|Lung Transplantation in Cystic Fibrosis
Dr Katy Hester & Professor Andrew Fisher .April 2010. Lung Transplantation in Cystic Fibrosis, Cardiopulmonary Transplant Unit, Freeman Hospital, Newcastle Upon Tyne, UK. Written for cfmedicine.com. Available from http://www.cysticfibrosismedicine.com
Since the 1980s, lung transplantation has been a treatment option for patients with cystic fibrosis (CF) who have severe, progressive lung disease despite optimum medical therapy. CF is one of the top three indications for lung transplantation and recipients with CF have the most favourable long term survival data, with 85% surviving the early post operative period and first year, 70% at 3 years and 50% 5-10 year survival. These data are reported by the International Society for Heart and Lung Transplantation, who also have published guidelines on referral criteria. Lung transplantation can lead to an increase from 20-25% FEV1 pre transplant to over 80% at 1 year post transplant. The aim of lung transplantation is both to increase life expectancy and to improve quality of life.
Referral for transplantation is made by the caring CF physician to a lung transplant centre when a patient is continuing to deteriorate, with severe lung disease, despite optimum medical therapy. There are a number of triggers for referral including an FEV1 of 30% or less, a rapid decline in lung function, increasing frequency of IV antibiotics, recurrent pneumothoraces or haemoptysis requiring intervention. It is better to communicate early with a transplant centre rather than when the patient has deteriorated to an extent whereby they may be too unwell for transplantation.
When a patient is referred to the transplant centre, they will be either seen in a pre transplant clinic, or admitted for assessment. There is usually a proforma to complete for the referral process that includes all information pertinent to transplantation. In some cases patients are kept under review by the transplant team in clinics until they are nearing the point where they may need to go onto the active waiting list for transplantation. They will then be brought into the transplant centre for a few days for a detailed assessment process. The assessment involves a number of tests and meetings as outlined:-
Blood tests (including full blood count, coagulation screen, liver function tests, renal function, bone profile, thyroid function, autoantibody screen, virology, fasting lipids and glucose, group and save, tissue typing/antibody screen) to highlight any abnormal organ function, viral infection (including hepatitis B and C and HIV) or exposure, and any antibodies that may reduce the number of potential donors that lungs could be received from.
Glomerular filtration rate (GFR) a formal chromium EDTA GFR is carried out to ensure adequate renal function, which is essential in the peri-operative period, and when receiving nephrotoxic drugs both post-operatively and long term.
Electrocardiogram (ECG) to detect any abnormalities eg ischaemia, conduction abnormalities, evidence of right heart strain etc.
Echocardiogram (ECHO) to assess LV/RV function, valves and any evidence of pulmonary hypertension etc.
Chest X-ray (CXR) to look at extent of disease, any pleural changes and any cavities close to the pleural surface etc.
Computed tomography (CT) more datailed view of extent of disease, any pleural changes.
Abdominal ultrasound to look for evidence of liver disease, portal hypertension, renal abnormalities, gallbladder changes.
Arterial blood gases (ABG) to establish degree of hypoxia and any hypercapnia. This is usually performed on air even if the patient is on long term oxygen.
Lung function testing is carried out to record degree of impairment, particularly looking at FEV1 in patients with CF.
6 minute walk test is performed with the physiotherapists, using oxygen if the patient usually has ambulatory oxygen. This gives an indication of the degree of functional impairment, and desaturation on exertion, which again is an indicator of severity of disease.
Bone densitometry testing is important to ascertain the presence and degree of any osteoporosis. Severe osteoporosis can lead to higher risk at surgery and needs to be optimally treated.
Body mass index (BMI) is calculated (Wt/ht2. Low BMI (<18) is associated with a poorer outcome following transplantation and often patients will need to reach a target weight by means of dietary supplementation prior to being listed for transplantation.
Perfusion scans are performed in patients with other conditions being assessed for single lung transplantation, but are not carried out for patients with CF as they would only be candidates for bilateral lung transplantation.
