BrMik lleBcal BmOttbi (1992) Vd 48, No 4, pp949-971 O The Bntah Camel] 1992

Lung transplantation for cystic fibrosis V Tsang MEHodson M H Yacoub Royal Brompton National Heart and Lung Hospital, London, UK

Significant progress has been made since the first successful human heart-lung transplantation (HLT) for pulmonary vascular disease performed in 1981. 1 The refinement of surgical techniques, use of cyclosporin as the main immunosuppressant, technique of distant organ procurement to expand the donor organ pool, and improved diagnosis and management of pulmonary infection and rejection have all contributed to this accomplishment. This has inevitably coincided with the extension of this procedure to other groups of patients with end stage heart and lung disease. Initially, HLT was offered to patients with cardiac disease associated with pulmonary hypertension. Because of the success, consideration was given to transplantation for parenchymal pulmonary diseases, initially pulmonary fibrosis and emphysema, and then suppurative lung disease such as in cystic fibrosis (CF). However, the application of HLT to patients with CF lagged behind because of concern related to the risk of sepsis, the systemic nature of the disease, malnourishment, and fear of recurrence of the epithelial CF defect in the transplanted lungs.

The first successful heart-lung transplants for CF were performed in the UK at Harefield and Papworth Hospitals in 1985.2^ Approximatley 150 CF patients have undergone this procedure worldwide with encouraging results. During this time, other options of lung transplantation have developed. Single lung transplantation would not be suitable for CF patients as the remaining native lung would be a source of infection. En bloc double lung transplantation without tracheal revascularisation has given poor results due to tracheal anastomotic dehiscence, and bilateral single lung transplantation requires further evaluation.

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This chapter reviews the experience with HLT for CF at Harefield and Brompton Hospitals. The potential and limitations of HLT, the technique which so far provides the best results for CF patients, are discussed. The number of transplant operations is still severely limited by the scarcity of suitable donor organs. THE DEMAND FOR LUNG TRANSPLANTATION Cystic fibrosis is inherited as an autosomal recessive disease,4 and is the commonest lethal genetic disorder affecting Caucasians.5 The incidence of new CF cases in UK is about 200 a year, representing a frequency of 1 in 2500 live births.6 The CF population in UK is approximately 6000, with a quarter over 15 years of age. Although a lower incidence of CF due to neonatal screening may be anticipated, the number of affected adults will steadily increase in the foreseeable future due to the progressive improvements in medical care.6 Over 50% of patients with CF are expected to live to the age of 30 years.7 More than 90% of deaths from CF are related to respiratory failure from progressive lung destruction and recurrent infections.8 Therefore, adult CF patients with end stage lung disease will increase, and probably represent the largest group of potential lung transplant recipients between the ages of 10 and 49 years in die UK. Some of this large group of young patients may potentially be salvaged by lung transplantation, and demands for this treatment from patients and their physicians are increasing as they become more aware of the encouraging outcome. However, scarce resources particularly donor shortage demand careful selection of CF patients referred for HLT. SELECTION OF POTENTIAL TRANSPLANT RECIPIENTS The selection criteria for HLT used in our unit are listed in Table 1. CF patients should only be accepted for HLT if they have relentlessly deteriorating respiratory disease despite the best medical treatment available. Adverse prognostic factors associated with poor life expectancy include oxygen dependence, FEVj of less than 30% of predicted value and clinical evidence of cor pulmonale. The patients themselves must positively want transplantation. There should be no intractable psychosocial instability which may interfere with their capability to cope with surgical stress, strict postoperative follow up and the treatment regimen. The selection of candidates for HLT must take the multisystemic nature of CF and its complications such as malabsorption and diabetes mellitus, into consideration. Patients with poor nutrition are excluded

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TaWe 1 Selection criteria for heart-lung transplantation in CF Indications 1 2 3

Deteriorating chronic respiratory failure in spite of maximal medical treatment Severely impaired quality of life Patient must positively want a transplant.

Strong contraindications 1 2 3 4 5

High dose corticosteroids. Psychosocial instability Active infection Mycobactena or Aspergillus Other end organ failure. Gross malnounshment

Increased risk factors 1 2 3 4

Previous thoracic surgery, e.g. abrasion pleurodesis, pleurectomy, or lobectomy. Chemical pleurodesis. Preoperative ventilation. Severe liver insufficiency (considered for combined heart, lung, and liver transplantation)

'Some centres may not accept these patients.

until this is corrected with aggressive nutritional management. Previous thoracic surgery may adversely affect the outcome of HLT. Previous thoracotomies for pleurodesis and lung resection are not an absolute contraindication, and the increased risk of the procedure related to intraoperative and postoperative bleeding can be minimised with the use of aprotinin.9 However, patients who have had a previous pleurectomy present considerable difficulties, and usually require freeing of the adhesions through a lateral thoracotomy done before the transplant procedure. Ideally steroid therapy should be completely withdrawn before HLT as it may interfere with tissue healing, and the trachea] anastomosis is of particular concern. High doses of steroids are a contraindication, but HLT has been performed in patients on 10 mg daily of prednisolone with no added complications. Patients with Cushingoid features including skin manifestations are excluded until these changes subside with the reduction in the steroid therapy. Insulin dependent diabetes mellitus, in the absence of microvascular complications, is no longer a contraindication. Indeed the diabetic control becomes easier postoperatively with the removal of the massively infected lungs. However many patients who are not diabetic before surgery may become transiently

