onto the transplant waiting list. It should be stressed that unfortunately there are more patients requiring transplantation than suitable donor organs and therefore being accepted onto the transplant waiting list does not guarantee that a suitable donor organ will be found for the patient. Indeed up to 40% of patients die on the transplant waiting list. The patient should be fully advised of the risks of transplantation and what to expect in the intensive care unit and during the postoperative period. They should understand that they will need to take lifelong daily immunosuppressive therapy and will require careful postoperative surveillance. It is also important to point out that obliterative bronchiolitis is a potential long term complication. Once on the waiting list patients face an uncertain time and transplant support groups are helpful.

POSTOPERATIVE MANAGEMENT

Routine postoperative immunosuppression comprises Azathioprine (or Mycophenolate Mofetil) and Cyclosporin A (or Tacrolimus). Intravenous Methylprednisolone is prescribed to treat acute rejection episodes. Acute allograft rejection is diagnosed by a combination of clinical and radiological findings together with respiratory function tests and histopathological examination of transbronchial lung biopsies specimens obtained at fibreoptic bronchoscopy (Figure 2).

It is usually impossible to differentiate allograft rejection from infection on clinical and radiological grounds alone and therefore bronchoscopy plays an important role postoperatively. Fibreoptic bronchoscopy is performed routinely immediately post-transplantation and at the end of the first postoperative week. Thereafter it is usually only performed if there are clinical indications as listed in Table 4. At bronchoscopy the anastomosis is inspected and broncho alveolar lavage specimens are taken for culture and sensitivity, opportunistic pathogen screen and immunocytochemistry. Transbronchial lung biopsy specimens are sent for histopathological examination and culture (Figure 3). Complications of lung transplantation are listed in Table 5. It can be appreciated that the specialist nature of the majority of these problems necessitate management by a transplant team. This is particularly important for cystic fibrosis patients.

Question 4.
Acute allograft rejection is:

1. Usually diagnosed clinically
2. Usually presents with typical radiographic features
3. Can be diagnosed by transbronchial lung biopsy
4. Occurs more commonly after BSLT and HLT than SLT
5. Is usually treated with intravenous Methylprednisolone

OBLITERATIVE BRONCHIOLITIS

This is the most serious late complication affecting up to 40% of adult patients within three years of surgery (Figure 4). The incidence is higher in children who receive transplantation under the age of 10 years. The diagnosis is made clinically in patients who develop progressive airflow obstruction often in the presence of infection. Common presenting features include reduced exercise capacity, cough and progressive deterioration in lung function. Chest radiography may be normal or may show hyper inflated lung fields secondary to air trapping.

Transbronchial lung biopsies (Figure 5) are usually not helpful as the affected bronchioles are randomly distributed throughout the lung and are peripheral in location and thus not routinely sampled at biopsy. The diagnosis may be confirmed by DTPA lung scan or high resolution thoracic CT scan. DTPA scanning may show patchy uptake and deposition of the radioisotope in large airways (Figure 6) and a mosaic appearance due to air trapping may be observed in an expiratory phase CT scan.

The aetiology of obliterative bronchiolitis is unclear but may reflect a form of chronic allograft rejection. It is also believed that obliterative bronchiolitis may be a final common pathway to a variety of pulmonary injuries which may include:
• Recurrent or persistent acute rejection
• Bacterial infection
• Viral infection
• The effects of pulmonary denervation
• Ischaemia.

It is interesting to note that the histological appearances of obliterative bronchiolitis seen in non-transplant patients with rheumatoid lung or respiratory syncytial virus infection are similar to those seen in transplant recipients.

Once the diagnosis of obliterative bronchiolitis is made immunosuppression is augmented with one or more of the following:
• High dose oral Prednisolone
• Conversion from Cyclosporin A to Tacrolimus or Rapamycin
• Conversion from Azathioprine to Mycophenolate Mofetil
• Total lymphoid irradiation
• IL-2 Receptor antibodies.

Unfortunately the majority of patients will not regain lost-lung function and will either stabilise at lower levels of lung function or deteriorate to end stage respiratory failure.

Question 5.
Obliterative bronchiolitis:

1. Has a higher incidence in children who receive transplantation under the age of 10 years
2. Is usually a clinical diagnosis with progressive airflow obstruction
3. Can be confirmed by transbronchial lung biopsies and DTPA and high resolution thoracic CT scans
4. Is probably multi-factorial in origin
5. Usually responds favourably to augmented immunosuppression

RESULTS

One and two year actuarial survival following both HLT and BSLT is of the order of 70% and 60% respectively and 80% and 70% respectively following SLT. Most survivors show a marked improvement in quality of life. Pulmonary function improves rapidly following surgery and FEV1 and FVC are usually in excess of 70% predicted following HLT and BSLT by the end of the third postoperative month. One year actuarial survival of 30% following re-transplantation for obliterative bronchiolitis has been reported. Such results together with the current shortage of donor organs worldwide has led many transplant centres to abandon re-transplantation.