Social workers who work specifically with the transplant team will meet with the patient and their family during the assessment period. They will discuss social support around the period of transplantation and practicalities such as work and benefits etc.
Pscychological assessment is sometimes needed in patients who have specific needs eg anxiety, depression.
There are different models for assessment at different centres, but often patients to be assessed will have the above tests carried out over several days of admission. During this time they have lots of time to meet with the team, particularly the transplant co-ordinators who will spend time going through all the details surrounding transplantation, answer any questions and give written information. An identified carer, which may be a member of family or friend, would be expected to attend with the patient as their support both through assessment and transplantation.
Over the course of the assessment all parameters are assembled and an overall assessment of the patients suitability and need for transplantation is made. All the information pertaining to each patient is discussed in a multi-disciplinary team meeting attended by transplant physicians, transplant surgeons, transplant co-ordinators, social workers, anaesthetists and microbiologists, who all play a role in the overall decision making. Any additional issues will be highlighted, for example the microbiologists may have isolated certain resistant pathogens on sputum culture, and will need to know of any allergies the patient has in order to work on a suitable peri-operative antibiotic regime. All parameters are taken into account, including FEV1 (usually less than 30%), hypoxia, poor 6 minute walk distance or desaturation, frequency of antibiotics etc in assessing how sick a patient is. Other variables which may prove to be of concern for a patient receiving a transplant such as low BMI, severe osteoporosis or certain sputum pathogens are also taken into account.
The team will reach a decision about listing for transplantation, which will then be discussed with the patient before they go home. A plan will be made for relevant contact following discharge, dependent on the outcome of the assessment.
After initial assessment, provided there are no contraindications to transplantation, and the patient is considered to be at the point of requiring transplantation they will be accepted onto the active list for lung transplantation. In practical terms this takes a few weeks to activate as there are several things such as tissue typing, dental review and vaccinations that need to take place before a patient is active on the list. Sometimes there may a few additional issues that need to addressed, such as a suitable antibiotic regimen for the perioperative period, or further imaging. In this situation, the decision to list may be deferred pending these results.
If the patient is felt to be a good potential candidate for transplantation but not quite at the point of needing to be actively listed, they will be kept under review by the transplant team, with a view to placing them on the active list at the appropriate point. This is usually when the life expectancy without transplant would be shorter than that predicted post transplantation.
Occasionally there may be reasons why a patient would not be a suitable candidate for transplantation. They may have a contraindication to transplantation, or may already be too sick, such that the risks of transplantation would be too great, and chances of survival too small.
In summary the potential outcomes are:-
• Currently too well – observe closely
Contraindications to lung transplantation are sometimes described as relative or absolute. In reality all potential contraindications to transplantation are considered in context with each individual and at each different centre.
There are several criteria that are considered relative contraindications to transplantation, including BMI<18, severe osteoporosis or extra pulmonary manifestations of CF that are not well controlled. Patients who are already in a critical condition or who have poor rehabilitation potential, would not do well following transplantation and would not be considered to be good candidates. Patients with highly resistant organisms (possibly further complicated by antibiotic allergies limiting treatment options) or those colonised with mycobacterium abscessus are considered to have relative contraindications to transplantation both due to evidence of poor outcome following transplantation, and inability to provide necessary antibiotic cover perioperatively. Pleural damage can make surgery technically more difficult and is also a relative contraindication to lung transplantation. Other issues such as a lack of social support or an unmanageable pshycological condition would also have to be carefully considered.
• Colonisation with Burkholderia cepacia genomavar III (cenocepacia) – this has been found to associated with an unacceptably low 1 year survival rate. Previously this was thought to be all cepacia genomavars, but this has since been demonstrated not to be the case for others including B. multivorans and B. stabilis.