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diabetic in the postoperative period because of the steroid therapy often required for treating episodes of acute rejection. Severe liver dysfunction is a major risk factor as this may impair the patient's ability to metabolise immunosuppressive drugs. A combined heart, lung and liver transplantation may be an option for some patients with severe lung and liver disease.2 Patients with aspergilloma involving the pleura are excluded. The infected pleural tissue may not be completely eradicated at tbe time of surgery, and may become a potential source of opportunistic infection after HLT. Patients with Aspergillus fumigatus in the sputum are only accepted for HLT after the fungus is eradicated by antifungal treatments. Mycobacteria infection is not acceptable in candidates for HLT, as in the presence of immunosuppression, it may prove fatal and must therefore be treated before surgery. Patients requiring preoperative ventilatory support carry a higher hospital mortality. Nevertheless, some patients can now be assisted by nasal ventilatory techniques and should not be excluded from transplantation, provided other vital organs are functioning and there is no evidence of systemic infection.10 PRE-TRANSPLANT EVALUATION A detailed in-patient assessment, including a full history, clinical examination, and laboratory investigations, is essential to identify the most suitable candidates who will benefit from HLT. Many patients referred for assessment may improve with conventional medical treatment, and do not need to be considered for transplantation at that time. During the assessment, the patients have the opportunity to visit the surgical centre and meet some patients already transplanted. Psychosocial evaluation of the potential recipients provides an insight into their suitability to cope with a life long period of strict medical regime and follow up. Patients with CF requiring HLT are usually younger than other potential transplant recipients, and they are usually well motivated. They are used to taking regular medications and frequent clinic attendances. Support provided by the family and relatives is of immense importance to the patients, who have to tolerate the stress associated with the surgery. Warner has recently reported that the proportion of children who do well after HLT is only a small percentage of those originally referred for assessment" He emphasizes the need for very careful counselling for both the patients and families and careful selection for the transplant waiting lists. Full clinical examination is performed and the chest size measurements are made. Lung function is fully assessed, in particular, FEV[

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and FVC and arterial blood gas analysis at rest and on exertion. Serial FEVi and FVC will supplement the clinical judgement on the timing for HLT. At the time of being accepted for transplantation, most patients have an ¥EV\ and FVC of about 30% predicted. Oxygen saturation at rest is usually between 80-90% with marked desaturation on exertion. In addition to the chest radiograph, a high resolution CT scan of the thorax is undertaken to assess the state of the pleura. Patients with CF often have extensive pleural thickening and adhesions. Detailed dental and ENT examinations are also required as the infected sinuses and teeth may become potential sources of post-operative infection.12 Cardiac assessment includes clinical evaluation, ECG, 24 hour tape and echocardiogram. Normal valves and left ventricular function are essential for the heart being used in a 'domino' procedure.2 Mild to moderate tricuspid regurgitation and right venticular dysfunction are acceptable. Only after careful counselling is the permission for the CF patient to become a heart donor for a 'domino' procedure obtained. Detailed haematological and biochemical investigations are completed. Any abnormalities in hepatic and renal functions must be further assessed. Coagulation studies, in view of possible liver dysfunction and hypersplenism, should be evaluated. The patients should be screened for any previous exposure to toxoplasmosis, Epstein-Barr virus, cytomegalovirus, hepatitis, herpes and human immunodeficiency viruses. Microbiological examination of the sputum is undertaken for pathogens, acid fast bacilli, and fungus to guide postoperative antimicrobial therapy. The majority of patients have sputum cultures positive for Pseudomonas aeruginosa. Patients with Pseudomonas cepacia have been successfully transplanted in our unit However, some centers have advocated the exclusion of these patients because of the high mortality and morbidity associated with P. cepacia.^ The patients should be informed of the risk of the procedure, the chances of success, and what to expect in the intensive care unit and post-operative period. They should be told that there is no guarantee a suitable donor organ will be found in time for them. During the waiting period, malnourished patients should have their nutritional status optimised. This is done by the oral route whenever possible with high calorie supplements, and gastrostomy feeding at night if necessary. Active infection should be treated vigorously. Once the patient is on the transplant waiting list, there must be a regular review of clinical status. Although it is not possible to predict the most appropriate time for HLT, deteriorating quality of life, lung function, and oxygen saturation are useful guidelines. It should be remembered that the waiting time can be very stressful for both the patient and the relatives.

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DONOR SELECTION The major criteria for donor and recipient matching for HLT and ABO blood group compatibility, cytomegalovirus (CMV) antibody status, and chest size measurements. Potential recipients are also screened for preformed antibodies against a panel of HLA antigens. Donor chest measurement is required to match the size of the potential recipient2 (Fig. 1). Ideally, the donor lungs should be slightly smaller than the recipient's chest cavity. Donor lungs which are too big may predispose to atelectasis and uneven ventilation due to compression; lungs which are too small may fail to obliterate the pleural space, with the possible risk of air leak, pleural effusion, and even empyema formation. CMV infection after transplantation is a major complication.14 The pathogen can be transmitted by donor organs. It has been shown that CMV antibody negative patients who receive organs from CMV positive donors, have a higher incidence of primary CMV pneumonitis. It has been our unit policy that CMV negative donor organs should be used for CMV negative recipients to minimise the considerable mortality and morbidity of postoperative CMV infection. Good donor heart and lung function are essential for the success of HLT. A few guidelines are used to determine organ suitability. With increasing demand and scarcity of suitable donors, the criteria for acceptance may have to change. The commonest cause of brain death in donors is trauma with brain injury. The potential donor should have no evidence of significant lung or cardiac injury. The donor should be less than 45 years old, preferably a non-smoker, and have no previous history of pulmonary, heart or malignant disease. Prolonged mechanical ventilation is undesirable, as the incidence of infections and atelectasis is increased. Lung fields should be clear on the chest radiographs, and the gas exchange should be normal (Pa,O2 > 15 kPa with a FiO2 of 0.3). There should be no systemic infection and ideally no infected bronchial secretions. We however accept donors with contaminated tracheobronchial secretions or treatable infection (excluding multiresistant Staphylococcus aureus). If in doubt, flexible bronchoscopy should show absence of mucous membrane inflammation or ulceration. The donor ECG should be normal. If arrhythmia or ST segment abnormality is present, echocardiogram and coronary angiogram may be required to exclude any organic lesions. The donor condition must be stabilised while the organ procurement teams are in transit, especially in cases of multiorgan donation where several surgical teams are involved. Good organ preservation is vital for the return of normal heart and lung function, as well as allowing die time for die organ to be trans-