PROGRAMME OF LONG TERM CARE

Following discharge from hospital patients are managed by the transplant unit in collaboration with the referring centre. Each patient receives a home micro-spirometer (Figure 7) on discharge and measures FEV1 and FVC on a daily basis. They are advised to contact the transplant centre should they develop a:
• Greater than 15% reduction in lung function on home testing on two consecutive occasions
• Cough
• Pyrexia in excess of 37.5%c
• Reduction in exercise tolerance.

Initially patients attend the transplant centre on a weekly basis but ultimately the frequency of outpatient appointments becomes less and less and eventually the majority of patients will attend the transplant centre for review every six months.

The referring centre is encouraged to play an active role in the management of the lung transplant recipient and indeed should patients develop problems the majority will present to their local centre. In such situations early communication and if necessary prompt referral to the transplant centre is essential.

If a transplant patient presents unwell to an Accident & Emergency Department the following approach may be useful:
• Treat any acute medical emergency.
• Take a full history including details of home spirometry record and perform a physical examination.
• Check FBC, U&E, LFTs, chest x-ray, arterial blood gas analysis on room air.
• Discuss the clinical presentation and above results with the transplant centre before deciding on further management.

Question 6.
Postoperatively lung transplant recipients:

1. Are usually managed by the referring centre alone
2. Receive a home micro-spirometer to measure FEV1 and FVC on a daily basis
3. Have a one year actuarial survival of 50%
4. Attain FEV1 and FVC following HLT and BSLT of 70% predicted at the end of the third postoperative month
5. Require lifelong immunosuppression

THE FUTURE

The major challenges facing lung transplant programmes are:
• Shortage of suitable donor organs
• The development of obliterative bronchiolitis
• The timing of surgery.

It is hoped that the development of new immunosuppressive agents together with improved diagnosis and treatment of rejection and pulmonary infection will reduce the incidence of obliterative bronchiolitis. Major immunological issues and concerns over possible transmission of infection have to be overcome before the use of animal organs (xenografting) can be successfully applied to human lung transplantation.

LEGENDS

Table 1.

Contraindications to lung transplantation

Strong Contra-indications

1. Non-compliance with treatment.
2. Infection with Human Immunodeficiency Virus I & II..
3. Hepatitis B surface antigen and Hepatitis C seropositivity.
4. Active aspergillus or mycobacterial infection.
5. Malignant disease within five years.
6. Bacterial species in sputum with no in-vitro antibiotic sensitivities.
7. Gross malnutrition.
8. Other end organ failure.
9. Prednisolone therapy > 10mg/d.
10. Age > 60 years. *
11. Significant osteoporosis

Risk Factors

1. Chemical pleurodesis.
2. Pre-operative ventilation.
3. Previous thoracic surgery (pleurectomy, abrasion pleurodesis).
4. Severe liver disease necessitating combined heart-lung and liver transplantation.

* Centres may have different policies and some have reported upper age limits of
65, 60 and 55 years respectively for SLT, BSLT and HLT.

Table 2. (The numbers within the table cells in tables 2a. and 2b. refer to the annotation below the tables)

Current indications for heart-lung, double-lung and single-lung transplantation

Table 2a. Parenchymal lung disease

Table 2b. Pulmonary vascular disease

HLT -----heart-lung transplantation
DLT ---- double-lung transplantation
SLT ----- single-lung transplantation
BSLT --- bilateral sequential lung transplantation.

1. Results of transplantation in the acute phase of the illness are poor.
2. Reperfusion pulmonary oedema in the early post-operative period is a serious risk.
3. Experience limited.

Table 3.

Donor selection

1. Brain stem death
2. No significant cardiac or pulmonary injury.
3. Clear lung fields on chest radiograph.
4. Age < 50 years.
5. Non-smoker.
6. Normal gas exchange (PaO2 > 15 kPa with an FiO2 of 35% and PaO2 > 40kPa on FiO2 of 100% and Peep of 5cm H2O).
7. No systemic or endobronchial infection or pneumonia.
8. No past history of pulmonary, cardiac or malignant disease.
9. Normal ECG.
10. No aspiration

Table 4.

Indications for bronchoscopy in lung transplant recipients

1. Reduction in lung function.
2. Reduction in exercise capacity
3. Unexplained cough.
4. Abnormality on chest radiograph
5. Unexplained pyrexia.

Table 5.

Complications of lung transplantation

General

1. Infection.
2. Acute rejection.
3. Airway complications.
4. Bleeding.
5. Multiple organ failure.
6. Complications of immunosuppression e.g. renal failure, bone marrow suppression.
7. Obliterative bronchiolitis.
8. Lympho-proliferative disorders.

Specific Cystic Fibrosis Related Problems

1. Malnutrition.
2. Liver disease.
3. Salt loss.
4. Diabetes Mellitus.
5. Persisting infection in upper respiratory tract.
6. Malabsorption of cyclosporin A.
7. Meconium ileus equivalent.

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