• Failure to identify an adequate perioperative antibiotic regime
• Systemic sepsis
• Ongoing issues with non-compliance
• Ongoing issues with substance addiction (including smoking)
The majority of donor lungs come from heart beating donors post brain death. The lungs are carefully assessed for suitability for transplantation by the retrieving team.
Formal tissue typing is not carried out, and matching is on ABO blood group compatibility and size.
Some centres carry out lung transplantation from non heart beating donors, i.e. after cardiac death in certain circumstances. Death may be following withdrawal of life sustaining treatment and cessation of circulation. Results are similar to that of transplant from heart beating donors.
Another option, although infrequently performed is living related lobar donor transplantation. With this procedure tworelatives would donate a lobe each – one left lower, one right lower lobe. These are transplanted into the recipient and act as their new left and right lungs. There is a potential risk however to both donors, and the recipient will be left with unoccupied space in the pleural cavity which may lead to increased risk of infection.
Research into improving the quality of ‘marginal’ lungs ex vivo is ongoing, with the hope of potentially increasing the donor pool.
Once on the active list for transplantation, the length of wait can vary. Patients on the active list are not listed in order of priority. Donor organs are allocated on the basis of suitability, being matched for blood group and height. After matching, a decision regarding allocation is made based on clinical need. An average waiting time on the list can be between 9 months and a year, but it can be longer or shorter than this. Whilst on the waiting list a patient will be in regular contact with the transplant centre, and the local centre should communicate with the transplant team any changes in condition / concerns. Some patients may be called in for potential transplants that are not able to proceed on several occasions as they are often called in whilst lungs are being assessed / retrieved and may have to be called off if the lungs are not suitable.
All patients with CF on the lung transplant list will require bilateral lung transplantation. Single lung transplantation cannot be performed due to ongoing infection in the remaining native lung. During the transplantation operation both donor lungs are transplanted sequentially. The operation is performed via a clamshell incision which is a transverse incision through the lower sternum as a modified bilateral thoracotomy. The patient will be put onto cardiopulmonary bypass as the native lungs are removed and then the donor lungs transplanted sequentially. In certain circumstances a heart lung transplant may be performed, but only if this is specifically indicated.
A transplant operation can take many hours to perform, and the patient will then be taken to ITU and remain intubated for a variable length of time. Following this they would go to a cardiothoracic transplant HDU where they will continue to recover and begin to exercise. Following transplant most patients will remain in hospital for 4-6 weeks, but there may be reasons that this is extended. When they are ready for discharge they will be initially sent to hospital accommodation for a while to get used to life outside of hospital again on their new drug regime.
Complications can occur in the early post operative period, and these differ from those that are seen further along post transplantation. Early potential problems include surgical complications such as anastamotic breakdown (failure of the suture line between the donor and recipient airways) this is now extremely rare. Other problems can occur with the anastamoses including stricture and granulation tissue obstruction but these would tend to occur later and can be treated with stenting if indicated. However this is rare with an incidence of less than 5% in most centres
Phrenic nerve damage can potentially occur during surgery leading to a unilateral, or rarely bilateral, raised hemidiaphragm.
Venous thrombosis and thromboembolism are potential risks post lung transplantation. This would usually present several days post transplantation with increasing oxygen requirements, possible haemoptysis etc and would be investigated by CTPA. Treatment would involve anticoagulation and possible thrombolysis / surgical intervention.
Infection is a risk in the early and late post operative period and most centres advise vaccination against influenza and pneumococcus prior to transplantation. In the early period post transplantation the patients are in single cubicles to reduce risk of infection. Patients are given a perioperative antibiotic regime that has been specifically selected for them on the basis of microbiological sensitivity testing carried out on their sputum prior to transplantation. If appropriate the recipient will also be given anti fungal cover. Anti viral cover is routine in those with donor – recipient CMV mismatch (see below). PCP prophylaxis is routine and tends to be continued lifelong. In the early period mediastinitis and collections including empyema can occur which would need to be treated with antibiotics and possible surgical exploration and drainage. Infection can occur in any site and is investigated with appropriate cultures etc. Infection is an ongoing risk post transplantation due to immunosuppression (see below).