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Fig. 1 Chest size measurements (for heart-lung transplant patients only) (1) Suprastemotch to xiphisterum (2) Suprasternotch to acromium (3) Acromium to costal margin (4) Greatest circumference of chest (5) Circumference at lower costal margin

ported over a longer distance, thereby increasing the donor pool. The organ ischaemic time should be kept to approximately 4 h, starting from discontinuation of donor ventilatory support to reperfusion of the transplanted organs. To increase donor availability, techniques have been developed to procure organs a long distance from the recipient hospital. At our unit, whole body hypothermic cardiopulmonary bypass technique is used with good clinical results.15 A portable cardiopulmonary bypass machine is used for uniform cooling of the lungs through the bronchia] and pulmonary circulation. Cold blood cardioplegia is used for heart preservation. An alternative method of preserving the donor lungs by first giving intravenous prostacyclin, followed by a single cold flush technique into the pulmonary artery has been described.16

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The pulmonary preservation fluid contains several additives including mannitol and prostacyclin. SURGERY In 1961, Lower and Shumway reported two dogs surviving 5 days after HLT, but their respiration was slow with an increased tidal volume. l ? Operation was performed via a right thoracotomy. Using cardiopulmonary bypass, anastomoses were performed at the aorta, trachea, superior and inferior vena cavae with preservation of the recipient dog's phrenic and vagus nerves. These early experimental HLTs on subprimates were uniformly unsuccessful in achieving long term survivors. It was soon discovered that subprimates differed in their responses to pulmonary denervation,18 compared to primates which resumed their normal respiratory pattern after HLT.19 In 1972, Castaneda et al performed a series of successful heart-lung autotransplantation in primates.20 Extended survival in primates after HLT with normal haemodynamics and pulmonary function was subsequently demonstrated.21 Three early attempts in human HLT ended in failure, primarily due to poor donor organ function and poor healing of the airway anastomosis.22 Success with human HLT did not materialise until several key obstacles were overcome. The surgical technique was modified,23 and the success in achieving long term survival of primates after HLT in the late 1970s was most likely due to the use of cyclosporin,24 This experimental work, together with the extensive experience with cardiac transplantation,25 led to a successful clinical heart-lung transplant program for patients with primary pulmonary hypertension in 1981 at Stanford.1 The technique of HLT consists of tracheal, aortic, and right atrial anastomoses. We introduced a technique in 1985 to enable the use of the recipient heart to allow the performance of domino heart transplantation with bi-caval anastomoses, instead of right atrial anastomosis.26 Organ ischaemic time must be minimised, and the donor and recipient operations must be well coordinated. Haemostasis in the posterior mediastinum must be achieved after the excision of the recipient's organs. Phrenic, vagal and recurrent laryngeal nerves must be protected. Recipient peri-trachea] tissue and a long length of trachea are left intact to optimise the healing of the tracheal anastomisis. The preservation of donor coronary-bronchial collateral circulation in HLT is essential. The low incidence of tracheal dehiscence has become a strong argument for the application of HLT in patients with CF. In addition, we have observed an extremely low incidence of accelerated coronary atherosclerosis in HLT recipients.

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The heart from the CF heart-lung transplant recipient is now routinely donated for cardiac transplantation to patients suffering from end stage heart disease—the 'domino' procedure.2 The surgical methods allowing die performance of domino heart transplantation have been described. The domino heart from a CF patient is theoretically advantageous for potential heart recipients with a moderately raised pulmonary vascular resistance. The donor heart has already been conditioned to cope with high pulmonary artery pressure, because of the pre-existing lung disease in the CF patient Therefore, all available organs are used without any wastage while the benefits of en bloc heart-lung graft are retained. Other options of lung transplantation The development of isolated lung transplantation in man lagged behind other organs due to a variety of reasons, especially poor healing of the bronchial anastomosis. The use of cyclosporin with minimal steroids proved to be an important factor in the development of lung transplantation, as the Toronto group demonstrated die deleterious effect of corticosteroids on bronchial healing.27 The role of abdominal omental wrap in revascularisation of the bronchial anastomosis early after lung transplantation was encouraging.28 However, the need for this procedure has recently been challenged in a prospective randomised trial comparing different types of wraps versus no wrap for bronchial anastomosis after isolated lung transplantation.29 In 1983, successful single lung transplantation for pulmonary fibrosis was reported,30 followed a few years later by double lung transplantation for advanced chronic obstructive lung disease.31 Single lung transplantation would be inappropriate for CF due to the risk of the transplanted lung becoming infected by sputum overspill from the remaining native CF lung. En bloc double lung transplantation for CF patients would be the other logical option, widiout the potential risk of chronic rejection of the heart as is the case after HLT. The donor heart can then be used for a patient with end stage heart disease. However, the high incidence of tracheal dehiscence after double lung transplantation, and late tracheal stenosis are of major concern.32 This leads us to evaluate some reliable methods of direct revascularisation of the bronchial arteries such as using the internal mammary artery.29 The early belief that obliterative bronchiolitis, a form of late graft rejection, would not develop in double lung transplant recipients,33 turned out to be erroneous.13 Bilateral single lung transplantation for CF is another option.13-34 The operation is done through a transverse thoraco-stemotomy and involves sequential replacements of the two lungs. The advantages include sep-

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arate bronchial anastomoses to reduce ischaemic airway complications, and improved exposure to reduce intraoperative haemorrhage, and in some cases this procedure can be performed without the need for full cardiopulmonary bypass. The intermediate and long term results of this procedure have not yet been evaluated and mere is concern about bronchial anastomotic healing in CF patients with infection at the site of the suture line. It is possible that any bronchial narrowing or distortion could interfere with clearing the transplanted lungs of infected secretions which are not uncommon in CF patients even after transplantation. IMMUNOSUPPRESSIVE THERAPY Immunosuppression is induced using cyclosporin, azathioprine, and methylprednisolone before the reperfusion of the transplanted organs. Maintenance immunosuppression, which these patients take for the rest of their lives, is cyclosporin and azathioprine. Cyclosporin (CyA) was first introduced into clinical transplantation by the work of Calne et al in 197835 and has become the immunosuppressive agent of choice.36 It appears to inhibit synthesis of interleukin 2, preventing the clonal expansion of T helper cells, with no significant effect on the B cells or the bone marrow. For CF transplant recipients, intravenous CyA is used in the early postoperative period to compensate for die unreliable enteral absorption. CyA is lipophilic, and its poor absorption explains the higher oral requirement in the CF patients compared to non-CF patients.37 The oral dosage commonly administered is 10-30 mg/kg body weight in 2 divided doses until the therapeutic range is obtained. The dosage is altered depending on the trough blood levels, monitored by specific monoclonal antibody radioimmunoassay. A therapeutic level must be maintained to minimise the risk of graft rejection. During the first month, whole blood CyA levels of 500 ng/ml are desirable and 250-350 ng/ml subsequently. Any deterioration of the renal parameters requires a reduction of the dose. Apart from its nephrotoxic effects, CyA is also hepatotoxic, and other side effects include hypertension, hyperkalaemia, convulsions, tremor, gum hypertrophy, hirsutism, and susceptibility to lymphoproliferative disease. Azathioprine, an anti-metabolite, was first used in renal transplantation in 1961, 38 and has remained an important component of conventional immunotherapy. It affects cellular proliferation, including both B and T cells. Azadiioprine is administered orally or intravenously at a dose of 1-2 mg/kg/day. This drug should be discontinued if there is leukopenia (less than 4 x 109 WBCs/1 of blood) or thrombocytopenia.

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Anti-thymocyte globulin (ATG) was introduced into cardiac transplantation by the Stanford group in 1973.25-39 It is prepared by immunizing horses or rabbits, with human thymocytes. Intravenous rabbit ATG has been used in our unit at a dose of 1 mg/kg on alternate days for the first 10 postoperative days to reduce the circulating T lymphocytes to 10—40 cells/mm3. Allergic reactions to ATG can be minimised by administering an anti-histamine before the infusion, and a subcutaneous test dose of ATG is recommended. Steroids were first used in clinical transplantation in 1963,4° and prednisolone has been an important part of conventional immunosuppression. The mechanism of its immunosuppressive effects is not well understood, however, it suppresses cellular RNA and DNA synthesis. Its potent anti-inflammatory effects provide an additional benefit in suppressing responses to lymphokines. It has been our policy that minimum steroids are used in the early post-operative period to reduce the risk of poor tissue healing. Intravenous methylprednisolone (125 mg) is given twice daily for the first 2 postoperative days until the blood cyclosporin level reaches 300 ng/ml. A low dose maintenance steroid regime may be used in patients with multiple rejection episodes. The potential complications include peptic ulceration, diabetes mellitus, hypertension, myopathy, and development of a Cushingoid appearance. POSTOPERATIVE CARE AND COMPLICATIONS The patients postoperative stay in the intensive care unit often depends on their preoperative clinical status, and is usually 3-4 days. Diuresis is encouraged to prevent fluid accumulation within the transplanted lungs. Negative crystalloid fluid balance is carefully monitored particularly as cyclosporin is nephrotoxic. Once cardio-respiratory stability is achieved, early extubation is the aim to reduce the risk of atelectasis and infections due to prolonged ventilation. Most patients will be off the ventilator within 48 hours. Nutritional support is important in this group of patients, since they may be already malnourished. Oral diet together with pancreatic enzyme replacement and vitamins should be initiated as soon as practicable. Patients can usually eat within a few days of surgery. If they are unable to eat, they should be fed via a nasogastric or gastrostomy tube or in some cases parenteral nutrition is required. Histamine-2 antagonists and oral antacids are commenced to prevent stress ulcer. Some CF patients without diabetes mellitus before HLT may have hyperglycaemia exaggerated by steroid therapy for rejection. This is managed with insulin. Other early extrapulmonary complications including meconium ileus equivalent, pancreatitis, and volvulus should be managed in the conventional way. Early mobilisation is en-

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couraged and the current average stay in hospital is between 4—6 weeks. During this time, patients learn to administer their own medications and complete a daily record book detailing the drugs they have taken, their temperature, weight, FEVj and FVC. The latter is monitored using a small portable respiratory function meter. In addition to maintaining therapeutic immunosuppression, the other major problem in the early postoperative period is infectious bronchopulmonary complications which constitute the commonest cause of early mortality and morbidity. Dyspnoea with a productive cough, fever and malaise are common presentations. Many different organisms are involved, particularly Pseudomonas aeruginosa and CMV. All patients with preoperative pseudomonal infection receive the appropriate intravenous anti-pseudomonal antibiotics for 2 weeks, based on the recipient's sputum culture and sensitivity obtained at the time of HLT. Nephrotoxic antibiotics are avoided to prevent cumulative damaging effect on renal function. Long term aerosol colomycin is used to minimise the potential risk of infected upper airway secretions contaminating the lung allografts. Following HLT, CMV infection is the cause of considerable mortality and morbidity.14 Treatment is with CMV hyperimmune globulin and gancyclovir. The importance of CMV matching policy has already been discussed. Because of the shortage of donors, the majority of which are CMV antibody positive, a CMV positive donor to CMV negative recipient may occasionally have to be accepted in HLT. If a donor/recipient mismatch occurs, a prophylactic treatment with CMV hyperimmune globulin and gancyclovir is recommended. Prophylactic septrin against Pneumocystis carinii should also be started as soon as possible. HLT patients also receive prophylactic oral acyclovir for 6 months to protect against herpes and Epstein-Barr viruses. MONITORING FOR PULMONARY REJECTION AND INFECTION Lung function is monitored closely and any deterioration of pulmonary parameters is immediately investigated with microbiological surveillance, chest radiographs, and if indicated, transbronchial biopsies and bronchoalveolar lavage. Early diagnosis of graft rejection is important to prevent permanent damage to the organ. Initially, it was thought that heart and lungs would be rejected concurrently,41 and this could be diagnosed by transvenous endomyocardial biopsy, devised by Caves. 42 The idea of concomitant cardiac and pulmonary rejections turned out to be erroneous43. Heart