Acute rejection is fairly common and occurs in approximately half of recipients in the first 6 months. Acute rejection can present with reduced lung function, dyspnoea, pyrexia, or new changes on CXR including pulmonary infiltrates and pleural effusion. As patients can be relatively asymptomatic, or have symptoms that could be confused with that of infection, patients are assessed routinely with lung function, CXR and bronchoscopy with transbronchial biopsies at 1 week (not in all cases), 1 month, 3 months, 6 months and 12 months post transplant. Evidence of rejection will be seen on biopsies and augmentation of immunosuppression given if indicated.
Metabolic derangement in the early period is common and close monitoring of electrolytes, in particular magnesium, potassium, sodium, calcium and renal function is required. Full blood count monitoring is also needed as the effect of immunosuppressive agents can be variable.
Bowel complications such as ileus / meconium ileus equivalent can occur post surgery. This is usually managed with laxatives, pancreatic enzymes and fluids. Surgery is rarely required but this needs careful management.
Drug complications are covered later on click here.
Infection is an ongoing risk, and patients should continue to receive appropriate vaccination and prophylaxis due to their ongoing immunosuppression. The organisms that previously colonised the recipients’ lungs are often isolated again as the upper airways and sinuses have continued to be colonised. These may be treated with nebulised antibiotics. Bacterial, viral and fungal infections can occur. Protozoal infection with PCP has decreased in incidence due to routine longterm prophylaxis, usually with co-trimoxazole.
Viral infections of any kind may occur, and recipients are at higher risk of respiratory viral infections but CMV infection is most common, particularly in those with a donor – recipient CMV mismatch. Those recipients who are CMV negative and receive lungs from a CMV positive donor are most at risk. Anti viral prophylaxis is given to these patients. CMV infection can be demonstrated on viral PCR or transbronchial biopsies.
The most common fungal infections are aspergillus and candida and are treated with anti-fungals if clinically indicated.
Diabetes is relatively commonly occurring post transplantation in recipients with CF. Patients are already more predisposed to the development of diabetes, and steroids, ciclosporin and tacrolimus all increase risk of developing diabetes. This can occur fairly soon after transplantation, is detected by blood glucose monitoring, and usually managed with insulin.
There is an increased incidence of malignancy in the post transplant population. In particular skin cancers and lymphoproliferative disorders. The risk of skin cancer is increased up to 20 times usual risk. Patients are advised to use high factor sun block. Over half of malignancies post transplant are skin related.
There is an incidence of up to 10% of post transplant lymphoproliferative disease (PTLD). Non Hodgkin’s B cell lymphoma is the most common and is related to previous EBV infection. Those who are EBV negative and receive lungs from an EBV positive donor have a higher incidence. This may present in the lung or in other organs including liver, gastrointestinal tract and central nervous system. Presentation may be asymptomatic nodules or lymphadenopathy and ‘B’ symptoms such as sweats and weight loss. Diagnosis is histological and treatment may include alterations to immunosuppression and chemotherapy.
Chronic rejection affects more than 50% of lung transplant recipients long term. This is characterised by obliteration of the small airways by fibroblast proliferation and is referred to as bronchiolitis obliterans syndrome (BOS) in the absence of any other cause of progressive airflow obstruction. BOS should be suspected in patients who have a drop of 20% or more in FEV1 that is sustained with no other obvious cause, such as infection or acute rejection. Presentation and clinical course can differ. BOS can present with rapid decline in function, gradual progressive decline, or initial rapid decline followed by relative stability. It can be detected by a fall in FEV1, declining FEF25-75, and HRCT which may show air trapping in expiratory phase imaging. Several factors are thought to predispose to BOS including CMV pneumonitis, recurrent acute rejection, gastro-oesophageal reflux disease, some respiratory infections including pseudomonas and HLA mismatching.The damage caused to the airways is irreversible, and treatment is aimed at limiting disease progression. Azithromycin has been shown to have benefit in limiting progression, and switching immunosuppression to second line agents such as tacrolimus can be useful. Patients are kept under regular surveillance at the transplant centre, and, if BOS is suspected by the local team the transplant centre should be informed.