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and lungs have been shown to reject independently.44.45 The diagnosis of acute lung rejection depends on clinical, lung function, radiographic, and histological criteria. Clinical features, such as malaise, cough, shortness of breath, fever, and fine inspiratory crepitations, are non-specific. The lung function may deteriorate with a low arterial oxygen saturation. In the early post transplant period, the chest radiograph may show patchy diffuse infiltration with prominent hilar shadows. Late rejection generally has less marked radiological changes, and it is best detected by monitoring dynamic lung functions. Transbronchial biopsy is performed when clinically indicated to diagnosis early lung rejection with minimal risk and is repeatable.46-47 Well described histological changes of pulmonary rejection support the diagnosis.48 Treatment of acute rejection is with 500 to 1000 mg daily intravenous methylprednisolone for 3 days (10 mg/kg/day in children) or augmented oral steroid therapy (lmg/kg/day) reducing over a period of 2 weeks or both, until the rejection is deemed to have resolved. Rabbit ATG and OKT3 have been used in patients with multiple or persistent rejection episodes. Infectious bronchopulmonary complications may present in a similar way to lung rejection. It is essential to identify the organisms and treatment should be started as soon as possible. Bronchoalveolar lavage is used for bacterial and viral culture. A sample of transbronchial lung biopsy is sent to culture for opportunistic organisms. Any significant changes of serological titres before and after HLT may be an indication of viral infection. Presumptive anti-microbial treatment should be initiated as soon as appropriate investigations are completed. Newer antibiotics, antifungal, and antiviral agents have provided an encouraging prospect for the management of infectious complications. RESULTS The largest experience in HLT and CF has been reported from the Harefield and Papworth groups. Between September 1984 and March 1991, a total of 79 CF patients underwent heart-lung transplantation at Harefield Hospital,49 and 58 of these patients donated their hearts as part of the domino procedure. Three patients underwent combined heart-lung and liver transplantation. There were 39 males and 40 females, ranging in age from 8—43 years. Five patients were under 10 years of age. Of the 79 patients, 31 died after HLT due to infection in 11 cases, multiorgan failure in 8, haemorrhage in 6, cerebral vascular accident in 2, obliterative bronchiolitis in 2, trachea! dehiscence in 1, and hyperacute rejection in 1. The actuarial patient survival for the whole group was 69% at 1 year, and 52% at 2 years (Fig. 2). No increase in incidence of rejection was observed in this group of patients. However, bacterial respiratory

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infections, predominantly Pseudomonas aeruginosa, were common in the early postoperative period.2.49

HEART-LUNG TRANSPLANTATION FOR CF Survival (n=79) Probability of •urvtvol

12

5

10

15

20

25

30

35

40

45

Time after transplantation in months

Fig. 2 Actuarial survival

Heart-lung transplantation results in a substantial improvement in lung function in most cases of CF. Their mean FEV] and FVC before surgery was 20% to 30% of their predicted values. The mean postoperative FVC was 71% at 1 year, 70% at 2 years, and 66% at 3 years of the predicted value (Fig. 3). The improvement however has been less marked compared to other parenchyma! lung disease groups, for example, emphysematous patients with a mean FEV! around 90% after surgery.50 This may be related to early recurrent chest infections in the CF patients, and perhaps the difficulty obtaining effective immunosuppression in the early post-operative period due to poor absorption of cyclosporin. At Papworth hospital, 32 CF patients were transplanted with a 1 year patient actuarial survival of 72%, and 58% at 2 years.50 More episodes of infection and rejection were treated in the CF patients, but the prevalence was not significantly different when compared with 61 non-CF patients who underwent HLT during the same period of time. By 3 months after HLT, the FEV! has reached 80% or more of the predicted value. Eleven CF patients, aged between 5 and 15 years, un-

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100-, 80-

60 -

40 O)

—

20 -

Pre op.

12

FVC

24

36

Time after transplant (months)

Fig. 3 Lung function

derwent HLT with a 1 year survival of 55%. 52 An increased incidence of pulmonary rejection was noted, and obliterative bronchiolitis appeared to be an important cause of late deaths. The North American groups report a 42% actuarial survival at 1 year in 33 CF patients, with sepsis as the main cause of death.53 The reasons for the difference in success rates between the North American and UK centers may be multifactorial but it is noteworthy that 10 of the 14 North American centers performed two or fewer HLT's for CF. This may explain the disparity in surgical experience and clinical management of complicated medical problems in these CF patients after HLT. The Toronto lung transplant group reported 17 CF patients underwent bilateral single lung transplantation, with a 58% 1 year actuarial survival rate.13 The FEVi of transplant survivors improved to 100% predicted normal at 1 year after HLT. Rejection was a frequent occurrence during the first 3 months after transplantation. The most frequent cause of morbidity and mortality was pneumonia resulting from P. cepacia. Airway complications remained problematic. However, only one case of airway stenosis, treated with a bronchial stent, was seen in the last 8 patients. The decreased incidence may be due to better lung preservation and anastomotic technique