|Drugs Post Transplantation
Immunosuppression post lung transplantation usually comprises 3 drugs. Prednisolone is used in conjunction with a cell cycle inhibitor – azathioprine or Mycophenolate Mofetil (MMF), and a calcineurin inhibitor – ciclosporin or tacrolimus. Side effects related to prednisolone are as usual, with significant problems including osteoporosis and steroid induced diabetes.
Ciclosporin tends to be the first line calcineurin inhibitor and is given twice daily. Trough levels are checked pre dose to ensure appropriate levels are obtained. This is done less frequently once stability is established. It is important that the specific brand is prescribed as there are various formulations with differing bioavailabilities. The emulsion based forms should be taken with pancreatic supplements. Grapefruit should be avoided as this can increase ciclosporin levels.
Ciclosporin can cause diabetes, hyperlipidaemia, abnormal liver function, hypertension, hirsuitism, neuropathy, nephrotoxicity, tremor and hyperkalaemia.
Drugs including macrolide antibiotics (eg clarithromycin, erythromycin) can greatly increase ciclosporin levels and nephrotoxicity and should not be given to patients on ciclosporin. NSAIDS and antifungals can also increase the nephrotoxicity of ciclosporin.
Tacrolimus is also given twice daily as an alternative to ciclosporin. Again, regular monitoring of levels is required. Macrolides and antifungals may increase levels leading to hyperkalaemia and renal failure. Tacrolimus can also induce diabetes. Patients may be switched from ciclosporin to tacrolimus for reasons including recurrent acute rejection and problematic hirsuitism.
Azathioprine alters white blood cell metabolism via purine metabolic pathways and reduces the total white cell count. It can cause bone marrow failure, so patients need to be advised about reporting infection, bruising or bleeding. Full blood count must be monitored. Allopurinol must be avoided due to increased risk of bone marrow failure.
Mycophenolate mofetil has a similar mechanism of action to azathioprine. Side effects include gastrointestinal upset and leukopenia.
|Follow up Post Transplantation
After discharge from hospital patients are followed up in clinic at the transplant centre. They are given a book to record daily medication, weight, Spirometry and temperature. Patients attending lung transplant follow up clinic will have a CXR and lung function tests to monitor for chronic rejection etc. Transbronchial biopsies are performed 4 to 5 times in the first year as outlined above. Following this bronchoscopy would usually only be performed if indicated.
Patients are encouraged to contact the transplant centre with any problems including illness and any potential changes to medication. Often the advice of the transplant centre will be to see their GP or go to their local hospital and for those doctors to liaise with the transplant centre. Care may need to be transferred to the transplant centre depending on the problem, but often patients live a long distance from the transplant centre so it is not practical to go there for every concern.
Transplant recipients of course can have unrelated medical or surgical conditions, and problems relating to CF, in addition to complications arising because of transplantation. The initial assessment in the patient’s local hospital should be as is standard. Patients with dyspnoea or sepsis should be assessed as usual with CXR, blood gases and routine bloods, lung function and sputum/blood/urine culture. Cultures should be done with the information that the patient is immunocompromised to ensure that atypical infections are looked for. Care should be taken with any drugs or antibiotics given to ensure no risks of interaction with immunosuppression, the prime example being macrolide antibiotics. Imaging should be compared to previous radiology to ensure any abnormalities are in fact new rather than long standing changes post transplantation. Any new changes on CXR or persistent reduction in lung function will need to be discussed with the transplant centre as are likely to require further investigation with CT and bronchoscopy.
The patient’s transplant centre will be happy to be contacted with any queries about their care at any point.
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