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FOLLOW UP Long term follow up is required with close monitoring of lung function and immunosuppression. Routine blood tests, chest radiographs (Fig. 4) blood cyclosporin levels, and lung function are undertaken at regular transplant outpatient visits. Transplanted recipients are given a home microspirometer for FEV] and FVC measurements to monitor their lung functions for any early deterioration. They should contact the transplant hospital if there is 5-10% drop in their FEVj or FVC compared to their stable levels. Further investigations include blood, sputum, and urine cultures, serological viral titres, bronchoalveolar lavage and transbronchial biopsy for histology and microbiological surveillance. One major long term complication of HLT is the development of obliterative bronchiolitis, with deteriorating lung function.54 The functional changes include both restrictive and obstructive patterns with a decrease in the diffusion capacity. The histological feature of obliterative bronchiolitis is typically obliteration of the bronchioles and small airways. In one report, 50% of long term survivors were affected.54 In our group of 79 CF patients, 17 developed obliterative bronchiolitis.49 The cumulative probability (70% confidence interval) of developing this complication at 1, 2 and 3—year postoperatively was 17% (12-23%), 23% (16-29%), and 48% (38-59%) respectively. Of these, 2 died after retransplantation and 2 are currently awaiting retransplantation. Two patients have successfully been retransplanted (one with a single lung) and both are very well at 27 and 9 months after surgery. The aetiology of obliterative bronchiolitis is still being evaluated. A relationship between acute persistent episodes of lung rejection and chronic rejection has been suggested.55 In addition, an association between viral infection and the subsequent development of obliterative bronchiolitis has been reported.56 It has been postulated that the upregulation of antigenic molecules (major histocompatibility complex class I and II) in virally infected cells of donor specificity increases the susceptibility of allograft to rejection. There may be a higher incidence of acute rejection and obliterative bronchiolitis in the younger patients.52 Better pulmonary preservation, improved management of infection, and surveillance of pulmonary rejection may prevent the development of obliterative bronchiolitis. This complication may also be related at least in part to ischaemic necrosis of the bronchiole. Currently we have devised and continued to use a technique for direct revascularisation of the bronchial arteries using the internal mammary artery. This could have a preventive effect on obliterative bronchiolitis. Further experience is required to clarify these issues. At present, retransplantation is the only effective management, if augmentation of immunosuppression fails.57

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A

Fig. 4A CXR before transplantation.

RECURRENCE OF DISEASE Cystic fibrosis is characterised by abnormally high (more negative) potential difference (PD) across the respiratory epithelium.58 Since HLT had emerged as a suitable treatment for CF patients with end stage lung disease, one obvious question raised was whether the donor lungs would regain the typically elevated PD found in the CF host airways. In vivo measurements of airway PD after HLT suggested that CF membrane defect has not recurred in the donor lungs after up to 2 years follow up.59 The upper airway above the trachea] anastomosis still retains the CF epithelial defect, and may remain colonised with P. aeruginosa. Early after HLT, bronchopulmonary infections with P. aeruginosa are common in patients with CF.2"45 Work is being carried out in our unit

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Fig. 4B CXR after transplantation.

to see if chronic colonisation of the upper airway and sinuses with P. aeruginosa and its drainage into the dependent lung allografts is a potential risk to the functioning of the transplanted lungs. Our management includes attention to sinus disease, whilst long term aerosol colomycin, and radical prophylactic sinus surgery has been advocated.12 QUALITY OF LIFE Many patients who have had a successful heart-lung transplant have returned to school, work, or higher education. There is no doubt that the quality of life after transplantation is better than before. Transplanted

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patients showed improved levels of social and emotional well being after HLT, as measured using the Nottingham Health Profile.2'60 'DOMINO' CARDIAC TRANSPLANTATION The domino procedure involves using the donor heart-lung grafts for the CF patients, then the donated heart from the CF patient can be transplanted into another patient.2 This helps to solve the problem of chronic shortage of organ donors. The presence of localised bacterial infection in the CF lungs is not considered a contraindication. The right ventricular hypertrophy found in these hearts, secondary to chronic respiratory failure, makes them especially suitable for potential heart transplant recipients with a moderate elevation of pulmonary vascular resistance, with which 'conventional' donor hearts will not be able to cope. We reported the use of domino hearts from 20 of the CF heart-lung recipients between September 1984 and October 1988.2 The recipients were 5 female and 15 male, age ranging from 10 to 65 years of age. The indications were cardiomyopathy in 11, ischaemic heart disease in 6, cardiac tumour in 1, complex congenital heart disease in 1, and retransplantation following failure of the initial donor heart in 1. There were 5 early deaths: 3 due to multiorgan failure and 2 due to rejection. There were no late deaths with a maximum follow up of 22 months. The 1 year actuarial patient survival was 75%. No angiographic evidence of coronary artery disease was present in the 12 patients 1 year after transplantation. CHALLENGES Even with the discovery of the CF gene and the new methods of medical treatment, many patients for several decades are likely to be at risk of a shortened lifespan because of chronic pulmonary infections. With the advance of HLT, CF patients with end-stage pulmonary disease unmanageable by conventional medical therapy are offered a second chance. Transplantation is an expensive form of treatment but it may be that the heavy costs of caring for a very sick CF patient requiring repeated hospital admissions and intravenous antipseudomonal antibiotics is more than the cost of a transplant The majority of heart-lung transplants for CF have been performed on patients in their 20s and 30s. The 1 year actuarial patient survival rates are 70-80%. The results of HLT in children have lagged behind those in adults. There is a definite impression that younger patients do not do so well. It would seem appropriate that great care is taken that

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no young patient is put on the waiting list who will still respond to conventional treatment Patients must realise that successful HLT is not going to cure their CF, which is a multisystem disease, but gives them an opportunity to survive and transfer from one treatment modality to another. They will be liable to episodes of infection and rejection for the rest of their lives, and careful monitoring is essential. Nevertheless, there seems little doubt that transplanted lungs do not acquire the CF epithelial defect. A proportion of patients develop obliterative bronchiolitis after HLT. In some cases this can be controlled by augmenting immunosuppression, but in other cases it is fatal unless the patient can be successfully re-transplanted. More research work is needed on the prevention and treatment of this complication. The scarcity of human donor organs and the increasing number of patients who would benefit from HLT requires strict potential recipient selection for the maximum benefit from HLT. In the mean time, everything possible must be done to make sure that as many suitable donor organs as possible are offered for transplantation. This involves the education of medical and nursing staff as well as the general public. Improved donor lung preservation and more specific control of rejection can be expected in the future. This will extend the application and improve the results of heart-lung and lung transplantation. Xenograft transplantation remains a theoretical option, and much research work needs to be done on immunological tolerance before the use of animal organs becomes a reality. REFERENCES 1 Reitz BA, Wallwork JL, Hunt SA et al Heart lung transplantation: successful therapy for patients with pulmonary vascular disease N Engl J Med 306: 557-564, 1982 2 Yacoub MH, Banner NR, Khangani A et al. Combined heart and lung transplantation for cystic fibrosis and subsequent Domino cardiac transplantation J Heart Transplant 9- 459-467, 1990 3 Scott J, Higenbottam T, Hutter J et al Heart-lung transplantation for cystic fibrosis. Lancet 2 192-194, 1988 4 Danks DM, Allan J, Andersen CM. Genetic study of fibrocystic disease of the pancreas. Ann Hum Genet 28: 323-356, 1965 5 Wood RE, Boot TF, Doershuk CF. State of the art cystic fibrosis. Am Rev Respir Dis 113- 833-878, 1976 6 British Paediatnc Association Working Party on Cystic Fibrosis. Cystic fibrosis in the United Kingdom 1977-85. An improving picture. Br Med J 297 1599-1602, 1988 7 Geddes DM. Cystic fibrosis: future trends in care. Thorax 43. 869-871, 1988 8 Penketh ARL, Wise A, Meams MB, Hodson ME, Batten JC. Cystic fibrosis in adolescents abd adults. Thorax 42: 526-532, 1987 9 Bidstrup BP, Royston D, Sapsford RN, Taylor KM Reduction in blood loss and blood use after canhopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 97. 364-372, 1989

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10 Hodson ME, Madden BP, Steven MH, Tsang VT, Yacoub MH. Non-invasive mechanical ventilation for cystic fibrosis—a potential bndge to transplantation Eur Respir J 524-527, 1991 11 Warner JO. Heart-lung transplantation: all the facts Arch Dis Child 66 1013-1017, 1991 12 Lewiston N, King V, Umetsu D et al Cystic fibrosis patients who have undergone heart-lung transplantation benefit from maxillary sinus antrostomy and repeated sinus lavage. Transplant Proc 23: 1207-1208, 1991 13 Ramirez JC, Patterson GA, Winton TL et al. Bilateral lung transplantation for cystic fibrosis. J Thorac Cardiovasc Surg 103- 287-294, 1992 14 Hutter JA, Wreghitt T, Scott JP, Higenbottam T, Wallwork JL. The importance of cytomegalovirus m heart lung transplant recipients Chest 95: 627-631, 1989 15 Yacoub MH, Banner NR. Recent developments in lung and heart-lung transplantation. In Morris and Tilney eds. Transplantation Reviews: 1990, Saunders Ch 1: ppl-29 16 Wallwork J, Jones K, Cavarocchi N, Hakim M, Higenbottam T Distant procurement of organs for clinical heart-lung transplants using a single flush technique. Transplantation 44: 654-658, 1987 17 Lower RR, Stofer RC, Hurley EJ, Shumway NE. Complete homograft replacement of the heart and both lungs Surgery 50 842-845, 1961 18 Nakae S, Webb WR, Theodondes T, Sugg WL Respiratory function following cardiopulmonary denervation in dog, cat and monkey. Surg Gynaecol Obstet 125. 1285-1292, 1967 19 Haghn J, Telander RL, Muzzah RE, Riser JC, Strobel CJ. Comparison of lung autotransplantation m the primate and dogs. Surg Forum 14' 196-198, 1963 20 Castaneda AR, Arnar O, Schmidt-Hableman P, Moller J, Zamora R. Cardiopulmonary autotransplantation m primates. J Cardiovasc Surg 37: 523-531, 1972 21 Castaneda AR, Zamora R, Schmidt-Habelmann P et al Cardiopulmonary antotransplantation in primates (baboons) Late functional results. Surgery 72: 1064-1070, 1972 22 Veith FJ. Lung transplantation. Surg Chn North Am 58- 357-364, 1978 23 Jamieson SW, Stinson EB, Oyer PE, Baldwin J, Shumway NE. Operative technique for heart-lung transplantation. J Thorac Cardiovasc Surg 87- 930-935, 1984 24 Reitz BA, Burton NA, Jamieson SW et al Heart and lung transplantation Autotransplantabon and allotransplantation in primates with extended survival J Thorac Cardiovasc Surg 80 360-372, 1980 25 Baumgartner WA, Reitz BA, Oyer PE, Stinson EB, Shumway NE. Cardiac homotransplantarJon Curr Probl Surg 16: 1-61, 1979 26 Yacoub MH, Khaghani A, Aravot D et al. Cardiac transplantation from live donors JAmColl Cardwl 11: 102A, 1988 27 Lima O, Cooper JD, Peters WJ et al Effect of methylprednisolone and azathioprine on bronchial hearing following lung autotransplantation. J Thorac Cardiovasc Surg 82. 211-215, 1981 28 Lima O, Goldberg M, Peters WJ et al Bronchial omentopexy in canine lung transplantation. J Thorac Cardiovasc Surg 83: 418-421, 1982 29 Khanghani A, Tadjkanmi S, Daly R et al. The influence of different types of wraps versus no wrap in single lung transplantation. A prospective randomised tnal J Heart Lung Transplant (in press) 1992 30 The Toronto Lung Transplant Group. Experience with smgle lung transplantation for pulmonary fibrosis. J Am Med Assoc 259 2258-2262, 1988 31 Cooper JD, Patterson GA, Grossman R et al Double lung transplant for advanced chrome obstructive lung disease. Am Rev Respir Dis 139 303-307, 1989 32 Patterson GA, Todd TR, Cooper JD et al Airway complications after double lung transplantation. J Thorac Cardiovasc Surg 99: 14-21, 1990 33 Cooper JD, Patterson GA, Grossman R et al. Double lung transplant for advanced chronic obstructive lung disease Am Rev Respir Dis 139: 303-307, 1989

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34 Pasque MK, Cooper JD, Kaiser LR et al Improved technique for bilateral lung transplantation: rationale and initial clinical experience. Ann Thorac Surg 49: 785-791, 1990 35 Calne RY, White DJG, Thiru S et al Cyclosponn A in patients receiving renal aUografts from cadaver donors. Lancet 2: 1323-1327, 1978 36 Kahan BD Cyclosponn. N Engl J Med 321: 1725-1738, 1989 37 Cooney GF, Rel SB, Shaw LM, Cavarocchi NC. Cyclosponn bioavailability in heartlung transplant candidates with cystic fibrosis. Transplantation 49 821-823, 1990 38 Calne R. Inhibition of the rejection of renal homografts m dogs by punne analogues. Transplant Bull 28: 65-81, 1961 39 Bieber CP, Gnepp RB, OyeT PE, Wong J, Stinson EB. Use of rabbit antithymocyte globulin in cardiac transplantation. Transplantation 22 478-488, 1976 40 Goodwin WE, Kaufmann JJ, Mims MM et al. Human renal transplantation Clinical experience with 6 cases of renal homotransplantation. J Urol 89 13-24, 1963 41 Reitz BA, Gaudiam VA, Hunt SA et al Diagnosis and treatment of allograft rejection in heart-lung transplant recipients. J Thorac Canhovasc Surg 85 354-361, 1983 42 Caves PK, Bilkngham ME, Stinson EB, Shumway NE. Senal transvenous biopsy of the transplanted human heart unproved management of acute rejection episodes Lancet I: 821-826, 1974 43 McGregor CGA, Baldwin JC, Jamieson SW et al. Isolated pulmonary rejection after combined heart-lung transplantation J Thorac Canhovasc Surg 90: 623-^626, 1985 44 Higenbottam T, Hutter JA, Stewart S, Wallwork J Transbronchial biopsy has eliminated the need for endomyocardial biopsy in heart-lung recipients J Heart Transplant 7: 435-439, 1988 45 Wahlers T, Khagkani A, Martin M, Banner N, Yacoub M. Frequency of acute heart and lung rejection after heart-lung transplantation. Transplant Proc 19: 3537-3538, 1987 46 Penketh ARL, Higenbottam T, Hutter J, Coutts C, Stewart S, Wallwork J Clinical experience in the management of pulmonary opportunistic infection and rejection in recipients of heart-lung transplants Thorax 43 762-769, 1988 47 Higenbottam T, Stewart S, Penketh A, Wallwork J. Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant patients. Transplantation 46: 532-539, 1988 48 Hutter JA, Stewart S, Higenbottam T, Scott JP, Wallwork J Histological changes in heart-lung transplant recipients during rejection episodes and at routine biopsy J Heart Transplant 7: 440-444, 1988 49 Madden BP, Hodson ME, Tsang V et al. Intermediate term results of heart-lung transplantation for cystic fibrosis Lancet 339 1583-1587,1992 50 Khagbaru A, Banner NR, Ozdogan E et al Medium-term results of combined heart and lung transplantatoin for emphysema. J Heart Lung Transplant 10: 15-21, 1991 51 de Leval MR, Smyth R, Whitehead B et al. Heart and lung transplantation for terminal cystic fibrosis. J Thorac Cardiovasc Surg 101. 633-642, 1991 52 Whitehead B, Helms P, Goodwin M et al. Heart-lung transplantation for cystic fibrosis Outcome. Arch Dis Child 66- 1022-1026, 1991 53 Fnst WH, Fox PW, Campbell SB, Loyd JE, Merrill WH Cystic fibrosis treated with heart-lung transplantation. North American results Transplant Proc 23 1205-1206, 1991 54 Burke CM, Theodore J, Baldwin JC et al. Twenty-eight cases of human heart-lung transplantation. Lancet l 517-519, 1986 55 Scott JP, Sharpies L, Mullins P et al Further studies on the natural history of obliterafjve bronchioins following heart-lung transplantation Transplant Proc 23: 1201-1202, 1991 56 Gnffith BP, Paradis IL, Zeevi A et al Immunology mediated disease of the airways after pulmonary transplantation. Ann Surg 208: 371-379, 1988 57 Glanville AR, Baldwin JC, Burke CM, Theodore J, Robin ED ObhteraOve bronchiohtis after heart-lung transplantation apparent arrest by augmented immunosuppression. Ann Intern Med 107: 300-304, 1987

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58 Knowles MD, Galzy J, Boucher R. Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis. N Engl J Med 305 1489-1495, 1981 59 Alton EWFW, Khagani A, Taylor RFH et al Effect of heart-lung transplantation on airway potential difference in patients with and without cystic fibrosis. Eur Respir J 4 5-9, 1991 60 Caine N, Sharpies LD, Smyth R et al Survival and quality of life of cystic fibrosis patients before and after heart-lung transplantation Transplant Proc 23 1203-1204, 1991